伊班膦酸钠间断静脉输注治疗北京绝经后骨质疏松症的疗效

 目的 评价新一代双膦酸盐类药物伊班膦酸钠间断静脉输注对北京绝经后骨质疏松症的疗效及安全性。方法 研究纳入绝经后骨质疏松女性60例,年龄48~74岁,绝经年限3~32年,随机分为2组,治疗组每3个月静脉输注伊班膦酸钠2mg,对照组每周口服阿仑膦酸钠70mg,疗程12个月。疗效指标为腰椎及髋部骨密度（采用双能X线骨密度仪测量）、骨吸收指标血I型胶原羧基末端肽（酶联免疫吸附法测量）及骨形成指标碱性磷酸酶（自动分析仪酶法检测）。安全性指标包括血尿生化指标、心电图及不良反应。结果 59例患者完成研究。治疗12个月后,伊班膦酸钠组腰椎2-4、股骨颈及大转子骨密度增幅达6.3%,2.5%和0.1% (腰椎P <0.001,股骨颈P <0.01)。阿仑膦酸钠组腰椎、股骨颈及大转子骨密度改变率为 3.7%,4.9和-0.5% (腰椎和股骨颈P <0.001)。两组间治疗前后骨密度均无明显差别。伊班膦酸钠和阿仑膦酸钠治疗后ALP及CTX浓度均快速、显著下降,ALP降低15.8%和17.2%,CTX降低78.1%及43.2%（均P <0.001）。两组血钙磷水平、肝肾功能在正常范围内,伊班膦酸钠组常见的不良反应是首次输液后肌肉疼痛和低热,占26.7%,反酸、上腹不适是阿仑膦酸钠组主要的不良反应,占13.3%,患者可以耐受这些轻度的不良反应。结论 新一代双膦酸类药物伊班膦酸钠对于治疗绝经后骨质疏松症是安全而有效的。     

Comparison of effects of alendronate and raloxifene on lumbar bone mineral density, bone turnover, and lipid metabolism in elderly women with osteoporosis

PURPOSE: To compare the effects of alendronate and raloxifene on lumbar bone mineral density (BMD), bone turnover, and lipid metabolism in elderly women with osteoporosis. SUBJECTS AND METHODS: One hundred twenty-two postmenopausal women with osteoporosis (mean age: 69.4 years) were randomly divided into 2 groups of 61 patients: the alendronate group and the raloxifene group. BMD of the lumbar spine, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of alkaline phosphatase (ALP), total cholesterol (TC), high and low density lipoprotein cholesterols (LDL-C and HDL-C, respectively), and triglycerides (TG) were measured during the 12-month-treatment period. RESULTS: The trial in 50 patients in the alendronate group and 52 patients in the raloxifene group could be completed. Both alendronate and raloxifene increased lumbar BMD (+8.0% and +2.4% at 12 months, respectively), followed by reductions of urinary NTX level and serum ALP level; however, the effects of alendronate were more pronounced than those of raloxifene. Only raloxifene reduced the serum levels of TC and LDL-C (-3.9% and -7.7% at 12 months, respectively), without any significant effect on the serum HDL-C and TG levels. CONCLUSION: The present study confirmed the efficacy of alendronate greater than raloxifene in increasing lumbar BMD through its effect on marked reduction of the bone turnover more than by raloxifene, and some beneficial effects of raloxifene on lipid metabolism in elderly women with osteoporosis.     

Determinants of one-year response of lumbar bone mineral density to alendronate treatment in elderly Japanese women with osteoporosis

The purpose of this study was to determine factors that could predict the one-year response of the lumbar bone mineral density (BMD) to alendronate treatment in elderly Japanese women with osteoporosis. Eighty-five postmenopausal women with osteoporosis, all of whom were between 55-88 years of age, were treated with alendronate (5 mg daily) for 12 months. Serum calcium, phosphorus, and alkaline phosphatase (ALP) and urinary NTX levels were measured at the baseline and 6 months, and lumbar (L1-L4) BMD was measured by dual energy X-ray absorptiometry at the baseline and 12 months. Multiple regression analysis was used to determine factors that were correlated with the percent change in lumbar BMD at 12 months. Lumbar BMD increased by 8.1 % at 12 months with a reduction in the urinary NTX level by 51.0 % at 6 months. Baseline lumbar BMD (R2=0.226, p < 0.0001) and percent changes in serum ALP and urinary NTX levels (R2=0.044, p < 0.05 and R2=0.103, p < 0.001, respectively) had a negative correlation with the percent change in lumbar BMD at month 12, while the baseline number of prevalent vertebral fractures (R2=0.163, p < 0.001), serum ALP level, and urinary NTX level (R2=0.074, p < 0.05 and R2=0.160, p < 0.001, respectively) had a positive correlation with it. However, baseline age, height, body weight, body mass index, years since menopause, serum calcium and phosphorus levels, and percent changes in serum calcium and phosphorus levels at 6 months did not have any significant correlation with the percent change in lumbar BMD at 12 months. These results suggest that lumbar BMD was more responsive to one-year of alendronate treatment in elderly osteoporotic Japanese women with lower lumbar BMD, more prevalent vertebral fractures, and higher bone turnover, who showed a greater decrease in bone turnover at 6 months, regardless of age, years since menopause, and physique. Alendronate may be efficacious in elderly Japanese women with evident osteoporosis that is associated with high bone turnover, and the percent changes in serum ALP and urinary NTX levels at 6 months could predict the one-year response of lumbar BMD to alendronate treatment.     

骨代谢相关基因多态性与盐酸雷洛昔芬对绝经后骨质疏松妇女骨密度和骨转换指标影响的关系

目的了解骨代谢相关基因多态性与盐酸雷洛昔芬( raloxifene,RLX)对绝经后骨质疏松妇女骨密度(bone mineral density, BMD)和骨转换指标影响的关系.方法为随机、对照和双盲试验,入选47～74岁68例无亲缘关系的绝经后骨质疏松汉族妇女,随机分为RLX组和安慰剂组(各34例),RLX组日服RLX 60 mg,安慰剂组服与RLX外观一致的安慰剂,共1年.在服药前、服药后6月和12月时,检测BMD和骨转换指标包括血清1型胶原羧基末端肽(C-telopeptide, CTX)和骨钙素(osteocalcin, BGP).分析雌激素受体1基因(estrogen receptor 1 gene,ESR1)Xba Ⅰ和PvuⅡ位点、ESR2基因RasⅠ位点、维生素D受体基因(vitamin D receptor, VDR)FokⅠ和CDX2结合位点的多态性. 结果共58例完成整个试验,研究结束时RLX组腰椎2～4(L2～4)、全髋部和大转子BMD增加的百分数,以及血清CTX和BGP水平下降的百分数与安慰剂组比较差异均有统计学意义(P<0.05或P<0.01).治疗后12个月,RLX组VDR FokⅠ FF基因型者(n=8)全髋部和大转子BMD值平均下降各为1.98%±4.86%和2.26%±4.73%,而Ff/ff基因型者(n=21)平均增加各为2.52%±2.75%和2.74%±2.97%(P<0.05);ESR1 PvuⅡ位点PP/Pp基因型者(n=17)全髋部BMD明显增加(2.12%±2.78%),而pp基因型者(n=12)呈下降(-1.34%±3.73%)(P<0.05).但上述5个位点多态性与安慰剂组各指标变化均无相关性. 结论 RLX对绝经后骨质疏松妇女BMD的作用受VDR基因FokⅠ和ESR1基因PvuⅡ多态性的调节.在临床选择该药物时,可根据应用对象的基因型做有益决策之用.     

Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women

OBJECTIVE: To determine the efficacy of estrogen + progestogen therapy with 1 mg 17beta-estradiol and 0.125 mg trimegestone in the prevention of postmenopausal osteoporosis. DESIGN: For this study, 360 healthy, postmenopausal women with osteopenia [lumbar spine bone mineral density (BMD) between -1.0 and -2.5 SD of the premenopausal mean value] were enrolled in a 2-year prospective, randomized study, and 70% completed. Treatments were 1 mg 17beta-estradiol + 0.125 mg trimegestone (n = 179) or placebo (n = 181), given as daily oral therapy. All received a daily supplement of 500 mg calcium and 400 IU vitamin D. BMD measurements at the lumbar spine, total hip, and femoral neck as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin), serum bone-specific alkaline phosphatase, serum CrossLaps, and urinary CrossLaps took place regularly. RESULTS: BMD increases relative to placebo were 6.3%, 3.9%, and 3.8% at the lumbar spine, total hip, and femoral neck, respectively (all P < 0.001). The biochemical markers of bone turnover were suppressed accordingly. Serum CrossLaps and urinary CrossLaps decreased rapidly, by 52% and 54%, respectively, whereas serum osteocalcin and serum bone-specific alkaline phosphatase revealed a more retarded decrease of 40% and 33%, respectively. Of the women receiving hormone therapy, 75% had amenorrhea from the first cycle, and 5% withdrew prematurely due to metrorrhagia or mastalgia. CONCLUSION: This new estrogen + progestogen therapy is efficient in increasing BMD in an osteopenic postmenopausal population. Furthermore, it is well tolerated, with few adverse events and an early bleeding control, which is likely to improve compliance to the treatment over the long term.     

Effect of raloxifene and clodronate on bone density in postmenopausal osteoporotic women

The aim of the present study was to determine the safety and efficacy of combined therapy with raloxifene (RLX) and clodronate (CLD) in postmenopausal women. We enrolled 45 women with postmenopausal osteoporosis. The patients were randomly assigned to two different therapeutic groups: RLX 60 mg/day (n = 23) and RLX 60 mg/day plus CLD 100 mg intramuscularly (i.m.) once every 10 days (n = 22); 1 g of calcium and 800 IU of vitamin D3 were also given daily to both groups. Lumbar and femoral bone mineral density (BMD) were assessed at baseline and after 12 months of therapy using the dual X-ray absorptiometry technique (Norland XR36). We measured the bone turnover markers NTx and CTx, bone alkaline phosphatase (BAP) and osteocalcin at baseline and after 12 months of therapy. Our data demonstrate that 1 year of combined RLX+CLD therapy induced a higher increase in lumbar BMD than treatment with RLX alone as well as a major decrease in bone resorption markers, suggesting an additive effect of CLD on bone mass and inhibition of bone turnover. Furthermore, after 1 year of therapy levels of bone formation markers (osteocalcin and BAP) had increased in both groups, but the increase in osteocalcin and BAP was significantly higher in the RLX+CLD treated group, suggesting that, in addition to its inhibitory effects on resorption, CLD might also have stimulatory effects on mature osteoblast activity.     

Relationship between PTH,sex steroid and bone turnover marker measurements and bone density in recently postmenopausal women

OBJECTIVE: It is conceivable that, since menopause accelerates the continuous bone loss determined by age, a specific configuration of bone mass determinants during the first postmenopausal years occurs. METHODS: To establish their value as indicators of bone mass in women with recent natural menopause, we assessed relationships between bone mineral density (BMD) and age, menopausal age, body mass index (BMI), PTH, sex steroid hormones (estradiol and testosterone), and several markers of bone turnover in urine (N-telopeptide and calcium/creatinine ratio) or serum (osteocalcin (OC), total alkaline phosphatase (ALP), total and ionic calcium (iCa), phosphate (P) and magnesium (Mg)) for a group of 118 women (mean of three measurements per subject) attending a third-level menopause unit. Multivariate analysis was used in addition to Pearson's correlation to detect relationships between variables. RESULTS: Several significant associations were detected between variables under Pearson's correlation analysis, but only a few were confirmed under multivariate analysis. Thus, among the clinical traits, age was the main predictor of BMD for femoral neck (P<0.05). Estradiol (E(2)) was the only parameter that attained significance as a predictor for lumbar spine BMD (P<0.05), whereas PTH and NTx levels emerged as predictors of BMD for femoral neck (P<0.05). CONCLUSION: In this group of recently postmenopausal women, hormonal status, as defined by E(2) and PTH, and a resorption marker (NTx), revealed, together with age, as the only significant predictors of BMD.     

Effects of nandrolone decanoate on bone mass in established osteoporosis

A double-blind, randomized, placebo-controlled study was conducted in 46 postmenopausal women with established osteoporosis in order to assess the long-term effects of nandrolone decanoate on the bone mineral density (BMD) of the lumbar vertebrae and of the distal third of the radius and on the biochemical markers of bone turnover. The patients received intramuscular injections of placebo or 50 mg nandrolone decanoate every 3 weeks for 18 months. Thirty-two of the initial 46 patients completed 1 year of study and 25 completed the whole study period of 18 months. Overall, vertebral BMD increased by 2.9% in the nandrolone decanoate group and fell by 2.3% in the placebo group. Radial BMD showed a slight but transient improvement, with a subsequent return to basal levels in the nandrolone decanoate group, whereas there was a progressive decrease in the placebo group. Patients treated with nandrolone decanoate also complained less of bone pain. Urinary hydroxyproline decreased significantly in treated patients, whereas osteocalcin tended to increase, but the change was not significant. HDL cholesterol concentrations decreased only slightly and haemoglobin increased significantly in the nandrolone decanoate group. Two patients treated with nandrolone decanoate withdrew from the study because of hirsutism and hoarseness. The results indicate that nandrolone decanoate exerts positive effects on vertebral BMD and on bone pain in patients with established postmenopausal osteoporosis.     

Comparison of effect of treatment with etidronate and alendronate on lumbar bone mineral density in elderly women with osteoporosis

The purpose of this open-labeled prospective study was to compare the treatment effects of cyclical etidronate and alendronate on the lumbar bone mineral density (BMD), bone resorption, and back pain in elderly women with osteoporosis. Fifty postmenopausal women with osteoporosis, age ranging from 55 to 86 years (mean: 70.7 years), were randomly divided into two groups with 25 patients in each group: the cyclical etidronate group (etidronate 200 mg daily for 2 weeks every 3 months) and the alendronate group (5 mg daily). The BMD of the lumbar spine (L1-L4) measured by DXA, the urinary cross-linked N-terminal telopeptides of type I collagen (NTX) level measured by the enzyme-linked immunosorbent assay, and back pain evaluated by the face scale score were assessed at baseline, 6 months, and 12 months. There were no significant differences in baseline characteristics including age, body mass index, years since menopause, lumbar BMD, urinary NTX level, and face scale score between the two treatment groups. Etidronate treatment sustained the lumbar BMD following a reduction in the urinary NTX level and improved back pain, while alendronate treatment reduced the urinary NTX level more significantly, resulting in an increase in the lumbar BMD, and similarly improved back pain. No serious adverse events were observed in either group. This study confirmed that alendronate treatment had a greater efficacy than etidronate treatment in increasing the lumbar BMD through the reduction of bone resorption in elderly women with osteoporosis.     

The effect of continuous oestradiol with intermittent norgestimate on bone mineral density and bone turnover in post-menopausal women

OBJECTIVE: To assess in post-menopausal women the efficacy and tolerability of a continuous oestradiol/intermittent norgestimate HRT regimen to prevent and to reverse post-menopausal loss of bone mineral density (BMD) and to determine the effects on serum bone turnover markers markers. METHODS: A 1-year, multicentre, international, placebo-controlled, randomised, double-blind clinical trial was conducted in 146 post-menopausal women with an intact uterus in order to assess the effect on bone loss of continuous oral 17beta-oestradiol (1 mg per day) combined with norgestimate (90 microg per day), for 3 consecutive days out of every 6-day treatment period (E2/iNGM). During a second year extension, all women agreeing to continue were on the E2/iNGM regimen. BMD was assessed prior to treatment and after 1 and 2 years or at the end of treatment in women stopping participation prematurely after at least 6 months of treatment. Serum bone turnover markers were determined prior to and at 1 year of treatment Adverse events were collected at three-monthly intervals during clinic visits over the treatment period. RESULTS: BMD in the lumbar spine, the primary endpoint, was evaluable in 117 subjects completing >6 months of treatment. BMD increased on average by 2.4% in women on the intermittent progestin regimen. It decreased by 1.4% in placebo treated women. The change from baseline and the difference between active and placebo treatment (Delta placebo) were highly significant (P < 0.0001). On E2/iNGM, also the BMD in the total hip increased (+1.49%, Delta placebo 3.73%, P < 0.0001). The serum markers for bone formation osteocalcin and type I collagen N-propeptide were significantly reduced compared to baseline by 31 and 44%, respectively and the bone resorption marker C-terminal crosslinked telopeptide of type I collagen by 59%. Minor increases (<10%) of markers in the placebo group were not significant. During a second year extension of the trial, all subjects were on active treatment. Subjects on placebo who lost (median+/-CI 95%) 0.66% (-2.3 to +0.5) of spine BMD during the first year now gained 4.41% (2.7-7.6). They also gained 1.6% (0.1-0.3.6) in the total hip. Subjects continuously on oestradiol/intermittent norgestimate (E2/iNGM) gained an additional 5.7% (2.3-13.5) in the lumbar spine and +0.1% (-0.6 to +2.2) at the total hip. Side effects reported by women on the intermittent progestin regimen significantly in excess over reports from the placebo group were uterine bleeding, abdominal and breast pain, but not headache. Back pain and weight gain was reported by significantly fewer women on active treatment compared to placebo. CONCLUSION: The continuous oestradiol/intermittent norgestimate HRT regimen is well tolerated, reduces bone turnover and prevents post-menopausal bone loss in healthy post-menopausal women.     

Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women

OBJECTIVES: The aim of the present study was to evaluate the effects of low doses of hormone replacement therapy (HRT) in normal young postmenopausal women. METHODS: In an open trial healthy, non-obese postmenopausal women received for 2 years a low-dose continuous combined HRT (LD-HRT) containing 1mg estradiol+0.5 mg norethisterone acetate each pill for 28 days, or 0.5 mg of 17beta-estradiol and 0.25 mg of norethisterone acetate (Ultra low dose, Ultra-LD-HRT) along with 1000 mg of calcium per day. Control group consisted of women receiving only 1000 mg of calcium per day, for 2 years. Menopausal symptoms were evaluated by the Green climacteric scale for the first 12 weeks of the study while bleeding profiles, bone mineral density (BMD) and bone turnover were assessed for 24 months. RESULTS: LD-HRT and Ultra-LD-HRT were effective in reducing menopausal clinical symptoms. In the control group, BMD significantly (P<0.05) decreased at the spine (-2.8+/-0.2%), and femoral neck (-2.8+/-0.7%). In LD-HRT treated group BMD showed a significant (P<0.05) increase at the spine (5.2+/-0.7%), and femoral neck (2.8+/-0.4%) after 24 months. In the Ultra-LD-HRT treated women spine and femoral neck BMD showed a significant (P<0.05) increase (2.0+/-0.3 and 1.8+/-0.3%, respectively) after 24 months. In these women treated with LD-HRT and Ultra-LD-HRT the BMD values were significantly (P<0.05) different from those measured in calcium-treated women. CONCLUSIONS: LD-HRT and Ultra-LD-HRT can alleviate subjective symptoms providing an effective protection against the postmenopausal decrease of BMD.     

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene

OBJECTIVE: Osteoporosis is a significant health problem in postmenopausal women. Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women. The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women. DESIGN: A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted. Women included 410 postmenopausal women aged 47 to 74 years. The four treatment groups were: lasofoxifene 0.25 mg/day, or 1.0 mg/day, raloxifene 60 mg/day, or placebo daily. All women received daily calcium and vitamin D supplements. The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement. Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women. RESULTS: Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P < or = 0.05) and with placebo treatment (P < or = 0.05). Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene. The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD. Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo. In general, the effects of lasofoxifene were greater than the responses to raloxifene. At 2 years, lasofoxifene significantly (P < or = 0.05) reduced low-density lipoprotein cholesterol levels by 20.6% and 19.7% with 0.25 mg/day and 1 mg/day, respectively, compared with raloxifene (12.1%) and placebo (3.2%). Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events. CONCLUSIONS: Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women.     

Bisphosphonates for prevention of postmenopausal osteoporosis

Our studies showed that 5 mg alendronate per day was the lowest, most effective dose that persistently prevented bone loss in recently postmenopausal women with normal bone mass. The effect on bone mass and biochemical markers was found comparable to that of commonly recommended regimens of postmenopausal HRT, and 5 mg alendronate per day is suggested as a new option for prevention of postmenopausal osteoporosis. HRT must, however, still be considered the first choice for this indication because of additional beneficial effects on other organ systems. The effect of alendronate was unaffected by bone or fat mass status, but increased with increasing postmenopausal age. The implications were that alendronate stabilized bone mass to a comparable extent in women at particular risk of osteoporosis because of thin body habitus or low bone mass and in healthy postmenopausal women with normal bone mass. Calcium supplementation was insufficient to prevent bone loss and did not add an effect on bone metabolism when combined with alendronate treatment in recently postmenopausal women. The gastrointestinal risk and adverse event profile of 5 mg alendronate per day was comparable to that of placebo, and this dose of alendronate appeared safe for long-term use. Bone loss resumed at a normal postmenopausal rate promptly after withdrawal of alendronate in early postmenopausal women consistent with a substantial underlying natural bone loss during early menopause. Oral ibandronate increased bone mass at all skeletal regions in elderly postmenopausal women with low bone mass, and 2.5 mg ibandronate per day was the lowest dose with this effect. The results are indicative of ibandronate as an option for secondary prevention of postmenopausal osteoporosis, but longer-term phase III trials should be performed before ibandronate can be recommended for this indication. The study showed that 2.5 mg ibandronate per day was efficient for prevention of bone loss and increment in bone mass in a population of women at particular risk of osteoporosis because of low bone mass. There were no differences between 2.5 mg ibandronate per day and placebo in terms of side effects, including complaints from the gastrointestinal tract, and ibandronate appeared safe for longer-term use in this dosing. Bone loss resumed at a normal postmenopausal rate when treatment was withdrawn. The response in bone mass and biochemical markers indicated that 2.5 mg ibandronate per day is equivalent to 10 mg alendronate per day in postmenopausal women. Our studies of two recently developed biochemical markers, urine CTX and serum total OC, showed that bone turnover was lowest in the premenopausal period, where these biochemical markers furthermore revealed a negative association with bone mass. It indicated that increased bone turnover contributes to a small premenopausal bone loss and resulting lowered bone mass. In consistence, a small premenopausal bone loss was observed in some regions of the hip. The biochemical markers increased at the time of menopause, consistent with initiation of the postmenopausal bone loss, and became gradually more negatively associated with bone mass as time past the menopause increased. The biochemical markers were furthermore higher in postmenopausal women with low bone mass, consistent with the characterization of postmenopausal osteoporosis as a condition with increased bone turnover. Our results consistently indicated a central role of increased bone turnover for development of low bone mass and osteoporosis. It is, however, also important to stress that the associations between biochemical markers and bone mass were too weak to allow for a valid individual estimation of bone mass based on biochemical markers. In contrast, the biochemical markers were shown as valid tools for monitoring and prediction of treatment effect of bisphosphonates. CTX, NTX, and total OC revealed the best performance characteristics in this respect. Six months after start of treatment, the level of suppression of these biochemical markers of bone resorption and formation accurately reflected the size of the 1-2 year response in bone mass in groups of women treated with bisphosphonate. This was a clear advance over bone densitometry, which has a precision error in the area of the anticipated yearly bone mass response during bisphosphonate therapy. The relationship was consistent during treatment with alendronate or ibandronate and in younger or elderly postmenopausal women. In individual patients, cut-off values of an about 40% decrease in urine CTX or NTX and an about 20% decrease in total OC validly predicted long-term prevention of bone loss. The sensitivity of prediction was high, but the specificity low. This implicated that the biochemical markers could be used as an exact method to detect "responders" to therapy, whereas "non-responders" to bisphosphonate treatment should be detected with bone densitometry in patients who do not reveal a decrease below the cut-off value in the biochemical marker during treatment. However, before such approach can be generally recommended the cut-off values of the biochemical markers should be validated in future clinical trials of bisphosphonate. Postmenopausal osteoporosis develops slowly over many years and mainly becomes a significant individual and socio-economic health problem 1-3 decades after the menopause. Prevention of postmenopausal osteoporosis by bisphosphonates is therefore likely to imply a treatment regimen of at least a decade, as presently recommended for HRT (Consensus Development Statement 1997). However, future cost-effectiveness studies should reveal when bisphosphonate treatment should ideally be initiated. Our studies showed that the bisphosphonates were effective over the range from general recommendation (recently postmenopausal women with normal bone mass) to a reservation for women at particular risk of osteoporosis (elderly women, thin women, or women with osteopenia). Presently available biochemical markers could be used for groupwise and individual monitoring and prediction of treatment response. Most presently available biochemical markers, however, have the drawback of a low specificity. Recent studies of CTX measured in serum are promising, and indicate that this new biochemical marker might have overcome these drawbacks due to a pronounced response to treatment and a low long-term biological variation (Christgau et al. 1998b, Rosen et al. 1998, and 2000).     

Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women. FOSIT-Study-Group. Fosamax International Trial

OBJECTIVES: To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. METHODS: This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients < or = 85-year-old with osteoporosis (lumbar spinal BMD > or = 2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. RESULTS: A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P < 0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P < 0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. CONCLUSIONS: Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis.     

Peripheral quantitative computed tomography (pQCT) is useful for monitoring bone mineral density of the patients who receive hormone replacement therapy

OBJECTIVE: A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS: Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS: The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION: Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.     

Decrease of bone formation in adult women with fragility fractures

Objectives: To compare bone mineral density (BMD) and some markers of bone metabolism in women with fragility fractures and in normal age-matched subjects. Methods: A 100 women with at least one vertebral deformity >25%, and 219 age-, BMI- and parity-matched healthy women, were recruited for the study. In all the patients fractures were symptomatic and occurred at least 1 year before densitometric measurement. Forearm bone mineral density (BMD) as well as biochemical assessment of some markers of bone turnover were measured in all the subjects. Results: BMD was significantly lower in the fracture than in the control group (0.326 ± 0.073 vs. 0.379 ± 0.079; P<0.001). Fractured women showed alkaline phosphatase (ALP) and osteocalcin (OC) serum levels significantly lower than controls, while no differences were found in fasting urinary calcium and hydroxyproline excretion. Women without fractures showed a significant correlation between ALP and both age and years since menopause (YSM). Such a correlation is lacking in the fracture group. Conclusions: Women with vertebral deformities likely due to a fracture had a forearm BMD and markers of bone formation lower than normal. Whether low bone density is due to a low peak of bone mass or to an increased postmenopausal bone loss sustained by an uncoupling between the two bone remodelling processes is still unclear.     

去势大鼠5种骨转换生化指标的动态变化

目的： 对去势大鼠骨质疏松动物模型形成过程中5种骨转换指标的变化及其相关性进行研究。方法: 将3月龄SD雌性大鼠分为3组：切除卵巢组(OVX)，假手术组(sham)和对照组(control)，术前和术后分别于1、1.5、2、2.5、3和4月检测血清骨钙素(OC)、碱性磷酸酶(ALP)、 骨碱性磷酸酶(BALP)、抗酒石酸酸性磷酸酶(TRAP)和羟脯氨酸(HYP)水平，并作大鼠胫骨病理切片检查。结果: OVX组血清OC、ALP、BALP、TRAP和HYP水平均明显高于sham组，其变化顺序依次为：TRAP/HYP→OC→ALP/BALP；5种指标之间呈显著正相关；术后3月OVX组大鼠胫骨小梁结构有病理改变。结论: 去势大鼠属于高转换型骨质疏松；在模型形成过程中，骨吸收指标的变化早于骨形成指标的改变；骨转换指标是反映绝经后早期骨量丢失的灵敏指标。     

Spotlight on Denosumab in Postmenopausal Osteoporosis

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.     

Effect of physical activity on bone turnover in young boys

AIMS: To evaluate the effect of the physical activity on bone turnover in young male soccer players at the Tanner's stage of 1-2. MATERIAL AND METHODS: 61 young soccer players (13,4 +/- 0,3 years old) who actively participated in soccer since 3,7 +/- 0,7 years were compared to 60 age and sex- matched non active subjects. Bone mineral density (BMD) of whole body, and in specific skeleton sites, fatty body mass (FBM) and lean body mass (LBM) were determined by a dual energy X-ray absorptiometry (DXA). Total plasma alkaline phosphatase (ALP) and plasma bone alkaline phosphatase (BALP), plasma osteocalcin (OC) and plasma collagen type I cross-linked C-telopeptide (CTX) were measured. RESULTS: BMD of the whole body and at the lumbar spine (L2-L4), femoral, lower limbs and LBM were significantly higher in young soccer players than in controls. The biochemical markers of bone turnover: ALP (6,7%), BALP (8,9%), OC (3%) and CTX (3,1%) were not significantly higher in sportsmen than in controls. The calcium was significantly higher in sportsmen than in controls. CONCLUSION: These results suggest that soccer practice induced an increase of bone mass in boys. The increase in the level of bone turnover evaluated by the new biochemical markers was not significant in the sportsmen.     

Calcitriol and alendronate combination treatment in menopausal women with low bone mass

Serum calcitriol levels decrease with advancing age in relation to reduced dietary intake or poor intestinal absorption of vitamin D. These decreased levels affect the development of senile osteopenia, which can be effectively prevented by the administration of alendronate and calcium. To evaluate the effect of a combined treatment with alendronate and calcitriol on bone mineral density (BMD), we followed 152 osteopenic postmenopausal women, aged 55-75 years, for 9 months. They were divided into three groups. The first group was treated every other day with 0.25 microgram of synthetic 1,25-dihydroxyvitamin D3 plus 10 mg alendronate. The second group received the same dose of alendronate plus calcium (500 mg/day). The third group received only calcium (500 mg/day). BMD measurements were made at the level of the lumbar spine and the femoral neck. At the beginning and at the end of the period of treatment the same biochemical analyses of bone metabolism were made. There were no significant differences in the baseline values of the three groups in the biological parameters. Alendronate plus calcium treatment led to a significant reduction in total alkaline phosphatase and hydroxy prolinuria as well as to a significant increase in lumbar and femoral bone density. The same changes were observed in the group treated with alendronate plus calcitriol except that femoral BMD did not significantly improve. These results show that continuous treatment for 9 months with calcitriol or calcium in combination with alendronate significantly increases both vertebral and femoral neck density (from 3.8% to 4.5% and from 0.61% to 2.36% respectively) in osteopenic postmenopausal women. The effects of both combinations on bone mass are clearly greater than those achieved by calcium monotherapy.