Oral bisphosphonates and atrial fibrillationBMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39513.481065.80 (Published 10 April 2008) Cite this as: BMJ 2008;336:784
All rapid responses
We would like to respond to the editorial by Sumit Majumdar entitled
‘Oral bisphosphonates and atrial fibrillation’, 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]) 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). In the same issue of the New England Journal of Medicine as
the HORIZON-PFT publication, 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). 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
As Majumdar indicated, the majority of patients eligible for
bisphosphonate therapy are at increased risk of atrial fibrillation, 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different animal species (unpublished data; Novartis).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). 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
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, 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.
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. 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
Erik Fink Eriksen, MD DMSc
Global Brand Medical Director
Novartis Pharma AG,
1. Majumdar SR. Oral bisphosphonates and atrial fibrillation. BMJ
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
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
I am an employee of Novartis Pharma AG
Competing interests: No competing interests
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-
3 Sleeswijk ME, Tulleken JE, Van Noord T, Meertens JH, Ligtenberg JJ,
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: No competing interests
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
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,
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;
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: No competing interests