Our data suggest that among older adults with diabetes, TZD use is associated with additional bone loss in women, but not in men. The magnitude of the additional bone loss associated with a year of TZD use was -0.6% per year for whole body. Over five years, for women using TZDs continuously, the average additional bone loss would be 3%. The average whole body bone loss among diabetic women who were not using a TZD in Health ABC was -0.4% per year. TZD use appears to increase whole body bone loss by a factor of 2.5. Bone loss is a potent predictor of fracture risk, suggesting that TZD use may be associated with a measurable burden on skeletal health.
Although type 2 diabetes is associated with higher BMD, previous studies suggest that the risk of nonvertebral fractures is increased by 30-60% in older adults with diabetes (19
). In addition, fracture severity may be worse with greater BMI (22
). We have previously reported an association between type 2 diabetes and bone loss in older women (11
). The rate of bone loss appears to increase the risk of fracture independent of baseline BMD (23
) and may be of particular concern in this population that already has a higher risk of fracture.
For both whole body and spine BMD, the estimated association with TZD use was not substantially altered by adjustment for potential confounders, including weight gain. However, estimates of hip BMD loss associated with TZD use were greater in multivariable adjusted models, mainly due to adjustment for weight change. This suggests that TZD use may have opposing effects on bone loss at the hip, increasing bone loss perhaps through PPAR-γ activation but at the same time preserving bone through the effects of weight gain.
In contrast to our findings, Watanabe et al. reported no effect of troglitazone, administered for 12 months, on lumbar spine BMD Z-score in a study of 25 patients with type 2 diabetes (8
). However, this study included only 14 women and did not report results separately by gender. The results of this previous study are not inconsistent with our observation that TZD use only affected bone loss in women. It is also possible that troglitazone has a different effect than the other TZDs on bone and that our results are driven by effects of TZDs other than troglitazone. This possibility is difficult to evaluate. Given the small numbers of users for each individual TZD, we combined the three TZDs and were unable to investigate the individual effects of each TZD on bone loss.
Our study was not designed to distinguish possible mechanisms by which TZDs may impact bone metabolism. From rodent models, there is evidence that TZDs may affect bone through an increase in bone marrow adiposity and a decrease in osteoblastogenesis, resulting in reduced bone formation (4
). TZDs are known to inhibit the aromatase pathway, the main source of estrogen in postmenopausal women (10
). TZDs also decrease testosterone levels in women with polycystic ovary syndrome (PCOS) (24
). The effect of TZDs on testosterone levels in men is more controversial. Vierhapper et al. found decreased levels of testosterone after short-term treatment with pioglitazone in healthy men (26
). However, Patel et al. reported that, in non-diabetic insulin resistant subjects, pioglitazone increased testosterone levels in men and decreased levels in women without PCOS (27
Our finding of increased bone loss with TZD use in women but not in men may be the result of increased bone turnover in women, providing a greater opportunity for TZDs to influence bone mass. It is also possible that TZDs may have different effects on androgens, and thus on bone metabolism, in women and men.
Inherent limitations of DXA measurements pose difficulties in studying changes in bone density associated with TZD use. Although DXA is the standard for measuring changes in BMD, increases in body weight, a common side effect of TZD use, may cause artifactual increases in BMD. Since DXA determines BMD by comparing the bone with surrounding soft tissue, changes in fat composition with weight gain may alter BMD results. Increases in tissue thickness, resulting from weight gain, could also introduce artifactual increases in DXA measurements. However, since the weight gain in this cohort was modest, changes in tissue thickness and in fat and lean tissue composition should be minimal (28
). In addition, the increased weight and body fat associated with TZD use would tend to artificially increase the BMD measurements and artificially reduce any observed bone loss. In this case, the bone loss we observed would tend to underestimate the actual bone loss.
DXA measurements may be artificially lowered by increased bone marrow fat, the opposite effect of weight gain (29
). Little is known about bone marrow changes with TZD use in humans. In rodent models, TZD use has been reported to increase (4
), and to have no effect on (5
), bone marrow fat. We did not have measurements of marrow fat and could not assess the extent or possible impact of any changes on DXA measurement of BMD.
Our measurement of lumbar spine BMD was derived from whole body scans rather than DXA scans specific for the spine since these were not available in Health ABC. Lumbar spine BMD derived from whole body scans correlates well with site-specific lumbar spine BMD and has also been shown to predict fracture risk (30
Some misclassification of TZD use is possible since we relied on self-reported medication use at annual visits. However, such misclassification would likely be nondifferential with respect to the outcome of change in BMD and would, therefore, attenuate any real association between duration of TZD use and bone loss.
Our models adjusted for potential confounders, including higher A1C levels, longer duration of diabetes and use of other hypoglycemic medications that are associated with TZD use. However, since our study is observational, rather than a randomized treatment, it remains vulnerable to bias from unmeasured or inadequately measured confounders. These methodological issues could be overcome with a well-designed clinical trial planned specifically to examine the impact of TZD use on bone density.
In conclusion, we found that TZD use is associated with bone loss at the whole body, lumbar spine and trochanter in older women, but not men, with type 2 diabetes. Because older women with type 2 diabetes are at increased risk of fracture, further study of the impact of TZDs on bone density and fracture risk is needed.