Case-control studies of patients with fractures have found that subjects with diabetes have at least a twofold higher risk of fracture than subjects without diabetes (1), with an increased risk of hip, humerus, and foot fractures in elderly diabetic subjects (2–4). Risk factors that contribute to increased fracture in diabetic subjects include number of falls (5,6), insulin use (7,8), functional disability (9–11), diabetes duration (7,12), and poor vision (7). Recent studies report that older women and African Americans have higher incidence of osteoporotic fractures (13). In addition, lower bone strength (bone mineral density [BMD]) might be expected to increase risk for the development of osteoporosis and fracture.

Type 2 diabetic patients are widely prescribed drugs called thiazolidinediones, which increase insulin sensitivity via activation of peroxisome proliferator–activated receptor (PPAR)-γ receptors. However, it is not known whether thiazolidinedione use has any effect on bone mass and thereby increases risk of fracture in type 2 diabetic patients. In animal studies, thiazolidinedione treatment was associated with bone loss in a mouse model (14,15), which was explained by possible imbalance in bone from increased apoptotic death of osteogenic cells and diminished bone formation (15), and also in ovariectomized rats (16). Other investigators did not find bone loss in troglitazone-treated mice (17). There is limited information on the effect of thiazolidinediones on BMD in humans. A recent study has suggested that thiazolidinedione use may cause bone loss in older women with type 2 diabetes (18). In the present study on 160 men with type 2 diabetes, we examined BMD in patients on rosiglitazone treatment compared with matched men with type 2 diabetes not on rosiglitazone treatment and found that rosiglitazone treatment increases bone loss in men with type 2 diabetes.

After institutional review board approval, we retrieved the clinical data for the previous 4 years of 354 subjects with diabetes and compared with BMD data of age- and BMI-matched nondiabetic subjects. Among 354 subjects with diabetes, we had follow-up BMD data for 32 men with type 2 diabetes receiving rosiglitazone (considered the study group) and 128 men with type 2 diabetes not receiving any thiazolidinedione (considered the control group). Clinical data included are history of smoking, alcohol consumption, hypertension, coronary artery disease, stroke, current medications, and duration of diabetes and family history of diabetes and osteoporosis. Other details collected include height, weight, BMI, abdominal girth, hip-to-waist measurements and ratio, and blood pressure. The dose of rosiglitazone was 4 mg twice a day. We excluded the data of the subjects with chronic renal insufficiency, hyperparathyroidism, and Cushing's syndrome and of those who were on glucocorticoids and gonadotropin-releasing hormone analogs.

BMD measurements were performed using dual-energy X-ray absorptiometry (DEXA) (Lunar Prodigy) at the lumbar spine: anteroposterior (AP) and lateral (L1–4) and the proximal femur (total hip, femoral neck, and trochanter) and 33% radius. The precision of DEXA scans is 1–1.8%. Annualized absolute change in BMD was calculated as the difference between the results of the baseline and follow-up hip scans divided by the time between scans in years. Annualized percentage of change in BMD was calculated by dividing the annualized absolute change by the baseline BMD. We compared the BMD data of subjects with diabetes and on rosiglitazone with those of subjects with diabetes and not on rosiglitazone using unpaired t test. A P value <0.05 on two-tailed testing was considered significant.

The BMD data at both AP spine and hip in subjects with diabetes were similar to those of subjects with no diabetes when matched for age and BMI (data not given here). Among men with type 2 diabetes, 160 subjects had a follow-up DEXA with a mean interval of 16 months, including 128 subjects with diabetes and not receiving rosiglitazone (control group) and 32 subjects with diabetes and receiving rosiglitazone (study group). The BMD and clinical characteristics of subjects with type 2 diabetes are shown in Table 1. There was no significant difference in the baseline BMD data at both AP spine and hip in subjects with type 2 diabetes with or without rosiglitazone. Since all of the follow-up DEXA data were not collected at exact similar intervals, annualized percentage changes were calculated. Annualized absolute percentage changes in both groups were compared, and the results are shown in Table 1.

BMD in subjects with type 2 diabetes was similar to that in nondiabetic subjects. This finding is consistent with that of a previous study (19). A novel finding in our report is the adverse effect of rosiglitazone, a thiazolidinedione, on skeletal health in humans. There was a significant difference in the BMD, with loss of bone at both the spine and hip in type 2 diabetic subjects on rosiglitazone (Table 1). This study confirms the results of previous animal studies and shows the possible adverse effect of rosiglitazone on skeletal health in men.

Osteoblasts and adipocytes are derived from a common multipotential mesenchymal stem cell progenitor (18–20). PPAR-γ is essential for normal adipocyte differentiation and proliferation as well as fatty acid uptake and storage. The thiazolidinediones rosiglitazone and pioglitazone are commonly used to increase insulin sensitivity for the treatment of type 2 diabetes (21). It has been shown that activation of PPAR-γ2 with rosiglitazone stimulates adipogenesis and inhibits osteoblastogenesis (22). This may be a potential mechanism for the loss of BMD observed in hips of rosiglitazone-treated diabetic men.

This study is retrospective. Limitations include that there were no bone turnover markers for comparison and that the data groups are not large enough to perform regression analyses for confounding factors such as age, duration of diabetes, use of insulin, association of hypertension, and other factors such as smoking and alcoholism. Nevertheless, this study shows a significant increase in bone loss both at total hip and femoral neck areas in type 2 diabetic men on rosiglitazone treatment. This suggests that thiazolidinedione treatment is a risk factor and can contribute to excess incidence of fractures in diabetes.

Table 1—

Annualized percentage change in BMD and clinical characteristics of diabetic subjects on rosiglitazone compared with diabetic subjects not on rosiglitazone with follow-up BMD

Diabetic subjects not on rosiglitazoneDiabetic subjects on rosiglitazoneP
n 128 32  
Total AP spine BMD    
    Baseline 1.133 ± 0.19 1.160 ± 0.17 NS 
    Annualized % change 2.3 ± 2.9 0.69 ± 2.4 0.03* 
Total hip BMD    
    Baseline 0.934 ± 0.14 0.915 ± 0.18 NS 
    Annualized % change −0.137 ± 1.9 −1.19 ± 1.8 0.006* 
Femoral neck BMD    
    Baseline 0.828 ± 0.13 0.839 ± 0.14 NS 
    Annualized % change −0.20 ± 1.25 −1.22 ± 1.3 0.0001* 
Age (years) 68 ± 10 70 ± 9 NS 
Basal metabolic index 30 ± 5.5 32 ± 4.8 NS 
A1C 8.1 ± 1.4 7.5 ± 2.1 NS 
Fasting glucose (mmol/l) 158 ± 52 160 ± 48 NS 
Serum creatinine (mg/dl) 1.2 ± 0.6 1.1 ± 0.8 NS 
Total cholesterol (mg/dl) 203 ± 60 199 ± 48 NS 
HDL cholesterol (mg/dl) 34 ± 18 38 ± 22 NS 
LDL cholesterol (mg/dl) 122 ± 46 120 ± 41 NS 
Hypertension (%) 92 82 NS 
Coronary artery disease (%) 62 56 NS 
Family history of diabetes (%) 62 70 NS 
Current smokers (%) 20 18 NS 
Diabetic subjects not on rosiglitazoneDiabetic subjects on rosiglitazoneP
n 128 32  
Total AP spine BMD    
    Baseline 1.133 ± 0.19 1.160 ± 0.17 NS 
    Annualized % change 2.3 ± 2.9 0.69 ± 2.4 0.03* 
Total hip BMD    
    Baseline 0.934 ± 0.14 0.915 ± 0.18 NS 
    Annualized % change −0.137 ± 1.9 −1.19 ± 1.8 0.006* 
Femoral neck BMD    
    Baseline 0.828 ± 0.13 0.839 ± 0.14 NS 
    Annualized % change −0.20 ± 1.25 −1.22 ± 1.3 0.0001* 
Age (years) 68 ± 10 70 ± 9 NS 
Basal metabolic index 30 ± 5.5 32 ± 4.8 NS 
A1C 8.1 ± 1.4 7.5 ± 2.1 NS 
Fasting glucose (mmol/l) 158 ± 52 160 ± 48 NS 
Serum creatinine (mg/dl) 1.2 ± 0.6 1.1 ± 0.8 NS 
Total cholesterol (mg/dl) 203 ± 60 199 ± 48 NS 
HDL cholesterol (mg/dl) 34 ± 18 38 ± 22 NS 
LDL cholesterol (mg/dl) 122 ± 46 120 ± 41 NS 
Hypertension (%) 92 82 NS 
Coronary artery disease (%) 62 56 NS 
Family history of diabetes (%) 62 70 NS 
Current smokers (%) 20 18 NS 

Data are means ± SD.

*

P < 0.05 is considered significant. Baseline BMD indicates BMD at the initiation of rosiglitazone.

View Large

S.Y. is supported by a research grant in aid from Proctor and Gamble and by the Veterans Health Administration. S.K.J. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Dietary Supplements.

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Published ahead of print at http//:care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2606.

See accompanying Editorial on p. 1670.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

DIABETES CARE
2007