QUALZICE: a QUALitative exploration of the experiences of the participants from the ZICE clinical trial (metastatic breast cancer) receiving intravenous or oral bisphosphonates.
ABSTRACT: This qualitative sub-study aimed to explore the experiences of participants on the National Cancer Research Institute ZICE clinical trial, a randomised trial assessing two types of bisphosphonate treatment in breast cancer patients with bone metastases. Participants in the clinical trial were randomly allocated to receive either zoledronate, delivered by an intravenous (IV) infusion at clinic, or oral ibandronate, taken at home.Qualitative research interviews were conducted with participant groups organised by treatment and location. Interviews covered experiences and understanding of bisphosphonate treatment, the experience of the delivery mechanisms (IV or oral), side effects and benefits, and quality of life issues. The analytic framework was interpretative phenomenological analysis.This paper reports on one of four superordinate themes: participants' experience of the ZICE trial, which explores the participants' experiences with clinical trial-related processes. Results show that participants were generally satisfied with their randomised treatment, although most participants had an initial preference for oral bisphosphonates. Some difficulties were reported from participants for both interventions: needle phobia, poor veins, difficulty with swallowing and gastric side effects, but pain control was improved with both modes of delivery. However, the infused bisphosphonate was reported to lose effectiveness after three weeks for some participants, whereas the oral bisphosphonate was reported to give consistent pain control. Geographical location and distance to travel made little difference to convenience of access to clinic as the reported lengths of travel time were similar due to traffic congestion in the urban areas. Most participants understood the trial processes, such as randomisation, and information about bisphosphonates but some participants showed little understanding of certain aspects of the trial. Some participants reported difficulties in accessing dental treatment due to their dentist's perceptions of bisphosphonate treatment.In trials of medicinal products, especially when testing for non-inferiority, participants' preferences and idiosyncrasies in relation to treatments should not be assumed. This study has shown that in a trial context, participants' views can usefully add to the main trial outcomes and they should be taken into account when prescribing in the real world.ISRCTN13914201. Main ZICE MREC: 05/MRE09/57. CRUK E/04/022.
Project description:OBJECTIVE:To explore the acceptability of different bisphosphonate regimens for the treatment of osteoporosis among patients, clinicians and managers, payers and academics. DESIGN:A systematic review of primary qualitative studies. Seven databases were searched from inception to July 2019. Screening, data extraction and quality assessment of full-articles selected for inclusion were performed independently by two authors. A framework synthesis was applied to extracted data based on the theoretical framework of acceptability (TFA). The TFA includes seven domains relating to sense-making, emotions, opportunity costs, burden, perceived effectiveness, ethicality and self-efficacy. Confidence in synthesis findings was assessed. SETTING:Any developed country healthcare setting. PARTICIPANTS:Patients, healthcare professionals, managers, payers and academics. INTERVENTION:Experiences and views of oral and intravenous bisphosphonates. RESULTS:Twenty-five studies were included, mostly describing perceptions of oral bisphosphonates. We identified, with high confidence, how patients and healthcare professionals make sense (coherence) of bisphosphonates by balancing perceptions of need against concerns, how uncertainty prevails about bisphosphonate perceived effectiveness and a number of individual and service factors that have potential to increase self-efficacy in recommending and adhering to bisphosphonates. We identified, with moderate confidence, that bisphosphonate taking induces concern, but has the potential to engender reassurance, and that both side effects and special instructions for taking oral bisphosphonates can result in treatment burden. Finally, we identified with low confidence that multimorbidity plays a role in people's perception of bisphosphonate acceptability. CONCLUSION:By using the lens of acceptability, our findings demonstrate with high confidence that a theoretically informed, whole-system approach is necessary to both understand and improve adherence. Clinicians and patients need supporting to understand the need for bisphosphonates, and clinicians need to clarify to patients what constitutes bisphosphonate treatment success. Further research is needed to explore perspectives of male patients and those with multimorbidity receiving bisphosphonates, and patients receiving intravenous treatment. PROSPERO REGISTRATION NUMBER:CRD42019143526.
Project description:Several studies documented declines in treatment adherence with generic forms of oral bisphosphonates in osteoporosis compared to branded forms, while others did not support this relation. Our aim was to compare medication adherence with brand versus generic forms of oral bisphosphonates. A new-user cohort study was conducted using routinely collected administrative and healthcare data linked at the individual level extracted from a nationwide representative sample of the French National Healthcare Insurance database. We included all patients aged 50 and older, new users of oral bisphosphonates for primary osteoporosis between 01/01/2009 and 31/12/2015. Two components of adherence were measured: implementation (continuous multiple-interval measure of medication availability version 7; CMA7) and persistence (time to discontinuation). The sample was composed of 1,834 in the "brand bisphosphonate" group and 1,495 patients in the "generic bisphosphonate" group. Initiating oral bisphosphonate treatment with brand was associated with a higher risk of discontinuation within 12 months (Hazard Ratio?=?1.08; 95%CI?= [1.02;1.14]). The risk of good implementation (CMA7???0.90) was significantly lower in "brand bisphosphonate" group (Risk Ratio = 0.90; 95%CI = [0.85; 0.95]). We did not find any evidence to support the hypothesis of a lower adherence to generic bisphosphonates. In fact, prescribing of generic bisphosphonates led to a higher persistence rate and to better implementation at 1 year.
Project description:OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis worldwide. Pain and reduced function are the main symptoms in this prevalent disease. There are currently no treatments for OA that modify disease progression; therefore analgesic drugs and joint replacement for larger joints are the standard of care. In light of several recent studies reporting the use of bisphosphonates for OA treatment, our work aimed to evaluate published literature to assess the effectiveness of bisphosphonates in OA treatment. METHODS: Literature databases were searched from inception to the 30th June 2012 for clinical trials of bisphosphonates to treat OA pain. Data was appraised and levels of evidence determined qualitatively using best evidence synthesis from the Cochrane Collaboration. The two largest studies were conducted with risedronate in the treatment of knee OA, for which meta-analyses were performed for pain and functional outcomes. RESULTS: Our searches found 13/297 eligible studies, which included a total of 3832 participants. The trials recruited participants with OA of the hand (n=1), knee (n=8), knee and spine (n=3), or hip (n=1). Our meta-analysis of the two largest knee studies using risedronate 15 mg showed odds ratios favouring placebo interventions for the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain (1.73), WOMAC function (2.03), and WOMAC stiffness (1.82). However, 8 trials (61.5%) reported that bisphosphonates improve pain assessed by VAS scores and 2 (38.5%) reported significant improvement in WOMAC pain scores compared to control groups. CONCLUSIONS: There is limited evidence that bisphosphonates are effective in the treatment of OA pain. Limitations of the studies we analysed included the differences in duration of bisphosphonate use, the dose and route of administration and the lack of long-term data on OA joint structure modification post-bisphosphonate therapy. Future more targeted studies are required to appreciate the value of bisphosphonates in treating osteoarthritis pain. TRIAL REGISTRATION: PROSPERO Register CRD42012002541.
Project description:To compare the efficacy of bazedoxifene and oral bisphosphonates for the prevention of nonvertebral fractures (NVFs) in women with higher risk of postmenopausal osteoporosis (i.e., the Fracture Risk Assessment Tool [FRAX] score ? 20%), based on currently available evidence from randomized controlled trials.Randomized controlled trials evaluating the NVF relative risk reduction (RRR) with oral bisphosphonates or bazedoxifene were identified by a systematic literature review and combined by means of a network meta-analysis. A subgroup of patients with a FRAX score of 20% or more in the bazedoxifene phase III osteoporosis study was selected as the population of interest on the basis of the bazedoxifene label. In one analysis (analysis 1), the placebo response of the subgroup with a FRAX score of 20% or more was the benchmark to select comparable bisphosphonate trials. Additional analyses incorporated the aggregate data from the bisphosphonate trials with all the FRAX subgroups (analysis 2) or with the individual patient data from the bazedoxifene trial (analysis 3).Nine identified bisphosphonate trials (alendronate, ibandronate, risedronate; N = 23,440 patients) with a similar placebo response as observed for the subgroup of high risk patients in the bazedoxifene trial were included in analysis 1. The results of the network meta-analysis of this study set suggest that bazedoxifene is expected to have an RRR of 0.43 (95% credible interval [CrI] -0.19 to 0.72) versus alendronate, 0.58 (95% CrI 0.05-0.81) versus ibandronate, and 0.39 (95% CrI -0.29 to 0.70) versus risedronate. Analyses in which treatment effects with bisphosphonates were projected to a population with a FRAX score of 20% or more with meta-regression approaches (analysis 2 and analysis 3) provide similar findings.Based on an indirect comparison of randomized trials, bazedoxifene is expected to have at least a comparable RRR of NVF as alendronate, ibandronate, and risedronate in women with higher risk of postmenopausal osteoporosis.
Project description:Introduction: Bisphosphonates are well known above all for their use in the treatment of osteoporosis. They also play an important role as accompanying therapy for advanced tumour diseases with extensive spread into the skeletal system. Their adjuvant use in the treatment of breast cancer without bony metastases is currently a subject of controversial discussion. The objective of the present evaluation is to describe the use of bisphosphonates in the therapy for breast cancer. We will show how frequently bisphosphonates are used, which bisphosphonates are preferred and what specific features patients under bisphosphonate therapy exhibit. Methods and Materials: The pseudonymous data set from the biobank of the German PATH foundation was used for the evaluation. From the total collective, 2492 patients were selected after consideration of the inclusion and exclusion criteria. The selected patient collective was divided into two groups (with and without bisphosphonate therapy) and the two groups compared with one another with the help of descriptive statistics. Results: 17.5?% of the 2492 patients had prescriptions for a bisphosphonate as part of their therapy. The most frequently administered bisphosphonate was zoledronate. Pathological (induced by tumour therapy) osteoporosis was the most frequently stated indication among the bisphosphonate patients, followed by consumption starting prior to the breast cancer therapy and treatment of bony metastases. Patients under bisphosphonate and antihormonal therapy frequently received an aromatase inhibitor as the active principle in the antihormonal therapy whereas patients under antihormonal therapy but without bisphosphonates more frequently received tamoxifen as active principle. Ten of the 2492 patients reported receiving bisphosphonate therapy as prophylaxis for bony metastases without a documented and approved indication. Use of bisphosphonates in the course of the GAIN, ICE, SUCCESS or, respectively, NATAN trials was reported by 29 of the 2492 patients. Conclusions: In the PATH collective, bisphosphonates were employed above all for the treatment of (tumour therapy-induced) osteoporosis and bony metastases. Off-label use and participation in clinical trials played only a minor role in this patient collective. Against the background of the uncertain data status for the adjuvant use of bisphosphonates, the development (and use) of standardised, validated questionnaires to record the indications for and frequency of use of bisphosphonate therapy is recommended.
Project description:<h4>Background</h4>Demineralized bone matrix is commonly used as a bone graft substitute, either alone or to supplement an osteoconductive material, because of its osteoinductive properties. The aging of the population has led to an increase in the number of prospective donors of demineralized bone matrix who have taken bisphosphonates to prevent osteoclast-mediated bone resorption. The aim of this study was to determine whether oral bisphosphonate usage affects the osteoinductivity of demineralized bone matrix from donors.<h4>Methods</h4>Sex-matched and age-matched pairs of samples were provided by four tissue banks (three or four pairs per bank). Demineralized bone matrix donors without bisphosphonate treatment had a mean age (and standard deviation) of 69.1 ± 2.5 years, and donors with bisphosphonate treatment had a mean age of 68.9 ± 2.0 years. Each pair included one donor known to have taken bisphosphonates and one who had not taken bisphosphonates. Demineralized bone matrix previously confirmed as osteoinductive was the positive control, and heat-inactivated demineralized bone matrix was the negative control. Demineralized bone matrix incubated with 1 mL of phosphate-buffered saline solution containing 0, 0.002, 2.0, or 2000 ng/mL of alendronate was also tested. Gelatin capsules containing 15 mg of demineralized bone matrix were implanted bilaterally in the gastrocnemius muscle of male nude mice (eight implants per group). The mice were killed thirty-five days after implantation, and hind limbs were recovered and processed for histological analysis. Osteoinductivity was measured with use of a qualitative score and by histomorphometry.<h4>Results</h4>Nine of fifteen samples from donors who had had bisphosphonate treatment and ten of fifteen samples from patients who had not had bisphosphonate treatment were osteoinductive. Qualitative mean scores were comparable (1.7 ± 0.4 for those without bisphosphonates and 1.9 ± 0.7 for those with bisphosphonates). Osteoinductive demineralized bone matrix samples produced ossicles of comparable size, regardless of bisphosphonate usage. Histomorphometric measurements of the area of new bone formation and residual demineralized bone matrix were also comparable. The addition of alendronate to control demineralized bone matrix did not affect its osteoinductivity.<h4>Conclusions</h4>Demineralized bone matrix samples from donors treated with bisphosphonates and donors not treated with bisphosphonates have the same ability to induce bone formation. However, it is not known if the quality of the new bone is affected, with subsequent consequences affecting bone remodeling.
Project description:Despite access to effective, safe, and affordable treatment for osteoporosis, at-risk women may choose not to start bisphosphonate therapy. Understanding the reasons women give for rejecting a clinician's offer of treatment during consultations and how clinician's react to these reasons may help clinicians develop more effective strategies for fracture prevention and medication adherence.We conducted a videographic evaluation of encounters in the Osteoporosis Choice randomized trial of a decision aid about bisphosphonates vs. usual primary care. Eligible videos involved consultations with women with an estimated 10-year fragility fracture risk >20% who verbalized at least one reason to not take bisphosphonates. Two reviewers independently reviewed eligible videos and verbatim transcripts, classifying patient views about bisphosphonate use, clinicians response to those views, and patient adherence at 6 months post visit.Eighteen video recordings (12 with decision aid) were eligible for analyses. We identified 37 reasons for and against bisphosphonate therapy. Eleven patients rejected treatment, offering 9 (average of 2 per patient) unique reasons against initiating bisphosphonates (most common: side effects 39% and distrust of medications in general 33%). When physicians conceded to patient views the outcome was no bisphosphonate use. Adherence to choices at 6 months was 100%.The expression of patient preferences is sometimes unfavorable to bisphosphonates treatment even among well-informed patients at high risk for osteoporotic fractures. At 6 months, patients who expressed concerns about these medicines behaved consistently with the decision made during the visit.
Project description:We evaluated the association between bisphosphonate use and (1) upper gastrointestinal cancer, (2) upper endoscopy, (3) incident Barrett's esophagus, and (4) prescription antacid initiation among Medicare beneficiaries. We found no bisphosphonate-cancer association and negative bisphosphonate-Barrett's association.Bisphosphonates can irritate the esophagus; a cancer association has been suggested. Widespread bisphosphonates use compels continued investigation of upper gastrointestinal toxicity.Using a 40% Medicare random sample denominator, inpatient, outpatient (2003-2011), and prescription (2006-2011) claims, we studied patients age 68 and older with osteoporosis and/or oral bisphosphonate use. Inverse propensity weighting estimated marginal structural models for the effect of bisphosphonate intensity (pills per month) and cumulative bisphosphonate pills received on upper gastrointestinal cancer risk. Secondary analyses of sub-cohorts without past bisphosphonates or upper endoscopy assessed bisphosphonate initiation and risk of (1) upper endoscopy, (2) incident Barrett's esophagus, and (3) prescription antacid initiation.The cohort included 1.64 million beneficiaries: 87.9% women, mean age, 76.8 (standard deviation (SD) 9.3); mean follow-up, 39.6 months; 38.1% received oral bisphosphonates. Cumulative bisphosphonate receipt, among users, ranged from 4 to 252 pills (5th to 95th percentile). We identified 2,308 upper gastrointestinal cancers (0.43/1000 person years). We found no association between cumulative bisphosphonate pills and cancer, odds ratio (OR) for each additional pill 1.00 (95% confidence interval (CI) 1.00, 1.00). In sub-cohorts, compared to none, lowest cumulative bisphosphonate use (one to nine pills) was associated with higher risk of endoscopy (OR 1.11, 95% CI 1.08-1.14) and antacid initiation (OR 1.13, 95% CI 1.10-1.16); higher intensity conferred no increased risk. Higher intensity and higher cumulative bisphosphonate category were associated with lower Barrett's risk.We found no bisphosphonate-cancer association and negative bisphosphonate-Barrett's association. Bisphosphonate initiation appears to identify patients susceptible to early irritating effects; clinicians might offer alternatives and delay endoscopy or antacids.
Project description:BACKGROUND: This paper presents the model and results to evaluate the use of teriparatide as a first-line treatment of severe postmenopausal osteoporosis (PMO) and glucocorticoid-induced osteoporosis (GIOP). The study's objective was to determine if teriparatide is cost effective against oral bisphosphonates for two large and high risk cohorts. METHODS: A computer simulation model was created to model treatment, osteoporosis related fractures, and the remaining life of PMO and GIOP patients. Natural mortality and additional mortality from osteoporosis related fractures were included in the model. Costs for treatment with both teriparatide and oral bisphosphonates were included. Drug efficacy was modeled as a reduction to the relative fracture risk for subsequent osteoporosis related fractures. Patient health utilities associated with age, gender, and osteoporosis related fractures were included in the model. Patient costs and utilities were summarized and incremental cost-effectiveness ratios (ICERs) for teriparatide versus oral bisphosphonates and teriparatide versus no treatment were estimated.For each of the PMO and GIOP populations, two cohorts differentiated by fracture history were simulated. The first contained patients with both a historical vertebral fracture and an incident vertebral fracture. The second contained patients with only an incident vertebral fracture. The PMO cohorts simulated had an initial Bone Mineral Density (BMD) T-Score of -3.0. The GIOP cohorts simulated had an initial BMD T-Score of -2.5. RESULTS: The ICERs for teriparatide versus bisphosphonate use for the one and two fracture PMO cohorts were €36,995 per QALY and €19,371 per QALY. The ICERs for teriparatide versus bisphosphonate use for the one and two fracture GIOP cohorts were €20,826 per QALY and €15,155 per QALY, respectively. CONCLUSIONS: The selection of teriparatide versus oral bisphosphonates as a first-line treatment for the high risk PMO and GIOP cohorts evaluated is justified at a cost per QALY threshold of €50,000.
Project description:Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P=0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47 vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.