Diabetes and Bones: An Underappreciated Complication

Diabetes can be weakening the skeleton despite apparently good bone mineral density scores. Fortunately, standard osteoporosis treatments appear to be just as successful in patients with diabetes.

The damage that diabetes can do to bones is a complication that many endocrinologists do not adequately appreciate, say researchers in the field. The danger is insidious because bone mineral density (BMD) scores cannot be taken at face value — diabetes patients are at much higher risk for fracture compared with healthy patients with the same BMD scores.

Guidelines for diabetes care recommend evaluating patients at least annually for long-term complications, such as heart, eye, kidney, and nerve disease, and skeletal complications should be added to that list, says Vikram V. Shanbhogue, MD, PhD, of the Endocrinology Department at Odense University Hospital in Denmark. He says that several European guidelines don’t even mention bone as a complication, and “the American Diabetes Association at least mentions bone fragility or osteoporosis as a comorbid condition in diabetes,” but the potential complication deserves a higher profile.

“I think it is important to emphasize the point that skeletal deterioration is another diabetic complication. We understand that patients who have poorly controlled diabetes are going to have worse bone quality, and that will predispose them to an increased fracture risk.” – Mishaela R. Rubin, MD, associate professor of medicine, Columbia University Medical Center, New York

The evaluation of a type 2 diabetes patient’s status is difficult because their BMD T-scores are hard to interpret — it appears that the risk point is as much as a half to a full standard deviation higher in type 2 diabetes, Shanbhogue says. So, a woman wit diabetes who has a T-score of -1.5 could have the same risk as a nondiabetic woman of the same age with a T-score of -2.5. “At -1.5, you would probably say it appears fine, but the patient still has an increased fracture risk,” he says.

Anne V. Schwartz, PhD, MPH, of the University of California, San Francisco, School of Medicine, estimates that although “a nondiabetic woman with a T-score of -2.5 would be at a clinical threshold where you’d start considering pharmacological treatment, [perhaps we] should start thinking about this at a -1.9 or -2 threshold for a diabetic woman.”

Evidence of Weakness
The source of this apparent bone weakness is not known for certain, but researchers are finding important differences between the bones of diabetes patients and people without diabetes. High-resolution peripheral quantitative computed tomography has shown “subtle differences in microscopic architecture [of the cortical bone] in diabetic patients,” according to Mishaela R. Rubin, MD, associate professor of medicine at Columbia University Medical Center, New York. The tests show that there is an increase in the volume of the pores in the cortical compartment.

“This increase in porosity could actually weaken the bone, rendering it to be easily fractured,” says Shanbhogue. “And the porosity is not picked up by our routine dual energy X-ray absorptiometry measurements.”

Another technique called reference point indentation tests the material quality of bone by measuring how far a tiny needle penetrates into the tibia. Deeper penetration reflects weaker bone quality, this time of the collagenous part of the skeleton. Rubin says that studies found a noticeable difference in this “organic matrix part of the bone,” with bone quality significantly lower in diabetic patients than in healthy people with similar BMD scores.

A Familiar Culprit?
The possible culprit in the decrease in bone quality could be a familiar one — the accumulation of advanced glycation end-products (AGEs) that underlies many complications, such as retinopathy and peripheral neuropathy. Rubin and her colleagues wondered whether the increase in glycation in diabetes patients with the “proteins in the collagen becoming encrusted in sugar” could be related to the lower strength of the bones. “We used a skin test to see what the accumulation of these sugar glycation products was in the skin. We found that the more they were present in skin, the weaker the bone material quality was in the diabetic patients. But in the healthy patients, that relationship didn’t exist at all,” Rubin says.

How to Treat?
Another bone-related difference in diabetic patients is a slowing in the bone remodeling cycle — which raises the question of whether treatments for osteoporosis, particularly anti-resorptive drugs that suppress bone turnover, are effective in diabetes patients. Schwartz recently published a review of clinical trials and observational studies of the effects of anti-resorptive and anabolic therapies in diabetes patients. “Post hoc analyses of randomized trials indicate that raloxifene has similar efficacy for prevention of vertebral fractures in diabetic compared with non-diabetic patients,” she says. “Evidence from randomized clinical trials is lacking for anti-fracture efficacy of other osteoporosis therapies in diabetes. However, observational studies suggest that bisphosphonates are effective in preventing fractures in diabetic patients.”

In a separate analysis, “we found similar anti-fracture efficacy in diabetics and nondiabetics in trials of alendronate and zoledronic acid,” Schwartz says. She adds the caveat that there is only evidence for the use of drugs in type 2 patients, with virtually no data on type 1 patients. And the drugs have not been tested for efficacy in patients with better T-scores.

Whom to Treat?
But the issues of which patients to treat and when to begin treatment are open questions with no clear answers. Schwartz believes that question is ripe for a new guideline, and that a literature review could produce enough evidence, if only at the expert opinion level.

Shanbhogue says: “Treatment has to be individualized and probably has to be multifactorial, and include more than just T-scores and the usual considerations for osteoporosis.”

He believes that when a patient begins to have other complications, a clinician should be aware that bone problems could be starting as well: “For example, detecting eye disease is physically very easy, so if a patient has eye disease, I think that you should go ahead and at least screen for bone disease. We have studied patients with type 1 diabetes, and it seems that in these patients, in the absence of the regular long-standing complications of diabetes such as eye, kidney, or nerve disease, their bone structure appears to be normal. But if they have a manifest complication, such as eye disease or the others, then it appears that they have compromises in bone structure. We are following up these patients to see if this compromised structure would actually lead to increased fractures.”

“The people with type 2 who have higher fracture risk are those with longer duration of diabetes — those with complications and those on insulin therapy.” – Anne V. Schwartz, PhD, MPH, University of California, San Francisco, School of Medicine

Schwartz says: “The people with type 2 who have higher fracture risk are those with longer duration of diabetes — those with complications and those on insulin therapy.” Insulin is anabolic for bones, so is not likely to be implicated in weakening them, but insulin therapy is a marker for longer duration of the condition and more complications.

Because many type 2 patients are overweight or obese — and thus may have acceptable-appearing bone mineral density scores — clinicians should not be lulled into a false sense of security.

“I think it is important to emphasize the point that skeletal deterioration is another diabetic complication,” Rubin says. “We know that these advanced glycation end-products accumulate in other tissues and can harm them. It is possible that the same thing is happening in the skeleton. We understand that patients who have poorly controlled diabetes are going to have worse bone quality, and that will predispose them to an increased fracture risk.”

— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the Endocrine Society’s new Clinical Practice Guideline on treating primary aldosteronism in the September issue.


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