Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians Reports of clinical trials should begin and end with up-to-date systematic reviews of other relevant evidence: a status report. Calcium intake in health maintenance – a systematic review Effect of vitamin D supplementation on inflammation: protocol for a systematic review [Optimization of calcium intake for the prevention of osteoporosis and osteoporotic fractures: a review of the evidence]. Discussion sections in reports of controlled trials published in general medical journals. Protocol for an overview of systematic reviews of interventions to reduce unscheduled hospital admissions among adults The risk of osteoporosis in oral steroid treatment for nasal polyposis: a systematic review. Discussion sections in reports of controlled trials published in general medical journals: islands in search of continents? The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Systematic reviews in public health: old chestnuts and new challenges. Guidelines for the prevention of falls in people over 65 Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. A Systematic Review of Bone Health in Cyclists European Respiratory Society guidelines for the management of adult bronchiectasis A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Systematic reviews in endodontics--examples of GIGO? Financial Conflicts of Interest and Conclusions About Neuraminidase Inhibitors for Influenza Can systematic reviews with sparse data be trusted? Osteoporosis in menopause. Weight Loss-Induced Reduction of Bone Mineral Density in Older Adults with Obesity Dietary and physical activity strategies to prevent type 2 diabetes in South Asian adults: protocol for a systematic review Screening for Postmenopausal Osteoporosis: A Review of the Evidence for the U.S. Preventive Services Task Force Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol Effectiveness of alternative listening devices to conventional hearing aids for adults with hearing loss: a systematic review protocol Physical activity increases bone mass during growth The burden and determinants of neck pain in workers: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. How Quickly Do Systematic Reviews Go Out of Date? A Survival Analysis Best Practice in Systematic Reviews: The Importance of Protocols and Registration An international registry of systematic-review protocols [Reviews, systematic reviews, and essays in public health]. Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study. VITAL-Bone Health: rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL). Evaluation of the Quality of Prognosis Studies in Systematic Reviews
The National Institutes of Health 's consensus conference ( 1 ) defined osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture . Bone strength reflects the integration of two main features : bone density and bone quality .Bone quality refers to architecture , turnover , damage accumulation ( e.g. , microfractures ) , and mineralization . Although osteoporosis can affect any bone , the hip , spine , and wrist are most likely to be affected . Osteoporosis affects an estimated 44 million Americans or 55 % of people 50 years of age or older . Another 34 million Americans are estimated to have low bone mass , meaning that they are at an increased risk for osteoporosis . Osteoporosis can be diagnosed by the occurrence of fragility fracture . In patients without fragility fracture , osteoporosis is often diagnosed by low bone density .  Dual x-ray absorptiometry ( DXA ) is the current gold st and ard test for diagnosing osteoporosis in people without an osteoporotic fracture .  Dual x-ray absorptiometry results are scored as st and ard deviations ( SDs ) from a young healthy norm ( usually female ) and reported as T-scores . For example , a T-score of 2 indicates a bone mineral density that is 2 SDs below the comparative norm . The international reference st and ard for the description of osteoporosis in postmenopausal women and in men age 50 years or older is a femoral neck bone mineral density of 2.5 SD or more below the young female adult mean ( 2 ) . Low bone density , as measured by DXA , is an imperfect predictor of fracture risk , identifying fewer than half the people who go on to have an osteoporotic fracture . Screening guidelines for women are well established ( 3 ) , and the American College of Physicians ( ACP ) recently published guidelines on screening for men ( 4 ) . This guideline presents the available evidence on various pharmacologic treatments to prevent fractures in men and women with low bone density or osteoporosis . Medications used to treat osteoporosis may affect different parts of the skeletal system differently , and efficacy for vertebral fractures does not necessarily imply efficacy for nonvertebral fractures . The target audience for this guideline is all clinicians and the target patient population is all adult men and women with low bone density or osteoporosis . These recommendations are based on the systematic evidence review by MacLean and colleagues ( 5 ) and the Agency for Healthcare Research and Quality sponsored Southern California Evidence -Based Practice Center evidence report ( 6 ) . The drugs currently approved for prevention of osteoporosis include alendronate , ib and ronate , risedronate , zoledronic acid , estrogen , and raloxifene . The drugs currently approved for treatment of osteoporosis include alendronate , ib and ronate , risedronate , calcitonin , teriparatide , zoledronic acid ( in postmenopausal women ) , and raloxifene . Testosterone , pamidronate , and etidronate are not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Methods The literature search done by MacLean and colleagues for the systematic review ( 5 ) included studies from MEDLINE ( 1966 to December 2006 ) , the ACP Journal Club data base , the Cochrane Central Register of Controlled Trials ( no date limits ) , the Cochrane Data base of Systematic Review s ( no date limits ) , Web sites of the United Kingdom National Institute of Health and Clinical Excellence ( no date limits ) , and the United Kingdom Health Technology Assessment Program ( January 1998 to December 2006 ) . The review ers limited their search to English- language publications and human studies . They derived evidence for comparative benefits of various treatments exclusively from r and omized , controlled trials , whereas they included evidence from other types of studies for short- and long-term harms . Two physicians independently abstract ed data about study population s , interventions , follow-up , and outcome ascertainment by using a structured form . For each group within a r and omized trial , a statistician extracted the sample size and number of persons reporting fractures . Two review ers , under the supervision of the statistician , independently abstract ed information about adverse events . The statistician or the principal investigator resolved disagreements . This guideline is based on an evaluation of 76 r and omized , controlled trials , 4 of which were identified in the up date d search , and 24 meta-analyses that were included in the efficacy analyses . The analyses of adverse events included 491 articles , representing 417 r and omized trials , 25 other controlled clinical trials , 11 open-label trials , 31 large observational studies , and 9 case reports of osteonecrosis among bisphosphonate users . MacLean and colleagues ' background article ( 5 ) includes details about the methods used for the systematic evidence review . The ACP rates the evidence and recommendations by using the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) system with minor modifications ( Table 1 ) . In addition , the evidence review ers used predefined criteria to assess the quality of systematic review s and r and omized trials , based on internal and external validity assessment s detailed in the Quality of Reporting of Meta-Analyses ( QUOROM ) statement ( 7 ) . Table 1 . The American College of Physicians ' Guideline Grading System The objective of this guideline is to synthesize the evidence for the following questions : What are the comparative benefits in fracture reduction among and also within the following treatments for low bone density :  bisphosphonates , specifically alendronate , risedronate , etidronate , ib and ronate , pamidronate , and zoledronic acid ; calcitonin ; estrogen for women ; teriparatide ; selective estrogen receptor modulators ( SERMs ) , specifically raloxifene and tamoxifen ; testosterone for men ; vitamins and minerals , specifically vitamin D and calcium ; and the combination of calcium plus vitamin D ? How does fracture reduction result ing from treatments vary among individuals with different risks for fracture as determined by bone mineral density ( borderline , low , or severe ) , previous fractures ( prevention vs. treatment ) , age , sex , glucocorticoid use , and other factors ( such as community-dwelling vs. institutionalized or vitamin Ddeficient vs. not ) ? What are the short- and long-term harms ( adverse effects ) of these therapies , and do these vary by specific sub population s ? Comparative Benefits of Drugs versus Placebo in Fracture Reduction Evidence from 24 meta-analyses ( 830 ) and 35 additional r and omized trials published after the meta-analyses ( 3165 ) described the effect of 9 of the 14 agents ( alendronate , etidronate , risedronate , calcitonin , estrogen , teriparatide , raloxifene , calcium , and vitamin D ) on fracture incidence . For 4 agents ( ib and ronate , pamidronate , zoledronic acid , and tamoxifen ) , the review ers found no meta-analyses and instead gathered the evidence from 14 r and omized trials ( 6679 ) . No studies were found that reported fracture rates for testosterone . Three r and omized trials ( 35 , 80 , 81 ) and 1 meta- analysis ( 82 ) evaluated the combination of calcium plus vitamin D  on fractures .  Bisphosphonates Good- quality evidence showed that alendronate , etidronate , ib and ronate , and risedronate prevent vertebral fractures . In addition , evidence from good- quality studies demonstrated that both alendronate and risedronate prevent nonvertebral and hip fractures . Two large r and omized trials showed that zoledronic acid prevents vertebral and nonvertebral fractures in high-risk population s and reduces the risk for hip fracture ( 67 , 74 ) . Ib and ronate has not been shown to reduce nonvertebral fractures ( 68 ) . Of the 6 fairly small trials that looked at vertebral fractures , 1 demonstrated a statistically significant reduction in fractures with pamidronate relative to placebo ( 0.14 [ 95 % CI , 0.03 to 0.72 ] ) ( 73 ) . However , after these data were pooled , the pooled risk estimate for fractures for pamidronate relative to placebo was not significant ( 0.52 [ CI , 0.21 to 1.24 ] ) ( 6 ) . Calcitonin Fair- quality evidence shows that calcitonin reduces vertebral fractures ( 83 , 84 ) . Good- quality evidence indicates that calcitonin does not reduce nonvertebral fractures ( 13 , 16 ) . Estrogen Good- quality evidence shows that estrogen reduces the incidence of vertebral ( 29 , 85 ) , nonvertebral ( 86 ) , and hip fractures ( 85 ) . Teriparatide Good- quality evidence shows that teriparatide prevents vertebral fractures . The evidence related to teriparatide preventing nonvertebral fractures is mixed ; 1 large r and omized trial showed a reduction in nonvertebral fractures ( 34 ) but 2 small trials did not ( 87 , 88 ) . SERMs Good- quality evidence shows that raloxifene prevents vertebral fractures , but that tamoxifen has no effect on vertebral fractures ( 8991 ) . In addition , both raloxifene and tamoxifen had no effect on hip fractures ( 91 ) . Tamoxifen is not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Testosterone No studies reported fracture rates for testosterone . Calcium and Vitamin D In the studies evaluated by MacLean and colleagues ( 5 ) , the evidence for the effect of calcium alone on reduction of fractures is complex . Most studies of pharmacologic agents for osteoporosis include calcium and vitamin D as part of the treatment regimen . Evidence from 1 meta- analysis ( 27 ) and several r and omized trials ( 35 , 48 , 51 , 92 ) showed no significant difference between calcium and placebo in preventing vertebral , nonvertebral , and hip fractures in postmenopausal women . However , nonadherence to therapy may influence this result , and 1 trial with a prespecified analysis of adherent patients found a reduction in fracture risk ( 48 ) . A recent meta- analysis ( 82 ) concluded that the relative risk ( RR ) for fracture with calcium alone was 0.90 ( CI , 0.80 to 1.00 ) , but it did not include a modestly large trial with negative results ( 35 ) . MacLean and colleagues ( 5 ) OBJECTIVE Scientific and ethical justification for new clinical trials requires them to have been design ed in the light of scientifically defensible assessment s of relevant previous research . Reliable interpretation of the results of new clinical trials entails setting them in the context of up date s of the review s upon which they were deemed scientifically and ethically justifiable . We have shown previously that most reports of r and omized trials published in five general medical journals in May 1997 and in May 2001 failed to set their results in the context of the findings from similar research . In the current study , we assess whether there had been progress in this respect in 2005 and also investigate the extent to which reports begin by referring to systematic review s providing the justification for the new research reported . DESIGN Assessment of the Introduction and Discussion sections in all reports of r and omized trials published during May 2005 in five general medical journals . SETTING Reports of r and omized trials in five general medical journals . PARTICIPANTS Annals of Internal Medicine , BMJ , JAMA , Lancet and New Engl and Journal of Medicine . INTERVENTIONS None . MAIN OUTCOME MEASURES The inclusion or mention of one or more systematic review s in the Introduction or Discussion section of each report assessed . RESULTS We found 18 reports of r and omized trials . The Introduction sections referred to systematic review s in five ( 27 % ) of these reports . None of the discussion sections of the 15 reports of trials that were not the first published trials to address the question studied placed the results of the new trial in the context of an up date d systematic review of other research . Although reference was made to relevant systematic review s in five of these 15 reports , there was no integration - quantitative or qualitative - of the results of the new trials in an up date of these review s. In the remaining ten reports there was no evidence that any systematic attempt had been made to set the new results in the context of previous trials . CONCLUSIONS There is no evidence of progress between 1997 and 2005 in the proportion of reports of trials published in general medical journals which discussed new results within the context of up-to- date systematic review s of relevant evidence from other controlled trials . Although the proportion of trials referring to systematic review s in Discussion sections has increased , the majority of reports continued to fail even to do this . Similarly , most research ers appear not to have considered a systematic review when design ing their trial . Research ers and journal editors do a disservice to the interests of the public and others involved in healthcare decision-making by acquiescing in this situation Background Calcium ( Ca ) is an essential nutrient for the human body . Despite lively research , there is uncertainty about Ca requirements in terms of desirable health outcomes including an upper intake level above which the potential for harm increases . Objectives The aim was to conduct a review to up date requirements and desirable or harmful health effects of Ca on the current scientific evidence . Methods We search ed Medline and Swemed from January 2000 to December 2011 and included all systematic review s that reported Ca supplementation or usual Ca intake on health outcomes . Meta-analyses , r and omized clinical trials and cohort studies were included in the second search between May 2009 and March 2011 and an additional search covering studies till the end of 2011 . This review concentrated on studies reporting independent effects of Ca , although a few recent trials report sole effects of Ca on health outcomes , most trials use Ca in combination with vitamin D vs. placebo . Results In total , we review ed 38 studies addressing the effects of Ca on bone , pregnancy-related outcomes , cancers , cardiovascular outcomes , obesity , and mortality .  There was a lot of heterogeneity in the study protocol s , which made it difficult to draw any strong conclusions . According to the literature , high Ca intake seems to have a small positive effect on bone mineral content ( BMC ) or bone mineral density ( BMD ) in children and postmenopausal women . We did not find any consistent evidence on the effects of Ca on bone health in premenopausal women or men . Also , the evidence that Ca supplementation reduces fracture incidence is scarce and inconsistent . Maternal diet may influence the peak bone mass of offspring but more studies are required . There was no overall effect of Ca intake on cancers . Ca was associated with a decreased risk of breast cancer and a slightly increased risk of prostate cancer in two of the three studies . No associations were found with other cancers . We found no consistent association between cardiovascular outcomes and  Ca  intake except for blood pressure . A small decrease of 2–4 mmHg in systolic blood pressure was found in pregnant and in hypertensive subjects with Ca supplementation . Review ed studies did not show consistent evidence relating Ca intake to either mortality or obesity . Conclusion Based on this evidence , there is no need to change the Nordic recommendations for Ca intake . However , due to heterogeneity in the studies it is difficult to interpret the results and provide single summary statement Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104 One of the main focuses of lifestyle modification for the prevention of osteoporosis and osteoporotic fractures  in Japan is improvement in dietary calcium intake . However , virtually no r and omized controlled trial to assess the preventive effects of administration of calcium on the risk of fractures has been conducted in Japan . In this study , we review ed all the scientific papers currently available from medical literature data bases to propose evidence -based recommendations on the preventive procedures for osteoporosis . The result of the present systematic review gives the evidence showing that calcium supplementation or optimal dietary calcium intake increases bone density in childhood and adolescence and reduces the risk of fracture due to osteoporosis in the elderly people regardless of the gender . The evidence also supports the current health policy guiding the elderly to increase their dietary calcium intake in daily life CONTEXT Reliable interpretation of the results of a controlled trial entails setting its results in the context of similar research . A previous study showed that most reports of controlled trials published in 5 general medical journals in May 1997 were deficient in this respect . We assessed the extent to which reports of controlled trials published in the same 5 journals discussed new results in light of the totality of evidence from other controlled trials . METHODS Assessment of the discussion sections in all 33 reports of r and omized trials published during May 2001 in Annals of Internal Medicine , BMJ , JAMA , The Lancet , and The New Engl and Journal of Medicine . RESULTS Three reports appeared to have been the first published trials to address the questions studied . In none of the remaining 30 reports were the results of the new trial discussed in the context of an up date d systematic review of other trials . Although reference was made to relevant systematic review s in 3 of these 30 reports , there was no integration , quantitative or qualitative , of the results of the new trials in an up date of these review s. In the remaining 27 reports , there was no evidence that any systematic attempt had been made to set the new results in the context of previous trials . CONCLUSIONS Between 1997 and 2001 , there was no evidence of progress in the proportion of reports of trials published in general medical journals that discussed the new results within the context of , or with reference to , up-to- date systematic review s of relevant evidence from other controlled trials Introduction Unscheduled hospital admissions are an increasing burden on health systems worldwide . To date , initiatives to reduce admissions have had limited success as it is unclear which strategies effectively reduce admissions and are supported by a strong evidence -base . Therefore , we will conduct an overview to find , assess and summarise all published peer- review ed systematic review s of r and omised controlled trials that examine the effect of an intervention on  unplanned admissions among adults . Methods and analysis This is a protocol for a systematic overview of review s. We will search four data bases : Ovid MEDLINE , PubMed , Cochrane Data base of Systematic Review s and the Cochrane Data base of Abstract s of Review s of Effects . We will consider systematic review s and meta-analyses of r and omised controlled trials in adults ( ≥16 years old ) evaluating the effect of any intervention on unscheduled hospital admissions including those to treat , monitor , diagnose or prevent a health problem . We will only include review s that identified unscheduled hospitalisations as a prespecified outcome . Two authors will independently screen articles for inclusion using a priori criteria . We will assess the quality of included review s and extract ratings of the quality of evidence from within each review . We will create a hierarchical list of interventions based on estimates of absolute admission reductions and the quality of the evidence . Presentation of results will align with guidelines in the Cochrane H and book of Systematic Review s of Interventions and the Preferred Reporting Items for Systematic Review s and Meta- Analysis statement . Ethics and dissemination Ethics approval is not required . We will su bmi t the results of this study for peer- review publication . The results will inform future research and could be used by healthcare managers , administrators and policymakers to guide re source allocation decisions and inform local implementation and optimisation of interventions to reduce unscheduled hospital admissions BACKGROUND Systemic glucocorticoids are often used in the treatment of chronic rhinosinusitis with nasal polyps ( CRSwNP ) , and osteoporosis is a well-known complication to steroid treatment , associated with significant morbidity . Nevertheless , the burden of steroid induced osteoporosis is unknown in patients with CRSwNP . We aim ed to assess the risk of acquiring osteoporosis caused by oral steroids in patients with CRSwNP , and provide recommendations on future research and guidelines . METHODOLOGY Cochrane Review Data base , EMBASE , Ovid Medline , and PubMed were search ed for studies including adult patients with CRSwNP treated with oral steroids .  Outcomes were Bone Mineral Density ( BMD ) and prevalence of fractures in relation to dose and duration of oral steroids . In addition , we review ed general guidelines for treatment with oral steroids . RESULTS We identified two studies ( n=243 ) that met the inclusion criteria . Doses and duration s of oral steroids were over 5 mg/day for more than 3 months and 1 mg/kg body weight/day for 6 to 10 days for 4 or more courses/year . The prevalence of low bone mass was 39 % and 61 % , respectively . It was not possible to quantify the overall risk of osteoporosis induced by oral steroids from the studies . No studies evaluated prevalence of fracture . CONCLUSIONS Registry studies and r and omized controlled trials would be needed to assess the risk of osteoporosis in CRSwNP patients and future guidelines should include recommendations regarding preventive treatment and recommendations on doses and duration s of oral steroids CONTEXT Several journals have adopted the Consoli date d St and ards of Reporting Trials ( CONSORT ) recommendations to make assessment of the quality of r and omized controlled trials ( RCTs ) easier . One of these recommendations is that the trial 's results be discussed in light of the totality of the available evidence . OBJECTIVE To assess the extent to which reports of RCTs published in 5 general medical journals have discussed new results in light of all available evidence . DESIGN Assessment of the discussion sections in all 26 reports of RCTs published during May 1997 in Annals of Internal Medicine , BMJ , JAMA , The Lancet , and The New Engl and Journal of Medicine . MAIN OUTCOME MEASURE The inclusion or mention of a systematic review in the discussion section of each article . RESULTS In only 2 articles were the RCT 's results discussed in the context of an up date d systematic review of earlier trials . In a further 4 articles , references were made to relevant systematic review s , but no attempts were made to integrate the results of the new trials in up date d versions of these review s. One article was probably the first published trial to address the question studied . The remaining 19 articles included no evidence that any systematic attempt had been made to set the reported trial 's results in the context of previous trials . CONCLUSION There is little evidence that journals have adequately implemented the CONSORT recommendation that results of an RCT be discussed in light of the totality of the available evidence Osteoporosis is a major public health issue leading to significant morbidity , loss of independence and excess loss of life . It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis ( 1 , 2 ) . This is associated with almost 1.5 million fractures annually , including 300,000 hip fractures ( 2 , 3 ) . A review of the evidence by Cumming in 1990 ( 4 ) and subsequently published r and omized clinical trials have shown that calcium and /or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women ( 5–9 ) . However , there are a limited number of calcium and /or vitamin D trials ( 10–13 ) and observational studies [ review of evidence by Cumming and Nevitt ( 14 ) and Kanis ( 15 ) ] , to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures . It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence ( 16–21 ) . To address these major health concerns of postmenopausal women , the Calcium-Vitamin D ( CaD ) trial of the Women ’s Health Initiative ( WHI ) was design ed to test the primary hypothesis that women who are r and omized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily , a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo . The objective of this paper is * The up date s are underlined for quick reference . INTRODUCTION A critical need exists for efficient , measurable systems of disease management that reconcile conflicts between socioeconomic responsibility and patient welfare . Clinical guidelines have become an important component of these systems because they address elements of care that are effective and that reduce the variability in our approach to patient management . The American Association of Clinical Endo-crinologists ( AACE ) 2001 Medical Guidelines for Clinical Practice for the Prevention and Management of Postmenopausal Osteoporosis address the prevention , diagnosis , and management of postmenopausal osteoporo-sis , a disorder that is recognized as a major public health problem because of its physical and socioeconomic consequences . They are intended to simplify medical decision making and to help physicians and their patients make good decisions about skeletal health and postmenopausal osteoporosis . The specific goals of these guidelines are to reduce the incidence of fractures related to osteoporosis and to achieve the highest quality of life for individual patients by using the most effective and efficient methods of diagnosis and management . In the preparation of this 2001 edition , reports in the peer- review ed literature dealing with prevention , diagnosis , and treatment of postmenopausal osteoporosis , which were published and indexed between 1996 ( the publication date of the previous edition of these guidelines ) and January 2001 , were identified by computer search , review ed , and grade d for clinical relevance and scientific merit . Although cost-effectiveness was carefully considered , variabilities in actual costs could not be accurately determined . Therefore , cost-effectiveness modeling was not undertaken . Whenever possible , recommendations were based on r and omized , prospect i ve , double-blind studies of well-defined patient population s. Studies that used the most relevant clinical endpoint , fracturing , were considered " level 1 " evidence . When level 1 evidence was not available , recommendations were based on cross-sectional studies , investigations that tested smaller or nonr and omized patient population s , or studies that tested secondary or surrogate clinical endpoints for fracture , such as bone mineral density ( BMD ) or bone turnover markers , in treated population s ( level 2 evidence ) . When stronger evidence was not available , review s , editorials , and expert opinions were used ( level 3 evidence ) . We recognize that the process of developing clinical guidelines necessarily results in a narrowing and codifica-tion of clinical choices , which can be inappropriate in some clinical situations . Because the application of objective information to the specific needs of patients is the ultimate responsibility of the practicing physician , clinical practice guidelines are not intended to be rigid or restrictive , nor The Bulletin ’s editorial team has decided to encourage systematic review s. This is an important decision and is to be welcomed . However it is possible that it will not be received positively by all . Some may feel that systematic review s are not suitable for answering wider public health questions , and that the new section will simply result in the publication of systematic review s addressing narrowly focused , clinical questions with a focus on r and omized controlled trials alone.1 There is no reason why this should be so , and there are far too many examples of systematic review s of non- clinical interventions ( including government policies ) , which include non-r and omized studies , to list.2 Systematic review s of qualitative research are also becoming more common.3 Nonetheless misconceptions about the scope and flexibility of systematic review s still surface occasionally and it never fails to surprise me when I stumble across one of these hoary old chestnuts . If it really were true that systematic review s were only for simple , individual-level interventions , systematic review ers working in public health would be very concerned . After all , public health problems require us to draw on complex sets of qualitative as well as quantitative evidence ; and some policy interventions have never been subjected to r and omized controlled trials ( RCTs ) but have been evaluated using other approaches ; everything from controlled and uncontrolled before- and -after studies , to time series analyses , to qualitative methods . In such cases , systematic review s that focused on RCTs alone would have little to say and we would end up producing many “ empty review s ” , which contain no studies at all . These would be undoubtedly quicker to do and quicker to read than the typical systematic review , but would be of limited use for making policy . However this is not the case . In public health we already have a wealth of review s that prioritize RCTs where they are available , but which draw upon a range of other evidence where they are appropriate to answering the review question .2 Take , as an example , transport policies , an important social determinant of health.4 Public health decision-makers have been interested in the effects on health of building new roads for decades , but there has never been a r and omized controlled trial , for obvious reasons . Yet it would make no sense to cl aim that there is no evidence to be review ed ; rather , there have been many controlled and uncontrolled studies that have examined the effects of new roads on respiratory symptoms , injuries , community severance , disturbance and a variety of other outcomes of public health importance . These studies have in fact been systematic ally review ed.5 Many other examples of review s of complex interventions that impact on public health could be given , which appear on the Cochrane Data base and elsewhere,6,7 and such review s are the main focus of the recently-established Cochrane Public Health Review Group . It is also worth noting that both the Cochrane and Campbell Collaboration include increasing numbers of review s that are relevant to low- and middle- income countries,8 though there is a particular need for more systematic review s that consider the effects on equity of the interventions that they include.9 Currently systematic review s have a “ utilitarian bias ” – they tend to be concerned more with the effects on population s and average effects than with distributional effects and impacts in disadvantaged subgroups . It is to be hoped that systematic review s su bmi tted to the Bulletin will routinely consider the effects of interventions on health inequities . The Cochrane Health Equity Field ( http://equity.cochrane.org/en/index.html ) was set up explicitly to further this agenda , to encourage systematic review authors to explicitly assess the effects of interventions not only on the whole population , but on the disadvantaged . So where does this leave non- systematic review s ? Should every review be a systematic review ? This is a difficult question to answer in a short editorial . My own view is that not all review s need to be systematic review s ; there is still a place for review papers that provide a broad overview , and that discuss a range of evidence and make a contribution to wider debates about what might work in particular setting s. However , while such discussion s help place evidence in context and suggest how it may be used , they should not be confused with the evidence -based conclusions of a transparent , scientific review , which systematic ally attempts to find all the relevant evidence , appraises its strengths and limitations in a transparent fashion , and draws that evidence together in such a way that the more robust studies are given greater weight . Finally , the challenges are many . Evidence on interventions to improve public health is in short supply , particularly evidence on social determinants . Systematic review ers therefore face a real challenge in making best use of the sometimes poor , often sparse and usually heterogeneous evidence available to them . It is easy to set narrow inclusion criteria for a review and then sift through the evidence before concluding that there is n’t enough – and what there is , is n’t very good anyway . Such “ evidential nihilism ” is probably not helpful to decision-makers , and public health systematic review ers need to continue to develop new methods and better frameworks within which different types of research evidence can be integrated to inform decision-making . Publishing systematic review s in the Bulletin should give an added impetus to this ongoing work . General practice p 994 Older people frequently fall . This is a serious public health problem , with a substantial impact on health and healthcare costs.1 These guidelines translate trial evidence about prevention of falls into recommendations that can be implemented in different setting s , with the aim of reducing the rate of falls and injurious falls in people over 65 ( see boxes 2 3 ) . # # # # Summary points Multifaceted interventions reduce falls in older people ( those over 65 ) Home assessment of older people at risk of falls without referral or direct intervention is not recommended Assessment of high risk residents in nursing homes with relevant referral is effective Evidence from well design ed single trials shows that assessment and modification of risk factors of older people who have presented to an accident and emergency department after a fall and the provision of hip protectors in residents of nursing homes are effective We up date d two previous systematic review s to include any new evidence up to March 1998 . 4 5 We electronically search ed Medline for all r and omised controlled trials and systematic review s by using the terms fall(s ) , accidental falls , fracture , elderly , aged , older , and senior . We followed up relevant references in papers , and we contacted research ers in prevention of falls for information about other trial evidence and about studies from journals not catalogued by the National Library of Medicine . For inclusion , studies had to be r and omised controlled trials of interventions design ed to minimise or prevent exposure to the risk factors for falling ( or fracture ) in people aged 65 years or over living in either community or residential care . Outcomes had to include the number of people who had fallen or the number of falls or fractures . We excluded drug or dietary treatments for the prevention of fractures . Trials that fulfilled the inclusion criteria were review ed and summarised Description This guideline up date s the 2008 American College of Physicians ( ACP ) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women . This guideline is endorsed by the American Academy of Family Physicians . Methods The ACP Clinical Guidelines Committee based these recommendations on a systematic review of r and omized controlled trials ; systematic review s ; large observational studies ( for adverse events ) ; and case reports ( for rare events ) that were published between 2 January 2005 and 3 June 2011 . The review was up date d to July 2016 by using a machine-learning method , and a limited up date to October 2016 was done . Clinical outcomes evaluated were fractures and adverse events . This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density , including pharmaceutical prescriptions , calcium , vitamin D , and estrogen . Evidence was grade d according to the GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) system . Target Audience and Patient Population The target audience for this guideline includes all clinicians . The target patient population includes men and women with low bone density and osteoporosis . Recommendation 1 ACP recommends that clinicians offer pharmacologic treatment with alendronate , risedronate , zoledronic acid , or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis . ( Grade : strong recommendation ; high- quality evidence ) . Recommendation 2 ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 3 ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinical ly recognized osteoporosis . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 4 ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 5 ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women . ( Grade : strong recommendation ; moderate- quality evidence ) . Recommendation 6 ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences , fracture risk profile , and benefits , harms , and costs of medications . ( Grade : weak recommendation ; low- quality evidence ) Context : Low bone mineral density ( BMD ) is a serious public health problem . Osteoporotic fractures are associated with low bone mass , occurring frequently in the hip and spine . Previous studies have demonstrated a positive relationship between BMD and weightbearing exercise but not a similar positive relationship with nonweightbearing exercise . There is concern that cycling , a weight-supported sport , does not benefit bone health . Objective : To systematic ally review the evidence suggesting that cyclists have impaired bone health at the femoral neck and lumbar spine . Data Sources : Articles in PubMed , Cochrane Library , and CINAHL were identified in December 2009 What is the start date for the search ? based on the following terms and combinations : bicycling , bone density , cyclist . Study Selection : Thirteen studies satisfied inclusion criteria : 2 prospect i ve studies ( level of evidence 2b ) and 11 cross-sectional studies ( level of evidence 2c ) . Data Extraction : Data included sample size , demographics , description of cycling and control criteria , and BMD ( g/cm2 ) at the lumbar spine , femoral neck , and hip . Results : Two prospect i ve studies showed a decrease in femoral neck , total hip , or lumbar spine BMD in cyclists over the study period . Four cross-sectional studies compared cyclists with sedentary controls , and 3 found cyclists ’ lumbar spine and femoral neck BMD similar to that of controls , whereas 1 found cyclists ’ BMD to be lower than that of controls . Seven cross-sectional studies compared cyclists with active controls : 2 found no differences in femoral neck and lumbar spine BMD between cyclists and controls ; 4 found that cyclists had lower lumbar spine BMD than did active controls , including runners ; and 1 reported a trend toward lower lumbar spine BMD in cyclists versus controls . Conclusions : There is concerning but inconsistent , limited- quality disease-oriented evidence —primarily from cross-sectional data —indicating that cyclists may be at risk for low bone mass , particularly at the lumbar spine . Additional longitudinal controlled intervention trials are needed Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients . There have been no previous international guidelines . The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature . A multidisciplinary group representing respiratory medicine , microbiology , physiotherapy , thoracic surgery , primary care , methodology and patients considered the most relevant clinical questions ( for both clinicians and patients ) related to management of bronchiectasis . Nine key clinical questions were generated and a systematic review was conducted to identify published systematic review s , r and omised clinical trials and observational studies that answered these questions . We used the GRADE approach to define the quality of the evidence and the level of recommendations . The result ing guideline addresses the investigation of underlying causes of bronchiectasis , treatment of exacerbations , pathogen eradication , long term antibiotic treatment , anti-inflammatories , mucoactive drugs , bronchodilators , surgical treatment and respiratory physiotherapy . These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes . The publication of the first ERS guidelines for bronchiectasis BACKGROUND survivors of hip fracture are at 5- to 10-fold risk of a second hip fracture . There is little consensus about secondary prevention . Many are given calcium and vitamin D , but the evidence supporting this is circumstantial . OBJECTIVE to compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers , bone mineral density and rate of falls in elderly women post-hip fracture . DESIGN r and omised controlled trial . SETTING orthogeriatric rehabilitation ward . METHODS 150 previously independent elderly women , recruited following surgery for hip fracture , were assigned to receive a single injection of 300,000 units of vitamin D(2 ) , injected vitamin D(2 ) plus 1 g/day oral calcium , 800 units/day oral vitamin D(3 ) plus 1 g/day calcium , or no treatment . Follow-up was one year , with measurement of 25-hydroxyvitamin D , parathyroid hormone , bone mineral density , and falls . RESULTS mean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups , more so in the group receiving combined oral vitamin D and calcium . Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later . Bone mineral density showed small but statistically significant differences of up to 4.6 % between actively treated groups and placebo . Relative risk of falling in the groups supplemented with vitamin D was 0.48 ( 95 % CI 0.26 - 0.90 ) compared with controls . CONCLUSION Vitamin D supplementation , either orally or with injected vitamin D , suppresses parathyroid hormone , increases bone mineral density and reduces falls . Effects may be more marked with calcium co-supplementation . The 300,000 units of injected vitamin D may not last a whole year Introduction Vitamin D has potential benefits for extraskeletal health . These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction . We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function ( EF ) , possibly through the abrogation of systemic inflammation . Methods and analysis We will conduct a systematic review of all r and omised controlled trials on  vitamin D supplementation and EF lasting 12 weeks or more . The search will cover the period 2000–2015 and include studies that describe direct measures of EF  , markers of endothelial cell ( EC ) activation  and if concurrently reported , indicators of systemic inflammation  . Study selection will follow the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis . If sufficient data are available , a meta- analysis will be conducted . The effect sizes will be generated using Hedges ’ g score , for both fixed and r and om effect models . I2 statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources . Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger 's test . Meta-regression analysis ( if feasible ) will be conducted with restricted maximum likelihood ( REML ) estimation method , controlling for potential confounders ( demographics , study methods , location , etc ) . A backward elimination process will be applied in the regression modelling procedure . Subgroup analysis , conditional on number of studies retrieved and their sample size , will be stratified on participant disease category , total dose administered , degree of 25(OH)D change and type of supplement used . Ethics and dissemination Formal ethical approval is not required as primary data will not be collected . The results will be disseminated through a peer- review ed publication , conference presentation and the popular press . Trial registration number International Prospect i ve Register for Systematic Review s ( PROSPERO ) number CRD42014013523 In many areas of medicine the amount of published information is increasing at an exponential rate , making it difficult for the clinician to condense the data to a manageable amount of valuable and useful information . Systematic review s have been suggested as a remedy for this information overload . Such review s are regarded as the highest level of evidence . Certain statistical methods , e.g. , meta- analysis , have also been introduced for the calculation of a more comprehensive summation of the compiled results from studies with small sample sizes . These findings would then serve as an authoritarian guide for evidence -based practice . Endodontists have lately jumped on the b and wagon of systematic review s and meta-analyses , and papers on various topics are being published . Well done , such comprehensive information would be very useful and authoritative for the practitioner . Alarmingly , the quality of these recent publications is negatively correlated to the frequency . This can have serious consequences in the clinical arena if spurious information is given a seal of approval when communicated as facts in refereed journals . A systematic literature review is design ed to focus on a single question and to synthesize all high- quality research reports relevant to the question . In these studies , however , sources of bias are often not controlled . Therefore , even the best review and meta- analysis becomes useless if it is based on poorly design ed research . Furthermore , these review s are mostly based on published data which are too often biased toward studies that show significant differences in results and /or outcome . “ Uninteresting ” conclusions tend not to be published . Endodontic literature , thus far , is short on well design ed and executed r and omized clinical trials . Furthermore , clinical protocol s often have many important “ proprietary ” modifications that make comparison difficult . This makes it very hard to undertake a systematic review to answer a narrow question . Such GIGO ( garbage in , garbage out ) can easily lead to biased conclusions and reinforce already existing biased comclusions . An example of such bias can be illustrated by a meta- analysis recently published . The study focused on assessing if there were differences in outcome between 1 and 2 treatment visits when treating teeth with apical periodontitis . Relevant publications on this topic are rare , and with the narrow inclusion criteria only 3 investigations were available for the review . However , the only factors connecting these 3 studies was the words “ single ” and “ two visits ” in the title . Beyond that , the selected studies are too different and inadequate for the study . Only 1 study is somewhat demonstrably r and omized , and outcome assessment s are based on 3 vastly different criteria . Two of the studies use calcium hydroxide as intracanal dressing , whereas the third uses no intervisit medication . Complexity of initial pathology and healing time are also clearly factors of great importance but not controlled . In addition , sample sizes in the component studies as well as the final cohort are all too small for the conclusions that there was no significant difference between 1or 2-visit treatment protocol s. To undertake and publish a meta- analysis on such an incomplete sample is counterproductive . Although the publication noted its numerous limitations , it will still communicate erroneous conclusions with a poor scientific foundation to the less informed reader . There are other examples of recently published systematic review s that are very ambiguous and tend to communicate spurious facts . One of these studies looks at the effect of smear-layer removal on sealing ability of root canal obturation . The study is entirely limited to laboratory experiments , with the majority of evaluations using dye leakage which is generally considered to be unreliable . This is an example of review ers lacking content expertise . The authors draw the conclusion , using defective review material , that removal of smear layer enhances the seal of the root filling . We may generally believe that this is the truth Industry funding and author financial conflicts of interest may influence the production and synthesis of scientific evidence ( 1 ) . Associations with the pharmaceutical company developing and marketing a drug have been found to influence the design of trials ( 2 ) , the conduct of trials ( 3 ) , and the reporting of trial results ( 47 ) . Furthermore , financial ties and industry funding seem to result in greater rates of favorable conclusions in clinical trials examining new drugs ( 812 ) . Fewer studies have considered the potential influence of financial conflicts of interest on the synthesis of clinical evidence in systematic review s ( 13 , 14 ) . Neuraminidase inhibitors , which are used in the prophylaxis and treatment of seasonal and p and emic influenza , have been the subject of ongoing uncertainty about their specific clinical benefits ( 15 , 16 ) . This is the result of not only the continuing emergence of strains with unknown drug responses but also the increasing awareness in the medical community that , until recently , its knowledge of the safety and efficacy of these drugs has been incomplete ( 17 ) . Despite the abundance of clinical trials and publications on neuraminidase inhibitors , the details of many key trials had not been disclosed ( 18 , 19 ) . As a result , systematic review ers analyzing and synthesizing evidence on the effectiveness of these agents have faced incomplete information , unresolved discrepancies in the data , and a high risk of publication and reporting biases among the primary clinical trials ( 20 , 21 ) . This prompted extensive efforts to access complete records of all published and unpublished clinical trials from manufacturers , culminating in the publication of several review s on the basis of comprehensive clinical study reports and potentially changing the way systematic review s will be undertaken in the future ( 2227 ) . Review s of neuraminidase inhibitors exhibit wide variation in their conclusions , ranging from strong endorsements of the use of these agents in the prophylaxis and treatment of influenza ( 28 , 29 ) to more conservative assessment s question ing the evidence on the drugs ' safety and efficacy ( 15 , 30 ) . The reasons for this discordance in review conclusions are likely multifactorial and may be related in part to the manner in which evidence is accessed , synthesized , and presented ( 23 , 27 ) , both in terms of the numerical results and the authors ' emphasis and interpretation ( 31 , 32 ) . Our aim was to determine whether there is an association between financial conflicts of interest and the favorable presentation of evidence in systematic review s on the use of neuraminidase inhibitors for the prophylaxis and treatment of influenza . Methods Data Sources Systematic review s were identified in PubMed , PubMed In Process , EMBASE , and the Cochrane Data base of Systematic Review s. Search es were done using the keywords influenza , neuraminidase inhibitors , oseltamivir , zanamivir , peramivir , and laninamivir . Articles were retrieved if the search terms appeared in the title or abstract or were included as data base-specific keywords . In PubMed and EMBASE , search es were also constrained to review publication types . We limited our search to English- language articles published since 1 January 2005 . These articles were manually review ed to identify those that focused on the use of neuraminidase inhibitors for influenza prophylaxis or treatment ( such as excluded articles primarily about drug development or other manufacturing processes ) . We selected all review s that used a systematic search protocol , which we defined as the inclusion and reporting of an explicit search strategy , including reasons for subsequent exclusion of articles . The final search es were done on 26 May 2014 . Cochrane review s are periodically up date d to incorporate new evidence , and the results and conclusions are resynthesized as indicated . The authors of these review s are typically different , and there may be differences in the methods as well as the results and language of the review . These up date d review s were included separately . Other Cochrane review s are occasionally rewritten by a subset of the authors for publication in medical journals as abridged versions to increase dissemination . These reports have separate peer review s and are prepared on the basis of a selection of the complete results . We considered these review s separately as well but also did a sensitivity analysis in which they were combined with the original Cochrane review s. Data Extraction Financial conflicts of interest were identified for all authors of the review s and included affiliations with or funding from the pharmaceutical company manufacturing any of the neuraminidase inhibitors under review . We defined financial conflicts of interest as employment , the funding of grants paid to an author or an author 's research group , and the funding of medical writers for the systematic review . These financial conflicts of interest were identified using information about affiliations or funding listed in the systematic review s , as well as in any other articles published by one of the authors during the 3 years before the publication of the index systematic review . In addition , we search ed authors ' personal and institutional Web sites ; lists of disclosures from GlaxoSmithKline ( Research Triangle Park , North Carolina ) and Roche Pharmaceuticals ( Basel , Switzerl and ) ; and performed Web search es combining the names of the authors , drugs , and pharmaceutical companies to identify any additional information about financial relationships . Details of the specific financial conflicts of interest identified for each author are listed in Appendix Table 1 . Appendix Table 1 . Financial Conflicts of Interest Among Authors of the Systematic Review s For each systematic review , we recorded whether prophylaxis or treatment was assessed , the forms of evidence to be included ( such as r and omized , controlled trials and observational studies ) , the specific clinical outcomes assessed , the population s examined , and whether meta-analyses were done . We also examined whether the review s included information about the validity or quality of the primary literature . In particular , we recorded whether there were statements addressing nonpublication of primary studies or publication bias , including tests done by the review ers to assess for bias in meta-analyses ( such as the Egger or Begg test [ 33 , 34 ] ) , difficulty in accessing comprehensive study data , and the prevalence or role of industry in conducting and funding the primary studies . Data Analysis Two investigators were provided with redacted copies of each review that did not include the review s ' authors , their affiliations , or information on financial conflicts of interest . These versions also did not contain the journal name , journal formatting , or the article 's acknowledgments or references . The investigators independently evaluated the review s and classified the prophylaxis and treatment assessment s as favorable or not favorable toward the use of neuraminidase inhibitors . They were instructed to do this grading on the basis of the entirety of the review text without restriction to conclusions or recommendations made in any specific section of the review , thus allowing them to take into account the emphasis and interpretation of the authors throughout the review . The agreement between the investigators was strong at 86 % ( Cohen , 0.72 ; P < 0.001 ) . Disagreements were resolved by a third investigator using the same redacted copies . Descriptive analyses were done to examine the associations between financial conflicts of interest and the grading of the systematic review s. A sensitivity analysis excluding the summary review s was done to further examine this association . We also assessed the association between financial conflicts of interest and the inclusion of statements addressing the validity or quality of the primary evidence . Role of the Funding Source This study was funded by the Australian National Health and Medical Research Council . The funding source had no role in the design and conduct of the study , analysis of the results , or the decision to su bmi t the manuscript for publication . Results We identified 827 published articles across the 4 data bases using the specified search criteria , with 26 systematic review s included in the final cohort ( Figure ) . Thirteen review s examined prophylaxis and 24 examined treatment of influenza , accounting for 37 distinct assessment s ( Appendix Table 2 ) . In terms of review methods , 7 were Cochrane systematic review s and 19 conducted and reported a meta- analysis ( 73 % ) . The evidence inclusion criteria were limited to r and omized , controlled trials for 14 of the systematic review s ( 54 % ) , and 5 included evidence from clinical study reports or patient-level data . The main population s examined were healthy adults ( 18 of 26 systematic review s ) , children ( 13 of 26 ) , and hospitalized patients ( 6 of 24 ) . The outcome measures for prophylaxis assessment s included influenza-like illness and laboratory-confirmed influenza . For the treatment assessment s , the outcomes were illness duration , influenza-related complications , hospitalization , and mortality , mostly in combination . Five review s were up date s of previous Cochrane review s , and 3 were summary review s based on Cochrane review s. Figure . Summary of evidence search and selection . Eligible systematic review s included those with outcomes related to the prophylaxis or treatment of influenza . Appendix Table 2 . Characteristics of Systematic Review s Examining Prophylaxis and Treatment Outcomes for Neuraminidase Inhibitors Association Between Financial Conflicts of Interest and Favorable Assessment s Seven of the 26 systematic review s ( 27 % ) , corresponding to 8 of the 37 assessment s ( 22 % ) , were associated with a financial conflict of interest ( Appendix Table 1 ) . We identified financial conflicts of interest in publications other than the index systematic review in 2 cases , and no additional Systematic review s are increasingly used to answer clinical questions . Their popularity is partly attributable to their apparent clinical superiority in providing quick summaries of evidence from the ever-growing medical literature ( more than 750,000 items annually [ 1 ] ) , but also thanks to the great impact of the Cochrane Collaboration in promoting the use of the systematic review [ 2 ] . We also note that many scientific journals favour systematic review s because they tend to contribute to higher journal impact factors . However , the rise of systematic review s should give cause for concern ; more than 8000 are being indexed in MEDLINE annually , reflecting a three-fold increase over the last decade [ 3 ] . We write ‘ concern ’ , because many of these review s across healthcare seem to fall short of essential requirements such as incorporating risk of bias assessment in meta-analyses ( only 16 % ) , search ing for unpublished data ( only 7 % ) , or not fully following a protocol ( only one-third [ 3 ] ) . A recent study of review s published in anaesthetic journals revealed similar shortfalls [ 4 ] . Further more , the quality of reporting is lower in some countries and in journals with lower impact factors [ 5 , 6 ] . The apparent poor quality of many published systematic review s greatly increases the risk of misleading conclusions , which ultimately could harm our patients [ 7 ] . Despite their veneer of sophistication , one has to bear in mind that systematic review s are , in essence , retrospective appraisal s of the evidence . Editors , writers and readers should exercise great caution when interpreting conclusions of review s that only include very few trials , even when they fulfill the required st and ards [ 3 ] . Despite great efforts to promote adequate quality of review s through international guidelines such as PRISMA , GRADE and the Cochrane H and book [ 8 ] , the majority of review s may suffer from threats to the validity of their findings due to risk of systematic errors ( bias ) , design errors ( i.e. , erroneous selection of patients , doses of medication , comparators , analyses , outcomes ) and r and om error ( play of chance ) [ 9 ] . In a previous publication in this journal , some of the method ological issues and requirements for authors and editors were thoroughly discussed [ 10 ] . But we believe that other issues need to be addressed , in particular the amount of information included in meta-analyses from systematic review s , with the power this brings OBJECTIVE To provide guidelines for the health care provider on the prevention , diagnosis , and clinical management of postmenopausal osteoporosis . OUTCOMES Strategies for identifying and evaluating high-risk individuals , the use of bone mineral density ( BMD ) and bone turnover markers in assessing diagnosis and response to management , and recommendations regarding nutrition , physical activity , and the selection of pharmacologic therapy to prevent and manage osteoporosis . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library on August 30 and September 18 , 2012 , respectively . The strategy included the use of appropriate controlled vocabulary ( e.g. , oteoporosis , bone density , menopause ) and key words ( e.g. , bone health , bone loss , BMD ) . Results were restricted to systematic review s , practice guidelines , r and omized and controlled clinical trials , and observational studies published in English or French . The search was limited to the publication years 2009 and following , and up date s were incorporated into the guideline to March 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , clinical practice guideline collection s , clinical trial registries , and national and international medical specialty societies Abstract Obesity in older adults is a growing public health problem , yet the appropriate treatment remains controversial partly due to evidence that weight loss reduces bone mass and may increase fracture risk . The purpose of this review is to summarize the research to date on the effects of diet-induced weight loss on bone health in obese ( body mass index 30 kg/m2 and above ) older ( aged 65 years or older ) adults . Observational studies have shown that weight loss in this population decreases total hip bone mineral density and increases the risk of frailty fractures ( composite of proximal femur , pelvis , and proximal humerus fractures ) . R and omized controlled trials have largely confirmed these earlier observations but have also shown that exercise , particularly progressive resistance training , can attenuate or even alleviate this bone loss . Further research incorporating outcomes concerning bone quality and mass are needed to identify the optimal exercise and nutritional regimens to counteract the bone loss Introduction Type 2 diabetes ( T2D ) is a major health concern among population s of South Asian ethnicity . Although dietary and physical activity interventions may reduce the risk of T2D , the effectiveness has been moderate among South Asians . This might ( in part ) be because this subgroup follows strategies that were originally developed for interventions among other population s. Therefore , this review aims to assess the evidence for the current dietary and physical activity strategies recommended in T2D prevention intervention studies and guidelines for South Asians . Methods and analysis Included will be all studies and guidelines on dietary and /or physical activity strategies to prevent T2D in adult South Asians . Two review ers will search online data bases from their start until the present date for published and unpublished experimental/quasiexperimental studies , with at least an abstract in English . References of identified articles and key review s will be screened for additional studies . Guidelines will be identified by search es in online data bases and websites of public organisations . Finally , expert consultations will be held to supplement any missing information . Trial quality will be assessed with the Quality Assessment Tool for Quantitative Studies Data , and guidelines with the Appraisal of Guidelines for Research & Evaluation II . Data on the strategies recommended , targeting and evidence on effectiveness will be extracted by two review ers and presented in tabular and narrative forms . Recommendations will be compared with the National Institute for Health and Care Excellence guidelines [ PH35 ] . Overall findings on  dietary and physical activity recommendations , as well as findings for specific subgroups ( eg , by sex ) , will be discussed . Ethics and dissemination Ethics assessment is not required . Start date : 1 January 2016 , finishing and reporting date 31 July 2016 . Results will be published in a peer- review ed scientific journal , the project report of EuroDHYAN ( www.eurodhyan.eu ) and in a PhD dissertation . Trial registration number The protocol is registered with the International Prospect i ve Register of Systematic Review s ( PROSPERO ) registration number CRD42015027067 Half of all postmenopausal women will have an osteoporosis-related fracture during their lives , including one quarter who will develop a vertebral deformity ( 1 ) and 15 % who will suffer a hip fracture ( 2 ) . Hip fractures are associated with high mortality rates and loss of independence ( 3 , 4 ) . Although many vertebral fractures are detected only incidentally on radiography , some cause severe pain , leading to 150 000 hospital admissions per year in persons older than 65 years of age , 161 000 physician office visits , and more than 5 million days of restricted activity in those 45 years of age or older ( 5 ) . Low bone density has been used to predict risk for fractures as well as to diagnose osteoporosis . Osteoporosis has been defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue , leading to enhanced bone fragility and a consequent increase in fracture risk ( 6 , 7 ) . This definition emphasizes that , in addition to bone mass , the structure of bone is an important factor in the pathogenesis of fractures . A World Health Organization working group ( 8) proposed that osteoporosis should be diagnosed in epidemiologic studies when  bone mineral density  is 2.5 SDs or more below the mean for healthy young adult women at the spine , hip , or wrist ( corresponding to a T-score 2.5 ) or when patients have a history of atraumatic fracture ( 9 ) . By the World Health Organization definition , up to 70 % of women older than 80 years of age have osteoporosis ( 10 ) . Age is also an important factor in the relationship between bone density and the absolute risk for fracture . Older women have a much higher fracture rate than younger women with the same bone density because of increasing risk from other factors , such as bone quality and tendency to fall ( 11 ) . Despite the high prevalence of osteoporosis and the effect of fractures on mortality , independence , and quality of life , it is not clear whether it is appropriate to screen asymptomatic postmenopausal women . Recent systematic review s and guidelines disagree about which women should be screened and when ( 12 - 20 ) . This disagreement reflects , in part , gaps in the evidence . For example , most guidelines recommend using risk factors to select patients for bone density testing , but because of inadequate data there is no consensus on which risk factors to use . As part of the U.S. Preventive Services Task Force up date of its 1996 recommendation ( 21 ) , we examined evidence on the benefits and harms of screening postmenopausal women for osteoporosis . Specifically , we addressed the role of risk factors in identifying high-risk women , techniques of bone density testing to identify fracture risks , effectiveness of treatment in reducing fracture risk , and harms of screening and treatment . Methods Additional methods used for this review , including determination of the quality of studies ( 22 ) , are detailed in Appendix Tables 1 , 2 , and 3 and in a separate report ( 23 ) . The analytic framework and key questions are detailed in the Appendix Figure . Relevant studies were identified from multiple search es of MEDLINE ( 1966 to May 2001 ) , HealthSTAR ( 1975 to May 2001 ) , and Cochrane data bases ; reference lists of systematic review s ; and experts . We also sent letters to manufacturers of bone density devices requesting additional information about the performance of their instruments , but we received no new data . Two review ers read each abstract to determine its eligibility . We included English- language abstract s that contained original data about postmenopausal women and osteoporosis and addressed screening or the effectiveness of risk factor assessment , bone density testing , or treatment . We considered screening to be the process of assessing postmenopausal women without known osteoporosis for risk of osteoporotic fractures by identification of risk factors , including low bone density . Postmenopausal women were those who had experienced surgical or natural menopause , regardless of age . Women with preexisting atraumatic fractures were not considered in the screening population because they had confirmed osteoporosis according to the World Health Organization definition . For studies of prediction , we selected articles that reported the relationship between risk factor assessment methods or bone density tests and bone density , bone loss , or fractures . We review ed studies of medications used for treatment and present results for bisphosphonates . We focused on r and omized , controlled trials of therapies reporting radiographically verified , nontraumatic fracture outcomes because fractures are a stronger measure of effectiveness than bone density . We excluded studies of primary prevention of osteoporosis , such as the role of nutrition , calcium consumption , and physical activity . We also excluded secondary causes of osteoporosis , such as corticosteroid use and certain chronic diseases , and studies that did not provide sufficient information to allow determination of the method for selecting patients and for analyzing data . Investigators read the full-text versions of the retrieved papers and reapplied the initial eligibility criteria . To assess the internal validity of individual studies , we applied a set of criteria developed by the third U.S. Preventive Services Task Force ( Appendix Table 1 ) ( 22 ) . In this paper , we highlight studies that are applicable to current practice st and ards , have high- quality internal validity ratings , and are most generalizable to the U.S. population of postmenopausal women under consideration for screening . We created an outcomes table to summarize the number of  hip and vertebral fractures  prevented based on age-specific prevalence rates and treatment effects obtained from results of the review ed studies . We conducted a sensitivity analysis to determine the influence of risk factors on the number needed to screen . This research was funded by the Agency for Healthcare Research and Quality under a contract to support the work of the U.S. Preventive Services Task Force . Agency staff and Task Force members participated in the initial design of the study and review ed interim analyses and the final manuscript . Additional reports were distributed for review to content experts and revised accordingly before preparation of this manuscript ( 23 , 24 ) . The authors are responsible for the content of the manuscript and the decision to su bmi t it for publication . Results Studies of Screening We identified no studies about the effectiveness of screening in reducing osteoporotic fractures . Without direct evidence from screening studies , recommendations about screening need to rely on evidence that risk factor assessment or bone density testing can adequately identify women who could ultimately benefit from treatment . Risk Factor Assessment Hundreds of studies report associations between risk factors and low bone density and fractures in postmenopausal women ( 24 ) . The most comprehensive study of risk factors in a U.S. population is the Study of Osteoporotic Fractures , a good- quality prospect i ve study of 9516 women 65 years of age and older ( 25 ) . In this study , 14 clinical risk factors were identified as significant predictors of hip fracture in multivariable models ( age ; maternal hip fracture ; no weight gain ; height ; poor self-rated health ; hyperthyroidism ; current use of benzodiazepines , anticonvulsants , or caffeine ; not walking for exercise ; lack of ambulation ; inability to rise from a chair ; poor scores on two measures of vision ; high resting pulse ; and any fracture since 50 years of age ) . The relative risk for hip fracture per decrease of 1 SD in calcaneal bone density was 1.6 ( 95 % CI , 1.3 to 1.9 ) . This was comparable to the magnitude of the relative risks of most of the other significant predictors in the model , which ranged from 1.2 to 2.0 . Women with at least 5 of the 14 risk factors had increased rates of hip fractures compared with those who had 0 to 2 risk factors at all levels of calcaneal bone density . To determine which risk factors could be important in women younger than 65 years of age , we review ed eight observational studies of risk factors and fractures of various types conducted in population s in which at least 50 % of participants were younger than 65 years of age . Table 1 lists risk factors that were statistically significant predictors for fractures in multivariable models ( 26 - 33 ) . These results could not be quantitatively combined because risk factors were defined differently in each study . Table 1 . Risk Factors for Fractures in Women 5065 Years of Age Results of risk factor studies have been used to assess risk in individuals . We identified 10 cross-sectional studies that described methods of determining risk for low bone density for individual women based on selected clinical risk factors ( Table 2 ) ( 34 - 43 ) . The most common method ologic limitations of these studies are lack of validation and lack of generalizability because of small numbers of patients or nonrepresentative patients . We also identified 8 studies of clinical risk factors to determine fracture risk ( Table 2 ) ( 44 - 51 ) . None of these studies received a good rating for internal validity . Four studies evaluated hip fracture outcomes , two evaluated vertebral fractures , and two evaluated all types of fractures . These studies described the association of risk factors with fractures known to have occurred already ( four casecontrol studies ) or how well they would predict fractures in the future ( four prospect i ve cohort studies ) . Table 2 . Studies of Risk Factor Assessment A recent study compared the performance of five clinical decision rules for bone density testing among 2365 postmenopausal women 45 years of age or older who were enrolled in a community-based study of osteoporosis in Canada ( 52 ) . These rules included guidelines from the National Osteoporosis Foundation ( 53 ) ; the Simple Calculated Osteoporosis Risk Estimation ( SCORE ) rule ( age , weight , ethnicity , estrogen use , Background The role of vitamin D in management of depression is unclear . Results from observational and emerging r and omized controlled trials ( RCTs ) investigating the efficacy of vitamin D in depression lack consistency - with some suggesting a positive association while others show a negative or inconclusive association . Methods / Design The primary aim of this study is to conduct a systematic review of RCTs to assess the effect of oral vitamin D supplementation versus placebo on depression symptoms measured by scales and the proportion of patients with symptomatic improvement according to the authors ’ original definition . Secondary aims include assessing the change in quality of life , adverse events and treatment discontinuation . We will conduct the systematic review and meta- analysis according to the recommendations of the Cochrane H and book for Systematic Review s of Interventions . We will search the Cochrane Central Register of Controlled Trials ( CENTRAL ) , MEDLINE ( 1966 to present ) , EMBASE ( 1980 to present ) , CINAHL ( 1982 to present ) , PsychINFO ( 1967 to present ) and Clinical Trials.gov . Unpublished work will be identified by search ing two major conferences : the International Vitamin Conference , the Anxiety Disorders and Depression Conference , while grey literature will be acquired by contacting authors of included studies . We will use the r and om-effects meta- analysis to synthesize the data by pooling the results of included studies . Discussion The results of this systematic review will be helpful in clarifying the efficacy of vitamin D supplementation and providing evidence to establish guidelines for implementation of vitamin D for depression in general practice and other relevant setting s. Study registration Unique identifier : CRD42013003849 Introduction Hearing loss is a major public health concern , affecting over 11 million people in the UK . While hearing aids are the most common clinical intervention for hearing loss , the majority of people that would benefit from using hearing aids do not take them up . Recent technological advances have led to a rapid increase of alternative listening devices to conventional hearing aids . These include hearing aids that can be customised using a smartphone , smartphone-based ‘ hearing aid ’ apps , personal sound amplification products and wireless hearing products . However , no systematic review has been published evaluating whether alternative listening devices are an effective management strategy for people with hearing loss . Methods and analysis The objective of this systematic review is to assess whether alternative listening devices are an effective intervention for adults with hearing loss . Methods are reported according to the Preferred Reporting Items for Systematic review s and Meta-analyses Protocol s ( PRISMA -P ) 2015 checklist . Retrospective or prospect i ve studies , r and omised controlled trials , non-r and omised controlled trials , and before-after comparison studies will be eligible for inclusion . We will include studies with adult participants ( ≥18 years ) with a mild or moderate hearing loss . The intervention should be an alternative listening device to a conventional hearing aid ( comparison ) . Studies will be restricted to outcomes associated with the consequences of hearing loss . We will search relevant data bases to identify published , completed but unpublished and ongoing trials . The overall quality of included evidence will be evaluated using the GRADE system , and meta- analysis performed if appropriate . Ethics and dissemination No ethical issues are foreseen . The findings will be reported at national and international conferences , primarily audiology , and ear , nose and throat , and in a peer- review ed journal using the PRISMA guidelines . Review registration number PROSPERO CRD4201502958 Background The incidence of fragility fractures has increased during the last half of the 1990′s . One important determinant of fractures is the bone mineral content ( BMC ) or bone mineral density ( BMD ) , the amount of mineralised bone . If we could increase peak bone mass ( the highest value of BMC reached during life ) and /or decrease the age-related bone loss , we could possibly improve the skeletal resistance to fracture . Objective This review evaluates the importance of exercise as a strategy to improve peak bone mass , including some aspects of nutrition . Design Publications within the field were search ed through Medline ( PubMed ) using the search words : exercise ,  physical activity  , bone mass , bone mineral content , bone mineral density , BMC , BMD , skeletal structure and nutrition . We included studies dealing with  exercise during growth and young adolescence . We preferably based our inferences on r and omised controlled trials ( RCT ) , which provide the highest level of evidence . Results Exercise during growth increases peak bone mass .  Moderate intensity exercise intervention programs are beneficial for the skeletal development during growth . Adequate nutrition must accompany the exercise to achieve the most beneficial skeletal effects by exercise . Conclusion Exercise during growth seems to enhance the building of a stronger skeleton through a higher peak bone mass and a larger bone size STUDY DESIGN Systematic review and best evidence synthesis . OBJECTIVES To describe the prevalence and incidence of  neck pain and disability in workers ; to identify risk factors for neck pain in workers ; to propose an etiological diagram ; and to make recommendations for future research . SUMMARY OF BACKGROUND DATA Previous review s of the etiology of neck pain in workers relied on cross-sectional evidence . Recently published cohorts and r and omized trials warrant a re- analysis of this body of research . METHODS We systematic ally search ed Medline for literature published from 1980 - 2006 . Retrieved articles were review ed for relevance . Relevant articles were critically appraised . Articles judged to have adequate internal validity were included in our best evidence synthesis . RESULTS One hundred and nine papers on the burden and determinants of neck pain in workers were scientifically admissible . The annual prevalence of neck pain varied from 27.1 % in Norway to 47.8 % in Québec , Canada . Each year , between 11 % and 14.1 % of workers were limited in their activities because of neck pain . Risk factors associated with neck pain in workers include age , previous musculoskeletal pain , high quantitative job dem and s , low social support at work , job insecurity , low physical capacity , poor computer workstation design and work posture , sedentary work position , repetitive work and precision work . We found preliminary evidence that gender , occupation , headaches , emotional problems , smoking , poor job satisfaction , awkward work postures , poor physical work environment , and workers ' ethnicity may be associated with neck pain . There is evidence that interventions aim ed at modifying workstations and worker posture are not effective in reducing the incidence of neck pain in workers . CONCLUSION Neck disorders are a significant source of pain and activity limitations in workers . Most neck pain results from complex relationships between individual and workplace risk factors . No prevention strategies have been shown to reduce the incidence of neck pain in workers Context Clinicians rely on systematic review s for current , evidence -based information . Contribution This survival analysis of 100 meta-analyses indexed in ACP Journal Club from 1995 to 2005 found that new evidence that substantively changed conclusions about the effectiveness or harms of therapies arose frequently and within relatively short time periods . The median survival time without substantive new evidence for the meta-analyses was 5.5 years . Significant new evidence was already available for 7 % of the review s at the time of publication and became available for 23 % within 2 years . Implication Clinical ly important evidence that alters conclusions about the effectiveness and harms of treatments can accumulate rapidly . The Editors Systematic review s have become increasingly common in recent years ( 1 ) and are recommended by many as the best sources of evidence to guide both clinical decisions ( 2 ) and health care policy ( 3 ) . For systematic review s to fulfill these roles , their findings must remain relatively stable for at least several years or effective mechanisms must exist for alerting end users to important changes in evidence . Yet , surprisingly little research has assessed the extent to which systematic review s become out of date or the rate at which this occurs ( 47 ) . Some organizations , such as the Cochrane Collaboration , recommend updating systematic review s every 2 years , but few empirical data guide this or other recommendations about updating . We sought to determine how quickly systematic review s meet explicitly defined criteria for changes in evidence of sufficient importance to warrant updating . We also sought to identify predictors of survival time , the time to such important changes in evidence . Survival time might vary depending on many factors , including the type of question posed by the original review ( for example , therapeutic or diagnostic ) , the types of studies included ( for example , r and omized trials or observational studies ) , and whether the systematic review provided quantitative synthesis . To limit such variation , we focused on systematic review s of r and omized , controlled trials that evaluated therapeutic benefit or harm by providing quantitative synthesis ( meta- analysis ) for at least 1 outcome . Methods Study Design and Sample We used a quasi-r and om process ( alphabetical sort order by author ) to select 100 systematic review s that were indexed in ACP Journal Club with an accompanying commentary between January 1995 and December 2005 ( with a search date no later than 31 December 2004 to ensure at least 1 full year for new evidence to appear ) . We chose this sampling frame because ACP Journal Club selects systematic review s that meet explicit quality st and ards and are deemed directly relevant to clinical practice ( 8) . We regarded the sample size of 100 as sufficiently large to achieve suitably narrow confidence intervals and to permit evaluation of up to 5 potential predictors of survival . Eligibility Criteria Eligible review s evaluated the benefit or harm of a specific drug , class of drug , device , or procedure ( invasive procedure or surgery ) and included r and omized or quasi-r and omized , controlled trials . We excluded evaluations of alternative and complementary medicines because the stability of review s of such therapies might differ substantially from review s of conventional therapies . We required that review s provide a point estimate and 95 % confidence interval for at least 1 outcome in the form of a relative risk , odds ratio , or absolute risk difference for binary outcomes and weighted mean differences for continuous outcomes . We excluded meta-analyses of individual-patient data , meta-regressions , and indirect meta-analyses because of the difficulty of determining whether new data would alter previous quantitative results . Two team members independently assessed eligibility , with disagreements resolved by consensus involving a third review er . When more than 1 review on the same topic was identified , only the earliest was included . Search ing For each review , search es for new trials included identifying new systematic review s on the same topic , su bmi tting relevant content terms to the Clinical Queries function in Ovid , applying the Related Articles function in PubMed to the 3 largest and the 3 most recent trials in the original review ( up to 6 trials in total ) , and using Scopus ( www . scopus .com/ scopus /home.url ) to identify new r and omized trials that cited the original review . When these search strategies yielded no eligible new trials , we conducted more comprehensive electronic search es and review ed relevant chapters in such sources as Clinical Evidence and UpTo Date to ensure that we had not missed new trials . Team members who had background s in both medicine and clinical research screened citations retrieved by the preceding methods to identify trials that would have met the inclusion criteria in the original review . Retrieved articles were screened in chronological order to ascertain quantitative or qualitative signals for the need for updating . The review protocol stopped when any criteria for updating were met . Each systematic review was discussed in detail , with the final statussignal for updating was or was not detectedadjudicated by consensus ( Figure 1 ) . Figure 1 . Overall process for determining updating status . ACP Journal Club Signals for the Need to Up date Systematic Review s In design ing criteria for comparing new findings with those in a previous review , we adapted methods used by other investigators to address similar problems with comparing 2 sets of results relating to the same question ( 913 ) , such as r and omized and nonr and omized studies of the same intervention . These investigators identified conflicting findings among different publications using a combination of quantitative thresholds for differences in effect magnitude and qualitative judgments about the language used to describe the results . We have similarly conceptualized quantitative and qualitative signals of potential changes in evidence that are sufficiently important to warrant updating previous systematic review s. Quantitative Signals Quantitative signals consisted of a change in statistical significance or relative change in effect magnitude of at least 50 % . We restricted these changes to those involving 1 of the primary outcomes of the original review or any mortality outcome . We also ignored trivial changes in statistical significance when the original and up date d meta-analytic results both had P values between 0.04 and 0.06so that quantitative signals of changes in evidence would represent robust indicators of the need to up date previous review s. Quantitative signals were detected by combining data from eligible new trials with the previous results using a fixed-effects approach . Use of fixed-effect models allowed pooling of the new trials with the previous meta-analytic result , as opposed to having to obtain original data from all of the included trials in each of 100 systematic review s. Although r and om-effects models are usually preferred to avoid spurious precision in the face of heterogeneity , our goal was to detect potential changes in evidence that would warrant a formal up date , not produce exact estimates of the up date d results . Qualitative Signals Qualitative signals included new information about harm sufficient to affect clinical decision making , important caveats to the original results , emergence of a superior alternate therapy , and important changes in certainty or direction of effect . Qualitative signals were detected by using explicit criteria for comparing the language in the original review with descriptions of findings in new systematic review s that addressed the same topic , pivotal trials , clinical practice guidelines , or recent editions of major textbooks ( for example , UpTo Date ) . Pivotal trials were defined as trials that had a sample size at least 3 times larger than that of the previous largest trial or were published in 1 of the 5 highest-impact general medical journals ( The New Engl and Journal of Medicine , Lancet , Journal of the American Medical Association , Annals of Internal Medicine , and the British Medical Journal ) . We defined 2 levels of importance for qualitative signals : potentially invalidating changes in evidence , which would make one no longer want clinicians or policymakers to base decisions on the original findings ( such as a pivotal trial that characterized treatment effectiveness in terms opposite of those in the original systematic review ) , and major changes in evidence , which would affect clinical decision making in important ways without invalidating the previous results ( such as the identification of patient population s for whom treatment is more or less beneficial ) . Major changes also included differing characterizations of effectiveness that were less extreme than those for potentially invalidating signals but that would still affect clinical decision making ( for example , a change from possibly beneficial to definitely beneficial ) . Of importance , such characterizations as possibly effective , probably effective , and promising , were all categorized as possibly effective . Thus , qualitative signals for changes in evidence captured substantive differences in the characterization of treatment effects , not merely semantic differences . Full definitions for each of the specific signals can be found at www.ohri.ca/UpdatingSystRevs . Data Collection For each review , we characterized the clinical content area , eligibility criteria for included trials , definitions of reported outcomes , number of included trials and participants , meta-analytic result for each outcome , identification of statistical heterogeneity , and excerpted quotations of the authors ' characterizations of the main results . We also abstract ed whether a given outcome was explicitly identified as 1 of the primary or main outcomes . We discounted identification of more than 3 such outcomes as inconsistent with the It is now just over six years [ 1 ] since many medical journals began requiring that trials be registered before considering the trial report for publication . Such a policy was set up explicitly to reduce what was considered to be widespread bias in favor of publication of ‘ ‘ positive ’ ’ trials and to ensure that all clinical trials be made public prior to participant enrollment . Given the importance of clinical trials for estimating the efficacy and safety of interventions , and their role in approval of new drugs and devices , such a policy seemed uncontroversial . Although it is known that some trials still go unregistered , there are strong incentives ( such as journal publication ) and , in some countries legally enforceable m and ates , for authors to register these studies before enrolling patients . The existence and widespread uptake of trial registration helps research ers , patients , and funders underst and how many trials are being undertaken and which interventions are being evaluated . It also allows studies to be traced from inception through to completion and publication [ 2 ] . However , well-conducted systematic review s — overviews of health care interventions that use a predefined , explicit methodology to find and synthesize all the relevant evidence —are generally considered higher-caliber evidence than are individual trials in decision-making for clinical practice and health policy . The superiority given to such review s derives from key aspects inherent to the process of carrying out a systematic review . This study type , if done properly , allows the review to come closer to estimating the true effect of an intervention than any single study can , for two main reasons . First , such review s collect and synthesize all relevant studies ; second , review s appraise each included study for risk of bias . However , there is increasing evidence of the existence of publication bias for systematic review s. A recent survey [ 3 ] indicates that nonpublication of completed studies may be as much of a problem for systematic review s as it is for trials . Other analyses [ 4,5 ] point to the existence of discrepancies between systematic review protocol s and the published report , with one study [ 5 ] showing that the outcomes included in published systematic review s may be biased toward ‘ ‘ positive ’ ’ findings . It is crucially important , therefore , that if the evidence from these studies is to be incorporated into clinical practice , the review is as rigorous and as fully reported as possible . For example , it should be obvious to readers whether there was a prespecified protocol for the review , that deviations are noted , and whether outcomes from the review are reported according to the original study plan . Increased clarity surrounding systematic review conduct and reporting would be possible if the protocol s for systematic review s , just like those for trials , were registered [ 6,7 ] . Systematic review s conducted under the auspices of the Cochrane Collaboration are registered early , at the protocol development stage . This registration helps minimize bias in the conduct and reporting of the review , reduce duplication of effort between groups , and keep systematic review s up date d. However , until now no overarching registry open to all research ers , worldwide , has existed for recording the existence and development of systematic review s from inception through to completion . This month , the Centre for Review s and Dissemination ( University of York , UK ) , supported by the UK National Institutes of Health Research and in collaboration with an international advisory group , announces PROSPERO , its international Prospect i ve Register of Ongoing Systematic Review s. Following months of public consultation , with many hundreds of respondents from 34 countries providing input on the proposed registration process and minimum data set , PROSPERO is now open for business [ 8 ] . Registration is free , is available to anyone around the world , and generates a unique identifying number for each registered systematic review , which can ( and should ) be reported in any publications that arise from the study . Investigators should use the registry to record the existence of the protocol for a planned or ongoing systematic review of health care interventions even before screening studies for inclusion in the systematic review . A minimum data set specifies the key items that are required for a systematic review to be meaningfully registered . Key data items include a statement of the research question , patients and population , study intervention(s ) and outcomes ; criteria for inclusion and exclusion of studies in the systematic review ; outline of search strategy ; and methods to assess risk of bias and for analysis of studies included in the systematic review . With a clear system in place for registration of new and ongoing systematic review s , PLoS Medicine announces its support for this initiative . The journal wishes to promote best practice in the conduct and reporting of systematic review s. Best practice includes registration during the protocol phase in PROSPERO or other appropriate registry , conduct of the review in accordance with a fully developed protocol , and reporting in line with the PRISMA guidelines [ 9 ] . PLoS Medicine and other PLoS journals will now start Support for prospect i ve registration of protocol s for systematic review s has been gathering momentum . The PRISMA statement , a guideline for reporting systematic review s and meta-analyses of studies that evaluate health-care interventions , advocates registration . Well-conducted systematic review s are accepted as the best- quality evidence to inform policy and practice , and the dramatic upward trend in the number of systematic review s published annually ( fi gure ) is set to continue . However , there is currently no single facility for identifying this type of research in advance of the appearance of the results of the review . There is concern about and evidence of publication and selective outcome -reporting biases associated with systematic review s. An open registry of review s captured at the protocol stage would facilitate good practice in systematic review s by providing transparency of the review process and outcomes . Discrepancies between the methods of the published review and those planned in the registered protocol could be more readily identifi ed . Registration might also encourage full publication of the review ’s fi ndings and transparency in changes to methods that could bias fi ndings . In both the prevention and revelation of potential bias , registration should improve quality and increase confi dence that policy or practice informed by the fi ndings of systematic review s are indeed drawing on best- quality evidence . A registry of protocol s of systematic review s could assist those planning new review s and updating existing ones . Easy access to information about ongoing review s should help to optimise the use of fi nite re sources by enabling funding and commissioning agencies to avoid unnecessary duplication and encourage collaboration . A comprehensive registry could also create opportunities for method ological and other research , both within and across disciplines . Existing access to systematic - review protocol s is limited to the outputs of individual organisations , such as the Cochrane and Campbell Collaborations and the Joanna Briggs Institute . The National Public Health Service for Wales is piloting an All Wales Systematic Review s Register , but , up to now , there has been no central ised comprehensive registry of systematic - review protocol s. We are developing an international facility to register the details of ongoing systematic review s in health and social care . Our registry is being established with the existing platform and infrastructure that supports the Data base of Abstract s of Review s of Eff ects ( DARE ) , the NHS Economic Evaluations Data base ( NHS EED ) and the Health Technology Assessment ( HTA ) data base produced by the Centre for Review s and Dissemination . The initial scope of the registry will be limited to systematic review s of the eff ectiveness of health interventions . However , the longterm aim is for the registry to include details of all ongoing systematic review s with a health-related outcome in the broadest sense . Ultimately , inclusion will encompass systematic review s of health-care interventions , and review s of the social determinants of health , of service delivery , and of risk factors and genetic associations . Our web-based registry will off er free public access , be electronically search able , and open to all prospect i ve registrants . Registration will require the provision of a minimum data set , the completeness of which will be checked automatically before registration . After acceptance , the registry ’s entry and protocol for the review , if available , will be loaded on the data base as a permanent entry and a unique identifi cation number issued . An audit trail for any amendments to the information will be available within the record . Links to result ing publications will be added . These provisions ensure that the registry will match the relevant criteria required of clinical trials registries Cad . Saúde Pública , Rio de Janeiro , 23(6):1252 - 1253 , jun , 2007 For the first time in the history of Cadernos de Saúde Pública/Reports in Public Health , the journal has recently design ated a specific Associate Editor to receive and h and le review and essay articles . The clash between “ traditional ” and systematic review s is now at the center of an instigating debate . Two quite recent articles conducting review s of review s ( Annu Rev Public Health 2006 ; 27:81 - 102 and BMC Med Res Method ol 2006 ; 6:35 ) question the supposedly unequivocal advantages of systematic over traditional review s , basically in the following terms : that the former do not necessarily confirm their self-ascribed rigor ( almost as if it were an intrinsic attribute of the systematic review process itself ) ; that on many occasions systematic review s have lost their critical perspective ; and finally that they fail to deal adequately with the gap between evidence and its translation into public policies . The above critiques sound pertinent , but in my view they stem from the uncomfortable coexistence of review s , systematic review s , and essays in public health , as if the undeniable rise of systematic review s in recent years ( especially in the field of epidemiology ) must necessarily have taken place at the expense of traditional review s and essays . In my point of view , such a clash is artificial . The mistakes have arisen from simplistic historical readings and conceptual views , as in a purported linear order between the application of statistical methods to public health and the emergence of clinical epidemiology and evidence -based medicine , and the subsequent translation into a view that public policies should likewise be based strictly on evidence . As Stephen Senn contends in Dicing with Death : Chance , Risk and Health , the historical facts do not precisely follow this sequence . British statistician Archie Cochrane ( immortalized in the Cochrane Library , including the Data base of Systematic Review s by the same name ) was initially commissioned to apply statistical analysis methods to evaluate the British National Health System , with a view towards reducing waste in the NHS and increasing its effectiveness and caseresolving capacity . The Cochrane Data base was thus born from the initial systematization of r and omized trials , where observational studies display what is considered second-order evidence , serving as the empirical basis for evidence -based medicine . However , the methods and techniques developed by Cochrane and his original group are not tributaries of the emergence of clinical epidemiology , which took place decades later , but converse very closely with the daily operation of the NHS . To some quantitative research ers , essays in public health sound like the “ ugly duckling ” of review s. Therein likes another conceptual error , in my view . Epidemiology has much to gain from encouragement for systematic review s , but much to lose if it foregoes critical review s and essays . An example is the seminal essay by Stephen J. Gould on the interface between public health , statistics , and psychology ( The Mismeasure of Man ) . Few realize that in parallel with this essay , Gould published an article reanalyzing empirical data through factor analysis , in Science ( 1978 ; 200:503 - 9 ) . Thus , there is nothing strange or bad about combining essays and the application of quantitative methods . In short , different watersheds for the review of findings and concepts all have their place . Bring on new review s , systematic review s , and essays , as long as they are based on quality and readability ! All three are more than welcome ! Review s , systematic review s , and essays in public health INTRODUCTION Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3 ) have yielded conflicting results . The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D ( 25-OH D ) , bone turnover markers , bone mineral density ( BMD ) , radius bone loss and incidence of fracture in postmenopausal women . METHODS 669 postmenopausal women ( mean age : 62.2 years ) belonging to a population -based cohort were followed prospect ively for a median of 11.2 years . At baseline , 25-OH D levels , BMD , bone turnover markers and clinical risk factors of osteoporosis were assessed . BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs . RESULTS 73 % and 35 % of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention . 11 % of women had levels below 30 nmol/l . Serum 25-OH D correlated modestly with intact PTH ( r(2)=0.023 , p<0.0001 ) , but not with bone turnover markers or BMD at the hip and radius after adjustment for age . When levels of 25-OH D were considered as a continuous variable , there was no significant association between 25-OH D levels and radius BMD loss or fracture risk . After adjustment for age , there was no significant difference in incidence of fracture , BMD , radius BMD loss , bone turnover markers , grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75 , 50 or 30 nmol/l . CONCLUSIONS In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency , vitamin D status may not be an important determinant of bone health RATIONALE Although vitamin D is widely used to promote skeletal health , definitive data on benefits and risks of supplemental vitamin D alone on bone are lacking . Results from large , r and omized controlled trials in the general population are sparse . Data on the effects of supplemental omega-3 fatty acids ( FAs ) on bone are also limited . DESIGN The VITamin D and OmegA-3 TriaL ( VITAL ) is a double-blind , placebo-controlled trial assessing the role of vitamin D3 ( 2000 IU/d ) and omega-3 FA ( 1g/d ) supplements in reducing risks of cancer and cardiovascular disease among U.S. men aged ≥50 and women aged ≥55 . To comprehensively test effects of supplemental vitamin D and /or omega-3 FAs on skeletal health , the VITAL : Effects on Fractures ancillary study is determining the effects of these supplements on incident fractures among 25,875 participants enrolled in the parent trial . Study investigators adjudicate fractures through a detailed review of medical records and radiological images ( hip and femur ) . In a complementary ancillary , VITAL : Effects on Structure and Architecture is determining the effects of supplemental vitamin D and /or omega-3 FAs on bone with detailed phenotyping during in-person visits . Comprehensive assessment s of bone density , turnover , structure/architecture , body composition , and physical performance are being performed at baseline and 2 years post-r and omization . CONCLUSION Results from these studies will clarify the relationship between supplemental vitamin D and /or omega-3 FAs on bone health outcomes , and inform clinical care and public health guidelines on the use of supplemental vitamin D for the primary prevention of fractures in women and men Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items
Summary Vitamin K may affect  bone mineral density and fracture incidence .
Since publication of a previous systematic review the integrity of some of the previous evidence has been question ed and further trials have been published .
Introduction This systematic review was design ed to assess the effectiveness of oral vitamin K supplementation for increasing bone mineral density  and reducing fractures in adults .