Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad spectrum of molecular pathways can produce larger, denser and stronger fracture calluses. However, untreated control animals in most of these studies also demonstrate robust structural and biomechanical healing, leaving unclear how these interventions might alter the healing of recalcitrant fractures in humans. This review describes the physiology of fracture healing, with a focus on aspects of natural repair that may be pharmacologically augmented to prevent or treat delayed or nonunion fractures (collectively referred to as DNFs). The agents covered in this review include recombinant BMPs, PTH/PTHrP receptor agonists, activators of Wnt/β‐catenin signaling, and recombinant FGF‐2. Agents from these therapeutic classes have undergone extensive preclinical testing and progressed to clinical fracture healing trials. Each can promote bone formation, which is important for the stability of bridged calluses, and some but not all can also promote cartilage formation, which may be critical for the initial bridging and subsequent stabilization of fractures. Appropriately timed stimulation of chondrogenesis and osteogenesis in the fracture callus may be a more effective approach for preventing or treating DNFs compared with stimulation of osteogenesis alone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:213–223, 2017.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/136027/1/jor23460.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/136027/2/jor23460_am.pd

Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture

Fractures typically heal via endochondral and intramembranous bone formation, which together form a callus that achieves union and biomechanical recovery. PTHrP, a PTH receptor agonist, plays an important physiological role in fracture healing as an endogenous stimulator of endochondral and intramembranous bone formation. Abaloparatide, a novel systemically‐administered osteoanabolic PTH receptor agonist that reduces fracture risk in women with postmenopausal osteoporosis, has 76% homology to PTHrP, suggesting it may have potential to improve fracture healing. To test this hypothesis, ninety‐six 12‐week‐old male rats underwent unilateral internally‐stabilized closed mid‐diaphyseal femoral fractures and were treated starting the next day with daily s.c. saline (Vehicle) or abaloparatide at 5 or 20 µg/kg/d for 4 or 6 weeks (16 rats/group/time point). Histomorphometry and histology analyses indicated that fracture calluses from the abaloparatide groups exhibited significantly greater total area, higher fluorescence scores indicating more newly‐formed bone, and higher fracture bridging scores versus Vehicle controls. Callus bridging score best correlated with callus cartilage score (r = 0.64) and fluorescence score (r = 0.67) at week 4, and callus area correlated with cartilage score (r = 0.60) and fluorescence score (r = 0.89) at Week 6. By micro‐CT, calluses from one or both abaloparatide groups had greater bone volume, bone volume fraction, bone mineral content, bone mineral density, and cross‐sectional area at both time points versus Vehicle controls. Destructive bending tests indicated greater callus maximum load and stiffness in one or both abaloparatide groups at both time points versus Vehicle controls. These results provide preliminary preclinical evidence for improved fracture healing with systemically‐administered abaloparatide. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop ResPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149317/1/jor24254_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149317/2/jor24254.pd

OPG‐Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice

Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF‐κB ligand (RANKL) inhibitor OPG‐Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG‐Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by μCT imaging and histologically. ONJ features in ZA and OPG‐Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG‐Fc but not ZA. Full recovery of tartrate‐resistant acid phosphatase‐positive (TRAP+) osteoclast numbers occurred after discontinuing OPG‐Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal‐related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a “drug holiday” in managing the ONJ patient. © 2015 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113163/1/jbmr2490-sup-0001-SupFigLeg-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/113163/2/jbmr2490.pd

RANKL Inhibition Through Osteoprotegerin Blocks Bone Loss in Experimental Periodontitis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141376/1/jper1300.pd

Host-derived RANKL is responsible for osteolysis in a C4-2 human prostate cancer xenograft model of experimental bone metastases

<p>Abstract</p> <p>Background</p> <p>C4-2 prostate cancer (CaP) cells grown in mouse tibiae cause a mixed osteoblastic/osteolytic response with increases in osteoclast numbers and bone resorption. Administration of osteoprotegerin (OPG) blocks these increases, indicating the critical role of RANKL in osteolysis in this model. The objective of our study was to investigate whether RANKL expressed by tumor cells (human origin) directly stimulates osteolysis associated with the growth of these cells in bone or whether the increased osteolysis is caused by RANKL expressed by the host environment cells (murine origin). The relative contribution of tumor-<it>vs. </it>host-derived RANKL has been difficult to establish, even with human xenografts, because murine and human RANKL are both capable of stimulating osteolysis in mice, and the RANKL inhibitors used to date (OPG and RANK-Fc) inhibit human and murine RANKL.</p> <p>Methods</p> <p>To address this question we used a neutralizing, antibody (huRANKL MAb), which specifically neutralizes the biological activities of human RANKL and thereby the contribution of C4-2 derived RANKL in this tibial injection model of experimental bone metastases.</p> <p>Results</p> <p>Administration of huRANKL MAb did not inhibit the osteolytic response of the bone to these cells, or affect the establishment and growth of the C4-2 tumors in this environment.</p> <p>Conclusion</p> <p>In conclusion, our results suggest that in this model, murine RANKL and not the tumor-derived human RANKL is the mediator of the osteolytic reaction associated with C4-2 growth in bone. We hypothesize that C4-2 cells express other factor/s inducing host production of RANKL, thereby driving tumor-associated osteolysis.</p

Proximal Femur Responses to Sequential Therapy With Abaloparatide Followed by Alendronate in Postmenopausal Women With Osteoporosis by 3D Modeling of Hip Dual-Energy X-Ray Absorptiometry (DXA)

Previous subgroup analyses from the ACTIVE trial in women with postmenopausal osteoporosis (NCT01343004) using three-dimensional (3D)-processing of dual X-ray absorptiometry (DXA) scans indicated greater increases in total hip cortical volumetric bone mineral density (Ct.vBMD) and estimated indices of hip strength following 18 months of abaloparatide (ABL) versus placebo or teriparatide. The current post hoc analyses describe hip 3D-DXA data for ACTIVExtend (NCT01657162), in which 18 months of ABL followed by 24 months of alendronate (ABL/ALN) increased hip and spine areal BMD (aBMD) and reduced fracture risk versus placebo (PBO) followed by ALN (PBO/ALN). In an ACTIVExtend subgroup (ABL/ALN, n = 204; PBO/ALN, n = 202), hip DXA scans retrospectively underwent 3D modeling via 3D-Shaper software. Changes from baseline in cortical and trabecular compartments were calculated for total hip and hip subregions (femoral neck, trochanter, and shaft). Estimated strength indices comprising cross-sectional moment of inertia, section modulus, and buckling ratio were calculated for each hip subregion. Correlations between bone turnover marker levels at the time of alendronate initiation and subsequent BMD gains with alendronate were also investigated within each group. Total hip trabecular and cortical 3D-DXA parameters increased from baseline in both groups (all p < 0.001), with greater average increases for ABL/ALN versus PBO/ALN (trabecular vBMD: 10.87% versus 4.3%; cortical thickness: 2.32% versus 1.14%; Ct.vBMD: 3.41% versus 1.86%; cortical surface BMD: 5.82% versus 3.0%; all p < 0.001). Strength indices in the ABL/ALN group improved in all subregions versus baseline (all p < 0.0001) and versus PBO/ALN (all p < 0.02). In the ABL/ALN group, collagen type I N-terminal propeptide (P1NP) levels at the time of alendronate initiation correlated with subsequent percent changes in all 3D-DXA parameters with 24 months of alendronate therapy. In conclusion, sequential ABL/ALN or PBO/ALN treatment improves trabecular and cortical 3D-DXA parameters at the hip, as well as strength indices of hip subregions, with greater increases with ABL/ALN versus PBO/ALN. © 2022 Radius Health, Inc. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Mid-coronal sections of the hip depict mean changes in volumetric BMD. Greater increases in cortical regions are shown by more green color for participants who received sequential therapy with abaloparatide followed by alendronate versus those who received placebo followed by alendronate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172340/1/jbm410612.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172340/2/jbm410612_am.pd

Original Publication:

Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening Per Aspenberg and Anna Fahlgren N.B.: When citing this work, cite the original article