Drug Safety

A spring evening back in May 1996 was Does Fosamax cause dead jaw syndrome? something of a high point for the folks at the In 2004, following a growing numbers of Battle global drug company Merck. Three Ameri- reports that associated dead jaw and intra- can television networks ran news ­stories cel- venous used for ebrating Merck’s latest blockbuster to fight treatment and the oral versions, including brittle bones—Fosamax, whose generic name alendronic acid, taken for , the over is alendronic acid (or alendronate sodium). United States Food and Drug ­Administration Reporters told tens of millions of ­viewers released a safety review which found that that the recently approved drug could cut the there may be a “class effect” and urged risk of a hip fracture in half, and one report changes to product labels.2 In 2005 Merck Fosamax described this as “almost miraculous.”1The added new wording to its Fosamax label, televangelism proved both efficacious and though the plaintiff’s lawyers say the word- prophetic: in the years since, the drug became ing was inadequate. Whether the association one of Merck’s top selling products, with sales is a causal one has been a source of increasing bursts in excess of $3bn (£1.8bn; €2.1bn) annually controversy within the medical literature in for several years during the past decade. recent years,3 made more complicated by the closeness of many leading doctors to the drug Fosamax on trial for the first time manufacturers. into Next week, in a district court room not too far A 2007 task force of the American Society away from those same network studios, Merck for Bone and Mineral Research concluded is scheduled to face the first trial involving its that although the association with the condi- court golden goose alendronic acid before Judge tion is “consistent with a role” for bisphos- John Keenan of the southern district of New phonates, they have “not been proven to York. Approximately 800 cases have been be causal.”4 Three quarters of the authors A New York judge has consolidated into a mass action, with plaintiffs from the task force disclosed financial ties to revealed internal Merck claiming that ­alendronic acid caused them to multiple drug companies, including Merck. suffer a rare condition called osteonecrosis of A 2008 Canadian consensus guideline from discussions about a possible the jaw, or dead jaw syndrome, and Merck oral surgeons concluded “a direct causal link failed to properly warn them of this devastat- has not been established.”5 This time more link between its widely ing ­complication. A company spokesperson than a third of the authors declared conflicts prescribed drug and dead has told the BMJ that Merck is vigorously of interest: the lead author has worked as a defending the action, arguing there is no proof consultant to six drug companies including jaw syndrome, finds of a causal link between the drug and the jaw Merck, and one author declared links to more Ray Moynihan condition, and that timely and appropriate than 12 companies. information about its drug has been provided Partly on the basis of these guidelines, to ­consumers and to the medical, scientific, Merck has argued strongly in pretrial filings and regulatory communities. that a causal link is not proved and that expert One of the first cases scheduled to be tried testimony to this effect from the plaintiff’s side involves Shirley Boles, a woman from ­Florida should be disallowed at trial. However, in a in her 70s who was first prescribed alendronic ruling that ran to over 100 pages, released acid in 1997 and continued taking it for almost late in July, Judge John Keenan ruled that a decade. According to documents filed with testimony on causation from key experts the court, after the extraction of two teeth in would be allowed, as long as it was not pre- 2002, Ms Boles had to undergo major oral sented as scientifically certain. “Their theory surgery, and she has developed persistent on the mechanism of causation is generally infections and exposed bone in her jaw that accepted as biologically plausible,” the judge have not healed for many years. wrote.6 He also ruled it was not the court’s Ms Boles’s symptoms are consistent with role to determine causation in this case, but what is now widely accepted as the signs the jury’s. of , and Merck has Discussing the plausibility of a link between received more than 1000 reports of people the widely prescribed bone drug and the rare claiming to have the condition. What is in dead jaw syndrome, Judge Keenan cited dispute is whether Merck’s drug is the cause. other expert bodies that support a possible The company’s outside counsel, Paul Strain, causal link, including the American Dental says Shirley Boles has a history of smoking Association.7 and medical problems that cause people to Importantly, the judge also referred three develop jaw problems. “The evidence will times to internal Merck documents and show that Ms Boles would have experienced ­comments by one of Merck’s own scientists, a dental and jaw-related problems whether she Dr Kimmel. At one point in the judge’s ruling, took Fosamax or not.” he revealed details of internal Merck emails:

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“In internal emails in 2005, Dr Kimmel wrote ­condition was “essentially zero,” except for to reach its sales targets and projected prof- that the reduction of bone remodelling is likely cases associated with radiation and a few seri- its for Fosamax, Merck recognized it had to reduce the jaw’s natural ability to heal, and ous diseases. “The prevalence rates found to expand the market for Fosamax beyond that placing too much of a healing demand on among persons with osteoporosis offer circum- osteoporotic women” by “shifting the treat- them in patients treated with bisphosphonates stantial support for the view that oral bisphos- ment threshold.”12 The document goes on to can lead to the death of jaw bone.”6 phonates increase the risk,” he wrote.6 provide evidence for this claim by referring A spokesperson to several of Merck’s internal marketing and for Merck told the A healthy business plan presentations. However the BMJ that Dr Kim- risk-benefit ratio? next page and a half of the document, where mel had examined Leaving aside the details of the internal marketing plans are dis- various theories potential risk of dead cussed, have been redacted under order of about the aetiology jaw syndrome, alen- the court—blanked out by thick black ink. of osteonecrosis of the dronic acid carries well Hopefully, once the trial begins in the New jaw, and that “emails established gastrointes- York court room, and the jury weighs the from Dr Kimmel can tinal side effects, with evidence from both sides, a lot of that black easily be taken out of its label stating “Some ink will be removed, the details of influential context in a litigation patients may develop marketing strategies will be made public, and setting.” In addition, severe digestive reac- a lot more light will be shone on the true risks the company’s gen- tions including irrita- and benefits of a class of drugs that has been eral counsel, Bruce tion, inflammation, prescribed more than 225 million times. N Kuhlik, said Merck or ulceration of the Ray Moynihan visiting editor, BMJ , Melbourne, had acted responsibly .”10 On Australia [email protected] in researching and the benefit side of Competing interests: None declared. In a ruling that ran to over 1 Moynihan R, Bero L, Ross-Degnan D , Henry D, Lee monitoring Forsamax, the equation, while K, Watkins J, et al. Coverage by the news media of conducting clinical 100 pages, Judge John Keenan media and market- the benefits and risks of . N Engl J Med trials involving more ing materials often 2000;342:1645-51, ruled that testimony on 2 Department of Health and Human Services, Public than 28 000 people. enthusiastically frame Health Service, Food and Drug Administration. 25 August Importantly, the causation from key experts risk reductions in rela- 2004. ODS post-marketing safety review. 3 Landis B, Richter M, Dojcinovic I, Hugentobler judge’s ruling also car- would be allowed tive terms, absolute M. Osteonecrosis of the jaw after treatment with ried some good news reductions are much bisphosphonates is irreversible, so the focus must be on prevention. BMJ 2006;333:982-3. for Merck: the judge restricted the nature of smaller. As a Cochrane review points out, 4 Khosla S, Burr D, Cauley J, Dempster D, Ebeling PR, the evidence that could be offered in court by while trials suggest that alendronic acid can Felsenberg D, et al. -associated osteonecrosis of the jaw: report of a task force of the several of the plaintiff’s nominated experts. reduce hip fractures by one half, in ­absolute American Society for Bone and Mineral Research. J Bone terms it is a reduction from 2% to 1%.11 Miner Res 2007;22:1479-91. 5 Khan AA, Sandor GKB, Dore E, Morrison AD, Alsahli M, How widespread is dead jaw syndrome? ­Moreover, because this drug is approved to Amin F, et al. Canadian consensus practice guidelines for Alongside the controversy about causality, treat and prevent osteoporosis—a condition bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2008;35:1391-7. several surveys have emerged offering tenta- which is basically a risk factor for future frac- 6 Document #4, Judge Daubert ruling. “Opinion and tive suggestions of the prevalence of this rare ture—it has been marketed to many relatively Order”, from Judge John F Keenan, United States District Court, Southern District of New York, Case but distressing problem—which occurs mainly healthy women, for whom the risks become 1:06-md-01789-JFK-JCF. Document 750 filed in older women taking bisphosphonates who ever more important. 07/27/2009: pages 21, 36, 45. have undergone dental work. A postal survey At it turns out, Shirley Boles, the Florida 7 American Dental Association. Dental management of patients receiving oral bisphosphonate therapy―expert from Australia suggested a rate between 1 in woman who developed osteonecrosis of the panel recommendations. July 2008. www.ada.org/ 2200 and 1 in 8500, increasing to a rate of jaw, did not even meet the standard defini- prof/resources/topics/topics_osteonecrosis_ bisphosphonate_report.pdf approximately 1 in 300-1100 cases if teeth tion for having osteoporosis when she was 8 Mavrokokki T, Cheng A, Stein B, Goss A. Nature and extractions were carried out.8 A survey con- first prescribed the drug. Rather she sim- frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg ducted by Kaiser Permanente in the United ply had what is described as , 2007;65:415-23. States, currently in press, but cited in court, essentially being at risk of being at risk of 9 Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, et al. Prevalence of osteonecrosis of the jaw in patients found osteonecrosis of the jaw occurred in a future fracture. According to filed docu- with oral bisphosphonate exposure. J Oral Maxillofac roughly 1 in 1000 respondents with exposure ments, a gynaecologist prescribed her the Surg published online 3 July 2009. 9 10 Merck. Product news. Statement by Merck & Co, Inc to oral bisphosphonates. drug because a Merck salesperson told him regarding Fosamax® (alendronate sodium) and rare Having just revised its prevalence esti- that for osteopenic patients like Ms Boles, cases of osteonecrosis of the jaw. 29 July 2009. www. merck.com/newsroom/press_releases/product/ mates upwards, Merck today estimates that Fosamax had proved efficacy—a fact also in fosamax_statement.html the rate is between 1.6 per 100 000 and 3.84 dispute in this case. 11 Wells GA, Cranney A, Peterson J, Boucher M, Shea per 100 000 patient-treatment years, and in According to the lawyers representing B, Welch V, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in filed documents it argues the surveys don’t those who have suffered with osteonecrosis postmenopausal women. Cochrane Database Syst Rev prove causation as they have no ­control of the jaw, Merck’s marketing deliberately 2008;(1):CD001155. 12 Document #3. Plaintiff steering committee’s brief in groups. targeted many people for whom the drug’s support of its rule 702/Daubert motion to limit the However, in the discussion of prevalence in benefits would be modest or negligible. A testimony of defendant’s witnesses. United States District Court, Southern District of New York. No.1:06- his court ruling, Judge Keenan cited experts document filed by the lead lawyer for the MD-01789-JFK-JFC: p32-3. who believed the background rate of this plaintiffs, Tim O’Brien, claims that “in order Cite this as: BMJ 2009;339:b3155

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