Overdiagnosis of bone fragility in the quest to prevent hip fracture

BMJ 2015;350:h2088 doi: 10.1136/bmj.h2088 (Published 26 May 2015) TOO MUCH MEDICINE Overdiagnosis of bone fragility in the quest to prevent
hip fracture
Despite widespread endorsement, Teppo Järvinen and colleagues argue that evidence for
stratifying risk of fracture and subsequent drug therapy to prevent hip fracture is insufficient to
warrant our current approach
Teppo LN Järvinen professor 1, Karl Michaëlsson professor 2, Jarkko Jokihaara registrar 3, Gary S Collins associate professor4, Thomas L Perry clinical assistant professor5, Barbara Mintzes senior lecturer 6, Vijaya Musini assistant professor 5, Juan Erviti head 7, Javier Gorricho senior evaluation officer 8, James M Wright professor 5, Harri Sievänen research director 9 1Department of Orthopaedics and Traumatology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; 2Department ofSurgical Sciences, Section of Orthopaedics, Uppsala University, Uppsala, Sweden ; 3Department of Hand Surgery, Tampere University Hospital,Tampere, Finland; 4Centre for Statistics in Medicine, Botnar Research Centre, University of Oxford, Oxford, UK ; 5Departments of Anesthesiology,Pharmacology, and Therapeutics and Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 6Faculty of Pharmacy andCharles Perkins Centre, University of Sydney, Sydney, Australia ; 7Drug Information Unit, Navarre Regional Health Service, Pamplona, Navarre,Spain; 8Department of Health, Government of Navarre, Pamplona, Navarre, Spain; 9UKK Institute for Health Promotion Research, Tampere, Finland Worldwide, about 1.5 million hip fractures occur each year.1 densitometry reliably identifies people at increased risk of Incidence is expected to increase because of population ageing.1 fracture, improving the cost effectiveness of pharmacotherapy.
Hip fractures are devastating injuries, resulting in disability, Alendronate, the first bone targeted drug shown to prevent hip increased mortality, and high treatment costs.1 Although hip fractures, was introduced in 1995.
fractures constitute a minority of fractures linked to osteoporosis, By the early 2000s, it became clear that a fracture prevention their consequences exceed those of all other fragility fractures strategy based on bone mineral density is not feasible. Most of combined.2 Vertebral fractures, recognised only by radiography, the fracture burden arises from uncommon events among people are of much less clinical concern (see appendix 1 on who do not have osteoporosis rather than from common events thebmj.com).3 4 We analyse the implications of stratifying in the relative few with the condition.7 fracture risk and prescribing drug treatment in the hope of preventing hip fractures.
With parallels to the Framingham Risk Score for predicting cardiovascular disease, a task force led by the WHO Before the late 1980s, osteoporosis was diagnosed after a bone Collaborating Centre for Metabolic Bone Diseases (University fracture. The advent of dual energy absorptiometry made it of Sheffield), introduced in 2008 a web based, fracture risk possible to measure bone mineral density at the lumbar spine prediction tool called FRAX (box 1). Its aim was to identify and proximal femur and allowed earlier diagnosis. In 1994 a people at high, 10 year risk of fracture who were "likely to World Health Organization (WHO) Study Group—supported benefit from pharmaceutical treatment."8 The threshold for high by several drug companies5—published the first diagnostic risk was determined by osteoporosis advocacy and national criteria for osteoporosis, defined as a T score < -2.5.6 The WHO guideline organisations. Despite concerns9 10 FRAX quickly report stated that a one standard deviation decrease in bone became a standard for clinical practice: since June 2011, over mineral density doubles the relative risk of osteoporotic 10 million assessments have been recorded by the FRAX fractures, and that osteoporosis is the main cause of fractures in ageing populations. The guideline also stated that bone Correspondence to: Teppo Jarvinen [email protected] Extra material supplied b Appendix 1: Vertebral fracturesAppendix 2: Systematic review of hip fracture rates For personal use only: See rights and repr BMJ 2015;350:h2088 doi: 10.1136/bmj.h2088 (Published 26 May 2015) Summary box
Clinical context—Hip fractures cause considerable morbidity and mortality and are associated with high healthcare costs. With a growing elderly population their incidence is predicted to riseDiagnostic change—Before the late 1980s, osteoporosis was diagnosed after a bone fracture. A new definition was introduced in 1994 based on low bone mineral density, expanding indications for pharmacotherapy. The introduction of fracture risk calculators exacerbated the trendRationale for change—Fractures are a function of bone fragility, which is measureable and can be improved with drugsLeap of faith—Identifying and treating patients with fragile bones is a cost effective strategy to prevent fractures, particularly hip fracturesImpact on prevalence—Current fracture risk predictors have at least doubled the number of candidates for drug treatment. Under US guidelines about 75% of white women aged over 65 years have become candidates for drug treatmentEvidence of overdiagnosis—Rates of hip fracture continue to decline, and most occur in people without osteoporosis. Our meta-analysis indicates that 175 postmenopausal women with bone fragility must be treated for about three years to prevent one hip fractureHarms from overdiagnosis—Being labelled as at risk of fracture imposes a psychological burden. Drug treatment is associated with adverse events, such as gastrointestinal problems, atypical femoral fractures, and osteonecrosis of the jawLimitations of evidence—Hip fractures are caused predominantly by falls in frail older adults. Few studies on preventive pharmacotherapy included adults aged ≥80, but evidence suggests no treatment benefit. Evidence is also sparse on treatment of men and optimum duration of treatment Box 1: Evolution of diagnosis of osteoporosis
Pre-densitometry (1940 to late 1980s)
Diagnosis based on fractures (such as vertebral collapse) in x ray images
Systemic cortical thinning and increased radiolucency in x ray images
Bone mineral density (late 1980s to present) Dual energy x ray absorptiometry of lumbar spine and hip region to measure bone mineral density
Operational definition of osteoporosis defined in 1994 as bone mineral density ≥2.5 SD below the average for a healthy woman aged
Established osteoporosis denotes the presence of a fragility fracture as well as low bone mineral density
Fracture prediction era (mid-2000s to present) Risk prediction tools used to estimate an individual's absolute risk of major osteoporotic fracture to identify those at high risk of fractures
and amenable to intervention Most commonly used tool is FRAX, a web based, multifactorial fracture risk prediction tool that assesses risk
using factors such as age, sex, weight, smoking, alcohol use, and fracture history with the option to include bone mineral density Other fracture prediction models that are well validated include Garvan and QFracture
Drivers of change
In Europe, NOGG criteria are used, rather than an arbitrary risk threshold. NOGG suggests drug intervention if the FRAX based The current approach assumes that bone fragility (assessed by estimate of the risk of fracture exceeds the prevalence of fragility bone mineral density or fracture risk calculators) predicts hip fracture in someone of the same age and sex. For example, fracture and that subsequent drug treatment prevents fractures.
NOGG suggests drug treatment for a typical UK woman aged Strong commercial involvement, both for bone densitometry 55 if her estimated 10 year risk exceeds 1.5% for hip fracture, and for pharmacotherapy, underpinned this trend. Organisations or 10% for all major fractures (fig 1[fl]). The proportion of supporting the development of FRAX, all heavily funded by women eligible for treatment increases with age, from about drug companies,9 launched a campaign for widespread screening 20% at the age of 50 to over 40% of those >80.12 13 Although for bone fragility. For example, the National Osteoporosis the NOGG threshold sounds more conservative, it paradoxically Foundation (NOF) in the United States and the UK's National advocates drug treatment for younger people with a low absolute Osteoporosis Guideline Group (NOGG) recommend screening risk of fracture but not for older people with higher absolute of all postmenopausal women and men aged ≥50.
Effect on prevalence
Evidence of too much medicine
In 2010, the prevalence of bone mineral density defined osteoporosis in Europe was 22% for women and 7% for men aged >65 and 47% and 16%, respectively, for women and men Estimating absolute fracture risk is intuitively attractive, aged >80.1 Quantifying the number of people at risk of fracture focusing on actual fractures rather than proxies such as bone is more challenging and depends on the risk threshold selected.
mineral density or relative risks of fracture. But it has a The NOF considers that a 10 year probability of hip fracture fundamental conceptual flaw: fewer than one in three hip >3% calculated by FRAX warrants intervention (fig fractures are attributable to bone fragility.14 Fractures are Applying these criteria to a large prospective cohort study, traumatic events induced by falls, mostly in frail older adults.15 Donaldson and colleagues estimated that at least 72% of US Incidence of hip fracture in women rises 44-fold from the age white women aged >65 years and 93% of those >75 would be of 55 to 85, and the effect of ageing is 11-fold greater than that recommended drug treatment.11 This is at least double the of reduced bone mineral density (fig 2).16 17 About a third of population that would be recommended drug treatment using generally healthy people aged ≥65 fall at least once a year,18 bone mineral density criteria.
and this proportion increases to a half by age 80.19 The question, For personal use only: See rights and repr BMJ 2015;350:h2088 doi: 10.1136/bmj.h2088 (Published 26 May 2015) "Do you have impaired balance?" can predict about 40% of all evidence also challenges the justification for the general use of hip fractures,20 whereas osteoporosis predicts less than 30%.14 calcium and vitamin D supplementation to prevent fractures.37 38 Ageing does result in bone fragility, but without a fall even The age adjusted incidence of hip fractures has fallen steadily fragile hips do not fracture.21 in most Western countries.39 40 This positive trend, observed in large population based cohort studies, does not seem to be attributable to drug treatment.41-43 A recent Canadian study from Overdiagnosis of bone fragility leads to overtreatment. As for a database of 65 659 hip fractures found that despite roughly most risk diseases, drug treatments eclipsed other forms of fivefold differences in provincial prescribing rates of treatment such as lifestyle modification and physical activity.
osteoporosis drugs in people aged >55, no differences were Sales of bone densitometry devices and bone building drugs found between provinces in hip fracture rates, in either sex or have exploded.23 The first bisphosphonate for osteoporosis any age group.44 Confounding by indication is an obvious generated a mere $0.3bn (£0.2bn; €0.3bn) in 1996, but the concern in studies of this type, but the consistency of evidence amount spent on these drugs tripled from 2001 to 20081 and is should raise doubts about the effectiveness of osteoporosis forecast to exceed $11bn in 2015.
medications in ordinary healthcare settings.
Bisphosphonates are the dominant drugs for fracture prevention.24 Our systematic review of the evidence base for bisphosphonates identified 33 randomised controlled trials of The viability of any medical intervention in a public health sufficient duration (≥ one year) to expect a preventive effect on system ultimately depends on evidence of cost effectiveness hip fractures (see appendix 2 on the bmj.com).25 In 23 trials and affordability. Evidence on cost effectiveness of reporting on hip fracture, 254/17 164 women taking pharmacological fracture prevention is completely lacking.45 bisphosphonates versus 289/14 080 taking placebo had hip Current assertions that drug treatment is cost effective are based fractures (relative risk 0.68, (95% confidence interval 0.57% to on computer modelled analyses that disregard the evidence gaps 0.80%); absolute risk reduction 0.57% for hip fracture over and extrapolate efficacy estimates derived from younger women three years (fig 3Accordingly, 175 women must be treated (aged 60-80) to their older peers (age >80) and to men.46 By for three years for each hip fracture prevented.
assuming a constant relative risk reduction for fractures irrespective of age, sex, and baseline fracture risk, they are likely Gaps in evidence
to overestimate absolute risk reduction.
But the evidence base is fraught with gaps. Although the mean age of patients with hip fracture in Europe is about 80 years, Evidence for alternative strategies
and over 75% of hip fractures occur among people older than The focus on drug treatment means that widely feasible 75,1 only three of the 23 trials in our systematic review included non-pharmacological interventions are overlooked. A recent sufficient women over 75 to allow analysis of hip fracture meta-analysis of various fall prevention programmes estimated incidence.26-28 All failed to show any significant effect on hip an overall relative reduction of fracture risk of 60% (95% fractures in this age group.27 29 Counterintuitively, the evidence confidence interval 34% to 78%) with exercise training.47 The thus suggests that those most prone to hip fractures do not benefit of physical activity on hip fractures not only shows a benefit from bisphosphonate treatment. This discouraging dose-response relation48 49 but is also comparable with that of finding was corroborated by a recent randomised trial of single drugs tested in idealised situations with highly selected dose zoledronic acid for osteoporosis in frail elderly women.30 participants. Smoking is a major modifiable risk factor for Also, although osteoporosis is primarily considered a female fractures,50 its effect described as greater than that of bone disease, 30-40% of hip fractures occur in elderly men.1 Two mineral density.51 The substantive approaches to preventing hip decades after the introduction of bisphosphonates, we still have fractures have not changed in nearly 25 years: stop smoking, no randomised trial evidence on hip fracture prevention in men.
be active, and eat well.52 This advice works for anyone, Evidence on optimal treatment duration is also sparse. The US regardless of bone fragility, and the benefits encompass the Food and Drug Administration recently published a pooled data entire human body.
analysis of randomised trials evaluating the effects of continuous versus time limited drug treatment.31 32 Among participants who Harms from diagnosis or treatment
received continuous bisphosphonate treatment for six or more years, vertebral and non-vertebral fracture rates were 9.3-10.6%, The prevailing tenet that early diagnosis and subsequent exceeding the 8.0-8.8% rate for participants who were switched intervention is always desirable ignores the psychological burden to placebo after three years. Data analyses were post hoc and associated with a disease label. In a random sample of 261 the number of women too small to draw firm conclusions, but women who had had bone densitometry, women found to have this is still the best available evidence, and at least provides no low bone mineral density were more likely to take measures to rationale for long-term use of bisphosphonates.
prevent fractures than those with normal density (94% v 56%; P<0.01).53 However, they also became more fearful of falling Although the dominant therapeutic class, bisphosphonates are (38% v 2%; P<0.01) and were more likely to limit their activities not the only drugs for building bone density (box 2). Denosumab to avoid falling (24% v 2%; P<0.01).
and strontium ranelate have some evidence of efficacy against hip fracture.33 34 However, the putative efficacy of strontium Oral bisphosphonates are associated with gastrointestinal ranelate rests on post hoc analysis.34 The European Medicines problems (typically nausea, indigestion, heartburn, vomiting, Agency and FDA have expressed concerns about the validity and retrosternal pain) leading up to 20% of patients to of the data on denosumab because of irregularities in discontinue treatment.54 They are also associated with atypical implementing the trial 35 and the counterintuitive effect on femoral fractures55 and osteonecrosis of the jaw.56 The most fracture prevention after two years of treatment.35 36 Recent recent data suggest the relative risk of atypical femoral fractures after four years of bisphosphonate use is 126, translating to 11 atypical femoral fractures a year among 10 000 long term users For personal use only: See rights and repr BMJ 2015;350:h2088 doi: 10.1136/bmj.h2088 (Published 26 May 2015) Box 2: Bone targeted pharmacotherapy
Bisphosphonates—Inhibit bone resorption by encouraging osteoclasts to undergo apoptosis, thereby slowing bone lossDenosumab—A human monoclonal antibody designed to inhibit maturation of osteoclasts by binding to and inhibiting RANK ligand, a protein that acts as the primary signal for bone resorptionOestrogen and selective oestrogen receptor modulators—Act on the oestrogen receptor to inhibit bone resorptionTeriparatide—Recombinant form of parathyroid hormone; when used intermittently, activates osteoblasts more than osteoclasts, leading to an increase in bone massStrontium ranelate—Human body easily takes up strontium and incorporates it into bones in the place of calcium, resulting in increased bone formation and reduced resorption of bisphosphonates.57 Similar skeletal complications are Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures in the associated with other antiresorptive therapies.58 community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone 2006;38:694-700.
Strontium ranelate is currently under renewed scrutiny for Kanis JA, Hans D, Cooper C, et al. Interpretation and use of FRAX in clinical practice.
Osteoporos Int 2011;22:2395-411.
increased cardiovascular risks. Even calcium and vitamin D Jarvinen TL, Jokihaara J, Guy P, et al. Conflicts at the heart of the FRAX tool. CMAJ supplementation has recently been associated with an increased risk of cardiovascular adverse events.
10 Collins GS, Michaelsson K. Fracture risk assessment: state of the art, methodologically 59-61 Treating 1000 people unsound, or poorly reported? Curr Osteoporos Rep 2012;10:199-207.
with calcium with or without vitamin D for five years is 11 Donaldson MG, Cawthon PM, Lui LY, et al. Estimates of the proportion of older white estimated to cause an additional six myocardial infarctions or women who would be recommended for pharmacologic treatment by the new US National Osteoporosis Foundation Guidelines. J Bone Miner Res 2009;24:675-80.
12 Kanis JA, McCloskey EV, Johansson H, et al. Case finding for the management of osteoporosis with FRAX—assessment and intervention thresholds for the UK. Osteoporos 13 Compston J, Bowring C, Cooper A, et al. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group The dominant approach to hip fracture prevention is neither (NOGG) update 2013. Maturitas 2013;75:392-6.
14 Stone KL, Seeley DG, Lui LY, et al. BMD at multiple sites and risk of fracture of multiple viable as a public health strategy nor cost effective.
types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res Pharmacotherapy can achieve at best a marginal reduction in 15 Jarvinen TL, Sievanen H, Khan KM, et al. Shifting the focus in fracture prevention from hip fractures at the cost of unnecessary psychological harms, osteoporosis to falls. BMJ 2008;336:124-6.
serious medical adverse events, and forgone opportunities to 16 Kanis JA, Johnell O, Oden A, et al. Risk of hip fracture according to the World Health have greater impacts on the health of older people. As such, it Organization criteria for osteopenia and osteoporosis. Bone 2000;27:585-90.
17 Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral is an intellectual fallacy we will live to regret.
density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-9.
18 Tinetti ME. Clinical practice. Preventing falls in elderly persons. N Engl J Med Contributors and sources: The authors have experience and research 19 Tinetti ME, Williams CS. Falls, injuries due to falls, and the risk of admission to a nursing interest in epidemiology and prevention of osteoporosis and fractures home. N Engl J Med 1997;337:1279-84.
20 Wagner H, Melhus H, Gedeborg R, et al. Simply ask them about their balance—future in elderly people and the evaluation of the harms and benefits of fracture risk in a nationwide cohort study of twins. Am J Epidemiol 2009;169:143-9.
pharmacotherapy. TLNJ conceptualised the article. TLNJ, HS, and KM 21 Sievanen H, Kannus P, Jarvinen TL. Bone quality: an empty term. PLoS Med 2007;4:e27.
22 Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for hip and other fractures.
wrote and revised the initial draft; all others provided substantive J Bone Miner Res 2005;20:1185-94.
intellectual input. VM and BM did the systematic review of efficacy of 23 Herndon MB, Schwartz LM, Woloshin S, et al. Implications of expanding disease definitions: the case of osteoporosis. Health Aff 2007;26:1702-11.
24 Poole KE, Compston JE. Bisphosphonates in the treatment of osteoporosis. BMJ Competing interests: We have read and understood BMJ policy on 25 Musini VM, Bassett KL, Wright JM. A systematic review of the efficacy of bisphosphonates.
declaration of interests and declare BM has provided expert testimony Ther Lett 2011;83 (Sep-Oct):1-2.
in a Canadian class action lawsuit on post-menopausal hormone therapy 26 European Medicines Agency. Scientific discussion: Aclasta EMEA-H-595-II-10-AR. and breast cancer risks. TLNJ is he Jane and Aatos Erkko foundation clinical professor of Orthopedics and Traumatology at the University of 27 McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001;344:333-40.
Helsinki and is supported by unrestricted academic grants from the 28 Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures Academy of Finland and the Sigrid Juselius Foundation. Authors from and mortality after hip fracture. N Engl J Med 2007;357:1799-809.
the University of British Columbia are supported by an operating grant 29 Boonen S, Black DM, Colon-Emeric CS, et al. Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women from the Government of British Columbia to the UBC Therapeutics with osteoporosis aged 75 and older. J Am Geriatr Soc 2010;58:292-9.
30 Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical This article is part of a series on overdiagnosis looking at the risks and trial. JAMA Intern Med 2015 Apr 13. [Epub ahead of print.] harms to patients of expanding definitions of disease and increasing 31 Food and Drug Administration. Background document for meeting of advisory committee for reproductive health drugs and drug safety and risk management advisory committee.
use of new diagnostic technologies.
Provenance and peer review: Not commissioned; externally peer 32 Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates for osteoporosis—where do we go from here? N Engl J Med 2012;366:2048-51.
33 Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-65.
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Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013;8:136.
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56 Ulmner M, Jarnbring F, Torring O. Osteonecrosis of the jaw in Sweden associated with 43 Feldstein AC, Weycker D, Nichols GA, et al. Effectiveness of bisphosphonate therapy in the oral use of bisphosphonate. J Oral Maxillofac Surg 2014;72:76-82.
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57 Schilcher J, Koeppen V, Aspenberg P, et al. Risk of atypical femoral fracture during and 44 Crilly RG, Kloseck M, Chesworth B, et al. Comparison of hip fracture and osteoporosis after bisphosphonate use. N Engl J Med 2014;371:974-6.
medication prescription rates across Canadian provinces. Osteoporos Int 2014;25:205-10.
58 Aspenberg P. Denosumab and atypical femoral fractures. Acta Orthopaed 2014;85:1.
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47 El-Khoury F, Cassou B, Charles MA, et al. The effect of fall prevention exercise 61 Bolland MJ, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and programmes on fall induced injuries in community dwelling older adults: systematic review risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access and meta-analysis of randomised controlled trials. BMJ 2013;347:f6234.
dataset and meta-analysis. BMJ 2011;342:d2040.
48 Feskanich D, Willett W, Colditz G. Walking and leisure-time activity and risk of hip fracture in postmenopausal women. JAMA 2002;288:2300-6.
Accepted: 25 March 2015
49 Michaelsson K, Olofsson H, Jensevik K, et al. Leisure physical activity and the risk of fracture in men. PLoS Med 2007;4:e199.
50 Olofsson H, Byberg L, Mohsen R, et al. Smoking and the risk of fracture in older men. J Cite this as: BMJ 2015;350:h2088 Bone Miner Res 2005;20:1208-15.
BMJ Publishing Group Ltd 2015 51 Kanis JA, Johnell O, Oden A, et al. Smoking and fracture risk: a meta-analysis. Osteoporos For personal use only: See rights and repr BMJ 2015;350:h2088 doi: 10.1136/bmj.h2088 (Published 26 May 2015) Fig 1 Age related 10 year risk of hip fracture in average man and woman with known osteoporosis (femoral neck T score
-2.5) with and without a history of fracture plus treatment thresholds for US National Osteoporosis Foundation (NOF) and UK National Osteoporosis Guideline Group (NOGG, fracture risk in someone of same age and sex regardless of bone Fig 2 Relative contributions of change in bone mineral density (red) and age (blue) on the 44-fold rise in hip fracture incidence
in women between age 55 and 8516 22 For personal use only: See rights and repr BMJ 2015;350:h2088 doi: 10.1136/bmj.h2088 (Published 26 May 2015) Fig 3 Meta-analysis of the efficacy of bisphosphonates for prevention of hip fractures with risk of bias assessed using
Cochrane risk of bias tool (see appendix 2 on thebmj.com for reference details) For personal use only: See rights and repr

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05wang 77.85

The Journal of Mental Health Policy and EconomicsJ Ment Health Policy Econ 7, 77-85 (2004) Should Clozapine Continue to be Restricted to Third-Line Status for Schizophrenia?: A Decision-Analytic Model Philip S. Wang,1* David A. Ganz,2 Joshua S. Benner,3 Robert J. Glynn,4 Jerry Avorn5 1MD, DrPH, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine,


Preventive journalism A media and coverage of professional's risk situations avian influenza ANDI ANDI LATIN AMERICAN NETWORK UNICEF Preventive journalism A media and coverage of professional's risk situations avian influenza ANDI – BRAZILIAN NEWS AGENCY FOR PREVENTIVE JOURNALISM AND COVERIAGE OF RISK SITUATIONS