Vitamin D and Calcium Supplementation Reverses Tenofovir-Caused Bone Mineral Density Loss in People Taking ART or PrEP: A Systematic Review and Meta-Analysis

Abstract

BackgroundThe decrease of bone mineral density (BMD) after the intake of Tenofovir disoproxil fumarate (TDF)-based drugs in people living with HIV/AIDS (PLWHA) and HIV-negative key populations under pre-exposure prophylaxis (PrEP) regimen raised concerns. Previous findings on the effects of vitamin D (VD) and calcium supplements and the recovery of BMD loss were inconclusive. The optimal doses of VD and calcium and its supplementary duration remained unknown. Therefore, we conducted a systematic review and meta-analysis to synthesize current evidence on VD and calcium supplements to inform clinical practice.MethodsWe searched PubMed, Web of Science, Cochrane library, and EMBASE databases for all placebo-controlled trials and prospective cohort studies published before March 5, 2021 that investigated VD and calcium supplements in participants taking TDF-based drugs. The keywords calcium, vitamin D, Tenofovir, and BMD were used for the searches. The primary outcome was changes of spine and hip BMD. A subgroup analysis was performed to determine the factors that were related to the effects of VD supplements on BMD. Locally weighted regression (loess) was used to determine the relationships of VD supplements, supplementary duration, and changes of BMD. This study was registered at PROSPERO (No. 42021231000).FindingsSeven eligible studies including 703 participants were included in the analyses. The meta-analysis found that VD and calcium supplementation was related to a significant increase of BMD in the spine and hip [standardized mean difference (SMD) 0.43; 95% CI, 0.25 to 0.61, p = 0.009]. Moreover, positive dose-response relationships were demonstrated between doses of VD and calcium supplements, supplementary duration, and BMD recovery. Patients who took VD with the dose level of 4,000 IU/D obtained the highest BMD improvement (SMD 0.59, 95% CI, 0.43 to 0.74). No side effects were reported on VD and calcium supplementation.InterpretationWe found the VD and calcium supplementation was associated with increases of BMD in participants taking TDF-based drugs. An optimal supplementary dose of 4,000 IU/D for VD was suggested for clinicians. The findings could be used in clinical practice to improve the BMD outcomes in people who were taking TDF-based drugs.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/.

Delayed Irreversible Fanconi Syndrome Associated With Vertebral Fracture After Tenofovir Discontinuation

“…Therefore, some experts suggest a spinal X-ray annually after TDF initiation to detect early bone abnormalities [13]. Of note, a meta-analysis of seven studies that included more than 700 participants reported statistically significant improvement in BMD with a mean difference of 0.4 points when supplemental vitamin D and calcium were prescribed to patients on TDF as an additional strategy to minimize the negative impact of TDF on BMD [15].…”

“…In real-world data, Fanconi syndrome incidence has ranged between one and five per 1,000 patients receiving TDF [13,14]. Although more than 50% of Fanconi syndrome cases are resolved within the first year following TDF discontinuation [15,16], delayed recovery has been observed in some cases [17]. Herein, we report a case of TDF-associated Fanconi syndrome, which resulted in bone mass loss and fragility fracture approximately four years following TDF discontinuation.…”

Biochemical Markers of Calcium and Bone Metabolism during and after Lactation in Ugandan Women with HIV on Universal Maternal Antiretroviral Therapy

“…The possible use of vitamin D and calcium to lower PTH and increase bone mineral density has been suggested, and some short‐term positive effects of vitamin D therapy with and without calcium supplementation have been demonstrated. ( 39 , 40 ) However, the benefits of vitamin D supplementation in individuals with good vitamin D status are unknown, and unexpected long‐term effects of calcium supplementation in African women and children have been reported. ( 41 ) Thus, further studies are needed to explore mechanisms in more detail and to investigate whether the use of TDF‐based ART by African women during pregnancy and lactation has long‐term consequences for the bone health of the mother and for the growth of the child.…”

Cardiometabolic health in people with HIV: expert consensus review

“…Summary of evidence: A systematic review and meta-analysis of people with and without HIV using tenofovir disoproxil fumarate as part of ART or PrEP, respectively, reported that vitamin D supplementation was correlated with improved BMD. 109 A randomized, double-blind, placebo-controlled study assessing vitamin D and calcium supplementation in ART-naive people with HIV initiating efavirenz/emtricitabine/tenofovir disoproxil fumarate reported smaller declines in total hip and lumbar spine BMD in participants receiving high-dose vitamin D and calcium. 110 An analysis of people with HIV taking dolutegravir-based ART in the prospective observational SCOLTA Project found that vitamin D supplementation was associated with improved BMD.…”