叶酸对去卵巢大鼠骨质疏松的保护作用

目的 探讨叶酸对去卵巢大鼠骨质疏松的保护作用.方法 40只3月龄雌性SD大鼠随机分为5组:假手术组、去卵巢组、乙烯雌酚组(乙烯雌酚0.03 mg·kg-1·d-1)、低剂量叶酸组(叶酸5 mg·kg-1·d-1)、高剂量叶酸组(叶酸20 mg·kg-1·d-1).各组大鼠于术后1周开始灌胃给药,治疗10周,假手术组和去卵巢组给予溶媒灌胃.测定大鼠血浆总同型半胱氨酸(tHcy)浓度,骨匀浆中碱性磷酸酶(ALP)和抗酒石酸酸性磷酸酶(TRACP)的水平;取右股骨和腰5椎体进行骨密度和骨生物力学测定,取腰6椎体和左股骨制备HE切片,观察骨组织的形态学变化.结果 与假手术组比较,去卵巢大鼠血浆tHcy浓度明显升高,腰椎和股骨骨密度显著减低(均P＜0.01),血浆tHcy浓度与腰椎骨密度呈负相关(r=-0.359,P=0.040).叶酸显著降低去卵巢大鼠血浆tHcy浓度(均P＜0.01).大剂量叶酸显著增加去卵巢大鼠骨匀浆ALP水平,降低TRACP水平,增加腰椎和股骨骨密度(均P＜0.01),改善腰椎和股骨的生物力学性能.结论 去卵巢大鼠存在高同型半胱氨酸血症,高同型半胱氨酸参与了去卵巢大鼠骨质疏松的发生.叶酸对去卵巢大鼠骨质疏松具有保护作用,其机制可能与改善同型半胱氨酸的代谢作用有关.

Abstract：

Objective To investigate the protective effect of folic acid(FA) on osteoporosis in ovariectomized(OVX) rats.Methods Forty three-month-old female SD Rats were divided into 5 groups, sham operation group, OVX group, diethylstilbestrol group(0.03mg·kg-1·d-1),low dose FA Group (5 mg·kg-1·d-1),and high dose FA group (20 mg·kg-1·d-1).Gastric gavage in each group was started from one week after being ovariectomized and lasted 10 weeks. Sham operation group and OVX group were treated with solvent. The rats were sacrificed at the end of 10th week after treatment. The total homocysteine(tHcy) in plasma, alkaline phosphatase(ALP), and tartrate-resistant acid phosphatase(TRACP) activity of bone homogenates were measured. The bone mineral density(BMD) and bone biomechanics were determined using L5 vertebrae and right femur. The bone tissue slices were made with L6 vertebrae and left femur and HE stained, and then the histomorphology was observed. Results Compared with sham operation group, plasma tHcy level was significantly increased(P＜0.01), BMD of lumbar vertebrae and femur was remarkedly decreased in OVX group(all P＜0.01). Plasma tHcy concentration was negatively correlated with lumbar BMD(r=-0.359, P=0.040). Plasma tHcy level in both groups treated with folic acid was significantly reduced(all P＜0.01). The ALP concentration in bone homogenates was higher, the TRACP concentration in bone homogenates was lower, and BMD and bone biomechanics of lumbar vertebrae and femur were increased in high dose FA group than those in OVX group(all P ＜0.01). Conclusions In OVX rats hyperhomocysteinemia existed and was involved in the development of osteoporosis. Folic acid could protect OVX rats from osteoporosis, due probably to improved homocysteine metabolism.     

IGF-1对去卵巢大鼠骨密度及骨力学强度的影响

目的 研究外源性胰岛素样生长因子-1(IGF-1)对去卵巢(OVX)骨质疏松大鼠骨密度、骨转换率、骨力学强度等方面的影响.方法 对大鼠施行双侧卵巢摘除术,术后3个月以骨密度测定证实骨质疏松的存在后,随机分为5组,分别以生理盐水、甲状旁腺激素1-34及3种不同剂量IGF-1进行干预.同时设立生理盐水干预的假手术大鼠作为对照.8周后检测血清钙、磷、骨钙素水平及碱性磷酸酶活性;测定腰椎骨密度、股骨力学强度;组织学染色测定股骨远端骨皮质厚度.结果 IGF-1虽未提高OVX大鼠腰椎骨密度却可以显著提高其股骨力学强度.血清学检测结果表明,IGF-1可降低血清钙、磷、骨钙素水平及碱性磷酸酶活性;组织学染色显示IGF-1可显著提高OVX大鼠股骨骨皮质厚度.结论 IGF-1可增加OVX大鼠股骨的力学强度,此作用可能是通过改善骨结构而非提高骨密度所实现的.     

Anabolic therapy for osteoporosis: Parathyroid hormone

Recombinant human parathyroid hormone (PTH 1–34) is the only anabolic agent currently approved for the treatment of osteoporosis. The term anabolic is based on mechanism of action. PTH stimulates bone formation, in contrast to antiresorptive agents, which reduce bone resorption and formation. Recent investigations involving the PTH(1-34) and PTH(1-84) peptides, alone and in combination or sequential regimens with antiresorptive agents, have provided a greater understanding of the place of PTH in the armamentarium against osteoporosis. These studies indicate that adding a bisphosphonate to PTH in previously untreated individuals does not produce additional bone benefit; however, sequential use of PTH followed-up by an antiresorptive agent is highly effective at increasing bone mineral density. Adding PTH after an antiresorptive agent also produces substantial bone density increments, though the magnitude of bone density increase may differ for different antiresorptive agents. PTH can repair underlying micro-architectural defects in bone, improve bone mass substantially, and perhaps change macro-architecture and geometry of bone. There are still many unanswered questions regarding PTH treatment of osteoporosis, including the optimal duration of treatment, optimal dosing regimen, mechanism of resistance to its effect after 18–24 months, and the effect of subsequent rechallenge.     

Bone loss in the oestrogen‐depleted rat is not exacerbated by sitagliptin,either alone or in combination with a thiazolidinedione

Antihyperglycaemic therapy on bone was evaluated in the ovariectomized (OVX), non‐diabetic adult rat. Animals were treated daily for 12 weeks with various doses of sitagliptin, pioglitazone, rosiglitazone, combinations of sitagliptin with pioglitazone or vehicle alone. Sitagliptin target engagement was confirmed by assessing inhibition of plasma dipeptidyl peptidase‐4 (DPP‐4) and oral glucose tolerance. Parameters related to bone health were evaluated in femur and vertebrae by dual‐energy X‐ray absorptiometry and histomorphometry. Bone mineral density (BMD) generally did not differ significantly between OVX‐sitagliptin‐treated animals and OVX‐vehicle controls. In lumbar vertebrae, however, there was significantly less BMD loss with increasing sitagliptin dose. Thiazolidinedione (TZD) treatment generally resulted in lower BMD; OVX‐TZD‐treated (but not OVX‐sitagliptin‐treated) animals also had lessened cortical thickness in central femur and profoundly greater bone marrow adiposity in lumbar vertebrae. These findings support prior findings with TZDs and suggest a neutral or beneficial impact of DPP‐4 inhibition on bone health.     

白藜芦醇对去卵巢骨质疏松大鼠血同型半胱氨酸和氧化应激指标的影响

目的 观察白藜芦醇对去卵巢骨质疏松大鼠血同型半胱氨酸(Hcy)和氧化应激指标的影响.方法 32只3月龄雌性Sprague-Dawley (SD)大鼠,按随机数字表法分为4组:去卵巢组、乙烯雌酚组、白藜芦醇组和假手术组,每组8只.去卵巢组、乙烯雌酚组和白藜芦醇组大鼠行双侧卵巢切除术复制骨质疏松模型.术后1周开始灌胃给药,假手术组和去卵巢组大鼠给予蒸馏水(每日一次),其余两组大鼠分别予乙烯雌酚0.03 mg·kg-1·d-1和白藜芦醇20 mg·kg-1·d-1.治疗10周后,测定大鼠血浆总Hcy (tHcy)、总抗氧化能力(TAC)、谷胱甘肽过氧化物酶(GSH-Px)和丙二醛水平,取L5椎体和右股骨进行骨密度测定.结果 与假手术组相比,去卵巢组血浆tHcy和丙二醛水平升高,TAC和GSH-Px水平下降;与去卵巢组相比,乙烯雌酚组和白藜芦醇组血浆tHcy和丙二醛浓度均明显降低,TAC和GSH-Px水平显著升高(F=19.709,117.219,7.020,20.544,P均＜0.01);白藜芦醇组血浆丙二醛浓度较乙烯雌酚组升高(F=117.219,P＜0.01).与假手术组相比,去卵巢组腰椎和股骨骨密度均明显降低;与去卵巢组相比,乙烯雌酚组腰椎和股骨骨密度明显升高,接近假手术组水平(P＞0.05);白藜芦醇组腰椎和股骨骨密度升高,但仍低于乙烯雌酚组和假手术组(F=48.518,43.263,P均＜0.01).血浆tHcy与腰椎和股骨骨密度呈负相关(r=-0.663,P＜0.001;r=-0.520,P =0.002),TAC与股骨骨密度呈正相关(r=0.539,P=0.001).结论 高Hcy血症和氧化应激与去卵巢大鼠骨质疏松关系密切.白藜芦醇可能通过降低血浆tHcy水平和改善氧化应激,对去卵巢大鼠骨质疏松发挥保护作用.     

甲状旁腺素1-34对骨质疏松大鼠治疗作用的实验研究

目的探讨甲状旁腺素134(hPTH134)对骨质疏松的治疗作用以及与血钙、磷、维生素D代谢和生长因子的关系。方法用摘除大鼠双侧卵巢的方式制备骨质疏松模型(OVX),实验动物分为4个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);hPTH134治疗组(PTH组,摘除大鼠双侧卵巢12w后用hPTH134治疗8w);盐酸雷洛昔芬治疗组(摘除大鼠双侧卵巢12w后用雷洛昔芬治疗8w);假手术组(Sham组,仅切除卵巢周围的脂肪组织约3g,术后12w纳入实验)。应用HOLOGIC第4代双能X线4500W骨密度仪测大鼠腰椎、股骨上段骨密度值(BMD);以骨形态计量学测股骨骨小梁面积、矿化沉积率;用ELISA法测定血清IGF1水平和血清25OHVitD浓度以及血淋巴细胞VitD受体(VDR)含量。结果hPTH134治疗组、盐酸雷洛昔芬治疗组均较OVX组腰椎、股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。hPTH134治疗组较盐酸雷洛昔芬治疗组股骨上段骨密度增高,两组之间差异有显著性(P<0.01)。hPTH134治疗组骨小梁面积明显增加、矿化沉积率增高。hPTH134治疗组、盐酸雷洛昔芬治疗组血清IGF1浓度值、血清25OHVitD浓度值升高,与OVX组比较差异有显著性(P<0.01)。各组血淋巴细胞VDR含量无明显变化,与OVX组比较差异无显著性(P>0.05)。结论hPTH134能够预防腰椎、股骨上段骨密度丢失,使骨小梁面积明显增加、矿化沉积率增高并且血清IGF1及血清25OHVitD浓度值升高,但对VDR含量无明显作用。     

Sequential treatment with basic fibroblast growth factor and PTH is more efficacious than treatment with PTH alone for increasing vertebral bone mass and strength in osteopenic ovariectomized rats

The study was designed 1) to determine whether treatment with basic fibroblast growth factor (bFGF) and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic ovariectomized rats, and 2) to assess whether prior and concurrent administration of the antiresorptive agents estrogen and risedronate suppresses the bone anabolic response to treatment with bFGF alone and sequential treatment with bFGF and PTH. Three-month-old female Sprague Dawley rats were ovariectomized (OVX) or sham-operated (sham) and maintained untreated for 1 yr. Baseline sham and OVX rats were killed at this time (15 months of age). Groups of rats were injected sc with estrogen (10 microg/kg, 4 d/wk), risedronate (5 microg/kg, 2 d/wk), or vehicle. At the end of the second week of antiresorptive treatment, catheters were inserted into the jugular veins of all rats, and vehicle or bFGF at a dose of 250 microg/kg was injected daily for 14 d. Three groups of rats were killed at the end of bFGF treatment. The remaining rats were continued on their respective antiresorptive therapy and injected sc with vehicle or synthetic human PTH-(1-34) at a dose of 80 microg/kg, 5 d/wk, for 8 wk. Lumbar vertebrae were processed for cancellous bone histomorphometry and biomechanical testing. Ovariectomy resulted in a decrease in vertebral bone mass and strength. Treatment of OVX rats for 14 d with bFGF markedly increased osteoblast surface, osteoid surface, and osteoid volume compared with vehicle treatment of sham and OVX rats. Furthermore, osteoid bridges were observed extending between preexisting trabeculae in bFGF-treated OVX rats. Prior and concurrent administration of estrogen and risedronate did not suppress these bone anabolic effects of bFGF. Treatment of OVX rats with PTH alone increased vertebral cancellous bone mass and strength to the level of vehicle-treated sham rats. Sequential treatment of OVX rats with bFGF and PTH further augmented vertebral bone mass and strength to a level above that observed in OVX rats treated with PTH alone. The improvements in bone mass and strength were associated with an increase in trabecular thickness in OVX rats treated with PTH alone and with an increase in trabecular thickness and node to terminus ratio, an index of trabecular connectivity, in OVX rats treated sequentially with bFGF and PTH. Cotreatment with estrogen and risedronate did not suppress the anabolic response of bone to bFGF and PTH. In fact, a trend for an even greater increase in cancellous bone mass and node to terminus ratio was observed in OVX rats treated with risedronate, bFGF, and PTH. These findings indicate that sequential treatment with bFGF and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic OVX rats.     

Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alendronate in elderly women with osteoporosis: a randomized controlled trial

OBJECTIVES: To determine whether secondary hyperparathyroidism (HPTH) due to hypovitaminosis D affects bone mineral density (BMD) response to alendronate (ALN) in elderly women with osteoporosis. DESIGN: Randomized, controlled trial with 1-year follow-up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Community-dwelling women aged 60 and older with a BMD T-score below -2.5 and secondary HPTH with vitamin D insufficiency. INTERVENTION: One hundred twenty subjects were randomly assigned to receive ALN 70 mg once a week alone or ALN 70 mg once a week plus calcitriol (1,25D3) 0.5 microg daily. MEASUREMENTS: BMD measured using dual-energy x-ray absorptiometry at the lumbar spine (L1-L4), femoral neck, and total hip and serum levels of intact PTH at baseline and 12 months. RESULTS: After 1 year, BMD of the lumbar spine, femoral neck, and total hip significantly increased from baseline in both groups (P<.001). Patients allocated to ALN plus 1,25D3 demonstrated a significantly higher increase in lumbar spine BMD than those receiving ALN alone (mean percentage+/-standard deviation 6.8+/-4.6 vs 3.7+/-3.2, P<.001). Serum levels of PTH did not change significantly at 1 year in the ALN group (mean percentage, -3.7+/-27.1, P=.13) but decreased significantly in the ALN plus 1,25D3 group (-32.1+/-22.1, P<.001). At 12 months, subjects with normalized PTH independent of therapy allocation had a greater increase in lumbar spine BMD than those with persistent HPTH (6.5+/-4.6% vs 3.7+/-3.4%, P<.001). Lumbar spine BMD changes showed a significant negative correlation with PTH at 1 year (correlation coefficient (rho) =-0.399, P<.001) and a positive correlation with PTH changes (i.e., baseline value - 1 year value; rho=0.295, P=.005). CONCLUSION: Persistence of secondary HPTH reduces BMD response to ALN in older women with osteoporosis.     

更年甘露饮加小剂量雌激素对去势大鼠股骨的影响

目的通过观察更年甘露饮加小剂量雌激素对去势大鼠股骨的影响，探索一种防治女性绝经期骨质疏松的新方法。方法雌性大鼠切除双侧卵巢预防用药3个月，检测各组大鼠血清激素水平、股骨骨密度（BMD）、光镜观察股骨结构，透射电镜观察子宫内膜腺上皮细胞超微结构。结果小剂量雌激素无改善作用，更年甘露饮加小剂量雌激素、常规剂量雌激素及更年甘露饮均能改善血清激素水平、股骨BMD及结构，其中更年甘露饮效果最弱，常规剂量雌激素对子宫内膜腺上皮细胞有明显刺激作用。结论更年甘露饮加小剂量雌激素改善去势大鼠血清激素水平、股骨BMD及结构的作用与单纯使用雌激素相似，对子宫内膜腺上皮细胞无明显刺激作用，可作为一种防治绝经期后女性骨质疏松的新方法。     

The search for calcium receptor antagonists (calcilytics)

The Ca(2+) receptor on the surface of parathyroid cells is the primary molecular entity regulating secretion of parathyroid hormone (PTH). Because of this, it is a particularly appealing target for new drugs intended to increase or decrease circulating levels of PTH. Calcilytic compounds are Ca(2+) receptor antagonists which increase the secretion of PTH. The first reported calcilytic compound was NPS 2143, an orally active molecule which elicits rapid, 3- to 4-fold increases in circulating levels of PTH. These rapid changes in plasma PTH levels are sufficient to increase bone turnover in ovariectomized, osteopenic rats. When administered together with an antiresorptive agent (estradiol), NPS 2143 causes an increase in trabecular bone volume and bone mineral density in osteopenic rats. The magnitude of these changes are far in excess of those caused by estradiol alone and are comparable with those achieved by daily administration of PTH or a peptide analog. These anabolic effects of NPS 2143 on bone are not associated with hyperplasia of the parathyroid glands. Calcilytic compounds can increase endogenous levels of circulating PTH to an extent that stimulates new bone formation. Such compounds could replace the use of exogenous PTH or its peptide fragments in treating osteoporosis.     

Short-term,high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis

PTH-related protein (PTHrP) is homologous with PTH. PTH, an effective anabolic agent for treating osteoporosis, has been shown to stimulate both bone resorption by osteoclasts and bone formation by osteoblasts. We examined whether PTHrP might share anabolic properties in osteoporosis. A 3-month double-blind, prospective, placebo-controlled, randomized clinical trial was performed in 16 healthy postmenopausal women with osteoporosis. All received calcium and vitamin D, and all continued their prior hormone replacement therapy. One group also received daily sc PTHrP (6.56 microg/kg x d, or approximately 400 microg/d), and the other group received placebo injections. The PTHrP group displayed a 4.7% increase in lumbar spine bone mineral density (BMD) and also demonstrated an increase in osteoblastic bone formation, as assessed using serum osteocalcin measurements. In contrast, there was no increase in bone-specific alkaline phosphatase and collagen-1 propeptide or either of two markers of osteoclastic bone resorption, N-telopeptide, or deoxypyridinoline. One subject in the placebo group withdrew from the study, but there were no significant adverse events in the PTHrP group. PTHrP administered sc in high doses for only 3 months appears to be a potent anabolic agent, producing a 4.7% increase in lumbar spine BMD. This compares very favorably to available antiresorptive drugs for osteoporosis and is similar to the increases in BMD at this early time point reported for PTH. Despite the high doses, PTHrP was well tolerated. Larger clinical trials are required to confirm these results and fully assess the anabolic potential of PTHrP in osteoporosis.     

Binge alcohol treatment increases vertebral bone loss following ovariectomy: compensation by intermittent parathyroid hormone

BACKGROUND: Postmenopausal estrogen deficiency and alcohol abuse are known risk factors for osteoporosis. Previous studies of the combined effect of alcohol and ovariectomy on bone loss using chronic alcohol-feeding models have not demonstrated additional alcohol-induced bone loss in ovariectomized (OVX) animals. Binge alcohol treatment causes rapid bone loss in male rats. We hypothesized that binge alcohol would cause additional bone loss in OVX rats. METHODS: Ninety-six adult (400 g) female Sprague-Dawley rats (48 sham-operated and 48 OVX, pair fed) were randomly divided into 4 treatment groups: (a) saline-treated, (b) binge alcohol-treated (3 g/kg alcohol as a 20% weight to volume alcohol/saline solution, intraperitoneal (IP), 3 times per week), (c) parathyroid hormone (PTH)-treated (80 microg/kg, SC, 5 d/wk), and (d) binge alcohol plus PTH. Rats were treated for either 2 or 4 weeks. Following treatment periods, blood was collected for alcohol concentration (BAC) measurements; lumbar vertebrae were removed for bone mineral density (BMD) levels, trabecular microarchitecture assessment, and vertebral compressive strength analysis. RESULTS: Peak binge BACs averaged 300 mg/dL. Alcohol and OVX decreased cancellous BMD: alcohol and OVX treatment in combination caused additional cancellous BMD loss and significant cortical BMD reductions. Compressive strength was also decreased by OVX and alcohol. Combination treatment resulted in further declines in bone strength. Micro-CT analysis revealed a significant effect of combined OVX and alcohol treatment resulting in decreased trabecular bone volume/total volume (BV/TV). Intermittent PTH administration compensated for losses of BMD, compressive strength, and restored BV/TV deficits caused by OVX, alcohol, or their combination. CONCLUSIONS: Bone loss following OVX can be significantly increased by concurrent binge alcohol treatment. The effects of alcohol and OVX are compensated by concurrent intermittent treatment with PTH. These results suggest that postmenopausal women who abuse alcohol may place their skeleton at additional risk for osteoporotic fracture.     

The effects of combination of alendronate and human parathyroid hormone(1-34) on bone strength are synergistic in the lumbar vertebra and additive in the femur of C57BL/6J mice

A cyclic PTH regimen is as effective as a daily regimen on bone density gain in humans and in improving bone quality in mice. Our previous murine study evaluated the effects of a cyclic PTH regimen in the absence of a bisphosphonate, whereas our human study addressed the effects of a cyclic PTH regimen in the presence of ongoing alendronate (ALN) treatment. Accordingly, the current study examined the effects of cyclic or daily PTH regimens in combination with ALN on bone quality and bone density in mice. Twenty-week-old, female C57BL/6J mice were treated with the following sc injections (n = 10): 1) vehicle for 5 d/wk (control); 2) ALN (20 microg/kg x d) 3 d/wk (ALN); 3) human PTH(1-34) (40 microg/kg x d) 5 d/wk (daily PTH); 4) daily PTH in addition to ALN (daily PTH plus ALN); 5) PTH 5 d/wk and vehicle 5 d/wk alternating weekly (cyclic PTH); 6) cyclic PTH in addition to ALN (cyclic PTH plus ALN); and 7) PTH and ALN alternating weekly (alt PTH and ALN). Bone mineral density was measured weekly by dual-energy x-ray absorptiometry, and at 7 wk, bone markers, bone structure, and bone strength were evaluated by biochemical assays, peripheral quantitative computed tomography and mechanical testing, respectively. At 7 wk, all treatments significantly increased femoral and vertebral bone mineral density. ALN slightly decreased endosteal circumference, whereas PTH increased periosteal circumference, resulting in significant increases in femoral cortical thickness in all groups. PTH and ALN enhanced bone strength synergistically in the lumbar vertebrae and additively in the femur. Combined therapy, however, had no effects on bone markers. The results show that combinations of ALN and PTH, in both daily and cyclic regimens, produce more beneficial effects than treatment with either agent alone, suggesting that the mechanisms of actions of ALN and PTH on bone quality may be complementary.     

雷洛昔芬对骨保护蛋白基因缺失小鼠的抗骨质疏松作用

目的 利用骨保护蛋白(osteoprotegerin,OPG)基因剔除小鼠模型研究选择性雌激素受体调节剂雷洛昔芬对雌鼠和雄鼠的抗骨质疏松作用.方法 取二月龄OPG基因剔除(OPG-/-)的雌鼠和雄鼠各20只.随机分为雷洛昔芬组(3 mg·kg-1·d-1)和安慰剂组,另取野生犁雌鼠10只作为对照组,1个月后杀鼠取材.测量骨密度、骨生物力学、骨形态计量学,并进行骨组织病理学检查及破骨细胞染色,评价雷洛昔芬的疗效.结果 OPG-/-小鼠呈现明显的骨质疏松表型.雷洛昔芬组的雌鼠较安慰剂组腰椎、股骨骨密度明显增高(均P<0.05);骨生物力学结果显示腰椎和股骨最大载荷(P<0.05或P<0.01),弹性模鼍(P<0.05或P<0.01),结构韧性(均P<0.01)均增高,提示骨折风险性下降;破骨细胞染色示腰椎和股骨破骨细胞面积明显减少(均P<0.01);HE染色示骨小梁数目增加,连接性上升;骨形态计量学结果显示骨形成率降低(P<0.05).雷洛昔芬组的雄鼠与安慰剂组相比较无上述改变.结论 选择性雌激素受体调节剂雷洛昔芬在OPG基因缺失的情况下仍可改善雌鼠骨质疏松,其作用不完全依赖于OPG基因.雷洛昔芬对OPG-/-雄鼠无效.     

An update on glucocorticoid-induced osteoporosis

In general, bone loss from glucocorticoid treatment occurs rapidly within the first 6 months of therapy. Glucocorticoids alter bone metabolism by multiple pathways; however, the bone loss is greatest in areas rich in trabecular bone. Preventive measures should be initiated early. It is the author's opinion that all subjects initiating treatment with prednisone at 7.5 mg or greater require calcium supplementation (diet plus supplement) at a dose of 1500 mg and vitamin D at a dose of 400 to 800 IU/d. If the patient is going to remain on this dose of glucocorticoid for more than 4 weeks, an antiresorptive agent should be started (e.g., estrogen, bisphosphonate, raloxifene). If a patient has established osteoporosis and is either initiating glucocorticoid therapy or is chronically treated with prednisone at 5 mg d or greater in addition to calcium and vitamin D supplementation, a potent antiresorptive agent (bisphosphonate) should be started. A bone mineral density measurement of either the lumbar spine or the hip may be helpful is assessing an individual's risk of osteoporosis, may improve compliance with treatment, and can be used to monitor the efficacy of the prescribed therapy. There is no reason to withhold treatment for glucocorticoid-induced bone loss until a bone mass measurement is taken, however. In motivated patients, a weight-bearing and resistance exercise program should be prescribed to help retain muscle strength and prevent depression. If hypercalciuria develops with glucocorticoid use, either thiazide diuretics or sodium restriction may be helpful. In patients who continue to lose bone or experience fracture's despite antiresorptive therapy while on glucocorticoids, bone-building anabolic agents (e.g., hPTH 1-34 or PTH 1-84) may be available someday soon.     

Efficacy and safety of human parathyroid hormone-(1-84) in increasing bone mineral density in postmenopausal osteoporosis

Daily sc injections of N-terminal analogs of PTH increase bone mass and decrease fractures in osteoporotic women. We investigated the efficacy and safety of human PTH-(1-84) (full-length PTH) in the treatment of postmenopausal osteoporosis in a double-blind, placebo-controlled study. The women (n = 50-53/group) self-administered PTH (50, 75, or 100 microg) or placebo by daily sc injection for 12 months. PTH treatment induced time- and dose-related increases in lumbar spine bone mineral density (BMD). The 100-microg dose increased BMD significantly at 3 months (+2.0%) and 12 months (+7.8%). BMD underestimated the anabolic effect of PTH in lumbar spine (bone mineral content, +10.0%) because bone area increased significantly (+2.0%). A nonsignificant decrease (-0.9%) in total hip BMD occurred during the first 6 months with the 100-microg dose, but this trend reversed (+1.6%) during the second 6 months. Bone turnover markers increased during the first half of the study and were maintained at elevated levels during the second 6 months. Protocol compliance was excellent (95-98%), and treatment was generally safe and well tolerated. Dose-related incidences of transient hypercalcemia occurred, but only one patient (100-microg group) was withdrawn because of repeated hypercalcemia. Thus, full-length PTH was efficacious and safe over 12 months.     

Serum osteoprotegerin and its ligand in cirrhotic patients referred for orthotopic liver transplantation: relationship with metabolic bone disease.

AIMS: A prospective study was carried out in 22 cirrhotic patients referred for orthotopic liver transplantation, in order to analyze serum osteoprotegerin (OPG) and RANKL levels and their relationship with metabolic bone disease. METHODS: Serum levels of OPG and RANKL were measured in all patients as well as bone markers, serum parathyroid hormone and 25-hydroxyvitamin D levels. OPG and RANKL values were compared with those obtained in 29 healthy controls. Bone mineral density (BMD) of the lumbar spine and proximal femur was measured by dual X-ray absorptiometry and spinal X-rays were obtained to assess vertebral fractures. RESULTS: Serum OPG levels were higher in cirrhotic patients than in controls (6.4+/-2 vs 2.7+/-0.7 pmol/l; P=0.001) and RANKL serum levels were lower in cirrhotic patients (0.215+/-0.6 vs 1.012+/-1.2 pmol/l; P=0.002), with an increased OPG:RANKL ratio when compared with the control group (280.3+/-334.5 vs 113+/-137.6; P=0.04). Ten patients had osteoporosis (45%) and up to 45% skeletal fractures. No differences were found in OPG levels between patients with and without osteoporosis by densitometric criteria or fractures. Negative correlations were found between OPG levels and femoral neck (R-0.46; P=0.03) and total hip BMD (R-0.48; P=0.025). By contrast, OPG values were not related to markers of bone turnover. CONCLUSIONS: OPG values are elevated in cirrhotic patients before liver transplantation, particularly in those with low bone mass at the proximal femur.     

Effects of various antireabsorptive treatments on bone mineral density in hypogonadal young women after allogeneic stem cell transplantation

Ovarian failure after allogeneic stem cell transplant (allo-SCT) is an important risk factor for development of osteoporosis. We investigated the effects of various antiresorptive treatments in long-term surviving females with ovarian failure after allo-SCT. A total of 60 women with osteoporosis or osteopenia were divided randomly into four groups of 15 women each. Group 1 was treated with calcium and vitamin D alone, group 2 received the same treatment in combination with hormone replacement therapy (HRT), group 3 received risedronate (35 mg weekly, orally for 1 year) and group 4 zoledronic acid (3 monthly doses of 4 mg (intravenous)). All groups were similar for age, body mass index, underlying disease and time elapsed from transplant. Lumbar and femoral bone mineral density (BMD) were measured at baseline and after 12 months, together with serum osteocalcin and urinary hydroxyproline. At 12 months, a significant decrease in lumbar and femoral BMD was observed in group 1 and a milder decrease in group 2. Risedronate treatment increased significantly lumbar BMD and prevented bone loss at the femoral neck. Zoledronic acid increased significantly both lumbar and femoral BMD. In groups 3 and 4 the hydroxyproline excretion was significantly reduced, while osteocalcin mildly increased only in group 4. In conclusion, bisphosphonate administration is useful to prevent and treat bone demineralization in young adult women after allo-SCT.     

高血压冠心病与骨质疏松骨量的相关性研究

目的探讨高血压冠心病与骨质疏松骨量的关系。方法93例骨质疏松及骨量减少的绝经后女性，其中无高血压和冠心病组（A组）53例，有高血压或冠心病组（B组）40例，经双能X线骨密度仪测定腰椎、髋部骨密度．生化检测各项血脂指标即总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）。比较2组血脂及各部位骨密度的相关性变化。结果2组患者TC、LDL-C及腰椎骨密度有显著性差异（P〈0．05），A组TC、LDL．C均高于B组，腰椎骨密度低于B组；Ward三角、左侧股骨近端总骨密度、TG、HDL．C2组间无显著性差异。结论心血管疾病与骨质疏松之间存在一定的相关性。     

Pitfalls in bone mineral measurement

In order to improve the reproducibility of bone mineral measurement, measurement needs to be repeated on the same position of the patients. Although lumbar bone mineral measurement is recommended in post menopausal osteoporosis, peripheral bone mineral reduction may precede lumbar bone mineral reduction in some secondary osteoporosis. The antiresorptive agents increase lumbar or proximal femoral bone mineral density; however, little changes are observed in peripheral bone mineral density by the treatment.