Osteoarthritis

Four studies have now shown that wedge insoles are not effective in reducing pain and improving function in knee osteoarthritis, Kim Bennell, Ph.D., says.

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Four studies have now shown that wedge insoles are not effective in reducing pain and improving function in knee osteoarthritis, Kim Bennell, Ph.D., says.

View Video Now.

Four studies have now shown that wedge insoles are not effective in reducing pain and improving function in knee osteoarthritis, Kim Bennell, Ph.D., says.

View Video Now.

Pain and depression work in an additive way to reduce function and make pain worse in patients with knee osteoarthritis, Daniel L. Riddle, Ph.D., says.

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Pain and depression work in an additive way to reduce function and make pain worse in patients with knee osteoarthritis, Daniel L. Riddle, Ph.D., says.

View Video Now.

Pain and depression work in an additive way to reduce function and make pain worse in patients with knee osteoarthritis, Daniel L. Riddle, Ph.D., says.

View Video Now.

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, according to 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 of up to a year old (N. Engl. J. Med. 2009;361:557-68; N. Engl. J. Med. 2009;361:569-79).

The current 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%.

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 polymethylmetacrylate 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 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).

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 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 deposited in a segmental pulmonary artery in one patient, but all cement leaks remained asymptomatic.

In a related commentary, orthopedic surgeons Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and 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 baseline disparity between treatment groups 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 included injecting bupivacaine, a long-acting local anesthetic, into fractures, which itself might have brought relief, they wrote.

By using conservative pain management with activity restriction and pain medications 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 reported no conflicts of interest. The study was funded by ZonMw, a Dutch organization for health care research and innovation, and Cook Medical, makers of the bone cement used in the trial.

“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,” Dr. Klazen and her colleagues wrote.

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, according to 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 of up to a year old (N. Engl. J. Med. 2009;361:557-68; N. Engl. J. Med. 2009;361:569-79).

The current 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%.

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 polymethylmetacrylate 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 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).

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 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 deposited in a segmental pulmonary artery in one patient, but all cement leaks remained asymptomatic.

In a related commentary, orthopedic surgeons Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and 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 baseline disparity between treatment groups 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 included injecting bupivacaine, a long-acting local anesthetic, into fractures, which itself might have brought relief, they wrote.

By using conservative pain management with activity restriction and pain medications 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 reported no conflicts of interest. The study was funded by ZonMw, a Dutch organization for health care research and innovation, and Cook Medical, makers of the bone cement used in the trial.

“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,” Dr. Klazen and her colleagues wrote.

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, according to 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 of up to a year old (N. Engl. J. Med. 2009;361:557-68; N. Engl. J. Med. 2009;361:569-79).

The current 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%.

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 polymethylmetacrylate 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 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).

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 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 deposited in a segmental pulmonary artery in one patient, but all cement leaks remained asymptomatic.

In a related commentary, orthopedic surgeons Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and 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 baseline disparity between treatment groups 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 included injecting bupivacaine, a long-acting local anesthetic, into fractures, which itself might have brought relief, they wrote.

By using conservative pain management with activity restriction and pain medications 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 reported no conflicts of interest. The study was funded by ZonMw, a Dutch organization for health care research and innovation, and Cook Medical, makers of the bone cement used in the trial.

“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,” Dr. Klazen and her colleagues wrote.

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.

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 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. It might be huge, but there still are doctors who do not believe it. I only converted recently because I researched it,” 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

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.

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 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. It might be huge, but there still are doctors who do not believe it. I only converted recently because I researched it,” 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

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.

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 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. It might be huge, but there still are doctors who do not believe it. I only converted recently because I researched it,” 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

The risk of subtrochanteric and diaphyseal femur fractures is not significantly increased in women who take bisphosphonates, even among those who are treated for up to 10 years, judging from findings from a secondary analysis of data from three large randomized bisphosphonate trials.

The findings follow several case reports that hinted at an increased risk of these atypical fractures in bisphosphonate users.

However, the current study, which included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up, showed that only 12 subtrochanteric or diaphyseal femur fractures occurred in 10 women, for a rate of 2.3 per 10,000 patient-years, Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues wrote.

The data that were analyzed in the current study were from the phase III Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT).

The relative hazard ratios for subtrochanteric and diaphyseal femur fractures were 1.03 for alendronate vs. placebo in FIT, 1.50 for zoledronic acid vs. placebo in HORIZON-PFT, and 1.33 for continued alendronate use vs. placebo in FLEX, the investigators reported (N. Engl. J. Med. 2010 March 24[doi: 10.1056/NEJMoa1001086

Even in the FLEX trial, which included up to 10 years of treatment with alendronate, the risk of femur fracture and atypical femur fracture was very low, with no significantly increased risk of fracture among those who continued treatment for the full 10 years and those who discontinued treatment, they wrote.

Because radiographs in those with fractures were generally not available, atypical features—such as those associated with cortical thickness and fracture morphology—could not be assessed. If this information had been available, it is likely that the femoral fracture rate would be even lower, noted the investigators. The findings support those from population-based studies, including one that found evidence of an increased incidence of hip and femur fractures with alendronate use, but that attributed that finding to the increased use of alendronate in high-risk patients rather than to the use of alendronate.

“Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals (resulting from the very low incidence of events) preclude definitive conclusions regarding the relative risk of treatment,” the investigators wrote.

However, based on data they analyzed, the investigators estimated that 3 years of bisphosphonate treatment in 1,000 women with osteoporosis would prevent about 100 fractures, comprising 71 vertebral fractures and 29 nonvertebral fractures (including 11 hip fractures).

Balanced against the annual rate of 2.3 subtrochanteric and diaphyseal femur fractures that were seen in the three trials, “the hypothetical risk is quite small,” they concluded

Additional research is needed to more fully address the matter of bisphosphonate use and the risk of subtrochanteric and diaphyseal fractures, Dr. Elizabeth Shane wrote in an accompanying editorial.

The current findings provide assurance that these types of fractures are extremely rare, and that many more common and equally devastating hip fractures are prevented than are caused by bisphosphonates.

That said, physicians should “reevaluate patients who are receiving long-term bisphosphonate therapy in the context of contemporary guidelines for treatment initiation, progress while receiving therapy, current bone mineral density measurement, and risk factors for fracture,” wrote Dr. Shane of Columbia University, New York (N. Engl. J. Med. 2010 March 24 [doi:10.1056/NEJMe1003064

It is reasonable to consider drug holidays, particularly in those with substantially reduced levels of bone turnover markers, but again, the evidence of persistent antifracture efficacy after discontinuation must be balanced with data showing that 10 vs. 5 years of alendronate use is associated with significantly fewer new vertebral and nonvertebral fractures in those with bone mineral density T scores of −2.5 or lower, she wrote.

Disclosures: This study was supported by Merck & Co. and Novartis. The investigators reported receiving grants, travel reimbursement, consulting fees, and lecture fees from Merck, Novartis, and several other pharmaceutical manufacturers, as well as from the National Osteoporosis Foundation. Dr. Shane reported receiving grants from Novartis, Merck, and other pharmaceutical manufacturers.

X-ray shows an atypical fracture in a patient on bisphosphonates for years.

Source Courtesy Dr. Melvin Rosenwasser, Columbia University

The risk of subtrochanteric and diaphyseal femur fractures is not significantly increased in women who take bisphosphonates, even among those who are treated for up to 10 years, judging from findings from a secondary analysis of data from three large randomized bisphosphonate trials.

The findings follow several case reports that hinted at an increased risk of these atypical fractures in bisphosphonate users.

However, the current study, which included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up, showed that only 12 subtrochanteric or diaphyseal femur fractures occurred in 10 women, for a rate of 2.3 per 10,000 patient-years, Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues wrote.

The data that were analyzed in the current study were from the phase III Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT).

The relative hazard ratios for subtrochanteric and diaphyseal femur fractures were 1.03 for alendronate vs. placebo in FIT, 1.50 for zoledronic acid vs. placebo in HORIZON-PFT, and 1.33 for continued alendronate use vs. placebo in FLEX, the investigators reported (N. Engl. J. Med. 2010 March 24[doi: 10.1056/NEJMoa1001086

Even in the FLEX trial, which included up to 10 years of treatment with alendronate, the risk of femur fracture and atypical femur fracture was very low, with no significantly increased risk of fracture among those who continued treatment for the full 10 years and those who discontinued treatment, they wrote.

Because radiographs in those with fractures were generally not available, atypical features—such as those associated with cortical thickness and fracture morphology—could not be assessed. If this information had been available, it is likely that the femoral fracture rate would be even lower, noted the investigators. The findings support those from population-based studies, including one that found evidence of an increased incidence of hip and femur fractures with alendronate use, but that attributed that finding to the increased use of alendronate in high-risk patients rather than to the use of alendronate.

“Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals (resulting from the very low incidence of events) preclude definitive conclusions regarding the relative risk of treatment,” the investigators wrote.

However, based on data they analyzed, the investigators estimated that 3 years of bisphosphonate treatment in 1,000 women with osteoporosis would prevent about 100 fractures, comprising 71 vertebral fractures and 29 nonvertebral fractures (including 11 hip fractures).

Balanced against the annual rate of 2.3 subtrochanteric and diaphyseal femur fractures that were seen in the three trials, “the hypothetical risk is quite small,” they concluded

Additional research is needed to more fully address the matter of bisphosphonate use and the risk of subtrochanteric and diaphyseal fractures, Dr. Elizabeth Shane wrote in an accompanying editorial.

The current findings provide assurance that these types of fractures are extremely rare, and that many more common and equally devastating hip fractures are prevented than are caused by bisphosphonates.

That said, physicians should “reevaluate patients who are receiving long-term bisphosphonate therapy in the context of contemporary guidelines for treatment initiation, progress while receiving therapy, current bone mineral density measurement, and risk factors for fracture,” wrote Dr. Shane of Columbia University, New York (N. Engl. J. Med. 2010 March 24 [doi:10.1056/NEJMe1003064

It is reasonable to consider drug holidays, particularly in those with substantially reduced levels of bone turnover markers, but again, the evidence of persistent antifracture efficacy after discontinuation must be balanced with data showing that 10 vs. 5 years of alendronate use is associated with significantly fewer new vertebral and nonvertebral fractures in those with bone mineral density T scores of −2.5 or lower, she wrote.

Disclosures: This study was supported by Merck & Co. and Novartis. The investigators reported receiving grants, travel reimbursement, consulting fees, and lecture fees from Merck, Novartis, and several other pharmaceutical manufacturers, as well as from the National Osteoporosis Foundation. Dr. Shane reported receiving grants from Novartis, Merck, and other pharmaceutical manufacturers.

X-ray shows an atypical fracture in a patient on bisphosphonates for years.

Source Courtesy Dr. Melvin Rosenwasser, Columbia University

The risk of subtrochanteric and diaphyseal femur fractures is not significantly increased in women who take bisphosphonates, even among those who are treated for up to 10 years, judging from findings from a secondary analysis of data from three large randomized bisphosphonate trials.

The findings follow several case reports that hinted at an increased risk of these atypical fractures in bisphosphonate users.

However, the current study, which included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up, showed that only 12 subtrochanteric or diaphyseal femur fractures occurred in 10 women, for a rate of 2.3 per 10,000 patient-years, Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues wrote.

The data that were analyzed in the current study were from the phase III Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT).

The relative hazard ratios for subtrochanteric and diaphyseal femur fractures were 1.03 for alendronate vs. placebo in FIT, 1.50 for zoledronic acid vs. placebo in HORIZON-PFT, and 1.33 for continued alendronate use vs. placebo in FLEX, the investigators reported (N. Engl. J. Med. 2010 March 24[doi: 10.1056/NEJMoa1001086

Even in the FLEX trial, which included up to 10 years of treatment with alendronate, the risk of femur fracture and atypical femur fracture was very low, with no significantly increased risk of fracture among those who continued treatment for the full 10 years and those who discontinued treatment, they wrote.

Because radiographs in those with fractures were generally not available, atypical features—such as those associated with cortical thickness and fracture morphology—could not be assessed. If this information had been available, it is likely that the femoral fracture rate would be even lower, noted the investigators. The findings support those from population-based studies, including one that found evidence of an increased incidence of hip and femur fractures with alendronate use, but that attributed that finding to the increased use of alendronate in high-risk patients rather than to the use of alendronate.

“Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals (resulting from the very low incidence of events) preclude definitive conclusions regarding the relative risk of treatment,” the investigators wrote.

However, based on data they analyzed, the investigators estimated that 3 years of bisphosphonate treatment in 1,000 women with osteoporosis would prevent about 100 fractures, comprising 71 vertebral fractures and 29 nonvertebral fractures (including 11 hip fractures).

Balanced against the annual rate of 2.3 subtrochanteric and diaphyseal femur fractures that were seen in the three trials, “the hypothetical risk is quite small,” they concluded

Additional research is needed to more fully address the matter of bisphosphonate use and the risk of subtrochanteric and diaphyseal fractures, Dr. Elizabeth Shane wrote in an accompanying editorial.

The current findings provide assurance that these types of fractures are extremely rare, and that many more common and equally devastating hip fractures are prevented than are caused by bisphosphonates.

That said, physicians should “reevaluate patients who are receiving long-term bisphosphonate therapy in the context of contemporary guidelines for treatment initiation, progress while receiving therapy, current bone mineral density measurement, and risk factors for fracture,” wrote Dr. Shane of Columbia University, New York (N. Engl. J. Med. 2010 March 24 [doi:10.1056/NEJMe1003064

It is reasonable to consider drug holidays, particularly in those with substantially reduced levels of bone turnover markers, but again, the evidence of persistent antifracture efficacy after discontinuation must be balanced with data showing that 10 vs. 5 years of alendronate use is associated with significantly fewer new vertebral and nonvertebral fractures in those with bone mineral density T scores of −2.5 or lower, she wrote.

Disclosures: This study was supported by Merck & Co. and Novartis. The investigators reported receiving grants, travel reimbursement, consulting fees, and lecture fees from Merck, Novartis, and several other pharmaceutical manufacturers, as well as from the National Osteoporosis Foundation. Dr. Shane reported receiving grants from Novartis, Merck, and other pharmaceutical manufacturers.

X-ray shows an atypical fracture in a patient on bisphosphonates for years.

Source Courtesy Dr. Melvin Rosenwasser, Columbia University

SAN FRANCISCO — The first update in recommendations for dietary intake of vitamin D since 1997 is expected in May and probably will include a conservative change from the status quo, according to one expert.

The Institute of Medicine's Food and Nutrition Board has been reviewing the literature, including consideration of associations between serum vitamin D levels and disease indicators.

“The grapevine says they are going to come in very conservative. They are going to require evidence from randomized, controlled trials, and those don't really exist today,” Dr. Neil Binkley said at a meeting sponsored by the American Diabetes Association.

The current Dietary Reference Intake (or Recommended Dietary Allowance) describes “adequate” intake as 200 IU/day for people up to age 50 years, 400 IU/day for those aged 51-70 years, and 600 IU/day for people older than 70 years.

Dr. Binkley of the University of Wisconsin in Madison expects the new intake recommendation for older adults to roughly double, from 400 IU/day to 800 or maybe 1,000 IU/day.

“This will be an evolution,” he said. “I think the next iteration coming out in May is going to be a step up, but it's probably not going to get us all the way there.”

Recent data suggest that much higher levels should be consumed daily to keep serum 25-hydroxyvitamin D levels (25[OH]D) in desired ranges, he explained. Generally, levels lower than 10 ng/mL indicate vitamin D deficiency, 10-30 ng/mL reflects vitamin D insufficiency, and a 25(OH)D level above 30 ng/mL is considered optimal.

Optimal levels may differ by bodily system, he noted. Serum 25(OH)D levels greater than 40 ng/mL may be best for bone health, whereas leg function appears to be better with levels above 38 ng/mL. But a level above 36 ng/mL has been associated with reduced risk for co-lorectal cancer, and levels of 36-40 ng/mL have been associated with lower risk for periodontal disease.

One study calculated that 2,600 IU/day of vitamin D supplementation would be needed to ensure that 97.5% of older women have 25(OH)D levels at or above desirable levels (J. Nutr. 2006;136:1123–6).

Other experts recommend that between 2,000 and 4,000 IU/day be consumed to reduce risks for cancer and autoimmune disease, Dr. Binkley said.

He aims for levels above 40 ng/mL in his patients to consistently hit targets above 30 ng/mL, he said.

As a general rule of thumb, for every 1,000 IU of supplemental vitamin D₃ ingested, circulating 25(OH)D goes up by roughly 6 ng/mL, he said. For a patient with a serum 25(OH)D level of 20 ng/mL, taking 2,000 IU/day of vitamin D₃ would boost serum levels to about 32 ng/mL, and more than 3,000 IU/day would be needed to reach 40 ng/mL.

People are unlikely to get adequate vitamin D from sunlight, and fortified foods contain roughly 40-100 IU per serving. “If we truly do need 1,000, 2,000 or 4,000 IU/day, that means you'd need to drink between 10 and 40 glasses of milk per day to get your vitamin D requirement” at current levels of food fortification, he said. “I'm hopeful that after the Institute of Medicine meets, food fortification will go up,” he added.

The American Academy of Pediatrics in 2008 recommended that children and adolescents get 400 IU/day of vitamin D, double the current Dietary Reference Intake. The National Osteoporosis Foundation recommends that people up to age 50 ingest 400-800 IU/day, and that adults aged 50 or older get 800-1,000 IU/day.

Observational studies suggest that low vitamin D levels are associated with increased risk for diabetes. Several studies found that children who received vitamin D supplementation had a lower risk for developing type 1 diabetes, and the Nurses Health Study found an association between low vitamin D status and higher risk for type 2 diabetes over 20 years of follow-up.

Two prospective studies with 36 patients each found no significant effect of vitamin D supplementation on diabetes risk, however, but these studies were too small, Dr. Binkley said.

A post hoc analysis of a randomized, controlled trial of 800 IU/day of vitamin D for fracture prevention in 3,314 women over age 70 found no protective effect against the development of type 2 diabetes, but compliance with vitamin D supplements in the trial was poor, he noted (Age Ageing 2009;38:606–9).

The Women's Health Study also found no significant reduction in risk for diabetes after a median 7-year follow-up in 33,951 women randomized to 1,000 mg/day of calcium plus 400 IU/day of vitamin D or placebo (Diabetes Care 2008;31:701–7). The vitamin D dose was too low, Dr. Binkley said, and the compliance rate was only around 60%.

“We need larger studies, with higher vitamin D doses,” he said.

Dr. Binkley said he has no conflicts of interest related to these topics.

The National Osteoporosis Foundation recommends that adults younger than 50 years ingest 400-800 IU/day of vitamin D. Those aged 50 years or older need 800-1,000 IU/day.

Source © Joss/Fotolia.com

SAN FRANCISCO — The first update in recommendations for dietary intake of vitamin D since 1997 is expected in May and probably will include a conservative change from the status quo, according to one expert.

The Institute of Medicine's Food and Nutrition Board has been reviewing the literature, including consideration of associations between serum vitamin D levels and disease indicators.

“The grapevine says they are going to come in very conservative. They are going to require evidence from randomized, controlled trials, and those don't really exist today,” Dr. Neil Binkley said at a meeting sponsored by the American Diabetes Association.

The current Dietary Reference Intake (or Recommended Dietary Allowance) describes “adequate” intake as 200 IU/day for people up to age 50 years, 400 IU/day for those aged 51-70 years, and 600 IU/day for people older than 70 years.

Dr. Binkley of the University of Wisconsin in Madison expects the new intake recommendation for older adults to roughly double, from 400 IU/day to 800 or maybe 1,000 IU/day.

“This will be an evolution,” he said. “I think the next iteration coming out in May is going to be a step up, but it's probably not going to get us all the way there.”

Recent data suggest that much higher levels should be consumed daily to keep serum 25-hydroxyvitamin D levels (25[OH]D) in desired ranges, he explained. Generally, levels lower than 10 ng/mL indicate vitamin D deficiency, 10-30 ng/mL reflects vitamin D insufficiency, and a 25(OH)D level above 30 ng/mL is considered optimal.

Optimal levels may differ by bodily system, he noted. Serum 25(OH)D levels greater than 40 ng/mL may be best for bone health, whereas leg function appears to be better with levels above 38 ng/mL. But a level above 36 ng/mL has been associated with reduced risk for co-lorectal cancer, and levels of 36-40 ng/mL have been associated with lower risk for periodontal disease.

One study calculated that 2,600 IU/day of vitamin D supplementation would be needed to ensure that 97.5% of older women have 25(OH)D levels at or above desirable levels (J. Nutr. 2006;136:1123–6).

Other experts recommend that between 2,000 and 4,000 IU/day be consumed to reduce risks for cancer and autoimmune disease, Dr. Binkley said.

He aims for levels above 40 ng/mL in his patients to consistently hit targets above 30 ng/mL, he said.

As a general rule of thumb, for every 1,000 IU of supplemental vitamin D₃ ingested, circulating 25(OH)D goes up by roughly 6 ng/mL, he said. For a patient with a serum 25(OH)D level of 20 ng/mL, taking 2,000 IU/day of vitamin D₃ would boost serum levels to about 32 ng/mL, and more than 3,000 IU/day would be needed to reach 40 ng/mL.

People are unlikely to get adequate vitamin D from sunlight, and fortified foods contain roughly 40-100 IU per serving. “If we truly do need 1,000, 2,000 or 4,000 IU/day, that means you'd need to drink between 10 and 40 glasses of milk per day to get your vitamin D requirement” at current levels of food fortification, he said. “I'm hopeful that after the Institute of Medicine meets, food fortification will go up,” he added.

The American Academy of Pediatrics in 2008 recommended that children and adolescents get 400 IU/day of vitamin D, double the current Dietary Reference Intake. The National Osteoporosis Foundation recommends that people up to age 50 ingest 400-800 IU/day, and that adults aged 50 or older get 800-1,000 IU/day.

Observational studies suggest that low vitamin D levels are associated with increased risk for diabetes. Several studies found that children who received vitamin D supplementation had a lower risk for developing type 1 diabetes, and the Nurses Health Study found an association between low vitamin D status and higher risk for type 2 diabetes over 20 years of follow-up.

Two prospective studies with 36 patients each found no significant effect of vitamin D supplementation on diabetes risk, however, but these studies were too small, Dr. Binkley said.

A post hoc analysis of a randomized, controlled trial of 800 IU/day of vitamin D for fracture prevention in 3,314 women over age 70 found no protective effect against the development of type 2 diabetes, but compliance with vitamin D supplements in the trial was poor, he noted (Age Ageing 2009;38:606–9).

The Women's Health Study also found no significant reduction in risk for diabetes after a median 7-year follow-up in 33,951 women randomized to 1,000 mg/day of calcium plus 400 IU/day of vitamin D or placebo (Diabetes Care 2008;31:701–7). The vitamin D dose was too low, Dr. Binkley said, and the compliance rate was only around 60%.

“We need larger studies, with higher vitamin D doses,” he said.

Dr. Binkley said he has no conflicts of interest related to these topics.

The National Osteoporosis Foundation recommends that adults younger than 50 years ingest 400-800 IU/day of vitamin D. Those aged 50 years or older need 800-1,000 IU/day.

Source © Joss/Fotolia.com

SAN FRANCISCO — The first update in recommendations for dietary intake of vitamin D since 1997 is expected in May and probably will include a conservative change from the status quo, according to one expert.

The Institute of Medicine's Food and Nutrition Board has been reviewing the literature, including consideration of associations between serum vitamin D levels and disease indicators.

“The grapevine says they are going to come in very conservative. They are going to require evidence from randomized, controlled trials, and those don't really exist today,” Dr. Neil Binkley said at a meeting sponsored by the American Diabetes Association.

The current Dietary Reference Intake (or Recommended Dietary Allowance) describes “adequate” intake as 200 IU/day for people up to age 50 years, 400 IU/day for those aged 51-70 years, and 600 IU/day for people older than 70 years.

Dr. Binkley of the University of Wisconsin in Madison expects the new intake recommendation for older adults to roughly double, from 400 IU/day to 800 or maybe 1,000 IU/day.

“This will be an evolution,” he said. “I think the next iteration coming out in May is going to be a step up, but it's probably not going to get us all the way there.”

Recent data suggest that much higher levels should be consumed daily to keep serum 25-hydroxyvitamin D levels (25[OH]D) in desired ranges, he explained. Generally, levels lower than 10 ng/mL indicate vitamin D deficiency, 10-30 ng/mL reflects vitamin D insufficiency, and a 25(OH)D level above 30 ng/mL is considered optimal.

Optimal levels may differ by bodily system, he noted. Serum 25(OH)D levels greater than 40 ng/mL may be best for bone health, whereas leg function appears to be better with levels above 38 ng/mL. But a level above 36 ng/mL has been associated with reduced risk for co-lorectal cancer, and levels of 36-40 ng/mL have been associated with lower risk for periodontal disease.

One study calculated that 2,600 IU/day of vitamin D supplementation would be needed to ensure that 97.5% of older women have 25(OH)D levels at or above desirable levels (J. Nutr. 2006;136:1123–6).

Other experts recommend that between 2,000 and 4,000 IU/day be consumed to reduce risks for cancer and autoimmune disease, Dr. Binkley said.

He aims for levels above 40 ng/mL in his patients to consistently hit targets above 30 ng/mL, he said.

As a general rule of thumb, for every 1,000 IU of supplemental vitamin D₃ ingested, circulating 25(OH)D goes up by roughly 6 ng/mL, he said. For a patient with a serum 25(OH)D level of 20 ng/mL, taking 2,000 IU/day of vitamin D₃ would boost serum levels to about 32 ng/mL, and more than 3,000 IU/day would be needed to reach 40 ng/mL.

People are unlikely to get adequate vitamin D from sunlight, and fortified foods contain roughly 40-100 IU per serving. “If we truly do need 1,000, 2,000 or 4,000 IU/day, that means you'd need to drink between 10 and 40 glasses of milk per day to get your vitamin D requirement” at current levels of food fortification, he said. “I'm hopeful that after the Institute of Medicine meets, food fortification will go up,” he added.

The American Academy of Pediatrics in 2008 recommended that children and adolescents get 400 IU/day of vitamin D, double the current Dietary Reference Intake. The National Osteoporosis Foundation recommends that people up to age 50 ingest 400-800 IU/day, and that adults aged 50 or older get 800-1,000 IU/day.

Observational studies suggest that low vitamin D levels are associated with increased risk for diabetes. Several studies found that children who received vitamin D supplementation had a lower risk for developing type 1 diabetes, and the Nurses Health Study found an association between low vitamin D status and higher risk for type 2 diabetes over 20 years of follow-up.

Two prospective studies with 36 patients each found no significant effect of vitamin D supplementation on diabetes risk, however, but these studies were too small, Dr. Binkley said.

A post hoc analysis of a randomized, controlled trial of 800 IU/day of vitamin D for fracture prevention in 3,314 women over age 70 found no protective effect against the development of type 2 diabetes, but compliance with vitamin D supplements in the trial was poor, he noted (Age Ageing 2009;38:606–9).

The Women's Health Study also found no significant reduction in risk for diabetes after a median 7-year follow-up in 33,951 women randomized to 1,000 mg/day of calcium plus 400 IU/day of vitamin D or placebo (Diabetes Care 2008;31:701–7). The vitamin D dose was too low, Dr. Binkley said, and the compliance rate was only around 60%.

“We need larger studies, with higher vitamin D doses,” he said.

Dr. Binkley said he has no conflicts of interest related to these topics.

The National Osteoporosis Foundation recommends that adults younger than 50 years ingest 400-800 IU/day of vitamin D. Those aged 50 years or older need 800-1,000 IU/day.

Source © Joss/Fotolia.com

The FRAX tool to calculate the risk of major osteoporotic fracture and recommendations increasing vitamin D₃ intake are key components of the North American Menopause Society's updated position statement on the management of osteoporosis in postmenopausal women.

Last updated in 2006, the 2010 statement (www.menopause.org/aboutmeno/consensus.aspx

Among the new recommendations is the use of the World Health Organization's FRAX (Fracture Risk Assessment) tool to calculate a patient's 10-year risk of major osteoporotic fracture (hip, shoulder, wrist, and spine). Developed by researchers led by Dr. John A. Kanis of the University of Sheffield (England), FRAX is based on individual patient models that integrate the fracture risks associated with clinical risk factors as well as bone mineral density at the femoral neck. “People have been intimidated by the language associated with bone density reports over the years,” Dr. Steven T. Harris, a member of the editorial board that drafted the updated position statement, said in an interview. “It's distressing to be told that you have osteopenia or osteoporosis. To be able to use the FRAX tool to reduce that to a number—some reasonable estimate of fracture risk—is very helpful.”

Dr. Utian, a member of the 2008-2009 NAMS Board of Trustees who reviewed the position statement, said that FRAX was included because clinicians have come to realize “some of the limitations of DXA and the overuse of DXA, which could lead to inappropriate therapies. While DXA is a valuable tool, the FRAX gives you an ability to speak to individuals and actually give them an idea of what their risk is. It also gives health care organizations the ability to set parameters at what level of risk they would consider therapy to be indicated.”

According to the statement, drug therapy is indicated for postmenopausal women with osteoporotic vertebral or hip fracture; BMD values consistent with osteoporosis (a T score of −2.5 or lower); or a T score from −1.0 to −2.5 and a 10-year FRAX risk of major osteoporotic fracture (hip, shoulder, wrist, and spine) of at least 20% or hip fracture of at least 3%.

Another new part of the NAMS statement recommends that postmenopausal women obtain 800-1,000 IU/day of vitamin D₃, up from the recommended dosage of 400-600 IU/day contained in the 2006 statement. “There is more and more evidence that even in temperate areas, there isn't enough sun exposure to guarantee vitamin D sufficiency, particularly during the winter months,” said Dr. Harris of the University of California, San Francisco. “I think that the recommended allowance of 800-1,000 IU/day will be increased again at some point, but I think it's a reasonable starting point.”

As for choice of a specific osteoporosis therapy, the statement emphasizes that no head-to-head trials comparing the effectiveness of pharmacologic therapies to reduce fracture risk have been conducted. Current approved treatment options include bisphosphonates, selective estrogen-receptor modulators (SERMs), parathyroid hormone, estrogens, and calcitonin.

According to the statement, bisphosphonates “are the first-line drugs for treating postmenopausal women with osteoporosis. They have reduced the risk of vertebral fractures by 40%-70% and reduced the incidence of nonvertebral fracture, including hip fracture, by about half this amount.”

The SERM raloxifene “prevents bone loss and reduces the risk of vertebral fractures, but its effectiveness in reducing other fractures is uncertain. Extraskeletal risks and benefits are important when considering raloxifene therapy.”

Disclosures: The development of the statement was supported by an unrestricted educational grant from the Alliance for Better Bone Health, a collaboration between Warner Chilcott and its affiliates and Sanofi-Aventis US. Dr. Utian and Dr. Harris disclosed relationships with multiple pharmaceutical firms.

The FRAX tool to calculate the risk of major osteoporotic fracture and recommendations increasing vitamin D₃ intake are key components of the North American Menopause Society's updated position statement on the management of osteoporosis in postmenopausal women.

Last updated in 2006, the 2010 statement (www.menopause.org/aboutmeno/consensus.aspx

Among the new recommendations is the use of the World Health Organization's FRAX (Fracture Risk Assessment) tool to calculate a patient's 10-year risk of major osteoporotic fracture (hip, shoulder, wrist, and spine). Developed by researchers led by Dr. John A. Kanis of the University of Sheffield (England), FRAX is based on individual patient models that integrate the fracture risks associated with clinical risk factors as well as bone mineral density at the femoral neck. “People have been intimidated by the language associated with bone density reports over the years,” Dr. Steven T. Harris, a member of the editorial board that drafted the updated position statement, said in an interview. “It's distressing to be told that you have osteopenia or osteoporosis. To be able to use the FRAX tool to reduce that to a number—some reasonable estimate of fracture risk—is very helpful.”

Dr. Utian, a member of the 2008-2009 NAMS Board of Trustees who reviewed the position statement, said that FRAX was included because clinicians have come to realize “some of the limitations of DXA and the overuse of DXA, which could lead to inappropriate therapies. While DXA is a valuable tool, the FRAX gives you an ability to speak to individuals and actually give them an idea of what their risk is. It also gives health care organizations the ability to set parameters at what level of risk they would consider therapy to be indicated.”

According to the statement, drug therapy is indicated for postmenopausal women with osteoporotic vertebral or hip fracture; BMD values consistent with osteoporosis (a T score of −2.5 or lower); or a T score from −1.0 to −2.5 and a 10-year FRAX risk of major osteoporotic fracture (hip, shoulder, wrist, and spine) of at least 20% or hip fracture of at least 3%.

Another new part of the NAMS statement recommends that postmenopausal women obtain 800-1,000 IU/day of vitamin D₃, up from the recommended dosage of 400-600 IU/day contained in the 2006 statement. “There is more and more evidence that even in temperate areas, there isn't enough sun exposure to guarantee vitamin D sufficiency, particularly during the winter months,” said Dr. Harris of the University of California, San Francisco. “I think that the recommended allowance of 800-1,000 IU/day will be increased again at some point, but I think it's a reasonable starting point.”

As for choice of a specific osteoporosis therapy, the statement emphasizes that no head-to-head trials comparing the effectiveness of pharmacologic therapies to reduce fracture risk have been conducted. Current approved treatment options include bisphosphonates, selective estrogen-receptor modulators (SERMs), parathyroid hormone, estrogens, and calcitonin.

According to the statement, bisphosphonates “are the first-line drugs for treating postmenopausal women with osteoporosis. They have reduced the risk of vertebral fractures by 40%-70% and reduced the incidence of nonvertebral fracture, including hip fracture, by about half this amount.”

The SERM raloxifene “prevents bone loss and reduces the risk of vertebral fractures, but its effectiveness in reducing other fractures is uncertain. Extraskeletal risks and benefits are important when considering raloxifene therapy.”

Disclosures: The development of the statement was supported by an unrestricted educational grant from the Alliance for Better Bone Health, a collaboration between Warner Chilcott and its affiliates and Sanofi-Aventis US. Dr. Utian and Dr. Harris disclosed relationships with multiple pharmaceutical firms.

The FRAX tool to calculate the risk of major osteoporotic fracture and recommendations increasing vitamin D₃ intake are key components of the North American Menopause Society's updated position statement on the management of osteoporosis in postmenopausal women.

Last updated in 2006, the 2010 statement (www.menopause.org/aboutmeno/consensus.aspx

Among the new recommendations is the use of the World Health Organization's FRAX (Fracture Risk Assessment) tool to calculate a patient's 10-year risk of major osteoporotic fracture (hip, shoulder, wrist, and spine). Developed by researchers led by Dr. John A. Kanis of the University of Sheffield (England), FRAX is based on individual patient models that integrate the fracture risks associated with clinical risk factors as well as bone mineral density at the femoral neck. “People have been intimidated by the language associated with bone density reports over the years,” Dr. Steven T. Harris, a member of the editorial board that drafted the updated position statement, said in an interview. “It's distressing to be told that you have osteopenia or osteoporosis. To be able to use the FRAX tool to reduce that to a number—some reasonable estimate of fracture risk—is very helpful.”

Dr. Utian, a member of the 2008-2009 NAMS Board of Trustees who reviewed the position statement, said that FRAX was included because clinicians have come to realize “some of the limitations of DXA and the overuse of DXA, which could lead to inappropriate therapies. While DXA is a valuable tool, the FRAX gives you an ability to speak to individuals and actually give them an idea of what their risk is. It also gives health care organizations the ability to set parameters at what level of risk they would consider therapy to be indicated.”

According to the statement, drug therapy is indicated for postmenopausal women with osteoporotic vertebral or hip fracture; BMD values consistent with osteoporosis (a T score of −2.5 or lower); or a T score from −1.0 to −2.5 and a 10-year FRAX risk of major osteoporotic fracture (hip, shoulder, wrist, and spine) of at least 20% or hip fracture of at least 3%.

Another new part of the NAMS statement recommends that postmenopausal women obtain 800-1,000 IU/day of vitamin D₃, up from the recommended dosage of 400-600 IU/day contained in the 2006 statement. “There is more and more evidence that even in temperate areas, there isn't enough sun exposure to guarantee vitamin D sufficiency, particularly during the winter months,” said Dr. Harris of the University of California, San Francisco. “I think that the recommended allowance of 800-1,000 IU/day will be increased again at some point, but I think it's a reasonable starting point.”

As for choice of a specific osteoporosis therapy, the statement emphasizes that no head-to-head trials comparing the effectiveness of pharmacologic therapies to reduce fracture risk have been conducted. Current approved treatment options include bisphosphonates, selective estrogen-receptor modulators (SERMs), parathyroid hormone, estrogens, and calcitonin.

According to the statement, bisphosphonates “are the first-line drugs for treating postmenopausal women with osteoporosis. They have reduced the risk of vertebral fractures by 40%-70% and reduced the incidence of nonvertebral fracture, including hip fracture, by about half this amount.”

The SERM raloxifene “prevents bone loss and reduces the risk of vertebral fractures, but its effectiveness in reducing other fractures is uncertain. Extraskeletal risks and benefits are important when considering raloxifene therapy.”

Disclosures: The development of the statement was supported by an unrestricted educational grant from the Alliance for Better Bone Health, a collaboration between Warner Chilcott and its affiliates and Sanofi-Aventis US. Dr. Utian and Dr. Harris disclosed relationships with multiple pharmaceutical firms.

Snowmass, Colo. — Serious questions exist about the safety and efficacy of the popular practice of high-dose vitamin D supplementation across a broad swath of the population.

One of these concerns is that not all of the extra calcium absorption promoted by boosting vitamin D is going into bone to prevent fractures. Some of it may actually be taken up by atherosclerotic plaque, increasing the risk of cardiovascular events, Dr. Lenore M. Buckley cautioned at a symposium sponsored by the American College of Rheumatology,

This is of particular concern in patients with known coronary disease and for those at high risk, including individuals with rheumatoid arthritis, systemic lupus erythematosus, diabetes, or psoriasis, added Dr. Buckley, professor of medicine at Virginia Commonwealth University, Richmond.

Discussing findings from a recent cross-sectional study involving 340 blacks with type 2 diabetes, Dr. Buckley said that serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries (J. Clin. Endo. Metab. 2010 Jan. 8 [Epub ahead of print]).

There is a noticeable, if anecdotal, increase in the number of physicians ordering serum vitamin D tests to screen for deficiency. The vitamin D assay has become one of the most-ordered lab tests in the United States, despite the assay's questionable reliability, its $40-$200 cost, and considerable unresolved debate as to what constitutes an optimal blood level. Medicare is considering changing its policy such that vitamin D tests for screening purposes would no longer be covered, according to Dr. Buckley.

There is solid evidence that vitamin D supplementation reduces fracture risk in the elderly, especially in those with low serum levels. But that's not what's driving the astounding recent growth in serum vitamin D screening and supplementation. The impetus for the upsurge in screening is the hope that it might protect against a broad range of chronic diseases, including cancers, dementia, autoimmune diseases, and cardiovascular disease.

The trouble is, that hope is driven mostly by epidemiologic data, which must be viewed as hypothesis generating rather than definitive. The classic example of how misleading epidemiologic associations can be is the expectation that estrogen replacement would reduce cardiovascular risk in postmenopausal women; when the Women's Health Initiative and other prospective trials were eventually carried out, it turned out that just the opposite was true, Dr. Buckley noted.

“The question we have to ask is: What does that low serum vitamin D level mean? Is it the thing that predisposes, or is it somehow a byproduct of illness?” she continued.

There is intriguing evidence to indicate that the optimal level of vitamin D to promote bone health, muscle strength, immunity, and other key functions may vary by race. Data from the National Health and Nutrition Examination Survey show that very few white children aged 1-12 years are vitamin D deficient using the classic threshold of 15 ng/mL. In contrast, about 10% of non-Hispanic black 1- to 6-year-olds are vitamin D deficient, as are close to 30% in the 7-12 age bracket (Pediatrics Sept. 2009 [doi:10-1542/peds.2009-0051]).

Many observers see this racial disparity as a public health problem reflecting unequal access to services. But there is a conundrum here: If vitamin D deficiency is rampant in black children, why do they have greater bone strength and muscle mass than do whites?

“It makes one wonder whether the definition of normal levels should vary by race,” according to the rheumatologist.

Support for this notion comes from studies showing that pushing serum vitamin D levels to 30 ng/mL or higher in whites reduces their parathyroid hormone levels, whereas pushing levels above 20 ng/ml in blacks—young or old—doesn't further decrease parathyroid hormone or increase bone density.

Dr. Buckley said she generally tries to get patients into the 20- to 29-ng/mL range, but in black patients and those with known cardiovascular disease, she aims for 15 ng/mL or slightly more, “and I worry that might be too high sometimes.”

She reserves expedited supplementation (50,000 IU weekly for 8 weeks) mainly for vitamin D–deficient elderly patients who are at high risk for fracture or fall. That's where there is supporting evidence of benefit. There is no evidence to support supplementation in young or middle-aged patients, whose increased fracture risk is decades away.

Fresh guidance in the form of updated recommendations on vitamin D from the Institute of Medicine is forthcoming. Rumor has it that the IOM report, due this spring, will recommend an increase in the currently recommended supplemental 400 IU/day for 50- to 70-year-olds who are not getting sufficient vitamin D from the sun. Her hope is the IOM will address the thorny issues of who should receive supplementation, and how fast it should be done.

Disclosures: Dr. Buckley reported having no financial relationships relevant to her talk.

To watch a video interview of Dr. Buckley, go to www.youtube.com/rheumatologynews

'What does that low serum vitamin D level mean? … Is it somehow a byproduct of illness?'

Source DR. BUCKLEY

This Month's Talk Back Question

What is your approach to advising patients about vitamin D and calcium supplementation?

Snowmass, Colo. — Serious questions exist about the safety and efficacy of the popular practice of high-dose vitamin D supplementation across a broad swath of the population.

One of these concerns is that not all of the extra calcium absorption promoted by boosting vitamin D is going into bone to prevent fractures. Some of it may actually be taken up by atherosclerotic plaque, increasing the risk of cardiovascular events, Dr. Lenore M. Buckley cautioned at a symposium sponsored by the American College of Rheumatology,

This is of particular concern in patients with known coronary disease and for those at high risk, including individuals with rheumatoid arthritis, systemic lupus erythematosus, diabetes, or psoriasis, added Dr. Buckley, professor of medicine at Virginia Commonwealth University, Richmond.

Discussing findings from a recent cross-sectional study involving 340 blacks with type 2 diabetes, Dr. Buckley said that serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries (J. Clin. Endo. Metab. 2010 Jan. 8 [Epub ahead of print]).

There is a noticeable, if anecdotal, increase in the number of physicians ordering serum vitamin D tests to screen for deficiency. The vitamin D assay has become one of the most-ordered lab tests in the United States, despite the assay's questionable reliability, its $40-$200 cost, and considerable unresolved debate as to what constitutes an optimal blood level. Medicare is considering changing its policy such that vitamin D tests for screening purposes would no longer be covered, according to Dr. Buckley.

There is solid evidence that vitamin D supplementation reduces fracture risk in the elderly, especially in those with low serum levels. But that's not what's driving the astounding recent growth in serum vitamin D screening and supplementation. The impetus for the upsurge in screening is the hope that it might protect against a broad range of chronic diseases, including cancers, dementia, autoimmune diseases, and cardiovascular disease.

The trouble is, that hope is driven mostly by epidemiologic data, which must be viewed as hypothesis generating rather than definitive. The classic example of how misleading epidemiologic associations can be is the expectation that estrogen replacement would reduce cardiovascular risk in postmenopausal women; when the Women's Health Initiative and other prospective trials were eventually carried out, it turned out that just the opposite was true, Dr. Buckley noted.

“The question we have to ask is: What does that low serum vitamin D level mean? Is it the thing that predisposes, or is it somehow a byproduct of illness?” she continued.

There is intriguing evidence to indicate that the optimal level of vitamin D to promote bone health, muscle strength, immunity, and other key functions may vary by race. Data from the National Health and Nutrition Examination Survey show that very few white children aged 1-12 years are vitamin D deficient using the classic threshold of 15 ng/mL. In contrast, about 10% of non-Hispanic black 1- to 6-year-olds are vitamin D deficient, as are close to 30% in the 7-12 age bracket (Pediatrics Sept. 2009 [doi:10-1542/peds.2009-0051]).

Many observers see this racial disparity as a public health problem reflecting unequal access to services. But there is a conundrum here: If vitamin D deficiency is rampant in black children, why do they have greater bone strength and muscle mass than do whites?

“It makes one wonder whether the definition of normal levels should vary by race,” according to the rheumatologist.

Support for this notion comes from studies showing that pushing serum vitamin D levels to 30 ng/mL or higher in whites reduces their parathyroid hormone levels, whereas pushing levels above 20 ng/ml in blacks—young or old—doesn't further decrease parathyroid hormone or increase bone density.

Dr. Buckley said she generally tries to get patients into the 20- to 29-ng/mL range, but in black patients and those with known cardiovascular disease, she aims for 15 ng/mL or slightly more, “and I worry that might be too high sometimes.”

She reserves expedited supplementation (50,000 IU weekly for 8 weeks) mainly for vitamin D–deficient elderly patients who are at high risk for fracture or fall. That's where there is supporting evidence of benefit. There is no evidence to support supplementation in young or middle-aged patients, whose increased fracture risk is decades away.

Fresh guidance in the form of updated recommendations on vitamin D from the Institute of Medicine is forthcoming. Rumor has it that the IOM report, due this spring, will recommend an increase in the currently recommended supplemental 400 IU/day for 50- to 70-year-olds who are not getting sufficient vitamin D from the sun. Her hope is the IOM will address the thorny issues of who should receive supplementation, and how fast it should be done.

Disclosures: Dr. Buckley reported having no financial relationships relevant to her talk.

To watch a video interview of Dr. Buckley, go to www.youtube.com/rheumatologynews

'What does that low serum vitamin D level mean? … Is it somehow a byproduct of illness?'

Source DR. BUCKLEY

This Month's Talk Back Question

What is your approach to advising patients about vitamin D and calcium supplementation?

Snowmass, Colo. — Serious questions exist about the safety and efficacy of the popular practice of high-dose vitamin D supplementation across a broad swath of the population.

One of these concerns is that not all of the extra calcium absorption promoted by boosting vitamin D is going into bone to prevent fractures. Some of it may actually be taken up by atherosclerotic plaque, increasing the risk of cardiovascular events, Dr. Lenore M. Buckley cautioned at a symposium sponsored by the American College of Rheumatology,

This is of particular concern in patients with known coronary disease and for those at high risk, including individuals with rheumatoid arthritis, systemic lupus erythematosus, diabetes, or psoriasis, added Dr. Buckley, professor of medicine at Virginia Commonwealth University, Richmond.

Discussing findings from a recent cross-sectional study involving 340 blacks with type 2 diabetes, Dr. Buckley said that serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries (J. Clin. Endo. Metab. 2010 Jan. 8 [Epub ahead of print]).

There is a noticeable, if anecdotal, increase in the number of physicians ordering serum vitamin D tests to screen for deficiency. The vitamin D assay has become one of the most-ordered lab tests in the United States, despite the assay's questionable reliability, its $40-$200 cost, and considerable unresolved debate as to what constitutes an optimal blood level. Medicare is considering changing its policy such that vitamin D tests for screening purposes would no longer be covered, according to Dr. Buckley.

There is solid evidence that vitamin D supplementation reduces fracture risk in the elderly, especially in those with low serum levels. But that's not what's driving the astounding recent growth in serum vitamin D screening and supplementation. The impetus for the upsurge in screening is the hope that it might protect against a broad range of chronic diseases, including cancers, dementia, autoimmune diseases, and cardiovascular disease.

The trouble is, that hope is driven mostly by epidemiologic data, which must be viewed as hypothesis generating rather than definitive. The classic example of how misleading epidemiologic associations can be is the expectation that estrogen replacement would reduce cardiovascular risk in postmenopausal women; when the Women's Health Initiative and other prospective trials were eventually carried out, it turned out that just the opposite was true, Dr. Buckley noted.

“The question we have to ask is: What does that low serum vitamin D level mean? Is it the thing that predisposes, or is it somehow a byproduct of illness?” she continued.

There is intriguing evidence to indicate that the optimal level of vitamin D to promote bone health, muscle strength, immunity, and other key functions may vary by race. Data from the National Health and Nutrition Examination Survey show that very few white children aged 1-12 years are vitamin D deficient using the classic threshold of 15 ng/mL. In contrast, about 10% of non-Hispanic black 1- to 6-year-olds are vitamin D deficient, as are close to 30% in the 7-12 age bracket (Pediatrics Sept. 2009 [doi:10-1542/peds.2009-0051]).

Many observers see this racial disparity as a public health problem reflecting unequal access to services. But there is a conundrum here: If vitamin D deficiency is rampant in black children, why do they have greater bone strength and muscle mass than do whites?

“It makes one wonder whether the definition of normal levels should vary by race,” according to the rheumatologist.

Support for this notion comes from studies showing that pushing serum vitamin D levels to 30 ng/mL or higher in whites reduces their parathyroid hormone levels, whereas pushing levels above 20 ng/ml in blacks—young or old—doesn't further decrease parathyroid hormone or increase bone density.

Dr. Buckley said she generally tries to get patients into the 20- to 29-ng/mL range, but in black patients and those with known cardiovascular disease, she aims for 15 ng/mL or slightly more, “and I worry that might be too high sometimes.”

She reserves expedited supplementation (50,000 IU weekly for 8 weeks) mainly for vitamin D–deficient elderly patients who are at high risk for fracture or fall. That's where there is supporting evidence of benefit. There is no evidence to support supplementation in young or middle-aged patients, whose increased fracture risk is decades away.

Fresh guidance in the form of updated recommendations on vitamin D from the Institute of Medicine is forthcoming. Rumor has it that the IOM report, due this spring, will recommend an increase in the currently recommended supplemental 400 IU/day for 50- to 70-year-olds who are not getting sufficient vitamin D from the sun. Her hope is the IOM will address the thorny issues of who should receive supplementation, and how fast it should be done.

Disclosures: Dr. Buckley reported having no financial relationships relevant to her talk.

To watch a video interview of Dr. Buckley, go to www.youtube.com/rheumatologynews

'What does that low serum vitamin D level mean? … Is it somehow a byproduct of illness?'

Source DR. BUCKLEY

This Month's Talk Back Question

What is your approach to advising patients about vitamin D and calcium supplementation?

WASHINGTON — Obese women are less likely to be screened for osteoporosis than are normal- or overweight women, according to findings from a study of more than 140,000 women included in an integrated health care plan database.

Previous studies have shown mixed results on the disparity in preventive health care for obese patients, compared with normal-weight patients, said Kristi Reynolds, Ph.D., of Kaiser Permanente in Pasadena, Calif., and her colleagues.

“It is largely unknown whether obesity is associated with the quality of care for osteoporosis, which is both preventable and treatable but is often undiagnosed and untreated,” the researchers said. Physicians may be less inclined to screen obese women for osteoporosis because body weight is associated with higher bone density, they noted.

Data from 146,975 health care provider visits between July 1, 2007, and June 30, 2008, were reviewed.

The average age of the women was 73 years; 35% were normal weight; 35% were overweight; and 19%, 7%, and 4% fell into obesity categories I, II, and III, respectively. Normal-weight body mass index (BMI) was defined as 18.5-24.9 kg/m

About 67% of the women had undergone bone mineral density testing within 4 years of the study, which was the criteria by which participants could be considered “screened.” Only 52% of women with a BMI of 40 kg/m

After controlling for age, race, and income, the odds ratio of osteoporosis screening for overweight women was 0.99, while the odds ratios for women in obese classes I, II, and III groups were 0.90, 0.77, and 0.60, respectively. The findings were presented in a poster at the the annual meeting of the Obesity Society.

The results suggest that many overweight and obese women aren't screened for osteoporosis. However, more research is needed to examine the health outcomes of screened versus unscreened women, and the factors that influence providers to screen women according to BMI, the researchers said.

The researchers are employees of Kaiser Permanente. They reported having no financial conflicts of interest.

WASHINGTON — Obese women are less likely to be screened for osteoporosis than are normal- or overweight women, according to findings from a study of more than 140,000 women included in an integrated health care plan database.

Previous studies have shown mixed results on the disparity in preventive health care for obese patients, compared with normal-weight patients, said Kristi Reynolds, Ph.D., of Kaiser Permanente in Pasadena, Calif., and her colleagues.

“It is largely unknown whether obesity is associated with the quality of care for osteoporosis, which is both preventable and treatable but is often undiagnosed and untreated,” the researchers said. Physicians may be less inclined to screen obese women for osteoporosis because body weight is associated with higher bone density, they noted.

Data from 146,975 health care provider visits between July 1, 2007, and June 30, 2008, were reviewed.

The average age of the women was 73 years; 35% were normal weight; 35% were overweight; and 19%, 7%, and 4% fell into obesity categories I, II, and III, respectively. Normal-weight body mass index (BMI) was defined as 18.5-24.9 kg/m

About 67% of the women had undergone bone mineral density testing within 4 years of the study, which was the criteria by which participants could be considered “screened.” Only 52% of women with a BMI of 40 kg/m

After controlling for age, race, and income, the odds ratio of osteoporosis screening for overweight women was 0.99, while the odds ratios for women in obese classes I, II, and III groups were 0.90, 0.77, and 0.60, respectively. The findings were presented in a poster at the the annual meeting of the Obesity Society.

The results suggest that many overweight and obese women aren't screened for osteoporosis. However, more research is needed to examine the health outcomes of screened versus unscreened women, and the factors that influence providers to screen women according to BMI, the researchers said.

The researchers are employees of Kaiser Permanente. They reported having no financial conflicts of interest.

WASHINGTON — Obese women are less likely to be screened for osteoporosis than are normal- or overweight women, according to findings from a study of more than 140,000 women included in an integrated health care plan database.

Previous studies have shown mixed results on the disparity in preventive health care for obese patients, compared with normal-weight patients, said Kristi Reynolds, Ph.D., of Kaiser Permanente in Pasadena, Calif., and her colleagues.

“It is largely unknown whether obesity is associated with the quality of care for osteoporosis, which is both preventable and treatable but is often undiagnosed and untreated,” the researchers said. Physicians may be less inclined to screen obese women for osteoporosis because body weight is associated with higher bone density, they noted.

Data from 146,975 health care provider visits between July 1, 2007, and June 30, 2008, were reviewed.

The average age of the women was 73 years; 35% were normal weight; 35% were overweight; and 19%, 7%, and 4% fell into obesity categories I, II, and III, respectively. Normal-weight body mass index (BMI) was defined as 18.5-24.9 kg/m

About 67% of the women had undergone bone mineral density testing within 4 years of the study, which was the criteria by which participants could be considered “screened.” Only 52% of women with a BMI of 40 kg/m

After controlling for age, race, and income, the odds ratio of osteoporosis screening for overweight women was 0.99, while the odds ratios for women in obese classes I, II, and III groups were 0.90, 0.77, and 0.60, respectively. The findings were presented in a poster at the the annual meeting of the Obesity Society.

The results suggest that many overweight and obese women aren't screened for osteoporosis. However, more research is needed to examine the health outcomes of screened versus unscreened women, and the factors that influence providers to screen women according to BMI, the researchers said.

The researchers are employees of Kaiser Permanente. They reported having no financial conflicts of interest.

SAN ANTONIO — Arzoxifene, a once-promising selective estrogen-receptor modulator, experienced a fatal meltdown in a phase III trial of over 9,000 women.

The drug was being developed for prevention of both fractures and breast cancer in postmenopausal women with osteoporosis or osteopenia. But some findings in the 9,354-patient randomized, double-blind, placebo-controlled, multinational GENERATIONS trial have ended that, Dr. Trevor Powles said at the San Antonio Breast Cancer Symposium.

The breast cancer prevention portion of GENERATIONS went well: After 48 months of follow-up, arzoxifene cut the incidence of invasive breast cancer by 56%, compared with placebo, and reduced estrogen-receptor–positive invasive breast cancer by 70%.

It also reduced the incidence of vertebral fractures by 41% after 36 months of follow-up in the subjects, who were aged 60-85 at enrollment. But it did not significantly reduce nonvertebral fractures.

“We need a SERM [selective estrogen-receptor modulator] that would reduce vertebral and nonvertebral fractures,” said Dr. Powles, a medical oncologist who is professor emeritus at the Institute of Cancer Research, London. Arzoxifene also linked to increased rates of venous thromboembolism, endometrial polyps, leg cramps, hot flashes, and cholelithiasis, while offering no better protection against cardiovascular events than placebo.

“The overall benefit/risk profile of arzoxifene does not represent a meaningful advancement in the treatment of osteoporosis, so further development of this drug will not take place,” he said.

The researchers are puzzling over how the earlier studies could have been so misleading. Arzoxifene is a benzothiophene SERM, like raloxifene, which is approved in postmenopausal women for the treatment and prevention of osteoporosis as well as for reducing invasive breast cancer risk in those at high risk for the cancer or who have osteoporosis. In early clinical studies, arzoxifene had greater effects on bone mineral density and bone turnover markers than raloxifene. It also resulted in increased bone density at nonvertebral sites and in the spine.

Disclosures: Eli Lilly & Co. funded the trial. Dr. Powles said he has no relevant financial relationships.

'We need a SERM that would reduce vertebral and nonvertebral fractures.'

Source DR. POWLES

SAN ANTONIO — Arzoxifene, a once-promising selective estrogen-receptor modulator, experienced a fatal meltdown in a phase III trial of over 9,000 women.

The drug was being developed for prevention of both fractures and breast cancer in postmenopausal women with osteoporosis or osteopenia. But some findings in the 9,354-patient randomized, double-blind, placebo-controlled, multinational GENERATIONS trial have ended that, Dr. Trevor Powles said at the San Antonio Breast Cancer Symposium.

The breast cancer prevention portion of GENERATIONS went well: After 48 months of follow-up, arzoxifene cut the incidence of invasive breast cancer by 56%, compared with placebo, and reduced estrogen-receptor–positive invasive breast cancer by 70%.

It also reduced the incidence of vertebral fractures by 41% after 36 months of follow-up in the subjects, who were aged 60-85 at enrollment. But it did not significantly reduce nonvertebral fractures.

“We need a SERM [selective estrogen-receptor modulator] that would reduce vertebral and nonvertebral fractures,” said Dr. Powles, a medical oncologist who is professor emeritus at the Institute of Cancer Research, London. Arzoxifene also linked to increased rates of venous thromboembolism, endometrial polyps, leg cramps, hot flashes, and cholelithiasis, while offering no better protection against cardiovascular events than placebo.

“The overall benefit/risk profile of arzoxifene does not represent a meaningful advancement in the treatment of osteoporosis, so further development of this drug will not take place,” he said.

The researchers are puzzling over how the earlier studies could have been so misleading. Arzoxifene is a benzothiophene SERM, like raloxifene, which is approved in postmenopausal women for the treatment and prevention of osteoporosis as well as for reducing invasive breast cancer risk in those at high risk for the cancer or who have osteoporosis. In early clinical studies, arzoxifene had greater effects on bone mineral density and bone turnover markers than raloxifene. It also resulted in increased bone density at nonvertebral sites and in the spine.

Disclosures: Eli Lilly & Co. funded the trial. Dr. Powles said he has no relevant financial relationships.

'We need a SERM that would reduce vertebral and nonvertebral fractures.'

Source DR. POWLES

SAN ANTONIO — Arzoxifene, a once-promising selective estrogen-receptor modulator, experienced a fatal meltdown in a phase III trial of over 9,000 women.

The drug was being developed for prevention of both fractures and breast cancer in postmenopausal women with osteoporosis or osteopenia. But some findings in the 9,354-patient randomized, double-blind, placebo-controlled, multinational GENERATIONS trial have ended that, Dr. Trevor Powles said at the San Antonio Breast Cancer Symposium.

The breast cancer prevention portion of GENERATIONS went well: After 48 months of follow-up, arzoxifene cut the incidence of invasive breast cancer by 56%, compared with placebo, and reduced estrogen-receptor–positive invasive breast cancer by 70%.

It also reduced the incidence of vertebral fractures by 41% after 36 months of follow-up in the subjects, who were aged 60-85 at enrollment. But it did not significantly reduce nonvertebral fractures.

“We need a SERM [selective estrogen-receptor modulator] that would reduce vertebral and nonvertebral fractures,” said Dr. Powles, a medical oncologist who is professor emeritus at the Institute of Cancer Research, London. Arzoxifene also linked to increased rates of venous thromboembolism, endometrial polyps, leg cramps, hot flashes, and cholelithiasis, while offering no better protection against cardiovascular events than placebo.

“The overall benefit/risk profile of arzoxifene does not represent a meaningful advancement in the treatment of osteoporosis, so further development of this drug will not take place,” he said.

The researchers are puzzling over how the earlier studies could have been so misleading. Arzoxifene is a benzothiophene SERM, like raloxifene, which is approved in postmenopausal women for the treatment and prevention of osteoporosis as well as for reducing invasive breast cancer risk in those at high risk for the cancer or who have osteoporosis. In early clinical studies, arzoxifene had greater effects on bone mineral density and bone turnover markers than raloxifene. It also resulted in increased bone density at nonvertebral sites and in the spine.

Disclosures: Eli Lilly & Co. funded the trial. Dr. Powles said he has no relevant financial relationships.

'We need a SERM that would reduce vertebral and nonvertebral fractures.'

Source DR. POWLES