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S Khosla

Publications and source records attributed to S Khosla.

At least 73 records · Page 4Linked to original sources
PubMed1999

Effects of androgens on the insulin-like growth factor system in an androgen-responsive human osteoblastic cell line.

Although androgens have significant effects on bone metabolism, the mediators of their effects are still unclear. As the insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have important effects on osteoblast proliferation and differentiation, we examined androgen effects on the IGF system in a conditionally immortalized human fetal osteoblastic cell line, hFOB/AR-6, which displays a mature osteoblastic phenotype and physiological levels of functional androgen receptors. The nonaromatizable androgen, 5alpha-dihydrotestosterone (5alphaDHT), and testosterone, but not dehydroepiandrosterone, increased IGF-I messenger RNA (mRNA) levels up to 4-fold in a dose (10(-12)-10(-6) M)- and time (2-72 h)-dependent fashion. These changes were prevented by the specific androgen receptor antagonist, hydroxyflutamide. In addition, 5alpha-DHT decreased IGFBP-4 mRNA and protein levels by 2- and 4-fold, respectively, and increased IGFBP-2 and -3 mRNA and protein levels by 6- and 7-fold (for mRNA) and 3- and 5-fold (for protein), respectively. hFOB/AR-6 cells expressed the type-I IGF receptor, but this was not regulated by 5alphaDHT. 5alphaDHT and IGFBP-3 specifically increased hFOB/AR-6 cell proliferation, and a monoclonal antibody specific for IGF-I blocked this effect. Thus, androgens increase the expression of IGF-I, IGFBP-2, and IGFBP-3, but decrease levels of the inhibitory IGFBP-4 in an androgen-responsive human osteoblastic cell line. Our data are consistent with the hypothesis that the effects of androgen on bone cells may be mediated at least in part by increases in IGF-I production and by differential regulation of IGFBPs.

Androgens↗
PubMed1999

Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes.

Both bone mass and serum leptin levels are increased in obesity. Because osteoblasts and adipocytes arise from a common precursor in bone marrow, we assessed the effects of human recombinant leptin on a conditionally immortalized human marrow stromal cell line, hMS2-12, with the potential to differentiate to either the osteoblast or adipocyte phenotypes. By RT-PCR and Western immunoblot analysis, the hMS2-12 cells expressed messenger RNA (mRNA) and protein for the leptin receptor. Leptin did not affect hMS2-12 cell proliferation, but resulted in dose- and time-dependent increases in mRNA and protein levels of alkaline phosphatase, type I collagen, and osteocalcin, and in a 59% increase in mineralized matrix. Leptin increased mRNA levels of lipoprotein lipase at 3 days, but decreased mRNA levels of adipsin and leptin at 9 days and decreased lipid droplet formation by 50%. Leptin did not affect the expression of Cbfa1 or peroxisome proliferator-activated receptor-gamma2, transcription factors involved in commitment to the osteoblast and adipocyte pathways, respectively. Thus, leptin acts on human marrow stromal cells to enhance osteoblast differentiation and to inhibit adipocyte differentiation. Our data support the hypothesis that leptin is a previously unrecognized, physiological regulator of these two differentiation pathways, acting primarily on maturation of stromal cells into both lineages.

Adipocytes↗
PubMed1999

Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells.

The identity of the paracrine mediator(s) of the antiresorptive action of estrogen on bone cells is controversial. Osteoprotegerin (OPG) was recently identified as a soluble member of the tumor necrosis factor (TNF) receptor (TNF-R) superfamily that is secreted by osteoblast lineage cells and acts by binding to and neutralizing its cognate ligand, OPG-L, a required factor for osteoclastogenesis. OPG prevents bone loss when administered to ovariectomized rats, induces osteoporosis when ablated in knock-out mice, and induces osteopetrosis when overexpressed in transgenic mice. In conditionally immortalized, human osteoblastic hFOB/ER-3 and hFOB/ER-9 cell lines containing physiological concentrations of approximately 800 and approximately 8,000 functional estrogen receptors (ER)/nucleus, respectively, we found that 17beta-estradiol dose- and time-dependently increased OPG mRNA and protein levels to maximal levels of 370% and 320%, respectively (P < 0.001); co-treatment with the "pure" antiestrogen ICI 182,780 abrogated these effects completely. 17beta-Estradiol also dose-dependently increased OPG mRNA and protein levels in normal human osteoblasts with approximately 400 ER/nucleus by 60% and 73%, respectively. Thus, estrogen enhancement of OPG secretion by osteoblastic cells may play a major role in the antiresorptive action of estrogen on bone.

Cells, Cultured↗
PubMed1999

Primary hyperparathyroidism and the risk of fracture: a population-based study.

While severe primary hyperparathyroidism (HPT) is clearly associated with osteitis fibrosa cystica, it remains uncertain whether mild, asymptomatic primary HPT adversely affects the skeleton. Thus, we assessed the incidence of age-related fractures in a large, population-based inception cohort of 407 cases of primary HPT (93 men and 314 women) recognized during the 28-year period, 1965-1992. Fracture risk was assessed by comparing new fractures at each site to the number expected from gender- and age-specific fracture incidence rates for the general population (standardized incidence ratios, SIRs). These community patients with primary HPT mostly had mild disease (mean +/- SD serum calcium, 10.9 +/- 0.6 mg/dl). Altogether, 471 fractures occurred during 5766 person-years of follow-up. Overall fracture risk was significantly increased in these patients (SIR 1.3, 95% confidence interval [CI] 1.1-1.5). Primary HPT was associated with an increased risk of vertebral (SIR 3.2, 95% CI 2.5-4.0), distal forearm (SIR 2.2, 95% CI 1.6-2.9), rib (SIR 2.7, 95% CI 2.1-3.5), and pelvic fractures (SIR 2.1, 95% CI 1. 1-3.5). The risk of proximal femur fractures was only marginally increased (SIR 1.4, 95% CI 1.0-2.0). By univariate analysis, increasing age and female gender were significant predictors of fracture risk, although higher serum calcium levels were also associated with increased fracture risk, and parathyroid surgery may have had a protective effect. By multivariate analysis, however, only age (relative hazard [RH] per 10-year increase, 1.6, 95% CI 1. 4-1.9) and female gender (RH 2.3, 95% CI 1.2-4.1) remained significant independent predictors of fracture risk. Thus, primary HPT among unselected patients in the community is associated with a significant increase in the risk of vertebral, Colles', rib, and pelvic fractures. These data have important implications for the current trend to recommend nonsurgical management for patients with mild primary HPT.

Adolescent↗
PubMed1999

The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line.

While androgens clearly have significant skeletal effects, the paracrine mediators of androgen action on bone are at present unclear. Interleukin-6 (IL-6) is a candidate cytokine that is produced by osteoblastic lineage cells and promotes osteoclastogenesis and bone resorption. Here, we assessed constitutive as well as IL-1beta- and tumor necrosis factor-alpha (TNF-alpha)-stimulated IL-6 mRNA expression by Northern analysis and protein secretion by immunoassay in a human androgen-responsive osteoblastic cell line (hFOB/AR-6) which contains approximately 4000 androgen receptors (ARs)/nucleus. Treatment with 5alpha-dihydrotestosterone (DHT) dose-dependently inhibited constitutive and TNF-alpha/IL-1beta-stimulated IL-6 mRNA steady-state levels in hFOB/AR-6 cells by 70-80% at 10-7 M. In addition, testosterone also suppressed TNF-alpha/IL-1beta-stimulated IL-6 mRNA levels by 57%, while the adrenal androgen dehydroepiandrosterone had no effect. Of note, the specific AR antagonist, hydroxyflutamide, also inhibited IL-6 mRNA levels by 70%. Consistent with the Northern analyses, treatment with 5alpha-DHT, testosterone, and hydroxyflutamide also inhibited IL-6 protein production by 79%, 62%, and 71%, respectively (p < 0.001), while these agents had no effect on IL-6 soluble receptor levels. Finally, we demonstrated that hydroxyflutamide treatment of hFOB/AR-6 cells markedly inhibited the activation and binding of NF-kappaB (a known stimulator of IL-6 gene transcription) to its response element, thus providing a potential mechanism for its effect on IL-6 production by osteoblasts. These data are consistent with the hypothesis that suppression of osteoblast IL-6 production by androgens may mediate, at least in part, the antiresorptive effects of androgens on bone. Moreover, our findings also indicate that hydroxyflutamide, which is a known AR antagonist in most tissues, may function as a selective AR modulator for effects on IL-6 production by osteoblasts.

Analysis of Variance↗
PubMed1999

Androgen effects on bone metabolism: recent progress and controversies.

Androgens have beneficial effects on skeletal development and maintenance in women and men. The detection and functional characterization of androgen receptors in bone cells has implicated bone tissue as a potential target tissue for androgens. Gonadal and adrenal androgens directly regulate various aspects of osteoblastic lineage cells, including proliferation, differentiation, mineralization, and gene expression. These effects may differ depending on the stage of differentiation, the number of androgen receptors, and other inherent characteristics (species, site, cell biology) of the osteoblastic cell system. In addition, recent studies have suggested that some of the anabolic and anti-resorptive effects of androgens on bone may be mediated by regulation of autocrine and paracrine factors in the bone microenvironment, including transforming growth factor-beta, insulin-like growth factors (and their binding proteins), and interleukin-6. This review summarizes the recent progress made in our knowledge of androgen receptor action, local androgen metabolism in bone, and direct and indirect effects of gonadal and adrenal androgens as well as androgen receptor antagonists on bone cells.

Androgens↗
PubMed1999

Immunoradiometric assay for intact human osteocalcin(1-49) without cross-reactivity to breakdown products.

BACKGROUND: Osteocalcin (Oc), a serum marker of bone turnover, circulates in several forms. We developed an assay for intact human Oc and investigated its clinical features. METHODS: We generated goat antibodies and N- and C-terminal Oc. The former was used on solid phase (polystyrene beads), and the latter was used as the tracer in an IRMA. RESULTS: The assay was linear with no cross-reactivity to Oc(1-43), total imprecision (CV) of <10%, and recovery of 100% +/- 10%. Assay values for intact Oc in EDTA plasma samples were unchanged at 18-25 degrees C for 6 h. Values for intact Oc in serum, EDTA plasma, and heparin plasma samples did not change after storage on ice for 8 h. Serum samples from patients with various conditions were stored at -70 or -135 degrees C for up to 5 years and yielded z-scores comparable to an Oc(1-43) IRMA for all conditions except for renal failure. In renal failure, the Oc(1-43) assay values were increased, whereas the intact assay values were in the reference interval. CONCLUSION: Decreases in Oc assay values are inhibited by calcium chelation, and slowed by reduced temperatures. The described assay for intact Oc allows improved specificity for bone compared with an assay for Oc(1-43).

Adolescent↗
PubMed1998

Effects of gonadal and adrenal androgens in a novel androgen-responsive human osteoblastic cell line.

While androgens have important skeletal effects, the mechanism(s) of androgen action on bone remain unclear. Current osteoblast models to study androgen effects have several limitations, including the presence of heterogeneous cell populations. In this study, we examined the effects of androgens on the proliferation and differentiation of a novel human fetal osteoblastic cell line (hFOB/AR-6) that expresses a mature osteoblast phenotype and a physiological number (approximately 4,000/nucleus) of androgen receptors (AR). Treatment with 5alpha-dihydrotestosterone (5alpha-DHT) inhibited the proliferation of hFOB/AR-6 cells in a dose-dependent fashion, while it had no effect on the proliferation of hFOB cells, which express low levels of AR (<200/nucleus). In hFOB/AR-6 cells, co-treatment with the specific AR antagonist, hydroxyflutamide abolished 5alpha-DHT-induced growth inhibition. Steady-state levels of transforming growth factor-beta1 (TGF-beta1) and TGF-beta-induced early gene (TIEG) mRNA decreased after treatment of hFOB/AR-6 cells with 5alpha-DHT, suggesting a role for the TGF-beta1-TIEG pathway in mediating 5alpha-DHT-induced growth inhibition of hFOB/AR-6 cells. In support of this, co-treatment of hFOB/AR-6 cells with TGF-beta1 (40 pg/ml) reversed the 5alpha-DHT-induced growth inhibition, whereas TGF-beta1 alone at this dose had no effect on hFOB/AR-6 cell proliferation. Furthermore, treatment of hFOB/AR-6 cells with 5alpha-DHT and testosterone (10(-8) M) inhibited basal and 1,25-(OH)2D3-induced alkaline phosphatase (ALP) activity and type I collagen synthesis without affecting osteocalcin production. Thus, in this fetal osteoblast cell line expressing a physiological number of AR, androgens decrease proliferation and the expression of markers associated with osteoblast differentiation. These studies suggest that the potential anabolic effect of androgens on bone may not be mediated at the level of the mature osteoblast.

Adrenal Glands↗
PubMed1998

Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines.

Osteoprotegerin (OPG), a newly discovered member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclastogenesis. The overexpression of OPG in transgenic mice leads to osteopetrosis, whereas targeted ablation of OPG in knock-out mice leads to severe osteoporosis. However, the production and regulation of OPG in normal human bone has not been studied. Thus, we assessed OPG mRNA expression and protein secretion in human osteoblastic lineage cells. 1,25-Dihydroxyvitamin D3 (10(-7) M) increased OPG mRNA levels by 90 and 50% in a fetal osteoblastic cell line (hFOB) and normal trabecular osteoblastic cells (hOB) cells, respectively, but did not affect OPG mRNA levels in a marrow stromal preosteoblastic (hMS) cell line. Interleukin (IL)-1beta (5 x 10(-9) M), tumor necrosis factor (TNF)-alpha (9 x 10(-9) M), and bone morphogenetic protein (BMP)-2 (100 ng/ml) also increased OPG mRNA levels in hFOB cells by 4-, 6-, and 4-fold, respectively. Treatment with 1,25-dihydroxyvitamin D3, IL-1beta, TNF-alpha, and BMP-2 increased OPG protein production by hFOB cells by 60, 390, 300, and 80%, respectively (P < 0.001). Because it is expressed in various types of human osteoblastic cells, and is stimulated by vitamin D, BMP-2 and cytokines, OPG may be an important paracrine modulator of bone remodeling.

Animals↗
PubMed1998

Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( approximately 150 kD) and binary (approximately 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.

Alkaline Phosphatase↗
PubMed1998

Genomic imprinting in ruminants: allele-specific gene expression in parthenogenetic sheep.

Studies in the mouse have established that both parental genomes are essential for normal embryonic development. Parthenogenetic mouse embryos (which have two maternal genomes and no paternal genome), for example, are growth-retarded and die at early postimplantation stages. The distinct maternal and paternal contributions are mediated by genomic imprinting, an epigenetic mechanism by which the expression of certain genes is dependent on whether they are inherited from mother or father. Although comparative studies have established that many imprinted mouse (and rat) genes are allele-specifically expressed in humans as well (and vice versa), so far imprinting studies have not been performed in other mammalian species. When considering evolutionary theories of genomic imprinting, it would be important to know how widely it is conserved among placental mammals. We have investigated its conservation in a bovid ruminant, the domestic sheep, by comparing parthenogenetic and normal control embryos. Our study establishes that, like in the mouse, parthenogenetic development in sheep is associated with growth-retardation and does not proceed beyond early fetal stages. These developmental abnormalities are most likely caused by imprinted genes. We demonstrate that, indeed, like in mice and humans, the growth-related PEG1/MEST and Insulin-like Growth Factor 2 (IGF2) genes are expressed from the paternal chromosome in sheep. These observations suggest that genomic imprinting is conserved in a third, evolutionarily rather diverged group of placental mammals, the ruminants.

Alleles↗
PubMed1998

Survival after the diagnosis of hyperparathyroidism: a population-based study.

BACKGROUND: Reports of increased mortality from cardiovascular disease and malignancy in primary hyperparathyroidism have been based primarily on patients who have undergone parathyroidectomy. In order to assess the true impact of primary hyperthyroidism on mortality in the general population, we assessed survival in a large inception cohort of Rochester, Minnesota residents with primary hyperparathyroidism initially diagnosed over a 28-year span, the majority of whom were followed with uncomplicated disease. METHODS: All Rochester residents with primary hyperparathyroidism first recognized in 1965 to 1992 were identified through the Rochester Epidemiology Project medical records linkage system. Included as cases were patients with pathologic confirmation of hyperthyroidism, hypercalcemia with inappropriately elevated parathyroid hormone levels, or hypercalcemia for more than a year with no other cause. Survival was estimated using the Kaplan Meier product-limit method. The Cox proportional hazards model was used to determine associations, as relative hazards (RR) with 95% confidence intervals (CI), of various risk factors with time to death. RESULTS: During the study period, 435 cases of primary hyperparathyroidism were identified. Altogether, parathyroid surgery was performed on 126 patients (29%), with a mean delay between the initial elevated serum calcium level and surgery of 3.3 years. Patients who underwent surgery had higher maximum serum calcium levels than the patients who were observed (mean+/-SD, 11.3+/-0.7 versus 10.7+/-0.4 mg/dL, P <0.00 1), but their mean ages were similar (54+/-16 versus 56+/-17 years). Overall survival in the patients with primary hyperthyroidism was better than expected (P=0.02), but by age-adjusted multivariate analysis, higher maximal serum calcium level was an independent predictor of mortality (RR=1.3 per mg/dL; 95% CI: 1.1-1.6; P <0.02). CONCLUSION: Overall survival is not adversely affected among unselected patients with mild primary HPT in the community, although patients with more severe disease, as manifested by higher serum calcium levels, may have an increased risk of death.

Calcium↗
PubMed1998

Fracture risk among patients with urolithiasis: a population-based cohort study.

In a population-based retrospective cohort study, 624 Rochester, Minnesota residents with an initial symptomatic episode of urolithiasis in 1950 to 1974 were followed for 11,909 person-years for subsequent age-related fractures. During this period of observation, the number of patients with a first vertebral fracture was over four times the number expected on the basis of vertebral fracture incidence rates in the general population of Rochester [standardized morbidity ratio (SMR), 4.3; 95% confidence interval, 3.4 to 5.3]. The risk of vertebral fracture was elevated among men as well as women, and was associated with increasing age and with the use of corticosteroids for more than six months. However, vertebral fracture risk was increased nearly fourfold (SMR 3.9; 95% confidence interval, 3.0 to 4.9) among the urolithiasis patients without such exposure, which suggests that corticosteroids do not completely account for the association with vertebral fractures. There was no increase in the risk of hip, pelvis, proximal humerus or distal forearm fractures in this cohort of patients, and their survival was not impaired. Additional studies are needed to define the pathophysiology of vertebral fractures among patients with urolithiasis.

Adolescent↗
PubMed1998

Effects of the circadian variation in serum cortisol on markers of bone turnover and calcium homeostasis in normal postmenopausal women.

Bone turnover has a circadian pattern, with bone resorption and, to a lesser extent, bone formation increasing at night. Serum cortisol also has a circadian pattern and is a potential candidate for mediating the circadian changes in bone turnover. Thus, we measured bone formation and resorption markers before (study A) and after (study B) elimination of the morning peak of cortisol. We also assessed effects of the circadian cortisol pattern on serum calcium, PTH, and urinary calcium excretion. Ten normal postmenopausal women, aged 63-75 yr (mean, 69 yr), were studied. Metyrapone was administered to block endogenous cortisol synthesis and either a variable (study A) or a constant (study B) infusion of cortisol was given to reproduce and then abolish the morning cortisol peak. Blood was sampled every 2 h for serum cortisol, ionized calcium, PTH, and bone formation markers [osteocalcin and carboxyl-terminal propeptide of type I collagen (PICP)], and timed 4-h urine samples were collected for measurement of calcium, phosphorus, sodium, potassium, and bone resorption markers (N-telopeptide of type I collagen and free deoxypyridinoline). During study A, serum osteocalcin had a circadian pattern, with a peak at 0400 h and a nadir at 1400 h. During study B, however, the afternoon nadir of serum osteocalcin was eliminated (P < 0.001 and P < 0.005 for the difference in the patterns of peak and nadir, respectively, on the 2 study days). In contrast, the circadian patterns of serum PICP and urinary N-telopeptide of type I collagen and free deoxypyridinoline were virtually identical during the two studies. Urinary calcium excretion declined after the cortisol peak, without differences between the 2 study days in phosphorus or sodium excretion or in serum PTH. We conclude that the circadian variation in serum cortisol is responsible for the circadian pattern of serum osteocalcin, but not that of PICP or bone resorption markers. The physiological variation in serum cortisol may also reduce urinary calcium excretion.

Aged↗
PubMed1998

A defect in renal calcium conservation may contribute to the pathogenesis of postmenopausal osteoporosis.

Although all postmenopausal women are estrogen deficient, women who have postmenopausal osteoporosis may have a defect, in addition to estrogen deficiency, that accounts for their higher rates of bone resorption and greater bone loss, relative to those who do not. To test the hypothesis that one defect is an impairment in renal calcium conservation, we measured renal calcium transport in 19 osteoporotic and 19 normal postmenopausal women, whose ages (median and 25th-75th percentile range) were 70 yr (range, 67-72) and 72 yr (range, 69-74), respectively. There was no difference between groups in values for serum ionized calcium and PTH concentrations or in renal filtered load of calcium. However, before PTH infusion, the osteoporotic women had lower (P = 0.0046) values for tubular reabsorption of calcium (TRCa) of 96.8% (range, 96.0-97.1) vs. 98.0% (range, 97.2-98.3) and higher (P = 0.0154) urinary calcium excretion of 0.194 mg/dL of glomerular filtrate (GF) (0.154-0.239) vs. 0.125 mg/dL of GF (0.103-0.173) than the normal women. After infusion of 200 U of synthetic PTH (synthetic 1-34 analog of human PTH), TRCa increased and calcium excretion decreased comparably in both groups, so that the differences between groups after intervention remained: for TRCa, 98.3% (97.7-98.6) vs. 98.9% (98.4-99.3; P = 0.0042); and for calcium excretion, 0.099 mg/dL of GF (0.080-0.138) vs. 0.066 mg/dL of GF, (0.045-0.097, P = 0.0180). In conclusion, postmenopausal women with osteoporosis have a PTH-independent defect in renal calcium conservation. This defect is of sufficient magnitude to contribute to the greater negative calcium balance in post-menopausal women with osteoporosis vs. their postmenopausal peers.

Absorption↗
PubMed1998

Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen.

Estrogen (E) deficiency associated with the menopause is the major cause of bone loss in aging women. However, men also lose significant amounts of bone with age, but they do not have the equivalent of menopause, and serum total testosterone (T) and E levels decline only marginally with age in men. Thus, it has been difficult to attribute bone loss in aging men to either T or E deficiency. Here, we show in a population-based, age-stratified sample of 346 men, aged 23-90 yr, that serum total T and E (estradiol plus estrone) levels decreased over the life span by 30% and 12%, respectively, but bioavailable (or nonsex hormone-binding globulin-bound) T and E levels decreased by 64% and 47%, respectively. In these men and in a parallel cohort of 304 women, aged 21-94 yr, serum PTH increased 84% and 64% over the life span, and urinary N-telopeptide of type I collagen (NTx) excretion, a bone resorption marker, increased 77% and 80% between age 50-85 yr in the men and women, respectively. By univariate analyses, serum bioavailable T and E levels correlated positively with bone mineral density (BMD) at the total body, spine, proximal femur, and distal radius and negatively with urinary NTx excretion in men and women. Urinary NTx excretion was also negatively associated with BMD in both sexes. By multivariate analyses, however, serum bioavailable E level was the consistent independent predictor of BMD in both men and postmenopausal women. Thus, bioavailable E levels decline significantly with age and are important predictors of BMD in men as well as women. These studies suggest that in contrast to traditional belief, age-related bone loss may be the result of E deficiency not just in postmenopausal women, but also in men.

Adult↗