Low Fractional Calcium Absorption Increases the Risk for Hip Fracture in Women with Low Calcium Intake

The fraction of calcium absorbed from the gut (fractional calcium absorption) varies widely from person to person, ranging from 10% to 70% (1-3). Cross-sectional studies in postmenopausal women have suggested that fractional calcium absorption increases with decreasing dietary calcium intake and decreases with advancing age (1, 4). It has been hypothesized that decreased ability to absorb calcium with age limits adaptation to low calcium intake and leads to secondary hyperparathyroidism, greater bone resorption, and increased risk for fracture (5, 6). However, to our knowledge, the association between fractional calcium absorption and subsequent risk for fracture has never been studied. To test the hypothesis that decreased fractional calcium absorption in older women with low calcium intake increases the risk for hip fracture, we measured fractional calcium absorption in a cohort of 5452 elderly women enrolled in the Study of Osteoporotic Fractures and followed them prospectively for incident hip and other nonspine fractures. Methods Participants From September 1986 to October 1988, 9704 women at least 65 years of age were recruited to participate in the baseline examination of the prospective Study of Osteoporotic Fractures. Women were recruited from population-based listings in four areas of the United States: Baltimore County, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania (7). We excluded black women (because of their low incidence of hip fracture), women who were unable to walk without help, and women who had a history of bilateral hip replacement. Beginning in August 1992, all surviving participants (93.3% of the original cohort) were invited to participate in a fourth examination, which was completed in July 1994. Of these participants, 6796 (77% of survivors) completed a fourth examination (6301 attended a clinic visit, and 495 had a home visit). Of women who completed a fourth clinic visit, 5452 (87%) had a measurement of fractional calcium absorption and were followed for incident fractures occurring after the fourth examination until 31 May 1997. The appropriate institutional review boards approved the study, and written informed consent was obtained from all participants. Fractional Calcium Absorption Calcium absorption testing was completed in the morning after a 5-hour fast. Participants were instructed not to take any calcium supplements for 12 hours before testing and to abstain from alcoholic beverages for 24 hours before testing. Fractional 45Ca absorption was estimated from the appearance of 45Ca in blood after ingestion of 50 g of labeled apple juice (containing 63 mg of calcium) and 120 g of unlabeled Speas Farm apple juice (Sundor Brands, Mt. Dora, Florida). The total calcium load was 215 mg. Labeled 45Ca was prepared by the Osteoporosis Research Center at Creighton University in Omaha, Nebraska, and was shipped to the four clinic sites, where it was mixed with the unlabeled juice. Actual dosing occurred midway through consumption of a standardized light test meal. Blood was drawn into a serum separator tube exactly 3 hours after ingestion of the tracer and was allowed to clot at room temperature. Serum was separated within 2 hours of collection and was frozen at 70 C until analysis. Frozen serum samples were later shipped on dry ice by overnight delivery to Creighton University, where fractional calcium absorption was estimated by using the single isotope method, as described elsewhere (8, 9). Other Measurements Participants completed a questionnaire and were interviewed at the fourth examination. They were asked about smoking status, physical activity, self-rated health, falls during the previous year, fractures since 50 years of age, and parental history of fracture. Participants were asked to bring all current prescription and nonprescription medications, including supplements and vitamins, to the clinic. Interviewers completed a medication history for each participant, including type of medication or supplement and total daily dosage. We determined use of calcium supplements by asking questions about dose and frequency of use of multivitamins, specific vitamin and mineral supplements, and antacids with calcium. The category of vitamin D supplements included vitamin D3, vitamin D2, and multivitamin supplements containing vitamin D. Dietary calcium intake was estimated by using the validated 60-item Block semi-quantitative food-frequency questionnaire, which was developed from the Second National Health and Nutrition Survey (10, 11). Total calcium intake was calculated by summing dietary calcium intake (mg/d) and daily dosage of calcium supplements (mg/d). Body weight and height were measured by using a balance-beam scale and a stadiometer (12). Weight change was calculated by subtracting weight at the baseline examination from weight at the fourth examination. We tested neuromuscular function by determining whether the participant could rise from a chair five times without using her arms. Bone mineral density (g/cm 2) of the proximal femur was measured by using dual-energy x-ray absorptiometry (QDR 1000, Hologic, Waltham, Massachusetts) (13, 14). Ascertainment of Fractures Every 4 months, we contacted participants about fractures by postcard or by telephone. We were able to complete 98% of these follow-up contacts. All fractures were confirmed by radiographic reports; hip fractures were also confirmed by reviewing preoperative radiographs (15). We excluded fractures that occurred because of major trauma. Self-reported vertebral fractures were also excluded because most vertebral fractures do not come to medical attention (16). The category all nonspine fractures included all nontraumatic, nonvertebral fractures. Wrist fractures were defined as all fractures of the distal radius or ulna, and humeral fractures were defined as fractures of only the proximal humerus. All nonspine fractures that occurred after the fourth examination and before 31 May 1997 were included in our analysis. Follow-up for fractures ranged from 0.6 years to 6.1 years (average follow-up, 4.8 years). Statistical Analysis The association between fractional calcium absorption and potential covariates was assessed by calculating the correlation coefficient between fractional calcium absorption and continuous variables and by examining mean values of fractional calcium absorption according to levels of categorical variables. Potential covariates were factors physiologically related to fractional calcium absorption and known risk factors for hip fracture. We used proportional hazards models to analyze the association between fractional calcium absorption and risk for fracture, including hip, any nonhip, wrist, and humeral fractures. The relative risk (approximated as hazards ratio) for fracture was expressed per 1-SD decrease in fractional calcium absorption. To examine whether the effect of fractional calcium absorption on risk for hip fracture could be explained by covariates related to fractional calcium absorption (defined as factors related to fractional calcium absorption at P 0.05), we added these covariates (health status, history of falling, previous fracture, inability to rise from a chair, dietary calcium intake, use of calcium supplements, use of vitamin D supplements, use of thiazide diuretics, bone mineral density at the femoral neck, body mass index, and weight change) to the model that contained age and fractional calcium absorption. Values for correlations between variables in multivariate models were 0.374 or less. To further assess the effect of calcium intake (dietary and supplemental), vitamin D supplement intake, and age on the association between fractional calcium absorption and risk for fractures (including hip, any nonhip, wrist, and humeral fractures), we stratified participants by dietary calcium intake (<400 mg/d or 400 mg/d), use of calcium supplements (yes or no), total calcium intake (<400 mg/d or 400 mg/d), use of vitamin D supplements (yes or no), and age (<75 years or 75 years). For all of these analyses, fractional calcium absorption was expressed as a continuous variable. In addition, for analyses of hip fracture stratified by calcium intake, fractional calcium absorption was expressed as a categorical variable ( 32.3% [median] or>32.3%). By including interaction terms, we also tested for the possibility of interactions between fractional calcium absorption and such variables as dietary calcium intake (<400 mg/d or 400 mg/d), total calcium intake (<400 mg/d or 400 mg/d), and age (<75 years or 75 years) for the prediction of risk for hip fracture. Finally, we examined the association between fractional calcium absorption and risk for hip fracture in analyses stratified by both dietary calcium intake and use of supplemental vitamin D. Role of the Funding Source Our study was funded by the National Institutes of Health, which had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Characteristics of the Study Sample Characteristics of the 5452 participants are shown in Table 1. Mean fractional calcium absorption (SD) was 32.8% 7.7% (range, 9.7% to 64.3%). Among the 2299 women in the cohort who took supplemental vitamin D (42%), 16% took less than 400 IU/d, 71% took 400 IU/d, and 7% took more than 400 IU/d. Twenty-nine women (0.5%) reported use of calcitonin injections, 30 women (0.6%) reported use of sodium fluoride, and 102 women (1.9%) reported use of etidronate. During an average of 4.8 years of follow-up, 729 women (13%) experienced at least one nonspine fracture (153 had hip fractures, 133 had wrist fractures, and 99 had humeral fractures). Table 1. Characteristics of Participants at Fourth Examination Factors Associated with Fractional Calcium Absorption Average fractional calcium absorption steadily decreased with advancing age, from 34.3% in persons 69 t