Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco

Abstract

Background: Pre-exposure prophylaxis (PrEP) trials are evaluating regimens containing tenofovir-disoproxil fumarate (TDF) for HIV prevention. We determined the baseline prevalence of low bone mineral density (BMD) and the effect of TDF on BMD in men who have sex with men (MSM) in a PrEP trial in San Francisco.

Methods/findings: We evaluated 1) the prevalence of low BMD using Dual Energy X-ray Absorptiometry (DEXA) in a baseline cohort of 210 HIV-uninfected MSM who screened for a randomized clinical trial of daily TDF vs. placebo, and 2) the effects of TDF on BMD in a longitudinal cohort of 184 enrolled men. Half began study drug after a 9-month delay to evaluate changes in risk behavior associated with pill-use. At baseline, 20 participants (10%) had low BMD (Z score≤-2.0 at the L2-L4 spine, total hip, or femoral neck). Low BMD was associated with amphetamine (OR = 5.86, 95% CI 1.70-20.20) and inhalant (OR = 4.57, 95% CI 1.32-15.81) use; men taking multivitamins, calcium, or vitamin D were less likely to have low BMD at baseline (OR = 0.26, 95% CI 0.10-0.71). In the longitudinal analysis, there was a 1.1% net decrease in mean BMD in the TDF vs. the pre-treatment/placebo group at the femoral neck (95% CI 0.4-1.9%), 0.8% net decline at the total hip (95% CI 0.3-1.3%), and 0.7% at the L2-L4 spine (95% CI -0.1-1.5%). At 24 months, 13% vs. 6% of participants experienced >5% BMD loss at the femoral neck in the TDF vs. placebo groups (p = 0.13).

Conclusions: Ten percent of HIV-negative MSM had low BMD at baseline. TDF use resulted in a small but statistically significant decline in BMD at the total hip and femoral neck. Larger studies with longer follow-up are needed to determine the trajectory of BMD changes and any association with clinical fractures.

Trial registration: ClinicalTrials.gov: NCT00131677.

Conflict of interest statement

Competing Interests: Dr. Kenneth Mayer has received educational and research grants from Gilead Sciences, the pharmaceutical company that manufactures tenofovir. Dr. Melanie Thompson's organization (AIDS Research Consortium of Atlanta) has received research grant funding from Gilead and other pharmaceutical companies and has had a prevention research consultancy with Gilead Sciences. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Study design and participant disposition.

The baseline only cohort shown in red shading includes 26 men who had only 1 DEXA scan performed, either during screening or after enrollment. The longitudinal cohort shown in green shading includes 184 men who had a baseline and at least 1 additional scan during study follow-up. Of the 210 participants who had a baseline DEXA scan, 178 had this scan performed during screening, and 32 shortly after enrollment (prior to the protocol amendment moving DEXA scans to screening). †Delayed arm participants who enrolled prior to protocol amendment had baseline DEXA performed at 9 months prior to starting study drug. DEXA, dual energy X-ray absorptiometry; TDF, tenofovir disoproxil fumarate.

Figure 2. Study design.

Participants were randomly assigned to one of four arms. Participants in the 2 immediate arms (TDF vs. placebo) initiated study drug at enrollment; those in the 2 delayed arms (TDF vs. placebo) initiated study drug at the 9 month visit. TDF, tenofovir disoproxil fumarate.

Figure 3. Mean percent change in BMD from baseline at the total spine, total hip, and femoral neck.

Trajectory of mean percent change in BMD at the femoral neck (a), total hip (b), and L2–L4 spine (c), by treatment arm. Solid lines represent the immediate arm, and dashed lines represent the delayed arm. Participants who discontinued study drug due to >5% BMD loss from baseline are included. BMD, bone mineral density.

Figure 4. Normal curves demonstrating percent changes in bone density at 24 months in the placebo vs. TDF groups, by anatomic site.

Distribution curves of percent BMD change from baseline at last scan at the femoral neck (a), total hip (b), L2–L4 spine (c). BMD, bone mineral density;TDF, tenofovir disoproxil fumarate.