Treatment of erosive osteoarthritis of the hand

Abstract

Provided herein are methods of treating erosive osteoarthritis (OA) in a subject in need thereof, methods of performing radiographic erosive progression, joint space narrowing, cartilage degradation and / or reduction of bone formation in a subject in need thereof (e.g., a subject suffering from erosive hand OA), methods of inhibiting the development of new erosive joints in a subject in need thereof (e.g., a subject suffering from erosive hand OA), and methods of reducing pain in a subject having erosive hand OA. Also provided herein are the use of denosumab in the manufacture of a medicament adapted for use in the methods described herein and pharmaceutical compositions comprising denosumab for use in the methods described herein.

Description

Technical Field

[0001] This application relates to a method for treating erosive osteoarthritis of the hand joints.

[0002] Cross - reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 359,948, filed on July 11, 2022, which is incorporated herein by reference in its entirety.

[0003] Incorporation by reference of electronically submitted materials The computer - readable nucleotide / amino acid sequence listing submitted simultaneously with this specification is incorporated herein by reference in its entirety and is identified as follows: a 15,822 - byte text file named "58297_SeqListing.xml" created on July 10, 2023.

Background Art

[0004] Radiographic erosive osteoarthritis (OA) of the interphalangeal (IP) finger joints is a highly prevalent disease (1 - 3) and is considered to be an inflammatory subtype of hand OA (4). It is characterized by a high disease burden, with the majority of patients suffering from substantial pain and disability (5, 6).

[0005] As a prominent feature of the X-ray of erosive deformative hand OA, resorption of articular cartilage is cited, which usually precedes the collapse of the subchondral bone endplate and osteolytic changes in the subchondral bone region of the bone end (11-13). Articular cartilage resorption is caused by chondrocytes in degenerated cartilage and undergoes hypertrophic differentiation. Both hypertrophic chondrocytes and osteoclasts release receptor activator of nuclear factor kappa-β ligand (RANKL). This is an important driver of osteoclast maturation and activation under physiological and pathological conditions (14-18). After the destruction of the joint tissue, repair processes such as remodeling of the subchondral bone plate and formation of bone nodules at the edges of the affected interphalangeal (IP) joints continue. The erosive characteristics and symptoms of remodeling can occur simultaneously in the same patient because the disease affects the proximal and distal IP joints in an unpredictable order, causing the disease to remain active until all joints progress to the end stage of remodeling (a process that can take decades to complete) (19).

Summary of the Invention

Problems to be Solved by the Invention

[0006] Existing treatment methods for erosive deformative hand OA only relieve subjective complaints, contribute to functional limitations, and do not attenuate or stop the structural damage in the IP finger joints that ultimately leads to severe disabilities and chronic pain (2, 7, 8-10). Therefore, alternative methods for treating erosive deformative hand OA are needed in the art.

Means for Solving the Problems

[0007] The data presented herein are from a single-site trial in which 100 patients with erosive osteoarthritis of the hand were randomized to receive either (a) 60 mg of the RANKL inhibitor denosumab once every approximately 3 months or (b) placebo for 48 weeks of blinded treatment followed by an open-label extension (OLE) period through week 96. Fifty-one and 49 patients received denosumab and placebo, respectively. The primary endpoint of the trial was the change in the total Ghent University Scoring System (GUSS™) score at week 24. The GUSS™ scoring system consists of three subdomains: subchondral plate; subchondral bone; and joint space. Specific features indicative of the underlying pathology of the disease are scored on a numerical scale from 0 to 100 in 10 increments, with the maximum score indicating a normal or fully recovered (i.e., non-erosive) joint. Secondary trial endpoints included the number of new erosive joints at week 48 and the total GUSS™ change at week 48. Exploratory clinical and safety assessments were also evaluated. At week 24, the overall change in GUSS™ was found to be statistically higher in the denosumab-treated patients compared to those receiving placebo (mean change in GUSS™ = 8.9 (95% CI: 1.0 to 16.9; p = 0.024)), and the change increased further at week 48 (ΔGUSS™ = 14.3 (95% CI: 4.6 to 24.0; p = 0.003)). Additionally, at week 48, the incidence of new erosive joints was significantly reduced in the denosumab-treated patients compared to those receiving placebo (1.9%) (7.0%) (OR = 0.23 (95% CI: 0.10 to 0.50); p < 0.001). During the OLE, both groups continued to remodel, and clinical endpoints (e.g., pain and function) changed significantly after 96 weeks of treatment. The same number of adverse events occurred in both groups. Collectively, these results indicate that denosumab has a structural modifying effect in erosive hand OA compared to placebo and significantly less erosive progression occurs after 24 weeks of denosumab treatment. This treatment effect was enhanced after 48 weeks, and symptomatic improvement was seen during longer treatment periods (e.g., after 96 weeks of treatment).

[0008] Disclosed herein is a method of treating hand osteoarthritis (OA) in a subject in need thereof. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., about 45 mg to less than 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 45 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 50 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 55 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 60 mg of denosumab administered once every about three months.

[0009] In some embodiments, the method comprises administering about 45 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 50 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 55 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 60 mg of denosumab to the subject once every about three months.

[0010] In some embodiments, the amount of denosumab is a. an average serum concentration of denosumab substantially similar to that achieved by administering 60 mg of denosumab once every about three months; and / or b. an area under the mean plasma curve (AUC 0-∞ ); and / or c. a mean plasma C at steady state substantially similar to that achieved by administering 60 mg of denosumab once every about three months maxand the average plasma C in the steady state min the difference between; and / or d. The average plasma C in the steady state, which is substantially the same as that achieved by administering 60 mg of denosumab once every about three months max to provide.

[0011] In some embodiments, the amount of denosumab is a. The average serum concentration of denosumab, which is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or b. The average plasma curve under area (AUC 0-∞ ), which is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or c. The average plasma C in the steady state, which is substantially the same as that achieved by administering 55 mg of denosumab once every about three months max and the average plasma C in the steady state min the difference between; and / or d. The average plasma C in the steady state, which is substantially the same as that achieved by administering 55 mg of denosumab once every about three months max to provide.

[0012] In some embodiments, the amount of denosumab is a. The average serum concentration of denosumab, which is substantially the same as that achieved by administering 50 mg of denosumab once every about three months; and / or b. The average plasma curve under area (AUC 0-∞ ), which is substantially the same as that achieved by administering 50 mg of denosumab once every about three months; and / or c. The average plasma C in the steady state, which is substantially the same as that achieved by administering 50 mg of denosumab once every about three months max and the average plasma C in the steady state min the difference between; and / or d. The average plasma C at steady state that is substantially the same as that achieved by administering denosumab at 50 mg once every about 3 months max is provided.

[0013] In some embodiments, the amount of denosumab is a. The average serum concentration of denosumab that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or b. The average plasma area under the curve (AUC 0-∞ ); and / or c. The difference between the average plasma C at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months and the average plasma C at steady state max ; and / or min d. The average plasma C at steady state that is substantially the same as that achieved by administering denosumab at 45 mg once every about 3 months is provided. max is provided.

[0014] In some embodiments, the subject is administered denosumab for at least 12 weeks. In some embodiments, the subject is administered denosumab for at least 24 weeks. In some embodiments, the subject is administered denosumab for at least 48 weeks. In some embodiments, the subject is administered denosumab for at least 96 weeks.

[0015] In some embodiments, the subject is administered denosumab once every about three months. In some embodiments, the subject is administered denosumab once every about three months for at least two cycles. In some embodiments, the subject is administered denosumab once every about three months for at least three cycles. In some embodiments, the subject is administered denosumab once every about three months for at least four cycles. In some embodiments, the subject is administered denosumab once every about three months for at least five cycles. In some embodiments, the subject is administered denosumab once every about three months for at least six cycles. In some embodiments, the subject is administered denosumab once every about three months for at least seven cycles. In some embodiments, the subject is administered denosumab once every about three months for at least eight cycles.

[0016] In some embodiments, denosumab is administered to the subject by injection. In some embodiments, denosumab is administered to the subject by subcutaneous injection. In some embodiments, denosumab is administered to the subject by injection into the subject's upper arm, upper thigh, or abdomen. In some embodiments, denosumab is administered to the subject by subcutaneous injection into the subject's upper arm, upper thigh, or abdomen.

[0017] In some embodiments, the method further comprises administering to the subject at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. In some embodiments, the method further comprises administering to the subject a stable dose of at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. In some embodiments, the method further comprises administering to the subject conventional supplements of oral calcium and vitamin D3. In some embodiments, the method further comprises administering to the subject conventional supplements of oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units).

[0018] In some embodiments, administration reduces radiographic progression in a subject. In some embodiments, administration reduces joint space narrowing in a subject. In some embodiments, administration reduces cartilage degradation in a subject. In some embodiments, administration reduces bone formation in a subject. In some embodiments, administration decreases the number of new erosive joints in a subject. In some embodiments, administration decreases the number of new erosive joints in a subject at week 48. In some embodiments, administration inhibits the development of new erosive joints in a subject. In some embodiments, administration decreases the number of "S / J" IP joints developing an "E" stage in a subject. In some embodiments, administration decreases the number of "S / J" IP joints developing an "E" stage in a subject at week 48. In some embodiments, administration inhibits the development of an "E" stage in "S / J" IP joints in a subject.

[0019] In some embodiments, administration improves erosive IP joint remodeling in a subject. In some embodiments, administration improves erosive IP joint remodeling in a subject at year 1. In some embodiments, administration improves erosive IP joint remodeling in a subject at year 2. In some embodiments, administration increases total GUSS™ in a subject. In some embodiments, administration increases total GUSS™ in a subject at week 12. In some embodiments, administration increases total GUSS™ in a subject at week 48.

[0020] In some embodiments, administration reduces pain in a subject. In some embodiments, administration reduces pain in a subject at week 96. In some embodiments, pain reduction is evaluated by the Numerical Rating Scale (NRS) for pain.

[0021] In some embodiments, administration improves joint function in a subject. In some embodiments, administration improves joint function in a subject as evaluated by the Australian-Canadian Osteoarthritis Hand Index (AUSCAN). In some embodiments, administration improves joint function in a subject as evaluated by the Functional Index for Hand Osteoarthritis (FIHOA).

[0022] In some embodiments, a subject does not exhibit dose-limiting toxicity (DLT) during denosumab administration. In some embodiments, a subject does not exhibit any grade 3 or grade 4 adverse events related to denosumab during denosumab administration. In some embodiments, a subject is not hypocalcemic during denosumab administration.

[0023] In some embodiments, a subject exhibits at least one symptom of inflammation clinically or by ultrasound prior to denosumab administration. In some embodiments, a subject exhibits at least one symptom of inflammation clinically or by ultrasound in at least one proximal interphalangeal joint prior to denosumab administration. In some embodiments, a subject exhibits at least one proximal interphalangeal joint in stage J or E with at least one symptom of inflammation prior to denosumab administration. In some embodiments, a subject exhibits at least one proximal interphalangeal joint in stage J or E with palpable swelling prior to denosumab administration.

[0024] In some embodiments, a subject is at least about 18 years old. In some embodiments, a subject is at least about 30 years old. In some embodiments, a subject is not diagnosed with vitamin D deficiency. In some embodiments, a subject is not diagnosed with a chronic inflammatory rheumatic disease. In some embodiments, a subject is not diagnosed with psoriasis. In some embodiments, a subject is not diagnosed with cancer. In some embodiments, a subject is not diagnosed with a chronic infectious disease.

[0025] In some embodiments, a subject has not been previously treated for erosive hand osteoarthritis. In some embodiments, a subject has been previously treated for erosive hand osteoarthritis.

[0026] In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from a tumor necrosis factor α (TNFα) blocker, an anti-interleukin-1α inhibitor, an anti-interleukin-1β inhibitor, and combinations thereof. In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, rituximab, and combinations thereof.

[0027] Also disclosed herein is the use of denosumab in the manufacture of a medicament adapted for use in a method of treating erosive rheumatoid arthritis in a subject in need thereof. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., about 45 mg to less than 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 45 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 50 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 55 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 60 mg of denosumab administered once every about three months.

[0028] In some embodiments, the method comprises administering about 45 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 50 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 55 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 60 mg of denosumab to the subject once every about three months.

[0029] In some embodiments, the amount of denosumab is a. An average serum concentration of denosumab that is substantially the same as that achieved by administering 60 mg of denosumab once every approximately three months; and / or b. An average plasma curve under area (AUC 0-∞ ) that is substantially the same as that achieved by administering 60 mg of denosumab once every approximately three months; and / or c. A difference between the average plasma C max at steady state and the average plasma C min at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every approximately three months; and / or d. An average plasma C max at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every approximately three months.

[0030] In some embodiments, the amount of denosumab is a. An average serum concentration of denosumab that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately three months; and / or b. An average plasma curve under area (AUC 0-∞ ) that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately three months; and / or c. A difference between the average plasma C max at steady state and the average plasma C min at steady state that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately three months; and / or d. An average plasma C max at steady state that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately three months.

[0031] In some embodiments, the amount of denosumab is a. An average serum concentration of denosumab that is substantially the same as that achieved by administering 50 mg of denosumab once every approximately three months; and / or b. An average plasma curve under area (AUC) substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months 0-∞ ; and / or c. A difference between the average plasma C max at steady state and the average plasma C min at steady state, substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months; and / or d. An average plasma C max at steady state, substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months.

[0032] In some embodiments, the amount of denosumab is a. An average serum concentration of denosumab substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or b. An average plasma curve under area (AUC 0-∞ ); substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or c. A difference between the average plasma C max at steady state and the average plasma C min at steady state, substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or d. An average plasma C max at steady state, substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months.

[0033] In some embodiments, the subject is administered denosumab for at least 12 weeks. In some embodiments, the subject is administered denosumab for at least 24 weeks. In some embodiments, the subject is administered denosumab for at least 48 weeks. In some embodiments, the subject is administered denosumab for at least 96 weeks.

[0034] In some embodiments, the subject is administered denosumab once every about three months. In some embodiments, the subject is administered denosumab once every about three months for at least two cycles. In some embodiments, the subject is administered denosumab once every about three months for at least three cycles. In some embodiments, the subject is administered denosumab once every about three months for at least four cycles. In some embodiments, the subject is administered denosumab once every about three months for at least five cycles. In some embodiments, the subject is administered denosumab once every about three months for at least six cycles. In some embodiments, the subject is administered denosumab once every about three months for at least seven cycles. In some embodiments, the subject is administered denosumab once every about three months for at least eight cycles.

[0035] In some embodiments, denosumab is administered to the subject by injection. In some embodiments, denosumab is administered to the subject by subcutaneous injection. In some embodiments, denosumab is administered to the subject by injection into the subject's upper arm, upper thigh, or abdomen. In some embodiments, denosumab is administered to the subject by subcutaneous injection into the subject's upper arm, upper thigh, or abdomen.

[0036] In some embodiments, the method further comprises administering to the subject at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. In some embodiments, the method further comprises administering to the subject a stable dose of at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. In some embodiments, the method further comprises administering to the subject conventional supplements of oral calcium and vitamin D3. In some embodiments, the method further comprises administering to the subject conventional supplements of oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units).

[0037] In some embodiments, administration reduces radiographic progression in a subject. In some embodiments, administration reduces joint space narrowing in a subject. In some embodiments, administration reduces cartilage degradation in a subject. In some embodiments, administration decreases the number of new erosive joints in a subject. In some embodiments, administration decreases the number of new erosive joints in a subject at week 48. In some embodiments, administration inhibits the development of new erosive joints in a subject. In some embodiments, administration decreases the number of "S / J" IP joints that develop into stage "E" in a subject. In some embodiments, administration decreases the number of "S / J" IP joints that develop into stage "E" in a subject at week 48. In some embodiments, administration inhibits the development of stage "E" in "S / J" IP joints in a subject.

[0038] In some embodiments, administration improves erosive IP joint remodeling in a subject. In some embodiments, administration improves erosive IP joint remodeling in a subject at year 1. In some embodiments, administration improves erosive IP joint remodeling in a subject at year 2. In some embodiments, administration increases the total GUSS™ in a subject. In some embodiments, administration increases the total GUSS™ in a subject at week 12. In some embodiments, administration increases the total GUSS™ in a subject at week 48.

[0039] In some embodiments, administration reduces pain in a subject. In some embodiments, administration reduces pain in a subject at week 96. In some embodiments, pain reduction is evaluated by the Numerical Rating Scale (NRS) for pain.

[0040] In some embodiments, administration improves joint function in a subject. In some embodiments, administration improves joint function in a subject as evaluated by the Australian-Canadian Osteoarthritis Hand Index (AUSCAN). In some embodiments, administration improves joint function in a subject as evaluated by the Functional Index for Hand Osteoarthritis (FIHOA).

[0041] In some embodiments, the subject does not exhibit dose-limiting toxicity (DLT) during denosumab administration. In some embodiments, the subject does not exhibit any grade 3 or grade 4 adverse events related to denosumab during denosumab administration. In some embodiments, the subject is not hypocalcemic during denosumab administration.

[0042] In some embodiments, the subject exhibits at least one symptom of inflammation clinically or by ultrasound prior to denosumab administration. In some embodiments, the subject exhibits at least one symptom of inflammation clinically or by ultrasound at at least one proximal interphalangeal joint prior to denosumab administration. In some embodiments, the subject exhibits at least one proximal interphalangeal joint in stage J or E along with at least one symptom of inflammation prior to denosumab administration. In some embodiments, the subject exhibits at least one proximal interphalangeal joint in stage J or E along with palpable swelling prior to denosumab administration.

[0043] In some embodiments, the subject is at least about 18 years old. In some embodiments, the subject is at least about 30 years old. In some embodiments, the subject is not diagnosed with vitamin D deficiency. In some embodiments, the subject is not diagnosed with a chronic inflammatory rheumatic disease. In some embodiments, the subject is not diagnosed with psoriasis. In some embodiments, the subject is not diagnosed with cancer. In some embodiments, the subject is not diagnosed with a chronic infectious disease.

[0044] In some embodiments, the subject has not been previously treated for erosive osteoarthritis of the hand. In some embodiments, the subject has been previously treated for erosive osteoarthritis of the hand.

[0045] In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from tumor necrosis factor α (TNFα) blockers, anti-interleukin-1α inhibitors, anti-interleukin-1β inhibitors, and combinations thereof. In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, ruxolitinib, and combinations thereof.

[0046] Also disclosed herein is a pharmaceutical composition comprising denosumab for use in a method of treating erosive rheumatoid arthritis in a subject in need thereof. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., about 45 mg to less than 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 45 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 50 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 55 mg of denosumab administered once every about three months. In some embodiments, the method comprises administering to the subject an amount of denosumab corresponding to about 60 mg of denosumab administered once every about three months.

[0047] In some embodiments, the method comprises administering about 45 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 50 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 55 mg of denosumab to the subject once every about three months. In some embodiments, the method comprises administering about 60 mg of denosumab to the subject once every about three months.

[0048] In some embodiments, the amount of denosumab is a. The average serum concentration of denosumab that is substantially the same as that achieved by administering 60 mg of denosumab once every about 3 months; and / or b. The average plasma area under the curve (AUC 0-∞ ); that is substantially the same as that achieved by administering 60 mg of denosumab once every about 3 months; and / or c. The difference between the average plasma C max at steady state and the average plasma C min at steady state, which is substantially the same as that achieved by administering 60 mg of denosumab once every about 3 months; and / or d. The average plasma C max at steady state, which is substantially the same as that achieved by administering 60 mg of denosumab once every about 3 months.

[0049] In some embodiments, the amount of denosumab is a. The average serum concentration of denosumab that is substantially the same as that achieved by administering 55 mg of denosumab once every about 3 months; and / or b. The average plasma area under the curve (AUC 0-∞ ); that is substantially the same as that achieved by administering 55 mg of denosumab once every about 3 months; and / or c. The difference between the average plasma C max at steady state and the average plasma C min at steady state, which is substantially the same as that achieved by administering 55 mg of denosumab once every about 3 months; and / or d. The average plasma C max at steady state, which is substantially the same as that achieved by administering 55 mg of denosumab once every about 3 months.

[0050] In some embodiments, the amount of denosumab is a. The average serum concentration of denosumab that is substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months; and / or b. Substantially the same mean plasma curve under area (AUC) achieved by administering 50 mg of denosumab once every about 3 months 0-∞ ; and / or c. Substantially the same difference between the mean plasma C max at steady state and the mean plasma C min at steady state achieved by administering 50 mg of denosumab once every about 3 months; and / or d. Substantially the same mean plasma C max at steady state achieved by administering 50 mg of denosumab once every about 3 months.

[0051] In some embodiments, the amount of denosumab is a. Substantially the same mean serum concentration of denosumab achieved by administering 45 mg of denosumab once every about 3 months; and / or b. Substantially the same mean plasma curve under area (AUC 0-∞ ) achieved by administering 45 mg of denosumab once every about 3 months; and / or c. Substantially the same difference between the mean plasma C max at steady state and the mean plasma C min at steady state achieved by administering 45 mg of denosumab once every about 3 months; and / or d. Substantially the same mean plasma C max at steady state achieved by administering 45 mg of denosumab once every about 3 months.

[0052] In some embodiments, the subject is administered denosumab for at least 12 weeks. In some embodiments, the subject is administered denosumab for at least 24 weeks. In some embodiments, the subject is administered denosumab for at least 48 weeks. In some embodiments, the subject is administered denosumab for at least 96 weeks.

[0053] In some embodiments, the subject is administered denosumab once every about three months. In some embodiments, the subject is administered denosumab once every about three months for at least two cycles. In some embodiments, the subject is administered denosumab once every about three months for at least three cycles. In some embodiments, the subject is administered denosumab once every about three months for at least four cycles. In some embodiments, the subject is administered denosumab once every about three months for at least five cycles. In some embodiments, the subject is administered denosumab once every about three months for at least six cycles. In some embodiments, the subject is administered denosumab once every about three months for at least seven cycles. In some embodiments, the subject is administered denosumab once every about three months for at least eight cycles.

[0054] In some embodiments, denosumab is administered to the subject by injection. In some embodiments, denosumab is administered to the subject by subcutaneous injection. In some embodiments, denosumab is administered to the subject by injection into the subject's upper arm, upper thigh, or abdomen. In some embodiments, denosumab is administered to the subject by subcutaneous injection into the subject's upper arm, upper thigh, or abdomen.

[0055] In some embodiments, the method further comprises administering to the subject at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. In some embodiments, the method further comprises administering to the subject a stable dose of at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. In some embodiments, the method further comprises administering to the subject a conventional supplement of oral calcium and vitamin D3. In some embodiments, the method further comprises administering to the subject a conventional supplement of oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units).

[0056] In some embodiments, administration reduces radiographic progression in a subject. In some embodiments, administration reduces joint space narrowing in a subject. In some embodiments, administration reduces cartilage degradation in a subject. In some embodiments, administration decreases the number of new erosive joints in a subject. In some embodiments, administration decreases the number of new erosive joints in a subject at week 48. In some embodiments, administration inhibits the development of new erosive joints in a subject. In some embodiments, administration decreases the number of "S / J" IP joints that develop an "E" stage in a subject. In some embodiments, administration decreases the number of "S / J" IP joints that develop an "E" stage in a subject at week 48. In some embodiments, administration inhibits the development of the "E" stage in "S / J" IP joints in a subject.

[0057] In some embodiments, administration improves erosive IP joint remodeling in a subject. In some embodiments, administration improves erosive IP joint remodeling in a subject at year 1. In some embodiments, administration improves erosive IP joint remodeling in a subject at year 2. In some embodiments, administration increases total GUSS™ in a subject. In some embodiments, administration increases total GUSS™ in a subject at week 12. In some embodiments, administration increases total GUSS™ in a subject at week 48.

[0058] In some embodiments, administration reduces pain in a subject. In some embodiments, administration reduces pain in a subject at week 96. In some embodiments, pain reduction is evaluated by the Numerical Rating Scale (NRS) for pain.

[0059] In some embodiments, administration improves joint function in a subject. In some embodiments, administration improves joint function in a subject as evaluated by the Australian-Canadian Osteoarthritis Hand Index (AUSCAN). In some embodiments, administration improves joint function in a subject as evaluated by the Functional Index for Hand Osteoarthritis (FIHOA).

[0060] In some embodiments, the subject does not exhibit dose-limiting toxicity (DLT) during denosumab administration. In some embodiments, the subject does not exhibit any grade 3 or grade 4 adverse events related to denosumab during denosumab administration. In some embodiments, the subject does not have hypocalcemia during denosumab administration.

[0061] In some embodiments, the subject exhibits at least one symptom of inflammation clinically or by ultrasound examination prior to denosumab administration. In some embodiments, the subject exhibits at least one symptom of inflammation clinically or by ultrasound examination at at least one proximal interphalangeal joint prior to denosumab administration. In some embodiments, the subject exhibits at least one proximal interphalangeal joint in stage J or E with at least one symptom of inflammation prior to denosumab administration. In some embodiments, the subject exhibits at least one proximal interphalangeal joint in stage J or E with palpable swelling prior to denosumab administration.

[0062] In some embodiments, the subject is at least about 18 years old. In some embodiments, the subject is at least about 30 years old. In some embodiments, the subject is not diagnosed with vitamin D deficiency. In some embodiments, the subject is not diagnosed with a chronic inflammatory rheumatic disease. In some embodiments, the subject is not diagnosed with psoriasis. In some embodiments, the subject is not diagnosed with cancer. In some embodiments, the subject is not diagnosed with a chronic infectious disease.

[0063] In some embodiments, the subject has not been previously treated for erosive osteoarthritis of the hand. In some embodiments, the subject has been previously treated for erosive osteoarthritis of the hand.

[0064] In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from tumor necrosis factor α (TNFα) blockers, anti-interleukin-1α inhibitors, anti-interleukin-1β inhibitors, and combinations thereof. In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, ruxolitinib, and combinations thereof.

[0065] Also disclosed herein is a method of performing radiographic synovial proliferation, joint space narrowing, cartilage degradation, and / or reduction of bone formation in a subject in need thereof. In some embodiments, the method reduces radiographic synovial proliferation in the subject. In some embodiments, the method reduces joint space narrowing in the subject. In some embodiments, the method reduces cartilage degradation in the subject. In some embodiments, the method reduces bone formation in the subject. In some embodiments, the method has one or more of the features of the methods described above.

[0066] Also disclosed herein is the use of denosumab in the manufacture of a medicament adapted for use in a method of performing radiographic synovial proliferation, joint space narrowing, cartilage degradation, and / or reduction of bone formation in a subject in need thereof. In some embodiments, the method reduces radiographic synovial proliferation in the subject. In some embodiments, the method reduces joint space narrowing in the subject. In some embodiments, the method reduces cartilage degradation in the subject. In some embodiments, the method reduces bone formation in the subject. In some embodiments, the method has one or more of the features of the methods described above.

[0067] Also disclosed herein is a pharmaceutical composition comprising denosumab for use in a method of performing in a subject in need thereof radiographic erosive progression, joint space narrowing, cartilage degradation and / or reduction of bone formation. In some embodiments, the method reduces radiographic erosive progression in the subject. In some embodiments, the method reduces joint space narrowing in the subject. In some embodiments, the method reduces cartilage degradation of the subject. In some embodiments, the method reduces bone formation in the subject. In some embodiments, the method has one or more of the features of the methods described above.

[0068] Also disclosed herein is a method of inhibiting the development of new erosive joints in a subject in need thereof. In some embodiments, the method inhibits the development of new erosive IP joints in the subject. In some embodiments, the method has one or more of the features of the methods described above.

[0069] Also disclosed herein is the use of denosumab in the manufacture of a medicament adapted for use in a method of inhibiting the development of new erosive joints in a subject in need thereof. In some embodiments, the method inhibits the development of new erosive IP joints in the subject. In some embodiments, the method has one or more of the features of the methods described above.

[0070] Also disclosed herein is a pharmaceutical composition comprising denosumab for use in a method of inhibiting the development of new erosive joints in a subject in need thereof. In some embodiments, the method inhibits the development of new erosive IP joints in the subject. In some embodiments, the method has one or more of the features of the methods described above.

[0071] Also disclosed herein is a method of reducing pain in a subject having erosive deformative hand OA. In some embodiments, the reduction of pain in the subject is evaluated by a Numerical Rating Scale (NRS) for pain. In some embodiments, the method has one or more of the features of the methods described above.

[0072] Also disclosed herein is the use of denosumab in the manufacture of a medicament adapted for use in a method of reducing pain in a subject having erosive osteoarthritis of the hand. In some embodiments, the method has one or more of the features of the methods described above.

[0073] Also disclosed herein is a pharmaceutical composition comprising denosumab for use in a method of reducing pain in a subject having erosive osteoarthritis of the hand. In some embodiments, the method has one or more of the features of the methods described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0074]

Figure 1A

Figure 1B

Figure 1C

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4

Mode for Carrying Out the Invention

[0075] Some embodiments of the present disclosure relate to a method of treating erosive osteoarthritis (OA) in a subject in need thereof, a method of performing radiographic erosive progression, joint space narrowing, cartilage degradation, and / or reduction of bone formation in a subject in need thereof (e.g., a subject suffering from erosive hand OA), a method of inhibiting the development of new erosive joints in a subject in need thereof (e.g., a subject suffering from erosive hand OA), and a method of reducing pain in a subject having erosive hand OA. Additional embodiments of the present disclosure relate to the use of denosumab in the manufacture of a medicament adapted for use in the methods described herein and to a pharmaceutical composition comprising denosumab for use in the methods described herein.

[0076] Definitions: As used herein, the terms "a", "an", "the", and similar referents in connection with the exemplary embodiments and claims are to be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context.

[0077] As used herein, "and / or" in terms such as "[A] and / or [B]" with respect to a selection includes [A] alone, [B] alone, and both [A] and [B].

[0078] The terms "comprising", "having", "including", and "containing" as used herein are to be construed as open-ended terms that include the recited component but do not exclude other elements (i.e., mean "including but not limited to") unless otherwise specified.

[0079] As used herein, the term “about,” when used in connection with a dosage or amount, includes a range of values that includes the particular dosage or amount or a dosage or amount recognized by one of ordinary skill in the art as providing the same effect as the particular dosage or amount. In some embodiments, the term “about” reflects a variation of 10% of the indicated value. In some embodiments, the term “about” reflects a variation of 5% of the indicated value. In some embodiments, the term “about” reflects a variation of 2% of the indicated value. In some embodiments, the term “about” reflects a variation of 1% of the indicated value.

[0080] As used herein, the terms “administer” and its cognates (e.g., “administering”) include both self-administration and administration to a patient by another person (e.g., a medical professional or a caregiver).

[0081] As used herein, the term “antibody” refers to a protein having a conventional immunoglobulin type that includes heavy and light chains and includes variable and constant regions. By way of non-limiting example, an antibody can be an IgG, which has a “Y-shaped” structure with two pairs of identical polypeptide chains, each pair having one “light” chain (e.g., having a molecular weight of about 25 kDa) and one “heavy” chain (e.g., having a molecular weight of about 50–70 kDa). As used herein, an “antibody” has variable and constant regions. In the IgG type, the variable region generally is about 100–110 or more amino acids, includes three complementarity-determining regions (CDRs), is primarily involved in antigen recognition, and is substantially different from other antibodies that bind different antigens. The constant region enables the antibody to recruit cells and molecules of the immune system. The variable region is made up of the N-terminal regions of each light and heavy chain, while the constant region is made up of the respective C-terminal portions of the heavy and light chains (Janeway et al., “Structure of the Antibody Molecule and the Immunoglobulin Genes”, Immunobiology: The Immune System in Health and Disease, 4 thed.Elsevier Science Ltd. / Garland Publishing,(1999)).

[0082] The general structure and properties of the CDRs of antibodies are described in the art. Briefly, in the antibody backbone, the CDRs are embedded within the frameworks in the variable regions of the heavy and light chains, where they form regions that are largely involved in antigen binding and antigen recognition. The variable regions typically contain at least three CDRs of the heavy or light chains (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service N.I.H., Bethesda, Md.; Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:877-883), and are within the framework regions (designated as framework regions 1-4, FR1, FR2, FR3, and FR4 by Kabat et al., 1991; see also Chothia and Lesk, 1987, supra).

[0083] An antibody can include any constant region known in the art. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha or epsilon, and the isotypes of antibodies are defined as IgM, IgD, IgG, IgA and IgE, respectively. IgG has several subclasses (including, but not limited to, IgG1, IgG2, IgG3 and IgG4). IgM has subclasses (including, but not limited to, IgM1 and IgM2). Embodiments of the present disclosure include all such classes or isotypes of antibodies. The light chain constant region can be, for example, a kappa or lambda light chain constant region, such as a human kappa or lambda light chain constant region. The heavy chain constant region can be, for example, an alpha, delta, epsilon, gamma or mu heavy chain constant region, such as a human alpha, human delta, human epsilon, human gamma or human mu heavy chain constant region. Thus, in some embodiments, the antibody is an antibody of isotype IgA, IgD, IgE, IgG or IgM and includes any one of IgG1, IgG2, IgG3 or IgG4.

[0084] As used herein, the term "chimeric antibody" refers to an antibody that contains domains from two or more different antibodies. A chimeric antibody can, for example, contain a constant domain from one species and a variable domain from a second species, or more generally can contain stretches of amino acid sequences from at least two species. A chimeric antibody can also contain domains from two or more different antibodies within the same species.

[0085] As used herein, the term "humanized," when used in reference to an antibody, refers to an antibody having at least a CDR region derived from a non-human source that has been engineered to have a structure and immunological function more similar to that of a true human antibody than the antibody of its original source. By way of non-limiting example, humanization can include grafting CDRs from a non-human antibody, such as a mouse antibody, onto a human antibody. Humanization can also include selected amino acid substitutions to make non-human sequences more similar to human sequences.

[0086] As used herein, the term "conservative amino acid substitution" refers to the substitution of an amino acid with another amino acid having similar properties, such as size, charge, hydrophobicity, hydrophilicity and / or aromaticity, and includes exchanges within one of the following five groups: I. Small aliphatic nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, Gly; II. Polar, negatively charged residues and their amides and esters: Asp, Asn, Glu, Gln, cysteic acid and homocysteic acid; III. Polar, positively charged residues: His, Arg, Lys; ornithine (Orn) IV. Large aliphatic, nonpolar residues: Met, Leu, Ile, Val, Cys, norleucine (Nle), homocysteine V. Large aromatic residues: Phe, Tyr, Trp, acetylphenylalanine.

[0087] As used herein, the terms "[X] weeks" and "[Y] years" refer to a specific point in time. By way of example, administration to improve erosive IP joint remodeling in the context of [Y] years refers to administration that results in improvement of erosive IP joint remodeling measured [Y] years after treatment, as compared to the baseline state.

[0088] The terms "at least one" and "one or more" are used interchangeably herein and include one of the indicated components and a plurality of the indicated components (e.g., 2, 3, 4, etc.).

[0089] As used herein, the term "an amount of denosumab corresponding to [dose X] of denosumab administered according to [schedule Y]" refers to one or more characteristics (e.g., mean serum concentration; mean plasma area under the curve (AUC 0~∞ ); mean plasma C at steady state max and the difference between mean plasma C at steady state min and mean plasma C at steady state max) refers to a denosumab dosing regimen (i.e., dose A of denosumab administered on schedule B) that generates a pharmacokinetic profile in a subject that is substantially the same as the pharmacokinetic profile in a subject to whom denosumab at [dose X] was administered on [schedule Y].

[0090] The terms "denosumab administration" and "denosumab treatment", when used in relation to a period, refer to the period during which a subject is administered denosumab according to a specific schedule (i.e., from the first dose to the end of the final cycle). As a non-limiting example, the period of "denosumab administration" or "denosumab treatment" for a subject who was administered denosumab once every approximately 3 months over 2 cycles is 6 months from the first dose.

[0091] As used herein, "erosive rheumatoid arthritis" is defined as radiographic evidence of ≥1 IP joint in the J phase (i.e., loss of joint space) or the E phase (i.e., subchondral erosion) according to the anatomic staging scoring system of Verbruggen and Veys.

[0092] As used herein, the term "previously treated", when used in relation to a subject, refers to a subject who has received at least one specific therapy prior to the administration of the first dose of a RANKL inhibitor (e.g., denosumab) to the subject.

[0093] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an animal, e.g., a human. In some embodiments, the "subject" or "patient" is a human.

[0094] As used herein, the term "substantially similar" when used in connection with a particular property includes a particular property recognized by one of ordinary skill in the art to provide an equivalent effect to the particular property. In some embodiments, when used in connection with a quantitative property, the term "substantially similar" reflects a variation of 10% of the numerical value corresponding to the quantitative property. In some embodiments, when used in connection with a quantitative property, the term "substantially similar" reflects a variation of 5% of the numerical value corresponding to the quantitative property. In some embodiments, when used in connection with a quantitative property, the term "substantially similar" reflects a variation of 2% of the numerical value corresponding to the quantitative property. In some embodiments, when used in connection with a quantitative property, the term "substantially similar" reflects a variation of 1% of the numerical value corresponding to the quantitative property.

[0095] As used herein, the terms "treatment" and its cognates (e.g., "treating" or "treatment") refer to ameliorating at least one symptom or sign of a disease in a subject, delaying the onset of at least one symptom or sign of a disease in a subject, or reducing the severity of at least one symptom or sign of a disease in a subject. "Treatment" and its cognates do not necessarily mean 100% or complete treatment. Rather, the degree of treatment recognized by one of ordinary skill in the art to have a potential benefit or therapeutic effect varies. "Treatment" and its cognates as used herein in connection with erosive deformative hand OA include, but are not limited to: reduction of erosive progression on radiograph; reduction of joint space narrowing; reduction of cartilage degradation; reduction of bone formation; inhibition of the development of new erosive joints; and reduction of pain. Improvement or reduction in the severity of any of these symptoms or signs can be readily evaluated according to methods and techniques known in the art or methods and techniques developed thereafter.

[0096] Non-limiting exemplary embodiment #1 By way of non-limiting example, some exemplary embodiments of the present disclosure include the following: 1. A method of treating subjects in need thereof for osteoarthritis (OA), the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg), administered once every about 3 months. 2. A method of treating radiographic progression, joint space narrowing, cartilage degradation and / or reduction of bone formation in subjects in need thereof, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg), administered once every about 3 months. 3. The method according to embodiment 2, wherein the subject is diagnosed with osteoarthritis (OA). 4. The method according to any one of embodiments 1 - 3, wherein the administration reduces radiographic progression in the subject. 5. The method according to any one of embodiments 1 - 4, wherein the administration reduces narrowing of the joint space in the subject. 6. The method according to any one of embodiments 1 - 5, wherein the administration reduces cartilage degradation in the subject. 7. The method according to any one of embodiments 1 - 6, wherein the administration reduces bone formation in the subject. 8. A method of inhibiting the development of new erosive joints in subjects in need thereof, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg), administered once every about 3 months. 9. The method according to embodiment 8, wherein the subject is diagnosed with osteoarthritis (OA). 10. The method according to any one of embodiments 1 - 9, wherein the administration inhibits the development of new erosive IP joints in the subject (e.g., at week 48). 11. Administration is a method according to any one of embodiments 1-10 that reduces the number of "S / J" IP joints that develop the "E" phase in a subject. 12. Administration is a method according to any one of embodiments 1-11 that inhibits the development of the "E" phase in "S / J" IP joints in a subject. 13. A method for reducing pain in a subject having erosive osteoarthritis (OA), the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) administered once every about three months. 14. Administration is a method according to any one of embodiments 1-13 that reduces pain in a subject as evaluated by a pain numerical rating scale (NRS). 15. Administration is a method according to any one of embodiments 1-14 that improves erosive IP finger joint remodeling in a subject (e.g., at one year; at two years). 16. Administration is a method according to any one of embodiments 1-15 that increases the total GUSS (trademark) in a subject (e.g., at 12 weeks; at 48 weeks). 17. Administration is a method according to any one of embodiments 1-16 that improves joint function in a subject. 18. Administration is a method according to any one of embodiments 1-17 that improves joint function in a subject as evaluated by the Australian-Canadian Osteoarthritis Hand Index (AUSCAN). 19. Administration is a method according to any one of embodiments 1-18 that improves joint function in a subject as evaluated by the Functional Index for Hand Osteoarthritis (FIHOA). 20. The subject does not exhibit dose-limiting toxicity (DLT) during denosumab administration, according to any one of embodiments 1-19. 21. The subject does not exhibit any grade 3 or grade 4 adverse events associated with denosumab during denosumab administration, according to any one of embodiments 1-20. 22. The subject is a method according to any one of embodiments 1 to 21 that is not hypocalcemic immediately before or during denosumab administration. 23. A method according to any one of embodiments 1 to 22, comprising administering denosumab to the subject in an amount corresponding to about 45 mg to less than 60 mg of denosumab administered once every about three months. 24. A method according to any one of embodiments 1 to 22, comprising administering denosumab to the subject in an amount corresponding to about 45 mg of denosumab administered once every about three months. 25. A method according to any one of embodiments 1 to 22, comprising administering denosumab to the subject in an amount corresponding to about 50 mg of denosumab administered once every about three months. 26. A method according to any one of embodiments 1 to 22, comprising administering denosumab to the subject in an amount corresponding to about 55 mg of denosumab administered once every about three months. 27. A method according to any one of embodiments 1 to 22, comprising administering denosumab to the subject in an amount corresponding to about 60 mg of denosumab administered once every about three months. 28. A method according to any one of embodiments 1 to 22, comprising administering about 45 mg of denosumab to the subject once every about three months. 29. A method according to any one of embodiments 1 to 22, comprising administering about 50 mg of denosumab to the subject once every about three months. 30. A method according to any one of embodiments 1 to 22, comprising administering about 55 mg of denosumab to the subject once every about three months. 31. A method according to any one of embodiments 1 to 22, comprising administering about 60 mg of denosumab to the subject once every about three months. 32. The amount of denosumab is a. an average serum concentration of denosumab that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months; and / or b. an average plasma curve area under the curve (AUC 0-∞ ); and / or c. The difference between the mean plasma C at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every approximately 3 months; and / or max and the mean plasma C at steady state min ; and / or d. The mean plasma C at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every approximately 3 months max A method according to any one of embodiments 1 to 22 that provides 33. The amount of denosumab is a. The mean serum concentration of denosumab that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately 3 months; and / or b. The mean plasma curve under area (AUC0-∞) that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately 3 months; and / or c. The difference between the mean plasma Cmax and the mean plasma Cmin at steady state that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately 3 months; and / or d. The mean plasma Cmax at steady state that is substantially the same as that achieved by administering 55 mg of denosumab once every approximately 3 months A method according to any one of embodiments 1 to 22 that provides 34. The amount of denosumab is a. The mean serum concentration of denosumab that is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months; and / or b. The mean plasma curve under area (AUC0-∞) that is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months; and / or c. The difference between the mean plasma Cmax and the mean plasma Cmin at steady state that is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months; and / or d. The mean plasma Cmax at steady state that is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months A method according to any one of embodiments 1 to 22, which provides 35. The amount of denosumab is a. an average serum concentration of denosumab that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or b. an area under the plasma curve (AUC0-∞) that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or c. a difference between the average plasma Cmax and the average plasma Cmin at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or d. an average plasma Cmax at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months A method according to any one of embodiments 1 to 22, which provides 36. A method according to any one of embodiments 1 to 35, wherein the subject is administered denosumab for at least 12 weeks. 37. A method according to any one of embodiments 1 to 36, wherein the subject is administered denosumab for at least 24 weeks. 38. A method according to any one of embodiments 1 to 37, wherein the subject is administered denosumab for at least 48 weeks. 39. A method according to any one of embodiments 1 to 38, wherein the subject is administered denosumab for at least 96 weeks. 40. A method according to any one of embodiments 1 to 39, wherein the subject is administered denosumab once every about 3 months. 41. A method according to any one of embodiments 1 to 40, wherein the subject is administered denosumab once every about 3 months for at least 2 cycles (e.g., 2 cycles; 3 cycles; 4 cycles; 5 cycles; 6 cycles; 7 cycles; 8 cycles; at least 2 cycles; at least 3 cycles; at least 4 cycles; at least 5 cycles; at least 6 cycles; at least 7 cycles; at least 8 cycles). 42. Denosumab is a method according to any one of embodiments 1 to 41, which is administered to a subject by injection (e.g., by subcutaneous injection). 43. Denosumab is a method according to any one of embodiments 1 to 42, which is administered to a subject by injection (e.g., by subcutaneous injection) into the upper arm, upper thigh or abdomen of the subject. 44. A method according to any one of embodiments 1 to 43, further comprising administering to the subject at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. 45. A method according to any one of embodiments 1 to 44, further comprising administering to the subject a stable dose of at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. 46. A method according to any one of embodiments 1 to 45, further comprising administering to the subject a conventional supplement of oral calcium and vitamin D3 (e.g., oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units)). 47. A method according to any one of embodiments 1 to 46, wherein the subject exhibits at least one symptom of inflammation in a clinical or ultrasound examination (e.g., at at least one interphalangeal joint of a finger) prior to denosumab administration. 48. A method according to any one of embodiments 1 to 47, wherein the subject exhibits at least one interphalangeal joint of a finger in stage J or E, together with at least one symptom of inflammation, prior to denosumab administration. 49. A method according to any one of embodiments 1 to 48, wherein the subject exhibits at least one interphalangeal joint of a finger in stage J or E, together with palpable swelling, prior to denosumab administration. 50. A method according to any one of embodiments 1 to 49, wherein the subject is at least about 18 years old (e.g., at least about 30 years old). 51. A method according to any one of embodiments 1 to 50, wherein the subject is not diagnosed with vitamin D deficiency, chronic inflammatory rheumatic disease, psoriasis, cancer or chronic infectious disease. 52. A method according to any one of embodiments 1 to 51, wherein the subject has not been previously treated for erosive osteoarthritis of the hand. 53. The subject is a method according to any one of Embodiments 1 to 51 that has been previously treated for erosive osteoarthritis of the hand. 54. The subject is a method according to Embodiment 53 that has been previously treated with at least one therapeutic agent selected from a tumor necrosis factor α (TNFα) blocker, an anti-interleukin-1α inhibitor, an anti-interleukin-1β inhibitor, and combinations thereof. 55. The subject is a method according to Embodiment 53 or 54 that has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, ruxolitinib, and combinations thereof.

[0097] Non-limiting exemplary Embodiment #2 Although not limited, some exemplary embodiments / features of the present disclosure include the following. 1. Use of denosumab in the manufacture of a medicament adapted for use in a method of treating erosive osteoarthritis of the hand (OA) in a subject in need thereof, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about three months. 2. Use of denosumab in the manufacture of a medicament adapted for use in a method of reducing erosive progression, joint space narrowing, cartilage degradation, and / or reduction of bone formation as seen on radiographs in a subject in need thereof, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about three months. 3. The subject is diagnosed with erosive osteoarthritis of the hand (OA), the use according to Feature 2. 4. The administration reduces erosive progression as seen on radiographs in the subject, the use according to any one of Features 1 to 3. 5. The administration reduces narrowing of the joint space in the subject, the use according to any one of Features 1 to 4. 6. Administration is for use according to any one of features 1 to 5 that reduces cartilage degeneration in a subject. 7. Administration is for use according to any one of features 1 to 6 that reduces bone formation in a subject. 8. Use of denosumab in the manufacture of a medicament adapted for use in a method of inhibiting the development of new erosive joints in a subject in need thereof, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) administered once every about 3 months. 9. The subject is diagnosed with erosive osteoarthritis of the hand (OA), use according to feature 8. 10. Administration is for use according to any one of features 1 to 9 that inhibits the development of new erosive IP joints in a subject (e.g., at week 48). 11. Administration is for use according to any one of features 1 to 10 that reduces the number of "S / J" IP joints that develop the "E" stage in a subject. 12. Administration is for use according to any one of features 1 to 11 that inhibits the development of the "E" stage in "S / J" IP joints in a subject. 13. Use of denosumab in the manufacture of a medicament adapted for use in a method of reducing pain in a subject having erosive osteoarthritis of the hand (OA), the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) administered once every about 3 months. 14. Administration is for use according to any one of features 1 to 13 that reduces pain as evaluated by the Numerical Rating Scale (NRS) in a subject. 15. Administration is for use according to any one of features 1 to 14 that improves erosive IP finger joint remodeling in a subject (e.g., at year 1; at year 2). 16. Administration is use according to any one of features 1 to 15 that increases total GUSS (trademark) in a subject (e.g., at the 12th week; at the 48th week). 17. Administration is use according to any one of features 1 to 16 that improves joint function in a subject. 18. Administration is use according to any one of features 1 to 17 that improves joint function evaluated by the Australian-Canadian Osteoarthritis Hand Index (AUSCAN) in a subject. 19. Administration is use according to any one of features 1 to 18 that improves joint function evaluated by the Functional Index for Hand Osteoarthritis (FIHOA) in a subject. 20. A subject is use according to any one of features 1 to 19 that does not show dose-limiting toxicity (DLT) during denosumab administration. 21. A subject is use according to any one of features 1 to 20 that does not show any grade 3 or grade 4 adverse events related to denosumab during denosumab administration. 22. A subject is use according to any one of features 1 to 21 that is not hypocalcemic immediately before or during denosumab administration. 23. The method includes administering denosumab to a subject in an amount corresponding to about 45 mg to less than 60 mg of denosumab administered once every about three months, and is use according to any one of features 1 to 22. 24. The method includes administering denosumab to a subject in an amount corresponding to about 45 mg of denosumab administered once every about three months, and is use according to any one of features 1 to 22. 25. The method includes administering denosumab to a subject in an amount corresponding to about 50 mg of denosumab administered once every about three months, and is use according to any one of features 1 to 22. 26. The method includes administering denosumab to a subject in an amount corresponding to about 55 mg of denosumab administered once every about three months, and is use according to any one of features 1 to 22. 27. The method includes administering denosumab to a subject in an amount corresponding to about 60 mg of denosumab administered once every about three months, and is use according to any one of features 1 to 22. 28. The method comprises administering denosumab at about 45 mg once every about three months, and is used according to any one of features 1 to 22. 29. The method comprises administering denosumab at about 50 mg once every about three months, and is used according to any one of features 1 to 22. 30. The method comprises administering denosumab at about 55 mg once every about three months, and is used according to any one of features 1 to 22. 31. The method comprises administering denosumab at about 60 mg once every about three months, and is a method according to any one of features 1 to 22. 32. The amount of denosumab is a. the average serum concentration of denosumab that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months; and / or b. the average plasma curve area under the curve (AUC 0-∞ ); and / or c. the difference between the average plasma C max at steady state and the average plasma C min at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months; and / or d. the average plasma C max at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months, and is used according to any one of features 1 to 22. 33. The amount of denosumab is a. the average serum concentration of denosumab that is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or b. the average plasma curve area under the curve (AUC0-∞) that is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or c. The difference between the mean plasma Cmax at steady state and the mean plasma Cmin at steady state, which is substantially the same as that achieved by administering 55 mg of denosumab once every approximately 3 months; and / or d. The mean plasma Cmax at steady state, which is substantially the same as that achieved by administering 55 mg of denosumab once every approximately 3 months A use according to any one of features 1 to 22, which provides the same. 34. The amount of denosumab is a. The mean serum concentration of denosumab, which is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months; and / or b. The mean plasma area under the curve (AUC0-∞), which is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months; and / or c. The difference between the mean plasma Cmax at steady state and the mean plasma Cmin at steady state, which is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months; and / or d. The mean plasma Cmax at steady state, which is substantially the same as that achieved by administering 50 mg of denosumab once every approximately 3 months A use according to any one of features 1 to 22, which provides the same. 35. The amount of denosumab is a. The mean serum concentration of denosumab, which is substantially the same as that achieved by administering 45 mg of denosumab once every approximately 3 months; and / or b. The mean plasma area under the curve (AUC0-∞), which is substantially the same as that achieved by administering 45 mg of denosumab once every approximately 3 months; and / or c. The difference between the mean plasma Cmax at steady state and the mean plasma Cmin at steady state, which is substantially the same as that achieved by administering 45 mg of denosumab once every approximately 3 months; and / or d. The mean plasma Cmax at steady state, which is substantially the same as that achieved by administering 45 mg of denosumab once every approximately 3 months A use according to any one of features 1 to 22, which provides the same. 36. The subject is for use according to any one of features 1 to 35, wherein denosumab is administered to the subject for at least 12 weeks. 37. The subject is for use according to any one of features 1 to 36, wherein denosumab is administered to the subject for at least 24 weeks. 38. The subject is for use according to any one of features 1 to 37, wherein denosumab is administered to the subject for at least 48 weeks. 39. The subject is for use according to any one of features 1 to 38, wherein denosumab is administered to the subject for at least 96 weeks. 40. The subject is for use according to any one of features 1 to 39, wherein denosumab is administered to the subject once every about 3 months. 41. The subject is for use according to any one of features 1 to 40, wherein denosumab is administered to the subject once every about 3 months for at least 2 cycles (e.g., 2 cycles; 3 cycles; 4 cycles; 5 cycles; 6 cycles; 7 cycles; 8 cycles; at least 2 cycles; at least 3 cycles; at least 4 cycles; at least 5 cycles; at least 6 cycles; at least 7 cycles; at least 8 cycles). 42. The medicament is for use according to any one of features 1 to 41, wherein the medicament is administered to the subject by injection (e.g., by subcutaneous injection). 43. The medicament is for use according to any one of features 1 to 42, wherein the medicament is administered to the subject by injection (e.g., by subcutaneous injection) into the upper arm, upper thigh or abdomen of the subject. 44. The method is for use according to any one of features 1 to 43, further comprising administering to the subject at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. 45. The method is for use according to any one of features 1 to 44, further comprising administering to the subject a stable dose of at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs. 46. The method is for use according to any one of features 1 to 45, further comprising administering to the subject conventional supplements of oral calcium and vitamin D3 (e.g., oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units)). 47. The subject is for use according to any one of features 1 to 46, showing at least one symptom of inflammation clinically or by ultrasound examination before denosumab administration (for example, in at least one interphalangeal joint of the fingers). 48. The subject is for use according to any one of features 1 to 47, showing at least one interphalangeal joint of the fingers in stage J or E together with at least one inflammatory symptom before denosumab administration. 49. The subject is for use according to any one of features 1 to 48, showing at least one interphalangeal joint of the fingers in stage J or E together with palpable swelling before denosumab administration. 50. The subject is for use according to any one of features 1 to 49 and is at least about 18 years old (for example, at least about 30 years old). 51. The subject is for use according to any one of features 1 to 50 and has not been diagnosed with vitamin D deficiency, chronic inflammatory rheumatic disease, psoriasis, cancer or chronic infectious disease. 52. The subject is for use according to any one of features 1 to 51 and has not been previously treated for erosive osteoarthritis of the hand. 53. The subject is for use according to any one of features 1 to 51 and has been previously treated for erosive osteoarthritis of the hand. 54. The subject is for use according to feature 53 and has been previously treated with at least one therapeutic agent selected from tumor necrosis factor α (TNFα) blockers, anti-interleukin-1α inhibitors, anti-interleukin-1β inhibitors and combinations thereof. 55. The subject is for use according to feature 53 or 54 and has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, ruxolitinib and combinations thereof.

[0098] Non-limiting exemplary embodiment #3 Without limitation, some exemplary embodiments / aspects of the present disclosure include the following. 1. A pharmaceutical composition comprising denosumab for use in a method of treating subjects in need thereof with osteoarthritis (OA), the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about 3 months. 2. A pharmaceutical composition comprising denosumab for use in a method of treating subjects in need thereof with radiographic progression, joint space narrowing, cartilage degeneration and / or reduced bone formation, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about 3 months. 3. The pharmaceutical composition according to item 2 for use, wherein the subject is diagnosed with osteoarthritis (OA). 4. The pharmaceutical composition according to any one of items 1 to 3 for use, wherein the administration reduces radiographic progression in the subject. 5. The pharmaceutical composition according to any one of items 1 to 4 for use, wherein the administration reduces narrowing of the joint space in the subject. 6. The pharmaceutical composition according to any one of items 1 to 5 for use, wherein the administration reduces cartilage degeneration in the subject. 7. The pharmaceutical composition according to any one of items 1 to 6 for use, wherein the administration reduces bone formation in the subject. 8. A pharmaceutical composition comprising denosumab for use in a method of inhibiting the development of new erosive joints in subjects in need thereof, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) of denosumab administered once every about 3 months. 9. A pharmaceutical composition for use according to clause 8, wherein the subject is diagnosed with erosive osteoarthritis (OA) of the hand. 10. A pharmaceutical composition for use according to any one of clauses 1 to 9, wherein administration inhibits the development of new erosive IP joints in the subject (e.g., at week 48). 11. A pharmaceutical composition for use according to any one of clauses 1 to 10, wherein administration reduces the number of "S / J" IP joints that develop stage "E" in the subject. 12. A pharmaceutical composition for use according to any one of clauses 1 to 11, wherein administration inhibits the development of stage "E" in "S / J" IP joints in the subject. 13. A pharmaceutical composition comprising denosumab for use in a method of reducing pain in a subject having erosive osteoarthritis (OA) of the hand, the method comprising administering to the subject an amount of denosumab corresponding to about 45 mg to about 60 mg (e.g., less than about 45 mg to 60 mg; about 45 mg to about 55 mg; about 45 mg to about 50 mg; about 45 mg; about 50 mg; about 55 mg; about 60 mg) administered once every about three months. 14. A pharmaceutical composition for use according to any one of clauses 1 to 13, wherein administration reduces pain as evaluated by the Numerical Rating Scale (NRS) in the subject. 15. A pharmaceutical composition for use according to any one of clauses 1 to 14, wherein administration improves erosive IP finger joint remodeling in the subject (e.g., at year 1; at year 2). 16. A pharmaceutical composition for use according to any one of clauses 1 to 15, wherein administration increases the total GUSS™ in the subject (e.g., at week 12; at week 48). 17. A pharmaceutical composition for use according to any one of clauses 1 to 16, wherein administration improves joint function in the subject. 18. A pharmaceutical composition for use according to any one of clauses 1 to 17, wherein administration improves joint function as evaluated by the Australian-Canadian Osteoarthritis Hand Index (AUSCAN) in the subject. 19. Administration is a pharmaceutical composition for use according to any one of clauses 1 to 18 that improves joint function as evaluated by the Functional Index of the Hand in Osteoarthritis (FIHOA) in a subject. 20. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 19 that does not exhibit dose-limiting toxicity (DLT) during denosumab administration. 21. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 20 that does not exhibit any grade 3 or grade 4 adverse events related to denosumab during denosumab administration. 22. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 21 that is not hypocalcemic immediately before or during denosumab administration. 23. The method comprises administering denosumab to the subject in an amount corresponding to about 45 mg to less than 60 mg of denosumab administered once every about three months, for use according to any one of clauses 1 to 22. 24. The method comprises administering denosumab to the subject in an amount corresponding to about 45 mg of denosumab administered once every about three months, for use according to any one of clauses 1 to 22. 25. The method comprises administering denosumab to the subject in an amount corresponding to about 50 mg of denosumab administered once every about three months, for use according to any one of clauses 1 to 22. 26. The method comprises administering denosumab to the subject in an amount corresponding to about 55 mg of denosumab administered once every about three months, for use according to any one of clauses 1 to 22. 27. The method comprises administering denosumab to the subject in an amount corresponding to about 60 mg of denosumab administered once every about three months, for use according to any one of clauses 1 to 22. 28. The method comprises administering about 45 mg of denosumab to the subject once every about three months, for use according to any one of clauses 1 to 22. 29. The method comprises administering about 50 mg of denosumab to the subject once every about three months, for use according to any one of clauses 1 to 22. 30. The method comprises administering denosumab at a dose of about 55 mg once every about three months, for use according to any one of clauses 1 to 22, a pharmaceutical composition. 31. The method comprises administering denosumab at a dose of about 60 mg once every about three months, for use according to any one of clauses 1 to 22, a pharmaceutical composition. 32. The amount of denosumab is a. an average serum concentration of denosumab that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months; and / or b. an area under the mean plasma curve (AUC 0-∞ ); and / or c. a difference between the mean plasma C max at steady state and the mean plasma C min at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months; and / or d. a mean plasma C max at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months, for use according to any one of clauses 1 to 22, a pharmaceutical composition. 33. The amount of denosumab is a. an average serum concentration of denosumab that is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or b. an area under the mean plasma curve (AUC0-∞) that is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or c. a difference between the mean plasma Cmax and the mean plasma Cmin at steady state that is substantially the same as that achieved by administering 55 mg of denosumab once every about three months; and / or d. a mean plasma Cmax at steady state that is substantially the same as that achieved by administering 55 mg of denosumab once every about three months A pharmaceutical composition for use according to any one of clauses 1 to 22, which provides 34. The amount of denosumab is a. an average serum concentration of denosumab that is substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months; and / or b. an area under the mean plasma curve (AUC0-∞) that is substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months; and / or c. a difference between the mean plasma Cmax and the mean plasma Cmin at steady state that is substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months; and / or d. a mean plasma Cmax at steady state that is substantially the same as that achieved by administering 50 mg of denosumab once every about 3 months A pharmaceutical composition for use according to any one of clauses 1 to 22, which provides 35. The amount of denosumab is a. an average serum concentration of denosumab that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or b. an area under the mean plasma curve (AUC0-∞) that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or c. a difference between the mean plasma Cmax and the mean plasma Cmin at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months; and / or d. a mean plasma Cmax at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about 3 months A pharmaceutical composition for use according to any one of clauses 1 to 22, which provides 36. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 35, in which denosumab is administered for at least 12 weeks. 37. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 36, in which denosumab is administered for at least 24 weeks. 38. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 37, which is administered denosumab for at least 48 weeks. 39. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 38, which is administered denosumab for at least 96 weeks. 40. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 39, which is administered denosumab once every about three months. 41. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 40, which is administered denosumab once every about three months for at least 2 cycles (for example, 2 cycles; 3 cycles; 4 cycles; 5 cycles; 6 cycles; 7 cycles; 8 cycles; at least 2 cycles; at least 3 cycles; at least 4 cycles; at least 5 cycles; at least 6 cycles; at least 7 cycles; at least 8 cycles). 42. The pharmaceutical composition is a pharmaceutical composition for use according to any one of clauses 1 to 41, which is administered to the subject by injection (for example, by subcutaneous injection). 43. The pharmaceutical composition is a pharmaceutical composition for use according to any one of clauses 1 to 42, which is administered to the subject by injection (for example, by subcutaneous injection) into the upper arm, upper thigh or abdomen of the subject. 44. The method further comprises administering to the subject at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs, and is a pharmaceutical composition for use according to any one of clauses 1 to 43. 45. The method further comprises administering to the subject a stable dose of at least one therapeutic agent selected from analgesics and non-steroidal anti-inflammatory drugs, and is a pharmaceutical composition for use according to any one of clauses 1 to 44. 46. The method further comprises administering to the subject conventional supplements of oral calcium and vitamin D3 (for example, oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units)), and is a pharmaceutical composition for use according to any one of clauses 1 to 45. 47. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 46, which shows at least one symptom of inflammation clinically or by ultrasound examination before denosumab administration (for example, in at least one interphalangeal joint of the fingers). 48. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 47, which shows at least one interphalangeal joint of the fingers in stage J or E together with at least one inflammatory symptom before denosumab administration. 49. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 48, which shows at least one interphalangeal joint of the fingers in stage J or E together with palpable swelling before denosumab administration. 50. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 49, which is at least about 18 years old (for example, at least about 30 years old). 51. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 50, which has not been diagnosed with vitamin D deficiency, chronic inflammatory rheumatic disease, psoriasis, cancer or chronic infectious disease. 52. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 51, which has not been previously treated for erosive osteoarthritis of the hand. 53. The subject is a pharmaceutical composition for use according to any one of clauses 1 to 51, which has been previously treated for erosive osteoarthritis of the hand. 54. The subject is a pharmaceutical composition for use according to clause 53, which has been previously treated with at least one therapeutic agent selected from tumor necrosis factor α (TNFα) blockers, anti-interleukin-1α inhibitors, anti-interleukin-1β inhibitors and combinations thereof. 55. The subject is a pharmaceutical composition for use according to clause 53 or 54, which has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, ruxolitinib and combinations thereof.

[0099] Agents targeting RANK-L Alternative embodiments of the present disclosure employ at least one agent that targets RANK-L in place of denosumab in a method, use, or pharmaceutical composition for use as described herein. As agents that target RANK-L, RANK-L antigen-binding proteins (e.g., anti-RANK-L antibodies, antigen-binding fragments thereof, and anti-RANK-L antibody protein products, some of which are disclosed in WO 2018 / 200918, WO 03 / 002713, and U.S. Pat. No. 7,364,736, each of which is incorporated herein by reference in its entirety) are included. In some agents, an RANK-L antigen-binding protein that binds to human RANK-L and has the amino acid sequence set forth in National Center for Biotechnology Information (NCBI) Reference Sequence No. NP003692 or Sequence No. 1 and is encoded by the polynucleotide sequence of Sequence No. 2 is employed in place of denosumab in a method, use, or pharmaceutical composition for use as described herein.

[0100] In some embodiments, the RANK-L antigen-binding protein is an anti-RANK-L antibody or an antibody-binding fragment thereof or an anti-RANK-L antibody protein product.

[0101] In one embodiment, the anti-RANK-L antibody is a monoclonal antibody. Thus, in some embodiments, the present disclosure provides a liquid composition comprising a monoclonal antibody. Additionally, in some embodiments, the liquid composition can be a polyclonal antibody composition. In some embodiments, the antibody comprises a sequence substantially similar to a naturally occurring antibody produced by a mammal, such as a mouse, rabbit, goat, horse, chicken, hamster, human, etc. In this regard, the antibody can be considered a mammalian antibody, such as a mouse antibody, rabbit antibody, goat antibody, horse antibody, chicken antibody, hamster antibody, human antibody, etc. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a chimeric antibody or a humanized antibody.

[0102] In some embodiments, the antibody is an anti-RANK-L antibody, such as an anti-RANK-L monoclonal antibody. In some embodiments, the anti-RANK-L antibody is an IgG2 antibody. In some embodiments, the anti-RANK-L antibody binds to human RANK-L, which, in some embodiments, comprises the amino acid sequence of SEQ ID NO: 1 and is encoded by the nucleotide sequence of SEQ ID NO: 2.

[0103] In some embodiments, the antibody is denosumab or a biosimilar thereof. Denosumab is known in the art. See, for example, International Nonproprietary Names for Pharmaceutical Substances (INN): Proposed INN: List 56, WHO Drug Information 20(3):211(2006); CAS registration number 615258-40-7. Denosumab is an immunoglobulin G2 (IgG2), also known as AMG 162, and is the active pharmaceutical ingredient of Prolia® and Xgeva®.

[0104] In some embodiments, the antibody comprises a light chain comprising CDR1, CDR2, and CDR3 as set forth in Table 1. In some embodiments, the antibody comprises a heavy chain comprising CDR1, CDR2, and CDR3 as set forth in Table 1. In some embodiments, the antibody comprises a sequence comprising the VH and VL sequences listed in Table 1 or the VH-IgG2 and VL-IgG kappa sequences listed in Table 1. In some embodiments, the RANK-L antibody binding protein is an antibody comprising the amino acid sequences of SEQ ID NOs: 3-8. In some embodiments, the anti-RANK-L antibody comprises the six CDR amino acid sequences of SEQ ID NOs: 3-8. In some embodiments, the anti-RANK-L antibody comprises the heavy chain (HC) complementarity determining region (CDR) 1 amino acid sequence of SEQ ID NO: 3, the HC CDR2 amino acid sequence of SEQ ID NO: 4, the HC CDR3 amino acid sequence of SEQ ID NO: 5, the light chain (LC) CDR1 amino acid sequence of SEQ ID NO: 6, the LC CDR2 amino acid sequence of SEQ ID NO: 7, and the LC CDR3 amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-RANK-L antibody comprises: (a) a heavy chain variable region (VH) comprising: (i) VH complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 3; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; and (b) a light chain variable region (VL) comprising: (i) VL complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 6; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8, and comprises a RANK-L binding domain. In some embodiments, the RANK-L binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-RANK-L antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-RANK-L antibody comprises a HC comprising the amino acid sequence of SEQ ID NO: 11 or 13 and a LC comprising the amino acid sequence of SEQ ID NO: 12.

[0105] [Table 1]

[0106] LC, light chain; HC, heavy chain; VL, variable light chain; VH, variable heavy chain. *During the recombinant production process, the terminal residues G and K can be clipped.

[0107] In some embodiments, the antibody comprises: i. a heavy chain (HC) CDR1 comprising the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 3 or a variant amino acid sequence of SEQ ID NO: 3 having one or two amino acid substitutions, ii. an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 4 or a variant amino acid sequence of SEQ ID NO: 4 having one or two amino acid substitutions, iii. an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 5 or a variant amino acid sequence of SEQ ID NO: 5 having one or two amino acid substitutions, iv. a light chain (LC) CDR1 comprising the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 6 or a variant amino acid sequence of SEQ ID NO: 6 having one or two amino acid substitutions, v. an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 7 or a variant amino acid sequence of SEQ ID NO: 7 having one or two amino acid substitutions, vi. An LC CDR3 comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 8, or a variant amino acid sequence of SEQ ID NO: 8 having one or two amino acid substitutions.

[0108] In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 9, or a variant amino acid sequence of SEQ ID NO: 9 having 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 or 2) amino acid substitutions.

[0109] In some embodiments, the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 10, or a variant amino acid sequence of SEQ ID NO: 10 having 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 or 2) amino acid substitutions.

[0110] In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11, an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identical to SEQ ID NO: 11, or a variant amino acid sequence of SEQ ID NO: 11 having 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 or 2) amino acid substitutions.

[0111] In some embodiments, the terminal lysine may be absent. In some embodiments, the terminal lysine may be present. In some embodiments, the terminal glycine-lysine may be absent. In some embodiments, the terminal glycine-lysine may be present. C-terminal lysine clipping is a common phenomenon that occurs during the bioproduction of monoclonal antibodies. In many cases, lysine residues are removed via carboxypeptidase D (CpD), thereby generating a mixture of antibody isoforms having 0 or 1 C-terminal lysine residue on each heavy chain. Further, after C-terminal lysine cleavage, peptidylglycine α-amidating monooxygenase (PAM) catalyzes the hydroxylation of glycine and the removal of glyoxylate from the glycine residue, leaving an amidated C-terminal proline. Thus, during the recombinant production of monoclonal antibodies, the product is often a mixture of C-terminal processing variants where the heavy chain C-terminus is (amidated) proline, glycine, or lysine.

[0112] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 12, an amino acid sequence that is at least 90% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 12, or a variant amino acid sequence of SEQ ID NO: 12 having 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1, or 2) amino acid substitutions.

[0113] In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0114] Subject, erosive rheumatoid arthritis, and efficacy In some embodiments of the methods of the present disclosure, the subject is a human subject. In some embodiments, the human subject is about 18 years of age or older. In some embodiments, the human subject is about 30 years of age or older.

[0115] In some embodiments, the subject meets at least one of the inclusion criteria of the clinical trial described in Example 1 of the present application. In some embodiments, the subject has erosive osteoarthritis of the hand (erosive hand OA) or a predisposition thereto. In some embodiments, the subject exhibits the presence of at least one IP joint in stage J or E with inflammatory symptoms defined clinically and by ultrasound.

[0116] In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from tumor necrosis factor α (TNFα) blockers, anti-interleukin-1α inhibitors, anti-interleukin-1β inhibitors, and combinations thereof. In some embodiments, the subject has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, ruxolitinib, and combinations thereof.

[0117] Dosing and Frequency The alternative methods disclosed herein include administering to the subject an RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab. In some embodiments, the method includes administering from about 45 mg to about 60 mg of an RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab. Optionally, the method includes administering to the subject about 45 mg, about 50 mg, about 55 mg, or about 60 mg of an RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab. In some embodiments, the RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab, is administered to the subject about once every about 3 months or about once every 80 to about 95 days, such as once every 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 days. In some embodiments, the method includes administering once every about 3 months, about 45 mg of denosumab to the subject. In some embodiments, the method includes administering once every about 3 months, about 60 mg of denosumab to the subject.

[0118] In some embodiments, the method comprises administering an amount corresponding to about 45 mg to about 60 mg of denosumab once every about three months. Optionally, this amount provides (a) an average serum concentration of denosumab that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months; (b) an average plasma area under the curve (AUC 0-∞ ); (c) a difference between the average plasma C max at steady state and the average plasma C min at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months, and / or (d) an average plasma C max at steady state that is substantially the same as that achieved by administering 60 mg of denosumab once every about three months. Optionally, this amount provides (a) an average serum concentration of denosumab that is substantially the same as that achieved by administering 45 mg of denosumab once every about three months; (b) an average plasma area under the curve (AUC 0-∞ ); (c) a difference between the average plasma C max at steady state and the average plasma C min at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about three months; and / or (d) an average plasma C max at steady state that is substantially the same as that achieved by administering 45 mg of denosumab once every about three months.

[0119] In some embodiments, the method comprises administering denosumab to a subject for at least 24 weeks, at least 48 weeks or at least 96 weeks (if not longer). In some embodiments, the method comprises administering denosumab to a subject for at least 1 year, 2 years, 3 years or more. In some embodiments, the method comprises administering denosumab to a subject once every about 3 months over at least 2 cycles, at least 4 cycles or at least 8 cycles, each cycle comprising from about 80 to about 95 days, such as 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 or 95 days.

[0120] Route of administration and pharmaceutical composition Agents that target RANK-L, such as anti-RANK-L antibodies, such as denosumab, can be administered to a subject via any suitable route of administration. For example, an anti-RANK-L antibody (e.g., denosumab) can be administered to a subject via parenteral, nasal, oral, pulmonary, topical, vaginal or rectal administration. The following considerations regarding routes of administration are provided merely to illustrate non-limiting exemplary embodiments and should in no way be construed as limiting the scope of the present disclosure.

[0121] Formulations suitable for parenteral administration include, but are not limited to, aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the blood of the intended recipient and the formulation isotonic, and aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizing agents, thickening agents, stabilizers, and preservatives. The term "parenteral" means administration by some other route than through the digestive tract, such as subcutaneously, intramuscularly, intracavity, or intravenously. Anti-RANK-L antibodies (e.g., denosumab) may be administered with a physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or a mixture of liquids, including, with or without the addition of pharmaceutically acceptable surfactants such as acetylated fatty glycerides, pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose or emulsifying agents, suspending agents, and other pharmaceutical adjuvants, including, but not limited to, water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, dimethyl sulfoxide, glycerol, ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides, or soaps or detergents.

[0122] Oils that can be used in parenteral formulations include, but are not limited to, petroleum, animal oils, vegetable oils, or synthetic oils. Non-limiting specific examples of oils include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum oil, and mineral oil. Fatty acids suitable for use in parenteral formulations include, but are not limited to, oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are non-limiting examples of suitable fatty acid esters.

[0123] In some embodiments, the parenteral formulation contains from about 0.5 wt% to about 25 wt% of an anti-RANK-L antibody (e.g., denosumab) in solution. Preservatives and buffers may be used. To minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. In some embodiments, the amount of surfactant in such formulations ranges from about 5 wt% to about 15 wt%. Suitable surfactants include, but are not limited to, polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide with hydrophobic bases formed by the condensation of propylene oxide with propylene glycol. In some embodiments, the parenteral formulation is provided in a sealed container, such as an ampoule and vial, for unit dose or multiple doses, and can be stored in a freeze-dried state that requires only the addition of a sterile liquid excipient, such as water, immediately prior to use. In some embodiments, immediate injection solutions and suspensions are prepared from sterile powders, granules, and tablets.

[0124] Injectable formulations are contemplated by the present disclosure. The requirements for an effective pharmaceutical carrier for injectable compositions are well known to those of skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)).

[0125] In some embodiments, the RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab, is administered to the subject by injection. In some embodiments, the RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab, is administered to the subject by subcutaneous injection. In some embodiments, the RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab, is administered to the upper arm, upper thigh or abdomen of the subject. In some embodiments, the RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab, is administered to the upper arm, upper thigh or abdomen of the subject by injection. In some embodiments, the RANK-L antigen-binding protein, such as an anti-RANK-L antibody, such as denosumab, is administered to the upper arm, upper thigh or abdomen of the subject by subcutaneous injection.

[0126] Safety In some embodiments, the method comprises administering an anti-RANK-L antibody (such as denosumab) in an amount that does not result in dose-limiting toxicity (DLT) during treatment with the anti-RANK-L antibody (such as denosumab). In some embodiments, the subject does not exhibit DLT during administration. In some embodiments, the subject does not exhibit any grade 3 or grade 4 adverse events associated with treatment with the anti-RANK-L antibody (such as denosumab) during the treatment period. In some embodiments, the subject does not exhibit any grade 3 or grade 4 adverse events associated with treatment with the anti-RANK-L antibody (such as denosumab) during the treatment period. In some embodiments, the treatment period is at least 1 month (such as 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1.5 years, 2 years).

[0127] In some embodiments, the subject does not have hypocalcemia. In some embodiments, the subject does not have hypocalcemia during administration of the anti-RANK-L antibody (such as denosumab). In some embodiments, the subject does not have hypocalcemia prior to administration of the anti-RANK-L antibody (such as denosumab).

[0128] The following examples are presented to further illustrate embodiments of the present disclosure and are in no way intended to limit its scope.

Example

[0129] Example 1. RANKL blockade for the treatment of erosive interphalangeal osteoarthritis (OA) This example describes a single-center, randomized, placebo-controlled, double-blind, phase 2 study in patients with erosive hand osteoarthritis (OA) (ClinicalTrials.gov Identifier: NCT02771860; EudraCT Number 2015-003223-53).

[0130] Method Study design and participants Patients were recruited from the rheumatology outpatient clinic of Ghent University Hospital in Belgium. This study was approved by the local ethics committee and was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided written informed consent.

[0131] Adult patients aged ≥30 years and diagnosed with erosive hand OA were considered eligible for the clinical study. Erosive hand OA was defined as radiographic evidence of ≥1 IP joint in J phase (i.e., loss of joint space) or E phase (i.e., subchondral erosion) according to the anatomic staging scoring system of Verbruggen and Veys (19).

[0132] The main inclusion criteria included the following: · Men and women aged ≥30 years; · Subjects with hand OA suffering from transient inflammatory episodes of the interphalangeal joints characteristic of what is called "inflammatory" or "erosive" hand OA; · Subjects with hand OA demonstrating inflammatory symptoms of the interphalangeal joints either clinically or by ultrasound examination; · Subjects with hand OA in which at least one interphalangeal joint has the typical radiographic appearance of a "J" or "E" stage joint as defined by the above criteria; · Subjects with hand OA in which at least one interphalangeal joint in the "J" or "E" stage exhibits palpable swelling; and · The ability to submit written informed consent, comply with the requirements of the research protocol, and the willingness to do so.

[0133] Readers scored the radiographs for eligibility.

[0134] Major exclusion criteria include the following: · Patients known to be hypersensitive to drug products of mammalian origin; · Patients with clinically significant hypersensitivity to any of the components of Prolia (registered trademark); · Current and / or previous treatment with any investigational drug within 90 days or within 5 half-lives, whichever is longer, of the product; · Previous administration of denosumab from a clinical trial or otherwise (e.g., commercial use); · Vitamin D deficiency [25(OH) vitamin D level < 20 ng / mL (< 49.9 nmol / L)]. · The possibility of supplementation and rescreening; · Subjects currently with hypocalcemia or hypercalcemia (normal serum calcium level: 8.5 - 10.5 mg or 2.12 - 2.62 mmol / L); · Patients currently on bisphosphonate (BP) treatment or patients using oral BP within 12 months of study enrollment or intravenous BP or ranelate strontium within 5 years of study enrollment; · Prior use of any chondroprotective agent within 90 days, such as chondroitin sulfate, glucosamine, avocado-soybean unsaponifiables, tetracycline, corticosteroids; · Any immunomodulatory agent that may affect inflammatory cytokine metabolism within 90 days, such as corticosteroids, methotrexate, sulfasalazine, leflunomide, D-penicillin, antimalarial agents, cytotoxic agents, TNF blockers, pre-use; · History of drug abuse or alcohol abuse in the past year; · Patients with chronic inflammatory rheumatic diseases (such as rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, gout, chondrocalcinosis or other autoimmune diseases, such as systemic lupus erythematosus); · History of squamous cell carcinoma or basal cell carcinoma of the skin or cancer or lymphoproliferative disease other than cervical dysplasia that has not recurred and has been completely successfully treated within the last two years; · History of any solid organ or bone marrow transplant; · Concurrent diseases: Severe renal dysfunction (glomerular filtration < 30 ml / min / 1.73m 2 or < 50% of normal value), poorly controlled diabetes, unstable ischemic heart disease, congestive heart failure (NYHA III, IV), poorly controlled cardiomyopathy or hyperparathyroidism, active inflammatory bowel disease, malabsorption, liver failure or chronic liver disease (serum AST / ALT level 3 times higher than normal value), recent stroke (within 3 months), chronic lower limb ulcer and any other symptoms (such as indwelling urinary catheter) (which, in the opinion of the investigator, will expose the subject to risk by participating in the protocol); · The subject has any impairment that impairs the ability of the subject to submit written informed consent and / or comply with the research procedures. · Pregnant or planning to become pregnant patients; If female subjects are of childbearing age, effective contraceptive measures must be used during the study and for 9 months after the last dose of the study drug. For men with a female partner who can become pregnant: The subject has refused to use one effective contraceptive method during the study period and for 10 months after the last dose of the study drug; · Lactating female subjects; · History of osteonecrosis of the jaw and / or recent (within 3 months) tooth extraction or other untreated dental surgery; or history of planned invasive dental treatment during the study.

[0135] Randomization and masking After screening, patients were randomly assigned in a 1:1 ratio to subcutaneous placebo or denosumab 60 mg every 12 weeks for 48 weeks using a block randomization scheme with a fixed block size of 4. The randomization list was generated by a colleague independent of the study and not involved in any procedures during the study. The study drug was provided by the hospital pharmacy. The drug therapy and placebo syringes were identical. Patients, outcome assessors, and data analysts remained masked to treatment assignment until the study database was locked.

[0136] Procedures The study drug was administered on-site by a dedicated nurse or physician at baseline, placebo control visits at weeks 12, 24, and 36, and non-blind extension periods at weeks 48, 72, and 84. All patients received routine supplements of oral calcium (1000 mg elemental calcium) and vitamin D3 (880 international units). All drug intakes, use of rescue medications, or changes in concomitant medications were recorded throughout the study. Patients were able to take stable doses of analgesics and / or non-steroidal anti-inflammatory drugs as rescue medications. Corticosteroid intake was not permitted.

[0137] Hand X-rays were taken at baseline and at weeks 24, 48, 72, and 96 (Figure 1A). Ultrasonography (US) was performed by experienced ultrasonographers with over 10 years of experience at baseline and at weeks 12 and 48. Synovial proliferation (0 - 3), effusion (0 - 3), power Doppler (PD) signal (0 - 3), and erosions (presence or absence) in the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints 2 - 5 were recorded. Clinical efficacy endpoints evaluated by the same trained physicians blinded to US results until week 96 included presence or absence of tenderness on palpation, soft tissue swelling of PIP and DIP joints 2 - 5, and grip strength (kg).

[0138] Endpoint reported by patients up to week 96 included pain numerical rating scale (NRS) (0 - 10), Australian - Canadian Osteoarthritis Hand Index (AUSCAN) (0 - 150), Functional Index for Hand Osteoarthritis (FIHOA) (0 - 30), and patient's global assessment of effectiveness on NRS (0 - 10).

[0139] Bone mineral density was measured by dual - energy X - ray absorptiometry at baseline, week 48, and week 96.

[0140] X - ray film evaluation The baseline X - ray film status and changes in the subchondral plate, subchondral bone, and joint space were measured in all PIP and DIP joints 2 - 5 according to the Ghent University Scoring System (GUSS™) (13). This scoring system consists of three sub - domains: subchondral plate; subchondral bone; and joint space. Specific features referring to the underlying pathology of the disease are scored on a numerical scale from 0 to 100 in 10 - point increments. The maximum score refers to a normal or fully recovered (i.e., non - erosive) joint. The total score for each joint is created by the equal - weighted sum of scores of all three sub - domains (minimum 0; maximum 300). Details of GUSS™ are described elsewhere and an educational atlas is available for use in clinical examination (13). Thus, the scoring system can change in a positive direction (i.e., more remodeling) or a negative direction (i.e., more erosive progression).

[0141] The presence of the anatomical stage was evaluated by the Verbruggen and Veys scoring system on radiographs at baseline and at 24, 48, 72, and 96 weeks (19). This categorical scoring system differentiates normal joints (N) from pre-ulcerative stages (S stage, i.e., the quiescent stage with minimal degenerative features such as subchondral sclerosis, narrowing of the joint space, and presence of small osteophytes, and stage J with partial or complete loss of the joint space), ulcerative stage (E), and remodeling stage (R, i.e., reappearance of the subchondral plate and joint space width, disappearance of ulcers in the subchondral bone, and development of osteophytes at the joint margin, and F, fused joints as an extreme symptom of remodeling).

[0142] The target joints were defined as IP joints in stage J or E on baseline radiographs with the presence of inflammatory activity defined by clinical soft tissue swelling and inflammation on ultrasound examination (i.e., either synovial proliferation or effusion). When several target joints were available, all were included for the efficacy analysis.

[0143] All radiographs were read independently by two trained assessors who were blinded to randomization and clinical data. The radiographs were read with knowledge of the time series. An inter-reader reliability analysis was performed for each reading of 20 patients. Intraclass correlation coefficient (ICC) and weighted kappa (κ) statistics were calculated for the GUSS (trademark) score and anatomical stage, respectively. If these did not exceed 0.80, retraining was performed for the following 20 patients until κ > 0.80. The intra-reader reliability was studied by repeated readings of a series of images (first 20 patients) by both readers at intervals of at least 1 month. The final score for radiograph scoring was the consensus score between the two readers. If there was no absolute agreement, a consensus score was created.

[0144] Evaluation items The primary efficacy endpoint was the change in total GUSS (trademark) at week 24. The secondary radiograph endpoints were the change in total GUSS (trademark) from baseline at week 48 and the percentage of new erosive joints (J / E) according to Verbruggen and Veys between baseline pre-erosive joints (i.e., baseline N, S, J joints) per patient at weeks 24 and 48. The exploratory clinical endpoints were the pain NRS, FIHOA, AUSCAN, and grip strength, number of tender joints (0 - 16), and number of clinically swollen joints (0 - 16) at week 24. The other imaging endpoints were the US joint synovitis score (0 - 96), US synovial proliferation score (0 - 48), US effusion score (0 - 48), US PD score (0 - 48) at week 12, and US erosion score (0 - 16) at week 48, as well as the percentage change from baseline in bone mineral density of the femoral neck and lumbar spine at weeks 48 and 96.

[0145] The safety endpoints included the number of (serious) adverse events, withdrawals due to adverse events, and changes in laboratory data over the course of the study.

[0146] Statistical Analysis Using a t-test with a two-sided significance level (α) of 0.05 and assuming a standard deviation (SD) of 29, a sample size of 46 patients in each treatment arm was required to detect a difference in mean change in GUSS (trademark) of 20 units between the placebo and treatment groups at week 24 to achieve 90% power. Considering an 8% dropout rate, a total of 100 patients were included in the study.

[0147] The primary efficacy analysis was performed by the intention-to-treat (ITT) approach (all participants were randomly assigned to groups and attended the baseline visit). Changes in GUSS™ were analyzed at the joint level by generalized estimating equations (GEE) that account for within-patient clustering. Robust standard errors were used to specify that the working correlation structure was exchangeable. The independent variables included in the model were treatment group, number of visits (categorized), the interaction between treatment group and number of visits, and the baseline value (continuous) of the dependent variable. Missing data were not imputed for descriptive statistics. For the analysis of the primary endpoint, data available at all time points were used in each analysis that accounts for the within-patient clustering effect by using the GEE model. Missing values after the last available visit or questionnaire or assessment due to the study being discontinued for any reason were imputed according to a predefined imputation model. Since there was only one primary outcome, no adjustment for multiple testing was performed. A prespecified sensitivity analysis for the primary endpoint was performed without imputation of missing data and with correction for baseline GUSS™ values.

[0148] For the primary outcome measure, a subgroup analysis (yes / no) was performed for intra-articular inflammatory activity. The interaction between the presence of baseline inflammation and the treatment effect on the change in GUSS™ score over 24 weeks was examined. Another descriptive efficacy analysis for the primary outcome measure was performed in a broad group of target joints (all joints showing progression to either J, E, or E / R stage throughout the study that were not defined as J or E at baseline).

[0149] The secondary imaging and exploratory evaluation items were performed in the protocol-compliant population (all patients who met the trial registration criteria, had no major protocol deviations, and completed the study) and were measured at the patient level (except for the total GUSS™ at week 48). The GEE model for continuous data was similar to the model for the primary endpoint. For binary evaluation item scales (e.g., presence or absence of E joint), GEE logistic regression was used for grouped binary data. The primary and secondary efficacy analyses were presented by odds ratio (OR) with point estimates of the difference between treatment groups or 95% confidence intervals (95% CIs) and two-sided p-values. A p-value less than 0.05 (p < 0.05) was considered statistically significant.

[0150] For the analysis from year 2, a similar GEE logistic regression model was used for the treatment groups (i.e., patients who received denosumab for 1 year (vs. 2 years)) based on the first randomization code from year 1. All statistical calculations were performed using R version 3.6.1 or IBM SPSS Statistics for Windows, version 25 (N.Y., USA).

[0151] Results Subjects and Target Joints Patients were screened for enrollment from March 2016 to July 2018. One hundred and thirty-six patients were screened, and 100 were randomized and received at least one dose of the study drug (Figure 1B). The most common reason for exclusion was not meeting one or more inclusion criteria (most often, no X-ray eligible joints with soft tissue swelling). Among the treated subjects, 49 were assigned to placebo (49%) and 51 to denosumab (51%) and included in the ITT analysis of the primary endpoint. Forty-six patients in the denosumab group and 46 patients in the placebo group completed the 48-week study. Five patients (9.8%) in the denosumab group (1 due to SAE, 3 due to withdrawal of consent, 1 due to protocol deviation (use of corticosteroids)) and 3 patients (6.1%) in the placebo group (all due to SAE) discontinued the study. Demographic baseline characteristics were well balanced between groups (Table 2). The mean number of X-ray affected joints per patient was 3.6 and 4.0 in the denosumab group and placebo group, respectively (p>0.05). One hundred and sixty-eight target joints were selected for the ITT analysis of the primary assessment item. All joints (n = 1590) were analyzed for secondary imaging endpoints. Ten joints were missing due to arthrodesis (n = 9) or arthroplasty (n = 1). All patients were included in the secondary clinical endpoints in the protocol compliance analysis.

[0152]

Table 2

[0153]

Table 3

[0154] Primary Radiographic Efficacy Endpoint The change in total GUSS (trademark) was found to be statistically higher in the denosumab group compared to the placebo group at week 24, showing more remodeling and less erosive progression (estimated mean difference in total GUSS (trademark) = 8.9 (95% CI: 1.0 - 16.9; p = 0.024)) (Figure 2A). This effect was confirmed at week 48 (estimated mean difference in total GUSS (trademark) = 14.3 (95% CI: 4.6 - 24.0; p = 0.003)). Inter-reader and intra-reader reliability data were excellent for all radiographic scores (Table 3).

[0155]

Table 4

[0156] Secondary imaging efficacy endpoint At the patient level, the incidence of new erosive joints was statistically higher in the placebo group compared to the denosumab group at week 48 (7.0% new E joints in placebo vs. 1.8% in denosumab) (Figure 2B). From baseline to week 48, the estimated odds ratio for erosive progression was 76.7% lower in the denosumab group compared to the placebo group (OR = 0.23 (95% CI: 0.11 - 0.50); p < 0.001).

[0157] Exploratory imaging endpoint Both the US effusion score and the US joint synovitis score at week 12 were significantly decreased in the denosumab group and the placebo group at weeks 12 and 48 compared to baseline. The US erosion score was significantly reduced in the denosumab group at week 48 compared to baseline. This was not the case for the placebo group. However, the adjusted mean of the group differences from baseline to week 48 was found to be not statistically significant (Table 4).

[0158] In this non-osteoporosis population, the mean bone mineral density T-scores at the lumbar spine and femoral neck increased consistently from baseline to week 96 in the denosumab treatment group. In the placebo group, improvement was seen at the lumbar spine at week 48 but not at the femoral neck. At week 48, the percentage change from baseline was 2.8 percentage points higher with denosumab treatment than with placebo at the lumbar spine (p < 0.001) (Table 5).

[0159] Sensitivity analysis with correction for baseline GUSS™ measurement and protocol compliance analysis of the primary endpoint without imputation showed results similar to those of the ITT (data not shown).

[0160] Testing for an interaction between the presence of baseline inflammation (yes / no) and treatment effect on changes in GUSS™ scores showed no significant interaction between inflammation and treatment at week 24 (p = 0.48) or week 48 (p = 0.18).

[0161]

Table 5

[0162]

Table 6

[0163] Descriptive efficacy analysis performed on an extensive target joint group (n = 198) (i.e., all joints showing progression to any of J, E, or E / R stage throughout the study that were not defined as stage J or E at baseline) showed a mean change in GUSS™ of 11.8 that was higher with denosumab than with placebo at week 24 (p = 0.004) (95% CI = 3.6 to 20.0) and a change of 19.7 with denosumab treatment at week 48 (95% CI = 9.4 to 29.9) (p < 0.001), supporting denosumab treatment.

[0164] Exploratory Clinical Endpoints The change in pain at week 24 (NRS) relative to the baseline was not significantly different between placebo and denosumab (-0.2 (95% CI: -1.0 to 0.6); p = 0.68) (Figure 3A). Total AUSCAN and FIHOA were numerically lower in the denosumab group than in the placebo group at week 24 by -2.8 (95% CI: -11.8 to 6.2) and -1.2 (95% CI: -3.1 to 0.7), respectively (Figure 3B), and did not reach statistical significance. The global opinion on the effectiveness of NRS patients was estimated to be 0.5 (95% CI: -0.7 to 1.8) higher in the denosumab group than in the placebo group at week 24 (p = 0.41). At week 48, the numerical differences in function (both AUSCAN and FIHOA) were numerically improved in the denosumab group compared to placebo but not statistically improved (Tables 6, 7).

[0165] Extension period At week 48, 92 patients entered the 1-year extension period, of which 46 received denosumab first and 46 received placebo first during the first year. Five patients discontinued early during the open-label extension.

[0166] In the second year, the target joints evolved to remodeling equivalent to that in the first year. Total GUSS (trademark) maintained an increase in both groups during the second year compared to the baseline, and showed a greater increase in the pre - placebo group at week 96 compared to the first denosumab group (estimated mean difference in total GUSS (trademark) at week 72 = 2.3 (95% CI: - 2.9 to 6.9; p = 0.32) and estimated mean difference in total GUSS (trademark) at week 96 = 3.5 (95% CI: - 1.1 to 8.1; p = 0.13)). Compared to week 48, the change in GUSS (trademark) score significantly increased at week 96 in the pre - placebo group (estimated mean difference in total GUSS (trademark) placebo = 25.7 (95% CI: 16.2 to 35.1) vs. estimated mean difference in total GUSS (trademark) denosumab = 9.9 (95% CI: - 1.3 to 21.1); p = 0.035). When including 18 newly developed target joints in the placebo group during the first year for the analysis at week 48, similar results were confirmed (estimated mean difference in total GUSS (trademark) placebo = 27.0 (95% CI: 17.9 to 36.0) vs. estimated mean difference in total GUSS (trademark) denosumab = 10.1 (95% CI: - 0.4 to 20.6); p = 0.017). During the extension period, only 3 new erosive joints occurred: 2 joints in stage J in 2 pre - placebo - treated patients; and 1 in stage E in a denosumab - treated patient (derived from J at the first year). Regarding the clinical exploratory endpoints, patients who received denosumab first during the first year showed a significant decrease in pain level at week 96 compared to the baseline and compared to patients in the first placebo group (respectively, denosumab pain NRS at week 96 = 2.42 vs. denosumab pain NRS at baseline = 4.68, p < 0.001 and denosumab pain NRS at week 96 = 2.42 vs. first placebo pain NRS at week 96 = 3.52, p = 0.028) (Figure 3A). Similar observations were made for FIHOA (mean difference within the denosumab group at week 96 vs. baseline, p = 0.042; mean difference between groups at week 96, p = 0.025), but not for AUSCAN, suggesting that clinical usefulness was induced only 2 years after treatment with denosumab (Tables 6, 7).

[0167]

Table 7

[0168]

Table 8

[0169] Safety Up to week 48, the incidence of adverse events was higher in the placebo group than in the denosumab group (Table 8). During the study, 14 serious adverse events were reported: 7 in the denosumab group and 7 in the placebo group (Table 8). Six patients discontinued the study due to adverse events (1 due to acute coronary event, 3 due to malignancies, 1 due to urticarial reaction and 1 due to subjective intolerance to calcium / vitamin D intake). The most common adverse events in both groups were infections and musculoskeletal complaints (in denosumab: n = 41 and n = 24 respectively; in placebo: n = 38 and n = 34 respectively). Cancer occurred in 3 patients (all assigned to placebo). Hypocalcemia at all time points during the study occurred in 5 patients in the denosumab group and 3 patients in the placebo group (Table 9). Three events (constipation and diverticulitis) were found to be related to the study drug (all received denosumab). During the extension period, 11 new serious adverse events occurred, but none were related to the study drug. Asymptomatic hypocalcemia occurred in 2 patients at week 72 (1 recovered and 1 persisted until week 96).

[0170]

Table 9

[0171]

Table 10

[0172] Discussion In this 48-week placebo-controlled double-blind clinical study, denosumab administered at a dose of 60 mg every 3 months reduced radiographic progression of erosive deformity in erosive hand OA compared with placebo, and no significant safety signals were identified. A significant effect was observed at week 24 and remained consistent and in some cases improved through 48 weeks of denosumab administration. Furthermore, fewer new erosive joints developed by week 48 in the denosumab group. Clinical assessment item scales did not change significantly between groups during the first 48 weeks of treatment, but significant improvement in pain and disability levels was noted during the extended period up to week 96, suggesting that long-term treatment with denosumab not only inhibits structural progression but also achieves clinical improvement over time. The safety profile of denosumab was found to be comparable to its use in previous studies and clinical care, despite a dosing regimen that was twice that used in the standard regimen for osteoporosis treatment (22). This is the first study to show consistent benefit against radiographic progression of erosive hand OA after 24 weeks and subsequent clinical benefit after long-term treatment.

[0173] Several previous studies in erosive hand osteoarthritis (OA) using tumor necrosis factor α blockers (i.e., adalimumab (23, 24) and etanercept (25)) and therapeutic agents such as rilonacept (26), an anti-interleukin-1α and β inhibitor, have not shown clinical efficacy in short-term and long-term studies. Although a post hoc analysis including only inflamed joints, only one study showed some beneficial effects on structural modification (23). In one recent 6-week study with corticosteroids, a significant effect on pain in hand OA was shown (27). Due to its short duration, no beneficial effects on structural modification and damage could be demonstrated. This study confirms the ability of denosumab to improve the long-term clinical condition by mainly affecting the radiographic progression of hand OA. This indicates its potential as a structural modifying drug in the treatment of erosive hand OA. In recent years, new selective cathepsin K inhibitors have shown structural improvement in patients with knee OA (28). However, in this relatively short trial, no benefit on pain levels was seen. These findings suggest that in the treatment of erosive hand OA, it may lead to a shift from pain relief to the prevention of structural or erosive damage, with a cumulative effect on pain and function over time. The ultimate goal of treating erosive hand OA, as with all other types of OA, is to avoid further joint space narrowing, cartilage degeneration, and bone formation, all characteristics of OA. By suppressing radiographic damage, the disease burden can be significantly reduced for many patients.

[0174] The hypothesis has been proposed that the osteoclastic activity of erosive destruction in erosive deformative hand OA is inhibited or further prevented by inhibiting RANKL, thereby delaying the progression of structural damage. Similar results have been seen in rheumatoid arthritis, a prototypical inflammatory arthritis characterized by erosive disease (21, 29 - 31). The development of erosions in patients with RA was prevented using denosumab. However, the administration of denosumab did not affect the symptoms and signs of inflammation in this treatment situation. The dosing regimen in RA was every 6 months, not every 3 months as used for the treatment of postmenopausal osteoporosis. The increased dosing frequency was triggered by evidence that the cellular source of RANKL increases strongly under chronic arthritis conditions and extends even to other cell types such as the synovial lining layer. Because of the similarity in the effect on structural progression in erosive deformative hand OA and RA, the same dosing regimen was adopted in this study. However, RA is different, and there is abundant evidence that erosive deformative hand OA is not primarily an inflammatory disease (32 - 35). Deterioration of cartilage and subchondral bone appears to drive the progression of erosive deformative hand OA, and inflammation is a secondary phenomenon. Therefore, it may be necessary to target other pathways to suppress the underlying inflammation in these patients. This may explain why neither the number of joint swellings nor the ultrasound examination assessment items related to inflammation (i.e., effusion, PD signal) responded to treatment in this study. However, the erosions on ultrasound examination decreased in line with the radiographic data. Therefore, despite the pathogenic differences between erosive hand OA and RA, the observations with denosumab treatment in erosive hand OA are similar to the results observed in RA.

[0175] In this study, two valid scoring methods for structural radiographs or erosive progression, namely GUSS™ and the Verbruggen and Veys anatomic stage, were used. Both systems confirmed a reduction in progression at week 24 for the former and week 48 for the latter. The quantitative scoring system, GUSS™, was developed to demonstrate short-term changes, and its advantages are demonstrated here. Confirmation of a similar evolution by another scoring system (i.e., Verbruggen and Veys) can serve as an internal validation. Excellent reliability was found between two experienced readers. Multiple clinical assessment item scales were included in this study, which were ultimately improved by sustained treatment with denosumab. Unfortunately, alternative assessment item scales for disease activity in erosive deformity hand OA are still lacking (36). Development of such tools could facilitate clinical trial research in hand OA. Disease activity and structural progression are undoubtedly related, but may not be related in terms of timing. This could explain the observation that denosumab treatment inhibits structural progression early, 6 months after the start of therapy, but its effect on clinical assessment items appears only during the 2-year follow-up period. The data indicate that RANKL inhibition is continuously necessary to maintain hand function and prevent the development of new erosive disease. In this context, the observation that the estimated odds ratio of erosive progression was 76.7% lower in the denosumab group compared with placebo in the first 48 weeks of the placebo-controlled trial supports the concept of osteoclast-dependent structural damage in erosive deformity hand OA.

[0176] In this non-osteoporosis population, no safety signals were found for the treatment with an extended dosing interval of denosumab. A greater number of non-serious and serious adverse events were reported in the placebo group. Adverse events that led to early discontinuation of 8 patients before week 48 were not related to the study drug. Hypercalcemia was rarely reported before the next administration of the study drug and was easily manageable. As expected, all BMD values increased in the denosumab group and only at the spine in the placebo group, which could be attributed to the administration of calcium and vitamin D. Inclusion of a specific subset of patients (i.e., those with clinical inflammation and signs of inflammation on ultrasound) is both an intensity and a limitation. This limits the generalization of the results to hand OA patients without signs of inflammation, while on the other hand, it increases the likelihood of observing effects due to the targeted treatment. Since hand OA is a heterogeneous disease, patient stratification in clinical trials may be required to identify hand OA patients who will benefit from a specific treatment. Another limitation of this study is that it was not powered or designed to include a pre-specified statistical comparison of efficacy between the denosumab treatment arms up to week 96. Finally, due to the continuous treatment until the end of the study, no safety conclusions can be drawn about the potential rebound effects on bone status in this non-osteoporosis population. In summary, this placebo-controlled trial provides the first proof of concept that structural damage in erosive deformity hand OA can be modulated by a targeted therapy. Clear benefits from treatment with 60 mg of denosumab every 3 months were observed in patients with erosive deformity hand OA by reducing radiographic progression and the development of new erosions. These improvements ultimately led to improvements in pain and disability after long-term treatment over 96 weeks.

[0177] References The following references are cited in the background art and Example 1. 1. Punzi L, Ramonda R, Sfriso P. Erosive osteoarthritis. Best practice & research Clinical rheumatology. 2004;18(5):739-58. 2. Kwok WY, Kloppenburg M, Rosendaal FR, van Meurs JB, Hofman A, Bierma-Zeinstra SM. Erosive hand osteoarthritis: its prevalence and clinical impact in the general population and symptomatic hand osteoarthritis. Ann Rheum Dis. 2011;70(7):1238-42. 3. Haugen IK, Englund M, Aliabadi P, Niu J, Clancy M, Kvien TK, et al. Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study. Ann Rheum Dis. 2011;70(9):1581-6. 4. Haugen IK, Mathiessen A, Slatkowsky-Christensen B, Magnusson K, Boyesen P, Sesseng S, et al. Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype? Osteoarthritis Cartilage. 2016;24(4):647-54. 5. Bijsterbosch J, Watt I, Meulenbelt I, Rosendaal FR, Huizinga TW, Kloppenburg M. Clinical burden of erosive hand osteoarthritis and its relationship to nodes. Annals of the rheumatic diseases. 2010;69(10):1784-8. 6. Wittoek R, Cruyssen BV, Verbruggen G. Predictors of functional impairment and pain in erosive osteoarthritis of the interphalangeal joints: comparison with controlled inflammatory arthritis. Arthritis and rheumatism. 2012;64(5):1430 - 6. 7. Kloppenburg M, Kroon FP, Blanco FJ, Doherty M, Dziedzic KS, Greibrokk E, et al. 2018 update of the EULAR recommendations for the management of hand osteoarthritis. Ann Rheum Dis. 2019;78(1):16 - 24. 8. Haugen IK, Slatkowsky-Christensen B, Boyesen P, van der Heijde D, Kvien TK. Cross-sectional and longitudinal associations between radiographic features and measures of pain and physical function in hand osteoarthritis. Osteoarthritis and cartilage. 2013;21(9):1191 - 8. 9. Meersseman P, Van de Vyver C, Verbruggen G, Elewaut D, Wittoek R. Clinical and radiological factors associated with erosive radiographic progression in hand osteoarthritis. Osteoarthritis and cartilage. 2015;23(12):2129 - 33. 10. Vanhaverbeke T, Pardaens L, Wittoek R. Natural disease progression in finger osteoarthritis: results from a 10 year follow-up cohort. Scandinavian journal of rheumatology. 2020;49(6):498-504. 11. Crain DC. Interphalangeal osteoarthritis. JAMA. 1961;175:1049-53. 12. Mannoni A, Briganti MP, Di Bari M, Ferrucci L, Costanzo S, Serni U, et al. Epidemiological profile of symptomatic osteoarthritis in older adults: a population based study in Dicomano, Italy. Annals of the rheumatic diseases. 2003;62(6):576-8. 13. Verbruggen G, Wittoek R, Vander Cruyssen B, Elewaut D. Morbid anatomy of ‘erosive osteoarthritis’ of the interphalangeal finger joints: an optimised scoring system to monitor disease progression in affected joints. Annals of the rheumatic diseases. 2010;69(5):862-7. 14. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrine reviews. 1999;20(3):345 - 57. 15. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF / RANKL - RANK interaction. The Journal of experimental medicine. 2000;191(2):275 - 86. 16. Komine M, Kukita A, Kukita T, Ogata Y, Hotokebuchi T, Kohashi O. Tumor necrosis factor - alpha cooperates with receptor activator of nuclear factor kappaB ligand in generation of osteoclasts in stromal cell - depleted rat bone marrow cell culture. Bone. 2001;28(5):474 - 83. 17. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL - 1 mediates TNF - induced osteoclastogenesis. The Journal of clinical investigation. 2005;115(2):282 - 90. 18. Zwerina J, Redlich K, Polzer K, Joosten L, Kronke G, Distler J, et al. TNF-induced structural joint damage is mediated by IL-1. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(28):11742-7. 19. Verbruggen G, Goemaere S, Veys EM. Systems to assess the progression of finger joint osteoarthritis and the effects of disease modifying osteoarthritis drugs. Clinical rheumatology. 2002;21(3):231-43. 20. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. The New England journal of medicine. 2006;354(8):821-31. 21. So H, Cheng IT, Lau SL, Chow E, Lam T, Hung VW, et al. Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomised, double-blind, placebo-controlled trial. Annals of the rheumatic diseases. 2021. 22. Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2015;26(12):2773 - 83. 23. Verbruggen G, Wittoek R, Vander Cruyssen B, Elewaut D. Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification. Ann Rheum Dis. 2012;71(6):891 - 8. 24. Chevalier X, Ravaud P, Maheu E, Baron G, Rialland A, Vergnaud P, et al. Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double - blind, placebo - controlled trial. Annals of the rheumatic diseases. 2015;74(9):1697 - 705. 25. Kloppenburg M, Ramonda R, Bobacz K, Kwok WY, Elewaut D, Huizinga TWJ, et al. Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial. Annals of the rheumatic diseases. 2018;77(12):1757-64. 26. Kloppenburg M, Peterfy C, Haugen IK, Kroon F, Chen S, Wang L, et al. Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1alpha and anti-interleukin-1beta dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis. Annals of the rheumatic diseases. 2019;78(3):413-20. 27. Kroon FPB, Kortekaas MC, Boonen A, Bohringer S, Reijnierse M, Rosendaal FR, et al. Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial. Lancet (London, England). 2019;394(10213):1993-2001. 28. Schieker M, Conaghan PG, Mindeholm L, Praestgaard J, Solomon DH, Scotti C, et al. Effects of Interleukin-1beta Inhibition on Incident Hip and Knee Replacement: Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial. Annals of internal medicine. 2020;173(7):509-15. 29. Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis and rheumatism. 2008;58(5):1299-309. 30. Takeuchi T, Tanaka Y, Ishiguro N, Yamanaka H, Yoneda T, Ohira T, et al. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE) - a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Annals of the rheumatic diseases. 2016;75(6):983-90. 31. Takeuchi T, Tanaka Y, Soen S, Yamanaka H, Yoneda T, Tanaka S, et al. Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial. Annals of the rheumatic diseases. 2019;78(7):899-907. 32. Wittoek R, Jans L, Lambrecht V, Carron P, Verstraete K, Verbruggen G. Reliability and construct validity of ultrasonography of soft tissue and destructive changes in erosive osteoarthritis of the interphalangeal finger joints: a comparison with MRI. Ann Rheum Dis. 2011;70(2):278-83. 33. Kortekaas MC, Kwok WY, Reijnierse M, Huizinga TW, Kloppenburg M. In erosive hand osteoarthritis more inflammatory signs on ultrasound are found than in the rest of hand osteoarthritis. Ann Rheum Dis. 2013;72(6):930-4. 34. Haugen IK, Boyesen P, Slatkowsky-Christensen B, Sesseng S, Bijsterbosch J, van der Heijde D, et al. Comparison of features by MRI and radiographs of the interphalangeal finger joints in patients with hand osteoarthritis. Ann Rheum Dis. 2012;71(3):345-50. 35. Damman W, Liu R, Bloem JL, Rosendaal FR, Reijnierse M, Kloppenburg M. Bone marrow lesions and synovitis on MRI associate with radiographic progression after 2 years in hand osteoarthritis. Ann Rheum Dis. 2017;76(1):214-7. 36. Wittoek R, Kroon FPB, Kundakci B, Abhishek A, Haugen IK, Berenbaum F, et al. Report from the Hand Osteoarthritis Working Group at OMERACT 2018: Update on Core Instrument Set Development. The Journal of rheumatology. 2019;46(9):1183-7.

[0178] Rationale for 2.45 mg Q3M dosing in Example Prolia (registered trademark) (denosumab) is approved for the treatment of postmenopausal osteoporosis (PMO). The recommended dose is 60 mg Q6M (every 6 months). In Example 1, denosumab was administered instead at 60 mg Q3M. This dosing was selected considering prior evidence including data from certain Phase 2 rheumatoid arthritis (RA) studies. Higher doses or dosing regimens at shorter intervals tended towards earlier effects or more inhibition of bone resorption (37, 38). In a Japanese study of RA patients, the effect on erosion scores was achieved by 60 mg of denosumab administered every 2 or 3 months, but not with 6-month dosing (38). RANKL levels in inflammatory conditions are thought to be higher than those in osteoporosis patients. Therefore, the denosumab dose used for osteoporosis treatment (60 mg Q6M) may not achieve sufficient osteoclast suppression. Thus, the dose in Example 1 (60 mg Q3M) was selected to ensure osteoclast suppression.

[0179] Active RA patients and patients with erosive deformative arthritis may vary. Since the inflamed joints are a rich source of RANKL, RA patients may potentially have higher RANKL levels. Therefore, various denosumab dosages may be desirable to reduce bone erosion compared to PMO and RA. In the study by Cohen et al. (37), the change in CTX% from baseline was measured at 3, 6, and 12 months in subjects receiving 60 mg Q6M or 180 mg Q6M. The 3-month suppression of CTx (a marker of osteoclast activity) was similar between these two groups of RA patients (-73%; Table 2 of Cohen et al.). This suggests that not all of the 60 mg dose of denosumab was consumed by 3 months.

[0180] The inventors believe that RANKL levels in patients with erosive deformative arthritis may not be as high as in RA patients. Therefore, there is a theoretical basis for using a dose of 45 mg Q3M instead of 60 mg Q3M. By reducing the dose to 45 mg Q3M, the dosing regimen is thought to maintain the benefits of denosumab while reducing the risk of potential adverse events.

[0181] This is further supported by CTX levels. Figure 4 (see also reference numeral 39, Figure 2E) shows serum CTX levels in osteoporosis subjects receiving placebo (□), denosumab 6 mg (●), 14 mg (△), 30 mg (◇) every 3 months. The dose of denosumab 30 mg Q3M was able to continuously suppress CTX in osteoporosis patients. In patients with erosive deformative hand OA, a slightly higher dose may be required to continuously suppress CTX during the 3-month dosing interval, and a dosing of 45 mg Q3M is likely to be justified.

[0182] References The following references are cited in Example 2: 37. Cohen et al,. ARTHRITIS & RHEUMATISM Vol.58, No.5, May 2008, pp 1299 - 1309. 38. Ishiguro et al., Rheumatology, Volume 58, Issue 6, June 2019, Pages 997 - 1005. 39. McClung M.et al., (2006) N Engl J Med;354:821 - 31.

[0183] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety as if each reference had been individually and specifically indicated to be incorporated by reference and were set forth in full herein.

[0184] The description of a range of values herein is intended to serve only as a shorthand way of referring individually to each separate value and each endpoint falling within the range, unless otherwise indicated herein, and each separate value and each endpoint is hereby incorporated herein as if it were individually recited herein.

[0185] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any examples or exemplary language (e.g., "such as") provided herein is intended merely to clarify the disclosure and does not limit the scope of the disclosure unless otherwise claimed. No language in this specification should be construed as indicating any non - claimed element as essential to the practice of the disclosure.

[0186] Exemplary embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the present disclosure. Variations of the exemplary embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors envision that those skilled in the art will adopt such variations as appropriate, and the inventors intend for the present disclosure to be practiced otherwise than as specifically described herein. Accordingly, the present disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by the applicable law. Further, all possible combinations of the above-described elements are included in the present disclosure as long as there is no specific indication to the contrary herein or as long as such combinations are not clearly inconsistent with the context.

Claims

1. A pharmaceutical composition comprising denosumab for use in a method of treating erosive osteoarthritis of the wrist (OA) in a person requiring such treatment, The method includes administering denosumab to the subject in an amount equivalent to approximately 45 mg to approximately 60 mg of denosumab administered once every three months. The aforementioned pharmaceutical composition.

2. A pharmaceutical composition comprising denosumab for use in a method for reducing erosive progression, joint space narrowing, cartilage degeneration and / or bone formation on radiographic images in subjects requiring such reduction, The method includes administering denosumab to the subject in an amount equivalent to approximately 45 mg to approximately 60 mg of denosumab administered once every three months. The aforementioned pharmaceutical composition.

3. A pharmaceutical composition comprising denosumab for use in a method for inhibiting the development of new erosive joints in subjects where such inhibition is necessary, The method includes administering denosumab to the subject in an amount equivalent to approximately 45 mg to approximately 60 mg of denosumab administered once every three months. The aforementioned pharmaceutical composition.

4. The subject is diagnosed with erosive osteoarthritis of the wrist (OA), and the pharmaceutical composition is as described in claim 2 or 3.

5. A pharmaceutical composition comprising denosumab for use in a method of reducing pain in subjects with erosive osteoarthritis of the wrist (OA), The method includes administering denosumab to the subject in an amount equivalent to approximately 45 mg to approximately 60 mg of denosumab administered once every three months. The aforementioned pharmaceutical composition.

6. The aforementioned administration reduces pain in the subject as assessed by the Numerical Rating Scale (NRS); The administration inhibits the development of new erosive IP joints in the subject and / or inhibits the development of phase E in the S / J IP joints in the subject; The administration reduces the number of S / J IP joints that develop phase E in the subject; The administration improves erosive IP finger joint remodeling in the subjects; The administration increases total GUSS (trademark) in the subject; Furthermore / or, The administration improves joint function in the subject. A pharmaceutical composition according to any one of claims 1 to 3 and 5.

7. The subjects mentioned above did not exhibit dose-limiting toxicity (DLT) during denosumab administration; and / or The aforementioned subjects do not exhibit any grade 3 or grade 4 adverse events related to denosumab during treatment with denosumab. A pharmaceutical composition according to any one of claims 1 to 3 and 5.

8. The subject is not hypocalcemia immediately before or during administration of denosumab, and is the pharmaceutical composition according to any one of claims 1 to 3 and 5.

9. The method described above, This includes administering denosumab to the subjects in an amount equivalent to approximately 45 mg to less than 60 mg of denosumab, administered once every three months; This includes administering approximately 45 mg of denosumab to the subject once every three months; or, This includes administering approximately 60 mg of denosumab to the subject once every three months. A pharmaceutical composition according to any one of claims 1 to 3 and 5.

10. The amount of denosumab is, a. Mean serum concentration of denosumab substantially similar to that achieved by administering 45 mg of denosumab once every three months; and / or b. A mean area under the plasma curve (AUC0-∞) substantially similar to that achieved by administering 45 mg of denosumab once every three months; and / or c. The difference between mean plasma Cmax and mean plasma Cmin at steady state, substantially similar to that achieved by administering 45 mg of denosumab once every three months; and / or d. Provides a steady-state mean plasma Cmax substantially similar to that achieved by administering 45 mg of denosumab once every three months. A pharmaceutical composition according to any one of claims 1 to 3 and 5.

11. The amount of denosumab is, a. Mean serum concentration of denosumab substantially similar to that achieved by administering 60 mg of denosumab once every three months; and / or b. A substantially similar mean area under the plasma curve (AUC) to that achieved by administering 60 mg of denosumab once every three months. ０－∞ ); and / or c. Mean steady-state plasma C levels substantially similar to those achieved by administering 60 mg of denosumab once every three months. ｍａｘ and mean plasma C in a steady state ｍｉｎ The difference between; and / or d. Mean steady-state plasma C levels substantially similar to those achieved by administering 60 mg of denosumab once every three months. ｍａｘ To provide A pharmaceutical composition according to any one of claims 1 to 3 and 5.

12. The subjects will be administered denosumab for at least 12 weeks; The subjects will be administered denosumab for at least 48 weeks; The subjects are administered denosumab for at least 96 weeks; and / or The subjects mentioned above will be administered denosumab once every three months for at least two cycles. A pharmaceutical composition according to any one of claims 1 to 3 and 5.

13. The pharmaceutical composition according to any one of claims 1 to 3 and 5, wherein denosumab is administered to the subject by injection.

14. The pharmaceutical composition according to any one of claims 1 to 3 and 5, further comprising administering to the subject at least one therapeutic agent selected from analgesics and nonsteroidal anti-inflammatory drugs.

15. The subjects described above exhibit at least one symptom of inflammation, either clinically or on ultrasound, prior to administration of denosumab; and / or The aforementioned subjects are those who have not been diagnosed with vitamin D deficiency, chronic inflammatory rheumatic disease, psoriasis, cancer, or chronic infectious disease. A pharmaceutical composition according to any one of claims 1 to 3 and 5.

16. The subject is a pharmaceutical composition according to any one of claims 1 to 3 and 5, which has not been previously treated for erosive osteoarthritis of the wrist.

17. The subject is a pharmaceutical composition according to any one of claims 1 to 3 and 5, which has been previously treated for erosive osteoarthritis of the wrist.

18. The pharmaceutical composition according to claim 17, wherein the subject has been previously treated with at least one therapeutic agent selected from tumor necrosis factor α (TNFα) blockers, anti-interleukin-1α inhibitors, anti-interleukin-1β inhibitors, and combinations thereof.

19. The pharmaceutical composition according to claim 17, wherein the subject has been previously treated with at least one therapeutic agent selected from adalimumab, etanercept, lutikizumab, and combinations thereof.

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