The current use of highly active antiretroviral therapy (HAART) has dramatically improved the survival of HIV-infected patients.1 HIV infection and HAART have been associated with numerous acute and long-term toxicities, particularly metabolic complications such as lipodystrophy, insulin resistance, diabetes, and dyslipidemia.2 Recently, disturbances of bone metabolism, including premature osteopenia, osteoporosis, and osteonecrosis, have been reported in HIV-infected subjects.3-5 The mechanism underlying these alterations remains not completely explained: several hypotheses have been considered, including prolonged use of protease inhibitors (PIs), nucleoside-related mitochondrial toxicity, lactic acidosis, lipodystrophy, immune reconstitution, nutritional and hormonal factors, prior AIDS-related wasting, and HIV infection itself.3,6,7 The direct effect of HIV on osteogenic cells, the activation of proinflammatory cytokines in the tumor necrosis factor family molecule RANKL, and the alterations in the metabolism of vitamin D and its derivatives have been also studied.8,9
The aim of this study was to evaluate the possible role of HAART duration and HIV infection itself and to correlate them with the diagnosis of osteopenia and/or osteoporosis.
This study involved HIV-infected subjects aged 30 to 50 years consecutively cared for at our outpatient clinic. Patients with a known history of bone disease, with a long bed rest period (>1 month), with menopause or amenorrhea, with concomitant endocrine diseases (eg, hypogonadism, hyper- or hypothyroidism, hypocortisolism), taking drugs affecting bone metabolism (corticosteroids, levothyroxine, lithium, or estrogens), or with drug or alcohol abuse with evidence of neoplasia, chronic diarrhea, or absorption dysfunction and/or a body mass index (BMI) <20% or >20% of normal ranges were excluded. Data on gender; age; BMI; risk factors for HIV infection; Centers for Disease Control and Prevention (CDC) stage; lipodystrophy (defined by body fat abnormalities consistent with lipoatrophy, lipoaccumulation, or both clinically evident to the patient and the physician); immunovirologic parameters (CD4+ cells and HIV RNA level); hepatitis C virus (HCV) coinfection; and duration of HIV positivity, HAART, and use of individual antiretroviral drugs were recorded. According to the quartiles of HAART duration, 4 groups were identified: G1, <1 year (n = 44); G2, 1 to 3 years (n = 41); G3, 3 to 5 years (n = 41); and G4, >5 years (n = 53). HIV RNA levels were measured by the branched chain DNA (bDNA) technique (Chiron; detection limit of 50 copies/mL), and CD4+ cell counts were measured by elite flow cytometer (Coulter Corporation, Miami, FL).
All subjects underwent to dual-energy x-ray absorptiometry (DEXA) scans (QDR 4500 Delphi system; Hologic, Bedford, MA) in the anteroposterior lumbar spine (L1-L4) and left hip sites to evaluate mean bone mineral density (BMD) and total mean t-score and z-score. All DEXA scans were performed at the same radiologic center by a single radiologist. The diagnosis of osteopenia and/or osteoporosis was based on World Health Organization (WHO) criteria.10
Comparisons between categoric groups were performed by the χ2 and Fisher exact tests. The Student t test was used for continuous variables. All P values were 2-tailed. Potential predictors of osteopenia and osteoporosis were evaluated by logistic regression analysis. Variables included were gender, age, risk factors for HIV infection, CDC stage, HCV serostatus, BMI, CD4 cell counts and HIV RNA levels on DEXA, HAART duration, and months of HIV positivity. The SAS software package, version 8.2, for Microsoft Windows was used for the analyses.
The study involved 179 HIV-infected consecutive subjects, mostly male (n = 112 [62.6%]) and heterosexual (n = 77 [43.0%]). Twenty-nine (16.2%) were classified as CDC stage C, 60 (33.5%) were HCV coinfected, and 54 (30.2%) had lipodystrophy. The median durations of HIV positivity and HAART were 102 months (interquartile range [IQR]: 52-171 months) and 41 months (IQR: 0-79 months), respectively. Ninety-six subjects (53.6%) had pathologic findings on DEXA, 77 (43.0%) had osteopenia, and 19 (10.6%) had osteoporosis: 17 in G1, 26 in G2, 26 in G3, and 27 in G4. Independent predictors of osteopenia and/or osteoporosis were older age (odds ratio [OR]: 1.11, 95% confidence interval [CI]: 1.03 to 1.20, P < 0.01 for each additional year), low BMI (OR = 0.82, 95% CI: 0.72 to 0.94, P < 0.01 for each additional unit), high HIV RNA levels (OR = 1.97, 95% CI: 1.26 to 3.08, P < 0.01 for each additional log10 copies/mL), and HAART duration (OR = 4.52, 95% CI: 1.21 to 16.86, P = 0.02 for G2 vs. G1; OR = 4.56, 95% CI: 1.13 to 18.35, P = 0.03 for G3 vs. G1; and OR = 2.90, 95% CI: 0.84 to 10.03, P = 0.09 for G4 vs. G1). Figure 1 shows the cases of osteopenia and/or osteoporosis according to HAART duration (based on the 4 groups considered) and HIV RNA levels.
Osteopenia and osteoporosis are frequent findings in HIV-infected subjects. Their pathogenesis is not completely understood. Similar to lipodystrophy, they were initially attributed to PI-based HAART, but further reports did not confirm this relation. A report of Tebas et al3 demonstrated that subjects receiving PI-containing HAART had a higher risk of osteopenia and/or osteoporosis, but antiretroviral-naive patients were not included in this study. In a more recent study, Bruera et al7 found osteopenia and/or osteoporosis in antiretroviral-naive and HAART patients, and both of these groups had a lower BMD compared with healthy controls. In this report, however, the role and duration of previous antiretroviral regimens were not assessed and the groups were not well balanced for age and BMI. In our study, we included subjects aged 30 to 50 years, excluding all those with clinical conditions possibly related to alterations of bone metabolism to avoid possible confounding factors. We did not include healthy controls because other reports have demonstrated the higher risk of osteopenia and/or osteoporosis in HIV-infected subjects compared with seronegative subjects.3,7
Almost half of our population had osteopenia and/or osteoporosis. Traditional risk factors, such as low BMI and older age, were also confirmed to be predictive in HIV-infected subjects. The correlation between higher HIV RNA levels and osteopenia and/or osteoporosis suggests a direct role of HIV on bone turnover cells. Further, the correlation between HAART duration >1 year and osteopenia and/or osteoporosis suggests a role of antiretroviral treatment, even if we cannot evaluate the role of individual drugs because of the high heterogeneity of regimens used; their role in the occurrence of bone alterations could be better evaluated in a prospective study.
To date, the occurrence of osteopenia and/or osteoporosis in HIV-infected subjects is of particular concern. Overall, our data suggest that this condition may be attributable to HAART and HIV infection itself.
Marco Bongiovanni, MD*
Alfonso Fausto, MD†
Paola Cicconi, MD*
Laura Menicagli, MD†
Sara Melzi, MD*
Valentina Emanuela Ligabo, MD*
Giampaolo Cornalba, MD‡
Teresa Bini, MD*
Francesco Sardanelli, MD†
Antonella d'Arminio Monforte, MD*
*Institute of Infectious Diseases and Tropical Medicine, L. Sacco Hospital University of Milan Milan, Italy, †Department of Radiology, Policlinico S. Donato, University of Milan, Milan, Italy ‡Department of Diagnostic and Interventional Radiology San Paolo Hospital University of Milan, Milan, Italy
1. Palella FJ, Delaney K, Moorman A, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med
2. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS
3. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS
4. Knobel H, Guelar A, Vallecillo G, et al. Osteopenia in HIV-infected patients: is it the disease or is it the treatment? AIDS
5. Mondy K, Yarasheski K, Powderly WG, et al. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis
6. Carr A, Miller J, Eisman J, et al. Osteopenia in HIV-infected men: association with asymptomatic lactic academia and lower weight pre- antiretroviral therapy. AIDS
7. Bruera D, Luna N, David DO, et al. Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy. AIDS
8. Konishi M, Takahashi K, Yoshimoto E, et al. Association between osteopenia/osteoporosis and the serum RANKL in HIV-infected patients. AIDS
9. Huang CJ, Muller F, Aukrust P, et al. Subnormal serum concentration of 1.25 dihydroxyvitamin D3 in HIV infection: correlation with degree of immunodeficiency and survival. J Infect Dis
10. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a WHO study group. World Health Organ Tech Rep Ser