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TZDs and fractures: What guidance do studies provide?
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The results of clinical trials, meta-analyses, observational studies and a recent prospective study reinforce concerns about an increased risk for fractures associated with the use of thiazolidinediones in patients with diabetes.
In the most recent study, Dormuth et al conducted a large population-based, prospective cohort study of 84,339 people with type 2 diabetes in British Columbia, Canada, who started treatment with either a TZD or a sulfonylurea. The researchers accessed a large prescription database, Pharmanet, and a source population of 42 million to extract data. They examined the occurrence of peripheral fractures and fractures of any kind in patients exposed to TZDs compared with sulfonylureas. The HR was 1.28 for the TZD group compared with those exposed to a sulfonylurea — a 28% higher incidence.
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A separate analysis conducted to compare pioglitazone (Actos, Takeda) with rosiglitazone (Avandia, GlaxoSmithKline) revealed an increased HR of 1.77 in women assigned pioglitazone but no increase with rosiglitazone. There was no significant difference in men between the TZDs as a class and sulfonylureas; however, a subgroup analysis showed a HR of 1.61 with pioglitazone compared with rosiglitazone. This finding was similar to the finding of the ADOPT trial, which did not indicate an increased risk in men assigned rosiglitazone and a meta-analysis that showed men did not have a change of fracture risk with TZDs as a class.
It is difficult to conclude definitively that one TZD had a higher risk than another in the study by Dormuth and colleagues, given an overlap in the confidence interval for the subgroup analyses. The average time in patient-years for any fracture was 1.71 for a sulfonylurea, 1.66 for rosiglitazone and 1.44 for pioglitazone. The researchers concluded that treatment with a TZD compared with a sulfonylurea was associated with an increased risk for fracture.
Loke et al conducted a meta-analysis of 10 randomized controlled trials of 13,715 patients and two observational studies of 31,679 patients with impaired glucose tolerance and type 2 diabetes. The researchers compared patients assigned a TZD with those who were not. The OR for TZDs was increased (OR=1.45; 95% CI, 1.18-1.79) for overall risk for fracture compared with controls. Pooled data from five randomized controlled trials showed that women had an increased OR of 2.23 (95% CI, 1.65-3.01) with TZDs compared with controls; however, men had no increased risk. The researchers reported a consistent decrease in bone mineral density with TZDs in four trials (two randomized controlled trials, two observational). Using single-pooled RR, the researchers found variability in the one-year number needed to harm (NNH) based on the population: NNH of 21 for older women (mean age, 72 years) not assigned insulin, NNH of 31 for older women (mean age, 65 years in the WHI observational study) and NNH of 55 for women in the metformin arm of the ADOPT study (mean age, 56 years — no previous oral agents).
Meier et al conducted a nested case-control study (1,020 patients with fracture vs. 3,728 patients without fracture) using data extracted from the U.K. General Practice Research Database of patients aged 30 to 79 years with a fracture diagnosis. The OR for patients using eight or more prescriptions of TZDs over 12 to 18 months was 2.43 (95% CI, 1.49-3.95) compared with non-TZD users. Both TZDs were used more frequently by the fracture group than by patients in the control group (OR=2.38 for rosiglitazone and OR=2.59 for pioglitazone). This increased risk for men and women was observed for hip and nonvertebral fractures only because numbers of vertebral and rib fractures were too low for a meaningful analysis.
The results of a few preclinical and clinical studies have indicated that the TZDs may reduce osteoblastic activity and accelerate bone loss, resulting in reduced BMD. However, the evidence is not entirely clear. The researchers from one study of 66 postmenopausal women with type 2 diabetes for at least two years found higher BMD with DXA scans at the femoral level compared with a control population but higher levels of certain bone resorption markers. Researchers from another study compared femoral neck and lumbar spine BMD in patients with and without type 2 diabetes. Patients with type 2 diabetes had a higher BMD but increased nonvertebral fracture risk (HR=1.33; 95% CI, 1-1.77). A subgroup analysis showed that only treated patients with type 2 diabetes exhibited the higher risk.
The researchers offered two explanations for the increased fracture risk, one related to increased complications in long-standing diabetes and the other related to glycation of collagen in bone with a resultant decrease in bone strength. Other researchers have theorized that insulin’s anabolic effect on bone formation occurs through binding to the osteoblastic insulin-like growth factor I receptor, resulting in reduced fracture risk.
Until the findings of randomized controlled trials can answer the question of causality, clinicians are encouraged to ensure that patients with type 2 diabetes who are prescribed a TZD be counseled on both the potential for this class of medications to increase their fracture risk and the methods of preventing bone loss through dietary and other approaches.
June Felice Johnson, BS, PharmD, is Associate Professor and Chair of the Department of Clinical Sciences at Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa.
For more information:
- de Liefde II. Osteoporos Int. 2005;16:1713-1720.
- Dormuth CR. Arch Intern Med. 2009;169:1395-1402.
- Isaia GC. Acta Diabetol. 1999;36:35-38.
- Kahn SE. Diabetes Care. 2008;31:845-851.
- Loke YK. CMAJ. 2009;180:32-39.
- Meier C. Arch Intern Med. 2008;168:820-825.
Fragility fractures in patients with type 2 diabetes pose an as yet unresolved problem with respect to both the incidence and causality of fragility fractures and this article underscores the issues. It is well established that, as a group, patients with type 2 diabetes sustain fragility fractures at bone mineral density and T-score values that are statistically significantly higher than matched groups without diabetes. Furthermore, fragility fractures in patients with type 2 diabetes often occur at skeletal sites such as foot and ankle while osteoporosis-related fractures at these sites are uncommon in postmenopausal osteoporosis. A satisfactory explanation for these differences is not yet forthcoming. It is possible that some of the oral therapies for management of type 2 diabetes such as TZDs may play a role but, as this article points out, that is far from established.
What remains unresolved is what might be done to minimize bone loss and fractures in type 2 diabetes. The simple approach would be to provide a bisphosphonate as prophylaxis is patients with type 2 diabetes but I have no idea how and when one might start this since the mechanisms remain unknown as does the DXA T-score at which intervention is indicated. One approach to consider would be to obtain a baseline level of a marker of bone resorption and a marker of bone formation and monitor for changes at six-month intervals. A significant change in bone remodeling over time may be a guide to initiate prophylaxis. To my knowledge, there is no literature to support this suggestion but, as pointed out by Dr. Johnson, TZDs do have an effect on these markers.
– Michael Kleerekoper, MD
Endocrine Today Editorial Board member