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.

A comparison of lower extremity muscle strength, obesity, and depression scores in elderly subjects with knee pain with and without radiographic evidence of knee osteoarthritis.

OBJECTIVE: To determine, in subjects with knee pain but no radiographic changes of tibiofemoral or patellofemoral compartment osteoarthritis (OA), whether mean body weight, quadriceps and hamstring strength, lower extremity muscle mass, depression scores, and perceptions of their general health status differed from those of subjects with symptomatic knee OA. METHODS: Subjects were 25 women and 10 men with knee pain and radiographic evidence of OA at the baseline examination, and 21 women and 16 men who had knee pain at the baseline examination but no radiographic evidence of knee OA at either baseline examination or followup evaluation performed, on average, 31 months later. These individuals were a subset of a cohort of 462 independently living elderly individuals recruited by telephone interview after random selection through random digit dialing of households in central Indiana. Data from an additional 134 subjects who had neither knee pain nor radiographic changes of OA at either the baseline or followup examination were analyzed for comparison. Lower extremity muscle strength was measured by isokinetic dynamometry, lean tissue (i.e., muscle) mass in the lower extremities by dual x-ray absorptiometry, depression by Center for Epidemiology Depression (CES-D) scale. knee pain by Western Ontario McMaster University OA instrument, and perceived general health status by the Medical Outcome Survey Short Form-36. RESULTS: In contrast to those with symptomatic knee OA, those who had knee pain but no radiographic evidence of OA were less obese, had hamstring as well as quadriceps weakness, and had CES-D scores high enough to qualify for a diagnosis of clinical depression. CONCLUSION: Among subjects with knee pain but no OA--and among women in this subset, in particular--knee pain may be a manifestation of depression. rather than of joint disease.

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.

Quadriceps strength in women with radiographically progressive osteoarthritis of the knee and those with stable radiographic changes.

OBJECTIVE: To explore the relationship between lower extremity weakness and the progression of established radiographic changes of knee osteoarthritis (OA). METHODS: The study cohort of 342 elderly subjects was recruited from central Indiana by random digit dialing. We analyzed 79 subjects who had definite radiographic changes of unilateral or bilateral knee OA at baseline and for whom baseline data for lower extremity muscle strength and lean tissue mass and baseline and followup assessments of knee pain were available. Radiographs were graded for severity of OA at baseline and again about 2.5 years later (mean 31.5 months). Knee pain was evaluated at the same examination. Strength of the knee flexors and extensors was assessed bilaterally at baseline by isokinetic dynamometry and lower extremity muscle mass by dual energy x-ray absorptiometry. RESULTS: Mean peak knee extensor strength of women with progressive OA, before and after adjustment for lower extremity muscle mass, was about 9% lower than that in those with stable radiographic changes, but this difference was not statistically significant. No difference was apparent between the 2 groups with respect to knee flexor (hamstring) strength. The decrease in quadriceps strength among women with progressive OA, relative to those with stable OA, did not appear to be attributable to knee pain, and knee extensor strength at baseline bore no apparent relationship to the development or progression of knee pain among those with OA. CONCLUSION: We have shown previously that quadriceps weakness may be of etiologic importance in development of knee OA. The absence of a significant difference in quadriceps strength between subjects with radiographically stable OA and those whose joint damage progressed suggests that factors other than quadriceps weakness are more important determinants of OA progression.

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.

Reduced quadriceps strength relative to body weight: a risk factor for knee osteoarthritis in women?

OBJECTIVE: To determine whether baseline lower extremity muscle weakness is a risk factor for incident radiographic osteoarthritis (OA) of the knee. METHODS: This prospective study involved 342 elderly community-dwelling subjects (178 women, 164 men) from central Indiana, for whom baseline and followup (mean interval 31.3 months) knee radiographs were available. Lower extremity muscle strength was measured by isokinetic dynamometry and lean tissue (i.e., muscle) mass in the lower extremities by dual x-ray absorptiometry. RESULTS: Knee OA was associated with an increase in body weight in women (P = 0.0014), but not in men. In both sexes, lower extremity muscle mass exhibited a strong positive correlation with body weight. In women, after adjustment for body weight, knee extensor strength was 18% lower at baseline among subjects who developed incident knee OA than among the controls (P = 0.053), whereas after adjustment for lower extremity muscle mass, knee extensor strength was 15% lower than in the controls (P not significant). In men, in contrast, adjusted knee extensor strength at baseline was comparable to that in the controls. Among the 13 women who developed incident OA, there was a strong, highly significant negative correlation between body weight and extensor strength (r = -0.740, P = 0.003), that is, the more obese the subject, the greater the reduction of quadriceps strength. In contrast, among the 14 men who developed incident OA, a modest positive correlation existed between weight and quadriceps strength (r = 0.455, P = 0.058). No correlation between knee flexor (hamstring) strength and knee OA was seen in either sex. CONCLUSION: Reduced quadriceps strength relative to body weight may be a risk factor for knee OA in women.

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.

Prevention of hip fractures: risk factor modification.

Factors that influence the risk of hip fracture have been identified, many of which can be eliminated or modified. Even those risk factors that cannot be modified are important for identifying at-risk patients, who may benefit most from therapies that after other risk factors. Bone mineral density (BMD) is the major measurable determinant of the risk of fragility fractures. However, recent prospective studies have identified factors that influence the risk of having a hip fracture independently of the risk associated with low BMD. Skeletal factors other than BMD that may increase the risk of hip fracture in women include hip geometry and height (tallness). Other factors, some of which are potentially modifiable, operate through effects on the risk of trauma, including decreased visual acuity, neuromuscular impairment, cognitive impairment, residence in a nursing home, poor general physical health, and use of medications that diminish alertness. Fall mechanics also play an important role in the etiology of hip fractures. Falls to the side, particularly those with impact on the hip or side of the leg, more often result in hip fractures than do other falls. Protection of the hip with external padding offers great promise in the prevention of hip fracture in patients with very low bone mass or with conditions that make falls almost inevitable. Increases in hip fracture rates in developing countries suggest a possible relationship with declining physical activity (particularly load-bearing activity). Although the role of exercise in the prevention of osteoporosis and hip fracture has not yet been proven, there is evidence of independent protective effects of both past physical activity and moderate levels of recent physical activity on the risk of hip fracture. Low body weight secondary to poor appetite or poor health (as opposed to intentional weight loss) has been associated with increased hip fracture risk, and nutritional deficiencies may also play a role in hip fracture pathogenesis. These are potentially modifiable. Future studies should be aimed at confirming the hip fracture risk factors identified, ascertaining their independence from other factors, assessing their prevalence, and determining the outcomes and costs involved in interventions to modify them.

Quadriceps weakness and osteoarthritis of the knee.

BACKGROUND: The quadriceps weakness commonly associated with osteoarthritis of the knee is widely believed to result from disuse atrophy secondary to pain in the involved joint. However, quadriceps weakness may be an etiologic factor in the development of osteoarthritis. OBJECTIVE: To explore the relation between lower-extremity weakness and osteoarthritis of the knee. DESIGN: Cross-sectional prevalence study. SETTING: Population-based, with recruitment by random-digit dialing. PARTICIPANTS: 462 volunteers 65 years of age or older. MEASUREMENTS: Radiographs of the knee were graded for the presence of osteoarthritis. Knee pain and function were assessed with the Western Ontario and McMaster Universities Arthritis Index, the strength of leg flexors and extensors was assessed with isokinetic dynamometry, and lower-extremity lean tissue mass was assessed with dual-energy x-ray absorptiometry. RESULTS: Among participants with osteoarthritis, quadriceps weakness, but not hamstring weakness, was common. The ratio of extensor strength to body weight was approximately 20% lower in those with than in those without radiographic osteoarthritis. Notably, among women with tibiofemoral osteoarthritis, extensor weakness was present in the absence of knee pain and was seen in participants with normal lower-extremity lean mass (extensor strength, 30.1 lb-ft for those with osteoarthritis and 34.8 lb-ft for those without osteoarthritis; P < 0.001). After adjustment for body weight, age, and sex, lesser quadriceps strength remained predictive of both radiographic and symptomatic osteoarthritis of the knee (odds ratio for prevalence of osteoarthritis per 10 lb-ft loss of strength, 0.8 [95% CI, 0.71 to 0.90] for radiographic osteoarthritis and 0.71 [CI, 0.51 to 0.87] for symptomatic osteoarthritis). CONCLUSION: Quadriceps weakness may be present in patients who have osteoarthritis but do not have knee pain or muscle atrophy; this suggests that the weakness may be due to muscle dysfunction. The data are consistent with the possibility that quadriceps weakness is a primary risk factor for knee pain, disability, and progression of joint damage in persons with osteoarthritis of the knee.

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.

Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women.

Although bone loss around the time of menopause is driven by estrogen deficiency, the roles of estrogens and androgens in the preservation of skeletal mass at other stages of life are less well understood. To address this issue we studied 231 women between the ages of 32 and 77 with multiple measurements of sex steroids and bone mass over a period of 2-8 yr. In all women bone mass was negatively associated with concentrations of sex-hormone binding globulin, and positively associated with weight. Bone loss occurred from all skeletal sites in peri- and postmenopausal women, but premenopausal women lost bone only from the hip (-0.3%/yr) and had positive rates of change in the radius and spine. Bone loss was significantly associated with lower androgen concentrations in premenopausal women, and with lower estrogens and androgens in peri- and postmenopausal women. Sex steroids are important for the maintenance of skeletal integrity before menopause, and for as long as 20-25 yr afterwards.

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.

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.

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.

Peak bone mass in young women.

Increasing peak bone mineral density (BMD) or content (BMC) in young women may help to reduce the incidence of osteoporosis. Identifying the age when peak bone content or density is attained is essential to develop strategies aimed at optimizing peak BMD and BMC. Total body bone mineral density (TBBMD) and content (TBBMC) were measured by a dual X-ray absorptiometer in healthy females (n = 247, aged 11-32 years). TBBMD and TBBMC were modeled separately as a nonlinear function of age. By age 22.1 +/- 2.5 years, 99% of peak BMD is attained, and by age 26.2 +/- 3.7 years, 99% of peak BMC is attained. Nonlinear relationships between weight and TBBMD or TBBMC were also modeled. In this model, the influence of several parameters, including age, weight, and height, on BMC and BMD were simultaneously assessed. A model with age and weight described the best fit for TBBMD, whereas age, weight, and height described the best fit for total body TBBMC.

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)