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Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building effects of teriparatide and abaloparatide, the only PTH1R agonists approved to reduce osteoporotic fracture risk in postmenopausal women. This study in 8-week-old female mice compared bone resorption and formation responses to these agents delivered at the same 10 μg/kg dose, and a 40 μg/kg abaloparatide dose was also included to reflect its 4-fold higher approved clinical dose. Peptides or vehicle were administered by daily supra-calvarial subcutaneous injection for 12 days, and local (calvarial) and systemic (L5 vertebral and tibial) responses were evaluated by histomorphometry. Terminal bone histomorphometry data indicated that calvarial resorption cavities were similar in both abaloparatide groups versus vehicle controls, whereas the teriparatide group had more calvarial resorption cavities compared with the vehicle or abaloparatide 40 μg/kg groups. The bone resorption marker serum CTX was significantly lower in the abaloparatide 40 μg/kg group and similar in the other two active treatment groups compared with vehicle controls. Both peptides increased trabecular bone formation rate (BFR) in L5 and proximal tibia versus vehicle, and L5 BFR was higher with abaloparatide 40 μg/kg versus teriparatide. At the tibial diaphysis, periosteal BFR was higher with abaloparatide 40 μg/kg versus vehicle or teriparatide, and endocortical BFR was higher with teriparatide but not with abaloparatide 10 or 40 μg/kg versus vehicle. Few differences in structural or microarchitectural bone parameters were observed with this brief duration of treatment. In summary, calvarial bone resorption cavity counts were higher in the teriparatide group versus the vehicle and abaloparatide 40 μg/kg groups, and the abaloparatide 40 μg/kg group had lower serum CTX versus vehicle. L5 and tibial trabecular bone formation indices were higher in all three active treatment groups versus vehicle. The abaloparatide 40 μg/kg group had higher L5 trabecular BFR and tibial periosteal BFR versus teriparatide, whereas tibial endocortical BFR was higher with teriparatide but not abaloparatide. Together, these findings in female mice indicate that an improved balance of bone formation versus bone resorption is established shortly after initiating treatment with abaloparatide., Highlights • PTH receptor (PTH-R) agonists increase bone density by stimulating bone formation. • PTH-R agonists differ in their propensity to increase bone resorption. • Female mice were treated for 12 d with PTH-R agonists abaloparatide or teriparatide. • The systemic resorption marker serum CTX was lower with abaloparatide vs vehicle. • Calvarial resorption cavities were higher with teriparatide but not abaloparatide.

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.