Factors associated with calcium absorption efficiency in pre- and perimenopausal women.

BACKGROUND: The amount of calcium ingested by an individual may affect several chronic conditions, including osteoporosis, hypertension, and colon cancer. However, individuals vary in their ability to absorb the calcium they consume. OBJECTIVE: The purpose of this study was to examine sources of interindividual variation in the efficiency of calcium absorption in women. DESIGN: Fractional calcium absorption was estimated in 142 healthy pre- and perimenopausal women. Dietary habits, lifestyle factors, calciotropic hormones, and vitamin D receptor gene polymorphisms were also assessed. RESULTS: Calcium absorption values averaged 35% and ranged from 17% to 58%. Fractional calcium absorption was positively associated with body mass index (r = 0.22, P = 0.007), dietary fat intake (r = 0.29, P = 0.001), serum 1,25 dihydroxyvitamin D [1,25(OH)(2)D] concentrations (r = 0.23, P = 0. 006), and parathyroid hormone concentrations (r = 0.21, P = 0.015). Fractional calcium absorption was inversely associated with total calcium intake (r = -0.18, P = 0.030), dietary fiber intake (r = -0. 19, P = 0.028), alcohol consumption (r = -0.14, P = 0.094), physical activity (r = -0.22, P = 0.007), and symptoms of constipation (r = -0.16, P = 0.059). In stepwise regression analysis, dietary fat, dietary fiber, serum 1,25(OH)(2)D, and alcohol consumption emerged as independent predictors of calcium absorption, explaining 21.02% of the observed variation. Women in the lowest tertile of the ratio of dietary fat to fiber had 19% lower fractional calcium absorption values than did women in the highest tertile of ratio of dietary fat to fiber (test of trend, P < 0.001). CONCLUSIONS: There is a wide range of calcium absorption values in healthy women. The amount of dietary fat consumed relative to dietary fiber appears to have an important role in determining differences in calcium absorption performance among individuals.

Measurement of fat mass using DEXA: a validation study in elderly adults.

The accuracy of total body fat mass and leg fat mass measurements by fan-beam dual-energy X-ray absorptiometry (DEXA) was assessed in 60 healthy elderly subjects (aged 70-79 yr). Total fat and leg fat mass at four leg regions (total leg, thigh, midthigh, and calf) were measured with the QDR 4500A (Hologic, Waltham, MA). The four-compartment model and multislice computed tomography scans were selected as criterion methods for total fat and leg fat mass, respectively. Total fat mass from DEXA was positively associated with fat mass from the four-compartment model with a standard error of the estimate ranging from 1.4 to 1.6 kg. DEXA fan-beam tended to overestimate fat mass for total leg and total thigh fat mass, whereas only marginal differences in fat mass measurements at the midthigh and calf were demonstrated (

Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss.

The identification of genes that contribute to bone mineral density (BMD) and bone loss has widespread implications for the understanding and prevention of osteoporosis. The objective of this study was to examine the relationship between the presence and absence of the apolipoprotein E*4 (APOE*4) allele and both BMD and annualized percentage rate of change in BMD at the lumbar spine and hip in a population of 392 healthy, pre-, peri-, and postmenopausal white women participating in the Women's Healthy Lifestyle Project. APOE genotype was analyzed by restriction enzyme analysis from genomic DNA. BMD at the lumbar spine and hip was measured at baseline and after a mean of 2.5 years using dual-energy X-ray absorptiometry (DXA). In premenopausal women, there were no significant differences in BMD or in the annualized percentage rate of change in BMD at the spine or hip when comparing women with and without the APOE*4 allele. In contrast, spine bone loss was significantly greater in peri- and postmenopausal women having an APOE*4 allele than in women without this allele (-1.75 + 1.5% per year vs. -0.98 +/- 1.4% per year, respectively, p = 0.018). Among peri- and postmenopausal women currently using hormone replacement therapy (HRT), there were no differences in the annualized percentage rate of change in spine BMD; whereas, among non-HRT users, there was a 2-fold higher rate of spine bone loss in women with an APOE*4 allele compared with women without this allele (-2.31 +/- 1.5% per year vs. -1.27 +/- 1.3% per year, respectively, p = 0.033; APOE*4 x HRT interaction, p = 0.076). In conclusion, this study shows the importance of APOE*4 allele in spine bone loss in peri- and postmenopausal women and, more importantly, it provides evidence for a genetic and lifestyle interaction in modulating spine bone loss.

Correlates of quantitative ultrasound in the Women's Healthy Lifestyle Project.

Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip fractures and is currently an FDA-approved tool to identify women at risk of osteoporosis. However, few studies have investigated the lifestyle and genetic correlates of QUS in women. This study investigated the cross-sectional associates of several lifestyle, demographic and genetic factors with calcaneal QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS)) in 393 women aged 45-53 years. Leisure-time and historical physical activity, dietary calcium and protein, body composition, vitamin D receptor genotypes, menopause status, other health behaviors, calcaneal QUS parameters and bone mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent physical activity and African-American race were the strongest correlates of SOS whereas dietary protein, calcium and recent physical activity were the strongest correlates of BUA. These predictors explained 13% and 6% of the variance in SOS and BUA, respectively. Smoking, alcohol intake, education, hormone replacement therapy, calcium and vitamin D supplements, historical physical activity and vitamin D receptor genotypes were not significantly associated with BUA or SOS. Lean body mass and premenopausal status were the strongest correlates of lumbar BMD whereas lean body mass, physical activity, African-American race and body mass index were significantly related to femoral neck BMD. Physical activity remained predictive of SOS after controlling for lumbar BMD. The spectrum and magnitude of risk factors for SOS and BUA, including lean body mass, physical activity, race, protein and calcium intake, parallel previously observed predictors of BMD.

Effect of a lifestyle intervention on bone mineral density in premenopausal women: a randomized trial.

BACKGROUND: The positive association between body weight and bone mineral density (BMD) is well documented; in contrast, the effect of changes in body weight on BMD is not well understood, particularly, in normal-weight populations. OBJECTIVE: We examined the effect of a lifestyle intervention aimed at lowering dietary fat intake and increasing physical activity to produce modest weight loss or prevent weight gain on BMD in a population of 236 healthy, premenopausal women aged 44-50 y. DESIGN: All women were participating in a clinical trial known as The Women's Healthy Lifestyle Project and were randomly assigned to intervention or control groups. Dual-energy X-ray absorptiometry of BMD at the lumbar spine and proximal femur were made before and after 18 mo of participation in the trial. RESULTS: The intervention group (n = 115) experienced a mean (+/-SD) weight loss of 3.2 +/- 4.7 kg over the 18 mo compared with a weight gain of 0.42 +/- 3.6 kg in the control group (n = 121) (P < 0.001). The annualized rate of hip BMD loss was 2-fold higher (P < 0.015) in the intervention group (0.81 +/- 1.3%) than in the control group (0.42 +/- 1.1%); a similar, although nonsignificant pattern was observed for the loss in spine BMD: 0.70 +/- 1.4% and 0.37 +/- 1.5% (P = 0.093) in the intervention and control groups, respectively. Large increases in physical activity attenuated spine BMD loss, but had no significant effect on BMD loss at the hip. CONCLUSIONS: The intervention group, who modified their lifestyle to lose weight, had a higher rate of BMD loss at the hip and lumbar spine than did the weight-stable control group. Recommendations for weight loss must be made with consideration that such an endorsement may result in BMD loss.

Cytokine production and bone mineral density at the lumbar spine and femoral neck in premenopausal women.

Cytokines such as interleukin-1 (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) can influence both bone resorption and bone formation. The objective of this cross-sectional study was to examine the relationship between cytokine production by peripheral blood mononuclear cells (PBMC) and bone mineral density (BMD); the annual rate of change in BMD was examined. Subjects participating in a randomized clinical trial entitled the Women's Healthy Lifestyle Project in Allegheny County, Pennsylvania were used. They included 50 healthy premenopausal women, aged 45-52 years, who had regular menses within the past 3 months and were not on replacement estrogens. Dual-energy X-ray absorptiometry measurements at the AP lumbar spine and femoral neck were made at baseline and at the first annual exam using a Hologic QDR 2000 densitometer. Cytokine production of IL-1beta, IL-6, and TNF-alpha by PBMC was measured at the annual exam. The median values for stimulated cytokine production by PBMC were 3.92 ng/ml, 31.3 ng/ml, and 1.05 ng/ml, for IL-1beta, IL-6, and TNF-alpha, respectively. There were modest correlations between cytokine production and cross-sectional BMD, ranging from r = -0.30 to r = -0.13. Trends of greater spinal bone loss were observed in women with "high" (>/=75th percentile) cytokine production of stimulated IL-1beta and IL-6 (IL-1beta: "high" = -1.56% +/- 0.70 versus "low" (<75th percentile) = -0.56% +/- 0.35, P = 0.21). In contrast, greater annual gains in femoral neck BMD were observed in those with high cytokine production of IL-1beta and IL-6 (IL-1beta: high = 3.39% +/- 1.16 versus low = -0. 85 +/- 0.58, P = 0.002). There was no association between stimulated TNF production and annual change in BMD. In this population of healthy premenopausal women, the relationship between cytokine production by PBMC and the rate of change in BMD was significantly different for the lumbar spine and femoral neck, possibly reflecting differences in the proportion of trabecular and cortical bone at these sites.

Are menopausal symptoms associated with bone mineral density and changes in bone mineral density in premenopausal women?

BACKGROUND: The relationship between menopausal symptoms and bone mineral density (BMD) was examined in 290 premenopausal women, ages 44-50 years, participating in a randomized clinical trial of a dietary and exercise intervention: The Women's Healthy Lifestyle Project. METHODS: Information on hot flashes (presence, absence), menstrual cycles (irregular, regular) and menstrual flow per period (variable, same) over the past 6 months was collected at entry. Participants reporting at least one menopausal symptom were classified as symptomatic and compared to those having no symptoms. Bone mineral density (BMD) at the lumbar spine (L1-L4), total hip and whole-body were made at baseline and at 30 months using a dual-energy X-ray absorptiometer (Hologic QDR 2000 densitometer). RESULTS: Baseline BMD at the spine, hip and whole-body were significantly reduced in women reporting menopausal symptoms compared to asymptomatic women, after adjustment for age, weight and intervention status (all p < 0.05). Women with irregular menstrual cycles had greater annualized rates of bone loss at the spine and hip than asymptomatic women (spine, -0.77 (1.6)% per year vs. -0.19 (1.0)% per year, p = 0.0043; hip, -0.37 (1.1)% per year vs. -0.04 (1.0)% per year, p = 0.061), after adjustments for age, percent change in weight, intervention status, and baseline BMD. Similar findings were not found for whole-body BMD. CONCLUSIONS: These results suggest that menopausal symptoms are useful for the effective identification of premenopausal women at higher risk of low BMD and perhaps, of osteoporosis.

Cohort studies and randomized controlled studies in endocrinology.

This article describes the basic skills for the design, implementation, and interpretation of randomized controlled studies. Strengths and limitations of each study design are discussed. Epidemiologic issues in the analysis and interpretation of studies, such as loss to follow-up and biases, are included. Numerous clinical examples are provided to better illustrate the epidemiologic methodology.

The epidemiology of quantitative ultrasound: a review of the relationships with bone mass, osteoporosis and fracture risk.

Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.

Determinants of premenopausal bone mineral density: the interplay of genetic and lifestyle factors.

Bone mineral density (BMD) is a reflection of both genetic and lifestyle factors. The interplay of genetic (vitamin D receptor [VDR] gene polymorphisms) and lifestyle factors on BMD at the lumbar spine and proximal femur was examined in 470 healthy premenopausal women, aged 44-50 years, using a Hologic QDR 2000 densitometer. The objective of this study was to examine the genetic and lifestyle determinants of premenopausal BMD. Each participant was genotyped for BsmI polymorphism at the VDR gene locus. The presence of a restriction site within VDR, specified as bb (189, 40.2%) (n, %) was associated with reduced spinal BMD, whereas absence of this site in BB (97, 20.6%) conferred greater spinal BMD, as did the genotype Bb (184, 39.1%). Associations between smoking, alcohol use, oral contraceptives, education level, multivitamins, number of children, degree of obesity, body weight, physical activity, dietary calcium intake, and VDR genotype to BMDs were examined. VDR genotype, body weight, degree of obesity, physical activity, and dietary calcium intake were all significant determinants of BMD. The association of VDR genotype with BMD at the femoral neck appeared to be modified by calcium intake (BB and Bb: 0.797 +/- 0.11 g/cm2 vs. 0.844 +/- 0.11 g/cm2, interaction term, p = 0.06) for low (< 1036 mg/day) and high (> or = 1036 mg/day; upper quartile) calcium intakes, respectively. A similar trend was demonstrated for physical activity. These findings suggest that prophylactic interventions aimed at achieving and maintaining optimal BMD, such as greater calcium intake or physical activity, may be important in maximizing one's genetic potential for BMD.

Estrogen replacement therapy. A survey of older women's attitudes.

OBJECTIVES: To understand the low prevalence of estrogen use among older women. To examine the reasons for the use and nonuse of estrogen replacement therapy. SUBJECTS AND METHODS: Nonblack women (n = 7667), aged 65 years or older, who participated in the Multicenter Study of Osteoporotic Fractures completed an estrogen questionnaire. RESULTS: Of the subjects, 1335 (17.4%) were currently using oral estrogens, 2084 (27.2%) were past users, and 4248 (55.4%) had never used oral estrogen therapy. The self-reported primary reasons for current users to have initiated therapy included hysterectomy (43.5%), menopausal symptoms (39.3%), prescribed by a physician (38.7%), or prevention or treatment of osteoporosis (33.6%). Of the 2084 former estrogen users (27.2%), the main reasons for starting therapy included prescribed by a physician (44.7%), menopausal symptoms (49.2%), and hysterectomy (28.5%). Approximately 30% of past estrogen users reported the primary reason for discontinuing therapy as "feeling that they didn't need it," whereas 16.4% reported undesirable side effects with bleeding as the most common (45.0%). The main reason women never started estrogen therapy (55.4%) was they feared that the medication was harmful (38.1%) or they felt they did not need it (29.5%). CONCLUSIONS: We conclude that older women in the United States remain skeptical about long-term estrogen use despite its potential for protection against 2 major chronic diseases, osteoporosis and cardiovascular disease. Greater understanding about the barriers to estrogen replacement therapy and improved knowledge of its risks and benefits may reduce the skepticism surrounding estrogen replacement therapy among older women.

The association between vitamin D receptor gene polymorphisms and bone mineral density at the spine, hip and whole-body in premenopausal women.

The genetic influence on bone mineral density (BMD) is thought to be mediated in part by alleles at the vitamin D receptor (VDR) locus. In order to assess the effect of VDR on BMD in premenopausal women, we studied 470 healthy white subjects, aged 44-50 years, participating in the Women's Healthy Lifestyle Project. Each participant was genotyped for the BsmI polymorphism at the VDR gene locus. BMD at the lumbar spine, hip and whole-body, and the whole-body soft tissue composition, were measured cross-sectionally using a Hologic QDR 2000 densitometer. The presence of a polymorphic restriction site at the VDR gene locus was specified as b, whereas absence of this site was B. The frequency distribution of the VDR genotype was: bb, 20.6%; Bb, 39.1%; and BB, 40.2%. Spinal BMD (mean +/- SD) was significantly lower in women with VDR genotype BB (1.038 +/- 0.11 g/cm2) as compared with those with genotype bb (1.069 +/- 0.12 g/cm2, p < 0.05). Trochanter BMD was 2.7% lower in those with genotype BB versus bb (0.685 +/- 0.10 g/cm2 vs 0.708 +/- 0.09 g/cm2). A similar trend was shown at each subregion of the hip, but not at the whole-body. In premenopausal women, allelic status at the VDR locus contributed to variations in spinal and trochanteric BMDs, but the absolute difference in BMDs was small, amounting to 0.26 and 0.23 standard deviations, respectively. It is concluded that in this population of healthy premenopausal women there was a significant association between polymorphisms at the VDR gene locus and both spinal and trochanteric BMDs, yet no association was demonstrated for the whole-body BMD.

Body composition and bone mineral density in premenopausal and early perimenopausal women.

Body composition appears to be an important determinant of bone mineral density (BMD). BMD at the femoral neck, lumbar spine, and whole-body and the whole-body soft-tissue composition were measured cross-sectionally in 334 healthy premenopausal and early perimenopausal women, aged 44-50 years, using a Hologic QDR densitometer. Correlations between lean mass and BMD at the hip, spine, and whole-body were greater (r = 0.40, r = 0.44, and r = 0.45, respectively, p < 0.0001) than those for fat mass (r = 0.19, r = 0.16, and r = 0.16, respectively, p < 0.01). There was a significant linear trend in femoral BMD from the lowest to highest category of lean mass (0.75 +/- 0.10 g/cm2, 0.80 +/- 0.10 g/cm2, and 0.86 +/- 0.09 g/cm2, p < 0.0001). Similar trends were demonstrated for spinal and whole-body density. For categories of fat mass, there was a significant linear trend at the hip (0.78 +/- 0.10 g/cm2, 0.79 +/- 0.10 g/cm2, and 0.83 +/- 0.10 g/cm2, p = 0.0106), but not at the spine or whole body. There was a 5.00% (3.62, 6.38; 95% confidence limits) difference in hip BMD per unit (standard deviation) of lean mass, while only a 0.73% (-0.66, 2.11) difference in hiP BMD per unit (SD) of fat mass. Differences in BMD were examined by categories of lean and fat mass (low, medium, high) for a total of nine possible combinations of lean and fat measures. BMD at the hip, spine, and whole-body were significantly higher in those with high lean mass than in those with low lean mass, irrespective of fat mass. Women with high lean/low fat had similar hip, spinal, and whole-body BMD as those with high lean/high fat, despite their significantly lower body weight (62.5 +/- 3.3 kg vs 85.7 +/- 5.4 kg, respectively, p < 0.0001). In premenopausal and early perimenopausal women, body weight alone may not be associated with increased bone mass unless a significant proportion of that weight is comprised of lean mass. The stronger association between lean mass and BMD than that for fat mass may be attributed to differences in determinants of lean mass, such as exercise, lifestyle factors, estrogen levels, or a combination of these factors.

Comparison of broadband ultrasound attenuation to single X-ray absorptiometry measurements at the calcaneus in postmenopausal women.

Broadband ultrasound attenuation (BUA), a radiation-free and portable technology, may be useful in assessing bone density and fracture risk. In this study, we compared cross-sectional BUA measurements to the more established single energy X-ray absorptiometry measurements of bone mineral density (BMD) at the calcaneus in 259 healthy postmenopausal women, aged 45-76 years. Paired measurements with repositioning of the subject's dominant heel were made consecutively by each method. A coefficient of variation (CV) for each method was calculated for each individual from the paired scans. BUA and BMD of the heel were also compared with BMD of the lumbar spine and femoral neck, as measured by dual energy X-ray absorptiometry. BUA was significantly correlated with BMD at the calcaneus (r = 0.66, P < 0.01). Heel BUA was also correlated with lumbar spine BMD (r = 0.43, P < 0.01) and femoral neck BMD (r = 0.43, P < 0.01) but the correlations were lower than those between heel BMD and spine (r = 0.63, P < 0.01) or femoral neck BMD (r = 0.62, P < 0.01). The mean CV for heel BUA (3.60 +/- 3.50%) was significantly greater than that for heel BMD (1.06 +/- 0.99%, P < 0.01). The moderate correlation of calcaneal BUA and BMD, the lower correlations of BUA than heel BMD with both spine and hip BMD, and lower precision of BUA indicate BUA does not predict bone density as effectively as absorptiometry, the current standard methodology.

Contributions of vitamin D intake and seasonal sunlight exposure to plasma 25-hydroxyvitamin D concentration in elderly women.

We investigated the contributions (1.00-8.03 micrograms/d, or 40-321 IU/d) of vitamin D intake and seasonal sunlight exposure to plasma 25(OH)D in 59 healthy women aged 70-97 y with a mean total vitamin D intake of 8.58 micrograms/d (343 IU/d). In the summer and winter, each subject had a fasting blood measurement and assessments of vitamin D intake and sunlight exposure. Vitamin D intake was significantly correlated with plasma 25(OH)D in the summer (r = 0.52, P < 0.01) and winter (r = 0.63, P < 0.01). The influence of sunlight exposure measured in the summer on the 25(OH)D concentration was dependent on the vitamin D intake. In subjects with lower vitamin D intakes (1.00-8.03 micrograms/d, or 40-321 IU/d), the wintertime 25(OH)D concentrations of those with low and high sunlight exposure were comparable. In subjects with higher vitamin D intakes (11.15-28.68 micrograms/d, or 446-1147 IU/d), however, the wintertime 25(OH)D concentrations of those with high sunlight exposure were lower than those with lower exposure [63.8 +/- 3.9 and 80.6 +/- 6.7 nmol/L, respectively, P = 0.066; P (intake by exposure interaction) < 0.05]. This suggests that the contribution of vitamin D intake to plasma 25(OH)D concentration may be influenced by sunlight exposure.