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.

Keywords: antiretroviral therapy–induced bone loss; human immunodeficiency virus; zoledronic acid.

Figure 1.

CONSORT (Consolidated Standards of Reporting Trials) diagram. The progress through the phases (enrollment, intervention allocation, follow-up, and data analysis) of a double-blind, randomized controlled trial in nonosteoporotic, viremic, antiretroviral therapy (ART)–naive, human immunodeficiency virus-infected adults comparing a single zoledronic acid (5 mg) infusion at the time of ART initiation with active placebo infusion is shown.

Figure 2.

Longitudinal change in bone resorption outcomes by treatment arm. A, Model-based mean longitudinal changes in C-terminal telopeptide of collagen (CTx) by treatment arm and weeks on study. B, Model-based mean CTx percentage change from baseline by treatment arm and weeks on study. C, Model-based mean longitudinal changes in osteocalcin by treatment arm and weeks on study. D, Model-based mean osteocalcin percentage change from baseline by treatment arm and weeks on study. For each of the 4 panels, the vertical bars are the 95% confidence intervals and the numbers below the time points signify the number of subjects in each treatment group at each time interval. Abbreviations: ART, antiretroviral therapy; PL, active placebo; ZOL, zoledronic acid.

Figure 3.

Longitudinal change in lumbar spine bone mineral density (BMD) outcomes by treatment arm. A, Model-based mean longitudinal changes in BMD at the lumbar spine by treatment arm and weeks on study. B, Model-based mean BMD at the lumbar spine percentage change from baseline (BL) by treatment arm and weeks on study. C, Model-based mean longitudinal changes in lumbar spine t scores by treatment arm and weeks on study. D, Model-based mean longitudinal changes in lumbar spine z scores by treatment arm and weeks on study. For each of the 4 panels, the vertical bars are the 95% confidence intervals and the numbers below the time points signify the number of subjects in each treatment group at each time interval. Abbreviations: ART, antiretroviral therapy; PL, active placebo; ZOL, zoledronic acid.