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A Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss
Ighovwerha Ofotokun1; Kehmia Titanji1; Aswani Vunnava1; Antonina Foster1; Anandi N. Sheth1; Cecile D. Lahiri1; Jeffrey L. Lennox1; Andrea Knezevic2; Kirk A. Easley2; M. N. Weitzmann1
1Emory Univ Sch of Med, Atlanta, GA, USA;2Emory Univ Rollins Sch of PH, Atlanta, GA, USA
HIV enhances bone loss, and close to 2/3 of HIV patients are osteopenic and 15% osteoporotic, leading to 2-9 fold higher fracture prevalence in the aging HIV population. Antiretroviral therapy (ART) further worsens this loss, inducing an additional 2-6% loss in bone mineral density (BMD), mostly within the first 48 weeks, providing a window for prophylaxis with long-acting antiresorptives such as zoledronic acid (ZA).
We randomized non-osteoporotic, viremic ART-naïve adult HIV-patients initiating ART with atazanavir/ritonavir+tenofovir/emtricitabine to a single ZA (5mg) vs. placebo (PL) infusion in a double-blinded placebo controlled phase 2 trial. Laboratory and safety measures, plasma bone turnover markers including C-terminal telopeptide of collagen (CTx), a sensitive marker of bone resorption, and BMD were performed at weeks 0, 12, 24, and 48. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints.
Of the 63 subjects enrolled, 84% were black, 16% white, and 21% women with a mean age of 39.6 years. Treatment with ZA was associated with a 74% reduction in bone resorption relative to PL at 12 weeks [CTx: 0.08 ng/ml (ZA) vs. 0.31 ng/ml (PL), p<0.001; mean difference= -0.23 ng/ml (95% CI: -0.31, -0.14)] with 65% and 56% relative reduction at 24 and 48 weeks respectively. ZA led to an 8% increase in lumbar spine BMD at 12 weeks relative to PL [1.305 g/cm2 vs. 1.204 g/cm2, p=0.003; mean difference=0.101 g/cm2 (95% CI: 0.035, 0.168)], with a greater increase of 11% at 24 and 48 weeks. Of note, BMD at the lumbar spine increased 1.9% (95% CI: 0.39, 4.22) from baseline to 48 weeks in the ZA arm but decreased 4.4% (95% CI: 2.63, 6.24) in the PL arm. Lumbar spine T- and Z-scores were significantly higher in patients receiving ZA vs. PL at weeks 12, 24, and 48 (all p<0.05). Significant trends were also observed at the hip and femoral neck. The rate of virologic suppression and mean CD4 T cell increase over 48 weeks were similar between the arms. ZA was well tolerated without major side effects.
In this single center proof-of-concept study, a single infusion of ZA at the time of ART initiation prevented ART-induced bone resorption and bone loss at key fracture-prone anatomical sites. These effects were observed as early as 12 weeks and persisted through 48 weeks, the period when ART-induced bone loss is most intense. Replication of these results in a confirmatory multicenter randomized clinical trial is warranted.