Bisphosphonates May Spur AF via Inflammation


MONT TREMBLANT, QUE. — An inflammatory mechanism may be responsible for the atrial fibrillation that occurs in some patients following the intravenous administration of potent bisphosphonates, Dr. Jason Roberts reported in a poster session at the annual meeting of the Canadian Rheumatology Association.

In a pivotal trial of once-yearly zoledronic acid for the prevention of postmenopausal osteoporosis that randomized 7,765 women to annual infusions of active drug or placebo for 3 years, serious atrial fibrillation (AF) was seen in 1.3% of women in the zoledronic acid group compared with 0.5% of those in the placebo group.

This difference was statistically significant (N. Engl. J. Med. 2007;356:1809–22).

A letter accompanying the published study noted that a similar but nonsignificant trend had been observed in an earlier trial of alendronate. The letter stated, “Parenteral administration of bisphosphonates stimulates the release of inflammatory cytokines and increased levels of inflammatory cytokines have been associated with an increased risk of atrial fibrillation” (N. Engl. J. Med. 2007;356:1895–6).

To explore a potential connection between bisphosphonate administration and AF, a comprehensive literature review was undertaken and yielded certain mechanistic insights, according to Dr. Roberts of the University of Toronto.

“AF, once thought to be an electrical problem, is increasingly being viewed as an inflammatory condition associated with important structural changes,” Dr. Roberts wrote.

Patients with AF have increased levels of inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α, and C-reactive protein. Atrial biopsies consistently show inflammatory changes, including myocyte necrosis and fibrosis.

The principal action of bisphosphonates is inhibition of osteoclastic bone resorption, but the potent nitrogen-containing aminobisphosphonates such as zoledronic acid, alendronate, pamidronate, risedronate, and ibandronate also have proinflammatory effects, with an acute phase reaction characterized by fever and flulike symptoms occurring following a first treatment with these drugs in more than one-third of patients (Clin. Exp. Immunol. 2005;139:101–11).

This response reflects the activation and proliferation of a subset of T cells referred to as gamma-delta T cells, according to Dr. Roberts.

Another effect of aminobisphosphonates is the inhibition of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, which is the biosynthetic route for the production of cholesterol (Ann. N.Y. Acad. Sci. 2006;1068:367–401).

Inhibition of FPPS results in accumulation of upstream metabolites including isopentenyl-5-pyrophosphate, which, like the aminobisphosphonates, directly activate gamma-delta T cells.

“Interestingly, statins, which inhibit an enzyme further upstream of IPP in the mevalonate pathway, have been shown to negate the proinflammatory effects of aminobisphosphonates,” Dr. Roberts wrote.

Given the observations that aminobisphosphonates have proinflammatory effects and that AF is an inflammatory condition, it is “reasonable” to postulate that aminobisphosphonates may increase the risk of AF through an inflammatory mechanism mediated via the mevalonate pathway, he noted.

If this turns out to be the case, the proinflammatory state associated with AF potentially could be prevented by statin therapy, he wrote.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also have shown promise in modulating these inflammatory effects, although neither of these drugs nor any of the statins are currently recommended for the sole purpose of preventing AF (J. Am. Coll. Cardiol. 2007;50:2021–8).


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