Treatment of long bone fractures with abaloparatide

Abstract

Provided herein is a method of accelerating long bone fracture healing, comprising daily administration of a therapeutically effective amount of abaloparatide in combination with surgical intervention for the long bone fracture, the daily administration being initiated before, during, or after the surgical intervention for the long bone fracture to accelerate long bone fracture healing.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 134,027, filed January 5, 2021, the contents of which are incorporated by reference in their entirety herein. [Background technology]

[0002] 2. Background of the Invention Approximately 15 million fractures occur each year in the United States, with over 500,000 involving the tibia and fibula. (Praemer, American Academy of Orthopaedic Surgeons, 1 st ed., 1992). Complications in fracture healing, such as delayed union or nonunion, are estimated to occur in 10%-20% of normal civilian injuries. Co-morbidities such as diabetes and aging can significantly increase the rate of delayed union. Delayed healing and nonunion are even more of a problem for military personnel than for civilians. As much as 50% higher rates of nonunion have been reported one year after injury for open tibial fractures sustained in combat. A return to duty rate of only 22% has been reported for U.S. soldiers with isolated type III open tibial fractures, less than half the return to work rate for injuries of similar severity in the civilian population. For soldiers unable to return to duty, orthopedic injuries caused the greatest amount of permanent disability. These injuries also cause significant emotional and psychiatric disturbances, and fewer than half of soldiers who sustain high-energy extremity trauma ever resume civilian work. (Doukas, J. Bone Joint Surg. Am. 2013 Jan 16;95(2):138-45). There is an unmet need for agents that speed or enhance long bone fracture healing. Summary of the Invention

[0003] BRIEF SUMMARY OF THE INVETION Provided herein is a method for treating a subject with a long bone fracture, comprising daily administration of abaloparatide.Administration can follow surgical intervention.Administration can also include pretreatment with abaloparatide prior to surgical treatment.Alternatively, in some embodiments, abaloparatide can be administered to avoid surgical intervention for nonunion.

[0004] In one aspect, a method is provided for accelerating or enhancing the healing of long bone fracture in a subject who needs to do so.The method comprises administering a therapeutically effective amount of abaloparatide to the subject after surgical intervention for long bone fracture.In some embodiments, administration is started 2 weeks after surgical intervention.Furthermore, in some embodiments, administration is daily administration for 3 months.

[0005] In some embodiments, the long bone fracture is a tibia fracture. In others, the long bone fracture is a fracture of the femur, humerus, radius, ulna, fibula, metatarsus, phalanges, metacarpals, or clavicle. In some embodiments, there are multiple long bone fractures, as in the case of multiple traumatic injuries.

[0006] In some embodiments, accelerated or enhanced healing is evidenced by fracture healing, callus formation, or both, as confirmed at 6, 12, or 24 weeks by at least one of a CT scan for fracture healing, bone mineral density, 3D volume of callus formation, fracture site consolidation by Dynamic Stereo X-Ray (DSX), and modified Radiographic Union Score for Tibial Fractures (mRUST) assessment. In some embodiments, union is accelerated as determined by an mRUST of >13 at 6, 12, or 24 weeks. In some embodiments, bone quality is confirmed by a bone mineral density scan (qCT) at 12 or 24 weeks, or both. In some embodiments, the cartilage stage of fracture repair is confirmed by detection of circulating levels of collagen X ("CXM"). In some embodiments, fracture site consolidation is achieved at 6 or 12 weeks.

[0007] In some embodiments, administering a therapeutically effective amount of abaloparatide elevates bone formation markers without elevating bone resorption markers.

[0008] In some embodiments, the surgical intervention is selected from internal fixation, external fixation, intramedullary nailing, bone grafting, prosthesis, or a combination thereof. In some embodiments, the surgical intervention is the implantation of an intramedullary (IM) rod.

[0009] In some embodiments, the administration is about 20 to about 100 μg of abaloparatide administered subcutaneously daily. In some embodiments, the administration is about 80 μg of abaloparatide administered subcutaneously daily.

[0010] In some embodiments, the administration is a daily transdermal administration of about 100 to about 400 μg of abaloparatide, hi some embodiments, the administration is a daily transdermal administration of 300 μg of abaloparatide.

[0011] In some embodiments, abaloparatide is administered daily for at least 2, 3, 4, 6, 12, or 18 months, hi some embodiments, abaloparatide is administered daily for 3 months.

[0012] In some embodiments, the method further includes pretreatment by administering a therapeutically effective amount of abaloparatide to the subject prior to the surgical intervention.

[0013] In some aspects, a method is provided for accelerating, promoting or enhancing long bone fracture healing in a subject in need of such a method.The method comprises administering a therapeutically effective amount of abaloparatide to the subject every day for 3 months after surgical intervention for long bone fracture.In some embodiments, the administration is a daily subcutaneous administration of 80 μg of abaloparatide.In some embodiments, the administration is a daily transdermal administration of 300 μg of abaloparatide.

[0014] In some embodiments of any of the above methods, the subject has an elevated risk for fracture, hi some embodiments, the elevated risk is due to smoking, diabetes, vascular disease, or a combination thereof.

[0015] In some embodiments, healing time is reduced by at least 25% compared to subjects not receiving abaloparatide therapy, hi some embodiments, healing time is shortened by 2 weeks, 6 weeks, 2 months, or even 6 months compared to healing without administration of abaloparatide. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description of the Invention Although there is no single consensus around the definition of nonunion, the US Food and Drug Administration (FDA) guidelines suggest 9 months without radiographic evidence of bone healing before treatment. Nonunion fractures are up to 97 times more likely to require surgical intervention to promote healing. Provided herein is a method of accelerating the healing rate of a subject with a long bone fracture by administering abaloparatide.

[0017] Abaloparatide is currently approved for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. Preclinical studies have shown improved fracture healing in rats with internally fixed femoral fractures. (Lanske, et al. “Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture,” J Orthop Res. 2019 Apr;37(4):812-820). Recent clinical trials comparing the efficacy of abaloparatide to teriparatide have shown greater bone mineral density gains and less hypercalcemia in the treatment of osteoporosis. (Sleeman, Am J Health Syst Pharm 76, 130-135 (2019);Miller, JAMA 316, 722-733 (2016)). Although several studies have been conducted to evaluate the efficacy of teriparatide in fracture healing (Shi, et al., Effectiveness of Teriparatide on Fracture Healing: A Systemic Review and Meta-Analysis, PLOS ONE, 2016: e0168691; Roberts et al. Anabolic Strategies to Augment Bone Fracture Healing. Curr Osteoporos Rep. 2018;16(3):289-298), the study described herein below in Example 1 is the first clinical trial to test the efficacy of abaloparatide in fracture healing. Due to the relatively high degree of interfragmentary motion (IFM) in tibial fractures, these long bone injuries heal preferentially through endochondral ossification, where a cartilage intermediate drives secondary bone formation.Without wishing to be bound by any particular theory, it is believed that abaloparatide could be effective in treating these fractures in humans because it binds to the PTH1 G-coupled protein receptor, which is highly expressed in both chondrocytes and osteoblasts, thereby affecting both the endochondral and intramembranous stages of fracture repair.

[0018] Example 1 shows a double-blind randomized fracture healing study in which patients with tibial fractures treated with intramedullary rods are randomized to abaloparatide therapy versus placebo therapy. Tibial fracture healing was selected as the primary long bone fracture of the study because the modified Radiographic Union Score for Tibia (mRUST) fracture cortex scoring system has been validated for grading callus formation and radiographic progression toward union in tibial shaft fractures, with a reported intraclass correlation coefficient (ICC) of 0.74 to 0.89. (Mitchell et al., J Orthop Trauma. 2019 Jun;33(6):301-307;Fiset, et al., J Bone Joint Surg Am. 2018 Nov 7;100(21): 1871-1878;Litrenta et al., 2015 Nov;29(11):516-20). Additionally, fracture biomarker assays may be used to indicate early bone healing (Working et al., Journal of Orthopaedic Research, 13 June 2020; Coghlan et al., Sci Transl Med 2017 Dec 6; 9: 419), as well as advanced dynamic imaging (Tashman, S, Journal of Biomechanical Engineering. 2003 Apr; 125 (2): 238-245) and biomechanical assessment of the quality of repair. In accordance with the present disclosure, a novel serum-based biomarker is also used to measure the endochondral stage of fracture repair by detection of circulating levels of collagen X ("CXM"), as it is speculated that abaloparatide works mechanistically to improve the endochondral stage of fracture healing. The measurements of tibial healing in the Example 1 study (CXM biomarker, dynamic imaging, biomechanics) are believed to detect meaningful changes in the rate of fracture healing following administration of abaloparatide.

[0019] Provided herein is a method for enhancing or accelerating long bone fracture healing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of abaloparatide.In some embodiments, administration follows surgical intervention, for example 2 weeks after surgical intervention for a long bone fracture.In some embodiments, administration of abaloparatide can be used to prevent the need for surgical intervention.In some embodiments, administration of abaloparatide can be initiated before or during surgical intervention.The long bone fracture can be a fracture of the tibia.Alternatively or additionally, for example in the case of trauma, the long bone fracture can be one or more fractures of the clavicle, humerus, radius, ulna, metacarpus, phalanges, femur, fibula and / or metatarsus.

[0020] As used herein, the terms "accelerating," "accelerate," "enhancing," "enhanced," "enhance," and the like refer to strengthening, hastening, or amplifying the quality, value, or extent of long bone fracture healing compared to healing without administration of abaloparatide.

[0021] Depending on the type of long bone fracture (e.g., transverse, oblique, spiral or comminuted) and the severity and number of fractures or fragments, there are several surgical interventions that can be used. They are generally grouped into three categories: internal fixation, external fixation and intramedullary nailing. For internal fixation, metal pins, plates, screws, etc. are placed in the bone to create and maintain alignment of the fractured bone. For external fixation, metal pins or screws are placed in the bone above and below the site of the fracture, which are then connected to a bar or mesh on the outside of the bone. In intramedullary nailing, a metal rod is inserted into the center of the bone to keep the bone aligned and stable. Recovery time can be 4-6 months to completely heal, or 9 months or more depending on the fracture and the age and health of the patient. In some embodiments, the human subject does not have osteoporosis.

[0022] In some embodiments, abaloparatide is delivered via a device and formulation for subcutaneous injection that delivers 80 μg of abaloparatide daily, such as the currently approved TYMLOS abaloparatide injection product.In some embodiments, the device and formulation are disclosed in U.S. Patent No. 7,803,770 issued on September 28, 2010; U.S. Patent No. 8,148,333 issued on April 3, 2012; and U.S. Patent No. 8,748,382 issued on June 10, 2014, all of which are expressly incorporated by reference in their entirety.

[0023] In some embodiments, the abaloparatide is delivered transdermally. In some embodiments, the transdermal device is a device, applicator and / or formulation disclosed in International Patent Application Publication WO2017 / 062922 published on April 13, 2017; WO2017 / 184355 published on October 26, 2017; WO2017 / 062727 published on April 13, 2017; WO2017 / 184355 published on October 26, 2017; WO2019 / 077519 published on April 24, 2019; and WO2020 / 17443 published on September 30, 2020, all of which are expressly incorporated by reference in their entirety. These transdermal devices can be deployed with a single-use applicator or application that can be used multiple times. In some embodiments, the abaloparatide formulation comprises a zinc salt (e.g., ZnCl2). In some embodiments, the transdermal device is a transdermal patch that delivers about 300 μg of abaloparatide, and the transdermal patch is administered daily.

[0024] In some embodiments, the healing time in subjects treated with abaloparatide is reduced by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% compared to the healing time in untreated subjects of the same age group, undergoing a similar surgical procedure, and having the same type of fracture. In some embodiments, the healing time in subjects treated with abaloparatide is reduced by at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 6 months, 1 year, or 18 months compared to the healing time in untreated subjects of the same age group, undergoing a similar surgical procedure, and having the same type of fracture. In some embodiments, the degree of reduction in fracture healing time in subjects treated with abaloparatide is correlated to the age of the subject compared to untreated subjects. For example, the highest reduction in fracture healing time may be observed in the oldest subjects treated with abaloparatide. In some embodiments, the percentage reduction in fracture healing time is higher in older subjects. In some embodiments, the percentage reduction in healing time in older subjects is at least 10%, at least 20%, at least 30%, at least 40% or at least 50% greater than the percentage reduction in healing time in younger subjects having the same type of fracture.

[0025] Generally, there are three stages of fracture healing: a hematoma formation or inflammatory stage, a repair stage where there is formation of cartilage and fibrous callus, and a remodeling stage where the callus is replaced with solid bone.

[0026] In some embodiments, callus formation is achieved at 6 weeks, 12 weeks, or 24 weeks. In some embodiments, fracture healing is achieved at 6 weeks or 12 weeks. In some embodiments, fracture healing is achieved at 6 months. In some embodiments, the rate or chance of nonunion is less than 25%. In some embodiments, the chance or rate of nonunion is less than 10%. In some embodiments, the chance or rate of nonunion is less than 5%.

[0027] Fracture healing and callus formation can be confirmed by CT scan, bone density and / or 3D volume of callus formation. Fracture healing and callus formation can be confirmed by fracture site hardness at 6 weeks, 12 weeks and / or 24 weeks by dynamic stereo X-ray (DSX). Fracture healing can be confirmed by mRUST radiographic assessment to evaluate fracture healing. In some embodiments, mRUST score is higher than 13.

[0028] In any of these embodiments, a therapeutically effective amount is clinically demonstrated to be effective in humans as shown in clinical trials. The terms "clinical efficacy", "clinically effective", and the like refer to efficacy shown in clinical trials run by the US Food and Drug Administration (FDA) or any foreign equivalents, such as the European Medicines Agency.

[0029] Also provided is a method of long bone fracture healing in a subject in need of healing of a long bone fracture, the method comprising administering to the subject a therapeutically effective amount of abaloparatide, wherein no surgical intervention is required due to non-union.

[0030] Examples are provided to better illustrate the claimed method and are not to be construed as limiting the scope of the claimed method provided herein.To the extent that specific ones are mentioned, the examples are for illustrative purposes and are not intended to limit the disclosure.It is understood that many variations can be made in the procedures described herein while still being within the scope of this disclosure.It is the intention of the inventors that such variations are included within the scope of this disclosure. EXAMPLES

[0031] Working Example Example 1: Abaloparatide Therapy to Accelerate Tibial Fracture Healing This is the first clinical intervention with abaloparatide aimed at speeding tibial fracture healing. The study is a double-blind, randomized, two-arm study of tibial fractures treated with intramedullary (IM) rods. After surgical treatment, patients will be randomized into two groups: tibial fractures treated with placebo and tibial fractures treated with abaloparatide. There will be 30 subjects per arm, for a total of 60 subjects. The duration of the study is expected to be approximately 3 years for 60 patients at 24 weeks per patient.

[0032] Placebo or abaloparatide therapy will begin 2 weeks after surgery and continue daily for 3 consecutive months at a dose of 80ug. All groups will receive either a placebo or an abaloparatide injection pen, with the pens identical in appearance. If subjects experience common side effects (headache or dizziness), they will reduce their daily injection dose to 40ug for 2 weeks, then resume the full 80ug dose. A full dose of the drug will be added upon completion of the study.

[0033] Patients return for follow-up assessment of healing at weeks 2, 6, 12, 18, and 24, or until union is achieved or malunion is diagnosed (6 months). The primary endpoint of this study is time to mRUST score >13. Secondary healing assessments include serum-based collagen X biomarkers ("CXM"), advanced dynamic imaging and quantitative CT scans, and standardized patient-reported outcomes.

[0034] Eight small (1 mm) tantalum beads (four proximal to the fracture and four distal to the fracture) were implanted into the participants' tibias at the time of surgical treatment to provide well-defined radiopaque landmarks, allowing the researchers to perform a full 3D kinematic analysis using high-speed biplane radiography.

[0035] Include criteria Patients were: male or female; aged 18 years or older; had minimal community ambulation prior to injury; had an open or closed diaphyseal tibial fracture (AO / OTA type 42); the open fracture must be Gustilo-Anderson type 1, 2 or 3A without significant periosteal injury; were scheduled to undergo surgical treatment for a unilateral diaphyseal tibial fracture; and had planned internal tibial fixation with intramedullary (IM) rods (widened / unwidened, locked / open).

[0036] exclusion criteria Hypercalcemia or hyperparathyroidism; Paget's disease or any other bone disease; bone cancer; high alkaline phosphatase levels in the blood; a fracture within the past year; a residual tibial implant; a concurrent injury or other fracture that significantly impairs mobility or function of the lower limb; an additional fracture due to polytrauma; significant wound infection; a history of significant radiation exposure (e.g., due to cancer treatment); Wolff-Parkinson-White syndrome; having / having chronic well-established, medically supported hypertension with a causative history of syncope; women who are pregnant or intend to become pregnant for the duration of the study and women who are breastfeeding; having a BMI > 35; patients who have previously received abaloparatide for a life maximum (2 years) or who will exceed the life maximum dose over the course of the study will be excluded from the study.

[0037] CT scan (12 and 24 weeks) Following surgical treatment, a 12-week CT scan is obtained to determine bone / fracture contours, implanted marker locations, and early callus formation. A 24-week CT is also obtained as a final quantitative assessment of healing. In addition to quantitative assessment of healing, bone mineral density (BMD) and the 3D volume of callus formation are quantified. Between scans for density calibration, a bone density calibration model is placed under the foot.

[0038] Venipuncture for fracture biomarkers and metabolic safety panel (weeks 0, 2, 6, 12, 18, 24) Blood (10 mL) is collected at the initial and each follow-up visit (0 / baseline, 2, 6, 12, 18 and 24 weeks). Five drops of blood are transferred from the collection syringe or tube to a 903 Protein Saver Card and 3 mL are set aside for the Vail Health Hospital Lab to perform a metabolic panel and bone specific alkaline phosphatase (BSALP) levels. These are preventative safety screens to ensure that no adverse effects occur due to the drug-related risks of hypercalcemia and increased ALP and BSALP levels. Additional blood is further processed by centrifugation to collect the supernatant / serum. The serum is transferred to cryovials, labeled with the data, sample volume and de-identified patient index, then placed at -80C. Biomarker data is stored until completion of the entire study and then sent for quantification using a validated ELISA-based bioassay.

[0039] Patient-reported outcome (PRO) assessments (0, 2, 6, 12, 18, 24 weeks) A customized electronic questionnaire will be collected capturing several standard PRO scales. PRO scores will be calculated and stored in a secure MySQL database. PROs will include BPI, SFMA, VR-12, PHQ-9 and PSQ-18. A fracture questionnaire will also be administered at the time of initial venipuncture.

[0040] Dynamic Stereo X-ray (DSX) imaging (6, 12, 24 weeks) The DSX provides dynamic three-dimensional assessment of the movement between the fracture fragments. The laboratory is equipped with an 18-camera 3D video-motion analysis system, a dual-belt equipped treadmill, 4 force plates and a DSX imaging system (all time-synchronized). The x-ray generator can produce 1 ms pulses at rates up to 250 images / s, providing low-dose unblurred images. Image detection is provided by 43 cm flat panel detectors (FPD's) capable of 3072x3072 pixel resolution at 30 frames / s (or 1536x1536 pixels at 60 frames / s) with a 14-bit dynamic range. Previous dynamic testing achieved accuracy better than 70 μm for tracking markers implanted in similar bones using a low-resolution (512x512 pixel) image intensifier. Using pixels sized 1 / 3-1 / 6, we expect to achieve accuracy in the range of 25-50 μm. Data are collected for three trials each of non-load-bearing to load-bearing transition and treadmill progression (1 m / s, if permitted). The 3D coordinates of the implanted markers are determined from bi-planar images using radiostereophotogrammetry techniques and smoothed using a 25 Hz fourth order, zero lag Butterworth low-pass filter. Transformations between marker-based coordinates and anatomical axes are determined from high-resolution CT scans. Rotations of the distal tibial fragment relative to the proximal fragment are calculated using fixed axes of the body in the following order: sagittal, coronal and transverse planes. Displacements are measured between the distal end of the proximal fragment and the centroid of the proximal end of the distal fragment (identified by CT) and expressed in a coordinate system fixed to the proximal fragment. Peak axial, shear translation and rotational / angular displacements between the tibial fragments are determined and averaged over the progression cycle. Fracture site stiffness was estimated by dividing the net force applied to the distal tibia (determined by inverse dynamics using Visual 3D; C-Motion) by the angular and linear displacements of the fracture in each plane.

[0041] Activity monitoring (daily) Participants will record their average walking per day and provide their daily mobility log at each subsequent visit (6, 12 and 24 weeks).

[0042] mRUST X-ray The modified RUST (mRUST) radiographic assessment is used to assess fracture healing. A combined DSX system A / P and lateral radiographs are used to obtain prior to the DSX dynamic test. It uses longer exposures (8 ms compared to 1 ms for dynamic imaging) to provide diagnostic quality images. mRUST scores each cortex on the AP and lateral radiographs as 1=no callus, 2=callus present, 3=bridging of callus, 4=remodeling, no fracture seen. The modified RUST score is the sum of these and therefore has a value of 4-16. The time to bridge 1-3 cortices is determined from the mRUST radiographs by at least two blinded investigators.

[0043] The primary endpoint for this trial is time to an mRUST score of >13, with secondary healing assessments (including CT scans, DSX imaging and patient-reported outcomes) scoring the treatment group better than that of the placebo group.

Claims

1. 1. A pharmaceutical composition for use in a method of accelerating long bone fracture healing in a subject in need thereof, said pharmaceutical composition comprising abaloparatide, said method comprising administering a therapeutically effective amount of abaloparatide to the subject following surgical intervention for a long bone fracture.

2. 2. The pharmaceutical composition of claim 1, wherein the long bone fracture is a tibia fracture.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein fracture healing, callus formation or both are confirmed at 6, 12 or 24 weeks by at least one of CT scan to assess fracture healing, bone mineral density, 3D volume of callus formation, fracture site hardness by dynamic stereo x-ray (DSX) and mRUST radiographic assessment.

4. 4. The pharmaceutical composition of claim 1, wherein union is accelerated as determined by modified radiographic union score (mRUST) for tibial fractures greater than 13 at 6, 12 or 24 weeks.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein bone quality is confirmed by bone mineral density scan (qCT) at 12 weeks or 24 weeks or both.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the cartilage stage of fracture repair is identified by detection of circulating levels of collagen X ("CXM").

7. 7. The pharmaceutical composition according to claim 1, wherein fracture site consolidation is achieved within 6 or 12 weeks.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein administration of a therapeutically effective amount of abaloparatide elevates bone formation markers without elevating bone resorption markers.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the surgical intervention is selected from: internal fixation, external fixation, intramedullary nailing, bone grafting, prosthesis or a combination thereof.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the surgical intervention is the implantation of an intramedullary (IM) rod.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein administration is a daily subcutaneous administration of 20 to 100 μg of abaloparatide.

12. 12. The pharmaceutical composition of claim 11, wherein the administration is a daily subcutaneous administration of 80 μg of abaloparatide.

13. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the administration is a daily transdermal administration of 100 to 400 μg of abaloparatide.

14. 14. The pharmaceutical composition of claim 13, wherein the administration is a daily transdermal administration of 300 μg of abaloparatide.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein abaloparatide is administered daily for at least 2 months, 3 months, 4 months, 6 months, 12 months, or 18 months.

16. 16. The pharmaceutical composition of claim 15, wherein abaloparatide is administered daily for three months.

17. A pharmaceutical composition described in any one of claims 1 to 16, wherein the method further comprises a step of pretreating the subject by administering a therapeutically effective amount of abaloparatide to the subject prior to surgical intervention.

18. 1. A pharmaceutical composition for use in a method of accelerating long bone fracture healing in a subject in need thereof, said pharmaceutical composition comprising abaloparatide, said method comprising administering a therapeutically effective amount of abaloparatide to the subject daily for three months following surgical intervention for a long bone fracture.

19. 19. The pharmaceutical composition of claim 18, wherein the administration is a daily subcutaneous administration of 80 μg of abaloparatide.

20. 19. The pharmaceutical composition of claim 18, wherein the administration is a daily transdermal administration of 300 μg of abaloparatide.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the subject is at high risk for fracture.

22. 22. The pharmaceutical composition of claim 21, wherein the increased risk is due to smoking, diabetes, vascular disease, or a combination thereof.

23. 23. The pharmaceutical composition of any of claims 1 to 22, wherein healing time is reduced by at least 25% compared to a subject not receiving abaloparatide therapy.