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It has been hypothesized that suppression of bone remodeling allows microdamage to accumulate, leading to increased bone fragility. This study evaluated the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties of cortical bone in the dog rib. Thirty-six female beagles, 1-2 years old, were divided into three groups. The control group (CNT) was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right ninth rib was assigned to cortical histomorphometry or microdamage analysis. The left ninth rib was tested to failure in three-point bending. Total cross-sectional bone area was significantly increased in both RIS and ALN compared with CNT, whereas cortical area did not differ significantly among groups. One-year treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS, 53%; ALN, 68%) without impairment of mineralization and significantly increased microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT. Although bone strength and stiffness were not significantly affected by the treatments, bone toughness declined significantly in ALN (20%). Regression analysis showed a significant nonlinear relationship between suppressed intracortical bone remodeling and microdamage accumulation as well as a significant linear relationship between microdamage accumulation and reduced toughness. This study showed that suppression of bone turnover by high doses of bisphosphonates is associated with microdamage accumulation and reduced some mechanical properties of bone.

The effectiveness of parathyroidectomy (PTHX) for the control of secondary hyperparathyroidism was assessed in 46 adult end-stage renal disease (ESRD) patients whose bone mineral content at the midshaft and distal radius was measured using single-photon absorptiometry (SPA) every 6 months before and after the surgery. They were compared to 46 age-, race-, and sex-matched ESRD patient controls who had not undergone surgery but who had had at least five SPA studies at similar intervals. Presurgery midradius bone mass was significantly lower for PTHX patients compared to controls. Comparing changes in bone mass of PTHX patients across surgery to controls in comparable time periods showed that PTHX patients lost significantly less bone mass after surgery. Similar results were obtained when rates of change in bone mass were evaluated. When patient characteristics were examined, the effect of surgery was found to be diminished in elderly patients and in oophorectomized patients. It is concluded that PTHX can have a salutary effect on renal osteodystrophy in the appendicular skeleton, but factors other than bone mass also need to be considered in identifying those patients who will benefit from surgery.

VER THE YEARS many definitions of osteoporosis have been 0 offered to describe variously the outcome events (fragility fractures), the process giving rise to porous bones, or the resultant diminution of bone mass. More consistency has been achieved in recent years by the development of definitions that cover the spectrum of its manifestations. from the reduced amount of bone present to some of the consequences of bone loss. A consensus development conference statement defined osteoporosis as "a disease characterized by low bonc mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk."'" The definition has survived the rigors of the most recent consensus development confcrence."' There are, however, a number of problems which need to be addressed in adapting a conceptual definition for clinical use. Some of these problems were recently discussed by an expert panel of the World Health Organization."' This paper summarizes these issues and proposes diagnostic criteria for osteoporosis for practical use.

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 for 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 (BMC) 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.

A group of 118 children, aged 5.3-14 years, were enrolled in a prospective study of calcium supplementation and bone mass. At entry to the study, questionnaires regarding the child's usual physical activity were administered to the children and their mothers. Repeated activity assessments at 6 month intervals indicated good within-person agreement for total activity and for most individual activities. Consistent positive associations were observed between bone mineral densities (BMD) in the radius, spine, and hip and most activities. A summary measure (total hours of weight-bearing activity) was significantly related to BMD in the radius and hip, independently of age or gender effects. Self-reported sports and play activities were associated with BMD, but neither time spent watching television nor hours of physical education classes were associated either positively or negatively with skeletal mass. These data suggest that important increments in skeletal mass may result from physical activity during childhood.

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.

The results of slow-release sodium fluoride (SR-NaF) treatment in two nonrandomized trials involving 65 patients with postmenopausal osteoporosis from the primary site and 121 patients from collaborative sites were compared with those obtained from 54 treated patients and 56 patients taking placebo from a randomized controlled trial. Spinal fracture data were analyzed separately in mild to moderate bone loss of lumbar spine (baseline L2-L4 bone density [BD] ≥ 65% young normal) and in severe bone loss (BD < 65%). Since demographic and fracture data were similar among fluoride-treated patients from the three trials at each stratum of bone loss, their data were combined. In mild to moderate bone loss, SR-NaF treatment in the combined group virtually eliminated new spinal fractures with 96.6% of patients remaining fracture-free. The Fluoride group had a markedly lower individual vertebral fracture rate (0.025 vs. 0.188/patient year, p = 0.0001) and group vertebral fracture rate (0.029 vs. 0.175/patient year, relative risk [RR] 0.12, p = 0.0001) than the Placebo group. In severe bone loss, the combined treated group had a significantly lower new spinal fracture rate than the Placebo group, although the differences were not as marked (group vertebral fracture rate of 0.150 vs. 0.276/patient year, RR 0.54, p = 0.03). In the combined fluoride-treated group, the L2-L4 bone mass rose by 4-6%/year for 4 years, and the femoral neck BD increased by 1-2%/year during first 2 years. The radial shaft BD did not change. The Placebo group did not show a change in bone mass at any site. The prevalence (percentage) of patients with related gastrointestinal side effects and nonvertebral fracture rates did not differ significantly between the combined SR-NaF group and the Placebo group (hip fracture rate of 0.0045/patient year in SR-NaF and 0.0053/patient year in Placebo; appendicular fracture other than hip (see text) rate of 0.0193/patient year in SR-NaF and 0.0159/patient year in Placebo). A subgroup analysis showed a low baseline L2-L4 BD, high prevalent spinal fractures, and reduced body weight to be important determinants of the development of spinal fracture during SR-NaF treatment. Concomitant medications (estrogen, vitamin D, thiazide and thyroid hormone) were not independent predictors of the spinal fracture risk. Only 17% of fluoride-treated patients were nonresponders (new spinal fractures or a fall/no change in L2-L4 bone mass). Thus, the effects of SR-NaF treatment on the spinal fracture rate from nonrandomized trials were similar to those of the treated group of the randomized trial but different from those of the Placebo group. The similarity of response of nonrandomized trials with that of the randomized controlled trial and the resultant combined analysis further validate the efficacy and safety of SR-NaF in the treatment of postmenopausal osteoporosis.

The utility of vertebral fracture assessment (VFA) by DXA to detect prevalent vertebral fracture in a multicenter setting was investigated by comparison to conventional radiography. While limited by lower image quality, overall performance of VFA was good but had a tendency to miss mild prevalent fractures. In osteoporosis clinical trials standardized spine radiographs are used to detect vertebral fractures as a study endpoint. Lateral spine imaging with dual X-ray absorptiometry (DXA) scanners, known as vertebral fracture assessment (VFA) by DXA, presents a potential alternative to conventional radiography with lower radiation dose and greater patient convenience. We investigated in a multicenter setting the ability of VFA to detect fractures in comparison with conventional radiography. The study examined 203 postmenopausal women who had imaging of the spine by DXA and radiography. Three radiologists experienced in vertebral fracture assessment independently read the VFA scans and radiographs using the Genant semiquantitative method on two occasions. Analyzing the data from all readable vertebrae, the kappa statistic, sensitivity, and specificity ranged from 0.64–0.77, 0.65–0.84, and 0.97–0.98, respectively. Considering only moderate and severe fractures improved the kappa statistic (0.80–0.91) and sensitivity (0.70–0.86). While image quality of VFA is inferior to radiography, the detection of vertebral fractures using visual scoring is feasible. However, VFA underperformed due to unreadable vertebrae and reduced sensitivity for mild fractures. Nevertheless, VFA correctly identified most moderate and severe vertebral fractures. Despite this limitation, VFA by DXA provides an important tool for clinical research.

Background Adherence to oral bisphosphonates is often low, but even adherent patients may remain at elevated fracture risk. The goal of this study was to estimate the proportion of bisphosphonate-adherent women remaining at high risk of fracture. Methods A retrospective cohort of women aged 50 years and older, adherent to oral bisphosphonates for at least two years was identified, and data were extracted from a multi-system health information exchange. Adherence was defined as having a dispensed medication possession ratio ≥ 0.8. The primary outcome was clinical occurrence of: low trauma fracture (months 7–36), persistent T-score ≤ − 2.5 (months 13–36), decrease in bone mineral density (BMD) at any skeletal site ≥ 5%, or the composite of any one of these outcomes. Results Of 7435 adherent women, 3110 had either pre- or post-adherent DXA data. In the full cohort, 7% had an incident osteoporotic fracture. In 601 women having both pre- and post-adherent DXA to evaluate BMD change, 6% had fractures, 22% had a post-treatment T-score ≤ − 2.5, and 16% had BMD decrease by ≥ 5%. The composite outcomes occurred in 35%. Incident fracture was predicted by age, previous fracture, and a variety of co-morbidities, but not by race, glucocorticoid treatment or type of bisphosphonate. Conclusion Despite bisphosphonate adherence, 7% had incident osteoporotic fractures and 35% had either fracture, decreases in BMD, or persistent osteoporotic BMD, representing a substantial proportion of treated patients in clinical practices remaining at risk for future fractures. Further studies are required to determine the best achievable goals for osteoporosis therapy, and which patients would benefit from alternate therapies.

A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In women peak BMD is highly heritable and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed to establish the heritability of peak BMD, identify QTL contributing to normal variation in BMD, and determine which QTL might be sex specific.BMD at the spine and hip were measured in 323 pairs of brothers aged 18-61 yr (264 white pairs; 59 black pairs). Heritability was calculated and linkage analysis performed with spine and hip BMD phenotypes.Heritability estimates ranged from 0.61 to 0.87 and were not significantly different between white and black men. A 9-cM genome-wide scan followed by genotyping with more closely spaced markers identified suggestive QTL (logarithm of the odds2.2) for BMD on chromosomes 1q (spine), 2p (spine), 2q (hip), 14p (spine), 18 (hip), and 21 (hip). Comparison with published data in 774 pairs of premenopausal sisters suggested that the QTL on 1q (spine), 2q (hip), 14p (spine), and 21q (hip) were male specific, whereas those on 2p (spine) and 18 (hip) were not sex specific.This study demonstrates that BMD in healthy men is highly heritable with similar estimates of the genetic contribution to BMD in both whites and blacks. Of the six QTL identified, three were specific for spine BMD and three were specific for hip BMD. When compared with published QTL for peak BMD in women from the same geographical region, four of the QTL appeared to be male specific. The occurrence of sex-specific genes in humans for BMD has potentially important implications for the pathogenesis and treatment of osteoporosis.

The role of the LRP5 gene in rare BMD-related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5 and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5 in our sample. Introduction: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been implicated as the cause of multiple distinct BMD-related rare Mendelian phenotypes. We sought to examine whether the LRP5 gene contributes to the observed variation in peak BMD in the normal population. Materials and Methods: We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5 using allele-specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5 SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population-based (ANOVA) and family-based (quantitative transmission disequilibrium test) association methodology. Results and Conclusions: The linkage disequilibrium pattern and haplotype block structure within the LRP5 gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5 SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for ∼0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5 is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.

Background: Race and sex differences in the effect of diet on bone mineral density (BMD) at the hip in the elderly are unknown. Objectives: This study related cross-sectional nutrient and dairy product consumption to hip BMD in white and black men and women aged60 y and evaluated the influence of nutrient and dairy product consumption on changes in BMD in a white cohort participating in a calcium, vitamin D, or placebo trial. Design: The Health Habits and History Questionnaire was used in 289 white women and 116 white men who participated in the trial and in 265 black women and 75 black men to predict total hip and femoral neck BMD or changes in BMD. Results: Blacks had higher calcium intakes than did whites (700 and 654 mg/d, respectively; P 0.0094), and men had higher calcium intakes than did women (735 and 655 mg/d, respectively; P 0.0007). For men, the correlation between total hip BMD and dairy calcium intake after adjustment for age, race, and weight was 0.23 (P 0.005); this relation was not significant in women (r 0.02, P 0.12). Similar results were found for femoral neck BMD. In the longitudinal study, calcium supplementation reduced bone loss from the total hip and femoral neck in those who consumed1.5 servings of dairy products/d and were 72 y old. Conclusions: Cross-sectional results indicated that higher dairy product consumption is associated with greater hip BMD in men, but not in women. Calcium supplementation protected both men and women from bone loss in the longitudinal study of whites. Am J Clin Nutr 2004;80:1066 –74.

Bisphosphonates are emerging as an important treatment for osteoporosis. But whether the reduced fracture risk associated with bisphosphonate treatment is due to increased bone mass, improved trabecular architecture and/or increased secondary mineralization of the calcified matrix remains unclear. We examined the effects of bisphosphonates on both the trabecular architecture and matrix properties of canine trabecular bone. Thirty-six beagles were divided into a control group and two treatment groups, one receiving risedronate and the other alendronate at 5-6 times the clinical dose for osteoporosis treatment. After one year, the dogs were killed, and samples from the first lumbar vertebrae were examined using a combination of micro-computed tomography, finite element modeling, and mechanical testing. By combining these methods, we examined the treatment effects on the calcified matrix and trabecular architecture independently. Conventional histomorphometry and microdamage data were obtained from the second and third lumbar vertebrae of the same dogs [Bone 28 (2001) 524]. Bisphosphonate treatment resulted in an increased apparent Young's modulus, decreased bone turnover, increased calcified matrix density, and increased microdamage. We could not detect any change in the effective Young's modulus of the calcified matrix in the bisphosphonate treated groups. The observed increase in apparent Young's modulus was due to increased bone mass and altered trabecular architecture rather than changes in the calcified matrix modulus. We hypothesize that the expected increase in the Young's modulus of the calcified matrix due to the increased calcified matrix density was counteracted by the accumulation of microdamage.

This study measured bone mineral content (BMC), bone mineral density (BMD), and bone area at the spine and hip to learn whether bone loss takes place premenopausally. Participants were 130 non-Hispanic white women 31 to 50 years of age who were in good general health and had taken no drugs that affect bone metabolism. Measurements were made by dual-energy x-ray absorptiometry at the L2-4 segment of the lumbar spine, in the femoral neck, and in the total hip. The studies were repeated at least twice over 1 to 9 years. Both BMC and bone area increased significantly over time in the spine, as did BMD. If, however, BMC was normalized by bone volume, there was no age-related change in volumetric density. Measurements of the total hip showed no significant change with age. BMD in the femoral neck declined at a rate of about 0.0036 g/cm2 per year. BMC was lost as well, so the drop in BMD was not an artifact of bone expansion. Changes in BMD correlated positively with weight change and estradiol levels and negatively with gonadotropin levels. Somewhat less bone loss was noted in subjects who gained more weight during the study. Higher levels of LH and FSH were documented in women who lost more than 1% of BMD per year. Estrogen levels were highest in women who manifested no bone loss. Declining BMD was more a result of a loss of BMC in women with high FSH levels, but due more to an expansion in bone area in those with relatively low FSH levels. The positive association between body weight change and BMD was not entirely mediated by higher estrogen. Premenopausal women more than 30 years of age in this study lost BMD at the femoral neck at an average annual rate of 0.4%. Bone loss was less in women who gained more weight but greater in those with reduced estrogen levels even in the absence of symptoms. Early bone loss might be preventable if premenopausal women with suboptimal sex hormone levels are detected at an early stage.

We recently demonstrated that suppressed bone remodeling allows microdamage to accumulate and causes reductions in some mechanical properties. However, in our previous study, 1 year treatment with high-dose etidronate (EHDP) did not increase microdamage accumulation in most skeletal sites of dogs in spite of complete remodeling suppression and the occurrence of spontaneous fractures of ribs and/or thoracic spinous processes. This study evaluates the effects of EHDP on microdamage accumulation and biomechanical properties before fractures occur. Thirty-six female beagles, 1-2 years old, were treated daily for 7 months with subcutaneous injections of saline vehicle (CNT) or EHDP at 0.5 (E-low) or 5 mg/kg per day (E-high). After killing, bone mineral measurement, histomorphometry, microdamage analysis, and biomechanical testing were performed. EHDP treatment suppressed intracortical and trabecular remodeling by 60%-75% at the lower dose, and by 100% at the higher dose. Osteoid accumulation caused by a mineralization deficit occurred only in the E-high group, and this led to a reduction of mineralized bone mass. Microdamage accumulation increased significantly by two- to fivefold in the rib, lumbar vertebra, ilium, and thoracic spinous process in E-low, and by twofold in the lumbar vertebra and ilium in E-high. However, no significant increase in damage accumulation was observed in ribs or thoracic spinous processes in E-high where fractures occur following 12 months of treatment. Mechanical properties of lumbar vertebrae and thoracic spinous processes were reduced significantly in both E-low and E-high. These findings suggest that suppression of bone remodeling by EHDP allows microdamage accumulation, but that osteoid accumulation reduces production of microdamage.

Bone densitometry, regardless of the specific technique, is not perfectly reproducible even when consistently performed in exact accordance with the manufacturer's recommendations. Precision must be quantified at each densitometry facility in precision studies of the various skeletal sites used for monitoring. The precision, as the root-mean-square standard deviation or root-mean-square coefficient of variation, is then used to determine the change in bone density that constitutes the least significant change and the minimum interval between follow-up measurements. Until precision studies are performed, the least significant change cannot be determined for any level of statistical confidence, making the interpretation of serial studies impossible.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib-pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10 of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

The effect of quantified resistance and high impact exercise training on bone mass as modified by age and oral contraceptive (OCont) use in young women was studied.Women were categorized by age (18-23 vs 24-31 yr) and OCont use, and were then randomized into either three sessions of resistance exercise plus 60 min.wk-1 of jumping rope or a control group for 24 months. Total body, spine, femoral neck, greater trochanter, Ward's area, and radial bone mineral density (BMD) and/or content (BMC), biochemical markers of bone turnover, dietary intake of calcium, lean body mass, maximal oxygen uptake, and strength were determined at baseline and every 6 months.Total body (TB) BMC percent change from baseline was higher in exercisers compared with nonexercisers at 6 and 24 months. OCont users had lower bone turnover at baseline and a decrease in TBBMC from baseline compared with non-OCont users at 24 months. Spine BMC and BMD decreased in the exercise and OCont group at 6 months and remained significantly below nonexercisers who used oral contraceptives at 2 yr. Femoral neck BMD also decreased in the exercise and oral contraceptive group at 6 months.Exercise prevented a decline in TBBMC seen in the nonexercisers. On the other hand, exercise in oral contraceptive users prevented the increase observed in the spine of the nonexercise plus OCont group.

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 subjectsor =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 (p0.05) than that of the groups exposed to water fluoride levelsor =4.32 andor =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 containingor =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 major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12–13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans). The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21–23 with lumbar spine BMD. Chromosome 5q33–35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11–12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12–13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. Bone mineral density is a complex trait that, presumably, is influenced by multiple genes. Interleukin-6 (IL-6) is an attractive candidate gene for osteoporosis susceptibility, because it has effects on bone cells and has been implicated in the pathogenesis of osteoporosis. Furthermore, previous investigators have identified an association between a 3' UTR polymorphism of the IL-6 gene and BMD. In this study, we searched for linkage and association between this IL-6 gene polymorphism and peak BMD in a large population (812 individuals) of healthy premenopausal sibpairs. Although previous investigators identified only 6 IL-6 alleles, we identified 17 alleles by modifying electrophoretic conditions and evaluating a very large population. We found no evidence for either linkage or association between the IL-6 gene locus and BMD of the spine or hip in either Caucasians or African Americans.

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. Insulin-like growth factor I (IGF-I) is an attractive candidate gene for osteoporosis susceptibility, because IGF-I has marked effects on bone cells and has been implicated in the pathogenesis of osteoporosis. The IGF-I gene contains a microsatellite repeat polymorphism approximately 1 kb upstream from the IGF-I gene transcription start site, and previous investigators have found a higher prevalence of the 192/192 genotype of this polymorphism among men with idiopathic osteoporosis compared to controls. In this study we used this IGF-I polymorphism to test for an association between this polymorphism and BMD in our large population of premenopausal women (1 sister randomly chosen from 292 Caucasian and 71 African-American families). We also used this polymorphism to detect linkage to BMD elsewhere in the IGF-I gene or in a nearby gene using sibling pair linkage analysis in healthy premenopausal sister pairs (542 sibling pairs: 418 Caucasian and 124 African-American). Neither test provided any evidence of linkage or association between the IGF-I gene locus and spine or femoral neck BMD in Caucasians or AfricanAmericans. (J Clin Endocrinol Metab 84: 4467‐ 4471, 1999)

Risedronate is a potent pyridinyl bisphosphonate being developed for bone diseases such as Paget's disease and osteoporosis. In this study, we compared the efficacy, safety, and tolerability of three different doses of oral risedronate in 62 patients with severe Paget's disease of bone [serum alkaline phosphatase (AP) >3 times the upper limit of normal]. Patients were treated at six study centers with either 10, 20, or 30 mg oral risedronate daily for 28 days and followed up to day 85. The primary efficacy parameter was percentage change from baseline in AP excess. The data show that there is a dose-response with risedronate: patients who received 30 mg oral risedronate for 28 days benefited most, with a mean percentage decrease in AP excess of 72.2% (20 mg: 57.9%; 10 mg: 48.0%). Time to response—the first time point when there was a ≥30% reduction from baseline in AP excess and ≥50% reduction from baseline in urinary hydroxyproline (HP)/creatinine–was also significantly shorter (median 29 days) in the 30 mg group compared with the other two groups (20 mg: 43 days and 10 mg: 71 days). Long-term follow-up data up to 33 months from the start of the study indicated that AP remained below baseline levels for all patients. Histologic evaluation of bone formed during risedronate therapy demonstrated that normal lamellar bone was formed as opposed to woven pagetic bone, with no evidence of osteomalacia. Risedronate was well tolerated. Transient decreases in serum calcium and increases in serum intact parathyroid hormone were observed, consistent with the pharmacology of risedronate. In conclusion, risedronate administered at daily doses of 10, 20, and 30 mg for 28 days was effective in reducing the biochemical indices of disease activity in patients with severe Paget's disease of bone. A daily dose of 30 mg was most effective without compromising safety or tolerability.

Lower cost, portable, peripheral bone mass measurement devices are being increasingly utilized for widespread bone mass testing. These devices are being placed in traditional medical settings as well as nontraditional settings, such as pharmacies and grocery stores. Increased bone mass testing is appropriate at menopause in women who are undecided whether to begin systemic estrogen replacement. Women may decide to begin estrogen replacement if they are aware they have low bone mass and understand that bone mass will predictably decline after the menopause (1). With the approval of alendronate and raloxifene for the prevention of osteoporosis, even women who cannot or will not utilize estrogen replacement may be offered preventive interventions if they are identified as having low bone mass. More accessible bone mass measurements and more approved pharmacologic interventions will shift the focus of osteoporosis management to strategies that emphasize the reduction of lifetime fracture risk as well as current fracture risk. It will also be an impetus to focus on earlier identification and intervention (2-4).

This paper describes data on bone mineral levels in the proximal femur of US adults based on the nationally representative sample examined during both phases of the third National Health and Nutrition Examination Survey (NHANES III, 1988-94), and updates data previously presented from phase 1 only. The data were collected from 14,646 men and women aged 20 years and older using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in four selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter and total. These variables are provided separately by age and sex for non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA). NHW in the southern United States had slightly lower BMD levels than NHW in other US regions, but these differences were not sufficiently large to prevent pooling of the data. The updated data provide valuable reference data on femur bone mineral levels of noninstitutionalized adults. The updated data on BMD for the total femur ROI of NHW have been selected as the reference database for femur standardization efforts by the International Committee on Standards in Bone Measurements.

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Bone mass and structure at the proximal femur are important predictors of hip fracture. The aims of this study were to compare in a large sample of elderly men and women the precision of measurements of bone mass and structure at multiple sites at the proximal femur, to examine their interrelationships, to establish their relationships with age and body size, and to examine criteria for defining geometric and architectural variables in bone structure. Women (n = 336) and men (n = 141) over the age of 60 years were studied cross-sectionally. Bone mineral density (BMD) and content (BMC) at the proximal femur were measured in duplicate by dual-energy X-ray absorptiometry (DXA). Shaft and total upper femur (hip) sites in addition to femoral neck, Ward's triangle and trochanter were measured. Structural variables, measured from radiographs and from DXA images, including cortical thickness at calcar femorale, lateral cotex and midfemur, width of the femur and medulla, Singh grade, hip and femoral axis length, femoral head and neck width and the center of mass of the femoral neck. BMD and BMC had high reproducibility and there were significant differences in reproducibility across sites. Among sites, total upper femur and shaft had the highest reproducibility. Duplicate measurements substantially improved reliability of the measurement and are recommended when the value is close to a diagnostic level or when it will be used to establish rates of change. Reproducibility of structural variables was also high except for the lateral cortex, center of mass and Singh grade. Variance due to measurement error did not change with either age or gender. Women were significantly different from men, after controlling for differences in body size, in all variables except Singh grade and medulla width. BMD and BMC were negatively related to age and positively to body size. Structural variables examined in relation to age and body size fell into two categories. The first comprised variables that were not age-related but were body-size-related suggesting that they could be classified as geometric variables. The second comprised variables that were both body-size-related and age-related, suggesting that they could be classified as architectural variables. Using these criteria, calcar and lateral cortex were architectural variables, whereas shaft width, hip and femoral axis length, femoral head and neck width, and center of mass were geometric in both men and women. In women, shaft cortex width and medulla width were age-related, whereas in men they were not. Singh grade showed no consistent pattern with age or body size in women and men.

This double-blind, placebo-controlled study was undertaken to determine 1) the efficacy of oral risedronate for prevention of bone loss in healthy, early postmenopausal patients with normal bone mass, 2) the effect on bone mass when treatment was stopped, and 3) the safety and tolerance of risedronate in this population. A group of 111 patients were randomized to oral placebo, risedronate 5 mg daily, or risedronate 5 mg cyclically, for 2 yr followed by 1 yr off treatment. Measurements included percentage change from baseline in lumbar spine bone mineral density (BMD) at 24 months; percentage change from baseline in BMD of the femoral neck, trochanteric region, and Ward's triangle region of the proximal femur; and changes in biochemical markers of bone turnover. After 2 yr, there was a mean increase in BMD of the lumbar spine of 1.4% from baseline and of 5.7% vs. placebo in the risedronate 5 mg daily group. There were decreases from baseline in BMD of 1.6% and 4.3% in the risedronate 5 mg cyclic and placebo groups, respectively. By the end of 24 months, trochanteric bone mass at the hip increased by 5.4% in the risedronate 5 mg daily group and by 3.3% in the risedronate 5 mg cyclic group vs. placebo. Bone mass was maintained at the femoral neck in the 2 active-treatment groups vs. a 2.4% mean loss with placebo. During the treatment-free follow-up, bone turnover increased toward baseline in both risedronate groups. By the end of that year, lumbar spine bone mass in all 3 groups was lower than at baseline. Oral risedronate was well tolerated. We conclude that risedronate (5 mg daily) increases bone mass and risedronate (5 mg cyclic) appears to prevent bone loss in early postmenopausal women with normal BMD.

Most estimates of osteoporosis in older U.S. adults have been based on its occurrence in white women, even though it is known to affect men and minority women. In the present study, we used dual-energy X-ray absorptiometry measurements of femoral bone mineral density (BMD) from the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) to estimate the overall scope of the disease in the older U.S. population. Specifically, we estimate prevalences of low femoral BMD in women 50 years and older and explore different approaches for defining low BMD in older men in that age range. Low BMD levels were defined in accordance with an approach proposed by an expert panel of the World Health Organization and used BMD data from 382 non-Hispanic white (NHW) men or 409 NHW women ages 20-29 years from the NHANES III dataset. For women, estimates indicate 13-18%, or 4-6 million, have osteoporosis (i.e., BMD2.5 standard deviations [SD] below the mean of young NHW women) and 37-50%, or 13-17 million, have osteopenia (BMD between 1 and 2.5 SD below the mean of young NHW women). For men, these numbers depend on the gender of the reference group used to define cutoff values. When based on male cutoffs, 3-6% (1-2-million) of men have osteoporosis and 28-47% (8-13 million) have osteopenia; when based on female cutoffs, 1-4% (280,000-1 million) have osteoporosis and 15-33% (4-9 million) have osteopenia. Most of the older U.S. adults with low femur BMD are women, but, regardless of which cutoffs are used, the number of men is substantial.

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.

The International Dual-Photon X-Ray Absorptiometry (DXA) Standardization Committee (IDSC) conducted a cross-calibration study among three models of DXA machines from three different manufacturers. In that study, 100 subjects were scanned on all three machines. A set of equations were derived to convert bone mineral density (BMD) on each machine to a “standardized BMD” (sBMD) such that sBMD from the same subject derived from different machines would be approximately the same. In a reanalysis of the cross-calibration data, we showed that the conversion method used in the IDSC study did not achieve several optimal properties desirable in such conversions. We derived new conversion equations to sBMD based on minimizing differences among sBMD from the three machines. More important is that the new conversions have no residual bias that was present in the IDSC conversions. The performance of the methods were compared on the cross-calibration data as well as an external data set. We conclude that the IDSC conversions are adequate for clinical use on other machines worldwide, but that researchers should standardize their own machines in a laboratory using the new method. (J Bone Miner Res 1997;12:1463‐1470)

To assess the ability of the urinary N-telopeptide of type I collagen (NTx) to monitor and predict therapeutic effects of hormone replacement therapy (HRT) in postmenopausal women.To assess the relationship between baseline or change in NTx (predictive variable), and change in lumbar and hip bone mineral density (BMD; outcome variable), we conducted a 2-year randomized controlled study at academic university and private practice medical centers in 236 healthy women 1 to 3 years postmenopausal; 227 women completed the study. Women received estrogen plus progesterone plus calcium (treated group) or calcium alone (control group).In the treated group NTx significantly (P0.0001) decreased, and spine and hip BMD significantly (P0.00001 and P0.005, respectively) increased; in the control group NTx did not change but BMD decreased significantly (P0.01). Subjects in the highest quartiles for baseline NTx (67 to 188 units) or decreasing NTx (-66% to -87%) through 6 months demonstrated the greatest gain in BMD in response to HRT (P0.05 and P0.005). For every increase of 30 units in baseline NTx the odds of gain in BMD in response to HRT increased by a factor of 5.0 (95% confidence interval [CI] 1.9 to 13.3); for every 30% decrease in NTx through 6 months, the odds of gaining BMD in response to HRT increased by a factor of 2.6 (95% CI 1.6 to 4.4). In the control group an increase of 30 units in mean NTx across the study indicated a higher odds of losing BMD by a factor of 3.2 (95% CI 1.6 to 6.5). A high baseline NTx (67 units) indicated a 17.3 times higher risk of BMD loss if not treated with HRT.These data support the clinical utility of NTx to monitor the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT.

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 (p0.05) different from zero for all bone mass and femoral geometry variables (0.35rMZ0.82). DZ pair correlations (rDZ) were lower than rMZ for all variables (0.04rDZ0.52) 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 (0.72H20.78), 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.

This paper describes bone mineral levels in the proximal femur of US adults based on a nationally representative sample of 7116 men and women aged 20 years and older. The data were collected in phase 1 of the third National Health and Nutrition Examination Survey (NHANES III, 1988-1991) using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in five selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter, Ward's triangle and total. These variables are provided separately by age and sex for non-HIspanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA). BMD and BMC in the five ROI tended to decline with age, whereas area did not. BMD and BMC were highest in NHB, intermediate in MA and lowest in NHW, but areas were highest in NHW, intermediate in NHB and lowest in MA. Men had greater BMD, BMC and area than women in all three race/ethnic groups. Differences by age, sex or race/ethnicity tended to be the largest in Ward's triangle, followed by the femur neck; patterns in the trochanter, intertrochanter and total ROI were reasonably similar to each other. This report provides extensive data on femur bone mineral levels of adults from one of the largest samples available to date and should be valuable as reference data for other studies which examine this skeletal site in adults.

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.

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/cm 2 per year, peripubertal vs prepubertal) and greater trochanter (0.050 vs 0.027 gm/cm 2 per year), less markedly in the femoral neck (0.047 vs 0.030 gm/cm 2 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. (J PEDIATR 1994;125:201-7)

Measurements of bone mass and several other skeletal characteristics can effectively identify women at high risk for fractures. These measurements are now widely available, and other clinical data cannot provide equivalent information. Treatments exist that will preserve bone mass and presumably reduce fracture risk (although for newer treatments this requires further study). It should also be noted that the prevention of very rapid bone loss may also protect against the development of micro-architectural abnormalities, thereby further reducing risk. Even in the very old, for whom preservation of bone mass may be of less value, there now appears to be an intervention that diminishes the impact trauma associated with falls. In this group bone mass measurements may also aid in identification of the highest risk groups. It is worth noting that measurement of bone mass may further serve to motivate patients to accept or to continue with a therapy.

We compared young female figure skaters, aged 10-23, with non-athletic control subjects to ascertain whether there were differences in skeletal densities at various sites. We also compared other characteristics of body size, including height, weight and percent body fat. Although the skaters were thinner and significantly more likely to have oligo- or amenorrhea, they had similar skeletal densities at upper body sites (spine, arms, ribs) and significantly greater densities in the pelvis and legs. These differences were not evident until the mid-teens, however, suggesting that there is little likelihood of selection bias as the cause of the observed differences.

Black adults have higher bone mass than whites in the United States, but it is not clear when black children gain bone mineral faster than white children. We performed a cohort study to compare the growth velocity of total-body bone mineral content (TBMC) between black and white children of the same sex at different ages and stages of sexual maturity. TBMC and total-body area were measured in a cohort of 188 black and white boys and girls aged 5 to 15 years annually for up to 4 years. Rates of change in TBMC and area were found to vary with age and with Tanner stage. For both TBMC and area, growth velocities between black and white children differed significantly across Tanner stages. Age-specific velocities were higher in black children during prepuberty and initial entry into puberty but reversed in subsequent Tanner stages. Despite earlier entry into each Tanner stage, black children spent only an average of only 0.2 year longer in Tanner stages II through IV, and total gain in TBMC from age 5 to 15 was not higher in whites. In conclusion, the higher bone mass in black adults compared with whites cannot be attributed to faster accrual during puberty. It is due to black children's higher rate of bone mineral accrual in prepuberty and plausibly in postpuberty. Most of the racial difference in TBMC velocity can be explained by growth in size. © 2010 American Society for Bone and Mineral Research.

Increased dietary intake of calcium during childhood, usually as calcium in milk, is associated with increased bone mass in adulthood; the increase in mass is important in modifying the later risk of fracture. Whether the increase is due to the calcium content of milk, however, is not certain.We conducted a three-year, double-blind, placebo-controlled trial of the effect of calcium supplementation (1000 mg of calcium citrate malate per day) on bone mineral density in 70 pairs of identical twins (mean [+/- SD] age, 10 +/- 2 years; range, 6 to 14). In each pair, one twin served as a control for the other; 45 pairs completed the study. Bone mineral density was measured by photon absorptiometry at two sites in the radius (at base line, six months, and one, two, and three years) and at three sites in the hip and in the spine (at base line and three years).The mean daily calcium intake of the twins given placebo was 908 mg, and that of the twins given calcium supplements was 1612 mg (894 mg from the diet and 718 mg from the supplement). Among the 22 twin pairs who were prepubertal throughout the study, the twins given supplements had significantly greater increases in bone mineral density at both radial sites (mean difference in the increase in bone mineral density: midshaft radius, 5.1 percent [95 percent confidence interval, 1.5 to 8.7 percent]; distal radius, 3.8 percent [95 percent confidence interval, 1.4 to 6.2 percent]) and in the lumbar spine (increase, 2.8 percent [95 percent confidence interval, 1.1 to 4.5 percent]) after three years; the differences in the increases at two of three femoral sites approached significance (Ward's triangle in the femoral neck, 2.9 percent; greater trochanter, 3.5 percent). Among the 23 pairs who went through puberty or were postpubertal, the twins given supplements received no benefit.In prepubertal children whose average dietary intake of calcium approximated the recommended dietary allowance, calcium supplementation increased the rate of increase in bone mineral density. If the gain persists, peak bone density should be increased and the risk of fracture reduced.

The relationships among bone mineral measurements at hip, wrist, and spine sites and anthropometric measurements which provided estimates of frame size, skinfold thickness, and muscularity were examined in a population of 140 children. The average age of the children at the time of measurement was 9.5 ± 2.5 years and all subjects were white. In this study population, the anthropometric measurements were generally highly intercorrelated. Univariate correlations among bone mass and density variables at the different sites were also high, especially in the female children. Model fitting procedures were employed to separate the effects of age, frame size, and fatness on the bone mass measures. Resulting models confirmed previous results which suggest that height is the best predictor of bone mass in children. As expected, models for bone mineral content and bone mineral density were similar. Models for hips and wrist sites were also similar in including an estimate of frame size, while in those for the spine hip circumference explained a greater percentage of the variance. It appears that there are several identifiable characteristics among the anthropometric variables which appear to exert differential effects on skeletal development in children.

Bone mass and anthropometrics were measured in 342 adult female twins, aged 25-79 (mean = 44.1 years) for the purpose of: (1) identifying which anthropometric measurements were most strongly associated with bone mass at various skeletal sites, and (2) determining the accuracy of combinations of these measurements in the prediction of bone mass. Among the eight skinfolds measured, the subscapular site was more strongly correlated with all bone mass measurements than any other skinfold. Similarly, calf circumference (among four sites) and biacromial width (among five frame size measurements) provided the strongest correlations within these groups of anthropometrics with all bone sites. The somewhat surprising consistency of these results was then tested in multivariable models for the prediction of bone mass. For the entire study group, each of the anthropometric measurements (subscapular skinfold, calf circumference and biacromial width) were independent, significant predictors of bone mass, even when height, weight and age were included in the models. These data suggest that frame size, muscularity and adiposity have independent effects on the skeleton, and that single measurements of each of these anthropometric characteristics are associated with all skeletal sites.

We have addressed the relative importance of peak bone mass and subsequent rate of loss in determining postmenopausal women's bone mass in old age, by examining longitudinal measurements of radial mid-shaft bone mass on various samples of healthy white postmenopausal women. Using both the variance estimate of age-specific rates of bone loss and the population variance in bone mass, we determined that rates of loss could contribute importantly to future bone mass. However, since we found a small negative correlation between initial bone mass and rate of loss, it was necessary to estimate the effect of bone loss as the complement of the contribution of initial bone mass. We found that the influence of bone loss (relative to initial bone mass) increases as the women age, such that by about age 70, the contribution of initial bone mass and rate of loss approached equality. However, estimated rates of bone loss were not very stable over time, so it was difficult to identify long-term ‘fast-losers’. We conclude that the rate of postmenopausal bone loss is an important contributor to osteoporosis at old age, but it is difficult to identify long-term fast-losers, thereby reducing the clinical value of assessments of rates of change in bone mass early in the postmenopause.