Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss are Cumulative in Mice Models

Abstract

Background: Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study.

Methods: We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry.

Results: Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p<0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A.

Conclusion: Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.

Keywords: ART; Antiretroviral Therapy; Estrogen Deficiency; HIV; IRBL; Immune Reconstitution Bone Loss; Menopause; Ovariectomy; bone; postmenopausal osteoporosis.