Osteoporosis

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

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.

The Food and Drug Administration on Oct. 13 issued a warning about the “possible” risk of the rare atypical femur fractures associated with bisphosphonate treatment in osteoporosis patients, after reviewing the final report on this association released Sept. 14 by the American Society for Bone and Mineral Research.

The FDA has requested that a warning about the association be added to the labels of all bisphosphonates approved for osteoporosis prevention and treatment, and that a medication guide explaining the risk and the symptoms of these fractures be provided to patients with each bisphosphonate prescription, said Dr. Sandra Kweder during the briefing.

The agency also is requiring a change to the “indications and usage” section of the bisphosphonate labels, which will note that the optimal duration of treatment with bisphosphonates is not clear when they are used to treat and/or prevent osteoporosis.

In March 2010, the FDA announced that it was reviewing reports of femur fractures associated with bisphosphonate use, and the report issued by an American Society for Bone and Mineral Research (ASBMR) task force concluded that long-term bisphosphonate treatment may be related to an increased risk of these fractures, described as atypical fractures of the subtrochanteric region of the hip and femoral shaft (http://onlinelibrary.wiley.com/doi/10.1002/jbmr.253/pdf

The ASBMR report “helped us understand these fractures a little bit better and makes us confident that this is something that is potentially more closely related to these drugs, particularly [during] long-term use, than we previously had evidence for,” said Dr. Kweder, deputy director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research.

These fractures affect the femoral shaft, are less likely to be associated with trauma than are typical osteoporotic fractures, are sometimes bilateral, and generally affect younger patients, she said. Affected patients have described dull aching thigh or groin pain weeks to months before complete fracture is identified, she noted. The data indicate that they are more common in patients who have been on treatment for more than 5 years.

Similar to the recommendations in the ASBMR report, the FDA's recommendations to health care professionals include evaluating any patient who presents with new thigh or groin pain for a femur fracture, stopping treatment in patients with evidence of a femoral shaft fracture, and periodically reevaluating the need for continued treatment, particularly in patients treated for more than 5 years.

The products affected are those approved for osteoporosis indications, such as alendronate (Fosamax), alendronate and cholecalciferol (Fosamax Plus D), risedronate sodium (Actonel), risedronate sodium with calcium carbonate (Actonel with Calcium), ibandronate sodium (Boniva), risedronate sodium (Atelvia), pamidronate injection (Aredia), and zoledronic acid injection (Reclast), as well as generic formulations of those drugs.

The FDA advisory is available at www.fda.gov/Drugs/DrugSafety/ucm229009.htmwww.fda.gov/medwatch/

The Food and Drug Administration on Oct. 13 issued a warning about the “possible” risk of the rare atypical femur fractures associated with bisphosphonate treatment in osteoporosis patients, after reviewing the final report on this association released Sept. 14 by the American Society for Bone and Mineral Research.

The FDA has requested that a warning about the association be added to the labels of all bisphosphonates approved for osteoporosis prevention and treatment, and that a medication guide explaining the risk and the symptoms of these fractures be provided to patients with each bisphosphonate prescription, said Dr. Sandra Kweder during the briefing.

The agency also is requiring a change to the “indications and usage” section of the bisphosphonate labels, which will note that the optimal duration of treatment with bisphosphonates is not clear when they are used to treat and/or prevent osteoporosis.

In March 2010, the FDA announced that it was reviewing reports of femur fractures associated with bisphosphonate use, and the report issued by an American Society for Bone and Mineral Research (ASBMR) task force concluded that long-term bisphosphonate treatment may be related to an increased risk of these fractures, described as atypical fractures of the subtrochanteric region of the hip and femoral shaft (http://onlinelibrary.wiley.com/doi/10.1002/jbmr.253/pdf

The ASBMR report “helped us understand these fractures a little bit better and makes us confident that this is something that is potentially more closely related to these drugs, particularly [during] long-term use, than we previously had evidence for,” said Dr. Kweder, deputy director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research.

These fractures affect the femoral shaft, are less likely to be associated with trauma than are typical osteoporotic fractures, are sometimes bilateral, and generally affect younger patients, she said. Affected patients have described dull aching thigh or groin pain weeks to months before complete fracture is identified, she noted. The data indicate that they are more common in patients who have been on treatment for more than 5 years.

Similar to the recommendations in the ASBMR report, the FDA's recommendations to health care professionals include evaluating any patient who presents with new thigh or groin pain for a femur fracture, stopping treatment in patients with evidence of a femoral shaft fracture, and periodically reevaluating the need for continued treatment, particularly in patients treated for more than 5 years.

The products affected are those approved for osteoporosis indications, such as alendronate (Fosamax), alendronate and cholecalciferol (Fosamax Plus D), risedronate sodium (Actonel), risedronate sodium with calcium carbonate (Actonel with Calcium), ibandronate sodium (Boniva), risedronate sodium (Atelvia), pamidronate injection (Aredia), and zoledronic acid injection (Reclast), as well as generic formulations of those drugs.

The FDA advisory is available at www.fda.gov/Drugs/DrugSafety/ucm229009.htmwww.fda.gov/medwatch/

The Food and Drug Administration on Oct. 13 issued a warning about the “possible” risk of the rare atypical femur fractures associated with bisphosphonate treatment in osteoporosis patients, after reviewing the final report on this association released Sept. 14 by the American Society for Bone and Mineral Research.

The FDA has requested that a warning about the association be added to the labels of all bisphosphonates approved for osteoporosis prevention and treatment, and that a medication guide explaining the risk and the symptoms of these fractures be provided to patients with each bisphosphonate prescription, said Dr. Sandra Kweder during the briefing.

The agency also is requiring a change to the “indications and usage” section of the bisphosphonate labels, which will note that the optimal duration of treatment with bisphosphonates is not clear when they are used to treat and/or prevent osteoporosis.

In March 2010, the FDA announced that it was reviewing reports of femur fractures associated with bisphosphonate use, and the report issued by an American Society for Bone and Mineral Research (ASBMR) task force concluded that long-term bisphosphonate treatment may be related to an increased risk of these fractures, described as atypical fractures of the subtrochanteric region of the hip and femoral shaft (http://onlinelibrary.wiley.com/doi/10.1002/jbmr.253/pdf

The ASBMR report “helped us understand these fractures a little bit better and makes us confident that this is something that is potentially more closely related to these drugs, particularly [during] long-term use, than we previously had evidence for,” said Dr. Kweder, deputy director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research.

These fractures affect the femoral shaft, are less likely to be associated with trauma than are typical osteoporotic fractures, are sometimes bilateral, and generally affect younger patients, she said. Affected patients have described dull aching thigh or groin pain weeks to months before complete fracture is identified, she noted. The data indicate that they are more common in patients who have been on treatment for more than 5 years.

Similar to the recommendations in the ASBMR report, the FDA's recommendations to health care professionals include evaluating any patient who presents with new thigh or groin pain for a femur fracture, stopping treatment in patients with evidence of a femoral shaft fracture, and periodically reevaluating the need for continued treatment, particularly in patients treated for more than 5 years.

The products affected are those approved for osteoporosis indications, such as alendronate (Fosamax), alendronate and cholecalciferol (Fosamax Plus D), risedronate sodium (Actonel), risedronate sodium with calcium carbonate (Actonel with Calcium), ibandronate sodium (Boniva), risedronate sodium (Atelvia), pamidronate injection (Aredia), and zoledronic acid injection (Reclast), as well as generic formulations of those drugs.

The FDA advisory is available at www.fda.gov/Drugs/DrugSafety/ucm229009.htmwww.fda.gov/medwatch/

Treatment for 6 weeks with teriparatide, a U.S.-approved drug that stimulates bone remodeling, led to significant, 1-year improvements in alveolar bone formation and clinical outcomes in a controlled, pilot study of 40 patients undergoing periodontal surgery.

Bone gain in the osseous defects of the 20 patients who were randomized to receive daily teriparatide injections became detectable early after treatment began and continued to improve during 12 months of follow-up, leading to a highly significant improvement in overall alveolar bone gain, compared with the 20 patients on placebo, Jill D. Bashutski, D.D.S., and her associates reported (N. Engl. J. Med. 2010 Oct. 16 [doi:10.1056/NEJMoa1005361]).

The teriparatide-treated patients also had significantly better 1-year improvements in periodontal probing depth and clinical attachment, reported Dr. Bashutski, a periodontist at the University of Michigan in Ann Arbor. The article's online publication was timed to coincide with Dr. Bashutski's presentation of the findings at the annual meeting of the American Society for Bone and Mineral Research in Toronto.

She and her associates used teriparatide, a recombinant agent that contains the first 34 amino acids of parathyroid hormone, because of its activity as an anabolic agent and prior evidence that it enhances bone remodeling and wound healing in areas of high bone turnover, such as fractures and surgical sites.

“We know that parathyroid hormone stimulates formation of preosteoblast cells, and these cells go on to eventually form bone.” The 6-week regimen of daily teriparatide injections produces “an initial incentive for bone formation to occur” during subsequent months, said Dr. Laurie K. McCauley, the principal investigator of the study and professor and chair of periodontics and oral medicine at the University of Michigan, in an interview.

The positive effects that teriparatide treatment had on the study outcomes of bone gain, probing depth, and clinical attachment were also all clinically significant, Dr. McCauley added. Teriparatide increased 1-year bone gain at a rate that was 10-fold higher than placebo. “That's huge,” she said.

The long-term sequence of events that teriparatide triggers likely explains how a 6-week course produced significant differences after 1 year, she said. “We know that most connective tissue healing goes on during the first 6 weeks. The thought was to augment that healing with this agent.”

The outcome from “this small trial provides preliminary evidence that an agent that stimulates bone formation might confer additional benefit over that achieved with standard care in patients with periodontitis,” commented Dr. Andrew Grey in an editorial that accompanied the article (N. Engl. J. Med. 2010 Oct. 16 [doi:10.1056/NEJMe1010459]). But many questions about this treatment remain, he said. “How durable is the effect of teriparatide? What is the optimal dosing regimen? Does teriparatide alter important [end points] such as tooth loss or the need for further operative intervention? Do antiresorptive agents, which cost considerably less than teriparatide, confer similar benefits?” asked Dr. Grey, an endocrinologist at the University of Auckland (New Zealand).

The study enrolled patients (aged 30-65 years) with severe periodontal disease at the University of Michigan from January 2005 to June 2009. All patients had normal levels of calcium and parathyroid hormone, a minimum vitamin D level of 16 ng/mL, and no osteoporosis. All patients underwent conventional surgery on an osseous defect. Starting 3 days before surgery, patients began daily treatment with either 20 mcg teriparatide or placebo, administered daily by subcutaneous injection, for 6 weeks. All patients also received a daily supplement of calcium and vitamin D.

Patients who were treated with teriparatide had significantly better resolution of their periodontal bone defects at 6, 9, and 12 months following baseline, compared with the placebo patients. At 12 months, the teriparatide-treated patients averaged a bone gain of 1.86 mm (29%), compared with baseline, whereas the placebo patients averaged a 0.16-mm (3%) gain from baseline.

Teriparatide treatment was also linked with a 2.42-mm (33%) average reduction in probing depth at the surgical site after 12 months, compared with baseline. The placebo group averaged a 1.32-mm (20%) reduction in probing depth from baseline, a statistically significant difference. Clinical attachment improved by 1.58 mm (22%) at 1 year, compared with baseline, in the teriparatide patients, significantly better than the 0.42-mm (7%) average attachment improvement in the placebo group. No improvements in probing depth occurred in the teriparatide and placebo patients in areas of severe, chronic periodontitis that did not undergo surgery.

At entry to the study, five patients in the teriparatide arm and nine in the placebo group had osteopenia on dual-energy x-ray absorptiometry examinations. At the 12-month follow-up, patients in both study arms showed no significant changes in bone density scores or in quality of life scores. Teriparatide treatment did not link with any pattern of adverse events that differed from the placebo group.

Although teriparatide is available for treating osteoporosis, its widespread use in patients who are undergoing periodontal surgery should await results from studies involving larger numbers of patients, Dr. McCauley said. She also cautioned against extrapolating the results to other types of bone surgery. Dr. McCauley said she would like to run studies on a delayed-release, topical formulation of teriparatide that would be implanted during surgery and would then release over the subsequent 6 weeks, precluding daily injections. Formulations of this type now exist, but have not reached the clinical-testing stage.

The study received partial funding from Eli Lilly & Co., the company that markets teriparatide (Forteo), but it was an investigator-initiated study. Dr. McCauley has received research grants and transportation support from Lilly. She has also received research grants and has been a consultant to Amgen Inc., but she has not received any honoraria or consulting fees. Dr. Bashutski said she has received travel expenses from the Colgate-Palmolive Co. Dr. Grey said that he has received travel expenses from Merck Sharp & Dohme (NZ) Ltd.

Improvements in periodontal probing depth and clinical attachment were significant.

Source DR. BASHUTSKI

Teriparatide increased 1-year bone gain at a rate that was 10-fold higher than placebo. 'That's huge.'

Source DR. McCAULEY

Treatment for 6 weeks with teriparatide, a U.S.-approved drug that stimulates bone remodeling, led to significant, 1-year improvements in alveolar bone formation and clinical outcomes in a controlled, pilot study of 40 patients undergoing periodontal surgery.

Bone gain in the osseous defects of the 20 patients who were randomized to receive daily teriparatide injections became detectable early after treatment began and continued to improve during 12 months of follow-up, leading to a highly significant improvement in overall alveolar bone gain, compared with the 20 patients on placebo, Jill D. Bashutski, D.D.S., and her associates reported (N. Engl. J. Med. 2010 Oct. 16 [doi:10.1056/NEJMoa1005361]).

The teriparatide-treated patients also had significantly better 1-year improvements in periodontal probing depth and clinical attachment, reported Dr. Bashutski, a periodontist at the University of Michigan in Ann Arbor. The article's online publication was timed to coincide with Dr. Bashutski's presentation of the findings at the annual meeting of the American Society for Bone and Mineral Research in Toronto.

She and her associates used teriparatide, a recombinant agent that contains the first 34 amino acids of parathyroid hormone, because of its activity as an anabolic agent and prior evidence that it enhances bone remodeling and wound healing in areas of high bone turnover, such as fractures and surgical sites.

“We know that parathyroid hormone stimulates formation of preosteoblast cells, and these cells go on to eventually form bone.” The 6-week regimen of daily teriparatide injections produces “an initial incentive for bone formation to occur” during subsequent months, said Dr. Laurie K. McCauley, the principal investigator of the study and professor and chair of periodontics and oral medicine at the University of Michigan, in an interview.

The positive effects that teriparatide treatment had on the study outcomes of bone gain, probing depth, and clinical attachment were also all clinically significant, Dr. McCauley added. Teriparatide increased 1-year bone gain at a rate that was 10-fold higher than placebo. “That's huge,” she said.

The long-term sequence of events that teriparatide triggers likely explains how a 6-week course produced significant differences after 1 year, she said. “We know that most connective tissue healing goes on during the first 6 weeks. The thought was to augment that healing with this agent.”

The outcome from “this small trial provides preliminary evidence that an agent that stimulates bone formation might confer additional benefit over that achieved with standard care in patients with periodontitis,” commented Dr. Andrew Grey in an editorial that accompanied the article (N. Engl. J. Med. 2010 Oct. 16 [doi:10.1056/NEJMe1010459]). But many questions about this treatment remain, he said. “How durable is the effect of teriparatide? What is the optimal dosing regimen? Does teriparatide alter important [end points] such as tooth loss or the need for further operative intervention? Do antiresorptive agents, which cost considerably less than teriparatide, confer similar benefits?” asked Dr. Grey, an endocrinologist at the University of Auckland (New Zealand).

The study enrolled patients (aged 30-65 years) with severe periodontal disease at the University of Michigan from January 2005 to June 2009. All patients had normal levels of calcium and parathyroid hormone, a minimum vitamin D level of 16 ng/mL, and no osteoporosis. All patients underwent conventional surgery on an osseous defect. Starting 3 days before surgery, patients began daily treatment with either 20 mcg teriparatide or placebo, administered daily by subcutaneous injection, for 6 weeks. All patients also received a daily supplement of calcium and vitamin D.

Patients who were treated with teriparatide had significantly better resolution of their periodontal bone defects at 6, 9, and 12 months following baseline, compared with the placebo patients. At 12 months, the teriparatide-treated patients averaged a bone gain of 1.86 mm (29%), compared with baseline, whereas the placebo patients averaged a 0.16-mm (3%) gain from baseline.

Teriparatide treatment was also linked with a 2.42-mm (33%) average reduction in probing depth at the surgical site after 12 months, compared with baseline. The placebo group averaged a 1.32-mm (20%) reduction in probing depth from baseline, a statistically significant difference. Clinical attachment improved by 1.58 mm (22%) at 1 year, compared with baseline, in the teriparatide patients, significantly better than the 0.42-mm (7%) average attachment improvement in the placebo group. No improvements in probing depth occurred in the teriparatide and placebo patients in areas of severe, chronic periodontitis that did not undergo surgery.

At entry to the study, five patients in the teriparatide arm and nine in the placebo group had osteopenia on dual-energy x-ray absorptiometry examinations. At the 12-month follow-up, patients in both study arms showed no significant changes in bone density scores or in quality of life scores. Teriparatide treatment did not link with any pattern of adverse events that differed from the placebo group.

Although teriparatide is available for treating osteoporosis, its widespread use in patients who are undergoing periodontal surgery should await results from studies involving larger numbers of patients, Dr. McCauley said. She also cautioned against extrapolating the results to other types of bone surgery. Dr. McCauley said she would like to run studies on a delayed-release, topical formulation of teriparatide that would be implanted during surgery and would then release over the subsequent 6 weeks, precluding daily injections. Formulations of this type now exist, but have not reached the clinical-testing stage.

The study received partial funding from Eli Lilly & Co., the company that markets teriparatide (Forteo), but it was an investigator-initiated study. Dr. McCauley has received research grants and transportation support from Lilly. She has also received research grants and has been a consultant to Amgen Inc., but she has not received any honoraria or consulting fees. Dr. Bashutski said she has received travel expenses from the Colgate-Palmolive Co. Dr. Grey said that he has received travel expenses from Merck Sharp & Dohme (NZ) Ltd.

Improvements in periodontal probing depth and clinical attachment were significant.

Source DR. BASHUTSKI

Teriparatide increased 1-year bone gain at a rate that was 10-fold higher than placebo. 'That's huge.'

Source DR. McCAULEY

Treatment for 6 weeks with teriparatide, a U.S.-approved drug that stimulates bone remodeling, led to significant, 1-year improvements in alveolar bone formation and clinical outcomes in a controlled, pilot study of 40 patients undergoing periodontal surgery.

Bone gain in the osseous defects of the 20 patients who were randomized to receive daily teriparatide injections became detectable early after treatment began and continued to improve during 12 months of follow-up, leading to a highly significant improvement in overall alveolar bone gain, compared with the 20 patients on placebo, Jill D. Bashutski, D.D.S., and her associates reported (N. Engl. J. Med. 2010 Oct. 16 [doi:10.1056/NEJMoa1005361]).

The teriparatide-treated patients also had significantly better 1-year improvements in periodontal probing depth and clinical attachment, reported Dr. Bashutski, a periodontist at the University of Michigan in Ann Arbor. The article's online publication was timed to coincide with Dr. Bashutski's presentation of the findings at the annual meeting of the American Society for Bone and Mineral Research in Toronto.

She and her associates used teriparatide, a recombinant agent that contains the first 34 amino acids of parathyroid hormone, because of its activity as an anabolic agent and prior evidence that it enhances bone remodeling and wound healing in areas of high bone turnover, such as fractures and surgical sites.

“We know that parathyroid hormone stimulates formation of preosteoblast cells, and these cells go on to eventually form bone.” The 6-week regimen of daily teriparatide injections produces “an initial incentive for bone formation to occur” during subsequent months, said Dr. Laurie K. McCauley, the principal investigator of the study and professor and chair of periodontics and oral medicine at the University of Michigan, in an interview.

The positive effects that teriparatide treatment had on the study outcomes of bone gain, probing depth, and clinical attachment were also all clinically significant, Dr. McCauley added. Teriparatide increased 1-year bone gain at a rate that was 10-fold higher than placebo. “That's huge,” she said.

The long-term sequence of events that teriparatide triggers likely explains how a 6-week course produced significant differences after 1 year, she said. “We know that most connective tissue healing goes on during the first 6 weeks. The thought was to augment that healing with this agent.”

The outcome from “this small trial provides preliminary evidence that an agent that stimulates bone formation might confer additional benefit over that achieved with standard care in patients with periodontitis,” commented Dr. Andrew Grey in an editorial that accompanied the article (N. Engl. J. Med. 2010 Oct. 16 [doi:10.1056/NEJMe1010459]). But many questions about this treatment remain, he said. “How durable is the effect of teriparatide? What is the optimal dosing regimen? Does teriparatide alter important [end points] such as tooth loss or the need for further operative intervention? Do antiresorptive agents, which cost considerably less than teriparatide, confer similar benefits?” asked Dr. Grey, an endocrinologist at the University of Auckland (New Zealand).

The study enrolled patients (aged 30-65 years) with severe periodontal disease at the University of Michigan from January 2005 to June 2009. All patients had normal levels of calcium and parathyroid hormone, a minimum vitamin D level of 16 ng/mL, and no osteoporosis. All patients underwent conventional surgery on an osseous defect. Starting 3 days before surgery, patients began daily treatment with either 20 mcg teriparatide or placebo, administered daily by subcutaneous injection, for 6 weeks. All patients also received a daily supplement of calcium and vitamin D.

Patients who were treated with teriparatide had significantly better resolution of their periodontal bone defects at 6, 9, and 12 months following baseline, compared with the placebo patients. At 12 months, the teriparatide-treated patients averaged a bone gain of 1.86 mm (29%), compared with baseline, whereas the placebo patients averaged a 0.16-mm (3%) gain from baseline.

Teriparatide treatment was also linked with a 2.42-mm (33%) average reduction in probing depth at the surgical site after 12 months, compared with baseline. The placebo group averaged a 1.32-mm (20%) reduction in probing depth from baseline, a statistically significant difference. Clinical attachment improved by 1.58 mm (22%) at 1 year, compared with baseline, in the teriparatide patients, significantly better than the 0.42-mm (7%) average attachment improvement in the placebo group. No improvements in probing depth occurred in the teriparatide and placebo patients in areas of severe, chronic periodontitis that did not undergo surgery.

At entry to the study, five patients in the teriparatide arm and nine in the placebo group had osteopenia on dual-energy x-ray absorptiometry examinations. At the 12-month follow-up, patients in both study arms showed no significant changes in bone density scores or in quality of life scores. Teriparatide treatment did not link with any pattern of adverse events that differed from the placebo group.

Although teriparatide is available for treating osteoporosis, its widespread use in patients who are undergoing periodontal surgery should await results from studies involving larger numbers of patients, Dr. McCauley said. She also cautioned against extrapolating the results to other types of bone surgery. Dr. McCauley said she would like to run studies on a delayed-release, topical formulation of teriparatide that would be implanted during surgery and would then release over the subsequent 6 weeks, precluding daily injections. Formulations of this type now exist, but have not reached the clinical-testing stage.

The study received partial funding from Eli Lilly & Co., the company that markets teriparatide (Forteo), but it was an investigator-initiated study. Dr. McCauley has received research grants and transportation support from Lilly. She has also received research grants and has been a consultant to Amgen Inc., but she has not received any honoraria or consulting fees. Dr. Bashutski said she has received travel expenses from the Colgate-Palmolive Co. Dr. Grey said that he has received travel expenses from Merck Sharp & Dohme (NZ) Ltd.

Improvements in periodontal probing depth and clinical attachment were significant.

Source DR. BASHUTSKI

Teriparatide increased 1-year bone gain at a rate that was 10-fold higher than placebo. 'That's huge.'

Source DR. McCAULEY

TORONTO – The stronger a patient's bones are when bisphosphonate treatment is stopped, the less likely the bones are to fracture later, based on an analysis of 437 patients.

In contrast, changes in bone mineral density following the end of bisphosphonate therapy had no significant link with subsequent fracture risk, Dr. Douglas C. Bauer said at the meeting.

The finding calls into doubt the common practice of running annual dual-energy x-ray absorptiometry examinations on patients who have withdrawn from bisphosphonate treatment.

Routine BMD measurement “1-2 years after stopping prolonged alendronate therapy may not be useful for predicting the patient's fracture risk,” said Dr. Bauer, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. The BMD at the time of alendronate discontinuation “was highly predictive of who was going to fracture.”

Patients who stopped alendronate therapy with a total hip BMD T score of −1.4 or greater had a 9% rate of clinical fracture during 5 years of follow-up. Patients with a T score of −2.1 to −1.5 when they stopped bisphosphonate treatment had a 23% fracture rate during 5 years of follow-up, and those who stopped with a T score lower than −2.1 had a 33% fracture rate over the next 5 years. The between-group differences were statistically significant.

These data “are helpful as I try to decide which of my patients I should leave on a bisphosphonate,” commented Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York. “Patients below −2.1 were at very high risk of fracture, but even those in the middle tertile, with less than −1.5, were at a risk almost as high.” Dr. Bauer's data “provides me with some comfort [on whom] I can stop safely.”

Dr. Bauer and his associates used data collected in the FLEX (Fracture Intervention Trial Long-Term Extension) study, which randomized 1,099 postmenopausal women who had completed 5 years of alendronate treatment to either continue on alendronate for another 5 years or switch to placebo (JAMA 2006;296:2927-38). They focused on the 437 patients who switched to placebo, and assessed the BMD measures that were associated with fracture risk during follow-up.

Even among patients who had relatively substantial bone loss during 1 year of follow-up, the amount of lost BMD did not significantly correlate with their follow-up fracture rate. The researchers saw no significant link to fracture rate among the 21% of patients who lost at least 3% of their BMD during the first year of follow-up, or among the 8% of patients who lost at least 5% of their BMD during 1 year of follow-up.

When a patient starts bisphosphonate treatment, the BMD typically rises sharply for a couple of years, and then plateaus and remains stable, Dr. Bauer said. After patients stop bisphosphonate treatment, their BMD usually declines gradually. Prior analysis of the FLEX data showed that patients who failed to reach a BMD of at least −2.5 usually benefited with fewer fractures when they remained on treatment. The new findings suggest that patients with T scores of less than −1.5 may also benefit from continued treatment. However, when patients reach an adequate BMD (greater than −1.5), “it's not unreasonable to talk with the patient about the potential risks and benefits of a drug holiday,” Dr. Bauer said.

The FLEX study was funded by Merck, which markets alendronate (Fosamax). Dr. Bauer has received research funding from Amgen, Merck, and Novartis.

BMD at the time of alendronate discontinuation 'was highly predictive of who was going to fracture.'

Source DR. BAUER

TORONTO – The stronger a patient's bones are when bisphosphonate treatment is stopped, the less likely the bones are to fracture later, based on an analysis of 437 patients.

In contrast, changes in bone mineral density following the end of bisphosphonate therapy had no significant link with subsequent fracture risk, Dr. Douglas C. Bauer said at the meeting.

The finding calls into doubt the common practice of running annual dual-energy x-ray absorptiometry examinations on patients who have withdrawn from bisphosphonate treatment.

Routine BMD measurement “1-2 years after stopping prolonged alendronate therapy may not be useful for predicting the patient's fracture risk,” said Dr. Bauer, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. The BMD at the time of alendronate discontinuation “was highly predictive of who was going to fracture.”

Patients who stopped alendronate therapy with a total hip BMD T score of −1.4 or greater had a 9% rate of clinical fracture during 5 years of follow-up. Patients with a T score of −2.1 to −1.5 when they stopped bisphosphonate treatment had a 23% fracture rate during 5 years of follow-up, and those who stopped with a T score lower than −2.1 had a 33% fracture rate over the next 5 years. The between-group differences were statistically significant.

These data “are helpful as I try to decide which of my patients I should leave on a bisphosphonate,” commented Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York. “Patients below −2.1 were at very high risk of fracture, but even those in the middle tertile, with less than −1.5, were at a risk almost as high.” Dr. Bauer's data “provides me with some comfort [on whom] I can stop safely.”

Dr. Bauer and his associates used data collected in the FLEX (Fracture Intervention Trial Long-Term Extension) study, which randomized 1,099 postmenopausal women who had completed 5 years of alendronate treatment to either continue on alendronate for another 5 years or switch to placebo (JAMA 2006;296:2927-38). They focused on the 437 patients who switched to placebo, and assessed the BMD measures that were associated with fracture risk during follow-up.

Even among patients who had relatively substantial bone loss during 1 year of follow-up, the amount of lost BMD did not significantly correlate with their follow-up fracture rate. The researchers saw no significant link to fracture rate among the 21% of patients who lost at least 3% of their BMD during the first year of follow-up, or among the 8% of patients who lost at least 5% of their BMD during 1 year of follow-up.

When a patient starts bisphosphonate treatment, the BMD typically rises sharply for a couple of years, and then plateaus and remains stable, Dr. Bauer said. After patients stop bisphosphonate treatment, their BMD usually declines gradually. Prior analysis of the FLEX data showed that patients who failed to reach a BMD of at least −2.5 usually benefited with fewer fractures when they remained on treatment. The new findings suggest that patients with T scores of less than −1.5 may also benefit from continued treatment. However, when patients reach an adequate BMD (greater than −1.5), “it's not unreasonable to talk with the patient about the potential risks and benefits of a drug holiday,” Dr. Bauer said.

The FLEX study was funded by Merck, which markets alendronate (Fosamax). Dr. Bauer has received research funding from Amgen, Merck, and Novartis.

BMD at the time of alendronate discontinuation 'was highly predictive of who was going to fracture.'

Source DR. BAUER

TORONTO – The stronger a patient's bones are when bisphosphonate treatment is stopped, the less likely the bones are to fracture later, based on an analysis of 437 patients.

In contrast, changes in bone mineral density following the end of bisphosphonate therapy had no significant link with subsequent fracture risk, Dr. Douglas C. Bauer said at the meeting.

The finding calls into doubt the common practice of running annual dual-energy x-ray absorptiometry examinations on patients who have withdrawn from bisphosphonate treatment.

Routine BMD measurement “1-2 years after stopping prolonged alendronate therapy may not be useful for predicting the patient's fracture risk,” said Dr. Bauer, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. The BMD at the time of alendronate discontinuation “was highly predictive of who was going to fracture.”

Patients who stopped alendronate therapy with a total hip BMD T score of −1.4 or greater had a 9% rate of clinical fracture during 5 years of follow-up. Patients with a T score of −2.1 to −1.5 when they stopped bisphosphonate treatment had a 23% fracture rate during 5 years of follow-up, and those who stopped with a T score lower than −2.1 had a 33% fracture rate over the next 5 years. The between-group differences were statistically significant.

These data “are helpful as I try to decide which of my patients I should leave on a bisphosphonate,” commented Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York. “Patients below −2.1 were at very high risk of fracture, but even those in the middle tertile, with less than −1.5, were at a risk almost as high.” Dr. Bauer's data “provides me with some comfort [on whom] I can stop safely.”

Dr. Bauer and his associates used data collected in the FLEX (Fracture Intervention Trial Long-Term Extension) study, which randomized 1,099 postmenopausal women who had completed 5 years of alendronate treatment to either continue on alendronate for another 5 years or switch to placebo (JAMA 2006;296:2927-38). They focused on the 437 patients who switched to placebo, and assessed the BMD measures that were associated with fracture risk during follow-up.

Even among patients who had relatively substantial bone loss during 1 year of follow-up, the amount of lost BMD did not significantly correlate with their follow-up fracture rate. The researchers saw no significant link to fracture rate among the 21% of patients who lost at least 3% of their BMD during the first year of follow-up, or among the 8% of patients who lost at least 5% of their BMD during 1 year of follow-up.

When a patient starts bisphosphonate treatment, the BMD typically rises sharply for a couple of years, and then plateaus and remains stable, Dr. Bauer said. After patients stop bisphosphonate treatment, their BMD usually declines gradually. Prior analysis of the FLEX data showed that patients who failed to reach a BMD of at least −2.5 usually benefited with fewer fractures when they remained on treatment. The new findings suggest that patients with T scores of less than −1.5 may also benefit from continued treatment. However, when patients reach an adequate BMD (greater than −1.5), “it's not unreasonable to talk with the patient about the potential risks and benefits of a drug holiday,” Dr. Bauer said.

The FLEX study was funded by Merck, which markets alendronate (Fosamax). Dr. Bauer has received research funding from Amgen, Merck, and Novartis.

BMD at the time of alendronate discontinuation 'was highly predictive of who was going to fracture.'

Source DR. BAUER

Major Finding: Postmenopausal women with osteoporosis who received an annual injection of zoledronic acid for 6 years maintained their femoral neck bone mineral density significantly better than did those treated with the drug for 3 years followed by 3 years on placebo.

Data Source: Extension of the HORIZON Pivotal Fracture Trial, a randomized, multicenter extension trial with 1,233 women.

Disclosures: The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen and Nycomed, and that he has received research contracts from Amgen, Merck, Novartis, and Roche/Genentech.

TORONTO — Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, according to results of a controlled study with more than 1,200 subjects.

Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the meeting.

“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco.

“These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.

On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said.

It may be possible to identify women who would benefit from a drug holiday, he added.

In light of the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment.

In a previous report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38).

The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.

The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).

Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo.

The average age of the study subjects was 76 years, and approximately 55% had a femoral neck T score of less than −2.5.

At the conclusion of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients who were treated with zoledronic acid, a statistically significant difference in the study's primary end point.

Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, a statistically significant difference.

The rate of morphometric vertebral fractures during the 3 years of the new study totaled 6% in the patients who were on placebo and 3% in those who were on zoledronic acid, a statistically significant difference.

The two treatment arms showed no significant difference in their rates of nonvertebral fractures. Continued zoledronic acid treatment also led to reduced blood levels of a marker of bone turnover compared with the patients who received placebo injections.

Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo. The researchers looked especially closely at cardiovascular events; the only significant, between-treatment difference was in new hypertensive adverse events, which occurred significantly more often in the patients who received placebo for 3 years.

The decision to continue bisphosphonate treatment long term must be individualized.

Source DR. BLACK

Major Finding: Postmenopausal women with osteoporosis who received an annual injection of zoledronic acid for 6 years maintained their femoral neck bone mineral density significantly better than did those treated with the drug for 3 years followed by 3 years on placebo.

Data Source: Extension of the HORIZON Pivotal Fracture Trial, a randomized, multicenter extension trial with 1,233 women.

Disclosures: The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen and Nycomed, and that he has received research contracts from Amgen, Merck, Novartis, and Roche/Genentech.

TORONTO — Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, according to results of a controlled study with more than 1,200 subjects.

Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the meeting.

“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco.

“These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.

On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said.

It may be possible to identify women who would benefit from a drug holiday, he added.

In light of the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment.

In a previous report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38).

The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.

The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).

Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo.

The average age of the study subjects was 76 years, and approximately 55% had a femoral neck T score of less than −2.5.

At the conclusion of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients who were treated with zoledronic acid, a statistically significant difference in the study's primary end point.

Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, a statistically significant difference.

The rate of morphometric vertebral fractures during the 3 years of the new study totaled 6% in the patients who were on placebo and 3% in those who were on zoledronic acid, a statistically significant difference.

The two treatment arms showed no significant difference in their rates of nonvertebral fractures. Continued zoledronic acid treatment also led to reduced blood levels of a marker of bone turnover compared with the patients who received placebo injections.

Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo. The researchers looked especially closely at cardiovascular events; the only significant, between-treatment difference was in new hypertensive adverse events, which occurred significantly more often in the patients who received placebo for 3 years.

The decision to continue bisphosphonate treatment long term must be individualized.

Source DR. BLACK

Major Finding: Postmenopausal women with osteoporosis who received an annual injection of zoledronic acid for 6 years maintained their femoral neck bone mineral density significantly better than did those treated with the drug for 3 years followed by 3 years on placebo.

Data Source: Extension of the HORIZON Pivotal Fracture Trial, a randomized, multicenter extension trial with 1,233 women.

Disclosures: The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen and Nycomed, and that he has received research contracts from Amgen, Merck, Novartis, and Roche/Genentech.

TORONTO — Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, according to results of a controlled study with more than 1,200 subjects.

Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the meeting.

“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco.

“These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.

On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said.

It may be possible to identify women who would benefit from a drug holiday, he added.

In light of the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment.

In a previous report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38).

The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.

The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).

Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo.

The average age of the study subjects was 76 years, and approximately 55% had a femoral neck T score of less than −2.5.

At the conclusion of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients who were treated with zoledronic acid, a statistically significant difference in the study's primary end point.

Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, a statistically significant difference.

The rate of morphometric vertebral fractures during the 3 years of the new study totaled 6% in the patients who were on placebo and 3% in those who were on zoledronic acid, a statistically significant difference.

The two treatment arms showed no significant difference in their rates of nonvertebral fractures. Continued zoledronic acid treatment also led to reduced blood levels of a marker of bone turnover compared with the patients who received placebo injections.

Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo. The researchers looked especially closely at cardiovascular events; the only significant, between-treatment difference was in new hypertensive adverse events, which occurred significantly more often in the patients who received placebo for 3 years.

The decision to continue bisphosphonate treatment long term must be individualized.

Source DR. BLACK

STOCKHOLM — Higher blood levels of the bone hormone osteoprotegerin are linked with a higher long-term risk of death in patients with chronic heart failure, reported Dr. Ragnhild R. Roysland.

The relationship between osteoprotegerin (OPG) and mortality in heart failure is independent of the conventional cardiovascular risk factors, based on a secondary analysis of results of the Italian GISSI-Heart Failure trial.

Osteoprotegerin, a cytokine that's a member of the tumor necrosis factor superfamily, is drawing increasing attention among cardiovascular researchers as a likely key player in what's known as “the calcification paradox.” In animal studies, low levels of OPG are associated with decreased skeletal calcification, osteoporosis, and increased calcification of the major arteries. But in recent human studies, increased OPG levels have been linked to a greater atherosclerotic burden; an increased risk of death following acute MI; and now, in GISSI-HF, to increased mortality in the setting of chronic HF, Dr. Roysland said at the congress.

The GISSI-HF study was a randomized clinical trial in which 6,975 Italian patients with chronic heart failure were assigned to rosuvastatin, fish oil, or placebo and followed up for a median of 3.9 years (Lancet 2008;372:1223–30;1231–9). Dr. Roysland presented a new substudy involving 1,229 GISSI-HF participants for whom baseline OPG levels were available.

The aim was to see if baseline OPG was predictive of all-cause mortality. This indeed proved to be the case. During follow-up 332 patients died. The mortality rate was 20% in those in the bottom tertile for baseline OPG with a value less than 1,210 ng/L, and more than twice as great at 45% in patients in the highest tertile, with an OPG of at least 1,923 ng/L. Patients with an intermediate-tertile baseline OPG of 1,210–1,922 ng/L split the difference in terms of mortality, said Dr. Roysland of Akershus University Hospital, Lørenskog, Norway.

Treatment assignment in GISSI-HF did not affect OPG levels. However, if a medication could be identified that reduces OPG levels and attenuates the risk associated with high OPG, then OPG could become an important marker to use in managing chronic HF in clinical practice. There is early evidence that treatments for osteoporosis reduce OPG levels in a non-HF population, but no studies have been done in patients with chronic HF, she said.

Dr. Marco Metra, a member of the ESC congress scientific program committee, said he'd reviewed all the HF studies being presented at the meeting. Two studies in addition to Dr. Roysland's consistently showed that HF patients with high levels of OPG have a poor prognosis. “We know that patients with heart failure have low levels of vitamin D and increased rates of osteoporosis and bone fractures. So the bone is in some way a target of heart failure,” said Dr. Metra of the University of Brescia (Italy).

Mortality for patients with high OPG levels, at 45%, was more than twice that in patients with low levels, at 20%.

Source DR. ROYSLAND

Disclosures: Dr. Roysland said she had no financial conflicts.

STOCKHOLM — Higher blood levels of the bone hormone osteoprotegerin are linked with a higher long-term risk of death in patients with chronic heart failure, reported Dr. Ragnhild R. Roysland.

The relationship between osteoprotegerin (OPG) and mortality in heart failure is independent of the conventional cardiovascular risk factors, based on a secondary analysis of results of the Italian GISSI-Heart Failure trial.

Osteoprotegerin, a cytokine that's a member of the tumor necrosis factor superfamily, is drawing increasing attention among cardiovascular researchers as a likely key player in what's known as “the calcification paradox.” In animal studies, low levels of OPG are associated with decreased skeletal calcification, osteoporosis, and increased calcification of the major arteries. But in recent human studies, increased OPG levels have been linked to a greater atherosclerotic burden; an increased risk of death following acute MI; and now, in GISSI-HF, to increased mortality in the setting of chronic HF, Dr. Roysland said at the congress.

The GISSI-HF study was a randomized clinical trial in which 6,975 Italian patients with chronic heart failure were assigned to rosuvastatin, fish oil, or placebo and followed up for a median of 3.9 years (Lancet 2008;372:1223–30;1231–9). Dr. Roysland presented a new substudy involving 1,229 GISSI-HF participants for whom baseline OPG levels were available.

The aim was to see if baseline OPG was predictive of all-cause mortality. This indeed proved to be the case. During follow-up 332 patients died. The mortality rate was 20% in those in the bottom tertile for baseline OPG with a value less than 1,210 ng/L, and more than twice as great at 45% in patients in the highest tertile, with an OPG of at least 1,923 ng/L. Patients with an intermediate-tertile baseline OPG of 1,210–1,922 ng/L split the difference in terms of mortality, said Dr. Roysland of Akershus University Hospital, Lørenskog, Norway.

Treatment assignment in GISSI-HF did not affect OPG levels. However, if a medication could be identified that reduces OPG levels and attenuates the risk associated with high OPG, then OPG could become an important marker to use in managing chronic HF in clinical practice. There is early evidence that treatments for osteoporosis reduce OPG levels in a non-HF population, but no studies have been done in patients with chronic HF, she said.

Dr. Marco Metra, a member of the ESC congress scientific program committee, said he'd reviewed all the HF studies being presented at the meeting. Two studies in addition to Dr. Roysland's consistently showed that HF patients with high levels of OPG have a poor prognosis. “We know that patients with heart failure have low levels of vitamin D and increased rates of osteoporosis and bone fractures. So the bone is in some way a target of heart failure,” said Dr. Metra of the University of Brescia (Italy).

Mortality for patients with high OPG levels, at 45%, was more than twice that in patients with low levels, at 20%.

Source DR. ROYSLAND

Disclosures: Dr. Roysland said she had no financial conflicts.

STOCKHOLM — Higher blood levels of the bone hormone osteoprotegerin are linked with a higher long-term risk of death in patients with chronic heart failure, reported Dr. Ragnhild R. Roysland.

The relationship between osteoprotegerin (OPG) and mortality in heart failure is independent of the conventional cardiovascular risk factors, based on a secondary analysis of results of the Italian GISSI-Heart Failure trial.

Osteoprotegerin, a cytokine that's a member of the tumor necrosis factor superfamily, is drawing increasing attention among cardiovascular researchers as a likely key player in what's known as “the calcification paradox.” In animal studies, low levels of OPG are associated with decreased skeletal calcification, osteoporosis, and increased calcification of the major arteries. But in recent human studies, increased OPG levels have been linked to a greater atherosclerotic burden; an increased risk of death following acute MI; and now, in GISSI-HF, to increased mortality in the setting of chronic HF, Dr. Roysland said at the congress.

The GISSI-HF study was a randomized clinical trial in which 6,975 Italian patients with chronic heart failure were assigned to rosuvastatin, fish oil, or placebo and followed up for a median of 3.9 years (Lancet 2008;372:1223–30;1231–9). Dr. Roysland presented a new substudy involving 1,229 GISSI-HF participants for whom baseline OPG levels were available.

The aim was to see if baseline OPG was predictive of all-cause mortality. This indeed proved to be the case. During follow-up 332 patients died. The mortality rate was 20% in those in the bottom tertile for baseline OPG with a value less than 1,210 ng/L, and more than twice as great at 45% in patients in the highest tertile, with an OPG of at least 1,923 ng/L. Patients with an intermediate-tertile baseline OPG of 1,210–1,922 ng/L split the difference in terms of mortality, said Dr. Roysland of Akershus University Hospital, Lørenskog, Norway.

Treatment assignment in GISSI-HF did not affect OPG levels. However, if a medication could be identified that reduces OPG levels and attenuates the risk associated with high OPG, then OPG could become an important marker to use in managing chronic HF in clinical practice. There is early evidence that treatments for osteoporosis reduce OPG levels in a non-HF population, but no studies have been done in patients with chronic HF, she said.

Dr. Marco Metra, a member of the ESC congress scientific program committee, said he'd reviewed all the HF studies being presented at the meeting. Two studies in addition to Dr. Roysland's consistently showed that HF patients with high levels of OPG have a poor prognosis. “We know that patients with heart failure have low levels of vitamin D and increased rates of osteoporosis and bone fractures. So the bone is in some way a target of heart failure,” said Dr. Metra of the University of Brescia (Italy).

Mortality for patients with high OPG levels, at 45%, was more than twice that in patients with low levels, at 20%.

Source DR. ROYSLAND

Disclosures: Dr. Roysland said she had no financial conflicts.

Major Finding: 101 patients randomized to vertebroplasty for acute osteoporotic compression fractures had a mean reduction of 5.2 points on a 10-point pain scale a month after the procedure; 101 randomized to conservative treatment had a mean reduction of 2.7 points.

Data Source: Randomized, open-label trial.

Disclosures: The authors reported no conflicts of interest. The study was funded by a ZonMw, a Dutch health care research organization, and Cook Medical, which makes the bone cement used in the trial. The commentators reported receiving consulting fees and travel and accommodation expenses from Medtronic Spinal and Biologics Europa BVBA for their role in the FREE balloon kyphoplasty trial.

Vertebroplasty provided quicker, stronger, and more durable pain relief from acute, osteoporotic vertebral compression fractures than did conservative pain management, judging from the findings of a randomized, open-label trial.

“In a subgroup of patients with acute [fractures] and persistent pain, percutaneous vertebroplasty is effective and safe,” concluded Dr. Caroline Klazen, a radiologist at St. Elisabeth Hospital in Tilburg, the Netherlands, and her colleagues (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)60954-3

Two previous studies found no benefit for vertebroplasty compared with bed rest, analgesics, and other conservative measures, but both trials included patients with fractures that were up to a year old (N. Engl. J. Med. 2009;361:557-68; N. Engl. J. Med. 2009;361:569-79).

The Lancet study pitted vertebroplasty against conservative treatment within a mean of 5.6 weeks of fracture symptom onset; vertebroplasty patients experienced greater pain relief initially and throughout the trial's year-long follow-up.

“Apparently,” vertebroplasty shortly after a fracture “is more effective for pain relief” than vertebroplasty performed months afterward, Dr. Klazen and her colleagues wrote.

Recruited from the radiology departments of six hospitals in the Netherlands and Belgium, 101 patients were randomized to vertebroplasty and 101 to conservative measures. Patients were at least 50 years old, and 69% were female.

All of the patients had radiologically confirmed compression fractures at or below thoracic vertebrae 5 with bone edema on magnetic resonance imaging and a minimum height loss of 15%, the authors noted.

They also had tenderness at the fracture level; bone density T scores at or below – 1; back pain for 6 weeks or less; and a pain score of at least 5 on a 10-point visual analog scale (VAS), with 10 being the worst pain.

In the vertebroplasty group, fractures were injected with a mean volume of 4.1 mL of polymethylmethacrylate bone cement under fluoroscopic guidance.

At 1 month, those injected with the bone cement had a mean reduction of 5.2 VAS points from baseline (95% CI, 5.88-4.72), compared with a mean reduction of 2.7 points (95% CI, 3.22-1.98) in those who were treated conservatively.

At 1 year, vertebroplasty subjects had a mean reduction of 5.7 VAS points from baseline (95% CI, 6.22-4.98); conservatively treated patients had a mean reduction of 3.7 points (95% CI, 4.35-3.05).

During the study, vertebroplasty patients used significantly less pain-relieving medication at day 1, week 1, and month 1, but the difference in drug use was not significant at later stages of follow-up.

The authors noted that the intervention was not blinded, and that “knowledge of the treatment assignment might have affected patient responses to questions or radiologist assessments.”

Computed tomographic scanning found that polymethylmethacrylate bone cement leaked out of 97 of the 134 vertebral bodies injected in the 101 vertebroplasty subjects. “Most leaks were discal or into segmental veins; none were into the spinal canal,” the authors noted.

Cement did deposit into a segmental pulmonary artery in one patient, however all cement leaks remained asymptomatic.

In a commentary, orthopedic surgeons Dr. Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and Dr. Jan Van Meirhaeghe, of St. Jan General Hospital in Brugge, Belgium, noted that the study “lends support to the large body of medical opinion that vertebroplasty has a part to play in the management of the pain of vertebral compression fractures” (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)61162-2

But they noted “an unexplained significant difference at baseline” in quality of life and disability measurements between the two groups that suggests “the control group might have been generally healthier than the vertebroplasty group.”

Dr. Klazen and her colleagues attributed the differences to chance.

Dr. Wardlaw and Dr. Van Meirhaeghe also noted that in the two previous studies that found no benefit for vertebroplasty, the comparators were sham treatments, not conservative pain management.

In one of the trials, the sham treatment included injecting bupivacaine, a long-acting local anesthetic, directly into fractures, which in itself might have brought relief, the commentators wrote.

By using conservative pain management as a comparator, Dr. Klazen and her colleagues noted, vertebroplasty was tested against “the reference treatment and thus provides the clinician with directly applicable information about how to best treat the patient.”

Dr. Klazen and her colleagues noted that ZonMw and Cook Medical, the sponsors of the study “had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.”

Major Finding: 101 patients randomized to vertebroplasty for acute osteoporotic compression fractures had a mean reduction of 5.2 points on a 10-point pain scale a month after the procedure; 101 randomized to conservative treatment had a mean reduction of 2.7 points.

Data Source: Randomized, open-label trial.

Disclosures: The authors reported no conflicts of interest. The study was funded by a ZonMw, a Dutch health care research organization, and Cook Medical, which makes the bone cement used in the trial. The commentators reported receiving consulting fees and travel and accommodation expenses from Medtronic Spinal and Biologics Europa BVBA for their role in the FREE balloon kyphoplasty trial.

Vertebroplasty provided quicker, stronger, and more durable pain relief from acute, osteoporotic vertebral compression fractures than did conservative pain management, judging from the findings of a randomized, open-label trial.

“In a subgroup of patients with acute [fractures] and persistent pain, percutaneous vertebroplasty is effective and safe,” concluded Dr. Caroline Klazen, a radiologist at St. Elisabeth Hospital in Tilburg, the Netherlands, and her colleagues (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)60954-3

Two previous studies found no benefit for vertebroplasty compared with bed rest, analgesics, and other conservative measures, but both trials included patients with fractures that were up to a year old (N. Engl. J. Med. 2009;361:557-68; N. Engl. J. Med. 2009;361:569-79).

The Lancet study pitted vertebroplasty against conservative treatment within a mean of 5.6 weeks of fracture symptom onset; vertebroplasty patients experienced greater pain relief initially and throughout the trial's year-long follow-up.

“Apparently,” vertebroplasty shortly after a fracture “is more effective for pain relief” than vertebroplasty performed months afterward, Dr. Klazen and her colleagues wrote.

Recruited from the radiology departments of six hospitals in the Netherlands and Belgium, 101 patients were randomized to vertebroplasty and 101 to conservative measures. Patients were at least 50 years old, and 69% were female.

All of the patients had radiologically confirmed compression fractures at or below thoracic vertebrae 5 with bone edema on magnetic resonance imaging and a minimum height loss of 15%, the authors noted.

They also had tenderness at the fracture level; bone density T scores at or below – 1; back pain for 6 weeks or less; and a pain score of at least 5 on a 10-point visual analog scale (VAS), with 10 being the worst pain.

In the vertebroplasty group, fractures were injected with a mean volume of 4.1 mL of polymethylmethacrylate bone cement under fluoroscopic guidance.

At 1 month, those injected with the bone cement had a mean reduction of 5.2 VAS points from baseline (95% CI, 5.88-4.72), compared with a mean reduction of 2.7 points (95% CI, 3.22-1.98) in those who were treated conservatively.

At 1 year, vertebroplasty subjects had a mean reduction of 5.7 VAS points from baseline (95% CI, 6.22-4.98); conservatively treated patients had a mean reduction of 3.7 points (95% CI, 4.35-3.05).

During the study, vertebroplasty patients used significantly less pain-relieving medication at day 1, week 1, and month 1, but the difference in drug use was not significant at later stages of follow-up.

The authors noted that the intervention was not blinded, and that “knowledge of the treatment assignment might have affected patient responses to questions or radiologist assessments.”

Computed tomographic scanning found that polymethylmethacrylate bone cement leaked out of 97 of the 134 vertebral bodies injected in the 101 vertebroplasty subjects. “Most leaks were discal or into segmental veins; none were into the spinal canal,” the authors noted.

Cement did deposit into a segmental pulmonary artery in one patient, however all cement leaks remained asymptomatic.

In a commentary, orthopedic surgeons Dr. Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and Dr. Jan Van Meirhaeghe, of St. Jan General Hospital in Brugge, Belgium, noted that the study “lends support to the large body of medical opinion that vertebroplasty has a part to play in the management of the pain of vertebral compression fractures” (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)61162-2

But they noted “an unexplained significant difference at baseline” in quality of life and disability measurements between the two groups that suggests “the control group might have been generally healthier than the vertebroplasty group.”

Dr. Klazen and her colleagues attributed the differences to chance.

Dr. Wardlaw and Dr. Van Meirhaeghe also noted that in the two previous studies that found no benefit for vertebroplasty, the comparators were sham treatments, not conservative pain management.

In one of the trials, the sham treatment included injecting bupivacaine, a long-acting local anesthetic, directly into fractures, which in itself might have brought relief, the commentators wrote.

By using conservative pain management as a comparator, Dr. Klazen and her colleagues noted, vertebroplasty was tested against “the reference treatment and thus provides the clinician with directly applicable information about how to best treat the patient.”

Dr. Klazen and her colleagues noted that ZonMw and Cook Medical, the sponsors of the study “had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.”

Major Finding: 101 patients randomized to vertebroplasty for acute osteoporotic compression fractures had a mean reduction of 5.2 points on a 10-point pain scale a month after the procedure; 101 randomized to conservative treatment had a mean reduction of 2.7 points.

Data Source: Randomized, open-label trial.

Disclosures: The authors reported no conflicts of interest. The study was funded by a ZonMw, a Dutch health care research organization, and Cook Medical, which makes the bone cement used in the trial. The commentators reported receiving consulting fees and travel and accommodation expenses from Medtronic Spinal and Biologics Europa BVBA for their role in the FREE balloon kyphoplasty trial.

Vertebroplasty provided quicker, stronger, and more durable pain relief from acute, osteoporotic vertebral compression fractures than did conservative pain management, judging from the findings of a randomized, open-label trial.

“In a subgroup of patients with acute [fractures] and persistent pain, percutaneous vertebroplasty is effective and safe,” concluded Dr. Caroline Klazen, a radiologist at St. Elisabeth Hospital in Tilburg, the Netherlands, and her colleagues (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)60954-3

Two previous studies found no benefit for vertebroplasty compared with bed rest, analgesics, and other conservative measures, but both trials included patients with fractures that were up to a year old (N. Engl. J. Med. 2009;361:557-68; N. Engl. J. Med. 2009;361:569-79).

The Lancet study pitted vertebroplasty against conservative treatment within a mean of 5.6 weeks of fracture symptom onset; vertebroplasty patients experienced greater pain relief initially and throughout the trial's year-long follow-up.

“Apparently,” vertebroplasty shortly after a fracture “is more effective for pain relief” than vertebroplasty performed months afterward, Dr. Klazen and her colleagues wrote.

Recruited from the radiology departments of six hospitals in the Netherlands and Belgium, 101 patients were randomized to vertebroplasty and 101 to conservative measures. Patients were at least 50 years old, and 69% were female.

All of the patients had radiologically confirmed compression fractures at or below thoracic vertebrae 5 with bone edema on magnetic resonance imaging and a minimum height loss of 15%, the authors noted.

They also had tenderness at the fracture level; bone density T scores at or below – 1; back pain for 6 weeks or less; and a pain score of at least 5 on a 10-point visual analog scale (VAS), with 10 being the worst pain.

In the vertebroplasty group, fractures were injected with a mean volume of 4.1 mL of polymethylmethacrylate bone cement under fluoroscopic guidance.

At 1 month, those injected with the bone cement had a mean reduction of 5.2 VAS points from baseline (95% CI, 5.88-4.72), compared with a mean reduction of 2.7 points (95% CI, 3.22-1.98) in those who were treated conservatively.

At 1 year, vertebroplasty subjects had a mean reduction of 5.7 VAS points from baseline (95% CI, 6.22-4.98); conservatively treated patients had a mean reduction of 3.7 points (95% CI, 4.35-3.05).

During the study, vertebroplasty patients used significantly less pain-relieving medication at day 1, week 1, and month 1, but the difference in drug use was not significant at later stages of follow-up.

The authors noted that the intervention was not blinded, and that “knowledge of the treatment assignment might have affected patient responses to questions or radiologist assessments.”

Computed tomographic scanning found that polymethylmethacrylate bone cement leaked out of 97 of the 134 vertebral bodies injected in the 101 vertebroplasty subjects. “Most leaks were discal or into segmental veins; none were into the spinal canal,” the authors noted.

Cement did deposit into a segmental pulmonary artery in one patient, however all cement leaks remained asymptomatic.

In a commentary, orthopedic surgeons Dr. Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and Dr. Jan Van Meirhaeghe, of St. Jan General Hospital in Brugge, Belgium, noted that the study “lends support to the large body of medical opinion that vertebroplasty has a part to play in the management of the pain of vertebral compression fractures” (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)61162-2

But they noted “an unexplained significant difference at baseline” in quality of life and disability measurements between the two groups that suggests “the control group might have been generally healthier than the vertebroplasty group.”

Dr. Klazen and her colleagues attributed the differences to chance.

Dr. Wardlaw and Dr. Van Meirhaeghe also noted that in the two previous studies that found no benefit for vertebroplasty, the comparators were sham treatments, not conservative pain management.

In one of the trials, the sham treatment included injecting bupivacaine, a long-acting local anesthetic, directly into fractures, which in itself might have brought relief, the commentators wrote.

By using conservative pain management as a comparator, Dr. Klazen and her colleagues noted, vertebroplasty was tested against “the reference treatment and thus provides the clinician with directly applicable information about how to best treat the patient.”

Dr. Klazen and her colleagues noted that ZonMw and Cook Medical, the sponsors of the study “had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.”

The use of oral bisphosphonates was not associated with esophageal or gastric cancer in a large cohort study in the United Kingdom, according to a large U.K. database analysis.

Oral bisphosphonates cause serious esophagitis in some users. Reflux esophagitis is a known risk factor for esophageal cancer, but it is not known whether bisphosphonates-associated esophagitis also predisposes patients to develop gastric cancer, said Chris R. Cardwell, Ph.D., of Queen's University Belfast (Ireland), and his associates.

“The U.S. Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate and a further 31 cases in patients using bisphosphonates in Europe and Japan, possibly indicating risk of malignancy,” the investigators noted.

They searched for a possible link between the drugs and esophageal or gastric cancer using the General Practice Research Database (GPRD), “the world's largest computerized database of anonymized longitudinal patient records,” which includes 500 general practices and covers about 6% of the population in the United Kingdom.

The investigators reviewed the records of 41,826 patients aged 40 years and older who used bisphosphonates and the same number of control patients matched for age, sex, and medical practice.

During a mean follow-up of 4.5 years, 287 of these patients developed esophageal or gastric cancer.

There were no significant differences between cases and controls in risk for esophageal cancer, gastric cancer, or both cancers combined.

This result did not change when the data were adjusted to account for possible confounders of gastric cancer risk, such as smoking, alcohol use, and use of drugs including NSAIDs, proton pump inhibitors, and H₂ receptor antagonists.

Moreover, the risk of these cancers was no higher in patients who took larger daily doses of bisphosphonates or in those who had a longer duration of bisphosphonate use, the investigators said (JAMA 2010;304:657-63).

In addition, the risk of gastric cancer was not significantly different between men and women exposed to bisphosphonates, and it did not differ across several different bisphosphonate medications.

There also was no association between cancer risk and bisphosphonate use in the subgroup of patients who had a history of gastroesophageal reflux disease.

Previous studies of this issue were limited by very small numbers of cases and short follow-up, lack of adjustment for potential confounders, and lack of differentiation between bisphosphonates by type, dosage, or duration of use, Dr. Cardwell and his associates noted.

“In conclusion … we found no evidence for a substantially increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.

Access to the GPRD database was funded by the Medical Research Council.

Dr. Cardwell reported no financial conflicts of interest.

The use of oral bisphosphonates was not associated with esophageal or gastric cancer in a large cohort study in the United Kingdom, according to a large U.K. database analysis.

Oral bisphosphonates cause serious esophagitis in some users. Reflux esophagitis is a known risk factor for esophageal cancer, but it is not known whether bisphosphonates-associated esophagitis also predisposes patients to develop gastric cancer, said Chris R. Cardwell, Ph.D., of Queen's University Belfast (Ireland), and his associates.

“The U.S. Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate and a further 31 cases in patients using bisphosphonates in Europe and Japan, possibly indicating risk of malignancy,” the investigators noted.

They searched for a possible link between the drugs and esophageal or gastric cancer using the General Practice Research Database (GPRD), “the world's largest computerized database of anonymized longitudinal patient records,” which includes 500 general practices and covers about 6% of the population in the United Kingdom.

The investigators reviewed the records of 41,826 patients aged 40 years and older who used bisphosphonates and the same number of control patients matched for age, sex, and medical practice.

During a mean follow-up of 4.5 years, 287 of these patients developed esophageal or gastric cancer.

There were no significant differences between cases and controls in risk for esophageal cancer, gastric cancer, or both cancers combined.

This result did not change when the data were adjusted to account for possible confounders of gastric cancer risk, such as smoking, alcohol use, and use of drugs including NSAIDs, proton pump inhibitors, and H₂ receptor antagonists.

Moreover, the risk of these cancers was no higher in patients who took larger daily doses of bisphosphonates or in those who had a longer duration of bisphosphonate use, the investigators said (JAMA 2010;304:657-63).

In addition, the risk of gastric cancer was not significantly different between men and women exposed to bisphosphonates, and it did not differ across several different bisphosphonate medications.

There also was no association between cancer risk and bisphosphonate use in the subgroup of patients who had a history of gastroesophageal reflux disease.

Previous studies of this issue were limited by very small numbers of cases and short follow-up, lack of adjustment for potential confounders, and lack of differentiation between bisphosphonates by type, dosage, or duration of use, Dr. Cardwell and his associates noted.

“In conclusion … we found no evidence for a substantially increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.

Access to the GPRD database was funded by the Medical Research Council.

Dr. Cardwell reported no financial conflicts of interest.

The use of oral bisphosphonates was not associated with esophageal or gastric cancer in a large cohort study in the United Kingdom, according to a large U.K. database analysis.

Oral bisphosphonates cause serious esophagitis in some users. Reflux esophagitis is a known risk factor for esophageal cancer, but it is not known whether bisphosphonates-associated esophagitis also predisposes patients to develop gastric cancer, said Chris R. Cardwell, Ph.D., of Queen's University Belfast (Ireland), and his associates.

“The U.S. Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate and a further 31 cases in patients using bisphosphonates in Europe and Japan, possibly indicating risk of malignancy,” the investigators noted.

They searched for a possible link between the drugs and esophageal or gastric cancer using the General Practice Research Database (GPRD), “the world's largest computerized database of anonymized longitudinal patient records,” which includes 500 general practices and covers about 6% of the population in the United Kingdom.

The investigators reviewed the records of 41,826 patients aged 40 years and older who used bisphosphonates and the same number of control patients matched for age, sex, and medical practice.

During a mean follow-up of 4.5 years, 287 of these patients developed esophageal or gastric cancer.

There were no significant differences between cases and controls in risk for esophageal cancer, gastric cancer, or both cancers combined.

This result did not change when the data were adjusted to account for possible confounders of gastric cancer risk, such as smoking, alcohol use, and use of drugs including NSAIDs, proton pump inhibitors, and H₂ receptor antagonists.

Moreover, the risk of these cancers was no higher in patients who took larger daily doses of bisphosphonates or in those who had a longer duration of bisphosphonate use, the investigators said (JAMA 2010;304:657-63).

In addition, the risk of gastric cancer was not significantly different between men and women exposed to bisphosphonates, and it did not differ across several different bisphosphonate medications.

There also was no association between cancer risk and bisphosphonate use in the subgroup of patients who had a history of gastroesophageal reflux disease.

Previous studies of this issue were limited by very small numbers of cases and short follow-up, lack of adjustment for potential confounders, and lack of differentiation between bisphosphonates by type, dosage, or duration of use, Dr. Cardwell and his associates noted.

“In conclusion … we found no evidence for a substantially increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.

Access to the GPRD database was funded by the Medical Research Council.

Dr. Cardwell reported no financial conflicts of interest.

MARINA DEL REY, CALIF. — As the debate unfolds over both whether bisphosphonates cause femur fractures and the degree to which the benefits of drugs still outweigh the risks, a phenomenon has emerged.

Women who have taken bisphosphonates for years are being seen in doctors' offices with thigh pain that is easy to mistake for hip or knee arthritis. They have a unique constellation of radiologic findings on imaging, and they either have permanent titanium rods placed in their thigh bones or go on to full femur fractures—sometimes bilaterally—and permanent disability.

No one can yet say for sure whether they would have had those fractures regardless of bisphosphonate use, nor can anyone say if femur fractures are limited to alendronate (Fosamax) users or are a bisphosphonate class effect.

But a trend is emerging, and with it a treatment protocol.

“The thinking [among colleagues] is that this is novel and specific to bisphosphonate treatment, but only time will tell,” Dr. Benjamin C. Bengs, an orthopedic surgeon at the University of California, Los Angeles, said in an interview.

The possibility must be added to the hip pain differential in women with long-standing use of the drugs, according to Dr. Bengs and others who were interviewed for this story.

Unusual Radiology Findings

For many of the doctors who were interviewed, the question isn't so much whether bisphosphonates cause femur fractures, but rather how to care for women with a long history of using the drugs, and how to recognize signs and symptoms of impending trouble.

Any woman with pain over the thigh and those x-ray findings is definitely a candidate for prophylactic rodding, said Dr. Bengs.

The unique findings on x-ray are cortical thickening that is most pronounced on the lateral side of the femur, accompanied by a beaking lesion, also on the lateral side of the femur. Intramedullary edema is often present.

The beaking lesion is the start of a horizontal or oblique stress fracture. In time, there generally develops a “little, lucent, dark line extending from the beak to the middle of the bone,” Dr. Joseph Robinson, a radiology fellow at Cedars-Sinai Medical Center in Los Angeles, said in an interview.

“Lateral stress fractures are unusual. In our area, they are all related to bisphosphonates,” Dr. Kambiz Motamedi, a diagnostic radiologist at UCLA Medical Center.

There is a strong belief “from our sports medicine folks and rheumatologists” that there is a relationship with bisphosphonates, he said.

Both Legs Must Be Examined

Standard hip x-rays don't go far enough down to detect the lesion, which is closer to the knee than the typical femur fracture would be, Dr. Robinson said. When they do a hip series, Cedars-Sinai radiologists are careful to image lower down so they don't miss it, he said, noting that they are also putting markers on skin to identify the source of pain.

If the lesion is found, it is imperative to image the other femur as well, said Dr. Stuart L. Silverman, a rheumatologist in private practice in Beverly Hills, Calif. The other femur can go on to fracture, often within 18 months, he said in an interview.

Dr. Bengs noted that in most case, rodding is the usual treatment. It takes only a matter of weeks to recover from hip-to-knee rod placement, he said. It takes months to recover from a fracture, however, and older patients usually lose 10%-15% of their strength and ambulation during their convalescence, he added.

“The fractures are devastating,” said UCLA and Cedars-Sinai rheumatologist Dr. Solomon N. Forouzesh, who is the medical director of the rehabilitation department at Brotman Medical Center in Culver City, Calif. He said he's seen two cases in his practice.

Active, Osteopenic Women at Risk

Active women who have osteopenia—not osteoporosis—appear to be most at risk, Dr. Nancy Lane, a University of California, Davis, rheumatologist, said in an interview. “What I think is going on” is that bisphosphonates, by reducing bone turnover, lead to the overmineralization of cortical bone, she explained. “Over time, the bones become brittle [and] fail from too much mineralization. They cannot dissipate the load.”

It's “probably best not [to use bisphosphonates] in people with low risk of fractures who are very active,” she said. In the past, she added, use of the drugs might have been “too aggressive.”

A Drug Holiday Is Advised

As the story unfolds, doctors are using bisphosphonates for shorter lengths of time than in the past, followed by a drug holiday and ongoing bone-density monitoring.

The risk of fracture seems to “start at about 3 years and peaks between 5 and 6 years,” Dr. Forouzesh said. To be ahead of the game, he advises not waiting until the risk peaks. “Back off ahead of time. I do a drug holiday in 3 or 4 years,” he said.

It's not clear at this point if the phenomenon—if it is truly real—is limited to alendronate or is a bisphosphonate class effect.

Alendronate has been on the market the longest and has been the most widely used agent, Dr. Lane noted. “I am sure over time” it will emerge with other members of the class, as well, she said.

Meanwhile, there are efforts to raise awareness of the issue. The American College of Rheumatology issued a bulletin on the matter in March (“Atypical Femoral Fractures With Long-Term Bisphosphonate Use,” which can be accessed online at

www.rheumatology.org/publications/hotline/2010_03_22_bisphosphonate.asp

At Cedars-Sinai, “we are trying to have [a conference] to make rheumatologists and others aware of how to deal with the problem,” Dr. Robinson said.

A New Finding Unraveled, Slowly

Doctors first became aware of the issue a few years ago.

“First, there were a lot of reports in Singapore of unusual hip fractures before the lesser trochanter, [with] unusual x-ray changes,” Dr. Silverman said.

Reports started to be seen in the United States, and physicians across the country began sharing their stories. Only by reexamining medical records did doctors realize that the patients shared a common history of bisphosphonate use, Dr. Bengs said.

At the present, it's “a slow-rolling snowball that might turn out to be a very big deal given the number of women on bisphosphonates. Further vigilance and analysis are required,” he said.

Many of the physicians who were interviewed for this story said they are concerned that women will go off the drugs because of press reports.

They point out that in a recent bisphosphonate manufacturer–sponsored study, investigators couldn't disprove a connection, but did conclude that the fractures are rare, and that the benefit of taking the drugs still outweighs the risks (N. Engl. J. Med. 2010;362:1761-71).

Another manufacturer-sponsored study showed that subtrochanteric femur fractures have occurred in people who have not used bisphosphonates (Osteoporos. Int. 2010;21[suppl. 1]:S7-24).

“We have a new radiologic finding, but no data that the incidence of the fractures has gone up,” Dr. Silverman said.

The Food and Drug Administration said that it is staying on top of the issue. The agency continues “to evaluate the issue of the use of bisphosphonates and atypical femur fracture,” a press person wrote in response to an e-mail inquiry.

The agency has no plans at present for an advisory committee meeting regarding the issue.

Concerned Women

As the issue continues to be examined, doctors are fielding questions from concerned women.

“My answer [to them] is that it's an unknown and unconfirmed [phenomenon], and that the data are not out there to answer the questions,” said Dr. Eric M. Ruderman of the division of rheumatology at Northwestern University in Chicago.

At present, Dr. Ruderman doesn't stop bisphosphonate use because of fracture concerns, but he does have his patients take a drug holiday after 7 years because evidence is lacking for benefit after that point, he said. He continues monitoring bone density thereafter to assess the need for further treatment.

Disclosures: Dr. Motamedi, Dr. Robinson, and Dr. Forouzesh said that they had no conflicts to disclose. Dr. Bengs disclosed he is a paid consultant for Amgen Inc. Dr. Lane disclosed research grants, royalties, consulting fees from and positions of influence and ownership interests in Amgen, Eli Lilly & Co., and Pfizer Inc. Dr. Ruderman disclosed that he is a consultant for Amgen and Pfizer. Dr. Silverman disclosed he has served as a speaker, member of a speakers bureau, advisor for Eli Lilly, Novartis Pharmaceuticals Corp., Procter & Gamble, and Roche Inc., and that he has received research support from Eli Lilly, Procter & Gamble, Roche, and Novartis.

This femur fractured 2 days after the image revealed cortical thickening and a beaklike stress fracture, perhaps from bisphosphonates.

Source Courtesy UCLA

Women with thigh pain may have a bisphosphonate-induced fracture, said Dr. Benjamin C. Bengs.

Source Courtesy Dr. Benjamin C. Bengs

MARINA DEL REY, CALIF. — As the debate unfolds over both whether bisphosphonates cause femur fractures and the degree to which the benefits of drugs still outweigh the risks, a phenomenon has emerged.

Women who have taken bisphosphonates for years are being seen in doctors' offices with thigh pain that is easy to mistake for hip or knee arthritis. They have a unique constellation of radiologic findings on imaging, and they either have permanent titanium rods placed in their thigh bones or go on to full femur fractures—sometimes bilaterally—and permanent disability.

No one can yet say for sure whether they would have had those fractures regardless of bisphosphonate use, nor can anyone say if femur fractures are limited to alendronate (Fosamax) users or are a bisphosphonate class effect.

But a trend is emerging, and with it a treatment protocol.

“The thinking [among colleagues] is that this is novel and specific to bisphosphonate treatment, but only time will tell,” Dr. Benjamin C. Bengs, an orthopedic surgeon at the University of California, Los Angeles, said in an interview.

The possibility must be added to the hip pain differential in women with long-standing use of the drugs, according to Dr. Bengs and others who were interviewed for this story.

Unusual Radiology Findings

For many of the doctors who were interviewed, the question isn't so much whether bisphosphonates cause femur fractures, but rather how to care for women with a long history of using the drugs, and how to recognize signs and symptoms of impending trouble.

Any woman with pain over the thigh and those x-ray findings is definitely a candidate for prophylactic rodding, said Dr. Bengs.

The unique findings on x-ray are cortical thickening that is most pronounced on the lateral side of the femur, accompanied by a beaking lesion, also on the lateral side of the femur. Intramedullary edema is often present.

The beaking lesion is the start of a horizontal or oblique stress fracture. In time, there generally develops a “little, lucent, dark line extending from the beak to the middle of the bone,” Dr. Joseph Robinson, a radiology fellow at Cedars-Sinai Medical Center in Los Angeles, said in an interview.

“Lateral stress fractures are unusual. In our area, they are all related to bisphosphonates,” Dr. Kambiz Motamedi, a diagnostic radiologist at UCLA Medical Center.

There is a strong belief “from our sports medicine folks and rheumatologists” that there is a relationship with bisphosphonates, he said.

Both Legs Must Be Examined

Standard hip x-rays don't go far enough down to detect the lesion, which is closer to the knee than the typical femur fracture would be, Dr. Robinson said. When they do a hip series, Cedars-Sinai radiologists are careful to image lower down so they don't miss it, he said, noting that they are also putting markers on skin to identify the source of pain.

If the lesion is found, it is imperative to image the other femur as well, said Dr. Stuart L. Silverman, a rheumatologist in private practice in Beverly Hills, Calif. The other femur can go on to fracture, often within 18 months, he said in an interview.

Dr. Bengs noted that in most case, rodding is the usual treatment. It takes only a matter of weeks to recover from hip-to-knee rod placement, he said. It takes months to recover from a fracture, however, and older patients usually lose 10%-15% of their strength and ambulation during their convalescence, he added.

“The fractures are devastating,” said UCLA and Cedars-Sinai rheumatologist Dr. Solomon N. Forouzesh, who is the medical director of the rehabilitation department at Brotman Medical Center in Culver City, Calif. He said he's seen two cases in his practice.

Active, Osteopenic Women at Risk

Active women who have osteopenia—not osteoporosis—appear to be most at risk, Dr. Nancy Lane, a University of California, Davis, rheumatologist, said in an interview. “What I think is going on” is that bisphosphonates, by reducing bone turnover, lead to the overmineralization of cortical bone, she explained. “Over time, the bones become brittle [and] fail from too much mineralization. They cannot dissipate the load.”

It's “probably best not [to use bisphosphonates] in people with low risk of fractures who are very active,” she said. In the past, she added, use of the drugs might have been “too aggressive.”

A Drug Holiday Is Advised

As the story unfolds, doctors are using bisphosphonates for shorter lengths of time than in the past, followed by a drug holiday and ongoing bone-density monitoring.

The risk of fracture seems to “start at about 3 years and peaks between 5 and 6 years,” Dr. Forouzesh said. To be ahead of the game, he advises not waiting until the risk peaks. “Back off ahead of time. I do a drug holiday in 3 or 4 years,” he said.

It's not clear at this point if the phenomenon—if it is truly real—is limited to alendronate or is a bisphosphonate class effect.

Alendronate has been on the market the longest and has been the most widely used agent, Dr. Lane noted. “I am sure over time” it will emerge with other members of the class, as well, she said.

Meanwhile, there are efforts to raise awareness of the issue. The American College of Rheumatology issued a bulletin on the matter in March (“Atypical Femoral Fractures With Long-Term Bisphosphonate Use,” which can be accessed online at

www.rheumatology.org/publications/hotline/2010_03_22_bisphosphonate.asp

At Cedars-Sinai, “we are trying to have [a conference] to make rheumatologists and others aware of how to deal with the problem,” Dr. Robinson said.

A New Finding Unraveled, Slowly

Doctors first became aware of the issue a few years ago.

“First, there were a lot of reports in Singapore of unusual hip fractures before the lesser trochanter, [with] unusual x-ray changes,” Dr. Silverman said.

Reports started to be seen in the United States, and physicians across the country began sharing their stories. Only by reexamining medical records did doctors realize that the patients shared a common history of bisphosphonate use, Dr. Bengs said.

At the present, it's “a slow-rolling snowball that might turn out to be a very big deal given the number of women on bisphosphonates. Further vigilance and analysis are required,” he said.

Many of the physicians who were interviewed for this story said they are concerned that women will go off the drugs because of press reports.

They point out that in a recent bisphosphonate manufacturer–sponsored study, investigators couldn't disprove a connection, but did conclude that the fractures are rare, and that the benefit of taking the drugs still outweighs the risks (N. Engl. J. Med. 2010;362:1761-71).

Another manufacturer-sponsored study showed that subtrochanteric femur fractures have occurred in people who have not used bisphosphonates (Osteoporos. Int. 2010;21[suppl. 1]:S7-24).

“We have a new radiologic finding, but no data that the incidence of the fractures has gone up,” Dr. Silverman said.

The Food and Drug Administration said that it is staying on top of the issue. The agency continues “to evaluate the issue of the use of bisphosphonates and atypical femur fracture,” a press person wrote in response to an e-mail inquiry.

The agency has no plans at present for an advisory committee meeting regarding the issue.

Concerned Women

As the issue continues to be examined, doctors are fielding questions from concerned women.

“My answer [to them] is that it's an unknown and unconfirmed [phenomenon], and that the data are not out there to answer the questions,” said Dr. Eric M. Ruderman of the division of rheumatology at Northwestern University in Chicago.

At present, Dr. Ruderman doesn't stop bisphosphonate use because of fracture concerns, but he does have his patients take a drug holiday after 7 years because evidence is lacking for benefit after that point, he said. He continues monitoring bone density thereafter to assess the need for further treatment.

Disclosures: Dr. Motamedi, Dr. Robinson, and Dr. Forouzesh said that they had no conflicts to disclose. Dr. Bengs disclosed he is a paid consultant for Amgen Inc. Dr. Lane disclosed research grants, royalties, consulting fees from and positions of influence and ownership interests in Amgen, Eli Lilly & Co., and Pfizer Inc. Dr. Ruderman disclosed that he is a consultant for Amgen and Pfizer. Dr. Silverman disclosed he has served as a speaker, member of a speakers bureau, advisor for Eli Lilly, Novartis Pharmaceuticals Corp., Procter & Gamble, and Roche Inc., and that he has received research support from Eli Lilly, Procter & Gamble, Roche, and Novartis.

This femur fractured 2 days after the image revealed cortical thickening and a beaklike stress fracture, perhaps from bisphosphonates.

Source Courtesy UCLA

Women with thigh pain may have a bisphosphonate-induced fracture, said Dr. Benjamin C. Bengs.

Source Courtesy Dr. Benjamin C. Bengs

MARINA DEL REY, CALIF. — As the debate unfolds over both whether bisphosphonates cause femur fractures and the degree to which the benefits of drugs still outweigh the risks, a phenomenon has emerged.

Women who have taken bisphosphonates for years are being seen in doctors' offices with thigh pain that is easy to mistake for hip or knee arthritis. They have a unique constellation of radiologic findings on imaging, and they either have permanent titanium rods placed in their thigh bones or go on to full femur fractures—sometimes bilaterally—and permanent disability.

No one can yet say for sure whether they would have had those fractures regardless of bisphosphonate use, nor can anyone say if femur fractures are limited to alendronate (Fosamax) users or are a bisphosphonate class effect.

But a trend is emerging, and with it a treatment protocol.

“The thinking [among colleagues] is that this is novel and specific to bisphosphonate treatment, but only time will tell,” Dr. Benjamin C. Bengs, an orthopedic surgeon at the University of California, Los Angeles, said in an interview.

The possibility must be added to the hip pain differential in women with long-standing use of the drugs, according to Dr. Bengs and others who were interviewed for this story.

Unusual Radiology Findings

For many of the doctors who were interviewed, the question isn't so much whether bisphosphonates cause femur fractures, but rather how to care for women with a long history of using the drugs, and how to recognize signs and symptoms of impending trouble.

Any woman with pain over the thigh and those x-ray findings is definitely a candidate for prophylactic rodding, said Dr. Bengs.

The unique findings on x-ray are cortical thickening that is most pronounced on the lateral side of the femur, accompanied by a beaking lesion, also on the lateral side of the femur. Intramedullary edema is often present.

The beaking lesion is the start of a horizontal or oblique stress fracture. In time, there generally develops a “little, lucent, dark line extending from the beak to the middle of the bone,” Dr. Joseph Robinson, a radiology fellow at Cedars-Sinai Medical Center in Los Angeles, said in an interview.

“Lateral stress fractures are unusual. In our area, they are all related to bisphosphonates,” Dr. Kambiz Motamedi, a diagnostic radiologist at UCLA Medical Center.

There is a strong belief “from our sports medicine folks and rheumatologists” that there is a relationship with bisphosphonates, he said.

Both Legs Must Be Examined

Standard hip x-rays don't go far enough down to detect the lesion, which is closer to the knee than the typical femur fracture would be, Dr. Robinson said. When they do a hip series, Cedars-Sinai radiologists are careful to image lower down so they don't miss it, he said, noting that they are also putting markers on skin to identify the source of pain.

If the lesion is found, it is imperative to image the other femur as well, said Dr. Stuart L. Silverman, a rheumatologist in private practice in Beverly Hills, Calif. The other femur can go on to fracture, often within 18 months, he said in an interview.

Dr. Bengs noted that in most case, rodding is the usual treatment. It takes only a matter of weeks to recover from hip-to-knee rod placement, he said. It takes months to recover from a fracture, however, and older patients usually lose 10%-15% of their strength and ambulation during their convalescence, he added.

“The fractures are devastating,” said UCLA and Cedars-Sinai rheumatologist Dr. Solomon N. Forouzesh, who is the medical director of the rehabilitation department at Brotman Medical Center in Culver City, Calif. He said he's seen two cases in his practice.

Active, Osteopenic Women at Risk

Active women who have osteopenia—not osteoporosis—appear to be most at risk, Dr. Nancy Lane, a University of California, Davis, rheumatologist, said in an interview. “What I think is going on” is that bisphosphonates, by reducing bone turnover, lead to the overmineralization of cortical bone, she explained. “Over time, the bones become brittle [and] fail from too much mineralization. They cannot dissipate the load.”

It's “probably best not [to use bisphosphonates] in people with low risk of fractures who are very active,” she said. In the past, she added, use of the drugs might have been “too aggressive.”

A Drug Holiday Is Advised

As the story unfolds, doctors are using bisphosphonates for shorter lengths of time than in the past, followed by a drug holiday and ongoing bone-density monitoring.

The risk of fracture seems to “start at about 3 years and peaks between 5 and 6 years,” Dr. Forouzesh said. To be ahead of the game, he advises not waiting until the risk peaks. “Back off ahead of time. I do a drug holiday in 3 or 4 years,” he said.

It's not clear at this point if the phenomenon—if it is truly real—is limited to alendronate or is a bisphosphonate class effect.

Alendronate has been on the market the longest and has been the most widely used agent, Dr. Lane noted. “I am sure over time” it will emerge with other members of the class, as well, she said.

Meanwhile, there are efforts to raise awareness of the issue. The American College of Rheumatology issued a bulletin on the matter in March (“Atypical Femoral Fractures With Long-Term Bisphosphonate Use,” which can be accessed online at

www.rheumatology.org/publications/hotline/2010_03_22_bisphosphonate.asp

At Cedars-Sinai, “we are trying to have [a conference] to make rheumatologists and others aware of how to deal with the problem,” Dr. Robinson said.

A New Finding Unraveled, Slowly

Doctors first became aware of the issue a few years ago.

“First, there were a lot of reports in Singapore of unusual hip fractures before the lesser trochanter, [with] unusual x-ray changes,” Dr. Silverman said.

Reports started to be seen in the United States, and physicians across the country began sharing their stories. Only by reexamining medical records did doctors realize that the patients shared a common history of bisphosphonate use, Dr. Bengs said.

At the present, it's “a slow-rolling snowball that might turn out to be a very big deal given the number of women on bisphosphonates. Further vigilance and analysis are required,” he said.

Many of the physicians who were interviewed for this story said they are concerned that women will go off the drugs because of press reports.

They point out that in a recent bisphosphonate manufacturer–sponsored study, investigators couldn't disprove a connection, but did conclude that the fractures are rare, and that the benefit of taking the drugs still outweighs the risks (N. Engl. J. Med. 2010;362:1761-71).

Another manufacturer-sponsored study showed that subtrochanteric femur fractures have occurred in people who have not used bisphosphonates (Osteoporos. Int. 2010;21[suppl. 1]:S7-24).

“We have a new radiologic finding, but no data that the incidence of the fractures has gone up,” Dr. Silverman said.

The Food and Drug Administration said that it is staying on top of the issue. The agency continues “to evaluate the issue of the use of bisphosphonates and atypical femur fracture,” a press person wrote in response to an e-mail inquiry.

The agency has no plans at present for an advisory committee meeting regarding the issue.

Concerned Women

As the issue continues to be examined, doctors are fielding questions from concerned women.

“My answer [to them] is that it's an unknown and unconfirmed [phenomenon], and that the data are not out there to answer the questions,” said Dr. Eric M. Ruderman of the division of rheumatology at Northwestern University in Chicago.

At present, Dr. Ruderman doesn't stop bisphosphonate use because of fracture concerns, but he does have his patients take a drug holiday after 7 years because evidence is lacking for benefit after that point, he said. He continues monitoring bone density thereafter to assess the need for further treatment.

Disclosures: Dr. Motamedi, Dr. Robinson, and Dr. Forouzesh said that they had no conflicts to disclose. Dr. Bengs disclosed he is a paid consultant for Amgen Inc. Dr. Lane disclosed research grants, royalties, consulting fees from and positions of influence and ownership interests in Amgen, Eli Lilly & Co., and Pfizer Inc. Dr. Ruderman disclosed that he is a consultant for Amgen and Pfizer. Dr. Silverman disclosed he has served as a speaker, member of a speakers bureau, advisor for Eli Lilly, Novartis Pharmaceuticals Corp., Procter & Gamble, and Roche Inc., and that he has received research support from Eli Lilly, Procter & Gamble, Roche, and Novartis.

This femur fractured 2 days after the image revealed cortical thickening and a beaklike stress fracture, perhaps from bisphosphonates.

Source Courtesy UCLA

Women with thigh pain may have a bisphosphonate-induced fracture, said Dr. Benjamin C. Bengs.

Source Courtesy Dr. Benjamin C. Bengs