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Population-based strategies to combat osteoporosis are urgently needed. The role of nutrition in such strategies has been particularly contentious. We examined the relationship among six key nutrients that are thought to affect bone metabolism and bone mineral density in the axial and appendicular skeleton using data from a population-based study in the northern United States. Data on the dietary intake of calcium, phosphorus, vitamin D, protein, fat, and total energy were obtained from a 7-day dietary record. Bone density measurements were made by dual photon absorptiometry in the lumbar spine and proximal femur, and by single photon absorptiometry in the distal and midradius. Among the 72 premenopausal women studied, there was a statistically significant positive association between protein intake and bone mineral in the distal radius and proximal femur, which was not altered by adjustment for age, weight, and physical activity. Among 218 postmenopausal women, no such relationship was found between protein intake and bone mineral, and the only significant findings in this group were negative associations between fat consumption and bone density in the lumbar spine and radius. Our results suggest that dietary protein intake may be a determinant of the peak bone mass attained by premenopausal white women. The relevance of this finding for the design of population strategies to maximize skeletal growth requires further investigation. [ABSTRACT FROM AUTHOR]

Recent reports of increases in serum 1,25-dihydroxyvitamin D [1,25(OH2)D] concentration with aging despite no changes or decreases in calcium absorption suggest that elderly women have intestinal resistance to vitamin D action. Thus, in 15 young adult (30 +/- 1 year) and 15 elderly (74 +/- 1 year) women (mean +/- SE), we assessed the responsiveness of intestinal calcium absorption to increases in circulating 1,25(OH)2D induced by 4 days of an experimental diet (150 mg calcium and 1600 mg phosphorus daily). True fractional calcium absorption (FCA) (44Ca mixed with food and 42Ca given intravenously, then their ratio in urine measured by mass spectrometry) was determined. Baseline serum intact parathyroid hormone (PTH) concentration was higher in the older women (P = 0.01) whereas serum 1,25(OH)2D concentration and true FCA were similar. In both groups, serum 1,25(OH)2D concentrations increased (P < 0.002) on the experimental diet. After 4 days on the diet, serum 1,25(OH)2D increased over baseline by 30.5 and 35.6% and, despite these increases, true FCA was 40 +/- 3 versus 40 +/- 4%/24 hours (NS between groups) in the young and elderly women, respectively. These data suggest that either elderly women have normal intestinal responsiveness to vitamin D or that the resistance to it is too mild to be detected by these methods. [ABSTRACT FROM AUTHOR]

Summary Using combined dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography, we demonstrate that men matched with women for femoral neck (FN) areal bone mineral density (aBMD) have lower volumetric BMD (vBMD), higher bone cross-sectional area, and relatively similar values for finite element (FE)-derived bone strength. Introduction aBMD by DXA is widely used to identify patients at risk for osteoporotic fractures. aBMD is influenced by bone size (i.e., matched for vBMD, larger bones have higher aBMD), and increasing evidence indicates that absolute aBMD predicts a similar risk of fracture in men and women. Thus, we sought to define the relationships between FN aBMD (assessed by DXA) and vBMD, bone size, and FE-derived femoral strength obtained from quantitative computed tomography scans in men versus women. Methods We studied men and women aged 40 to 90 years and not on osteoporosis medications. Results In 114 men and 114 women matched for FN aBMD, FN total cross-sectional area was 38% higher (P< 0.0001) and vBMD was 16% lower (P<0.0001) in the men. FE models constructed in a subset of 28 women and 28 men matched for FN aBMD showed relatively similar values for bone strength and the load-to-strength ratio in the two groups. Conclusions In this cohort of young and old men and women from Rochester, MN, USA who are matched by FN aBMD, because of the offsetting effects of bone size and vBMD, femoral strength and the load-to-strength ratio tended to be relatively similar across the sexes. [ABSTRACT FROM AUTHOR]

Summary: Bone strength at the ultradistal radius, quantified by micro-finite element modeling, can be predicted by variables obtained from high-resolution peripheral quantitative computed tomography scans. The specific formula for this bone strength surrogate (−555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) should be validated and tested in fracture risk assessment. Introduction: The purpose of this study was to identify key determinants of ultradistal radius (UDR) strength and evaluate their relationships with age, sex steroid levels, and measures of habitual skeletal loading. Methods: UDR failure load (~strength) was assessed by micro-finite element (μFE) modeling in 105 postmenopausal controls from an earlier forearm fracture case-control study. Predictors of bone strength obtained by high-resolution peripheral quantitative computed tomography (HRpQCT) in this group were then evaluated in a population-based cohort of 214 postmenopausal women. Sex steroids were measured by mass spectrometry. Results: A surrogate variable (−555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) predicted UDR strength modeled by μFE ( R = 0.81), and all parameters except total cross-sectional area declined with age. Evaluated cross-sectionally, the 21% fall in predicted bone strength between ages 40-49 years and 80+ years more resembled the change in trabecular volumetric bone mineral density (vBMD) (−15%) than that in cortical area (−41%). In multivariable analyses, measures of body composition and physical activity were stronger predictors of UDR trabecular vBMD, cortical area, total cross-sectional area, and predicted bone strength than were sex steroid levels, but bio-available estradiol and testosterone were correlated with body mass. Conclusions: Bone strength at the UDR, as quantified by μFE, can be predicted from variables obtained by HRpQCT. Predicted bone strength declines with age with changes in UDR trabecular vBMD and cortical area, related in turn to reduced skeletal loading and sex steroid levels. The predicted bone strength formula should be validated and tested in fracture risk assessment. [ABSTRACT FROM AUTHOR]

Summary: Compared to white women, lower areal bone mineral density (aBMD) in middle-aged Vietnamese immigrants is due to reduced trabecular volumetric bone mineral density (vBMD), which in turn is associated with greater trabecular separation along with lower estrogen levels. Introduction: The epidemiology of osteoporosis in Asian populations is still poorly known, but we previously found a deficit in lumbar spine aBMD among postmenopausal Southeast Asian women, compared to white women, that persisted after correction for bone size. This issue was revisited using more sophisticated imaging techniques. Methods: Twenty Vietnamese immigrants (age, 44-79 years) were compared to 162 same-aged white women with respect to aBMD at the hip, spine and wrist, vBMD at the hip and spine by quantitative computed tomography and vBMD and bone microstructure at the ultradistal radius by high-resolution pQCT. Bone turnover and sex steroid levels were assessed in a subset (20 Vietnamese and 40 white women). Results: The aBMD was lower at all sites among the Vietnamese women, but femoral neck vBMD did not differ from middle-aged white women. Significant differences in lumbar spine and ultradistal radius vBMD in the Vietnamese immigrants were due to lower trabecular vBMD, which was associated with increased trabecular separation. Bone resorption was elevated and bone formation depressed among the Vietnamese immigrants, although trends were not statistically significant. Serum estradiol was positively associated with trabecular vBMD in the Vietnamese women, but their estrogen levels were dramatically lower compared to white women. Conclusions: Although reported discrepancies in aBMD among Asian women are mainly an artifact of smaller bone size, we identified a specific deficit in the trabecular bone among a sample of Vietnamese immigrants that may be related to low estrogen levels and which needs further study. [ABSTRACT FROM AUTHOR]

A diverse array of bone density, structure, and strength parameters were significantly associated with distal forearm fractures in postmenopausal women, but most of them were also correlated with femoral neck areal bone mineral density (aBMD), which provides an adequate measure of bone fragility at the wrist for routine clinical purposes. This study seeks to test the clinical utility of approaches for assessing forearm fracture risk. Among 100 postmenopausal women with a distal forearm fracture (cases) and 105 with no osteoporotic fracture (controls), we measured aBMD and assessed radius volumetric bone mineral density, geometry, and microstructure; ultradistal radius failure load was evaluated in microfinite element (μFE) models. Fracture cases had inferior bone density, geometry, microstructure, and strength. The most significant determinant of fracture in five categories were bone density (femoral neck aBMD; odds ratio (OR) per standard deviation (SD), 2.0; 95% confidence interval (CI), 1.4–2.8), geometry (cortical thickness; OR, 1.5; 95% CI, 1.1–2.1), microstructure (structure model index (SMI); OR, 0.5; 95% CI, 0.4–0.7), and strength (µFE failure load; OR, 1.8; 95% CI, 1.3–2.5); the factor-of-risk (applied load in a forward fall ÷ μFE failure load) was 15% worse in cases (OR, 1.9; 95% CI, 1.4–2.6). Areas under receiver operating characteristic curves (AUC) ranged from 0.62 to 0.68. The predictors of forearm fracture risk that entered a multivariable model were femoral neck aBMD and SMI (combined AUC, 0.71). Detailed bone structure and strength measurements provide insight into forearm fracture pathogenesis, but femoral neck aBMD performs adequately for routine clinical risk assessment. [ABSTRACT FROM AUTHOR]

In bone marrow aspirates from postmenopausal women, systemic estrogen treatment decreased differentiation of mononuclear progenitor cells toward a more mature osteoclast phenotype. This was not associated with changes in surface receptor for proresorptive cytokines. Although mechanisms by which estrogen (E) decreases bone resorption have been extensively studied in rodents, little information is available in humans. In bone marrow aspirates from 34 early postmenopausal women randomly assigned to receive 4 weeks of treatment (100 μg/day of transdermal 17β-estradiol) or no treatment, we assessed osteoclast differentiation and surface receptors using flow cytometry with fluorescent-labeled specific antibodies. E treatment decreased ( P < 0.05) the proportion of bone marrow mononuclear cells (BMMNCs) expressing the calcitonin receptor (CTR), a late osteoclast phenotype marker. There was an increase in c-Fms concentration in osteoclast lineage cells ( P < 0.05) and in the proportion of BMMNCs expressing TNFR2 ( P < 0.05), but there were no significant effects on other surface receptors for proresorptive factors (RANK, TNFR1, TREM2, or OSCAR). Changes in serum CTx and TRAP 5b, markers for bone resorption, correlated directly ( P < 0.05) with the proportion of BMMNCs expressing CTR and, for TRAP 5b only, TNFR2 and inversely with c-Fms concentration (all P < 0.05). E reduces bone resorption, in part, by decreasing differentiation of BMMNCs into mature osteoclasts. This action cannot be explained by decreased concentrations of surface receptors for proresorptive factors. The roles of increases in c-Fms concentration and the proportion of TNFR2(+) cells are unclear. [ABSTRACT FROM AUTHOR]

In men, measurement of serum testosterone and estradiol levels with immunoassays correlated with mass spectroscopic measurements, and correlations of sex steroids with volumetric bone mineral density were similar. While immunoassays have been used extensively for measurement of serum testosterone (T) and estradiol (E2) levels, there is concern about their specificity, particularly at low E2 levels as present in men. We compared T and E2 measured by mass spectroscopy to levels measured by immunoassay in men ( n = 313, age 22 to 91 years) and related these to volumetric bone mineral density (vBMD) at various skeletal sites. Serum T and non-SHBG bound (or bioavailable) T levels by immunoassay correlated well with the corresponding mass spectroscopy measurements ( R = 0.90 and 0.95, respectively, P < 0.001); the correlations for serum E2 measured using the two techniques were less robust ( R = 0.63 for total E2 and 0.84 for bioavailable E2, P < 0.001). Overall relationships between serum bioavailable T and E2 levels with vBMD at various skeletal sites were similar for the immunoassay and mass spectroscopic measures. Although E2 levels with immunoassay correlate less well with the mass spectroscopic measurements than do the T measurements in men, our findings indicate that the fundamental relationships observed previously between vBMD and the sex steroids by immunoassay are also present with the mass spectroscopic measurements. [ABSTRACT FROM AUTHOR]

One-year treatment of osteoporotic postmenopausal women with transdermal estrogen resulted in significant decreases in bone marrow adipocyte volume and prevented increases in adipocyte number as compared to placebo-treated controls. Estrogen treatment also prevented increases in mean adipocyte size over 1 year. Aging is associated not only with bone loss but also with increases in bone marrow adipocytes. Since osteoblasts and adipocytes are derived from a common precursor, it is possible that with aging, there is a preferential “switch” in commitment of this precursor to the adipocyte over the osteoblast lineage. We tested the hypothesis that the apparent “age-related” increase in marrow adipocytes is due, at least in part, to estrogen (E) deficiency. Reanalysis of bone biopsies from a randomized, placebo-controlled trial involving 56 postmenopausal osteoporotic women (mean age, 64 years) treated either with placebo (PL, n = 27) or transdermal estradiol (0.1 mg/d, n = 29) for 1 year. Adipocyte volume/tissue volume (AV/TV) and adipocyte number (Ad#) increased (by ∼20%, P < 0.05) in the PL group, but were unchanged (Ad#) or decreased (AV/TV, by −24%, P < 0.001) in the E group. E treatment also prevented increases in mean adipocyte size over 1 year. These findings represent the first in vivo demonstration in humans that not only ongoing bone loss, but also the increase in bone marrow adipocyte number and size in postmenopausal osteoporotic women may be due, at least in part, to E deficiency. [ABSTRACT FROM AUTHOR]

Introduction: Approaches for recognizing vertebral fractures remain controversial. Methods: An age-stratified population sample of 512 postmenopausal women was followed with serial radiographs for up to 12 years (4455 person-years). Results: 112 women experienced a new vertebral fracture (20% reduction in any vertebral height from baseline) within this study period, for an annual age-adjusted (to US white women ≥50 years of age in 2000) incidence of 23 per 1000. Depending on the morphometric definition used, the prevalence of vertebral deformities at baseline ranged from 3 to 90%. A recent method to standardize vertebral heights produced the best agreement with a qualitative clinical reading of the films [kappa (κ), 0.53]. Almost all of the different baseline definitions predicted future vertebral fractures, but most of the predictive power was attributable to the severe (e.g., 4 SD) deformities included within more generous (e.g., 3 SD) classifications. Whereas the generous definitions were more sensitive, and the restrictive ones more specific, their overall abilities to predict a new vertebral fracture were roughly comparable as evaluated by the c-index (analogous to the area under an ROC curve). Conclusion: This result suggests that the choice of a morphometry definition depends on the particular application and, in particular, on whether it is more important to maximize sensitivity or specificity. [ABSTRACT FROM AUTHOR]

The ability of regional data from whole body scans to provide an accurate assessment of site-specific BMD, osteoporosis prevalence and fracture risk has not been fully explored. To address these issues, we measured total body (TBBD) and site-specific BMD in an age-stratified population sample of 351 women (21–93 years) and 348 men (22–90 years). We found an excellent correlation between AP lumbar spine and total body lumbar spine subregion BMD ( r 2=0.92), but weaker ones for total hip compared to pelvis region ( r 2=0.72) or between total wrist and left arm subregion from the whole body scan ( r 2=0.83). The error in estimating site-specific BMD from total body regions ranged from 4.3% (lumbar spine) to 11.2% (femoral neck) in women and from 4.9 to 11.1%, respectively, in men. Site-specific versus regional measurements at the lumbar spine and total hip/pelvis provided comparable overall estimates of osteoporosis prevalence, but disagreed on the status of individuals; measurements at whole body regions underestimated osteoporosis as assessed at the femoral neck or total wrist. All measurements were associated with a history of various fractures [age adjusted odds ratios (OR), 1.3 to 2.1 in women and 1.2 to 1.5 in men] and were generally interchangeable, but femoral neck BMD provided the best estimate of osteoporotic fracture risk in women (OR, 2.9; 95% CI, 1.7–5.0). Although there are strong correlations between BMD from dedicated scans of the hip, spine and distal forearm and corresponding regions on the whole body scan, the measurements provide somewhat different estimates of osteoporosis prevalence and fracture risk. [ABSTRACT FROM AUTHOR]

Although bone mineral density (BMD) is a strong predictor of fractures, it is only a surrogate for bone strength. Bone structural parameters can now be measured on BMD scans, but it is unclear whether they would be more useful for risk assessment. We measured structural parameters using the Hip Structural Analysis Program and evaluated their association, compared with standard hip BMD, with fracture risk in a population-based sample of 213 postmenopausal women and 200 men ⩾50 years of age. Altogether, 38% of the women and 27% of the men had experienced a fracture due to moderate trauma (half involved hip, spine or distal forearm), while 23% and 36%, respectively, had a previous fracture due to severe trauma. In logistic regression analyses adjusted for age, the hip BMD and structural parameters were all associated with moderate trauma fractures generally, and osteoporotic fractures specifically, in women, but the best predictor in a multivariate model was femoral neck BMD (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.9-4.0). BMD and the structural parameters were strongly correlated, however, and could be interchanged with little reduction in predictive power. These variables were less predictive of moderate trauma fractures in men. The best model included age (OR per 10 years, 1.5; 95% CI, 1.1-2.1), femoral neck section modulus (OR, 1.6; 95% CI, 1.1-2.5) and intertrochanteric buckling ratio (OR, 1.6; 95% CI, 1.3-2.0). Correction for body size did not alter these relationships. Fractures due to severe trauma were best predicted by structural parameters: in women, femoral neck buckling ratio (OR, 1.2; 95% CI, 1.04-1.5) and, in men, intertrochanteric buckling ratio (OR, 1.4; 95% CI, 1.2-1.6). These data suggest that selected structural variables as assessed by dual-energy X-ray absorptiometry would be as good as standard BMD measurements for predicting fracture risk. Because of the strong correlations, however, some judgment can be used in selecting the variables easiest to measure. [ABSTRACT FROM AUTHOR]

: The epidemiology of bone loss in populations of African heritage is still poorly known. We compared a convenience sample of 47 African-American (AA) residents of Rochester, Minnesota (32 women, 15 men) and 66 recent immigrants from Somalia (all women) with 684 white subjects (349 women, 335 men) previously recruited from an age-stratified random sample of community residents. Areal bone mineral density (BMD, g/cm2) and volumetric bone mineral apparent density (BMAD, g/cm3) were determined for lumbar spine and proximal femur using the Hologic QDR 2000 for white subjects and the QDR 4500 for the others; the instruments were cross-calibrated from data on 20 volunteers. Lumbar spine BMD was 18% higher in AA (p<0.001) and 4% lower in Somali (p= 0.147) than white women. Femoral neck BMD was 27% higher in AA women but also 11% greater in Somali women (both p<0.001) compared with whites. Lumbar spine BMD was 6% higher (p= 0.132) and femoral neck BMD 21% higher (p<0.001) in AA than white men. No Somali men were studied. After correcting for bone size differences, both lumbar spine (p<0.01) and femoral neck BMAD (p<0.001) were greater for Somali than white women, but the difference between Somali and AA women persisted. Lumbar spine and femoral neck BMAD values also remained significantly greater for AA women (both p<0.001) and men (p<0.05; p<0.001) compared with whites. Weight was associated with BMAD at both skeletal sites in all groups, but adjustment for differences in weight did not reduce the discrepancy in BMAD values between Somali and AA women or between the latter group and whites. This heterogeneity among different ethnic groups of African heritage may provide an opportunity for research to better explain race-specific differences in bone metabolism. [ABSTRACT FROM AUTHOR]

: Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23–90 years) and women (n= 304; age range 21–93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R= 0.39, p<0.001) and women (R= 0.18, p<0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 ± 6 pg/ml vs 134 ± 6 pg/ml, respectively, p<0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 ± 7 pg/ml vs 188 ± 7 pg/ml, respectively, p= 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=–0.27, p<0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency. [ABSTRACT FROM AUTHOR]

Factors contributing to the pathogenesis of osteoporosis in women are well defined. However, changes in bone mineral metabolism in aging men and the role of various factors in the pathogenesis of age-related bone loss in men are less well understood. To further clarify these changes, serum and urine biochemical parameters, and lumbar spine, hip, and total body bone mineral density (BMD) were evaluated in a small sample of 45 healthy men aged 20–80 years, and multiple regression models were developed to predict age-related bone loss. Serum calcium, phosphate, albumin, creatinine clearance, osteocalcin, C-terminal propeptide of type I procollagen, log-free androgen index, dehydroepiandrosterone sulfate (DHEA-S), and androstenedione decreased with age, and serum sex hormone binding globulin and urine total and free pyridinoline increased with age. Femoral neck BMD decreased with age, but remained stable at the other sites measured. Multiple regression analysis indicated that serum phosphate, DHEA-S, and intact parathyroid hormone (PTH) predicted lumbar spine BMD. Age, serum phosphate, and PTH predicted femoral neck BMD. Urine-free deoxypyridinoline alone predicted femoral greater trochanter BMD. Weight, serum creatinine, and urine-free deoxypyridinoline predicted total body BMD. We conclude that predictor variables of bone density vary by skeletal site in healthy men. Alterations in adrenal androgens, phosphate, and PTH may be important in the pathogenesis of bone loss with aging in men. [ABSTRACT FROM AUTHOR]

: The epidemiology of bone loss in populations of Asian heritage is still poorly known. This study compared the skeletal status of a convenience sample of 396 Southeast Asian immigrants (172 Vietnamese, 171 Cambodians and 53 Laotians) residing in Rochester, Minnesota in 1997 with 684 white subjects previously recruited from an age-stratified random sample of community residents. Areal bone mineral density (BMD, g/cm2) and volumetric bone mineral apparent density (BMAD, g/cm3) were determined for lumbar spine and proximal femur using the Hologic QDR 2000 instrument for the white population and the QDR 4500 for Southeast Asian subjects; the machines were cross-calibrated from data on 20 volunteers. Lumbar spine BMD was 7% higher in white than Southeast Asian women ( p < 0.001), and similar results were observed for the femoral neck; lumbar spine BMD was 12% higher in white than nonwhite men ( p < 0.001). Race-specific discrepancies were reduced by calculating BMAD: for premenopausal women, lumbar spine and femoral neck differences between whites and Southeast Asians were eliminated; for postmenopausal women the lumbar spine differences persisted ( p < 0.0001), while femoral neck BMAD was actually higher for Southeast Asians. There were no race-specific differences in femoral neck BMAD among men of any age ( p= 0.312), but lumbar spine BMAD was less for younger ( p= 0.042) but not older ( p= 0.693) Southeast Asian men. There were differences among the Southeast Asian subgroups, but no clear pattern emerged. Predictors of lumbar spine BMAD in Southeast Asian women were age ( p < 0.001), weight ( p= 0.015) and gravidity ( p= 0.037). Even after adjusting for bone size using BMAD, 32% and 9% of Southeast Asian women and men, respectively, would be considered to have osteoporosis at the femoral neck and 25% and 4%, respectively, at the lumbar spine. These findings indicate a need for culturally sensitive educational interventions for Southeast Asians and for physicians to pursue diagnosis and treatment to prevent osteoporosis-related disabilities in this population. [ABSTRACT FROM AUTHOR]

: Previous studies showed differences in bone and mineral metabolism in African-Americans and Caucasians: reductions in serum 25-hydroxyvitamin D [25(OH)D], urinary calcium and skeletal remodeling and moderate secondary hyperparathyroidism. Diurnal studies were carried out in 7 African-American and 7 white normal premenopausal women matched for age, weight and height to further characterize these racial differences in calcium homeostasis. Serum 25(OH)D was significantly lower and serum intact parathyroid hormone (PTH) was significantly higher in the African-American compared with the white women, whereas serum total calcium, Ca2+, phosphorus and 1,25-dihydroxyvitamin D [1,25(OH)2D] were not different in the two groups. Serum intact PTH increased significantly at night in the white women and did not change in the African-American women. Urinary calcium was 47% lower in the African-American than in the white women during the day but was not different at night. Urinary calcium declined at night by 53% in the white women and by 40% in the African-American women. Stepwise multivariate analysis showed that determinants of urinary calcium were mean 24 h serum intact PTH and serum Ca2+ in the two groups together, mean 24 h serum intact PTH, body mass index (BMI) and serum 25(OH)D in the white women, and BMI in the African-American women. Urinary N-telopeptide of type I collagen, a marker of bone resorption, increased by over 60% at night in both groups and was 25% lower in African-American compared with white women, but the difference was not statistically different. Urinary free deoxypyridinoline also increased at night in both groups and was not racially different. Thus, African-American women show higher serum intact PTH and greater conservation of calcium than white women throughout the day. In both groups, maintenance of serum calcium at night is achieved by increased bone resorption and renal conservation of calcium. [ABSTRACT FROM AUTHOR]

: In a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years), we evaluated the relationship of bone density assessed at a variety of skeletal sites by dual-energy X-ray absorptiometry (DXA) with various muscle mass estimates obtained also from the DXA scan and with physical activity by interview and strength assessed both subjectively and objectively. All these parameters declined with age as judged from these cross-sectional data. All estimates of total skeletal muscle mass were strongly correlated with bone density at different skeletal sites. Muscle mass, in turn, was correlated with physical activity and hand strength. In multivariate models including these variables, muscle mass was the strongest determinant of bone density, accounting for 6–53% (mean 27%) of the variance at the different skeletal sites. Physical activity (and/or a physical activity × age interaction) was an independent predictor of bone mass in 48% of the site-specific models and accounted for 0.03–39% (mean 10%) of the variance, while hand strength (and/or a hand strength × age interaction) accounted for up to 4% (mean 1%) of the variance as an independent predictor of bone density in a third of the models. Although these variables together accounted for a large proportion of the variance in bone density, other potential predictors were not assessed in these analyses. The dramatic decline in physical activity over life seemed unable to completely explain the age-related loss of bone mass, and additional research is needed to determine whether the relationship of muscle mass with bone density is a direct one or due instead to other factors such as circulating hormone levels. [ABSTRACT FROM AUTHOR]

: There is growing awareness that therapeutic decision-making may be confounded by discrepancies in the prevalence of osteoporosis by World Health Organization criteria when bone density is measured at different skeletal sites. To explore this issue, we measured bone density at a variety of skeletal sites in a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years). Men had greater areal bone mineral density (BMD, g/cm2) than women at almost every subregion on total body, anteroposterior (AP) and lateral lumbar spine, proximal femur and forearm scans by dual-energy X-ray absorptiometry. However, adjustment for height or, where possible, calculation of bone mineral apparent density (BMAD, g/cm3) reduced or eliminated these differences. In addition, three different patterns of change in bone density over life were observed at the various skeletal sites as judged from cross-sectional data: no apparent age-related bone loss (e.g., AP spine BMD in men); linear bone loss over life in both sexes beginning in young adulthood (e.g., femoral neck BMD); and bone loss beginning around the time of menopause or a comparable age in men (e.g., midradius BMD). The various adjustments for bone size and the different patterns of age-related change in bone density had profound effects on the estimated prevalence of osteoporosis by World Health Organization criteria, which ranged from 2% to 45% among postmenopausal women and from 0 to 36% among men 50 years of age and older depending upon the skeletal parameter that was assessed. These observations emphasize the difficulties involved in attempts to standardize BMD scores and definitions of osteoporosis for clinical use. [ABSTRACT FROM AUTHOR]

: We evaluated age- and sex-specific differences in bone density at a variety of skeletal sites in a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years) by dual-energy X-ray absorptiometry. Several patterns of age-related bone loss were observed, but adjustments for height (or, where possible, calculation of bone mineral apparent density) dampened the apparent rate of bone loss from most skeletal sites as judged from cross-sectional measurements at baseline. Cross-sectional data also overestimated the rate of bone loss observed longitudinally over 4 years at many sites, particularly the hip and spine; conversely, in some forearm regions, cross-sectional rates of loss underestimated the bone loss seen prospectively. Longitudinal rates of bone loss were generally greater among individuals age 70 years or older compared with younger men and women, but some of the latter effect was due to a greater proportion of younger women on hormone replacement therapy, whose rate of bone loss was generally less. These observations highlight the limitations of cross-sectional data for defining the patterns of bone loss over life at different skeletal sites. [ABSTRACT FROM AUTHOR]

This population-based study documents an increase in most types of fractures following the occurrence of a clinically recognized vertebral fracture among 820 Rochester, Minnesota, residents. During 4349 person-years of follow-up, 896 new fractures were observed. Relative to incidence rates in the community, there was a 2.8-fold increase in the risk of any fracture, which was greater in men (standardized incidence ratio (SIR), 4.2; 95% CI, 3.2–5.3) than women (SIR, 2.7; 95% CI, 2.4–3.0). The estimated cumulative incidence of any fracture after 10 years was 70%. The greatest increase in risk was for subsequent fractures of the axial skeleton, in particular a 12.6-fold increase (95% CI, 11–14) in additional vertebral fractures. There was a lesser increase in most limb fractures, including a 2.3-fold increase (95% CI, 1.8–2.9) in hip fractures and a 1.6-fold increase (95% CI, 1.01–2.4) in distal forearm fractures. There was a slightly greater association with distal forearm fractures among those whose first vertebral fracture occurred before age 70 years but a similar relationship with hip fractures, including cervical and intertrochanteric hip fractures separately, regardless of age at the initial vertebral fracture. There was also an equivalent increase in subsequent fracture risk whether the initial vertebral fracture was attributed to severe or moderate trauma. These data show that vertebral fractures represent an important risk factor for fractures in general, not just those of the spine and hip. [ABSTRACT FROM AUTHOR]

It has been suggested that the decrease in vitamin D stores with aging is a contributory cause of age-related osteoporosis. We studied this question by measuring bone mineral density (BMD) of the mid-radius, distal radius, and lumbar spine assessed by single and dual photon absorptiometry in 122 women, aged 33-94 years, selected from a random sample of Rochester, MN residents. We measured serum 25-hydroxyvitamin D (25OHD), the major storage form of vitamin D, as well as 25OHD3 (representing both endogenous and exogenous sources of vitamin D), and 25OHD2 (representing only exogenous sources). Both baseline serum total 25OHD (r = -0.29, P less than 0.001) and the metabolite 25OHD3 (r = -0.41, P less than 0.001), were negatively associated with age at baseline. After adjusting for the effect of age by multiple regression analysis, there was no association between serum levels of 25OHD2, 25OHD3, or total 25OHD and BMD for any of the three skeletal scanning sites. Thus, in a northern American population we cannot demonstrate that reduced bioavailability of vitamin D plays a major role in age-related bone loss. [ABSTRACT FROM AUTHOR]

Based on a presumption that the morphometric approach to vertebral fracture assessment is beset by false positive deformities, it has been suggested that more stringent criteria should be used to assess vertebral fracture outcomes in clinical trials of osteoporosis therapies. We applied a variety of criteria in the reanalysis of a randomized trial of sodium fluoride therapy for women with established osteoporosis. Although progressively more severe criteria reduced the cumulative incidence of a new vertebral fracture in both those receiving a placebo and the fluoride-treated patients, differences between the two groups were not magnified and none of the suggested approaches produced a statistically significant result. These findings indicate that the false positive rate associated with morphometric assessment of vertebral fractures is not so great as supposed from theoretical considerations that assume independence among the measurements. Our findings also provide some reassurance that differences in the criteria used to define a vertebral fracture are not the controlling influence in the likelihood that a particular clinical trial will find a result favoring one treatment over another. [ABSTRACT FROM AUTHOR]

We have assessed urinary deoxypyridinoline (Dpd) levels by immunoassay in women who participated in a double-masked, placebo-controlled trial of the bone loss prevention effects of estrogen replacement therapy (ERT). Ninety-one women who had undergone recent surgical menopause were randomdized to receive either placebo or 0.025, 0.05 or 0.1 mg/day transdermal 17β-estradiol for 2 years. Mean Dpd levels in the postmenopausal women were significantly elevated ( p<0.0001) above mean Dpd levels in a reference population of healthy, premenopausal women. Subjects in the placebo group lost 6.4% of lumbar spine bone mineral density (BMD) and 4.9% of mid-radius bone mineral content (BMC) over 2 years. Dpd levels at baseline were inversely correlated with BMD and BMC changes in the placebo group. The placebo group and subjects receiving 0.025 mg/day 17β-estradiol who had Dpd levels increased above the reference interval cut-off (mean + 2 standard deviations, 7.5 nmol/mmol) lost 2 times more bone mass than did those with Dpd levels below it. Dpd levels decreased significantly ( p<0.01) from baseline at 6 months following initiation of treatment with 0.05 or 0.1 mg/day 17β-estradiol, changes that correlated with increased lumbar spine BMD and with changes in mid-radius BMC. At 12 months, Dpd levels were lower than baseline and placebo in all three treatment groups. These data suggest utility of this Dpd immunoassay in assessing changes in bone resorption induced by surgical menopause and ERT. [ABSTRACT FROM AUTHOR]

In a 4-year controlled, prospective trial, histomorphometric analysis was used to compare the tissue-level skeletal effects of fluoride therapy in 43 postmenopausal women (75 mg NaF/day) with those of 35 matching placebo subjects; all subjects received 1500 mg/day elemental calcium supplement. In addition to an initial, baseline biopsy, a second biopsy was obtained after 6, 18, 30 or 48 months. Measurements were made on a third biopsy obtained from 8 subjects following at least 72 months of fluoride therapy. The change in cancellous bone volume or trabecular thickness in fluoride-treated subjects was not different from a change in placebo-treated subjects. However, paired analysis in the fluoride-treated subjects indicated that bone volume was increased between the first and second biopsies ( p<0.005). Both osteoid length and width were significantly increased in fluoride compared with placebo subjects; however, only the osteoid surface increased linearly ( r=0.63, p<0.001). The mineral apposition rate and relative tetracycline-covered bone surface were not different between fluoride and placebo treatment, although they were decreased in both groups in the second biopsy. The tetracycline-covered bone surface returned to normal in the third biopsy. Definitive evidence for osteomalacia is a prolonged mineralization lag time, which following fluoride treatment was found to be increased 9-fold in the second biopsy and 4-fold in the third biopsy. Further evidence for osteomalacia was increased osteoid thickness by 6 months, evidence of focal areas of interstitial mineralization defects, and broad tetracycline labels of low fluorescence intensity. In the third biopsies, osteoclastic resorption was observed beneath osteoid seams. Fluoride therapy increased the cortical width compared with placebo treatment ( p<0.02), and increased the osteoid surface in Haversian canals, but did not change the osteoid width, resorption surface or cortical porosity. After an initial rise, serum fluoride levels remained constant, and the urine values fell slightly. The bone fluoride concentration rose throughout the treatment period, and was correlated with the change in osteoid-covered bone surface ( r=0.56, p<0.001). Although we found definitive evidence for osteomalacia, the cause of the osteomalacia was not determined in this study. On the other hand, the presence of bone resorption beneath unmineralized osteoid and of osteocyte halos is suggestive of hyperparathyroidism. Thus, it is possible that the strong stimulus for bone formation brought about by fluoride therapy resulted in relative calcium deficiency. [ABSTRACT FROM AUTHOR]

The aims of the study were to evaluate the use of bone-specific biochemical markers of turnover in type I osteoporosis, to test for evidence of heterogeneity of bone turnover in this condition, and to attempt to devise an 'uncoupling index' by using the relationship between bone-specific biochemical markers of bone formation and bone resorption. In women with type I osteoporosis (mean age 64 years, SD 5; n=63) the mean level of serum osteocalcin, a specific biochemical marker of bone formation, was 9.9 ng/ml (SD 2.0), which was higher than the level in normal postmenopausal women (mean age 65 years, SD 6; n=8.9 ng/ml (SD 2.0; p<0.01). The variance of serum osteocalcin levels in the two groups was similar. Compared with this 11% increase in the biochemical marker for bone formation, the markers of bone resorption, total urinary deoxypyridinoline (bone-specific), pyridinoline and hydroxyproline were increased by 40% ( p<0.0001), 61% ( p<0.0001) and 25% ( p<0.01), respectively. Furthermore, these biochemical markers of bone resorption had greater variance in women in type I osteoporosis than in the normal postmenopausal women ( p<0.001). The urinary excretion of the free crosslinks deoxypyridinoline, pyridinoline and glycosylated pyridinoline were increased by 26% ( p<0.001), 17% ( p<0.01) and 13% (NS) respectively. An 'uncoupling index' was calculated for the difference between urinary deoxypyridinoline and serum osteocalcin using the results from the normal women and expressed as z-scores. We conclude that the pyridinium crosslinks of collagen enable better discrimination between normal and osteoporotic women than does hydroxyproline. In osteoporosis there appears to be heterogeneity of bone resorption. Finally, an uncoupling index indicated that in osteoporosis bone resorption was increased to a greater extent than bone formation as compared with normal postmenopausal women. [ABSTRACT FROM AUTHOR]

There is a need to identify vertebral fractures from radiographs taken at a single point in time, but considerable controversy surrounds the methods to be used. We extended a data set to comprise baseline radiographs of the thoracic and lumbar spine on an age-stratified random sample of 762 Rochester, Minnesota, women and used revised methods to define vertebral deformities morphometrically. Changes in the method of measuring vertebral heights, changes in the source of normal values for vertebral measurements and changes in the criteria for assessing vertebral deformity had little impact on estimated prevalence and incidence in this population. The prevalence of any vertebral deformity was estimated at 25.3 per 100 Rochester women aged 50 years and over (95% CI, 22.3-28.2), while the incidence of a new deformity in this group was estimated at 17.8 per 1000 person-years (95% CI, 16.0-19.7). Projected nationally, these data suggest that over 500 000 white women in the United States develop vertebral deformities for the first time each year and that over 7 million white women aged 50 years and over might be affected at any given time. These estimates are limited by the absence of a reliable 'gold standard' with which to determine false positive and false negative rates associated with this or any other morphometric method. Information on the health consequences of vertebral deformities of various sorts would be most helpful in choosing between alternative approaches to defining them. [ABSTRACT FROM AUTHOR]

The influence of reproductive factors on bone mass at six skeletal sites was assessed in an age-stratified random sample of white women residing in Rochester, Minnesota. After age-adjustment, whether or not women had ever breastfed, total duration of breastfeeding and duration of breastfeeding per child were not associated with reduced bone mineral, but breastfeeding for more than 8 months was associated with greater bone mineral at some sites. There were no consistent effects on bone mineral, after adjusting for age, of gravidity or parity, age at menarche, age at first delivery, use of oral contraceptives or estrogen replacement therapy, various sex hormones, nor any of the other reproductive factors assessed. There was a strong protective effect of obesity, which was also correlated with a number of the reproductive variables. While animal studies suggest that pregnancy and lactation may be associated with calcium loss from the skeleton, these data indicate that such factors have little long-term impact on bone mass in humans and little potential for identifying women at high risk of osteoporosis later in life. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors (IGF)-I and IGF-II are produced by osteoblasts and are important paracrine/autocrine regulators of osteoblast proliferation and differentiation. Estrogen has been reported to increase gene expression of IGF-I in rodent osteoblasts. However, because species differences have been demonstrated in expression of various aspects of the IGF system in bone cells, it is not known whether this action also occurs in human osteoblasts. Thus, we assessed the effects of estrogen treatment on IGF-I and IGF-II gene expression in vitro in a recently developed human fetal osteoblast cell line that has high levels of estrogen receptors. As assessed by a quantitative reverse transcriptase-polymerase chain reaction method, treatment of hFOB/ER9 cells with 17β-estradiol (E2) increased steady state levels of IGF-I mRNA in a time- and dose- dependent fashion with a maximal increase of 319% ± 33% ( P < 0.01) of control occurring after treatment with 10−7 M E2 for 48 hours. In contrast, E2 did not alter steady state levels of IGF-II mRNA. The pure (type 2) antiestrogens ICI 182,780 (10−7 M) and ICI 164,384 (10−6 M) blocked the E2- induced increase in IGF-I mRNA levels. Interestingly, 4-hydroxytamoxifen (10−7 M), a documented pure antiestrogen in reproductive tissues, also increased IGF-I mRNA to levels similar to those observed in E2-treated cells. Since E2 was shown to mediate its effects on some target genes through a cAMP-dependent pathway, we studied the interaction between E2 and agents that are known to increase intracellular cAMP. Forskolin (10−8 M) and dibutyryl cAMP (10−3 M) increased IGF-I mRNA levels sixfold, and cotreatment with E2 did not affect these changes, consistent with a possible mediation of the estrogen effect on IGF-I gene expression by cAMP. We conclude that in human osteoblastic cells, the IGF-I gene is a target for estrogen action, suggesting that IGF-I may mediate part of the effects of estrogen in human bone. [ABSTRACT FROM AUTHOR]

To explore possible changes in proximal femur (hip) fracture incidence over time, an earlier study among Rochester, Minnesota residents for 1928-1977 was updated through 1982. Reanalysis of data demonstrated rising age-adjusted rates for men over this time. Crude rates rose for women as well, but age adjusted rates leveled off in the mid-1950s, as did overall rates, since the majority of hip fractures were in women. Secular trends were primarily due to changes in the incidence of initial hip fractures associated with moderate trauma, the sort usually attributed to osteoporosis. No differences were noted in trends for cervical vs. intertrochanteric femur fractures; and, excluding the low values for 1928-1942, no significant trends were noted for women within various age groups. Our results for women conflict with estimates from a number of other studies, but these differences may provide a basis for hypothesis development. [ABSTRACT FROM AUTHOR]

To explore possible changes in proximal femur (hip) fracture incidence over time, an earlier study among Rochester, Minnesota residents for 1928-1977 was updated through 1982. Reanalysis of data demonstrated rising age-adjusted rates for men over this time. Crude rates rose for women as well, but age adjusted rates leveled off in the mid-1950s, as did overall rates, since the majority of hip fractures were in women. Secular trends were primarily due to changes in the incidence of initial hip fractures associated with moderate trauma, the sort usually attributed to osteoporosis. No differences were noted in trends for cervical vs. intertrochanteric femur fractures; and, excluding the low values for 1928-1942, no significant trends were noted for women within various age groups. Our results for women conflict with estimates from a number of other studies, but these differences may provide a basis for hypothesis development. [ABSTRACT FROM AUTHOR]

We have characterized the noncollagenous proteins of bovine bone using two high-resolution gel electrophoretic techniques. Proteins were extracted from bone tissue by extended dialysis against 0.5 M EDTA. In some cases, a preextraction was done in guanidine HCl. Bovine plasma was also examined to identify the proteins in bone that might also be present in blood. We have scored 160 major, reproducible spots on our standard preparation bone map. These comprise about 40 individual protein groups. There are many more minor spots present which puts the total number present over 200. Of these groups, 15 are not present on plasma maps. Bone proteins identified in this way include actin, bone Gla-protein, and osteonectin. The remainder are unknown. Bone Gla-protein is present in bovine bone in four isoelectric forms, pI=3.95−4.50. Electroblotting analysis of EDTA and guanidine HCl extracted material failed to reveal any higher molecular weight immunologically reactive species. The plasma proteins found in bone include, but are not limited to albumin, apo A-I lipoprotein, IgG, IgM, transferrin, α-2-HS-glycoprotein, and hemoglobin. Extraction with guanidine HCl plus EDTA significantly enriches the yield for the nonplasma proteins but does not appear to extract any additional bone proteins. [ABSTRACT FROM AUTHOR]

To define the role of parathyroid gland function in the pathophysiology of bone loss in type I (postmenopausal) osteoporosis, we measured serum intact parathyroid hormone (PTH) concentration by immunoradiometric assay (IRMA) and by multisite immunochemiluminometric assay (ICMA) in 63 postmenopausal osteoporotic women (PMOp) with vertebral compression fractures and in 75 age-comparable postmenopausal normal women (PMNl). Also, tetracycline-based histomorphometric indices in cancellous bone were assessed in iliac biopsy samples from 61 PMOp and 28 PMNl women. Serum PTH concentrations by IRMA were similar in PMOp and PMNl (medians, 3.92 and 3.77 pmol/l; NS) but were significantly lower in PMOp by the more sensitive ICMA (medians, 2.82 and 3.14 pmol/l; P<0.01). By multiple linear regression analysis, serum PTH was directly related ( P<0.001) to activation frequency, bone resorption rate, bone formation rate, and the calculated rate of bone loss. For each unit (pmol/l) increase in serum PTH by ICMA, activation frequency increased by 1.3%/year more ( P=0.01), bone resorption rate increased by 3.9%/year more ( P=0.003), and the rate of cancellous bone loss was 2.8% greater ( P= 0.0003) in the PMOp women compared with the PMNl women. Concentrations of serum estradiol, but not serum estrone, had a weak opposing effect to PTH, especially for bone formation rate. These data suggest that in PMOp the bone has increased sensitivity to the biologic effects of PTH. This may represent one of the fundamental pathophysiologic defects in PMOp and, in the setting of estrogen deficiency, may explain, in part, their greater rate of bone loss. [ABSTRACT FROM AUTHOR]

Pamidronate (aminohydroxypropylidine bisphosphonate, APD) is an effective agent for treatment of Paget's disease of bone, and it has also been thought to be effective for treatment of osteoporosis. We desired to study a newer, time-release preparation of pamidronate, and carried out a placebo-controlled, double-masked study of postmenopausal osteoporosis. The original formulation was in a rapidly dissolving gelatin capsule. We encountered four episodes of esophagitis in 49 enrolled patients. We therefore discontinued treatment with this preparation and later began the study again using a standard tablet preparation. We encountered an additional case of erosive esophagitis in 1 patient of 40 receiving this tablet preparation. No patient was receiving concomitant medication which could cause esophagitis. Two of the patients gave a past history of hiatal hernia and 1 gave a history of gastric ulcer 27 years previously. The diagnosis of esophagitis was confirmed in all cases by endoscopy. Healing of the esophagitis promptly ensued after discontinuation of the pamidronate and the use of antacid medication. [ABSTRACT FROM AUTHOR]

A personal narrative is presented which explores the author's experience of looking into the early research work of Pierre Delmas which is related to bone turnover.