Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Correction: Variability in patient sociodemographics, clinical characteristics, and healthcare service utilization among 107,302 treatment seeking smokers in Ontario: A cross-sectional comparison.

[This corrects the article DOI: 10.1371/journal.pone.0235709.].

Variability in patient sociodemographics, clinical characteristics, and healthcare service utilization among 107,302 treatment seeking smokers in Ontario: A cross-sectional comparison.

BACKGROUND: Since 2005, the Smoking Treatment for Ontario Patients (STOP) program has provided smoking cessation treatment of varying form and intensity to smokers through 11 distinct treatment models, either in-person at partnering healthcare organizations or remotely via web or telephone. We aimed to characterize the patient populations reached by different treatment models. METHODS: We linked self-report data to health administrative databases to describe sociodemographics, physical and mental health comorbidity, healthcare utilization and costs. Our sample consisted of 107,302 patients who enrolled between 18Oct2005 and 31Mar2016, across 11 models operational during different time periods. RESULTS: Patient populations varied on sociodemographics, comorbidity burden, and healthcare usage. Enrollees in the Web-based model were youngest (median age: 39; IQR: 29-49), and enrollees in primary care-based Family Health Teams were oldest (median: 51; IQR: 40-60). Chronic Obstructive Pulmonary Disease and hypertension were the most common physical health comorbidities, twice as prevalent in Family Health Teams (32.3% and 30.8%) than in the direct-to-smoker (Web and Telephone) and Pharmacy models (13.5%-16.7% and 14.7%-17.7%). Depression, the most prevalent mental health diagnosis, was twice as prevalent in the Addiction Agency (52.1%) versus the Telephone model (25.3%). Median healthcare costs in the two years up to enrollment ranged from $1,787 in the Telephone model to $9,393 in the Addiction Agency model. DISCUSSION: While practitioner-mediated models in specialized and primary care settings reached smokers with more complex healthcare needs, alternative settings appear better suited to reach younger smokers before such comorbidities develop. Although Web and Telephone models were expected to have fewer barriers to access, they reached a lower proportion of patients in rural areas and of lower socioeconomic status. Findings suggest that in addition to population-based strategies, embedding smoking cessation treatment into existing healthcare settings that reach patient populations with varying disparities may enhance equitable access to treatment.

Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

The effect of a clinical decision support system on prompting an intervention for risky alcohol use in a primary care smoking cessation program: a cluster randomized trial.

BACKGROUND: Clinical decision support systems (CDSSs) may promote practitioner adherence to evidence-based guidelines. This study examined if the addition of a CDSS influenced practitioner delivery of a brief intervention with treatment-seeking smokers who were drinking above recommended alcohol consumption guidelines, compared with practitioners who do not receive a CDSS prompt. METHODS: This was a cluster randomized controlled trial conducted in primary health care clinics across Ontario, Canada, implementing the Smoking Treatment for Ontario Patients (STOP) smoking cessation program. Clinics randomized to the intervention group received a prompt when a patient reported consuming alcohol above the Canadian Cancer Society (CCS) guidelines; the control group did not receive computer alerts. The primary outcome was an offer of an appropriate educational alcohol resource, an alcohol reduction workbook for patients drinking above the CCS guidelines, and an abstinence workbook to patients scoring above 20 points in the AUDIT screening tool; the secondary outcome was patient acceptance of the resource. The tertiary outcome was patient abstinence from smoking, and alcohol consumption within CCS guidelines, at 6-month follow-up. Results were analyzed using a generalized estimation approach for fitting logistic regression using a population-averaged method. RESULTS: Two hundred and twenty-one clinics across Ontario were randomized for this study; 110 to the intervention arm and 111 to the control arm. From the 15,222 patients that enrolled in the smoking cessation program, 15,150 (99.6% of patients) were screened for alcohol use and 5715 patients were identified as drinking above the CCS guidelines. No statistically significant difference between groups was seen in practitioner offer of an educational alcohol resource to appropriate patients (OR = 1.19, 95% CI 0.88-1.64, p = 0.261) or in patient abstinence from smoking and drinking within the CCS guidelines at 6-month follow-up (OR = 0.93, 95% CI 0.71-1.22, p = 0.594). However, a significantly greater proportion of patients in the intervention group accepted the alcohol resource offered to them by their practitioner (OR = 1.48, 95% CI 1.01-2.16, p = 0.045). CONCLUSION: A CDSS may not increase the likelihood of practitioners offering an educational alcohol resource, though it may have influenced patients' acceptance of the resource. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, number NCT03108144 , registered on April 11, 2017, "retrospectively registered".

A method for co-creation of an evidence-based patient workbook to address alcohol use when quitting smoking in primary care: a case study.

PLAIN ENGLISH SUMMARY: The purpose of this paper is to describe a patient engagement event designed to create an educational workbook with smokers who drink alcohol at harmful levels. The goal was to create a workbook that combined scientific evidence with patients' values, preferences, and needs. Fourteen adult smokers who drink alcohol were invited to the Centre for Addiction and Mental Health (CAMH) to take part in a four-hour event to help design the workbook with the CAMH research team. Participants provided their opinions and ideas to create an outline for the workbook, including activities, images, and titles. The workbook - called Self-Awareness - is currently being offered in a smoking cessation program in 221 primary care clinics across Ontario to help smokers quit or reduce their harmful alcohol use. The patient engagement event was a useful way to co-create educational materials that incorporate both scientific research and patient needs. ABSTRACT: Background Evidence-based medicine is the integration of best research evidence with clinical expertise and patient values. There are few methodologies on how to design evidence-based programs and resources to include patient values. The latter is an important aspect of patient-centered care, and is essential for patients to trust the recommendations and empower them as consumers to make informed choices. This manuscript describes a participatory research approach to design patient-facing educational materials that incorporate both evidence-based and community-sensitive principles. These materials are intended to support smokers to reduce or stop harmful alcohol consumption. Methods Adult smokers who report consuming alcohol were invited to a co-creation meeting at the Centre for Addiction and Mental Health's Nicotine Dependence Service to guide the adaptation of evidence-based materials. The four-hour event consisted of individual reflections, group discussions, and consensus-building interactions. Detailed notes were taken and then incorporated into the material. Results Fourteen individuals participated in the event. The end product was a descriptive outline of an educational resource - entitled Self-Awareness - incorporating material from evidence-based workbooks and patient-driven features. Participants collaboratively selected the resource's content, structure, and titles. Conclusions This model describes a participatory research method that emphasizes the value of the patient perspective; preliminary evidence finds this adaptation approach can increase the adoption of resources. The process described in this article could be replicated in other settings to co-create evidence-based resources, interventions, and programs that reflect the needs of the community. Trial registration ClinicalTrials.gov NCT03108144. Retrospectively registered 11 April 2017.

Combining alcohol interventions with tobacco addictions treatment in primary care-the COMBAT study: a pragmatic cluster randomized trial.

BACKGROUND: Tobacco and alcohol use present multiplicative risk for aerodigestive cancers. Reducing alcohol consumption improves smoking cessation outcomes and reduces cancer risk. Risky alcohol consumption and smoking are often treated separately despite concurrent treatment potentially leading to better outcomes for each. However, no rapidly scalable program exists for combined interventions in primary care clinics spread across wide geographic areas. This cluster randomized trial aims to report on the effects of a novel clinical decision support system (CDSS) on intervention rates by primary care practitioners addressing risky alcohol use in a smoking cessation program. METHODS/DESIGN: We will be implementing a clinical decision support system (CDSS) in 221 primary care sites participating in the Smoking Treatment for Ontario Patients (STOP) program across Ontario, Canada. Sites will be blindly allocated to one of two clinical decision support systems guiding practitioners to provide a risky alcohol use intervention to smokers attempting to quit using nicotine replacement therapy (NRT). Risky alcohol use is defined as drinking above the Canadian Cancer Society's low-risk drinking guidelines. Primary analysis will measure the proportion of risky drinkers offered an alcohol intervention in each CDSS arm at baseline. Patients will be contacted by phone or email to track smoking cessation and alcohol consumption rates at 6- and 12-month follow-up. DISCUSSION: Upon completion of the trial, the effect of different clinical decision support systems on practitioner behaviour, and on client tobacco and alcohol use, will be discussed. If the CDSS successfully promotes SBIRT for risky alcohol use in a primary care setting and/or improves patient-level outcomes, including smoking cessation rates and alcohol use reduction, this tool can be used as a model for other web-based behaviour change interventions integrated into primary care practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03108144.

Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study.

It has been suggested that normalization of bone turnover may improve clinical outcome in Paget's disease of bone (PDB) by preventing complications such as fractures and the development of osteoarthritis. Here we investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a 3-year extension of the Paget's Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalizing bone turnover using zoledronic acid as the treatment of first choice. Symptomatic treatment continued in 232 subjects in whom bisphosphonates were only given for the treatment of bone pain. The primary outcome was fracture and secondary outcomes were orthopedic procedures, quality of life, and bone pain, adjusted for baseline characteristics. Serum total alkaline phosphatase (ALP) concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a nonsignificant increase in fracture risk (hazard ratio = 1.90; 95% CI, 0.91 to 3.98; p = 0.087), orthopedic procedures (1.81; 95% CI, 0.71 to 4.61; p = 0.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42). We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover. © 2016 American Society for Bone and Mineral Research.

Association between adherence to free nicotine replacement therapy and successful quitting.

INTRODUCTION: Providing free nicotine replacement therapy (NRT) can be a cost-effective strategy for increasing quit attempts and cessation rates at a population level. However, the optimal amount of NRT to provide is unknown. Associations between duration of NRT use and abstinence may be overestimated as a result of reverse causality due to discontinuation following relapse. We examined the association between adherence to 10weeks of cost-free NRT and quit success at 6-month follow-up, after controlling for reverse causation by excluding participants who reported nonadherence due to relapse. METHODS: Individuals 18years or older who smoked at least 10 cigarettes daily and intended to quit within 30days received 10weeks of NRT at a smoking cessation workshop. There were 3922 participants who attended one of 114 workshops in 70 different localities in Ontario, Canada from 2007 to 2008. RESULTS: At end of treatment participants were asked whether they had used "all" of the NRT (20%), "most" of it (28%), "some" of it (47%), or whether they "did not use any" of it (5%). After controlling for reverse causation and adjusting for potential confounding variables, poorer quit success was reported by those who used either some (AOR=0.43, 95% CI=0.26-0.69, p=0.001) or none (AOR=0.30, 95% CI=0.09-0.95, p=0.041) of the NRT versus all 10weeks. Post-estimation contrasts revealed using some versus most of the NRT was also associated with poorer quit success (p=0.026). CONCLUSIONS: After controlling for reverse causation, adherence to 10weeks of cost-free NRT was associated with successful abstinence at six months post-treatment.

Individualized Treatment for Tobacco Dependence in Addictions Treatment Settings: The Role of Current Depressive Symptoms on Outcomes at 3 and 6 Months.

INTRODUCTION: Individuals with concurrent tobacco dependence and other addictions often report symptoms of low mood and depression and as such may have more difficulty quitting smoking. We hypothesized that current symptoms of depression would be a significant predictor of quit success among a group of smokers receiving individualized treatment for tobacco dependence within addiction treatment settings. METHODS: Individuals in treatment for other addictions were enrolled in a smoking cessation program involving brief behavioral counseling and individualized dosing of nicotine replacement therapy. The baseline assessment included the Patient Health Questionnaire (PHQ9) for depression. Smoking cessation outcomes were measured at 3 and 6 months post-enrollment. Bivariate associations between cessation outcomes and PHQ9 score were analyzed. RESULTS: Of the 1,196 subjects enrolled to date, 1,171 (98%) completed the PHQ9. Moderate to severe depression (score >9) was reported by 28% of the sample, and another 29% reported mild depression (score between 5 and 9). Contrary to the extant literature and other findings by our own group, there was no association between current depression and cessation outcome at either 3 months (n = 1,171) (17.0% in those with PHQ9 > 9 vs. 19.8% in those with PHQ9 < 5, p = .32) or 6 months (n = 834) (17.8% vs. 18.9%, p = .74). CONCLUSIONS: Contrary to our hypothesis, depression severity as measured by the PHQ9 did not predict cessation outcome in this clinical population. A possible explanation may be the individualized treatment and supportive environment of an addictions treatment setting. These data indicate that patients in an addictions treatment setting can successfully quit smoking regardless of current depressive symptoms.

Modelling the cost effectiveness of interventions for osteoporosis: issues to consider.

Expenditure on treating osteoporotic fractures and on preventative intervention is considerable and is likely to rise in forthcoming years due to the association between fracture risk and age. With funders such as the National Institute for Health and Care Excellence and the Pharmaceutical Benefits Advisory Committee explicitly considering cost-effectiveness analyses within the process of producing guidance, it is imperative that economic models are as robust as possible. This article details issues that need to be considered specifically related to health technology assessments of interventions for osteoporosis, and highlights limitations within the current evidence base. A likely direction of impact on cost effectiveness of addressing the key issues has been included alongside a tentative categorization of the level of these impacts. It is likely that cost-effectiveness ratios presented in previous models that did not address the identified issues were favourable to interventions.

Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).

CONTEXT: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3. OBJECTIVE: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3. DESIGN: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1. RESULTS: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients. CONCLUSION: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.

Randomized controlled trial of mailed Nicotine Replacement Therapy to Canadian smokers: study protocol.

BACKGROUND: Considerable public health efforts are ongoing Canada-wide to reduce the prevalence of smoking in the general population. From 1985 to 2005, smoking rates among adults decreased from 35% to 19%, however, since that time, the prevalence has plateaued at around 18-19%. To continue to reduce the number of smokers at the population level, one option has been to translate interventions that have demonstrated clinical efficacy into population level initiatives. Nicotine Replacement Therapy (NRT) has a considerable clinical research base demonstrating its efficacy and safety and thus public health initiatives in Canada and other countries are distributing NRT widely through the mail. However, one important question remains unanswered--do smoking cessation programs that involve mailed distribution of free NRT work? To answer this question, a randomized controlled trial is required. METHODS/DESIGN: A single blinded, panel survey design with random assignment to an experimental and a control condition will be used in this study. A two-stage recruitment process will be employed, in the context of a general population survey with two follow-ups (8 weeks and 6 months). Random digit dialing of Canadian home telephone numbers will identify households with adult smokers (aged 18+ years) who are willing to take part in a smoking study that involves three interviews, with saliva collection for 3-HC/cotinine ratio measurement at baseline and saliva cotinine verification at 8-week and 6-month follow-ups (N = 3,000). Eligible subjects interested in free NRT will be determined at baseline (N = 1,000) and subsequently randomized into experimental and control conditions to receive versus not receive nicotine patches. The primary hypothesis is that subjects who receive nicotine patches will display significantly higher quit rates (as assessed by 30 day point prevalence of abstinence from tobacco) at 6-month follow-up as compared to subjects who do not receive nicotine patches at baseline. DISCUSSION: The findings from the proposed trial are timely and highly relevant as mailed distribution of NRT require considerable resources and there are limited public health dollars available to combat this substantial health concern. In addition, findings from this randomized controlled trial will inform the development of models to engage smokers to quit, incorporating proactive recruitment and the offer of evidence based treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01429129.

Future intentions regarding quitting and reducing cigarette use in a representative sample of Canadian daily smokers: implications for public health initiatives.

Pre-cessation reduction is associated with quitting smoking. However, many smokers reduce the amount consumed but may not quit altogether. Using a representative sample of adult current daily smokers, this project explored future intentions of smokers regarding cigarette consumption. This information is important because it can provide a framework within which to plan tobacco cessation initiatives. A random digit dialing telephone survey was conducted of 889 Canadian current daily smokers, 18 years and older. The response rate was 65% (of households with a smoker in residence, 65% agreed to participate). Analyses focused on the 825 respondents who smoked at least 10 cigarettes per day at some point in their lives. As part of this survey, respondents were asked their future plans about their smoking (maintain, increase, reduce, quit). Of these 825 respondents, the majority of respondents had plans to change their cigarette use, with 55% planning to quit, 18.8% to reduce and 22.5% to maintain the amount they smoked (3.4% did not know and 2 respondents planned to increase). Most smokers who planned to reduce their smoking saw it as a step towards quitting smoking completely. These results present a picture of smokers, the majority of whom appear to be in some form of transition. Many smokers planned to reduce, of which the overwhelming majority saw their reduction as a step towards quitting. Opportunities exist to capitalize on these intentions to change in efforts to promote tobacco cessation.

Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone.

Paget disease of bone (PDB) is a common disorder characterized by increased bone turnover at one of more sites throughout the skeleton. Genetic factors play an important role in the pathogenesis of PDB, and the most important predisposing gene is SQSTM1, which is mutated in about 10% of patients. Here we investigated the relationship between SQSTM1 mutation status, disease severity, and clinical outcome in 737 patients who took part in a randomized study of two different management strategies for the disease. Mutations of SQSTM1 were detected in 80 of 737 (10.9%) patients. Mutation carriers had an earlier age at diagnosis (59.4 ± 11.5 versus 65.0 ± 10.4 years, p < .0001) and a greater number of affected bones (3.2 ± 1.2 versus 2.1 ± 1.2, p < .001) and more commonly required orthopedic surgery (26.2% versus 16.1%, p = .024) and bisphosphonate therapy (86.3% versus 75.2%, p = .01) than those without mutations. Quality of life, as assessed by the short-form-36 (SF36) physical summary score, was significantly reduced in carriers (34.0 ± 11.3 versus 37.1 ± 11.4, p = .036). During the study, fractures were more common in carriers (12.5% versus 5.3%, p = .011), although most of these occurred in unaffected bone. This study demonstrates that SQSTM1 mutations are strongly associated with disease severity and complications of PDB. Genetic testing for SQSTM1 mutations may be of value in identifying individuals at risk of developing severe disease, but further studies will be required to determine if a program of genetic testing and early intervention in these individuals would be cost-effective or be of benefit in preventing these complications.

Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone.

Bisphosphonates are widely regarded as the treatment of choice for Paget's disease of bone (PDB) because of their potent inhibitory effects on bone turnover, but the effects of bisphosphonate therapy on symptoms and complications of PDB have been little studied. Here we report the results of a randomized trial that compared the effects of symptomatic treatment with intensive bisphosphonate therapy in a cohort of 1324 patients with PDB who were followed up for a median of 3 years (range 2 to 5 years). The symptomatic treatment group was treated only if they had pagetic bone pain, for which they were first given analgesics or anti-inflammatory drugs, followed by bisphosphonates if they did not respond. The intensive group received repeat courses of bisphosphonates irrespective of symptoms with the aim of reducing and maintaining serum alkaline phosphatase (ALP) levels within the normal range. The endpoints were fracture, orthopedic surgery, quality of life, bone pain, and hearing thresholds. Serum ALP levels were significantly lower in the intensive treatment group than in with the symptomatic treatment group within 4 months of commencing treatment and remained lower throughout the study (p < .001). There was no difference between the groups in quality of life (as assessed by the SF36 questionnaire), in overall bodily pain, or in pagetic bone pain. Hearing thresholds, as assessed by audiometry did not change significantly and did not differ between the treatment groups. Clinical fractures occurred in 46 of 661 patients (7.0%) in the intensive treatment group compared with 49 of 663 patients (7.4%) in the symptomatic treatment group, and orthopedic surgery was required in 50 of 661 patients (7.3%) in the intensive treatment group and in 55 of 663 patients (8.3%) in the symptomatic treatment group. These differences were not significant. Subgroup analyses of patients with elevated ALP levels at baseline and those who did or did not receive bisphosphonates during the study yielded similar results to those in the study group as a whole. We conclude that striving to maintain normal ALP levels with intensive bisphosphonate therapy confers no clinical advantage over symptom-driven management in patients with established PDB. Neither management strategy had a significant beneficial impact on pain or quality of life (Clinical trial registration number ISRCTN12989577).

The cost-effectiveness of an RCT to establish whether 5 or 10 years of bisphosphonate treatment is the better duration for women with a prior fracture.

PURPOSE: Five years of bisphosphonate treatment have proven efficacy in reducing fractures. Concerns exist that long-term bisphosphonate treatment may actually result in an increased number of fractures. This study evaluates, in the context of England and Wales, whether it is cost-effective to conduct a randomized controlled trial (RCT) and what sample size may be optimal to estimate the efficacy of bisphosphonates in fracture prevention beyond 5 years. METHOD: An osteoporosis model was constructed to evaluate the cost-effectiveness of extending bisphosphonate treatment from 5 years to 10 years. Two scenarios were run. The 1st uses long-term efficacy data from published literature, and the 2nd uses distributions elicited from clinical experts. RESULTS: of a proposed RCT were simulated. The expected value of sample information technique was applied to calculate the expected net benefit of sampling from conducting such an RCT at varying levels of participants per arm and to compare this with proposed trial costs. Results. Without further information, the better duration of bisphosphonate treatment was estimated to be 5 years using the published data but 10 years using the elicited expert opinions, although in both cases uncertainty was substantial. The net benefit of sampling was consistently high when between 2000 and 5000 participants per arm were recruited. CONCLUSIONS: An RCT to evaluate the long-term efficacy of bisphosphonates in fracture prevention appears to be cost-effective for informing decision making in England and Wales.

Impact of osteoporosis treatment adherence on fracture rates in North America and Europe.

Fragility fractures associated with osteoporosis constitute a significant public health concern. Clinical trials have shown that a variety of agents--bisphosphonates, raloxifene, calcitonin, hormone replacement therapy, teriparatide, and strontium ranelate--can reduce the risk of osteoporosis-related fragility fractures. However, low levels of compliance and persistence in the real-life setting mean that efficacy benefits observed in clinical trials with these agents may not translate into equivalent effectiveness in daily practice. The aim of this review is to provide a comprehensive evaluation of compliance and persistence data from retrospective/observational studies, with particular reference to studies that consider the effects on fracture rates. PubMed of the National Center for Biotechnology Information (NCBI) and Web of Science databases were searched for publications detailing observational or retrospective analyses of adherence, compliance, and persistence with osteoporosis therapies. In addition, authors provided relevant studies that were not retrieved using the search criteria. In total, 17 unique publications were identified. Analysis of the publications indicated that low compliance and persistence rates for osteoporosis therapies in the real-life setting result in increased rates of fragility fractures. The results emphasize the importance of good treatment compliance and persistence with osteoporosis therapies in order to achieve a significant therapeutic benefit and thereby reduce the burden that osteoporosis and associated fractures place on individuals and healthcare systems.