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

Abstract

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

Effects of Intermittent Administration of Parathyroid Hormone and Parathyroid Hormone‐Related Protein on Fracture Healing: A Narrative Review of Animal and Human Studies

“…Further studies with increased clarity on the osteoblastic and osteoclastic responses of both agents relative to fracture healing may be valuable to discern potential clinical applications. The most recent study of abaloparatide and fracture healing was a rat study that compared two doses (5 and 20 μg/kg/d) in 12‐week‐old rats for 4 or 6 weeks . Abaloparatide treatment resulted in greater callus area and volume, higher bridging scores, and greater callus maximum load and stiffness versus vehicle controls.…”

“…The most recent study of abaloparatide and fracture healing was a rat study that compared two doses (5 and 20 μg/kg/d) in 12-week-old rats for 4 or 6 weeks. (85) Abaloparatide treatment resulted in greater callus area and volume, higher bridging scores, and greater callus maximum load and stiffness versus vehicle controls.…”

“…The results of human subject studies are also supportive of PTH promoting fracture healing yet are fewer and not as overwhelming. The doses used in animal Lanske et al, (85) 2019 BMD = bone marrow density; BV = bone volume; TV = tissue volume; BMC = bone mineral content.…”

The Efficacy of PTH and Abaloparatide to Counteract Immobilization-Induced Osteopenia Is in General Similar

“…In contrast to treatment with PTH, no studies have previously investigated the effect of ABL in relation to disuse-induced bone loss in rats. However, ABL has previously been studied in intact ( 42 , 43 ), ovariectomized ( 44 , 45 ), and orchiectomized animals ( 46 , 47 ), as well as during fracture healing in mice ( 26 ) and rats ( 48 ). These studies have demonstrated bone anabolic properties of ABL in accordance with those established in the present study.…”

Effects of systemically administered abaloparatide, an osteoanabolic PTHrP analog, as an adjuvant therapy for spinal fusion in rats

“…[29][30][31][32] Abaloparatide also improved the early bridging and biomechanical stability of long bone fractures in rats, with bridging showing significant relationships with the extent of callus chondrogenesis and osteogenesis. 33 Spinal fusion is associated with chondrogenesis and osteogenesis, 2,3,6 and chondrogenic responses have been demonstrated with high-dose teriparatide therapy in spinal fusion models 3,4 and with abaloparatide in mesenchymal cell cultures. 34 The current study is the first to examine the effects of abaloparatide as a postoperative adjuvant therapy in animals undergoing noninstrumented PLF.…”