Three-dimensional structural analysis of the proximal femur in an age-stratified sample of women.

INTRODUCTION: Aging is associated with worsening bone structure and increasing risk of hip fracture. However, the commonly used clinical tool, dual-energy x-ray absorptiometry, does not provide information on changes with age or disease separately in trabecular versus cortical bone or in bone geometry. Here we used 3D quantitative computed tomography (QCT) to analyze age-related changes in femoral volumetric bone mineral density (vBMD) and structure in a well characterized, population-based cohort of Rochester, Minnesota women. METHODS: MIAF-Femur (MIAF: medical image analysis framework) was used for the analysis of CT datasets from 358 women age 20 to 97 years. Integral, "apparent" cortical (rather than true cortical vBMD, due to volume averaging effects) and trabecular vBMD, volume, and bone mineral content (BMC) as well as cortical thickness of the femur head, neck, trochanter, inter-trochanteric, and proximal shaft volumes of interest (VOIs) were measured. In addition, changes in vBMD in the superior, inferior, posterior and anterior quadrants of the femur neck were assessed. RESULTS: Cross-sectional percent decreases in vBMD across life were 2- to 5-fold higher in trabecular versus cortical bone at all sites in the femur, although absolute changes in the trabecular and cortical bone were fairly similar. In addition, the slopes of the relationships of trabecular vBMD with age were generally similar in pre- and postmenopausal women, whereas apparent cortical vBMD in the femur neck, trochanter, inter-trochanteric region, and proximal shaft remained relatively stable in premenopausal women but decreased significantly with age following the menopause. Bone volume increased at all sites, more so in pre- compared to postmenopausal women. Age-related BMC changes were not significant in premenopausal women, but BMC losses were highly significant in postmenopausal women. Detailed analyses of femur neck cortical bone showed that percent apparent vBMD decreases in the superior quadrants were 2- to 3-fold greater than in the inferior quadrants; changes in absolute values were most different (~2-fold) between the superior-posterior and inferior-posterior quadrants. CONCLUSIONS: These data demonstrate that patterns of changes with age within the femur differ in the trabecular versus cortical bone. In the cortical compartment which, due to limitations in spatial resolution, contains some subcortical bone and should be regarded as an "apparent" cortical VOI, the superior quadrants in the femur neck undergo the greatest decreases. These findings may have important implications for understanding the structural basis for increased hip fracture risk with aging.

Better tools for assessing osteoporosis.

Some 30 years ago, we applied the newly described method of dual photon absorptiometry (DPA) to demonstrate that osteoporotic women with vertebral fractures had lost substantially more bone from the vertebrae than controls. This opened a whole new field of research into the determinants of bone loss and fractures in the axial skeleton and set the stage for subsequent development of dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT), which are now the standard methods for assessing osteoporosis severity and treatment efficacy.

Relationship of age to bone microstructure independent of areal bone mineral density.

Previous studies using dual-energy X-ray absorptiometry (DXA) have demonstrated that age is a major predictor of bone fragility and fracture risk independent of areal bone mineral density (aBMD). Although this aBMD-independent effect of age has been attributed to poor bone "quality," the structural basis for this remains unclear. Because high-resolution peripheral quantitative computed tomography (HRpQCT) can assess bone microarchitecture, we matched younger and older subjects for aBMD at the ultradistal radius and assessed for possible differences in trabecular or cortical microstructure by HRpQCT. From an age-stratified, random sample of community adults, 44 women aged <50 years (mean age 41.0 years) were matched to 44 women aged ≥50 years (mean age 62.7 years) by ultradistal radius aBMD (mean ± SEM, younger and older aBMD 0.475 ± 0.011 and 0.472 ± 0.011 g/cm², respectively), and 57 men aged <50 years (mean age 41.3 years) were matched to 57 men aged ≥50 years (mean age 68.1 years; younger and older aBMD both 0.571 ± 0.008 g/cm²). In these matched subjects, there were no sex-specific differences in trabecular microstructural parameters. However, significant differences were noted in cortical microstructure (all p < 0.05): Older women and men had increased cortical porosity (by 91% and 56%, respectively), total cortical pore volume (by 77% and 61%, respectively), and mean cortical pore diameter (by 9% and 8%, respectively) compared with younger subjects. These findings indicate that younger and older women and men matched for DXA aBMD have similar trabecular microarchitecture but clearly different cortical microstructure, at least at an appendicular site represented by the radius. Further studies are needed to define the extent to which this deterioration in cortical microstructure contributes to the aBMD-independent effect of age on bone fragility and fracture risk at the distal radius and other sites of osteoporotic fractures.

Relationship of femoral neck areal bone mineral density to volumetric bone mineral density, bone size, and femoral strength in men and women.

UNLABELLED: 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.

Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women.

Intermittent parathyroid hormone (PTH) 1-34 treatment stimulates bone formation, but the molecular mechanisms mediating this effect have not been previously studied in humans. Thus, we used magnetic activated cell sorting to isolate hematopoietic lineage negative (lin-)/alkaline phosphatase positive (AP+) osteoprogenitor cells from bone marrow of 20 postmenopausal women treated with PTH (1-34) for 14 days and 19 control subjects. Serum PINP and CTX increased in PTH-treated subjects (by 97% and 30%, respectively, P<0.001). Bone marrow lin-/AP+ cells from PTH-treated subjects showed an increase in the RANKL/OPG mRNA ratio (by 7.5-fold, P=0.011) and in the mRNAs for c-fos (a known PTH-responsive gene, by 42%, P=0.035) and VEGF-C (by 57%, P=0.046). Gene Set Enrichment Analysis (GSEA, testing for changes in pre-specified pathways) demonstrated that PTH had no effect on osteoblast proliferation, apoptosis, or differentiation markers. However, PTH treatment resulted in a significant decrease (GSEA P-value, 0.005) in a panel of BMP target genes in the lin-/AP+ cells. Our findings thus identify several future directions for studying mechanisms of PTH action in humans. First, given the increasing evidence that PTH induces angiogenesis, the role of increased VEGF-C production by bone marrow osteoprogenitor cells in mediating this effect and the anabolic response to PTH warrants further study. Second, while the observed inhibition of BMP target gene expression by PTH is not consistent with the anabolic effects of PTH on bone and requires further validation, these data do generate the hypothesis that an inhibition of BMP signaling by PTH may, over time, limit the availability of mature osteoblasts on bone surfaces and thereby contribute to the observed waning of the anabolic response to PTH.

Relationship of testosterone and osteocalcin levels during growth.

Recent studies in mice have demonstrated that osteocalcin (OCN) regulates testosterone (T) production in males but not in females. We hypothesized that this novel bone-testis axis may be most relevant during rapid skeletal growth to help maximize bone size. Thus we measured serum T, total and undercarboxylated (UC) OCN, and periosteal circumference at the radius in 56 boys (bone age 4 to 20 years). T was correlated with OCN (bone-age-adjusted r = 0.30, p = .024), with a similar trend for UC OCN. T began to increase in the boys at bone age 11 years, and OCN peaked at bone age 14 years. Thus we divided the boys into three groups: 4 to 10 years (n = 16), 11 to 14 years (n = 18), and 15 to 20 years (n = 22). In boys of bone age 11 to 14 years (but not the other two groups), OCN was correlated with T (r = 0.57, p = .013), with a similar trend for UC OCN; T, in turn, was correlated with periosteal circumference (r = 0.75, p < .001). Collectively, these findings support the recent observations in mice of a novel bone-testis axis. Moreover, our data suggest that in human males, this axis may be most relevant during rapid skeletal growth, when T levels are rising under the influence of the hypothalamic-pituitary axis and OCN is increasing due to skeletal growth. During this phase, OCN may further stimulate testicular T production, which, in turn, contributes to an increase in bone size.

Association of hip strength estimates by finite-element analysis with fractures in women and men.

Finite-element analysis (FEA) of quantitative computed tomography (QCT) scans can estimate site-specific whole-bone strength. However, it is uncertain whether the site-specific detail included in FEA-estimated proximal femur (hip) strength can determine fracture risk at sites with different biomechanical characteristics. To address this question, we used FEA of proximal femur QCT scans to estimate hip strength and load-to-strength ratio during a simulated sideways fall and measured total hip areal and volumetric bone mineral density (aBMD and vBMD) from QCT images in an age-stratified random sample of community-dwelling adults age 35 years or older. Among 314 women (mean age ± SD: 61 ± 15 years; 235 postmenopausal) and 266 men (62 ± 16 years), 139 women and 104 men had any prevalent fracture, whereas 55 Women and 28 men had a prevalent osteoporotic fracture that had occurred at age 35 years or older. Odds ratios by age-adjusted logistic regression analysis for prevalent overall and osteoporotic fractures each were similar for FEA hip strength and load-to-strength ratio, as well as for total hip aBMD and vBMD. C-statistics (estimated areas under ROC curves) also were similar [eg, 0.84 to 0.85 (women) and 0.75 to 0.78 (men) for osteoporotic fractures]. In women and men, the association with prevalent osteoporotic fractures increased below an estimated hip strength of approximately 3000 N. Despite its site-specific nature, FEA-estimated hip strength worked equally well at predicting prevalent overall and osteoporotic fractures. Furthermore, an estimated hip strength below 3000 N may represent a critical level of systemic skeletal fragility in both sexes that warrants further investigation.

Determinants of forearm strength in postmenopausal women.

UNLABELLED: 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(2) = 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.

The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed?

Over a decade ago, we proposed a "unitary" model for the pathogenesis of osteoporosis that identified estrogen deficiency as the predominant cause of both the early, accelerated, and late slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. While this was a plausible model then, new data over the intervening years suggest a need to modify these concepts. Indeed, based largely on rodent studies, a "revisionist" view of the pathogenesis of osteoporosis has been proposed recently that attempts a paradigm shift from the estrogen-centric model to one in which bone loss is largely independent of estrogen deficiency and is driven instead by cell-autonomous age-related factors. However, detailed clinical investigative studies using quantitative computed tomography demonstrate that the onset of cortical bone loss in humans is closely tied to estrogen deficiency; thus the estrogen-centric view is likely correct for cortical bone, which comprises over 80% of the skeleton and is the major structural determinant of fracture risk at most skeletal sites. By contrast, these same studies also demonstrate that trabecular bone loss begins in sex hormone-replete young adults of both sexes. This suggests that a significant proportion of trabecular bone loss is either estrogen-independent or, as suggested by some studies, requires higher levels for its regulation. In this perspective, we critically review these and other findings, leading us to conclude that our original model requires modification but not revision.

Regulation of circulating sclerostin levels by sex steroids in women and in men.

Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels. E treatment of postmenopausal women (n = 17) for 4 weeks led to a 27% decrease in serum sclerostin levels [versus +1% in controls (n = 18), p < .001]. Similarly, in 59 elderly men, we eliminated endogenous E and T production and studied them under conditions of physiologic T and E replacement, and then following withdrawal of T or E, we found that E, but not T, prevented increases in sclerostin levels following induction of sex steroid deficiency. In both sexes, changes in sclerostin levels correlated with changes in bone-resorption, but not bone-formation, markers (r = 0.62, p < .001, and r = 0.33, p = .009, for correlations with changes in serum C-terminal telopeptide of type 1 collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E but not by T. Moreover, consistent with recent data indicating important effects of Wnts on osteoclastic cells, our findings suggest that in humans, changes in sclerostin production may contribute to effects of E on bone resorption.

Relation of age, gender, and bone mass to circulating sclerostin levels in women and men.

Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population-based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean ± SEM) were significantly higher in men than women (33.3 ± 1.0 pmol/L versus 23.7 ± 0.6 pmol/L, p < .001). In pre- and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4- and 4.6-fold in the women and men, respectively. Moreover, for a given total-body bone mineral content, elderly subjects (age ≥ 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age-related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age-related impairment in bone formation.

Trabecular bone deficits among Vietnamese immigrants.

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.

Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women.

CONTEXT: Intermittent PTH treatment stimulates bone formation, but the mechanism(s) of this effect remain unclear. Sclerostin is an inhibitor of Wnt signaling, and animal studies have demonstrated that PTH suppresses sclerostin production. OBJECTIVE: The objective of the study was to test whether intermittent PTH treatment of postmenopausal women alters circulating sclerostin levels. DESIGN: Prospective study. SETTING: The study was conducted at a clinical research unit. PARTICIPANTS AND INTERVENTIONS: Participants included 27 postmenopausal women treated with PTH (1-34) for 14 d and 28 control women. MAIN OUTCOME MEASURES: Serum sclerostin levels were measured. RESULTS: Circulating sclerostin levels decreased significantly in the PTH-treated subjects, from (mean ± SEM) 551 ± 32 to 482 ± 31 pg/ml (-12.7%, P < 0.0001) but did not change in the control women (baseline, 559 ± 34 pg/ml; end point, 537 ± 40 pg/ml, P = 0.207; P = 0.017 for difference in changes between groups). Bone marrow plasma was obtained in a subset of the control and PTH-treated subjects (n = 19 each) at the end of the treatment period, and marrow plasma and peripheral serum sclerostin levels were significantly correlated (R = 0.64, P < 0.0001). Marrow plasma sclerostin levels were 24% lower in PTH-treated compared with control women, but perhaps due to the smaller sample size, this difference was not statistically significant (P = 0.173). CONCLUSIONS: Circulating sclerostin levels correlate with bone marrow plasma levels and are reduced by intermittent PTH therapy in postmenopausal women. Further studies are needed to assess the extent to which decreases in sclerostin production contribute to the anabolic skeletal response to PTH.

Relation of vertebral deformities to bone density, structure, and strength.

Because they are not reliably discriminated by areal bone mineral density (aBMD) measurements, it is unclear whether minimal vertebral deformities represent early osteoporotic fractures. To address this, we compared 90 postmenopausal women with no deformity (controls) with 142 women with one or more semiquantitative grade 1 (mild) deformities and 51 women with any grade 2-3 (moderate/severe) deformities. aBMD was measured by dual-energy X-ray absorptiometry (DXA), lumbar spine volumetric bone mineral density (vBMD) and geometry by quantitative computed tomography (QCT), bone microstructure by high-resolution peripheral QCT at the radius (HRpQCT), and vertebral compressive strength and load-to-strength ratio by finite-element analysis (FEA) of lumbar spine QCT images. Compared with controls, women with grade 1 deformities had significantly worse values for many bone density, structure, and strength parameters, although deficits all were much worse for the women with grade 2-3 deformities. Likewise, these skeletal parameters were more strongly associated with moderate to severe than with mild deformities by age-adjusted logistic regression. Nonetheless, grade 1 vertebral deformities were significantly associated with four of the five main variable categories assessed: bone density (lumbar spine vBMD), bone geometry (vertebral apparent cortical thickness), bone strength (overall vertebral compressive strength by FEA), and load-to-strength ratio (45-degree forward bending ÷ vertebral compressive strength). Thus significantly impaired bone density, structure, and strength compared with controls indicate that many grade 1 deformities do represent early osteoporotic fractures, with corresponding implications for clinical decision making.

Circulating osteogenic cells: characterization and relationship to rates of bone loss in postmenopausal women.

There is increasing evidence that osteogenic cells are present not only in bone marrow (BM) but also in peripheral blood (PB). Since staining for alkaline phosphatase (AP) identifies osteoprogenitor cells in BM, we sought to further characterize BM versus PB hematopoietic lineage negative (lin-)/AP+ cells and to compare gene expression in PB lin-/AP+ cells from postmenopausal women undergoing rapid versus slow bone loss. PB lin-/AP+ cells were smaller than their BM counterparts, and both were negative for the pan-hematopoietic marker, CD45. BM and PB lin-/AP+ cells were capable of mineralization in vitro. Using whole genome linear amplification followed by quantitative polymerase chain reaction (QPCR) analysis, we found that relative to the BM cells, PB lin-/AP+ cells expressed similar levels of a number of key osteoblast marker genes (runx2, osterix, osteopontin, OPG, periostin), consistent with the PB cells being in the osteoblastic lineage. Importantly, however, compared to the BM cells, PB lin-/AP+ cells expressed lower levels of mRNAs for AP, type I collagen, and for a panel of proliferation markers, but higher levels of osteocalcin, osteonectin, and PTHR1 mRNAs, as well as those for RANKL and ICAM-1, both of which are important in supporting osteoclastogenesis. Using microarray followed by QPCR analysis, we further demonstrated that, compared to postmenopausal women undergoing slow bone loss, PB lin-/AP+ cells from women undergoing rapid bone loss expressed lower levels of mRNAs for hydroxyprostaglandin dehydrogenase, interferon regulator factor 3, Wnt1-induced secreted protein 1, and TGFbeta2, but higher levels of the Smad3 interacting protein, zinc finger DHHC-type containing 4 and col1alpha2. These data thus demonstrate that while PB lin-/AP+ cells express a number of osteoblastic genes and are capable of mineralization, they are a relatively quiescent cell population, both in terms of cell proliferation and matrix synthesis. However, their higher expression of RANKL and ICAM-1 mRNAs as compared to BM lin-/AP+ cells suggests a role for the PB lin-/AP+ cells in regulating osteoclastogenesis that warrants further investigation. Our study also provides "proof-of-concept" for the use of PB lin-/AP+ cells in clinical-investigative studies, and identifies several pathways that could potentially regulate rates of bone loss in postmenopausal women.

Assessing forearm fracture risk in postmenopausal women.

UNLABELLED: 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. INTRODUCTION: This study seeks to test the clinical utility of approaches for assessing forearm fracture risk. METHODS: 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 (microFE) models. RESULTS: 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 (microFE failure load; OR, 1.8; 95% CI, 1.3-2.5); the factor-of-risk (applied load in a forward fall / microFE 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). CONCLUSIONS: Detailed bone structure and strength measurements provide insight into forearm fracture pathogenesis, but femoral neck aBMD performs adequately for routine clinical risk assessment.

Age-dependence of femoral strength in white women and men.

Although age-related variations in areal bone mineral density (aBMD) and the prevalence of osteoporosis have been well characterized, there is a paucity of data on femoral strength in the population. Addressing this issue, we used finite-element analysis of quantitative computed tomographic scans to assess femoral strength in an age-stratified cohort of 362 women and 317 men, aged 21 to 89 years, randomly sampled from the population of Rochester, MN, and compared femoral strength with femoral neck aBMD. Percent reductions over adulthood were much greater for femoral strength (55% in women, 39% in men) than for femoral neck aBMD (26% in women, 21% in men), an effect that was accentuated in women. Notable declines in strength started in the mid-40s for women and one decade later for men. At advanced age, most of the strength deficit for women compared with men was a result of this decade-earlier onset of strength loss for women, this factor being more important than sex-related differences in peak bone strength and annual rates of bone loss. For both sexes, the prevalence of "low femoral strength" (<3000 N) was much higher than the prevalence of osteoporosis (femoral neck aBMD T-score of -2.5 or less). We conclude that age-related declines in femoral strength are much greater than suggested by age-related declines in femoral neck aBMD. Further, far more of the elderly may be at high risk of hip fracture because of low femoral strength than previously assumed based on the traditional classification of osteoporosis.

Relation of serum serotonin levels to bone density and structural parameters in women.

Recent studies have demonstrated an important role for circulating serotonin in regulating bone mass in rodents. In addition, patients treated with selective serotonin reuptake inhibitors (SSRIs) have reduced areal bone mineral density (aBMD). However, the potential physiologic role of serotonin in regulating bone mass in humans remains unclear. Thus we measured serum serotonin levels in a population-based sample of 275 women and related these to total-body and spine aBMD assessed by dual-energy X-ray absorptiometry, femur neck total and trabecular volumetric BMD (vBMD) and vertebral trabecular vBMD assessed by quantitative computed tomography (QCT), and bone microstructural parameters at the distal radius assessed by high-resolution peripheral QCT (HRpQCT). Serotonin levels were inversely associated with body and spine aBMD (age-adjusted R = -0.17 and -0.16, P < .01, respectively) and with femur neck total and trabecular vBMD (age-adjusted R = -0.17 and -0.25, P < .01 and < .001, respectively) but not lumbar spine vBMD. Bone volume/tissue volume, trabecular number, and trabecular thickness at the radius were inversely associated with serotonin levels (age-adjusted R = -0.16, -0.16, and -0.14, P < .05, respectively). Serotonin levels also were inversely associated with body mass index (BMI; age-adjusted R = -0.23, P < .001). Multivariable models showed that serotonin levels remained significant negative predictors of femur neck total and trabecular vBMD, as well as trabecular thickness at the radius, after adjusting for age and BMI. Collectively, our data provide support for a physiologic role for circulating serotonin in regulating bone mass in humans.

Bone structure at the distal radius during adolescent growth.

The incidence of distal forearm fractures peaks during the adolescent growth spurt, but the structural basis for this is unclear. Thus, we studied healthy 6- to 21-yr-old girls (n = 66) and boys (n = 61) using high-resolution pQCT (voxel size, 82 microm) at the distal radius. Subjects were classified into five groups by bone-age: group I (prepuberty, 6-8 yr), group II (early puberty, 9-11 yr), group III (midpuberty, 12-14 yr), group IV (late puberty, 15-17 yr), and group V (postpuberty, 18-21 yr). Compared with group I, trabecular parameters (bone volume fraction, trabecular number, and thickness) did not change in girls but increased in boys from late puberty onward. Cortical thickness and density decreased from pre- to midpuberty in girls but were unchanged in boys, before rising to higher levels at the end of puberty in both sexes. Total bone strength, assessed using microfinite element models, increased linearly across bone age groups in both sexes, with boys showing greater bone strength than girls after midpuberty. The proportion of load borne by cortical bone, and the ratio of cortical to trabecular bone volume, decreased transiently during mid- to late puberty in both sexes, with apparent cortical porosity peaking during this time. This mirrors the incidence of distal forearm fractures in prior studies. We conclude that regional deficits in cortical bone may underlie the adolescent peak in forearm fractures. Whether these deficits are more severe in children who sustain forearm fractures or persist into later life warrants further study.