Compositions for improved fracture healing

Abstract

The present invention relates to compositions for use as an adjunct in orthopedic treatments, such as: i) the treatment of delayed fracture healing resulting in delayed healing or non-union; ii) fusion procedures of any of the skeletal system, such as the skull, spine, foot and ankle, or upper limb; and iii) use as a bone void filler to promote filling of bone in osteopenic states following blast injury in combat or non-combat related trauma such as road traffic accidents.

Description

[Technical Field]

[0001] The present invention relates to compositions for use as an adjunct in orthopedic treatment, for example in the treatment of delayed fracture healing or any fusion procedure of the skeletal system. [Background technology]

[0002] The total economic impact of musculoskeletal health conditions is $126 billion in the United States alone, resulting in approximately 68 million fractures per year requiring orthopedic intervention. Of these 68 million fractures, approximately 300,000 per year progress to the slow (delayed healing) or incomplete (nonunion) healing stage. The term nonunion generally refers to a fracture that does not heal within nine months. In the UK, approximately 850,000 new fractures occur each year, the majority of which heal without significant complications. The rate of nonunion of fractures has been suggested to be 5-10%. This rate can be explained by fragility fractures due to low bone mineral density in elderly patients. With the global population growing and aging, the incidence of fragility fractures continues to increase worldwide. An estimated 200 million people worldwide suffer from osteoporosis, of which 40% of women and 15-30% of men will experience one or more fragility fractures during their remaining lifetime. Typically, these patients exhibit impaired fracture healing, resulting in increased surgical intervention, increased risk of complications, and the development of delayed healing and nonunion. Furthermore, certain fractures are known to have a reduced likelihood of healing; for example, scaphoid fractures have an associated risk of nonunion approaching 50%. Patient factors, as well as the type of fracture (location, blood supply, open / closed), also determine fracture healing; for example, diabetics and patients on long-term steroid and immunosuppressive therapy also exhibit impaired fracture healing.

[0003] Delayed fracture healing and non-union pose particularly difficult problems for caregivers and patients, who are supported by health systems and social services. Management typically requires significant resources and long-term treatment that is often unsuccessful.

[0004] Several studies have analyzed the health economics of nonunion, all showing significant increases in hospital length of stay, number of surgeries, and subsequent treatment duration. A 2007 study by Kanakaris et al. found that the average cost of treating a nonunion ranged from £15,660 to £17,200, depending on the fracture location and treatment modality used. Another study by Dahabreh et al. analyzed 25 fractures with nonunion and focused their economic analysis on the direct medical costs of inpatient and outpatient care from the time of the initial injury. A total of 127 hospital visits, a mean length of hospital stay of 34.08 days, and a mean of 5.36 surgeries were recorded per fracture. The mean total cost of treating a fracture that developed a nonunion was £21,183.05. This contrasts with costs of £3,003 to £3,119 for the same fractures that were successfully treated and had an uncomplicated clinical course. Patil et al. published a paper focusing on tibial and femoral nonunions treated with an Ilizarov frame. The authors' average number of surgeries prior to surgical intervention was three. Estimated costs were based on a 2004-2005 evaluation by their hospital's financial department and were limited to the final phase of 41 complicated cases using the Ilizarov frame. Average expenditures totaled £29,204, representing the direct medical costs of this treatment option alone.

[0005] The cost to the UK National Health Service (NHS) of treating nonunions has been reported to range from £7,000 to £79,000 per person. However, this does not take into account the individual's injury status or loss of income, nor does it consider the long-term burden of disease, so the actual cost to society is likely to be much greater. Therefore, the overall burden on the NHS in the UK is significant. Based on an estimated 85,000 nonunions per year in the UK, the financial cost, based on available data, is estimated to be between £595 million and £67 billion, regardless of the patient's pain burden, associated depression, disability from work, and time off work, with a consequent negative impact on productivity and therefore a national economic impact.

[0006] The majority of health systems in Europe are tax-based and government-funded. Consequently, reducing this burden by 50% would result in significant savings to health budgets and contribute to improved quality of life. In the best-case scenario, a 50% reduction would result in savings of between £297.5 million and £36 billion per year.

[0007] Delayed and nonunion fractures are typically controlled with a combination of surgical and biologic approaches. Surgical approaches include debridement of the nonunion and internal fixation (e.g., plating or overreaming and intramedullary nailing) or external fixation systems (e.g., Ilizarov circular frames). Biologic approaches focus on filling the bone defect and accelerating the fracture repair process, either in the form of autologous bone grafts or bone graft substitutes, both allogeneic and synthetic. Platelet-rich plasma and bone marrow aspirate are also used in conjunction with bone grafts to promote fracture healing; these are harvested from the patient or donor, typically from national tissue banks in the UK rather than commercial sources. Additionally, the use of orthobiologics, primarily bone morphogenetic proteins (BMPs) 2 and 7, has been initiated; several studies have demonstrated their ability to induce ectopic bone formation by recruiting stem cells from distant sites and inducing osteoblast and chondrocyte differentiation at the fracture site. However, its relatively high cost of BMP-7, at £3,000 per vial, has prevented it from becoming as popular as expected. Nevertheless, the benefits of orthobiologics in the treatment of nonunion fractures are emerging, with one study reporting a 47% cost savings when treating nonunions with BMP-7 compared with conventional treatment alone. Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, it is desirable to develop compositions that can assist in the treatment of chronic bone injuries and fractures where there is delayed or progressive non-union, or that can be used in fusion procedures in any skeletal system, and that can reduce the incidence of surgical procedures in such treatment. [Means for solving the problem]

[0009] Ideally, such a composition would also be able to reduce the time it takes for fractures to heal.

[0010] Therefore, according to the present invention, i) parathyroid hormone or a derivative thereof in an amount of about 0.1 ng / ml to about 50 ng / ml; ii) one or more osteoclast inhibitors, and iii) solid or liquid phase bone void fillers; 1. A composition comprising: a bone void filler material selected from the group consisting of calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, and carboxymethylcellulose. 、 polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof; The composition is provided, wherein the one or more osteoclast inhibitors are contained in an amount of about 1 ng / ml to about 6000 ng / ml.

[0011] In one embodiment of the invention, the osteoclast inhibitor comprises a bisphosphonate or a derivative thereof; strontium ranelate, denosumab, or romosozumab; or a combination of any two or more thereof.

[0012] As used herein, the term "bone void filler" refers to a bioinert, physiologically acceptable substance that is introduced into cavities, holes, or voids in human or animal bones, for example, caused by disease or injury, to provide an osteoconductive matrix to promote bone repair. Bone void fillers are also gradually absorbed by the body or dissolve over time.

[0013] The compositions of the present invention are intended for intra-operative use, i.e., prepared and used in a sterile operating room during a surgical procedure, and are intended for implantation into an indicated patient to provide a therapeutic effect as an adjunct to surgical care.

[0014] The compositions of the present invention are intended for use as an adjunct in orthopedic treatment. Exemplary uses of the compositions include, but are not limited to, i) the treatment of delayed fracture healing, where delayed healing or nonunion occurs, whether due to fracture-specific factors (e.g., fracture location or whether the fracture is open or closed) or patient-specific factors, ii) as an adjunct in fusion procedures for any of the skeletal system, such as the skull, spine, foot and ankle, or upper extremity, and iii) as a bone void filler to promote bone refill in bone-poor conditions following blast injury in combat or non-combat-related trauma, such as road traffic accidents.

[0015] In one embodiment of the present invention, the composition comprises, as separate entities, parathyroid hormone or a derivative thereof (referred to herein as PTH), one or more osteoclast inhibitors, such as bisphosphonates or derivatives thereof, or other osteoclast inhibitors, such as strontium ranelate, denosumab, or romosozumab, or a combination of any two or more thereof, and a bone void filler. Chemically, in this embodiment, PTH and the one or more osteoclast inhibitors are separate molecules present within the matrix of the bone void filler.

[0016] In another embodiment of the invention, the composition comprises PTH in a conjugated form with one or more osteoclast inhibitors in combination with a bone void filler. In all other respects, these two embodiments are the same.

[0017] In one embodiment of the present invention, the composition comprises a bone void filler, such as a calcium sulfate-based bone void filler, which has a primary mechanism of action (PMOA) that is enhanced by the addition of an active agent. The PMOA is thereby transformed from the osteoconduction of calcium sulfate alone to include osteoinduction and osteogenesis. The active agent comprises parathyroid hormone or a derivative thereof in an amount of about 0.1 ng / ml to about 50 ng / ml; and one or more osteoclast inhibitors (e.g., a bisphosphonate or a derivative thereof; strontium ranelate; denosumab; or romosozumab; or a combination of any two or more thereof).

[0018] In this form, the PMOA of the device is activated by calcium sulfate, which acts as a bone scaffold that allows the conduction of bone cells within the bone void, encouraging bone filling. For example, the addition of any form of PTH and any form of osteoclast inhibitor to calcium sulfate can potentiate the action of the PMOA, resulting in a medical device with the additional two properties of osteoinductivity and osteogenicity described above, encouraging new bone formation.

[0019] The parathyroid hormone or derivatives thereof used in the compositions of the present invention may be in any form or derived from any form, whether produced by recombinant means or synthetically, for example.

[0020] The use of PTH serves two purposes in the compositions of the present invention: first, as a stem cell recruiter (e.g., mesenchymal stem cells), increasing the number of cellular substrates available for use in the fracture repair process; and second, to extend the lifespan of osteoblasts, which are involved in the fracture repair process. These effects have been demonstrated in animals administered high systemic doses of PTH and may provide further evidence in humans. However, to date, there have been few studies using locally administered PTH, and no studies have used PTH delivered via the preferred delivery method of the present invention, detailed below.

[0021] Examples of parathyroid hormone derivatives that may be used in the compositions of the present invention include, but are not limited to, parathyroid hormone-related protein (PTHrP), 1-34 human recombinant / synthetic parathyroid hormone (1-34rhPTH), 1-84 human recombinant / synthetic parathyroid hormone (1-84rhPTH), H05AA03 parathyroid hormone, teriparatide acetate, preotactic parathyroid hormone, teriparatide, abaloparatide, or a combination of any two or more thereof.

[0022] Parathyroid hormone or a derivative thereof is present in an amount of about 0.1 ng / ml to about 50 ng / ml, more typically about 0.25 ng / ml to about 40 ng / ml, more typically about 0.5 ng / ml to about 30 ng / ml, and more typically about 1 ng / ml to about 20 ng / ml. In another embodiment, the amount of parathyroid hormone or a derivative thereof may be about 2 ng / ml to about 18 ng / ml, or about 5 ng / ml to about 15 ng / ml.

[0023] In essence, the compositions of the present invention act in two ways: PTH increases the number of cells available at the fracture site for the fracture repair process, and one or more osteoclast inhibitors, such as bisphosphonates (or derivatives thereof; strontium ranelate, denosumab, or romosozumab; or a combination of any two or more thereof), suppress unwanted osteoclast activity at this stage.

[0024] PTH-based therapy has been observed to have complex effects on bone healing depending on the specific route of administration, combination with other drugs, and delivery interval.

[0025] The inventors have shown that the PTH cellular response is dose-dependent and that the therapeutic effect can be enhanced by combining it with an osteoclast inhibitor (e.g., zoledronic acid) in a sustained-release formulation designed to completely release the active ingredient within a period of up to six weeks to maximize clinical efficacy and promote rapid healing.

[0026] Compelling feasibility studies (both in vitro and in vivo) have shown that the present invention promotes osteoblast viability, indicating its potential to accelerate fracture healing and prevent nonunions in both acute and chronic fractures.

[0027] Furthermore, the inventors have demonstrated that the present invention can improve clinical outcomes in patients with acute fractures who are at high risk for non-union, whether due to fracture-specific factors (site, open / closed fracture) or patient-specific factors, and in patients with chronic injuries who develop delayed, i.e., non-union fractures.

[0028] When one or more osteoclast inhibitors include bisphosphonates, one or more bisphosphonates may be present in the compositions of the present invention. Examples of bisphosphonates suitable for use in the compositions of the present invention include, but are not limited to, zoledronic acid, alendronate, etidronate (e.g., disodium salt), pamidronate (e.g., disodium salt), ibandronic acid, risedronate (e.g., disodium salt), and / or clodronate (e.g., disodium salt), or any combination of two or more thereof. In addition, compounds such as strontium ranelate and / or denosumab (commercially available under the trade names Prolia® and Xgeva®) or romosozumab (commercially available under the trade name Evenity®) can be used alone or in combination with each other, or can be used in combination with any of the bisphosphonates listed above.

[0029] When the bisphosphonate includes zoledronic acid, alendronic acid, or ibandronic acid, the zoledronic acid, alendronic acid, or ibandronic acid is typically contained in an amount of about 50 ng / ml to about 300 ng / ml, more typically about 75 ng / ml to about 250 ng / ml, and even more typically about 100 ng / ml to about 200 ng / ml.

[0030] When the bisphosphonate includes etidronate, the etidronate is typically present in an amount of about 300 ng / ml to about 1500 ng / ml, more typically about 500 ng / ml to about 1250 ng / ml, even more typically about 750 ng / ml to about 1200 ng / ml, and even more typically about 900 ng / ml to about 1100 ng / ml.

[0031] When the bisphosphonate includes pamidronate, pamidronate is typically included in an amount of about 0.01 nmol / ml to about 20 nmol / ml, more typically about 1 nmol / ml to about 18 nmol / ml, even more typically about 5 nmol / ml to about 15 nmol / ml, and even more typically about 8 nmol / ml to about 12 nmol / ml.

[0032] When the bisphosphonate includes risedronate, risedronate is typically contained in an amount of about 0.01 ng / ml to about 50 ng / ml, more typically about 1 ng / ml to about 40 ng / ml, even more typically about 2 ng / ml to about 30 ng / ml, even more typically about 5 ng / ml to about 25 ng / ml, even more typically about 6 ng / ml to about 20 ng / ml, even more typically about 7 ng / ml to about 15 ng / ml, and even more typically about 8 ng / ml to about 12 ng / ml.

[0033] When the bisphosphonate includes clodronate, clodronate is typically present in an amount of about 500 ng / ml to about 3000 ng / ml, more typically about 550 ng / ml to about 2800 ng / ml, even more typically about 600 ng / ml to about 2700 ng / ml, and even more typically about 700 ng / ml to about 2600 ng / ml.

[0034] In one embodiment of the invention, the bisphosphonate comprises or is zoledronic acid.

[0035] In embodiments contemplated within the scope of the present invention, the composition may further comprise one or more additives selected from vitamin D and its derivatives or isomers, hydroxyapatite and its derivatives or isomers, vitamin E and its derivatives or isomers, selenium, zinc, magnesium, phosphate, or collagen and its derivatives or isomers. Examples of vitamin D derivatives include 1,25(OH)2 vitamin D3 and its synthetic derivatives, 1,24(OH)2 vitamin D3, calcitonin, and calcipotriol.

[0036] According to a further aspect of the invention, the composition may further be combined with stem cells, for example mesenchymal stem cells.

[0037] In one embodiment of the invention, the bone void filler comprises calcium sulfate, for example calcium sulfate hemihydrate.

[0038] The compositions of the present invention may be employed in a form suitable for injection into the body or in the form of solid setting pellets for implantation into the body.

[0039] In one form, the composition arrives unmixed and is then mixed in the operating room during surgery as a paste. While in paste form, it is stretched and spread into a rubber mold to create pellets. The paste usually sets in about 5-10 minutes, depending on what is mixed into it (i.e., size / solute complexity). Pellets are typically about 2 mm in diameter (for use in the upper extremities) or about 5 mm in diameter (for use in the lower extremities).

[0040] The compositions of the present invention can be administered to the affected area of ​​a patient by any method apparent to a medical professional. However, according to one embodiment of the present invention, the composition is mixed with a bone void filler, such as calcium sulfate paste, for direct injection into the fracture site. In acute fractures, percutaneous techniques under fluoroscopic guidance can be used. Meanwhile, in chronic injuries, a small incision and osteotomy or drilling may be required to access the fracture site. Once injected into the bone cavity, the setting time is approximately 8 minutes, followed by complete absorption over 2-3 weeks, during which time any added compounds are eluted. After this period, the composition is completely absorbed, leaving no clinical or radiographic evidence.

[0041] However, other bone void fillers as defined herein may also be used to deliver the composition to the patient's body.

[0042] According to a further aspect of the present invention, i) parathyroid hormone or its derivatives, ii) one or more osteoclast inhibitors, and iii) calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, carboxymethylcellulose 、 a bone void filler selected from polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof; A kit of materials for producing the compositions defined herein is provided, comprising:

[0043] The kit may include a bone void filler such as calcium sulfate powder, PTH (typically in liquid form), and one or more osteoclast inhibitors (also typically in liquid form) such as a bisphosphonate (or a derivative thereof; strontium ranelate, denosumab, or romosozumab; or a combination of any two or more thereof). All three components are typically mixed together with an additional small aliquot of sterile water to form a fast-setting paste that can be injected in liquid form into the bone defect to immobilize it, or the paste can be placed into a sterile custom rubber mold included in the kit to create a solid pellet.

[0044] According to a further aspect of the present invention, there is provided a method for producing the compositions described herein, the method comprising: i) parathyroid hormone or a derivative thereof in an amount of about 0.1 ng / ml to about 50 ng / ml; and ii) one or more osteoclast inhibitors; and iii) a solid or liquid phase bone void filler for delivering the composition to a subject; The bone void filler may be selected from calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, and carboxymethylcellulose. 、 polymethylmethacrylate (PMMA) bone cement, or a combination of any two or more thereof; the one or more osteoclast inhibitors are contained in an amount of about 1 ng / ml to about 6000 ng / ml; The method comprises combining parathyroid hormone or a derivative thereof with the one or more osteoclast inhibitors and an amount of a bone void filler.

[0045] According to a further aspect of the present invention, there is provided a composition as described herein for the treatment of bone fractures or for bone fusion. Treatment typically involves administering the composition to a patient, which may be administered in liquid form by injection into the bone defect and immobilized therein, or as one or more solid pellets.

[0046] According to a further aspect of the present invention, there is provided a method of delivering the compositions described herein into the human or animal body.

[0047] The invention will now be further explained with reference to the drawings. [Brief explanation of the drawings]

[0048] Figures 1 and 2 demonstrate the efficacy of the present invention in a sheep tibial nonunion severe partial defect model at three doses. The doses were within the therapeutic range of 0.1 ng / ml to approximately 50 ng / ml for PTH and 1 ng / ml to approximately 6000 ng / ml for osteoclast inhibitors. This is an established large animal model of nonunion (Reichert et al., TISSUE ENGINEERING: Part B Volume 00, Number 00, 2009).

[0049] Dose 1 to Dose 3 were used, each containing a range of different concentrations of the components. These doses corresponded to a 1:2:5 ratio relative to each other and were used to demonstrate the composition of the present invention, which contained PTH in a therapeutic range of 0.1 ng / ml to approximately 50 ng / ml and an osteoclast inhibitor in a therapeutic range of 1 ng / ml to approximately 6000 ng / ml. In this study, the bisphosphonate selected for the composition was zoledronic acid in combination with 1-34 teriparatide. The control used was conventional calcium sulfate pellets.

[0050] [Figure 1]FIG. 1 shows radiographs taken immediately after surgery and at 6 weeks of ovine tibiae treated with a control or a composition of the present invention (containing a parathyroid hormone amount within the therapeutic range of 0.1 ng / ml to about 50 ng / ml and an osteoclast inhibitor amount within the therapeutic range of 1 ng / ml to about 6000 ng / ml (Dose 1)).

[0051] [Figure 2] FIG. 2 shows radiographs taken immediately after surgery and six weeks after treatment of sheep tibias treated with two different compositions of the present invention (containing parathyroid hormone levels within the therapeutic range of 0.1 ng / ml to approximately 50 ng / ml and osteoclast inhibitor levels within the therapeutic range of 1 ng / ml to approximately 6000 ng / ml (Dose 2 and Dose 3)).

[0052] [Figure 3] FIG. 3 is a graph showing the optimal concentration of zoledronate required for bone resorption.

[0053] [Figure 4] FIG. 4 is a graph showing the optimal concentration of zoledronate required in relation to osteoclast number.

[0054] [Figure 5] FIG. 5 is a graph showing the dissolution / release profile of a composition of the invention in terms of the amount of zoledronic acid and rhPTH(1-34) polypeptide released over time.

[0055] [Figure 6] FIG. 6 shows cross-sectional CT scans of sheep tibias taken three weeks after the start of treatment using a control or three different compositions of the present invention.

[0056] [Figure 7] FIG. 7 shows cross-sectional CT scans of sheep tibias taken six weeks after the start of treatment using a control or three different compositions of the present invention.

[0057] [Figure 8] FIG. 8 shows cross-sectional CT scans of sheep tibias treated with a control or three different compositions of the present invention, taken 12 weeks after the start of treatment. DETAILED DESCRIPTION OF THE INVENTION

[0058] In Figure 1, a control containing calcium sulfate alone was used to treat a sheep model of non-union. Immediate post-operative radiographs show pellets of the composition of the present invention present in the bone defect.

[0059] However, an X-ray taken six weeks after surgery still showed the partially resorbed pellet and almost no callus. Callus is a bulge of new, immature bone seen on an X-ray and is an important stage in bone healing. The lack of callus formation means that the bone defect has not repaired, which subsequently delays the patient's recovery.

[0060] The right side of Figure 1 shows a similar situation, but this time using a composition of the present invention (Dose 1). Dose 1 corresponds to a composition of the present invention containing a parathyroid hormone amount within the therapeutic range of 0.1 ng / ml to approximately 50 ng / ml and an osteoclast inhibitor amount within the therapeutic range of 1 ng / ml to approximately 6000 ng / ml. Here too, pellets of the composition of the present invention present in the bone defect are visible in an X-ray taken immediately after surgery.

[0061] However, radiographs taken 6 weeks after surgery clearly show bridging calluses across the bone defect site, indicating that the bone defect (e.g., severe segmental defects) is filling with new bone, at a much faster rate than the calcium sulfate control.

[0062] A similar demonstration was performed in Figure 2. In both examples in Figure 2, compositions of the present invention (Dose 2 and Dose 3) were used. Different concentration ranges of components were used, from Dose 1 to Dose 3. These doses correspond to a 1:2:5 ratio relative to each other. Dose 2 and Dose 3 correspond to a 2:5 ratio relative to each other with respect to the compositions of the present invention, and contain parathyroid hormone amounts within the therapeutic range of 0.1 ng / ml to approximately 50 ng / ml and osteoclast inhibitor amounts within the therapeutic range of 1 ng / ml to approximately 6000 ng / ml. Again, pellets of the compositions of the present invention present in the bone defect are visible in the radiograph taken immediately after surgery.

[0063] However, radiographs taken 6 weeks after surgery clearly show large bridging calluses across the bone defect. As with Dose 1 in Figure 1, this indicates that the severe segmental defect is filling with new bone, and at a much faster rate than the calcium sulfate control.

[0064] These x-rays therefore demonstrate significantly superior bone callus formation at six weeks using the compositions of the present invention compared to a control containing calcium sulfate alone. The presence of callus at the doses employed by the compositions of the present invention is important in patient recovery for non-union fractures.

[0065] The graphs in Figures 3 and 4 show the optimal concentration of zoledronate (derived from zoledronic acid as a bisphosphonate) required to inhibit bone resorption by a proportional reduction in osteoclast numbers.

[0066] Figures 3 and 4 show the results of approximately 10% of zoledronic acid. -6 The optimal efficacy of zoledronic acid was demonstrated at the M concentration, where the amount of osteoclast activity (measured by bone resorption) was significantly reduced compared to lower concentrations of zoledronic acid, correlating with a reduction in osteoclast numbers.

[0067] The dissolution profile shown in Figure 5 demonstrates that the compositions of the present invention can achieve controlled release over a period of time to enhance the bone repair process. 20,000 minutes corresponds to 47.6 days, or just under 7 weeks.

[0068] Figures 6-8 show CT scans of sheep tibias taken three weeks after treatment with either the control or three different compositions of the present invention. Again, the compositions of the present invention contain different concentration ranges of PTH, corresponding to a 1:2:5 ratio relative to each other, while the control contains calcium sulfate only.

[0069] Figure 6 shows a tomographic CT scan demonstrating early callus formation in pellets in situ at week 3 relative to the control. The amount of callus formed gradually increases with increasing dose from dose 1 to dose 3.

[0070] Figure 7 shows a cross-sectional CT scan demonstrating abundant callus formation at 6 weeks of treatment relative to the control. The amount of callus formed gradually increases with increasing dose from Dose 1 to Dose 3.

[0071] Figure 8 shows cross-sectional CT scans demonstrating greater bone mass at 12 weeks of treatment versus controls. The amount of new bone formation increases progressively with increasing dose from Dose 1 to Dose 3.

[0072] This study demonstrates that PTH has a positive effect on fracture healing, and qualitative assessments showed greater bone formation in PTH-treated animals compared with control-treated animals. This was particularly evident at early time points. Longitudinal assessments using CT and radiographs are important because a 12-week assessment would mask any positive effects of PTH on early fracture healing. In all three PTH-treated animals, there was evidence of more rapid bridging of the osteotomy gap than in control-treated animals. This is important because early fracture healing may lead to reduced nonunion or delayed fracture union.

[0073] Comprehensive studies of the use of calcium sulfate-based bone substitutes in revision lower limb arthroplasty have reported an average resorption period of 6 to 8 weeks (Kallala et al; Bone Joint Res, 2018;7:570-579; McPherson et al; Dissolvable Antibiotic Beads in Treatment of Periprosthetic Joint Infection and Revision Arthroplasty - The Use of Synthetic Pure Calcium Sulfate (Stimulan®) Impregnated with Vancomycin & Tobramycin. Reconstr Rev 2013;3:32-43).

[0074] The present invention therefore demonstrates that the compositions of the present invention, containing parathyroid hormone in a therapeutic range of 0.1 ng / ml to about 50 ng / ml and osteoclast inhibitor in a therapeutic range of 1 ng / ml to about 6000 ng / ml, can achieve this goal, while also demonstrating excellent bone callus formation and enhanced bone healing at six weeks. Alternatives such as calcium phosphate and hydroxyapatite result in resorption over several months rather than weeks.

[0075] Therefore, it is clearly evident that the PMOA of the bone void filler of the present invention is enhanced by the addition of PTH or a derivative thereof in an amount of about 0.1 ng / ml to about 50 ng / ml, and one or more osteoclast inhibitors.

[0076] PMOA can be varied from being exclusively osteoconductive as a bone void filler alone, and can be varied to include osteoinduction and osteogenesis with the addition of other components.

[0077] The bone void filler, PTH and one or more osteoclast inhibitors have a synergistic effect, enhancing the PMOA of the bone void filler.

[0078] It should of course be understood that the present invention is not limited to the above-described embodiments which are set forth for purposes of illustration only. <Additional Notes> Aspects of the present invention include the following. <Section 1> i) parathyroid hormone or a derivative thereof in an amount of about 0.1 ng / ml to about 50 ng / ml; ii) one or more osteoclast inhibitors, and iii) solid or liquid phase bone void fillers; A composition comprising: the bone void filler material is selected from calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, carboxymethyl cellulose, polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof; The composition, wherein the one or more osteoclast inhibitors are contained in an amount of about 1 ng / ml to about 6000 ng / ml. <Section 2> The composition according to <Item 1>, wherein the one or more osteoclast inhibitors include bisphosphonate or a derivative thereof; strontium ranelate, denosumab, or romosozumab; or a combination of any two or more of these. <Section 3> The composition according to <Item 2>, wherein the bisphosphonate is selected from zoledronic acid, alendronic acid, etidronate, pamidronate, ibandronic acid, risedronate, and / or clodronate, or a combination of any two or more thereof. <Section 4> When the bisphosphonate contains zoledronic acid, alendronic acid, or ibandronic acid, the zoledronic acid, alendronic acid, or ibandronic acid is contained in an amount of about 50 ng / ml to about 300 ng / ml; When the bisphosphonate contains etidronate, the etidronate is contained in an amount of about 300 ng / ml to about 1500 ng / ml; When the bisphosphonate comprises pamidronate, the pamidronate is typically present in an amount of about 0.01 nmol / ml to about 20 nmol / ml; When the bisphosphonate comprises risedronate, risedronate is typically present in an amount of from about 0.01 ng / ml to about 50 ng / ml; and / or When the bisphosphonate includes clodronate, the clodronate is typically included in an amount of about 500 ng / ml to about 3000 ng / ml. The composition according to <Item 3>. <Section 5> The composition according to any one of <Item 1> to <Item 4>, wherein the bisphosphonate comprises zoledronic acid or is zoledronic acid. <Section 6> The composition according to any one of <Item 1> to <Item 5>, wherein the derivative of parathyroid hormone is selected from parathyroid hormone-related protein (PTHrP), 1-34 human recombinant parathyroid hormone (1-34rhPTH), 1-84 human recombinant parathyroid hormone (1-84rhPTH), H05AA03 parathyroid hormone, preotactic parathyroid hormone, teriparatide, abaloparatide, or a combination of any two or more thereof. <Section 7> The composition according to any one of <Item 1> to <Item 6>, further comprising one or more additives selected from vitamin D and its derivatives or isomers, hydroxyapatite and its derivatives or isomers, vitamin E and its derivatives or isomers, selenium, zinc, magnesium, phosphate, and collagen and its derivatives or isomers. <Section 8> The composition according to any one of <Item 1> to <Item 7>, further comprising stem cells. <Section 9> The composition according to <Item 8>, wherein the stem cells are mesenchymal stem cells. <Section 10> The composition according to any one of <Item 1> to <Item 9>, wherein the composition is in a solid form. <Section 11> The composition according to any one of <Item 1> to <Item 9>, wherein the composition is liquid. <Section 12> i) parathyroid hormone or its derivatives, ii) one or more osteoclast inhibitors, and iii) bone void filler; A method for producing the composition according to any one of <Item 1> to <Item 11>, comprising combining: <Section 13> The composition according to any one of <Item 1> to <Item 11>, for treating bone fractures or for bone fusion surgery. <Section 14> A method for supplying the composition according to any one of <Item 1> to <Item 11> into the human body or animal body. <Section 15> The method according to <Item 14>, wherein the composition is delivered by injection or in the form of a solid pellet. <Section 16> i) parathyroid hormone or its derivatives, ii) one or more osteoclast inhibitors, and iii) a bone void filler selected from calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, carboxymethyl cellulose, polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof; A material kit for producing the composition according to any one of <Item 1> to <Item 11>, comprising:

Claims

1. i) parathyroid hormone or a derivative thereof in an amount of 0.1 ng / ml to 50 ng / ml; ii) one or more osteoclast inhibitors in an amount between 1 ng / ml and 6000 ng / ml; and iii) solid or liquid phase bone void fillers; A composition comprising:

2. The composition of claim 1, wherein the bone void filler is selected from calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, carboxymethyl cellulose, polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof.

3. 3. The composition of claim 1 or claim 2, wherein the one or more osteoclast inhibitors comprise a bisphosphonate or a derivative thereof; strontium ranelate, denosumab, or romosozumab; or a combination of any two or more thereof.

4. 4. The composition of claim 3, wherein the bisphosphonate is selected from zoledronic acid, alendronic acid, etidronate, pamidronate, ibandronic acid, risedronate and / or clodronate, or a combination of any two or more thereof.

5. The one or more osteoclast inhibitors i) zoledronic acid, alendronic acid or ibandronic acid, ii) etidronate, iii) pamidronate, iv) risedronate, and / or v) Clodronate The composition according to any one of claims 1 to 4, comprising:

6. 6. The composition of any one of claims 1 to 5, wherein the one or more osteoclast inhibitors include or are zoledronic acid.

7. The composition described in claim 6, wherein the zoledronic acid is contained in an amount of 50 ng / ml to 300 ng / ml.

8. The composition described in claim 6, wherein the zoledronic acid is contained in an amount of 75 ng / ml to 250 ng / ml or an amount of 100 ng / ml to 200 ng / ml.

9. The one or more osteoclast inhibitors are i) etidronate in an amount of 300 ng / ml to 1500 ng / ml; ii) pamidronate in an amount between 1 nmol / ml and 18 nmol / ml; iii) risedronate in an amount between 1 ng / ml and 40 ng / ml, and / or iv) clodronate in an amount of 500 ng / ml to 3000 ng / ml; The composition according to any one of claims 1 to 5, comprising:

10. 10. The composition of any one of claims 1 to 9, wherein the derivative of parathyroid hormone is selected from the group consisting of parathyroid hormone-related protein (PTHrP), 1-34 human recombinant parathyroid hormone (1-34rhPTH), 1-84 human recombinant parathyroid hormone (1-84rhPTH), H05AA03 parathyroid hormone, teriparatide, abaloparatide, and combinations of any two or more thereof.

11. The composition according to any one of claims 1 to 10, further comprising one or more additives selected from the group consisting of vitamin D and derivatives or isomers thereof, hydroxyapatite and derivatives or isomers thereof, vitamin E and derivatives or isomers thereof, selenium, zinc, magnesium, phosphate, and collagen and derivatives or isomers thereof.

12. The composition according to any one of claims 1 to 11, further comprising stem cells.

13. The composition of claim 12 , wherein the stem cells are mesenchymal stem cells.

14. The composition according to any one of claims 1 to 13, wherein the composition is in a solid form.

15. The composition according to any one of claims 1 to 13, wherein the composition is in a liquid form.

16. A composition according to any one of claims 1 to 15 for use in the treatment of bone fractures or for use in bone fusion surgery.

17. The composition of any one of claims 1 to 16, wherein the composition is administered by injection or in the form of a solid pellet.

18. A composition described in any one of claims 1 to 17, wherein the parathyroid hormone or a derivative thereof and the one or more osteoclast inhibitors are formulated to be released from the composition at a constant rate for at least 7 weeks.

19. The bone void filler, i) calcium sulfate, ii) calcium sulfate, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, carboxymethyl cellulose, polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof; or iii) (a) calcium sulfate, and (b) monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, autograft bone material, allograft, synthetic allograft, ceramic, bioglass, collagen sponge, carboxymethyl cellulose, polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof; The composition of any one of claims 1 to 18, comprising:

20. i) the parathyroid hormone or a derivative thereof; ii) the one or more osteoclast inhibitors, and iii) the bone void filler; 20. A method for making the composition of any one of claims 1 to 19, comprising combining:

21. i) the parathyroid hormone or a derivative thereof; ii) the one or more osteoclast inhibitors, and iii) the bone void filler; A material kit for producing the composition of any one of claims 1 to 19, comprising:

Images