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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
Methyl Chloride Contamination Found in Generic Clopidogrel
CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.
In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.
“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”
Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.
Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.
Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.
The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.
In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.
According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.
“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”
The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. “When this drug is taken long-term, what will it mean for a patient’s safety,” Dr. Gurbel queried.
Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi-Aventis were all employees of the company that markets clopidogrel (Plavix).
Dr. Gurbel has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi-Aventis, and Schering Plough.
Dr. Paul A. Gurbel |
The report by Dr. Thethi raises concerns for me. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel. I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report.
I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent. You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.
The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. When this drug is taken long-term, what will it mean for a patient’s safety?
Clopidogrel is unusual because it has so many different formulations available. In his talk, Dr. Thethi noted that more than a half-dozen clopidogrel salts are sold in addition to the bisulfate form of brand-name clopidogrel.
Dr. Paul A. Gurbel is director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi Aventis, and Schering Plough
Dr. Paul A. Gurbel |
The report by Dr. Thethi raises concerns for me. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel. I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report.
I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent. You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.
The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. When this drug is taken long-term, what will it mean for a patient’s safety?
Clopidogrel is unusual because it has so many different formulations available. In his talk, Dr. Thethi noted that more than a half-dozen clopidogrel salts are sold in addition to the bisulfate form of brand-name clopidogrel.
Dr. Paul A. Gurbel is director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi Aventis, and Schering Plough
Dr. Paul A. Gurbel |
The report by Dr. Thethi raises concerns for me. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel. I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report.
I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent. You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.
The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. When this drug is taken long-term, what will it mean for a patient’s safety?
Clopidogrel is unusual because it has so many different formulations available. In his talk, Dr. Thethi noted that more than a half-dozen clopidogrel salts are sold in addition to the bisulfate form of brand-name clopidogrel.
Dr. Paul A. Gurbel is director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi Aventis, and Schering Plough
CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.
In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.
“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”
Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.
Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.
Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.
The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.
In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.
According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.
“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”
The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. “When this drug is taken long-term, what will it mean for a patient’s safety,” Dr. Gurbel queried.
Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi-Aventis were all employees of the company that markets clopidogrel (Plavix).
Dr. Gurbel has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi-Aventis, and Schering Plough.
CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.
In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.
“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”
Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.
Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.
Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.
The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.
In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.
According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.
“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”
The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. “When this drug is taken long-term, what will it mean for a patient’s safety,” Dr. Gurbel queried.
Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi-Aventis were all employees of the company that markets clopidogrel (Plavix).
Dr. Gurbel has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi-Aventis, and Schering Plough.
FROM THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION
Major Finding: Eleven different generic formulations of clopidogrel contained methyl chloride contamination at levels of 10 ppm to more than 100 ppm. Samples of brand-name clopidogrel (Plavix) contained no detectable methyl chloride.
Data Source: Headspace gas chromatography testing of samples from 11 different formulations of generic clopidogrel obtained in Europe or India, and brand-name clopidogrel.
Disclosures: Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi Aventis were all employees of the company that markets clopidogrel (Plavix).
Calcium Supplements Tied to Higher MI Risk
Major Finding: People taking a calcium supplement showed a statistically significant 24% excess relative risk for MI, a 15% excess relative risk for stroke, and a 16% excess relative risk for MI or stroke.
Data Source: Meta-analysis of nine studies that compared calcium supplements with placebo in a total of more than 28,000 people.
Disclosures: Dr. Reid said that he had no relevant disclosures.
TORONTO — Calcium supplements appear to cause more harm than good, according to a meta-analysis of 28,000 participants in nine trials that include a new analysis of more than 16,000 participants in the Women's Health Initiative, but the re-analysis has raised concerns among the WHI's original investigators.
“We calculate that for every 1,000 people treated with calcium for 5 years, it will lead to four additional myocardial infarctions, four additional strokes, and two additional deaths, while preventing three fractures,” Dr. Ian R. Reid said at the meeting.
“I don't prescribe calcium supplements to anyone anymore for preventing bone fractures. People should get calcium from their diet,” said Dr. Reid, a professor of medicine at the University of Auckland, New Zealand.
“We believe there is a fundamental difference between dietary calcium and supplemental calcium.” He speculated that a calcium supplement, even at a relatively modest dose of 500 mg, produces a “borderline hypercalcemia” that persists for several hours and raises the risk for myocardial infarction or stroke, the same way that people in the highest quartile for normal blood calcium levels have an increased risk for cardiovascular disease events.
But the researchers who ran the Women's Health Initiative (WHI) study questioned the legitimacy of the new analysis beyond a hypothesis-generating exercise.
“The WHI investigators have concerns about the reanalysis and whether omitting the subgroups with favorable results is appropriate,” commented Dr. JoAnn E. Manson, professor of medicine at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, both in Boston, and a WHI coinvestigator.
Dr. Reid and his associates initially documented their finding that calcium supplements raise cardiovascular risk in a pair of meta-analyses published online last July (BMJ 2010;341:c3691). They reported that calcium supplement use was linked with a statistically significant 27% and 31% relatively increased risk for myocardial infarction in two separate meta-analyses.
To further explore the impact of calcium supplements on cardiovascular risk, they received permission from the National Heart, Lung, and Blood Institute to reanalyze data collected in a WHI study of more than 36,000 postmenopausal women randomized to receive a daily supplement with 500 mg calcium plus vitamin D or placebo.
The original report from the WHI investigators showed that the calcium plus vitamin D treatment did not significantly increase or decrease coronary or cerebrovascular risk in generally healthy postmenopausal women during 7 years of treatment (Circulation 2007;115:846-54).
But the WHI study design allowed the participants to take more calcium supplements in addition to their study agent, if they wanted to do so. At baseline, more than 19,000 (54%) of the women in the study reported using a calcium supplement on their own, and at the end of the study 69% reported the practice, Dr. Reid said. To address the possible confounding this may have caused, he focused his analysis on the 16,718 women in the WHI study who reported not using a personal calcium supplement at entry into the study.
In this subgroup, the MI rate ran 2.5% in women randomized to calcium supplement treatment, and 2.0% among women in the placebo arm, a 22% relative increased MI rate with the calcium supplement that was statistically significant. The rate of MI or stroke ran a relative 16% higher among the women taking the calcium supplement, which was also statistically significant. The results showed no significant effect of calcium supplementation on stroke rate. “We saw the same effect as in the meta-analysis,” Dr. Reid said.
But if Dr. Reid's analysis did not start with a prior hypothesis, this finding can only be considered hypothesis generating, not hypothesis testing, Dr. Manson said in an interview. “Many subgroups were tested in the WHI, and some would be expected to show significant effect modification by chance,” she pointed out. In addition, randomization made background levels of calcium use similar in the two treatment arms and thereby neutralized background calcium use as a possible confounder. Dr. Manson also noted that if supplemental calcium posed a risk, the event rates should have been highest among women taking both the study calcium dose and an additional dose on their own.
When the Auckland researchers added the results from the WHI subanalysis to their previously reported meta-analysis, they “just reinforced the trends and made them more significant,” Dr. Reid said in an interview.
When data from the WHI subgroup that did not use personal calcium supplements at baseline were added to the meta-analysis, the results showed that those who did take supplements had a 24% relative excess of MIs, a 15% relative excess of stroke, and a 16% relative excess of MI or stroke, he reported.
“What we now have is six or seven very large trials, and [the results they show] for myocardial infarction all line up very consistently, without significant heterogeneity. When you look at risk vs. benefit, the evidence for an increased risk of myocardial infarction is stronger than the evidence that calcium supplements prevent bone fractures. It's hard to justify continuing calcium supplements,” Dr. Reid said.
The evidence for an increased MI risk is stronger than the evidence that supplements prevent bone fractures.
Source DR. REID
There are concerns about 'whether omitting the subgroups with favorable results is appropriate.'
Source DR. MANSON
Major Finding: People taking a calcium supplement showed a statistically significant 24% excess relative risk for MI, a 15% excess relative risk for stroke, and a 16% excess relative risk for MI or stroke.
Data Source: Meta-analysis of nine studies that compared calcium supplements with placebo in a total of more than 28,000 people.
Disclosures: Dr. Reid said that he had no relevant disclosures.
TORONTO — Calcium supplements appear to cause more harm than good, according to a meta-analysis of 28,000 participants in nine trials that include a new analysis of more than 16,000 participants in the Women's Health Initiative, but the re-analysis has raised concerns among the WHI's original investigators.
“We calculate that for every 1,000 people treated with calcium for 5 years, it will lead to four additional myocardial infarctions, four additional strokes, and two additional deaths, while preventing three fractures,” Dr. Ian R. Reid said at the meeting.
“I don't prescribe calcium supplements to anyone anymore for preventing bone fractures. People should get calcium from their diet,” said Dr. Reid, a professor of medicine at the University of Auckland, New Zealand.
“We believe there is a fundamental difference between dietary calcium and supplemental calcium.” He speculated that a calcium supplement, even at a relatively modest dose of 500 mg, produces a “borderline hypercalcemia” that persists for several hours and raises the risk for myocardial infarction or stroke, the same way that people in the highest quartile for normal blood calcium levels have an increased risk for cardiovascular disease events.
But the researchers who ran the Women's Health Initiative (WHI) study questioned the legitimacy of the new analysis beyond a hypothesis-generating exercise.
“The WHI investigators have concerns about the reanalysis and whether omitting the subgroups with favorable results is appropriate,” commented Dr. JoAnn E. Manson, professor of medicine at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, both in Boston, and a WHI coinvestigator.
Dr. Reid and his associates initially documented their finding that calcium supplements raise cardiovascular risk in a pair of meta-analyses published online last July (BMJ 2010;341:c3691). They reported that calcium supplement use was linked with a statistically significant 27% and 31% relatively increased risk for myocardial infarction in two separate meta-analyses.
To further explore the impact of calcium supplements on cardiovascular risk, they received permission from the National Heart, Lung, and Blood Institute to reanalyze data collected in a WHI study of more than 36,000 postmenopausal women randomized to receive a daily supplement with 500 mg calcium plus vitamin D or placebo.
The original report from the WHI investigators showed that the calcium plus vitamin D treatment did not significantly increase or decrease coronary or cerebrovascular risk in generally healthy postmenopausal women during 7 years of treatment (Circulation 2007;115:846-54).
But the WHI study design allowed the participants to take more calcium supplements in addition to their study agent, if they wanted to do so. At baseline, more than 19,000 (54%) of the women in the study reported using a calcium supplement on their own, and at the end of the study 69% reported the practice, Dr. Reid said. To address the possible confounding this may have caused, he focused his analysis on the 16,718 women in the WHI study who reported not using a personal calcium supplement at entry into the study.
In this subgroup, the MI rate ran 2.5% in women randomized to calcium supplement treatment, and 2.0% among women in the placebo arm, a 22% relative increased MI rate with the calcium supplement that was statistically significant. The rate of MI or stroke ran a relative 16% higher among the women taking the calcium supplement, which was also statistically significant. The results showed no significant effect of calcium supplementation on stroke rate. “We saw the same effect as in the meta-analysis,” Dr. Reid said.
But if Dr. Reid's analysis did not start with a prior hypothesis, this finding can only be considered hypothesis generating, not hypothesis testing, Dr. Manson said in an interview. “Many subgroups were tested in the WHI, and some would be expected to show significant effect modification by chance,” she pointed out. In addition, randomization made background levels of calcium use similar in the two treatment arms and thereby neutralized background calcium use as a possible confounder. Dr. Manson also noted that if supplemental calcium posed a risk, the event rates should have been highest among women taking both the study calcium dose and an additional dose on their own.
When the Auckland researchers added the results from the WHI subanalysis to their previously reported meta-analysis, they “just reinforced the trends and made them more significant,” Dr. Reid said in an interview.
When data from the WHI subgroup that did not use personal calcium supplements at baseline were added to the meta-analysis, the results showed that those who did take supplements had a 24% relative excess of MIs, a 15% relative excess of stroke, and a 16% relative excess of MI or stroke, he reported.
“What we now have is six or seven very large trials, and [the results they show] for myocardial infarction all line up very consistently, without significant heterogeneity. When you look at risk vs. benefit, the evidence for an increased risk of myocardial infarction is stronger than the evidence that calcium supplements prevent bone fractures. It's hard to justify continuing calcium supplements,” Dr. Reid said.
The evidence for an increased MI risk is stronger than the evidence that supplements prevent bone fractures.
Source DR. REID
There are concerns about 'whether omitting the subgroups with favorable results is appropriate.'
Source DR. MANSON
Major Finding: People taking a calcium supplement showed a statistically significant 24% excess relative risk for MI, a 15% excess relative risk for stroke, and a 16% excess relative risk for MI or stroke.
Data Source: Meta-analysis of nine studies that compared calcium supplements with placebo in a total of more than 28,000 people.
Disclosures: Dr. Reid said that he had no relevant disclosures.
TORONTO — Calcium supplements appear to cause more harm than good, according to a meta-analysis of 28,000 participants in nine trials that include a new analysis of more than 16,000 participants in the Women's Health Initiative, but the re-analysis has raised concerns among the WHI's original investigators.
“We calculate that for every 1,000 people treated with calcium for 5 years, it will lead to four additional myocardial infarctions, four additional strokes, and two additional deaths, while preventing three fractures,” Dr. Ian R. Reid said at the meeting.
“I don't prescribe calcium supplements to anyone anymore for preventing bone fractures. People should get calcium from their diet,” said Dr. Reid, a professor of medicine at the University of Auckland, New Zealand.
“We believe there is a fundamental difference between dietary calcium and supplemental calcium.” He speculated that a calcium supplement, even at a relatively modest dose of 500 mg, produces a “borderline hypercalcemia” that persists for several hours and raises the risk for myocardial infarction or stroke, the same way that people in the highest quartile for normal blood calcium levels have an increased risk for cardiovascular disease events.
But the researchers who ran the Women's Health Initiative (WHI) study questioned the legitimacy of the new analysis beyond a hypothesis-generating exercise.
“The WHI investigators have concerns about the reanalysis and whether omitting the subgroups with favorable results is appropriate,” commented Dr. JoAnn E. Manson, professor of medicine at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, both in Boston, and a WHI coinvestigator.
Dr. Reid and his associates initially documented their finding that calcium supplements raise cardiovascular risk in a pair of meta-analyses published online last July (BMJ 2010;341:c3691). They reported that calcium supplement use was linked with a statistically significant 27% and 31% relatively increased risk for myocardial infarction in two separate meta-analyses.
To further explore the impact of calcium supplements on cardiovascular risk, they received permission from the National Heart, Lung, and Blood Institute to reanalyze data collected in a WHI study of more than 36,000 postmenopausal women randomized to receive a daily supplement with 500 mg calcium plus vitamin D or placebo.
The original report from the WHI investigators showed that the calcium plus vitamin D treatment did not significantly increase or decrease coronary or cerebrovascular risk in generally healthy postmenopausal women during 7 years of treatment (Circulation 2007;115:846-54).
But the WHI study design allowed the participants to take more calcium supplements in addition to their study agent, if they wanted to do so. At baseline, more than 19,000 (54%) of the women in the study reported using a calcium supplement on their own, and at the end of the study 69% reported the practice, Dr. Reid said. To address the possible confounding this may have caused, he focused his analysis on the 16,718 women in the WHI study who reported not using a personal calcium supplement at entry into the study.
In this subgroup, the MI rate ran 2.5% in women randomized to calcium supplement treatment, and 2.0% among women in the placebo arm, a 22% relative increased MI rate with the calcium supplement that was statistically significant. The rate of MI or stroke ran a relative 16% higher among the women taking the calcium supplement, which was also statistically significant. The results showed no significant effect of calcium supplementation on stroke rate. “We saw the same effect as in the meta-analysis,” Dr. Reid said.
But if Dr. Reid's analysis did not start with a prior hypothesis, this finding can only be considered hypothesis generating, not hypothesis testing, Dr. Manson said in an interview. “Many subgroups were tested in the WHI, and some would be expected to show significant effect modification by chance,” she pointed out. In addition, randomization made background levels of calcium use similar in the two treatment arms and thereby neutralized background calcium use as a possible confounder. Dr. Manson also noted that if supplemental calcium posed a risk, the event rates should have been highest among women taking both the study calcium dose and an additional dose on their own.
When the Auckland researchers added the results from the WHI subanalysis to their previously reported meta-analysis, they “just reinforced the trends and made them more significant,” Dr. Reid said in an interview.
When data from the WHI subgroup that did not use personal calcium supplements at baseline were added to the meta-analysis, the results showed that those who did take supplements had a 24% relative excess of MIs, a 15% relative excess of stroke, and a 16% relative excess of MI or stroke, he reported.
“What we now have is six or seven very large trials, and [the results they show] for myocardial infarction all line up very consistently, without significant heterogeneity. When you look at risk vs. benefit, the evidence for an increased risk of myocardial infarction is stronger than the evidence that calcium supplements prevent bone fractures. It's hard to justify continuing calcium supplements,” Dr. Reid said.
The evidence for an increased MI risk is stronger than the evidence that supplements prevent bone fractures.
Source DR. REID
There are concerns about 'whether omitting the subgroups with favorable results is appropriate.'
Source DR. MANSON
From the Annual Meeting of the American Society for Bone and Mineral Research
Atypical Breaks Tied to Time on Bisphosphonates
Major Finding: The rate of atypical femur fractures in patients with osteoporosis who were treated with a bisphosphonate rose with increased duration of use. On average, 50 atypical fractures occurred for every 100,000 patients treated for 5 years, 100 atypical fractures occurred per 100,000 patients treated for 6 years, and almost 250 atypical fractures occurred per 100,000 patients treated for 12 years.
Data Source: Review of radiographs from 1,448 Kaiser California patients with a diaphyseal femur fracture during 2007-2009, including 135 that met the atypical criteria.
Disclosures: Dr. Ott said that she had no disclosures.
TORONTO — Patients with osteoporosis who are on bisphosphonate therapy clearly face an increased treatment-linked risk for atypical femur fractures, but at a low rate that is dwarfed by the number of typical hip fractures the drugs prevent.
The risk for atypical fracture appears to rise substantially as time on the drug increases, but an atypical fracture can occur at any time, prompting experts to stress that a bisphosphonate should be given only to a patient who needs the treatment. And the prodromal thigh or groin pain that precedes a majority of atypical fractures should alert physicians to stop bisphosphonate treatment, although stopping the drug is no guarantee against a subsequent atypical fracture.
Above all, experts agreed, atypical fracture risk is no reason to deny bisphosphonate treatment to patients who need it, because these drugs improve bone mineral density and prevent typical hip fractures, and because in appropriate patients this benefit far exceeds the atypical fracture risk.
This consensus pervaded the meeting One multispeaker session reviewed the data compiled by and the recommendations from an ASBMR task force, while several other speakers reported some of the incidence data that task force members considered when writing their recommendations (J. Bone Miner. Res. 2010 Oct. 25 [doi:10.1002/jbmr.253]).
“The message is that for patients with osteoporosis at high risk of having a fracture, treatment with a bisphosphonate will benefit far more than the risk for an atypical fracture,” said Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York, and co-chair of the task force.
The largest and most comprehensive look at atypical fracture rates came from data compiled from the 2.6 million beneficiaries older than 45 years enrolled in Kaiser California. During 2007-2009, 15,819 people had femur fractures, excluding those from major trauma, those secondary to Paget's disease or metastatic lesions, or periprosthetic fractures. The researchers reviewed the radiographs for 1,448 of these fractures located in the diaphyseal region.
Of the reviewed fractures, the researchers identified 135 as atypical, based on their location in the diaphyseal portion of the femur, either in the shaft or subtrochanteric region, as well as other features: a transverse fracture, usually with lateral cortical thickening especially at the fracture site, and flaring of the lateral cortex, Dr. Susan Ott of the University of Washington, Seattle, reported at the meeting. The 135 patients with atypical fractures were 98% women, with an average age of 71 years and an average body mass index of 26.6 kg/m
All but 4% of the atypical fracture patients received a bisphosphonate at the time of fracture, and were on their regimen for an average of 6 years. Two-thirds had prodromal thigh pain, and 26% had bilateral atypical fractures. In all, 60% of the fractures occurred in the femur shaft, and 40% were in the subtrochanteric region.
The most common age at fracture was 65-69 years. The fracture rate rose steadily with increasing years of bisphosphonate use, with most fractures occurring in patients who had used the drugs for at least 5 years. The number of fractures per 100,000 people exposed rose steadily with increasing years of use, reaching 50 per 100,000 when bisphosphonate use continued for 5 years and 100 fractures per 100,000 patients in those using the drug for 6 years, and then continuing to rise steadily with added years of use, reaching a high of nearly 250 fractures for every 100,000 patients exposed to a bisphosphonate for 12 years.
“These data do not suggest you should stop using bisphosphonates, especially in women with osteoporosis. Bisphosphonates look pretty safe for the first few years,” Dr. Ott said. But, she added, “the data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.”
The ASBMR task force reviewed Dr. Ott's data before issuing its recommendations last month. The data “were very informative for establishing incidence rates for these fractures,” Dr. Shane said in an interview.
Two other talks at the meeting presented further data documenting the risks of atypical and typical fractures with bisphosphonate treatment, as follows:
▸ Patients taking a bisphosphonate face a risk of about 1 additional subtrochanteric hip fracture for every 100 typical hip fractures prevented, according to an analysis of national data during 1996-2007. The new data present no direct evidence for a role of bisphosphonate use in causing subtrochanteric hip fractures. But the temporal link between the steady increase in bisphosphonate use in elderly women during 1996-2007 and the concurrent rise in subtrochanteric fractures also in elderly women strongly suggests that a causal link exists, John Wang, Ph.D., a statistician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said at the meeting.
His finding was based on an analysis of subtrochanteric fracture rates from the Nationwide Inpatient Sample during 1996-2007, along with data on bisphosphonate use from the Medical Expenditure Panel Survey. The analysis also showed that the start of widespread bisphosphonate use in 1996, quickly followed by even broader use over the following years, had a temporal relationship with subtrochanteric fractures, which began rising in 2000.
▸ Analysis of data collected on residents of Olmsted County, Minn. through the Rochester Epidemiology Project showed that the annual, population-based rate of first, nonhip femoral fractures associated with minimal or moderate trauma was 7 per 100,000 residents during 1984-1995, and 12 per 100,000 residents during 1996-2007, a significant difference. (Routine prescribing of bisphosphonates began in 1996.) This and related findings in the population-based analysis show that “bisphosphonate therapies may have a modest potential impact on nonhip femoral fractures observed across the whole population,” said Dr. Alvin Ng, a physician at the Mayo Clinic in Rochester.
Dr. Wang and Dr. Ng had no disclosures. Dr. Shane has been a consultant to Amgen and has received research support from Merck, Novartis, and Eli Lilly & Co.
'The data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.'
Source DR. OTT
View on the News
New Approach to Bisphosphonate Use
DR. EBELING said that he has served as a speaker for Merck & Co., Eli Lilly, Novartis, and Sanofi-Aventis; that he has been on advisory boards for Merck, Amgen, and Novartis; has received educational grants from Amgen, Eli Lilly, and Sanofi-Aventis; and has received research grants from Merck, Novartis, and Amgen.
The task force assembled by the ASBMR recommended several steps for physicians to take when they prescribe a bisphosphonate to reduce atypical fracture risk.
Patients with a low absolute fracture risk should not receive a bisphosphonate, said Dr. Peter R. Ebeling, a task force member, summarizing the group's recommendations at the meeting.
Another step is minimizing the duration of bisphosphonate treatment. This means realizing that patients with secondary causes of rapid bone loss may not need long-term bisphosphonate treatment. Continued use of the drugs beyond 5 years should be evaluated annually, said Dr. Ebeling, professor and chairman of medicine at the University of Melbourne.
Patients without a recent fracture and with a femoral neck T score of more than −2.5 after 5 years of continuous bisphosphonate treatment should receive consideration for a drug holiday. Patients who are taken off bisphosphonate treatment should undergo an annual assessment of their clinical status, markers of bone turnover, bone density, and their fracture risk.
Because most patients who developed an atypical fracture on bisphosphonate treatment had prodromal pain in their thigh or groin, physicians should alert patients to watch for and promptly report such pain. During regular examinations of patients on a bisphosphonate or another potent antiresorptive drug, physicians should ask if prodromal pain exists. When suspicious pain occurs, the patient needs “urgent” radiographic assessment of both femora, Dr. Ebeling said. If the radiographs appear normal, perform a follow-up examination by MRI or radionuclide scintigraphy scanning. Physicians should be aware that bilateral, atypical femur fractures can occur.
If a patient has a fracture while on a bisphosphonate, treatment with the that or any other potent antiresorptive drug should stop. At that time, assess the patient's calcium and vitamin D status and prescribe adequate supplementation if needed. The physician should consider prescribing teriparatide to improve fracture healing, particularly if it appears that the fracture has not healed by 4-6 weeks following surgical repair. In patients who should not receive teriparatide, such as those with a history of breast cancer or skeletal irradiation, consider another option such as treatment with raloxifene.
Major Finding: The rate of atypical femur fractures in patients with osteoporosis who were treated with a bisphosphonate rose with increased duration of use. On average, 50 atypical fractures occurred for every 100,000 patients treated for 5 years, 100 atypical fractures occurred per 100,000 patients treated for 6 years, and almost 250 atypical fractures occurred per 100,000 patients treated for 12 years.
Data Source: Review of radiographs from 1,448 Kaiser California patients with a diaphyseal femur fracture during 2007-2009, including 135 that met the atypical criteria.
Disclosures: Dr. Ott said that she had no disclosures.
TORONTO — Patients with osteoporosis who are on bisphosphonate therapy clearly face an increased treatment-linked risk for atypical femur fractures, but at a low rate that is dwarfed by the number of typical hip fractures the drugs prevent.
The risk for atypical fracture appears to rise substantially as time on the drug increases, but an atypical fracture can occur at any time, prompting experts to stress that a bisphosphonate should be given only to a patient who needs the treatment. And the prodromal thigh or groin pain that precedes a majority of atypical fractures should alert physicians to stop bisphosphonate treatment, although stopping the drug is no guarantee against a subsequent atypical fracture.
Above all, experts agreed, atypical fracture risk is no reason to deny bisphosphonate treatment to patients who need it, because these drugs improve bone mineral density and prevent typical hip fractures, and because in appropriate patients this benefit far exceeds the atypical fracture risk.
This consensus pervaded the meeting One multispeaker session reviewed the data compiled by and the recommendations from an ASBMR task force, while several other speakers reported some of the incidence data that task force members considered when writing their recommendations (J. Bone Miner. Res. 2010 Oct. 25 [doi:10.1002/jbmr.253]).
“The message is that for patients with osteoporosis at high risk of having a fracture, treatment with a bisphosphonate will benefit far more than the risk for an atypical fracture,” said Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York, and co-chair of the task force.
The largest and most comprehensive look at atypical fracture rates came from data compiled from the 2.6 million beneficiaries older than 45 years enrolled in Kaiser California. During 2007-2009, 15,819 people had femur fractures, excluding those from major trauma, those secondary to Paget's disease or metastatic lesions, or periprosthetic fractures. The researchers reviewed the radiographs for 1,448 of these fractures located in the diaphyseal region.
Of the reviewed fractures, the researchers identified 135 as atypical, based on their location in the diaphyseal portion of the femur, either in the shaft or subtrochanteric region, as well as other features: a transverse fracture, usually with lateral cortical thickening especially at the fracture site, and flaring of the lateral cortex, Dr. Susan Ott of the University of Washington, Seattle, reported at the meeting. The 135 patients with atypical fractures were 98% women, with an average age of 71 years and an average body mass index of 26.6 kg/m
All but 4% of the atypical fracture patients received a bisphosphonate at the time of fracture, and were on their regimen for an average of 6 years. Two-thirds had prodromal thigh pain, and 26% had bilateral atypical fractures. In all, 60% of the fractures occurred in the femur shaft, and 40% were in the subtrochanteric region.
The most common age at fracture was 65-69 years. The fracture rate rose steadily with increasing years of bisphosphonate use, with most fractures occurring in patients who had used the drugs for at least 5 years. The number of fractures per 100,000 people exposed rose steadily with increasing years of use, reaching 50 per 100,000 when bisphosphonate use continued for 5 years and 100 fractures per 100,000 patients in those using the drug for 6 years, and then continuing to rise steadily with added years of use, reaching a high of nearly 250 fractures for every 100,000 patients exposed to a bisphosphonate for 12 years.
“These data do not suggest you should stop using bisphosphonates, especially in women with osteoporosis. Bisphosphonates look pretty safe for the first few years,” Dr. Ott said. But, she added, “the data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.”
The ASBMR task force reviewed Dr. Ott's data before issuing its recommendations last month. The data “were very informative for establishing incidence rates for these fractures,” Dr. Shane said in an interview.
Two other talks at the meeting presented further data documenting the risks of atypical and typical fractures with bisphosphonate treatment, as follows:
▸ Patients taking a bisphosphonate face a risk of about 1 additional subtrochanteric hip fracture for every 100 typical hip fractures prevented, according to an analysis of national data during 1996-2007. The new data present no direct evidence for a role of bisphosphonate use in causing subtrochanteric hip fractures. But the temporal link between the steady increase in bisphosphonate use in elderly women during 1996-2007 and the concurrent rise in subtrochanteric fractures also in elderly women strongly suggests that a causal link exists, John Wang, Ph.D., a statistician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said at the meeting.
His finding was based on an analysis of subtrochanteric fracture rates from the Nationwide Inpatient Sample during 1996-2007, along with data on bisphosphonate use from the Medical Expenditure Panel Survey. The analysis also showed that the start of widespread bisphosphonate use in 1996, quickly followed by even broader use over the following years, had a temporal relationship with subtrochanteric fractures, which began rising in 2000.
▸ Analysis of data collected on residents of Olmsted County, Minn. through the Rochester Epidemiology Project showed that the annual, population-based rate of first, nonhip femoral fractures associated with minimal or moderate trauma was 7 per 100,000 residents during 1984-1995, and 12 per 100,000 residents during 1996-2007, a significant difference. (Routine prescribing of bisphosphonates began in 1996.) This and related findings in the population-based analysis show that “bisphosphonate therapies may have a modest potential impact on nonhip femoral fractures observed across the whole population,” said Dr. Alvin Ng, a physician at the Mayo Clinic in Rochester.
Dr. Wang and Dr. Ng had no disclosures. Dr. Shane has been a consultant to Amgen and has received research support from Merck, Novartis, and Eli Lilly & Co.
'The data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.'
Source DR. OTT
View on the News
New Approach to Bisphosphonate Use
DR. EBELING said that he has served as a speaker for Merck & Co., Eli Lilly, Novartis, and Sanofi-Aventis; that he has been on advisory boards for Merck, Amgen, and Novartis; has received educational grants from Amgen, Eli Lilly, and Sanofi-Aventis; and has received research grants from Merck, Novartis, and Amgen.
The task force assembled by the ASBMR recommended several steps for physicians to take when they prescribe a bisphosphonate to reduce atypical fracture risk.
Patients with a low absolute fracture risk should not receive a bisphosphonate, said Dr. Peter R. Ebeling, a task force member, summarizing the group's recommendations at the meeting.
Another step is minimizing the duration of bisphosphonate treatment. This means realizing that patients with secondary causes of rapid bone loss may not need long-term bisphosphonate treatment. Continued use of the drugs beyond 5 years should be evaluated annually, said Dr. Ebeling, professor and chairman of medicine at the University of Melbourne.
Patients without a recent fracture and with a femoral neck T score of more than −2.5 after 5 years of continuous bisphosphonate treatment should receive consideration for a drug holiday. Patients who are taken off bisphosphonate treatment should undergo an annual assessment of their clinical status, markers of bone turnover, bone density, and their fracture risk.
Because most patients who developed an atypical fracture on bisphosphonate treatment had prodromal pain in their thigh or groin, physicians should alert patients to watch for and promptly report such pain. During regular examinations of patients on a bisphosphonate or another potent antiresorptive drug, physicians should ask if prodromal pain exists. When suspicious pain occurs, the patient needs “urgent” radiographic assessment of both femora, Dr. Ebeling said. If the radiographs appear normal, perform a follow-up examination by MRI or radionuclide scintigraphy scanning. Physicians should be aware that bilateral, atypical femur fractures can occur.
If a patient has a fracture while on a bisphosphonate, treatment with the that or any other potent antiresorptive drug should stop. At that time, assess the patient's calcium and vitamin D status and prescribe adequate supplementation if needed. The physician should consider prescribing teriparatide to improve fracture healing, particularly if it appears that the fracture has not healed by 4-6 weeks following surgical repair. In patients who should not receive teriparatide, such as those with a history of breast cancer or skeletal irradiation, consider another option such as treatment with raloxifene.
Major Finding: The rate of atypical femur fractures in patients with osteoporosis who were treated with a bisphosphonate rose with increased duration of use. On average, 50 atypical fractures occurred for every 100,000 patients treated for 5 years, 100 atypical fractures occurred per 100,000 patients treated for 6 years, and almost 250 atypical fractures occurred per 100,000 patients treated for 12 years.
Data Source: Review of radiographs from 1,448 Kaiser California patients with a diaphyseal femur fracture during 2007-2009, including 135 that met the atypical criteria.
Disclosures: Dr. Ott said that she had no disclosures.
TORONTO — Patients with osteoporosis who are on bisphosphonate therapy clearly face an increased treatment-linked risk for atypical femur fractures, but at a low rate that is dwarfed by the number of typical hip fractures the drugs prevent.
The risk for atypical fracture appears to rise substantially as time on the drug increases, but an atypical fracture can occur at any time, prompting experts to stress that a bisphosphonate should be given only to a patient who needs the treatment. And the prodromal thigh or groin pain that precedes a majority of atypical fractures should alert physicians to stop bisphosphonate treatment, although stopping the drug is no guarantee against a subsequent atypical fracture.
Above all, experts agreed, atypical fracture risk is no reason to deny bisphosphonate treatment to patients who need it, because these drugs improve bone mineral density and prevent typical hip fractures, and because in appropriate patients this benefit far exceeds the atypical fracture risk.
This consensus pervaded the meeting One multispeaker session reviewed the data compiled by and the recommendations from an ASBMR task force, while several other speakers reported some of the incidence data that task force members considered when writing their recommendations (J. Bone Miner. Res. 2010 Oct. 25 [doi:10.1002/jbmr.253]).
“The message is that for patients with osteoporosis at high risk of having a fracture, treatment with a bisphosphonate will benefit far more than the risk for an atypical fracture,” said Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York, and co-chair of the task force.
The largest and most comprehensive look at atypical fracture rates came from data compiled from the 2.6 million beneficiaries older than 45 years enrolled in Kaiser California. During 2007-2009, 15,819 people had femur fractures, excluding those from major trauma, those secondary to Paget's disease or metastatic lesions, or periprosthetic fractures. The researchers reviewed the radiographs for 1,448 of these fractures located in the diaphyseal region.
Of the reviewed fractures, the researchers identified 135 as atypical, based on their location in the diaphyseal portion of the femur, either in the shaft or subtrochanteric region, as well as other features: a transverse fracture, usually with lateral cortical thickening especially at the fracture site, and flaring of the lateral cortex, Dr. Susan Ott of the University of Washington, Seattle, reported at the meeting. The 135 patients with atypical fractures were 98% women, with an average age of 71 years and an average body mass index of 26.6 kg/m
All but 4% of the atypical fracture patients received a bisphosphonate at the time of fracture, and were on their regimen for an average of 6 years. Two-thirds had prodromal thigh pain, and 26% had bilateral atypical fractures. In all, 60% of the fractures occurred in the femur shaft, and 40% were in the subtrochanteric region.
The most common age at fracture was 65-69 years. The fracture rate rose steadily with increasing years of bisphosphonate use, with most fractures occurring in patients who had used the drugs for at least 5 years. The number of fractures per 100,000 people exposed rose steadily with increasing years of use, reaching 50 per 100,000 when bisphosphonate use continued for 5 years and 100 fractures per 100,000 patients in those using the drug for 6 years, and then continuing to rise steadily with added years of use, reaching a high of nearly 250 fractures for every 100,000 patients exposed to a bisphosphonate for 12 years.
“These data do not suggest you should stop using bisphosphonates, especially in women with osteoporosis. Bisphosphonates look pretty safe for the first few years,” Dr. Ott said. But, she added, “the data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.”
The ASBMR task force reviewed Dr. Ott's data before issuing its recommendations last month. The data “were very informative for establishing incidence rates for these fractures,” Dr. Shane said in an interview.
Two other talks at the meeting presented further data documenting the risks of atypical and typical fractures with bisphosphonate treatment, as follows:
▸ Patients taking a bisphosphonate face a risk of about 1 additional subtrochanteric hip fracture for every 100 typical hip fractures prevented, according to an analysis of national data during 1996-2007. The new data present no direct evidence for a role of bisphosphonate use in causing subtrochanteric hip fractures. But the temporal link between the steady increase in bisphosphonate use in elderly women during 1996-2007 and the concurrent rise in subtrochanteric fractures also in elderly women strongly suggests that a causal link exists, John Wang, Ph.D., a statistician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said at the meeting.
His finding was based on an analysis of subtrochanteric fracture rates from the Nationwide Inpatient Sample during 1996-2007, along with data on bisphosphonate use from the Medical Expenditure Panel Survey. The analysis also showed that the start of widespread bisphosphonate use in 1996, quickly followed by even broader use over the following years, had a temporal relationship with subtrochanteric fractures, which began rising in 2000.
▸ Analysis of data collected on residents of Olmsted County, Minn. through the Rochester Epidemiology Project showed that the annual, population-based rate of first, nonhip femoral fractures associated with minimal or moderate trauma was 7 per 100,000 residents during 1984-1995, and 12 per 100,000 residents during 1996-2007, a significant difference. (Routine prescribing of bisphosphonates began in 1996.) This and related findings in the population-based analysis show that “bisphosphonate therapies may have a modest potential impact on nonhip femoral fractures observed across the whole population,” said Dr. Alvin Ng, a physician at the Mayo Clinic in Rochester.
Dr. Wang and Dr. Ng had no disclosures. Dr. Shane has been a consultant to Amgen and has received research support from Merck, Novartis, and Eli Lilly & Co.
'The data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.'
Source DR. OTT
View on the News
New Approach to Bisphosphonate Use
DR. EBELING said that he has served as a speaker for Merck & Co., Eli Lilly, Novartis, and Sanofi-Aventis; that he has been on advisory boards for Merck, Amgen, and Novartis; has received educational grants from Amgen, Eli Lilly, and Sanofi-Aventis; and has received research grants from Merck, Novartis, and Amgen.
The task force assembled by the ASBMR recommended several steps for physicians to take when they prescribe a bisphosphonate to reduce atypical fracture risk.
Patients with a low absolute fracture risk should not receive a bisphosphonate, said Dr. Peter R. Ebeling, a task force member, summarizing the group's recommendations at the meeting.
Another step is minimizing the duration of bisphosphonate treatment. This means realizing that patients with secondary causes of rapid bone loss may not need long-term bisphosphonate treatment. Continued use of the drugs beyond 5 years should be evaluated annually, said Dr. Ebeling, professor and chairman of medicine at the University of Melbourne.
Patients without a recent fracture and with a femoral neck T score of more than −2.5 after 5 years of continuous bisphosphonate treatment should receive consideration for a drug holiday. Patients who are taken off bisphosphonate treatment should undergo an annual assessment of their clinical status, markers of bone turnover, bone density, and their fracture risk.
Because most patients who developed an atypical fracture on bisphosphonate treatment had prodromal pain in their thigh or groin, physicians should alert patients to watch for and promptly report such pain. During regular examinations of patients on a bisphosphonate or another potent antiresorptive drug, physicians should ask if prodromal pain exists. When suspicious pain occurs, the patient needs “urgent” radiographic assessment of both femora, Dr. Ebeling said. If the radiographs appear normal, perform a follow-up examination by MRI or radionuclide scintigraphy scanning. Physicians should be aware that bilateral, atypical femur fractures can occur.
If a patient has a fracture while on a bisphosphonate, treatment with the that or any other potent antiresorptive drug should stop. At that time, assess the patient's calcium and vitamin D status and prescribe adequate supplementation if needed. The physician should consider prescribing teriparatide to improve fracture healing, particularly if it appears that the fracture has not healed by 4-6 weeks following surgical repair. In patients who should not receive teriparatide, such as those with a history of breast cancer or skeletal irradiation, consider another option such as treatment with raloxifene.
From the Annual Meeting of the American Society for Bone and Mineral Research
High Vitamin D Intake May Prevent Fractures
Major Finding: People taking 792–2,000 IU/day of vitamin D had a statistically significant, 14% reduced rate of any nonvertebral fracture and a significant, 30% reduced rate of hip fractures compared with control subjects who did not receive a vitamin D supplement.
Data Source: Meta-analysis of 11 double-blind, randomized, controlled trials with individual participant data available for 31,022 subjects with an average age of 76.
Disclosures: Dr. Bischoff-Ferrari said that she had no disclosures.
TORONTO — A daily vitamin D dose of at least 792 IU was linked with significantly reduced rates of nonvertebral fractures and hip fractures in a meta-analysis of data from 11 randomized, controlled trials.
But the benefit from vitamin D appeared blunted when combined with a higher calcium dose, or when patients received vitamin D once yearly, Dr. Heike A. Bischoff-Ferrari reported.
In the meta-analysis, patients in the highest quartile for daily vitamin D intake, 792–2000 IU, had a statistically significant 14% reduced rate of any nonvertebral fracture and a significant 30% reduced rate of hip fractures after adjusting for age, gender, and type of dwelling, said Dr. Bischoff-Ferrari, a rheumatologist at the University of Zurich.
Her meta-analysis pooled individual participant data from 12 double-blind, randomized, controlled trials that examined the impact of vitamin D supplements on fracture rate in people aged 65 years or older published through June 2010, and for which she could obtain individual participant data. The primary analysis focused on the 11 studies of the 12 in which participants received the supplement at least monthly, with 31,022 people enrolled. The twelfth study tested once annual dosing, and the researchers included those data in a separate analysis. The participants' average age was 76 years, and about 90% were women.
The analysis divided the study subjects into the control group, with more than 15,000 people, and then into quartiles of their received amount of vitamin D, including both their study-treatment dose and any additional vitamin D intake. The analysis also took into account adherence to treatment. Each vitamin D quartile contained nearly 4,000 people, with a daily dose range of 792–2,000 IU forming the top quartile. Only the top quartile of vitamin intake linked with statistically significant differences, compared with the controls, for any nonvertebral fracture and for hip fracture.
An additional analysis that looked at the interaction of calcium supplements along with vitamin D showed that, with a daily calcium dose below 1,000 mg/day, a high-dose vitamin D supplement (792–2,000 IU/day) linked with a statistically significant reduction in nonvertebral fractures, but when the daily calcium supplement delivered 1,000 mg or more, this amount of vitamin D did not associate with any significant change in fracture rate, suggesting an adverse effect from higher calcium intake.
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Major Finding: People taking 792–2,000 IU/day of vitamin D had a statistically significant, 14% reduced rate of any nonvertebral fracture and a significant, 30% reduced rate of hip fractures compared with control subjects who did not receive a vitamin D supplement.
Data Source: Meta-analysis of 11 double-blind, randomized, controlled trials with individual participant data available for 31,022 subjects with an average age of 76.
Disclosures: Dr. Bischoff-Ferrari said that she had no disclosures.
TORONTO — A daily vitamin D dose of at least 792 IU was linked with significantly reduced rates of nonvertebral fractures and hip fractures in a meta-analysis of data from 11 randomized, controlled trials.
But the benefit from vitamin D appeared blunted when combined with a higher calcium dose, or when patients received vitamin D once yearly, Dr. Heike A. Bischoff-Ferrari reported.
In the meta-analysis, patients in the highest quartile for daily vitamin D intake, 792–2000 IU, had a statistically significant 14% reduced rate of any nonvertebral fracture and a significant 30% reduced rate of hip fractures after adjusting for age, gender, and type of dwelling, said Dr. Bischoff-Ferrari, a rheumatologist at the University of Zurich.
Her meta-analysis pooled individual participant data from 12 double-blind, randomized, controlled trials that examined the impact of vitamin D supplements on fracture rate in people aged 65 years or older published through June 2010, and for which she could obtain individual participant data. The primary analysis focused on the 11 studies of the 12 in which participants received the supplement at least monthly, with 31,022 people enrolled. The twelfth study tested once annual dosing, and the researchers included those data in a separate analysis. The participants' average age was 76 years, and about 90% were women.
The analysis divided the study subjects into the control group, with more than 15,000 people, and then into quartiles of their received amount of vitamin D, including both their study-treatment dose and any additional vitamin D intake. The analysis also took into account adherence to treatment. Each vitamin D quartile contained nearly 4,000 people, with a daily dose range of 792–2,000 IU forming the top quartile. Only the top quartile of vitamin intake linked with statistically significant differences, compared with the controls, for any nonvertebral fracture and for hip fracture.
An additional analysis that looked at the interaction of calcium supplements along with vitamin D showed that, with a daily calcium dose below 1,000 mg/day, a high-dose vitamin D supplement (792–2,000 IU/day) linked with a statistically significant reduction in nonvertebral fractures, but when the daily calcium supplement delivered 1,000 mg or more, this amount of vitamin D did not associate with any significant change in fracture rate, suggesting an adverse effect from higher calcium intake.
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Major Finding: People taking 792–2,000 IU/day of vitamin D had a statistically significant, 14% reduced rate of any nonvertebral fracture and a significant, 30% reduced rate of hip fractures compared with control subjects who did not receive a vitamin D supplement.
Data Source: Meta-analysis of 11 double-blind, randomized, controlled trials with individual participant data available for 31,022 subjects with an average age of 76.
Disclosures: Dr. Bischoff-Ferrari said that she had no disclosures.
TORONTO — A daily vitamin D dose of at least 792 IU was linked with significantly reduced rates of nonvertebral fractures and hip fractures in a meta-analysis of data from 11 randomized, controlled trials.
But the benefit from vitamin D appeared blunted when combined with a higher calcium dose, or when patients received vitamin D once yearly, Dr. Heike A. Bischoff-Ferrari reported.
In the meta-analysis, patients in the highest quartile for daily vitamin D intake, 792–2000 IU, had a statistically significant 14% reduced rate of any nonvertebral fracture and a significant 30% reduced rate of hip fractures after adjusting for age, gender, and type of dwelling, said Dr. Bischoff-Ferrari, a rheumatologist at the University of Zurich.
Her meta-analysis pooled individual participant data from 12 double-blind, randomized, controlled trials that examined the impact of vitamin D supplements on fracture rate in people aged 65 years or older published through June 2010, and for which she could obtain individual participant data. The primary analysis focused on the 11 studies of the 12 in which participants received the supplement at least monthly, with 31,022 people enrolled. The twelfth study tested once annual dosing, and the researchers included those data in a separate analysis. The participants' average age was 76 years, and about 90% were women.
The analysis divided the study subjects into the control group, with more than 15,000 people, and then into quartiles of their received amount of vitamin D, including both their study-treatment dose and any additional vitamin D intake. The analysis also took into account adherence to treatment. Each vitamin D quartile contained nearly 4,000 people, with a daily dose range of 792–2,000 IU forming the top quartile. Only the top quartile of vitamin intake linked with statistically significant differences, compared with the controls, for any nonvertebral fracture and for hip fracture.
An additional analysis that looked at the interaction of calcium supplements along with vitamin D showed that, with a daily calcium dose below 1,000 mg/day, a high-dose vitamin D supplement (792–2,000 IU/day) linked with a statistically significant reduction in nonvertebral fractures, but when the daily calcium supplement delivered 1,000 mg or more, this amount of vitamin D did not associate with any significant change in fracture rate, suggesting an adverse effect from higher calcium intake.
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Calcium Supplements May Increase CVD Risk
Major Finding: People taking a calcium supplement showed a statistically significant 24% excess relative risk for MI, a 15% excess relative risk for stroke, and a 16% excess relative risk for MI or stroke.
Data Source: Meta-analysis of nine studies that compared calcium supplements with placebo in a total of more than 28,000 people.
Disclosures: Dr. Reid said that he had no relevant disclosures.
TORONTO — Calcium supplements appear to cause more harm than good, according to a meta-analysis of 28,000 participants in nine trials that includes a new analysis of more than 16,000 participants in the Women's Health Initiative, but the reanalysis has raised concerns among the WHI's original investigators.
“We calculate that for every 1,000 people treated with calcium for 5 years, it will lead to four additional myocardial infarctions, four additional strokes, and two additional deaths, while preventing three fractures,” Dr. Ian R. Reid said.
“I don't prescribe calcium supplements to anyone anymore for preventing bone fractures. People should get calcium from their diet,” said Dr. Reid of the University of Auckland, New Zealand. He speculated that a calcium supplement, even at a relatively modest dose of 500 mg, produces a “borderline hypercalcemia” that persists for several hours and raises the risk for MI or stroke, the same way that people in the highest quartile for normal blood calcium levels have an increased risk for cardiovascular disease events.
But the researchers who ran the Women's Health Initiative (WHI) study questioned the legitimacy of the new analysis beyond a hypothesis-generating exercise.
“The WHI investigators have concerns about the reanalysis and whether omitting the subgroups with favorable results is appropriate,” said Dr. JoAnn E. Manson of Harvard University and Brigham and Women's Hospital, both in Boston, and a WHI coinvestigator.
Dr. Reid and his associates initially reported that calcium supplement use was linked with a statistically significant 27% and 31% relatively increased risk for MI in two separate meta-analyses published online last July (BMJ 2010;341:c3691).
To further explore the impact of calcium supplements on cardiovascular risk, they reanalyzed data collected in a WHI study of more than 36,000 postmenopausal women randomized to receive a daily supplement with 500 mg calcium plus vitamin D or placebo. The original report from the WHI investigators showed that the calcium plus vitamin D did not significantly increase or decrease coronary or cerebrovascular risk in generally healthy postmenopausal women during 7 years of treatment (Circulation 2007;115:846–54).
But at baseline, more than 19,000 (54%) of the women in the study reported using a calcium supplement on their own, and at the end of the study 69% reported the practice, Dr. Reid said. To address the possible confounding, he focused on the 16,718 women in the WHI study who reported not using a personal calcium supplement at entry.
In this subgroup, the MI rates ran 2.5% in women randomized to calcium supplements and 2.0% in the placebo arm, a 22% relative increase that was statistically significant. The rate of MI or stroke ran a relative 16% higher among the women taking calcium, which was also statistically significant. The results showed no significant effect of calcium supplementation on stroke rate, Dr. Reid said.
But if Dr. Reid's analysis did not start with a prior hypothesis, this finding can only be considered hypothesis generating, not hypothesis testing, Dr. Manson said in an interview. “Many subgroups were tested in the WHI, and some would be expected to show significant effect modification by chance,” she pointed out.
When data from the WHI subgroup that did not use personal calcium supplements at baseline were added to the meta-analysis, the results showed that those who did take supplements had a 24% relative excess of MIs, a 15% relative excess of stroke, and a 16% relative excess of MI or stroke, Dr. Reid reported.
'I don't prescribe calcium supplements to anyone anymore for preventing bone fractures.'
Source DR. REID
Major Finding: People taking a calcium supplement showed a statistically significant 24% excess relative risk for MI, a 15% excess relative risk for stroke, and a 16% excess relative risk for MI or stroke.
Data Source: Meta-analysis of nine studies that compared calcium supplements with placebo in a total of more than 28,000 people.
Disclosures: Dr. Reid said that he had no relevant disclosures.
TORONTO — Calcium supplements appear to cause more harm than good, according to a meta-analysis of 28,000 participants in nine trials that includes a new analysis of more than 16,000 participants in the Women's Health Initiative, but the reanalysis has raised concerns among the WHI's original investigators.
“We calculate that for every 1,000 people treated with calcium for 5 years, it will lead to four additional myocardial infarctions, four additional strokes, and two additional deaths, while preventing three fractures,” Dr. Ian R. Reid said.
“I don't prescribe calcium supplements to anyone anymore for preventing bone fractures. People should get calcium from their diet,” said Dr. Reid of the University of Auckland, New Zealand. He speculated that a calcium supplement, even at a relatively modest dose of 500 mg, produces a “borderline hypercalcemia” that persists for several hours and raises the risk for MI or stroke, the same way that people in the highest quartile for normal blood calcium levels have an increased risk for cardiovascular disease events.
But the researchers who ran the Women's Health Initiative (WHI) study questioned the legitimacy of the new analysis beyond a hypothesis-generating exercise.
“The WHI investigators have concerns about the reanalysis and whether omitting the subgroups with favorable results is appropriate,” said Dr. JoAnn E. Manson of Harvard University and Brigham and Women's Hospital, both in Boston, and a WHI coinvestigator.
Dr. Reid and his associates initially reported that calcium supplement use was linked with a statistically significant 27% and 31% relatively increased risk for MI in two separate meta-analyses published online last July (BMJ 2010;341:c3691).
To further explore the impact of calcium supplements on cardiovascular risk, they reanalyzed data collected in a WHI study of more than 36,000 postmenopausal women randomized to receive a daily supplement with 500 mg calcium plus vitamin D or placebo. The original report from the WHI investigators showed that the calcium plus vitamin D did not significantly increase or decrease coronary or cerebrovascular risk in generally healthy postmenopausal women during 7 years of treatment (Circulation 2007;115:846–54).
But at baseline, more than 19,000 (54%) of the women in the study reported using a calcium supplement on their own, and at the end of the study 69% reported the practice, Dr. Reid said. To address the possible confounding, he focused on the 16,718 women in the WHI study who reported not using a personal calcium supplement at entry.
In this subgroup, the MI rates ran 2.5% in women randomized to calcium supplements and 2.0% in the placebo arm, a 22% relative increase that was statistically significant. The rate of MI or stroke ran a relative 16% higher among the women taking calcium, which was also statistically significant. The results showed no significant effect of calcium supplementation on stroke rate, Dr. Reid said.
But if Dr. Reid's analysis did not start with a prior hypothesis, this finding can only be considered hypothesis generating, not hypothesis testing, Dr. Manson said in an interview. “Many subgroups were tested in the WHI, and some would be expected to show significant effect modification by chance,” she pointed out.
When data from the WHI subgroup that did not use personal calcium supplements at baseline were added to the meta-analysis, the results showed that those who did take supplements had a 24% relative excess of MIs, a 15% relative excess of stroke, and a 16% relative excess of MI or stroke, Dr. Reid reported.
'I don't prescribe calcium supplements to anyone anymore for preventing bone fractures.'
Source DR. REID
Major Finding: People taking a calcium supplement showed a statistically significant 24% excess relative risk for MI, a 15% excess relative risk for stroke, and a 16% excess relative risk for MI or stroke.
Data Source: Meta-analysis of nine studies that compared calcium supplements with placebo in a total of more than 28,000 people.
Disclosures: Dr. Reid said that he had no relevant disclosures.
TORONTO — Calcium supplements appear to cause more harm than good, according to a meta-analysis of 28,000 participants in nine trials that includes a new analysis of more than 16,000 participants in the Women's Health Initiative, but the reanalysis has raised concerns among the WHI's original investigators.
“We calculate that for every 1,000 people treated with calcium for 5 years, it will lead to four additional myocardial infarctions, four additional strokes, and two additional deaths, while preventing three fractures,” Dr. Ian R. Reid said.
“I don't prescribe calcium supplements to anyone anymore for preventing bone fractures. People should get calcium from their diet,” said Dr. Reid of the University of Auckland, New Zealand. He speculated that a calcium supplement, even at a relatively modest dose of 500 mg, produces a “borderline hypercalcemia” that persists for several hours and raises the risk for MI or stroke, the same way that people in the highest quartile for normal blood calcium levels have an increased risk for cardiovascular disease events.
But the researchers who ran the Women's Health Initiative (WHI) study questioned the legitimacy of the new analysis beyond a hypothesis-generating exercise.
“The WHI investigators have concerns about the reanalysis and whether omitting the subgroups with favorable results is appropriate,” said Dr. JoAnn E. Manson of Harvard University and Brigham and Women's Hospital, both in Boston, and a WHI coinvestigator.
Dr. Reid and his associates initially reported that calcium supplement use was linked with a statistically significant 27% and 31% relatively increased risk for MI in two separate meta-analyses published online last July (BMJ 2010;341:c3691).
To further explore the impact of calcium supplements on cardiovascular risk, they reanalyzed data collected in a WHI study of more than 36,000 postmenopausal women randomized to receive a daily supplement with 500 mg calcium plus vitamin D or placebo. The original report from the WHI investigators showed that the calcium plus vitamin D did not significantly increase or decrease coronary or cerebrovascular risk in generally healthy postmenopausal women during 7 years of treatment (Circulation 2007;115:846–54).
But at baseline, more than 19,000 (54%) of the women in the study reported using a calcium supplement on their own, and at the end of the study 69% reported the practice, Dr. Reid said. To address the possible confounding, he focused on the 16,718 women in the WHI study who reported not using a personal calcium supplement at entry.
In this subgroup, the MI rates ran 2.5% in women randomized to calcium supplements and 2.0% in the placebo arm, a 22% relative increase that was statistically significant. The rate of MI or stroke ran a relative 16% higher among the women taking calcium, which was also statistically significant. The results showed no significant effect of calcium supplementation on stroke rate, Dr. Reid said.
But if Dr. Reid's analysis did not start with a prior hypothesis, this finding can only be considered hypothesis generating, not hypothesis testing, Dr. Manson said in an interview. “Many subgroups were tested in the WHI, and some would be expected to show significant effect modification by chance,” she pointed out.
When data from the WHI subgroup that did not use personal calcium supplements at baseline were added to the meta-analysis, the results showed that those who did take supplements had a 24% relative excess of MIs, a 15% relative excess of stroke, and a 16% relative excess of MI or stroke, Dr. Reid reported.
'I don't prescribe calcium supplements to anyone anymore for preventing bone fractures.'
Source DR. REID
Atypical Fractures Rise With Bisphosphonate Use
Major Finding: On average, 50 atypical fractures occurred for every 100,000 patients treated for 5 years, 100 atypical fractures occurred per 100,000 patients treated for 6 years, and almost 250 atypical fractures occurred per 100,000 patients treated for 12 years.
Data Source: Review of radiographs from 1,448 Kaiser California patients with a diaphyseal femur fracture, including 135 that met the atypical criteria.
Disclosures: Dr. Ott, Dr. Wang, and Dr. Ng had no disclosures. Dr. Shane has been a consultant to Amgen and has received research support from Merck, Novartis, and Eli Lilly & Co.
TORONTO — Patients with osteoporosis who are on bisphosphonate therapy clearly face an increased treatment-linked risk for an atypical femur fracture, but at a low rate that is dwarfed by the number of typical hip fractures the drugs prevent.
The risk for atypical fracture appears to rise substantially as time on the drug increases, but an atypical fracture can occur at any time, prompting experts to stress that a bisphosphonate should be given only to a patient who needs the treatment. And the prodromal thigh or groin pain that precedes a majority of atypical fractures should alert physicians to stop bisphosphonate treatment, although stopping the drug is no guarantee against a subsequent atypical fracture.
Above all, experts agreed, atypical fracture risk is no reason to deny bisphosphonate treatment to patients who need it, because these drugs improve bone mineral density and prevent typical hip fractures, and because in appropriate patients this benefit far exceeds the atypical fracture risk.
This consensus on how to view bisphosphonates and their risk for causing atypical fractures pervaded the meeting One multispeaker session during the meeting reviewed the data compiled by and the recommendations from an ASBMR task force that were published online last month, while several other speakers reported some of the incidence data that task force members considered when writing their recommendations (J. Bone Miner. Res. 2010 Oct. 25 [doi:10.1002/jbmr.253]).
“The message is that for patients with osteoporosis at high risk of having a fracture, treatment with a bisphosphonate will benefit far more that the risk for an atypical fractures,” said Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York, and co-chair of the task force.
The largest and most comprehensive look at atypical fracture rates came from data compiled from the 2.6 million beneficiaries older than 45 years enrolled in Kaiser California. During January 2007-December 2009, 15,819 people had femur fractures, excluding those from major trauma, those secondary to Paget's disease or metastatic lesions, or periprosthetic fractures. The researchers reviewed the radiographs for 1,448 of these fractures located in the diaphyseal region.
Of the reviewed fractures, the researchers identified 135 as atypical, Dr. Susan Ott of the University of Washington, Seattle, reported at the meeting. The 135 patients with atypical fractures were 98% women, with an average age of 71 years and an average body mass index of 26.6 kg/m
All but 4% of the atypical fracture patients received a bisphosphonate at the time of fracture, and were on their regimen for an average of 6 years. Two-thirds had prodromal thigh pain, and 26% had bilateral atypical fractures. In all, 60% of the fractures occurred in the femur shaft, and 40% were in the subtrochanteric region.
The most common age at fracture was 65–69 years, with a majority of atypical fracture patients aged 65 or older. The fracture rate rose steadily with increasing years of bisphosphonate use, with most fractures occurring in patients who had used the drugs for at least 5 years, even though these long-term users represented a small minority of all Kaiser patients who used a bisphosphonate during the 3 years studied. The number of fractures per 100,000 people exposed rose steadily with increasing years of use, reaching 50 per 100,000 when bisphosphonate use continued for 5 years and 100 fractures per 100,000 patients in those using the drug for 6 years, and then continuing to rise steadily with added years of use, reaching a high of nearly 250 fractures for every 100,000 patients exposed to a bisphosphonate for 12 years.
“These data do not suggest you should stop using bisphosphonates, especially in women with osteoporosis. Bisphosphonates look pretty safe for the first few years,” Dr. Ott said. But, she added, “the data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.”
The ASBMR task force reviewed Dr. Ott's data before issuing its recommendations last month. The data “were very informative for establishing incidence rates for these fractures,” Dr. Shane said in an interview.
In another talk at the meeting, John Wang, Ph.D., a statistician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, presented additional data documenting the relative risks of atypical and typical fractures with bisphosphonate treatment.
Patients taking a bisphosphonate face a risk of about 1 additional subtrochanteric hip fracture for every 100 typical hip fractures prevented, according to an analysis of national data during 1996–2007. The new data present no direct evidence for a role of bisphosphonate use in causing subtrochanteric hip fractures, which along with femoral shaft fractures constitute the “atypical” category. But the temporal link between the steady increase in bisphosphonate use among elderly American women during 1996–2007 and the concurrent rise in subtrochanteric fractures also in elderly American women strongly suggests that a causal link exists, Dr. Wang said.
He analyzed data on U.S. subtrochanteric fracture rates from the Nationwide Inpatient Sample from 1996 to 2007, along with data on U.S. bisphosphonate use from the Medical Expenditure Panel Survey. The analysis suggested that bisphosphonate use led to one subtrochanteric fracture for every 100 typical hip fractures prevented, Dr. Wang said, which was similar to the relationship in Dr. Ott's data.
“We have shown a temporal relationship; one precedes the other,” Dr. Wang said in an interview. “That is the first step in showing a causal relationship.” Proof would require a prospective study of atypical fracture incidence in highly compliant patients, he said.
Dr. John Wang discusses data on subtrochanteric femoral fractures in an interview at
Source Mitchel L. Zoler/Elsevier Global Medical Newswww.rheumatologynews.com
Recommended Steps to Minimize Risk
Despite substantial evidence linking long-term bisphosphonate use and an increased rate of atypical femur fractures, bisphosphonates remain an effective and attractive drug class for treating osteoporosis.
The task force assembled by the ASBMR recommended several steps for physicians to take when they prescribe a bisphosphonate to reduce atypical fracture risk.
Patients with a low absolute fracture risk should not receive a bisphosphonate, said Dr. Peter R. Ebeling, a task force member, summarizing the group's recommendations at the meeting.
Patients with secondary causes of rapid bone loss may not need long-term bisphosphonate treatment. Continued use beyond 5 years should be evaluated annually, said Dr. Ebeling of the University of Melbourne.
Patients without a recent fracture and with a femoral neck T score of more than −2.5 after 5 years of continuous bisphosphonate treatment should receive consideration for a drug holiday. Patients taken off bisphosphonate treatment should undergo an annual assessment of their clinical status, markers of bone turnover, bone density, and their fracture risk.
Because a majority of patients who developed an atypical fracture on bisphosphonate treatment had prodromal pain in their thigh or groin, physicians should alert patients to watch for and promptly report such pain. When suspicious pain occurs, the patient needs “urgent” radiographic assessment of both femora, even for unilateral pain, Dr. Ebeling said. If the radiographs appear normal, perform a follow-up examination by MRI or radionuclide scintigraphy scanning.
If a patient has a fracture while on a bisphosphonate, treatment with the bisphosphonate or any other potent antiresorptive drug should stop. At that time, assess the patient's calcium and vitamin D status and prescribe adequate supplementation if needed. The physician should consider prescribing teriparatide to improve fracture healing, particularly if it appears that the fracture has not healed by 4–6 weeks following surgical repair.
Dr. Ebeling has served as a speaker for Merck & Co., Eli Lilly, Novartis, and Sanofi-Aventis; been on advisory boards for and received research grants from Merck, Amgen, and Novartis; and received educational grants from Amgen, Eli Lilly, and Sanofi-Aventis.
Physicians should alert patients to watch for and promptly report prodromal pain in their thigh or groin.
Source DR. EBELING
Major Finding: On average, 50 atypical fractures occurred for every 100,000 patients treated for 5 years, 100 atypical fractures occurred per 100,000 patients treated for 6 years, and almost 250 atypical fractures occurred per 100,000 patients treated for 12 years.
Data Source: Review of radiographs from 1,448 Kaiser California patients with a diaphyseal femur fracture, including 135 that met the atypical criteria.
Disclosures: Dr. Ott, Dr. Wang, and Dr. Ng had no disclosures. Dr. Shane has been a consultant to Amgen and has received research support from Merck, Novartis, and Eli Lilly & Co.
TORONTO — Patients with osteoporosis who are on bisphosphonate therapy clearly face an increased treatment-linked risk for an atypical femur fracture, but at a low rate that is dwarfed by the number of typical hip fractures the drugs prevent.
The risk for atypical fracture appears to rise substantially as time on the drug increases, but an atypical fracture can occur at any time, prompting experts to stress that a bisphosphonate should be given only to a patient who needs the treatment. And the prodromal thigh or groin pain that precedes a majority of atypical fractures should alert physicians to stop bisphosphonate treatment, although stopping the drug is no guarantee against a subsequent atypical fracture.
Above all, experts agreed, atypical fracture risk is no reason to deny bisphosphonate treatment to patients who need it, because these drugs improve bone mineral density and prevent typical hip fractures, and because in appropriate patients this benefit far exceeds the atypical fracture risk.
This consensus on how to view bisphosphonates and their risk for causing atypical fractures pervaded the meeting One multispeaker session during the meeting reviewed the data compiled by and the recommendations from an ASBMR task force that were published online last month, while several other speakers reported some of the incidence data that task force members considered when writing their recommendations (J. Bone Miner. Res. 2010 Oct. 25 [doi:10.1002/jbmr.253]).
“The message is that for patients with osteoporosis at high risk of having a fracture, treatment with a bisphosphonate will benefit far more that the risk for an atypical fractures,” said Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York, and co-chair of the task force.
The largest and most comprehensive look at atypical fracture rates came from data compiled from the 2.6 million beneficiaries older than 45 years enrolled in Kaiser California. During January 2007-December 2009, 15,819 people had femur fractures, excluding those from major trauma, those secondary to Paget's disease or metastatic lesions, or periprosthetic fractures. The researchers reviewed the radiographs for 1,448 of these fractures located in the diaphyseal region.
Of the reviewed fractures, the researchers identified 135 as atypical, Dr. Susan Ott of the University of Washington, Seattle, reported at the meeting. The 135 patients with atypical fractures were 98% women, with an average age of 71 years and an average body mass index of 26.6 kg/m
All but 4% of the atypical fracture patients received a bisphosphonate at the time of fracture, and were on their regimen for an average of 6 years. Two-thirds had prodromal thigh pain, and 26% had bilateral atypical fractures. In all, 60% of the fractures occurred in the femur shaft, and 40% were in the subtrochanteric region.
The most common age at fracture was 65–69 years, with a majority of atypical fracture patients aged 65 or older. The fracture rate rose steadily with increasing years of bisphosphonate use, with most fractures occurring in patients who had used the drugs for at least 5 years, even though these long-term users represented a small minority of all Kaiser patients who used a bisphosphonate during the 3 years studied. The number of fractures per 100,000 people exposed rose steadily with increasing years of use, reaching 50 per 100,000 when bisphosphonate use continued for 5 years and 100 fractures per 100,000 patients in those using the drug for 6 years, and then continuing to rise steadily with added years of use, reaching a high of nearly 250 fractures for every 100,000 patients exposed to a bisphosphonate for 12 years.
“These data do not suggest you should stop using bisphosphonates, especially in women with osteoporosis. Bisphosphonates look pretty safe for the first few years,” Dr. Ott said. But, she added, “the data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.”
The ASBMR task force reviewed Dr. Ott's data before issuing its recommendations last month. The data “were very informative for establishing incidence rates for these fractures,” Dr. Shane said in an interview.
In another talk at the meeting, John Wang, Ph.D., a statistician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, presented additional data documenting the relative risks of atypical and typical fractures with bisphosphonate treatment.
Patients taking a bisphosphonate face a risk of about 1 additional subtrochanteric hip fracture for every 100 typical hip fractures prevented, according to an analysis of national data during 1996–2007. The new data present no direct evidence for a role of bisphosphonate use in causing subtrochanteric hip fractures, which along with femoral shaft fractures constitute the “atypical” category. But the temporal link between the steady increase in bisphosphonate use among elderly American women during 1996–2007 and the concurrent rise in subtrochanteric fractures also in elderly American women strongly suggests that a causal link exists, Dr. Wang said.
He analyzed data on U.S. subtrochanteric fracture rates from the Nationwide Inpatient Sample from 1996 to 2007, along with data on U.S. bisphosphonate use from the Medical Expenditure Panel Survey. The analysis suggested that bisphosphonate use led to one subtrochanteric fracture for every 100 typical hip fractures prevented, Dr. Wang said, which was similar to the relationship in Dr. Ott's data.
“We have shown a temporal relationship; one precedes the other,” Dr. Wang said in an interview. “That is the first step in showing a causal relationship.” Proof would require a prospective study of atypical fracture incidence in highly compliant patients, he said.
Dr. John Wang discusses data on subtrochanteric femoral fractures in an interview at
Source Mitchel L. Zoler/Elsevier Global Medical Newswww.rheumatologynews.com
Recommended Steps to Minimize Risk
Despite substantial evidence linking long-term bisphosphonate use and an increased rate of atypical femur fractures, bisphosphonates remain an effective and attractive drug class for treating osteoporosis.
The task force assembled by the ASBMR recommended several steps for physicians to take when they prescribe a bisphosphonate to reduce atypical fracture risk.
Patients with a low absolute fracture risk should not receive a bisphosphonate, said Dr. Peter R. Ebeling, a task force member, summarizing the group's recommendations at the meeting.
Patients with secondary causes of rapid bone loss may not need long-term bisphosphonate treatment. Continued use beyond 5 years should be evaluated annually, said Dr. Ebeling of the University of Melbourne.
Patients without a recent fracture and with a femoral neck T score of more than −2.5 after 5 years of continuous bisphosphonate treatment should receive consideration for a drug holiday. Patients taken off bisphosphonate treatment should undergo an annual assessment of their clinical status, markers of bone turnover, bone density, and their fracture risk.
Because a majority of patients who developed an atypical fracture on bisphosphonate treatment had prodromal pain in their thigh or groin, physicians should alert patients to watch for and promptly report such pain. When suspicious pain occurs, the patient needs “urgent” radiographic assessment of both femora, even for unilateral pain, Dr. Ebeling said. If the radiographs appear normal, perform a follow-up examination by MRI or radionuclide scintigraphy scanning.
If a patient has a fracture while on a bisphosphonate, treatment with the bisphosphonate or any other potent antiresorptive drug should stop. At that time, assess the patient's calcium and vitamin D status and prescribe adequate supplementation if needed. The physician should consider prescribing teriparatide to improve fracture healing, particularly if it appears that the fracture has not healed by 4–6 weeks following surgical repair.
Dr. Ebeling has served as a speaker for Merck & Co., Eli Lilly, Novartis, and Sanofi-Aventis; been on advisory boards for and received research grants from Merck, Amgen, and Novartis; and received educational grants from Amgen, Eli Lilly, and Sanofi-Aventis.
Physicians should alert patients to watch for and promptly report prodromal pain in their thigh or groin.
Source DR. EBELING
Major Finding: On average, 50 atypical fractures occurred for every 100,000 patients treated for 5 years, 100 atypical fractures occurred per 100,000 patients treated for 6 years, and almost 250 atypical fractures occurred per 100,000 patients treated for 12 years.
Data Source: Review of radiographs from 1,448 Kaiser California patients with a diaphyseal femur fracture, including 135 that met the atypical criteria.
Disclosures: Dr. Ott, Dr. Wang, and Dr. Ng had no disclosures. Dr. Shane has been a consultant to Amgen and has received research support from Merck, Novartis, and Eli Lilly & Co.
TORONTO — Patients with osteoporosis who are on bisphosphonate therapy clearly face an increased treatment-linked risk for an atypical femur fracture, but at a low rate that is dwarfed by the number of typical hip fractures the drugs prevent.
The risk for atypical fracture appears to rise substantially as time on the drug increases, but an atypical fracture can occur at any time, prompting experts to stress that a bisphosphonate should be given only to a patient who needs the treatment. And the prodromal thigh or groin pain that precedes a majority of atypical fractures should alert physicians to stop bisphosphonate treatment, although stopping the drug is no guarantee against a subsequent atypical fracture.
Above all, experts agreed, atypical fracture risk is no reason to deny bisphosphonate treatment to patients who need it, because these drugs improve bone mineral density and prevent typical hip fractures, and because in appropriate patients this benefit far exceeds the atypical fracture risk.
This consensus on how to view bisphosphonates and their risk for causing atypical fractures pervaded the meeting One multispeaker session during the meeting reviewed the data compiled by and the recommendations from an ASBMR task force that were published online last month, while several other speakers reported some of the incidence data that task force members considered when writing their recommendations (J. Bone Miner. Res. 2010 Oct. 25 [doi:10.1002/jbmr.253]).
“The message is that for patients with osteoporosis at high risk of having a fracture, treatment with a bisphosphonate will benefit far more that the risk for an atypical fractures,” said Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York, and co-chair of the task force.
The largest and most comprehensive look at atypical fracture rates came from data compiled from the 2.6 million beneficiaries older than 45 years enrolled in Kaiser California. During January 2007-December 2009, 15,819 people had femur fractures, excluding those from major trauma, those secondary to Paget's disease or metastatic lesions, or periprosthetic fractures. The researchers reviewed the radiographs for 1,448 of these fractures located in the diaphyseal region.
Of the reviewed fractures, the researchers identified 135 as atypical, Dr. Susan Ott of the University of Washington, Seattle, reported at the meeting. The 135 patients with atypical fractures were 98% women, with an average age of 71 years and an average body mass index of 26.6 kg/m
All but 4% of the atypical fracture patients received a bisphosphonate at the time of fracture, and were on their regimen for an average of 6 years. Two-thirds had prodromal thigh pain, and 26% had bilateral atypical fractures. In all, 60% of the fractures occurred in the femur shaft, and 40% were in the subtrochanteric region.
The most common age at fracture was 65–69 years, with a majority of atypical fracture patients aged 65 or older. The fracture rate rose steadily with increasing years of bisphosphonate use, with most fractures occurring in patients who had used the drugs for at least 5 years, even though these long-term users represented a small minority of all Kaiser patients who used a bisphosphonate during the 3 years studied. The number of fractures per 100,000 people exposed rose steadily with increasing years of use, reaching 50 per 100,000 when bisphosphonate use continued for 5 years and 100 fractures per 100,000 patients in those using the drug for 6 years, and then continuing to rise steadily with added years of use, reaching a high of nearly 250 fractures for every 100,000 patients exposed to a bisphosphonate for 12 years.
“These data do not suggest you should stop using bisphosphonates, especially in women with osteoporosis. Bisphosphonates look pretty safe for the first few years,” Dr. Ott said. But, she added, “the data argue that if a patient does not have osteoporosis, then bisphosphonates are not the appropriate drug.”
The ASBMR task force reviewed Dr. Ott's data before issuing its recommendations last month. The data “were very informative for establishing incidence rates for these fractures,” Dr. Shane said in an interview.
In another talk at the meeting, John Wang, Ph.D., a statistician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, presented additional data documenting the relative risks of atypical and typical fractures with bisphosphonate treatment.
Patients taking a bisphosphonate face a risk of about 1 additional subtrochanteric hip fracture for every 100 typical hip fractures prevented, according to an analysis of national data during 1996–2007. The new data present no direct evidence for a role of bisphosphonate use in causing subtrochanteric hip fractures, which along with femoral shaft fractures constitute the “atypical” category. But the temporal link between the steady increase in bisphosphonate use among elderly American women during 1996–2007 and the concurrent rise in subtrochanteric fractures also in elderly American women strongly suggests that a causal link exists, Dr. Wang said.
He analyzed data on U.S. subtrochanteric fracture rates from the Nationwide Inpatient Sample from 1996 to 2007, along with data on U.S. bisphosphonate use from the Medical Expenditure Panel Survey. The analysis suggested that bisphosphonate use led to one subtrochanteric fracture for every 100 typical hip fractures prevented, Dr. Wang said, which was similar to the relationship in Dr. Ott's data.
“We have shown a temporal relationship; one precedes the other,” Dr. Wang said in an interview. “That is the first step in showing a causal relationship.” Proof would require a prospective study of atypical fracture incidence in highly compliant patients, he said.
Dr. John Wang discusses data on subtrochanteric femoral fractures in an interview at
Source Mitchel L. Zoler/Elsevier Global Medical Newswww.rheumatologynews.com
Recommended Steps to Minimize Risk
Despite substantial evidence linking long-term bisphosphonate use and an increased rate of atypical femur fractures, bisphosphonates remain an effective and attractive drug class for treating osteoporosis.
The task force assembled by the ASBMR recommended several steps for physicians to take when they prescribe a bisphosphonate to reduce atypical fracture risk.
Patients with a low absolute fracture risk should not receive a bisphosphonate, said Dr. Peter R. Ebeling, a task force member, summarizing the group's recommendations at the meeting.
Patients with secondary causes of rapid bone loss may not need long-term bisphosphonate treatment. Continued use beyond 5 years should be evaluated annually, said Dr. Ebeling of the University of Melbourne.
Patients without a recent fracture and with a femoral neck T score of more than −2.5 after 5 years of continuous bisphosphonate treatment should receive consideration for a drug holiday. Patients taken off bisphosphonate treatment should undergo an annual assessment of their clinical status, markers of bone turnover, bone density, and their fracture risk.
Because a majority of patients who developed an atypical fracture on bisphosphonate treatment had prodromal pain in their thigh or groin, physicians should alert patients to watch for and promptly report such pain. When suspicious pain occurs, the patient needs “urgent” radiographic assessment of both femora, even for unilateral pain, Dr. Ebeling said. If the radiographs appear normal, perform a follow-up examination by MRI or radionuclide scintigraphy scanning.
If a patient has a fracture while on a bisphosphonate, treatment with the bisphosphonate or any other potent antiresorptive drug should stop. At that time, assess the patient's calcium and vitamin D status and prescribe adequate supplementation if needed. The physician should consider prescribing teriparatide to improve fracture healing, particularly if it appears that the fracture has not healed by 4–6 weeks following surgical repair.
Dr. Ebeling has served as a speaker for Merck & Co., Eli Lilly, Novartis, and Sanofi-Aventis; been on advisory boards for and received research grants from Merck, Amgen, and Novartis; and received educational grants from Amgen, Eli Lilly, and Sanofi-Aventis.
Physicians should alert patients to watch for and promptly report prodromal pain in their thigh or groin.
Source DR. EBELING
Osteotomy Use Drops as Knee Arthroplasties Rise
Major Finding: In Sweden during 1998–2007, use of high-tibial osteotomy to treat severe knee osteoarthritis fell, to a 2% rate of all knee repair surgeries in 2007. Concurrently, use of total-knee arthroplasty rose, especially in patients younger than 55 years.
Data Source: Review of 3,196 knee surgeries during 1998–2007, using data from the Swedish national health agency.
Disclosures: Dr. W-Dahl had no disclosures.
BRUSSELS — Use of high-tibial osteotomy as surgical treatment for knee osteoarthritis dwindled during the decade ending in 2007, according to data collected on nearly 2,900 Swedish patients during the 10-year period.
During the same decade, use of total-knee arthroplasty (TKA) for knee osteoarthritis increased, especially in patients younger than 55 years, said Annette W-Dahl, Ph.D.
Despite diminished use, the revision rate following high-tibial osteotomy (HTO) remained modest, with a 29% rate after 10 years. That performance record for HTO suggests that using it first has the potential to delay significantly the need for TKA in patients with severe knee osteoarthritis, making HTO an attractive option for younger patients, said Dr. W-Dahl, a researcher in the department of orthopedics at Lund (Sweden) University.
During 1998–2007, HTO use in Sweden fell from about 5% of primary knee reconstructions for osteoarthritis in 1998 to about 2% 10 years later. In contrast, use of TKA rose from 78% in 1998 to about 90% in 2007. Use of a third surgical option, unicompartmental knee arthroplasty, also dropped during the decade studied, from 17% in 1998 to 8% in 2007.
Use of HTO also lags today in the United States, with an annual rate probably similar to Sweden's, commented Dr. Jeffrey N. Katz, professor of medicine at Harvard Medical School in Boston and director of the orthopedics and arthritis center for outcomes research at Brigham and Women's Hospital in that city. It remains unclear whether use of HTO actually delays the time when a patient with severe osteoarthritis needs TKA, he added.
The new analysis used data collected by the Swedish National Board of Health and Welfare. During the decade reviewed, surgeons performed 3,196 HTOs in 2,893 patients. Two-thirds were men, and their average age was 52 years, with 62% of the patients being younger than 55 years, and 97% aged 65 years or younger. The annual tally of HTOs fell from nearly 400 in 1998 to about 260 in 2007.
Analysis of patients younger than 55 years showed that use of TKA in this age group jumped from about 100 in 1998 to more than 500 in 2007. Concurrently, use of HTO dropped from about 230 in 1998 to about 180 in 2007; use of unicompartmental knee arthroplasty remained relatively stable throughout the decade, with about 100 cases done each year, Dr. W-Dahl said at the congress, which was organized by the Osteoarthritis Research Society International.
The cumulative need for revision surgery in patients who initially underwent HTO surgery ran 29% during the period studied, with women having a statistically significant 30% higher revision rate, compared with men, after adjustment for age and year of surgery.
Among patients younger than 65 years, 27% of the HTO patients required a revision, compared with 16% of patients who underwent unicompartmental knee arthroplasty and 8% with a TKA.
Women who underwent high-tibial osteotomy had a 30% higher revision rate than men.
Source DR. W-DAHL
Major Finding: In Sweden during 1998–2007, use of high-tibial osteotomy to treat severe knee osteoarthritis fell, to a 2% rate of all knee repair surgeries in 2007. Concurrently, use of total-knee arthroplasty rose, especially in patients younger than 55 years.
Data Source: Review of 3,196 knee surgeries during 1998–2007, using data from the Swedish national health agency.
Disclosures: Dr. W-Dahl had no disclosures.
BRUSSELS — Use of high-tibial osteotomy as surgical treatment for knee osteoarthritis dwindled during the decade ending in 2007, according to data collected on nearly 2,900 Swedish patients during the 10-year period.
During the same decade, use of total-knee arthroplasty (TKA) for knee osteoarthritis increased, especially in patients younger than 55 years, said Annette W-Dahl, Ph.D.
Despite diminished use, the revision rate following high-tibial osteotomy (HTO) remained modest, with a 29% rate after 10 years. That performance record for HTO suggests that using it first has the potential to delay significantly the need for TKA in patients with severe knee osteoarthritis, making HTO an attractive option for younger patients, said Dr. W-Dahl, a researcher in the department of orthopedics at Lund (Sweden) University.
During 1998–2007, HTO use in Sweden fell from about 5% of primary knee reconstructions for osteoarthritis in 1998 to about 2% 10 years later. In contrast, use of TKA rose from 78% in 1998 to about 90% in 2007. Use of a third surgical option, unicompartmental knee arthroplasty, also dropped during the decade studied, from 17% in 1998 to 8% in 2007.
Use of HTO also lags today in the United States, with an annual rate probably similar to Sweden's, commented Dr. Jeffrey N. Katz, professor of medicine at Harvard Medical School in Boston and director of the orthopedics and arthritis center for outcomes research at Brigham and Women's Hospital in that city. It remains unclear whether use of HTO actually delays the time when a patient with severe osteoarthritis needs TKA, he added.
The new analysis used data collected by the Swedish National Board of Health and Welfare. During the decade reviewed, surgeons performed 3,196 HTOs in 2,893 patients. Two-thirds were men, and their average age was 52 years, with 62% of the patients being younger than 55 years, and 97% aged 65 years or younger. The annual tally of HTOs fell from nearly 400 in 1998 to about 260 in 2007.
Analysis of patients younger than 55 years showed that use of TKA in this age group jumped from about 100 in 1998 to more than 500 in 2007. Concurrently, use of HTO dropped from about 230 in 1998 to about 180 in 2007; use of unicompartmental knee arthroplasty remained relatively stable throughout the decade, with about 100 cases done each year, Dr. W-Dahl said at the congress, which was organized by the Osteoarthritis Research Society International.
The cumulative need for revision surgery in patients who initially underwent HTO surgery ran 29% during the period studied, with women having a statistically significant 30% higher revision rate, compared with men, after adjustment for age and year of surgery.
Among patients younger than 65 years, 27% of the HTO patients required a revision, compared with 16% of patients who underwent unicompartmental knee arthroplasty and 8% with a TKA.
Women who underwent high-tibial osteotomy had a 30% higher revision rate than men.
Source DR. W-DAHL
Major Finding: In Sweden during 1998–2007, use of high-tibial osteotomy to treat severe knee osteoarthritis fell, to a 2% rate of all knee repair surgeries in 2007. Concurrently, use of total-knee arthroplasty rose, especially in patients younger than 55 years.
Data Source: Review of 3,196 knee surgeries during 1998–2007, using data from the Swedish national health agency.
Disclosures: Dr. W-Dahl had no disclosures.
BRUSSELS — Use of high-tibial osteotomy as surgical treatment for knee osteoarthritis dwindled during the decade ending in 2007, according to data collected on nearly 2,900 Swedish patients during the 10-year period.
During the same decade, use of total-knee arthroplasty (TKA) for knee osteoarthritis increased, especially in patients younger than 55 years, said Annette W-Dahl, Ph.D.
Despite diminished use, the revision rate following high-tibial osteotomy (HTO) remained modest, with a 29% rate after 10 years. That performance record for HTO suggests that using it first has the potential to delay significantly the need for TKA in patients with severe knee osteoarthritis, making HTO an attractive option for younger patients, said Dr. W-Dahl, a researcher in the department of orthopedics at Lund (Sweden) University.
During 1998–2007, HTO use in Sweden fell from about 5% of primary knee reconstructions for osteoarthritis in 1998 to about 2% 10 years later. In contrast, use of TKA rose from 78% in 1998 to about 90% in 2007. Use of a third surgical option, unicompartmental knee arthroplasty, also dropped during the decade studied, from 17% in 1998 to 8% in 2007.
Use of HTO also lags today in the United States, with an annual rate probably similar to Sweden's, commented Dr. Jeffrey N. Katz, professor of medicine at Harvard Medical School in Boston and director of the orthopedics and arthritis center for outcomes research at Brigham and Women's Hospital in that city. It remains unclear whether use of HTO actually delays the time when a patient with severe osteoarthritis needs TKA, he added.
The new analysis used data collected by the Swedish National Board of Health and Welfare. During the decade reviewed, surgeons performed 3,196 HTOs in 2,893 patients. Two-thirds were men, and their average age was 52 years, with 62% of the patients being younger than 55 years, and 97% aged 65 years or younger. The annual tally of HTOs fell from nearly 400 in 1998 to about 260 in 2007.
Analysis of patients younger than 55 years showed that use of TKA in this age group jumped from about 100 in 1998 to more than 500 in 2007. Concurrently, use of HTO dropped from about 230 in 1998 to about 180 in 2007; use of unicompartmental knee arthroplasty remained relatively stable throughout the decade, with about 100 cases done each year, Dr. W-Dahl said at the congress, which was organized by the Osteoarthritis Research Society International.
The cumulative need for revision surgery in patients who initially underwent HTO surgery ran 29% during the period studied, with women having a statistically significant 30% higher revision rate, compared with men, after adjustment for age and year of surgery.
Among patients younger than 65 years, 27% of the HTO patients required a revision, compared with 16% of patients who underwent unicompartmental knee arthroplasty and 8% with a TKA.
Women who underwent high-tibial osteotomy had a 30% higher revision rate than men.
Source DR. W-DAHL
Middle-Aged Americans Lead Rise in Knee Replacement
Major Finding: The number of total knee replacements done on Americans aged 45–64 rose from 68,000 in 1997 to 221,000 in 2007, more than tripling. The number done in Americans aged 65–84 rose from 183,000 in 1997 to 303,000 in 2007, a 66% increase.
Data Source: The Nationwide Inpatient Sample, annual data collection sponsored by the Agency for Healthcare Research and Quality.
Disclosures: Dr. Losina and Dr. Katz had no relevant disclosures.
BRUSSELS — Middle-aged Americans seem to have embraced total knee replacement, with the number of surgeries more than tripling from 68,000 in 1997 to 221,000 in 2007, according to data collected in the Nationwide Inpatient Sample.
This increase, which helped to drive an overall doubling of all U.S. total knee replacements during 1997–2007, did not result merely from the growing prevalence of obesity and the demographic growth of the 45- to 64-year-old age group, judging from the findings from further analysis of the data.
Those two factors accounted for, at most, a quarter of the increase, Elena Losina, Ph.D., reported in a poster at the congress.
A combination of additional factors may explain the rest of the rise, Dr. Losina said in an interview. These include:
▸ A rise in sports injuries that have led to posttraumatic arthritis, a trend exacerbated by the increased sports participation that began in the late 20th century.
▸ Increased willingness of surgeons to perform total knee replacement on patients younger than 65.
▸ Increased familiarity and comfort with the surgery – which did not become available until the late 1970s – leading to increased demand by younger patients.
“It's a combination of more early, advanced arthritis, shifting indications, and more willingness to operate,” said Dr. Losina, codirector of the Orthopedics and Arthritis Center for Outcomes Research at Brigham and Women's Hospital in Boston. hMore and more patients have been referred and at least consider surgery.”
“Are patients in the [45- to 64-year-old] age group being offered surgery and accepting surgery more often? Is it because there is more osteoarthritis because of injury? Does it reflect patient demand in that age group? It's all speculation,” agreed Dr. Jeffrey N. Katz, director of the center, and professor of medicine and orthopedic surgery at Harvard Medical School in Boston.
Some of the same factors also drove increased knee-replacement rates in patients aged 65–84 years, but the slope of the rise was not nearly as steep. In the group aged 65–84 years old, the number of U.S. total knee replacement surgeries rose 66% from 183,000 in 1997 to 303,000 in 2007. The absolute rise of 120,000 additional surgeries in the elderly clearly trailed the 153,000 increase in middle-aged U.S. adults.
But these numbers may not remain on their current trajectory. The surgery is not sustainable, Dr. Losina said at the congress, which was sponsored by the Osteoarthritis Research Society International.
“I think the growth will level off. I think Medicare will be capped, forcing patients to pay for knee replacement out of pocket, and eligibility criteria will tighten,” she said. Currently, “we don't know what proportion of the surgery is appropriate,” she added.
Another unknown is what middle-aged patients who receive knee replacements can expect about the eventual need for revision surgery. “It would be very surprising if revision rates were not higher in younger patients,” said Dr. Katz, who coauthored the poster.
Younger patients sometimes try to resume the activities that initially drove them to knee surgery. “We need to study [revision] data from younger patients. The burden of revision in younger patients is unknown; it hasn't been studied.” Dr. Losina said.
“We know that prosthetic knees are durable in older patients, but in older patients there is a strong, competing risk from mortality,” she said. In the elderly, the revision rate for total knee replacement is roughly 1% per year following surgery.
“It's a very successful surgery. People are miserable and can't move and function because of their knee problems and total knee replacement brings them back to life. I think that explains the greater willingness” to use knee surgery on younger patients. “But we need to understand the societal and population implications of the trend we see,” Dr. Losina said.
Her study used data collected in the Nationwide Inpatient Sample by the Agency for Healthcare Research and Quality, which currently collects data from more than 1,000 hospitals in 42 states.
The data showed a doubling of knee surgery overall from 1997 to a national total of 550,000 in 2007, a period when the U.S. population grew by just 15%.
To watch an interview with Dr. Elena Losina on knee surgery rates, visit
Source Mitchel L. Zoler/Elsevier Global Medical Newswww.rheumatologynews.com
Major Finding: The number of total knee replacements done on Americans aged 45–64 rose from 68,000 in 1997 to 221,000 in 2007, more than tripling. The number done in Americans aged 65–84 rose from 183,000 in 1997 to 303,000 in 2007, a 66% increase.
Data Source: The Nationwide Inpatient Sample, annual data collection sponsored by the Agency for Healthcare Research and Quality.
Disclosures: Dr. Losina and Dr. Katz had no relevant disclosures.
BRUSSELS — Middle-aged Americans seem to have embraced total knee replacement, with the number of surgeries more than tripling from 68,000 in 1997 to 221,000 in 2007, according to data collected in the Nationwide Inpatient Sample.
This increase, which helped to drive an overall doubling of all U.S. total knee replacements during 1997–2007, did not result merely from the growing prevalence of obesity and the demographic growth of the 45- to 64-year-old age group, judging from the findings from further analysis of the data.
Those two factors accounted for, at most, a quarter of the increase, Elena Losina, Ph.D., reported in a poster at the congress.
A combination of additional factors may explain the rest of the rise, Dr. Losina said in an interview. These include:
▸ A rise in sports injuries that have led to posttraumatic arthritis, a trend exacerbated by the increased sports participation that began in the late 20th century.
▸ Increased willingness of surgeons to perform total knee replacement on patients younger than 65.
▸ Increased familiarity and comfort with the surgery – which did not become available until the late 1970s – leading to increased demand by younger patients.
“It's a combination of more early, advanced arthritis, shifting indications, and more willingness to operate,” said Dr. Losina, codirector of the Orthopedics and Arthritis Center for Outcomes Research at Brigham and Women's Hospital in Boston. hMore and more patients have been referred and at least consider surgery.”
“Are patients in the [45- to 64-year-old] age group being offered surgery and accepting surgery more often? Is it because there is more osteoarthritis because of injury? Does it reflect patient demand in that age group? It's all speculation,” agreed Dr. Jeffrey N. Katz, director of the center, and professor of medicine and orthopedic surgery at Harvard Medical School in Boston.
Some of the same factors also drove increased knee-replacement rates in patients aged 65–84 years, but the slope of the rise was not nearly as steep. In the group aged 65–84 years old, the number of U.S. total knee replacement surgeries rose 66% from 183,000 in 1997 to 303,000 in 2007. The absolute rise of 120,000 additional surgeries in the elderly clearly trailed the 153,000 increase in middle-aged U.S. adults.
But these numbers may not remain on their current trajectory. The surgery is not sustainable, Dr. Losina said at the congress, which was sponsored by the Osteoarthritis Research Society International.
“I think the growth will level off. I think Medicare will be capped, forcing patients to pay for knee replacement out of pocket, and eligibility criteria will tighten,” she said. Currently, “we don't know what proportion of the surgery is appropriate,” she added.
Another unknown is what middle-aged patients who receive knee replacements can expect about the eventual need for revision surgery. “It would be very surprising if revision rates were not higher in younger patients,” said Dr. Katz, who coauthored the poster.
Younger patients sometimes try to resume the activities that initially drove them to knee surgery. “We need to study [revision] data from younger patients. The burden of revision in younger patients is unknown; it hasn't been studied.” Dr. Losina said.
“We know that prosthetic knees are durable in older patients, but in older patients there is a strong, competing risk from mortality,” she said. In the elderly, the revision rate for total knee replacement is roughly 1% per year following surgery.
“It's a very successful surgery. People are miserable and can't move and function because of their knee problems and total knee replacement brings them back to life. I think that explains the greater willingness” to use knee surgery on younger patients. “But we need to understand the societal and population implications of the trend we see,” Dr. Losina said.
Her study used data collected in the Nationwide Inpatient Sample by the Agency for Healthcare Research and Quality, which currently collects data from more than 1,000 hospitals in 42 states.
The data showed a doubling of knee surgery overall from 1997 to a national total of 550,000 in 2007, a period when the U.S. population grew by just 15%.
To watch an interview with Dr. Elena Losina on knee surgery rates, visit
Source Mitchel L. Zoler/Elsevier Global Medical Newswww.rheumatologynews.com
Major Finding: The number of total knee replacements done on Americans aged 45–64 rose from 68,000 in 1997 to 221,000 in 2007, more than tripling. The number done in Americans aged 65–84 rose from 183,000 in 1997 to 303,000 in 2007, a 66% increase.
Data Source: The Nationwide Inpatient Sample, annual data collection sponsored by the Agency for Healthcare Research and Quality.
Disclosures: Dr. Losina and Dr. Katz had no relevant disclosures.
BRUSSELS — Middle-aged Americans seem to have embraced total knee replacement, with the number of surgeries more than tripling from 68,000 in 1997 to 221,000 in 2007, according to data collected in the Nationwide Inpatient Sample.
This increase, which helped to drive an overall doubling of all U.S. total knee replacements during 1997–2007, did not result merely from the growing prevalence of obesity and the demographic growth of the 45- to 64-year-old age group, judging from the findings from further analysis of the data.
Those two factors accounted for, at most, a quarter of the increase, Elena Losina, Ph.D., reported in a poster at the congress.
A combination of additional factors may explain the rest of the rise, Dr. Losina said in an interview. These include:
▸ A rise in sports injuries that have led to posttraumatic arthritis, a trend exacerbated by the increased sports participation that began in the late 20th century.
▸ Increased willingness of surgeons to perform total knee replacement on patients younger than 65.
▸ Increased familiarity and comfort with the surgery – which did not become available until the late 1970s – leading to increased demand by younger patients.
“It's a combination of more early, advanced arthritis, shifting indications, and more willingness to operate,” said Dr. Losina, codirector of the Orthopedics and Arthritis Center for Outcomes Research at Brigham and Women's Hospital in Boston. hMore and more patients have been referred and at least consider surgery.”
“Are patients in the [45- to 64-year-old] age group being offered surgery and accepting surgery more often? Is it because there is more osteoarthritis because of injury? Does it reflect patient demand in that age group? It's all speculation,” agreed Dr. Jeffrey N. Katz, director of the center, and professor of medicine and orthopedic surgery at Harvard Medical School in Boston.
Some of the same factors also drove increased knee-replacement rates in patients aged 65–84 years, but the slope of the rise was not nearly as steep. In the group aged 65–84 years old, the number of U.S. total knee replacement surgeries rose 66% from 183,000 in 1997 to 303,000 in 2007. The absolute rise of 120,000 additional surgeries in the elderly clearly trailed the 153,000 increase in middle-aged U.S. adults.
But these numbers may not remain on their current trajectory. The surgery is not sustainable, Dr. Losina said at the congress, which was sponsored by the Osteoarthritis Research Society International.
“I think the growth will level off. I think Medicare will be capped, forcing patients to pay for knee replacement out of pocket, and eligibility criteria will tighten,” she said. Currently, “we don't know what proportion of the surgery is appropriate,” she added.
Another unknown is what middle-aged patients who receive knee replacements can expect about the eventual need for revision surgery. “It would be very surprising if revision rates were not higher in younger patients,” said Dr. Katz, who coauthored the poster.
Younger patients sometimes try to resume the activities that initially drove them to knee surgery. “We need to study [revision] data from younger patients. The burden of revision in younger patients is unknown; it hasn't been studied.” Dr. Losina said.
“We know that prosthetic knees are durable in older patients, but in older patients there is a strong, competing risk from mortality,” she said. In the elderly, the revision rate for total knee replacement is roughly 1% per year following surgery.
“It's a very successful surgery. People are miserable and can't move and function because of their knee problems and total knee replacement brings them back to life. I think that explains the greater willingness” to use knee surgery on younger patients. “But we need to understand the societal and population implications of the trend we see,” Dr. Losina said.
Her study used data collected in the Nationwide Inpatient Sample by the Agency for Healthcare Research and Quality, which currently collects data from more than 1,000 hospitals in 42 states.
The data showed a doubling of knee surgery overall from 1997 to a national total of 550,000 in 2007, a period when the U.S. population grew by just 15%.
To watch an interview with Dr. Elena Losina on knee surgery rates, visit
Source Mitchel L. Zoler/Elsevier Global Medical Newswww.rheumatologynews.com
Knee Rehab Deferred Cartilage Repair Surgery : Combination of gradual pace, use of knee loading to guide intensity, and education yields benefits.
Major Finding: A 3-month program of intensive knee rehabilitation produced a significant, 30% improvement in knee extension and flexion in patients with articular cartilage lesions who were scheduled for repair surgery. After the program ended, 64% of participants said they no longer needed immediate surgery.
Data Source: Single-center study of 48 patients with articular cartilage lesions.
Disclosures: Dr. Risberg said she had no conflicts of interest.
BRUSSELS — A carefully designed, 3-month program of rehabilitation exercise and education in patients with articular cartilage lesions who were scheduled for cartilage repair surgery led to significant improvements in knee function in a single-center study with 48 patients.
Following the 3-month rehabilitation intervention, 64% of the patients said they no longer needed immediate surgery, said May Arna Risberg, Ph.D.
“I believe this [rehabilitation] program works for these patients. We will publish the program, and continue to use it ourselves, and we hope others will use it,” said Dr. Risberg, professor of sports medicine at the Norwegian School of Sport Sciences in Oslo. Gradually increasing knee loading using an individualized schedule may explain the rehab program's success, she said.“P
“Patients with cartilage lesions are very different from osteoarthritis patients. You need to go much slower with progression of their knee loading. Rehab for cartilage needs to be slow and long,” she said in an interview.
All 48 patients in the study had undergone prior rehab sessions run by other clinicians using different protocols. But aside from the focus on a gradual pace, an emphasis on using knee loading to guide the program's intensity, and a strong education component, the rehab program tested by Dr. Risberg didn't involve any novel approaches or exercise regimens.
Participating patients attended rehab sessions of the Oslo CARE (cartilage, active, rehab, and education) program an average of twice a week. Sessions included warm-up stretches, gait retraining, neuromuscular exercises, step-up and step-down exercises, and strength exercise for knee and hip muscles. Both the step and strength exercises featured gradually increasing loading over time. The program also included educational sessions and materials.
The study enrolled patients who had a focal femoral-condyle defect in the articular cartilage of one knee, diagnosed by arthroscopy, and who were scheduled for repair surgery. Their age averaged 34 years, (range, 17–50); 70% were men, and 84% had a medial femoral-condyle lesion. Participants had had their symptoms for an average of 47 months prior to the study.
Analysis of training diaries and responses in biweekly questionnaires showed that 79% of participants adhered to their rehab regimens, and 88% had follow-up assessments an average of 104 days after they entered the study.
At follow-up, participants averaged a 30% improvement over baseline in both extension and flexion of their injured knee, Dr. Risberg reported at the meeting, sponsored by the Osteoarthritis Research Society International. They also averaged improvements of 21%, 31%, and 37% in the triple, crossover, and one-leg hop tests, respectively, compared with baseline, all statistically significant increases.
They also had significant improvements in measures of pain, activity, and quality of life. Dr. Risberg cited the finding that nearly two-thirds of patients said they no longer needed immediate knee surgery as the best demonstration of their improvement.
She cautioned that despite completing the 3-month program, some patients had no significant response to their rehabilitation, and that additional studies should test the program in more patients with longer follow-up.
Major Finding: A 3-month program of intensive knee rehabilitation produced a significant, 30% improvement in knee extension and flexion in patients with articular cartilage lesions who were scheduled for repair surgery. After the program ended, 64% of participants said they no longer needed immediate surgery.
Data Source: Single-center study of 48 patients with articular cartilage lesions.
Disclosures: Dr. Risberg said she had no conflicts of interest.
BRUSSELS — A carefully designed, 3-month program of rehabilitation exercise and education in patients with articular cartilage lesions who were scheduled for cartilage repair surgery led to significant improvements in knee function in a single-center study with 48 patients.
Following the 3-month rehabilitation intervention, 64% of the patients said they no longer needed immediate surgery, said May Arna Risberg, Ph.D.
“I believe this [rehabilitation] program works for these patients. We will publish the program, and continue to use it ourselves, and we hope others will use it,” said Dr. Risberg, professor of sports medicine at the Norwegian School of Sport Sciences in Oslo. Gradually increasing knee loading using an individualized schedule may explain the rehab program's success, she said.“P
“Patients with cartilage lesions are very different from osteoarthritis patients. You need to go much slower with progression of their knee loading. Rehab for cartilage needs to be slow and long,” she said in an interview.
All 48 patients in the study had undergone prior rehab sessions run by other clinicians using different protocols. But aside from the focus on a gradual pace, an emphasis on using knee loading to guide the program's intensity, and a strong education component, the rehab program tested by Dr. Risberg didn't involve any novel approaches or exercise regimens.
Participating patients attended rehab sessions of the Oslo CARE (cartilage, active, rehab, and education) program an average of twice a week. Sessions included warm-up stretches, gait retraining, neuromuscular exercises, step-up and step-down exercises, and strength exercise for knee and hip muscles. Both the step and strength exercises featured gradually increasing loading over time. The program also included educational sessions and materials.
The study enrolled patients who had a focal femoral-condyle defect in the articular cartilage of one knee, diagnosed by arthroscopy, and who were scheduled for repair surgery. Their age averaged 34 years, (range, 17–50); 70% were men, and 84% had a medial femoral-condyle lesion. Participants had had their symptoms for an average of 47 months prior to the study.
Analysis of training diaries and responses in biweekly questionnaires showed that 79% of participants adhered to their rehab regimens, and 88% had follow-up assessments an average of 104 days after they entered the study.
At follow-up, participants averaged a 30% improvement over baseline in both extension and flexion of their injured knee, Dr. Risberg reported at the meeting, sponsored by the Osteoarthritis Research Society International. They also averaged improvements of 21%, 31%, and 37% in the triple, crossover, and one-leg hop tests, respectively, compared with baseline, all statistically significant increases.
They also had significant improvements in measures of pain, activity, and quality of life. Dr. Risberg cited the finding that nearly two-thirds of patients said they no longer needed immediate knee surgery as the best demonstration of their improvement.
She cautioned that despite completing the 3-month program, some patients had no significant response to their rehabilitation, and that additional studies should test the program in more patients with longer follow-up.
Major Finding: A 3-month program of intensive knee rehabilitation produced a significant, 30% improvement in knee extension and flexion in patients with articular cartilage lesions who were scheduled for repair surgery. After the program ended, 64% of participants said they no longer needed immediate surgery.
Data Source: Single-center study of 48 patients with articular cartilage lesions.
Disclosures: Dr. Risberg said she had no conflicts of interest.
BRUSSELS — A carefully designed, 3-month program of rehabilitation exercise and education in patients with articular cartilage lesions who were scheduled for cartilage repair surgery led to significant improvements in knee function in a single-center study with 48 patients.
Following the 3-month rehabilitation intervention, 64% of the patients said they no longer needed immediate surgery, said May Arna Risberg, Ph.D.
“I believe this [rehabilitation] program works for these patients. We will publish the program, and continue to use it ourselves, and we hope others will use it,” said Dr. Risberg, professor of sports medicine at the Norwegian School of Sport Sciences in Oslo. Gradually increasing knee loading using an individualized schedule may explain the rehab program's success, she said.“P
“Patients with cartilage lesions are very different from osteoarthritis patients. You need to go much slower with progression of their knee loading. Rehab for cartilage needs to be slow and long,” she said in an interview.
All 48 patients in the study had undergone prior rehab sessions run by other clinicians using different protocols. But aside from the focus on a gradual pace, an emphasis on using knee loading to guide the program's intensity, and a strong education component, the rehab program tested by Dr. Risberg didn't involve any novel approaches or exercise regimens.
Participating patients attended rehab sessions of the Oslo CARE (cartilage, active, rehab, and education) program an average of twice a week. Sessions included warm-up stretches, gait retraining, neuromuscular exercises, step-up and step-down exercises, and strength exercise for knee and hip muscles. Both the step and strength exercises featured gradually increasing loading over time. The program also included educational sessions and materials.
The study enrolled patients who had a focal femoral-condyle defect in the articular cartilage of one knee, diagnosed by arthroscopy, and who were scheduled for repair surgery. Their age averaged 34 years, (range, 17–50); 70% were men, and 84% had a medial femoral-condyle lesion. Participants had had their symptoms for an average of 47 months prior to the study.
Analysis of training diaries and responses in biweekly questionnaires showed that 79% of participants adhered to their rehab regimens, and 88% had follow-up assessments an average of 104 days after they entered the study.
At follow-up, participants averaged a 30% improvement over baseline in both extension and flexion of their injured knee, Dr. Risberg reported at the meeting, sponsored by the Osteoarthritis Research Society International. They also averaged improvements of 21%, 31%, and 37% in the triple, crossover, and one-leg hop tests, respectively, compared with baseline, all statistically significant increases.
They also had significant improvements in measures of pain, activity, and quality of life. Dr. Risberg cited the finding that nearly two-thirds of patients said they no longer needed immediate knee surgery as the best demonstration of their improvement.
She cautioned that despite completing the 3-month program, some patients had no significant response to their rehabilitation, and that additional studies should test the program in more patients with longer follow-up.
Colchicine Averts Postpericardiotomy Syndrome
STOCKHOLM – Daily, prophylactic treatment with colchicine for 1 month following cardiac surgery safely cut the incidence of postpericardiotomy syndrome by more than half in a placebo-controlled trial with 360 patients, the first large, controlled trial to ever assess a treatment for this common, post-surgical complication.
“Colchicine is safe and effective for the primary prevention of PPS [postpericardiotomy syndrome] and its related complications,” Dr. Massimo Imazio said at the annual Congress of the European Society of Cardiology. “The main limitation of the study is the lack of standardized criteria for diagnosing PPS,” which means that some patients counted as developing PPS may have had a mild form of the syndrome. Notably, the study constituted the first attempt to apply objective PPS diagnostic criteria, said Dr. Imazio, a cardiologist at Maria Vittoria Hospital in Torino, Italy.
The study employed a “simple and sound methodology,” and finding that colchicine treatment prevented one episode of PPS for every eight cardiac surgery patients treated, the number needed to treat, “is very good,” commented Dr. Andre Keren, professor of medicine and director of the Heart Failure and Heart Muscle Disease Center at Hadassah University Hospital in Jerusalem. The new study “was a carefully performed trial in which colchicine provided effective and safe treatment,” Dr. Keren said.
Results from prior reports indicated that 10%–40% of all patients undergoing cardiac surgery developed PPS. The new findings supported that, with a PPS incidence of 21% among patients in the placebo group followed for 12 months. In addition, 85% of all PPS cases occurred during the first 30 days following surgery, a finding that prompted Dr. Imazio to recommend limiting colchicine treatment to the first postoperative month.
The Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) trial enrolled patients aged 18 years or older who underwent cardiac surgery. Their average age was 66, and two-thirds were men. Enrolled patients most frequently had undergone isolated coronary artery bypass grafting, in 47%, followed by isolated valve surgery, in 30%, a combined procedure, in 19%, isolated aortic surgery in 3%, and other types of surgery making up the remaining cases.
Starting on the third day after surgery, patients received either 1 mg oral colchicine b.i.d. for 1 day followed by 0.5 mg b.i.d. or placebo for 29 days. Patients weighing less than 70 kg received 0.5 mg b.i.d. on the first postoperative day followed by 0.5 mg daily for 29 days.
The researchers diagnosed PPS when patients developed at least two of the following conditions during follow-up: a fever lasting longer than the first postoperative week with no evidence of systemic or local infection, pleuritic chest pain, friction rub, pleural effusion, or new or worsening pericardial effusion.
During the first 12 months after surgery, 38 of the 180 placebo patients, 21%, developed PPS by these criteria compared with 16 patients in the colchicine arm, 9%, a statistically significant difference. Pleural effusion occurred most often, in 26% of the placebo patients and in 12% of those on colchicine, followed by new or worsening pericardial effusion, in 23% of placebo patients and 13% in the active-treatment arm.
No patient in the study developed a serious side effect. Side effects, most often gastrointestinal intolerance, occurred in 5% of placebo patients and in 9% on colchicine, a nonsignificant difference. GI intolerance is a well-established adverse effect of colchicine.
Until now, colchicine, a generic anti-inflammatory drug, has primarily been known as a treatment for gouty arthritis. The study did not receive commercial funding, but Acarpia, a Portuguese company, supplied the colchicine and placebo tablets used in the study. Dr. Imazio said that he and his associates had no disclosures.
STOCKHOLM – Daily, prophylactic treatment with colchicine for 1 month following cardiac surgery safely cut the incidence of postpericardiotomy syndrome by more than half in a placebo-controlled trial with 360 patients, the first large, controlled trial to ever assess a treatment for this common, post-surgical complication.
“Colchicine is safe and effective for the primary prevention of PPS [postpericardiotomy syndrome] and its related complications,” Dr. Massimo Imazio said at the annual Congress of the European Society of Cardiology. “The main limitation of the study is the lack of standardized criteria for diagnosing PPS,” which means that some patients counted as developing PPS may have had a mild form of the syndrome. Notably, the study constituted the first attempt to apply objective PPS diagnostic criteria, said Dr. Imazio, a cardiologist at Maria Vittoria Hospital in Torino, Italy.
The study employed a “simple and sound methodology,” and finding that colchicine treatment prevented one episode of PPS for every eight cardiac surgery patients treated, the number needed to treat, “is very good,” commented Dr. Andre Keren, professor of medicine and director of the Heart Failure and Heart Muscle Disease Center at Hadassah University Hospital in Jerusalem. The new study “was a carefully performed trial in which colchicine provided effective and safe treatment,” Dr. Keren said.
Results from prior reports indicated that 10%–40% of all patients undergoing cardiac surgery developed PPS. The new findings supported that, with a PPS incidence of 21% among patients in the placebo group followed for 12 months. In addition, 85% of all PPS cases occurred during the first 30 days following surgery, a finding that prompted Dr. Imazio to recommend limiting colchicine treatment to the first postoperative month.
The Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) trial enrolled patients aged 18 years or older who underwent cardiac surgery. Their average age was 66, and two-thirds were men. Enrolled patients most frequently had undergone isolated coronary artery bypass grafting, in 47%, followed by isolated valve surgery, in 30%, a combined procedure, in 19%, isolated aortic surgery in 3%, and other types of surgery making up the remaining cases.
Starting on the third day after surgery, patients received either 1 mg oral colchicine b.i.d. for 1 day followed by 0.5 mg b.i.d. or placebo for 29 days. Patients weighing less than 70 kg received 0.5 mg b.i.d. on the first postoperative day followed by 0.5 mg daily for 29 days.
The researchers diagnosed PPS when patients developed at least two of the following conditions during follow-up: a fever lasting longer than the first postoperative week with no evidence of systemic or local infection, pleuritic chest pain, friction rub, pleural effusion, or new or worsening pericardial effusion.
During the first 12 months after surgery, 38 of the 180 placebo patients, 21%, developed PPS by these criteria compared with 16 patients in the colchicine arm, 9%, a statistically significant difference. Pleural effusion occurred most often, in 26% of the placebo patients and in 12% of those on colchicine, followed by new or worsening pericardial effusion, in 23% of placebo patients and 13% in the active-treatment arm.
No patient in the study developed a serious side effect. Side effects, most often gastrointestinal intolerance, occurred in 5% of placebo patients and in 9% on colchicine, a nonsignificant difference. GI intolerance is a well-established adverse effect of colchicine.
Until now, colchicine, a generic anti-inflammatory drug, has primarily been known as a treatment for gouty arthritis. The study did not receive commercial funding, but Acarpia, a Portuguese company, supplied the colchicine and placebo tablets used in the study. Dr. Imazio said that he and his associates had no disclosures.
STOCKHOLM – Daily, prophylactic treatment with colchicine for 1 month following cardiac surgery safely cut the incidence of postpericardiotomy syndrome by more than half in a placebo-controlled trial with 360 patients, the first large, controlled trial to ever assess a treatment for this common, post-surgical complication.
“Colchicine is safe and effective for the primary prevention of PPS [postpericardiotomy syndrome] and its related complications,” Dr. Massimo Imazio said at the annual Congress of the European Society of Cardiology. “The main limitation of the study is the lack of standardized criteria for diagnosing PPS,” which means that some patients counted as developing PPS may have had a mild form of the syndrome. Notably, the study constituted the first attempt to apply objective PPS diagnostic criteria, said Dr. Imazio, a cardiologist at Maria Vittoria Hospital in Torino, Italy.
The study employed a “simple and sound methodology,” and finding that colchicine treatment prevented one episode of PPS for every eight cardiac surgery patients treated, the number needed to treat, “is very good,” commented Dr. Andre Keren, professor of medicine and director of the Heart Failure and Heart Muscle Disease Center at Hadassah University Hospital in Jerusalem. The new study “was a carefully performed trial in which colchicine provided effective and safe treatment,” Dr. Keren said.
Results from prior reports indicated that 10%–40% of all patients undergoing cardiac surgery developed PPS. The new findings supported that, with a PPS incidence of 21% among patients in the placebo group followed for 12 months. In addition, 85% of all PPS cases occurred during the first 30 days following surgery, a finding that prompted Dr. Imazio to recommend limiting colchicine treatment to the first postoperative month.
The Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) trial enrolled patients aged 18 years or older who underwent cardiac surgery. Their average age was 66, and two-thirds were men. Enrolled patients most frequently had undergone isolated coronary artery bypass grafting, in 47%, followed by isolated valve surgery, in 30%, a combined procedure, in 19%, isolated aortic surgery in 3%, and other types of surgery making up the remaining cases.
Starting on the third day after surgery, patients received either 1 mg oral colchicine b.i.d. for 1 day followed by 0.5 mg b.i.d. or placebo for 29 days. Patients weighing less than 70 kg received 0.5 mg b.i.d. on the first postoperative day followed by 0.5 mg daily for 29 days.
The researchers diagnosed PPS when patients developed at least two of the following conditions during follow-up: a fever lasting longer than the first postoperative week with no evidence of systemic or local infection, pleuritic chest pain, friction rub, pleural effusion, or new or worsening pericardial effusion.
During the first 12 months after surgery, 38 of the 180 placebo patients, 21%, developed PPS by these criteria compared with 16 patients in the colchicine arm, 9%, a statistically significant difference. Pleural effusion occurred most often, in 26% of the placebo patients and in 12% of those on colchicine, followed by new or worsening pericardial effusion, in 23% of placebo patients and 13% in the active-treatment arm.
No patient in the study developed a serious side effect. Side effects, most often gastrointestinal intolerance, occurred in 5% of placebo patients and in 9% on colchicine, a nonsignificant difference. GI intolerance is a well-established adverse effect of colchicine.
Until now, colchicine, a generic anti-inflammatory drug, has primarily been known as a treatment for gouty arthritis. The study did not receive commercial funding, but Acarpia, a Portuguese company, supplied the colchicine and placebo tablets used in the study. Dr. Imazio said that he and his associates had no disclosures.