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     

Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. effect of adding hormone replacement therapy.

OBJECTIVES: To compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis and to assess the efficacy of either bisphosphonate in combination with hormone replacement therapy (HRT). PATIENTS AND METHODS: In this pragmatic study, the main efficacy criterion was the mean annual change in bone mineral density (BMD). Patients who had a past or current history of etidronate or alendronate treatment for postmenopausal osteoporosis with at least 18 months follow-up and an evaluation in 1999 were eligible. Recruitment was in an outpatient clinic with a special focus on metabolic bone diseases. Osteoporosis was defined as at least one low-energy fracture or as a lumbar spine or femoral neck BMD decrease to at least 2.5 SD below the mean in young women. HRT was not an exclusion criterion provided treatment duration was longer than 1 year. Etidronate was given cyclically (14-day courses in a dosage of 400 mg/d separated by 76-day intervals with calcium and vitamin D supplementation) and alendronate was given daily in a dosage of 10 mg/d. RESULTS: Of the 99 patients who met our inclusion criteria, 53 received etidronate (including 23 on HRT) and 46 alendronate (18 on HRT). Repeat BMD measurements were obtained in 88 patients, including 11 who stopped their bisphosphonate therapy within the first year of use because of adverse events. Lumbar spine BMD (mean +/- SD) increased significantly both in the etidronate group (+2.1% +/- 0.7%/year) and in the alendronate group (+5.3% +/- 0.9%/year). The increase was significantly greater with alendronate (P< 0.01). The lumbar spine BMD increase was largest in the patients on alendronate and HRT (+6.5% +/- 1.4%/year) and was smallest (and nonsignificant) in the patients on etidronate without HRT (+ 1.2% +/- 0.8%). Femoral neck BMD showed no significant changes in any group. In the intention-to-treat analysis, fractures occurred in 12 etidronate patients (22.6%) and six (13.0%) alendronate patients (nonsignificant). Adverse events requiring bisphosphonate discontinuation before the scheduled date of the follow-up BMD measurement occurred in one patient (1.9%) in the etidronate group (generalized osteomalacia) and in ten patients (21.7%) in the alendronate group (upper or lower gastrointestinal tract symptoms in six and four patients, respectively; P < 0.01). CONCLUSION: Both etidronate and alendronate significantly increased lumbar BMD, but the effect was significantly more marked with alendronate. Conversely, adverse effects, most notably gastrointestinal symptoms, were more common with alendronate, so that premature treatment discontinuation because of adverse events were more common in the alendronate group. Both differences should be taken into account when selecting the best drug for a patient with postmenopausal osteoporosis.     

抗骨吸收和促骨形成药物在骨质疏松症治疗中的联合应用

骨质疏松症是一种以骨量减少、骨组织细微结构受损,导致脆性骨折为特征的一种常见疾病。随着人类寿命延长和老年人口的增加,骨质疏松症患病率持续增高,且所致的疼痛和骨折严重影响患者的生活质量,故骨质疏松症的治疗非常重要。目前抗骨质疏松症药物的疗效和安全性比较明确,是防治骨质疏松症的主要手段,但临床上发现单药治疗作用有限,基于不同的作用机制,有学者提出抗骨质疏松症药物的联合治疗。本文针对抗骨质疏松症药物中的两类即抗骨吸收和促骨形成药物之间的联合应用进展做一综述。     

hPTH 1–34 treatment of osteoporosis with added hormone replacement therapy: Biochemical,kinetic and histological responses

Twelve patients with vertebral fracture osteoporosis were recruited into a trial of treatment with hPTH 1–34 by daily injection for 1 year combined (from the 5th month) with an anti-resorptive agent (oestrogen, n=9; nandrolone, n=3). Treatment outcomes were monitored by biochemical and radiotracer measurements together with histomorphometry of transiliac biopsies before and at the end of treatment following double in vivo pre-labelling with demethylchlortetracyc-line. Indices of whole body bone formation, obtained from the analysis of⁸⁵Sr data, showed substantial increases (P<0.005) for all three indices measured) while biochemical (hydroxyproline) and kinetic measurements of bone resorption showed modest and equivocal changes only. As a result calcium balance improved. Gastrointestinal calcium absorption showed a tendency to improve, while urine calcium decreased; but these changes were statistically not significant except for radiocalcium absorption in the oestrogen treated subgroup. Histomorphometry revealed substantial increases in cancellous bone volume as reported previously with hPTH 1–34 given alone. However, iliac (as distinct from whole body) indices related to bone formation and resorption appeared to have returned towards pre-treatment values by the time of the second biopsy under the influence of the anti-resorptive agent given with the hPTH 1–34. It is confirmed that hPTH 1–34 therapy can increase iliac cancellous bone mass (as well as spinal cancellous bone mass as reported earlier) without a long-term increment in whole body bone resorption, providing the hPTH is combined with an anti-resorptive agent.     

雌激素替代疗法对绝经期骨质疏松伴牙周病患者系统治疗的影响

目的 研究雌激素替代疗法对绝经期雌激素降低伴骨质疏松女性牙周病患者进行牙周系统治疗的临床疗效。 方法 观察38名绝经期女性雌激素、骨密度测量水平及牙周各项指标,根据身体状况随机分为两组,对照组采取牙周系统治疗,实验组补充雌激素结合牙周系统治疗。术后3个月、6个月记录各项指标进行对比研究。 结果 38名绝经期女性患者雌激素水平及骨密度存在不同程度降低,实验组12例患者补充雌激素3个月后雌激素恢复或接近正常（P<0.05）,统计学上有显著性差异;6个月骨密度测量出现不同程度改善（P>0.05）,但统计学上无显著性差异;附着丧失水平较未补充雌激素组降低（P>0.05）,但统计学上无显著性差异。 结论 雌激素替代疗法可以有效提高绝经期女性雌激素、骨密度水平及牙周病患者牙周系统治疗的疗效。     

Combination anabolic and antiresorptive therapy for osteoporosis: Opening the anabolic window

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently increased our options. By stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities in addition to increasing bone mass. The only anabolic agent currently approved for osteoporosis by the US Food and Drug Administration, teriparatide (recombinant human parathyroid hormone [1–34]), has emerged as a major approach to selected patients with osteoporosis. Recombinant human parathyroid hormone (1–84) is also available in Europe. Teriparatide increases bone density and bone turnover, improves microarchitecture, and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. A current concept in the mechanism of teriparatide action is related to its effect to stimulate processes associated with bone formation before it stimulates processes associated with bone resorption. This sequence of events has led to the concept of the anabolic window, the period of time when teriparatide is maximally anabolic. Newer approaches to the use of teriparatide alone and in combination with antiresorptive agents have led to ways in which the anabolic window can be expanded.     

Combination/sequential therapies for anabolic and antiresorptive skeletal agents for osteoporosis

In this paper, we focus upon the use of anabolic skeletal therapy for the treatment of postmenopausal and other forms of osteoporosis. The only anabolic skeletal agent currently available is a recombinant bioactive fragment of parathyroid hormone, PTH(1-34), known as teriparatide. The full length molecule, human PTH(1-84) is being investigated at this time as are other PTH molecules. Teriparatide improves bone quality by actions on bone turnover, bone density, bone size, and microarchitecture. In postmenopausal women with osteoporosis, teriparatide reduces the incidence for vertebral and nonvertebral fractures. In individuals who have been treated previously with an antiresorptive agent, the subsequent actions of teriparatide on bone density are delayed transiently if bone turnover is markedly suppressed. Combination therapy with teriparatide or PTH(1-84) and an antiresorptive does not appear, at this time, to offer advantages over the use of PTH or an antiresorptive alone. To maintain the gains in bone density with PTH, it is important to follow its use with an antiresorptive agent.     

Effects of parathyroid hormone alone or in combination with antiresorptive therapy on bone mineral density and fracture risk – a meta-analysis

Aim The effects of parathyroid hormone (PTH) alone or in combination with antiresorptive therapy on changes in bone mineral density (BMD) and fracture risk were studied. Materials and methods Randomised placebo controlled trials were retrieved from the PubMed, Web of Science or Embase databases. Results PTH alone or in combination with antiresorptive drugs reduced vertebral [relative risk (RR)=0.36, 95% confidence interval (CI): 0.28–0.47, 2p<0.01] and non-vertebral (RR=0.62, 95% CI: 0.48–0.82, 2p<0.01) fracture risk and increased spine BMD by 6.6% (95% CI: 5.2–8.1%, 2p<0.01) and hip BMD non-significantly by 1.0% (95% CI: −0.1 to 2.1%, 2p=0.08) during 11–36 months of follow-up (13 trials). The gain in spine and hip BMD tended to increase with the length of the PTH treatment. No significant effect of study duration on fracture risk could be demonstrated. The major adverse events were hypercalcaemia, nausea and discomfort at the injection sites. Only limited data are currently available on fracture risk reduction with PTH plus antiresorptive therapies. Conclusion Although the number of studies on non-vertebral fractures is limited, our pooled analysis revealed that PTH alone or in combination with antiresorptive drugs would appear to be able to reduce the risk of vertebral and non-vertebral fractures and to increase spine and perhaps hip BMD. However, these analyses were based on cross-sectional data – i.e. based on indirect comparisons – and further studies with a direct comparison of study duration are necessary. No studies comparing PTH, PTH plus antiresorptive drugs and antiresorptive drug versus placebo in a factorial design are available; consequently, we were unable to draw any conclusions on the superiority of PTH plus antiresorptive drug versus antiresorptive drug or PTH alone with respect to BMD or fractures.     

Timing of follow-up densitometry in hormone replacement therapy users for optimal osteoporosis prevention

The objectives of the study were (1) to determine the time interval for repeat dual-energy X-ray absorptiometry (DXA) to detect significant bone loss, i.e., greater than the coefficient of variation (CV) of the center (2.8 × CV%) and (2) to assess how long hormone replacement therapy can be maintained to avoid undetected development of low bone mass and to not unduly delay appropriate treatment. A total of 3,826 healthy women, aged 40–65 years, participated in a prospective cohort study, 807 of whom were treated with transdermal estrogen replacement therapy and 626 with transdermal estrogen/progesterone regimens. The untreated group included the remaining 2,393 women. Between 1996 and 2002 they underwent a baseline DXA scan, and DXA scans were then repeated annually. There were no differences among the study groups at entry into the study. Treatment with estrogen was a protective factor for loss of bone mass at the lumbar spine (odds ratio [OR] =0.431, 95% confidence interval [CI] 0.344 to 0.522) and at the femoral neck (OR =0.433, 95% CI 0.352 to 0.521). Treatment with estrogen/progesterone also showed a protective effect against significant changes in follow-up BMD (>2.8 × 1.05% CV of densitometry at L1–L4, >2.8 × 2.3% CV at the femoral neck). In the treated group, significant differences in BMD at the lumbar spine (OR =1.593, 95% CI 1.423 to 2.355) did not appear within the first 3 years, and differences in BMD at the femoral neck (OR =3.555, 95% CI 2.782 to 4.905) did not appear within the first 4 years. It is concluded that in women aged 45–65 years, receiving transdermal hormone replacement therapy without risk factor for loss of bone mass, such as age < 55 years and body mass index <25 kg/m², periodical follow-up densitometries would not be necessary, provided that the duration of estrogen or estrogen/progesterone therapy is shorter than 3 years.     

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 BMD. 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.     

Prevention and treatment of osteoporosis with ovarian hormones

A considerable body of evidence has now been assembled demonstrating loss of ovarian function is associated with increased skeletal remodeling and acceleration of bone loss. The available data suggest that this is probably the most significant risk factor of osteoporosis for most women. The presence of other risk factors may well magnify the effect of menopause either by reducing peak bone mass, enhancing rate of bone loss, or by increasing the risk of falls and injury in later life. Estrogen therapy reverses the increased remodeling and reduces the rate of bone loss significantly. Controlled studies have confirmed that this effect persists as long as estrogens are prescribed (at least 10 years) and ceases after therapy is stopped, when there is an acceleration of bone loss that is similar to that following oophorectomy. Consequently, the earlier estrogen therapy is begun, and the longer it is continued, the more effective are the results. The available data suggest that a minimum of 5-10 years treatment may be necessary to reduce the likelihood of hip fracture by about 50%, and vertebral fracture risk may be cut by as much as 90%. Certain progestogens may also inhibit bone loss, but their addition to estrogen in sequential or combination therapy does not appear to modify the effects of estrogen significantly.     

Osteoporosis and hormone replacement therapy

Hormone replacement therapy prevents bone loss and the increase in bone resorption due to the hormone deficiency in oestrogen in postmenopausal women. The WHI (Women's Health Initiative) randomised, double-blind study against placebo, demonstrated that which all the epidemiological trials had already suggested: replacement therapy can reducing by around 30% the risk of fractures in postmenopausal women. Administration of hormone replacement therapy requires account being taken of (in view of the uncertainties regarding the anti-fracture effect of low dose therapy): the duration (in view of the absence of remnant effect of the product on bone loss and on the risk of fracture) and the benefit/risk ration (in view of the benefits demonstrated on climacteric disorders, but the increase in risk of breast cancer). The menopause is the occasion to assess individual risks, notably vascular and of fractures, taking into account the clinical risk factors and measurement of bone density.     

激素替代联合二磷酸盐预防和治疗绝经后骨质疏松症疗效的系统评价

目的 评价联合与单一用激素替代和二磷酸盐预防和治疗绝经后骨质疏松的疗效性和安全性.方法 计算机检索MEDLINE(1966～2008.10)、Embase(1984～2005)、PubMed(1966～2008.10)、Cocharane图书馆(CENTRAL 2008年第三期)、中国生物医学文献光盘数据库(1978～2006年)和中国期刊全文数据(1979～2008.10),并手工检索相关领域其他杂志.对纳入文献进行质量评价.数据分析采用RevMan 5.0,对于异质性小的研究合并效应量.结果 共纳入13 个随机对照试验,包括3341 例患者.Meta 分析结果显示:①联合治疗组与二磷酸盐单一用药组比较,在增加腰椎骨密度和减少骨折风险方面无明显差别,在降低骨转化标志物及药物副作用方面无优势.②联合治疗组与激素替代单一治疗组比较,在增加腰椎骨密度、药物副作用方面具有明显优势,在减少骨折风险、降低骨转化标志物方面无明显差别.结论 激素替代联合二磷酸盐预防和治疗绝经后骨质疏松症疗效优于激素替代单一治疗,但与二磷酸盐单一治疗比较并没有优势,且副作用明显增加.     

Prevention and treatment of glucocorticoid-induced osteoporosis

Glucocorticoids continue to be used for many inflammatory diseases, and glucocorticoid-induced osteoporosis (GIOP) remains the most common secondary form of metabolic bone disease. Recent meta-analyses suggest that both active and native vitamin D can help maintain lumbar spine bone mineral density (BMD), particularly in patients receiving lower-dose glucocorticoid therapy. Recent randomized, controlled clinical trials have shown that oral bisphosphonates are superior to vitamin D in maintaining BMD and should be continued for as long as a person receives glucocorticoid treatment. Similar to the oral bisphosphonates, intravenous ibandronate has been shown to preserve BMD and also to significantly reduce vertebral fracture risk. Increasing evidence supports a role for parathyroid hormone to prevent or treat GIOP as well. Despite effective therapies, many at-risk patients fail to receive treatment for GIOP, and even among those who initiate treatment, half discontinue within 1 to 2 years. New approaches to evidence implementation are being tested to improve the quality of osteoporosis care and decrease fracture risk among long-term glucocorticoid users.     

Parathyroid hormone monotherapy and cotherapy with antiresorptive agents restore vertebral bone mass and strength in aged ovariectomized rats

Previous studies have shown that parathyroid hormone (PTH) monotherapy and cotherapy with estrogen or risedronate augment vertebral bone mass and bone strength in young, ovariectomized (OVX) rats. The current study was designed to determine whether PTH has similar bone anabolic effects in aged OVX rats at a much later stage of estrogen depletion. Female Sprague Dawley rats were subjected to sham surgery or bilateral ovariectomy at three months of age and maintained untreated for one year after surgery to allow for the development of vertebral osteopenia in OVX rats. Groups of baseline control and OVX rats were sacrificed at the end of this pretreatment period. The remaining OVX rats were then treated for ten weeks with vehicle, antiresorptive agents alone (estrogen, risedronate, or calcitonin), or PTH alone. Other groups of OVX rats were treated concurrently with PTH and each of the antiresorptive agents. The first and fourth lumbar vertebral bodies were processed undecalcified for quantitative bone histomorphometry and biomechanical testing, respectively. As expected, bone mass and compressive strength were decreased in the lumbar vertebral body of baseline OVX rats compared to baseline control rats. This bone loss was associated with decreases in trabecular number and width and an increase in trabecular separation. Treatment with estrogen, risedronate, or calcitonin alone failed to reverse the changes in bone mass, structure, and strength induced by ovariectomy. In contrast, treatment of OVX rats with PTH alone restored vertebral cancellous bone volume and ash density to the level of vehicle-treated control rats and increased vertebral maximum load, stress, and normalized load to well above this level. The hormone significantly increased trabecular width, but not number, in the lumbar vertebral body of OVX rats. Concurrent treatments with PTH and the antiresorptive agents did not augment cancellous bone and biomechanical competence to a greater, or lesser, extent than treatment with PTH alone. Compressive strength correlated significantly with bone mass and trabecular width in the lumbar vertebral body. These results indicate that PTH completely restores lost bone mass and improves bone strength in the vertebral body of aged OVX rats with established osteopenia. With our previous study in younger OVX rats, the current study demonstrates that the anabolic effect of PTH is independent of age and the stage of estrogen depletion in the rat skeleton.     

Coherence treatment of postmenopausal osteoporosis with growth hormone and calcitonin

Summary Fourteen women with postmenopausal osteoporosis, all having at least one vertebral crush fracture, were randomly assigned to two treatment arms, each lasting 24 months. The coherence treatment group (7 patients) was treated in the following sequence: human growth hormone (hGH) 7 IU subcutaneously daily for 2 months, followed by 3 months of salmon calcitonin (CT), 100 MRC units every other day. After a 3 month rest period, this sequence was repeated twice. The contrast group (7 patients) was treated intermittently with salmon CT given in the same time periods and at the same dose as in the coherence treatment group. Bone mass was measured every 4 months by neutron activation analysis for total body calcium (TBCa) and by single photon absorptiometry for bone mineral content (BMC) of the distal radius. Although there were no significant differences between the two groups (two-way ANOVA), the rate of change in TBCa in the coherence treatment group was significantly different from zero (F=3.8,P<.05) and was +2.3%/year. The increase in bone mass appeared to be sustained throughout the 2 year study, in contrast with previous studies where a plateau effect was observed with calcitonin given alone or continuously with growth hormone. No significant change was found in bone histomorphometric values measured before and after treatment in 4 patients from each group.     

截瘫患者骨质疏松症的防治措施

骨质疏松症是截瘫患者众多常见并发症中一类不可忽视的并发症,具有渐进性和不显性,常常被人们所忽视.笔者从生活饮食习惯、药物治疗、物理治疗、动态监测等方面对骨质疏松的防治措施作一综述.