The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis

Background: We conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on bone mineral density (BMD) and the risk of osteoporosis, low bone mass and fractures, among people taking it as pre-exposure prophylaxis (PrEP), HIV treatment and HBV treatment. Methods: We searched MEDLINE and EMBASE for randomized controlled trials published from 1997-2018 reporting BMD, osteoporosis, low bone mass and/or fractures in treatment-naive patients taking compared with not taking TDF for 48 +/- 4 weeks. We pooled outcomes using DerSimonian random-effects models. Results: Our search yielded 5,178 abstracts, representing 3,865 articles, with 25 meeting the inclusion criteria. TDF was associated with greater BMD decline when taken as PrEP (lumbar spine: mean difference [MD]=-0.82%, 95% CI=-1.28, -0.37%, I-2=38%; total hip: MD=-0.81%, 95% CI=-1.22, -0.40%, I-2=48%) and HIV treatment (lumbar spine: MD=-1.62%, 95% CI=-2.30, -0.95%, I-2=93%; total hip: MD=-1.75%, 95% CI=-2.08, -1.42%, I-2=83%; femoral neck: MD=-1.26%, 95% CI=-2.15, -0.38%, I-2=43%) in comparison to those not taking TDF. Eight studies reported on incident osteoporosis or low bone mass, with variable results. Pooled results from five PrEP studies showed that TDF was not associated with increased fractures compared with no PrEP (RR=1.12, 95% CI=0.752, 1.74, I-2=26%). Conclusions: TDF caused greater decreases in BMD than did comparators when used for all three indications and the magnitude of this decrease was larger for HIV treatment compared with PrEP. Fractures were not increased among PrEP patients. The clinically significant BMD decline caused by TDF and current expansion of PrEP use suggest attention to the adverse bone effects of TDF will increase in importance.