A Single-dose Zoledronic Acid Infusion Prevents Antiretroviral Therapy–induced Bone Loss in Treatment-naive HIV-infected Patients: A Phase IIb Trial

Abstract

Background. Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among HIV-infected individuals. ART-induced bone loss is most intense within the first 48 weeks of therapy, providing a window for prophylaxis with long-acting antiresorptives.Methods. In a phase 2, double-blind, placebo-controlled trial, we randomized 63 nonosteoporotic, ART-naive adults with HIV initiating ART with atazanavir/ritonavir + tenofovir/emtricitabine to a single zoledronic acid (ZOL) infusion (5 mg) vs placebo to determine the efficacy of ZOL in mitigating ART-induced bone loss. Plasma bone turnover markers and bone mineral density (BMD) were performed at weeks 0, 12, 24, and 48 weeks. Primary outcome was change in C-terminal telopeptide of collagen at 24 weeks. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints.Results. The ZOL arm had a 65% reduction in bone resorption relative to the placebo arm at 24 weeks (0.117 ng/mL vs 0.338 ng/mL; P < .001). This effect of ZOL occurred as early as 12 weeks (73% reduction; P < .001) and persisted through week 48 (57% reduction; P < .001). The ZOL arm had an 8% higher lumbar spine BMD at 12 weeks relative to the placebo arm (P = .003), and remained 11% higher at 24 and 48 weeks. Similar trends were observed in the hip and femoral neck.Conclusions. A single dose of ZOL administered at ART initiation prevented ART-induced bone loss through the first 48 weeks of ART, the period when ART-induced bone loss is most pronounced. Validation of these results in larger multicenter randomized clinical trials is warranted.Clinical Trials Registration. NCT01228318.

Tenofovir Disoproxil Fumarate as Pre-Exposure Prophylaxis for HIV Prevention in Women with Osteoporosis: A Case Report and Review of the Literature

“…Clinical trials have shown smaller reductions in BMD with co-administration of anti-resorptive therapy, such as zolendronate, and calcium and vitamin D supplementation in HIV-infected patients who were starting antiretroviral therapy [20,21]. In this case, the patient had been compliant with her anti-resorptive therapy and vitamin D and calcium supplementation, which may have ameliorated any negative impacts of FTC/TDF on her BMD.…”

Physiological and pathophysiological bone turnover — role of the immune system

“…As a proof of concept, zoledronic acid was demonstrated to ameliorate bone loss associated with T-cell reconstitution in mice, without evidence of impediment to early T-cell reconstitution 97 . The results of a phase II clinical study to test this concept of prophylaxis against bone loss in treatment naive HIV-infected patients initiating cART have now been published 98 . These data reveal that a single administration of zoledronic acid significantly protect patients through the first 48 weeks, the period when ART-induced bone loss is most pronounced, at the lumbar spine, hip and femoral neck 98 .…”

Bone Loss in HIV Infection

“…In a meta-analysis of the effects of bisphosphonates in HIV-infected patients with low BMD, a mean increase in BMD of 2.85% at the lumbar spine, 1.18% at the femoral neck, and 2.12% at the total hip was seen at 48 weeks [121]. Interestingly, in a phase IIb trial of viremic, cART-naïve, HIV-infected patients without osteoporosis, our group demonstrated that a single infusion of zoledronic acid at the start of therapy with TDF/FTC + ATV/RTV prevented BMD loss at the lumbar spine, hip and femoral neck at 48 weeks [122••]. Although the long-term effects of bisphosphonates in the HIV population on clinically important outcomes such as fracture remain to be determined, these data are promising.…”