Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures.

OBJECTIVE: The efficacy and safety of cenobamate relative to other antiseizure medications (ASMs) has not been evaluated. An indirect treatment comparison (network meta-analysis) was performed to determine if adjunctive cenobamate increases the odds ratio (OR) for ≥50% responder rate or for withdrawals due to treatment-emergent adverse events (TEAEs) leading to ASM discontinuation versus adjunctive therapy with other ASMs. METHODS: A systematic literature review was conducted to identify randomized, double-blind, placebo-controlled trials (maintenance phase ≥ 12 weeks) assessing adjunctive ASMs in adults with uncontrolled focal seizures. Cenobamate was compared to a group of seven other ASMs, and to subgroups of branded (brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel) and older (lamotrigine, levetiracetam, and topiramate) ASMs at FDA-recommended daily maintenance doses (FDA-RDMD), at all doses, and at maximum and minimum daily doses. Statistical significance was set at p < 0.05. RESULTS: Twenty-one studies were eligible for analysis. The placebo-adjusted ≥ 50% responder rate for FDA-RDMD of cenobamate was superior (OR 4.200; 95% CI 2.279, 7.742) to FDA-RDMD of all seven assessed (OR 2.202 95% CI 1.915, 2.532; p = 0.044) and branded ASMs (OR 2.148; 95% CI 1.849, 2.494; p = 0.037). There was no significant difference for ≥50% responder rate between FDA-RDMD of cenobamate and FDA-RDMD of older ASMs (OR 2.617; 95% CI 1.767, 3.878; p = 0.202). No significant differences were identified for ≥50% responder rate when comparing all doses and maximum/minimum doses of cenobamate to all seven, branded, and older ASMs. Cenobamate demonstrated comparable TEAE withdrawal rates to all seven ASMs, branded ASMs, and older ASMs across each of the four dose ranges (all p > 0.05). SIGNIFICANCE: Patients receiving FDA-RDMD of cenobamate were more likely to have ≥50% seizure reduction compared with FDA-RDMD of the seven assessed ASMs and branded ASMs, without an increase in treatment discontinuation due to TEAEs.

Efficacy and safety profiles of manidipine compared with amlodipine: a meta-analysis of head-to-head trials.

Abstract The aim of this meta-analysis was to compare the efficacy and safety profile of manidipine 20 mg with that of amlodipine 10 mg. A systematic research of quantitative data produced or published between 1995 and 2009 was performed. Head-to-head randomized controlled trials (RCTs) of 12 months minimum duration reporting comparative efficacy (changes in systolic and diastolic blood pressure) and safety (total adverse events and ankle oedema), were included. Four high-quality RCTs, accounting for 838 patients (436 received manidipine and 402 received amlodipine) were included. The efficacy of manidipine and amlodipine was statistically equivalent: effect size for DBP = -0.08 (p = 0.22) and SBP = -0.01 (p = 0.83). The global safety of manidipine was significantly better than amlodipine: the relative risk (RR) for adverse event was 0.69 (0.56-0.85), and particularly for ankle oedema RR was 0.35 (0.22-0.54). Publication bias was not significant and the robustness of the analyses was good. These data suggest a better efficacy/safety ratio of manidipine over amlodipine.

Efficacy and safety of piroxicam revisited. A global meta-analysis of randomised clinical trials.

BACKGROUND: The relative efficacy/safety profiles of traditional (non-selective) NSAIDs (t-NSAIDs) have been repeatedly challenged. To better understand the efficacy and safety profile of piroxicam, a widely used NSAID, a meta-analysis of comparative RCTs was carried out according to the QUOROM guidance. METHODS: A systematic comprehensive research (years 1980-2006) of any comparative randomised controlled trial (of over 7-day duration) with piroxicam for the treatment of osteoarticular conditions was conducted. Conservative analyses were stratified by comparator, outcome, indication, duration, and doses. Publication bias and robustness were exhaustively investigated. RESULTS: Seventy-five comparative trials were ultimately included for analyses. Regarding global efficacy, piroxicam was more effective than naproxen [OR=1.37 (1.05; 1.77)] and nabumetone [OR=1.72 (1.26; 2.34)], while equivalent to other NSAIDS [OR=1.06 (0.96; 1.18)]. For pain and articular swelling, piroxicam was statistically equivalent to all other NSAIDs. For mobility, piroxicam appeared to be more effective than indomethacin, while equivalent to all other NSAIDs. Piroxicam was globally safer than other NSAIDs OR=0.83 [0.73; 0.96], notably indomethacin [OR=0.53 (0.43; 0.64], naproxen [OR=0.75 (0.65; 0.85)] and salicylates [OR=0.36 (0.17; 0.75)]. From a global GI safety point of view, piroxicam was better tolerated than indomethacin [OR=0.46 (0.36; 0.58)], naproxen [OR=0.66 (0.53; 0.83)] and salicylates [OR=0.45 (0.27; 0.78)] while less tolerated when compared to meloxicam [OR=1.49 (1.05; 2.13)]. Major GI effects were comparable among piroxicam users as in comparator drugs users [OR=1.33 (0.96; 1.84)], except for meloxicam [OR=2.37 (1.13; 4.97)]. The skin safety of piroxicam was statistically comparable to those of comparators [OR=1.01 (0.68; 1.51)]. CONCLUSION: This meta-analysis of RCTs support a similar to more favourable efficacy/safety profile of piroxicam as compared to other t-NSAIDs.

Development and validation of a Markov microsimulation model for the economic evaluation of treatments in osteoporosis.

OBJECTIVE: Markov models are increasingly used in economic evaluations of treatments for osteoporosis. Most of the existing evaluations are cohort-based Markov models missing comprehensive memory management and versatility. In this article, we describe and validate an original Markov microsimulation model to accurately assess the cost-effectiveness of prevention and treatment of osteoporosis. METHODS: We developed a Markov microsimulation model with a lifetime horizon and a direct health-care cost perspective. The patient history was recorded and was used in calculations of transition probabilities, utilities, and costs. To test the internal consistency of the model, we carried out an example calculation for alendronate therapy. Then, external consistency was investigated by comparing absolute lifetime risk of fracture estimates with epidemiologic data. RESULTS: For women at age 70 years, with a twofold increase in the fracture risk of the average population, the costs per quality-adjusted life-year gained for alendronate therapy versus no treatment were estimated at €9105 and €15,325, respectively, under full and realistic adherence assumptions. All the sensitivity analyses in terms of model parameters and modeling assumptions were coherent with expected conclusions and absolute lifetime risk of fracture estimates were within the range of previous estimates, which confirmed both internal and external consistency of the model. CONCLUSION: Microsimulation models present some major advantages over cohort-based models, increasing the reliability of the results and being largely compatible with the existing state of the art, evidence-based literature. The developed model appears to be a valid model for use in economic evaluations in osteoporosis.

Levetiracetam extended release and levetiracetam immediate release as adjunctive treatment for partial-onset seizures: an indirect comparison of treatment-emergent adverse events using meta-analytic techniques.

The safety profiles of once-daily adjunctive levetiracetam (LEV) extended release (XR) (1000mg/day) and adjunctive LEV immediate release (IR) (500mg twice daily) were compared using data from three randomized, placebo (PBO)-controlled phase III clinical trials in patients with partial-onset seizures. MedDRA 9.0 treatment-emergent adverse events (TEAEs) were indirectly compared using meta-analytic techniques, including calculation of risk difference (RD) and mixed-effects analysis. Statistical significance was set at 10% alpha risk, the normative value for these analyses. Data from 555 patients older than 16 (204 LEV IR, 70 LEV XR, 281 PBO) were analyzed. Following adjustment for incidence of placebo TEAEs, LEV XR showed statistically significantly lower rates of TEAEs than LEV IR across nervous system disorders (RD=-18%, P=0.03), psychiatric disorders (RD=-11%, P=0.08), and metabolism and nutrition disorders (RD=-3%, P=0.08). Among nervous system disorders, the RD for headache favored LEV XR (RD=-11%, P=0.08). These results suggest that adjunctive LEV XR may be associated with a lower incidence of nervous system, psychiatric, and nutritional and metabolic TEAEs as compared with LEV IR. However, this difference was observed at a broad scale and not at a specific TEAE level except for headache.

Macro-economic factors influencing the architectural business model shift in the pharmaceutical industry.

INTRODUCTION: Technological innovations, new regulations, increasing costs of drug productions and new demands are only few key drivers of a projected alternation in the pharmaceutical industry. The purpose of this review is to understand the macro economic factors responsible for the business model revolution to possess a competitive advantage over market players. Areas covered: Existing literature on macro-economic factors changing the pharmaceutical landscape has been reviewed to present a clear image of the current market environment. Expert commentary: Literature shows that pharmaceutical companies are facing an architectural alteration, however the evidence on the rationale driving the transformation is outstanding. Merger & Acquisitions (M&A) deals and collaborations are headlining the papers. Q1 2016 did show a major slowdown in M&A deals by volume since 2013 (with deal cancellations of Pfizer and Allergan, or the downfall of Valeant), but pharmaceutical analysts remain confident that this shortfall was a consequence of the equity market volatility. It seems likely that the shift to an M&A model will become apparent during the remainder of 2016, with deal announcements of Abbott Laboratories, AbbVie and Sanofi worth USD 45billion showing the appetite of big pharma companies to shift from the fully vertical integrated business model to more horizontal business models.

Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis.

OBJECTIVE: To assess the structural and symptomatic efficacy of oral glucosamine sulfate and chondroitin sulfate in knee osteoarthritis through independent meta-analyses of their effects on joint space narrowing, Lequesne Index, Western Ontario MacMaster University Osteoarthritis Index (WOMAC), visual analog scale for pain, mobility, safety, and response to treatment. METHODS: An exhaustive systematic research of randomized, placebo-controlled clinical trials published or performed between January 1980 and March 2002 that assessed the efficacy of oral glucosamine or chondroitin on gonarthrosis was performed using MEDLINE, PREMEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Contents, BIOSIS Previews, HealthSTAR, EBM Reviews, manual review of the literature and congressional abstracts, and direct contact with the authors and manufacturers of glucosamine and chondroitin. Inclusion, quality scoring, and data abstraction were performed systematically by 2 independent reviewers who were blinded to sources and authors. Conservative approaches were used for clear assessment of potential efficacy. RESULTS: Our results demonstrated a highly significant efficacy of glucosamine on all outcomes, including joint space narrowing and WOMAC. Chondroitin was found to be effective on Lequesne Index, visual analog scale pain, mobility, and responding status. Safety was excellent for both compounds. CONCLUSIONS: Our study demonstrates the structural efficacy of glucosamine and indistinguishable symptomatic efficacies for both compounds. Regarding the relatively sparse data on glucosamine and joint space narrowing and the absence of data on structural effects of chondroitin, further studies are needed to investigate the relationship among time, dose, patient baseline characteristics, and structural efficacy for an accurate, disease-modifying characterization of these 2 compounds.

Importance of alfacalcidol in clinical conditions characterized by high rate of bone loss.

In postmenopausal osteoporosis, the administration of alfacalcidol to women resulted in an increase in trabecular bone mineral density (BMD), prevention of cortical bone loss, and a significant reduction in the incidence of further vertebral fractures. There is now robust evidence that alfacalcidol may be particularly active in conditions characterized by an increased rate of bone loss. Alfacalcidol 1 microg/day fully prevented vertebral bone loss over 3 years in women after the first year of menopause. In a large cohort of individuals starting treatment with high dose corticosteroid (CS, 46.6 mg equivalent prednisolone per day), the spinal bone loss observed in untreated patients was fully prevented by administration of 1 microg/day alfacalcidol. In patients with established CS-induced osteoporosis, with or without prevalent vertebral fractures, 1 microg/day of alfacalcidol, given for 3 years, increased lumbar spine density, reduced back pain, and showed a significant reduction in the rate of new vertebral fractures, compared to native vitamin D. In cardiac transplant recipients, alfacalcidol and calcium reduced spinal and femoral bone loss, compared to a control group treated with etidronate and calcium. Alfacalcidol-treated patients experienced fewer new vertebral fractures over the 2-year followup. When alfacalcidol and vitamin D3 were compared in elderly women with radiologic evidence of vertebral fracture, fractional calcium absorption was increased after 3 months with alfacalcidol but was unchanged with vitamin D3. In a recent metaanalysis of 14 studies of native vitamin D and 19 studies of D-hormone analogs (alfacalcidol and calcitriol), the D-analogs exerted a higher preventive effect on bone loss and fracture rates in patients with no exposure to CS. In head-to-head studies comparing D-analogs and native vitamin D in patients receiving CS, this metaanalysis identified significant effects favoring D-analogs for femoral neck BMD and spinal fractures. In conclusion, improvement in bone turnover, increase in BMD, and reduction in fracture rates have been described during alfacalcidol treatment in situations characterized by a high rate of bone loss, including CS-induced osteoporosis, early postmenopausal bone loss, and organ transplant. Compared to plain vitamin D, alfacalcidol exerts higher bone-protective effects, thus allowing the doses to be minimized and lowering the risk of adverse effects, including hypercalcemia.

Postmarketing Safety Profile of Subcutaneous Interferon Beta-1a Given 3 Times Weekly: A Retrospective Administrative Claims Analysis.

BACKGROUND: Health insurance administrative claims databases represent a valuable source of information regarding the safety profile of marketed products as used in actual clinical practice in a broader range of patients than that assessed in clinical trials. Interferon beta-1a administered subcutaneously 3 times weekly (IFN ß-1a SC tiw), which was approved in 2002 by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS), has over a decade of postmarketing experience. To date, however, its postmarketing safety profile has not been described using a real-world evidence source such as administrative claims data. OBJECTIVE: To describe the safety profile of IFN ß-1a SC tiw as presented in its U.S. prescribing information (PI) for patients with MS initiating IFN ß-1a SC tiw therapy using data from U.S. health care administrative claims databases. METHODS: This study featured an observational and retrospective "new start" cohort design using data from the Truven MarketScan Commercial and Medicare Supplemental health care administrative claims databases. Patients were eligible for inclusion if they were aged ≥ 18 years; had ≥ 1 diagnosis for MS recorded between January 1, 2006, and December 31, 2012; had ≥ 2 prescriptions for IFN ß-1a SC tiw; and had ≥ 90 days of continuous eligibility pre-index date and ≥ 180 days of continuous eligibility post-index date. Patients with a prescription for IFN ß-1a SC tiw without a MS diagnosis were excluded. Patients were followed from first prescription for IFN ß-1a SC tiw (index date) until date of therapy switch or discontinuation, end of insurance eligibility, or end of observation period. Adverse events (AEs) examined were those listed in the Warnings and Precautions, Adverse Reactions, and Postmarketing Experience sections of the 2014 U.S. PI. Outcomes of interest were identified at the Medical Dictionary for Regulatory Activities (version 17.1) Preferred Term level and then coded to the corresponding ICD-9-CM criteria. Descriptive analyses of patient demographic, health status, health care utilization, and adherence status were performed, and incidence rates (IRs) per 100 person-years of labeled AEs with corresponding 95% CIs were calculated. The IR calculation was based on events that presented after therapy initiation and that were not present in the 90-day pre-index period. RESULTS: The top 6 AEs included influenza-like symptoms (IR = 15.65, 95% CI = 14.96-16.36); malaise (IR = 15.33, 95% CI = 14.65-16.04; fatigue (IR = 15.02, 95% CI = 14.35-15.72); abdominal pain (IR = 10.18, 95% CI = 9.67-10.70); chest pain (IR = 8.48, 95% CI = 8.03-8.95); and depression (IR = 7.75, 95% CI = 7.32-8.20). In contrast, the 6 lowest IRs were for maculo-papular rash (IR = 0.01, 95% CI = 0.00-0.04; injection-site necrosis (IR = 0.01, 95% CI = 0.00-0.03); erythema multiforme (IR = 0.01, 95% CI = 0.00-0.04); hypoesthesia (IR = 0.00, 95% CI = 0.00-0.02); Stevens-Johnson Syndrome (IR = 0.00, 95% CI = 0.00-0.02); and xerophthalmia (IR = 0.00, 95% CI = 0.00-0.02). CONCLUSIONS: Study results show strong convergence between the real-world safety profile of IFN ß-1a SC tiw and its U.S. label. Our findings demonstrate the value of using real-world evidence obtained from administrative claims to complement clinical trial and postmarketing surveillance data in order to characterize the safety profile of established products, such as IFN ß-1a SC tiw, in the postmarketing context.

Primary prevention of osteoporosis: mass screening scenario or prescreening with questionnaires? An economic perspective.

UNLABELLED: This study focuses on the controversy surrounding selective approaches to screen for osteoporosis. Seven screening approaches were compared in terms of cost-effectiveness and incremental cost-effectiveness ratios in a sample of 4035 postmenopausal women. Our results show that certain prescreening strategies are more efficient than DXA-based approaches. These results are of considerable value for health policy decision-makers and the scientific community. INTRODUCTION: There is no general consensus on the most efficient strategy to use bone densitometry for osteoporosis screening. Two distinct approaches have progressively emerged: mass screening using DXA and prescreening strategies using user-friendly risk indices. This study was designed to compare the efficiency of these approaches. MATERIALS AND METHODS: A database of 4035 medical records from postmenopausal women above 45 years was analyzed. In the first scenario, women were systematically referred to DXA if above 45, 50, or 65 years of age. The second scenario involved the validated prescreening tools SCORE, ORAI, OST, and OSIRIS and assessed two separate ways of handling their results (theoretical and pragmatic). The cost of a DXA test was set as the median Belgian value: 40.14 Euros. All strategies were compared in terms of cost exposed per osteoporotic patient detected and in terms of incremental cost-effectiveness ratios. RESULTS: In the systematic DXA strategies, the cost per patient detected ranged from 123 Euros when measuring all women >45 years of age to 91 Euros when focusing on women >65 years of age. The corresponding percentage of cases detected ranged from 100% (age > 45 years) to 50% (age > 65 years). When considering prescreening under the theoretical and pragmatic scenarios, the OSIRIS index provided the best efficiency, with costs of 74 Euros (theoretical) to 85 Euros (pragmatic) per case detected, followed by ORAI (75 Euros and 96 Euros), OST (84 Euros and 94 Euros), and SCORE (96 Euros and 103 Euros). The corresponding percentage of cases detected ranged from 89% (SCORE) to 75% (OSIRIS). The cost-effectiveness analysis showed that mass screening strategies over 50 and 65 years of age and using ORAI were best. CONCLUSIONS: Our study sets the grounds for considering, in a health economics perspective, prescreening tools as valuable, cost-effective, approaches to significantly reduce the economic burden of osteoporosis screening.

Strategies for the prevention of hip fracture.

Hip fractures are associated with 10% to 20% excess mortality in the first year and cause functional disability in most survivors. An estimated 17% of white women in the United States will sustain a hip fracture after the age of 50 years. Despite the availability of evidence-based guidelines for hip fracture prevention, routine screening and preventive measures have not been incorporated into standard primary care practice. Many physicians lack adequate knowledge to initiate bone mineral density testing and treatment with preventive medications to decrease the incidence of osteoporosis and fractures. Furthermore, patients are less likely to request information about bone health than about diseases for which systematic screening and prevention protocols have been established. This review describes preventive measures to decrease hip fracture in postmenopausal women, including screening by bone mineral density testing, risk factor assessment, and chemoprevention. Existing guidelines are summarized, and dilemmas regarding their implementation are discussed.

Development and validation of the ORACLE score to predict risk of osteoporosis.

OBJECTIVE: To develop and validate a composite index, the Osteoporosis Risk Assessment by Composite Linear Estimate (ORACLE), that includes risk factors and ultrasonometric outcomes to screen for osteoporosis. SUBJECTS AND METHODS: Two cohorts of postmenopausal women aged 45 years and older participated in the development (n = 407) and the validation (n = 202) of ORACLE. Their bone mineral density was determined by dual energy x-ray absorptiometry and quantitative ultrasonometry (QUS), and their historical and clinical risk factors were assessed (January to June 2003). Logistic regression analysis was used to select significant predictors of bone mineral density, whereas receiver operating characteristic (ROC) analysis was used to assess the discriminatory performance of ORACLE. RESULTS: The final logistic regression model retained 4 biometric or historical variables and 1 ultrasonometric outcome. The ROC areas under the curves (AUCs) for ORACLE were 84% for the prediction of osteoporosis and 78% for low bone mass. A sensitivity of 90% corresponded to a specificity of 50% for identification of women at risk of developing osteoporosis. The corresponding positive and negative predictive values were 86% and 54%, respectively, in the development cohort. In the validation cohort, the AUCs for identification of osteoporosis and low bone mass were 81% and 76% for ORACLE, 69% and 64% for QUS T score, 71% and 68% for QUS ultrasonometric bone profile index, and 76% and 75% for Osteoporosis Self-assessment Tool, respectively. ORACLE had the best discriminatory performance in identifying osteoporosis compared with the other approaches (P < .05). CONCLUSION: ORACLE exhibited the highest discriminatory properties compared with ultrasonography alone or other previously validated risk indices. It may be helpful to enhance the predictive value of QUS.

Health-related quality of life in total hip and total knee arthroplasty. A qualitative and systematic review of the literature.

BACKGROUND: Total hip and total knee arthroplasties are well accepted as reliable and suitable surgical procedures to return patients to function. Health-related quality-of-life instruments have been used to document outcomes in order to optimize the allocation of resources. The objective of this study was to review the literature regarding the outcomes of total hip and knee arthroplasties as evaluated by health-related quality-of-life instruments. METHODS: The Medline and EMBASE medical literature databases were searched, from January 1980 to June 2003, to identify relevant studies. Studies were eligible for review if they met the following criteria: (1). the language was English or French, (2). at least one well-validated and self-reported health-related quality of life instrument was used, and (3). a prospective cohort study design was used. RESULTS: Of the seventy-four studies selected for the review, thirty-two investigated both total hip and total knee arthroplasties, twenty-six focused on total hip arthroplasty, and sixteen focused on total knee arthroplasty exclusively. The most common diagnosis was osteoarthritis. The duration of follow-up ranged from seven days to seven years, with the majority of studies describing results at six to twelve months. The Short Form-36 and the Western Ontario and McMaster University Osteoarthritis Index, the most frequently used instruments, were employed in forty and twenty-eight studies, respectively. Seventeen studies used a utility index. Overall, total hip and total knee arthroplasties were found to be quite effective in terms of improvement in health-related quality-of-life dimensions, with the occasional exception of the social dimension. Age was not found to be an obstacle to effective surgery, and men seemed to benefit more from the intervention than did women. When improvement was found to be modest, the role of comorbidities was highlighted. Total hip arthroplasty appears to return patients to function to a greater extent than do knee procedures, and primary surgery offers greater improvement than does revision. Patients who had poorer preoperative health-related quality of life were more likely to experience greater improvement. CONCLUSIONS: Health-related quality-of-life data are valuable, can provide relevant health-status information to health professionals, and should be used as a rationale for the implementation of the most adequate standard of care. Additional knowledge and scientific dissemination of surgery outcomes should help to ensure better management of patients undergoing total hip or total knee arthroplasty and to optimize the use of these procedures.

Interest of biochemical markers of bone turnover for long-term prediction of new vertebral fracture in postmenopausal osteoporotic women.

OBJECTIVE: To analyse the interest of baseline levels and short-term (3-months) changes in serum osteocalcin (BGP), serum bone-specific alkaline phosphatase (BALP) and urinary C-telopeptide of type I collagen/creatinine ratio (U-CTX) to predict 3-years changes in bone mineral density (BMD) and spinal deformity index (SDI) in postmenopausal osteoporotic women. METHODS: Data were derived from a cohort of 603 osteoporotic women corresponding to the placebo arm of a 3-years prospective, double-blind study. RESULTS: Baseline values of BALP, BGP and U-CTX were negatively and significantly correlated with baseline spinal BMD. Significant correlations were also observed between the changes in BMD observed after 36 months at the spine and baseline BALP (r=0.20, P=0.0001), BGP (r=0.09, P=0.05) and U-CTX (r=-0.11, P=0.02). At 3 years, 71 women (15.9%) showed an increase in their SDI, corresponding to the occurrence of at least one new vertebral deformity. Baseline values of the four bone turnover markers (BTM) were not significantly related to the occurrence of new vertebral deformities. However, when considering the changes in the BTM observed after 3-months of follow-up, BGP (P=0.003) and U-CTX (P=0.047) were identified as significant predictors of an increase of SDI. The associated odds ratios (95% confidence interval (CI)) were 10.922 (2.218-53.78) for unit changes of log BGP and 1.369 (1.003-1.867) for unit changes of logU-CTX. The relative risk (RR) (IC 95%) of having a new vertebral fracture over 36 months was 0.31 (0.15-0.65) when being in the lowest quartile of 3-months changes in BGP as compared with the highest. CONCLUSION: We conclude that two sequential measurements of BGP and U-CTX performed at 3-months intervals could be of interest to identify postmenopausal osteoporotic women with the highest risk to present new vertebral deformities.

Osteoporosis prevalence in men varies by the normative reference.

Controversy surrounds which normative data should be used to estimate osteoporosis prevalence in men. Prevalence estimates may vary significantly when different normative standards are applied. Five normative datasets (NHANES female norms, local female norms, Hologic densitometer manufacturer female norms, NHANES male norms, Hologic male norms) were used to estimate the prevalence of osteoporosis by World Health Organization diagnostic criteria in a study population of 311 consecutive men between the age of 30 and 91 (mean 60.3 yr) referred to an outpatient osteoporosis center between January 1996 and December 1998. Statistically significant variations were seen in osteoporosis prevalence measured at three anatomical sites. The greatest relative variation was seen for the total femur, where osteoporosis prevalence ranged from 7.0% (NHANES and Hologic female norms) to 15.6% (NHANES male norms). The least relative variation was seen at the lumbar spine, where prevalence ranged from 18.1% (Hologic female norms) to 29.6% (local female norms). When considering osteoporosis at any site, prevalence was lowest (23.5%) based on Hologic female norms and highest (35.8%) based on local female norms. Interpretation of prevalence data should include an assessment of how normative standards influence reporting of the population at high risk of fracture.

Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.

OBJECTIVE: To determine whether the use of metformin in type 2 diabetic patients with various kidney functions is associated with an increased risk of lactic acidosis (LA). RESEARCH DESIGN AND METHODS: This study was a retrospective analysis of U.K. patient records from the Clinical Practice Research Datalink database from 1 January 2007 to 31 December 2012. Inclusion criteria were 1) diagnosis of type 2 diabetes before 1 January 2007, 2) treatment with metformin, and 3) at least one assessment of renal function between 2007 and 2012. Renal function was assessed by glomerular filtration rate and categorized as normal (N), mildly reduced (Mi), moderately reduced (Mo), or severely reduced (Se) function. The outcome of the study was LA. RESULTS: A total of 77,601 patients treated with metformin for type 2 diabetes were identified. There were 35 LA events (10.37 [95% CI 7.22-14.42] per 100,000 patient-years) of which none were fatal and 23 were linked to a comorbidity. No significant difference in the incidence of LA was observed across N, Mi, Mo and Se renal function groups (7.6 [0.9-27.5], 4.6 [2.00-9.15], 17 [10.89-25.79], and 39 [4.72-140.89] cases per 100,000 patient-years, respectively). CONCLUSIONS: The overall LA incidence rate for patients on metformin in this study was within the range of rates reported in the literature for patients with type 2 diabetes, and no significant difference was observed among patients with N, Mi, Mo, and Se function.

Compliance with pharmacotherapy and direct healthcare costs in patients with Parkinson's disease: a retrospective claims database analysis.

BACKGROUND: Parkinson's disease (PD) is a progressive neurological disorder for which, at present, there is no cure. Current therapy is largely based on the use of dopamine agonists and dopamine replacement therapy, designed to control the signs and symptoms of the disease. The majority of current treatments are administered in tablet form and can involve multiple daily doses, which may contribute to sub-optimal compliance. Previous studies with small groups of patients suggest that non-compliance with treatment can result in poor response to therapy and may ultimately increase direct and indirect healthcare costs. OBJECTIVE: To determine the extent of non-compliance within the general PD population in the USA as well as the patient characteristics and healthcare costs associated with compliance and non-compliance. METHODS: A retrospective analysis from a managed care perspective was conducted using data from the USA PharMetrics patient-centric claims database. PharMetrics claims data were complete from 31 December 2005 to 31 December 2009. Patients were included if they had at least two diagnoses for PD between 31 December 2005 and 31 December 2008, were older than 18 years of age, were continuously enrolled for at least 12 months after the date of the most recent PD diagnosis, and had no missing or invalid data. The follow-up period was the most recent 12-month block of continuous enrollment that occurred between 2006 and 2009. Patients were required to have at least one PD-related prescription within the follow-up period. The medication possession ratio (MPR) was used to categorise patients as compliant or non-compliant. Direct all-cause annual healthcare costs for patients with PD were estimated for each patient, and regression analyses were conducted to determine predictors for non-compliance. RESULTS: A total of 15,846 patients were included, of whom 46 % were considered to be non-compliant with their prescribed medication (MPR <0.8). Predictors of non-compliance included prescription of a medication administered in multiple daily doses (p < 0.0001), a period of <2 years since the initial PD diagnosis (p = 0.0002), a diagnosis of gastrointestinal disorder (p < 0.0001), and a diagnosis of depression (p < 0.0001). Non-compliance was also found to be related to age, with a lower odds of non-compliance in patients aged 41-80 years than in patients aged ≥81 years (p < 0.05). Although total drug mean costs were higher for compliant patients than non-compliant patients (driven mainly by the cost of PD-related medications), the mean costs associated with emergency room and inpatient visits were higher for patients non-compliant with their prescribed medication. Overall, the total all-cause annual healthcare mean cost was lower for compliant ($77,499) than for non-compliant patients ($84,949; p < 0.0001). CONCLUSION: Non-compliance is prevalent within the general USA PD population and is associated with a recent PD diagnosis, certain comorbidities, and multiple daily treatment dosing. Non-compliance may increase the burden on the healthcare system because of greater resource usage compared with the compliant population. Treatments that require fewer daily doses may have the potential to improve compliance, which in turn could reduce the economic burden associated with PD.

Gastrointestinal disorders in Parkinson's disease: prevalence and health outcomes in a US claims database.

The majority of patients with Parkinson's Disease (PD) will eventually develop gastrointestinal disorders (GIDs) such as dysphagia, constipation and gastroesophageal reflux. The objectives of this study were to examine the incidence of GIDs in PD patients in a US population, and to examine subsequent PD-related outcomes in patients with GIDs. In a US administrative health claims database, GID incidence increased over time to reach 65% at four years after PD diagnosis. To further investigate this relationship, a subset of patients was analysed in greater detail. Continuously treated PD patients with and without GIDs were matched by age, gender, comorbidities, treatment regime, US region and plan type. Their emerging health outcomes were followed up for two years. Outcomes included neuropsychiatric, motor and urogenital disturbances, as well as healthcare utilization and costs. Patients with GIDs had higher rates of psychosexual dysfunction, anxiety, depression, ataxia, pain, movement disorders, urinary incontinence and falls. Emergency room admissions, the number of drugs for pain, sleep and depression, PD-related healthcare costs and non PD-related healthcare costs also increased during the observation period in GID patients. This study indicated that GIDs may be associated with deleterious effects on some PD-related outcomes.

Differential effects of D-hormone analogs and native vitamin D on the risk of falls: a comparative meta-analysis.

The aim of this meta-analysis was to compare the antifall efficacy of native vitamin D to that of its hydroxylated analogs alfacalcidol and calcitriol. Randomized clinical trials comparing oral native vitamin D and its analogs alfacalcidol and calcitriol to a placebo were included. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, a hand search of abstracts, as well as reference lists. The time range was January 1995 to May 2007. Data were abstracted and scored by two investigators. The core analysis was based on double-blind trials, while open trials were included as a robustness analysis. Relative risks (RRs) for falls while allocated to D-hormone analogs or vitamin D were calculated. Publication bias and robustness were formally tested. Fourteen trials including 21,268 subjects were included. Using double-blind data only, vitamin D-hormone analogs provided a statistically significant lower level of risk for falling compared to native vitamin D: RR = 0.79 (95% confidence interval 0.64-0.96) vs. 0.94 (0.87-1.01) (intergroup difference P = 0.049). The dropout rates observed in the two sets of trials were comparable: 0.33% per month. Publication bias investigation did not report any significant trend for selective publication favoring active treatment arms. Upon current evidence, D-hormone analogs seem to prevent falls to a greater extent than their native compound. Long-term, prospective, head-to-head, confirmatory trials are required to address the exact role of vitamin D and D-hormone analogs in the prevention of falls and fractures.

Utility values associated with osteoporotic fracture: a systematic review of the literature.

We reviewed studies that have estimated the impact of osteoporotic fracture on quality-adjusted life years (QALY) and to determine reference values for countries that would like to carry out cost-utility analyses but that do not have their own values. The computerized medical literature databases Medline and EMBASE were searched from January 1990 to December 2006. The search was carried out in two steps. The first step was to identify studies that related to quality of life in osteoporosis. As part of the second step, only the studies that translated quality of life into a utility value (one single value for health status ranging 0-1) and calculated a utility loss over a period of at least 1 year were selected. From the 152 studies identified in the first analysis, only 16 were retained after the second step. Ten studies investigated utility values for hip fractures, 11 for vertebral fractures, five for distal forearm fractures, and four for other osteoporotic fractures and fracture interactions. Utility values differed substantially between studies, partly due to the valuation technique used, the severity of fractures, and the sample size. This review suggests that there is no meaningful average value across different studies, different samples, different countries, or different instruments. Although we tried to determine the best available values, these values do not preclude the need for country-specific studies. Finally, we also make recommendations regarding the design and methodology for such studies.