Practical guidance for engaging patients in health research, treatment guidelines and regulatory processes: results of an expert group meeting organized by the World Health Organization (WHO) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

There is increasing emphasis on patient-centred research to support the development, approval and reimbursement of health interventions that best meet patients' needs. However, there is currently little guidance on how meaningful patient engagement may be achieved. An expert working group, representing a wide range of stakeholders and disciplines, was convened by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the World Health Organization (WHO). Through a structured, collaborative process the group generated practical guidance to facilitate optimal patient engagement in clinical development and regulatory decisions. Patient engagement is a relational process. The principles outlined in this report were based on lessons learned through applied experience and on an extensive dialogue among the expert participants. This practice guidance forms a starting point from which tailoring of the approach to suit different chronic diseases may be undertaken.

Cost-effectiveness of vitamin D and calcium supplementation in the treatment of elderly women and men with osteoporosis.

BACKGROUND: The supplementation with vitamin D and calcium has been recommended for elderly, specifically those with increased risk of fractures older than 65 years. This study aims to assess the cost-effectiveness of vitamin D and calcium supplementation in elderly women and men with osteoporosis and therefore to assess if this recommendation is justified in terms of cost-effectiveness. METHODS: A validated model for economic evaluations in osteoporosis was used to estimate the cost per quality-adjusted life-year (QALY) gained of vitamin D/calcium supplementation compared with no treatment. The model was populated with cost and epidemiological data from a Belgian health-care perspective. Analyses were conducted in women and men with a diagnosis of osteoporosis (i.e. bone mineral density T-score ≤-2.5). A literature search was conducted to describe the efficacy of vitamin D and calcium in terms of fracture risk reduction. RESULTS: The cost per QALY gained of vitamin D/calcium supplementation was estimated at €40 578 and €23 477 in women and men aged 60 years, respectively. These values decreased to €7912 and €10 250 at the age of 70 years and vitamin D and calcium supplementation was cost-saving at the age of 80 years, meaning that treatment cost was less than the costs of treating osteoporotic fractures of the no-treatment group. CONCLUSION: This study suggests that vitamin D and calcium supplementation is cost-effective for women and men with osteoporosis aged over 60 years. From an economic perspective, vitamin D and calcium should therefore be administrated in these populations including those also taking other osteoporotic treatments.

Changes in structure and symptoms in knee osteoarthritis and prediction of future knee replacement over 8 years.

The objective of this study was to assess the association between changes in joint space width (JSW, i.e., structure) or Western Ontario and McMaster Universities (WOMAC) score (i.e., symptoms) over 3 years in patients with knee osteoarthritis and the occurrence of knee replacement over 8 years. We followed 133 subjects with primary knee osteoarthritis prospectively for a mean of 8 years. JSW (standard radiography) and symptoms (total WOMAC score) were assessed every year for 3 years. The rate of knee replacement was recorded for the following 5 years. Logistic regressions were performed according to the intention-to-treat principle. After 8 years' follow-up, ten patients (7.5 %) had undergone a knee replacement. The changes in JSW or WOMAC score over 3 years were significantly associated with the occurrence of knee replacement during the following 5 years (p = 0.02 and p = 0.03, respectively). Each 0.1-mm narrowing of JSW over 3 years was associated with a 14 % (95 % CI 3-25 %) increased risk for knee replacement. For every 10 % increase in WOMAC score, the risk for joint replacement was increased by 16 % (95 % CI 1-33 %). When JSW and WOMAC score were included in the same statistical model, they were still significantly associated with risk for knee replacement (p = 0.02 and p = 0.03, respectively), but JSW change was the only variable that remained significant after adjusting for all potential confounders. Our results suggest that changes in symptoms and, more particularly, in structure over 3 years in patients with osteoarthritis reflect a clinically relevant progression of the disease.

Potential Clinical and Economic Impact of Nonadherence with Osteoporosis Medications.

This study aims to estimate the potential clinical and economic implications of therapeutic adherence to bisphosphonate therapy. A validated Markov microsimulation model was used to estimate the impact of varying adherence to bisphosphonate therapy on outcomes (the number of fractures and the quality-adjusted life-years [QALYs]), health-care costs, and the cost-effectiveness of therapy compared with no treatment. Adherence was divided into persistence and compliance, and multiple scenarios were considered for both concepts. Analyses were performed for women aged 65 years with a bone mineral density T-score of -2.5. Health outcomes and the cost-effectiveness of therapy improved significantly with increasing compliance and/or persistence. In the case of real-world persistence and with a medical possession ratio (MPR; i.e., the number of doses taken divided by the number of doses prescribed) of 100%, the QALY gain and the number of fractures prevented represented only 48 and 42% of the values estimated assuming full persistence, respectively. These proportions fell to 27 and 23% with an MPR value of 80%. The costs per QALY gained, for branded bisphosphonates (and generic alendronate), were estimated at 19,069 (4,871), 32,278 (11,985), and 64,052 (30,181) for MPR values of 100, 80, and 60%, respectively, assuming real-world persistence. These values were 16,997 (2,215), 24,401 (6,179), and 51,750 (20,569), respectively, assuming full persistence. In conclusion, poor compliance and failure to persist with osteoporosis medications results not only in deteriorating health outcomes, but also in a decreased cost-effectiveness of drug therapy. Adherence therefore remains an important challenge for health-care professionals treating osteoporosis.

Potential clinical and economic impact of nonadherence with osteoporosis medications.

This study aims to estimate the potential clinical and economic implications of therapeutic adherence to bisphosphonate therapy. A validated Markov microsimulation model was used to estimate the impact of varying adherence to bisphosphonate therapy on outcomes (the number of fractures and the quality-adjusted life-years [QALYs]), health-care costs, and the cost-effectiveness of therapy compared with no treatment. Adherence was divided into persistence and compliance, and multiple scenarios were considered for both concepts. Analyses were performed for women aged 65 years with a bone mineral density T-score of -2.5. Health outcomes and the cost-effectiveness of therapy improved significantly with increasing compliance and/or persistence. In the case of real-world persistence and with a medical possession ratio (MPR; i.e., the number of doses taken divided by the number of doses prescribed) of 100%, the QALY gain and the number of fractures prevented represented only 48 and 42% of the values estimated assuming full persistence, respectively. These proportions fell to 27 and 23% with an MPR value of 80%. The costs per QALY gained, for branded bisphosphonates (and generic alendronate), were estimated at 19,069 euros (4,871 euros), 32,278 euros (11,985 euros), and 64,052 euros (30,181 euros) for MPR values of 100, 80, and 60%, respectively, assuming real-world persistence. These values were 16,997 euros (2,215 euros), 24,401 euros (6,179 eruos), and 51,750 euros (20,569 euros), respectively, assuming full persistence. In conclusion, poor compliance and failure to persist with osteoporosis medications results not only in deteriorating health outcomes, but also in a decreased cost-effectiveness of drug therapy. Adherence therefore remains an important challenge for health-care professionals treating osteoporosis.

Cost-effectiveness of osteoporosis screening followed by treatment: the impact of medication adherence.

OBJECTIVE: To estimate the impact of medication adherence on the cost-effectiveness of mass-screening by bone densitometry followed by alendronate therapy for women diagnosed with osteoporosis. METHODS: A validated Markov microsimulation model with a Belgian health-care payer perspective and a lifetime horizon was used to assess the cost per quality-adjusted life year (QALY) gained of the screening/treatment strategy compared with no intervention. Real-world adherence to alendronate therapy and full adherence over 5 years were both investigated. The real-world adherence scenario employed adherence data from published observational studies, and medication adherence was divided into persistence, compliance, and primary adherence. Uncertainty was investigated using one-way and probabilistic sensitivity analyses. RESULTS: At 65 years of age, the costs per QALY gained because of the screening/treatment strategy versus no intervention are euro32,008 and euro16,918 in the real-world adherence and full adherence scenarios, respectively. The equivalent values are euro80,836 and euro40,462 at the age of 55 years, and they decrease to euro10,600 and euro1229 at the age of 75 years. Sensitivity analyses show that the presence of the upfront cost of case finding has a substantial role in the impact of medication adherence on cost-effectiveness. CONCLUSION: This study indicates that nonadherence with osteoporosis medications substantially increases the incremental cost-effectiveness ratio of osteoporosis screening strategies. All aspects of medication adherence (i.e., compliance, persistence, and primary adherence) should therefore be reported and included in pharmacoeconomic analyses, and especially in the presence of the upfront cost of case finding (such as screening cost).

Loss of hip bone mineral density over time is associated with spine and hip fracture incidence in osteoporotic postmenopausal women.

The objective of the study assess the relationship between bone mineral density (BMD) loss over time and fracture incidence in postmenopausal women. This is a posthoc analysis that includes women from the placebo group of two large randomized controlled trials having assessed the efficacy of a new anti-osteoporotic drug. BMD was assessed every 6 months during 3 years at the lumbar spine, the femoral neck and the total proximal femur. Vertebral fractures were assessed using a semiquantitative method. Hip fractures were based on written documentation. All patients received calcium and vitamin D. In the present study that included 1,775 patients (with complete data at baseline and after 3 years), the logistic regression analysis, adjusted for covariates, showed that 3-year change in lumbar BMD was not statistically associated with the new vertebral fractures after 3 years. However, femoral neck and total proximal femur BMD changes was statistically correlated with the incidence of new vertebral fractures (P < 0.001). When considering change in BMD after the first year of follow-up, a decrease in total proximal femur BMD was statistically associated with an increase in the incidence of new vertebral fractures during the last 2 years of follow-up (P = 0.048). The 3-year change in femoral neck and total proximal BMD was statistically correlated with the incidence of hip and fragility fracture after 3 years (all P < 0.001). In this elderly osteoporotic population receiving calcium and vitamin D, a decrease in hip BMD after 1 or 3 year of follow-up, is associated with an increased risk of fracture incidence. However, spine BMD changes do not influence vertebral fracture incidence.

Meta-analyses indexed in PsycINFO had a better completeness of reporting when they mention PRISMA.

OBJECTIVES: To investigate the effect of the explicit mention of PRISMA, a statement designed to help authors report meta-analyses (MAs), on the reporting completeness of MAs. STUDY DESIGN AND SETTING: Two investigators evaluated a random sample of 206 MAs indexed in PsycINFO in 2016; 100 explicitly mentioned PRISMA and 106 did not. Two authors independently evaluated the 27 PRISMA items and extracted factors that could potentially be associated with reporting completeness. The data were analyzed descriptively. RESULTS: Among our 206 MAs, perfect adherence to PRISMA was found in less than 4%, of which 87% explicitly followed PRISMA. The following items were encountered significantly more frequently in MAs that explicitly mentioned PRISMA than in those that did not: summary, protocol, information sources, search strategy, study characteristics, results of individual studies, funding, study selection, risk of bias in individual studies, and bias across studies. The journal's impact factor, endorsement of PRISMA by the journal, number of authors, country of author, open access, and design of the included studies were significantly and positively associated with the explicit mention of PRISMA. CONCLUSIONS: Even if far from optimal, the explicit mention of PRISMA has a positive influence on the reporting completeness of MAs from PsycINFO.

Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to assess the safety of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus electronic databases. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with topical NSAIDs in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, vascular, cardiac, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue. RESULTS: The search strategy identified 1209 records, from which 25 papers were included in the qualitative synthesis and 19 were included in the meta-analysis, after exclusions. Overall, more total AEs (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.04-1.29; I2 = 0.0%) and more withdrawals due to AEs (OR 1.49, 95% CI 1.15-1.92; I2 = 0.0%) were observed with topical NSAIDs compared with placebo. The same results were achieved with topical diclofenac, largely driven by an increase in skin and subcutaneous tissue disorders (OR 1.73, 95% CI 0.96-3.10), although the difference was not statistically significant compared with placebo. No significant difference in the odds for gastrointestinal disorders was observed between topical NSAIDs and placebo (OR 0.96, 95% CI 0.73-1.27). CONCLUSIONS: Topical NSAIDs may be considered safe in the management of OA, especially with regard to low gastrointestinal toxicity. The use of topical NSAIDs in OA should be considered, taking into account their risk: benefit profile in comparison with other anti-OA treatments.

Safety of Intra-articular Hyaluronic Acid Injections in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

BACKGROUND: Some controversy exists regarding the safety of intra-articular hyaluronic acid (IAHA) in the management of osteoarthritis (OA). OBJECTIVE: The objective of this study was to re-assess the safety profile of IAHA in patients with OA, through a comprehensive meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with IAHA in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, cardiac, vascular, respiratory, nervous system, skin and subcutaneous tissue disorders, musculoskeletal, renal and urinary disorders, infections and infestations, and hypersensitivity reaction. RESULTS: Database searches initially identified 1481 records. After exclusions according to the selection criteria, 22 studies were included in the qualitative synthesis, and nine studies having adequate data were ultimately included in the meta-analysis. From the studies excluded according to the pre-specified selection criteria, 21 with other pharmacological OA treatments permitted during the trials were a posteriori included in a parallel qualitative synthesis, from which eight studies with adequate data were finally included in a parallel meta-analysis. Since this meta-analysis was designed to assess safety, the exclusion criterion on concomitant anti-OA medication was crucial. However, due to the high number of studies that allowed mainly concomitant oral non-steroidal anti-inflammatory drugs (NSAIDs), we decided to include them in a post hoc parallel analysis in order to compare the results from the two analyses. No statistically significant difference in odds was found between IAHA and placebo for all types of SOC-related disorders, except for infections and infestations, for which significantly lower odds were found with IAHA compared with placebo, both overall (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.40-0.93; I2 = 0%) and in studies without concomitant anti-OA medication (OR = 0.49, 95% CI 0.27-0.89). There were significant increased odds of reporting serious AEs with IAHA compared with placebo, both overall (OR = 1.78, 95% CI 1.21-2.63; I2 = 0%) and in studies with concomitant anti-OA medication (OR = 1.78, 95% CI 1.10-2.89), but not in studies without concomitant anti-OA medication (OR = 1.78, 95% CI 0.92-3.47). CONCLUSIONS: Using the available data on studies without any concomitant anti-OA medication permitted during clinical trials, IAHA seems not to be associated with any safety issue in the management of OA. However, this evidence was associated with only a "low" to "moderate" certainty. A possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation.

Safety of Symptomatic Slow-Acting Drugs for Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

BACKGROUND: Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are an important drug class in the treatment armamentarium for osteoarthritis (OA). OBJECTIVE: We aimed to re-assess the safety of various SYSADOAs in a comprehensive meta-analysis of randomized placebo-controlled trials, using, as much as possible, data from full safety reports. METHODS: We performed a systematic review and random-effects meta-analyses of randomized, double-blind, placebo-controlled trials that assessed adverse events (AEs) with various SYSADOAs in patients with OA. The databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus were searched. The primary outcomes were overall severe and serious AEs, as well as AEs involving the following Medical Dictionary for Regulatory Activities (MedDRA) system organ classes (SOCs): gastrointestinal, cardiac, vascular, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue, renal and urinary system. RESULTS: Database searches initially identified 3815 records. After exclusions according to the selection criteria, 25 studies on various SYSADOAs were included in the qualitative synthesis, and 13 studies with adequate data were included in the meta-analyses. Next, from the studies previously excluded according to the protocol, 37 with mainly oral nonsteroidal anti-inflammatory drugs (NSAIDs) permitted as concomitant medication were included in a parallel qualitative synthesis, from which 18 studies on various SYSADOAs were included in parallel meta-analyses. This post hoc parallel inclusion was conducted because of the high number of studies allowing concomitant anti-OA medications. Indeed, primarily excluding studies with concomitant anti-OA medications was crucial for a meta-analysis on safety. The decision for parallel inclusion was made for the purpose of comparative analyses. Glucosamine sulfate (GS), chondroitin sulfate (CS) and avocado soybean unsaponifiables (ASU; Piascledine®) were not associated with increased odds for any type of AEs compared with placebo. Overall, with/without concomitant OA medication, diacerein was associated with significantly increased odds of total AEs (odds ratio [OR] 2.22; 95% confidence interval [CI] 1.58-3.13; I2 = 52.8%), gastrointestinal disorders (OR 2.85; 95% CI 2.02-4.04; I2 = 62.8%) and renal and urinary disorders (OR 3.42; 95% CI 2.36-4.96; I2 = 17.0%) compared with placebo. In studies that allowed concomitant OA medications, diacerein was associated with significantly more dermatological disorders (OR 2.47; 95% CI 1.42-4.31; I2 = 0%) and more dropouts due to AEs (OR 3.18; 95% CI 1.85-5.47; I2 = 13.4%) than was placebo. No significant increase in serious or severe AEs was found with diacerein versus placebo. CONCLUSIONS: GS and CS can be considered safe treatments for patients with OA. All eligible studies on ASU included in our analysis used the proprietary product Piascledine® and allowed other anti-OA medications; thus, the safety of ASU must be confirmed in future studies without concomitant anti-OA medications. Given the safety concerns with diacerein, its usefulness in patients with OA should be assessed, taking into account individual patient characteristics.

Adverse Health Events Related to Self-Medication Practices Among Elderly: A Systematic Review.

BACKGROUND: Older adults often resort to self-medication to relieve symptoms of their current illnesses; however, the risks of this practice are multiplied in old age. In particular, this age group is more vulnerable to adverse drug events because of the physiological changes that occur due to senescence. OBJECTIVE: The aim of the study was to obtain an overview of the adverse health events related to self-medication among subjects aged 60 years and over through a systematic review of the literature. METHODS: A study of relevant articles was conducted among databases (MEDLINE, PsycINFO, and EBM Reviews-Cochrane Database of Systematic Reviews). Eligibility criteria were established and applied by two investigators to include suitable studies. The results and outcomes of interest were detailed in a descriptive report. RESULTS: The electronic search identified 4096 references, and the full texts of 74 were reviewed, of which four were retained in the analysis: three had a cross-sectional design and one prospectively followed elderly subjects. The first study showed a 26.7% prevalence of adverse drug reactions (ADRs) among elders, the second study found a 75% prevalence of side effects, and, finally, a prospective study showed an ADR incidence of 4.5% among self-medicated elders. These studies showed that adverse health events related to self-medication are relatively frequently reported. They also highlighted that analgesics and anti-inflammatory drugs are the most self-medicated products, while vitamins and dietary supplements also appear to be frequently self-administered, but by older individuals. CONCLUSIONS: Studies on self-medication in the elderly and its adverse health effects are clearly lacking. There is a need to perform prospective studies on this topic to gain a clear understanding of the extent of this problem and to enhance the awareness of health professionals to better inform seniors.

Publication outcomes of the abstracts presented at the 2011 European Congress on Osteoporosis, Osteoarthritis and Musculo-Skeletal Diseases (ECCEO-IOF11): A position paper of the European Society for Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculo-Skeletal Diseases (ESCEO) and the International Osteoporosis and Other Skeletal Diseases Foundation (IOF).

UNLABELLED: The publication outcomes of the abstracts presented during the ECCEO-IOF 2011 reflect a high research productivity, support the robustness of the selection process conducted by the Scientific Advisory Committee and suggest that IOF-ESCEO WCO is successful in its mission to promote and disseminate research. BACKGROUND AND OBJECTIVE: The European (now World) Congress on Osteoporosis, Osteoarthritis and Musculo-Skeletal Diseases (IOF-ESCEO WCO, formerly ECCEO-IOF) is the largest worldwide event fully dedicated to the clinical, epidemiological, translational and economic aspects of bone, joint and muscle diseases. The role of the Scientific Advisory Committee is to select abstracts for oral communication or poster presentation based on a short summary of the research. The aim of the present survey was to determine the publication rate in international peer reviewed journals of abstracts accepted at the IOF-ESCEO WCO 2011 Meeting (formerly ECCEO-IOF11), the relationship, if any, between the presentation format of the abstract and its subsequent full publication and the impact factor of the journal in which research was published. RESULTS: Of 619 abstracts accepted at the 2011 ECCEO-IOF11 annual meeting, 45 were accepted for oral communication and 574 accepted for poster presentation. In the subsequent 3 years (2011-2014), 191 abstracts were published as a full-length manuscript (30.9 %). The publication rate was significantly higher for oral communications (75.6 %) than for poster presentations (27.4 %; p < 0.0001). Publications derived from oral communications were published in journals with a higher impact factor (8.3 ± 10.1) than those arising from poster presentations (4.0 ± 2.3; p < 0.0001), but there was no difference in the time to publication (OC 16.3 [IQR 8.4-23.3] months vs PP 11.3 [IQR 5.3-21.4]; p = 0.14). CONCLUSION: These results indicate a high research productivity and an appropriate selection of oral communication by the Scientific Advisory Committee of ESCEO-IOF.

The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: There is growing evidence that vitamin D plays a role on several tissues including skeletal muscle. OBJECTIVE: The aim was to summarize with a meta-analysis, the effects of vitamin D supplementation on muscle function. DATA SOURCES: A systematic research of randomized controlled trials, performed between 1966 and January 2014 has been conducted on Medline, Cochrane Database of Systematics Reviews, Cochrane Central Register of Controlled and completed by a manual review of the literature and congressional abstracts. STUDY SELECTION: All forms and doses of vitamin D supplementation, with or without calcium supplementation, compared with placebo or control were included. Out of the 225 potentially relevant articles, 30 randomized controlled trials involving 5615 individuals (mean age: 61.1 years) met the inclusion criteria. DATA EXTRACTION: Data were extracted by two independent reviewers. DATA SYNTHESIS: Results revealed a small but significant positive effect of vitamin D supplementation on global muscle strength with a standardized mean difference (SMD) of 0.17 (P = .02). No significant effect was found on muscle mass (SMD 0.058; P = .52) or muscle power (SMD 0.057; P = .657). Results on muscle strength were significantly more important with people who presented a 25-hydroxyvitamin D level <30 nmol/L. Supplementation seems also more effective on people aged 65 years or older compared to younger subjects (SMD 0.25; 95% CI 0.01 to 0.48 vs SMD 0.03; 95% CI -0.08 to 0.14). CONCLUSIONS: Vitamin D supplementation has a small positive impact on muscle strength, but additional studies are needed to define optimal treatment modalities, including dose, mode of administration, and duration.

Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Signals of an increased risk of myocardial infarction (MI) have been identified with dabigatran etexilate in randomized controlled trials (RCTs). METHODS AND RESULES: We conducted searches of the published literature and a clinical trials registry maintained by the drug manufacturer. Criteria for inclusion in our meta-analysis included all RCTs and the availability of outcome data for MI, other cardiovascular events, major bleeding, and all-cause mortality. Among the 501 unique references identified, 14 RCTs fulfilled the inclusion criteria. Stratification analyses by comparators and doses of dabigatran etexilate were conducted. Peto odds ratio (ORPETO) values using the fixed-effect model (FEM) for MI, other cardiovascular events, major bleeding, and all-cause mortality were 1.34 (95% CI 1.08 to 1.65, P=0.007), 0.93 (95%CI 0.83 to 1.06, P=0.270), 0.88 (95% CI 0.79 to 0.99, P=0.029), and 0.89 (95% CI 0.80 to 1.00, P=0.041). When compared with warfarin, ORPETO values using FEM were 1.41 (95% CI 1.11 to 1.80, P=0.005), 0.94 (95%CI 0.83 to 1.06, P=0.293), 0.85 (95% CI 0.76 to 0.96, P=0.007), and 0.90 (95% CI 0.81 to 1.01, P=0.061), respectively. In RCTs using the 150-mg BID dosage, the ORPETO values using FEM were 1.45 (95% CI 1.11 to 1.91, P=0.007), 0.95 (95% CI 0.82 to 1.09, P=0.423), 0.92 (95% CI 0.81 to 1.05, P=0.228), and 0.88 (95% CI 0.78 to 1.00, P=0.045), respectively. The results of the 110-mg BID dosage were mainly driven by the RE-LY trial. CONCLUSIONS: This meta-analysis provides evidence that dabigatran etexilate is associated with a significantly increased risk of MI. This increased risk should be considered taking into account the overall benefit in terms of major bleeding and all-cause mortality.

Risk of nonvertebral fractures among elderly postmenopausal women using antidepressants.

OBJECTIVE: To examine the association between antidepressants, including TCAs, SSRIs, and miscellaneous antidepressants and the risk of nonvertebral fractures among women with osteoporosis. MATERIALS AND METHODS: This study was a post-hoc analysis of pooled data from two international, phase III, randomized, placebo-controlled, double-blind studies (the Spinal Osteoporosis Therapeutic Intervention [SOTI] and TReatment Of Peripheral OSteoporosis [TROPOS]). A nested case-control study was performed in the placebo treated population. Adjusted logistic regression models were used to estimate the risk of nonvertebral fracture associated with the use of antidepressants. RESULTS: After 3 years of follow-up, 391 nonvertebral fractures cases were identified and matched to 1955 controls. Compared with non-users of antidepressants, antidepressants use was associated with an increased risk of nonvertebral fractures (adjusted OR=1.64; 95%CI, 1.03-2.62]). Particularly, there was a 2-fold risk increase (95%CI, 1.07-3.79) of nonvertebral fracture for current users of SSRIs and a 2.1-fold risk increase for subjects who were current users of TCAs (95%CI, 1.02-4.30). Among patients categorized as recent or past users, none of the classes of antidepressants were statistically associated with increased risk of nonvertebral fracture. CONCLUSIONS: Our findings confirm that both SSRIs and TCAs increase the risk of nonvertebral fracture in current users.

The importance of integrating medication adherence into pharmacoeconomic analyses: the example of osteoporosis.

Adherence to medications is poor and suboptimal in many chronic diseases. Nonadherence can reduce treatment effectiveness and can have an impact on healthcare costs. As a consequence, it may alter the cost-effectiveness of drug therapies. This article emphasizes the importance of integrating medication compliance and persistence into pharmacoeconomic evaluations, using osteoporosis as an example. A limited number of studies carried out to date have suggested important economic implications of poor adherence to osteoporosis medications. Therefore, compliance and persistence should be an integral part of clinical studies and pharmacoeconomic analyses in order to estimate the cost-effectiveness of drug therapies in current community practice. Measuring adherence and incorporating it into health economic modeling may, however, pose particular challenges.

Overcoming problems with adherence to osteoporosis medication.

Nonadherence to pharmacological treatment in osteoporosis is a well-recognized problem. As in other chronic diseases, adherence to osteoporosis treatment is poor, resulting in enormous burden on patients and healthcare resources. Most importantly, low adherence rates consistently result in increased rates of fractures. However, it seems that efforts to evaluate and improve rates of both compliance and persistence are increasing. The extension of dosing intervals may be an element, among others, allowing improvements in therapeutic adherence. Improved patient education, enhancing healthcare provider-patients interaction, taking into account patient's preferences and involving them in treatment decisions may improve adherence.

The clinical and economic burden of non-adherence with oral bisphosphonates in osteoporotic patients.

OBJECTIVES: This study aims to estimate the clinical and economic burden of non-adherence with oral bisphosphonates in osteoporotic patients and the potential cost-effectiveness of adherence-enhancing interventions. METHODS: A validated Markov microsimulation model estimated costs and outcomes (i.e. the number of fractures and the quality-adjusted life-year (QALY)) for three adherence scenarios: no treatment, real-world adherence and full adherence over 3 years. The real-world adherence scenario employed data from a published observational study. The incremental cost per QALY gained was estimated and compared across the three adherence scenarios. RESULTS: The number of fractures prevented and the QALY gain obtained at real-world adherence levels represented only 38.2% and 40.7% of those expected with full adherence, respectively. The cost per QALY gained of real-world adherence compared with no treatment was estimated at euro 10279, and full adherence was found to be cost-saving compared with real-world adherence. CONCLUSIONS: This study suggests that more than half of the potential clinical benefits from oral bisphosphonates in patients with osteoporosis are lost due to poor adherence with treatment. Depending on their cost, interventions with improved adherence to therapy have the potential to be an attractive use of resources.

Poor adherence to oral bisphosphonate treatment and its consequences: a review of the evidence.

Poor therapeutic adherence is a major issue faced by physicians today. This paper summarizes the adherence rates with oral bisphosphonate (OBP) treatment in clinical practice and their impact on clinical outcomes. Studies systematically demonstrated that overall compliance and persistence with OBPs among osteoporotic women are poor. Although extending dosing intervals improved adherence, the gains are suboptimal. Most importantly, low compliance and persistence rates consistently resulted in increased rates of fractures. The results emphasize the importance of adherence to treatment to achieve optimal antifracture efficacy. There is an urgent need to implement strategies and to encourage physicians to take measures that increase patients' awareness of the need to use osteoporosis medications as directed in order to benefit from them fully.