Everyone seems to know someone with diabetes, or you may be diabetic yourself. More than 10 percent of adults in the US have diabetes. With more Americans becoming overweight and less active, the number of adults with diabetes is on the rise.
Diabetes mellitus is categorized into “Type 1” and “Type 2.” Fewer than 10 percent of people with diabetes have type 1, which is usually diagnosed in children and young adults when their bodies stop making insulin. They require daily insulin treatment to survive.
The majority of diabetics have type 2 diabetes. Type 2 diabetics make plenty of insulin but their body tissues are resistant and don't properly respond to the action of insulin. Sometimes diet, weight loss, and exercise are able to control high blood sugars and even eliminate diabetes. Other times, the addition of medicines is required to bring blood sugars into the normal range.
You may be surprised to learn that diabetes is a risk factor for fractures. In recent years, an explosion of medical research has reported that diabetes and some of the agents used to treat it have adverse effects on bone health. Both type 1 and type 2 diabetes have negative effects on bone that result in an increased risk of fracture.
TYPE 1 DIABETES
Just a few weeks before her 55th birthday, then Supreme Court nominee Sonia Sotomayor tripped at the airport and fractured her right ankle. A few hours later, she was sporting a knee-high cast and walking on crutches to hearings in the Capitol that led up to her confirmation. Why should such a minor spill cause a fracture?
The media theorized that her fracture may have happened because she was older, worked indoors with little sunlight exposure, and had a sedentary profession. No one mentioned the connection to her history of diabetes, which I believe is the main contributing factor. I have neither the details of her fracture nor her medical history. However, Justice Sotomayor has openly talked about being diagnosed with type 1 diabetes at age eight and how she has been taking insulin ever since.
The problem is best characterized by the title of a commentary, “Sugar and Bone: A Not-So Sweet Story” by Dr. Clifford Rosen, an endocrinologist at the Maine Medical Center. In an accompanying article, researchers from the University of Utah showed that high blood sugars are not good for the growing skeleton of adolescent girls. Therefore, girls with type 1 diabetes may not be able to reach their optimal peak bone mass, which results in smaller and weaker bones. A comparable study has not yet been done in boys.
Type 1 diabetics have low bone mass and an increased risk for adult osteoporosis and fractures. The mechanisms behind this observation are being actively investigated. High blood sugar may actually be toxic to bone. Various hormonal factors are also implicated. However, there is little doubt that diabetes itself causes problems in the skeleton. The propensity for fracture among type 1 diabetics is related to two factors: their bone density is lower than normal and their bones are more fragile. This is the result of a higher rate of bone turnover, with increased bone breakdown out of proportion to bone formation. If a fracture occurs, bone healing is slower and the new bone made could be of poorer quality.
Some but not all studies suggest that tighter control of diabetes may influence patient outcomes. Bone health may benefit from “tight control,” which refers to the management of blood sugars in a narrow range rather than allowing large fluctuations. The better the control is, the stronger the bone will be. Lower bone mass is more likely if diabetes is diagnosed before puberty. It is also associated with the presence of other complications of diabetes. Osteoporosis and fractures must be added to the list of diabetes complications from long-term high blood sugars.
TYPE 2 DIABETES
In contrast, type 2 diabetics may have average or above average bone mineral density. Despite this, they still have an increased fracture risk—a paradox for sure! What's the reason for this inconsistency?
It is not clear, but diabetes is a complex disease that affects everything in your body, including bone. Bones of type 2 diabetics are more fragile. The reasons for the increased fragility are still being investigated but high blood sugars are thought to play an important role.
Studies show that diabetics may not make new bone well. Based on bone markers, type 2 diabetics have low bone turnover. The primary reason is reduced bone formation and not the increased bone breakdown that is typically seen in postmenopausal osteoporosis.
Other risk factors beyond bone mass may play a role. For example, diabetics have a greater risk of falling. This could be due to numbness or decreased feeling in the feet combined with balance and vision problems. Medicines that are taken for diabetes may also contribute to the increased fracture risk.
Over many years, physicians observed that diabetics had a disproportionate number of hip fractures. Diabetics have at least twice the risk of fracture compared to people with normal blood sugars. The increased risk includes fractures of the hip, upper arm (humerus), ankle, and foot.
Newly diagnosed diabetics are not at high risk for fracture. The increased fracture risk with type 2 diabetes is observed after five years or longer. Studies using DXA measurements shed some light on this observation. The actual bone density may be higher than average for age but type 2 diabetes is associated with more rapid bone loss.
In the Health, Aging, and Body Composition study or Health ABC study for short, a large group of men and women (3,075 subjects) ages seventy to seventy-nine was followed for four years. Older white women with diabetes had more rapid bone loss at the hip than women with normal blood sugars. However, bone loss in both men and black women with diabetes was no different than in those with normal blood sugars.
Similar findings were observed in the Study of Osteoporotic Fractures (SOF). Older women with diabetes had a higher rate of bone loss at the hip than those without diabetes. In contrast to Health ABC, a comparable effect was seen in older men who participated in the Study of Osteoporosis in Men (MrOS). Older men with diabetes had 60 percent greater loss of bone density at the hip than those older men who did not have diabetes.
The Study of Women's Health Across the Nation (SWAN) followed younger women who were going through menopause. Over three years of observation, bone loss at the hip was an astounding ten times greater among women with diabetes than among women without diabetes. In contrast, the rate of bone loss at the spine was not higher in diabetics. Diabetic women also had double the fracture rate of nondiabetic women.
More rapid bone loss, which causes a decrease in bone strength, increases the risk of fracture. On measurement of bone density in type 2 diabetics, using the usual T-score categories (normal, low bone mass, and osteoporosis) or calculated FRAX score may underestimate their fracture risk. All diabetics have a heightened risk of fracture regardless of their bone density.
Factors Leading to Fractures in Diabetes
Both types of diabetes are associated with an increased number of fractures. The factors leading to the higher risk of fractures are quite different.
| Type 1 Diabetes | Type 2 Diabetes |
| Increased bone turnover due to increased bone breakdown | Low bone turnover due to decreased bone formation |
| Low bone mass | Normal to above normal bone mass |
| High blood sugar and growing skeleton | Rapid bone loss |
| Decreased adult bone density | Other factors beyond bone mass |
| Treatment with TZDs |
DIABETES MEDICINES
Thiazolidinediones, or “TZDs,” are a class of oral diabetic drugs for people with type 2 diabetes. They are effective in lowering and controlling blood sugars. They help control blood sugar levels by making the cells of the body more sensitive to the action of insulin. Many times they are used in combination with other diabetic medicines. Unfortunately, these effective diabetes medicines may have a negative effect on your bone.
Drugs Called Thiazolidinediones: TZDs
Rezulin (generic name troglitazone), the first drug in the thiazolidinediones (TZDs) class, was introduced in the late 1990s. It was withdrawn from the US market in 2000 due to a serious side effect (liver problems).
Avandia (rosiglitazone), which was approved in 1999, became widely used as an effective treatment for control of blood sugars in type 2 diabetics. Avandia's annual sales peaked at $2.2 billion in 2006 but have decreased markedly since because in 2007 new research found that Avandia had a potential for increased risk of heart problems and fractures. The FDA placed a “black box warning” on the label for heart failure and heart attacks.
The controversy about Avandia's effect on the heart continued, and some called for its removal from the market. After considerable review by the FDA, in September 2010 they instituted a “restricted program” for Avandia and its combination products to limit its use in new patients because of the risk of heart attack and stroke. These new safety measures will undoubtedly further decrease the use of Avandia. In addition, the patent for Avandia expires in 2012.
Avandia's “cousin” Actos (pioglitazone) has benefited, and its sales have increased. In 2010, Actos ranked number nine in US prescription medicine sales, generating $3.5 billion. The sales figures for Avandia and Actos mean that many, many diabetics are taking these medicines.
AVANDIA: FRACTURE IS AN UNEXPECTED CONSEQUENCE
In clinical trials of most new drugs, measures of bone health are not typically included in tests of safety. Researchers were surprised by a larger number of fractures found in a study of diabetes medicines.
The ADOPT study (A Diabetes Outcome Progression Trial) compared Avandia with two other diabetes medicines, Micronase (glyburide) and Glucophage (metformin). At the end of 2006, the researchers reported in the New England Journal of Medicine their four-year findings from treating more than four thousand diabetic men and women. At the conclusion of the paper, the researchers briefly added the unexpected finding of a higher rate of fractures, which had been identified in one of the three medicine groups prior to the article's publication. Women, but not men, who were treated with Avandia had more fractures than women in the other drug groups. The fractures were primarily of the upper arm, hand, and foot.
Because of the sites of fracture, debate has centered on whether these are osteoporotic fractures. The female subjects were in their midfifties and had been diagnosed with diabetes for two years or less. Hip and spine fractures are not typical for women in their fifties, so you would not expect those fractures; but arm and leg fractures are common. Later, other studies found similar rates of fracture.
Fractures are now listed on the Avandia prescribing information under Warnings and Precautions: “Increased incidence of bone fracture in female patients.”
ACTOS IS ASSOCIATED WITH FRACTURES, TOO
Whether or not there was also a fracture problem with Actos was answered by the manufacturer's analysis of its clinical trial database of more than fifteen thousand patients. Women, but not men, receiving Actos (pioglitazone) had a higher number of fractures. The majority of the fractures were also in the arm or lower leg.
In March 2007, a letter to healthcare providers notified doctors of this new safety information. Increased fracture risk observed in women is now included in the Actos prescribing information under Precautions. The full prescribing label includes additional information about fractures that was gathered during the PROACTIVE study (Prospective Pioglitazone Clinical Trial in Macrovascular Events). Over an almost-three-year period, women with type 2 diabetes taking Actos had double the number of fractures compared to women on placebo.
MEN, TOO?
Overall, TZDs appear to have a less pronounced effect on bone in men than in women. However, the study period for the clinical trials using TZD drugs was short—four years or less. Over a longer term and with aging, would use of TZDs add additional risk on top of the increased risk from the diabetes itself?
Observational studies suggest that men may also be susceptible to bone loss associated with TZD therapy. One large British study suggested that older men and women are both at increased fracture risk as a result of taking TZDs. Although the FDA warnings and precautions for TZDs and fracture include only women, women and men with low bone mass and higher risk of fracture may want to use another type of diabetes medicine for control of their blood sugars.
TZDs: Mechanism of Action
Are the negative bone effects just a fluke observation? No, there is consistency across multiple studies. Scientists have explained the fracture findings based on the action of the TZDs. The mediator of the insulinsensitizing effect of TZDs is found in numerous tissues, including bone. (The mediator is called the nuclear receptor peroxisome proliferatoractivated receptor or PPAR-gamma for short.)
In the bone marrow, this mediator acts as a switch to determine whether certain stem cells become bone-building cells (osteoblasts) or fat cells. Once the mediator is turned on by the TZDs, more fat cells are produced and, as a result, fewer osteoblasts are made.
In just a matter of a few months, these changes were measured indirectly with bone turnover markers in women. Their markers for building-bone osteoblasts were decreased while markers of bone breakdown were normal. After a short time (fourteen weeks), older, healthy women given Avandia had measurable bone loss at both the hip and spine. That is quick!
Another concern raised by decreased bone formation associated with TZDs is delay in fracture healing. This finding is based on lab mice, but further research in this important area is underway.
TREATMENT
Few data are available to guide treatment in diabetics beyond the use of the general measures: adequate calcium and vitamin D, good nutrition, and exercise. In a reanalysis of data from a Fosamax trial, it was determined that postmenopausal diabetic women tended to not gain as much bone density as nondiabetics taking Fosamax. Also of note, the diabetics in the placebo group lost bone more rapidly at the hip.
Research is needed to guide the design of strategies for improving diabetics' bone health. Since TZDs are effective in controlling blood sugars, are there ways to prevent the associated bone loss? Just like any new insights, new questions are raised that need answers.
At the present time, TZDs should not be used if you are at higher risk for fracture. If you are taking TZDs, monitor your bone density with regular DXA measurements every two years.
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The Bare Bones
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