Persistent bisphosphonate use and the risk of osteoporotic fractures in clinical practice: a database analysis study

INTRODUCTION: International guidelines on the treatment and prevention of osteoporosis recommend the use of bisphosphonates to prevent fractures in this population. However, low persistent use of bisphosphonates could considerably limit the prevention of fractures in clinical practice. OBJECTIVE: This study aimed to investigate the association between persistent use of bisphosphonates and the risk of osteoporotic fractures in clinical practice. METHODS: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of more than two million subjects in defined areas in the Netherlands. Persistence with bisphosphonate therapy was assessed during a period of 3 years. A nested matched case control study (cases:controls = 1:10) was performed to study the association between persistent bisphosphonate use and hospitalisation for osteoporotic fractures and analysed by conditional logistic regression analysis. The analyses were adjusted for patient characteristics such as previous hospitalisations for fractures, co-morbidity and co-medication. RESULTS: 14,760 new female users of bisphosphonates were identified of which 541 women had a hospitalisation for osteoporotic fracture after start of bisphosphonate treatment (1-3 years follow-up). One-year persistence rates increased from 33% with alendronate daily to 48% with alendronate weekly, an increase of 15%. Similar results were obtained with risedronate daily and weekly. One year persistent use of bisphosphonates resulted in a statistical significant 26% lower fracture rate (OR 0.74; 95%CI 0.57-0.95) whereas 2 year persistent use resulted in a 32% lower rate (OR 0.68; 95%CI 0.47-0.96). CONCLUSIONS: Persistent use of bisphosphonates decreases the risk of osteoporotic fractures in clinical practice. Approximately 6% of fractures among users of bisphosphonates could be prevented if persistence was improved by 20%. However, current persistence with bisphosphonate therapy is suboptimal and strategies that further increase persistence are likely to further prevent the number of fractures.     

Relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures

ABSTRACT

Objectives: To investigate the relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures.

Methods: The PHARMO database was used to identify new female bisphosphonate users, aged ≥ 45 years or with diagnosed post-menopausal osteoporosis in the period of January 1996 – June 2004. Within this cohort a matched case–control study was performed. Cases were defined as patients who were hospitalized for an osteoporotic fracture and were matched to ten controls without a fracture by duration of follow-up. The duration of compliant bisphosphonate use (i.e., medication possession ratio ≥ 80%) preceding the outcome date was determined.

Results: Of 14 760 new female bisphosphonate users, 387 fracture patients fulfilled the inclusion criteria. These cases were matched to 3950 controls. Increasing duration of compliant bisphosphonate use was associated with a decreased risk of fracture (trend p < 0.01). Adjusted for several cofactors, 1–2 years of compliant bisphosphonate use and 3–4 years of compliant bisphosphonate use decreased fracture risk by 12% and 46%, respectively, compared to < 1 year of compliant bisphosphonate use (OR 0.88; 95% CI 0.66–1.18 and OR 0.54; 95% CI 0.35–0.84, respectively). Unexpectedly, 5–6 years of compliant bisphosphonate use was no longer associated with a decreased risk of fractures compared to < 1 year of compliant bisphosphonate use (OR 1.12, 95% CI 0.66–1.88).

Conclusions: These results show a direct link between duration of compliant bisphosphonate use and fracture risk, and confirm the importance of continuing the use of bisphosphonates to maintain optimal bone protection. However, this link is inconclusive for bisphosphonate use for more than 4 years.     

Cost-effectiveness of bisphosphonate therapies for women with postmenopausal osteoporosis: implications of improved persistence with less frequently administered oral bisphosphonates

ABSTRACT

Objective: Studies have shown that weekly bisphosphonate dosing results in improved persistence compared to daily dosing among patients with postmenopausal osteoporosis, yet more than 50% of patients discontinue therapy within a year. An oral, less frequent administration bisphosphonate provides an opportunity to improve persistence, a parameter not well modeled in previous cost-effectiveness analyses of osteoporosis therapies.

Research design and methods: We developed a Markov model to estimate the effect of improved persistence on the cost-effectiveness of bisphosphonates among postmenopausal women with established osteoporosis (vertebral fracture and bone mineral density T-score ≤ –2.5) and an average age of 78 years. Fracture risks, clinical efficacy, mortality, resource use, costs, and utilities were obtained from the published literature. Persistence rates were derived primarily from a published clinical trial. Approximately 50% greater persistence with a monthly versus a weekly therapy was assumed on the basis of the PERSIST study, a 6-month, randomized, head-to-head prospective study that investigated treatment persistence in postmenopausal osteoporotic women on monthly versus weekly bisphosphonate therapy. Persistence was extrapolated to a maximum of 5 years. Following discontinuation, treatment benefit declined linearly and proportionally to the duration of active treatment.

Results: Based on model estimates, more fractures were avoided (versus no treatment) with monthly bisphosphonate (58.1 per 1000 treated women) than with weekly bisphosphonates (33.8 per 1000 treated women), resulting in lower fracture care costs per woman ($7317 and $7548, respectively). The incremental cost per quality-adjusted life-year gained was lower with a monthly bisphosphonate ($13?749) than with weekly bisphosphonates ($16?657) when compared to no treatment. The incremental cost per quality-adjusted life-year of a monthly bisphosphonate was $9476 when compared to a weekly bisphosphonate.

Conclusions: In postmenopausal women with established osteoporosis, improvement in persistence with a less frequently administered oral bisphosphonate therapy could augment the fracture benefit and thereby improve cost-effectiveness. Further studies are required to refine the estimates of cost-effectiveness in order to address limited availability of adherence and fracture risk data.     

Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies

ABSTRACT

Objective: The objective was to compare the efficacy of bisphosphonates regarding the prevention of vertebral fractures in postmenopausal women with osteoporosis.

Methods: Seven randomized placebo controlled trials investigating the effects of zoledronic acid (one study), alendronate (three studies), ibandronate (one study), and risedronate (two studies) in terms of fractures with a follow-up of 3 years were identified with a systematic literature search. The endpoint of interest was vertebral fractures. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison (MTC). With MTC the relative treatment effect of one intervention to another can be obtained in the absence of head-to-head evidence. MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics.

Results: There is a 98% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all four bisphophonates compared. Zoledronic acid showed an OR of 0.28 (95% Credible Interval 0.22; 0.35) relative to placebo, an OR of 0.57 (0.36; 0.92) relative to ibandronate, an OR of 0.54 (0.39; 0.75) relative to alendronate, and an OR of 0.49 (0.34; 0.69) relative to risedronate. Alendronate, ibandronate, and risedronate showed comparable vertebral fracture reductions. Indirect comparisons using a conservative random effects model supported these findings.

Conclusion: An indirect comparison of findings from placebo controlled randomized studies indicates that zoledronic acid provides a greater vertebral fracture risk reduction in postmenopausal women with osteoporosis than ibandronate, alendronate, or risedronate.     

Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of phase III studies

ABSTRACT

Objective: The marketed doses of ibandronate, 150?mg once-monthly oral and 3?mg quarterly intravenous (IV) injection, produce greater increases in lumbar spine bone mineral density than treatment with the 2.5?mg oral daily dose. This meta-analysis assessed whether these doses also reduce fracture risk relative to placebo.

Study design and methods: Individual patient data from the intent-to-treat populations of the BONE, IV fracture prevention, MOBILE, and DIVA studies were grouped into three dose levels based on annual cumulative exposure (ACE), defined as the annual dose (mg) × bioavailability (0.6%, oral; 100%, IV) or placebo. Six key non-vertebral fractures (NVFs) (clavicle, humerus, wrist, pelvis, hip, and leg), all NVFs, and all clinical fractures were examined.

Results: This meta-analysis included 8710 patients. Cox proportional-hazards models estimated the adjusted relative risk (RR) for fracture with ibandronate versus placebo, and time to fracture was compared using log-rank tests. The high-dose group (ACE?≥?10.8?mg) showed significant reductions in the adjusted RR of key NVFs (34.4%, p?=?0.032), all NVFs (29.9%, p?=?0.041), and clinical fractures (28.8%, p?=?0.010) relative to placebo. The high-dose group also had significantly longer time to fracture versus placebo for key NVFs (p?=?0.031), all NVFs (p?=?0.025), and clinical fractures (p?=?0.002). Study limitations included: not all studies were placebo-controlled; a limited number of baseline characteristics were available for multivariate analyses.

Conclusion: Ibandronate at dose levels of ACE?≥?10.8?mg, which includes the marketed 150?mg once-monthly oral and 3?mg quarterly IV injection regimens, may provide significant non-vertebral and clinical fracture efficacy.     

Impact of treatment efficacy and dosing frequency on cost-effectiveness of bisphosphonate treatment for osteoporosis: a perspective

Abstract

Background:

Osteoporosis is a chronic disease that presents a large economic burden both on the affected individual and on society. Osteoporotic fractures are a cause of significant morbidity and mortality. Given the high prevalence of osteoporosis and related costs, understanding the factors that determine the cost-effectiveness of osteoporosis therapy is important for physicians and managed-care organizations. Bisphosphonates are considered first-line therapy for osteoporosis, and pharmacological differences between them relate not only to differences in efficacy and safety, but also have an impact on health economics. Efficacy and persistence with therapy influence fracture risk-reduction and should be considered when determining the best osteoporosis therapy for each patient.     

经皮椎体成形术治疗骨质疏松性椎体骨折不愈合

目的 探讨经皮椎体成形术治疗骨质疏松性椎体骨折不愈合的临床效果.方法 回顾性分析自2006年9月至2010年7月本院采用经皮椎体成形术治疗骨质疏松性椎体骨折不愈合患者15例的临床资料.术前、术后2d、6个月进行疼痛视觉模拟评分(VAS),评价临床治疗效果,记录骨水泥注入量及手术并发症.结果 随访6 ～ 12个月,术后6个月和术后2 d VAS评分明显低于术前[(2.4±0.4)分、(4.4±0.5)分比(9.3±0.6)分,差异有统计学意义,t=3.2407、4.9427,均P＜0.01].术后6个月与术后2 d VAS 评分比较差异无统计学意义(P＞0.05).骨水泥注入量为2.9～4.5 ml,平均3.4ml.所有患者均无骨水泥渗漏导致的临床并发症.结论 经皮椎体成形术治疗骨质疏松性椎体骨折不愈合是安全、有效的.     

椎体成形术治疗压缩性骨折的效果评价

目的探讨经皮椎体成形术（PVP）治疗压缩性骨折的临床效果。方法应用经皮椎体成形术治疗骨质疏松性椎体压缩骨折患者80例,其中胸椎病变36例,腰椎病变44例,在C形臂X线机透视导向下,经皮穿刺病变椎体后注入3．0～6．5ml骨水泥（平均4．9ml）。术毕患者保持仰卧6h观察,抗感染治疗1—3d并复查平片或CT。观察止痛效果有效率和并发症。结果治疗80例93个椎体,均行单侧穿刺,64例疼痛完全缓解,17例明显缓解,4例部分缓解。术后CT证实少量骨水泥渗漏11例,随访6-18个月,所有患者疼痛无反复,无严重并发症发生。结论PVP术治疗压缩性骨折不仅可以迅速缓解患者的疼痛,而且可长期提高患者的生活质量。     

Oral nitrogen-containing bisphosphonates: a systematic review of randomized clinical trials and vertebral fractures

ABSTRACT

Background: Vertebral fractures are the most common osteoporotic fracture. They are associated with increased morbidity and mortality, and also predict future vertebral and non-vertebral fracture risk. Bisphosphonates are the current mainstay for the treatment of postmenopausal osteoporosis. Health authority guidelines request that assessment of vertebral fracture risk reduction is part of the evaluation of bisphosphonate efficacy. In this review, we compare the published evidence for the efficacy of the nitrogen-containing oral bisphosphonates in reducing the risk of vertebral fractures.

Methods: A review of publications in the treatment of postmenopausal osteoporosis and the most frequently prescribed oral bisphosphonate therapies (alendronate, ibandronate and risedronate) was carried out using the Dialog (Embase and Medline) and Cochrane online scientific citation databases. Eligible publications were those reporting randomized, placebo-controlled trials that included vertebral fracture as the primary or secondary endpoint (any time-point).

Results: Of 159 publications identified, six studies assessing alendronate, ibandronate and risedronate met the pre-defined eligibility criteria. In total, 14?083 women were included in the studies, with 8182 patients receiving active treatment. Most studies were 3?years in duration. Discontinuation rates varied from 11 to 45%, being highest in those studies that specified one or more vertebral fracture as part of the inclusion criteria. Across these studies, the reduction in the risk of vertebral fractures ranged from 41 to 62% (44–48% for alendronate; 41–49% for risedronate; 62% for ibandronate).

Conclusions: Nitrogen-containing oral bisphosphonates effectively reduce the risk of osteoporotic vertebral fracture, with the magnitude of effect ranging from 41 to 62%.     

经皮穿刺球囊扩张椎体成形术治疗骨质疏松性压缩性骨折的临床疗效分析

目的：分析探讨经皮穿刺球囊扩张椎体成形术（PKP）在骨质疏松性压缩性骨折（OVCF）治疗中的临床疗效。方法：收集2007年8月～2010年8月在本院诊治的骨质疏松性压缩性骨折患者48例,患者均经进行双光子骨密度测定、磁共振显影、术前X线、CT/MRI等临床影像学检测进行病症诊断。在C型臂X线机透视下,采用经皮穿刺双侧（或单侧）椎弓根入路,在X线透视注射骨水泥。术后观察X线下患者椎体高度变化,采用视觉模式数字评分法对患者疼痛程度进行衡量评价。结果：术后随访48例患者病椎椎体高度均无再塌陷或高度丢失。术后3 d内,患者胸、腰背疼痛症状明显缓解,无症状加重者,且未出现脊神经损伤症状,患者中4例出现骨水泥于椎体前方少量外溢但未出现严重并发症。手术前后VAS分别为（8.75±0.77）分及（2.31±1.32）分,P〈0.01;伤椎体高度分别为（14.4±3.1）mm及（24.8±2.7）mm,P〈0.01。结论：经皮穿刺球囊扩张椎体成形术作为一种新型微创技术,在骨质疏松性压缩性骨折治疗中疗效显著,能有效改善患者术后的生存质量。     

经皮椎体成形术治疗老年人骨质疏松椎体压缩性骨折

目的：探讨经皮椎体成形术治疗老年人骨质疏松椎体压缩性骨折的效果。方法采用C臂X线透视下经皮椎体成形术治疗骨质疏松性椎体压缩骨折患者56例,所有患者均统计术前、术后Cobb角、VAS评分,以及术后并发症。结果所有患者均顺利完成手术,手术时间30～55 min,术中注入骨水泥2～5 mL,56例患者术后疼痛均明显减少或消失。 VAS：术前（7．9±1．5）分,术后（2．3±1．2）分;Cobb角：术前（25．8±4．9）°,术后（12．6±3．6）°。术后3～7 d患者在腰围保护下可以下床活动,经过2～14个月的随访,所有腰椎骨折患者疼痛均消失,未发生神经损伤、肺栓塞、骨水泥椎管内渗漏等并发症。结论经皮椎体成形术治疗老年人骨质疏松性椎体压缩性骨折疗效显著,可在短时间内解除患者痛苦,恢复正常活动,是一种安全有效的治疗手段。     

单双侧穿刺经皮椎体成形术治疗单节段椎体压缩性骨折的中远期临床疗效观察

目的 比较经皮单侧穿刺和双侧穿刺椎体成形术(PVP)治疗单一节段骨质疏松性椎体压缩性骨折的中、远期临床疗效.方法 接受单节段PVP治疗的患者共95例,进行平均26.4个月术后随访,其中接受单侧穿刺PVP患者44例,失访2例,接受双侧穿刺PVP患者51例,失访4例.手术前后分别使用VAS疼痛评分和SF-36评分,评估两种术式对于患者中远期临床疗效的影响.结果 单侧组和双侧组的VAS术后即时评分(2.69±0.55)分、(2.50±0.39)分,末次随访评分(2.63±0.46)分、(2.48±0.32)分,均明显低于术前评分(7.56±0.73)分、(7.45±0.54)分(t=1.895,1.801,均P＜0.01),单侧组和双侧组的SF-36末次随访评分(84.92±2.88)分、(86.71±2.73)分,均明显高于术前评分(58.35±2.69)分、(57.93±2.45)分(P＜0.01),但单侧组和双侧组间各时间点的VAS评分以及SF-36评分均差异无统计学意义(P＞0.05).单侧穿刺的手术时间、透射次数、骨水泥用量均明显低于双侧穿刺组(P＜0.01);而两组的骨水泥渗漏率和邻近椎体再发骨折率均差异无统计学意义.结论 相较于双侧穿刺,单侧穿刺PVP针对骨质疏松性压缩性骨折的治疗同样可以获得相对满意的中远期术后疗效,同时减少了手术时间,避免了术中过度的放射暴露.