不同双膦酸盐类药物抑制破骨细胞特征曲线的意义

目的比较双膦酸盐类药物唑来膦酸、伊班膦酸和帕米膦酸对体外培育破骨细胞的具体抑制作用,绘制特征性曲线并指导临床治疗。方法通过体外培育小鼠骨髓细胞,分化获得破骨细胞并将其分为唑来膦酸组、伊班膦酸组、帕米膦酸组、对照组。其中,唑来膦酸组培养液中加入唑来膦酸,药物的阶梯浓度为:10-3、10-2、10-1、1、10、102、103μmol/L。同时,伊班膦酸组与帕米膦酸组加入相应药物的阶梯浓度相同,对照组加入磷酸盐缓冲液。观察双膦酸盐类药物对破骨细胞形成、迁移、粘附、骨破坏的抑制作用特征并进行比较,绘制特征性曲线。结果随着药物浓度逐级增大,多核细胞数量随浓度增加而减少。唑来膦酸、伊班膦酸和帕米膦酸的最低有效抑制浓度分别为1、10、102μmol/L。三者50%有效浓度分别为0.66、5.58、51.9μmol/L。结论临床治疗骨质疏松症时建议参考破骨细胞抑制特征曲线,为唑来膦酸、伊班膦酸和帕米膦酸的静脉应用提供科学依据。     

Pamidronate is superior to ibandronate in decreasing bone resorption,interleukin-6 and beta 2-microglobulin in multiple myeloma

OBJECTIVES: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third-generation aminobisphosphonate, in bone turnover and disease activity in MM patients. METHODS: Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N-terminal cross-linking telopeptide of type-I collagen (NTX) and tartrate-resistant acid phosphatase type 5b (TRACP-5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, beta 2-microglobulin), and interleukin-6 (IL-6) were also studied. RESULTS: In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL-6, paraprotein, CRP, and beta 2-microglobulin from the second month of treatment, having no effect on bone formation. TRACP-5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL-6, and beta 2-microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP-5b, starting at the fourth month (P = 0.014), that being continued throughout the 10-month follow-up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP-5b, IL-6, and beta 2-microglobulin from the second month for patients of both groups. CONCLUSIONS: These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL-6, and possibly tumour burden in MM. TRACP-5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.     

Prospective study of histomorphometry,biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic-therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1-collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre-therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre-therapy with high turnover bone disease (HTO) in TM and low-turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low-turnover disease.     

Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma

AIM: Bisphosphonates are potent inhibitors of osteoclastic activity and are used in the treatment of multiple myeloma (MM) in combination with chemotherapy. The effect of pamidronate on markers of bone resorption [cross-linked N-telopeptides of type I collagen (NTx)], markers of bone formation [serum alkaline phosphatase (BAP) and osteocalcin (OSC)], interleukin-6 (IL-6), beta2-microglobulin, CRP, paraprotein and disease-related pain and skeletal events has been evaluated in 62 newly diagnosed patients with MM. PATIENTS AND METHODS: The patients were randomly assigned to two groups: the first included 32 patients under chemotherapy and pamidronate (group I) and the second 30 patients on chemotherapy only (group II). Pamidronate was administered at a monthly dose of 90 mg iv, and the above parameters were evaluated at the beginning of this study and after 1, 3, 6, 9, 12 and 14 months of treatment. RESULTS: The addition of pamidronate to chemotherapy resulted in a significant reduction of NTx, IL-6 and paraprotein from the 3rd month and of beta2-microglobulin, CRP and pain from the 6th month of treatment. No changes of NTx, IL-6, beta2-microglobulin, CRP or skeletal events were observed in patients of group II, while paraprotein was significantly reduced after 6 months of treatment. The differences in NTx, IL-6, paraprotein and beta2-microglobulin were statistically significant between the two groups. Multivariate analysis revealed a significant correlation between changes of NTx, changes of IL-6 in both groups and reduction of pain and paraprotein in group I. CONCLUSIONS: These results suggest that pamidronate may have a synergistic action with chemotherapy in decreasing osteoclastic activity, in reducing markers of myeloma activity and myeloma related pain and in improving the quality of life in patients with MM.     

帕米膦酸二钠治疗恶性肿瘤骨转移的观察

目的 :观察帕米膦酸二钠 (搏宁 )对恶性肿瘤骨转移的临床疗效。方法 :3 8例恶性肿瘤患者静点搏宁 60～ 90 m g/次 ,部分病例联合静脉化疗 (n=16)。结果 :搏宁对骨痛治疗的有效率为78.95 % ,联合化疗的疗效 (有效率 87.5 % )优于单用搏宁 (有效率 72 .7% )。活动能力改善有效率为84.4% ,9例血钙增高患者经治疗后血钙复常率为 77.78%。不良反应主要为发热、食欲减退、恶心、全身酸痛等。结论 :搏宁能有效地缓解骨转移疼痛及改善活动功能障碍 ,提高患者的生活质量 ,与化疗联用疗效更好     

Pamidronate treatment of bone fibrous dysplasia in nine children with McCune-Albright syndrome

McCune-Albright syndrome is a rare genetic disorder consisting of skin and bone dysplasia and peripheral endocrinopathies. Little data have been collected regarding bisphosphonate treatment of bone fibrous dysplasia in paediatric patients with this syndrome. The aim of our study was to investigate the therapeutic efficacy of pamidronate in these patients. Nine patients with moderate to severe forms of bone fibrous dysplasia were treated with pamidronate intravenously (0.5-1 mg/kg/daily for 2-3 d) at 0.5-1-y intervals. Patients were treated over a time period of 0.5-3.5 y. During treatment no spontaneous fracture occurred. Bone pain and gait abnormality due to pain disappeared after 2-3 therapeutic cycles. Cranial asymmetry and limb length discrepancy remained unchanged. Elevated serum alkaline phosphatase and urine hydroxyproline values were reduced by the treatment, demonstrating drug activity at the lesional level. The effectiveness of pamidronate was also seen at the non-lesional level through an increase in bone density. Radiographic and scintigraphic evidence of lesion healing was not attained. Pamidronate treatment can ameliorate the course of bone fibrous dysplasia in children and adolescents with McCune-Albright syndrome.     

Osteoporosis at presentation of childhood ALL: management with pamidronate

Vertebral fractures at diagnosis of childhood acute lymphoblastic leukemia (ALL) are an uncommon but recognized problem. Clinical issues associated with pathological fractures in these children include pain control and the potential for further treatment-associated fractures and long-term bony morbidity. The authors report the successful use of pamidronate in two children who presented with vertebral compression fractures at diagnosis of ALL. Both patients had pain and low bone mineral density at baseline. In addition to standard chemotherapy, pamidronate (1 mg/kg, IV) was given bimonthly. Initial rapid symptom relief and gradual improvement of bone mineral density was demonstrated in both patients.     

Attempted randomized controlled trial of pamidronate versus calcium and calcitriol supplements for management of steroid-induced osteoporosis in children and adolescents

OBJECTIVES: To describe an attempted interventional trial for glucocorticoid-induced osteoporosis in children and adolescents and to discuss the reasons for trial failure to inform future interventional studies in this important group of patients. METHODS: Prospective randomized controlled trial comparing the effect of bisphosphonate therapy with calcium and vitamin D supplementation on bone mineral accrual is described. For non-trial patients, retrospective analysis of the effect of calcium and vitamin D supplementation combined with bisphosphonate treatment on bone mineral accrual. RESULTS: Only 12 patients were enrolled in the trial over 4 years. Bisphosphonate recipients (n = 5) had a mean annual percentage increase in lumbar spine bone mineral density of 8.76 +/- 5.2% compared to 6.6 +/- 4.0% in the calcium/vitamin-treated group (difference not significant). Mean annual change in lumbar spine areal bone mineral density in non-trial patients (n = 11) was 3.72 +/- 2.5%. CONCLUSION: Conducting a randomized controlled trial in this group of corticosteroid users is difficult, given the unpredictable nature of the underlying disease and intermittent need for steroid treatment. The trial failed through inadequate recruitment combined with discontinued interventions.     

Bones, groans and blasts

A 14-year-old girl presented with the acute onset of gastrointestinal symptoms due to hypercalcaemia. Chest X-ray revealed osteolytic lesions in the ribs which in conjunction with a normal parathyroid hormone level raised the possibility of malignancy. Despite the absence of blast cells in her blood film, the bone marrow biopsy was diagnostic of acute lymphoblastic leukaemia. She responded well to treatment with pamidronate and chemotherapy.