Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis.

Treatment with teriparatide (rDNA origin) injection [teriparatide, recombinant human parathyroid hormone (1-34) [rhPTH(1-34)]] reduces the risk of vertebral and nonvertebral fragility fractures and increases cancellous bone mineral density in postmenopausal women with osteoporosis, but its effects on cortical bone are less well established. This cross-sectional study assessed parameters of cortical bone quality by peripheral quantitative computed tomography (pQCT) in the nondominant distal radius of 101 postmenopausal women with osteoporosis who were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or teriparatide 20 microg (n = 38) or 40 microg (n = 28). We obtained measurements of moments of inertia, bone circumferences, bone mineral content, and bone area after a median of 18 months of treatment. The results were adjusted for age, height, and weight. Compared with placebo, patients treated with teriparatide 40 microg had significantly higher total bone mineral content, total and cortical bone areas, periosteal and endocortical circumferences, and axial and polar cross-sectional moments of inertia. Total bone mineral content, total and cortical bone areas, periosteal circumference, and polar cross-sectional moment of inertia were also significantly higher in the patients treated with teriparatide 20 microg compared with placebo. There were no differences in total bone mineral density, cortical thickness, cortical bone mineral density, or cortical bone mineral content among groups. In summary, once-daily administration of teriparatide induced beneficial changes in the structural architecture of the distal radial diaphysis consistent with increased mechanical strength without adverse effects on total bone mineral density or cortical bone mineral content.     

Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women

Introduction: We evaluated effects of teriparatide (rDNA origin) injection [teriparatide, rhPTH (1–34), TPTD] on hip structure among a subset 558 postmenopausal women enrolled in the Fracture Prevention Trial. Methods: Patients were randomized to once-daily, self-administered subcutaneous injections of placebo (N = 189), teriparatide 20 μg (TPTD20; N = 186), or 40 μg (TPTD40; N = 183) for a median of 20 months. Repeated dual energy X-ray absorptiometry (DXA) hip scans were analyzed with the Hip Structure Analysis (HSA) program to derive structural geometry. Results and conclusions: There were no significant differences in age or body size between groups at baseline, 1 year, or study termination. At the femoral neck, teriparatide increased bone mass and improved bone geometric strength in both treatment groups compared to the placebo group, with the response being dose-related. The mean difference (95% CI) in bone cross-sectional area (CSA) in the TPTD20 was 3.5% (1.8% to 5.3%), and 6.3% (4.5% to 8.2%) in TPTD40 at study termination, compared to placebo controls. Teriparatide treatment increased bending strength, with the mean difference in section modulus being 3.6% (1.4% to 5.8%) and 6.8% (4.6% to 9.1%) greater in the TPTD20 and TPTD40 groups, respectively. Compared to placebo, local cortical instability characterized by the buckling ratio decreased by 5.5% (3.5% to 7.5%) and 8.6% (6.6% to 10.5%) in the TPTD20 and TPTD40 groups, respectively, during the study period. The changes at the intertrochanteric region were comparable to those at the narrow neck although between-group differences were slightly smaller. Except for an inconsequential (1%) improvement in section modulus in TPTD20, teriparatide effects did not reach significance at the femoral shaft. In conclusion, teriparatide treatment improved axial and bending strength, and increased cortical thickness and stability at the femoral neck and intertrochanteric region. Teriparatide treatment effects were not apparent at the purely cortical femoral shaft.     

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.     

Effect of raloxifene after recombinant teriparatide [hPTH(1–34)] treatment in postmenopausal women with osteoporosis

Summary Loss of bone mineral density occurs after discontinuation of teriparatide, if no subsequent treatment is given. Sequential raloxifene prevented rapid bone loss at lumbar spine and further increased bone mineral density (BMD) at femoral neck, whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Introduction We compared the sequential effects of raloxifene treatment with a placebo on teriparatide-induced increases in bone mineral density (BMD). A year of open-label raloxifene extended the study to assess the response with and without delay after discontinuation of teriparatide. Methods Following a year of open-label teriparatide 20 μg/day treatment, postmenopausal women with osteoporosis were randomly assigned to raloxifene 60 mg/day (n = 157) or a placebo (n = 172) for year 2, followed by a year of open-label raloxifene. BMD was measured by dual energy x-ray absorptiometry. Results The raloxifene and placebo groups showed a decrease in lumbar spine (LS) BMD in year 2 for raloxifene and placebo groups (−1.0 ± 0.3%, P = 0.004; and −4.0 ± 0.3%, P < 0.001, respectively); the decrease was less with raloxifene (P < 0.001). Open-label raloxifene treatment reversed the LS BMD decrease with a placebo, resulting in similar decreases 2 years after randomization (−2.6 ± 0.4% (raloxifene-raloxifene) and −2.7 ± 0.4% (placebo-placebo). At study end, LS and femoral neck (FN) BMD were higher than pre-teriparatide levels, with no significant differences between the raloxifene-raloxifene and placebo-raloxifene groups, respectively (LS: 6.1 ± 0.5% vs. 5.1 ± 0.5%; FN: 3.4 ± 0.6% vs. 3.0 ± 0.5%). Conclusion Sequential raloxifene prevented rapid bone loss at the LS and increased FN BMD whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Preliminary data presented previously at the International Osteoporosis Foundation World Congress on Osteoporosis, Toronto Canada June 2–6, 2006, abstract published: Adami S, Munoz-Torres M, Econs MJ, Sipos A, Xie L, Dalsky GP, McClung M, Felsenberg D, Brown JP, Brandi ML, San Martin J. Effect of raloxifene after teriparatide treatment in postmenopausal women with osteoporosis. Osteoporos Int. 2006;17(Suppl 2):S137.     

国产重组人甲状旁腺素(1-34)对绝经后骨质疏松症的治疗作用研究

目的评价国产重组人甲状旁腺素(1-34)治疗绝经后骨质疏松症的临床疗效和安全性。方法入选绝经后骨质疏松症患者37例,年龄64.2±8.1岁,采用自身前后对照试验设计,每日皮下注射重组人甲状旁腺素(1-34)20μg,同时口服钙尔奇D600 0.6g/d,试验时间6个月,观察患者治疗前后骨密度变化、骨折发生情况,以及血尿常规、肝肾功、电解质、心电图改变等。结果试验期间有1例脱落;经过6个月治疗后,患者L1骨密度增加23.2%(P<0.05),L2骨密度增加18.0%(P<0.05),L3骨密度增加12.5%(P<0.05),L4骨密度增加19.9%(P<0.05),腰椎平均骨密度增加17.8%(P<0.05),股骨颈骨密度增加2.2%(P>0.05),大粗隆骨密度降低6.0%(P>0.05),Wards区骨密度降低1.3%(P>0.05);试验期间新发骨折2例,1例右肱骨骨折,另1例腰椎压缩骨折,无其他严重不良事件发生。结论重组人甲状旁腺素(1-34)治疗绝经后骨质疏松症有效,对腰椎骨密度改善显著,不良反应较轻。     

The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.

Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.     

Effect of hormone replacement therapy on bone quality in early postmenopausal women.

HRT is an effective prophylaxis against postmenopausal bone loss. Infrared imaging of paired iliac crest biopsies obtained at baseline and after 2 years of HRT therapy demonstrate an effect on the mineral crystallinity and collagen cross-links that may affect bone quality. Several studies have demonstrated that hormonal replacement therapy (HRT) is an effective prophylaxis against postmenopausal bone loss, although the underlying mechanisms are still debated. Infrared spectroscopy has been used previously for analyzing bone mineral crystallinity and three-dimensional structures of collagen and other proteins. In the present study, the technique of Fourier transform infrared microscopic imaging (FTIRI) was used to investigate the effect of estrogen on bone quality (arbitrarily defined as mineral/matrix ratio, mineral crystallinity/maturity, and relative ratio of collagen cross-links [pyridinoline/ deH-DHLNL]) at the ultrastructural level, in mineralized, thin tissue sections from double (before and after administration of HRT regimen; cyclic estrogen and progestogen [norethisterone acetate]) iliac crest biopsy specimens from 10 healthy, early postmenopausal women who were not on any medication with known influence on calcium metabolism. FTIRI allows the analysis of undemineralized thin tissue sections (each image analyzes a 400 x 400 microm2 area with a spatial resolution of approximately 6.3 mm). For each bone quality variable considered, the after-treatment data exhibited an increase in the mean value, signifying definite changes in bone properties at the molecular level after HRT treatment. Furthermore, these findings are consistent with suppressed osteoclastic activity.     

The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human parathyroid hormone(1–34)]

Teriparatide, the active fragment of human parathyroid hormone (hPTH 1–34), is an anabolic agent for the treatment of osteoporosis. Important questions remain regarding management strategy beyond the recommended 18- to 24-month course of teriparatide treatment. We followed 21 men for up to 2 years after discontinuing teriparatide. Twelve men (57%) chose treatment with bisphosphonate immediately after teriparatide withdrawal, while 9 (43%) opted for no pharmacologic agent. At the end of 1 year lumbar spine bone density increased an additional 5.1±1.0% in the bisphosphonate group, while it declined by 3.7±1.7% in those on no medication (P<0.002). In six men who delayed initiation of bisphosphonate until 1 year after teriparatide withdrawal, their subsequent gains in the second year, 2.6±1.7%, still placed them below the peak gains they achieved on teriparatide. In contrast, the 12 men who began bisphosphonates immediately and continued treatment for the entire 2-year post-PTH period had continued gains at the lumbar spine, 8.9±1.5% above their post-PTH values (P=0.002). For the 4-year period, including 2 years of teriparatide and 2 years of bisphosphonate, the total gains at the lumbar spine were 23.6±2.9%. Men, who received bisphosphonate in only the 2nd year post-teriparatide, had cumulative gains of 11.1±3.4%. Three men who did not receive any bisphosphonate at any time during the post-PTH period had cumulative gains of only 5.5±3.7%. These findings suggest that the use of bisphosphonates following teriparatide is an important component of any strategy utilizing this anabolic drug for osteoporosis in men. The immediate use of bisphosphonates after teriparatide withdrawal may help to optimize gains in bone density at the lumbar spine.     

rhPTH(1-34)对骨质疏松大鼠的作用及对sclerostin的影响

[目的]探讨人重组甲状旁腺素1-34(rhPTH1-34)对骨质疏松的治疗作用以及与血钙、磷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,实验动物分为3个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);rhPTH1-34治疗组(PTH组,摘除大鼠双侧卵巢12周后用rhPTH1-34治疗8周);假手术组(sham组,仅切除卵巢周围的脂肪组织约3 g,术后12周纳入实验)。应用第4代双能X线骨密度仪测量大鼠股骨上段骨密度值(BMD);用ELISA法测定血清硬化蛋白(sclerostin)水平及骨钙素(BGP)浓度;用自动生化仪测定血清碱性磷酸酶(ALP)。[结果]rhPTH1-34治疗组、sham组均较OVX组股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。rhPTH1-34治疗组血清BGP浓度值升高及sclerostin值降低,与OVX组比较差异有显著性(P<0.01)。各组血清钙、磷含量无明显变化,与OVX组比较差异无显著性,ALP值治疗组与OVX组无明显差异。[结论]rhPTH1-34能够预防股骨上段骨密度丢失,并且血清BGP浓度值升高及sclerostin值降...     

Sonographic assessment of carotid artery in postmenopausal women receiving long-term low-dose hormone replacement therapy

<正>Objective: The aim of this study was to determine the influence of long-term low-dose hormone replacement therapy (HRT) on the intima-media wall of the carotid artery in postmenopausal women by ultrasound. Methods: 146 postmenopausal women were divided into the HRT group(n = 68, HRT over 5 years after menopause) and the control group(n= 78, no HRT). The intima-media thickness (IMT) of the carotid arteries was measured bilaterally, the characteristics of the atherosclerotic plaques were described, the peak systolic velocity (PSV) and resistance index (RI) were measured by ultrasound examination. Results: The IMT of HRT group was significantly smaller than that of the control group, (0. 089±0. 22) cm vs (0. 093±0. 29) cm, (P<0. 01). The occurrence of plaques was reduced in HRT group than the control group (7. 7% vs 12. 7% , P<0. 05). The plaques were most frequently found at the bifurcation of the arteries. The soft and mixed plaques in HRT group were found significantly less than that of the control group (soft 1.7% vs 4.5%, mixed 3.1%vs 6. 7% , both P<0. 05) , while the hard plaques in HRT group were more than those of the control group(2. 6% vs 1. 3%, P<0. 05). The maximum plaque thickness of HRT group was less than that of control group (0. 191±0. 057) cm vs (0. 226±0. 073) cm, (P<0. 05). The internal carotid artery PSV and RI in the two groups were similar [PSV (65. 61±26. 55) cm/s vs (64. 82±27. 22) cm/s, RI (0. 67±0. 082) vs (0. 68±0. 075) , both P>0. 05]. Conclusion: Our study indicated that HRT may has an effect to reduce the carotid IMT thickness, inhibit the plaque formation, and make the plaques harder and more stable. The long-term low-dose HRT may protect the postmenopausal women against the artherosclerosis of the carotid artery.     

绝经期骨质疏松雌激素替代治疗临床研究

１９９５￣１９９８三年中,对绝经期骨质疏松（ＭＯＰ）１１１例进行为期２年的前瞻性雌激素替代治疗（ＨＲＴ）研究,其中５６人应用利维爱（Ｌｉｖｉａｌ）为研究组,５５人应用尼尔雌醇为对照组,经过２年随诊,终点结论是ＨＲＴ对缓解更年期症状,提高患生活质量,增加骨密度（ＢＭＤ）都有效果,但研究组明显优于对照组,具有统计学意义。ＨＲＴ的副作用为血：治疗组５．３５％,对照组１０．９％,乳房胀痛：治疗组７．１４     

低剂量与长期性激素替代疗法对绝经后妇女血脂水平的影响

目的探讨绝经后妇女低剂量与长期的性激素替代疗法(HRT)对血脂水平的影响。方法研究对象为北京协和医院女职工141人,年龄50~87岁、平均68岁,其中绝经后低剂量HRT 5~31年63人为HRT组。以年龄匹配78人为对照组。空腹12~14 h取静脉血,分离血清,检测血脂、脂蛋白和载脂蛋白等九项指标。结果HRT组与对照组比较:甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白AⅠ(ApoAⅠ)、脂蛋白(a)[Lp(a)]两组之间差异无统计学意义;总胆固醇(TC)、TC/HDL-C、载脂蛋白E(ApoE)、载脂蛋白CIII(ApoCIII)和载脂蛋白B(ApoB)差异有统计学意义。结论绝经后妇女经低剂量与长期的HRT可使TC、ApoB、ApoCIII、ApoE、TC/HDL-C水平明显下降。血脂水平的下降对心血管系统有保护作用,并可降低心血管事件发生和发展的危险性。     

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. INTRODUCTION: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. METHODS: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis. RESULTS AND CONCLUSIONS: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.     

Time-dependent changes in skeletal response to teriparatide: escalating vs. constant dose teriparatide (PTH 1-34) in osteoporotic women

Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6-12 months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 μg daily for 18months or 20 μg daily for 6 months, then 30 μg daily for 6 months, and then 40 μg daily for 6 months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6 months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18 months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific.     

重组人甲状旁腺素（1-34)与雌激素对去卵巢大鼠骨代谢的影响

目的观察重组人甲状旁腺素(1-34)与雌激素单用和联用对去卵巢大鼠骨代谢的影响。方法选用雌性4月龄SD大鼠45只,随机分为5组:①假手术(Sham)8只;②去卵巢(OVX)9只;③雌激素治疗组(OVX E)10只:OVX2个月后给予苯甲酸雌二醇治疗6w;④PTH治疗组(OVX PTH)9只:OVX2个月后给予rhPTH(1-34)治疗6w;⑤雌激素与PTH联合治疗组(OVX E PTH)9只:OVX2个月后给予rhPTH(1-34)和E2联合治疗6w。观察各组大鼠胫骨近端松质骨骨小梁形态计量学参数,椎体生物力学指标及部分血清骨生化代谢指标。结果雌激素治疗组和PTH治疗组的骨静态参数均表现为骨量增加;雌激素治疗组的骨形成参数和骨吸收参数降低;PTH治疗组的骨形成指标明显升高,而骨吸收指标虽较Sham高,但较OVX组有所降低;E2与PTH联合治疗组与单用E2组和单用PTH组比较,骨量明显提高,骨转换率参数介于单用E2和单用PTH组之间。3个治疗组的生物力学指标较OVX组均有明显提高,其中E2与PTH联合治疗组改善最明显。结论雌激素和PTH可使去卵巢大鼠松质骨骨量增加和改善生物力学性能,两者联合治疗有协同作用。     

rhPTH(1-34)对成骨细胞增殖、Collagen I及Osterix mRNA表达的影响

目的 观察间歇给予重组人甲状旁腺激素(1-34)[rhPTH(1-34)]对体外成骨细胞增殖、I型胶原蛋白(CoHagen I)及Osterix mRNA表达的影响,初步探讨rhPTH(1-34)对体外成骨细胞的作用机制.方法 体外培养新生大鼠成骨细胞,间歇循环给予0、10-11、10-10、10-9、10-8、10-7 M rhPTH(1-34)干预,(24 h为一循环,前12h给药),共2次,用MTT法检测细胞的增殖;RT-PCR法半定量测定成骨细胞Collagen I、Ostefix mRNA的表达.结果 显示rhPTH(1-34)可明显促进成骨细胞的增殖(P<0.05),促进成骨细胞Collagen I和Ostefix mRNA表达(P<0.05),101-9 M增殖、表达最明显,呈剂量依赖关系.结论 rhPTH(1-34)可促进成骨细胞的增殖、分化,可能是通过Collagen I和Ostefix mRNA表达来调节.     

rhPTH(1-34)对成骨细胞增殖、Collagen I及Osterix mRNA表达的影响

目的 观察间歇给予重组人甲状旁腺激素(1-34)[rhPTH(1-34)]对体外成骨细胞增殖、I型胶原蛋白(CoHagen I)及Osterix mRNA表达的影响,初步探讨rhPTH(1-34)对体外成骨细胞的作用机制.方法 体外培养新生大鼠成骨细胞,间歇循环给予0、10-11、10-10、10-9、10-8、10-7 M rhPTH(1-34)干预,(24 h为一循环,前12h给药),共2次,用MTT法检测细胞的增殖;RT-PCR法半定量测定成骨细胞Collagen I、Ostefix mRNA的表达.结果 显示rhPTH(1-34)可明显促进成骨细胞的增殖(P<0.05),促进成骨细胞Collagen I和Ostefix mRNA表达(P<0.05),101-9 M增殖、表达最明显,呈剂量依赖关系.结论 rhPTH(1-34)可促进成骨细胞的增殖、分化,可能是通过Collagen I和Ostefix mRNA表达来调节.     

Parathyroid hormone [PTH(1-34)] and parathyroid hormone-related protein [PTHrP(1-34)] promote reversion of hypertrophic chondrocytes to a prehypertrophic proliferating phenotype and prevent terminal differentiation of osteoblast-like cells.

The effects of parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) on late events in chondrocyte differentiation were investigated by a dual in vitro model where conditions of suspension versus adhesion culturing are permissive either for apoptosis or for the further differentiation of hypertrophic chondrocytes to osteoblast- like cells. Chick embryo hypertrophic chondrocytes maintained in suspension synthesized type II and type X collagen and organized their extracellular matrix, forming a tissue highly reminiscent of true cartilage, which eventually mineralized. The formation of mineralized cartilage was associated with the expression of alkaline phosphatase (ALP), arrest of cell growth, and apoptosis, as observed in growth plates in vivo. In this system, PTH/PTHrP was found to repress type X collagen synthesis, ALP expression, and cartilage matrix mineralization. Cell proliferation was resumed, whereas apoptosis was blocked. Hypertrophic chondrocytes cultured in adherent conditions in the presence of retinoic acid underwent further differentiation to osteoblast-like cells (i.e., they resumed cell proliferation, switched to type I collagen synthesis, and produced a mineralizing bone-like matrix). In this system, PTH addition to culture completely inhibited the expression of ALP and matrix mineralization, whereas cell proliferation and expression of type I collagen were not affected. These data indicate that PTH/PTHrP inhibit both the mineralization of a cartilage-like matrix and apoptosis (mimicked in the suspension culture) and the production of a mineralizing bone-like matrix, characterizing further differentiation of hypertrophic chondrocytes to osteoblasts like cells (mimicked in adhesion culture). Treatment of chondrocyte cultures with PTH/PTHrP reverts cultured cells in states of differentiation earlier than hypertrophic chondrocytes (suspension), or earlier than mineralizing osteoblast-like cells (adhesion). However, withdrawal of hormonal stimulation redirects cells toward their distinct, microenvironment-dependent, terminal differentiation and fate.     

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.