Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.

Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

Inhibition of vascular endothelial growth factor in young adult mice causes low bone blood flow and bone strength with no effect on bone mass in trabecular regions.

OBJECTIVE: To determine the effect of an antibody to vascular endothelial growth factor (VEGF) on bone blood flow, bone strength, and bone mass in the young adult mouse. METHODS: Ten-week-old male BALB/cJ mice were body weight-randomized into either a rodent anti-VEGF monoclonal antibody (anti-VEGF, B20-4.1.1; 5 mg/kg 2×/wk.; n = 12) group or a vehicle (VEH; n = 12) group. After 42 days, mice were evaluated for bone blood flow at the distal femur by 18F-NaF-PET/CT and then necropsied. Samples from trabecular and cortical bone regions were evaluated for bone strength by mechanical testing, bone mass by peripheral quantitative computed tomography (pQCT), and micoarchitecture (MicroCT). Hydration of the whole femur was studied by proton nuclear magnetic resonance relaxometry (1H NMR). RESULTS: Distal femur blood flow was 43% lower in anti-VEGF mice than in VEH mice (p = 0.009). Ultimate load in the lumbar vertebral body was 25% lower in anti-VEGF than in VEH mice (p = 0.013). Bone mineral density (BMD) in the trabecular region of the proximal humeral metaphysis by pQCT, and bone volume fraction and volumetric BMD by MicroCT were the same in the two groups. Volume fraction of bound water (BW) of the whole femur was 14% lower in anti-VEGF than in VEH mice (p = 0.003). Finally, BW, but not cortical tissue mineral density, helped section modulus explain the variance in the ultimate moment experienced by the femur in three-point bending. CONCLUSION: Anti-VEGF caused low bone blood flow and bone strength in trabecular bone regions without influencing BMD and microarchitecture. Low bone strength was also associated with low bone hydration. These data suggest that bone blood flow is a novel bone property that affects bone quality.