Tenofovir disoproxil fumarate-associated bone loss: does vitamin D-binding protein play a role?

Abstract

Initiation of antiretroviral therapy, particularly of regimens that contain tenofovir disoproxil fumarate (TDF), results in increased bone turnover and a reduction in bone mineral density. In addition, TDF has been associated with increased parathyroid hormone (PTH) and efavirenz with reduced vitamin D [25(OH)D] concentrations [1]. The mechanism of bone loss in patients receiving TDF remains incompletely understood. A recent study by Hsieh et al.[2] examined changes in bone-regulatory hormones and bone biomarkers in a single-arm study of 134 antiretroviral therapy-naïve Chinese patients who initiated TDF, lamivudine and efavirenz. Consistent with previous studies, the authors observed statistically significant increases in PTH and bone turnover [collagen type 1 cross-linked C-telopeptide (CTx) and total procollagen type 1 N-terminal propeptide (P1NP)] at 24 and 48 weeks. Although no change in 25(OH)D was observed, vitamin D–binding protein concentrations increased from baseline, prompting the authors to propose a potential role for this plasma protein in TDF-associated bone loss. We recently completed a clinical trial with a similar focus on vitamin D, bone turnover and bone mineral density [3]. Sixty-four patients with well controlled HIV on TDF, emtricitabine and efavirenz were randomized to remain on their treatment or to switch antiretroviral therapy to darunavir/ritonavir for 48 weeks. The switching strategy was associated with significant increases in 25(OH)D concentration, reductions in bone turnover (CTx and P1NP) and a 2–3% increase in bone mineral density at the hip, femoral neck and lumbar spine. Notably, the reductions in CTx and P1NP and the improvement in bone mineral density occurred in the absence of changes in vitamin D–binding protein (Fig. 1), PTH, estimated glomerular filtration rate or renal tubular function [3].Fig. 1: Plasma vitamin D binding protein concentrations in the MIDAS trial [3].DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.Our results, as well as those of Hsieh et al.[2], are consistent with a direct effect of TDF on bone [4]. Although the increased bone turnover observed by Hsieh et al. may be the result of increased PTH concentrations with TDF exposure, the reduction in bone turnover markers in our patients who discontinued TDF was not accompanied by a reduction in PTH levels. The improved vitamin D status in our patients who switched therapy may have contributed to the decrease in bone turnover; however, the increase in bone mineral density in those switching off TDF was not explained by the increase in 25(OH)D, and the study by Hsieh et al.[2] demonstrates that TDF-induced increases in bone turnover may occur in the absence of changes in 25(OH)D status. Severe proximal tubulopathy may result in osteomalacia [5]. Both our data and those of Hsieh et al.[2] confirm that TDF-associated changes in bone turnover markers (and in our study, bone mineral density) may occur in the absence of changes in renal tubular function [6]. Moreover, our data do not support the hypothesis that TDF causes an increase in vitamin D–binding protein concentration, nor do they suggest that reductions in vitamin D–binding protein contribute to the improved bone mineral density that was observed following TDF discontinuation. Acknowledgements Conflicts of interest There are no conflicts of interest.