“Heartburn pills taken by thousands of women ‘raise risk of hip fractures by up to 50 per cent’,” the Daily Mail reported today. The headline is based on a large new study of drugs called proton pump inhibitors (PPIs), which are commonly used to treat heartburn, acid reflux and ulcers.
The study found that post-menopausal women who regularly took PPIs for at least two years were 35% more likely to suffer hip fracture than non-users, a figure that increases to 50% for women who were current or former smokers. However, although this increase in risk is large, the overall risk of fractures remains small.
This was a large, well conducted study that suggests that long-term use of PPIs is associated with a small increase in risk of hip fracture, although the researchers point out that the risk seems to be confined to women with a history of smoking. Unlike previous research, this study took careful account of other factors that might affect risk such as body weight and calcium intake.
Women who are concerned about their use of PPIs are advised to consult their GP.
Where did the story come from?
The study was carried out by researchers from Massachusetts General Hospital, Boston University and Harvard Medical School and was funded by the US National Institutes of Health. The study was published in the
peer-reviewed British Medical Journal.
Although the Mail’s headline is technically correct, it gives the impression that these drugs carry a very large increase in the risk of hip fracture. In fact, the study found that, in absolute terms, the increase in risk for regular users was small. Researchers found that among the women in the study who regularly used PPIs, about 2 in every 1,000 fractured a hip each year. In non-users, this figure was about 1.5 in every 1,000. This is a increase of about 5 fractures a year in every 10,000 women taking PPIs.
The Mail did point out this “absolute difference” towards the end of its story. Both the Mail and the BBC included comments from independent experts.
What kind of research was this?
The researchers point out that PPIs are among the most commonly used drugs worldwide. In the US they are available over the counter, but in the UK are available only on prescription. They are used for symptoms of heartburn,
gastro-oesophageal reflux disease (GORD) and
stomach ulcers. PPIs are thought to work by reducing acid production in the stomach. Concern has grown over a potential association between long-term use of these drugs and bone fractures, although the researchers say that previous studies have had conflicting results and many did not take other factors (called
confounders) that might affect the risk of fracture into account.
In their
cohort study of nearly 80,000 post-menopausal women, the researchers set out to examine the association between long-term use of PPIs and the risk of hip fracture. Unlike a
randomised controlled trial, a cohort study cannot prove cause and effect. However, cohort studies enable researchers to follow large groups of people for long periods and they are useful for looking at potential long-term risks and benefits of treatments. The study was
prospective, which means it followed participants in time, rather than collecting information retrospectively. This makes it more reliable.
What did the research involve?
This study took its data from a large ongoing US study called the Nurses Health Study, which began in 1976 and which sent health questionnaires every two years to 121,700 female nurses aged 30-55.
From 1982 participants were asked to report all previous hip fractures and in each biennial questionnaire, women were asked if they had sustained a hip fracture over the previous two years. Those who reported a hip fracture were sent a follow-up questionnaire asking for more details. Fractures from bad accidents, such as falling down a flight of stairs, were excluded from the study. A review of medical records for 30 of the women validated all self-reported fractures.
From 2000 to 2006 the women were asked if they had regularly used a PPI in the previous two years. In earlier questionnaires (1994, 1996, 1998 and 2000), the women were also asked if they had regularly used other drugs for acid reflux, called H2 blockers.
The biennial questionnaires also included questions on other factors including menopausal status, body weight, leisure activities, smoking and alcohol use, use of hormone replacement therapy (HRT) and other medicines. Researchers used a validated food frequency questionnaire to calculate the women’s total intake of calcium and vitamin D.
They then analysed the data for any association between regular use of PPIs and hip fracture, adjusting their findings for key confounders such as body weight, physical activity, smoking, and alcohol and calcium intake. They also took into account whether the reasons for using a PPI might have affected the results.
Finally, they carried out a systematic review combining their results with 10 previous studies on the risk of hip fracture and the long-term use of PPIs.
What were the basic results?
The researchers documented 893 hip fractures during the period of the study. They also found that, in 2000, 6.7% of women regularly used a PPI – a figure that had risen to 18.9% by 2008.
- Amongst women who had regularly taken a PPI at any time, there were 2.02 hip fractures per 1,000 person years, compared with 1.51 fractures per 1,000 person years among non-users.
- Women who regularly used PPIs for at least two years had a 35% higher risk of hip fracture than non-users (age adjusted hazard ratio (HR) 1.35; 95%
confidence interval (CI) 1.13 to 1.62), with longer use associated with increasing risk. Adjustment for risk factors, including body mass index, physical activity and intake of calcium did not alter this association (HR 1.36; CI 1.13 to 1.63).
The increased risk did not change when researchers also took into account the reasons for PPI use:
- Current and former smokers who regularly used PPIs were 51% more likely to have a hip fracture than non-users (HR 1.51; (CI) 1.20 to 1.91).
- Among women who never smoked there was no association between PPI use and hip fracture (HR 1.06; (CI) 0.77 to 1.46).
- In a meta-analysis of these results with 10 previous studies, the risk of hip fracture in users of PPI was higher compared with non-users of PPIs (pooled odds ratio 1.30; CI 1.25 to 1.36).
The researchers also found that two years after women stopped taking PPIs, their risk of hip fracture returned to a similar level to that in women who had never taken them. Also, women taking H2 blockers had a “modest” increased risk of hip fracture but the risk was higher in women who took PPIs.
How did the researchers interpret the results?
The researchers conclude that their results provide “compelling evidence” of a risk between PPI use and hip fracture. They say the findings suggest that the need for long-term, continuous use of PPIs should be carefully evaluated, particularly among people who have smoked or are still smokers.
They suggest that PPIs may increase the risk of fracture by impairing the absorption of calcium, although in this study the risk of fracture was not affected by dietary calcium intake. The finding that the risk was confined to women with a history of smoking (an established risk factor for fracture) indicates that smoking and PPIs may act together (have a “synergistic effect”) on fracture risk.
Conclusion
This large study had several strengths. Unlike some previous studies, it collected information on and took into account other key risk factors for fracture, including body weight, smoking, alcohol use and physical activity. It also looked at the women’s use of PPIs every two years (rather than just asking them once) and took into account variations in use during this time in their analysis.
However, as the authors note, it also had some limitations:
- It did not ask about the brands of PPI used, nor the doses of PPI the women took, both of which could affect risk of fracture.
- The information about hip fracture was self-reported and not confirmed by medical records (although a smaller study has found self-reporting of hip fracture to be reliable).
- Also, the study did not record the women’s bone mineral density (BMD). Low BMD is an important risk factor for fracture and adding a measure of this could have strengthened the study.
Finally, because this was a cohort study, other factors both measured and unmeasured may have affected the results, even though researchers took many of these into account in their analysis. Socio-economic status and education, for example, were not established. Because this was a study of registered nurses, the applicability of the results to other socio-economic groups might be limited.
This study found that the long-term, regular use of these drugs is associated with a small increased risk in hip fracture among older women, a risk that seems to be confined to past or current smokers. Women who regularly take PPIs and who are concerned about these findings are advised to talk to their GP. Whether any change in use of this commonly prescribed drug is needed requires further study.
Links To The Headlines
Indigestion drugs taken by millions linked to hip fractures. The Daily Telegraph, February 1 2012
Heartburn pills taken by thousands of women 'raise risk of hip fractures by up to 50 per cent'. Daily Mail, February 1 2012
Ulcer drugs 'link to fractures'. BBC News, February 1 2012
Links To Science
Khalili H, Huang ES, Jacobson BC, et al.
Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. British Medical Journal. Published online January 31 2012
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After many years of delays, the agency said in August it would complete the first part of the dioxin reassessment, which would have set a toxicological threshold for the first time, by January 31.
The draft reassessment has been sharply criticized by the food industry for being too restrictive and being based on shaky science. Health and environmental groups expressed outrage at the continued delay.
"Shame on EPA Administrator Lisa Jackson for denying parents the information they need to protect their children from the health impacts of dioxin," said Lois Marie Gibbs, executive director of the Center for Health, Environment & Justice, a group among dozens pressuring EPA on the issue. "This is America -- parents have the right to know."
Dioxins are released into the air during certain industrial processes, like cement production and are also naturally occurring. According to new government data, air releases of dioxin rose 10 percent between 2009 and 2010. Dioxins are ingested by food animals, via grazing and contaminated feed, and are bioaccumulated -- a reality that has concerned regulators and public health authorities because dioxins are linked to reproductive and developmental problems, immune system damage and cancer.
The World Health Organization (WHO) estimates that 90 percent of human exposure to dioxins is via food, particularly meat, dairy, fish and shellfish. The food industry worries that the EPA reassessment would have recommended an exposure threshold that is lower than the level of exposure many Americans already face through their daily diet.
In December, the Food Industry Dioxin Working Group (FIDWG) -- an ad hoc coalition made up of groups like United Egg Producers, the American Farm Bureau and the American Frozen Food Institute -- sent a letter to a senior White House policy adviser expressing "deep concern" over the effort. The letter was also sent to key officials at the EPA, U.S. Department of Agriculture, Food and Drug Administration, Health and Human Services, and the White House Office of Management and Budget.
The EPA's acceptable level for dioxin exposure, otherwise known as a reference oral dose (RfD), is expected to be .7 picograms per kilogram of body weight per day. Similar thresholds set by the World Health Organization and the European Union are between 1-4 picograms per kilogram of bodyweight per day.
If EPA finalized an RfD for dioxin it would not be a regulatory action, but it could be used as the basis for future regulation and would likely fuel some people to alter their dietary choices.
As the food industry pointed out recently in a letter to the Obama administration, some common food items could easily put someone over the draft RfD.
"Under EPA's proposal...nearly every American - particularly young children - could easily exceed the daily RfD after consuming a single meal or heavy snack," according to the industry groups. "The implications of this action are chilling. EPA is proposing to create a situation in which most U.S. agricultural products could arbitrarily be classified as unfit for consumption. The impact on agricultural production - conventional, organic, livestock/poultry/dairy, fruits, grains and vegetables - may be significant, as will be the loss of trade markets, all without evidence of additional health protection."
The American Chemistry Council, which represents chemical companies, says that EPA needs to take more time to ensure the reassessment is based on sound science, and claims that the agency is "ignoring the most recent peer-reviewed science." Many lawmakers and advocates say the reassessment is years overdue and that further delays are the result of undue influence of industry.
Just how long has this reassessment been in the works? EPA first began work on assessing the risks of dioxin exposure in the 1980s. The most recent human health reassessment was submitted by EPA to the National Academy of Sciences (NAS) in 2003, during the Bush administration. In 2006, NAS submitted recommendations to EPA on the reassessment. In May 2010, the agency released a draft reanalysis and the agency says it's working expeditiously to get a final guidance out, but major industry opposition remains.
"The American public has been waiting for the completion of this dioxin study since 1985 and cannot afford any further delays," Rep. Edward Markey (D-MA) said a letter to EPA this month to urge the agency to meet its deadline. "Despite worldwide agreement about the toxicity of these chemicals and their persistence in the environment, EPA has yet to release its findings on how dangerous these chemicals are to public health."
According to CDC, dioxins and polychlorinated biphenyls (PCBs) have a similar toxicity.
"Human health effects from low environmental exposures are unclear," says CDC on its resource page. "People who have been unintentionally exposed to large amounts of these chemicals have developed a skin condition called chloracne, liver problems, and elevated blood lipids (fats). Laboratory animal studies have shown various effects, including cancer and reproductive problems."
For more information on dioxin exposure, see
FDA's resource guide here.
The decline is in sharp contrast to
the decade-long drug-industry advertising spree that began in 1997, when the
Food and Drug Administration loosened its regulations and allowed direct-to-consumer advertising of prescription drugs on TV.
Some industry analysts attribute part of the decline to
controversy over such ads. Employers and
health insurance companies have long complained that TV ads drive consumers to the latest, often most expensive, pills. And doctors complain that their patients often pressure them into prescribing these heavily advertised drugs.
Perhaps the most well-known criticism of TV advertising of pharmaceuticals arose in 2004 when Merck withdrew the once heavily advertised painkiller
Vioxx after studies showed it increased the risk of heart attacks and strokes.
AdvaMed's Ubl calls MDUFMA III a "game-changer," AngioDynamics' CEO says the Navilyst deal hits the reset button and a clutch of former reps of a Symmetry Medical subsidiary consent to judgement in a lawsuit accusing them of cooking the books.
Say hello to MassDevice +3, a bite-sized view of the top three med-tech stories of the day. This feature of MassDevice.com's coverage highlights our 3 biggest and most influential stories from the day's news to make sure you're up to date on the headlines that continue to shape the medical device industry.
If you read nothing else today, make sure you're still in the know with MassDevice +3.
News Well,
510(k) reforms,
Food & Drug Administration (FDA),
MDUFMA,
Mergers & Acquisitions,
Plus 3,
Wall Street Beat
Writing in the
Morbidity and Mortality Weekly Report, the CDC said it is working with the Pennsylvania State Health Department to investigate an 18-state outbreak of illnesses associated with handling small turtles.
From Aug. 5, 2010 to Sept. 26, 2011, 132 cases of infection from Salmonella Paratyphi B var. L (+) tartrate + were reported, according to the CDC. (If that serotype doesn't sound very scary, consider what the infection is called -- paratyphoid fever)
Many of those stricken were kids, who don't pay much mind to safe-turtle handling practices. Median age of the outbreak cases was 6 years old.
"Although many reptiles carry Salmonella, small turtles pose a greater risk to young children because they are perceived as safe pets, are small enough to be placed in the mouth, and can be handled as toys," the CDC wrote.
Health authorities keep reminding people that
pets can be pathogen carriers, and emphasize the importance of hand washing after touching them. Last year, the CDC reported at least 214 people sickened by their Salmonella-laden
African dwarf frogs, and at least 71 individuals (more than half of them younger than 5) infected with Salmonella from
backyard chicks and ducklings.
Salmonella can make people sick with diarrhea, vomiting, fever and severe abdominal cramps. Young children are especially at risk for illness because their immune systems are still developing.
In the epidemiologic investigation of this latest turtle outbreak, 56 ill individuals were interviewed to determine their possible exposure to Salmonella, and 36 (64 percent) of them reported handling turtles. Fourteen people identified turtles too small to be legally traded, according to the CDC.
Five samples of turtle tank water collected from patients' homes tested positive for the outbreak Salmonella strain.
The sale of turtles with shells smaller than 4 inches has been
banned by the Food and Drug Administration since 1975, after thousands of infants and small children were diagnosed with turtle-associated salmonellosis. Before the ban, epidemiologic studies indicated that 14 percent of reported salmonellosis in the United States was attributable to pet turtles.
Despite the ban, transient vendors on the street, at flea markets and at fairs continue to peddle the turtles as pets, the report notes.
The CDC observed that in 2007, the Independent Turtle Farmers of Louisiana
sought to overturn the prohibition on the sale of tiny turtles, but a federal district court upheld the FDA's authority to enforce the ban.
Given this latest outbreak, the CDC says the ban is being ignored, and
efforts to educate the public about the risks of small turtles aren't working. It suggests examining those efforts.
In its
final investigation update Wednesday, the Centers for Disease Control and Prevention said 20 people in seven states were infected with an antibiotic-resistant strain of
Salmonella Typhimurium.
That's one more case than was reported in the CDC's
Jan. 5 update. "This particular outbreak appears to be over," the CDC stated.
New Hampshire and New York each reported six outbreak cases, while Maine reported four. Hawaii, Kentucky, Massachusetts and Vermont each reported one individual sickened by the outbreak strain of bacteria.
Their illnesses began around Oct. 8, 2011. The ill people ranged in age from one year to 79 years. Median age was 45. Of 17 ill people with information available, 8 were hospitalized.
The epidemiologic investigation showed that among 19 of the ill people who provided food histories, 14 - or 74 percent - reported eating ground beef in the week before they were sick. Fourteen of those reported buying the ground beef from Hannaford stores.
Testing by public health labs in New York and Maine isolated the outbreak strain of Salmonella Typhimurium from two different samples of leftover ground beef purchased from Hannaford supermarkets and collected from unrelated case patients' homes.
On Dec. 15, when the USDA's Food Safety and Inspection Service (FSIS) announced the recall of an undisclosed amount of fresh ground beef sold by Hannaford, it said the Scarborough, ME-based grocery chain kept only "limited records," so that the agency could not determine who had supplied the contaminated beef.
Hannaford regrinds its own beef using meat from several suppliers.
The
Portland Press Herald reported Jan. 28 that FSIS plans to close its investigation into the source of the contaminated beef.
Daniel Engeljohn, FSIS assistant administrator, told the newspaper Hannaford ground meat from various suppliers without cleaning the equipment in between batches, which he said raised the possibility of cross-contamination from commingling.
Although there is no requirement that retailers clean grinding equipment between batches of meat from different suppliers, Engeljohn said the USDA recommends it, along with more detailed information about suppliers in grinding logs. He said those recommendations may soon become requirements.
U.S. Rep. Chellie Pingree, D-ME, of Maine, has said that if the USDA does not issue new rules on its own, she will propose legislation mandating it do so.
"We definitely need stricter regulations for large retailers so they are required to keep more detailed records on the ground beef they sell, so it's possible to track down the source of contamination," she said in a prepared statement.
CDC Outbreak Map:
Medtronic and Boston Scientific throw their support behind the tentative agreement, which more than doubles the FDA's medical device review user fees over the next 5 years, but Cook Medical isn't convinced that the agency can keep its promises.
Medical device makers and industry lobbyists lined up in support of the tentative agreement inked with the FDA to double user fees in exchange for performance goals, but some voices in the crowd said 'nay.'
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