Effect of long-term exposure to fluoride in drinking water on risks of bone fractures.

Findings on the risk of bone fractures associated with long-term fluoride exposure from drinking water have been contradictory. The purpose of this study was to determine the prevalence of bone fracture, including hip fracture, in six Chinese populations with water fluoride concentrations ranging from 0.25 to 7.97 parts per million (ppm). A total of 8266 male and female subjects > or =50 years of age were enrolled. Parameters evaluated included fluoride exposure, prevalence of bone fractures, demographics, medical history, physical activity, cigarette smoking, and alcohol consumption. The results confirmed that drinking water was the only major source of fluoride exposure in the study populations. A U-shaped pattern was detected for the relationship between the prevalence of bone fracture and water fluoride level. The prevalence of overall bone fracture was lowest in the population of 1.00-1.06 ppm fluoride in drinking water, which was significantly lower (p < 0.05) than that of the groups exposed to water fluoride levels > or =4.32 and < or =0.34 ppm. The prevalence of hip fractures was highest in the group with the highest water fluoride (4.32-7.97 ppm). The value is significantly higher than the population with 1.00-1.06 ppm water fluoride, which had the lowest prevalence rate. It is concluded that long-term fluoride exposure from drinking water containing > or =4.32 ppm increases the risk of overall fractures as well as hip fractures. Water fluoride levels at 1.00-1.06 ppm decrease the risk of overall fractures relative to negligible fluoride in water; however, there does not appear to be similar protective benefits for the risk of hip fractures.

Trace element levels in drinking water and cognitive function among elderly Chinese.

The relation between trace element levels in drinking water and cognitive function was investigated in a population-based study of elderly residents (n = 1,016) in rural China in 1996-1997. Cognitive function was measured using a Chinese translation of the Community Screening Interview for Dementia. A mixed effects model was used to evaluate the effect of each of the elements on cognitive function while adjusting for age, sex, and educational level. Several of the elements examined had a significant effect on cognitive function when they were assessed in a univariate context. However, after adjustment for other elements, many of these results were not significant. There was a significant quadratic effect for calcium and a significant zinc-cadmium interaction. Cognitive function increased with calcium level up to a certain point and then decreased as calcium continued to increase. Zinc showed a positive relation with cognitive function at low cadmium levels but a negative relation at high levels.

Rates of growth and loss of bone mineral in the spine and femoral neck in white females.

This study characterizes the rates of growth and loss of bone mass as a function of age in white females. It combines longitudinal data from several studies of bone mass on healthy white female subjects ranging from age 6 to 90 years. Rates of change in bone area, bone mineral content (BMC) and bone mineral density (BMD) are estimated separately for the spine and the femoral neck of each individual using linear regression. The individual rates of change are then fitted as a nonparametric function of age using weighted moving averages, resulting in a curve of age-specific mean change as a function of age. When the curves of BMD were compared between the hip and the femoral neck, the cessation of bone growth and the onset of bone loss were found to occur at an earlier age at the hip than at the spine. No significant differences in the ages of maximum rates of growth or maximum loss were found between the two skeletal sites. This information will be useful for designing interventions to promote bone growth or retard bone loss.

Linkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12-13.

Osteoporosis is a leading public health problem that is responsible for substantial morbidity and mortality. A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Recent linkage of three Mendelian BMD-related phenotypes, autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessive osteopetrosis to chromosome 11q12-13 led us to evaluate this region to determine if the underlying gene(s) could also contribute to variation in BMD in the normal population. We performed a linkage study in a sample of 835 premenopausal Caucasian and African-American sisters to identify genes underlying BMD variation. A maximum multipoint LOD score of 3.50 with femoral neck BMD was obtained near the marker D11S987, in the same chromosomal region as the three Mendelian traits mentioned above. Our results suggest that the gene(s) underlying these Mendelian phenotypes also play a role in determining peak BMD in the normal population and are the first using linkage methods to establish a chromosomal location for a gene important in determining peak BMD. These findings support the hypothesis that a gene responsible for one or more of the rare Mendelian BMD traits linked to chromosome 11q12-13 has an important role in osteoporosis in the general population.

Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens.

The purpose of this study was to determine whether bone density in older men was associated with serum sex steroids or sex hormone binding globulin (SHBG). Bone density and sex steroids were measured in men over age 65 at 6-mo intervals for an average of 2.1 yr. Bone density was significantly positively associated with greater serum E2 concentrations (+0.21 < r < +0.35; 0.01 < P < 0.05) at all skeletal sites. There were weak negative correlations between serum testosterone and bone density (-0.20 < r < -0.28; 0.03 < P < 0.10) at the spine and hip. SHBG was negatively associated only with bone density in the greater trochanter (r = -0.26, P < 0.05). Greater body weight was associated with lower serum testosterone and SHBG, and greater E2. Because of these associations, regression models which adjusted for age, body weight, and serum sex steroids were constructed; these accounted for 10-30% of the variability in bone density, and showed consistent, significant positive associations between bone density and serum E2 concentrations in men, even after adjustments for weight and SHBG. These data suggest that estrogens may play an important role in the development or maintenance of the male skeleton, much as is the case for the female skeleton. These data also indicate that, within the normal range, lower serum testosterone concentrations are not associated with low bone density in men.

Reduced rates of skeletal remodeling are associated with increased bone mineral density during the development of peak skeletal mass.

Two related studies were conducted to assess the associations between markers of skeletal modeling and remodeling in healthy children. Members of monozygotic twin pairs, aged 6-14, enrolled in a clinical trial of calcium supplementation, were studied at the end of the period of supplementation and for 3 years thereafter. Supplemented children had significantly higher rates of gain in bone mineral density (BMD) (+3% on average) during the period of supplementation accompanied by significantly lower concentrations of serum osteocalcin (OC, -15%). During postsupplement follow-up, both differences in BMD and OC disappeared. Black females, age matched to the baseline ages of the white children, had significantly lower serum concentrations of both OC and tartrate-resistant acid phosphatase (TRAP) at all ages and higher BMDs. When stratified on serum TRAP concentrations, regardless of race, children with lower concentrations had significantly higher BMDs, and no racial differences were apparent. In regression models accounting for 70-80% of the variability in BMD in children, body size and TRAP, but not race, remained significantly associated with BMD. The skeletal advantages seen with calcium supplementation and black race appear to be associated with reduced rates of skeletal turnover. Given that markers of turnover during growth reflect both skeletal modeling and remodeling, and there is no apparent advantage to reduced skeletal modeling, it seems probable that reduced remodeling is the factor that accounts for the increases in bone mass.

Hematopoietic bone marrow hyperplasia: correlation of spinal MR findings, hematologic parameters, and bone mineral density in endurance athletes.

PURPOSE: To determine the frequency of hematopoietic hyperplasia on spinal magnetic resonance (MR) images in endurance athletes and to correlate MR alterations with clinical parameters. MATERIALS AND METHODS: In 15 endurance athletes, MR images of the lumbar spine were analyzed for hematopoietic hyperplasia; vertebral T1 and T2 were determined. Bone mineral density (BMD) was determined, blood tests were performed, and maximum oxygen consumption (VO2max) was measured. RESULTS: Nine subjects showed evidence of hematopoietic hyperplasia: Eight showed T1 prolongation, and six had patchy or diffuse T1 hypointensity. No definite correlation existed between hematopoietic hyperplasia and duration of training, hematologic results, or VO2max levels. Borderline significance existed between hematopoietic hyperplasia and anemia (P = .103) and intensity of training (P = .09). BMD had no statistically significant effect on T1. CONCLUSION: Changes in BMD do not appear to contribute to MR marrow changes that are consistent with hematopoietic hyperplasia. Depleted iron reserves or increased hematopoiesis probably contribute to hematopoietic hyperplasia in endurance athletes.

The genetics of proximal femur geometry, distribution of bone mass and bone mineral density.

To estimate genetic effects on femoral neck geometry and the distribution of bone mineral within the proximal femur a cross-sectional twin analysis was carried out at a university hospital that compared correlations in these traits in pairs of mono- and dizygotic female twins. Monozygotic (MZ, n = 51 pairs, age 49.1 +/- 9.3 years) and dizygotic (DZ, n = 26 pairs, age 45.7 +/- 11.3 years) twins were randomly selected from a larger sample of twins previously studied. Measurements of bone mineral density (BMD), femoral neck angles and length, cross-sectional area and moment of interia, the center of mass of the narrowest cross-section of the femoral neck, and BMDs of regions within the femoral neck were made. A summary index of the resistance of the femoral neck to forces experienced in a fall with impact on the greater trochanter (Fall Index, FI) was calculated. MZ pair intraclass correlations (rMZ) were significantly (p < 0.05) different from zero for all bone mass and femoral geometry variables (0.35 < rMZ < 0.82). DZ pair correlations (rDZ) were lower than rMZ for all variables (0.04 < rDZ < 0.52) except femoral neck length (rDZ = 0.38, rMZ = 0.36). After adjustment for BMD of the femoral neck, rMZ was significantly greater than rDZ, yielding high heritability estimates for regional BMDs (0.72 < H2 < 0.78), the center of mass of the femoral neck (H2 = 0.70, -0.04 to 1.43 95% CI) and the resistance of the femoral neck to forces experienced in a fall (FI, H2 = 0.94, 0.06 to 1.85 95% CI), but not for femoral neck length. Adjustments for age did not alter these findings. It is concluded that there are significant familial influences on the distribution of femoral bone mass and on the calculated structural strength of the proximal femur, but not on femoral neck length. If the assumptions of the twin model are correct, this is evidence for genetic factors influencing these traits.

Choosing between predictors of fractures.

The identification of those at highest risk of osteoporotic fractures is a clinical goal that requires appropriate statistical comparisons of potential predictors of fractures. This article provides a formal approach of comparing individual predictors (e.g., bone mass at one site vs bone mass at another), or sets of predictors (e.g., bone mass vs other risk factors), and contrasts newer methods, such as bootstrapping, to receiver-operating-characteristics (ROC) curves, which have been previously used. The advantages of the bootstrapping approach are illustrated using time-to-fracture data from a published study demonstrating the use of baseline bone mass measurements in the prediction of fractures in 521 subjects with variable lengths of follow-up, extending to 12.5 years. Bone mineral density (BMD) was shown to be significantly better than bone mineral content (BMD) in predicting fractures in free-living subjects, but not in retirement-community subjects. Bone mineral apparent density (BMAD) was also compared with BMC and BMD and shown not to improve fracture prediction in these subjects.

Bone mineral density during treatment of central precocious puberty.

Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.

Pathogenesis of osteoporosis.

Fractures, the clinical outcome associated with osteoporosis, have a complex pathogenesis involving, in most cases, both trauma to the bone and increased skeletal fragility. Recent evidence also suggests that the geometry of the bone is important in determining fracture risk, and geometric properties are in part genetically determined. Skeletal fragility is largely determined by bone mass and the microstructure of bone. Loss of trabeculae and their connections has been well documented and undoubtedly contributes to risk of some fractures. Microdamage has also been shown to occur within the skeleton and could contribute to fragility. Peak bone mass is a major factor in determination of subsequent fracture risk and it has both genetic and environmental determinants. Twin studies have suggested a major genetic contribution and that a few genes may be responsible, but these genes have not been clearly identified. Nutrition, especially calcium intake, and exercise also contribute to the determination of peak bone mass and are especially important during the major period of bone acquisition up to the age of 18. Bone loss among women begins in the perimenopausal period, although loss from the hip begins earlier. The loss is associated with both estrogen and androgen concentrations. Later in life other factors such as the development of secondary hyperparathyroidism may contribute to the continued loss of bone. Males lose bone at about half the rate of females, but the underlying contributing factors are not well documented. The pathogenesis of osteoporotic fractures is complex, but this allows for the development of multiple interventions, which may reduce the frequency of such fractures.

Longitudinal and cross-sectional analysis of raloxifene effects on tibiae from ovariectomized aged rats.

To extend and confirm previous data, we examined the effects of raloxifene on the proximal tibia of ovariectomized rats, aged 6 months, longitudinally and cross-sectionally by computed tomography (pQCT) and then compared the effects to those of orally dosed estrogen. Comparative analysis of phantoms and rat bones showed that the pQCT is precise and correlates with a Hologic QDR 1000W (DXA) with R = 0.999 but is capable of measuring significant differences between groups when the DXA cannot. This may reflect the ability of the pQCT to determine bone volume, mineral content (mg) and volumetric mineral density (mg/cm3), compared with two-dimensional analyses performed with DXA. Longitudinal analysis of the proximal tibia in vivo showed a significant 17% reduction in mineral density 31 days after ovariectomy. Examination of the images from ovariectomized rats showed a progressive increase in the cross-sectional area of the proximal tibiae, loss of trabecular bone, widening of marrow spaces and thinning of the cortical bone wall opposite the fibula. Regression analysis of the dose-dependent protective effects of raloxifene showed the half-maximal efficacy on tibiae mineral density to be ED50 = 0.4 mg/kg/day per os by pQCT and 0.2 mg/kg/day by DXA. By comparison, 17 alpha ethynyl estradiol showed dose-dependent effects with ED50 = 0.013 mg/kg/day per os by pQCT. Both raloxifene and ethynyl estradiol had beneficial effects on serum lipids, producing 50% reduction of cholesterol at 0.1 mg/kg/day raloxifene and 80% reduction with 0.01 mg/kg/day ethynyl estradiol. However, raloxifene up to 10 mg/kg/day had little effect on uterine weight, whereas 0.01 mg/kg/day ethynyl estradiol increased uterine wet weight by 300%.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of patients with low bone mass by single photon absorptiometry and single-energy X-ray absorptiometry.

Single-photon absorptiometry measurements at the radius and calcaneus have been shown in a number of prospective studies to predict the risk of all fractures as well as measurements at the spine or hip. Single-energy X-ray absorptiometry should do as well or better. These methods should be useful in selecting patients for therapy to treat or prevent osteoporosis.

Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity.

OBJECTIVE: To establish rates of skeletal mineralization in children and adolescents, and to identify factors that influence these rates. DESIGN: Three-year observational study. SETTING: University hospital. SUBJECTS: Ninety white children, aged 6 to 14 years. MEASUREMENTS: Bone mineral density of the radius, spine, and hip was measured at baseline and 3 years later. Physical activity was assessed by questionnaires at 6-month intervals and dietary calcium intake by diet diary 1 day per month for 36 months. Sexual maturation (Tanner stage) was determined by an endocrinologist at 6-month intervals, as necessary to classify children as prepubertal, peripubertal, or postpubertal. RESULTS: Skeletal mineralization accelerated markedly at puberty in the spine (0.077 vs 0.027 gm/cm2 per year, peripubertal vs prepubertal) and greater trochanter (0.050 vs 0.027 gm/cm2 per year), less markedly in the femoral neck (0.047 vs 0.030 gm/cm2 per year), and only slightly in the radius. Nearly one third (15 gm) of the total skeletal mineral in the lumbar spine of adult women (approximately 52 gm) was accumulated in the 3 years around the onset of puberty. Increases in height and weight were the strongest correlates of skeletal mineralization: weight changes were more strongly correlated with trabecular bone sites and changes in height with cortical bone sites. Increases in calf muscle area were strongly associated with mineralization, particularly in peripubertal children, and physical activity was associated with more rapid mineralization in prepubertal children. CONCLUSIONS: Puberty has varying effects on skeletal mineralization depending on skeletal site; trabecular bone is apparently more sensitive to changing hormone concentrations. Physical activity and normal growth are also positively associated with skeletal mineralization, also depending on skeletal site and sexual maturation.

Geometric structure of the femoral neck measured using dual-energy x-ray absorptiometry.

An algorithm was developed to estimate the strength of the femoral neck from data generated by the dual-energy x-ray absorptiometry (DXA). This algorithm considers shape of the proximal femur as well as cross-sectional moment of inertia (CSMI) in the estimate. Proximal femora (10) from cadavers of white adults and an aluminum step wedge were scanned with the Lunar DPX to validate the calculation of CSMI. After scanning, each femoral neck was sectioned at its narrowest portion for direct measurement of CSMI. Three healthy young women were scanned five times each to evaluate the reproducibility of geometric measurements using DXA. There was a strong linear association between the CSMI measured directly and using DXA in both cadaver bones (r2 = 0.96) and the aluminum step wedge (r2 = 0.99). The coefficient of variation for CSMI from repeated measurements using DXA was less than 3%. This indicates that it is possible to estimate reproducibly the bending rigidity of bone from DXA measurements. The data from 306 normal subjects were analyzed to investigate geometric changes in the femoral neck with age. Although there was no strong correlation between CSMI and age in normal subjects of either sex, safety factor (SF, an index of strength of the femoral neck during walking) and fall index (FI, an index of the strength of the femoral neck during a fall) decrease with age in both sexes. We observed an alteration of the geometric structure of the femoral neck with age that may increase the stress on the femoral neck and decrease SF and FI.

Do variations in hip geometry explain differences in hip fracture risk between Japanese and white Americans?

Despite lower femoral neck bone mass, Japanese women have a substantially lower incidence of hip fracture than North American whites. Reasons for this discrepancy were sought in a study of 57 Japanese and 119 white American women aged 50-79. All women were in good health. Bone mineral content (BMC) in the femoral neck, femoral neck length (NL), femoral neck angle (theta), cross-sectional moment of inertia (CSMI), safety factor (SF), and fall index (FI) were calculated using dual x-ray absorptiometry. Height and weight were greater in Americans than in Japanese (1.62 versus 1.52 m; p < 0.0001 and 66.0 versus 49.4 kg; p < 0.0001, respectively). Mean BMC in the femoral neck and CSMI were greater in Americans than in Japanese (3.91 versus 3.02 g; p < 0.0001 and 0.99 versus 0.57 cm4; p < 0.0001, respectively). NL was longer in Americans (5.6 versus 4.4 cm; p < 0.0001) and theta was larger in Americans (130 versus 128 degrees; p < 0.01), whereas SF and FI were less in Americans than in Japanese (3.41 versus 5.12; p < 0.0001 and 1.00 versus 1.40; p < 0.0001, respectively). These results indicate that despite lower bone mass, Japanese women have lower risks of structural failure in the femoral neck, attributable primarily to shorter femoral necks and, to a lesser degree, a smaller femoral neck angle. Geometric characteristics of the femoral neck in Japanese women are associated with their lower hip fracture risk, and the measurement of proximal femoral geometry, combined with bone mass, may provide further clinical information about the risk of hip fracture.

Correlations of alcohol consumption with related covariates and heritability estimates in older adult males over a 14- to 18-year period: the NHLBI Twin Study.

Consistent maximum-likelihood heritability estimates of consumption of alcoholic beverages were observed at three separate times during a 14- to 18-year period in adult twin males initially aged 42-56 years in 1969-1973. Log transformation of the average number of drinks/week of the returnees to all three examinations was examined relative to potential covariates representing both antecedents of drinking alcohol and consequences of alcohol consumption. Significant relationships were noted for 38 of the covariates at one or more of the separate examinations, including positive correlations with smoking, coffee consumption, high-density lipoprotein cholesterol, mean corpuscular volume, systolic blood pressure, uric acid and behavioral measures, and negative correlations with blood urea nitrogen, red blood cell count, tea consumption, and tricep skinfolds. Analysis of the average alcohol consumption adjusted for nine independent covariates selected from multiple stepwise regression resulted in a modest decline in maximum-likelihood heritability estimates compared with unadjusted data, but little difference from heritability estimates obtained when abstainers from alcohol (no alcoholic beverages consumed at all three examinations) were excluded. The most striking effect of omitting abstainers from alcohol was the decline in the intraclass correlations in dizygotic twins. Bivariate analyses of alcohol and individual covariates revealed the phenotypic correlation between alcohol consumption and a measure of hostility was primarily environmental, that for high-density lipoprotein, smoking and coffee drinking with alcohol was primarily genetic, and the phenotypic correlation between alcohol consumption and mean corpuscular volume had both significant genetic and environmental correlations.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual-energy x-ray absorptiometry of raloxifene effects on the lumbar vertebrae and femora of ovariectomized rats.

A new potential therapeutic agent for postmenopausal osteoporosis, raloxifene, previously known as keoxifene, was evaluated by x-ray densitometry and more traditional techniques in quantitating the short-term (4-5 weeks) effects of ovariectomy on bones from 6-month-old rats. A Hologic QDR 1000/W and, to a limited extent, a Lunar DPXL, was used to quantitate ovariectomy, estrogen replacement, and raloxifene effects on vertebrae, femora, and tibiae. Both instruments performed well with precisions of 1.6% (Hologic) and 0.9% (Lunar) for anesthetized rats, which improved to 0.4% (Hologic) and 0.5% (Lunar) when the same rats were frozen. The lumbar vertebrae L1-4 showed a 12% decrease in bone mineral density 4 weeks after ovariectomy, compared with a 9% decrease for femora. Tibiae were also examined, but edge-detection problems prevented reproducible analysis of this site in vivo. The decrease in bone mineral density postovariectomy, especially for femora, was found to include both an increase in the projected area and a slight but not significant decrease in the bone mineral content of L1-4 and femora. These changes in density parameters of femora were supported by a decrease in dry weight and volume and a marginal increase in the second moment of inertia I for the identical femora examined ex vivo. Examination of individual lumbar vertebrae L1-5 suggested that the bone mineral density of L3 changes most dramatically in response to ovariectomy, but present techniques lack the spatial resolution and precision to quantitate bone changes reliably in individual vertebrae. 17 beta-Estradiol administered at 100 micrograms/kg/day subcutaneously inhibited ovariectomy effects on L1-4 bone mineral density, femoral moment of inertia, dry weight, and volume and to a lesser extent, femoral bone mineral density. A nonsteroidal compound, raloxifene HCl, at 1 mg/kg/day per os, had bone effects and effects on body weight that were largely indistinguishable from those of 17 beta-estradiol; however, raloxifene did not produce the uterotrophic effects observed with estrogen. The half-maximal efficacious dose of raloxifene on L1-4 bone mineral density was between 0.1 and 1.0 mg/kg/day per os. These data show that dual-energy x-ray absorptiometry compares favorably with traditional methods in quantitating bone changes caused by ovariectomy in small rodents, that L1-4 is a more sensitive region than whole femora in evaluating the effect of estrogen deficiency on bone loss, and the raloxifene may have promise as a treatment for conditions characterized by excessive bone loss after ovariectomy.