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Editorial |
University of Cincinnati College of Medicine Department of Internal Medicine Division of Endocrinology Cincinnati, Ohio 45219
Address all correspondence and requests for reprints to: Nelson B. Watts, M.D., University of Cincinnati Bone Health and Osteoporosis Center, 222 Piedmont Avenue, Suite 4300, Cincinnati, Ohio 45219. E-mail: nelson.watts{at}uc.edu.
"... Any reduction of bone mass in diabetics that is revealed by sophisticated analysis is of no medical or economic importance... Further extensive studies of bone metabolism in diabetics are unlikely to yield results of practical importance... " (1).
Despite this pronouncement from 1980, there have been further studies and they do have practical importance. It now seems clear that patients with type 1 diabetes have increased risk of fracture compared with people without diabetes, due in large part to reduced bone mineral density (BMD). Patients with type 2 diabetes appear to have increased BMD, possibly due in part to an anabolic effect of hyperinsulinemia and in part because of obesity. Obesity may also be associated with reduced fracture risk by providing some cushioning in the event of a fall. In addition, patients with type 2 diabetes have reduced bone turnover and may have reduced levels of PTH. All this should protect patients with type 2 diabetes from fracture. However, counter-forces are also at work. Bone loss appears to be more rapid in patients with type 2 diabetes (2). Insulin resistance might counter the beneficial effects of hyperinsulinemia. Hyperglycemia may cause hypercalciuria, hypomagnesemia, and lower levels of 25-hydroxyvitamin D that could have negative effects on bone. IGF-I, which is anabolic for bone, may be reduced. Advanced glycosylation products might adversely affect bone collagen. Microangiopathy and inflammation could have negative effects on bone. Renal disease in diabetes potentially reduces bone strength. Visual impairment, foot problems, cognitive dysfunction, peripheral neuropathy, and hypoglycemia in patients with type 2 diabetes increase the risk of falling and injury. So how does all this add up?
The study of Dobnig et al. (3) in this issue suggests that, on balance, these effects are neutral, at least as assessed in men and women above the age of 70 residing in nursing homes in Austria. This was a well-done study carried out by mobile teams that visited 95 nursing home sites, assessed peripheral bone density (by ultrasound), biochemical parameters of mineral metabolism, and bone turnover markers, and prospectively collected data on hip and other nonvertebral fractures over 2 yr. Compared with control subjects, despite increased ultrasound stiffness at the heel, radius, and phalanges and decreased levels of parathyroid hormone and osteocalcin, patients with type 2 diabetes had no difference in fracture rates compared with control subjects.
Unfortunately, this doesn’t fully resolve the question. Nursing home patients might not be the best control group, as their risk of fracture is high. Several other (and larger) studies have been done in community-dwelling subjects. Most have shown an increased risk of hip (4, 5, 6, 7, 8, 9, 10), proximal humerus (6, 7, 11), forearm (9), foot (6, 12), and ankle fractures (1, 6, 7, 12) as well as all nonvertebral fractures combined (6, 9, 13, 14) in patients with type 2 diabetes. It is particularly instructive to look at publications from the Study of Osteoporotic Fractures. The initial studies showed a numerically higher risk of fracture in patients with type 2 diabetes that was not statistically significant (15), but, as the study went on and more fractures occurred, the difference became statistically significant (6, 10).
Failure to see a relationship between type 2 diabetes and fracture may be due to the size of the study group, the duration of diabetes, therapies for diabetes, the length of follow-up, age, whether both men and women are included, whether different races are included, fracture sites considered, and adjustments made for different risk factors. It certainly seems appropriate to adjust for age, BMD, and body weight or body mass index. However, if part of the increased risk of fracture in diabetic patients is due to increased frailty and falling, adjustments should not be made for these factors. Despite the findings of Dobnig et al. (3) reported in this issue, it seems likely that the risk for hip and nonvertebral fracture is increased in patients with type 2 diabetes.
But wait, there’s more....
A second paper in this month’s issue adds a new twist to the story. Schwartz et al. (16) report data from the Health, Aging and Body Composition (Health ABC) study suggesting that treatment of diabetic women with thiazolidinediones (TZDs) is associated with an increased rate of bone loss. The Health ABC Study is a prospective evaluation of the role of body composition as a mediator of morbidity and mortality in older subjects. In this examination of the role of TZDs on BMD, the presence of diabetes was ascertained by history and fasting glucose and oral glucose tolerance testing. The use of hypoglycemic medications was gathered during interviews at annual visits, and BMD was determined serially every 2 yr. After adjusting for key factors related to BMD and diabetes, in women (but not men), use of TZDs was associated with a significant 50% increase in the annualized rate of whole-body bone loss. The potentially negative effects of TZDs on bone density in diabetic patients contrasts with a recent report suggesting that other treatments for diabetes tend to reduce the risk of fracture (8). Although the Schwartz et al. (16) study is observational, with several important limitations acknowledged by the authors, it is the largest study to date that examines the effect of TZDs on bone mass in diabetic patients. Moreover, the results are consistent with some recent studies of TZDs in animals and have important clinical implications.
TZDs are a relatively new class of oral agents that have rapidly gained wide usage, with an estimated 20 million prescriptions written in 2004. These compounds are effective and generally well-tolerated and complement other antidiabetic drugs (17). TZDs are ligands for peroxisome proliferator activated receptor-
(PPAR), a family of nuclear receptors that regulate gene transcription. PPARs are most abundant in adipocytes and regulate their differentiation and function. There is lesser expression of PPARs in pancreatic islet cells, liver, skeletal muscle, vascular endothelium, and bone. Activation of PPAR improves glucose metabolism by enhancing tissue sensitivity to insulin, primarily through actions on adipose cells. One of the mediators of enhanced insulin sensitivity is adiponectin, a hormone secreted from fat cells in response to TZDs as well as other stimuli (18). Receptors for adiponectin have been demonstrated in bone, and in vitro studies suggest that adiponectin stimulates osteoblast differentiation (19, 20), one reason to hope that TZDs would be beneficial to bone health.
There is no published information on effects of TZDs on bone density from clinical trials of the currently available compounds rosiglitazone and pioglitazone. A small study of troglitazone, the first available TZD, suggested a trend toward increased BMD in diabetic subjects treated for 1 yr (21). This study was limited in that there was no control group and variation in BMD among the treated patients was sufficient to raise questions about the overall effect. Furthermore, troglitazone has been withdrawn from the market because of hepatotoxicity. The absence of informative intervention trials on the effects of TZDs on bone health in diabetic patients leaves the observations of Schwartz et al. (16) as the most compelling information on the topic at present. Importantly, this report is supported by emerging research in animal models.
Recent studies in rodent models indicate that exposure to TZD has important effects on bone (22, 23, 24). These studies examined the effects of rosiglitazone on bone mass in mice using a variety of techniques, including histomorphometry. All showed that administration of TZD for several weeks reduced bone mass compared with controls. The common mechanism suggested in each of these studies was a shift in the flow of mesenchymal precursor cells from osteoblastic to adipogenic lineages, an effect mediated by PPAR. This effect led to reduced bone formation and loss of bone density. The concordant results among these studies make these findings credible, and the common mechanism is consistent with the known biology of PPAR. Taken together with the results reported by Schwartz et al. (16), the results raise questions about a potentially significant side effect of TZD. Given that use of these drugs is becoming more common and that their indication may expand with ongoing trials of their effects on other aspects of metabolism and vascular disease, it is important to have more information from human studies on TZD and bone. This is a question for which a randomized clinical trial is imperative.
Given the evidence that patients with type 2 diabetes are at increased risk of fracture and may have accelerated bone loss (at least those treated with TZDs), what should clinicians do? There is some evidence that antiresorptive agents are effective for increasing BMD in patients with diabetes (25), but they might not be effective for bone loss induced by TZDs, and bone-active agents are probably not effective in reducing fracture risk caused by nonskeletal risk factors such as falling. Until more is known, it is not unreasonable to consider diabetes as a risk factor for fracture; patients with type 2 diabetes are certainly not protected from fracture and deserve at least the same screening for osteoporosis that is recommended for nondiabetic subjects. Osteoporosis treatments should be prescribed for patients with type 2 diabetes at high risk of fracture due to skeletal-related risk factors.
Footnotes
Abbreviations: BMD, Bone mineral density; PPAR, peroxisome proliferator activated receptor-; TZD, thiazolidinedione.
Received June 8, 2006.
Accepted June 29, 2006.
References
insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113:846–855[CrossRef][Medline]This article has been cited by other articles:
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  O. P. Lazarenko, S. O. Rzonca, W. R. Hogue, F. L. Swain, L. J. Suva, and B. Lecka-Czernik Rosiglitazone Induces Decreases in Bone Mass and Strength that Are Reminiscent of Aged Bone Endocrinology, June 1, 2007; 148(6): 2669 - 2680. [Abstract] [Full Text] [PDF]
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 E. Al-Ozairi, L. Sibal, and P. Home Counterpoint: A Diabetes Outcome Progression Trial (ADOPT): Good for Sulfonylureas? Diabetes Care, June 1, 2007; 30(6): 1677 - 1680. [Full Text] [PDF]
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 B. J. Goldstein Clinical Translation of "A Diabetes Outcome Progression Trial": ADOPT Appropriate Combination Oral Therapies in Type 2 Diabetes J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1226 - 1228. [Full Text] [PDF]
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