激素替代疗法联合阿仑膦酸钠治疗绝经后骨质疏松的临床研究

目的观察激素替代疗法(HRT)联合阿仑膦酸钠治疗绝经后骨质疏松患者的疗效。方法采用随机、对照研究。69例绝经后骨质疏松症患者,随机分为联合用药组(联合组)、雌激素替代治疗组(雌激素组)和阿仑膦酸钠治疗组(阿仑膦酸钠组),每组23例。联合组每2周服尼尔雌醇片1mg,每3个月末10d加服安宫黄体酮6mg/d,同时给予阿仑膦酸钠70mg,每周1次口服。雌激素组为安慰剂+尼尔雌醇片和安宫黄体酮,阿仑膦酸钠组为安慰剂+阿仑膦酸钠。所有受试者均加服钙尔奇D600mg/d(每片含元素钙600mg和VitD125IU)。观察各组治疗后患者腰椎骨密度、血钙、血磷等骨代谢指标的变化及疼痛症状改善情况。结果通过1年治疗,3组患者的L1～4骨密度均有显著上升,其中联合组骨密度的上升更为明显(P<0.01),骨痛症状明显缓解,总有效率为100%,联合组的显效率高于其他两组。结论HRT联合阿仑膦酸钠治疗绝经后骨质疏松症,较单独用药更能有效地改善骨痛,提高骨密度值。     

Extended safety profile of oral clodronate after long-term use in primary breast cancer patients.

INTRODUCTION: Long-term safety and tolerance is paramount when treating women who are otherwise healthy after the primary adjuvant therapy of breast cancer. Efficacy and limited safety results of a large-scale clinical trial, using adjuvant oral clodronate to prevent bone metastases in primary breast cancer patients, have been reported previously, demonstrating a reduction in the rate of bone metastases during treatment. Here we present expanded safety and tolerability results for clodronate treatment from this trial (cut-off date extended from June 1997 to June 2000). STUDY DESIGN AND METHODS: For this randomised, double-blind, placebocontrolled, multicentre study, patients were enrolled and randomised to receive oral clodronate (Bonefos) 1600 mg/day or placebo for 2 years. The total median treatment period plus follow-up was 5.5 years. Adverse events (AEs) and laboratory parameters were followed up regularly for the total study period. The 95% CIs were estimated for the difference in the rate of AEs between the treatment groups. PATIENTS: A total of 1079 women with primary operable breast cancer were enrolled to the study; 538 received clodronate and 541 received placebo. RESULTS: Overall incidence of AEs (96.5% of the patients) was the same in both treatment groups, although gastrointestinal disorders were significantly more frequent in the clodronate group during the total study period (66% vs 56.2%; 95% CI 4.0-15.6; p < 0.05). This was mainly due to an increase in non-severe diarrhoea beginning 3-4 months after treatment start. Serious AEs (SAEs) were reported for 39.4% of the patients receiving clodronate and 44.5% of those receiving placebo; no drug-related (clodronate or placebo) SAEs were identified. Clodronate significantly lowered mortality (98 deaths vs 129 deaths; hazard ratio 0.77; 95% CI 0.59-1.00; p = 0.047) reducing the risk of death over the total study period by 23%. AEs caused 58 early discontinuations (five drug-related events) in the clodronate group and 43 discontinuations (three drug-related events) in the placebo group. CONCLUSION: These results indicate that in women with early breast cancer receiving adjuvant systemic therapy, oral clodronate for 2 years is generally well tolerated with no serious long-term sequelae, providing a safe, long-term therapy in the adjuvant setting.     

New bisphosphonates in the treatment of bone diseases

Bisphosphonates are pyrophosphate analogues, in which the oxygen in P-O-P has been replaced by a carbon, resulting in a P-C-P structure. They are characterised by a strong anti-osteoclastic activity and for this pharmacological property they are now considered the treatment of choice for Paget's disease of the bone, malignant hypercalcaemia and bone metastases. Etidronate, clodronate and pamidronate have been registered in several countries for these indications. Etidronate and alendronate are also extensively used for the prevention and treatment of postmenopausal and senile osteoporosis. In this article, we review the most recent findings on the newest bisphosphonates, which will become available in the near future. The aminobisphosphonate risedronate is undergoing a huge programme of clinical development for the treatment of osteoporosis. In a study of the prevention of early postmenopausal bone loss, oral risedronate 5 mg fully prevented the bone loss observed in the placebo group. Similar effects have been observed with an intermittent dosage regimen of oral risedronate 30 mg/day for 2 out of 12 weeks, which corresponds to 5 mg/day in terms of cumulative dose. With lower doses [5 mg on alternate fortnights (2 weeks)] the prevention of bone loss was half that observed with continuous 5 mg/day therapy, indicating that this might not yet be the maximum effective dose. The use of intermittent intravenous bisphosphonates for osteoporosis therapy has been pioneered by studies with clodronate, pamidronate and alendronate. This treatment regimen has been chosen for an extensive clinical development programme for ibandronate. In a phase 2 study, this new bisphosphonate was administered as an intravenous bolus (0.25, 0.5, 1 or 2 mg) every 3 months for a year, with increases in spinal bone mass of 5.2%. Tiludronate, alendronate and risedronate have been recently introduced for the treatment of Paget's disease of bone. Daily doses of tiludronate 400 mg, alendronate 40 mg and risedronate 30 mg for 3 to 6 months have been shown to be superior to etidronate 400 mg/day. The intravenous administration of ibandronate, zoledronate and alendronate (40 mg, 10 mg and 5 mg, respectively) have achieved the normalisation of serum alkaline phosphatase in more than 70% of the patients and these treatments may provide an alternative for patients intolerant oral bisphosphonates. Intravenous ibandronate has been also developed for the treatment of hypercalcaemia of malignancy. The effective doses ranged from 2 to 4 mg. Zoledronate appears to be the most powerful bisphosphonate under investigation, and the effective doses used in cancer hypercalcaemia are as low as 1 to 2 mg. The new generation of bisphosphonates are likely to increase clinical options in terms of administration regimens, but their real advantage over those already available in terms of clinical efficacy remains uncertain.     

Effect of Concomitant Administration of Clodronate and Estramustine Phosphate on their Bioavaibility in Patients with Metastasized Prostate Cancer

Abstract: Estramustine phosphate is generally used as a second-line treatment in patients with advanced prostate cancer. The bone metastases due to the cancer are often treated simultaneously with clodronate in order to relieve the bone pain. Therefore, the interaction of clodronate (800 mg orally four times daily) and estramustine phosphate (280 mg orally twice daily) on their bioavailability was studied in twelve patients with prostate carcinoma and bone metastases. The drugs were first given separately, each to six patients, for five days, and then concomitantly for the same period. The bioavailabilities of the drugs were calculated on the last day of each treatment period. When clodronate was given alone, its concentrations in serum and AUC for one dose interval (6 hr) did not differ from those obtained with the drug given concomitantly with estramustine phosphate, nor did the combination of estramustine phosphate change the excretion of clodronate in urine. The serum concentrations of estramustine phosphate were elevated by about 80% when the drug was given together with clodronate. The AUC for one dose interval (12 hr) was also significantly higher for estramustine phosphate with clodronate than without clodronate. The urinary excretion of estrone, a major metabolite of estramustine phosphate, was also significantly higher after the admission with clodronate. The results suggest that clodronate increases the oral bioavailability of estramustine phosphate.     

阿法骨化醇对大剂量糖皮质激素治疗肾小球疾病所致的骨质疏松的影响

目的：观察阿法骨化醇联合钙剂对肾脏病患者发生糖皮质激素性骨质疏松的预防作用。方法：28例病人随机分为治疗组16例,阿法骨化醇1μg日一次口服和碳酸钙750 mg日三次口服;对照组12例,碳酸钙750 mg日三次口服。治疗前及以后每3个月检查血清白蛋白、钙、磷、24小时尿蛋白定量、甲状旁腺素,腰椎和股骨颈骨密度,观察6个月。结果：两组患者腰椎和股骨颈骨密度均呈下降趋势,治疗6个月时,治疗组骨密度高于对照组（腰椎0.967±0.105,0.896±0.131,P〈0.05;股骨颈1.078±0.124,0.925±0.107,P〈0.05）,对照组骨密度较治疗前明显下降。结论：阿法骨化醇合用钙剂对预防慢性肾脏病患者发生糖皮质激素性骨质疏松是安全有效的药物。     

Changes of bone mineral density in pre-menopausal women with differentiated thyroid cancer receiving L-thyroxine suppressive therapy

OBJECTIVE: We studied the effect of levothyroxine (L-T(4)) suppressive therapy on bone mineral density (BMD) in pre-menopausal women with total thyroidectomy and radioactive iodine ((131)I) ablation therapy post-operatively for differentiated thyroid cancer (DTC). PATIENTS AND METHODS: We prospectively studied 26 athyroid pre-menopausal women (median age 39 years, range 28-48 years) receiving suppressive L-T(4) therapy postoperatively for 48 months. BMD was measured by dual energy X-ray absorptiometry (DEXA) at the femoral neck, femoral trochanter and Ward's triangle, before (basal) and during (12th and 48th month) the follow-up period. None of the women gave a medical history that could possibly affect bone metabolism. Patients were free of thyroid cancer in clinical and laboratory examinations at the time of the study. Paired t-test was used for comparisons among BMD measurements during the suppressive therapy. RESULTS: There were statistically significant decreases of BMD at all measured regions during (12th and 48th month) L-T(4) suppressive therapy. The overall decreases in BMD at the femoral neck, femoral trochanter and Ward's triangle were 7.5%, 10.9% and 3.4%, respectively, at the end of the follow-up period. The coefficient of variation (CV) of all BMD measurements was around 10%, showing a rather homogenous group of patients. Our patients had a statistically significant decrease in their body mass index (BMI) and weight at the end of the follow-up period. However, there was no significant correlation between the decrease in BMI and BMD. Patients did not experience significant adverse effects from L-T(4) suppressive therapy during the study. CONCLUSION: L-T(4) suppressive therapy for at least 1 year in pre-menopausal women with DTC causes a reduction in BMD of the femoral neck, femoral trochanter and Ward's triangle.     

Remission rates with venlafaxine extended release in Greek outpatients with generalized anxiety disorder. A double-blind, randomized, placebo controlled study

The primary endpoints in this study were the remission rates [final Hamilton Rating Scale for Anxiety (HAM-A) total score < or =7] and reduction from baseline in the HAM-A total score in patients with generalized anxiety disorder (GAD) and no associated depression. Patients with GAD (DSM-IV and HAM-A total score >18) were randomly assigned to treatment with venlafaxine XR or placebo for 8 weeks. A 1-week placebo run-in period preceded the double-blind phase. Patients with a >20% drop in their total HAM-A score during the run-in period, were excluded from the double-blind phase. All patients started therapy with 75 mg/day venlafaxine XR or matched placebo. Patients with less than 30% decrease in their HAM-A total score at the end of the second week, doubled their dose. Patients on the 150 mg/day dose underwent a 1-week taper period. Of the 24 patients in the venlafaxine XR group, 62.5% achieved remission versus 9.1% in the placebo group (P=0.0006). The mean decrease from baseline in HAM-A total score was 19.2 points for the venlafaxine XR group and 10.8 points for the placebo group (P<0.001). Eleven placebo-treated patients and seven venlafaxine XR treated patients doubled their dose at the end of the second week of double-blind treatment. No patient interrupted therapy because of side-effects. No changes in systolic or diastolic blood pressure were observed. Venlafaxine XR 75-150 mg/day was well tolerated. The remission rates achieved with venlafaxine 75-150 mg/day in non-depressed GAD patients were high with good tolerability.     

Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis

OBJECTIVE: The FACT study (Fosamax Actonel Comparison Trial) was a 1-year-head-to-head trial comparing the efficacy and tolerability of once weekly (DW) alendronate 70 mg and OW risedronate 35 mg for the treatment of postmenopausal osteoporosis. The present analysis was performed to determine the percentage of patients who had changes during the study in BMD and biochemical markers (BCMs) of bone turnover above or below specific cut-off points. A subgroup analysis of upper gastrointestinal (UGI) tolerability was also performed. RESEARCH DESIGN AND METHODS: 1053 postmenopausal women with low BMD were randomized to alendronate 70 mg OW (N = 520) or risedronate 35 mg OW (N = 533). The percentage of patients who had measured BMD gains > or = 3%, and > or = 5% after 12 months at the hip trochanter, total hip, femoral neck, and lumbar spine (LS) was analyzed. The percentage of patients who experienced any bone loss, and those with measured losses of 3% or more at these sites after 12 months, was determined. The percentage of patients achieving reductions in urinary N-telopeptide of type 1 human collagen (NTX) > or = 40%, and serum C-telopeptide of type 1 collagen (CTx) > or = 60%, bone-specific phosphatase (BSAP) > or = 30%, and N terminal propeptide of type 1 procollagen (P1NP) > or = 50% at 3 months and 12 months was also determined. Tolerability, based on adverse experience reporting, was evaluated in a subgroup of patients with history of UGI disorders at baseline. RESULTS: A greater percentage of alendronate- than risedronate-treated patients had measured BMD gains (> or = 0%) (p < 0.05) at all sites at 12 months. Significantly more (p < 0.01) alendronate- than risedronate-treated patients had measured gains in BMD > or = 3% and > or = 5% at the hip trochanter, total hip, and LS spine. Significantly more (p < 0.05) risedronate- than alendronate-treated patients had an apparent loss of BMD (> 0% and > or = 3% loss) at the same sites. After 3 months, significantly (p < 0.001) more alendronate- than risedronate- treated patients achieved predefined reductions in all BCMs. Similar tolerability was demonstrated in both treatment groups, regardless of whether or not patients had a history of UGI disorders at baseline. CONCLUSIONS: Significantly more alendronate- than risedronate-treated patients achieved predefined increases in BMD at 12 months and reductions in BCMs at 3 months. Significantly more risedronate- than alendronate-treated patients were classified as apparent 'non-responders' (i.e. experienced any bone loss) after 12 months of therapy. The tolerability profiles of the two medications were similar.     

Inadequate dietary intake but not renal tubular acidosis is associated with bone demineralization in primary biliary cirrhosis

BACKGROUND: Metabolic bone disease associated with primary biliary cirrhosis (PBC) is inadequately characterized. Renal tubular acidosis (RTA) may lead to bone loss through chronic mobilization of skeletal calcium salts to buffer increased acid load. AIM: To evaluate the prevalence of RTA in PBC and establish the relationships among bone mineral density (BMD), renal function and nutritional status. METHODS: We enrolled 69 female patients with compensated PBC and 35 control patients with chronic hepatitis C. RTA was searched in all patients, and 24-h dietary recalls were collected at enrolment. BMD was measured by dual-energy X-ray absorptiometry at the femur neck, lumbar spine and radius ultradistalis sites. RESULTS: No patients received a diagnosis of RTA. BMD values (Z-scores) showed only little deviation from normal population with no difference between PBC and controls. Osteopoenic PBC patients (T-score < 1) showed significantly lower daily phosphorus intake [median: 672 (288-1374) vs. 921 (253-1923) mg/day; P = 0.037], with a trend towards lower caloric intake than their nonosteopoenic counterparts. CONCLUSIONS: Renal tubular acidosis is uncommon in compensated PBC. Cholestasis is not associated with an increased risk of bone demineralization. Inadequate dietary intake may be a preventable factor contributing to bone loss in PBC.     

A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder

This multinational, randomized, double-blind, flexible-dose study evaluated the short- and long-term antidepressant tolerability and efficacy of escitalopram and paroxetine. Tolerability was assessed by monitoring adverse events throughout the study, and discontinuation events during brief treatment interruption and tapered withdrawal. Discontinuation-emergent effects were evaluated in two separate double-blind periods. First, to mimic the consequences of non-compliance, patients were randomized to one of two treatment interruption periods (placebo-substitution for 3-5 days). Second, patients were randomized to a 1-2-week tapered withdrawal period randomly scheduled between weeks 28 and 31. The pre-specified primary efficacy endpoint was the mean change from baseline in total Montgomery-Asberg Depression Rating Scale (MADRS) score at week 8, using the principle of last observation carried forward. A total of 323 patients entered 8 weeks of double-blind treatment and received at least one flexible dose of escitalopram (10-20 mg/day) or paroxetine (20-40 mg/day). Patients who demonstrated evidence of a significant clinical improvement (Clinical Global Impression-Improvement of 1 or 2) at week 8 entered a 19-week, double-blind maintenance period during which they were treated with the same dose they received at week 8, followed by a 1-2-week tapered withdrawal period. A total of 89 patients (28%) withdrew during the study; significantly (P<0.01) more patients withdrew from the paroxetine group (34%) than from the escitalopram group (21%), and significantly (P<0.05) more paroxetine patients withdrew due to lack of efficacy. The mean MADRS total score improved for both treatment groups from baseline to week 8, with no statistical difference between groups. In severely depressed patients (baseline MADRS total score >or=30), escitalopram was superior (P<0.05) to paroxetine at week 27 (end of maintenance treatment). There was a high prevalence of sexual dysfunction at baseline: the mean Arizona Sexual Experience Scale (ASEX) score was approximately 20 points in both treatment groups. Mean total ASEX scores increased slightly above baseline values during the acute period and declined slightly below baseline values towards the end of the maintenance period. During taper and cessation of treatment, patients in the paroxetine group demonstrated significantly more discontinuation symptoms relative to escitalopram based on the Discontinuation Emergent Signs and Symptoms scores.     

Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease

Risedronate is a novel orally administered pyridinyl bisphosphonate indicated for the prevention or treatment of postmenopausal and glucocorticoid-induced osteoporosis and Paget's disease. The drug reduces bone turnover and decreases resorption chiefly through osteoclastic effects, with no undesirable effects on cortical porosity or thickness or on cancellous bone volume. Four randomised, double-blind trials have been carried out in 4873 patients with postmenopausal osteoporosis. In 2 of these studies, the primary end-point of vertebral fracture incidence was reduced by risedronate 5mg once daily by up to 65 and 49% relative to placebo after 1 and 3 years, respectively. Across all 4 trials, risedronate improved lumbar spine, femoral neck and femoral trochanter bone mineral density (BMD) statistically significantly relative to placebo. The drug also prevented bone loss in a study in 383 women with recent menopause, and reduced the risk of hip fracture in elderly women with confirmed osteoporosis in a trial involving a total of 9331 patients. Risedronate 5 mg/day plus estrogen has been shown to be superior to estrogen alone in a 12-month double-blind study in 524 women with at least 1-year's history of menopause. Two randomised, double-blind and placebo-controlled 12-month studies in a total of 518 patients have shown risedronate 5 mg/day to prevent or reverse bone loss in patients receiving glucocorticoid therapy. Risedronate 30 mg/day was associated with statistically significant reductions in mean serum levels of alkaline phosphatase (ALP) in noncomparative studies in patients with Paget's disease. ALP normalisation rates ranged from 53.8 to 65% across two 84-day treatment cycles in 2 of these trials in 180 patients. In a randomised, double-blind study in 123 patients, risedronate 30 mg/day for 2 months evoked significantly greater serum ALP responses than etidronate 400 mg/day for 6 months. The overall tolerability profile of risedronate was similar to that of placebo in clinical studies, with no evidence of acute-phase reactions or mineralisation defects, or excess incidence of upper GI lesions, in patients receiving the drug. CONCLUSIONS: Risedronate is an effective and well tolerated novel bisphosphonate that is suitable for first-line therapy in Paget's disease. The rapid and sustained reductions in vertebral fracture incidence and BMD changes seen in patients with postmenopausal and glucocorticoid-induced osteoporosis indicate the drug to be a valuable treatment option with first-line potential, particularly in patients for whom hormonal therapy is inappropriate. The effects of the drug on hip fracture incidence in elderly women with confirmed osteoporosis point to a particular role in older patients, or those with more advanced disease.     

Antiresorption therapy and reduction in fracture susceptibility in the osteoporotic elderly patient: open study

The identification of risk factors for osteoporosis has been an essential step towards the understanding of the onset of the disease as well as of the osteoporosis-related fractures due to bone fragility. The present study has been aimed at assessing whether a correlation may exist between the increment in bone mass, consequent to an antiresorption therapy, and the reduction in the incidence of fractures. Moreover, the possibility that such a reduction might result from the action of other factors, such as the changes in bone microstructure, has been investigated. A total of 2,000 osteoporotic women (mean age: 68 +/- 9 years) were enrolled in the study and divided at random into 4 treatment groups. Each group received one of the following treatments: Alendronate 10 mg/daily (1,000 patients), Clodronate 100 mg/weekly i.m. (800 patients), Risedronate 5 mg/dailt (100 patients), and Raloxifene 60 mg/daily (100 patients). Clinical evaluation was based on bone mineral density (BMD) assay on lumbar vertebrae (L1-L4) by means of a DEXA (Lunar DPX) mineralometer, as well as on the incidence of fractures following both 12- and 24-month treatment periods. The results showed an overlapping pattern in patients treated with Alendronate or Risedronate, namely a significant increment in BMD after a 24-month treatment period, whereas such an increment in BMD was less evident in patients receiving either Clodronate or Risedronate after a 24-month treatment period. In addition, a total of 18 osteoporosis-related fractures were observed during the entire study period; 10 out of 18 fractures occurred in the Alendronate treated group, whereas the remaining 8 fractures were observed in the Clodronate treated group. Fourteen fractures were detected in patients over 80-year old, whereas the remaining 4 occurred in patients aged from 70 to 79 years and appeared to be independent of both the T-score assigned and the BMD increment obtained as a result of the therapy. Such findings suggest that the plain monitoring of BMD appears not to be adequate to anticipate clearly the danger of the probable onset of additional fractures, while the higher incidence of fractures in patients over 80-year old evidences that "old age" has to be considered the most serious risk factor for osteoporosis, since it is also the real responsible factor for changes taking place in bone microstructure.     

Glucocorticoid osteoporosis

Postmenopausal women are at greatest risk of rapid bone loss and fracture with glucocorticoids and should be actively considered for prophylactic measures. In men and premenopausal women receiving glucocorticoids, the decision to use anti-osteoporosis prophylaxis is less clear and depends upon baseline bone mineral density [BMD], anticipated dose and duration of glucocorticoids. Based upon evidence the order of choice for prophylaxis would be a bisphosphonate followed by a vitamin D metabolite or hormone replacement therapy [HRT]. Calcium alone appears unable to prevent rapid bone loss in patients starting glucocorticoids. HRT should clearly be considered if hypogonadism is present. In patients receiving chronic low dose glucocorticoids, treatment with calcium and vitamin D may be sufficient to prevent further bone loss. However since fracture risk is a function of multiple factors including the degree of reduction in BMD as well as the duration of exposure, treatment with therapy to increase BMD will reduce fracture risk even in patients receiving chronic low dose glucocorticoids.     

A comparison of teriparatide and calcitonin therapy in postmenopausal Asian women with osteoporosis: a 6-month study

OBJECTIVE: The number of hip fractures is expected to double in the next 20 years, with current estimates that Asia will account for 37% of these cases. As bone mineral density (BMD) may be used as a measure of fracture risk, we sought to compare the effects of teriparatide with salmon calcitonin treatment on changes in BMD, biochemical bone markers, and safety in postmenopausal Asian women with osteoporosis. METHODOLOGY: A total of 104 patients (n = 47 teriparatide [20 g/day subcutaneously] and n = 57 calcitonin [100 IU/day subcutaneously]) were enrolled in Hong Kong, Singapore, Philippines, Malaysia, and Thailand. Calcium (> or = 500 mg/day) and vitamin D (200-400 IU/day) supplements were taken throughout the 6-month controlled, randomized study. RESULTS: Teriparatide was associated with a 5.03 +/- 4.77% increase in lumbar spine BMD (p < 0.0001, mean +/- SD change from baseline), whereas changes in lumbar spine BMD for patients on calcitonin were not statistically significant (mean change of 0.36 +/- 4.12%, p = 0.16). Comparison of the two groups indicated that teriparatide treatment improved lumbar spine BMD statistically significantly more than calcitonin (p < 0.0001). No statistically significant changes were observed for total hip or femoral neck BMD. Serum bone-specific alkaline phosphatase (BSAP) increased by 55.9% (median change from baseline, p < 0.0001) in the teriparatide group, and remained stable with calcitonin (5.0% change, p = 0.24); osteocalcin increased by 156.15% (median change from baseline, p < 0.0001) with teriparatide, and decreased with calcitonin (-15.25%, p = 0.03). Similar rates of adverse events were observed, with nausea and dizziness the most commonly reported for both groups (teriparatide versus calcitonin, 13.0% versus 23.2% p = 0.21, 10.9% versus 21.4% p = 0.19, respectively). There were no clinically relevant changes observed in laboratory parameters. CONCLUSIONS: Both treatments were similarly tolerated, however teriparatide was associated with greater increases in lumbar spine BMD and bone formation markers, demonstrating the unique mechanism of action and safety of this treatment for osteoporosis in these Asian women.     

Intravenous clodronate for acute pain induced by osteoporotic vertebral fracture

Even though newly developed drugs may in the future preserve bone mass and reduce the risk of fracture, patients with osteoporosis will continue to suffer from episodes of painful vertebral fracture for many years to come. For this reason, the treatment of acute pain induced by this pathology is still a clinically important issue. The aim of this study was to assess the effect of intravenous disodium clodronate (300 mg) on three pain conditions (at rest, on pressure and on motion) associated with recent osteoporotic vertebral fractures. The effects of disodium clodronate were compared with those of paracetamol in 30 patients during a 30-day observation period. The results showed higher pain remission rate in patients receiving disodium clodronate intravenously than in those receiving paracetamol. The rapid onset of analgesic activity produced by intravenous administration of disodium clodronate after vertebral fracture represents a definite clinical indication.     

Comparative studies on effect of risedronate and alfacalcidol against glucocorticoid-induced osteoporosis in rheumatoid arthritic patients

Osteoporosis is a common adverse reaction induced by glucocorticoid treatment. Bisphosphonate, vitamin D(3) (VD(3)) or vitamin K(2) (VK(2)) is recommended as first or second choice of drug for treatment of glucocorticoid-induced osteoporosis. In the present study, the treatment effect of risedronate against glucocorticoid-induced osteoporosis in rheumatoid arthritic patients was compared with that of alfacalcidol. Twelve patients were randomized to receive either risedronate (2.5 mg) or alfacalcidol (0.5 microg) daily for 48 weeks. Each patient also received 800 mg of calcium supplementation (800 mg/day) daily. Bone mineral density (BMD) and the biochemical markers of bone turnover were measured before (baseline) and 12, 24, and 48 weeks after treatment with risedronate or alfacalcidol, and the percentage changes in these parameters from baseline were compared.The BMD values 12, 24 and 48 weeks after treatment with risedronate increased by 3.9%, 4.1% and 5.2%, respectively, which were significantly higher than those after treatment with alfacalcidol (2.8%, 2.1% and 2.5%, respectively). Urinary excretion of N-telopeptides of type I collagen and deoxypyridinoline after risedronate treatment were more significantly decreased than that after alfacalcidol treatment. The present findings at least suggest that risedronate is more useful for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with rheumatoid arthritis than alfacalcidol, although the number of patients studied was small.     

Recombinant full-length parathyroid hormone (1-84)

Full-length parathyroid hormone (PTH) 1-84 is a recombinant version of human PTH. It is approved in the EU for the treatment of postmenopausal women with osteoporosis who have a high risk of fractures. Once-daily subcutaneous administration of PTH(1-84) stimulates new bone formation and increases bone mass. In the pivotal, randomised, double-blind, multicentre, 18-month TOP trial in 2532 postmenopausal women with osteoporosis, subcutaneous PTH(1-84) 100 microg/day significantly reduced the incidence of new or worsened vertebral fractures relative to placebo (primary endpoint). Moreover, the increase from baseline in bone mineral density (BMD) at the lumbar spine, total hip, femoral neck and trochanter was also significantly greater than in the placebo group. In another well designed study (PaTH; n = 238), 1 year of subcutaneous PTH(1-84) 100 microg/day followed by 1 year of alendronate 10 mg/day resulted in significantly greater increases in total spine, femoral neck and total hip BMD at 24 months compared with patients who received placebo for the second year. During the first year, PTH(1-84) in combination with alendronate was no more effective than PTH(1-84) monotherapy in terms of increasing areal lumbar spine BMD. PTH(1-84) is generally well tolerated, although patients should be monitored for elevated serum calcium.     

Raloxifene: a review of its use in postmenopausal osteoporosis

Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue. In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12- to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus < or =0.5% with placebo. Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected. Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months' follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene. Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in < or =6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium. CONCLUSIONS: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteonorosis.     

A combination of subtherapeutic doses of chemically modified doxycycline (CMT-8) and a bisphosphonate (clodronate) inhibits bone loss in the ovariectomized rat: a dynamic histomorphometric and gene expression study

Recent studies have demonstrated that tetracyclines can reduce bone loss in the ovariectomized (OVX) rat model of osteoporosis. In the current study, a non-antimicrobial, chemically modified doxycycline (CMT-8), alone or in combination with a bisphosphonate (Clodronate), was evaluated in this model. Forty-two, 6month old, female rats were randomly assigned to the following groups, (6/ group): a) sham/vehicle, b) OVX/vehicle; c) OVX/1 mg/day CMT-8; d) OVX/2 mg/day CMT-8, e) OVX/1 mg/week Clodronate; and f) OVX/1 mg/day CMT-8 + 1 mg/week Clodronate, CMT-8 was administered by oral gavage, Clodronate injected S/C. Following sham surgery or OVX, the rats were treated for 90 days with CMT-8 or vehicle alone, injected at three different times with fluorochrome labels, the rats were sacrificed, and the tibiae excised for analysis by dynamic bone histomorphometry. Femurs were aseptically removed and analyzed for collagen, collagenase and osteopontin mRNAs by Northern and dot blot analysis. As expected, OVX decreased trabecular bone volume (BV/TV by 73.8% vs. sham p<.01), and also reduced trabecular thickness, numbers, and increased spacing. Bone loss in the OVX animals was partially prevented with either 2 mg/day CMT-8 or 1 mg/wk Clodronate (p<.01), while the 1 mg/day CMT-8 had no effect. Interestingly, the efficacy of the combination therapy of CMT-8 and Clodronate was significantly better than either treatment by itself, maintaining bone mass and structural indices at levels identical to sham values. OVX rats mRNA for collagen, collagenase and osteopontin were elevated indicating high-turnover bone loss. Only COMBO therapy significantly reduced the collagenase and osteopontin mRNA. In summary, CMT-8 mono-therapy (2 mg) alone partially inhibited bone loss in this animal model of osteoporosis. However, 1 mg/day (CMT-8) monotherapy had no effect on bone loss or bone mRNA levels and when combined with Clodronate, interacted to increase efficacy. Thus, a combination of a suboptimal dose of CMT-8 and a bisphosphonate appears to increase the amount of bone by suppressing resorption in a model of osteoporosis.     

骨吸收抑制剂治疗绝经后骨质疏松的临床评价

目的　评价不同类型骨吸收抑制剂在临床原发性骨质疏松症治疗中的疗效。方法　30 0例原发性骨质疏松症患者分成三组 ,每组 10 0例 ,所有患者均排除继发性骨质疏松。性激素类组 :服用利维爱 2 5mg ,隔日 1次 ;降钙素组 :密钙息 5 0IU ,肌注 ,第 1周每天 1次 ,第 2周隔日 1次 ,以后每周 2次 ;二膦酸盐组 :阿仑膦酸钠 10mg ,每天 1次。治疗 2年后随访 :腰椎骨密度 (BMD)、胫骨骨超声 (QUS)、尿羟脯氨酸 (HOP)、骨钙素和新骨折。结果　临床骨痛降钙素缓解速度最快 ,性激素类药物可迅速有效地缓解妇女更年期症状。治疗 2年后 ,腰椎骨密度明显上升 (P <0 0 5 ) ,二膦酸盐组上升 5 1% ,性激素类组上升 4 2 % ,降钙素上升 0 97% ;胫骨骨超声显著提高 (P <0 0 5 ) ,性激素组上升 2 1% ,降钙素组 1 8% ,二膦酸盐组 1 7% ;新骨折共 4例 :二膦酸盐组 2例 ,降钙素组和性激素组各 1例 ;尿羟脯氨酸仅二膦酸盐组明显下降 ;骨钙素各组无明显变化。结论　骨吸收抑制剂是骨质疏松治疗的重要手段 ,性激素类药物是治疗伴有绝经后综合症骨质疏松患者的首选药物 ,二膦酸盐对骨量较低且伴有骨痛的患者有良好的疗效 ,降钙素治疗骨质疏松疼痛临床疗效显著。