In this analysis of data in a diverse group of 107 HIV-infected men, we found no statistically significant relationship between serum leptin levels and whole-body BMD or BMC. However, in the 33 subjects with <3
kg of appendicular fat, we found a robust inverse association between leptin and bone density that was statistically significant, despite the small number of subjects. Adjusting the model for potential confounders such as age, race, LBM, serum insulin, and total and trunk fat did not significantly change the results.
Studies in HIV-negative individuals have shown differing relationships between circulating leptin and BMD in men and women. Reports in women have consistently found a positive association between leptin and BMD [6
], while those in men have found either no association or an inverse relationship [6
]. These inconsistencies led us to speculate that the relationship between leptin and BMD may be affected by fat distribution. We analyzed the data both in our entire cohort, as well as in those with peripheral lipoatrophy as defined by <3
kg of appendicular fat. This definition of peripheral lipoatrophy was based on various studies in which participants with clinically evident lipoatrophy were found to have an average of 3
kg of appendicular fat [21
]. In an earlier study of HIV infected individuals, Madeddu et al. observed an inverse relationship between circulating leptin concentrations and whole-body BMD in both men and women [22
]. In contrast, in our study of men, we found an inverse relationship only among those with lipoatrophy defined using an objective measure (limb fat by DEXA). The reasons for these divergent results in both men with HIV infection (our study versus that of Madeddu) and seronegative men are not known. The results of the current study raise the possibility that differing relationships between leptin and BMD in men versus women in the general population may be explained by different distribution of fat in the sexes (i.e., central versus peripheral). In other words, fat distribution may modify the relationship between leptin and bone density. Indeed, one study in children found significant differences in circulating leptin concentrations depending on the distribution of body fat [12
], and an in vitro
study found differing levels of leptin mRNA in subcutaneous versus intra-abdominal fat [11
This study has a number of limitations. First, we were able to assess only whole body BMD and BMC and did not have direct regional measurements of BMD in the spine or hip. Second, it is a cross-sectional study and our findings are associative in nature. Furthermore, the data used in this study are from the early HAART era, and although antiretroviral medications were not identified as potential confounders in our analyses, we have limited information regarding the duration of medication exposure. Despite the fact that current antiretroviral regimens differ from those in this study, we believe that our findings provide insight regarding the relationship between leptin and bone density. The strengths of our study include the uniformity of gender and study measurements and the ability to objectively measure body fat distribution using whole body DEXA scans in a population with a wide range of body sizes and total and regional fat content. Lastly, the study was performed prior to the widespread use of tenofovir, thereby eliminating the confounding effects of this medication on bone density.
In summary, this study further extends our knowledge by suggesting a role for not just total fat but also fat distribution in explaining the relationship between serum leptin concentrations and bone density. We found that peripheral fat modified the relationship between bone density and leptin levels in HIV-infected men. Specifically, an inverse association between bone density and leptin levels was observed only in subjects with low amounts of peripheral fat. Further studies are required to confirm our findings and further clarify the relationship between fat distribution, bone density and circulating leptin concentrations.