Citations

In the bone marrow cavity, adipocyte numbers increase, whereas osteoblast progenitor numbers decrease with aging. Because adipocytes and osteoblasts share a common progenitor, it is possible that this shift is due to an increase in adipocyte-lineage cells at the expense of osteoblast-lineage commitment. Estrogens inhibit adipocyte differentiation, and in both men and women, circulating estrogens correlate with bone loss with aging. In bone cells, estrogens stimulate expression of TGF-β and suppress mesenchymal cell adipogenesis. Using a tripotential mesenchymal cell line, we have examined whether estradiol suppression of adipocyte differentiation is due to stimulation of TGF-β and the mechanism by which TGF-β suppresses adipogenesis. We observed that estradiol-mediated suppression of adipogenic gene expression required at least 48 h treatment. TGF-β expression increased within 24 h of estradiol treatment, and TGF-β inhibition reversed estradiol influences on adipogenesis and adipocyte gene expression. Connective tissue growth factor (CTGF) mediates TGF-β suppression of adipogenesis in mouse 3T3-L1 cells. CTGF expression was induced within 24 h of TGF-β treatment, whereas estradiol-mediated induction required 48 h treatment. Moreover, estradiol-mediated induction of CTGF was abrogated by TGF-β inhibition. These data support that estradiol effects on adipogenesis involves TGF-β induction, which then induces CTGF to suppress adipogenesis.

Abstract Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, because areal bone mineral density (aBMD) measurements by dual-energy x-ray absorptiometry cannot assess bone microstructural properties critical to determining bone quality and strength. To better define the skeletal effects of MGUS, we performed aBMD and high-resolution peripheral quantitative computed tomography volumetric bone mineral density (vBMD) measurements in 50 MGUS patients (20 females, 30 males; mean ± SEM age, 70.5 ± 1.4 years) and 100 matched control subjects. Relative to controls, MGUS patients had decreased aBMD at the femoral neck (P = .05) and total femur (P < .05) but no differences at other sites. In contrast, high-resolution peripheral quantitative computed tomography showed markedly diminished cortical thickness (P < .05) and increased endocortical area (P < .01). Average vBMD (P < .01), cortical vBMD (P < .001), and trabecular thickness (P < .01) were all significantly decreased in MGUS patients, suggestive of impaired bone formation. Serum levels of the Wnt pathway inhibitor Dickkopf-related protein 1 (P < .001) and osteoclast-activating factor MIP-1α (P < .05) also were significantly elevated in MGUS patients. Our data provide the first evidence of altered bone microstructure in MGUS and suggest that cytokines elevated in osteolytic myeloma also may be associated with bone loss in MGUS.

To address the epidemiology of rib fractures, an age- and sex-stratified random sample of 699 Rochester, Minnesota, adults age 21–93 years was followed in a long-term prospective study. Bone mineral density (BMD) was assessed at baseline, and fractures were ascertained by periodic interview and medical record review. During 8560 person-years of followup (median, 13.9 years), 56 subjects experienced 67 rib fracture episodes. Risk factors for falling predicted rib fractures as well as BMD, but both were strongly age-related. After age-adjustment, BMD was associated with rib fractures in women but not men. Importantly, rib fractures attributed to severe trauma were associated with BMD in older individuals of both sexes. Self-reported heavy alcohol use doubled fracture risk but did not achieve significance due to limited statistical power. Bone density, along with heavy alcohol use and other risk factors for falling, contributes to the risk of rib fractures, but no one factor predominates. Older women with rib fractures, regardless of cause, should be considered for an osteoporosis evaluation, and strategies to prevent falling should be considered in both sexes.

Osteoporosis and age-related bone loss are important public health concerns. Therefore, there is a high level of interest in the development of medical interventions and lifestyle changes that reduce the incidence of osteoporosis and age-related bone loss. Decreased bone mineral density is associated with high cholesterol, and patients on statins have increased bone mineral densities, strongly implicating cholesterol as a negative regulator of bone homeostasis. In this study, using both molecular and pharmacological approaches, we have been able to demonstrate that the primary cholesterol metabolite, 27-hydroxycholesterol, through its actions on both estrogen receptors and liver X receptors, decreases osteoblast differentiation and enhances osteoclastogenesis, resulting in increased bone resorbtion in mice. Induction of the short heterodimer partner protein by estrogens in osteoblasts can attenuate the liver X receptor-mediated actions of 27-hydroxycholesterol in bone. These data establish a mechanistic link between cholesterol and bone quality, highlight an unexpected target of estrogens in osteoblasts, and define a signaling axis, the therapeutic exploitation of which is likely to yield novel antiosteoporotic drugs.

Abstract There remains little consensus on the link between vitamin levels and muscle mass or strength. We therefore investigated the association of serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone (PTH) levels with skeletal muscle mass and strength. We studied 311 men (mean age, 56 years; range, 23–91 years) and 356 women (mean age, 57 years; range, 21–97 years) representing an age-stratified, random sample of community adults. Multivariate linear regression models were used to examine the association of skeletal muscle mass (by total body dual-energy X-ray absorptiometry) and strength (handgrip force and isometric knee extension moment) with each of 25(OH)D, 1,25(OH)2D, and PTH quartiles, adjusted for age, physical activity, fat mass, and season. We found no consistent association between 25(OH)D or PTH and any of our measurements of muscle mass or strength, in either men or women. However, in subjects younger than 65 years, there was a statistically significant association between low 1,25(OH)2D levels and low skeletal mass in both men and women and low isometric knee extension moment in women, after adjustment for potential confounders. Modestly low 25(OH)D or high PTH levels may not contribute significantly to sarcopenia or muscle weakness in community adults. The link between low 25(OH)D and increased fall risk reported by others may be due to factors that affect neuromuscular function rather than muscle strength. The association between low 1,25(OH)2D and low skeletal mass and low knee extension moment, particularly in younger people, needs further exploration. © 2011 American Society for Bone and Mineral Research

Abstract We have recently identified delta-like 1/fetal antigen 1 (Dlk1/FA1) as a novel regulator of bone mass that functions to mediate bone loss under estrogen deficiency in mice. In this report, we investigated the effects of estrogen (E) deficiency and E replacement on serum (s) levels of Dlk1/FA1 (s-Dlk1FA1) and its correlation with bone turnover markers. s-Dlk1/FA1 and bone turnover markers (serum cross-linked C-telopeptide [s-CTX] and serum osteocalcin) were measured in two cohorts: a group of pre- and postmenopausal women (n = 100) and a group of postmenopausal women, where half had received estrogen-replacement therapy (ERT, n = 166). s-Dlk1/FA1 and s-CTX were elevated in postmenopausal E-deficient women compared with premenopausal E-replete women (both p &lt; 0.001). s-Dlk1/FA1 was correlated with s-CTX (r = 0.30, p &lt; 0.01). ERT in postmenopausal women decreased s-Dlk1/FA1, as well as s-CTX and s-osteoclacin (all p &lt; .0001). Changes in s-Dlk1 were significantly correlated with those observed in s-CTX (r = 0.18, p &lt; 0.05) and s-osteocalcin (r = 0.28, p &lt; 0.001). In conclusion, s-Dlk1/FA1 is influenced by E-deficiency and is correlated with bone turnover. Increased levels of s-Dlk1/FA1 in postmenopausal women may be a mechanism mediating the effects of estrogen deficiency on bone turnover. © 2011 American Society for Bone and Mineral Research

Abstract 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 &lt; .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. © 2011 American Society for Bone and Mineral Research

Abstract Fractures are increased among men with prostate cancer, especially those on androgen-deprivation therapy (ADT), but few data are available on men with localized prostate cancer. The purpose of this investigation was to estimate fracture risk among unselected community men with prostate cancer and systematically assess associations with ADT and other risk factors for fracture. In a population-based retrospective cohort study, 742 Olmsted County, MN, men with prostate cancer first diagnosed in 1990–1999 (mean age 68.2 ± 8.9 years) were followed for 6821 person-years. We estimated cumulative fracture incidence, assessed relative risk by standardized incidence ratios, and evaluated risk factors in time-to-fracture regression models. All together, 482 fractures were observed in 258 men (71 per 1000 person-years). Overall fracture risk was elevated 1.9-fold, with an absolute increase in risk of 9%. Relative to rates among community men generally, fracture risk was increased even among men not on ADT but was elevated a further 1.7-fold among ADT-treated compared with untreated men with prostate cancer. The increased risk following various forms of ADT was accounted for mainly by associations with pathologic fractures (14% of all fractures). Among men not on ADT (62% of the cohort), more traditional osteoporosis risk factors were implicated. In both groups, underlying clinical characteristics prompting different treatments (indication bias) may have been partially responsible for the associations seen with specific therapies. To the extent that advanced-stage disease and pathologic fractures account for the excess risk, the effectiveness of fracture prevention among men with prostate cancer may be limited. © 2011 American Society for Bone and Mineral Research

Abstract 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. © 2011 American Society for Bone and Mineral Research.

abstract Context: Large increases in systemic free fatty acid (FFA) availability in the absence of a corresponding increase in fatty acid oxidation can create a host of metabolic abnormalities. These adverse responses are thought to be the result of fatty acids being shunted into hepatic very low-density lipoprotein-triglyceride production and/or intracellular lipid storage and signaling pathways because tissues are forced to increase nonoxidative FFA disposal. Objective: The objective of the study was to examine whether variations in postabsorptive nonoxidative FFA disposal within the usual range predict insulin resistance and hypertriglyceridemia. Design: We measured: systemic FFA turnover using a continuous iv infusion of [9–10, 3H]palmitate; substrate oxidation with indirect calorimetry combined with urinary nitrogen excretion; whole-body and peripheral insulin sensitivity with the labeled iv glucose tolerance test minimal model. Setting: the study was conducted at the Mayo Clinic General Clinical Research Center. Participants: Participants included healthy, postabsorptive, nonobese adults (21 women and 21 men). Interventions: There were no interventions. Main Outcome Measures: Nonoxidative FFA disposal (micromoles per minute), defined as the FFA disappearance rate minus fatty acid oxidation. Results: Women had 64% greater nonoxidative FFA disposal rate than men but a better lipid profile and similar insulin sensitivity. There was no significant correlation between nonoxidative FFA disposal and whole-body sensitivity, peripheral insulin sensitivity, or fasting serum triglyceride concentrations in men or women. Conclusions: Healthy nonobese women have greater rates of nonoxidative FFA disposal than men, but this does not appear to relate to adverse health consequences. Understanding the sex-specific interaction between adipose tissue lipolysis and peripheral FFA removal will help to discover new approaches to treat FFA-induced abnormalities.