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Rapid Responses: Rapid Responses published:
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Drugs for pre-osteoporosis: an example of prejudice-based medicine?
- Juliet E Compston, Alun Cooper, Cyrus Cooper, Roger Francis, John Kanis, Eugene McCloskey, David Reid, Peter Selby for the National Osteoporosis Guideline Group (10 February 2008)
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Osteoporosis is not a controversial condition
- Ego Seeman, Pierre Delmas (15 February 2008)
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More disease mongering?
- Onisillos Sekkides (20 February 2008)
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Osteoporosis is a disease which can be treated
- Rene RIZZOLI, Jean-Yves Reginster (28 February 2008)
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Drugs for pre-osteoporosis: prevention or disease mongering?
- Pablo Alonso-Coello, Gordon Guyatt, Alberto Lopez (6 March 2008)
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Drugs for pre-osteoporosis: prevention or disease mongering?
- Ray Moynihan (6 March 2008)
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Excellent Paper
- Robert Marx, 9380 SW 150th Street, #170, Miami, FL 33176 (7 March 2008)
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Juliet E Compston, Professor of Bone Medicine University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, Alun Cooper, Cyrus Cooper, Roger Francis, John Kanis, Eugene McCloskey, David Reid, Peter Selby for the National Osteoporosis Guideline Group
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Dr Alonso-Coello and colleagues attack industry and some health care professionals for advocating bone protective therapy for women with osteopenia. In putting their case they reveal their ignorance of major advances that have occurred in the prediction of fracture risk, in particular the utility of clinical risk factors in improving fracture risk prediction. The majority of women who suffer a fragility fracture do not have osteoporosis as defined by a bone mineral density T-score below -2.5 SD,1 and one reason for this is that many women have clinical risk factors that increase fracture risk independently of bone mineral density.2 Hence, a woman with osteopenia (a term that covers a wide range of bone densities) may have a higher fracture probability than one with a T score below -2.5 SD.. The recommendation by the authors that treatment decisions should be based on the assessment of absolute risk of fracture is hardly a revelation; similar statements by experts in the field can be found in numerous publications over the past 5 years and this strategy forms the basis of current European guidelines and of the forthcoming WHO report and risk algorithm. Investigation of the ability of drug therapies to reduce fracture incidence in high risk women, regardless of whether they have osteopenia or osteoporosis, has necessitated the analyses that are so maligned by Alonso-Coello and colleagues. Other misconceptions and inaccuracies must also be mentioned. Whilst there may have been isolated examples of inappropriate marketing, there is widespread acceptance among health care professionals for the need to incorporate cost-effectiveness into decisions about treatment and, as acknowledged by the authors, treatment of women at high risk of fracture is cost-effective.3 The description of the “rare but catastrophic osteonecrosis of the jaw” as a side-effect of oral alendronate therapy is scare-mongering and unbalanced; a causal relationship between oral bisphosphonates in the doses used for osteoporosis and osteonecrosis of the jaw has not been firmly established.4 Finally, potential conflicts of interest exist in many forms: personal prejudices, as well as financial incentives can be a barrier to objectivity. For those of us fortunate enough to have been involved in osteoporosis research and patient care over these last two decades, the emergence of technologies for non-invasive assessment of bone mass and of a range of effective therapeutic options has heralded a revolution in care for what was previously regarded as an inevitable consequence of aging. Indeed, the pace of these advances and their translation to improving human health has resulted in more rapid progress in management than that seen in cardiovascular disease and diabetes mellitus. Furthermore, the health economic basis for appropriate utilisation of these translational discoveries is established and provides a rational use of scarce healthcare resources. At a time when governmental research agencies such as the MRC and NIHR are calling for translation of medical research to improve human health, it seems anachronistic for our national medical journal to be espousing the view that such research, honestly undertaken, simply represents the end-product of an unholy alliance between corporate giants and unethical investigators. The tone and content of the analysis by Dr Alonso-Coello and colleagues does a disservice both to sufferers from the disease and to those in the field who strive to reduce the enormous mortality and morbidity attributable to osteoporotic fractures. 1. Siris ES, Chen YT, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:1108-12. 2. Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J et al.The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007;18:1033-46. 3. Kanis JA, Adams J, Borgström F, Cooper C, Jönsson B, Preedy D et al. The cost-effectiveness of alendronate in the management of osteoporosis. Bone. 2008;42:4-15. 4. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D et al for the American Society for Bone and Mineral Research. Bisphosphonate- associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-91. Competing interests: Prof Compston has received payment for consultancy work and/or speaking engagements from Procter & Gamble, Eli Lilly, GSK/Roche, Amgen, Pfizer, Servier, Shire, Novartis, Nycomed and Wyeth and has been reimbursed for attending scientific conferences by Procter & Gamble, Eli Lilly, and Servier. She receives funding for a grant from Procter & Gamble and Servier and has acted as an expert witness in several cases of glucocorticoid-induced osteoporosis and in an alendronate patent dispute. |
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Ego Seeman, Professor of Medicine Austin Health, University of Melbourne, Australia, Pierre Delmas
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Contrary to the view expressed by Alonso-Coello et al, osteoporosis is not controversial for those who suffer its consequences - fracture. Bone mineral density (BMD) is a continuous variable (like blood pressure, serum cholesterol and body weight) that confers a gradient of risk; the lower the BMD, the higher the risk of fracture (1,2). However, BMD is normally distributed. There are many more individuals within the 'bell' of the bell shaped curve of BMD than in the tails of its distribution so, in numerical terms, most of the population burden of fractures (numbers, morbidity, mortality cost) arise from the large number of individuals at modest risk with BMD between - 1 and -2.5 SD (osteopenia) rather than from the smaller numbers at high risk (osteoporosis). Reducing this disease burden among the many at moderate risk has been eloquently written about by Professor G Rose many years ago (3,4). This is indeed a challenge because of concerns of exposing many individuals to the uncommon adverse events. However, there is progress. Patients with osteopenia with a fracture are at higher risk for fracture than patients with osteoporosis alone (5). Persons with osteopenia coming to sustain fractures have structural abnormalities that can be detected using high resolution quantitative computed tomography while those with high bone remodeling are also at higher risk for fracture. These persons can be identified (6) and drugs have now been shown to be effective in reducing fracture risk (5). No one is suggesting that all women with osteopenia should be treated. Quite the contrary, efforts by the WHO led by Professor J Kanis to use absolute risk to target treatment to those who need it while avoiding needlessly exposing those at low risk is of highest priority. Alonso-Costello et al trivialize the important public health problem of fragility fractures in the title of their paper and in almost every paragraph that follows. Emotive language is not evidence. To suggest that declaration of potential conflict of interest is evidence of collusion, “entwined”ť collaborations motivated by self serving interests is demeaning, for the authors they insult, and to themselves. We are all accountable for words we use, including these authors. 1. Siris ES, Chen YT, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, Berger ML 2004 Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108-1112. 2. Sanders K, Nicholson G, Watts J, et al. 2006 Half the Burden of Fragility Fractures in the Community Occur in Women Without Osteoporosis. When Is Fracture Prevention Cost Effective? Bone 38:694-700. Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD 2005 Identification of Osteopenic Women at High Risk of Fracture: The OFELY Study. J Bone Miner Res 20:1813-1819. 3. Rose G. Sick individuals and sick populations. Int J Epidemiol 1985;14:32-8. 4. Rose G. The strategy of preventative medicine. New York: Oxford Univ. Press; 1992. 5. Seeman E, Devogelaer J, Lorenc R, Spector T, Brixen K, Balogh A, et al. Strontium ranelate reduces the risk of vertebral fractures in patients with osteopenia J Bone Miner Res 2007 Ego Seeman
Pierre Delmas
Competing interests: Dr Delmas has received consultant / speaker fees from Amgen, GSK, Eli Lilly, MSD, Novartis, Nycomed, Procter and Gamble, Roche, Sanofi-Aventis and UCB. Dr Seeman is medical advisory committee member with MSD, Servier, Eli Lilly, Proctor and Gamble, Sanofi Aventis, Novaritis. Speaker at national and international meetings with some of these companies from time to time. |
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Onisillos Sekkides, Editor London, NW1
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Could people stop pretending that the pharma industry doesn't undertake "market shaping" for its products prior to launch, and even after launch. There are no end of "medical education" agencies that will openly admit this is what the do for their clients. Competing interests: None declared |
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Rene RIZZOLI, Head, Division of Bone Diseases, Chairman, Department of Rehabilitation and Geriatrics Geneva University Hospital and Faculty of Medicine, 1211 Geneva 14, Switzerland, Jean-Yves Reginster
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28 February 2008 Dear Sir, By stating that drug marketing is being directed at women with osteopenia and thus at those with only a low risk of fracture, Alonso-Coello and colleagues are simply misinterpreting the significant advances in the management of osteoporosis which have occurred over the last few years (1). Indeed, 1. At the age of 50, one out of 2 women and one out 5 men are at risk of fracture for the rest of their life; thus, osteoporosis cannot be considered as a controversial issue (2). 2. Just as stroke can occur in normotensive subjects, inferring factors other than blood pressure are involved, fracture is not restricted to DXA- diagnosed osteoporosis. Indeed, this technique on which the diagnosis is based does not capture all determinants of bone fragility. This highlights the need to move toward a fracture risk-based intervention threshold, to identify patients at increased risk of fracture and to target them for efficacious therapy (2). 3. Most of the registered treatments are associated with a greater than 50% reduction in vertebral fracture risk. Considering this high efficacy of treatment in patients with increased fracture risk, a cost-effective management is likely to be achieved due to the low number of patients needed to be treated to avoid one fracture (3). 4. All drugs have possible side effects. The risk/benefit ratio will be determined by the risk of side effects. For instance, with a risk as low as 1/ 100'000 for osteonecrosis of the jaw, the ratio is likely to be favorable for bisphosphonates (4). We disagree with Alonso-Coello and colleagues if they imply that a disease is promoted in otherwise healthy subjects. Osteoporosis is a debilitating disease, associated with significant morbidity and increased mortality. The aim of osteoporosis management is thus: 1. to identify patients at increased risk of fracture; 2. to allow them to benefit from efficacious available treatments, and 3. to thereby decrease the burden of the disease. By doing so, we are not exposing patients who are at low risk of fracture to the possibility of dangerous side effects. René Rizzoli, MD, Professor of Medicine, Head, Division of Bone Diseases, WHO Collaborating Center for Osteoporosis Prevention, Chairman, Department of Rehabilitation and Geriatrics, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland, <Rene.Rizzoli@medecine.unige.ch> Jean-Yves Reginster, MD, Professor of Medicine, President of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO,) Chairman, School of Public Health Sciences, University of Ličge, Ličge, Belgium 1. Alonso-Coello P, Garcia-Franco AL, Guyatt G, Moynihan R. Drugs for pre- osteoporosis: prevention or disease mongering? Bmj 2008;336(7636):126-9. 2. Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008;doi: 10.1007/s00198-008 -0560-z. 3. Delmas PD, Rizzoli R, Cooper C, Reginster JY. Treatment of patients with postmenopausal osteoporosis is worthwhile. The position of the International Osteoporosis Foundation. Osteoporos Int 2005;16(1):1-5. 4. Rizzoli R, Burlet N, Cahall D, Delmas PD, Fink EF, Felsenberg D, et al. Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone 2008;doi:10.1016/j.bone.2008.01.003. Competing interests: None declared |
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Pablo Alonso-Coello, Researcher Iberoamerican Cochrane Center-Department of Clinical Epidemiology and, Gordon Guyatt, Alberto Lopez
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We have read with interest the letters from Dr. Compston et al on behalf of the National Osteoporosis Guideline Group, Dr. Seeman and Dr. Rizzoli. Both Dr. Compston and Dr. Seeman note that most fractures occur in women who do not have osteoporosis. Dr. Seeman further notes "Reducing this disease burden among the many at moderate risk has been eloquently written about by Professor G Rose many years ago". Dr. Rizzoli states that the goal of management is to “to identify patients at increased risk of fracture” and “to to allow them to benefit from efficacious available treatments” without specifying the absolute risk of fracture to which he is referring. Such statements are easily interpreted as support for widespread treatment of very large numbers of woman at "moderate risk" - women who are at very low risk in absolute terms. Dr. Compston's, Seeman's and Rizzoli’s letters provide safeguards against such interpretation; the material we reviewed did not Dr. Compston accuses us of ignorance of risk models of osteoporosis. When she subsequently acknowledges that we are in fact quite aware of risk assessment and the desirability of treating only those at highest absolute risk she accuses us of failing to provide a revelation. We plead guilty of failure to provide a revelation, but not to the charge of ignorance. Dr. Compston accuses us of scare-mongering by mentioning the possibility of osteonecrosis of the jaw. This rare but serious side-effect is acknowledged as causally linked to alendronate in the web of the National Osteoporosis Foundation that Dr. Compston represents (1). Is she suggesting that occurrence of rare and serious side effects (even if absolute proof of causation is unavailable) should not be included in the balance when considering desirable and undesirable consequences of treating women "at risk"? We hope not. Our intention is not to trivialise the problem of fragility fractures but to point out that the population at risk of being medicalised by being labelled “osteopenic” is growing. The problems with the reanalyses we examined include increasing the likelihood of women, without their prior consent, receiving first a label of “at risk”, and subsequently of receiving a treatment that, given full information delivered in an unbiased way, they would not choose. We agree with Dr. Seeman that the absolute risk algorithm developed by the WHO will, if adhered to, avoid the exposure of low risk women to unnecessary interventions. Nevertheless, even “high risk” women are at low absolute risk. There is a psychological cost to labelling a woman as “high risk”. Indeed, many women are likel to be disinclined to take a medication the appropriate duration of which has not been established, associated with cost, inconvenience and side effects (some potentially serious) for a small absolute risk reduction. The women will nevertheless be left carrying the label of “at risk”. If the industry and osteoporosis researchers funded by the industry are scrupulous in recommending that only women with clinical risk factors undergo bone mineral density testing, that only those at highest risk following testing be labelled "at risk", and that those highest risk women be presented with a balanced case on the desirable and undesirable consequences of treatment (with, for instance, a well-constructed decision aid) we would have no problem. In the articles and advertisements that we addressed, we have seen no evidence of such scrupulousness. Pablo Alonso-Coello, Gordon Guyatt, Alberto Lopez
Competing interests: None declared |
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Ray Moynihan, Cojoint lecturer Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia
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My clinical colleagues have dealt adequately in their reply with the only alleged inaccuracy in our article, which we respectfully suggest is not an inaccuracy at all. As a writer, rather than a clinician, I would ask that in the interests of a more informed public debate about fractures, Professors Compston, Seeman and Delmas might use their no doubt considerable influence with the dozen or so drug companies to which they have collectively declared competing interests, and request that all internal documents, both contemporary and historical, relating to the marketing of all osteoporosis drugs be made publicly available. Obviously certain commercial-in-confidence material would appropriately need to be removed before such documents were released publicly. However, it is possible that such marketing documents would include accounts of how those companies work with what they call “key opinion leaders”, to try and inform public and clinical opinions towards their products, and the relevant disease states. I look forward to hearing of the outcome, if any such request is put to any of the relevant pharmaceutical companies. Competing interests: None declared |
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Robert Marx, Professor of Surgery and Chief University of Miami Miller School of Medicine, 9380 SW 150th Street, #170, Miami, FL 33176
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Gentlemen: Congratulations on your excellent paper "Drugs for Pre-Osteoporosis: Prevention or Disease Mongering "BMJ 2008:336:126-129. You are very correct to expose the overt influence bisphsohonate drug companies have had in the prescribing practices of physicians throughout the world and how their drug company supported studies have messaged the data to embelish results beyond real therapuetic value. As the oral and maxillofacial surgoen who first described Bisphosphonate Induced Osteonecrosis of the Jaws (BIONJ), 65% of our patients with such exposed bone often with secondary infection were taking mostly alendronate for "pre-osteoporosis". If any of our data base is of interst to you, please do nto hesitate to contact me at rmarx@med.miami.edu. Sincerely, Competing interests: None declared |
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