Abaloparatide treatment increases bone formation, bone density and bone strength without increasing bone resorption in a rat model of hindlimb unloading.

Disuse osteoporosis can result from prolonged bed rest, paralysis, casts, braces, fractures and other conditions. Abaloparatide (ABL) is a PTHrP analog that increases bone density and strength by stimulating osteogenesis with limited effects on bone resorption. We examined skeletal responses to abaloparatide in young adult male rats with normal weight-bearing and with hindlimb unloading via a pelvic harness. Rats were allocated to four groups (10-12 per group): normal weight-bearing plus vehicle treatment (CON-VEH), normal weight-bearing plus ABL treatment (CON-ABL), hindlimb-unloading plus vehicle (HLU-VEH), or hindlimb-unloading plus ABL (HLU-ABL). Rats received ABL (25 µg/kg/day, s.c.) or vehicle throughout the 28-day unloading period and were then sacrificed, at which time HLU-VEH rats exhibited reduced bone formation and significant deficits in tibial, femoral, and vertebral bone mass compared with CON-VEH. ABL treatment increased serum osteocalcin in CON and HLU animals while having no effect on the osteoclast marker TRACP-5b. Longitudinal peripheral quantitative computed tomography (pQCT) indicated that ABL increased trabecular and cortical bone mass in the tibia. ABL was also associated with improved trabecular and cortical bone mass and architectural parameters at the femur, tibia, and vertebrae by µCT. Tibial histomorphometry indicated increased trabecular and endocortical bone formation with HLU-ABL versus HLU-VEH and with CON-ABL versus CON-VEH, and ABL was also associated with lower trabecular and endocortical osteoclast surfaces. Vertebral finite element analysis indicated higher ultimate load and stiffness for CON-ABL versus CON-VEH and for HLU-ABL versus HLU-VEH. In summary, ABL was associated with improved trabecular and cortical bone density and architecture in normal weight-bearing and hindlimb-unloaded rats, with higher bone formation and no difference in bone resorption. ABL was also associated with improved bone biomechanical parameters. These results provide rationale for investigating the ability of abaloparatide to prevent or treat disuse osteoporosis in humans.

Abaloparatide improves cortical geometry and trabecular microarchitecture and increases vertebral and femoral neck strength in a rat model of male osteoporosis.

Androgen deficiency is a leading cause of male osteoporosis, with bone loss driven by an inadequate level of bone formation relative to the extent of bone resorption. Abaloparatide, an osteoanabolic PTH receptor agonist used to treat women with postmenopausal osteoporosis at high risk for fracture, increases bone formation and bone strength in estrogen-deficient animals without increasing bone resorption. This study examined the effects of abaloparatide on bone formation, bone mass, and bone strength in androgen-deficient orchiectomized (ORX) rats, a male osteoporosis model. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery. Eight weeks later, sham-operated rats received vehicle (saline; n = 10) while ORX rats (n = 10/group) received vehicle (Veh) or abaloparatide at 5 or 25 µg/kg (ABL5 or ABL25) by daily s.c. injection for 8 weeks, followed by sacrifice. Dynamic bone histomorphometry indicated that the tibial diaphysis of one or both abaloparatide groups had higher periosteal mineralizing surface, intracortical bone formation rate (BFR), endocortical BFR, and cortical thickness vs Veh controls. Vertebral trabecular BFR was also higher in both abaloparatide groups vs Veh, and the ABL25 group had higher trabecular osteoblast surface without increased osteoclast surface. By micro-CT, the vertebra and distal femur of both abaloparatide-groups had improved trabecular bone volume and micro-architecture, and the femur diaphysis of the ABL25 group had greater cortical thickness with no increase in porosity vs Veh. Biomechanical testing indicated that both abaloparatide-groups had stronger vertebrae and femoral necks vs Veh controls. These findings provide preclinical support for evaluating abaloparatide as an investigational treatment for male osteoporosis.