Michael Kleerekoper, MD, MACE, has joined the faculty at the University of Toledo Medical School where he is Professor in the Department of Internal Medicine and section chief of the Endocrinology Division. The author of numerous journal studies, Dr. Kleerekoper serves on the editorial boards for Endocrine Today, Endocrine Practice, Journal of Clinical Densitometry, Journal of Women's Health, Osteoporosis International and Calcified Tissue International. Dr. Kleerekoper is also a founding board member of the newly formed Academy of Women’s Health.

Type 2 diabetes and minimal trauma fractures

When I think of minimal trauma fractures — fractures occurring after a fall from a standing height or lesser trauma — I think of osteoporosis, both primary and secondary. When it comes to fractures in patients with type 2 diabetes I don’t know what to think, yet I am encountering this in the clinic with increasing regularity. I spent several hours on the web trying to find out more but aside from confirming the epidemiology, the prediction, etiology and management remains unclear.

What is clear is that patients with type 2 diabetes have a higher bone mineral density than age-, sex- and ethnicity-matched patients without diabetes, even when a higher BMI is taken into consideration; those who sustain a minimal trauma fracture do so with a higher average BMD at all measurement sites than patients without diabetes who sustain similar fractures; fractures occur at the common sites of osteoporosis-related fractures — spine, hip, wrist and ribs; fractures are more common at unusual sites such as the foot and ankle; and therapy with thiazolidinediones (TZDs) is an apparent additional risk factor for fracture but we cannot, to my knowledge, risk stratify our patients on TZDs.

Some other associations are obvious. If your patient has episodes of hypoglycemia it should be no surprise that any sudden and uncontrolled fall may result in fracture; similarly with a misstep in patients with peripheral neuropathy or patients who have gait disturbance after a stroke. Preventive measures in these circumstances are straightforward, minimize the likelihood of hypoglycemia and provide walking aids for those with neuropathy or post-stroke.

As for the rest, which is the majority of patients:

There appears to be an association between pentosidine levels and risk of fracture. Pentosidine is a biomarker for advanced glycation end products (AGEs). Several reliable assays are available for this and the higher the level of pentosidine the greater the likelihood of fracture. Basically this means the worse the glycemic control in type 2 diabetes the greater the risk for fracture — as with all other complications of type 2 diabetes.

Low levels of adiponectin and a low adiponectin to high-molecular-weight adiponectin ratio have also been linked epidemiologically to an increased risk for fracture. Adiponectin is a member of a large family of protein hormones and cytokines secreted by fat cells known collectively as adipokines. In the circulation there is both adiponectin and high-molecular-weight adiponectin, and assays are available for both. Adiponectin is an important regulator of insulin sensitivity and, seemingly paradoxically, production of adiponectin is reduced in obesity. Type 2 diabetes is characterized by low levels of adiponectin and a lower ratio of adiponectin to high-molecular-weight adiponectin. Once again, the worse the control of type 2 diabetes, the more likely are the complications including fractures.

From my reading it is unclear that either pentosidine or adiponectin are better markers of long-term control of diabetes than HbA1c but the clinical implementation of these assays is still limited and it would be no great surprise if over time they replace HbA1c or serve as adjuncts to HbA1c to help us and our patients maintain better control of their disease.

Important as all of the above might be in theory, none of it is really yet helpful in making a decision about which of our patients might be at greatest risk for fragility fracture and should be considered for prophylaxis to prevent fracture.

As already noted, BMD does not help too often. What about biochemical markers of bone turnover? The jury is still out but I am increasingly measuring them in patients who I am seeing in clinic for their diabetes, not their bones. My experience is still small but most have values within the reference interval, and the few with elevated levels have an identifiable non-diabetes related cause such as vitamin D deficiency. When the bone turnover levels are OK I cannot justify recommending anything but supplemental calcium and vitamin D, optimize glycemic control and minimize fall risk.

Then there are a few in whom the markers of resorption and/or formation are below the lower limit of the reference interval or close to it. They really trouble me because I am convinced that oversuppression of bone remodeling is not a good thing but there are no therapeutic options. Teriparatide is the only FDA-approved formation stimulation option. Good luck tying to get insurance coverage for this without first trying one of the other FDA-approved therapies for osteoporosis, which in my mind are contraindicated. In fairness, there was no statistical relationship between baseline markers and anti-fracture effectiveness in any of the clinical trials of the FDA-approved anti-resorptive therapies, but I don’t know of any specific data in patients with suppressed remodeling at baseline.

Where does this leave us? Just another reason to do our best to work with our patients about how to optimize control of their diabetes — and I didn’t need the hours of literature-searching and two pages of typing to arrive at this conclusion. But, I will close with a short list of suggested reading:

Khazai NB. Curr Opin Endocrinol Diabetes Obes. 2009;16:435-445.

Yamamoto M. Diabetes Care. 2009;32:2263-2268.

Lecka-Czernik B. Curr Opin Investig Drugs. 2009;10:1085-1090.

Petit MA. J Bone Miner Res. 2009; Jul 13.

Schwartz AV. J Clin Endocrinol Metab. 2009;94:2380-2386.

Kanazawa I. J Endocrinol. 2009;160:265-273.

Melton LJ III. J Clin Endocrinol Metab. 2008;93:4804-4809.

Melton LJ III. J Bone Miner Res. 2008;23:1334-42.