Background/Purpose: Male osteoporosis, a disease of reduced bone mass leading to an increased risk of fragility fractures, often results from androgen deficiency caused by hypogonadism or androgen deprivation therapy. Abaloparatide (ABL) is an anabolic PTHrP analog that reduced the incidence of new vertebral and nonvertebral in postmenopausal women with osteoporosis at a high risk for fractures by increasing bone formation and bone mineral density (BMD) ¹. These attributes suggest ABL may have utility for increasing bone mass and strength in men with osteoporosis. The effects of ABL on bone mass were studied in orchiectomized (ORX) rats, a commonly used preclinical model of male osteoporosis.

Methods: 40 Male SD rats underwent sham or ORX surgery at 4 months of age. After an 8-week bone depletion period, ORX rats received vehicle (VEH) or ABL at 5 (ABL5) or 25 (ABL25) μg/kg/d by daily sc injection for 8 weeks (n = 10/group), while sham controls (n = 10) received VEH. Animals underwent dual X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) scans after 0, 4, and 8 weeks of treatment, followed by necropsy.

Results: DXA conducted 8 weeks after surgery showed the VEH group had significantly lower areal bone mineral content (aBMC) and density (aBMD) at the whole body, lumbar spine, total femur, and proximal femur (including the hip) vs Sham controls, indicating ORX-induced osteopenia at the treatment baseline (BL). Between BL and week 8, whole body aBMD increased by 13.8% and 17.3% in the ABL5 and ABL25 groups, respectively, versus 6.3% in VEH controls (both P < 0.001). Lumbar spine aBMD increased from BL to week 8 by 24.5% and 29.1% in the ABL5 and ABL25 groups, versus 7.6% in VEH controls (both P < 0.001). Total femur aBMD increased by 19.3% and 26.0% from BL to week 8 in the ABL5 and ABL25 groups, versus 7.2% in VEH controls (both P < 0.001). Proximal femur aBMD (including the hip) increased from BL to week 8 by 16.9% and 23.2% in the ABL5 and ABL25 groups, vs 5.0% in VEH controls (both P < 0.001). By treatment week 8, aBMD values for all four of these sites in the ABL5 and/or ABL25 groups were fully restored to the levels of Sham controls. pQCT of the tibial diaphysis showed significantly greater gains from BL to week 8 in cortical thickness for the ABL5 (7.3%) and ABL25 (7.1%) groups compared with VEH controls (0.9%; both P < 0.05). Tibial diaphysis cortical volumetric BMC (vBMC) was also significantly increased from BL to week 8 in the ABL5 (11.7%) and ABL25 (13.2%) groups compared with VEH controls (6.3%; both P < 0.05). pQCT of the proximal tibial metaphysis showed greater gains in trabecular vBMD in the ABL5 (96.4%) and ABL25 (163.0%) groups from BL to week 8 compared with VEH controls (6.9%; both P < 0.05).

Conclusion: Androgen deficiency via ORX led to significant deficits in bone mass for the whole body and for axial and appendicular sites in mature male rats. Abaloparatide fully reversed the ORX-related deficit in whole body bone mass by promoting the accrual of cortical and trabecular bone. These data provide preclinical support for investigations into the effects of abaloparatide in men with osteoporosis.

1. Miller, JAMA 2016;316:722-33

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abaloparatide-a-novel-pthrp-analog-increased-bone-mass-and-density-at-cortical-and-trabecular-sites-in-an-orchiectomized-rat-model-of-male-osteoporosis/