Background/Purpose: Estrogen deficiency and glucocorticoid (GC) therapy are the main causes of postmenopausal and secondary osteoporosis, respectively. Bone loss in both states relate to a negative bone balance (bone resorption exceeding formation), driven primarily by increased bone resorption in the case of estrogen deficiency, and by decreased bone formation with GC therapy.¹ Both conditions increase in the risk of fragility fractures, including vertebral fractures.¹ Abaloparatide (ABL), an anabolic PTHrP analog, increased bone formation and reduced the risk of new vertebral and nonvertebral fracture in women with postmenopausal osteoporosis at high risk of fracture.² In estrogen-deficient ovariectomized (OVX) rats, ABL increased bone formation, bone mineral density (BMD) and bone strength without increasing bone resorption.^{3, 4} The current study assessed effect of ABL on BMD in a rabbit bone loss model that combines increased bone resorption via OVX⁵ plus impaired bone formation via GC therapy.⁶

Methods: 32 6-month-old female New Zealand White rabbits underwent OVX, 24 of which received the GC methylprednisolone (OVX + GC; daily, SC) starting 1 day after OVX. Another 8 rabbits had sham surgery and did not receive GC (Sham). After a 6-week bone depletion period, OVX + GC rabbits continued to receive GC and treatment began with daily SC vehicle (VEH) or ABL at 5 μg/kg (ABL5) or 25 μg/kg (ABL25) (all n = 8). The remaining OVX and Sham controls received VEH. Lumbar vertebra areal BMD (LV BMD) was assessed before surgery and at treatment week 0, 4, 8 and 12 by dual X-ray absorptiometry (DXA). Animals were sacrificed after 12 weeks of treatment.

Results: The OVX + GC VEH group showed an absolute reduction in LV BMD of 30.4% between the start and end of the bone depletion, indicating osteopenia prior to treatment initiation. LV BMD in the OVX + GC VEH group was significantly lower vs OVX controls at the end of the bone depletion period, demonstrating a significant independent contribution of GC to osteopenia. Progressive bone loss continued in the OVX + GC VEH group throughout the treatment period; by treatment week 12 their LV BMD was 49.8% lower than before the bone depletion period, 47.2% lower than Sham controls, and 36.6% lower than OVX VEH controls. ABL dose-dependently increased LV BMD, and by treatment week 8 the effect of ABL25 on LV BMD was significant compared with OVX + GC VEH controls (P < 0.05). By treatment week 12, LV BMD in the ABL25 group was increased by 15.7% vs treatment week 0, whereas LV BMD in the OVX + GC VEH controls decreased by 27.8% over that time (P = 0.0001).

Conclusion: These data indicate that ABL robustly increased BMD in rabbits rendered severely osteopenic by the combined effects of OVX plus GC therapy. These findings also provide preclinical support for investigating the potential of ABL for increasing BMD in patients with bone loss caused by GC therapy.

1. Canalis, Osteoporos Int 2007;18:1319-28; 2. Miller, JAMA 2016;316:722-33; 3. Varela JBMR 2017;32:24-33; 4. Varela, Bone 2017;95:143-50. 5. Khan, JBMR 2016;31:615-29; 6. Luppen JBMR 2002;17:301-10.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abaloparatide-an-osteoanabolic-pthrp-analog-increased-bone-mineral-density-in-rabbits-with-glucocorticoid-induced-osteopenia/