Total Bone Mineral Density Over Time in HIV-Infected Men and Women
Background: Osteopenia is common in the era of effective antiretroviral therapy (ART), yet the etiology is unclear. We evaluated the association of host factors, disease severity, and ART to changes in total body bone mineral density (total BMD) over time in HIV-infected men (n = 283) and women (n = 96).
Methods: Total BMD was measured annually by whole-body dual-energy absorptiometry (DXA), and medical, dietary, and behavioral history was collected. The median time from first to last DXA was 2.5 years (range 0.9-6.8 years). Using a repeated measures regression model, we identified variables independently associated with percent change in total BMD between consecutive DXA exams (n = 799 intervals), adjusted for age, race, sex, menopause, and smoking. We estimated percent change in total BMD over an average interval (1 year) standardized for representative levels of each determinant in males, premenopausal women, and postmenopausal women.
Results: Median baseline age, CD4, and viral load were 42 years, 364 cells per cubic millimeter, and 2.7 log₁₀ copies per milliliter, respectively. The estimated change in total BMD for those not on ART was -0.37% per year [95% confidence interval (CI) -0.76 to -0.02] for men, -0.08% per year (95% CI -0.49 to 0.33) for premenopausal women, and -1.07% per year (95% CI -1.86 to -0.28) for postmenopausal women. Greater loss of total BMD was associated with lower albumin, lower body mass index, prednisone/hydrocortisone use, tenofovir use, and longer duration of didanosine. Strength training and long duration of d4T and saquinavir prevented or mitigated bone loss. For those on ART for 3 years (not including the above agents), the rate of loss was -0.57% per year (95% CI -1.00 to -0.14) for men, -0.28% (95% CI -0.71 to 0.15) for premenopausal women, and -1.27% (95% CI -2.07 to -0.47) for postmenopausal women. Postmenopausal women had greater loss than premenopausal women and men.
Conclusions: Low body weight, low albumin, catabolic steroid use, and menopause may accelerate bone loss, and strength training may be protective. Tenofovir and didanosine may also have a deleterious effect on BMD.

Low bone mineral density (BMD) is frequently observed among HIV-infected adults and children. The etiology is poorly understood and probably multifactorial. The long-term clinical outcomes are not known. Most cases of bone loss in HIV-infected individuals result in mild osteopenia; osteoporosis is less prevalent. As HIV-infected patients live longer due to more effective antiretroviral therapy (ART), they are exposed to numerous factors over time which may have an impact on BMD, including traditional risk factors (aging, genetic predisposition, menopause, low calcium and vitamin D intake and low sun exposure, lack of weight-bearing exercise, smoking, catabolic steroid use, and weight change) and HIV-associated factors (chronic HIV infection and various and changing treatment regimens).

Cross-sectional studies in HIV-infected adults show conflicting results regarding the association of low BMD with ART. Most of these studies selected specific patient groups based on current treatment regimen, wasting, or lipodystrophy status, making it difficult to compare across studies or to generalize across HIV-infected subgroups. In addition, the cross-sectional design of these studies makes it impossible to know for certain if the risk factors preceded the bone loss.

Our understanding of the independent effects of host factors, medications, and HIV disease factors is limited by the lack of prospective studies in men and women with careful control for confounding by host factors. Few studies have a baseline measure of BMD before treatment. In 1 clinical trial, ART-naive patients randomized to tenofovir-based highly active antiretroviral therapy (HAART) had a greater decrease in lumbar spine BMD over time compared with patients on stavudine (d4T)-based HAART. A few other studies examined change in BMD or bone mineral content (BMC) over time. Mondy et al followed patients for 72 weeks and found an overall increase in lumbar spine (2.6%) and hip (2.4%) BMD among those with undetectable HIV viral load and with greater increases in CD4 count, but no difference by protease inhibitor (PI)-based HAART compared with nonnucleoside reverse transcriptase inhibitor-based HAART. Other studies have found decreasing BMD in patients on dual-nucleoside reverse transcriptase inhibitor, stable BMD among patients using nelfinavir-containing HAART, and slightly increasing BMD among patients using indinavir-containing HAART. Dolan et al found lower baseline BMD in HIV-infected compared with HIV-negative persons, but a similar rate of change over time between the groups. McDermott et al found decreases in extremity BMC in PI-based HAART users and increases in those on nelfinavir. Decreases in trunk BMC were observed among those on zidovudine and increases in those on d4T. Finally, tenofovir is associated with bone loss.

To better understand the evolution and predictors of change in BMD over time, we followed a heterogeneous cohort of HIV-infected men and women in the Nutrition for Healthy Living Study for a median of 2.5 years (range 0.9-6.8 years). We performed annual assessments of total body BMD by dual-energy x-ray absorptiometry (DXA) and semiannual measurements of demographics, disease severity, body mass index (BMI), physical activity, steroid use, ART, and dietary intake.