Véronique Rabenda

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.

Adherence to treatment of osteoporosis: a need for study

SummaryAdherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis.IntroductionSeveral medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients.MethodsAn extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting.ResultsThe impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence.ConclusionAdherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

Antidepressant medications and osteoporosis

Use of antidepressant medications that act on the serotonin system has been linked to detrimental impacts on bone mineral density (BMD), and to osteoporosis. This article reviews current evidence for such effects, and identifies themes for future research. Serotonin receptors are found in all major types of bone cell (osteoblasts, osteocytes, and osteoclasts), indicating an important role of the neuroendocrine system in bone. Observational studies indicate a complex relationship between depression, antidepressants, and fracture. First, the presence of depression itself increases fracture risk, in relation with decreased BMD and an increase in falls. A range of aspects of depression may operate, including behavioral factors (e.g., smoking and nutrition), biological changes, and confounders (e.g., comorbidities and concomitant medications). A substantial proportion of depressed patients receive antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). Some of these have been linked to decreased BMD (SSRIs) and increased fracture risk (SSRIs and tricyclic agents). Current use of SSRIs and tricyclics increases fracture risk by as much as twofold versus nonusers, even after adjustment for potential confounders. While there is a dose-response relationship for SSRIs, the effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. The increase in risk is the greatest in the early stages of treatment, with a dramatic increase after initiation, reaching a peak within 1 month for tricyclics and 8 months for SSRIs. Treatment-associated increased risk diminishes towards baseline in the year following discontinuation. The body of evidence suggests that SSRIs should be considered in the list of medications that are risk factors for osteoporotic fractures.

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.

Partial adherence: a new perspective on health economic assessment in osteoporosis

SummaryPartial adherence in osteoporosis increases the risk for fragility fracture and has considerable impact on cost-effectiveness. This review highlights a number of avenues for further research, such as improved definition of thresholds of compliance and persistence, as well as gap length, offset times, and fraction of benefit.IntroductionA number of economic models have been developed to evaluate osteoporosis therapies and support decisions regarding efficient allocation of health care resources. Adherence to treatment is seldom incorporated in these models, which may reduce their validity for decision-making since adherence is poor in real-world clinical practice.MethodsAn ad hoc working group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review key issues concerning the incorporation of partial adherence in health economic models.ResultsObservational data have shown that poor adherence is associated with an increase in the risk for fragility fracture. Health economic modelling indicates that full adherence is associated with more quality-adjusted life years gained than partial adherence, as well as higher treatment costs and lower fracture-related costs. Although adherence appears as an important driver of cost-effectiveness, the effect is dependent on a range of other variables, such as offset time, fraction of benefit, fracture risk, fracture efficacy, fracture-related costs, and drug cost, some of which are poorly defined. Current models used to evaluate cost-effectiveness in osteoporosis may oversimplify the contributions of compliance and persistence.ConclusionPartial adherence has a significant impact on cost-effectiveness. Further research is required to optimise thresholds of compliance and persistence, the impact of gap length, offset times, and fraction of benefit.

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).

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.

Prevalence and impact of osteoarthritis and osteoporosis on health-related quality of life among active subjects

Background and aims: To assess the prevalence and impact of osteoarthritis (OA) and osteoporosis (OP) on health-related quality of life (HRQOL) among active subjects employed in the public workforce in Belgium. Methods: A cohort of 3440 subjects employed by the Liège City Council was prospectively followed for 6 months. The employees were asked to fill in a monthly log in a health record book, of data regarding their healthcare consumption due to OA and OP. HRQOL was assessed using the Medical Outcomes Study Short Form-36 (SF-36). Results: 1811 subjects (52.6%) filled in at least one questionnaire. The mean duration of follow-up was 3.46 months. The self-reported prevalence of OA and OP at entry to the study were respectively 34.1% and 5.3%. 3.6% of subjects reported suffering from both OA and OP. Subjects with OA and both OA and OP had significantly lower scores on all SF-36 dimensions compared with normal subjects, reflecting a worse HRQOL. The OP group had significantly lower mean scores for physical functioning and pain compared with controls. Subjects with both OA and OP had significantly lower values for physical functioning, physical role and pain when compared with the OA and OP groups. Conclusions: The results of this survey of a large sample of active subjects show that self-reported osteoarthritis and osteoporosis are common in the workplace. Both diseases have a major impact on health-related quality of life compared with that of people without self-reported musculoskeletal diseases.

Relationship between bone mineral density changes and risk of fractures among patients receiving calcium with or without vitamin D supplementation: a meta-regression

SummarySurrogate measures of fracture risk, such as effects on bone mineral density, may be of great interest to assess the efficacy of available osteoporosis treatments. Our results suggest that bone mineral density (BMD) changes cannot be used as a surrogate of anti-fracture efficacy, among patients receiving calcium, with or without vitamin D.IntroductionThe purpose of this study is to examine the association between changes in bone mineral density with reduction in the risk of fractures in patients receiving calcium with or without vitamin D.MethodsWe selected all randomized placebo-controlled clinical trials of calcium with or without vitamin D supplementation. To be included in this analysis, the studies were required to report both BMD (hip/proximal femur and/or lumbar spine) and the incidence of fractures. Meta-regression analyses were used to examine the associations of changes in BMD with reduction in risk of fracture over the duration of each study. The change in BMD was the difference between changes (from baseline) observed in the active treatment group and placebo group.ResultsA total of 15 randomized trials (n = 47,365) were identified, most of whom (77%) came from the Women’s Health Initiative trial. Results show that larger increases in BMD at the lumbar spine were not associated with greater reduction in fracture risk. Concerning hip BMD changes, we found a statistically significant relationship between hip BMD changes and reduction in risk. However, results were not quite significant after excluding the both largest studies, in which BMD changes were measured in very small subset of patients. These points may have largely biased our results.ConclusionsIn conclusion, there was no evidence of a relationship between BMD changes and reduction in risk of fractures among patients receiving calcium with or without vitamin D supplementation. Calcium and/or Vitamin D may reduce fracture rates through a mechanism independent of bone density.

Flurbiprofen in the symptomatic management of rheumatoid arthritis: a valuable alternative

Background:  The withdrawal of certain cyclooxygenase‐2 selective drugs and the availability of over‐the‐counter non‐steroidal anti‐inflammatory drugs (NSAIDs) have increased the pressure for researching and prescribing conventional NSAIDs with a favourable efficacy/tolerance ratio in inflammatory diseases, particularly rheumatoid arthritis. The aim of this comprehensive meta‐analysis was to evaluate the absolute and relative efficacy and safety of flurbiprofen in the management of rheumatoid arthritis.