Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study.

Background: Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives: 1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods: The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: • Stage 1A - we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. • Stage 1B - we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. • Stage 2 - we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates. Results: Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting. Conclusions: Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs. Future work: Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting. Limitations: Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates. Trial registration: This trial is registered as ISRCTN10491361. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in Health Technology Assessment; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.

Bisphosphonates are drug treatments commonly used to treat osteoporosis. Alendronate is the most used and is taken by mouth, weekly at a specific time of the week, which can be challenging. Less than one in four people continue this treatment beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered. The most acceptable and best value-for-money regimen is unclear. Our aim was to determine how effective alternative bisphosphonates are compared to alendronate at preventing fractures and whether reduction in fracture risk was achieved at a reasonable financial cost, but acceptable to patients. The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: a review of the published evidence on patients' and doctors' views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by interviews with patients and healthcare professionals. Stage 1B: an update of an existing study on how effective bisphosphonates are in preventing fragility fractures caused by osteoporosis and whether they are good value for money. Stage 2: identification of questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatments. Taking bisphosphonate medication often involves quite a lot of effort by patients, particularly when taking alendronate tablets. A yearly infusion of zoledronate treatment was more acceptable, easier to engage with and the most effective treatment compared to alendronate. However, the cost of administering zoledronate in hospital made alendronate better value for money. Bisphosphonates are effective in reducing the risk of fracture, but 'continuing with treatment', particularly alendronate tablets, remains a challenge. A yearly infusion of zoledronate offers an acceptable and effective treatment, but further research is needed to support patients and healthcare professionals in making decisions about the various treatments, benefits and cost savings of administering zoledronate outside of hospital and in the community.

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with osteoporosis at high risk of fracture in Belgium.

This study evaluated the cost-effectiveness of sequential treatment with romosozumab-to-alendronate compared to alendronate monotherapy and teriparatide-to-alendronate, in postmenopausal osteoporotic women from a Belgian healthcare perspective. Romosozumab-to-alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide-to-alendronate for osteoporotic women at high risk of fracture in Belgium. PURPOSE: This study aimed to evaluate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate compared to alendronate monotherapy and teriparatide followed by alendronate, in postmenopausal osteoporotic women at high risk of fracture, from a Belgian healthcare perspective. Romosozumab is reimbursed in Belgium since December 2021. METHODS: A Markov microsimulation model was used to evaluate the cost-effectiveness of romosozumab-to-alendronate compared to alendronate monotherapy and to teriparatide-to-alendronate over a lifetime horizon. Patients transition between five different health states every 6 months based on fracture risks or death. The model was populated with Belgium-specific epidemiological and cost data, where available. The fracture risk reduction of romosozumab treatment was collated from the ARCH study, and from a published network meta-analysis. Costs were included from a healthcare perspective (NIHDI). Cost-effectiveness was reported in terms of costs per quality-adjusted life year (QALY), reported in Euro (€) 2022. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: Romosozumab-to-alendronate was associated with 0.12 additional QALYs at an additional cost of €2314 compared to alendronate monotherapy, resulting in an ICER of €19,978. Compared to teriparatide-to-alendronate, romosozumab-to-alendronate was found to be dominant, with higher QALYs and lower costs. The base-case results were robust to uncertainty in the input parameters when conducting the sensitivity analysis. CONCLUSION: Sequential treatment with romosozumab followed by alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide followed by alendronate for postmenopausal women with osteoporosis at high risk of fracture in Belgium.

Cost-effectiveness of sequential treatment with abaloparatide followed by alendronate vs. alendronate monotherapy in women at increased risk of fracture: A US payer perspective.

OBJECTIVES: Emerging evidence supports sequential therapy with anabolic followed by antiresorptive in patients at high-risk of fragility fractures. This study assessed the cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) [(ABL/ALN)] compared to ALN monotherapy and to sequential treatment starting with antiresorptive therapy (ALN/ABL/ALN). METHODS: A previously validated Markov microsimulation model was used to estimate the cost-effectiveness of sequential ABL/ALN compared to ALN monotherapy and to sequential ALN/ABL/ALN from a lifetime US payer perspective. In line with practice guidelines, patients were assumed to receive ABL for 18 months followed by 5 years of ALN, or ALN monotherapy for 5 years, or a sequence of ALN for 2 years followed by 18 months of ABL and then by 3 years ALN. Evaluation was conducted for patients aged 50-80 years old with a BMD T-score ≤-3.5 and without a history of prior fracture, or with a T-score between -2.5 and -3.5 and a history of ≥ 1 osteoporotic fracture. RESULTS: Sequential ABL/ALN was cost-effective (threshold of US$150,000 per QALY) vs generic ALN monotherapy in women ≥60 years with a BMD T-score ≤-3.5 and in women with BMD T-score between -2.5 and -3.5 and history of osteoporotic fracture. In all simulated populations, sequential ABL/ALN therapy was dominant (lower costs, more QALYs) compared with sequential ALN/ABL/ALN, resulting from limited effect of ABL in patients previously treated with an antiresorptive agent. CONCLUSIONS: Sequential ABL/ALN therapy is cost-effective vs ALN monotherapy for US postmenopausal women aged ≥60 years at increased risk of fractures.

Cost-effectiveness of denosumab for high-risk postmenopausal women with osteoporosis in Thailand.

Aims: This study assessed the cost-effectiveness of denosumab for treating postmenopausal women with osteoporosis (PMO) at high risk of fracture in Thailand.Materials and methods: A published Markov cohort cost-effectiveness model was populated with country-specific data as available and other published data as needed. The model used a societal perspective, lifetime horizon, efficacy data from network meta-analysis of trials, and included costs for direct medical and non-medical care, informal care, and osteoporosis treatments to compare denosumab to no pharmacologic treatment (calcium and vitamin D supplements only) and to oral weekly alendronate. The base case (high-risk population) included postmenopausal women with femoral neck T-score ≤-2.5, mean age 65 years at entry, and history of vertebral fracture.Results: High-risk women with osteoporosis using denosumab had the greatest number of life years and quality-adjusted life-years (QALYs) with higher reductions in hip and vertebral fracture incidence compared with patients with no pharmacologic treatment. The incremental cost-effectiveness ratio (ICER) was 119,575 Thai Baht (THB) per QALY for denosumab versus no pharmacologic treatment and 199,186 THB per QALY for denosumab versus alendronate. Among Thai postmenopausal women with high-risk of fractures, denosumab was cost-effective compared with no pharmacologic treatment at a willingness-to-pay threshold of 160,000 THB per QALY. One-way sensitivity analysis showed models were most sensitive to changes in denosumab pricing.Limitations: Data from other countries used when country-specific data were unavailable may not accurately reflect the true experience in Thailand. The model focused explicitly on hip, vertebral, and wrist fractures, and therefore provides a conservative estimate of the overall potential impact of osteoporosis-related fracture. The fracture risk was not adjusted to reflect potential changes in risk after denosumab treatment discontinuation.Conclusions: In Thailand, denosumab offers a cost-effective osteoporosis treatment option versus no pharmacologic treatment in postmenopausal women at high risk of fracture.

Cost-effectiveness Analysis of Sequential Treatment of Abaloparatide Followed by Alendronate Versus Teriparatide Followed by Alendronate in Postmenopausal Women With Osteoporosis in the United States.

BACKGROUND: The US Food and Drug Administration has recently approved abaloparatide (ABL) for treatment of women with postmenopausal osteoporosis (PMO) at high risk of fracture. With increasing health care spending and drug prices, it is important to quantify the value of newly available treatment options for PMO. OBJECTIVE: To determine cost-effectiveness of ABL compared with teriparatide (TPTD) for treatment of women with PMO in the United States. METHODS: A discrete-event simulation (DES) model was developed to assess cost-effectiveness of ABL from the US health care perspective. The model included three 18-month treatment strategies with either placebo (PBO), TPTD, or ABL, all followed by additional 5-year treatment with alendronate (ALN). High-risk patients were defined as women with PMO ⩾65 years old with a prior vertebral fracture. Baseline clinical event rates, risk reductions, and patient characteristics were based on the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. RESULTS: Over a 10-year period, the DES model yielded average total discounted per-patient costs of $10 212, $46 783, and $26 837 and quality-adjusted life-years (QALYs) of 6.742, 6.781, and 6.792 for PBO/ALN, TPTD/ALN, and ABL/ALN, respectively. Compared with TPTD/ALN, ABL/ALN accrued higher QALYs at lower cost and produced an incremental cost-effectiveness ratio (ICER) of $333 266/QALY relative to PBO/ALN. In high-risk women, ABL/ALN also had more QALYs and less cost over TPTD/ALN and yielded an ICER of $188 891/QALY relative to PBO/ALN. Conclusion and Relevance: ABL is a dominant treatment strategy over TPTD. In women with PMO at high risk of fracture, ABL is an alternative cost-effective treatment.

Cost-effectiveness of denosumab versus oral alendronate for elderly osteoporotic women in Japan.

We constructed a Markov microsimulation model among hypothetical cohorts of community-dwelling elderly osteoporotic Japanese women without prior hip or vertebral fractures over a lifetime horizon. Compared with weekly oral alendronate for 5 years, denosumab every 6 months for 5 years is cost-saving or cost-effective at a conventionally accepted threshold. INTRODUCTION: The objective of the study was to examine the cost-effectiveness of subcutaneous denosumab every 6 months for 5 years compared with weekly oral alendronate for 5 years in Japan. METHODS: We calculated incremental cost-effectiveness ratios [ICERs] (2016 US dollars [$] per quality-adjusted life year [QALY]), using a Markov microsimulation model among hypothetical cohorts of community-dwelling osteoporotic Japanese women without prior hip or vertebral fractures at various ages of therapy initiation (65, 70, 75, and 80 years) over a lifetime horizon from three perspectives: societal, healthcare sector, and government. RESULTS: Denosumab was cost-saving compared with alendronate at ages 75 and 80 years from any of the three perspectives. The ICERs of denosumab compared with alendronate were $25,700 and $5000 per QALY at ages 65 and 70 years from a societal perspective and did not exceed a willingness-to-pay of $50,000 per QALY from the other two perspectives. In deterministic sensitivity analyses, results were sensitive to changes in the effectiveness of denosumab for reducing hip fracture and clinical vertebral fracture and the rate ratio of non-persistence with denosumab compared to alendronate. In probabilistic sensitivity analyses, the probabilities of denosumab being cost-effective compared with alendronate were 89-100% at a willingness-to-pay of $50,000 per QALY. CONCLUSIONS: Among community-dwelling elderly osteoporotic women in Japan, denosumab every 6 months for 5 years is cost-saving or cost-effective at a conventionally accepted threshold of willingness-to-pay at all ages examined, compared with weekly alendronate for 5 years. This study provides insight to clinicians and policymakers regarding the relative economic value of osteoporosis treatments in elderly women.

Comparison of Calipers for Matching on the Disease Risk Score.

Previous studies have compared calipers for propensity score (PS) matching, but none have considered calipers for matching on the disease risk score (DRS). We used Medicare claims data to perform 3 cohort studies of medication initiators: a study of raloxifene versus alendronate in 1-year nonvertebral fracture risk, a study of cyclooxygenase 2 inhibitors versus nonselective nonsteroidal antiinflammatory medications in 6-month gastrointestinal bleeding, and a study of simvastatin + ezetimibe versus simvastatin alone in 6-month cardiovascular outcomes. The study periods for each cohort were 1998 through 2005, 1999 through 2002, and 2004 through 2005, respectively. In each cohort, we calculated 1) a DRS, 2) a prognostic PS which included the DRS as the independent variable in a PS model, and 3) the PS for each patient. We then nearest-neighbor matched on each score in a variable ratio and a fixed ratio within 8 calipers based on the standard deviation of the logit and the natural score scale. When variable ratio matching on the DRS, a caliper of 0.05 on the natural scale performed poorly when the outcome was rare. The prognostic PS did not appear to offer any consistent practical benefits over matching on the DRS directly. In general, logit-based calipers or calipers smaller than 0.05 on the natural scale performed well when DRS matching in all examples.

Cost-minimization study comparing annual infusion of zoledronic acid or weekly oral alendronate in women with low bone mineral density.

Cost-minimization study to assess the annual direct costs of 2 antiresorptive strategies in postmenopausal women with low bone mineral densities (BMDs). Patients were randomly assigned to receive 70 mg of oral weekly alendronate or a 1-time 5mg of intravenous zoledronic acid. All medical and nonmedical direct costs were recorded for 1 yr. Student's t-test or the Chi-squared test was used. A total of 101 postmenopausal women were enrolled with a mean age of 58.3 ± 7.6 yr and a postmenopausal period of 13.5 ± 8.3 yr. A total of 50 patients completed 1 yr of alendronate and 51 patients received zoledronic acid. At baseline, no differences were seen between the 2 groups in anthropometric measures, comorbidities, and bone mineral density. The costs for medical attention for low bone mass were $81,532 (US Dollars) for the alendronate group and $69,251 for the zoledronic acid group; the cost per patient was $1631 in the alendronate group vs $1358 in the zoledronic acid group (p<0.0001). Therefore, zoledronic acid treatment provided an annual savings of 15% of the direct costs compared with oral alendronate treatment. Moreover, there was a significant increase in lumbar spine T-scores in the zoledronic acid group when compared with the alendronate group. Annual zoledronic acid infusion as an antiresorptive treatment in women with low BMD provides significant monetary savings when compared with weekly alendronate therapy for 1 yr. Zoledronic acid infusion is also linked to higher increase in BMD and compliance.

Association between refill compliance to oral bisphosphonate treatment, incident fractures, and health care costs--an analysis using national health databases.

SUMMARY: The study estimates the cost of poor and suboptimal refill compliance by estimating fracture costs and assessing the association between refill compliance with oral bisphosphonates and incident fractures using Danish health registers. Patients with poor and suboptimal refill compliance had more major osteoporotic fractures, and the direct costs related to hospital care, primary care, and pharmaceutical treatment for these excess fractures reached almost 14 M DKK (2.5 M USD) for the study population which compares to a national annual excess cost of around 17 M DKK (3.1 M USD) using 2011 prescription prevalence. INTRODUCTION: Adherence to oral anti-osteoporosis treatment has been shown in several studies to be relatively low and the potential impact on fracture burden is high. The aim of the study was to assess the association between refill compliance and all-cause health care costs. METHODS: A national dataset was extracted with all treatment-naive patients who began oral bisphosphonate (BP) treatment for osteoporosis in Denmark between 1997 and 2006 (N = 54,876, 87 % women). Patients who survived for at least 2 years (N = 47,176) were divided into groups based on Medication Possession Ratio (MPR). Logistic regressions were used to derive difference in the probability of incident fractures between the three MPR groups. Fracture costs (related to medication use, primary care practice, specialists, and hospitals) were derived by comparing cost 12 months before and after fracture. RESULTS: For alendronate, the adjusted risk of major osteoporotic fractures was significantly reduced (OR 0.768; 0.686-0.859), including fractures of the hip (0.718; 0.609-0.846) and humerus (0.54; 0.431-0.677) with MPR ≥ 0.8. The risk reduction was lower with etidronate. Over 2 years, a total of 171 hip fractures and 53 other major osteoporotic fractures were attributed to suboptimal or poor refill compliance, with an excess cost of 13.7 M DKK (2.5 M USD). CONCLUSIONS: Poor refill compliance is not unusual in patients on oral bisphosphonates, and we demonstrate that this is accompanied by excess major osteoporotic fractures and health care costs at the societal level.

Generic alendronate use among Medicare beneficiaries: are Part D data complete?

BACKGROUND: Generic alendronate was approved in the United States on February 6, 2008. Medicare beneficiaries might pay for generic alendronate out-of-pocket without having claims submitted, resulting in misclassification of generic alendronate use in Medicare data. OBJECTIVES: To estimate the completeness of generic alendronate use in 2008 Medicare Part D data; to identify factors associated with staying on branded alendronate versus switching to a generic product. METHODS: We identified Medicare beneficiaries highly adherent (medication possession ratio ≥80%) with branded alendronate during 1/1/06-2/6/07 ("2007 cohort") and during 1/1/07-2/6/08 ("2008 cohort"). The outcome was medication status at the end of follow-up (12/31/2007 or 12/31/2008), classified as continued branded alendronate, switched to generic alendronate, switched to another bisphosphonate or presumed discontinued bisphosphonate therapy. Cox regression estimated the hazard ratio (HR) for discontinuation in 2008 compared to 2007. Multinomial logistic regression identified factors associated with medication status for the 2008 cohort. RESULTS: Among 15,310 subjects using branded alendronate in the 2008 cohort, 81% switched to generic alendronate. The proportion presumably discontinuing bisphosphonate therapy was 8.9% in 2008 compared to 7.7% in the 2007 cohort (adjusted HR, 1.15; 95% confidence interval, 1.05, 1.26). Factors associated with staying on branded alendronate in 2008 were higher income, eligibility for a low income subsidy and use of Fosamax® plus vitamin D. CONCLUSION: Evaluation of Medicare prescription drug data suggests that the amount of missing claims for generic alendronate in 2008 was not substantial, and misclassification of exposure in studies examining alendronate use post-generic product availability should be minimal.

Influence of socioeconomic factors on the adherence of alendronate treatment in incident users in Norway.

PURPOSE: To examine whether socioeconomic factors influence adherence to alendronate drug treatment among incident users in Norway during 2005-2009. METHODS: The study included 7610 incident alendronate users in 2005 (40-79 years), followed until 31 December 2009. Mean age was 66.6 years, and 86.7% of the patients were women. Data were drawn from the Norwegian Prescription Database and linked to marital status, education and income. Adherence was measured by the medication possession ratio (MPR). MPR was defined as the number of dispensed defined daily doses divided by the number of days each patient was included in the study. A patient was adherent if MPR ≥ 80%. ORs with 95%CI were estimated using logistic regression. RESULTS: Among all patients, 45.5% was adherent throughout 4.2 years. A slightly higher proportion of women than men were adherent. Adjusted for all covariates, women aged 70-79 years had an OR of 1.27 (95%CI 1.10-1.45) for adherence compared with those 40-59 years. In women, high household income predicted adherence of alendronate use. In men, a middle educational level compared with a low level, predicted adherence (adjusted OR = 1.47 (95%CI 1.10-1.96)). After adjustments, previous marriage reduced the odds of being adherent compared with present marriage, in both men and women. CONCLUSIONS: In women, the most important factors for being adherent were high age and high income. In men, a middle educational level predicted adherence. Previous marriage reduced the odds of being adherent in both women and men.

Analysis of the comparative effectiveness of 3 oral bisphosphonates in a large managed care organization: adherence, fracture rates, and all-cause cost.

BACKGROUND: Despite widespread availability and use of oral bisphosphonates, fracture rates and associated medical costs are still high. Differences in fracture risk among these agents, if any, have not been quantified due to the lack of high-quality, head-to-head, randomized, controlled trials assessing this outcome. Randomized, placebo-controlled trials have shown that alendronate and risedronate reduce rates of both vertebral and nonvertebral fractures, whereas only reduction in vertebral fractures has been found for ibandronate. OBJECTIVE: To determine if there were any differences among 3 oral bisphosphonates in adherence, total cost of care, and effectiveness in reducing fracture rates in a large managed care population. METHODS: Administrative, longitudinal pharmacy and medical claims data were obtained from 14 geographically diverse health plans in the United States covering approximately 14 million members. Sampled members had at least 1 pharmacy claim for alendronate, risedronate, or ibandronate during the intake period (January 1, 2005, through October 31, 2007). The date of the first pharmacy claim for osteoporosis medications within the intake period was the index date. Members were followed for either 12, 24, or 36 months, depending on length of continuous health plan eligibility. Medication possession ratio (MPR) was measured using a total days supply that was calculated by multiplying the total quantity dispensed by the suggested days supply per unit of dispensing based on manufacturer-recommended dosing. For members who switched bisphosphonate strengths or medications, the estimated days supply was summed for all osteoporosis medications during the follow-up, including overlapping days supply. Outcomes included (a) the first incident fracture and percentages of members with at least 1 fracture after 6 months post-index; (b) the number of days from index to the first incident fracture, measured as time to event in Cox proportional hazards regression analysis; and (c) total all-cause health care costs (health plan allowed amount including member cost share). RESULTS: A total of 45,939 members were included (n = 24,909 alendronate, n = 13,834 risedronate, n = 7,196 ibandronate). In the 12-month analysis, MPRs were comparable (means = 0.57-0.58) for the 3 medications. After 24 months, MPRs had dropped for all medications, but those of both alendronate (mean = 0.50, 95% CI = 0.49-0.50) and risedronate (mean = 0.50, 95% CI = 0.49-0.51) were slightly higher than that of ibandronate (mean = 0.47, 95% CI = 0.46-0.48). At 36 months, again the MPRs had dropped for all 3 medications (means = 0.44-0.47) but were similar. There were no statistically significant differences among agents in the percentages of subjects with at least 1 fracture at 12, 24, or 36 months (36-month rates: alendronate 4.41%, risedronate 4.38%, ibandronate 6.28%, P = 0.102). The numbers of subjects with fracture(s) per month of follow-up were 0.0020 for alendronate, 0.0021 for risedronate, and 0.0022 for ibandronate (P = 0.087 overall). However, after adjusting for member characteristics, alendronate users had a 12% lower risk of experiencing any incident fracture than ibandronate users (hazard ratio = 0.88, 95% CI = 0.78-0.99, P = 0.034) within the follow-up period. In the first 12 post-index months, ibandronate users had higher mean [SD] unadjusted total all-cause health care costs ($7,464 [$15,975]) compared with alendronate ($7,233 [$16,671]) and risedronate ($ 6,983 [$16,870], P less than 0.001 for both comparisons), differences of approximately $19 per month and $40 per month, respectively. The results of the unadjusted 24-month analysis were similar, but there were no significant cost differences at 36 months. Total cost differences for the 3 medication groups were nonsignificant at 12, 24, and 36 months after adjusting for member characteristics. CONCLUSIONS: This retrospective analysis of an administrative claims database in a large managed care population showed similar rates of adherence and total adjusted all-cause health care costs for alendronate, risedronate, and ibandronate. Absolute unadjusted rates of fracture were small and did not significantly differ among agents, but after controlling for differences in member characteristics, the risk of fracture was 12% lower for alendronate users than for ibandronate users.

Incurred sample accuracy assessment: design of experiments based on standard addition.

It is commonly acknowledged that random and systematic analytical errors contribute to poor data quality, and moreover, to imprecise and inaccurate pharmacokinetic parameters. To investigate the random errors in GLP bioanalysis, common ground has been found in today's bioanalysis to assess the reproducibility of the method by reanalyzing part of the incurred samples. The undesired systematic errors in bioanalysis affecting the trueness of the method and leading to inaccurate data remain relatively unattended so far. In order to obtain both precise and accurate data it is suggested in this paper to apply standard addition experiments to calculate the relative systematic errors as an estimate for the incurred sample accuracy. This approach, which can be seen as an important extension to current guidelines in GLP bioanalysis, is illustrated by assessing the accuracy of the bioanalytical results for a bioequivalence study for alendronate.

Retrospective study of two biochemical markers for the risk assessment of oral bisphosphonate-related osteonecrosis of the jaws: can they be utilized as risk markers?

PURPOSE: the purpose of this retrospective study was to examine the possibility of utilizing serum C-terminal telopeptide cross-link of type I collagen (s-CTX) and serum osteocalcin (s-OC) as risk markers for oral bisphosphonate-related osteonecrosis of the jaws (BRONJ). PATIENTS AND METHODS: the s-CTX values and the s-OC values were measured from 23 patients (one male, 22 females) diagnosed with BRONJ using clinical and radiographic examinations. The two biochemical markers were evaluated during a regular checkup for osteoporosis management. For the control group of s-CTX study, s-CTX values were obtained from 61 independently recruited postmenopausal women who have been on bisphosphonate therapy for >6 months. The s-CTX values of the ONJ group and the control group were compared. Because of retrospective nature of this study, the control group for s-OC study could not be established. A single sample t-test was performed for the s-OC value from the ONJ group. RESULT: twenty-three ONJ patients had taken alendronate for osteoporosis treatment, and the s-CTX testing results were low levels of 10-192 pg/ml (mean: 93.2 ± 49.4 pg/ml). Mean of s-CTX of the control (n=61) was 125 ± 85.7 pg/ml. The duration of BP therapy ranged between 1 and 10 years (4.82 ± 2.6). The s-OC level was estimated between 0.2 and 5.4 ng/ml (1.91 ± 1.51 ng/ml). The mean s-CTX value of the control group was higher but without significance (P=0.12). The s-OC values of the ONJ group were significantly lower than the lowest value of the reference range (P<0.001). CONCLUSION: as a result of the s-CTX and s-OC testings at the diagnosis of BRONJ, the values of the two markers were decreased. The decrease of the s-OC values implies a problem during the bone-formation process. Therefore, we can assume that in this patient group, invasive dental surgery contributes to an increase in the risk of BRONJ incidence. This result may imply that, during bisphosphonate therapy, simultaneous consideration of s-CTX showing inhibition of bone resorption and s-OC indicating the degree of bone formation might be a set of risk markers assessing risk prediction for BRONJ before invasive dental surgery.

Discontinuity and failures of therapy with bisphosphonates: joint assessment of predictors with multi-state models.

BACKGROUND: Data from a cohort of women treated with bisphosphonates were used to illustrate that multi-state models may be the useful tools of analysis where two causes of treatment failure are the ultimate outcome of interest, and the sequence of recurrent episodes of treatment starting and discontinuing is also of concern. METHODS: All the 11 863 women resident in the Italian Region of Lombardy, aged 45 years or over and who received bisphosphonates for the first time during 2003 entered into the study and were followed up until December 2005. Multi-state models with in-treatment and treatment-free periods as transient states, and fractures and gastrointestinal-related events as competing causes of failure, were fitted to the data. The effect of several covariates on transition rates between states was estimated. RESULTS: One half of the women was treated with bisphosphonates for less than 27% of the period of observation. Negative prognostic factors for treatment discontinuation were younger age and the use of alendronate at once-daily dosing, with low refill compliance during follow-up. The risk of fracture was higher for older women who experienced fracture before entry in the cohort, and for those who switched between drugs, had low refill compliance, experienced episodes of treatment discontinuation and used corticosteroids during follow-up. CONCLUSIONS: The use of multi-state models in pharmacoepidemiology provides non-biased estimates of the effect of covariates in predicting treatment discontinuation, restarting and failures. Our analyses emphasize the importance of maximising compliance in order to reduce the risks of both treatment discontinuation and fracture.

Cost-effectiveness of a fixed dose combination of alendronate and cholecalciferol in the treatment and prevention of osteoporosis in the United Kingdom and The Netherlands.

OBJECTIVE: To evaluate the cost-effectiveness of a fixed dose combination of alendronate 70 mg and cholecalciferol 2800 IU (alendronate/vitamin D3; Fosavance) versus no treatment, alendronate with dietary vitamin D supplements and ibandronate in the treatment of osteoporosis in the UK and Netherlands. METHODS: A patient simulation model was developed. One-year cycles included health states related to hip, vertebral, wrist and proximal humerus fractures, as well as death due to hip fractures and other causes. Effect of treatment was extracted from alendronate and ibandronate clinical trials. Direct costs and utilities were derived from other literature. Analyses were performed for women with a history of vertebral fractures and osteoporosis aged 50, 60, 70 and 80 years. Probabilistic sensitivity analyses were undertaken to estimate the uncertainty of outcomes. RESULTS: In the UK, alendronate/vitamin D3 was cost-effective compared to no treatment in women 70 years and older with osteoporosis ( pound17 439 per quality-adjusted life year [QALY] gained) and women 60 years and older with a history of vertebral fractures ( pound29 283 per QALY gained). For women 80 years of age alendronate/vitamin D3 was cost-saving combined with QALY gains. Alendronate/vitamin D3 was cost-saving relative to alendronate with dietary supplements. Relative to ibandronate, alendronate/vitamin D3 was cost-effective in women 50 years ( pound19 095 per QALY gained) and economically dominant in women 60 years or older. Comparable results were observed for the Netherlands. CONCLUSIONS: Given the underlying assumptions and data used, this economic modelling study showed that alendronate/vitamin D3 is cost-effective in women 70 years or older with osteoporosis and in women 60 years or older with a history of vertebral fractures in the UK and Netherlands. Alendronate/vitamin D3 is economically dominant over ibandronate in women with a history of vertebral fractures aged 60 and over and cost-saving relative to alendronate with dietary supplements.

Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women.

UNLABELLED: Adherence is now one of the major issues in the management of osteoporosis and several papers have suggested that vertebral fractures might be increased in patients who do not follow appropriately their prescriptions. This paper relates the strong relationship existing between adherence to anti-osteoporosis treatment and the risk of subsequent hip fracture. INTRODUCTION: A study was performed to investigate adherence to bisphosphonate (BP) therapy and the impact of adherence on the risk of hip fracture (Fx). METHODS: An exhaustive search of the Belgian national social security database was conducted. Patients enrolled in the study were postmenopausal women, naive to BP, who received a first prescription of alendronate. Compliance at 12 months was quantified using the medication possession ratio (MPR). Persistence was calculated as the number of days from the initial prescription to a gap of more than 5 weeks after completion of the previous refill. A logistic regression model was used to estimate the impact of compliance on the risk of hip fracture. The impact of persistence on hip fracture risk was analysed using the Cox proportional hazards model. RESULTS: The mean MPR at 12 months was significantly higher among patients receiving weekly (n = 15.021) compared to daily alendronate (n = 14,136) (daily = 58.6%; weekly = 70.5%; p < 0.001). At 12 months, the rate of persistence was 39.45%. For each decrease of the MPR by 1%, the risk of hip Fx increased by 0.4% (OR: 0.996; CI 95%: 0.994-0.998; p < 0.001). The relative risk reduction for hip Fx was 60% (HR: 0.404; CI 95%: 0.357-0.457; p < 0.0001) for persistent compared to non-persistent patients. CONCLUSION: These results confirm that adherence to current therapeutic regimens remains suboptimal.

Factors affecting long-term compliance of osteoporotic patients with bisphosphonate treatment and QOL assessment in actual practice: alendronate and risedronate.

The aim of our study was to examine compliance with a daily dose of 5 mg alendronate (ALN) and 2.5 mg risedronate (RDN) in actual practice, and to determine the causes of noncompliance through a questionnaire. In addition, we studied the quality of life (QOL) of patients through another disease-related questionnaire. The overall compliance rate remained at approximately 40% one year after the initial dose. The rates did not differ significantly between the ALN group (783 patients) and the RDN group (491 patients). The compliances in the female group and the rheumatism group were better than in the male group and the nonrheumatism group. From the questionnaire, 36% of noncompliant patients showed adverse effects (AEs), and the other noncompliant patients stopped the medication in spite of having no AEs. A logistic regression analysis of factors that might have affected long-term compliance included AEs, an understanding of the disease, the method of ingestion, visiting medical facilities, the shape of the tablet, the cost of the drug, and the explanation of the doctor or pharmacist. This analysis showed that noncompliance occurred mainly due to AEs, the inconvenience of visiting a medical facility, unusual methods of ingestion, and a poor understanding of the disease. According to the results of the questionnaire for QOL assessment, the patients who continued the medication for more than 1 year had improved scores for pain in both the ALN and RDN groups. Osteoporotic treatment needs long-term patient compliance. To improve compliance, it is very important that doctors and pharmacists ensure that patients understand the purpose of this therapy.