Osteoporosis

Major Finding: Five of six black lupus patients who were given 2,000 IU vitamin D daily repleted serum 25-hydroxyvitamin D to 30 ng/mL or more at 3 months.

Data Source: A phase 1 study of 18 patients.

Disclosures: The study was funded by the National Institutes of Health. The principal investigator said she had no disclosures.

VANCOUVER, B.C. — A daily dose of at least 2,000 IU of vitamin D is required to elevate serum 25-hydroxyvitamin D levels above 30 ng/mL, the minimum threshold for optimal immune health, according to results from an open-label, phase I study of vitamin D repletion in 18 black patients with lupus.

Starting from a baseline mean 25-hydroxyvitamin D (25[OH]D) level of 13.3 ng/mL, six patients received 800 IU vitamin D once daily; six received 2,000 IU once daily; and six received 4,000 IU once daily, reported Dr. Diane Kamen, a rheumatologist at the Medical University of South Carolina in Charleston.

After 12 weeks, 67% (four patients) in the 800-IU group, 83% (five) in the 2,000-IU group, and 67% (four) in the 4,000-IU group repleted to 30 ng/mL or greater.

In the 4,000-IU group, levels in 33% (two patients) rose above 40 ng/mL. That level was not reached at the lower doses.

The results are important, Dr. Kamen said in an interview after the meeting, because although there is growing awareness that such high doses of vitamin D are needed to restore 25(OH)D levels in patients with autoimmune disease, the rheumatology literature still contains recommendations for doses of 600-800 IU/day.

“That's just not going to cut it; 2,000 IU a day is the minimum effective dose for repletion,” especially if patients avoid the sun to prevent lupus flares, Dr. Kamen said.

Physicians “need to know to recommend those higher doses, and to monitor levels” of 25(OH)D to make sure they are maintained, she said.

The 18 patients were enrolled from a population of blacks living on the Sea Islands of South Carolina and Georgia, a population known as the Gullah in whom there is a high incidence of lupus.

An earlier Gullah study found that 43% of 187 subjects had 25(OH)D levels below 10 ng/mL; in some, levels were undetectable.

Lower levels correlated with higher SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) scores and higher anti-dsDNA antibody levels, Dr. Kamen said.

The mean age in the phase I study was 44 years; the mean prednisone dose 4.3 mg/day, and the mean SLEDAI score 2.4. In all, 17 of 18 of the subjects were women, 50% (9) took hydroxychloroquine, and 50% (9) were anti-dsDNA antibody positive.

Compliance with the treatment regimen was 99%, by pill count. The doses were very well tolerated and safe, Dr. Kamen said.

Although 2,000 IU per day elevated 25(OH)D levels in most patients to at least 30 ng/mL, there's debate about whether target blood levels should be higher in lupus patients.

“We know that 30 ng/mL is the minimum accepted as normal,” Dr. Kamen said, noting that secondary hyperparathyroidism can begin below that level.

“I tell my patients at high risk for conditions influenced by vitamin D, such as osteoporosis and inflammatory conditions, that we want them to stay between 40 and 60 ng/mL,” she said, but “it's a gray zone” that awaits further research.

Levels of 25(OH)D are known to be low in lupus patients, but no one can say for sure whether that is a cause or a consequence of the disease, or if it results from the medications that are used to treat it, such as prednisone and hydroxy-chloroquine.

Major Finding: Five of six black lupus patients who were given 2,000 IU vitamin D daily repleted serum 25-hydroxyvitamin D to 30 ng/mL or more at 3 months.

Data Source: A phase 1 study of 18 patients.

Disclosures: The study was funded by the National Institutes of Health. The principal investigator said she had no disclosures.

VANCOUVER, B.C. — A daily dose of at least 2,000 IU of vitamin D is required to elevate serum 25-hydroxyvitamin D levels above 30 ng/mL, the minimum threshold for optimal immune health, according to results from an open-label, phase I study of vitamin D repletion in 18 black patients with lupus.

Starting from a baseline mean 25-hydroxyvitamin D (25[OH]D) level of 13.3 ng/mL, six patients received 800 IU vitamin D once daily; six received 2,000 IU once daily; and six received 4,000 IU once daily, reported Dr. Diane Kamen, a rheumatologist at the Medical University of South Carolina in Charleston.

After 12 weeks, 67% (four patients) in the 800-IU group, 83% (five) in the 2,000-IU group, and 67% (four) in the 4,000-IU group repleted to 30 ng/mL or greater.

In the 4,000-IU group, levels in 33% (two patients) rose above 40 ng/mL. That level was not reached at the lower doses.

The results are important, Dr. Kamen said in an interview after the meeting, because although there is growing awareness that such high doses of vitamin D are needed to restore 25(OH)D levels in patients with autoimmune disease, the rheumatology literature still contains recommendations for doses of 600-800 IU/day.

“That's just not going to cut it; 2,000 IU a day is the minimum effective dose for repletion,” especially if patients avoid the sun to prevent lupus flares, Dr. Kamen said.

Physicians “need to know to recommend those higher doses, and to monitor levels” of 25(OH)D to make sure they are maintained, she said.

The 18 patients were enrolled from a population of blacks living on the Sea Islands of South Carolina and Georgia, a population known as the Gullah in whom there is a high incidence of lupus.

An earlier Gullah study found that 43% of 187 subjects had 25(OH)D levels below 10 ng/mL; in some, levels were undetectable.

Lower levels correlated with higher SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) scores and higher anti-dsDNA antibody levels, Dr. Kamen said.

The mean age in the phase I study was 44 years; the mean prednisone dose 4.3 mg/day, and the mean SLEDAI score 2.4. In all, 17 of 18 of the subjects were women, 50% (9) took hydroxychloroquine, and 50% (9) were anti-dsDNA antibody positive.

Compliance with the treatment regimen was 99%, by pill count. The doses were very well tolerated and safe, Dr. Kamen said.

Although 2,000 IU per day elevated 25(OH)D levels in most patients to at least 30 ng/mL, there's debate about whether target blood levels should be higher in lupus patients.

“We know that 30 ng/mL is the minimum accepted as normal,” Dr. Kamen said, noting that secondary hyperparathyroidism can begin below that level.

“I tell my patients at high risk for conditions influenced by vitamin D, such as osteoporosis and inflammatory conditions, that we want them to stay between 40 and 60 ng/mL,” she said, but “it's a gray zone” that awaits further research.

Levels of 25(OH)D are known to be low in lupus patients, but no one can say for sure whether that is a cause or a consequence of the disease, or if it results from the medications that are used to treat it, such as prednisone and hydroxy-chloroquine.

Major Finding: Five of six black lupus patients who were given 2,000 IU vitamin D daily repleted serum 25-hydroxyvitamin D to 30 ng/mL or more at 3 months.

Data Source: A phase 1 study of 18 patients.

Disclosures: The study was funded by the National Institutes of Health. The principal investigator said she had no disclosures.

VANCOUVER, B.C. — A daily dose of at least 2,000 IU of vitamin D is required to elevate serum 25-hydroxyvitamin D levels above 30 ng/mL, the minimum threshold for optimal immune health, according to results from an open-label, phase I study of vitamin D repletion in 18 black patients with lupus.

Starting from a baseline mean 25-hydroxyvitamin D (25[OH]D) level of 13.3 ng/mL, six patients received 800 IU vitamin D once daily; six received 2,000 IU once daily; and six received 4,000 IU once daily, reported Dr. Diane Kamen, a rheumatologist at the Medical University of South Carolina in Charleston.

After 12 weeks, 67% (four patients) in the 800-IU group, 83% (five) in the 2,000-IU group, and 67% (four) in the 4,000-IU group repleted to 30 ng/mL or greater.

In the 4,000-IU group, levels in 33% (two patients) rose above 40 ng/mL. That level was not reached at the lower doses.

The results are important, Dr. Kamen said in an interview after the meeting, because although there is growing awareness that such high doses of vitamin D are needed to restore 25(OH)D levels in patients with autoimmune disease, the rheumatology literature still contains recommendations for doses of 600-800 IU/day.

“That's just not going to cut it; 2,000 IU a day is the minimum effective dose for repletion,” especially if patients avoid the sun to prevent lupus flares, Dr. Kamen said.

Physicians “need to know to recommend those higher doses, and to monitor levels” of 25(OH)D to make sure they are maintained, she said.

The 18 patients were enrolled from a population of blacks living on the Sea Islands of South Carolina and Georgia, a population known as the Gullah in whom there is a high incidence of lupus.

An earlier Gullah study found that 43% of 187 subjects had 25(OH)D levels below 10 ng/mL; in some, levels were undetectable.

Lower levels correlated with higher SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) scores and higher anti-dsDNA antibody levels, Dr. Kamen said.

The mean age in the phase I study was 44 years; the mean prednisone dose 4.3 mg/day, and the mean SLEDAI score 2.4. In all, 17 of 18 of the subjects were women, 50% (9) took hydroxychloroquine, and 50% (9) were anti-dsDNA antibody positive.

Compliance with the treatment regimen was 99%, by pill count. The doses were very well tolerated and safe, Dr. Kamen said.

Although 2,000 IU per day elevated 25(OH)D levels in most patients to at least 30 ng/mL, there's debate about whether target blood levels should be higher in lupus patients.

“We know that 30 ng/mL is the minimum accepted as normal,” Dr. Kamen said, noting that secondary hyperparathyroidism can begin below that level.

“I tell my patients at high risk for conditions influenced by vitamin D, such as osteoporosis and inflammatory conditions, that we want them to stay between 40 and 60 ng/mL,” she said, but “it's a gray zone” that awaits further research.

Levels of 25(OH)D are known to be low in lupus patients, but no one can say for sure whether that is a cause or a consequence of the disease, or if it results from the medications that are used to treat it, such as prednisone and hydroxy-chloroquine.

Rosiglitazone and pioglitazone are both associated with an increased risk of fracture in postmenopausal women with type 2 diabetes, according to a matched case-control study that used data from the Translating Research into Action for Diabetes trial.

After controlling for age, sex, race/ethnicity, body mass index, and health plan, Dori Bilik of the University of Michigan, Ann Arbor, and colleagues, found that both of the thiazolidinediones (TZDs) were associated with a 71% increase in the risk of fracture for women aged 50 and older.

TRIAD enrolled 11,927 patients with diabetes in 2000-2001. All of the patients were at least aged 18 years and in managed care for at least 18 months before the baseline patient survey.

“Our study shows that increased fracture risk is associated with higher TZD dose, but no difference between rosiglitazone and pioglitazone is apparent, suggesting a class effect of TZDs on fracture risk,” said senior author Dr. William Herman of the University of Michigan Ann Arbor, in a press release.

Higher TZD doses were associated with a statistically significant 42% increase in the odds of fractures for women age 50 and older, but not for women under 50 or for men (J. Clin. Endocrinol. Metab. 2010; doi:10.1210/jc2009-2638).

The Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases funded the study. The authors did not report other conflicts of interest.

Rosiglitazone and pioglitazone are both associated with an increased risk of fracture in postmenopausal women with type 2 diabetes, according to a matched case-control study that used data from the Translating Research into Action for Diabetes trial.

After controlling for age, sex, race/ethnicity, body mass index, and health plan, Dori Bilik of the University of Michigan, Ann Arbor, and colleagues, found that both of the thiazolidinediones (TZDs) were associated with a 71% increase in the risk of fracture for women aged 50 and older.

TRIAD enrolled 11,927 patients with diabetes in 2000-2001. All of the patients were at least aged 18 years and in managed care for at least 18 months before the baseline patient survey.

“Our study shows that increased fracture risk is associated with higher TZD dose, but no difference between rosiglitazone and pioglitazone is apparent, suggesting a class effect of TZDs on fracture risk,” said senior author Dr. William Herman of the University of Michigan Ann Arbor, in a press release.

Higher TZD doses were associated with a statistically significant 42% increase in the odds of fractures for women age 50 and older, but not for women under 50 or for men (J. Clin. Endocrinol. Metab. 2010; doi:10.1210/jc2009-2638).

The Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases funded the study. The authors did not report other conflicts of interest.

Rosiglitazone and pioglitazone are both associated with an increased risk of fracture in postmenopausal women with type 2 diabetes, according to a matched case-control study that used data from the Translating Research into Action for Diabetes trial.

After controlling for age, sex, race/ethnicity, body mass index, and health plan, Dori Bilik of the University of Michigan, Ann Arbor, and colleagues, found that both of the thiazolidinediones (TZDs) were associated with a 71% increase in the risk of fracture for women aged 50 and older.

TRIAD enrolled 11,927 patients with diabetes in 2000-2001. All of the patients were at least aged 18 years and in managed care for at least 18 months before the baseline patient survey.

“Our study shows that increased fracture risk is associated with higher TZD dose, but no difference between rosiglitazone and pioglitazone is apparent, suggesting a class effect of TZDs on fracture risk,” said senior author Dr. William Herman of the University of Michigan Ann Arbor, in a press release.

Higher TZD doses were associated with a statistically significant 42% increase in the odds of fractures for women age 50 and older, but not for women under 50 or for men (J. Clin. Endocrinol. Metab. 2010; doi:10.1210/jc2009-2638).

The Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases funded the study. The authors did not report other conflicts of interest.

The Food and Drug Administration issued a warning to physicians and consumers that proton pump inhibitors may increase the risk of hip, wrist, and spine fractures.

The agency said that it is changing the labeling for prescription and over-the-counter versions of proton pump inhibitors (PPIs) to reflect new safety information that is the result of the FDA's review of seven epidemiologic studies. Most of the observed risk was in people older than age 50 years and those who took high doses or used the drugs for more than a year, said the agency.

Prescription PPIs include esomeprazole (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex). There are OTC versions of Prilosec, Zegerid, and Prevacid.

“When prescribing proton pump inhibitors, health care professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition,” Dr. Joyce Korvick, the deputy director for safety in the FDA's Division of Gastroenterology Products, in a statement.

The agency did not have access to the raw data in the studies; it merely reviewed what was published. However, said the FDA, it accepted the results because the studies appear to be well designed.

The full agency communication is online located at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm

The Food and Drug Administration issued a warning to physicians and consumers that proton pump inhibitors may increase the risk of hip, wrist, and spine fractures.

The agency said that it is changing the labeling for prescription and over-the-counter versions of proton pump inhibitors (PPIs) to reflect new safety information that is the result of the FDA's review of seven epidemiologic studies. Most of the observed risk was in people older than age 50 years and those who took high doses or used the drugs for more than a year, said the agency.

Prescription PPIs include esomeprazole (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex). There are OTC versions of Prilosec, Zegerid, and Prevacid.

“When prescribing proton pump inhibitors, health care professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition,” Dr. Joyce Korvick, the deputy director for safety in the FDA's Division of Gastroenterology Products, in a statement.

The agency did not have access to the raw data in the studies; it merely reviewed what was published. However, said the FDA, it accepted the results because the studies appear to be well designed.

The full agency communication is online located at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm

The Food and Drug Administration issued a warning to physicians and consumers that proton pump inhibitors may increase the risk of hip, wrist, and spine fractures.

The agency said that it is changing the labeling for prescription and over-the-counter versions of proton pump inhibitors (PPIs) to reflect new safety information that is the result of the FDA's review of seven epidemiologic studies. Most of the observed risk was in people older than age 50 years and those who took high doses or used the drugs for more than a year, said the agency.

Prescription PPIs include esomeprazole (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex). There are OTC versions of Prilosec, Zegerid, and Prevacid.

“When prescribing proton pump inhibitors, health care professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition,” Dr. Joyce Korvick, the deputy director for safety in the FDA's Division of Gastroenterology Products, in a statement.

The agency did not have access to the raw data in the studies; it merely reviewed what was published. However, said the FDA, it accepted the results because the studies appear to be well designed.

The full agency communication is online located at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm

Far from protecting older women from falls and fractures, yearly high-dose oral vitamin D raised the risk of falls by 15% and that of fractures by 26%, according to an Australian study.

These risks were highest in the 3-month period immediately after each annual dose, said Kerrie M. Sanders, Ph.D., of the University of Melbourne and her associates.

As this study used the “largest total annual dose of vitamin D (500,000 IU) reported in any large randomized controlled trial,” it is possible that these adverse outcomes are related to the dosage, or perhaps to the once-a-year regimen. But the levels of 25-hydroxycholecalciferol achieved in these subjects can also occur with other dosing regimens, so it appears that the safety of all high-dose vitamin D supplementation warrants further examination, they noted.

Dr. Sanders and her colleagues performed their single-center study in 2,256 white women aged at least 70. They were considered at risk for hip fracture because of their family or personal histories or because they reported recent falls.

The subjects were randomly assigned to receive a single oral dose of vitamin D (cholecalciferol) or a matching placebo at the same time every year for 3-5 years. Lab studies in a subgroup of the subjects showed that the active treatment raised levels of 25-hydroxycholecalciferol an average of 41%, as expected.

There were 5,404 falls during follow-up, involving 74% of the women taking vitamin D and 68% of those taking placebo. The rate of falls was 83 per 100 person-years with vitamin D, compared with 73 per 100 person-years with placebo, a statistically significant difference.

The increase in falls with active treatment was noted in falls that produced fractures and those that didn't, and in falls that produced soft-tissue injury.

A total of 155 women taking vitamin D sustained 171 fractures during follow-up, compared with 125 women taking placebo who sustained 135 fractures. This translates to a rate of 4.9 fractures per 100 person-years with active treatment and 3.9 fractures per 100 person-years with placebo.

These risks of falls and of fractures did not change after the data were adjusted to account for subjects' calcium intake.

“Contrary to our hypothesis, participants receiving annual high-dose oral cholecalciferol experienced 15% more falls and 26% more fractures than [did] the placebo group. Women not only experienced excess fractures after more frequent falls but also experienced more fractures that were not associated with a fall,” the investigators noted (JAMA 2010;303:1815-22).

The reason for these counterproductive effects is not yet known, but it is possible that the once-a-year oral regimen—compared with either a regimen that divides the oral doses or one that uses intramuscular doses—is at fault. “It is reasonable to speculate that high serum levels of vitamin D or metabolites resulting from the large annual dose, subsequent decrease in the levels, or both might be causal,” they wrote.

In an accompanying editorial, Dr. Bess Dawson-Hughes and Susan S. Harris, D.Sc., of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, said that these study findings should not detract from the importance of “correcting widespread vitamin D deficiency and insufficiency.

“There is no evidence for adverse effects of more frequent, lower-dose regimens, so daily, weekly, or monthly dosing with vitamin D₃ appears to be the best option for clinicians at this time,” they noted (JAMA 2010;303:1861-2).

Disclosures: This study was supported by the National Health and Medical Research Council and the Australian Government Department of Health and Ageing. No conflicts of interest were reported by Dr. Sanders and her associates, Dr. Dawson-Hughes, or Dr. Harris.

Far from protecting older women from falls and fractures, yearly high-dose oral vitamin D raised the risk of falls by 15% and that of fractures by 26%, according to an Australian study.

These risks were highest in the 3-month period immediately after each annual dose, said Kerrie M. Sanders, Ph.D., of the University of Melbourne and her associates.

As this study used the “largest total annual dose of vitamin D (500,000 IU) reported in any large randomized controlled trial,” it is possible that these adverse outcomes are related to the dosage, or perhaps to the once-a-year regimen. But the levels of 25-hydroxycholecalciferol achieved in these subjects can also occur with other dosing regimens, so it appears that the safety of all high-dose vitamin D supplementation warrants further examination, they noted.

Dr. Sanders and her colleagues performed their single-center study in 2,256 white women aged at least 70. They were considered at risk for hip fracture because of their family or personal histories or because they reported recent falls.

The subjects were randomly assigned to receive a single oral dose of vitamin D (cholecalciferol) or a matching placebo at the same time every year for 3-5 years. Lab studies in a subgroup of the subjects showed that the active treatment raised levels of 25-hydroxycholecalciferol an average of 41%, as expected.

There were 5,404 falls during follow-up, involving 74% of the women taking vitamin D and 68% of those taking placebo. The rate of falls was 83 per 100 person-years with vitamin D, compared with 73 per 100 person-years with placebo, a statistically significant difference.

The increase in falls with active treatment was noted in falls that produced fractures and those that didn't, and in falls that produced soft-tissue injury.

A total of 155 women taking vitamin D sustained 171 fractures during follow-up, compared with 125 women taking placebo who sustained 135 fractures. This translates to a rate of 4.9 fractures per 100 person-years with active treatment and 3.9 fractures per 100 person-years with placebo.

These risks of falls and of fractures did not change after the data were adjusted to account for subjects' calcium intake.

“Contrary to our hypothesis, participants receiving annual high-dose oral cholecalciferol experienced 15% more falls and 26% more fractures than [did] the placebo group. Women not only experienced excess fractures after more frequent falls but also experienced more fractures that were not associated with a fall,” the investigators noted (JAMA 2010;303:1815-22).

The reason for these counterproductive effects is not yet known, but it is possible that the once-a-year oral regimen—compared with either a regimen that divides the oral doses or one that uses intramuscular doses—is at fault. “It is reasonable to speculate that high serum levels of vitamin D or metabolites resulting from the large annual dose, subsequent decrease in the levels, or both might be causal,” they wrote.

In an accompanying editorial, Dr. Bess Dawson-Hughes and Susan S. Harris, D.Sc., of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, said that these study findings should not detract from the importance of “correcting widespread vitamin D deficiency and insufficiency.

“There is no evidence for adverse effects of more frequent, lower-dose regimens, so daily, weekly, or monthly dosing with vitamin D₃ appears to be the best option for clinicians at this time,” they noted (JAMA 2010;303:1861-2).

Disclosures: This study was supported by the National Health and Medical Research Council and the Australian Government Department of Health and Ageing. No conflicts of interest were reported by Dr. Sanders and her associates, Dr. Dawson-Hughes, or Dr. Harris.

Far from protecting older women from falls and fractures, yearly high-dose oral vitamin D raised the risk of falls by 15% and that of fractures by 26%, according to an Australian study.

These risks were highest in the 3-month period immediately after each annual dose, said Kerrie M. Sanders, Ph.D., of the University of Melbourne and her associates.

As this study used the “largest total annual dose of vitamin D (500,000 IU) reported in any large randomized controlled trial,” it is possible that these adverse outcomes are related to the dosage, or perhaps to the once-a-year regimen. But the levels of 25-hydroxycholecalciferol achieved in these subjects can also occur with other dosing regimens, so it appears that the safety of all high-dose vitamin D supplementation warrants further examination, they noted.

Dr. Sanders and her colleagues performed their single-center study in 2,256 white women aged at least 70. They were considered at risk for hip fracture because of their family or personal histories or because they reported recent falls.

The subjects were randomly assigned to receive a single oral dose of vitamin D (cholecalciferol) or a matching placebo at the same time every year for 3-5 years. Lab studies in a subgroup of the subjects showed that the active treatment raised levels of 25-hydroxycholecalciferol an average of 41%, as expected.

There were 5,404 falls during follow-up, involving 74% of the women taking vitamin D and 68% of those taking placebo. The rate of falls was 83 per 100 person-years with vitamin D, compared with 73 per 100 person-years with placebo, a statistically significant difference.

The increase in falls with active treatment was noted in falls that produced fractures and those that didn't, and in falls that produced soft-tissue injury.

A total of 155 women taking vitamin D sustained 171 fractures during follow-up, compared with 125 women taking placebo who sustained 135 fractures. This translates to a rate of 4.9 fractures per 100 person-years with active treatment and 3.9 fractures per 100 person-years with placebo.

These risks of falls and of fractures did not change after the data were adjusted to account for subjects' calcium intake.

“Contrary to our hypothesis, participants receiving annual high-dose oral cholecalciferol experienced 15% more falls and 26% more fractures than [did] the placebo group. Women not only experienced excess fractures after more frequent falls but also experienced more fractures that were not associated with a fall,” the investigators noted (JAMA 2010;303:1815-22).

The reason for these counterproductive effects is not yet known, but it is possible that the once-a-year oral regimen—compared with either a regimen that divides the oral doses or one that uses intramuscular doses—is at fault. “It is reasonable to speculate that high serum levels of vitamin D or metabolites resulting from the large annual dose, subsequent decrease in the levels, or both might be causal,” they wrote.

In an accompanying editorial, Dr. Bess Dawson-Hughes and Susan S. Harris, D.Sc., of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, said that these study findings should not detract from the importance of “correcting widespread vitamin D deficiency and insufficiency.

“There is no evidence for adverse effects of more frequent, lower-dose regimens, so daily, weekly, or monthly dosing with vitamin D₃ appears to be the best option for clinicians at this time,” they noted (JAMA 2010;303:1861-2).

Disclosures: This study was supported by the National Health and Medical Research Council and the Australian Government Department of Health and Ageing. No conflicts of interest were reported by Dr. Sanders and her associates, Dr. Dawson-Hughes, or Dr. Harris.

TORONTO — Bone mineral density loss in adolescents receiving depot medroxyprogesterone acetate for contraception was substantially or fully reversible following discontinuation of the drug, based on study results.

In girls who lost more than 5% of bone mineral density (BMD) during treatment, complete recovery was less likely, reported Dr. Zeev Harel, professor of pediatrics at Brown University, Providence, R.I.

The study involved 98 healthy adolescents aged 12-18 who initiated depot medroxyprogesterone acetate (DMPA) intramuscular injections for contraception and provided BMD data for up to 300 weeks after cessation of DMPA. BMD was assessed by dual-energy x-ray absorptiometry (DXA).

At the time of DMPA cessation, participants showed mean BMD declines from baseline at the lumbar spine (2.7%), hip (4.1%), and femoral neck (3.9%). Within 60 weeks of DMPA discontinuation, mean BMD values for the lumbar spine had returned to baseline levels. By 240 weeks, they had increased by 4.7% above baseline. Full recovery of mean BMD was not seen until 240 weeks in the hip and 180 weeks in the femoral neck.

Postcessation gains were smaller in girls who exhibited a 5% or greater BMD loss during treatment; mean BMD remained below baseline at 240 weeks (Contraception 2010;81:281-91).

Pfizer funded the study. Dr. Harel has financial ties with Merck & Co., Teva/Duramed, Ortho-McNeil, GlaxoSmithKline, Novartis, and Warner Chilcott.

TORONTO — Bone mineral density loss in adolescents receiving depot medroxyprogesterone acetate for contraception was substantially or fully reversible following discontinuation of the drug, based on study results.

In girls who lost more than 5% of bone mineral density (BMD) during treatment, complete recovery was less likely, reported Dr. Zeev Harel, professor of pediatrics at Brown University, Providence, R.I.

The study involved 98 healthy adolescents aged 12-18 who initiated depot medroxyprogesterone acetate (DMPA) intramuscular injections for contraception and provided BMD data for up to 300 weeks after cessation of DMPA. BMD was assessed by dual-energy x-ray absorptiometry (DXA).

At the time of DMPA cessation, participants showed mean BMD declines from baseline at the lumbar spine (2.7%), hip (4.1%), and femoral neck (3.9%). Within 60 weeks of DMPA discontinuation, mean BMD values for the lumbar spine had returned to baseline levels. By 240 weeks, they had increased by 4.7% above baseline. Full recovery of mean BMD was not seen until 240 weeks in the hip and 180 weeks in the femoral neck.

Postcessation gains were smaller in girls who exhibited a 5% or greater BMD loss during treatment; mean BMD remained below baseline at 240 weeks (Contraception 2010;81:281-91).

Pfizer funded the study. Dr. Harel has financial ties with Merck & Co., Teva/Duramed, Ortho-McNeil, GlaxoSmithKline, Novartis, and Warner Chilcott.

TORONTO — Bone mineral density loss in adolescents receiving depot medroxyprogesterone acetate for contraception was substantially or fully reversible following discontinuation of the drug, based on study results.

In girls who lost more than 5% of bone mineral density (BMD) during treatment, complete recovery was less likely, reported Dr. Zeev Harel, professor of pediatrics at Brown University, Providence, R.I.

The study involved 98 healthy adolescents aged 12-18 who initiated depot medroxyprogesterone acetate (DMPA) intramuscular injections for contraception and provided BMD data for up to 300 weeks after cessation of DMPA. BMD was assessed by dual-energy x-ray absorptiometry (DXA).

At the time of DMPA cessation, participants showed mean BMD declines from baseline at the lumbar spine (2.7%), hip (4.1%), and femoral neck (3.9%). Within 60 weeks of DMPA discontinuation, mean BMD values for the lumbar spine had returned to baseline levels. By 240 weeks, they had increased by 4.7% above baseline. Full recovery of mean BMD was not seen until 240 weeks in the hip and 180 weeks in the femoral neck.

Postcessation gains were smaller in girls who exhibited a 5% or greater BMD loss during treatment; mean BMD remained below baseline at 240 weeks (Contraception 2010;81:281-91).

Pfizer funded the study. Dr. Harel has financial ties with Merck & Co., Teva/Duramed, Ortho-McNeil, GlaxoSmithKline, Novartis, and Warner Chilcott.

Treatment with vitamin A analogues such as isotretinoin and acitretin does not increase fracture risk, according to findings from a nationwide Danish case-control study.

Of all fractures sustained in a single year, no form of systemic or topical vitamin A analogues was associated with fracture risk at any skeletal site, said Dr. Peter Vestergaard and his associates at Aarhus (Denmark) University Hospital.

Previous research has yielded conflicting results. Some studies have found that high-dose therapy is related to an increased risk of fracture and adverse bone changes, including hyperostosis, hypercalcemia, impaired bone turnover, and decreased bone mineral density, while other studies have found no such association.

The results of this large population-based study show that “even very large daily doses of 14 mg of vitamin A analogues (equivalent to 14,000 micrograms of retinol equivalents per day) were not associated with an increased risk of fractures. It thus seems that vitamin A analogues are safe in terms of fractures, even at very high doses,” Dr. Vestergaard and his colleagues wrote (Arch. Dermatol. 2010;146:478-82).

They used data from 124,655 cases of fracture that occurred in 2000 and 373,962 control cases matched for age and sex. The data were adjusted to account for the severity of the underlying disease requiring treatment with vitamin A analogues, as well as for the concomitant use of drugs known to affect fracture risk, such as corticosteroids and antiepileptic agents.

There was no association between any form of vitamin A analogue and fracture risk at any site. Moreover, no trend was found between increasing dose or increasing duration of treatment and any fracture risk, the investigators reported.

There also was no association with fracture risk when the use of individual vitamin A analogues was analyzed.

“Even though some studies have reported a decreased BMD with high doses of vitamin A as retinol in dietary intake or as supplements, the decrease may not have been of such magnitude that it altered bone biomechanical competence,” Dr. Vestergaard and his associates noted.

In an editorial accompanying the report, Dr. John J. DiGiovanna of Brown University, Providence, noted that these results are particularly reassuring because the investigators examined “a large population of humans treated under real therapeutic conditions” and because the end point (fracture) was clinically important.

The main weakness of the study was that it could not completely account for potentially confounding factors such as smoking habits, body mass index, vitamin D status, and sun exposure, he wrote (Arch. Dermatol. 2010; 146:551-3).

“While it is reassuring to see this evidence of retinoid drug safety in relation to bone demineralization in a large population, the treatment of patients must rely on personalized prescription. Sound measures for good skeletal health, including adequate nutrition (especially vitamin D and calcium, etc.) and healthy physical activity, should be encouraged.

“Monitoring may be indicated for individuals with a family or personal history of osteoporosis, advanced age, and exposure to agents known to cause demineralization, and possibly those requiring long-term or high-dose retinoid drug therapy,” Dr. DiGiovanna added.

This study was supported by the Danish Medical Research Council. Dr. Vestergaard reported receiving support from Servier, Bayer Pharmaceuticals, Eli Lilly and Company, Novartis, and Sanofi-Aventis. Dr. DiGiovanna reported receiving support from Basilea, Hoffman La Roche, Allergan, and Cipher Pharmaceuticals.

Treatment with vitamin A analogues such as isotretinoin and acitretin does not increase fracture risk, according to findings from a nationwide Danish case-control study.

Of all fractures sustained in a single year, no form of systemic or topical vitamin A analogues was associated with fracture risk at any skeletal site, said Dr. Peter Vestergaard and his associates at Aarhus (Denmark) University Hospital.

Previous research has yielded conflicting results. Some studies have found that high-dose therapy is related to an increased risk of fracture and adverse bone changes, including hyperostosis, hypercalcemia, impaired bone turnover, and decreased bone mineral density, while other studies have found no such association.

The results of this large population-based study show that “even very large daily doses of 14 mg of vitamin A analogues (equivalent to 14,000 micrograms of retinol equivalents per day) were not associated with an increased risk of fractures. It thus seems that vitamin A analogues are safe in terms of fractures, even at very high doses,” Dr. Vestergaard and his colleagues wrote (Arch. Dermatol. 2010;146:478-82).

They used data from 124,655 cases of fracture that occurred in 2000 and 373,962 control cases matched for age and sex. The data were adjusted to account for the severity of the underlying disease requiring treatment with vitamin A analogues, as well as for the concomitant use of drugs known to affect fracture risk, such as corticosteroids and antiepileptic agents.

There was no association between any form of vitamin A analogue and fracture risk at any site. Moreover, no trend was found between increasing dose or increasing duration of treatment and any fracture risk, the investigators reported.

There also was no association with fracture risk when the use of individual vitamin A analogues was analyzed.

“Even though some studies have reported a decreased BMD with high doses of vitamin A as retinol in dietary intake or as supplements, the decrease may not have been of such magnitude that it altered bone biomechanical competence,” Dr. Vestergaard and his associates noted.

In an editorial accompanying the report, Dr. John J. DiGiovanna of Brown University, Providence, noted that these results are particularly reassuring because the investigators examined “a large population of humans treated under real therapeutic conditions” and because the end point (fracture) was clinically important.

The main weakness of the study was that it could not completely account for potentially confounding factors such as smoking habits, body mass index, vitamin D status, and sun exposure, he wrote (Arch. Dermatol. 2010; 146:551-3).

“While it is reassuring to see this evidence of retinoid drug safety in relation to bone demineralization in a large population, the treatment of patients must rely on personalized prescription. Sound measures for good skeletal health, including adequate nutrition (especially vitamin D and calcium, etc.) and healthy physical activity, should be encouraged.

“Monitoring may be indicated for individuals with a family or personal history of osteoporosis, advanced age, and exposure to agents known to cause demineralization, and possibly those requiring long-term or high-dose retinoid drug therapy,” Dr. DiGiovanna added.

This study was supported by the Danish Medical Research Council. Dr. Vestergaard reported receiving support from Servier, Bayer Pharmaceuticals, Eli Lilly and Company, Novartis, and Sanofi-Aventis. Dr. DiGiovanna reported receiving support from Basilea, Hoffman La Roche, Allergan, and Cipher Pharmaceuticals.

Treatment with vitamin A analogues such as isotretinoin and acitretin does not increase fracture risk, according to findings from a nationwide Danish case-control study.

Of all fractures sustained in a single year, no form of systemic or topical vitamin A analogues was associated with fracture risk at any skeletal site, said Dr. Peter Vestergaard and his associates at Aarhus (Denmark) University Hospital.

Previous research has yielded conflicting results. Some studies have found that high-dose therapy is related to an increased risk of fracture and adverse bone changes, including hyperostosis, hypercalcemia, impaired bone turnover, and decreased bone mineral density, while other studies have found no such association.

The results of this large population-based study show that “even very large daily doses of 14 mg of vitamin A analogues (equivalent to 14,000 micrograms of retinol equivalents per day) were not associated with an increased risk of fractures. It thus seems that vitamin A analogues are safe in terms of fractures, even at very high doses,” Dr. Vestergaard and his colleagues wrote (Arch. Dermatol. 2010;146:478-82).

They used data from 124,655 cases of fracture that occurred in 2000 and 373,962 control cases matched for age and sex. The data were adjusted to account for the severity of the underlying disease requiring treatment with vitamin A analogues, as well as for the concomitant use of drugs known to affect fracture risk, such as corticosteroids and antiepileptic agents.

There was no association between any form of vitamin A analogue and fracture risk at any site. Moreover, no trend was found between increasing dose or increasing duration of treatment and any fracture risk, the investigators reported.

There also was no association with fracture risk when the use of individual vitamin A analogues was analyzed.

“Even though some studies have reported a decreased BMD with high doses of vitamin A as retinol in dietary intake or as supplements, the decrease may not have been of such magnitude that it altered bone biomechanical competence,” Dr. Vestergaard and his associates noted.

In an editorial accompanying the report, Dr. John J. DiGiovanna of Brown University, Providence, noted that these results are particularly reassuring because the investigators examined “a large population of humans treated under real therapeutic conditions” and because the end point (fracture) was clinically important.

The main weakness of the study was that it could not completely account for potentially confounding factors such as smoking habits, body mass index, vitamin D status, and sun exposure, he wrote (Arch. Dermatol. 2010; 146:551-3).

“While it is reassuring to see this evidence of retinoid drug safety in relation to bone demineralization in a large population, the treatment of patients must rely on personalized prescription. Sound measures for good skeletal health, including adequate nutrition (especially vitamin D and calcium, etc.) and healthy physical activity, should be encouraged.

“Monitoring may be indicated for individuals with a family or personal history of osteoporosis, advanced age, and exposure to agents known to cause demineralization, and possibly those requiring long-term or high-dose retinoid drug therapy,” Dr. DiGiovanna added.

This study was supported by the Danish Medical Research Council. Dr. Vestergaard reported receiving support from Servier, Bayer Pharmaceuticals, Eli Lilly and Company, Novartis, and Sanofi-Aventis. Dr. DiGiovanna reported receiving support from Basilea, Hoffman La Roche, Allergan, and Cipher Pharmaceuticals.

The use of proton pump inhibitors does not appear to raise the risk of hip fracture in postmenopausal women but may raise the risk of spine, forearm, wrist, and total fractures modestly.

Several large epidemiologic studies have suggested that PPI use may be associated with an increased risk for osteoporotic fractures, but other studies have found no such link. Shelly L. Gray, Pharm.D., and her associates examined the issue using data from the Women's Health Initiative, a large study of an ethnically diverse cohort of postmenopausal women followed at 40 U.S. medical centers for a mean of 7.8 years.

For this analysis, data on 161,806 women aged 50-79 years were included. A total of 3,396 (2%) of these study subjects were taking omeprazole or lansoprazole at baseline.

Women who took PPIs were more likely than those who did not to have osteoporosis or a history of fractures, obesity, treated diabetes, or a history of several health conditions; to take other medications chronically; and to have poorer self-reported health and physical function. “We did our best to adjust for these baseline differences, but, like all observational studies, residual or unmeasured confounding could explain increased associations for some fracture types,” said Dr. Gray of the University of Washington School of Pharmacy, Seattle, and her colleagues.

During more than a million person-years of follow-up, there were 1,500 hip fractures, 4,881 forearm or wrist fractures, 2,315 clinical spine fractures, and 21,247 total fractures.

After the data were adjusted to account for possible confounding factors, PPI use was not related to hip fracture risk. There also was no association between hip fracture risk and longer duration of PPI use, Dr. Gray and her associates reported (Arch. Intern. Med. 2010;170:765-71).

In addition, there were no differences between women who used PPIs and women who didn't in the change in bone mineral density over time. Similarly, there was no consistent relationship between duration of PPI use and risk of any fracture.

However, the drugs raised the relative risk of clinical spine fracture by 47% (hazard ratio, 1.47); the relative risk of forearm or wrist fracture by 26% (HR, 1.26); and the relative risk of total fractures by 25% (HR, 1.25).

Although these findings leave many questions unresolved, “based on the accumulation of evidence, it is prudent for clinicians to periodically reevaluate the need for long-term PPI therapy,” the investigators said.

For older patients who do require the treatment, “it is reasonable to focus on using the lowest effective dose, ensuring adequate dietary calcium intake, and adding calcium supplements when necessary,” they added.

In an editorial comment accompanying this report, Dr. Mitchell H. Katz of the San Francisco Department of Public Health characterized the increases in nonhip fractures as “modest” but said that PPIs are so widely used that those modest increases “add up to a lot of morbidity on a population level” (Arch. Intern. Med. 2010;170:747-8).

“We should offer treatments other than PPIs for functional dyspepsia, prescribe short courses of PPI treatment (after disclosure of possible risks and benefits), and consider a trial of discontinuing PPI therapy in patients who are asymptomatic.

“Once our patients fully appreciate the adverse effects of PPIs, they themselves may prefer other treatments, including tincture of time”; behavioral changes such as eating smaller meals, losing weight, quitting smoking, and reducing stress; and nonmedical interventions such as raising the head of the bed, Dr. Katz said.

The WHI Program was funded by the National Heart, Lung, and Blood Institute.

Dr. Gray reported no financial conflicts of interest. Her associate, Andrea Z. LaCroix, Ph.D., reported ties to Pfizer Inc., Procter & Gamble Co., and Sanofi-Aventis. Dr. Katz is an independent consultant for Health Management Associates.

The use of proton pump inhibitors does not appear to raise the risk of hip fracture in postmenopausal women but may raise the risk of spine, forearm, wrist, and total fractures modestly.

Several large epidemiologic studies have suggested that PPI use may be associated with an increased risk for osteoporotic fractures, but other studies have found no such link. Shelly L. Gray, Pharm.D., and her associates examined the issue using data from the Women's Health Initiative, a large study of an ethnically diverse cohort of postmenopausal women followed at 40 U.S. medical centers for a mean of 7.8 years.

For this analysis, data on 161,806 women aged 50-79 years were included. A total of 3,396 (2%) of these study subjects were taking omeprazole or lansoprazole at baseline.

Women who took PPIs were more likely than those who did not to have osteoporosis or a history of fractures, obesity, treated diabetes, or a history of several health conditions; to take other medications chronically; and to have poorer self-reported health and physical function. “We did our best to adjust for these baseline differences, but, like all observational studies, residual or unmeasured confounding could explain increased associations for some fracture types,” said Dr. Gray of the University of Washington School of Pharmacy, Seattle, and her colleagues.

During more than a million person-years of follow-up, there were 1,500 hip fractures, 4,881 forearm or wrist fractures, 2,315 clinical spine fractures, and 21,247 total fractures.

After the data were adjusted to account for possible confounding factors, PPI use was not related to hip fracture risk. There also was no association between hip fracture risk and longer duration of PPI use, Dr. Gray and her associates reported (Arch. Intern. Med. 2010;170:765-71).

In addition, there were no differences between women who used PPIs and women who didn't in the change in bone mineral density over time. Similarly, there was no consistent relationship between duration of PPI use and risk of any fracture.

However, the drugs raised the relative risk of clinical spine fracture by 47% (hazard ratio, 1.47); the relative risk of forearm or wrist fracture by 26% (HR, 1.26); and the relative risk of total fractures by 25% (HR, 1.25).

Although these findings leave many questions unresolved, “based on the accumulation of evidence, it is prudent for clinicians to periodically reevaluate the need for long-term PPI therapy,” the investigators said.

For older patients who do require the treatment, “it is reasonable to focus on using the lowest effective dose, ensuring adequate dietary calcium intake, and adding calcium supplements when necessary,” they added.

In an editorial comment accompanying this report, Dr. Mitchell H. Katz of the San Francisco Department of Public Health characterized the increases in nonhip fractures as “modest” but said that PPIs are so widely used that those modest increases “add up to a lot of morbidity on a population level” (Arch. Intern. Med. 2010;170:747-8).

“We should offer treatments other than PPIs for functional dyspepsia, prescribe short courses of PPI treatment (after disclosure of possible risks and benefits), and consider a trial of discontinuing PPI therapy in patients who are asymptomatic.

“Once our patients fully appreciate the adverse effects of PPIs, they themselves may prefer other treatments, including tincture of time”; behavioral changes such as eating smaller meals, losing weight, quitting smoking, and reducing stress; and nonmedical interventions such as raising the head of the bed, Dr. Katz said.

The WHI Program was funded by the National Heart, Lung, and Blood Institute.

Dr. Gray reported no financial conflicts of interest. Her associate, Andrea Z. LaCroix, Ph.D., reported ties to Pfizer Inc., Procter & Gamble Co., and Sanofi-Aventis. Dr. Katz is an independent consultant for Health Management Associates.

The use of proton pump inhibitors does not appear to raise the risk of hip fracture in postmenopausal women but may raise the risk of spine, forearm, wrist, and total fractures modestly.

Several large epidemiologic studies have suggested that PPI use may be associated with an increased risk for osteoporotic fractures, but other studies have found no such link. Shelly L. Gray, Pharm.D., and her associates examined the issue using data from the Women's Health Initiative, a large study of an ethnically diverse cohort of postmenopausal women followed at 40 U.S. medical centers for a mean of 7.8 years.

For this analysis, data on 161,806 women aged 50-79 years were included. A total of 3,396 (2%) of these study subjects were taking omeprazole or lansoprazole at baseline.

Women who took PPIs were more likely than those who did not to have osteoporosis or a history of fractures, obesity, treated diabetes, or a history of several health conditions; to take other medications chronically; and to have poorer self-reported health and physical function. “We did our best to adjust for these baseline differences, but, like all observational studies, residual or unmeasured confounding could explain increased associations for some fracture types,” said Dr. Gray of the University of Washington School of Pharmacy, Seattle, and her colleagues.

During more than a million person-years of follow-up, there were 1,500 hip fractures, 4,881 forearm or wrist fractures, 2,315 clinical spine fractures, and 21,247 total fractures.

After the data were adjusted to account for possible confounding factors, PPI use was not related to hip fracture risk. There also was no association between hip fracture risk and longer duration of PPI use, Dr. Gray and her associates reported (Arch. Intern. Med. 2010;170:765-71).

In addition, there were no differences between women who used PPIs and women who didn't in the change in bone mineral density over time. Similarly, there was no consistent relationship between duration of PPI use and risk of any fracture.

However, the drugs raised the relative risk of clinical spine fracture by 47% (hazard ratio, 1.47); the relative risk of forearm or wrist fracture by 26% (HR, 1.26); and the relative risk of total fractures by 25% (HR, 1.25).

Although these findings leave many questions unresolved, “based on the accumulation of evidence, it is prudent for clinicians to periodically reevaluate the need for long-term PPI therapy,” the investigators said.

For older patients who do require the treatment, “it is reasonable to focus on using the lowest effective dose, ensuring adequate dietary calcium intake, and adding calcium supplements when necessary,” they added.

In an editorial comment accompanying this report, Dr. Mitchell H. Katz of the San Francisco Department of Public Health characterized the increases in nonhip fractures as “modest” but said that PPIs are so widely used that those modest increases “add up to a lot of morbidity on a population level” (Arch. Intern. Med. 2010;170:747-8).

“We should offer treatments other than PPIs for functional dyspepsia, prescribe short courses of PPI treatment (after disclosure of possible risks and benefits), and consider a trial of discontinuing PPI therapy in patients who are asymptomatic.

“Once our patients fully appreciate the adverse effects of PPIs, they themselves may prefer other treatments, including tincture of time”; behavioral changes such as eating smaller meals, losing weight, quitting smoking, and reducing stress; and nonmedical interventions such as raising the head of the bed, Dr. Katz said.

The WHI Program was funded by the National Heart, Lung, and Blood Institute.

Dr. Gray reported no financial conflicts of interest. Her associate, Andrea Z. LaCroix, Ph.D., reported ties to Pfizer Inc., Procter & Gamble Co., and Sanofi-Aventis. Dr. Katz is an independent consultant for Health Management Associates.

Major Finding: In a substudy of 15 adolescent girls with significant bone loss while using depot medroxyprogesterone acetate, only 1 participant had a “sufficient” serum vitamin D level of greater than 30 ng/mL.

Data Source: Subset of a prospective study of 181 adolescent girls on depot medroxyprogesterone acetate.

Disclosures: The study was sponsored by Pfizer/Pharmacia, and one of the investigators was employed by that company. Dr. Harel disclosed financial relationships with Merck, Teva/Duramed, Ortho-McNeil, GlaxoSmithKline, Novartis, and Warner Chilcott.

LAS VEGAS — Abnormally low levels of vitamin D were seen in a subset of 15 adolescent girls who had substantial losses in bone mineral density while using depot medroxyprogesterone acetate for contraception, according to preliminary results from a prospective study presented at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology.

The girls were among 181 adolescents using depot medroxyprogesterone acetate (Depo-Provera, Pfizer) in a prospective study. Bone mineral density (BMD) losses of 5% or more were seen at the lumbar spine in 25% and at the hip in 50% of the study participants.

The relative estrogen deficiency associated with depot medroxyprogesterone acetate (DMPA) did not correlate with the magnitude of BMD loss, according to Dr. Zeev Harel of Brown University in Providence, R.I.

Moreover, serum estradiol remained above 40–50 pg/mL in almost all participants, Dr. Harel said. This level is considered to be sufficient to conserve bone in elderly women.

Dr. Harel and his colleagues examined a subset of 15 young women who lost at least 5% of BMD from baseline. Their average age was 17 years, and they were an average of 61 months post menarche. Body mass index was within the normal range, and none of the women was obese. Their ethnicity was diverse and they resided in various U.S. locations.

Investigators noted BMD losses in the majority of the 15 girls after two or three DMPA injections, but some participants did not exhibit BMD losses until after their 10th or 13th injection.

Serum 25-hydroxyvitamin D (25[OH]D) levels were available for 14 of the 15 girls, and all but 1 had low levels of vitamin D. Levels above 30 ng/mL are considered sufficient, levels between 20 and 30 ng/mL are referred to as “insufficient,” and levels below 20 ng/mL are referred to as “deficient.” Seven of the 14 participants (50%) were vitamin D insufficient, 6 (43%) were vitamin D deficient, and 1 (7%) had normal levels of vitamin D.

The mean serum 25(OH)D level among the participants was about 25 ng/mL, in the insufficient range. Mean levels of parathyroid hormone, on the other hand, were in the normal range.

In an interview, Dr. Harel expressed surprise at these results. “I was expecting probably less than 30% [of the participants would have low levels of vitamin D],” he said “We were surprised specifically because when we drew the blood we did it at the end of the summer. Typically we absorb vitamin D from the sun. Also, most of the patients were [white]. We know that vitamin D deficiency is common in African Americans and Hispanics. Also, they were not extremely obese. We know we can find vitamin D deficiency in obesity. And we also had representatives from states that were really sunny, California for example.”

Dr. Harel emphasized that the results were preliminary. Additional studies would require a comparison group of young women on depot medroxyprogesterone acetate who did not experience declines in BMD. And he said that it would be important to study whether vitamin D supplementation would reverse the decline in BMD.

Still, Dr. Harel found results sufficiently worrisome to recommend close monitoring of young women on depot medroxyprogesterone acetate. “We know in the adult elderly population that many are aware of their vitamin D status. In adolescents still we are in the beginning,” he said.

He recommended that total 25(OH)D status be measured in all adolescent girls using depot medroxyprogesterone acetate.

“And if it's low—deficient or insufficient—treat it accordingly. The current recommendation if we have a patient with vitamin D deficiency is to take 50,000 IU once a week for 8 weeks and then repeat the total 25(OH)D. Those who have insufficient vitamin D, we typically treat with 800 IU of vitamin D a day and we do it for 3 months, and then again we repeat the total 25(OH)D,” he said.

The results were surprising, given that the cohort comprised mostly white, nonobese women who had sun exposure.

Source DR. HAREL

Major Finding: In a substudy of 15 adolescent girls with significant bone loss while using depot medroxyprogesterone acetate, only 1 participant had a “sufficient” serum vitamin D level of greater than 30 ng/mL.

Data Source: Subset of a prospective study of 181 adolescent girls on depot medroxyprogesterone acetate.

Disclosures: The study was sponsored by Pfizer/Pharmacia, and one of the investigators was employed by that company. Dr. Harel disclosed financial relationships with Merck, Teva/Duramed, Ortho-McNeil, GlaxoSmithKline, Novartis, and Warner Chilcott.

LAS VEGAS — Abnormally low levels of vitamin D were seen in a subset of 15 adolescent girls who had substantial losses in bone mineral density while using depot medroxyprogesterone acetate for contraception, according to preliminary results from a prospective study presented at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology.

The girls were among 181 adolescents using depot medroxyprogesterone acetate (Depo-Provera, Pfizer) in a prospective study. Bone mineral density (BMD) losses of 5% or more were seen at the lumbar spine in 25% and at the hip in 50% of the study participants.

The relative estrogen deficiency associated with depot medroxyprogesterone acetate (DMPA) did not correlate with the magnitude of BMD loss, according to Dr. Zeev Harel of Brown University in Providence, R.I.

Moreover, serum estradiol remained above 40–50 pg/mL in almost all participants, Dr. Harel said. This level is considered to be sufficient to conserve bone in elderly women.

Dr. Harel and his colleagues examined a subset of 15 young women who lost at least 5% of BMD from baseline. Their average age was 17 years, and they were an average of 61 months post menarche. Body mass index was within the normal range, and none of the women was obese. Their ethnicity was diverse and they resided in various U.S. locations.

Investigators noted BMD losses in the majority of the 15 girls after two or three DMPA injections, but some participants did not exhibit BMD losses until after their 10th or 13th injection.

Serum 25-hydroxyvitamin D (25[OH]D) levels were available for 14 of the 15 girls, and all but 1 had low levels of vitamin D. Levels above 30 ng/mL are considered sufficient, levels between 20 and 30 ng/mL are referred to as “insufficient,” and levels below 20 ng/mL are referred to as “deficient.” Seven of the 14 participants (50%) were vitamin D insufficient, 6 (43%) were vitamin D deficient, and 1 (7%) had normal levels of vitamin D.

The mean serum 25(OH)D level among the participants was about 25 ng/mL, in the insufficient range. Mean levels of parathyroid hormone, on the other hand, were in the normal range.

In an interview, Dr. Harel expressed surprise at these results. “I was expecting probably less than 30% [of the participants would have low levels of vitamin D],” he said “We were surprised specifically because when we drew the blood we did it at the end of the summer. Typically we absorb vitamin D from the sun. Also, most of the patients were [white]. We know that vitamin D deficiency is common in African Americans and Hispanics. Also, they were not extremely obese. We know we can find vitamin D deficiency in obesity. And we also had representatives from states that were really sunny, California for example.”

Dr. Harel emphasized that the results were preliminary. Additional studies would require a comparison group of young women on depot medroxyprogesterone acetate who did not experience declines in BMD. And he said that it would be important to study whether vitamin D supplementation would reverse the decline in BMD.

Still, Dr. Harel found results sufficiently worrisome to recommend close monitoring of young women on depot medroxyprogesterone acetate. “We know in the adult elderly population that many are aware of their vitamin D status. In adolescents still we are in the beginning,” he said.

He recommended that total 25(OH)D status be measured in all adolescent girls using depot medroxyprogesterone acetate.

“And if it's low—deficient or insufficient—treat it accordingly. The current recommendation if we have a patient with vitamin D deficiency is to take 50,000 IU once a week for 8 weeks and then repeat the total 25(OH)D. Those who have insufficient vitamin D, we typically treat with 800 IU of vitamin D a day and we do it for 3 months, and then again we repeat the total 25(OH)D,” he said.

The results were surprising, given that the cohort comprised mostly white, nonobese women who had sun exposure.

Source DR. HAREL

Major Finding: In a substudy of 15 adolescent girls with significant bone loss while using depot medroxyprogesterone acetate, only 1 participant had a “sufficient” serum vitamin D level of greater than 30 ng/mL.

Data Source: Subset of a prospective study of 181 adolescent girls on depot medroxyprogesterone acetate.

Disclosures: The study was sponsored by Pfizer/Pharmacia, and one of the investigators was employed by that company. Dr. Harel disclosed financial relationships with Merck, Teva/Duramed, Ortho-McNeil, GlaxoSmithKline, Novartis, and Warner Chilcott.

LAS VEGAS — Abnormally low levels of vitamin D were seen in a subset of 15 adolescent girls who had substantial losses in bone mineral density while using depot medroxyprogesterone acetate for contraception, according to preliminary results from a prospective study presented at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology.

The girls were among 181 adolescents using depot medroxyprogesterone acetate (Depo-Provera, Pfizer) in a prospective study. Bone mineral density (BMD) losses of 5% or more were seen at the lumbar spine in 25% and at the hip in 50% of the study participants.

The relative estrogen deficiency associated with depot medroxyprogesterone acetate (DMPA) did not correlate with the magnitude of BMD loss, according to Dr. Zeev Harel of Brown University in Providence, R.I.

Moreover, serum estradiol remained above 40–50 pg/mL in almost all participants, Dr. Harel said. This level is considered to be sufficient to conserve bone in elderly women.

Dr. Harel and his colleagues examined a subset of 15 young women who lost at least 5% of BMD from baseline. Their average age was 17 years, and they were an average of 61 months post menarche. Body mass index was within the normal range, and none of the women was obese. Their ethnicity was diverse and they resided in various U.S. locations.

Investigators noted BMD losses in the majority of the 15 girls after two or three DMPA injections, but some participants did not exhibit BMD losses until after their 10th or 13th injection.

Serum 25-hydroxyvitamin D (25[OH]D) levels were available for 14 of the 15 girls, and all but 1 had low levels of vitamin D. Levels above 30 ng/mL are considered sufficient, levels between 20 and 30 ng/mL are referred to as “insufficient,” and levels below 20 ng/mL are referred to as “deficient.” Seven of the 14 participants (50%) were vitamin D insufficient, 6 (43%) were vitamin D deficient, and 1 (7%) had normal levels of vitamin D.

The mean serum 25(OH)D level among the participants was about 25 ng/mL, in the insufficient range. Mean levels of parathyroid hormone, on the other hand, were in the normal range.

In an interview, Dr. Harel expressed surprise at these results. “I was expecting probably less than 30% [of the participants would have low levels of vitamin D],” he said “We were surprised specifically because when we drew the blood we did it at the end of the summer. Typically we absorb vitamin D from the sun. Also, most of the patients were [white]. We know that vitamin D deficiency is common in African Americans and Hispanics. Also, they were not extremely obese. We know we can find vitamin D deficiency in obesity. And we also had representatives from states that were really sunny, California for example.”

Dr. Harel emphasized that the results were preliminary. Additional studies would require a comparison group of young women on depot medroxyprogesterone acetate who did not experience declines in BMD. And he said that it would be important to study whether vitamin D supplementation would reverse the decline in BMD.

Still, Dr. Harel found results sufficiently worrisome to recommend close monitoring of young women on depot medroxyprogesterone acetate. “We know in the adult elderly population that many are aware of their vitamin D status. In adolescents still we are in the beginning,” he said.

He recommended that total 25(OH)D status be measured in all adolescent girls using depot medroxyprogesterone acetate.

“And if it's low—deficient or insufficient—treat it accordingly. The current recommendation if we have a patient with vitamin D deficiency is to take 50,000 IU once a week for 8 weeks and then repeat the total 25(OH)D. Those who have insufficient vitamin D, we typically treat with 800 IU of vitamin D a day and we do it for 3 months, and then again we repeat the total 25(OH)D,” he said.

The results were surprising, given that the cohort comprised mostly white, nonobese women who had sun exposure.

Source DR. HAREL

Major Finding: The prevalence of aortic valve ring stenosis was 38% in women aged 65 years and older who took nitrogen-containing bisphosphonates, vs. 59% in women who didn't take bisphosphonates.

Data Source: A cross-sectional study of 3,710 women aged 45–84 years.

Disclosures: Dr. Elmariah has received grant support from the New York Academy of Medicine; the National Heart, Lung, and Blood Institute; and GlaxoSmithKline.

WASHINGTON — Nitrogen-containing bisphosphonates were associated with a significantly decreased prevalence of cardiovascular calcification in women older than 65 years, based on data from 3,710 women who are part of a large, ongoing study.

“Early on in the analysis, we came across a very unexpected finding,” said Dr. Sammy Elmariah of Mount Sinai School of Medicine in New York. “The association with bisphosphonate use was dependent on the patient's age.”

The data were taken from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal cohort study of 6,814 asymptomatic men and women aged 45–84 years.

Overall, the bisphosphonate users were more likely to be older and white. In the current study, Dr. Elmariah and his colleagues examined the impact of bisphosphonates on cardiovascular calcification in women.

Clinical studies have shown that bisphosphonates have an effect on serum lipids, Dr. Elmariah said. Some experimental data, including data from animal models and dialysis patients, suggest that nitrogen-containing bisphosphonates (NCBPs) may limit cardiovascular calcification. In addition, the results of one recent study showed that patients on bisphosphonates for osteoporosis had a slower progression of aortic stenosis, he noted.

The prevalence of aortic valve ring stenosis was 38% in women aged 65 years and older who used NCBPs, which was significantly lower than in non-NCBP users of the same age (59%). Aortic valve ring stenosis prevalence also was 38% in women younger than 65 years who used NCBPs; it was significantly lower at 17% among similarly aged non-NCBP users.

Significant patterns also were seen for stenosis of the thoracic aorta and mitral annulus. The relationship between bisphosphonate use and the decrease in cardiovascular calcification in the 65-years-and-older group did not reach statistical significance for the prevalence of aortic valve stenosis and coronary artery stenosis, but the trends were similar.

This study is the first evaluation of the relationship between bisphosphonate use and the prevalence of cardiovascular calcification in a healthy patient population, Dr. Elmariah said.

Cardiovascular calcification was measured using cardiac CT. Bisphosphate use was defined as use of either oral or intravenous bisphosphonates at the time of the cardiac CT. The average age of the NCBP users was 67 years, and the average age of the nonusers was 62 years. Approximately 60% of the women were white.

After adjustment for variables including age, body mass index, diabetes, hypertension, smoking, race, insurance status, education, and income level, the significance remained, Dr. Elmariah said.

“We get a fairly dramatic reduction in the prevalence of cardiovascular calcification in bisphosphonate users over the age of 65,” he added.

When the researchers divided the study population into 10-year age groups, they saw a gradual reduction in cardiovascular calcification with increasing age, he noted.

The study was limited by its cross-sectional design and by the lack of data on the duration of bisphosphonate use. “It's unclear whether this finding is due to true age-related differences in the pathogenesis of cardiovascular calcification or in the effect of bisphosphonates,” said Dr. Elmariah. But the results merit additional studies to tease out the reason for the age-related impact of bisphosphonates on cardiovascular calcification in women, he said.

NCBPs significantly cut cardiovascular calcification in women over 65, said Dr. Sammy Elmariah.

Source Courtesy Dr. Sammy Elmariah

Major Finding: The prevalence of aortic valve ring stenosis was 38% in women aged 65 years and older who took nitrogen-containing bisphosphonates, vs. 59% in women who didn't take bisphosphonates.

Data Source: A cross-sectional study of 3,710 women aged 45–84 years.

Disclosures: Dr. Elmariah has received grant support from the New York Academy of Medicine; the National Heart, Lung, and Blood Institute; and GlaxoSmithKline.

WASHINGTON — Nitrogen-containing bisphosphonates were associated with a significantly decreased prevalence of cardiovascular calcification in women older than 65 years, based on data from 3,710 women who are part of a large, ongoing study.

“Early on in the analysis, we came across a very unexpected finding,” said Dr. Sammy Elmariah of Mount Sinai School of Medicine in New York. “The association with bisphosphonate use was dependent on the patient's age.”

The data were taken from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal cohort study of 6,814 asymptomatic men and women aged 45–84 years.

Overall, the bisphosphonate users were more likely to be older and white. In the current study, Dr. Elmariah and his colleagues examined the impact of bisphosphonates on cardiovascular calcification in women.

Clinical studies have shown that bisphosphonates have an effect on serum lipids, Dr. Elmariah said. Some experimental data, including data from animal models and dialysis patients, suggest that nitrogen-containing bisphosphonates (NCBPs) may limit cardiovascular calcification. In addition, the results of one recent study showed that patients on bisphosphonates for osteoporosis had a slower progression of aortic stenosis, he noted.

The prevalence of aortic valve ring stenosis was 38% in women aged 65 years and older who used NCBPs, which was significantly lower than in non-NCBP users of the same age (59%). Aortic valve ring stenosis prevalence also was 38% in women younger than 65 years who used NCBPs; it was significantly lower at 17% among similarly aged non-NCBP users.

Significant patterns also were seen for stenosis of the thoracic aorta and mitral annulus. The relationship between bisphosphonate use and the decrease in cardiovascular calcification in the 65-years-and-older group did not reach statistical significance for the prevalence of aortic valve stenosis and coronary artery stenosis, but the trends were similar.

This study is the first evaluation of the relationship between bisphosphonate use and the prevalence of cardiovascular calcification in a healthy patient population, Dr. Elmariah said.

Cardiovascular calcification was measured using cardiac CT. Bisphosphate use was defined as use of either oral or intravenous bisphosphonates at the time of the cardiac CT. The average age of the NCBP users was 67 years, and the average age of the nonusers was 62 years. Approximately 60% of the women were white.

After adjustment for variables including age, body mass index, diabetes, hypertension, smoking, race, insurance status, education, and income level, the significance remained, Dr. Elmariah said.

“We get a fairly dramatic reduction in the prevalence of cardiovascular calcification in bisphosphonate users over the age of 65,” he added.

When the researchers divided the study population into 10-year age groups, they saw a gradual reduction in cardiovascular calcification with increasing age, he noted.

The study was limited by its cross-sectional design and by the lack of data on the duration of bisphosphonate use. “It's unclear whether this finding is due to true age-related differences in the pathogenesis of cardiovascular calcification or in the effect of bisphosphonates,” said Dr. Elmariah. But the results merit additional studies to tease out the reason for the age-related impact of bisphosphonates on cardiovascular calcification in women, he said.

NCBPs significantly cut cardiovascular calcification in women over 65, said Dr. Sammy Elmariah.

Source Courtesy Dr. Sammy Elmariah

Major Finding: The prevalence of aortic valve ring stenosis was 38% in women aged 65 years and older who took nitrogen-containing bisphosphonates, vs. 59% in women who didn't take bisphosphonates.

Data Source: A cross-sectional study of 3,710 women aged 45–84 years.

Disclosures: Dr. Elmariah has received grant support from the New York Academy of Medicine; the National Heart, Lung, and Blood Institute; and GlaxoSmithKline.

WASHINGTON — Nitrogen-containing bisphosphonates were associated with a significantly decreased prevalence of cardiovascular calcification in women older than 65 years, based on data from 3,710 women who are part of a large, ongoing study.

“Early on in the analysis, we came across a very unexpected finding,” said Dr. Sammy Elmariah of Mount Sinai School of Medicine in New York. “The association with bisphosphonate use was dependent on the patient's age.”

The data were taken from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal cohort study of 6,814 asymptomatic men and women aged 45–84 years.

Overall, the bisphosphonate users were more likely to be older and white. In the current study, Dr. Elmariah and his colleagues examined the impact of bisphosphonates on cardiovascular calcification in women.

Clinical studies have shown that bisphosphonates have an effect on serum lipids, Dr. Elmariah said. Some experimental data, including data from animal models and dialysis patients, suggest that nitrogen-containing bisphosphonates (NCBPs) may limit cardiovascular calcification. In addition, the results of one recent study showed that patients on bisphosphonates for osteoporosis had a slower progression of aortic stenosis, he noted.

The prevalence of aortic valve ring stenosis was 38% in women aged 65 years and older who used NCBPs, which was significantly lower than in non-NCBP users of the same age (59%). Aortic valve ring stenosis prevalence also was 38% in women younger than 65 years who used NCBPs; it was significantly lower at 17% among similarly aged non-NCBP users.

Significant patterns also were seen for stenosis of the thoracic aorta and mitral annulus. The relationship between bisphosphonate use and the decrease in cardiovascular calcification in the 65-years-and-older group did not reach statistical significance for the prevalence of aortic valve stenosis and coronary artery stenosis, but the trends were similar.

This study is the first evaluation of the relationship between bisphosphonate use and the prevalence of cardiovascular calcification in a healthy patient population, Dr. Elmariah said.

Cardiovascular calcification was measured using cardiac CT. Bisphosphate use was defined as use of either oral or intravenous bisphosphonates at the time of the cardiac CT. The average age of the NCBP users was 67 years, and the average age of the nonusers was 62 years. Approximately 60% of the women were white.

After adjustment for variables including age, body mass index, diabetes, hypertension, smoking, race, insurance status, education, and income level, the significance remained, Dr. Elmariah said.

“We get a fairly dramatic reduction in the prevalence of cardiovascular calcification in bisphosphonate users over the age of 65,” he added.

When the researchers divided the study population into 10-year age groups, they saw a gradual reduction in cardiovascular calcification with increasing age, he noted.

The study was limited by its cross-sectional design and by the lack of data on the duration of bisphosphonate use. “It's unclear whether this finding is due to true age-related differences in the pathogenesis of cardiovascular calcification or in the effect of bisphosphonates,” said Dr. Elmariah. But the results merit additional studies to tease out the reason for the age-related impact of bisphosphonates on cardiovascular calcification in women, he said.

NCBPs significantly cut cardiovascular calcification in women over 65, said Dr. Sammy Elmariah.

Source Courtesy Dr. Sammy Elmariah

Early results from two small studies show that the long-term use of oral bisphosphonates could harm bone quality and potentially lead to an increased risk for femur fractures, but the Food and Drug Administration is advising patients to stay on their medication unless advised by their physicians to stop.

The studies showed an association between the use of bisphosphonate treatments for 4 or more years and decreasing bone quality, possibly because the bisphosphonates altered the material properties of the bone. The two studies were presented at the annual meeting of the American Academy of Orthopaedic Surgeons in New Orleans.

Brian Gladnick, and colleagues from the Hospital for Special Surgery in New York, conducted a prospective pilot study in which they evaluated the bone composition of 21 postmenopausal women who presented to the emergency department with proximal femoral fractures. Of the patients enrolled in the study, 12 had a history of bisphosphonate use for an average of 8.5 years; 9 had never been treated with bisphosphonates.

The researchers performed bone core biopsies for each patient and analyzed both the micro-architecture and material properties of the bone. No difference in the bone micro-architecture was observed, but among the patients who had been treated with bisphosphonates, the investigators found reduced bone tissue heterogeneity. Specifically, those who had received bisphosphonates had reduced mineral content and crystal size, compared with the control group.

In a second study, researchers at Columbia University in New York evaluated the bone structure of 111 postmenopausal women with primary osteoporosis. Of that group, 61 had been taking bisphosphonates for at least 4 years. The other 50 women had been taking calcium and vitamin D supplements.

The researchers at Columbia saw improved structural integrity early in the bisphosphonate treatment. However, the trends began to reverse after 4 years of treatment. After that point, continued treatment was associated with decreased axial strength and structural integrity.

“The message here is bisphosphonates are not bad drugs, but perhaps we need to know more about the long-term effects,” Dr. Melvin Rosenwasser, professor of orthopaedic surgery at Columbia University and one of the investigators on the Columbia study.

The FDA advised physicians to be aware of the possible risk of atypical subtrochanteric femur fractures in patients taking bisphosphonates, but said that at this point they saw no “clear connection” between bisphosphonate use and the risk of these fractures.

“FDA is working closely with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather additional information that may provide more insight into this issue,” the agency said in a statement.

The FDA has been following the issue since 2008, when case reports showed that atypical subtrochanteric femur fractures were occurring in osteoporotic women using bisphosphonates. In June 2008, the FDA requested information from all bisphosphonate manufacturers about this potential safety issue. The agency's review of the information did not show an increased risk for women using bisphosphonates.

Some of the manufacturers of bisphosphonate therapies (Fosamax, Actonel, Boniva, and Reclast) issued statements pledging to continue to monitor reports of atypical fractures, but stand by the benefits of the therapies.

The best information available to date indicates that atypical subtrochanteric fractures are rare, said Dr. Elizabeth Shane, an endocrinologist and professor of medicine at Columbia University who also co-chairs the American Society for Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force. Preliminary estimates are that less than 1 in 10,000 patients taking bisphosphonates suffers from this type of fracture, she said. Contrast that with the fact that treating 1,000 women for 3 years with bisphosphonates can prevent 100 fractures, and the benefit of taking these drugs far outweighs the risks, she said.

And indeed, a study published a week after the FDA's statement suggested that the risk of subtrochanteric femur fractures is not significantly increased in women taking bisphosphonates, even among those treated for up to 10 years.

That study included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up and 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 at San Francisco and his colleagues wrote.

The analysis included data 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 the FIT trial, 1.50 for zoledronic acid vs. placebo in the HORIZON-PFT trial, and 1.33 for continued alendronate use vs. placebo in the FLEX trial (N. Engl. J. Med. 2010 March 24[doi10.1056/NEJMoa1001086

Dr. Shane noted in an interview that “[i]t may well be that this type of fracture is associated with bisphosphonates, but we don't yet know who is vulnerable and we need more information and more research in order to determine that.”

The Hospital for Special Surgery study was supported by a grant from the National Institutes of Health. The Columbia researchers received no compensation for their study. Dr. Shane receives research support from Eli Lilly, Merck, and Novartis. The three-study analysis was supported by Merck and Novartis. The investigators reported financial relationships with Merck and Novartis.

“We don't yet know who is vulnerable” to rare instances of atypical femur fracture, Dr. Elizabeth Shane said.

Source Courtesy Columbia University Medical Center

A typical osteoporotic fracture (left) is contrasted with an atypical subtrochanteric fracture in a patient after many years of bisphosphonate therapy.

Source Images courtesy Dr. Melvin Rosenwasser, Columbia University

My Take

Smoke Signals May Be False Alarm

It's against the law to shout “fire” in a crowded theater (unless there really is a fire).

Recent misleading reports in the lay press of cases of “atypical” femur fractures in patients taking Fosamax, and recent (non–peer reviewed) reports of orthopedic research suggesting a strong link between bisphosphonates and subtrochanteric femur fractures appear to be in that vein.

In a statement, the FDA said, “At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures.” We have reviewed the data (J. Clin. Endocrinol. Metab. 2010 Feb. 19 [

doi:10.1210/jc.2009-1947

Because of the small number of cases reported, it is unlikely that a sufficiently large series of such fractures could be assembled to begin to tease out risk factors for the fractures.

Lost in the “smoke” is the serious problem caused by osteoporosis, the deaths and disability associated with fractures and the benefits of alendronate and similar drugs in reducing the risk of fractures. Life is about balancing benefits with risks. For the vast majority of patients with osteoporosis, the benefits of alendronate and other approved treatments for osteoporosis far outweigh the risks.

NELSON B. WATTS, M.D., is an endocrinologist and director of the University of Cincinnati's bone health and osteoporosis center. He disclosed that he has relationships with several pharmaceutical companies, including Amgen Inc., Procter & Gamble, Sanofi-Aventis, and Novartis Pharmaceuticals Corp., which manufactures the bisphosphonate Reclast (zoledronic acid).

Early results from two small studies show that the long-term use of oral bisphosphonates could harm bone quality and potentially lead to an increased risk for femur fractures, but the Food and Drug Administration is advising patients to stay on their medication unless advised by their physicians to stop.

The studies showed an association between the use of bisphosphonate treatments for 4 or more years and decreasing bone quality, possibly because the bisphosphonates altered the material properties of the bone. The two studies were presented at the annual meeting of the American Academy of Orthopaedic Surgeons in New Orleans.

Brian Gladnick, and colleagues from the Hospital for Special Surgery in New York, conducted a prospective pilot study in which they evaluated the bone composition of 21 postmenopausal women who presented to the emergency department with proximal femoral fractures. Of the patients enrolled in the study, 12 had a history of bisphosphonate use for an average of 8.5 years; 9 had never been treated with bisphosphonates.

The researchers performed bone core biopsies for each patient and analyzed both the micro-architecture and material properties of the bone. No difference in the bone micro-architecture was observed, but among the patients who had been treated with bisphosphonates, the investigators found reduced bone tissue heterogeneity. Specifically, those who had received bisphosphonates had reduced mineral content and crystal size, compared with the control group.

In a second study, researchers at Columbia University in New York evaluated the bone structure of 111 postmenopausal women with primary osteoporosis. Of that group, 61 had been taking bisphosphonates for at least 4 years. The other 50 women had been taking calcium and vitamin D supplements.

The researchers at Columbia saw improved structural integrity early in the bisphosphonate treatment. However, the trends began to reverse after 4 years of treatment. After that point, continued treatment was associated with decreased axial strength and structural integrity.

“The message here is bisphosphonates are not bad drugs, but perhaps we need to know more about the long-term effects,” Dr. Melvin Rosenwasser, professor of orthopaedic surgery at Columbia University and one of the investigators on the Columbia study.

The FDA advised physicians to be aware of the possible risk of atypical subtrochanteric femur fractures in patients taking bisphosphonates, but said that at this point they saw no “clear connection” between bisphosphonate use and the risk of these fractures.

“FDA is working closely with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather additional information that may provide more insight into this issue,” the agency said in a statement.

The FDA has been following the issue since 2008, when case reports showed that atypical subtrochanteric femur fractures were occurring in osteoporotic women using bisphosphonates. In June 2008, the FDA requested information from all bisphosphonate manufacturers about this potential safety issue. The agency's review of the information did not show an increased risk for women using bisphosphonates.

Some of the manufacturers of bisphosphonate therapies (Fosamax, Actonel, Boniva, and Reclast) issued statements pledging to continue to monitor reports of atypical fractures, but stand by the benefits of the therapies.

The best information available to date indicates that atypical subtrochanteric fractures are rare, said Dr. Elizabeth Shane, an endocrinologist and professor of medicine at Columbia University who also co-chairs the American Society for Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force. Preliminary estimates are that less than 1 in 10,000 patients taking bisphosphonates suffers from this type of fracture, she said. Contrast that with the fact that treating 1,000 women for 3 years with bisphosphonates can prevent 100 fractures, and the benefit of taking these drugs far outweighs the risks, she said.

And indeed, a study published a week after the FDA's statement suggested that the risk of subtrochanteric femur fractures is not significantly increased in women taking bisphosphonates, even among those treated for up to 10 years.

That study included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up and 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 at San Francisco and his colleagues wrote.

The analysis included data 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 the FIT trial, 1.50 for zoledronic acid vs. placebo in the HORIZON-PFT trial, and 1.33 for continued alendronate use vs. placebo in the FLEX trial (N. Engl. J. Med. 2010 March 24[doi10.1056/NEJMoa1001086

Dr. Shane noted in an interview that “[i]t may well be that this type of fracture is associated with bisphosphonates, but we don't yet know who is vulnerable and we need more information and more research in order to determine that.”

The Hospital for Special Surgery study was supported by a grant from the National Institutes of Health. The Columbia researchers received no compensation for their study. Dr. Shane receives research support from Eli Lilly, Merck, and Novartis. The three-study analysis was supported by Merck and Novartis. The investigators reported financial relationships with Merck and Novartis.

“We don't yet know who is vulnerable” to rare instances of atypical femur fracture, Dr. Elizabeth Shane said.

Source Courtesy Columbia University Medical Center

A typical osteoporotic fracture (left) is contrasted with an atypical subtrochanteric fracture in a patient after many years of bisphosphonate therapy.

Source Images courtesy Dr. Melvin Rosenwasser, Columbia University

My Take

Smoke Signals May Be False Alarm

It's against the law to shout “fire” in a crowded theater (unless there really is a fire).

Recent misleading reports in the lay press of cases of “atypical” femur fractures in patients taking Fosamax, and recent (non–peer reviewed) reports of orthopedic research suggesting a strong link between bisphosphonates and subtrochanteric femur fractures appear to be in that vein.

In a statement, the FDA said, “At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures.” We have reviewed the data (J. Clin. Endocrinol. Metab. 2010 Feb. 19 [

doi:10.1210/jc.2009-1947

Because of the small number of cases reported, it is unlikely that a sufficiently large series of such fractures could be assembled to begin to tease out risk factors for the fractures.

Lost in the “smoke” is the serious problem caused by osteoporosis, the deaths and disability associated with fractures and the benefits of alendronate and similar drugs in reducing the risk of fractures. Life is about balancing benefits with risks. For the vast majority of patients with osteoporosis, the benefits of alendronate and other approved treatments for osteoporosis far outweigh the risks.

NELSON B. WATTS, M.D., is an endocrinologist and director of the University of Cincinnati's bone health and osteoporosis center. He disclosed that he has relationships with several pharmaceutical companies, including Amgen Inc., Procter & Gamble, Sanofi-Aventis, and Novartis Pharmaceuticals Corp., which manufactures the bisphosphonate Reclast (zoledronic acid).

Early results from two small studies show that the long-term use of oral bisphosphonates could harm bone quality and potentially lead to an increased risk for femur fractures, but the Food and Drug Administration is advising patients to stay on their medication unless advised by their physicians to stop.

The studies showed an association between the use of bisphosphonate treatments for 4 or more years and decreasing bone quality, possibly because the bisphosphonates altered the material properties of the bone. The two studies were presented at the annual meeting of the American Academy of Orthopaedic Surgeons in New Orleans.

Brian Gladnick, and colleagues from the Hospital for Special Surgery in New York, conducted a prospective pilot study in which they evaluated the bone composition of 21 postmenopausal women who presented to the emergency department with proximal femoral fractures. Of the patients enrolled in the study, 12 had a history of bisphosphonate use for an average of 8.5 years; 9 had never been treated with bisphosphonates.

The researchers performed bone core biopsies for each patient and analyzed both the micro-architecture and material properties of the bone. No difference in the bone micro-architecture was observed, but among the patients who had been treated with bisphosphonates, the investigators found reduced bone tissue heterogeneity. Specifically, those who had received bisphosphonates had reduced mineral content and crystal size, compared with the control group.

In a second study, researchers at Columbia University in New York evaluated the bone structure of 111 postmenopausal women with primary osteoporosis. Of that group, 61 had been taking bisphosphonates for at least 4 years. The other 50 women had been taking calcium and vitamin D supplements.

The researchers at Columbia saw improved structural integrity early in the bisphosphonate treatment. However, the trends began to reverse after 4 years of treatment. After that point, continued treatment was associated with decreased axial strength and structural integrity.

“The message here is bisphosphonates are not bad drugs, but perhaps we need to know more about the long-term effects,” Dr. Melvin Rosenwasser, professor of orthopaedic surgery at Columbia University and one of the investigators on the Columbia study.

The FDA advised physicians to be aware of the possible risk of atypical subtrochanteric femur fractures in patients taking bisphosphonates, but said that at this point they saw no “clear connection” between bisphosphonate use and the risk of these fractures.

“FDA is working closely with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather additional information that may provide more insight into this issue,” the agency said in a statement.

The FDA has been following the issue since 2008, when case reports showed that atypical subtrochanteric femur fractures were occurring in osteoporotic women using bisphosphonates. In June 2008, the FDA requested information from all bisphosphonate manufacturers about this potential safety issue. The agency's review of the information did not show an increased risk for women using bisphosphonates.

Some of the manufacturers of bisphosphonate therapies (Fosamax, Actonel, Boniva, and Reclast) issued statements pledging to continue to monitor reports of atypical fractures, but stand by the benefits of the therapies.

The best information available to date indicates that atypical subtrochanteric fractures are rare, said Dr. Elizabeth Shane, an endocrinologist and professor of medicine at Columbia University who also co-chairs the American Society for Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force. Preliminary estimates are that less than 1 in 10,000 patients taking bisphosphonates suffers from this type of fracture, she said. Contrast that with the fact that treating 1,000 women for 3 years with bisphosphonates can prevent 100 fractures, and the benefit of taking these drugs far outweighs the risks, she said.

And indeed, a study published a week after the FDA's statement suggested that the risk of subtrochanteric femur fractures is not significantly increased in women taking bisphosphonates, even among those treated for up to 10 years.

That study included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up and 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 at San Francisco and his colleagues wrote.

The analysis included data 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 the FIT trial, 1.50 for zoledronic acid vs. placebo in the HORIZON-PFT trial, and 1.33 for continued alendronate use vs. placebo in the FLEX trial (N. Engl. J. Med. 2010 March 24[doi10.1056/NEJMoa1001086

Dr. Shane noted in an interview that “[i]t may well be that this type of fracture is associated with bisphosphonates, but we don't yet know who is vulnerable and we need more information and more research in order to determine that.”

The Hospital for Special Surgery study was supported by a grant from the National Institutes of Health. The Columbia researchers received no compensation for their study. Dr. Shane receives research support from Eli Lilly, Merck, and Novartis. The three-study analysis was supported by Merck and Novartis. The investigators reported financial relationships with Merck and Novartis.

“We don't yet know who is vulnerable” to rare instances of atypical femur fracture, Dr. Elizabeth Shane said.

Source Courtesy Columbia University Medical Center

A typical osteoporotic fracture (left) is contrasted with an atypical subtrochanteric fracture in a patient after many years of bisphosphonate therapy.

Source Images courtesy Dr. Melvin Rosenwasser, Columbia University

My Take

Smoke Signals May Be False Alarm

It's against the law to shout “fire” in a crowded theater (unless there really is a fire).

Recent misleading reports in the lay press of cases of “atypical” femur fractures in patients taking Fosamax, and recent (non–peer reviewed) reports of orthopedic research suggesting a strong link between bisphosphonates and subtrochanteric femur fractures appear to be in that vein.

In a statement, the FDA said, “At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures.” We have reviewed the data (J. Clin. Endocrinol. Metab. 2010 Feb. 19 [

doi:10.1210/jc.2009-1947

Because of the small number of cases reported, it is unlikely that a sufficiently large series of such fractures could be assembled to begin to tease out risk factors for the fractures.

Lost in the “smoke” is the serious problem caused by osteoporosis, the deaths and disability associated with fractures and the benefits of alendronate and similar drugs in reducing the risk of fractures. Life is about balancing benefits with risks. For the vast majority of patients with osteoporosis, the benefits of alendronate and other approved treatments for osteoporosis far outweigh the risks.

NELSON B. WATTS, M.D., is an endocrinologist and director of the University of Cincinnati's bone health and osteoporosis center. He disclosed that he has relationships with several pharmaceutical companies, including Amgen Inc., Procter & Gamble, Sanofi-Aventis, and Novartis Pharmaceuticals Corp., which manufactures the bisphosphonate Reclast (zoledronic acid).