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Rapid Responses: Rapid Responses published:
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Oral bisphosphonates: prevention of osteoporotic fracture or disease mongering?
- Dr. Basavaraj Shivayogi Hadapad (15 March 2008)
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Re: Oral bisphosphonates: prevention of osteoporotic fracture or disease mongering?
- Ellen CG Grant (15 April 2008)
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Clarification of zoledronic acid and atrial fibrillation
- Erik F Eriksen (2 June 2008)
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Dr. Basavaraj Shivayogi Hadapad, Associate Professor of Ayurveda Katurba Medical College, Manipal University, Manipal. India, 576104
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Dear Editor, accepting post menopausal osteoporosis as a disease is ethically and scientifically complex. Diagnostic criteria set by the World Health Organization considers bone density of young white women as "normal" and judge the bones of older women against this standard, which is questionable. A WHO meeting to define diagnosis of osteoporosis was funded in part by three pharmaceutical companies to conceptualize asymptomatic, age related physiologic change as a disease. This disease diagnostic criteria automatically makes healthy post menopausal women as “diseased” because their bones are being compared with those of much younger women! Asymptomatic postmenopausal women are treated with HRT without knowing through what mechanism hormones act, for prevention and cure of chronic diseases including osteoporosis and osteoporotic fractures based on very poor evidence of benefits. Use of HRT has increased among postmenopausal women in western countries. As estimated 20 million women world wide were using it in the late 1990’s. Sir George Pickering, professor of medicine at the Oxford and John's Hopkins Universities, once said about drug treatment of asymptomatic mild- moderate high blood pressure patients: "the patient loses the rights enshrined in the preamble to the American Constitution written in 1772 by Thomas Jafferson, of life, liberty, and pursuit of happiness." Antihypertensive drugs "may or may not change his longevity; liberty he hardly could have what with all the restrictions put on him, and happiness becomes a thing of the past," which happens in postmenopausal women too. Professor Wadel and his team in a meta-analysis of 11 separate study populations and over 2000 fractures published in British Medical Journal concluded that bone mineral density "cannot identify individuals who will have a fracture." The relation between bone density and fracture risk is also the subject of scientific controversy and it is not accurate predictor of risk of fracture in individual to be used as a guide to therapy - oral bisphosphonates. Ayurveda: Traditional Indian medical wisdom does not explain asymptomatic condition as a disease and treat. Age related physiological change like menopause in women and asymptomatic low bone density is considered as natural phenomenon that is called “swabhavika”. Any intervention against non linear body’s physiology causes complications not only atrial fibrillation. Predicting epidemics of diseases in general and osteoporotic fracture in particular are brought on by the medical business to scare the common man! In an editorial do epidemiologists cause epidemic? The Lancet brings out the truth. Let us, instead, concentrate on doing maximum good to the suffering humanity. References: 1. Green C, Bassett K, Foerster V, Kazanjian A. Bone mineral density testing: does the evidence support its selective use in well women? Vancouver, BC: British Columbia Office of Health Technology Assessment, 1997. 2. Stephen R. Rapp, Mark A. Espeland, Sally A. Shumaker, Victor W. Henderson, Robert L. Brunner, JoAnn E. Manson, Margery L. S. Gass, Marcia L. Stefanick, Dorothy S. Lane, Jennifer Hays, Karen C. Johnson, Laura H. Coker, Maggie Dailey, Deborah Bowen, for the WHIMS Investigators. Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women. JAMA 2003; 289: 2673-2684 3. Terence J Wilkin. Changing perceptions in osteoporosis.BMJ 1999; 318:862-865 4. Deborah Marshal, Olof Johnell, Hans Wadel. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254-1259 Competing interests: None declared |
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Ellen CG Grant, Physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU
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What connects osteoporosis, atrial fibrillation, adverse effects of HRT and alcohol? A simple answer is deficiencies of zinc and magnesium which are universally common and impair hundreds of enzyme systems. Rather than rush to give hormones (which are listed as Group 1 highest level carcinogens by WHO) or other drugs with unwanted side- effects, it would be much more useful to make essential nutrient analyses readily available in the NHS. It would also be wonderful to stop claiming that either alcohol drinking or hormone use is beneficial. Such claims are mostly based on flawed interpretations of epidemiological studies. 1 Mutlu M, Argun M, Kilic E, Saraymen R, Yazar S. Magnesium, zinc and copper status in osteoporotic, osteopenic and normal post-menopausal women. J Int Med Res. 2007 Sep-Oct;35(5):692-5. 2 McLaren-Howard J. Grant ECG, Davies S. Hormone replacement therapy and osteoporosis: bone enzymes and nutrient imbalances. JNEM 1998;8:129- 138. 3 Sleeswijk ME, Tulleken JE, Van Noord T, Meertens JH, Ligtenberg JJ, Zijlstra JG. Efficacy of magnesium-amiodarone step-up scheme in critically ill patients with new-onset atrial fibrillation: a prospective observational study. J Intensive Care Med. 2008 Jan-Feb;23(1):61-6. 4 Marcus GM, Smith LM, Whiteman D, Tseng ZH, Badhwar N, Lee BK, Lee RJ, Scheinman MM, Olgin JE. Alcohol intake is significantly associated with atrial flutter in patients under 60 years of age and a shorter right atrial effective refractory period. Pacing Clin Electrophysiol. 2008 Mar;31(3):266-72. 5 Elisaf M, Merkouropoulos M, Tsianos EV, Siamopoulos KC. Pathogenetic mechanisms of hypomagnesemia in alcoholic patients. J Trace Elem Med Biol. 1995 Dec;9(4):210-4. Competing interests: None declared |
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Erik F Eriksen, Global Brand Medical Director Novartis Pharma AG, CH-4002 Basel
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We would like to respond to the editorial by Sumit Majumdar entitled ‘Oral bisphosphonates and atrial fibrillation’,[1] in which the manufacturers of zoledronic acid are invited to allay concerns about the observation in one clinical trial (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly [HORIZON] Pivotal Fracture Trial [PFT])[2] of an apparent association between intravenous administration of zoledronic acid and increased incidence of atrial fibrillation serious adverse events (SAEs). It should be noted that the overall incidence of new-onset atrial fibrillation in this trial was not significantly different between the zoledronic acid and placebo groups (2.4% vs. 1.9%; P=0.12).[2] In the same issue of the New England Journal of Medicine as the HORIZON-PFT publication,[2] a similar, albeit non-significant, association of serious atrial fibrillation was reported by Cummings et al with oral alendronate (alendronate, 1.5%; placebo, 1.0%; P=0.07).[3] Merck later released all their atrial fibrillation data on their website and disputed any relationship, and later publications have also refuted any association between oral bisphosphonate use and new-onset atrial fibrillation.[1,4–6] As Majumdar indicated, the majority of patients eligible for bisphosphonate therapy are at increased risk of atrial fibrillation,[1] so it is important to explore a potential for increased risk with any medication used in these patients. A causal relationship between zoledronic acid and onset of atrial fibrillation is, however, unlikely for several reasons. Firstly, bisphosphonates are cleared rapidly from the circulation via renal excretion. So, the myocardium would only be exposed to zoledronic acid 2–3 days after the infusion every year. Secondly, zoledronic acid has no known mechanistic properties that are associated with cardiac arrhythmia, and no adverse cardiovascular effects were observed during preclinical toxicology trials of up to 18 months in three different animal species (unpublished data; Novartis). Moreover, a recent randomised, placebo-controlled trial involving annual intravenous administration of zoledronic acid to patients after surgical hip fracture repair found no evidence of an association between active treatment and increased incidence of atrial fibrillation (zoledronic acid, 2.8%; placebo, 2.6%; P=0.79), or atrial fibrillation as an SAE (zoledronic acid, 1.1%; placebo, 1.3%; P=0.84).[7] Note that this trial population had a higher baseline risk of hypertension, atherosclerosis, and tachyarrhythmias than the HORIZON-PFT population (unpublished data; Novartis),[2,7] and therefore was at higher risk of treatment-emergent atrial fibrillation. As there is no evidence that induction of atrial fibrillation is a class effect of bisphosphonates,[1,5,6] the editorial suggested that the onset of atrial fibrillation might be related to events occurring secondary to intravenous bisphosphonate administration, such as transient hypocalcaemia or increased proinflammatory cytokine release, which manifest as so-called post-dose symptoms, seen in a proportion of patients mainly after intravenous bisphosphonate administration. However, these mechanisms are not supported by the timing of atrial fibrillation onset. For example, in 94% of the zoledronic acid-treated patients who developed atrial fibrillation SAEs, onset occurred more than 30 days after infusion,[2] when no circulating drug is detectable. Moreover, post-hoc analysis of data from the HORIZON-PFT trial has shown that patients with atrial fibrillation SAEs did not have more electrolyte disturbances than placebo-treated patients. Also, no association between post-dose symptoms and risk of atrial fibrillation was established. In fact, the incidence of atrial fibrillation was actually higher in patients who did not develop post-dose symptoms than in those who did (unpublished data; Novartis). The existence of an acute adverse effect of zoledronic acid infusion on cardiac rhythm is also refuted by electrocardiographic (ECG) data: in the HORIZON-PFT study, ECG measurements performed on 559 patients before and 9–11 days after treatment showed a higher incidence of atrial fibrillation in the placebo group than in those receiving zoledronic acid (2.8% vs. 2.1%).[2] As the HORIZON-PFT data demonstrated an association of zoledronic acid with atrial fibrillation SAEs, but not with overall incidence, the influence of adverse event classification on this finding should also be considered. For example, 90% of patients reported as having serious atrial fibrillation were patients admitted to hospital due to tachyarrhythmia (unpublished data; Novartis). Since hospital admission automatically generated a record of ‘serious adverse event’ it is possible that the criteria for classification of SAEs may underlie this finding. Recent independent reviews provide further reassurance on this issue. For example, in a recent review by the Food and Drug Administration (FDA) of spontaneous post-marketing reports of atrial fibrillation occurring in association with oral and intravenous bisphosphonate use, they were unable to identify a population of bisphosphonate users at increased risk of the condition, and recommended that the use of bisphosphonates should continue without modification.[5] A detailed review by the FDA of the relationship between bisphosphonates and AF is ongoing. To further elucidate any possible association of atrial fibrillation with bisphosphonate treatment, Novartis plans to perform an ECG telemetry study, which will monitor cardiac function at various timepoints up to 1 year after zoledronic acid infusion. The results of these investigations will clarify the relationship between bisphosphonate administration and atrial fibrillation. Erik Fink Eriksen, MD DMSc
References 1. Majumdar SR. Oral bisphosphonates and atrial fibrillation. BMJ 2008;336:784-5. 2. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-22. 3. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007;356:1895-6 [letter]. 4. Karam R, Camm J, McClung M. Yearly zoledronic acid in postmenopausal osteoporosis. N Engl J Med 2007;357:712 [letter]. 5. Food and Drug Administration. Early Communication of an Ongoing Safety Review. Available at: http://www.fda.gov/Cder/Drug/early_comm/bisphosphonates.htm. Site accessed April 22nd, 2008. 6. Sørensen HT, Christensen S, Mehnert F, Pedersen L, Chapurlat RD, Cummings SR, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008;336:813-6. 7. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799-809. Competing interests: I am an employee of Novartis Pharma AG |
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