Bone Density in Non-Insulin-Dependent Diabetes Mellitus: The Rotterdam Study

Low bone mineral density is often mentioned as a complication of diabetes mellitus. Most studies indicate that it is a complication for patients with insulin-dependent diabetes mellitus, especially those with poor metabolic control [1]. However, conflicting findings have been reported in patients with noninsulin-dependent diabetes mellitus: Some authors report elevated [2-6], some report decreased [7-9], and others report unaltered [10-12] bone density. Heterogeneity of the patients in the studies (for example, with regard to whether they were receiving insulin), differences in measurement techniques and regions of interest, the use of an inappropriate group of persons for comparison, and the absence of control for several possible confounders may explain the dissimilar results. Additionally, several previous studies were restricted to patients with previously diagnosed noninsulin-dependent diabetes mellitus. To address the effect of noninsulin-dependent diabetes mellitus on bone density, studies should include persons with untreated noninsulin-dependent diabetes mellitus; studies that exclude them may address the effect of antidiabetic therapy rather than the effect of noninsulin-dependent diabetes mellitus. In addition, we know of no study that has linked the effect of noninsulin-dependent diabetes mellitus on bone mineral density to the occurrence of fractures. We investigated the associations among noninsulin-dependent diabetes mellitus, bone mineral density, and fractures in 5931 unselected men and women, aged 55 years or more, who were examined in the population-based Rotterdam Study. Methods Study Population The Rotterdam Study is a prospective follow-up study of persons aged 55 years or more; its intent is to investigate the incidence of and the risk factors for chronic disabling diseases. Its rationale and design have been described previously [13]. All 10 275 inhabitants of a district in Rotterdam who were aged 55 years or more were invited to participate in the study, which consisted of an initial home interview by a trained research assistant and a series of medical examinations made during two visits to the research center. The study was approved by the Medical Ethics Committee of the Erasmus University, and written informed consent was obtained from all participants. For the present study, institutionalized persons (n = 1114) were ineligible for examination at the research center. Interview data were collected for 77% of the remaining eligible persons; the overall response rate for the Rotterdam Study was 78%. Bone mineral density was measured in 2481 men and 3450 women; scan data were unavailable for 563 persons. Most of these persons took part in a pilot study (n = 338) in which no scans were obtained; maintenance procedures accounted for the remaining missing scan data. Measurements During the home interview, a medical history was obtained using a questionnaire administered by an interviewer; medication use was verified by examining pills. To estimate the frequency of fractures, participants were asked about the number and types of fractures they had had during the preceding 5 years. All participants at the research center, except for those using antidiabetic medication, were given a 37.5% oral glucose solution (75 g of glucose) while in a nonfasting state. Venous glucose levels were then measured before and after 2 hours; noninsulin-dependent diabetes mellitus was diagnosed if at least one measurement was 11.1 mmol/L or more or if the participant used antidiabetic medication. Bone mineral density was measured at the lumbar spine and proximal femur using a Lunar DPX-L densitometer (Lunar Corp., Madison, Wisconsin). Standard positioning was used for anterior-posterior scans of the lumbar spine and proximal femur. The right proximal femur was scanned unless the participant had a history of prosthesis implantation, in which case the left side was scanned. The in vivo coefficient of variation for bone mineral density, calculated from 12 participants who were each scanned twice on the same day, was 3.2% at the femoral neck, 3.1% at the Ward triangle, 2.5% at the greater trochanter, and 0.9% at the lumbar spine. Quality assurance, including calibration, was done routinely every morning using the standard provided by the manufacturer. When height and weight were measured, participants wore indoor clothing and no shoes. Body mass index (weight in kg/height in m2) was calculated as a measure of obesity. The waist-to-hip ratio was used as an indicator of central obesity. Waist circumference was measured midway between the lower rib margin and the iliac crest; hip circumference was measured at the point of maximum circumference over the buttocks with the tape held horizontally [14]. Osteoarthritis was scored using standard radiographs of the hips in a random subsample of 1136 men and 1697 women, according to the method proposed by Kellgren and colleagues [15]. Participants were classified as having osteoarthritis if they had a Kellgren score of at least 2 at the right hip or if they had a hip prosthesis due to osteoarthritis. For current and past smokers, the number of pack-years was calculated as the average number of packs of cigarettes smoked per day multiplied by the total years of smoking. Falling was recorded as never, less than once per month, less than once per week but more than once per month, and more than once per week. In the analysis, however, falling was regarded as a dichotomous variable. Impairment in activities of daily living was assessed using a questionnaire adapted from the Stanford Health Assessment Questionnaire [16]. Because impaired function of the lower extremities in particular will influence bone mineral density, a disability index was calculated for the lower limbs by averaging scores for arising, walking, bending, and getting in and out of a car. Each of these four categories was scored on a scale ranging from 0 to 3, where 0 indicates no impairment and 3 indicates inability to do the activity. Disability was then categorized as absent (0), mild (>0 to 1), or severe (>1). Data Analysis Men and women were analyzed separately. Patients newly diagnosed with noninsulin-dependent diabetes mellitus and those who were already being treated for it were analyzed in combination and separately. Furthermore, analyses were done with and without patients receiving insulin. A chi-square test was done for differences in proportions. A Student t-test was used for continuous variables. Multiple linear regression analysis was used to evaluate the association between noninsulin-dependent diabetes mellitus and bone mineral density and to control for possible confounders. Effect modification by age was studied by including interaction terms for age and the presence of noninsulin-dependent diabetes mellitus in the model. To examine selective nonresponse to the research-center visit of participants with diabetes, we calculated the age-adjusted prevalence of antidiabetic medication use in participants who were interviewed only, and compared this prevalence with that in participants who had both the interview and the examination at the research center. There appeared to be no selective nonresponse in women; the age-adjusted prevalence of current antidiabetic medication use was similar for those with and without a visit to the center (5.0% compared with 4.9%; P = 0.9). In men, however, this prevalence was significantly higher in participants who did not visit the center (4.2% compared with 10.0%; P = 0.0001). Logistic regression was used to study the association between noninsulin-dependent diabetes mellitus and a fracture (regardless of cause) in the preceding 5 years. Vertebral fractures were excluded from the analyses because participants were often unaware of them. All other self-reported fractures were included in the analyses. The association between diabetes and fracture frequency was expressed as an odds ratio with a 95% CI. Two-sided P values were calculated for all analyses. Analyses of variance and covariance were used to estimate multiple adjusted mean values. Results Among the 2481 men and 3450 women with bone mineral density measurements, 243 men and 335 women were classified as having noninsulin-dependent diabetes mellitus. Ninety-four men and 140 women were already being treated with antidiabetic medication. Table 1 shows the characteristics of the men and women with and without noninsulin-dependent diabetes mellitus. As expected, persons who had this condition were older than those who did not have it. The body mass index of women with noninsulin-dependent diabetes mellitus was substantially higher than that of women without diabetes; this was not true for men. The group of participants with noninsulin-dependent diabetes mellitus included more current users of loop diuretics. Furthermore, the group of women with noninsulin-dependent diabetes mellitus included a higher percentage of current thiazide users. Serum creatinine levels were substantially higher in men with diabetes than in men without diabetes; this was not true for women. Both men and women with noninsulin-dependent diabetes mellitus reported a higher frequency of impairment in function of the lower extremities. Although the difference was not significant, men with noninsulin-dependent diabetes mellitus tended to fall more often than men without diabetes. Table 1. Characteristics of Men and Women with and without Non-Insulin-Dependent Diabetes Mellitus* Table 2 shows bone mineral density according to diabetic status in men and women. After adjustment for age and body mass index, both men and women with noninsulin-dependent diabetes mellitus had substantially higher bone mineral density at all sites than participants without diabetes. The difference was approximately 3% and was similar for men and women. There was no interaction between the effects of diabetes and age. Adjustment for all potential confounders measured, inc