To our knowledge this is the largest and most comprehensive study to evaluate the associations of baseline serum leptin and adiponectin with rates of BMD change. In women, higher adiponectin levels predicted greater hip aBMD loss independent of age, race, BMI, diabetes, baseline BMD, and weight change. The effect of leptin on hip aBMD loss in women was largely explained by weight change. Among men, neither leptin nor adiponectin were associated with rates of hip aBMD change. Leptin and adiponectin levels were not associated with whole body aBMD or trabecular lumbar spine vBMD change.
Higher adiponectin levels were associated with greater hip aBMD loss in women, but not men. There have been several cross-sectional studies that have reported that adiponectin is inversely associated with BMD.27,28,33
. Three prospective studies found an inverse association between adiponectin and BMD.15,29,30
The study in Estonia reported that higher adiponectin was associated with higher lumbar spine aBMD loss.15
However, their study did not control for measures of adiposity. The Swedish longitudinal study reported that higher adiponectin (measured on average 12 years before BMD) was associated with lower aBMD of lumbar spine, proximal femur, and whole body in older men and women.29
However, this study did not adjust for BMI or body composition measures and failed to assess longitudinal change in BMD over time. Finally the Rancho Bernardo Study found that an inverse association between adiponectin (measured on average 4 years before BMD) and femoral neck, total hip, and radial aBMD in women and men.16
However, adiponectin was not associated with bone change in the Rancho Bernardo Study at any of these sites in men or women.
A recent study showed that recombinant adiponectin induced RANKL and inhibited OPG mRNA expression in human osteoblasts in a dose and time dependent manner leading to osteoclast formation.24
The observation that the rate of bone loss was higher with greater levels of adiponectin may reflect greater osteoclast activation and bone resorption. Population based longitudinal studies evaluating the association of adiponectin and markers of bone turnover are needed.
We found no association between leptin and changes in hip, whole body, and trabecular lumbar spine BMD. After adjusting for weight change, the association between leptin and hip aBMD change was no longer significant in women. Also, the association between leptin and whole body aBMD (in women) change was confounded by site, NSAID use, lean mass, and baseline whole body aBMD. In men, the association of leptin with hip and whole body aBMD change was largely explained by BMI. Prior cross-sectional reports have shown that leptin is positively associated with BMD11,13,33–35
. Few studies have assessed the association between leptin and BMD longitudinally.15,16
The twelve month prospective study in Estonia among 35 women mean age 69.7 years, reported that higher leptin was correlated with lower loss of whole body aBMD.15
However, this study did not adjust for measures of adiposity. The Rancho Bernardo Study found that leptin (measured on average 4 years before the BMD measurement) predicted higher femoral neck, total hip, lumbar spine, and radial aBMD in women but not men. However, consistent with our findings, they failed to find an association between leptin and hip aBMD change over 4 years.
We previously reported a roughly two-fold risk in incident fractures among men in the top tertile for adiponectin.36
Thus, it is unclear why the association of adiponectin with hip aBMD change was confined to women. The annual rate of hip aBMD loss in men was approximately 0.15 percentage points higher in the top quartile of adiponectin compared to the medium and low tertiles; however there was no statistical trend or difference by groups. Adiponectin was 40% higher in women compared to men, despite greater body fat in women. However, it is uncertain if sex differences in adiponectin account for these differential associations. Consistent with our findings, a previous study in mice showed that there was a stronger inverse correlation for adiponectin and bone mass in female mice compared to male mice.37
The association between adiponectin and bone may be influenced by sex hormones.30
Future prospective studies that control for sex hormones are needed.
Strengths of this study include a large sample size, reliable ascertainment of exposures and outcomes, adjustment for many potential confounders, long follow-up period, and multiple time points for assessment of hip and whole body aBMD data. Nevertheless, our study has several limitations. We measured leptin and adiponectin at baseline only and could not account for changes in over time. Also, trabecular lumbar spine vBMD was only measured in the Pittsburgh cohort and at two time points; thus power is potentially an issue in this particular analysis. In addition, survival bias may impact our findings because healthier individuals with higher baseline BMD are more likely to have to have a repeat BMD measurement.38
However, there were no significant differences in baseline leptin or adiponectin among participants who died or remained alive, and among those that did or did not return for a follow-up. Finally, we adjusted for many covariates, but lacked sufficient data to adjust for insulin (a hormone associated with leptin and adiponectin) and bone markers (i.e., osteocalcin, PINP, or CTX) which are related to BMD and body weight.
In summary, in a large cohort of older adults, higher adiponectin was associated with greater annual hip aBMD loss in women only; supporting evidence that adiponectin may have an important role in bone health. Identification of potential mediators in the causal pathway may better explain these findings.