Effect of teriparatide [rhPTH(1-34)] on BMD when given to postmenopausal women receiving hormone replacement therapy.

The effects of teriparatide when given in combination with HRT were studied in postmenopausal women with low bone mass or osteoporosis. The data provide evidence that the adverse event profile for combination therapy with teriparatide + HRT together is consistent with that expected for each treatment alone and that the BMD response is greater than for HRT alone. INTRODUCTION: Teriparatide [rhPTH(1-34)], given as a once-daily injection, activates new bone formation in patients with osteoporosis. Hormone replacement therapy (HRT) prevents osteoporosis by reducing bone resorption and formation. Combination therapy with these two compounds, in small clinical trials, increased BMD and reduced vertebral fracture burden. The purpose of this study was to determine whether teriparatide provided additional effect on BMD when given in combination with HRT. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study was conducted in postmenopausal women with either low bone mass or osteoporosis. Patients were randomized to placebo subcutaneous plus HRT (n = 125) or teriparatide 40 microg/day (SC) plus HRT (TPTD40 + HRT; n = 122) for a median treatment exposure of 13.8 months. Approximately one-half of the patients in each group were pretreated with HRT for at least 12 months before randomization. Patients received 1000 mg calcium and 400-1200 IU of vitamin D daily as oral supplementation. BMD was measured by DXA. RESULTS: Compared with HRT alone, TPTD40 + HRT produced significant (p < 0.001) increases in spine BMD (14% versus 3%), total hip (5.2% versus 1.6%), and femoral neck (5.2% versus 2%) at study endpoint. BMD, in whole body and ultradistal radius, was higher, and in the one-third distal radius was lower, in the combination therapy but not in the HRT group. Serum bone-specific alkaline phosphatase and urinary N-telopeptide/Cr were increased significantly (p < 0.01) in the women receiving TPTD40 + HRT compared with HRT. A similar profile of BMD and bone markers was evident in both randomized patients as well as in subgroups of patients not pretreated or pretreated with HRT. Patients tolerated both the treatments well. Nausea and leg cramps were more frequently reported in the TPTD40 + HRT group. CONCLUSIONS: Adding teriparatide, a bone formation agent, to HRT, an antiresorptive agent, provides additional increases in BMD beyond that provided by HRT alone. The adverse effects of teriparatide when added to HRT were similar to the adverse effects described for teriparatide administered alone. Whether teriparatide was initiated at the same time as HRT or after at least 1 year on HRT, the incremental increases over HRT alone were similar.     

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.     

Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate.

We investigated the effects of 18 months of treatment with teriparatide in patients previously treated with long-term antiresorptive therapy using bone turnover markers and bone densitometry. Previous raloxifene treatment allowed for teriparatide-induced early bone marker and BMD increases comparable with previously published results for treatment-n?ive patients. Conversely, previous alendronate treatment reduced the bone marker and BMD response. INTRODUCTION: Teriparatide [rhPTH(1-34)] has been shown to increase BMD and reduce the risk of fracture in postmenopausal women with osteoporosis. Our objective was to investigate the skeletal effects of 18 months of treatment with teriparatide in women whose osteoporosis was previously treated with either alendronate or raloxifene. MATERIALS AND METHODS: Daily subcutaneous injections of 20 microg teriparatide were administered for 18 months to 59 postmenopausal women, 60-87 years of age, with BMD T-scores 相似文献   

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1–34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1‐year multicenter, multinational, randomized, partial double‐blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual‐energy X‐ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total‐hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52‐week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N‐terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β‐C‐telopeptide of type I collagen [β‐CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA‐based BMD (e.g., quantitative computed tomography and finite‐element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. © 2011 American Society for Bone and Mineral Research.     

Effects of raloxifene on bone metabolism and serum lipids in postmenopausal women on chronic hemodialysis

BACKGROUND: Premature amenorrhea and hypoestrogenism and lack of hormone replacement therapy after menopause have been frequently reported in uremic women on dialysis. Therefore, in addition to renal osteodystrophy, postmenopausal women on dialysis could be at risk of osteoporosis. In addition, these patients are at higher risk for hyperlipidemia, arteriosclerosis, and subsequent coronary heart disease and stroke. Recent evidence has suggested that hormone replacement therapy (HRT) in postmenopausal women could have several beneficial effects as well as potentially serious risks. Great efforts have been made to identify therapeutic alternatives that would have the benefits of estrogen on brain and bone without its adverse effects on breast and endometrium. In the present study, we evaluated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on bone metabolism and serum lipids in postmenopausal women on chronic hemodialysis. METHODS: We performed a prospective, blind, placebo-controlled, and randomized study. Fifty postmenopausal women on chronic hemodialysis with proven severe osteopenia or osteoporosis by bone densitometry were selected. After a written informed consent, patients were randomized into two groups: 25 women on placebo and 25 women on the study drug, raloxifene hydrochloride, at a dose of 60 mg/day. In all patients, we performed a baseline bone mineral density (BMD) analysis and simultaneously evaluated different biochemical parameters, serum lipids (total low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol and triglycerides) and serum markers of bone resorption (pyridinoline crosslinks). BMD was reassessed after 1 year of therapy. Bone resorption markers were determined every 3 months for 1 year. RESULTS: After 1 year on raloxifene therapy, lumbar spine BMD (trabecular bone) significantly improved, whereas femoral neck BMD (cortical bone) did not change significantly. No changes in BMD were observed at trabecular or cortical sites in the placebo group. Serum pyridinoline levels showed a significant decrease after 6 months on raloxifene that persisted thereafter. Low-density lipoprotein (LDL)-cholesterol decreased significantly in the raloxifene group with no changes in serum triglycerides, total cholesterol, or HDL cholesterol. No significant side effects were observed in the raloxifene group. CONCLUSION: The study demonstrates that after one year on raloxifene, postmenopausal women on hemodialysis have a significant increase in trabecular BMD, decrease in bone resorption markers and LDL-cholesterol values, suggesting that SERMs could constitute a therapeutic alternative to improve bone metabolism and control of hyperlipidemia in these patients. The possible long-term effects of raloxifene remain to be determined.     

坤泰胶囊辅助治疗对绝经后骨质疏松症妇女骨密度、骨代谢和激素水平的影响

目的探讨坤泰胶囊辅助治疗对绝经后骨质疏松症患者骨密度、激素水平和骨代谢的影响。方法 150例绝经后骨质疏松症患者被随机分为治疗组、联合治疗组和对照组,每组50例。治疗组给予雷洛昔芬,联合治疗组给予雷洛昔芬加坤泰胶囊治疗,治疗12个月。检测治疗后两组患者髋部及腰椎的骨密度(bone mineral density,BMD)改变,同时测定血清雌二醇(estradiol,E2)、黄体生成素(luteinizing hormone,LH)、促卵泡剌激素(follicle stimulating hormone,FSH)、骨钙素(OC)和I型胶原交联C-末端肽(CTX-1)的水平,并记录治疗期间出现的药物不良反应。结果对照组的腰椎和髋部BMD在1年后较基线时有不同程度降低,比较差异有统计学意义(P0. 05);治疗1年后,治疗组和联合治疗组髋部及腰椎BMD都有不同程度的升高,且组间比较差异有明显的统计学意义(P0. 05);同时治疗组和联合治疗组血清CTX-1水平均降低,OC水平均升高,两组比较有明显的统计学意义(P0. 05);各组血清FSH和LH水平均降低,E2水平升高,两组比较有明显的统计学意义(P0. 05)。两组患者治疗时均未发现明显药物不良反应。结论坤泰胶囊辅助治疗有助于降低骨转换率,改善性激素水平,改善绝经后女性骨质疏松患者髋部及腰部的骨密度。     

Effect of prior and ongoing raloxifene therapy on response to PTH and maintenance of BMD after PTH therapy

Summary Women with osteoporosis on raloxifene were randomized to 1-34hPTH + raloxifene or raloxifene alone for one year. In the PTH + raloxifene group, bone turnover increased 125–584%, spine BMD increased 9.6%, hip BMD increased 1.2–3.6% and radius BMD declined 4.3%. During the follow-up year, on continued raloxifene, BMD declined slightly at all sites except the femoral neck. Introduction The influence of prior antiresorptives on response to 1–34PTH and the ability to maintain BMD gains might differ for antiresorptive agents with different potencies. The objectives were to evaluate biochemical and bone density responses to 1–34PTH in patients on prior and ongoing raloxifene and to determine whether raloxifene maintains bone gains. Methods Forty-two postmenopausal women with osteoporosis on raloxifene were randomized to raloxifene alone or 1–34PTH daily for 12 months (continuing raloxifene). Women were then followed for 12 months on raloxifene alone. Bone turnover markers and BMD were measured at baseline and at 3, 6, 12, 18 and 24 months. Results Biochemical indices increased rapidly during PTH treatment with peak increments of 125–584% for the three markers (p < 0.001 vs. baseline). After one year of PTH, mean BMD increases were 9.6% for spine, 2.7% for total hip, 3.6% for trochanter (all p < 0.005) and 1.2% in femoral neck (NS), while BMD declined 4.3% in the radius (p = 0.003). After PTH withdrawal, on continued raloxifene, BMD declined slightly (0.7–2.9% losses; NS) at all sites, except the femoral neck, where BMD increased modestly (p = 0.04). At 24 months, spine and femoral neck BMD remained significantly higher than baseline, while radius BMD remained significantly lower (all p < 0.04). Conclusion Substantial gains in BMD of the spine and hip, but not the radius, are seen with one year of PTH treatment in patients on prior raloxifene. After PTH is discontinued, raloxifene partially maintains PTH-induced BMD gains in the spine and hip.     

Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial.

Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis. In this 24-month study, we report changes in bone turnover and bone mass after 12 months of daily injections of human parathyroid hormone 1-34 [hPTH(1-34)] and 12 months off treatment in postmenopausal women (mean age, 63 years) with osteoporosis treated with glucocorticoid and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy X-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SEM) change in BMD of the lumbar spine by QCT and DXA in the PTH group at 24 months was 45.9+/-6.4% and 12.6+/-2.2% (p < 0.001). The change in total hip and femoral neck BMD was not significant at 12 months but increased to 4.7+/-0.9% (p < 0.01) and 5.2+/-1.3% at 24 months, respectively, as compared with a relatively small change of 1.3+/-0.9% and 2.6+/-1.7% in the estrogen-only group. The mean percent differences in BMD of the lumbar spine by QCT and DXA between the groups at 24 months were 43.1% and 11.9%, respectively (p < 0.001). The mean percent differences over the estrogen-only group in hip BMD were 3.4% for total hip (p < 0.01) and 2.6% for femoral neck at 24 months. Biochemical markers of bone turnover increased to more than 150% during the first 6 months of therapy, remained elevated throughout the 12-month treatment period, and returned to baseline values within 6 months of discontinuing the PTH treatment. These results suggest that PTH dramatically increases bone mass in the lumbar spine and hip in postmenopausal women with glucocorticoid-induced osteoporosis who are taking hormone replacement therapy. However, the maximum effect of this anabolic agent on bone mass at the hip after 12 months of treatment requires at least 6-12 months after the PTH treatment is discontinued.     

Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene

Many postmenopausal women treated with teriparatide for osteoporosis have previously received antiresorptive therapy. In women treated with alendronate (ALN) or raloxifene (RLX), adding versus switching to teriparatide produced different responses in areal bone mineral density (aBMD) and biochemistry; the effects of these approaches on volumetric BMD (vBMD) and bone strength are unknown. In this study, postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months were randomly assigned to add or switch to teriparatide 20 µg/day. Quantitative computed tomography scans were performed at baseline, 6 months, and 18 months to assess changes in vBMD; strength was estimated by nonlinear finite element analysis. A statistical plan specifying analyses was approved before assessments were completed. At the spine, median vBMD and strength increased from baseline in all groups (13.2% to 17.5%, p < 0.01); there were no significant differences between the Add and Switch groups. In the RLX stratum, hip vBMD and strength increased at 6 and 18 months in the Add group but only at 18 months in the Switch group (Strength, Month 18: 2.7% Add group, p < 0.01 and 3.4% Switch group, p < 0.05). In the ALN stratum, hip vBMD increased in the Add but not in the Switch group (0.9% versus –0.5% at 6 months and 2.2% versus 0.0% at 18 months, both p ≤ 0.004 group difference). At 18 months, hip strength increased in the Add group (2.7%, p < 0.01) but not in the Switch group (0%); however, the difference between groups was not significant (p = 0.076). Adding or switching to teriparatide conferred similar benefits on spine strength in postmenopausal women with osteoporosis pretreated with ALN or RLX. Increases in hip strength were more variable. In RLX‐treated women, strength increased more quickly in the Add group; in ALN‐treated women, a significant increase in strength compared with baseline was seen only in the Add group.     

Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women

SUMMARY: A randomized trial was conducted in osteopenic postmenopausal women to compare the efficacy of tibolone versus raloxifene on BMD of the lumbar spine and hip. Tibolone increased lumbar spine and total hip BMD to a statistically significantly greater extent than raloxifene after two years of treatment. INTRODUCTION: Both tibolone, a selective tissue estrogenic activity regulator (STEAR), and raloxifene, a selective estrogen receptor modulator (SERM), are known to prevent postmenopausal bone loss. However, no head-to-head studies to compare the efficacy on bone have been performed. METHODS: A double-blind, randomized trial was conducted in osteopenic postmenopausal women aged 60-79 years to compare the effects of tibolone 1.25 mg/day to raloxifene 60 mg/day on bone mineral density (BMD). Serum osteocalcin and serum type I collagen C-telopeptides were measured as biochemical markers of bone metabolism. RESULTS: Three hundred and eight subjects were allocated to treatment. Both treatments significantly increased lumbar spine BMD, however the increase was significantly larger after tibolone treatment than after raloxifene treatment (at year 1: 2.2% versus 1.2%, p<0.01 and at year 2: 3.8% versus 2.1%, p<0.001). After 2 years of treatment, the increase in total hip BMD in the tibolone group was significantly larger than in the raloxifene group (p<0.05). Both treatments significantly reduced type I collagen C-telopeptides and osteocalcin levels when compared to baseline. CONCLUSIONS: Tibolone 1.25 mg/day for 2 years prevents postmenopausal bone loss in older women and results in a larger increase of BMD both at the lumbar spine and hip than raloxifene.     

Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis.

The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied. Changes in five biochemical markers, obtained from a subset of women enrolled in the Fracture Prevention Trial, were examined. Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis. INTRODUCTION: Early reductions in biochemical markers of bone turnover with antiresorptive therapy negatively correlate with subsequent increases in BMD. We undertook this analysis to determine if early changes in biochemical markers with teriparatide therapy predict subsequent increases in BMD. MATERIALS AND METHODS: In the Fracture Prevention Trial, 1637 postmenopausal women with osteoporosis were randomized to receive daily, self-administered, subcutaneous injections of placebo, teriparatide 20 microg/day, or teriparatide 40 microg/day. Serum concentrations of two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and the carboxy-terminal extension peptide of procollagen type 1 [PICP]) and urinary concentrations of two bone resorption markers (free deoxypyridinoline [DPD] and N-terminal telopeptide [NTX]) were assessed in a trial population subset (n = 520) at baseline and at 1, 3, 6, and 12 months. We also assessed serum concentrations of another bone formation marker, the amino-terminal extension peptide of procollagen type 1 (PINP), in a subset of 771 women at baseline and 3 months. Lumbar spine (LS) BMD was measured by DXA at baseline and 18 months. Femoral neck BMD was measured at baseline and 12 months. RESULTS AND CONCLUSION: Baseline bone turnover status correlated positively and significantly with BMD response. The highest correlations occurred for the LS BMD response to teriparatide 20 microg/day. Among all studied biochemical markers, increases in PICP at 1 month and PINP at 3 months correlated best with increases in LS BMD at 18 months (0.65 and 0.61, respectively; p < 0.05). The relationships between these two biochemical markers and the LS BMD response were stronger than the corresponding relationships for the femoral neck BMD response. Using receiver operator curve analysis, we determined that the increases in PICP at 1 month and PINP at 3 months were the most sensitive and accurate predictors of the LS BMD response.     

Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial

Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.     

Estrogen receptor (ER) gene polymorphism may predict the bone mineral density response to raloxifene in postmenopausal women on chronic hemodialysis

The estrogen receptor (ER) gene has been considered as a candidate genetic marker for osteoporosis, and PvuII and XbaI polymorphisms of the ERalpha gene have been associated with low bone mineral density (BMD). We investigated whether ER polymorphism could predict the response of BMD in 28 postmenopausal women on hemodialysis with marked osteopenia or osteoporosis, randomized to receive raloxifene, a selective estrogen receptor modulator (SERM), or placebo for 1 year. BMD was assessed by dual X-ray absorptiometry and PvuII and XbaI restriction fragment-length polymorphism of the ER gene was determined using polymerase chain reaction. Baseline lumbar spine or femoral neck BMD parameters were not different between patients presenting either homozygous PP or xx when compared with heterozygous Pp or Xx genotypes. After 1 year, patients on raloxifene, presenting with PP or xx genotypes (but not those with Pp or Xx), showed a significantly higher mean lumbar spine BMD (0.942 +/- 0.18 vs. 0.925 +/- 0.17 g/cm2, p < .01) and lower serum pyridinoline (19.7 +/- 9.7 vs. 30.6 +/- 16.5 nmol/L, p < .02) when compared with baseline values. No changes were detected in the placebo-treated patients or in the femur neck sites. In conclusion, after 1 year on raloxifene, postmenopausal osteoporotic women on chronic hemodialysis, homozygous for the P or x (PP or xx) alleles of the ER, exhibited a better lumbar spine BMD response and decreased serum pyridinoline values when compared with heterozygous women (Pp or Xx), suggesting that ERalpha allelic variants may explain, at least in part, the different outcomes after treatment of osteoporosis with SERM.     

Selective estrogen receptor modulators in chronic renal failure

BACKGROUND: In addition to renal osteodystrophy, postmenopausal women on dialysis could be at risk of osteoporosis. Hormone replacement therapy (HRT) could have beneficial effects as well as potentially serious risks, especially in uremic women, due to the pharmacokinetics of estradiol in renal failure. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone and serum lipid levels, without its adverse effects on the breast and endometrium, in nonuremic women. METHODS: Recent data on the effect of the SERM raloxifene in bone and lipid metabolism in osteoporotic postmenopausal women on dialysis is reviewed. Since the estrogen receptor (ER) gene has been suggested as a candidate marker for osteoporosis, we investigated whether ER polymorphism could have predicted the BMD response to raloxifene. RESULTS: Hemodialyzed women on raloxifene demonstrated increased trabecular bone mineral density (BMD) and decreased bone resorption markers. Similarly, LDL-cholesterol values dropped significantly. ER gene polymorphism analysis of baseline BMD parameters did not differ between PP/xx or Pp/Xx groups. Nevertheless, patients on raloxifene with PP/xx genotypes, but not those with Pp/Xx, showed a higher trabecular BMD after one year on treatment, suggesting that homozygous women for P or x alleles of the ER have a better BMD response to raloxifene. CONCLUSION: Raloxifene and, most likely, other SERMs, could represent a good alternative to HRT in postmenopausal uremic women.     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

Prevention of bone loss in paraplegics over 2 years with alendronate.

To assess the effects of long-term treatment of bone loss with alendronate in a group of paraplegic men, 55 patients were evaluated in a prospective randomized controlled open label study that was 2 years in duration comparing alendronate and calcium with calcium alone. Bone loss was stopped at all cortical and trabecular infralesional sites (distal tibial epiphysis, tibial diaphysis, total hip) with alendronate 10 mg daily. INTRODUCTION: Bone loss after spinal cord injury (SCI) leads to increased fracture risk in the lower limbs of paraplegics. The aim of this study was to document long-term treatment of bone loss with alendronate in a group of paraplegic men with complete motor lesion after SCI. MATERIALS AND METHODS: Sixty-five men with complete motor post-traumatic medullary lesion between T1 and L2 with total motor and sensory loss (Frankel classification, stage A) or with total motor and partial sensory loss (Frankel classification, stage B) after SCI were included in this prospective randomized controlled open label study that was 2 years in duration. The patients were randomized to either the treatment group with alendronate 10 mg daily and elemental calcium 500 mg daily or to the control group with elemental calcium 500 mg daily alone. The primary endpoint was defined as the effect over 24 months of alendronate and calcium compared with calcium alone on the BMD values at the distal tibial epiphysis (as a surrogate for trabecular bone in the paralyzed zone). The secondary endpoints were changes in BMD at supra- and infralesional sites of measurement. Biochemical markers of bone turnover were assessed. RESULTS: Fifty-five subjects, 0.1-29.5 years post-SCI, completed the study over 24 months. BMD at the distal tibial epiphysis significantly decreased from baseline in the calcium group (-10.8 +/- 2.7% at 24 months, p < 0.001), whereas it remained stable in the alendronate plus calcium group (-2.0 +/- 2.9% at 24 months, p = not significant versus baseline), leading to a significant intergroup difference over time (p = 0.017). At the tibial diaphysis, similar significant results were observed. At the ultradistal radius and the radial shaft, BMD did not change significantly from baseline in either treatment group. At the total hip, BMD decreased significantly in the calcium group (-4.1 +/- 1.6%, p = 0.038) but remained stable in the alendronate plus calcium group (+0.43 +/- 1.2%), with a significant intergroup difference (p = 0.037). At the lumbar spine, BMD increased significantly (p < 0.0001) from baseline in both groups. Biochemical markers of bone resorption were significantly decreased with alendronate versus baseline and control. Alendronate and calcium were generally safe and well tolerated. CONCLUSIONS: In paraplegic men, SCI bone loss was stopped at all measured cortical and trabecular infralesional sites over 24 months with alendronate 10 mg daily.     

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.     

Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism.

In a large proportion of the patients with primary hyperparathyroidism (PHPT), a variable degree of osteopenia is the only relevant manifestation of the disease. Low bone mineral density (BMD) in patients with PHPT is an indication for surgical intervention because successful parathyroidectomy results in a dramatic increase in BMD. However, low BMD values are almost an invariable finding in elderly women with PHPT, who are often either unwilling or considered unfit for surgery. Bisphosphonates are capable of suppressing parathyroid hormone (PTH)-mediated bone resorption and are useful for the prevention and treatment of postmenopausal osteoporosis. In this pilot-controlled study, we investigated the effects of oral treatment with alendronate on BMD and biochemical markers of calcium and bone metabolism in elderly women presenting osteoporosis and mild PHPT. Twenty-six elderly patients aged 67-81 years were randomized for treatment with either oral 10 mg alendronate on alternate-day treatment or no treatment for 2 years. In the control untreated patients a slight significant decrease was observed for total body and femoral neck BMD, without significant changes in biochemical markers of calcium and bone metabolism during the 2 years of observation. Urine deoxypyridinoline (Dpyr) excretion significantly fell within the first month of treatment with alendronate, while serum markers of bone formation alkaline phosphatase and osteocalcin fell more gradually and the decrease became significant only after 3 months of treatment; thereafter all bone turnover markers remained consistently suppressed during alendronate treatment. After 2 years in this group we observed statistically significant increases in BMD at lumbar spine, total hip, and total body (+8.6 +/- 3.0%, +4.8 +/- 3.9%, and +1.2 +/- 1.4% changes vs. baseline mean +/- SD) versus both baseline and control patients. Serum calcium, serum phosphate, and urinary calcium excretion significantly decreased during the first 3-6 months but rose back to the baseline values afterward. Increase in serum PTH level was statistically significant during the first year of treatment. These preliminary results may make alendronate a candidate as a supportive therapy in patients with mild PHPT who are unwilling or are unsuitable for surgery, and for whom osteoporosis is a reason of concern.     

Early changes in biochemical markers of bone turnover and their relationship with bone mineral density changes after 24?months of treatment with teriparatide

Summary

We report the changes in biochemical markers of bone formation during the first 6?months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6?months of treatment.

Introduction

The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24?months of teriparatide.

Methods

We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n?=?181 treatment-na?ve) who had at least one post-baseline bone marker determination. Teriparatide (20 ??g/day) was administered for up to 24?months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6?months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24?months.

Results

Significant increases in formation markers occurred after 1?month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1?month was lower in previously treated versus treatment-na?ve patients, but after 6?months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24?months.

Conclusions

This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs.     

杜仲壮骨胶囊联合雷洛昔芬治疗绝经后骨质疏松症临床研究

目的探索杜仲壮骨胶囊联合雷洛昔芬治疗绝经后骨质疏松症临床疗效。方法 158例绝经后骨质疏松症患者随机分为治疗组(n=79)和对照组(n=79)。对照组给予雷洛昔芬治疗,治疗组给予杜仲壮骨胶囊联合雷洛昔芬治疗,为期治疗12个月。检测治疗前后两组患者股骨颈、腰椎及髋部的骨密度,同时测定血清骨代谢指标:骨碱性磷酸酶(BALP)、I型原胶原N-端前肽(PINP)和血清I型胶原交联C-末端肽(S-CTX)、碱性磷酸酶(ALP)、骨钙素(BGP)的水平,记录两组治疗总有效率和药物不良反应。结果治疗组的治疗总有效率为93.67%,而对照组的为78.48%,两组比较差异有统计学意义(P0.05)。治疗12个月,两组股骨颈、髋部及腰椎密度都有不同程度的升高,其中治疗组骨密度变化更明显,和对照组比较差异有明显的统计学意义(P0.05);同时各组血清S-CTX、PINP和ALP水平均降低,BALP和BGP水平均升高,而治疗组改变更明显,两组比较差异有明显的统计学意义(P0.05)。两组患者药物不良反应比较差异有明显的统计学意义(P0.05)。结论杜仲壮骨胶囊联合雷洛昔芬治疗绝经后骨质疏松症,安全有效,较雷洛昔芬单独治疗效果更佳。