Thiazolidinediones for Bone Health" src="https://www.diabeticlive.com/wp-content/uploads/2011/08/Evidence-Mounts-Against-Thiazolidinediones-for-Bone-Health.gif" alt="Evidence Mounts Against Thiazolidinediones for Bone Health” width=”300″ height=”293″ />Thiazolidinediones are suspected to have an adverse effect on bone density and to increase the risk of bone fracture in patients with diabetes. However, there have been no randomized studies showing that antiresorptive drugs would protect bone health in these settings.
According to Dr. Jonathan Graf, speaking at an osteoporosis conference sponsored by the University of California, resorptive drugs such as bisphosphonates, denosumab, and parathyroid hormone have not been tested in humans for efficacy in reducing risk of bone fracture in diabetics who are taking thiazolidinediones. However, randomized studies conducted on mice have suggested that adding a bisphosphonate would contribute to bone health.
The current recommendation of physicians is to avoid using thiazolidinedione to treat diabetes in patients who are at a high risk for bone fracture. However, such risk may be reduced by prescribing lower doses. There are at least two thiazolidinediones (rosiglitazone and pioglitazone) which are available in lower doses. When prescribed in combination with metformin, the drugs provide a similar level of diabetes control as a high dose of glitazone, said Dr. Graf.
Some preliminary data has also suggested that lower doses of thiazolidinediones combined with incretin drugs could control diabetes while having fewer adverse effects on bone health. Evidence has even suggested that incretins may promote bone growth.
“There is not a lot of evidence out there to steer you one way or the other,” said Dr. Graf, but it is becoming impossible to ignore the adverse effect that thiazolidinediones have on bone health.
The prospective cohort study of 84,339 diabetic men and women revealed that risk of bone fracture was 28% higher in individuals taking thiazolidinediones than in those taking sulfonylureas. The risk also increased with cumulative exposure to thiazolidinediones. Meanwhile, pioglitazone increased risk of bone fracture in men but rosiglitazone did not.
Another cohort study of 20,964 diabetics over 65 on Medicare found that both men and women on thiazolidinedione monotherapy showed a higher risk of peripheral fractures than those treated with sulfonylureas or metformin.
The fracture risk appears to be higher in men than in women, according to previous trials. A meta-analysis of 10 trials and 2 observational studies across 45,484 total diabetics showed that women taking thiazolidinediones doubled their risk of bone fracture but men did not, compared to control groups.
An observational study found that thiazolidinedione therapy and its duration were shown to be associated with significant increases in risk of nonvertebral bone fractures in older patients. The patients showed a fourfold increase in risk of femur and hip fracture, three times the risk of forearm fracture and twice the risk of humerus fracture.
A randomized, double-blind study of around 3,600 patients, called A Diabetes Outcome Progression Trial (ADOPT), found that the four-year fracture rate of rosiglitazone doubled in women, both pre- and postmenopausal. However, that risk did not increase in men. The study found that the fracture rate was 15% for patients on risiglitazone, 8% for those on glyburide, and 7% for those on metformin. Additionally, three separate studies showed increased loss of bone density in women only weeks after they began treatment with thiazolidinediones. The effects were especially pronounced in postmenopausal women.
Tiazolidinediones likely cause increased risk of fracture by decreasing insulin-like growth factor 1 expression (which has the side effect of decreasing bone growth), by decreasing osteoblastogenesis and by promoting osteoblast differentiation.
“Just like glucocorticoids, they have several mechanisms that affect bone,” said Dr. Graf.