The role of interleukin-1 in postmenopausal bone loss

Interleukin-1 (IL-1), a cytokine best known for its ability to stimulate lymphocyte proliferation, has recently been shown to stimulate bone resorption and modulate bone formation in vivo. Consequently, the authors have devised a series of studies to investigate the relationship between bone remodeling, menopause, and monocyte IL-1-secretion. In a first study, monocytes from osteoporotic patients were found to produce more IL-1 than monocytes from control subjects. IL-1 activity was also found to reflect histomorphometric indices of bone formation, but not of bone resorption. In a second study, devised to assess the effect of menopause on the relationship between IL-1 and bone turnover, a significant correlation was found between IL-1 and BGP in premenopausal osteoporotic women and osteoporotic men, but not in both postmenopausal osteoporotic subjects and normal subjects of either sex. In a third study, IL-1 from untreated postmenopausal women was found to be higher than in either untreated premenopausal or estrogen/progesterone-treated postmenopausal women. A significant negative correlation was found between IL-1 and years since menopause in both the healthy and osteoporotic postmenopausal women. Premenopausal IL-1 levels were achieved within eight years of menopause in the healthy but not in the osteoporotic subjects. In osteoporotic women, high IL-1 levels were evident as long as 15 years after menopause. IL-1 also correlated inversely with mineral density as measured by quantitative computer tomography. In prospective study, treatment with estrogen/progesterone caused a significant increase in IL-1 activity. This data indicates that monocyte IL-1 production mirrors the rate of bone turnover in both the healthy and osteoporotic patient, and that alteration in IL-1 production may underlie the postmenopausal acceleration of bone loss and its inhibition by ovarian steroids.     

Age and menopause-related changes in indices of bone turnover

Age-related bone loss has been attributed to a decline in bone formation due to decreased osteoblast function. However, studies examining the relationship between age or menopausal status and indices of bone formation such as serum osteocalcin have yielded conflicting results. To examine these relationships we studied indices of bone formation and resorption and bone mineral density in 247 normal women, including 96 postmenopausal women ranging in age from 20-75 yr. A cubic polynomial regression best fit the relationship between age and serum osteocalcin (r = 0.32; n = 228; P = 0.0001) and urinary hydroxyproline/creatinine excretion (r = 0.40; n = 228; P = 0.0001), with both indices declining before the menopause, rising at the menopause, and subsequently falling through the seventh and eighth decades. While a significant decline in osteocalcin levels was observed in the postmenopausal group older than 60 yr, levels in subjects older than 60 yr remained higher (+31%) than those in late premenopausal subjects. Urinary calcium to creatinine excretion rose in the premenopausal years, increased markedly after the menopause, and remained at this level subsequently. Urinary hydroxyproline/creatinine, but not serum osteocalcin or urinary calcium/creatinine excretion, was a significant predictor of bone mineral density at the lumbar spine and the femoral neck independent of age. These data are consistent with the hypothesis that age-related bone loss after the menopause occurs in the presence of initially increased but subsequently decreasing bone turnover with maintenance of a relative excess of bone resorption.     

Age-related changes in bone mineral density and serum bone-related proteins in premenopausal and postmenopausal Japanese women

The purpose of this cross-sectional study was to characterize the age-related change in bone metabolism during the pre- and postmenopausal periods, and to define the standard levels of three serum markers of bone metabolism, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), carboxyterminal propeptide of type I procollagen (PICP), and bone gla protein (BGP), in Japanese adult women. The bone mineral density (BMD) of the lumbar spine (L2-L4) and the serum levels of ICTP, PICP and BGP were determined in a total of 207 healthy Japanese women (108 premenopausal and 99 postmenopausal). The lumbar BMD decreased significantly with increasing age not only in postmenopausal women (P<0.001) but also in premenopausal women (P=0.014). There was a clear gap in the serum levels of ICTP, PICP and BGP between the premenopausal and postmenopausal group (P<0.001), but those were absolutely the same within each group except for ICTP in the postmenopausal women. These findings and the values of serum ICTP, PICP and BGP in pre- and postmenopausal women obtained in this study are expected to be very useful for treatment of postmenopausal osteoporosis.     

The relationship among circulating insulin-like growth factor components, biochemical markers of bone turnover and bone mineral density in postmenopausal women under the age of 60

OBJECTIVES: The changes in circulating IGF components after the menopause and the potential role of new markers of bone turnover and circulating IGF components in predicting bone mass in postmenopausal women are still controversial and the relationship between these two systems has not been investigated. The aims of this study were to investigate the changes in circulating IGF components after the menopause, to evaluate whether new markers of bone turnover and circulating IGF components reflect bone mass in postmenopausal women under the age of 60 and to study the relationship between these two systems. DESIGN, PATIENTS AND MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, osteocalcin (OST), bone specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPYD) and N-telopeptide of type I collagen (NTX) were measured in 31 premenopausal women aged 31-43 and 65 postmenopausal women aged 47-60: this latter group comprised 30 normal healthy women and 35 osteoporotic women. RESULTS: Compared with premenopausal women or normal postmenopausal women, serum IGF-1 and IGFBP-3 levels were significantly lower in osteoporotic postmenopausal women while no significant differences in serum levels of IGF-II, IGFBP-1 and IGFBP-2 were observed. The correlations between bone turnover markers and circulating IGF components (except between serum BAP and IGF-II), and between bone turnover markers and bone mineral density (BMD) in postmenopausal women were not significant. However, serum IGF-I and IGFBP-3 correlated positively with BMD of the lumbar spine and/or Ward's triangle even if age, BMI and menopause duration were taken into account in a multiple regression analysis model. CONCLUSIONS: Circulating IGF-I and IGFBP-3 may be involved in the mechanism of bone loss in postmenopausal women under the age of 60. They may also provide indirect information on the current bone microenvironment different from that provided by new markers of bone turnover.     

绝经前、后女性骨代谢指标与白介素-1β受体拮抗剂的关系

目的探讨白介素-1β及其受体拈抗剂在绝经后女性骨代谢中的作用。方法选择绝经后女性128名,绝经前女性47名。用酶联免疫法测定受试者血清白介素-1β（IL-1β）、IL-1受体拮抗剂（IL-1Ra）、血清骨钙素（BGP）、尿I型胶原C末端肽（CTX）水平。用放射免疫法测定总雌二醇（E2）。结果绝经后女性组受试者L24、股骨颈、大转子的骨密度、E2、IL-1Ra／IL-1β比值和BGP较绝经前女性低,但CTX较高。L24、股骨颈骨密度、BGP与IL-1Ra／IL-1β旱正相关（r=0．709、r=0．801、r=0．729,P=0．023、P=0．021、P=0．005）。L24、股骨颈、大转子骨密度与IL-1β负相关（r=-0．855、r=-0．921、r=-0．725,P=0．002;P=0．005、P=0．024）。CTX与IL-1Ra／IL-1β负相关、与IL-1β正相关（r=-0．774,P=0．037;r=-901,P=0．036）。IL-1Ra与IL-1β正相关（r=0．981,P=0．005）。L24、大转子骨密度、BGP与E2正相关（r=0．664、r=0．700、r=0．621,P=0．012、P=0．003、P=0．009）。IL-1Ra、IL-1Ra／IL-1β与E2正相关（r=0．874,P=0．004;r=0．802,P=0．024）。结论绝经后女性骨代谢处于高分解、低合成的负平衡状态,性激素水平降低影响IL-1Ra与IL-1β的平衡可能起重要作用。     

20～75岁妇女血清护骨素、核因子-κB受体活化子配体的变化与年龄、停经、骨生化指标和骨密度的关系

目的　研究血清护骨素 (OPG)和核因子 κB受体活化子配体 (RANKL)与年龄、停经、骨生化指标和骨密度的关系 ,了解影响血清OPG和RANKL的因素。方法　在 5 0 4例 2 0～ 75岁的绝经前和绝经后妇女中 ,以双能X线吸收仪测定腰椎和股骨各处骨密度。按WHO标准 ,将绝经后妇女分为骨量正常、骨量减少和骨质疏松 3组。测定血清骨钙素 (BGP)、尿Ⅰ型胶原交联N端肽 (NTx)、血清OPG和RANKL ,计算RANKL/OPG比值。结果　年龄与血清OPG正相关 (r =0 4 4 2 ,P <0 0 0 1) ,与血清RANKL负相关 (r=- 0 2 6 3,P <0 0 0 1)。绝经后妇女的血清OPG(10 7 6± 3 0 )ng/L明显高于绝经前妇女 (72 0± 1 8)ng/L ,而血清RANKL(4 7± 0 4 )ng/L显著低于绝经前妇女 (5 8± 0 3)ng/L。校正年龄、停经年限和体重指数后 ,血清OPG、RANKL与腰椎和股骨各处骨密度无相关性。血清OPG与尿NTx/肌酐正相关 ;血清RANKL与血清BGP负相关。血清OPG和RANKL在绝经后骨质疏松组、骨量减少组和正常骨量组间差异无显著性。多元逐步回归分析显示 ,年龄、停经年限和骨转换指标是决定血清OPG RANKL系统的独立因素。结论　随年龄而升高的血清OPG可能是人体对抗绝经后骨吸收加快的一个代偿性反应 ,随年龄而下降的血清RANKL可能有益于恢复绝经后妇女的骨     

Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy

CONTEXT: Biochemical markers of bone turnover may reflect bone structure during anabolic treatment. OBJECTIVE: The objective was to evaluate associations between changes in biochemical markers and structural and dynamic bone parameters during teriparatide treatment. DESIGN: This study was a randomized, multicenter, double-blind, placebo-controlled fracture prevention trial, with 20-month median treatment duration for biopsy subset. SETTING: The trial was conducted at 11 clinical study sites. PATIENTS: Sixty-one postmenopausal women with osteoporosis who had paired transiliac biopsy specimens participated in the study. INTERVENTIONS: Once-daily sc injections of either placebo or teriparatide (20 or 40 microg) were administered. MAIN OUTCOME MEASURES: The study measured: 1) serum and urinary biochemical markers of bone formation [bone alkaline phosphatase and procollagen I C-terminal propeptide (PICP)] and resorption (N-telopeptide and deoxypyridinoline); and 2) structural and dynamic analyses of bone biopsies, including two-dimensional (2D) histomorphometry and three-dimensional (3D) micro-computed tomography evaluations measured at baseline (n = 57) and 12 (n = 21) or 22 (n = 36) months. RESULTS: U-N-telopeptide/creatinine and serum-PICP correlated with bone structure and dynamic indices at baseline, respectively. Changes in bone alkaline phosphatase at 1 month correlated with changes at 22 months in 2D wall thickness (r = 0.73; P = 0.001), trabecular bone volume (trabecular bone volume per total volume, BV/TV) (r = 0.58; P < 0.05), marrow star volume (r = -0.51; P = 0.05); 3D trabecular thickness (r = 0.49; P < 0.05), and BV/TV (r = 0.54; P < 0.05). Changes in PICP at 1 month correlated with changes in wall thickness (r = 0.60; P = 0.01), and 2D BV/TV (r = 0.51; P < 0.05) at 22 months. Changes in markers at 6 or 12 months were not associated with changes in structural or dynamic parameters. CONCLUSIONS: Early (1-month) changes in biochemical markers of bone formation, but not resorption, correlated with improvements in bone structure after 22 months of teriparatide therapy.     

A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women

OBJECTIVE: To examine functional interleukin-6 (IL-6) -174 G-->C allelic variants in relation to bone turnover and bone mineral density (BMD) in postmenopausal women. METHODS: Four hundred thirty-four healthy women living in the community (mean +/- SD age 71.7 +/- 5.7 years) were genotyped for the IL-6 -174 G-->C polymorphism. Serum levels of C-telopeptide of type I collagen (CTx), a marker of bone resorption, and osteocalcin (OC), a marker of bone formation, were determined. BMD at the hip and forearm was measured by dual-energy x-ray absorptiometry. RESULTS: CTx levels differed significantly (P = 0.006) among IL-6 genotypes (mean +/- SEM 0.275 +/- 0.02 ng/ml, 0.325 +/- 0.01 ng/ml, and 0.356 +/- 0.02 ng/ml in women with the CC genotype [n = 68], the GC genotype [n = 204], and the GG genotype [n = 162], respectively). Compared with the GG group, age-adjusted odds ratios for high bone resorption were 0.65 (95% confidence interval [95% CI] 0.41-1.0, P = 0.06) and 0.37 (95% CI 0.18-0.73, P = 0.0047) in GC and CC subjects, respectively. In contrast, OC levels did not differ by genotype. BMD at the hip and forearm was 1.5-5% higher in CC subjects compared with GG subjects (P not significant). When the cohort was divided according to the median age (70.5 years), BMD was significantly decreased in older compared with younger postmenopausal women with the GG and GC genotypes (-9.6% on average; P < 0.01), but not in those with the CC genotype (-5.1% on average; P not significant). CONCLUSION: Compared with the GC and GG IL-6 -174 G-->C genotypes, the CC genotype is associated with lower bone resorption and lesser decrease in bone mass in older postmenopausal women. These results suggest that IL-6 -174 G-->C alleles may be significant determinants of the risk for osteoporosis in elderly subjects.     

Role of serum FSH measurement on bone resorption in postmenopausal women

In vitro and animals models have shown follicle-stimulating hormone (FSH) effects on osteoclastic function, and FSH levels seem to influence bone loss independently of estrogen concentrations in humans. Our aim was to evaluate the role of serum FSH measurement in the assessment of bone resorption in postmenopausal women. We conducted a cross-sectional study including 92 postmenopausal healthy women aged 56.2 (3.6) and 7.2 (4) years since menopause. Serum FSH, luteinizing hormone (LH), estradiol (E2) and bone turnover markers as osteocalcin (OC) and C-terminal telopeptide of type I collagen (CTX) were measured. We analyzed the relationship between serum levels of gonadotropins, E2, and bone turnover markers. Serum levels of OC and CTX were positively related to FSH (r = 0.234, P = 0.047 and r?=?0.384, P?=?0.003) and LH (r?=?0.319, P?=?0.012 and r?=?0.273, P?=?0.038). There was no relationship with E2 levels. When gonadotropins levels were divided into quartiles, we found significant differences in bone turnover markers between the first and the fourth quartile. OC levels were higher in the highest quartile of FSH (P?=?0.024) and LH (P?=?0.001). Serum CTX was also higher in the highest quartile of FSH (P?=?0.004) and LH (P?=?0.039). FSH levels could explain approximately 14.7% of the chances in CTX. In summary, gonadotropins were related to bone turnover in postmenopausal healthy women. Moreover, the rise in FSH appears to contribute to higher bone resorption. Our results suggest that the measurement of FSH could be usefulness to perform a more comprehensive assessment of bone loss in these women.     

The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women

OBJECTIVE: To assess the effect of a dietary soy protein supplement containing isoflavones on lipids and indices of bone resorption in postmenopausal women. DESIGN: Placebo-controlled, double-blind, randomized study. PATIENTS: One hundred and six postmenopausal women were randomized to dietary soy supplementation (n = 51) or placebo (n = 55) for 3 months, of which 78 were included in the final analysis. MEASUREMENTS: Lipid profiles including total, low-density lipoprotein (LDL) and HDL cholesterol as well as triacylglycerol were measured. Pyridinoline and deoxypyridinoline were used as markers of bone resorption. Urinary isoflavone excretion was measured to assess compliance. RESULTS: There was a significantly greater increase in urinary isoflavone excretion detected in the soy group compared to placebo. Lipid profiles improved with significant decreases in LDL cholesterol (-0.60 +/- 0.10 vs.-0.29 +/- 0.09 mmol/l, P < 0.05), triacylglycerol (-0.22 +/- 0.07 vs. +0.01 +/- 0.05 mmol/l, P < 0.005) and the LDL : HDL ratio (-0.32 +/- 0.10 vs. +0.20 +/- 0.10, P < 0.005) in the soy group compared to placebo. There were no significant differences between the soy and placebo groups for urinary excretion of pyridinoline (-3.8 +/- 3.1 vs.-0.8 +/- 3.1 nmol/mmolCr, P = 0.4) or deoxypyridinoline (-0.8 +/- 0.9 vs.-0.3 +/- 0.7 nmol/mmolCr, P = 0.4). CONCLUSIONS: In postmenopausal women, dietary supplementation with soy protein containing isoflavones does not appear to have oestrogenic effects on markers of bone resorption. Soy protein favourably affected lipids; however, these effects (fall in triacylglycerol and no change in HDL) differ from those observed with oral oestrogen. These findings suggest that soy may not have biologically significant oestrogenic effects on bone resorption and we hypothesize that the lipid effects may be mediated, at least in part, through nonoestrogenic mechanisms.     

Analysis of the contribution of dydrogesterone to bone turnover changes in postmenopausal women commencing hormone replacement therapy

Although gestagens have been reported to influence bone metabolism, whether these contribute to the beneficial effects of hormone replacement therapy (HRT) on the skeleton of postmenopausal women is currently unclear. To address this question, we compared changes in bone turnover markers after commencing HRT in 26 postmenopausal women randomized to receive 8 weeks of treatment with 2 mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone daily. Serum and second morning void urine samples were obtained at baseline (twice) and after 1, 2, 4, and 8 weeks. Serum estradiol was measured by RIA, urinary total deoxypyridinoline (DPD) excretion by high pressure liquid chromatography, and serum osteocalcin and C-terminal procollagen peptide by enzyme-linked immunosorbent assay. The increase in serum estradiol after treatment with estradiol alone was slightly, but significantly, greater than that in the combination group (P = 0.04). Although estradiol suppressed urinary DPD excretion to a greater extent when given alone (P = 0.02), osteocalcin levels were significantly higher in this group than in women receiving combination therapy (P = 0.04). To assess the effect of dydrogesterone on the balance between formation and resorption in more detail, we subsequently compared the ratio between formation and resorption markers in the two treatment groups. We found that osteocalcin/DPD and C-terminal procollagen peptide/DPD ratios were significantly higher in women treated with estradiol alone (P < 0.0001 and P = 0.002, respectively), suggesting that dydrogesterone may reduce formation relative to resorption. These results suggest that gestagens may reduce estrogen's beneficial effects on the skeleton of postmenopausal women, as assessed over the first 8 weeks of replacement therapy.     

Bone turnover across the menopause transition: correlations with inhibins and follicle-stimulating hormone

CONTEXT: Longitudinal clinical studies demonstrate that increases in bone turnover that occur in perimenopausal women correlate better with elevated serum FSH than with changes in serum estradiol (E2). This perimenopausal rise in FSH is due to a selective decrease in ovarian inhibin B (InhB). Our previous demonstration that inhibins suppress both osteoblast and osteoclast development suggests that changes in serum inhibins may regulate osteoblast and osteoclast differentiation and thereby bone turnover, independent of changes in sex steroids. OBJECTIVE: The objective of this study was to determine whether decreased serum inhibin A (InhA) and InhB levels correlate with increases in markers of bone turnover in women across the menopause transition and to evaluate serum inhibins as better predictors of bone turnover markers across the menopause transition than FSH or bioavailable E2. DESIGN: We studied a cross-sectional age-stratified population sample of 188 pre- and postmenopausal women not using oral contraceptives or hormone replacement therapy (age, 21-85 yr). RESULTS: Serum InhA and InhB levels significantly correlated inversely with markers of bone formation and bone resorption in pre- and perimenopausal women and with markers of bone formation in postmenopausal women (InhA only). FSH was not significantly correlated with bone turnover in either pre- or postmenopausal women; however, FSH was significantly correlated with bone resorption (C-terminal collagen I cross-link) in perimenopausal women (age, 45-54 yr). Using multivariate analyses, serum InhA better predicted bone formation and resorption markers in premenopausal women than either FSH or bioavailable E2. CONCLUSIONS: Decreases in inhibin levels across the menopause transition are associated with increasing bone turnover, regardless of changes in sex steroids or FSH.     

Alendronate increases bone mass and reduces bone markers in postmenopausal African-American women

Previous studies indicated that aminobisphosphonate alendronate sodium, a potent inhibitor of bone resorption, increases bone mineral density (BMD) at the hip and spine, reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. The purpose of the present study was to investigate whether alendronate increases BMD and reduces markers of bone turnover in African-American postmenopausal women. In a multicenter, randomized, double-blind, placebo-controlled study, 65 African-American women, aged 45 to 88 yr, were randomly assigned to either placebo (n = 33) or alendronate 10 mg daily (n = 32) for 2 yr. Mean BMD T scores of the lumbar spine at baseline were -3.18 in the placebo-treated group and -3.09 in the alendronate-treated group. All women took 500 mg elemental calcium daily in the form of calcium carbonate and 500 IU vitamin D. Alendronate significantly increased BMD and reduced markers of bone formation and resorption, compared with placebo. At 2 yr, mean changes +/- SE in BMD were 6.5% +/- 0.7% for the lumbar spine (P < 0.001), 4.5% +/- 1.0% for the femoral neck (P < 0.001), 6.4% +/- 0.6% for the femoral trochanter (P < 0.001), 4.1% +/- 0.7% for the total hip (P < 0.001), 0.7% +/- 0.5% for the one third forearm (NS), and 2.0% +/- 0.4% for the total body (P < 0.001) in women treated with alendronate, compared with 0.9% +/- 0.6% (NS), 0.5% +/- 1.1% (NS), -0.2 +/- 0.8 (NS), -1.1 +/- 0.7% (NS), -0.8% +/- 0.6% (NS), and -1.2% +/- 0.6% (P < 0.05) for the lumbar spine, femoral neck, trochanter, total hip, one third forearm, and total body, respectively, in women treated with placebo. At 2 yr, mean serum bone-specific alkaline phosphatase had declined by 46.3% with alendronate (P < 0.001) and 13.6% with placebo (P < 0.01), and mean urinary N-telopeptide of type I collagen/creatinine ratio had declined by 70.5% with alendronate (P < 0.001) and 6.7% with placebo (NS). The incidence of adverse experiences was not different between the two groups. We conclude that in postmenopausal African-American women with osteoporosis, alendronate, 10 mg daily for 2 yr, increases BMD at the lumbar spine, hip, and total body and reduces markers of bone remodeling and is well tolerated.     

Effects of potassium alkali and calcium supplementation on bone turnover in postmenopausal women

Potassium citrate may improve calcium balance by conferring an alkali load. Calcium supplementation slows postmenopausal bone loss by inhibiting PTH secretion. This study explores whether combined treatment with potassium citrate and calcium citrate is more effective than either agent alone in inhibiting bone loss. In a crossover study involving 18 postmenopausal women, the following treatments were compared: potassium citrate (4.3 g or 40 mmol/d), calcium citrate (800 mg or 20 mmol/d), combined treatment, and placebo. During the last 2 d of each 2-wk phase, serum and 24-h urine were collected for assessment of calcium metabolism, alkali load, and bone turnover markers. Compared with placebo, potassium citrate provided an alkali load and significantly decreased urinary calcium without changing serum PTH (sPTH) or bone turnover markers. Calcium citrate significantly increased absorbed calcium, marginally decreased sPTH, and significantly reduced bone resorption markers. Combined treatment retained key features of potassium citrate and calcium citrate. However, more alkali was delivered than with potassium citrate alone, and absorbed calcium did not differ from calcium citrate alone. Compared with placebo, combined treatment increased urinary calcium, marginally reduced sPTH, provided a clear alkali load, and reduced the bone resorption markers serum type I collagen C-telopeptide and urinary N-telopeptide by 20.4% (P < 0.0001) and 18.2% (P = 0.005), respectively. A significant trend was noted for the decrease in bone resorption markers as treatment changed from placebo to potassium citrate to calcium citrate to combined treatment. In postmenopausal women, combined treatment with potassium citrate and calcium citrate inhibits bone resorption by providing an alkali load and increasing absorbed calcium.     

Evaluation of bone mineral density of the peripheral skeleton in pre- and postmenopausal women with newly diagnosed endogenous Cushing's syndrome

OBJECTIVE: Cushing's syndrome (CS) is a well recognized cause of bone loss. Although many previous studies have shown decreased bone mineral density (BMD) in the lumbar spina and proximal femur of patients with endogenous CS, so far, the data estimating BMD in their peripheral skeleton are sparse. The aim of the present study was to evaluate BMD in the forearm and heel of women with newly diagnosed CS and to investigate its possible correlation with serum osteocalcin (BGP) and 24-hour urinary free cortisol levels (UFC). PATIENTS AND METHODS: BMD in the forearm (distal and ultradistal area) of 29 (13 premenopausal and 16 postmenopausal) women with newly diagnosed CS (18 with pituitary adenoma, 10 with adrenal tumor and 1 with ectopic) was measured by dual x-ray absorptiometry (DEXA) and was compared with BMD of 29 age, body mass index (BMI)- and oestrogen status matched healthy controls. Furthermore, in 18 (9 premenopausal and 9 postmenopausal) of the above patients (14 with pituitary adenoma, 5 with adrenal tumor and 1 with ectopic) broadband ultrasound attenuation (BUA) by quantitative ultrasound (QUS) of the heel was estimated and 18 age-, BMI- and oestrogen status matched healthy women served as controls. In all the patients serum BGP and UFC were measured at the time of diagnosis of CS. RESULTS: Compared to their matched controls, BMD in the forearm and BUA values in the heel did not differ in the premenopausal women with CS, while in the postmenopausal group BMD in the forearm was decreased (P < 0.05) but not BUA. Apart from a weak negative correlation between serum BGP and BMD in the ultradistal site of the forearm in premenopausal women (P = 0.05), serum BGP and UFC did not show significant correlation with BMD or BUA. CONCLUSIONS: BMD in the forearm is reduced only in postmenopausal women with newly diagnosed endogenous CS, while BUA in the heel is unaffected in both pre- and postmenopausal patients. Moreover, serum BGP and UFC do not seem to be relevant markers for assessing bone loss in the peripheral skeleton at the time of diagnosis of hypercortisolemia.     

基质金属蛋白酶-1、-2与女性年龄、骨转换生化指标及骨密度的关系

目的 探讨血清基质金属蛋白酶（MMP）-1、MMP-2与女性年龄、骨密度（BMD）及骨转换生化指标之间的关系。方法用ELISA测定591例20-80岁女性志愿者血清MMP-1、MMP-2、血清骨碱性磷酸酶（BAP）、血清骨钙素（OC）和血清Ⅰ型胶原氨基末端肽（NTX）,用DEXA测定腰椎1-4正位总体、股骨颈、Ward三角区、总髋部的BMD。结果（1）MMP-1、MMP-2与年龄呈正相关。（2）绝经后妇女MMP-2水平高于绝经前妇女（P〈0．001）。（3）MMP-2与BMD呈负相关（P〈0．05）,但多元线性回归分析表明MMP-2不是BMD的预测因子。（4）MMP-2与血清BAP、OC、NTX正相关（P〈0．01）。（5）绝经后骨质疏松症患者血清MMP-2水平高于年龄匹配的正常对照组、骨量减少组（P〈0．01）。结论血清MMP-2与骨转换生化指标相关联。血清MMP-2水平升高可能为高骨转换过程（如绝经后骨质疏松症）中的一种伴随表现。     

Calcitonin and postmenopausal bone loss

In order to establish the role of calcitonin (CT) in postmenopausal bone loss, we studied CT metabolism in 25 pre- and postmenopausal women. Postmenopausal women presented a highly significant reduction of CT basal levels compared to premenopausal females (p less than 0.01). Also, production rates of CT in osteoporotics were significantly lower than in either young premenopausal (18-25 years old), older premenopausal (35-40 years old), or postmenopausal healthy subjects. In a study in rabbits, we found that injection of CT, along with equimolar amounts of anti-SCT antibodies extracted from serum of pagetic patients, did not inhibit the hypocalcemic response to the hormone, thus demonstrating that resistance to CT treatment cannot be accounted for by antibody production. In a subsequent clinical study in patients with Paget's disease of bone, we found that 200 IU/day of salmon CT (SCT), given by nasal spray, improved both clinically and biochemically the activity of the disease, as demonstrated by 37 +/- 4% decrease of serum alkaline phosphatase and 35 +/- 5% fall of urinary excretion of hydroxyproline after six months of therapy. The effectiveness of CT as nasal spray was further tested in healthy women at an early stage of menopause. A 12-month course of intranasal SCT counteracted early postmenopausal bone loss, presumably by inhibiting bone resorption. In conclusion, intranasal CT seems to be a very attractive alternative to be considered for the prevention of postmenopausal osteoporosis.     

The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes

Estrogens protect healthy women from cardiovascular disease. However, epidemiological data suggest that women with diabetes are denied the cardioprotection associated with estrogens. Whether or not hormonal replacement therapy (HRT) confers cardiovascular benefits in postmenopausal women with diabetes is not known. The aim of this study was to examine the effects of HRT on the microvascular reactivity and endothelial function of individuals with and without diabetes. We studied the following groups of individuals: premenopausal healthy women [n = 28, age 41 +/- 8 yr (mean +/- SD)], premenopausal women with type 2 diabetes (n = 16, age 43 +/- 6 yr); postmenopausal healthy women (n = 12, age 57 +/- 4 yr), postmenopausal women with diabetes (n = 17, age 62 +/- 5 yr); postmenopausal healthy women on HRT (n = 13, age 51 +/- 5 yr), postmenopausal women with diabetes on HRT (n = 11, age 57 +/- 7 yr). We used laser Doppler flowmetry to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium independent). The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women (180 +/- 67%; increase over baseline) compared to premenopausal diabetic women (87 +/- 41%; P < 0.001). endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT (143 +/- 52) compared with postmenopausal diabetic women on HRT (86 +/- 61), postmenopausal healthy women without HRT (104 +/- 43), and postmenopausal diabetic women without HRT (74 +/- 28; P < 0.001). A similar pattern of responses was observed in the endothelium-independent vasodilation (premenopausal healthy women, 126 +/- 56; premenopausal diabetic women, 88 +/- 26; postmenopausal healthy women on HRT, 121 +/- 37; postmenopausal diabetic women on HRT, 88 +/- 41; postmenopausal healthy women without HRT, 84 +/- 36; and postmenopausal diabetic women without HRT, 73 +/- 36; P < 0.001). Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes (248.9 +/- 56 ng/ml) and postmenopausal women with diabetes on HRT (257.7 +/- 49 ng/ml) had lower sICAM levels compared with the postmenopausal diabetic women without HRT (346.4 +/- 149 ng/ml; P < 0.05). We conclude that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent. However, the use of HRT among women with diabetes is associated with lower sICAM levels, suggesting an attenuation in endothelial activation.     

Body composition,bone mineral density,and circulating leptin levels in postmenopausal Turkish women

OBJECTIVE: We analyzed the relationship between serum leptin levels and bone mineral density (BMD) values as well as the relationship between serum leptin levels and whole body composition, whether or not they were associated. In addition, we also investigated whether lean mass or fat mass is a better predictor of BMD in postmenopausal Turkish women. DESIGN AND MEASUREMENTS: One hundred consecutive postmenopausal women with a mean age of 55.1 +/- 6.3 years who visited our outpatient clinic for the evaluation of osteoporosis were recruited. Skin fold thickness at four sites and waist:hip ratio were measured. Body mass index (BMI) was calculated in kg/m(2). Serum concentrations of leptin, insulin, and estradiol were evaluated. Bone formation and resorption markers were also determined. The BMD values were measured by dual energy X-ray absorptiometry (DEXA) at the lumbar spine and femoral neck. Whole body composition (lean mass, fat mass, and percentage of fat), total bone mineral content (BMC) in g, and total BMD were also measured by DEXA. RESULTS: Serum leptin levels did not correlate with BMD values at all skeleton sites measured. Leptin correlated positively with fat mass, percentage of fat, and BMI (r = 0.738 and P = 0.00, r = 0.536 and P = 0.00, r = 0.356 and P = 0.00, respectively). Lean mass correlated with BMD at all sites measured (r = 0.339 and P = 0.00, r = 0.312 and P = 0.01, r = 0.523 and P = 0.00, r = 0.636 and P = 0.00). Lean mass correlated with BMI (r = 0.636, P = 0.00) but not with serum leptin (r = -0.021, P = 0.881), and it was an independent determinant of BMD at all skeleton sites measured. CONCLUSION: Our study showed that lean mass is a better predictor than fat mass of bone mineral density and that serum leptin levels are not associated with BMD.     

Effects of intranasal 17beta-estradiol on bone turnover and serum insulin-like growth factor I in postmenopausal women.

Estrogen therapy, using either oral or transdermal routes, decreases bone turnover and prevents postmenopausal bone loss. It has been suggested that oral and transdermal 17beta-estradiol (E2) may have different effects on serum insulin-like growth factor I (IGF-I), a potent bone-forming growth factor. In this study we investigated the effects of a new route of administration, the intranasal E2 spray (S21400), on bone turnover and circulating IGF-I and IGF-binding protein-3 (IGFBP-3). Four hundred and twenty early postmenopausal women (<5 yr since menopause; mean age, 52 yr) were enrolled in a 3-month, double blind, placebo-controlled study of four doses of intranasal E2 (100, 200, 300, and 400 microg/day), two doses of oral E2 valerate (1 or 2 mg/day), and placebo. One hundred and twelve women were further treated for 12 months with intranasal E2 (300 microg/day, i.e. the dose that has been shown to be adequate for the majority of postmenopausal women). Markers of bone resorption (urinary type I collagen C telopeptides) and formation [serum osteocalcin, serum type I collagen N-terminal extension propeptide (PINP), and serum bone alkaline phosphatase (BAP)] were measured at baseline, 1 month, 3 months, and 15 months. Serum IGF-I and IGFBP-3 were measured at baseline, 1 month, and 3 months. Urinary type I collagen C telopeptides decreased significantly in all active treatment groups as soon as 1 month (P<0.001 vs. placebo) and continued to decrease at 3 months with a dose effect for intranasal E2. Serum osteocalcin and PINP did not change at 1 month for oral E2 (1 and 2 mg), but decreased significantly at 3 months. In contrast, formation markers increased significantly at 1 month for the two highest doses of intranasal E2 (P<0.01 vs. placebo for osteocalcin and BAP) and did not decrease at 3 months. Oral E2 induced a marked decrease in circulating IGF-I as early as 1 month, which was amplified at 3 months (-29% and -32% for 1 and 2 mg, respectively), whereas no significant change from placebo was observed for intranasal E2 during the 3-month period. Changes in circulating IGF-I correlated significantly (P<0.01) with changes in osteocalcin, PINP, and BAP at 3 months. Oral and intranasal E2 did not induce any significant change from placebo in serum IGFBP-3 at both 1 and 3 months. After 1 yr of treatment with intranasal E2 (300 microg/day), both resorption and formation markers decreased, reaching the levels in premenopausal women, regardless of the type of treatment during the first 3 months. We conclude that E2 administered by this new nasal route normalizes bone turnover to premenopausal levels. The delayed decrease in bone formation observed with intranasal E2 compared to oral E2 may be related to different effects on serum IGF-I levels.