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1.  Three-dimensional Structural Analysis of the Proximal Femur in an Age-Stratified Sample of Women 
Bone  2013;55(1):179-188.
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 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 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 post-menopausal 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 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.
doi:10.1016/j.bone.2013.02.009
PMCID: PMC3650123  PMID: 23486182
osteoporosis; femur; aging
2.  Better tools for assessing osteoporosis 
The Journal of Clinical Investigation  2012;122(12):4323-4324.
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.
doi:10.1172/JCI66746
PMCID: PMC3533568  PMID: 23154276
3.  Role of RANK ligand in mediating increased bone resorption in early postmenopausal women 
Journal of Clinical Investigation  2003;111(8):1221-1230.
Studies in rodents have implicated various cytokines as paracrine mediators of increased osteoclastogenesis during estrogen deficiency, but increases in RANKL, the final effector of osteoclastogenesis, have not been demonstrated. Thus, we isolated bone marrow mononuclear cells expressing RANKL on their surfaces by two-color flow cytometry using FITC-conjugated osteoprotegerin-Fc (OPG-Fc-FITC) as a probe. The cells were characterized as preosteoblastic marrow stromal cells (MSCs), T lymphocytes, or B lymphocytes by using Ab’s against bone alkaline phosphatase (BAP), CD3, and CD20, respectively, in 12 premenopausal women (Group A), 12 early postmenopausal women (Group B), and 12 age-matched, estrogen-treated postmenopausal women (Group C). Fluorescence intensity of OPG-Fc-FITC, an index of the surface concentration of RANKL per cell, was increased in Group B over Groups A and C by two- to threefold for MSCs, T cells, B cells, and total RANKL-expressing cells. Moreover, in the merged groups, RANKL expression per cell correlated directly with the bone resorption markers, serum C-terminal telopeptide of type I collagen and urine N-telopeptide of type I collagen, in all three cell types and inversely with serum 17β-estradiol for total RANKL-expressing cells. The data suggest that upregulation of RANKL on bone marrow cells is an important determinant of increased bone resorption induced by estrogen deficiency.
doi:10.1172/JCI200317215
PMCID: PMC152939  PMID: 12697741
4.  Effects of Intermittent Parathyroid Hormone Treatment on Osteoprogenitor Cells in Postmenopausal Women 
Bone  2011;49(3):349-355.
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.
doi:10.1016/j.bone.2011.05.003
PMCID: PMC3143310  PMID: 21600325
postmenopausal women; PTH; anabolic; osteoporosis
5.  Relationship of Testosterone and Osteocalcin Levels During Growth 
Journal of Bone and Mineral Research  2011;26(9):2212-2216.
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 4–20 years). T was correlated with OCN (bone age-adjusted r = 0.30, P = 0.024), 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 3 groups: 4–10 years (n = 16), 11–14 years (n = 18), and 15–20 years (n = 22). In boys of bone age 11–14 years (but not the other two groups) OCN was correlated with T (r = 0.57, P = 0.013), with a similar trend for UC OCN; T, in turn, was correlated with periosteal circumference (r = 0.75, P < 0.001). 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.
doi:10.1002/jbmr.421
PMCID: PMC3304458  PMID: 21590731
6.  Association of Hip Strength Estimates by Finite Element Analysis with Fractures in Women and Men 
Finite element (FE) analysis of quantitative computed tomography (QCT) scans can estimate site-specific whole bone strength. However, it is uncertain whether the site-specific detail included in FE-estimated proximal femur (hip) strength can determine fracture risk at sites with different biomechanical characteristics. To address this question, we used FE analysis 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 adults, age ≥ 35 years. 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, while 55 women and 28 men had a prevalent osteoporotic fracture that had occurred age ≥ 35 years. Odds ratios by age-adjusted logistic regression analysis for prevalent overall and osteoporotic fractures each were similar for FE hip strength and load-to-strength ratio, as well as total hip aBMD and vBMD. C-statistics (estimated areas under ROC curves) were also similar (e.g., 0.84–0.85 [women] and 0.75–0.78 [men] for osteoporotic fractures). In women and men, the association with prevalent osteoporotic fractures increased below an estimated hip strength of ~3000 N. Despite its site-specific nature, FE-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.
doi:10.1002/jbmr.347
PMCID: PMC3201782  PMID: 21305605
finite element analysis; fractures; bone density; quantitative computed tomography; hip; proximal femur
7.  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. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.262
PMCID: PMC3179298  PMID: 20928874
OSTEOPOROSIS; MENOPAUSE; AGING
8.  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. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.217
PMCID: PMC3179347  PMID: 20721932
SCLEROSTIN; OSTEOPOROSIS; AGING
10.  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 < 0.001). Similarly, in 59 elderly men in whom we eliminated endogenous E and T production, 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 formation, markers (R = 0.62, P < 0.001 and R = 0.33, P = 0.009 for correlations with changes in serum C-terminal telopeptide of type I collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E, but not 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.
doi:10.1002/jbmr.128
PMCID: PMC3132405  PMID: 20499362
Estrogen; testosterone; sclerostin; bone turnover
11.  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. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.128
PMCID: PMC3132405  PMID: 20499362
ESTROGEN; TESTOSTERONE; SCLEROSTIN; BONE TURNOVER
12.  Relation of Vertebral Deformities to Bone Density, Structure, and Strength 
Journal of Bone and Mineral Research  2010;25(9):1922-1930.
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. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.150
PMCID: PMC3153401  PMID: 20533526
bone density; bone quality; finite-element analysis; QCT; vertebral fracture
13.  Assessing forearm fracture risk in postmenopausal women 
Purpose
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 areal bone mineral density (aBMD) and assessed radius volumetric BMD, geometry and microstructure using high-resolution peripheral QCT; ultradistal radius failure load was evaluated in micro-finite element (μFE) 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 SD, 2.0; 95% 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 ROC 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.
doi:10.1007/s00198-009-1047-2
PMCID: PMC2889027  PMID: 19714390
Bone density; Bone quality; Colles’ fracture; Epidemiology; Risk assessment
14.  Circulating Osteogenic Cells: Characterization and Relationship to Rates of Bone Loss in Postmenopausal Women 
Bone  2010;47(1):83-92.
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 TGFβ2, but higher levels of the Smad3 interacting protein, zinc finger DHHC-type containing 4 and col1α2. 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.
doi:10.1016/j.bone.2010.03.018
PMCID: PMC2891408  PMID: 20362080
osteoporosis; bone loss; menopause; osteoblast; progenitors
15.  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. © 2010 American Society for Bone and Mineral Research.
doi:10.1359/jbmr.091033
PMCID: PMC3153366  PMID: 19874201
bone strength; osteoporosis; aging; finite-element analysis; biomechanics
16.  Quantitative 45Ca autoradiography of human bone 
Bone from 7 terminally ill men who received 45Ca ½ to 23 days before death was studied by quantitative autoradiography. Short-term exchangeable calcium was located on bone surfaces, and had an apparent mass of 3.4 Gm. The time of maximal surface 45Ca activity was 2.5 days. Diffuse activity of low intensity from long-term exchange accounted for 16.9 ± 3.3 per cent (mean ± S.E.) of total uptake; in the 2 patients having plasma 45Ca measurements; the rate of diffuse uptake ranged from 10 to 25 per cent of the normal accretion rate. However, focal activity of intermediate intensity accounted for 49.8 to 68.4 per cent of uptake and was believed to be due to both long-term exchange and secondary mineralization. An unexpected finding was that 7.5 ± 1.6 per cent of activity was associated with bone resorption surfaces. Because of the terminal illness, bone formation was suppressed, and only 5.9 ± 2.4 per cent of activity was associated with hot spots.
PMCID: PMC3078128  PMID: 5286527
17.  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. © 2010 American Society for Bone and Mineral Research
doi:10.1359/jbmr.090721
PMCID: PMC3153390  PMID: 19594297
serotonin; bone density; bone structure; SSRI; osteoporosis
18.  Comparison of Sex Steroid Measurements in Men by Immunoassay versus Mass Spectroscopy and Relationships with Cortical and Trabecular Volumetric Bone Mineral Density 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00198-008-0591-5
PMCID: PMC2636568  PMID: 18338096
Assays; Osteoporosis; Bone
19.  Effects of Estrogen Therapy on Bone Marrow Adipocytes in Postmenopausal Osteoporotic Women 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00198-008-0574-6
PMCID: PMC2652842  PMID: 18274695
Osteoporosis; adipocytes; bone
20.  Effects of Sex and Age on Bone Microstructure at the Ultradistal Radius: A Population-Based Noninvasive In Vivo Assessment 
In a population-based cross-sectional study, we examined effects of sex and age on bone microstructure at the wrist using high-resolution 3-D pQCT. Compared with women, men had thicker trabeculae in young adulthood and had less microstructural damage with aging. These findings may contribute to the virtual immunity of men to age-related increases in wrist fractures.
Introduction
Although changes in bone microstructure contribute to fracture risk independently of BMD, it has not heretofore been possible to assess this noninvasively in population-based studies.
Materials and Methods
We used high-resolution 3-D pQCT imaging (voxel size, 89 μm) to define, in a random sample of women (n = 324) and men (n = 278) 21–97 years of age, sex and age effects on bone microstructure at the wrist.
Results
Relative to young women (age, 20–29 years), young men had greater trabecular bone volume/tissue volume (BV/TV; by 26%, p = 0.001) and trabecular thickness (TbTh; by 28%, p < 0.001) but similar values for trabecular number (TbN) and trabecular separation (TbSp). Between ages 20 and 90 years, cross-sectional decreases in BV/TV were similar in women (−27%) and in men (−26%), but whereas women had significant decreases in TbN (−13%) and increases in TbSp (+24%), these parameters had little net change over life in men (+7% and −2% for TbN and TbSp, respectively; p < 0.001 versus women). However, TbTh decreased to a greater extent in men (−24%) than in women (−18%; p = 0.010 versus men).
Conclusions
Whereas decreases with age in trabecular BV/TV are similar in men and women, the structural basis for the decrease in trabecular volume is quite different between the sexes. Thus, over life, women undergo loss of trabeculae with an increase in TbSp, whereas men begin young adult life with thicker trabeculae and primarily sustain trabecular thinning with no net change in TbN or TbSp. Because decreases in TbN have been shown to have a much greater impact on bone strength compared with decreases in TbTh, these findings may help explain the lower life-long risk of fractures in men, and specifically, their virtual immunity to age-related increases in distal forearm fractures.
doi:10.1359/JBMR.050916
PMCID: PMC1352156  PMID: 16355281
osteoporosis; aging; bone structure; pQCT
21.  Relationship of Volumetric Bone Density and Structural Parameters at Different Skeletal Sites to Sex Steroid Levels in Women 
Context
Although estrogen clearly plays a central role in regulating bone mass in women, studies in men have suggested that there may be a threshold bioavailable (bio) estradiol (E2) level below which aging men begin to lose bone and that the threshold for estrogen deficiency in cortical bone may be considerably lower than that in trabecular bone. There are no data testing this in women.
Objective
Our objective was to assess volumetric bone mineral density (vBMD) and bone geometry by quantitative computed tomography and relate these to circulating bio E2 and bio testosterone levels.
Design
We studied a cross-sectional, age-stratified population sample of 235 women (age, 21–97 yr).
Results
vBMD/structural parameters were not related to sex steroid levels in young premenopausal women (age, 20–39 yr) with a median bio E2 level of 17 pg/ml (63 pmol/liter). By contrast, bio E2 and bio testosterone levels were both significantly associated with trabecular and cortical vBMD and cortical area at multiple sites in late postmenopausal women (age ≥ 60 yr) who had a median bio E2 level of 3 pg/ml (11 pmol/liter). Late premenopausal and early postmenopausal women (age, 40–59 yr) with an intermediate median bio E2 level of 11 pg/ml (42 pmol/liter) showed age-adjusted correlations of bio E2 levels with trabecular but not with cortical vBMD.
Conclusions
In women, bio E2 levels are associated with vBMD and some structural bone parameters at low but not high bio E2 levels. Similar to findings in men, the threshold for estrogen deficiency in cortical bone in women appears to be lower than that in trabecular bone.
doi:10.1210/jc.2005-0396
PMCID: PMC1352154  PMID: 15998772
bio, Bioavailable; BMD, bone mineral density; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; E2, estradiol; ER, estrogen receptor; QCT, quantitative computed tomography; T, testosterone; vBMD, volumetric bone mineral density
22.  Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men 
Journal of Clinical Investigation  2000;106(12):1553-1560.
Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus, we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men (mean age 68 years), studying them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E, withdrawing only T, or only E, or continuing both. Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones. By two-factor ANOVA, E played the major role in preventing the increase in the bone resorption markers, whereas T had no significant effect. By contrast, serum osteocalcin, a bone formation marker, decreased in the absence of both hormones, and both E and T maintained osteocalcin levels. We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.
PMCID: PMC381474  PMID: 11120762
25.  Panel Summary 
Public Health Reports  1989;104(Suppl):34-36.
PMCID: PMC1580351  PMID: 19313221

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