Based on WHO criteria, osteopenia was diagnosed in 264 patients (53.7%), 54.6% among men [95% confidence interval (CI), 49.4–59.7) and 51.1% among women (95% CI, 42.6–59.6). Osteopenia was diagnosed in 50.0% (95% CI, 40.0–60.0) and 54.8% (95% CI, 37.5–72.5) of premenopausal and menopausal women, respectively. Osteoporosis was diagnosed in 132 patients (26.8%), 33.7% among men (95% CI, 28.8–38.6) and 8.3% among women (95% CI, 3.6–13.0). Osteoporosis was diagnosed in 3.9% (95% CI, 0.2–7.8) and 22.6% (95% CI, 7.9–37.3) of premenopausal and menopausal women, respectively. Table 3 shows the distribution of median BMD according to gender, site and patients' diagnostic category. Osteoporosis predominated at the femoral neck for men (median BMD, 0.66 g/cm2) and for women (median BMD, 0.59 g/cm2).
Correlates of low bone density
Among men, the following factors significantly associated with the diagnosis of bone mass loss in the univariable model were included in the multivariable analysis: age, follow-up time since HIV diagnosis, transmission group, AIDS clinical stage, HIV plasma viral load < 500 copies/ml, log-based plasma viral load, tobacco consumption, physical activity, cumulative exposure to antiretroviral drug class, BMI < 20.6 kg/m2 and lipodystrophy. Independent factors associated with the diagnosis of osteoporosis were older age, homosexual HIV transmission, low BMI and HIV plasma viral load < 500 copies/ml (Table 4). Only older age and lower BMI were marginally associated with osteopenia (Table 4). In women, all bone disorders were pooled without distinction between osteopenia and osteoporosis because of the lower number of observations in each subgroup. Factors analysed in the multivariable model were menopausal status, age, follow-up time since HIV diagnosis, transmission group, AIDS clinical stage, HIV plasma viral load < 500 copies/ml, log-based plasma viral load zenith, CD4 lymphocyte count nadir, alcohol consumption, calcium intake > 1 g/day, physical activity, cumulative exposure to antiretroviral drug class and lipodystrophy. Older age [odds ratio (OR), 1.69; 95% CI, 1.10–2.60; P = 0.02] and low CD4 cell count nadir (OR, 1.43; 95% CI, 1.10–1.85; P = 0.008) were identified as factors associated with reduced BMD. To explore further whether the association between low HIV plasma RNA and osteoporosis in men was related to antiretroviral exposure, the effect of cumulative exposure to HAART was analysed without adjustment for HIV plasma RNA. Three different multivariable models were developed but in none was the treatment variable effect significant: cumulative exposure to any antiretroviral drug (OR, 1.01; 95% CI, 1.00–1.02; P = 0.07), cumulative exposure to HAART (OR, 1.02; 95% CI, 0.95–1.10; P = 0.58), and naive versus drug experienced status (OR, 0.28; 95% CI, 0.06–1.31; P = 0.11). Furthermore, this analysis was carried out for each drug class, again without being significant: cumulated NRTI (OR, 1.01; 95% CI, 1.00–1.02; P = 0.06), cumulated NNRTI (OR, 1.01; 95% CI, 1.00–1.03, P = 0.43) and cumulated PI (OR, 1.01; 95% CI, 1.00–1.03; P = 0.09).
This cross-sectional survey within the Aquitaine cohort of HIV-infected patients was conducted to estimate the prevalence of BMD disorders and to investigate associated factors. Among the 492 patients, representative of the Aquitaine cohort, who were recruited, the percentage of bone abnormalities was 80.5%, with 53.7% osteopenia and 26.8% osteoporosis. Osteoporosis prevalence was high in spite of the young age of the population and reflected well the early demineralization problem faced by HIV-infected patients. This frequency is higher than that reported in other studies, which had prevalence rates ranging from 0% to 22% [11,13,18,22–31], with narrow boundaries.
Another interesting finding of this osteodensitometry-based survey is the site of bone demineralization. For men, there is preferentially cortical anatomic osteoporosis, whereas for women, there are trabecular abnormalities. Apart from HIV disease, male osteoporosis in normal populations has a cortical predominance, especially in secondary osteoporosis, whereas for women, the postmenopausal osteoporosis is classically trabecular, first involving the spine. The few studies that have described BMD abnormalities according to the anatomic site have been inconclusive [4,17,24].
The main strength of our study is the relatively large number of patients included and the number of pathological fractures (10.2%). No publication provides such an estimate and we could only identified some individual case reports . The potential impact of BMD reduction on fracture risk remains unclear for HIV-infected patients. This may be because the majority are young, have few visual or balance problems and are not prone to falls. As the HIV-infected population gets older, clinicians may see an increase in the fracture rate.
The main limitation in the interpretation of our report is the absence of French references for the T-score for men. This could explain the surprising high male prevalence of BMD disorders detected in our group. There is a French reference of BMD values for women, but an American database had to be used for males in the three anatomic sites. Consequently, we may have overestimated the frequency of male osteoporotic events, because Americans have a diet that is richer in vitamin D than the French and so have a higher bone mineralization peak. By using an American reference, we are perhaps overinterpreting the BMD results from the whole body and the femoral neck. For males, we have compared the T-scores obtained for the spine here based on data in American databases with the T-scores that we would have obtained using French databases, in order to see if the use of a non-French reference database was important, and found no statistical significance between the two sets of T-scores (data not shown). The gender stratification, imposed by the difference in reference frame between men and women, led to a loss in statistical power of the study as it generated two weaker samples statistically. This element partly explains the low number of associated factors highlighted in multivariate analysis.
Among the factors found to be associated with BMD, some were expected, such as older age or lower BMI, but others are described for the first time, such as homosexual HIV transmission group, low HIV plasma RNA and low CD4 cell count nadir. The link with homosexual transmission group could indicate that this is a proxy for the abuse of substances that might be toxic for bone metabolism or coinfection, such as human herpes virus 8 and Kaposi disease. Our finding of higher risk of BMD disorder with low plasma viral load does not agree with some previously published reports [15,18], which hypothesized a potential role of the virus itself. In our study, low plasma viral load was the consequence of successful reduction of viral replication with antiretroviral drug exposure. This indicates, indirectly, a bone harmful effect of treatment itself; however, the investigations of the effect of the antiretroviral treatment, unadjusted for the plasma viral load, did not show a significant difference. Therefore, an effect on bone of antiretroviral drugs does not explain why a plasma viral load < 500 copies/ml arose as a risk factor for the osteoporotic men.
The potential effect of CD4 cell count nadir has been studied previously among HIV-positive women and was not recognized as a factor associated with weakening osteopathies . Such a linkage in our study is an original finding. CD4 cell count nadir is directly linked to the severity and length of immunosuppression. This suppression will lead to immunological disorders and an increase in proinflammatory cytokines, inducing modifications of bone tissue metabolism at the beginning of an early demineralization. Another possible explanation of the effect of the CD4 cell nadir observed is that patients with a low CD4 cell nadir are those who have been treated for a longer period with antiretroviral drugs. This would also indirectly support a negative role for antiretroviral drugs on bone metabolism.
The cumulated exposure to PI drugs was significantly associated with bone abnormalities in univariate analysis, as seen by Nolan et al. and Moore et al., but this factor was not significant in the multivariate model. Finally, neither lipodystrophy nor reduced physical activity was associated with early demineralization.
In consideration of the high frequency of diagnosed osteoporosis, it would be useful to propose osteodensitometry for HIV-infected patients in a targeted way: that is for patients with both the traditional risk factors of osteoporosis and the specific risk factors of HIV infection highlighted in this study. Moreover, our analysis indicates a cortical prevalence of bone demineralization, especially for men; consequently, particularly vigilant is suggested for this risk, in particular for femoral neck fractures.
Ongoing studies will provide better knowledge of the physiopathological mechanisms at the initiation of early demineralization among HIV-infected patients, thus allowing better diagnostic, preventive and therapeutic evaluation to support care for this chronic infection in the coming years.
Composition of the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine. C. Cazanave, M. Dupon, V. Lavignolle-Aurillac, N. Barthe, S. Lawson-Ayayi, H. Dutronc, N. Mehsen, T. Schaeverbeke, P. Mercie. P. Morlat, J.L. Pellegrin, R. Thiébaut and F. Dabis (TISSOS Study Group); F. Dabis (Coordinator); G. Chêne, F. Dabis, S. Lawson-Ayayi, C. Lewden, R. Thiébaut (epidemiology and methodology); M. Bonarek, F. Bonnal, F. Bonnet, N. Bernard, O. Caubet, L. Caunègre, J. Ceccaldi, C. De La Taille, S. de Witte, M. Dupon, H. Dutronc, S. Farbos, T. Galpérine, K. Lacombe, D. Lacoste, S. Lafarie, P. Loste, D. Malvy, P. Mercié, P. Morlat, D. Neau, A. Ochoa, J.L. Pellegrin, J.M. Ragnaud, S. Tchamgoué, J.F. Viallard (infectious diseases and internal medicine); P. Blanco, J.F. Moreau (immunology); H. Fleury, M.E. Lafon, B. Masquelier, I. Pellegrin (virology); D. Breilh (pharmacology); G. Miremont-Salamé (pharmacovigilance); E. Balestre, M.J. Blaizeau, M. Decoin, S. Delveaux, S. Geffard, C. Hannapier, S. Labarrère, V. Lavignolle-Aurillac, B. Uwamaliya-Nziyumvira (data collection and data management); G. Palmer, D. Touchard (data processing).
Note: Preliminary results have been presented in part at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, July 2005 [abstract TuPe2.2B19] and at the Thirteenth Conference on Retroviruses and Opportunistic Infections. Denver, February 2006 [abstract 229].
This study was supported by a grant from Ensemble contre le SIDA/SIDACTION (15th call for proposals). The Aquitaine cohort is supported by a multiyear grant of the French Agency for Research on AIDS and viral Hepatitis (ANRS).
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
bone mineral density; HIV; osteopenia; osteoporosis