Treatment options for glucocorticoid-induced osteoporosis

ABSTRACT

Introduction

Glucocorticoid (GC) induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. It develops in a dose and time dependent manner, due to a rapid and transient increase in bone resorption, followed by the inhibition of bone formation.     

Do bisphosphonates reduce early micromotion and Periprosthetic bone loss in total knee arthroplasty? A review of the evidence

Early micromotion of implant components and periprosthetic bone loss in patients undergoing total knee arthroplasty are thought to contribute to late aseptic loosening. In the pursuit of longer implant survival, the administration of bisphosphonates may be advocated as a means to buffer implants against microinstability and periprosthetic bone loss. A bibliographic search identified one metaanalysis and two randomised controlled trials dealing with this topic. Current evidence supports the hypothesis that the inhibiting effects of bisphosphonates on bone resorption reduce implant micromotion and periprosthetic bone loss at the one-year follow-up. Tested bisphosphonates include clodronate, pamidronate and alendronate. However, a decline in periprosthetic BMD is observed at the three-year follow-up following a sixmonth course of bisphosphonate administration. Length of follow-up in available studies is currently too short to determine whether bisphosphonates increase the longevity of implants. Furthermore, the optimal dose, modality and length of bisphosphonate administration have yet to be determined.     

Prevention of Bone Loss by Clodronate in Early Postmenopausal Women with Vertebral Osteopenia: A Dose-Finding Study

This double-masked, placebo-controlled study was undertaken to determine the efficacy and safety of oral clodronate in the prevention of bone loss in early postmenopausal women with vertebral osteopenia. Altogether 610 women with a mean age of 53 years were recruited for the study. They were 1–5 years postmenopausal and their lumbar spine bone mineral density (BMD) was at least 1 standard deviation below the mean of premenopausal women (T-score ≤−1). The subjects were randomized into five study groups to receive either placebo, clodronate 65 mg, 400 mg or 800 mg daily, or intermittent clodronate in 3 month cycles with 400 mg daily for 15 days followed with no treatment for 75 days for 3 years. One hundred and eighty-seven of 509 women who completed the primary study continued in the extension study of 2 years in which previous placebo users were switched to clodronate 800 mg daily, while previous users of 400 mg or 800 mg of clodronate used either placebo or 800 mg of clodronate daily. In the primary study clodronate was administered in the evening, and in the extension 1 h before breakfast on an empty stomach. In the primary study mean changes in lumbar spine BMD were −3.4% in the placebo group and +0.4% in 800 mg clodronate group [difference between groups at 3 years 3.8% (95% CI 2.7% to 4.9%, p<0.0001)], and in the trochanter area BMD −1.1% in the placebo group, and + 0.4% in the 800 mg clodronate group [difference between groups at 3 years 1.5% (95% CI 0.05% to 2.9%)]. During the extension study mean changes in lumbar spine BMD were +1.5% in the clodronate group and −0.2 % in the placebo group [difference between groups 1.7% (CI 0.4% to 3.0%, p = 0.010)] and in trochanter BMD were +2.5% in the clodronate group and no change in the placebo group [difference between groups 2.1% (CI 0.3% to 3.9%, p = 0.007)]. No statistically significant differences between the placebo and 800 mg clodronate groups were found in the femoral neck BMD. In the primary study the urinary excretion of type I collagen aminoterminal telopeptide (NTX) decreased by 44% (p<0.0001 compared with placebo) and that of deoxypyridinoline by 18% (p<0.0001) in the clodronate 800 mg group. In the extension study urinary NTX decreased by 51% (p<0.0001) in those who were switched to 800 mg of clodronate and increased by 67% (p<0.0001) in those who stopped using that dose. There was no difference in the frequency of gastrointestinal complaints between clodronate- and placebo-treated patients in the primary study, but they were more common among women who received clodronate in the extension phase. Clodronate in daily doses of 400–800 mg caused a slight elevation of aminotransferase levels, usually within the reference range. In bone biopsies no defect in mineralization was found. In conclusion, clodronate in a daily dose of 800 mg prevents early postmenopausal bone loss at the sites of the skeleton in which cancellous bone predominates. It effectively reduces bone resorption and bone turnover rate. Antifracture efficacy of clodronate remains to be established by prospective, placebo-controlled trials. Received: 4 March 2002 / Accepted: 9 July 2002     

Treatment of Paget's disease of bone with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate

Summary 4-amino-1-hydroxybutylidene-1,1-bis-phosphonate (AHButBP) was given intravenously (2.5–25 mg/day for 4 days) to 14 patients with Paget's disease of bone, five of whom had been treated with dichloromethylidene bisphosphonate (Cl₂MBP) 32 months earlier. In the nine patients who had not been treated previously with bisphosphonates, the short course of AHButBP induced a suppression of serum alkaline phosphatase and urinary hydroxyproline values down to 30% of initial values. The biochemical suppression of the disease was sustained for 2–18 months and the time to relapse did correlate to the logarithm of the dose (P<0.001). In the five patients previously treated for Paget's disease, an apparent resistence to treatment with AHButBP was observed. However, in these patients both serum alkaline phosphatase and urinary hydroxyproline fell to or even below the nadir values which had previously been achieved with Cl₂MBP, irrespective of the degree of relapse. Thus the degree of suppression of Paget's disease of bone, achievable after treatment with bisphosphonates, seems to be constant for each patient, such that normal levels of serum alkaline phosphatase and urinary hydroxyproline cannot usually be attained in patients with extremely active disease.     

Bisphosphonate-induced Osteonecrosis of the Jaws: Review, Clinical Implications and Case Report

The introduction of bisphosphonates has increased in the last decade following their indication for metastatic bone diseases, osteoporosis, hypercalcaemia of malignancy and Paget’s disease. Although bisphosphonates have been used clinically for more than three decades there have been no documented long-term complications of their effects on the jaws until recently, where there is now growing evidence of the influence of bisphosphonates on osteonecrosis of the jaws. The aim of this paper is to report a case of this newly described complication, to review this phenomenon, including the clinical implications and to reiterate current clinical guidelines for management of patients in which bisphosphonate therapy is indicated. To the best of our knowledge this is the first reported case of bisphosphonate-induced necrosis of the jaw in South Africa.     

The use of etidronate and calcium versus calcium alone in the treatment of postmenopausal osteopenia: Results of three years of treatment

The purpose of this open, prospective, controlled, randomized trial was to study the effect of intermittent, cyclic etidronate on the bone mass of osteoporotic postmenopausal women with or without fractures. Eligible subjects were asymptomatic women less than 75 years old who had been amenorrhoeic for at least 1 year. Those with secondary osteoporosis were excluded. Subjects also had to be ambulant with a bone mineral density (BMD) of the lumbar spine >1 SD below that of age matched controls (Z-score < –1 SD). Eighty patients were enrolled, of whom 65 were recruited through a screening programme conducted in the practices of two general practitioners. The remaining patients were from other referrals. The subjects were randomized to two groups of 40 women. Treatment regimens were as follows. The etidronate group was treated with etidronate 400 mg once daily for 14 days followed by 76 days of 500 mg of elementary calcium once daily; this cycle was repeated every 3 months. The calcium group took 500 mg of elementary calcium once daily. The groups were not different in age, height, weight, time since menopause, BMD at baseline and prevalent vertebral fractures. In 50 patients (28 in the etidronate group and 22 in the calcium group) no vertebral fractures were present (67%). Sixty-four patients (35 in the etidronate group and 29 in the calcium group) completed the 3 years of the study. In the etidronate group the mean BMD of the lumbar spine, femoral neck, trochanter and Ward's triangle increased by 5.7%, 1.4%, 7.1% and 10.9% from baseline values respectively (p<0.05 at all sites except for the femoral neck). In the calcium group no significant changes from baseline were found at any time point at any site after 3 years, except for the femoral neck, where BMD at 156 weeks decreased significantly by 3% (p<0.003). In 3 patients, all in the calcium group, six new fractures were found. There were no serious adverse effects. We conclude that intermittent, cyclic treatment with etidronate causes a significant increase in the BMD of the lumbar spine and the proximal femur in osteopenic postmenopausal women, and that treatment is safe and has no serious adverse effects.     

北京地区老年髋部脆性骨折患者术后抗骨质疏松症药物治疗现状及影响因素分析

目的 评估北京地区老年髋部脆性骨折患者术后抗骨质疏松症药物（AOM）治疗现状并探讨其影响因素。方法 横断面研究。纳入2018年11月—2019年11月北京积水潭医院、北京医院、北京安贞医院、北京市昌平区医院、北京市顺义区医院、北京市房山区良乡医院收治的髋部脆性骨折患者1 963例,总结其人口学特征,并收集患者入院后30、120、365 d的临床资料,AOM治疗及健康基本补充剂使用情况。通过单因素和多因素logistic回归分析AOM治疗的影响因素。结果 1 963例老年髋部脆性骨折患者,住院时年龄65~102（79.3±7.2）岁,≥80岁患者占56.7%（1 113/1 963）;男性患者占30.8%（604/1 963）,女性患者占69.2%（1 359/1 963）;股骨颈骨折846例,股骨粗隆间骨折1 077例,股骨粗隆下骨折40例。综合3个时间点,在髋部骨折后1年内,33.0%（648/1 963）的患者接受过AOM治疗,71.0%（1 394/1 963）的患者使用过健康基本补充剂。入院后30、120、365 d患者AOM治疗率分别为23.0%（451/1 963）、17.9%（353/1 963）、21.0%（412/1 963）,健康基本补充剂使用率分别为59.0%（1 158/1 963）、45.0%（883/1 963）、38.0%（746/1 963）。单因素分析结果显示,年龄≥80岁[粗比值比（OR）=0.645,95%可信区间（CI） 0.495~0.840]、男性（粗OR=0.760,95% CI 0.581~0.996）、共管模式（粗OR=3.025,95% CI 0.973~9.405）、居住地农村（粗OR=0.523,95% CI 0.388~0.704）、AOM服用史（粗OR=7.612,95% CI 2.227~26.020）、既往骨质疏松症史（粗OR=5.065,95% CI 3.149~8.147）、骨质疏松评估（粗OR=1.379,95% CI 1.105~2.451）是AOM治疗的影响因素。多因素分析结果显示,年龄≥80岁（调整后OR=0.618,95% CI 0.488~0.781）、男性（调整后OR=0.716,95% CI 0.565~0.908）、居住地农村（调整后OR=0.492,95% CI 0.375~0.645）是AOM治疗的危险因素;共管模式（调整后OR=2.632,95% CI 1.004~6.897）、AOM服用史（调整后OR=4.870,95% CI 2.080~11.402）、既往骨质疏松症史（调整后OR=4.804,95% CI 3.253~7.096）、骨质疏松评估（调整后OR=1.393,95% CI 1.041~1.862）是AOM治疗的保护因素。结论 北京地区老年髋部脆性骨折患者的AOM治疗率偏低。年龄≥80岁、男性、在农村居住的髋部脆性骨折患者治疗率较低,可采取共管模式,术前进行骨质疏松诊断与评估,提高骨质疏松治疗率。     

Factors predicting the acute effect of pamidronate on serum calcium in hypercalcemia of malignancy

Summary In this study we retrospectively reviewed results of the first 9 days of treatment with pamidronate at doses of 30 mg (n=13), 45 mg (n=9), and 90 mg (n=13) in an attempt to see what factors influenced the response of serum calcium to pamidronate.The nadir of serum calcium obtained post treatment was correlated with pretreatment levels of nephrogenous cyclic adenosine monophosphate (NcAMP), the renal tubular threshold for phosphate reabsorption (TmPO4), and the renal tubular threshold for calcium reabsorption (TmCa). Using the post treatment serum calcium levels, patients were divided into good and poor responders depending on whether a normal serum calcium was obtained.Pretreatment NcAMP was significantly correlated with the magnitude of the response of serum calcium (r=0.45, P=0.0001). Pretreatment NcAMP was significantly higher in the poor responders (mean±SEM): 65.0±9.4 nmol/liter GF (poor responders) versus 29.6±6.3 (good responders), P=0.004. NcAMP as a predictor of the acute response of serum calcium showed a sensitivity of 93% and a specificity of 72%. Pretreatment TmPO4 was negatively correlated with the serum calcium response post treatment (r=-0.41, P=0.003). However, though TmPO4 tended to be lower in the poor responders, this was not statistically significant [0.65 mmol/liter GF±0.09 (poor responders) versus 0.76 mmol/liter GF±0.06 (good responders)]. As a predictor of the acute response of serum calcium, TmPO4 was less good with a sensitivity of 70% and specificity of 58%. No significant correlation was present between TmCa and the serum calcium response. A significant negative correlation was evident between NcAMP and TmPO4 (r=-0.35, P=0.003), however, no significant correlation was evident between NcAMP and TmCa or TmPO4 and TmCa.These results suggest that in a hypercalcemic patient where evidence exists for the presence in circulation of a factor with PTH-like activity (i.e., NcAMP is elevated or TmPO4 is low) the response of serum calcium to pamidronate is less good. NcAMP would appear to be a useful predictor of the response of serum calcium, whereas TmPO4 is less discriminating.     

双膦酸盐对肺癌细胞增殖的影响

背景与目的双膦酸盐在临床上被广泛用于多种骨病的治疗，在动物实验中可减少乳腺癌及前列腺癌细胞骨转移的发生，抑制和减少肿瘤在骨上的发展及负累，但对同样易于发生骨转移的肺癌的作用尚缺少研究。本实验的目的是研究几种双膦酸盐（阿仑膦酸钠、埃本膦酸钠、亚甲基二膦酸钠及因卡膦酸二钠）对不同肺癌细胞体外增殖的抑制作用，并验证这种抑制作用的广泛性或者选择性。方法采用磺酰罗丹明B染色法检测不同浓度的双膦酸盐药物对肺癌细胞及人正常肝细胞体外增殖的影响。结果不同浓度的双膦酸盐药物作用72h后，能小同程度地抑制肺癌细胞的增殖，亚甲基二膦酸钠的抑制效果很小，埃本膦酸钠及因昔膦酸二钠的作用介于业甲基二膦酸钠和阿仑膦酸钠之间。不同的双膦酸盐对人正常肝细胞的影响具有差异性，亚甲基二膦酸钠、埃奉膦酸钠及因卡膦酸二钠均表现出低毒性，而阿仑膦酸钠的毒性显著。不同的肺癌细胞对双膦酸盐的敏感性也有明显差异，H446及SPC—A1相对较为耐受，而H460及A549则较为敏感。结论双膦酸盐药物对肺癌细胞及人正常肝细胞均有不同程度的抑制增殖作用，且这种作用与药物种类、浓度和肺癌细胞的种类有关。     

A review of Paget's disease of bone with a focus on the efficacy and safety of zoledronic acid 5 mg

ABSTRACT

Background: Paget's disease of bone, the second most common metabolic bone disease in the United States, is characterized by localized areas of excessive bone resorption coupled with accelerated bone formation, resulting in new bone that is less structurally organized and is weaker than normal bone. Complications of Paget's disease can include bone pain, osteoarthritis, skeletal deformity, hearing loss, and fractures. The objective of this review is to provide a comprehensive overview of current standards of treatment in Paget's disease.

Scope: A review of literature from 1974 to 2007 was performed on topics such as epidemiology, etiology, treatment of Paget's disease of bone, and bisphos­phonates.

Findings: Paget's disease affects an estimated 2–7% of persons of age 55 years or older in North America and western Europe. Antiresorptive treatment with bisphos­phonates is the standard treatment, but there may be limitations to oral therapy. Intravenous pamidronate is efficacious and has long been available, but its use is hindered by an impractical recommended dosing regimen of 30?mg IV over 4?h for three consecutive days. In two identical, double-blind, 6-month trials, 96% of patients treated with a one-time intravenous treatment of zoledronic acid 5?mg achieved therapeutic response, compared with 74% treated with 60 days of daily oral treatment with risedronate 30?mg (?p < 0.001). One limitation of this review is that historical data are not reviewed in the same level of detail as newer treatments, because recent advances in pharmacotherapy of Paget's disease have reduced the clinical utility of the older drugs.

Conclusion: The etiology of Paget's disease is unclear, but some evidence suggests genetic and viral com­ponents. Bisphosphonates restore normal bone turnover and relieve bone pain, but oral formulations may be limited by complicated dosing regimens and poor gastro­intestinal absorption. The bisphosphonate, zoledronic acid is administered as a single intravenous infusion and offers antiresorptive efficacy and longer-lasting remission.