Correlates of Osteoprotegerin Levels in Women and Men

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23–90 years) and women (n= 304; age range 21–93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R= 0.39, p<0.001) and women (R= 0.18, p<0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 ± 6 pg/ml vs 134 ± 6 pg/ml, respectively, p<0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 ± 7 pg/ml vs 188 ± 7 pg/ml, respectively, p= 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=–0.27, p<0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency. Received: 14 August 2001 / Accepted: 20 November 2001     

The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis

Summary It has been debated whether postmenopausal osteoporosis is characterized by high or low bone turnover and whether circulating levels of sex steroids contribute to the occurrence of osteoporotic fractures. We examined 154 70-year-old women with or without osteoporotic fractures, and 178 early postmenopausal women with a “rapid” or a “slow” bone loss. In all participants, we determined markers of bone formation (serum alkaline phosphatase (AP) and serum bone Gla protein (BGP)), markers of bone resorption (fasting urinary calcium/creatinine (FU Ca/Cr) and hydroxyproline/creatinine (FU Hpr/Cr)), and serum estrone (E₁), estradiol (E₂), androstenedione (A), and fat mass. The 70-year-old womenwith osteoporotic fractures had significantly elevated AP (P<0.001), BGP (P<0.001), and FU Hpr/Cr (P<0.001) compared with the groupwithout fractures. In the group of early postmenopausal women, the “rapid” bone losers had significantly increased FU Hpr/Cr (P<0.001) and FU Ca/Cr (P<0.001). E₁, E₂, A, and the fat mass did not differ in the groups with and without osteoporotic fractures, whereas the “rapid” bone losers had significantly lower E₁ (P<0.05), E₂ (P<0.05), and fat mass (P<0.01) than the ‘slow” bone losers. It is concluded that patients with manifest osteoporosis and early postmenopausal women with a rapid bone loss have increased biochemical markers of bone turnover. Moreover, the present study demonstrates that early postmenopausal women with an “excessive” bone loss have significantly decreased serum estrogens, whereas it is not possible to detect low estrogens in women with osteoporotic fractures.     

Not All Postmenopausal Women on Chronic Steroid and Estrogen Treatment are Osteoporotic: Predictors of Bone Mineral Density

Chronic steroid use results in osteoporosis, and postmenopausal women are believed to be at a high risk for steroid-induced bone loss. The purpose of this study was to determine predictors of bone mineral density (BMD) in postmenopausal women on both chronic steroid and hormone replacement therapy. Seventy-six postmenopausal women (≥3 years postmenopausal, ≥2 years of steroid treatment of ≥5 mg/day of prednisone, and ≥1 year of hormone replacement therapy) were recruited into this study. Measurements of BMD of the lumbar spine and femoral neck were obtained in all subjects. Risk factors for osteoporosis were obtained by questionnaire. Discriminant analysis was performed to determine predictors of BMD. Osteoporosis, defined by a T score of <−2.5, was present in the lumbar spine or femoral neck in 34 of the 76 subjects. Based on these criteria, women with osteoporosis were significantly older, were more years postmenopausal, and had a lower body mass index (BMI) than women who did not have osteoporosis. Predictors of osteoporosis for both the femoral neck and spine included a low BMI (P < 0.05), more years postmenopausal (P < 0.01), and more years on steroids (P < 0.01). Low BMI was the only significant predictor of osteoporosis in the lumbar spine (P < 0.05), whereas for the femoral neck both years on steroids (P < 0.05) and BMI (P < 0.05) were significant predictors of low BMD. In summary, not all postmenopausal women on chronic steroid and hormone replacement therapy are osteoporotic but a low BMI, more years on steroids, and more years postmenopausal were significant predictors of osteoporosis in these subjects. Received: 8 November 1997 / Accepted: 21 May 1997     

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.     

甲状旁腺素的生物学研究与成骨作用

甲状旁腺素(PTH)是由甲状旁腺主细胞合成分泌的、含有84个氨基酸的碱性单链多肽,是调节血钙、磷水平的主要激素之一,可促使血钙水平升高,血磷水平下降。PTH可精细调节骨的合成、分解代谢,对成骨细胞和破骨细胞的分化、成熟、凋亡发挥重要作用。本文综述了PTH的化学结构、生理作用、生物学研究成果及PTH的临床应用。PTH对Ⅰ型骨质疏松(绝经后骨质疏松症)、Ⅱ型骨质疏松(老年骨质疏松症)、雌激素缺乏的年轻妇女及糖皮质激素所致的骨质疏松症均有治疗作用,能显著升高骨密度,并能降低患者骨质疏松性骨折发生率,加速骨折愈合。甲状旁腺素在临床骨质疏松治疗、骨质疏松性骨折的治疗中都具有重要的应用价值。     

Osteoporosis in otherwise healthy perimenopausal and early postmenopausal women: Physical and biochemical characteristics

Population studies have shown that about 3–5% of perimenopausal women already have osteoporosis according to the WHO definition of osteoporosis for postmenopausal women ( t -score–2.5). In general, this bone loss arises from well-characterized diseases or conditions that affect acquisition of peak bone mass and/or the rate of bone loss after peak bone mass has been attained. However, there often remains a subset of these women, with no identifiable cause of bone loss. This group has so far been little studied. We prospectively evaluated a group of 60 perimenopausal and early postmenopausal women (mean age 52.2±2.5 years) who were found to have apparently unexplained low bone mass, and we compared them to 120 controls matched for age and menopausal status. These women were extensively investigated, including by detailed questionnaire and laboratory testing. Of the 60 women with osteoporosis, only three were found to have previously undiagnosed disorders (two with subclinical hyperthyroidism and one with elevated serum PTH levels) that might have contributed to their low bone mass. On the other hand, osteoporotic patients were characterized by a significantly lower body weight, higher prevalence of personal and parental histories of fractures and a higher level of bone turnover as assessed by increased serum osteocalcin and bone alkaline phosphatase levels and urinary type I collagen C-telopeptide (CTX) excretion, as compared to controls. These findings support theories of a genetic contribution to osteoporosis and underline the predictive value of a previous history of personal and familial fracture in the identification of osteoporosis in early postmenopausal women.     

IL-33与绝经后骨质疏松女性骨密度和骨代谢指标相关性研究

目的 探索血清白细胞介素-33(IL-33)与绝经后骨质疏松女性骨密度和骨代谢指标相关性。方法 采用酶联免疫吸附法测定50例绝经后骨质疏松患者和50例正常绝经后妇女血清IL-33水平。采用双能X线骨密度仪(DXA)测量患者和对照组的骨密度(BMD)。检测维生素D、钙、碱性磷酸酶(ALP)、甲状旁腺激素(PTH)水平,以及1型胶原C末端肽(CTX)和1型前胶原N端前肽(P1NP)等骨转换指标。结果 在绝经后骨质疏松症女性中,IL-33水平显著低于健康对照组[(3.53±2.45) pg/mL vs (13.72±5.39) pg/mL,P=0.007];Spearman相关分析表明血清IL-33水平与年龄、BMI、PTH、CTX和P1NP水平呈负相关,与腰椎BMD和股骨颈BMD呈正相关。多元回归分析表明,年龄、BMI、腰椎BMD、PTH、股骨颈BMD和血清CTX和P1NP水平是骨质疏松症患者血清IL-33水平降低的独立预测因子。结论 血清IL-33降低是绝经后骨质疏松患者股骨颈和腰椎骨密度降低和骨转换增速的危险因素。     

Circulating Sex Steroids,Sex Hormone-Binding Globulin,and Longitudinal Changes in Forearm Bone Mineral Density in Postmenopausal Women and Men: The Tromsø Study

Bone loss during advancing age in women and men is partly the result of sex steroid deficiency. As the contribution of circulating sex steroids and sex hormone-binding globulin (SHBG) to bone loss remains uncertain, we sought to determine whether levels of sex steroids or SHBG predict change in bone mineral density (BMD) in women and men. A population-based study in the city of Tromsø of 6.5 years’ duration (range 5.4-7.4) included 927 postmenopausal women aged 37–80 years and 894 men aged 25–80 years. Total estradiol and testosterone, calculated free levels, and SHBG were measured at baseline, and BMD change at the distal forearm was determined using BMD measurements in 1994–1995 and 2001. Bone loss was detected in postmenopausal women and men. Free estradiol and SHBG predicted age-adjusted bone loss in postmenopausal women, but only free estradiol was associated after further adjustment for body mass index and smoking in mixed models (P < 0.05). After same adjustment, only SHBG persisted as a significant independent predictor of bone loss in men (P < 0.001). However, only 1% of the variance in bone loss was accounted for by these measurements. We therefore conclude that the relations between sex steroids and bone loss are weak and measurements of sex steroids are unlikely to assist in clinical decision making.     

Longitudinal Alveolar Bone Loss in Postmenopausal Osteoporotic/Osteopenic Women

The purpose of this 2-year longitudinal clinical study was to investigate alveolar (oral) bone height and density changes in osteoporotic/osteopenic women compared with women with normal lumbar spine bone mineral density (BMD). Thirty-eight postmenopausal women completed this study; 21 women had normal BMD of the lumbar spine, while 17 women had osteoporosis or osteopenia of the lumbar spine at baseline. All subjects had a history of periodontitis and participated in 3- to 4-month periodontal maintenance programs. No subjects were current smokers. All patients were within 5 years of menopause at the start of the study. Four vertical bitewing radiographs of posterior sextants were taken at baseline and 2-year visits. Radiographs were examined using computer-assisted densitometric image analysis (CADIA) for changes in bone density at the crestal and subcrestal regions of interproximal bone. Changes in alveolar bone height were also measured. Radiographic data were analyzed by the t-test for two independent samples. Osteoporotic/osteopenic women exhibited a higher frequency of alveolar bone height loss (p<0.05) and crestal (p<0.025) and subcrestal (p<0.03) density loss relative to women with normal BMD. Estrogen deficiency was associated with increased frequency of alveolar bone crestal density loss in the osteoporotic/osteopenic women and in the overall study population (p<0.05). These data suggest that osteoporosis/osteopenia and estrogen deficiency are risk factors for alveolar bone density loss in postmenopausal women with a history of periodontitis. Received: 9 April 1998 / Accepted: 18 August 1998     

A Population‐Based Assessment of Rates of Bone Loss at Multiple Skeletal Sites: Evidence for Substantial Trabecular Bone Loss in Young Adult Women and Men

Using QCT, we made a longitudinal, population‐based assessment of rates of bone loss over life at the distal radius, distal tibia, and lumbar spine. Cortical bone loss began in perimenopause in women and later in life in men. In contrast, trabecular bone loss began in young adulthood in both sexes. Introduction: Although conventional wisdom holds that bone loss begins at menopause in women and later in life in men, this has not been examined longitudinally in population‐based studies using precise technology capable of distinguishing cortical and trabecular bone. Materials and Methods: In an age‐ and sex‐stratified population sample (n = 553), we measured volumetric BMD (vBMD) of trabecular and cortical bone by QCT annually for up to 3 yr at the distal radius (DR) and distal tibia (DT) (n = 552) and trabecular vBMD at baseline and 3 yr at the lumbar spine (LS) (n = 474). Results: Substantial cortical bone loss began in middle life in women but began mainly after age 75 in men. In contrast, substantial trabecular bone loss began in young adult women and men at all three skeletal sites and continued throughout life with acceleration during perimenopause in women. Women experienced 37% and men experienced 42% of their total lifetime trabecular bone loss before age 50 compared with 6% and 15%, respectively, for cortical bone. Median rates of change in trabecular bone (%/yr) were ?0.40, ?0.24, and ?1.61 in young adult women and ?0.38, ?0.40, and ?0.84 in young adult men at the DR, DT, and LS, respectively (all p < 0.001). The early trabecular bone loss did not consistently correlate with putative causal factors, except for a trend with IGF‐related variables at DT in women. However, in postmenopausal women and, to a lesser extent, in older men, higher rates of cortical and trabecular bone loss were associated with lower levels of biologically‐active sex steroids and with higher levels of follicle‐stimulating hormone and bone turnover markers. Conclusions: The late onset of cortical bone loss is temporally associated with sex steroid deficiency. However, the early‐onset, substantial trabecular bone loss in both sexes during sex steroid sufficiency is unexplained and indicates that current paradigms on the pathogenesis of osteoporosis are incomplete.     

Relationship between serum intact parathyroid hormone concentrations and bone remodeling in type I osteoporosis: Evidence that skeletal sensitivity is increased

To define the role of parathyroid gland function in the pathophysiology of bone loss in type I (postmenopausal) osteoporosis, we measured serum intact parathyroid hormone (PTH) concentration by immunoradiometric assay (IRMA) and by multisite immunochemiluminometric assay (ICMA) in 63 postmenopausal osteoporotic women (PMOp) with vertebral compression fractures and in 75 age-comparable postmenopausal normal women (PMNl). Also, tetracycline-based histomorphometric indices in cancellous bone were assessed in iliac biopsy samples from 61 PMOp and 28 PMNl women. Serum PTH concentrations by IRMA were similar in PMOp and PMNl (medians, 3.92 and 3.77 pmol/l; NS) but were significantly lower in PMOp by the more sensitive ICMA (medians, 2.82 and 3.14 pmol/l;P<0.01). By multiple linear regression analysis, serum PTH was directly related (P<0.001) to activation frequency, bone resorption rate, bone formation rate, and the calculated rate of bone loss. For each unit (pmol/l) increase in serum PTH by ICMA, activation frequency increased by 1.3%/year more (P=0.01), bone resorption rate increased by 3.9%/year more (P=0.003), and the rate of cancellous bone loss was 2.8% greater (P= 0.0003) in the PMOp women compared with the PMNl women. Concentrations of serum estradiol, but not serum estrone, had a weak opposing effect to PTH, especially for bone formation rate. These data suggest that in PMOp the bone has increased sensitivity to the biologic effects of PTH. This may represent one of the fundamental pathophysiologic defects in PMOp and, in the setting of estrogen deficiency, may explain, in part, their greater rate of bone loss.     

Estrogen inhibits Dlk1/FA1 production: A potential mechanism for estrogen effects on bone turnover

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 < 0.001). s‐Dlk1/FA1 was correlated with s‐CTX (r = 0.30, p < 0.01). ERT in postmenopausal women decreased s‐Dlk1/FA1, as well as s‐CTX and s‐osteoclacin (all p < .0001). Changes in s‐Dlk1 were significantly correlated with those observed in s‐CTX (r = 0.18, p < 0.05) and s‐osteocalcin (r = 0.28, p < 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     

Vitamin D status and bone turnover in women with acute hip fracture

Hypovitaminosis D is common in elderly women. Few data are available on vitamin D status and bone turnover in women with acute hip fracture. The aims of this study were to determine whether elderly Italian women with an acute hip fracture also had low vitamin D levels and an increase of bone turnover compared with elderly women with osteoporosis but without fractures. Seventy-four women with acute osteoporotic hip fracture and 73 women with postmenopausal osteoporosis were studied. All women were self-sufficient and had adequate sunlight exposure. To exclude the effect of trauma on serum 25-hydroxycolecalciferol levels and bone markers (bone alkaline phosphatase and C-terminal telopeptides of Type I collagen as indices of bone formation and bone resorption), blood samples were drawn within 24 hours of the fracture. Current data indicated that in our patients the prevalence of hypovitaminosis D is common although to a lesser extent than in women who are housebound. Women with acute hip fractures had a higher prevalence of vitamin deficiency defined as serum 25-hydroxycolecalciferol lower than 12 ng/mL, compared with women with osteoporosis. Moreover, the presence of fracture did not influence the rate of bone formation, whereas the increase in bone resorption could be attributed to an older age of women with acute hip fracture because of similar values of parathyroid hormone levels in the two groups.     

Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men.

Several lines of evidence implicate estrogen deficiency as a cause of bone loss in elderly men. Thus, in 50 elderly men (mean age +/- SD, 69.1 +/- 6.0 years), we performed a randomized blinded study to assess the effect of 6 months of treatment with 60 mg/day of raloxifene (a selective estrogen receptor modulator [SERM] that has an agonist effect on bone but is not feminizing) versus placebo on bone turnover markers. The mean changes in bone turnover markers, serum sex steroid, or lipid levels with treatment did not differ between groups. However, changes in urinary cross-linked N-telopeptide of type I collagen (NTX) excretion were related directly to the baseline serum estradiol level in the raloxifene (r = 0.57; p = 0.004) but not in the placebo-treated (r = 0.15; p = 0.485) men (p = 0.015 for the difference between groups). Moreover, the men in whom NTX excretion decreased after raloxifene treatment had significantly lower baseline estradiol levels (mean +/- SEM, 22 +/- 2 pg/ml) than the men in whom urinary NTX excretion didn't change or increased after raloxifene therapy (30 +/- 3 pg/ml; p = 0.03), and no such difference was found in the placebo group. Thus, raloxifene has no significant effect on bone turnover markers or lipid levels in elderly men. However, the association noted between baseline estradiol levels and the change in urine NTX excretion in the raloxifene-treated men suggests that a subset of men with low estradiol levels may respond to raloxifene or other SERMs, and further studies are needed to directly test this possibility.     

白藜芦醇在绝经后骨质疏松症中抗氧化机制的研究进展

绝经后骨质疏松症(PO)是一种全身性骨骼疾病,由雌激素缺乏和衰老引起,其特征是低骨密度(BMD)和骨组织的微结构恶化,并导致骨质疏松性骨折的风险增高。在PO的发生发展过程中,潜在的致病机制是复杂和多方面的,雌激素缺乏是骨吸收增加和骨质流失加速的重要原因。同时,由于雌激素的缺乏和机体的衰老导致氧化应激(OS)水平的升高,是PO发生的主要机制之一。针对老年绝经后骨质疏松患者的治疗目前较为有效的是采用雌激素替代疗法,但也增加了患乳腺癌、子宫癌和心血管事件发生的风险。因此,寻找有效的抗氧化应激药物以治疗PO受到了越来越多研究者的关注。其中以白藜芦醇(RES)为代表的天然植物化合物,是一种具有抗氧化和抗衰老作用的天然抗氧化剂。它能通过多种通路抑制体内氧化应激,促进成骨分化和减少骨量丢失,并调节骨转换的能力,从而有效治疗PO。本文就白藜芦醇在PO中的抗氧化机制及其研究进展做一综述。     

【特刊综述】骨骼两性异形中的雄激素和雌激素

骨骼是表达雄激素、雌激素受体以及类固醇代谢酶的一种内分泌组织。循环性激素的生物活性通过六种性激素结合球蛋白以及在骨组织中的局部转变来进行调节,例如,睾酮通过芳香酶转变成雌二醇,或通过5α还原酶转变成双氢睾酮。由于高分辨外周CT应用的增多,我们对造成骨骼强度性别差异的结构基础的认识在近几年有很大进步。这些对微小结构的观察是理解性激素对男性峰值骨量及对骨皮质和骨小梁之间转变的影响的基础。最近的研究利用Cre／LoxP技术使我们在整体基因敲除小鼠上机械的认识精确到性激素及其在成骨细胞、破骨细胞、骨细胞以及其它造成男性骨质疏松的细胞上的核受体的直接作用。同时,这些研究加强了这样的观点：雄激素和雌激素的缺乏通过与例如胰岛素样生长因子1、炎症、氧化应激、骨骼代谢的中枢神经系统控制、机械负荷的适应等的交互作用发挥直接和多种效应。这篇综述将总结性激素在男性骨骼自身平衡作用这个领域有关方面最近的进展。     

Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption

The aims of the study were to evaluate the use of bone-specific biochemical markers of turnover in type I osteoporosis, to test for evidence of heterogeneity of bone turnover in this condition, and to attempt to devise an uncoupling index by using the relationship between bone-specific biochemical markers of bone formation and bone resorption. In women with type I osteoporosis (mean age 64 years, SD 5;n=63) the mean level of serum osteocalcin, a specific biochemical marker of bone formation, was 9.9 ng/ml (SD 2.0), which was higher than the level in normal postmenopausal women (mean age 65 years, SD 6;n=8.9 ng/ml (SD 2.0;p<0.01). The variance of serum osteocalcin levels in the two groups was similar. Compared with this 11% increase in the biochemical marker for bone formation, the markers of bone resorption, total urinary deoxypyridinoline (bone-specific), pyridinoline and hydroxyproline were increased by 40% (p<0.0001), 61% (p<0.0001) and 25% (p<0.01), respectively. Furthermore, these biochemical markers of bone resorption had greater variance in women in type I osteoporosis than in the normal postmenopausal women (p<0.001). The urinary excretion of the free crosslinks deoxypyridinoline, pyridinoline and glycosylated pyridinoline were increased by 26% (p<0.001), 17% (p<0.01) and 13% (NS) respectively. An uncoupling index was calculated for the difference between urinary deoxypyridinoline and serum osteocalcin using the results from the normal women and expressed asz-scores. We conclude that the pyridinium crosslinks of collagen enable better discrimination between normal and osteoporotic women than does hydroxyproline. In osteoporosis there appears to be heterogeneity of bone resorption. Finally, an uncoupling index indicated that in osteoporosis bone resorption was increased to a greater extent than bone formation as compared with normal postmenopausal women.     

Role of parathyroid hormone in mediating age-related changes in bone resorption in men

Osteoporosis in men is an important and growing public health problem. While there has been extensive work done on defining the mechanism(s) of the age-related increase in bone resorption in women, our knowledge regarding the pathogenesis of bone loss in elderly men is still incomplete. We previously demonstrated that the age-related increase in serum PTH contributes substantially to the increased bone resorption in elderly women, since suppression of PTH levels by an intravenous calcium infusion decreased bone resorption markers to a greater extent in elderly compared to premenopausal women. In the present study, we tested the hypothesis that the comparable increase in PTH levels in elderly men (age 70–78 years) was driving bone resorption to a greater extent in these men than in younger men (age 40–50 years). PTH secretion was suppressed by an intravenous calcium infusion and the corresponding changes in the bone resorption marker, urine N-telopeptide of type I collagen (NTx) were assessed. In contrast to our previous findings in pre- versus postmenopausal women, suppression of PTH secretion in elderly men did not result in a greater decrease in urine NTx excretion than in the younger men (change in NTx excretion in the elderly men, -2.79±1.99 nmol/mmol Cr, versus that in the younger men, –5.07±1.39 nmol/mmol Cr, P=0.356). Collectively, these data suggest that the relationship between the age-related increase in serum PTH levels and bone resorption differs between elderly men and women. Since both estrogen and testosterone can attenuate the bone resorbing effects of PTH, it is possible that this difference may be due to the much milder degree of sex steroid deficiency in elderly men as compared to postmenopausal women.     

Osteoporosis and vitamin-D deficiency among postmenopausal women with osteoarthritis undergoing total hip arthroplasty

BACKGROUND: Several epidemiological studies have shown a lower prevalence of osteoporotic hip fractures in patients with osteoarthritis. Other studies have demonstrated elevated bone mineral density in patients with osteoarthritis. The prevailing view is that there may be an inverse relationship between osteoarthritis and osteoporosis. The purposes of the present study were to describe a subgroup of patients with osteoarthritis who were found to have osteoporosis and to assess the vitamin-D status and other risk factors for low bone density in osteoarthritic subjects with and without osteoporosis. METHODS: The bone mineral density of the spine, the proximal part of the femur, and the total body was measured with dual-energy x-ray absorptiometry in sixty-eight postmenopausal white women who were scheduled to undergo total hip replacement for advanced osteoarthritis. The serum levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, intact parathyroid hormone, osteocalcin, and bone-specific alkaline phosphatase and the urinary level of N-telopeptide were measured. Information from validated lifestyle, dietary, and demographic questionnaires was also evaluated. RESULTS: Seventeen (25%) of the sixty-eight women had occult osteoporosis (as indicated by a T score of less than -2.5). Fifteen (22%) of the sixty-eight subjects had vitamin-D deficiency, and three (4%) had an elevated serum parathyroid hormone level. Only two of the seventeen osteoporotic women had vitamin-D deficiency. On the basis of these numbers, vitamin-D status was not correlated with bone density (p = 0.32). Analysis of the relationship between the number of years since menopause and osteoporosis or markers of elevated bone turnover showed that osteoporosis was detected throughout the postmenopausal period. CONCLUSION: A substantial portion of these sixty-eight white women with osteoarthritis of the hip had occult osteoporosis and hypovitaminosis D. Vitamin-D deficiency was not restricted to the group with low bone density. These results support the need to consider the presence of both osteoporosis and vitamin-D deficiency in women with advanced osteoarthritis.     

Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized,controlled trial

Raloxifene effectively reduces the incidence of vertebral fractures in patients with postmenopausal osteoporosis. Recent data suggest that low-dose monofluorophosphate (MFP) plus calcium reduces the vertebral fracture rate in postmenopausal women with moderate osteoporosis. The objective of this study was to evaluate the combination of raloxifene and MFP in the treatment of postmenopausal women with osteopenia, osteoporosis and severe osteoporosis. A total of 596 postmenopausal women with osteopenia, osteoporosis and severe osteoporosis (mean femoral neck T-score of –2.87 SD) were randomized to treatment with 60 mg/day raloxifene HCl and 20 mg/day fluoride ions (as MFP) or 20 mg/day fluoride and placebo for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements. Changes in bone mineral density (BMD), as primary endpoint, and the rate of osteoporotic fractures and biochemical markers, as secondary endpoints, were assessed. As compared with MFP, raloxifene plus MFP was associated with significantly greater mean increases in the BMD of the femoral neck (1.37% versus 0.33%; P=0.004), total hip (0.89% versus –0.42%; P<0.001) and lumbar spine (8.80% versus 5.47% P<0.001). In the raloxifene plus MFP group, 16 patients sustained 17 osteoporotic fractures, as compared with 22 patients sustaining 34 incident osteoporotic fractures in the MFP group (P=0.313). One patient in the raloxifene plus MFP group sustained multiple osteoporotic fractures, as compared with eight patients in the MFP group (P=0.020). MFP alone significantly increased the serum bone alkaline phosphatase (bone ALP) and the urinary C-terminal crosslinking telopeptide of type I collagene (U-CTX). The addition of raloxifene in the combination arm blunted the rise in bone ALP, which remained nevertheless significant, and abolished the increase in U-CTX. The combination of raloxifene with MFP was generally well tolerated. This study demonstrates that, in postmenopausal women with osteopenia, osteoporosis and severe osteoporosis, the combination therapy of raloxifene plus MFP favorably influences the BMD and the bone formation and resorption balance, and may reduce the risk of multiple osteoporotic fractures compared to MFP alone.