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Although osteopenia is common in HIV-infected patients, there is by now limited data on the evolution of bone mineral density in this population. We aimed to evaluate the course of osteopenia over a 2-year period in HIV-1-infected men, and to identify risk factors for abnormal bone mineral density (BMD) decline.HIV-1-infected men on combined antiretroviral therapy (cART) screened in the ANRS 120 Fosivir trial, diagnosed with low BMD (−2.5 ≤T-score <−1), not receiving antiosteoporotic agents, with sequential dual-energy-X ray-absorptiometry (DXA) available at baseline were eligible for this study and had a second DXA performed between months 24 and 36.We enrolled 94 men with a median age of 46 years [interquartile range (IQR), 41–53], BMI 22 kg/m2 (21–25) and a CD4+ cell nadir of 164/μl (69–261). They were receiving cART for a median of 7.5 years (5.8–9.5). Over a median interval of 2.6 years (2.3–2.9) between the two DXA tests, the mean change in BMD was −0.5 ± 1.7% per year (P = 0.010) at the lumbar spine and −0.4 ± 1.8% per year (P = 0.033) at the hip. BMD fell by more than the smallest detectable difference (SDD) in, respectively, 25.5 and 27.7% of patients at the lumbar spine and hip. Tenofovir (TDF) exposure was independently associated with a larger decline in BMD at both sites [lumbar spine, OR = 2.4 (1.2–4.9); hip, OR = 2.8 (1.3–5.9)].Although osteopenia overall modestly changes over 2 years in long-term cART-treated patients, a quarter of patients experienced a significant loss (>1 SDD) associated with TDF exposure.