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 Res.

ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis.

Purpose: In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods: Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results: Five hundred fifty-eight women from ACTIVE's ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan-Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions: Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.