Reduced bone mineral density (BMD) and abnormalities in fat redistribution, glucose homeostasis, and lipid metabolism are prevalent among HIV-infected patients on highly active antiretroviral therapy (HAART). The relationship between the metabolic and skeletal complications of HIV is unclear. Fifty-one HIV patients on HAART (aged 30-54 yr, 86% male) and 21 HIV-negative control subjects (aged 31-51 yr, 82% male) were examined with oral glucose tolerance testing, a fasting lipid profile, and dual x-ray absorptiometry, and markers of bone formation (serum osteocalcin) and resorption (urinary deoxypyridinoline). HIV-infected subjects had a higher prevalence of either osteopenia or osteoporosis (World Health Organization criteria) at the spine, hip, or forearm, compared with HIV-negative controls (63% vs. 32%, P = 0.02) and evidence of increased bone resorption (urine deoxypyridinoline, 14.7 +/- 6.5 vs. 10.9 +/- 2.5 nmol/mmol creatinine, P = 0.012). Among the HIV-infected patients, those with reduced bone mineral density (n = 32) were similar to the group with normal BMD (n = 19) in the use of protease inhibitors, duration of HAART therapy, or other demographic variables. Plasma glucose 2 h after a glucose load (odds ratio 1.02 per 1 mg/dl increase, 95% confidence interval 1.01-1.05, P = 0.009) and central adiposity (trunk fat/total fat) (odds ratio 1.09 per 1% ratio increase, 95% confidence interval 1.00-1.18, P = 0.012) were associated with reduced BMD. These associations remained significant in a multivariate model including age and body mass index. Bone resorption was associated with female gender (P < 0.001) and non-high-density lipoprotein cholesterol (P = 0.034) in a multivariate linear regression model controlling for age, body mass index, protease inhibitor use, duration of HAART, and extremity fat. Reduced BMD is prevalent in HIV-infected patients on HAART and is related to central adiposity and postload hyperglycemia. Bone resorption is independently associated with female gender and dyslipidemia. HIV-infected patients with metabolic abnormalities may represent a population that would benefit from bone density screening.