User login
Denosumab Builds Bone in Men With Low BMD
HOUSTON – One year of denosumab for treatment of men with low bone mineral density resulted in significant increases in bone density at the lumbar spine and all other measured skeletal sites in the phase III ADAMO trial.
The drug’s effects on BMD were similar regardless of patient age, baseline testosterone level, initial BMD, and estimated 10-year osteoporotic fracture risk, according to Dr. Ugis Gruntmanis of the Dallas Veterans Affairs Medical Center and the University of Texas Southwestern Medical Center.
"The increases in bone mineral density in this population were similar to those observed in earlier trials in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy," he reported at the annual meeting of the Endocrine Society.
Moreover, the adverse event profile for denosumab (Prolia) in ADAMO was indistinguishable from that with placebo.
"There was no osteonecrosis of the jaw or atypical femur fractures in this study. You really wouldn’t expect to see that in a study of this size," the endocrinologist added.
ADAMO is a multicenter, double-blind, randomized, phase III clinical trial in which 242 men with low BMD were randomized to 60 mg of denosumab or to placebo given subcutaneously every 6 months for 1 year. The primary end point in ADAMO was change in BMD at the lumbar spine from baseline through 12 months. At the 12-month mark, all patients were placed on open-label denosumab for another year; the 24-month secondary outcomes are not in yet.
Participants had to have a BMD T-score of -2.0 or less and -3.5 or greater at the lumbar spine or femoral neck, or a prior major osteoporotic fracture along with a T-score of -1.0 or less and -3.5 at the lumbar spine or femoral neck. The men’s average age was 65 years, 94% were white, and one-quarter had a history of a major osteoporotic fracture. All subjects received daily calcium and vitamin D supplements.
At the 6-month mark, lumbar spine BMD had improved by 4.3% over baseline in the denosumab group compared with 0.9% in controls. At 1 year, the denosumab group averaged a 5.7% increase over baseline while the placebo group remained flat at a 0.9% gain.
Total hip BMD improved by 2.4% at 12 months in the denosumab group compared with 0.3% in controls, and by 0.6% at the distal one-third of the radius compared with a 0.3% loss with placebo; both of those differences favoring denosumab were statistically significant. So were the denosumab-induced BMD gains at the femoral neck and trochanter.
In subgroup analyses, the 15% of men with a baseline serum testosterone below 250 ng/dL had a 4.4% greater gain in lumbar spine BMD than with placebo, while those with a testosterone of 250 ng/dL or above had a similar 4.8% net gain.
Men with a baseline FRAX score placing them in the lowest tertile for 10-year major osteoporotic fracture risk, at less than 6.4%, had an absolute 5.1% greater gain in lumbar spine BMD than with placebo, while those with a 10-year risk of 6.4%-11.2% had a net 5.3% gain in lumbar spine BMD and men with a greater than 11.2% fracture risk had a net placebo-subtracted 4.0% gain; the denosumab-driven BMD gains in these three fracture risk groups were statistically similar, according to Dr. Gruntmanis.
One of the secondary end points in ADAMO was the change in the bone resorption biomarker CTX-1 between baseline and day 15 of the study. The CTX-1 level plunged by 81% in the denosumab group by day 15, with 60% suppression at 12 months.
Osteoporosis and fractures remain widely underrecognized and undertreated in men, Dr. Gruntmanis said. An estimated 2 million American men have osteoporosis. Worldwide, 39% of all osteoporotic fractures occur in men above age 50.
He reported receiving research grants from Amgen, Novartis, GlaxoSmithKline, and Procter & Gamble.
HOUSTON – One year of denosumab for treatment of men with low bone mineral density resulted in significant increases in bone density at the lumbar spine and all other measured skeletal sites in the phase III ADAMO trial.
The drug’s effects on BMD were similar regardless of patient age, baseline testosterone level, initial BMD, and estimated 10-year osteoporotic fracture risk, according to Dr. Ugis Gruntmanis of the Dallas Veterans Affairs Medical Center and the University of Texas Southwestern Medical Center.
"The increases in bone mineral density in this population were similar to those observed in earlier trials in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy," he reported at the annual meeting of the Endocrine Society.
Moreover, the adverse event profile for denosumab (Prolia) in ADAMO was indistinguishable from that with placebo.
"There was no osteonecrosis of the jaw or atypical femur fractures in this study. You really wouldn’t expect to see that in a study of this size," the endocrinologist added.
ADAMO is a multicenter, double-blind, randomized, phase III clinical trial in which 242 men with low BMD were randomized to 60 mg of denosumab or to placebo given subcutaneously every 6 months for 1 year. The primary end point in ADAMO was change in BMD at the lumbar spine from baseline through 12 months. At the 12-month mark, all patients were placed on open-label denosumab for another year; the 24-month secondary outcomes are not in yet.
Participants had to have a BMD T-score of -2.0 or less and -3.5 or greater at the lumbar spine or femoral neck, or a prior major osteoporotic fracture along with a T-score of -1.0 or less and -3.5 at the lumbar spine or femoral neck. The men’s average age was 65 years, 94% were white, and one-quarter had a history of a major osteoporotic fracture. All subjects received daily calcium and vitamin D supplements.
At the 6-month mark, lumbar spine BMD had improved by 4.3% over baseline in the denosumab group compared with 0.9% in controls. At 1 year, the denosumab group averaged a 5.7% increase over baseline while the placebo group remained flat at a 0.9% gain.
Total hip BMD improved by 2.4% at 12 months in the denosumab group compared with 0.3% in controls, and by 0.6% at the distal one-third of the radius compared with a 0.3% loss with placebo; both of those differences favoring denosumab were statistically significant. So were the denosumab-induced BMD gains at the femoral neck and trochanter.
In subgroup analyses, the 15% of men with a baseline serum testosterone below 250 ng/dL had a 4.4% greater gain in lumbar spine BMD than with placebo, while those with a testosterone of 250 ng/dL or above had a similar 4.8% net gain.
Men with a baseline FRAX score placing them in the lowest tertile for 10-year major osteoporotic fracture risk, at less than 6.4%, had an absolute 5.1% greater gain in lumbar spine BMD than with placebo, while those with a 10-year risk of 6.4%-11.2% had a net 5.3% gain in lumbar spine BMD and men with a greater than 11.2% fracture risk had a net placebo-subtracted 4.0% gain; the denosumab-driven BMD gains in these three fracture risk groups were statistically similar, according to Dr. Gruntmanis.
One of the secondary end points in ADAMO was the change in the bone resorption biomarker CTX-1 between baseline and day 15 of the study. The CTX-1 level plunged by 81% in the denosumab group by day 15, with 60% suppression at 12 months.
Osteoporosis and fractures remain widely underrecognized and undertreated in men, Dr. Gruntmanis said. An estimated 2 million American men have osteoporosis. Worldwide, 39% of all osteoporotic fractures occur in men above age 50.
He reported receiving research grants from Amgen, Novartis, GlaxoSmithKline, and Procter & Gamble.
HOUSTON – One year of denosumab for treatment of men with low bone mineral density resulted in significant increases in bone density at the lumbar spine and all other measured skeletal sites in the phase III ADAMO trial.
The drug’s effects on BMD were similar regardless of patient age, baseline testosterone level, initial BMD, and estimated 10-year osteoporotic fracture risk, according to Dr. Ugis Gruntmanis of the Dallas Veterans Affairs Medical Center and the University of Texas Southwestern Medical Center.
"The increases in bone mineral density in this population were similar to those observed in earlier trials in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy," he reported at the annual meeting of the Endocrine Society.
Moreover, the adverse event profile for denosumab (Prolia) in ADAMO was indistinguishable from that with placebo.
"There was no osteonecrosis of the jaw or atypical femur fractures in this study. You really wouldn’t expect to see that in a study of this size," the endocrinologist added.
ADAMO is a multicenter, double-blind, randomized, phase III clinical trial in which 242 men with low BMD were randomized to 60 mg of denosumab or to placebo given subcutaneously every 6 months for 1 year. The primary end point in ADAMO was change in BMD at the lumbar spine from baseline through 12 months. At the 12-month mark, all patients were placed on open-label denosumab for another year; the 24-month secondary outcomes are not in yet.
Participants had to have a BMD T-score of -2.0 or less and -3.5 or greater at the lumbar spine or femoral neck, or a prior major osteoporotic fracture along with a T-score of -1.0 or less and -3.5 at the lumbar spine or femoral neck. The men’s average age was 65 years, 94% were white, and one-quarter had a history of a major osteoporotic fracture. All subjects received daily calcium and vitamin D supplements.
At the 6-month mark, lumbar spine BMD had improved by 4.3% over baseline in the denosumab group compared with 0.9% in controls. At 1 year, the denosumab group averaged a 5.7% increase over baseline while the placebo group remained flat at a 0.9% gain.
Total hip BMD improved by 2.4% at 12 months in the denosumab group compared with 0.3% in controls, and by 0.6% at the distal one-third of the radius compared with a 0.3% loss with placebo; both of those differences favoring denosumab were statistically significant. So were the denosumab-induced BMD gains at the femoral neck and trochanter.
In subgroup analyses, the 15% of men with a baseline serum testosterone below 250 ng/dL had a 4.4% greater gain in lumbar spine BMD than with placebo, while those with a testosterone of 250 ng/dL or above had a similar 4.8% net gain.
Men with a baseline FRAX score placing them in the lowest tertile for 10-year major osteoporotic fracture risk, at less than 6.4%, had an absolute 5.1% greater gain in lumbar spine BMD than with placebo, while those with a 10-year risk of 6.4%-11.2% had a net 5.3% gain in lumbar spine BMD and men with a greater than 11.2% fracture risk had a net placebo-subtracted 4.0% gain; the denosumab-driven BMD gains in these three fracture risk groups were statistically similar, according to Dr. Gruntmanis.
One of the secondary end points in ADAMO was the change in the bone resorption biomarker CTX-1 between baseline and day 15 of the study. The CTX-1 level plunged by 81% in the denosumab group by day 15, with 60% suppression at 12 months.
Osteoporosis and fractures remain widely underrecognized and undertreated in men, Dr. Gruntmanis said. An estimated 2 million American men have osteoporosis. Worldwide, 39% of all osteoporotic fractures occur in men above age 50.
He reported receiving research grants from Amgen, Novartis, GlaxoSmithKline, and Procter & Gamble.
AT THE ANNUAL MEETING OF THE ENDOCRINE SOCIETY
Major Finding: Lumbar spine bone mineral density improved by 5.7% after 12 months of denosumab compared with a 0.9% gain with placebo in men with baseline low bone mineral density.
Data Source: The ADAMO trial was a phase III, double-blind, randomized, multicenter study involving 242 men.
Disclosures: The trial was sponsored by Amgen. Dr. Gruntmanis received a research grant from the company.
Only High Vitamin D Intake Cuts Fracture Risk
Only high intake of vitamin D supplementation with 800 IU or more per day appears to reduce the risk of fracture significantly in the elderly, according to the latest meta-analysis on the subject reported online July 4 in the New England Journal of Medicine.
Such high levels of supplementation appear to reduce the risk of hip fracture by 30% and the risk of nonvertebral fracture by 14% in people aged 65 years and older, said Dr. Heike A. Bischoff-Ferrari, of the Center on Aging and Mobility at the University of Zurich, and her associates.
Many previous meta-analyses of the protective effect of vitamin D supplements, like the numerous clinical trials they reviewed, have produced markedly conflicting results. Some have found reductions in fracture risk of up to 20%, others have found no beneficial effect, and a few have even found negative effects on fracture risk.
Dr. Bischoff-Ferrari and her colleagues reasoned that many of these clinical trials, as well as the meta-analyses that pooled their findings, were flawed by relying on the doses of vitamin D that were prescribed for subjects rather than the actual amount that subjects took. Many also were flawed in that they did not take into account subjects’ baseline levels of 25-hydroxyvitamin D, an indicator of the degree of their vitamin D deficiency.
So for their meta-analysis, the investigators included only double-blind, randomized, controlled trials that either recorded subjects’ actual intake of oral vitamin D supplements or controlled for their adherence to prescribed supplementation. Thus, the investigators were able to include only 11 studies, with a pooled population of 31,022 subjects, in their meta-analysis.
The intention-to-treat analysis, which examined the prescribed supplementation, showed a nonsignificant 10% reduction in the risk of hip fracture. However, a comparison of subjects’ actual intake of vitamin D supplements showed a significant 30% reduction in risk of hip fracture at the highest levels of intake (800-2,000 IU daily).
"Notably, there was no reduction in risk of hip fracture at any actual intake level lower than 792 IU per day," Dr. Bischoff-Ferrari and her associates said (N. Engl. J. Med. 2012 July 4 [doi: 10.1056/NEJMoa1109617]).
Similarly, the intention-to-treat analysis showed a nonsignificant 7% reduction in the risk of nonvertebral fracture, while a comparison of actual intake levels showed a significant 14% decline in risk at the highest levels of intake.
Internal validation analyses supported these results, and indicated that there was a dose-response relationship between vitamin D dose actually ingested and fracture risk. Several sensitivity analyses also bolstered the findings, and showed that the benefit of vitamin D supplements extended across several subgroups of patients, including all ages and both sexes.
"Previous meta-analyses have suggested that the benefits of vitamin D may be limited to older persons who live in institutions. Our subgroup analyses suggest that at the highest actual intake level, the risk of hip fracture is reduced among all persons 65 years of age or older, whether they live in the community or in an institution.
"Our data further suggest that persons who are most vulnerable to vitamin D deficiency – those 85 years of age or older and those with very low baseline levels of 25-hydroxyvitamin D – benefit from vitamin D supplementation at least as much as others do," they added.
Overall, the study results support the Institute of Medicine’s recommendation that people aged 65 years and older receive 800 IU of vitamin D each day, the investigators noted.
In addition, "our findings suggest that some previous high-quality trials of vitamin D supplementation either showed no benefit owing to lower-than-intended doses of vitamin D or showed an unexpected benefit owing to higher-than-intended doses," they said.
This study was supported by the Swiss National Foundation, the European Commission Framework 7 Program, and DSM Nutritional Products. Dr. Bischoff-Ferrari reported ties to DSM Nutritional Products, Amgen, MSD, Novartis, Roche, and Nestle, and her associates reported ties to numerous industry sources.
Vitamin D is like most nutrients in that people who have different levels at baseline and then receive identical supplementation may or may not show a measurable response to the supplementation, said Dr. Robert P. Heaney.
"Unfortunately, most of the randomized, controlled trials of vitamin D that have been published to date have paid little attention to baseline status. Among 31,022 patients whose results were analyzed by [Dr. Bischoff-Ferrari and colleagues], data on baseline concentrations of 25-hydroxyvitamin D were available for only 4,383 patients (barely 14%)," he noted.
"The question of how much vitamin D is enough is likely to remain muddled as long as meta-analyses focus on trial methodology rather than on biology," Dr. Heaney added.
Nonetheless, "given the congruence of the findings of this latest meta-analysis with the guidelines from the Endocrine Society [1,500-2,000 IU/ day], it would appear to be prudent, and probably helpful as well, to ensure an intake at the upper end of the range at which Bischoff-Ferrari et al. found a reduction in fracture risk," he concluded.
Dr. Heaney is with the osteoporosis research center at Creighton University in Omaha, Neb. He reported ties to Coca-Cola, the International Dairy Foods Commission, the Federal Trade Commission, the National Dairy Council, and the Council for Responsible Nutrition. These remarks were taken from his editorial accompanying Dr. Bischoff-Ferrari’s report (N. Engl. J. Med. 2012 July 4 [doi:10.1056/NEJMe1206858]).
Vitamin D is like most nutrients in that people who have different levels at baseline and then receive identical supplementation may or may not show a measurable response to the supplementation, said Dr. Robert P. Heaney.
"Unfortunately, most of the randomized, controlled trials of vitamin D that have been published to date have paid little attention to baseline status. Among 31,022 patients whose results were analyzed by [Dr. Bischoff-Ferrari and colleagues], data on baseline concentrations of 25-hydroxyvitamin D were available for only 4,383 patients (barely 14%)," he noted.
"The question of how much vitamin D is enough is likely to remain muddled as long as meta-analyses focus on trial methodology rather than on biology," Dr. Heaney added.
Nonetheless, "given the congruence of the findings of this latest meta-analysis with the guidelines from the Endocrine Society [1,500-2,000 IU/ day], it would appear to be prudent, and probably helpful as well, to ensure an intake at the upper end of the range at which Bischoff-Ferrari et al. found a reduction in fracture risk," he concluded.
Dr. Heaney is with the osteoporosis research center at Creighton University in Omaha, Neb. He reported ties to Coca-Cola, the International Dairy Foods Commission, the Federal Trade Commission, the National Dairy Council, and the Council for Responsible Nutrition. These remarks were taken from his editorial accompanying Dr. Bischoff-Ferrari’s report (N. Engl. J. Med. 2012 July 4 [doi:10.1056/NEJMe1206858]).
Vitamin D is like most nutrients in that people who have different levels at baseline and then receive identical supplementation may or may not show a measurable response to the supplementation, said Dr. Robert P. Heaney.
"Unfortunately, most of the randomized, controlled trials of vitamin D that have been published to date have paid little attention to baseline status. Among 31,022 patients whose results were analyzed by [Dr. Bischoff-Ferrari and colleagues], data on baseline concentrations of 25-hydroxyvitamin D were available for only 4,383 patients (barely 14%)," he noted.
"The question of how much vitamin D is enough is likely to remain muddled as long as meta-analyses focus on trial methodology rather than on biology," Dr. Heaney added.
Nonetheless, "given the congruence of the findings of this latest meta-analysis with the guidelines from the Endocrine Society [1,500-2,000 IU/ day], it would appear to be prudent, and probably helpful as well, to ensure an intake at the upper end of the range at which Bischoff-Ferrari et al. found a reduction in fracture risk," he concluded.
Dr. Heaney is with the osteoporosis research center at Creighton University in Omaha, Neb. He reported ties to Coca-Cola, the International Dairy Foods Commission, the Federal Trade Commission, the National Dairy Council, and the Council for Responsible Nutrition. These remarks were taken from his editorial accompanying Dr. Bischoff-Ferrari’s report (N. Engl. J. Med. 2012 July 4 [doi:10.1056/NEJMe1206858]).
Only high intake of vitamin D supplementation with 800 IU or more per day appears to reduce the risk of fracture significantly in the elderly, according to the latest meta-analysis on the subject reported online July 4 in the New England Journal of Medicine.
Such high levels of supplementation appear to reduce the risk of hip fracture by 30% and the risk of nonvertebral fracture by 14% in people aged 65 years and older, said Dr. Heike A. Bischoff-Ferrari, of the Center on Aging and Mobility at the University of Zurich, and her associates.
Many previous meta-analyses of the protective effect of vitamin D supplements, like the numerous clinical trials they reviewed, have produced markedly conflicting results. Some have found reductions in fracture risk of up to 20%, others have found no beneficial effect, and a few have even found negative effects on fracture risk.
Dr. Bischoff-Ferrari and her colleagues reasoned that many of these clinical trials, as well as the meta-analyses that pooled their findings, were flawed by relying on the doses of vitamin D that were prescribed for subjects rather than the actual amount that subjects took. Many also were flawed in that they did not take into account subjects’ baseline levels of 25-hydroxyvitamin D, an indicator of the degree of their vitamin D deficiency.
So for their meta-analysis, the investigators included only double-blind, randomized, controlled trials that either recorded subjects’ actual intake of oral vitamin D supplements or controlled for their adherence to prescribed supplementation. Thus, the investigators were able to include only 11 studies, with a pooled population of 31,022 subjects, in their meta-analysis.
The intention-to-treat analysis, which examined the prescribed supplementation, showed a nonsignificant 10% reduction in the risk of hip fracture. However, a comparison of subjects’ actual intake of vitamin D supplements showed a significant 30% reduction in risk of hip fracture at the highest levels of intake (800-2,000 IU daily).
"Notably, there was no reduction in risk of hip fracture at any actual intake level lower than 792 IU per day," Dr. Bischoff-Ferrari and her associates said (N. Engl. J. Med. 2012 July 4 [doi: 10.1056/NEJMoa1109617]).
Similarly, the intention-to-treat analysis showed a nonsignificant 7% reduction in the risk of nonvertebral fracture, while a comparison of actual intake levels showed a significant 14% decline in risk at the highest levels of intake.
Internal validation analyses supported these results, and indicated that there was a dose-response relationship between vitamin D dose actually ingested and fracture risk. Several sensitivity analyses also bolstered the findings, and showed that the benefit of vitamin D supplements extended across several subgroups of patients, including all ages and both sexes.
"Previous meta-analyses have suggested that the benefits of vitamin D may be limited to older persons who live in institutions. Our subgroup analyses suggest that at the highest actual intake level, the risk of hip fracture is reduced among all persons 65 years of age or older, whether they live in the community or in an institution.
"Our data further suggest that persons who are most vulnerable to vitamin D deficiency – those 85 years of age or older and those with very low baseline levels of 25-hydroxyvitamin D – benefit from vitamin D supplementation at least as much as others do," they added.
Overall, the study results support the Institute of Medicine’s recommendation that people aged 65 years and older receive 800 IU of vitamin D each day, the investigators noted.
In addition, "our findings suggest that some previous high-quality trials of vitamin D supplementation either showed no benefit owing to lower-than-intended doses of vitamin D or showed an unexpected benefit owing to higher-than-intended doses," they said.
This study was supported by the Swiss National Foundation, the European Commission Framework 7 Program, and DSM Nutritional Products. Dr. Bischoff-Ferrari reported ties to DSM Nutritional Products, Amgen, MSD, Novartis, Roche, and Nestle, and her associates reported ties to numerous industry sources.
Only high intake of vitamin D supplementation with 800 IU or more per day appears to reduce the risk of fracture significantly in the elderly, according to the latest meta-analysis on the subject reported online July 4 in the New England Journal of Medicine.
Such high levels of supplementation appear to reduce the risk of hip fracture by 30% and the risk of nonvertebral fracture by 14% in people aged 65 years and older, said Dr. Heike A. Bischoff-Ferrari, of the Center on Aging and Mobility at the University of Zurich, and her associates.
Many previous meta-analyses of the protective effect of vitamin D supplements, like the numerous clinical trials they reviewed, have produced markedly conflicting results. Some have found reductions in fracture risk of up to 20%, others have found no beneficial effect, and a few have even found negative effects on fracture risk.
Dr. Bischoff-Ferrari and her colleagues reasoned that many of these clinical trials, as well as the meta-analyses that pooled their findings, were flawed by relying on the doses of vitamin D that were prescribed for subjects rather than the actual amount that subjects took. Many also were flawed in that they did not take into account subjects’ baseline levels of 25-hydroxyvitamin D, an indicator of the degree of their vitamin D deficiency.
So for their meta-analysis, the investigators included only double-blind, randomized, controlled trials that either recorded subjects’ actual intake of oral vitamin D supplements or controlled for their adherence to prescribed supplementation. Thus, the investigators were able to include only 11 studies, with a pooled population of 31,022 subjects, in their meta-analysis.
The intention-to-treat analysis, which examined the prescribed supplementation, showed a nonsignificant 10% reduction in the risk of hip fracture. However, a comparison of subjects’ actual intake of vitamin D supplements showed a significant 30% reduction in risk of hip fracture at the highest levels of intake (800-2,000 IU daily).
"Notably, there was no reduction in risk of hip fracture at any actual intake level lower than 792 IU per day," Dr. Bischoff-Ferrari and her associates said (N. Engl. J. Med. 2012 July 4 [doi: 10.1056/NEJMoa1109617]).
Similarly, the intention-to-treat analysis showed a nonsignificant 7% reduction in the risk of nonvertebral fracture, while a comparison of actual intake levels showed a significant 14% decline in risk at the highest levels of intake.
Internal validation analyses supported these results, and indicated that there was a dose-response relationship between vitamin D dose actually ingested and fracture risk. Several sensitivity analyses also bolstered the findings, and showed that the benefit of vitamin D supplements extended across several subgroups of patients, including all ages and both sexes.
"Previous meta-analyses have suggested that the benefits of vitamin D may be limited to older persons who live in institutions. Our subgroup analyses suggest that at the highest actual intake level, the risk of hip fracture is reduced among all persons 65 years of age or older, whether they live in the community or in an institution.
"Our data further suggest that persons who are most vulnerable to vitamin D deficiency – those 85 years of age or older and those with very low baseline levels of 25-hydroxyvitamin D – benefit from vitamin D supplementation at least as much as others do," they added.
Overall, the study results support the Institute of Medicine’s recommendation that people aged 65 years and older receive 800 IU of vitamin D each day, the investigators noted.
In addition, "our findings suggest that some previous high-quality trials of vitamin D supplementation either showed no benefit owing to lower-than-intended doses of vitamin D or showed an unexpected benefit owing to higher-than-intended doses," they said.
This study was supported by the Swiss National Foundation, the European Commission Framework 7 Program, and DSM Nutritional Products. Dr. Bischoff-Ferrari reported ties to DSM Nutritional Products, Amgen, MSD, Novartis, Roche, and Nestle, and her associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Check Vitamin D in Adolescents Before Bariatric Surgery
HOUSTON – Fifty-four percent of 219 obese adolescents being evaluated for bariatric surgery were deficient in vitamin D, including 9% who were severely deficient, a retrospective analysis of preoperative laboratory measures found.
Eighty-two percent of the adolescents had insufficient levels of 25-hydroxyvitamin D (25OHD) in their blood, Dr. Marisa Censani and her associates reported at the annual meeting of the Endocrine Society.
The findings are so striking that all morbidly obese adolescents should be screened for vitamin D deficiency, and those who are deficient should be treated to replete vitamin D levels, suggested Dr. Censani of Columbia University, New York.
It’s particularly important to screen adolescents before bariatric surgery procedures, some of which have been associated with bone loss, which results from weight loss and decreased calcium and vitamin D absorption. Preoperative vitamin D deficiency could put adolescent patients at greater risk because they have not reached their peak bone mass, she said.
Previous studies have shown that obese adults undergoing bariatric surgery commonly are vitamin D deficient before surgery, but these are some of the first data in preoperative adolescent patients.
Of all adolescents undergoing bariatric surgery at her institution from March 2006 to June 2011, 219 had records on serum 25OHD and parathyroid hormone levels. The cohort was 65% female, 43% white, 35% Hispanic, and 15% African American, with the rest being other races/ethnicities. Patients had a mean age of 16 years (ranging from 13-18 years) and a mean body mass index of 48 kg/m2.
The mean serum 25OHD level was 21 ng/mL, which was considered insufficient. The study defined adequate levels of serum 25OHD as at least 30 ng/mL, insufficient levels as 20-29 ng/mL, deficient levels as less than 20 ng/mL, and severely deficient levels as less than 10 ng/mL.
Only 18% of patients had sufficient 25OHD levels. Twenty-nine percent had insufficient levels, 45% were vitamin D deficient, and 9% were severely deficient.
Patients with the highest BMIs were most likely to have deficient levels of 25OHD. Every kilogram increase in BMI correlated with a 0.2-ng decrease in 25OHD levels, Dr. Censani said.
Vitamin D deficiency was most common in African Americans, 82% of whom were deficient and none of whom had levels in the normal range. Fifty-nine percent of Hispanics and 37% of whites had vitamin D deficiency. Race was the strongest predictor of 25OHD levels.
Roughly 80% of African American patients were deficient in vitamin D and the rest had insufficient levels. In Hispanics, nearly 60% were deficient in vitamin D, close to 25% had insufficient levels, and about 25% had adequate levels. In whites, deficient or insufficient levels each were seen in nearly 40% of patients, with adequate levels in more than 20%.
Clear secondary hyperparathyroidism was seen in 5% of patients, though serum parathyroid levels varied inversely with 25OHD. African American race, BMI, and parathyroid levels explained 21% of the variance in 25OHD levels between patients.
To be eligible for bariatric surgery, adolescents had to have reached Tanner stage IV or V and had to have a BMI greater than 50, or above 35 kg/m2 if they had comorbidities.
A physician in the audience challenged Dr. Censani’s recommendation that all obese adolescents be screened and possibly treated for vitamin D deficiency, saying there is no evidence yet of clinical benefit from that approach. Dr. Censani agreed that more research is needed to support this strategy.
The current study was limited by the lack of a community-based, nonobese control group and lack of data on dietary calcium and vitamin D intake, sun exposure, or bone mineral density. The study’s large size and relatively good ethnic diversity are strengths, she said.
The U.S. adolescent obesity rate has more than tripled in the past 30 years, with 16% of children and adolescents now overweight, 4% obese, and 4% morbidly obese, studies suggest.
Dr. Censani reported having no financial disclosures. The National Institutes of Health funded the study.
25-hydroxyvitamin D, 25OHD, Dr. Marisa Censani, the Endocrine Society, vitamin D deficiency, parathyroid hormone levels,
HOUSTON – Fifty-four percent of 219 obese adolescents being evaluated for bariatric surgery were deficient in vitamin D, including 9% who were severely deficient, a retrospective analysis of preoperative laboratory measures found.
Eighty-two percent of the adolescents had insufficient levels of 25-hydroxyvitamin D (25OHD) in their blood, Dr. Marisa Censani and her associates reported at the annual meeting of the Endocrine Society.
The findings are so striking that all morbidly obese adolescents should be screened for vitamin D deficiency, and those who are deficient should be treated to replete vitamin D levels, suggested Dr. Censani of Columbia University, New York.
It’s particularly important to screen adolescents before bariatric surgery procedures, some of which have been associated with bone loss, which results from weight loss and decreased calcium and vitamin D absorption. Preoperative vitamin D deficiency could put adolescent patients at greater risk because they have not reached their peak bone mass, she said.
Previous studies have shown that obese adults undergoing bariatric surgery commonly are vitamin D deficient before surgery, but these are some of the first data in preoperative adolescent patients.
Of all adolescents undergoing bariatric surgery at her institution from March 2006 to June 2011, 219 had records on serum 25OHD and parathyroid hormone levels. The cohort was 65% female, 43% white, 35% Hispanic, and 15% African American, with the rest being other races/ethnicities. Patients had a mean age of 16 years (ranging from 13-18 years) and a mean body mass index of 48 kg/m2.
The mean serum 25OHD level was 21 ng/mL, which was considered insufficient. The study defined adequate levels of serum 25OHD as at least 30 ng/mL, insufficient levels as 20-29 ng/mL, deficient levels as less than 20 ng/mL, and severely deficient levels as less than 10 ng/mL.
Only 18% of patients had sufficient 25OHD levels. Twenty-nine percent had insufficient levels, 45% were vitamin D deficient, and 9% were severely deficient.
Patients with the highest BMIs were most likely to have deficient levels of 25OHD. Every kilogram increase in BMI correlated with a 0.2-ng decrease in 25OHD levels, Dr. Censani said.
Vitamin D deficiency was most common in African Americans, 82% of whom were deficient and none of whom had levels in the normal range. Fifty-nine percent of Hispanics and 37% of whites had vitamin D deficiency. Race was the strongest predictor of 25OHD levels.
Roughly 80% of African American patients were deficient in vitamin D and the rest had insufficient levels. In Hispanics, nearly 60% were deficient in vitamin D, close to 25% had insufficient levels, and about 25% had adequate levels. In whites, deficient or insufficient levels each were seen in nearly 40% of patients, with adequate levels in more than 20%.
Clear secondary hyperparathyroidism was seen in 5% of patients, though serum parathyroid levels varied inversely with 25OHD. African American race, BMI, and parathyroid levels explained 21% of the variance in 25OHD levels between patients.
To be eligible for bariatric surgery, adolescents had to have reached Tanner stage IV or V and had to have a BMI greater than 50, or above 35 kg/m2 if they had comorbidities.
A physician in the audience challenged Dr. Censani’s recommendation that all obese adolescents be screened and possibly treated for vitamin D deficiency, saying there is no evidence yet of clinical benefit from that approach. Dr. Censani agreed that more research is needed to support this strategy.
The current study was limited by the lack of a community-based, nonobese control group and lack of data on dietary calcium and vitamin D intake, sun exposure, or bone mineral density. The study’s large size and relatively good ethnic diversity are strengths, she said.
The U.S. adolescent obesity rate has more than tripled in the past 30 years, with 16% of children and adolescents now overweight, 4% obese, and 4% morbidly obese, studies suggest.
Dr. Censani reported having no financial disclosures. The National Institutes of Health funded the study.
HOUSTON – Fifty-four percent of 219 obese adolescents being evaluated for bariatric surgery were deficient in vitamin D, including 9% who were severely deficient, a retrospective analysis of preoperative laboratory measures found.
Eighty-two percent of the adolescents had insufficient levels of 25-hydroxyvitamin D (25OHD) in their blood, Dr. Marisa Censani and her associates reported at the annual meeting of the Endocrine Society.
The findings are so striking that all morbidly obese adolescents should be screened for vitamin D deficiency, and those who are deficient should be treated to replete vitamin D levels, suggested Dr. Censani of Columbia University, New York.
It’s particularly important to screen adolescents before bariatric surgery procedures, some of which have been associated with bone loss, which results from weight loss and decreased calcium and vitamin D absorption. Preoperative vitamin D deficiency could put adolescent patients at greater risk because they have not reached their peak bone mass, she said.
Previous studies have shown that obese adults undergoing bariatric surgery commonly are vitamin D deficient before surgery, but these are some of the first data in preoperative adolescent patients.
Of all adolescents undergoing bariatric surgery at her institution from March 2006 to June 2011, 219 had records on serum 25OHD and parathyroid hormone levels. The cohort was 65% female, 43% white, 35% Hispanic, and 15% African American, with the rest being other races/ethnicities. Patients had a mean age of 16 years (ranging from 13-18 years) and a mean body mass index of 48 kg/m2.
The mean serum 25OHD level was 21 ng/mL, which was considered insufficient. The study defined adequate levels of serum 25OHD as at least 30 ng/mL, insufficient levels as 20-29 ng/mL, deficient levels as less than 20 ng/mL, and severely deficient levels as less than 10 ng/mL.
Only 18% of patients had sufficient 25OHD levels. Twenty-nine percent had insufficient levels, 45% were vitamin D deficient, and 9% were severely deficient.
Patients with the highest BMIs were most likely to have deficient levels of 25OHD. Every kilogram increase in BMI correlated with a 0.2-ng decrease in 25OHD levels, Dr. Censani said.
Vitamin D deficiency was most common in African Americans, 82% of whom were deficient and none of whom had levels in the normal range. Fifty-nine percent of Hispanics and 37% of whites had vitamin D deficiency. Race was the strongest predictor of 25OHD levels.
Roughly 80% of African American patients were deficient in vitamin D and the rest had insufficient levels. In Hispanics, nearly 60% were deficient in vitamin D, close to 25% had insufficient levels, and about 25% had adequate levels. In whites, deficient or insufficient levels each were seen in nearly 40% of patients, with adequate levels in more than 20%.
Clear secondary hyperparathyroidism was seen in 5% of patients, though serum parathyroid levels varied inversely with 25OHD. African American race, BMI, and parathyroid levels explained 21% of the variance in 25OHD levels between patients.
To be eligible for bariatric surgery, adolescents had to have reached Tanner stage IV or V and had to have a BMI greater than 50, or above 35 kg/m2 if they had comorbidities.
A physician in the audience challenged Dr. Censani’s recommendation that all obese adolescents be screened and possibly treated for vitamin D deficiency, saying there is no evidence yet of clinical benefit from that approach. Dr. Censani agreed that more research is needed to support this strategy.
The current study was limited by the lack of a community-based, nonobese control group and lack of data on dietary calcium and vitamin D intake, sun exposure, or bone mineral density. The study’s large size and relatively good ethnic diversity are strengths, she said.
The U.S. adolescent obesity rate has more than tripled in the past 30 years, with 16% of children and adolescents now overweight, 4% obese, and 4% morbidly obese, studies suggest.
Dr. Censani reported having no financial disclosures. The National Institutes of Health funded the study.
25-hydroxyvitamin D, 25OHD, Dr. Marisa Censani, the Endocrine Society, vitamin D deficiency, parathyroid hormone levels,
25-hydroxyvitamin D, 25OHD, Dr. Marisa Censani, the Endocrine Society, vitamin D deficiency, parathyroid hormone levels,
AT THE ANNUAL MEETING OF THE ENDOCRINE SOCIETY
Major Finding: Fifty-four percent of obese adolescents being evaluated for bariatric surgery had vitamin D deficiency, including 8% with a severe deficiency.
Data Source: This was a retrospective analysis of preoperative laboratory measures from adolescents undergoing bariatric surgery at one institution from March 2006 to June 2011.
Disclosures: Dr. Censani reported having no financial disclosures. The National Institutes of Health funded the study.
With Testosterone Replacement, Men Shed Pounds
HOUSTON – Long-term testosterone replacement therapy in men with hypogonadism brought impressive reductions in body weight and waist circumference in a 5-year observational study.
"This is an amazing response. I don’t know of many other therapies where you have more than 90% of treated patients respond in a positive way," observed Farid Saad, Ph.D. He referred to the fact that 90% of the 255 men treated for hypogonadism lost at least 5 kg from their initial body weight and 97% experienced shrinkage in waist circumference, with a 10-cm or greater reduction in 46% of men. That’s a lot of belt notches.
This 5-year study of testosterone replacement in hypogonadal men features what’s easily the longest follow-up reported anywhere to date. The average 36-pound weight loss and substantial waist shrinkage were "unintended and unexpected," because prior 1- to 2-year-long studies showed less impressive changes, explained Dr. Saad, at the annual meeting of the Endocrine Society.
The 255 study participants averaged just under 61 years of age. Nearly all were obese or overweight, as is typical in male hypogonadism. All had a serum testosterone level below 350 ng/dL, along with testosterone deficiency–related symptoms. Serum testosterone levels normalized within the first 6-9 months of treatment with slow-acting intramuscular testosterone undecanoate and remained in the normal range thereafter.
"If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination."
The men went from a mean baseline body weight of 106 kg to 90 kg over the course of 5 years. A total of 76% of participants lost 10 kg or more of their initial body weight, 53% lost at least 15 kg, and 31% dropped at least 20 kg. The weight loss was continuous; the men lost a mean of 4% of their initial body weight at 1 year, 9% at 3 years, and 13.2% after 5 years. Only 5% of men gained weight during follow-up.
Waist circumference declined by a mean of 8.8 cm from 107.2 cm at baseline. And mean body mass index dropped from 34 to 29 kg/m2.
Study participants were not placed on a structured diet or exercise program, although they did receive advice on the importance of making lifestyle changes.
Three men have developed prostate cancer, but that’s less than the background rate in the general population.
"I think now the general understanding at the major urologic conferences is that testosterone does not increase the risk of prostate cancer. And I wouldn’t expect other side effects because testosterone is a natural substance and we don’t use supraphysiologic doses, we just bring testosterone levels in these hypogonadal men back to normal. I say, in a maybe not very scientific way, that if testosterone [were] harmful to men, then nature would have made a major mistake," according to Dr. Saad, head of global medical affairs–andrology at Bayer Pharma in Berlin.
He added that it would be nice to confirm the findings of this observational study in a prospective randomized controlled trial, but no ethics committee in the world would approve such a study because testosterone deficiency carries elevated risks of osteoporosis, cardiovascular disease, and diabetes. And the treatment for testosterone deficiency as spelled out in Endocrine Society guidelines is testosterone replacement to normal physiologic levels.
Two other studies presented at the conference confirmed Dr. Saad’s weight loss and waist circumference shrinkage findings. Dr. Youssef El Douaihy of Maimonides Medical Center, New York, reported that during a median 6.7-year follow-up of 130 hypogonadal men on testosterone replacement therapy, the subjects lost a mean of 14.3 kg or 13% of their initial body weight. They also experienced a mean 11-cm decrease in waist circumference.
And Dr. Michael Zitzmann of the University of Munster, Germany, presented a series of 334 patients with male hypogonadism treated for up to 15 years with intramuscular testosterone undecanoate. The prevalence of metabolic syndrome dropped from 88% to 52% within the first 2 years. Highly significant reductions in blood pressure, resting heart rate, body weight, body mass index, waist circumference, fasting blood glucose, LDL cholesterol, and triglycerides were documented, all highly significant differences.
Why the big weight loss in patients on long-term testosterone replacement therapy? Dr. Saad speculated that the explanation might lie in the combined improvements in vitality, virility, and motivation to change, all of which in recent studies have been shown to be triggered by normalization of testosterone levels.
"Testosterone may be of value as a facilitator of lifestyle change," he asserted.
Dr. Gary Wittert concurred.
"It’s extremely motivating to men to see their testosterone level come up to normal and the associated improvement in body weight, erectile dysfunction, and the significant improvement in lower urinary tract symptoms. So the message is quite clear: If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination," declared Dr. Wittert, professor of medicine at the University of Adelaide, Australia, who is a testosterone clinical trialist not involved in these studies.
Dr. Saad noted that another attribute of testosterone normalization that may be highly relevant to progressive long-term weight loss is that testosterone increases fat-free mass. He cited a recent pilot study in which hypogonadal men with spinal cord injury received transdermal testosterone replacement. In 1 year, their fat-free mass increased by an average of 3.5 kg and their resting energy expenditure rose by 112 kcal/day (Horm. Metab. Res. 2011;43:574-9).
"If you accumulate that over 5 years, it could be a major contributor to the weight loss the men in our study experienced," Dr. Saad observed.
Dr. Vineeth Mohan, who chaired a session where Dr. Saad presented his findings, said the new data raise the possibility that a large weight loss in a patient treated for male hypogonadism could be an indicator that natural testosterone production has recovered and replacement therapy is no longer needed. That would make sense, since adipose tissue is a powerful suppressor of testosterone production.
"I might look at that loss of a significant amount of body weight as a signal that the testosterone axis has improved, and perhaps as an opportunity for reassessment," said Dr. Mohan, an endocrinologist at the Cleveland Clinic Foundation in Weston, Fla.
He reported having no financial conflicts.
HOUSTON – Long-term testosterone replacement therapy in men with hypogonadism brought impressive reductions in body weight and waist circumference in a 5-year observational study.
"This is an amazing response. I don’t know of many other therapies where you have more than 90% of treated patients respond in a positive way," observed Farid Saad, Ph.D. He referred to the fact that 90% of the 255 men treated for hypogonadism lost at least 5 kg from their initial body weight and 97% experienced shrinkage in waist circumference, with a 10-cm or greater reduction in 46% of men. That’s a lot of belt notches.
This 5-year study of testosterone replacement in hypogonadal men features what’s easily the longest follow-up reported anywhere to date. The average 36-pound weight loss and substantial waist shrinkage were "unintended and unexpected," because prior 1- to 2-year-long studies showed less impressive changes, explained Dr. Saad, at the annual meeting of the Endocrine Society.
The 255 study participants averaged just under 61 years of age. Nearly all were obese or overweight, as is typical in male hypogonadism. All had a serum testosterone level below 350 ng/dL, along with testosterone deficiency–related symptoms. Serum testosterone levels normalized within the first 6-9 months of treatment with slow-acting intramuscular testosterone undecanoate and remained in the normal range thereafter.
"If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination."
The men went from a mean baseline body weight of 106 kg to 90 kg over the course of 5 years. A total of 76% of participants lost 10 kg or more of their initial body weight, 53% lost at least 15 kg, and 31% dropped at least 20 kg. The weight loss was continuous; the men lost a mean of 4% of their initial body weight at 1 year, 9% at 3 years, and 13.2% after 5 years. Only 5% of men gained weight during follow-up.
Waist circumference declined by a mean of 8.8 cm from 107.2 cm at baseline. And mean body mass index dropped from 34 to 29 kg/m2.
Study participants were not placed on a structured diet or exercise program, although they did receive advice on the importance of making lifestyle changes.
Three men have developed prostate cancer, but that’s less than the background rate in the general population.
"I think now the general understanding at the major urologic conferences is that testosterone does not increase the risk of prostate cancer. And I wouldn’t expect other side effects because testosterone is a natural substance and we don’t use supraphysiologic doses, we just bring testosterone levels in these hypogonadal men back to normal. I say, in a maybe not very scientific way, that if testosterone [were] harmful to men, then nature would have made a major mistake," according to Dr. Saad, head of global medical affairs–andrology at Bayer Pharma in Berlin.
He added that it would be nice to confirm the findings of this observational study in a prospective randomized controlled trial, but no ethics committee in the world would approve such a study because testosterone deficiency carries elevated risks of osteoporosis, cardiovascular disease, and diabetes. And the treatment for testosterone deficiency as spelled out in Endocrine Society guidelines is testosterone replacement to normal physiologic levels.
Two other studies presented at the conference confirmed Dr. Saad’s weight loss and waist circumference shrinkage findings. Dr. Youssef El Douaihy of Maimonides Medical Center, New York, reported that during a median 6.7-year follow-up of 130 hypogonadal men on testosterone replacement therapy, the subjects lost a mean of 14.3 kg or 13% of their initial body weight. They also experienced a mean 11-cm decrease in waist circumference.
And Dr. Michael Zitzmann of the University of Munster, Germany, presented a series of 334 patients with male hypogonadism treated for up to 15 years with intramuscular testosterone undecanoate. The prevalence of metabolic syndrome dropped from 88% to 52% within the first 2 years. Highly significant reductions in blood pressure, resting heart rate, body weight, body mass index, waist circumference, fasting blood glucose, LDL cholesterol, and triglycerides were documented, all highly significant differences.
Why the big weight loss in patients on long-term testosterone replacement therapy? Dr. Saad speculated that the explanation might lie in the combined improvements in vitality, virility, and motivation to change, all of which in recent studies have been shown to be triggered by normalization of testosterone levels.
"Testosterone may be of value as a facilitator of lifestyle change," he asserted.
Dr. Gary Wittert concurred.
"It’s extremely motivating to men to see their testosterone level come up to normal and the associated improvement in body weight, erectile dysfunction, and the significant improvement in lower urinary tract symptoms. So the message is quite clear: If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination," declared Dr. Wittert, professor of medicine at the University of Adelaide, Australia, who is a testosterone clinical trialist not involved in these studies.
Dr. Saad noted that another attribute of testosterone normalization that may be highly relevant to progressive long-term weight loss is that testosterone increases fat-free mass. He cited a recent pilot study in which hypogonadal men with spinal cord injury received transdermal testosterone replacement. In 1 year, their fat-free mass increased by an average of 3.5 kg and their resting energy expenditure rose by 112 kcal/day (Horm. Metab. Res. 2011;43:574-9).
"If you accumulate that over 5 years, it could be a major contributor to the weight loss the men in our study experienced," Dr. Saad observed.
Dr. Vineeth Mohan, who chaired a session where Dr. Saad presented his findings, said the new data raise the possibility that a large weight loss in a patient treated for male hypogonadism could be an indicator that natural testosterone production has recovered and replacement therapy is no longer needed. That would make sense, since adipose tissue is a powerful suppressor of testosterone production.
"I might look at that loss of a significant amount of body weight as a signal that the testosterone axis has improved, and perhaps as an opportunity for reassessment," said Dr. Mohan, an endocrinologist at the Cleveland Clinic Foundation in Weston, Fla.
He reported having no financial conflicts.
HOUSTON – Long-term testosterone replacement therapy in men with hypogonadism brought impressive reductions in body weight and waist circumference in a 5-year observational study.
"This is an amazing response. I don’t know of many other therapies where you have more than 90% of treated patients respond in a positive way," observed Farid Saad, Ph.D. He referred to the fact that 90% of the 255 men treated for hypogonadism lost at least 5 kg from their initial body weight and 97% experienced shrinkage in waist circumference, with a 10-cm or greater reduction in 46% of men. That’s a lot of belt notches.
This 5-year study of testosterone replacement in hypogonadal men features what’s easily the longest follow-up reported anywhere to date. The average 36-pound weight loss and substantial waist shrinkage were "unintended and unexpected," because prior 1- to 2-year-long studies showed less impressive changes, explained Dr. Saad, at the annual meeting of the Endocrine Society.
The 255 study participants averaged just under 61 years of age. Nearly all were obese or overweight, as is typical in male hypogonadism. All had a serum testosterone level below 350 ng/dL, along with testosterone deficiency–related symptoms. Serum testosterone levels normalized within the first 6-9 months of treatment with slow-acting intramuscular testosterone undecanoate and remained in the normal range thereafter.
"If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination."
The men went from a mean baseline body weight of 106 kg to 90 kg over the course of 5 years. A total of 76% of participants lost 10 kg or more of their initial body weight, 53% lost at least 15 kg, and 31% dropped at least 20 kg. The weight loss was continuous; the men lost a mean of 4% of their initial body weight at 1 year, 9% at 3 years, and 13.2% after 5 years. Only 5% of men gained weight during follow-up.
Waist circumference declined by a mean of 8.8 cm from 107.2 cm at baseline. And mean body mass index dropped from 34 to 29 kg/m2.
Study participants were not placed on a structured diet or exercise program, although they did receive advice on the importance of making lifestyle changes.
Three men have developed prostate cancer, but that’s less than the background rate in the general population.
"I think now the general understanding at the major urologic conferences is that testosterone does not increase the risk of prostate cancer. And I wouldn’t expect other side effects because testosterone is a natural substance and we don’t use supraphysiologic doses, we just bring testosterone levels in these hypogonadal men back to normal. I say, in a maybe not very scientific way, that if testosterone [were] harmful to men, then nature would have made a major mistake," according to Dr. Saad, head of global medical affairs–andrology at Bayer Pharma in Berlin.
He added that it would be nice to confirm the findings of this observational study in a prospective randomized controlled trial, but no ethics committee in the world would approve such a study because testosterone deficiency carries elevated risks of osteoporosis, cardiovascular disease, and diabetes. And the treatment for testosterone deficiency as spelled out in Endocrine Society guidelines is testosterone replacement to normal physiologic levels.
Two other studies presented at the conference confirmed Dr. Saad’s weight loss and waist circumference shrinkage findings. Dr. Youssef El Douaihy of Maimonides Medical Center, New York, reported that during a median 6.7-year follow-up of 130 hypogonadal men on testosterone replacement therapy, the subjects lost a mean of 14.3 kg or 13% of their initial body weight. They also experienced a mean 11-cm decrease in waist circumference.
And Dr. Michael Zitzmann of the University of Munster, Germany, presented a series of 334 patients with male hypogonadism treated for up to 15 years with intramuscular testosterone undecanoate. The prevalence of metabolic syndrome dropped from 88% to 52% within the first 2 years. Highly significant reductions in blood pressure, resting heart rate, body weight, body mass index, waist circumference, fasting blood glucose, LDL cholesterol, and triglycerides were documented, all highly significant differences.
Why the big weight loss in patients on long-term testosterone replacement therapy? Dr. Saad speculated that the explanation might lie in the combined improvements in vitality, virility, and motivation to change, all of which in recent studies have been shown to be triggered by normalization of testosterone levels.
"Testosterone may be of value as a facilitator of lifestyle change," he asserted.
Dr. Gary Wittert concurred.
"It’s extremely motivating to men to see their testosterone level come up to normal and the associated improvement in body weight, erectile dysfunction, and the significant improvement in lower urinary tract symptoms. So the message is quite clear: If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination," declared Dr. Wittert, professor of medicine at the University of Adelaide, Australia, who is a testosterone clinical trialist not involved in these studies.
Dr. Saad noted that another attribute of testosterone normalization that may be highly relevant to progressive long-term weight loss is that testosterone increases fat-free mass. He cited a recent pilot study in which hypogonadal men with spinal cord injury received transdermal testosterone replacement. In 1 year, their fat-free mass increased by an average of 3.5 kg and their resting energy expenditure rose by 112 kcal/day (Horm. Metab. Res. 2011;43:574-9).
"If you accumulate that over 5 years, it could be a major contributor to the weight loss the men in our study experienced," Dr. Saad observed.
Dr. Vineeth Mohan, who chaired a session where Dr. Saad presented his findings, said the new data raise the possibility that a large weight loss in a patient treated for male hypogonadism could be an indicator that natural testosterone production has recovered and replacement therapy is no longer needed. That would make sense, since adipose tissue is a powerful suppressor of testosterone production.
"I might look at that loss of a significant amount of body weight as a signal that the testosterone axis has improved, and perhaps as an opportunity for reassessment," said Dr. Mohan, an endocrinologist at the Cleveland Clinic Foundation in Weston, Fla.
He reported having no financial conflicts.
AT THE ANNUAL MEETING OF THE ENDOCRINE SOCIETY
Major Finding: Long-term testosterone replacement therapy led to an average 36-pound weight loss and 3.5-inch reduction in waist circumference in hypogonadal men.
Data Source: This was an uncontrolled prospective observational cohort study of 255 patients with male hypogonadism who were placed on intramuscular testosterone undecanoate for up to 5 years in what is by far the longest follow-up of any study of testosterone replacement therapy.
Disclosures: This study was funded by Bayer Pharma and presented by a Bayer employee.
Less Zoledronic Acid May Work in Breast Cancer
CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.
The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.
Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."
Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "
Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.
At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.
The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.
Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.
An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.
Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.
Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."
"So don’t change your current approach, but stay tuned," he told attendees.
Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.
CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.
The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.
Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."
Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "
Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.
At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.
The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.
Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.
An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.
Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.
Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."
"So don’t change your current approach, but stay tuned," he told attendees.
Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.
CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.
The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.
Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."
Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "
Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.
At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.
The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.
Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.
An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.
Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.
Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."
"So don’t change your current approach, but stay tuned," he told attendees.
Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Effect of Vitamin D on Nonskeletal Tissue Yet Unknown
Available data are not strong enough to show a definitive association between vitamin D levels and risk of obesity, diabetes, cancer, heart disease, or maternal-fetal health, according to a comprehensive review of available research.
"The efficacy issue [of vitamin D] remains a major question mark," said Dr. Clifford J. Rosen in an interview. He chaired the group that wrote the scientific statement published by Endocrine Society (Endocr. Rev. 2012 May 17 [doi:10.1210/er.2012-1000]).
The scientific statement takes a comprehensive look at basic and clinical evidence related to the effect of vitamin D and various organ systems.
Although some observational studies have shown that benefits of vitamin D may extend beyond bone health, the findings are inconsistent, the authors noted.
"We need large randomized controlled trials and dose-response data to test the effects of vitamin D on chronic disease outcomes including autoimmunity, obesity, diabetes, hypertension, and heart disease," said Dr. Rosen, professor of medicine at Tufts University, Boston, in a statement.
Dr. Robert H. Eckel, past president of the American Heart Association, said he agreed with the findings of the report. He said that physicians should be aware of low vitamin D levels and should correct the deficiencies, but they should not make any strong statements about vitamin D levels and risk for conditions such as heart disease or cancer, due to lack of sufficient evidence.
He added that ultimately, data from large, well-designed trials "may be informative in uncovering a relationship that’s more meaningful." Dr. Eckel, who is a professor of medicine at University of Colorado at Denver, Aurora, was not involved in the study.
Interest in vitamin D as a therapeutic option for the prevention of chronic disease has been growing in recent years, the authors noted. "In a 2-month span during the summer of 2011, there were more than 500 publications centered on vitamin D, most of which were related to its relationship to nonskeletal tissues," they wrote. But the results, they added, are confounded and difficult to interpret.
By organ or disorder, the authors came to the following conclusions:
• Skin. "There are no large-scale, randomized, placebo-controlled clinical trials demonstrating that vitamin D metabolites are superior to other types of treatment for various proliferative skin disorders or for the prevention of skin cancer."
• Obesity and diabetes mellitus. "The ever-expanding obesity epidemic has been associated with a rising prevalence of vitamin D deficiency, but a cause-and-effect relationship has not been established. ... There remains a paucity of randomized controlled trials of vitamin D for the prevention of diabetes; hence, few conclusions can be firmly established."
• Fall prevention and improvement in quality of life. Citing the public health implication of fall prevention, and the report by the Institute of Medicine, the authors wrote, "The absolute threshold level of [vitamin D] needed to prevent falls in an elderly population is not known in part because of lack of true dose-ranging studies. ... Selecting patients at risk for falls and defining the appropriate dose remains as areas in need of further research."
• Cancer. "Despite biological plausibility for a role of vitamin D in cancer prevention, most recent systematic reviews and meta-analyses, as well as a comprehensive review by the IOM Committee, have found that the evidence that vitamin D reduces cancer incidence and/or mortality is inconsistent and inconclusive as to causality."
• Cardiovascular disease. Although there is a possibility that vitamin D supplementation may lower cardiovascular risk, "additional research, particularly from randomized trials, is needed."
• The placenta and maternal-fetal health. "There is insufficient evidence to recommend a particular maternal intake of vitamin D or [serum 25-hydroxyvitamin D] blood level during pregnancy to achieve any purported nonskeletal benefit of vitamin D," the authors wrote, but they added that "the biological plausibility may be sufficient to justify clinical trials to test whether vitamin D supplementation during pregnancy will prevent type 1 diabetes in the offspring."
"We’re hopeful that some of the intervention trial [on vitamin D] will get underway, and although they’re expensive, their findings can help change practice," said Dr. Rosen.
Dr. Rosen reported no relevant conflicts of interest.
Available data are not strong enough to show a definitive association between vitamin D levels and risk of obesity, diabetes, cancer, heart disease, or maternal-fetal health, according to a comprehensive review of available research.
"The efficacy issue [of vitamin D] remains a major question mark," said Dr. Clifford J. Rosen in an interview. He chaired the group that wrote the scientific statement published by Endocrine Society (Endocr. Rev. 2012 May 17 [doi:10.1210/er.2012-1000]).
The scientific statement takes a comprehensive look at basic and clinical evidence related to the effect of vitamin D and various organ systems.
Although some observational studies have shown that benefits of vitamin D may extend beyond bone health, the findings are inconsistent, the authors noted.
"We need large randomized controlled trials and dose-response data to test the effects of vitamin D on chronic disease outcomes including autoimmunity, obesity, diabetes, hypertension, and heart disease," said Dr. Rosen, professor of medicine at Tufts University, Boston, in a statement.
Dr. Robert H. Eckel, past president of the American Heart Association, said he agreed with the findings of the report. He said that physicians should be aware of low vitamin D levels and should correct the deficiencies, but they should not make any strong statements about vitamin D levels and risk for conditions such as heart disease or cancer, due to lack of sufficient evidence.
He added that ultimately, data from large, well-designed trials "may be informative in uncovering a relationship that’s more meaningful." Dr. Eckel, who is a professor of medicine at University of Colorado at Denver, Aurora, was not involved in the study.
Interest in vitamin D as a therapeutic option for the prevention of chronic disease has been growing in recent years, the authors noted. "In a 2-month span during the summer of 2011, there were more than 500 publications centered on vitamin D, most of which were related to its relationship to nonskeletal tissues," they wrote. But the results, they added, are confounded and difficult to interpret.
By organ or disorder, the authors came to the following conclusions:
• Skin. "There are no large-scale, randomized, placebo-controlled clinical trials demonstrating that vitamin D metabolites are superior to other types of treatment for various proliferative skin disorders or for the prevention of skin cancer."
• Obesity and diabetes mellitus. "The ever-expanding obesity epidemic has been associated with a rising prevalence of vitamin D deficiency, but a cause-and-effect relationship has not been established. ... There remains a paucity of randomized controlled trials of vitamin D for the prevention of diabetes; hence, few conclusions can be firmly established."
• Fall prevention and improvement in quality of life. Citing the public health implication of fall prevention, and the report by the Institute of Medicine, the authors wrote, "The absolute threshold level of [vitamin D] needed to prevent falls in an elderly population is not known in part because of lack of true dose-ranging studies. ... Selecting patients at risk for falls and defining the appropriate dose remains as areas in need of further research."
• Cancer. "Despite biological plausibility for a role of vitamin D in cancer prevention, most recent systematic reviews and meta-analyses, as well as a comprehensive review by the IOM Committee, have found that the evidence that vitamin D reduces cancer incidence and/or mortality is inconsistent and inconclusive as to causality."
• Cardiovascular disease. Although there is a possibility that vitamin D supplementation may lower cardiovascular risk, "additional research, particularly from randomized trials, is needed."
• The placenta and maternal-fetal health. "There is insufficient evidence to recommend a particular maternal intake of vitamin D or [serum 25-hydroxyvitamin D] blood level during pregnancy to achieve any purported nonskeletal benefit of vitamin D," the authors wrote, but they added that "the biological plausibility may be sufficient to justify clinical trials to test whether vitamin D supplementation during pregnancy will prevent type 1 diabetes in the offspring."
"We’re hopeful that some of the intervention trial [on vitamin D] will get underway, and although they’re expensive, their findings can help change practice," said Dr. Rosen.
Dr. Rosen reported no relevant conflicts of interest.
Available data are not strong enough to show a definitive association between vitamin D levels and risk of obesity, diabetes, cancer, heart disease, or maternal-fetal health, according to a comprehensive review of available research.
"The efficacy issue [of vitamin D] remains a major question mark," said Dr. Clifford J. Rosen in an interview. He chaired the group that wrote the scientific statement published by Endocrine Society (Endocr. Rev. 2012 May 17 [doi:10.1210/er.2012-1000]).
The scientific statement takes a comprehensive look at basic and clinical evidence related to the effect of vitamin D and various organ systems.
Although some observational studies have shown that benefits of vitamin D may extend beyond bone health, the findings are inconsistent, the authors noted.
"We need large randomized controlled trials and dose-response data to test the effects of vitamin D on chronic disease outcomes including autoimmunity, obesity, diabetes, hypertension, and heart disease," said Dr. Rosen, professor of medicine at Tufts University, Boston, in a statement.
Dr. Robert H. Eckel, past president of the American Heart Association, said he agreed with the findings of the report. He said that physicians should be aware of low vitamin D levels and should correct the deficiencies, but they should not make any strong statements about vitamin D levels and risk for conditions such as heart disease or cancer, due to lack of sufficient evidence.
He added that ultimately, data from large, well-designed trials "may be informative in uncovering a relationship that’s more meaningful." Dr. Eckel, who is a professor of medicine at University of Colorado at Denver, Aurora, was not involved in the study.
Interest in vitamin D as a therapeutic option for the prevention of chronic disease has been growing in recent years, the authors noted. "In a 2-month span during the summer of 2011, there were more than 500 publications centered on vitamin D, most of which were related to its relationship to nonskeletal tissues," they wrote. But the results, they added, are confounded and difficult to interpret.
By organ or disorder, the authors came to the following conclusions:
• Skin. "There are no large-scale, randomized, placebo-controlled clinical trials demonstrating that vitamin D metabolites are superior to other types of treatment for various proliferative skin disorders or for the prevention of skin cancer."
• Obesity and diabetes mellitus. "The ever-expanding obesity epidemic has been associated with a rising prevalence of vitamin D deficiency, but a cause-and-effect relationship has not been established. ... There remains a paucity of randomized controlled trials of vitamin D for the prevention of diabetes; hence, few conclusions can be firmly established."
• Fall prevention and improvement in quality of life. Citing the public health implication of fall prevention, and the report by the Institute of Medicine, the authors wrote, "The absolute threshold level of [vitamin D] needed to prevent falls in an elderly population is not known in part because of lack of true dose-ranging studies. ... Selecting patients at risk for falls and defining the appropriate dose remains as areas in need of further research."
• Cancer. "Despite biological plausibility for a role of vitamin D in cancer prevention, most recent systematic reviews and meta-analyses, as well as a comprehensive review by the IOM Committee, have found that the evidence that vitamin D reduces cancer incidence and/or mortality is inconsistent and inconclusive as to causality."
• Cardiovascular disease. Although there is a possibility that vitamin D supplementation may lower cardiovascular risk, "additional research, particularly from randomized trials, is needed."
• The placenta and maternal-fetal health. "There is insufficient evidence to recommend a particular maternal intake of vitamin D or [serum 25-hydroxyvitamin D] blood level during pregnancy to achieve any purported nonskeletal benefit of vitamin D," the authors wrote, but they added that "the biological plausibility may be sufficient to justify clinical trials to test whether vitamin D supplementation during pregnancy will prevent type 1 diabetes in the offspring."
"We’re hopeful that some of the intervention trial [on vitamin D] will get underway, and although they’re expensive, their findings can help change practice," said Dr. Rosen.
Dr. Rosen reported no relevant conflicts of interest.
Did the IOM Get Vitamin D Targets Wrong?
NEW ORLEANS – When the Institute of Medicine released updated recommendations on calcium and vitamin D intake in late 2010, the report became the backbone for clinical guidance. But since then, they have been hotly debated among those who say that the recommendations were too weak, and others who say that it has been inappropriately used to herald vitamin D as the next wonder substance, with little scientific evidence backing that claim.
The IOM guidelines "fail the smell test," said Dr. Neil Binkley, a geriatrician and research scientist at the University of Wisconsin–Madison. The recommended intake for a 1-year-old (600 IU/day) is the same as for a 70-year-old. That would make the recommended dietary allowance for vitamin D one of the few RDAs that do not adjust for age, he said at the annual meeting of the American College of Physicians.
In addition, the recommendations were formulated from a public health standpoint. That makes them less useful for determining the best recommended dietary allowance for an individual patient. Knowing an individual’s particular risk factors and variables in his or her life are crucial for determining an appropriate intake, he said.
Vitamin D deficiency is likely a growing issue, not just in the United States, but worldwide. Vitamin D is not commonly found in food, but is easily synthesized from sunlight. Centuries ago, humans wore less clothing and did not wear sunscreen. Now, of course, avoidance of sun exposure is common practice and has likely contributed to lower serum vitamin D levels in modern humans, he said.
For instance, a recent study showed that two traditional sub-Saharan tribes – the Maasai and the Hadzabe – who wear little clothing, do not use sunscreen, and have darkly pigmented skin (putting them at greater risk for vitamin D deficiency) – had a mean serum 25-hydroxyvitamin D concentration of 46 ng/mL (or 115 nmol/L), according to a study (Br. J. Nutr. 2012 Jan. 23 [doi:10.1017/S0007114511007161]).
This serum concentration is much greater than the IOM’s target of "sufficient" levels (defined as greater than 30 nmol/L). Levels between 20 and 30 nmol/L are considered insufficient, and less than 12 is considered deficient. According to these IOM figures, some 80% of whites have sufficient levels, whereas 71% of African Americans and 46% of Mexican Americans have low levels of serum vitamin D. Dr. Binkley said that he considers the IOM cut-offs to be conservative, but even according to those numbers, as much as a third of the U.S. population may be deficient.
Guidelines subsequently issued by the Endocrine Society called for higher RDAs than that recommended by the IOM, underscoring the lack of consensus around what constitutes a sufficient vitamin D intake, said Dr. Binkley.
There’s also lack of consensus around who should be screened for serum vitamin D levels. The Endocrine Society has called for screening of those "at risk," but then categorizes so many people as being at risk that it’s essentially equivalent to total population screening, said Dr. Binkley. He supports screening, in particular of older adults with a history of falls, and of others with a history of nontraumatic fractures. But he does not advocate total population screening.
What should physicians do? First, recognize that not all patients are the same and that a serum concentration of 20 ng/L may not be sufficient for every individual. Also, just urging sun exposure may not be enough for some patients, either. Multiple studies in the literature have shown that serum concentrations can vary widely among individuals, even when they have had equivalent levels of sun exposure, said Dr. Binkley.
Lab tests for serum vitamin D levels have improved over the years, but they are far from perfect.
So what are adequate levels? According to several studies in sun-exposed individuals, 20 ng/mL seems low and levels in the mid-30s seem reasonable, said Dr. Binkley. "I think we need to be above 30," he said, noting that, for many patients, that means a daily intake of 1,000-2,000 IU of vitamin D daily.
That advice jibes with a statement the American Association of Clinical Endocrinologists issued shortly after the IOM report. AACE recommended that an optimal range for most patients should be 30-50 ng/mL. To achieve that, it would be necessary to take 1,000-2,000 IU of vitamin D daily. The group also said that physicians should use the IOM recommendations "in conjunction with clinical judgment to determine the proper vitamin D requirement for any given patient."
The evidence seems to support that higher serum levels (greater than 30 ng/mL) are associated with reduced fracture and fall risk, but that at super-high levels, vitamin D actually increases falls and fractures, said Dr. Binkley. It’s not clear why that is. In the study, women were given a megadose of 500,000 IU of vitamin D once a year; findings suggested that a big blast of the vitamin is not helpful, he said (JAMA 2010:303:1815-22).
The data show that for each additional 1,000 IU daily, the serum level goes up by about 6 ng/mL. Increases will be greater for patients who start with lower serum levels. To determine what’s optimal, it’s probably necessary to measure serum levels periodically, Dr. Binkley said.
If you write a prescription, you’re likely to get the less optimal form of vitamin D, that is, vitamin D2. Humans make vitamin D3 when they are exposed to sunlight, but only D2 is available in prescription form. Dr. Binkley said that he prefers patients to take D3, which is available over the counter. But if he’s going for a big repletion – say a typical 50,000 IU dose – he has to use the D2 form.
It is possible to have vitamin D intoxication. Most studies have never documented anyone with serum levels greater than 70 ng/mL. Patients who have levels above 70 are probably getting too much vitamin D, he said.
Equally intoxicating is the hype surrounding vitamin D, which recently has been touted as a veritable fountain of youth. Almost every tissue in the body has a vitamin D receptor and it is produced locally by many tissues. But the evidence does not support the notion that low levels are responsible for a laundry list of diseases, Dr. Binkley said. It is plausible that low vitamin D contributes to impaired immune function, diabetes, vascular disease, and a higher risk for bone loss and fractures, among other conditions. Sufficient vitamin D may also reduce cancer risk.
But so far, too many studies show association, and not causation. "We need to stay tuned," said Dr. Binkley, noting that there need to be more randomized, prospective studies and no more meta-analyses.
The IOM report "is too weak," but trying to get patients to serum vitamin D levels greater than 40 ng/mL is not responsible, Dr. Binkley stressed.
Dr. Binkley has consulting arrangements with Eli Lilly and Merck, and grants from those companies as well as Amgen and Tarsa, but none relate to vitamin D.
NEW ORLEANS – When the Institute of Medicine released updated recommendations on calcium and vitamin D intake in late 2010, the report became the backbone for clinical guidance. But since then, they have been hotly debated among those who say that the recommendations were too weak, and others who say that it has been inappropriately used to herald vitamin D as the next wonder substance, with little scientific evidence backing that claim.
The IOM guidelines "fail the smell test," said Dr. Neil Binkley, a geriatrician and research scientist at the University of Wisconsin–Madison. The recommended intake for a 1-year-old (600 IU/day) is the same as for a 70-year-old. That would make the recommended dietary allowance for vitamin D one of the few RDAs that do not adjust for age, he said at the annual meeting of the American College of Physicians.
In addition, the recommendations were formulated from a public health standpoint. That makes them less useful for determining the best recommended dietary allowance for an individual patient. Knowing an individual’s particular risk factors and variables in his or her life are crucial for determining an appropriate intake, he said.
Vitamin D deficiency is likely a growing issue, not just in the United States, but worldwide. Vitamin D is not commonly found in food, but is easily synthesized from sunlight. Centuries ago, humans wore less clothing and did not wear sunscreen. Now, of course, avoidance of sun exposure is common practice and has likely contributed to lower serum vitamin D levels in modern humans, he said.
For instance, a recent study showed that two traditional sub-Saharan tribes – the Maasai and the Hadzabe – who wear little clothing, do not use sunscreen, and have darkly pigmented skin (putting them at greater risk for vitamin D deficiency) – had a mean serum 25-hydroxyvitamin D concentration of 46 ng/mL (or 115 nmol/L), according to a study (Br. J. Nutr. 2012 Jan. 23 [doi:10.1017/S0007114511007161]).
This serum concentration is much greater than the IOM’s target of "sufficient" levels (defined as greater than 30 nmol/L). Levels between 20 and 30 nmol/L are considered insufficient, and less than 12 is considered deficient. According to these IOM figures, some 80% of whites have sufficient levels, whereas 71% of African Americans and 46% of Mexican Americans have low levels of serum vitamin D. Dr. Binkley said that he considers the IOM cut-offs to be conservative, but even according to those numbers, as much as a third of the U.S. population may be deficient.
Guidelines subsequently issued by the Endocrine Society called for higher RDAs than that recommended by the IOM, underscoring the lack of consensus around what constitutes a sufficient vitamin D intake, said Dr. Binkley.
There’s also lack of consensus around who should be screened for serum vitamin D levels. The Endocrine Society has called for screening of those "at risk," but then categorizes so many people as being at risk that it’s essentially equivalent to total population screening, said Dr. Binkley. He supports screening, in particular of older adults with a history of falls, and of others with a history of nontraumatic fractures. But he does not advocate total population screening.
What should physicians do? First, recognize that not all patients are the same and that a serum concentration of 20 ng/L may not be sufficient for every individual. Also, just urging sun exposure may not be enough for some patients, either. Multiple studies in the literature have shown that serum concentrations can vary widely among individuals, even when they have had equivalent levels of sun exposure, said Dr. Binkley.
Lab tests for serum vitamin D levels have improved over the years, but they are far from perfect.
So what are adequate levels? According to several studies in sun-exposed individuals, 20 ng/mL seems low and levels in the mid-30s seem reasonable, said Dr. Binkley. "I think we need to be above 30," he said, noting that, for many patients, that means a daily intake of 1,000-2,000 IU of vitamin D daily.
That advice jibes with a statement the American Association of Clinical Endocrinologists issued shortly after the IOM report. AACE recommended that an optimal range for most patients should be 30-50 ng/mL. To achieve that, it would be necessary to take 1,000-2,000 IU of vitamin D daily. The group also said that physicians should use the IOM recommendations "in conjunction with clinical judgment to determine the proper vitamin D requirement for any given patient."
The evidence seems to support that higher serum levels (greater than 30 ng/mL) are associated with reduced fracture and fall risk, but that at super-high levels, vitamin D actually increases falls and fractures, said Dr. Binkley. It’s not clear why that is. In the study, women were given a megadose of 500,000 IU of vitamin D once a year; findings suggested that a big blast of the vitamin is not helpful, he said (JAMA 2010:303:1815-22).
The data show that for each additional 1,000 IU daily, the serum level goes up by about 6 ng/mL. Increases will be greater for patients who start with lower serum levels. To determine what’s optimal, it’s probably necessary to measure serum levels periodically, Dr. Binkley said.
If you write a prescription, you’re likely to get the less optimal form of vitamin D, that is, vitamin D2. Humans make vitamin D3 when they are exposed to sunlight, but only D2 is available in prescription form. Dr. Binkley said that he prefers patients to take D3, which is available over the counter. But if he’s going for a big repletion – say a typical 50,000 IU dose – he has to use the D2 form.
It is possible to have vitamin D intoxication. Most studies have never documented anyone with serum levels greater than 70 ng/mL. Patients who have levels above 70 are probably getting too much vitamin D, he said.
Equally intoxicating is the hype surrounding vitamin D, which recently has been touted as a veritable fountain of youth. Almost every tissue in the body has a vitamin D receptor and it is produced locally by many tissues. But the evidence does not support the notion that low levels are responsible for a laundry list of diseases, Dr. Binkley said. It is plausible that low vitamin D contributes to impaired immune function, diabetes, vascular disease, and a higher risk for bone loss and fractures, among other conditions. Sufficient vitamin D may also reduce cancer risk.
But so far, too many studies show association, and not causation. "We need to stay tuned," said Dr. Binkley, noting that there need to be more randomized, prospective studies and no more meta-analyses.
The IOM report "is too weak," but trying to get patients to serum vitamin D levels greater than 40 ng/mL is not responsible, Dr. Binkley stressed.
Dr. Binkley has consulting arrangements with Eli Lilly and Merck, and grants from those companies as well as Amgen and Tarsa, but none relate to vitamin D.
NEW ORLEANS – When the Institute of Medicine released updated recommendations on calcium and vitamin D intake in late 2010, the report became the backbone for clinical guidance. But since then, they have been hotly debated among those who say that the recommendations were too weak, and others who say that it has been inappropriately used to herald vitamin D as the next wonder substance, with little scientific evidence backing that claim.
The IOM guidelines "fail the smell test," said Dr. Neil Binkley, a geriatrician and research scientist at the University of Wisconsin–Madison. The recommended intake for a 1-year-old (600 IU/day) is the same as for a 70-year-old. That would make the recommended dietary allowance for vitamin D one of the few RDAs that do not adjust for age, he said at the annual meeting of the American College of Physicians.
In addition, the recommendations were formulated from a public health standpoint. That makes them less useful for determining the best recommended dietary allowance for an individual patient. Knowing an individual’s particular risk factors and variables in his or her life are crucial for determining an appropriate intake, he said.
Vitamin D deficiency is likely a growing issue, not just in the United States, but worldwide. Vitamin D is not commonly found in food, but is easily synthesized from sunlight. Centuries ago, humans wore less clothing and did not wear sunscreen. Now, of course, avoidance of sun exposure is common practice and has likely contributed to lower serum vitamin D levels in modern humans, he said.
For instance, a recent study showed that two traditional sub-Saharan tribes – the Maasai and the Hadzabe – who wear little clothing, do not use sunscreen, and have darkly pigmented skin (putting them at greater risk for vitamin D deficiency) – had a mean serum 25-hydroxyvitamin D concentration of 46 ng/mL (or 115 nmol/L), according to a study (Br. J. Nutr. 2012 Jan. 23 [doi:10.1017/S0007114511007161]).
This serum concentration is much greater than the IOM’s target of "sufficient" levels (defined as greater than 30 nmol/L). Levels between 20 and 30 nmol/L are considered insufficient, and less than 12 is considered deficient. According to these IOM figures, some 80% of whites have sufficient levels, whereas 71% of African Americans and 46% of Mexican Americans have low levels of serum vitamin D. Dr. Binkley said that he considers the IOM cut-offs to be conservative, but even according to those numbers, as much as a third of the U.S. population may be deficient.
Guidelines subsequently issued by the Endocrine Society called for higher RDAs than that recommended by the IOM, underscoring the lack of consensus around what constitutes a sufficient vitamin D intake, said Dr. Binkley.
There’s also lack of consensus around who should be screened for serum vitamin D levels. The Endocrine Society has called for screening of those "at risk," but then categorizes so many people as being at risk that it’s essentially equivalent to total population screening, said Dr. Binkley. He supports screening, in particular of older adults with a history of falls, and of others with a history of nontraumatic fractures. But he does not advocate total population screening.
What should physicians do? First, recognize that not all patients are the same and that a serum concentration of 20 ng/L may not be sufficient for every individual. Also, just urging sun exposure may not be enough for some patients, either. Multiple studies in the literature have shown that serum concentrations can vary widely among individuals, even when they have had equivalent levels of sun exposure, said Dr. Binkley.
Lab tests for serum vitamin D levels have improved over the years, but they are far from perfect.
So what are adequate levels? According to several studies in sun-exposed individuals, 20 ng/mL seems low and levels in the mid-30s seem reasonable, said Dr. Binkley. "I think we need to be above 30," he said, noting that, for many patients, that means a daily intake of 1,000-2,000 IU of vitamin D daily.
That advice jibes with a statement the American Association of Clinical Endocrinologists issued shortly after the IOM report. AACE recommended that an optimal range for most patients should be 30-50 ng/mL. To achieve that, it would be necessary to take 1,000-2,000 IU of vitamin D daily. The group also said that physicians should use the IOM recommendations "in conjunction with clinical judgment to determine the proper vitamin D requirement for any given patient."
The evidence seems to support that higher serum levels (greater than 30 ng/mL) are associated with reduced fracture and fall risk, but that at super-high levels, vitamin D actually increases falls and fractures, said Dr. Binkley. It’s not clear why that is. In the study, women were given a megadose of 500,000 IU of vitamin D once a year; findings suggested that a big blast of the vitamin is not helpful, he said (JAMA 2010:303:1815-22).
The data show that for each additional 1,000 IU daily, the serum level goes up by about 6 ng/mL. Increases will be greater for patients who start with lower serum levels. To determine what’s optimal, it’s probably necessary to measure serum levels periodically, Dr. Binkley said.
If you write a prescription, you’re likely to get the less optimal form of vitamin D, that is, vitamin D2. Humans make vitamin D3 when they are exposed to sunlight, but only D2 is available in prescription form. Dr. Binkley said that he prefers patients to take D3, which is available over the counter. But if he’s going for a big repletion – say a typical 50,000 IU dose – he has to use the D2 form.
It is possible to have vitamin D intoxication. Most studies have never documented anyone with serum levels greater than 70 ng/mL. Patients who have levels above 70 are probably getting too much vitamin D, he said.
Equally intoxicating is the hype surrounding vitamin D, which recently has been touted as a veritable fountain of youth. Almost every tissue in the body has a vitamin D receptor and it is produced locally by many tissues. But the evidence does not support the notion that low levels are responsible for a laundry list of diseases, Dr. Binkley said. It is plausible that low vitamin D contributes to impaired immune function, diabetes, vascular disease, and a higher risk for bone loss and fractures, among other conditions. Sufficient vitamin D may also reduce cancer risk.
But so far, too many studies show association, and not causation. "We need to stay tuned," said Dr. Binkley, noting that there need to be more randomized, prospective studies and no more meta-analyses.
The IOM report "is too weak," but trying to get patients to serum vitamin D levels greater than 40 ng/mL is not responsible, Dr. Binkley stressed.
Dr. Binkley has consulting arrangements with Eli Lilly and Merck, and grants from those companies as well as Amgen and Tarsa, but none relate to vitamin D.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF PHYSICIANS
Vitamin D Levels Correspond to Disability in MS
NEW ORLEANS – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study.
The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco.
They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments.
Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.
"The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same," she said at the annual meeting of the American Academy of Neurology.
Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise.
The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.
Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end.
Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant.
The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).
Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).
Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS.
The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.
NEW ORLEANS – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study.
The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco.
They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments.
Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.
"The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same," she said at the annual meeting of the American Academy of Neurology.
Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise.
The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.
Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end.
Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant.
The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).
Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).
Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS.
The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.
NEW ORLEANS – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study.
The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco.
They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments.
Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.
"The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same," she said at the annual meeting of the American Academy of Neurology.
Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise.
The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.
Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end.
Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant.
The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).
Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).
Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS.
The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.
FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY
Major Finding: For every 10-ng/mL increase in 25-hydroxyvitamin D levels in patients with multiple sclerosis, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% CI, –0.091 to –0.003; P = .037).
Data Source: This was a 5-year observational study involving 469 subjects
Disclosures: The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.
Hormonal Contraceptives Insignificantly Lower Vitamin B12 Levels
Hormonal contraception caused serum levels of vitamin B12 to decrease over a period of 3 years, but the reduction did not appear to be clinically significant or to impact bone mineral density in a large study limited to women of child-bearing age.
"This longitudinal study adds to the literature by demonstrating a cause and effect relationship between OC use and serum B12 levels. In addition, we observed lower B12 levels among DMPA [depot medroxyprogesterone acetate] users, which has not been previously reported in the literature," lead author Dr. Abbey B. Berenson reported online March 28 in the journal Contraception (Contraception 2012 March 28 [doi: 10.1016/j.contraception.2012.02.015]). "However, levels still remained in the normal range for almost all users. By and large, these findings agree with previous cross-sectional and case-control studies on the effect of OCs on serum B12 levels.
Dr. Berenson, of the department of obstetrics and gynecology and the Center for Interdisciplinary Research at The University of Texas Medical Branch, Galveston, and her associate, Dr. Mahbubur Rahman, recruited 703 women aged 16-33 years. The women were asked to choose one of three birth control methods: 245 chose an OC (0.15 mg desogestrel+20 mcg EE taken for 21 days, followed by 2 days of placebo and 5 days of 10 mcg EE); 240 chose DMPA; and 218 chose a nonhormonal method (barrier method, 53%; tubal ligation, 33%; copper T, 10%; and partner vasectomy, 4%). DMPA and the OC were dispensed every 3 months. Nonhormonal contraceptive users also attended a clinic every 3 months and were offered a supply of condoms at each visit.
At each 6-month visit over the course of 3 years, study participants underwent weight and height measurements, BMD measures of the lumbar spine and femoral neck via dual energy X-ray absorptiometry, and serum B12 measures via immunoassay.
The mean age of the study participants was 24 years, 36% were Hispanic, 35% were non-Hispanic white, and 29% were non-Hispanic black.
Women in all three groups had a decrease in mean B12 levels over the 3-year time period. Those taking an OC or DMPA had greater B12 decreases than women using nonhormonal contraception (P less than .001). During the first 6 months of use, for example, women in the OC and DMPA groups experienced B12 decreases of 97 pg/mL and 64 pg/mL, respectively, which represented declines of 20% and 13% from their baseline values. At the same time, women in the nonhormonal group experienced a decrease of 14 pg/mL, or a decline of 3% from the baseline value. Over the remaining 30 months of the study, B12 levels did not further decline among women in the OC group, but dropped another 22 pg/mL in the women in the DMPA group, and fell another 17 pg/mL in the women in using nonhormonal contraception.
After adjusting for age, whole body lean mass, duration of use, contraceptive methods, race/ethnicity, smoking status, and duration of previous DMPA use, the researchers found no significant association between mean B12 levels and mean BMD at the spine (P = .107) or femoral neck (P = .877).
Very few women had B12 deficiency, defined as a B12 level of less than 180 pg/mL: There were four in the nonhormonal group, two in the DMPA group, and nine in the OC group.
The researchers noted that the manner by which hormonal contraception causes a decrease in serum B12 remains unclear. "One possible mechanism is a deficiency in the level of serum B12 binders resulting in a false low B12 level in OC users," they hypothesized. "However, several studies have shown no difference in the level of mean unsaturated B12 binders between OC users and nonusers, suggesting that absorption is not affected and that redistribution of B12 throughout the body could be responsible. However, the mechanism of this redistribution is unknown. Furthermore, the mechanism of suppression of B12 levels among DMPA users, which was less severe than that observed among OC users in our study, has not been determined."
The observation that B12 levels were not associated with BMD, regardless of type of contraceptive use, contrasted with findings from several previous studies. "All but one of these prior studies, however, focused on postmenopausal women, who may react differently," the researchers noted. "The one study that did include reproductive-age women was limited to European adolescents who adhered to a specific diet plan (one group consumed a macrobiotic diet for up to 6 years followed by a vegetarian/omnivorous diet, while the other group ate an omnivorous diet throughout their life). Furthermore, it differed from the current study in that it was cross-sectional in design and included males as well as females. These differences could explain the variation in findings between their study and ours."
The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Institutes of Health.
Hormonal contraception caused serum levels of vitamin B12 to decrease over a period of 3 years, but the reduction did not appear to be clinically significant or to impact bone mineral density in a large study limited to women of child-bearing age.
"This longitudinal study adds to the literature by demonstrating a cause and effect relationship between OC use and serum B12 levels. In addition, we observed lower B12 levels among DMPA [depot medroxyprogesterone acetate] users, which has not been previously reported in the literature," lead author Dr. Abbey B. Berenson reported online March 28 in the journal Contraception (Contraception 2012 March 28 [doi: 10.1016/j.contraception.2012.02.015]). "However, levels still remained in the normal range for almost all users. By and large, these findings agree with previous cross-sectional and case-control studies on the effect of OCs on serum B12 levels.
Dr. Berenson, of the department of obstetrics and gynecology and the Center for Interdisciplinary Research at The University of Texas Medical Branch, Galveston, and her associate, Dr. Mahbubur Rahman, recruited 703 women aged 16-33 years. The women were asked to choose one of three birth control methods: 245 chose an OC (0.15 mg desogestrel+20 mcg EE taken for 21 days, followed by 2 days of placebo and 5 days of 10 mcg EE); 240 chose DMPA; and 218 chose a nonhormonal method (barrier method, 53%; tubal ligation, 33%; copper T, 10%; and partner vasectomy, 4%). DMPA and the OC were dispensed every 3 months. Nonhormonal contraceptive users also attended a clinic every 3 months and were offered a supply of condoms at each visit.
At each 6-month visit over the course of 3 years, study participants underwent weight and height measurements, BMD measures of the lumbar spine and femoral neck via dual energy X-ray absorptiometry, and serum B12 measures via immunoassay.
The mean age of the study participants was 24 years, 36% were Hispanic, 35% were non-Hispanic white, and 29% were non-Hispanic black.
Women in all three groups had a decrease in mean B12 levels over the 3-year time period. Those taking an OC or DMPA had greater B12 decreases than women using nonhormonal contraception (P less than .001). During the first 6 months of use, for example, women in the OC and DMPA groups experienced B12 decreases of 97 pg/mL and 64 pg/mL, respectively, which represented declines of 20% and 13% from their baseline values. At the same time, women in the nonhormonal group experienced a decrease of 14 pg/mL, or a decline of 3% from the baseline value. Over the remaining 30 months of the study, B12 levels did not further decline among women in the OC group, but dropped another 22 pg/mL in the women in the DMPA group, and fell another 17 pg/mL in the women in using nonhormonal contraception.
After adjusting for age, whole body lean mass, duration of use, contraceptive methods, race/ethnicity, smoking status, and duration of previous DMPA use, the researchers found no significant association between mean B12 levels and mean BMD at the spine (P = .107) or femoral neck (P = .877).
Very few women had B12 deficiency, defined as a B12 level of less than 180 pg/mL: There were four in the nonhormonal group, two in the DMPA group, and nine in the OC group.
The researchers noted that the manner by which hormonal contraception causes a decrease in serum B12 remains unclear. "One possible mechanism is a deficiency in the level of serum B12 binders resulting in a false low B12 level in OC users," they hypothesized. "However, several studies have shown no difference in the level of mean unsaturated B12 binders between OC users and nonusers, suggesting that absorption is not affected and that redistribution of B12 throughout the body could be responsible. However, the mechanism of this redistribution is unknown. Furthermore, the mechanism of suppression of B12 levels among DMPA users, which was less severe than that observed among OC users in our study, has not been determined."
The observation that B12 levels were not associated with BMD, regardless of type of contraceptive use, contrasted with findings from several previous studies. "All but one of these prior studies, however, focused on postmenopausal women, who may react differently," the researchers noted. "The one study that did include reproductive-age women was limited to European adolescents who adhered to a specific diet plan (one group consumed a macrobiotic diet for up to 6 years followed by a vegetarian/omnivorous diet, while the other group ate an omnivorous diet throughout their life). Furthermore, it differed from the current study in that it was cross-sectional in design and included males as well as females. These differences could explain the variation in findings between their study and ours."
The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Institutes of Health.
Hormonal contraception caused serum levels of vitamin B12 to decrease over a period of 3 years, but the reduction did not appear to be clinically significant or to impact bone mineral density in a large study limited to women of child-bearing age.
"This longitudinal study adds to the literature by demonstrating a cause and effect relationship between OC use and serum B12 levels. In addition, we observed lower B12 levels among DMPA [depot medroxyprogesterone acetate] users, which has not been previously reported in the literature," lead author Dr. Abbey B. Berenson reported online March 28 in the journal Contraception (Contraception 2012 March 28 [doi: 10.1016/j.contraception.2012.02.015]). "However, levels still remained in the normal range for almost all users. By and large, these findings agree with previous cross-sectional and case-control studies on the effect of OCs on serum B12 levels.
Dr. Berenson, of the department of obstetrics and gynecology and the Center for Interdisciplinary Research at The University of Texas Medical Branch, Galveston, and her associate, Dr. Mahbubur Rahman, recruited 703 women aged 16-33 years. The women were asked to choose one of three birth control methods: 245 chose an OC (0.15 mg desogestrel+20 mcg EE taken for 21 days, followed by 2 days of placebo and 5 days of 10 mcg EE); 240 chose DMPA; and 218 chose a nonhormonal method (barrier method, 53%; tubal ligation, 33%; copper T, 10%; and partner vasectomy, 4%). DMPA and the OC were dispensed every 3 months. Nonhormonal contraceptive users also attended a clinic every 3 months and were offered a supply of condoms at each visit.
At each 6-month visit over the course of 3 years, study participants underwent weight and height measurements, BMD measures of the lumbar spine and femoral neck via dual energy X-ray absorptiometry, and serum B12 measures via immunoassay.
The mean age of the study participants was 24 years, 36% were Hispanic, 35% were non-Hispanic white, and 29% were non-Hispanic black.
Women in all three groups had a decrease in mean B12 levels over the 3-year time period. Those taking an OC or DMPA had greater B12 decreases than women using nonhormonal contraception (P less than .001). During the first 6 months of use, for example, women in the OC and DMPA groups experienced B12 decreases of 97 pg/mL and 64 pg/mL, respectively, which represented declines of 20% and 13% from their baseline values. At the same time, women in the nonhormonal group experienced a decrease of 14 pg/mL, or a decline of 3% from the baseline value. Over the remaining 30 months of the study, B12 levels did not further decline among women in the OC group, but dropped another 22 pg/mL in the women in the DMPA group, and fell another 17 pg/mL in the women in using nonhormonal contraception.
After adjusting for age, whole body lean mass, duration of use, contraceptive methods, race/ethnicity, smoking status, and duration of previous DMPA use, the researchers found no significant association between mean B12 levels and mean BMD at the spine (P = .107) or femoral neck (P = .877).
Very few women had B12 deficiency, defined as a B12 level of less than 180 pg/mL: There were four in the nonhormonal group, two in the DMPA group, and nine in the OC group.
The researchers noted that the manner by which hormonal contraception causes a decrease in serum B12 remains unclear. "One possible mechanism is a deficiency in the level of serum B12 binders resulting in a false low B12 level in OC users," they hypothesized. "However, several studies have shown no difference in the level of mean unsaturated B12 binders between OC users and nonusers, suggesting that absorption is not affected and that redistribution of B12 throughout the body could be responsible. However, the mechanism of this redistribution is unknown. Furthermore, the mechanism of suppression of B12 levels among DMPA users, which was less severe than that observed among OC users in our study, has not been determined."
The observation that B12 levels were not associated with BMD, regardless of type of contraceptive use, contrasted with findings from several previous studies. "All but one of these prior studies, however, focused on postmenopausal women, who may react differently," the researchers noted. "The one study that did include reproductive-age women was limited to European adolescents who adhered to a specific diet plan (one group consumed a macrobiotic diet for up to 6 years followed by a vegetarian/omnivorous diet, while the other group ate an omnivorous diet throughout their life). Furthermore, it differed from the current study in that it was cross-sectional in design and included males as well as females. These differences could explain the variation in findings between their study and ours."
The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Institutes of Health.
FROM CONTRACEPTION
Major Finding: During the first 6 months after the women started hormonal contraception, B12 levels declined by 97 pg/mL (20%) in the OC group and by 64 pg/mL (13%) in the DMPA group. Women in the nonhormonal contraception group experienced a decrease of 14 pg/mL (3%).
Data Source: A 3-year study of 703 women, aged 16-33, who chose one of three birth control methods and who had measures of serum B12 and BMD every 6 months.
Disclosures: The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Institutes of Health.
Narcotics in Place of NSAIDs Mean More Falls, Fractures
SNOWMASS, COLO. – The guideline-endorsed demotion of nonsteroidal anti-inflammatory drugs in favor of narcotic analgesics for chronic pain has led to a marked increase in falls, fractures, and other bad outcomes among elderly arthritis patients.
“The real take-home message here is that current guidelines for the treatment of pain should be revisited,” Dr. Bruce N. Cronstein asserted at the conference.
Since the cyclo-oxygenase-2 (COX-2)-selective NSAID rofecoxib (Vioxx) was taken off the market in late 2004 because of a scandal related to cover-up of an increased risk of myocardial infarction, prescriptions for narcotic analgesics in elderly patients with arthritis have risen sharply. This trend accelerated following the 2007 publication of an American Heart Association scientific statement on the treatment of chronic pain in patients with or at increased risk for heart disease (Circulation 2007;115:1634-42). The AHA guidelines elevated short-term use of narcotic analgesics to first-tier status alongside aspirin, acetaminophen, and tramadol, while demoting both COX-2-selective and nonselective NSAIDs to second-tier status.
Data supporting the unintended consequences of such changes in treatment priorities come from a study by Dr. Cronstein, Dr. Paul R. Esserman professor of medicine at New York University, and his associates. They conducted a nested case-control study of 3,830 elderly patients with osteoarthritis (OA) in the Geisinger Health Plan in Danville, Pa., who had fractures and 11,490 others matched for age and Charlson Comorbidity Index without fractures. In a multivariate analysis, patients on narcotic analgesics had a threefold greater risk of falls or fractures than those on either COX-2-selective or nonselective NSAIDs.
Thus, the use of narcotic analgesics as the sole prescription medication for pain relief in elderly OA patients more than doubled after Vioxx was withdrawn from the market. The patients on narcotic analgesics with or without a COX-2-selective NSAID had a fourfold greater rate of falls or fractures than those on nonselective NSAIDs or COX-2-selective agents.
Dr. Cronstein noted that the AHA guidelines focus on the evidence of increased cardiovascular risk associated with nearly all NSAIDs without considering how the drugs stack up in terms of overall safety – noncardiovascular as well as cardiovascular – compared with the other major analgesic group: narcotic analgesics. And it turns out that the NSAIDs look pretty good in comparison, he added.
“You're trading off falls and fractures for MIs – and it turns out that in patients over age 65, the mortality from hip fracture is significantly greater than it is for MI,” said Dr. Cronstein, who is also director of the Clinical and Translational Science Institute.
He cited a large Medicare study conducted that examined the comparative safety of analgesics in elderly arthritis patients and concluded that narcotic analgesics come up short.
The investigators, at Brigham and Women's Hospital, Boston, sifted through the population of Medicare beneficiaries in Pennsylvania and New Jersey to identify elderly patients with rheumatoid arthritis or osteoarthritis (OA) who were started on a nonselective NSAID, a COX-2-selective NSAID, or a narcotic analgesic during 1999-2005. They came up with 4,280 propensity score–matched patients in each of the three groups.
The composite incidence of fractures of the hip, pelvis, humerus, or radius was 26 per 1,000 person-years in patients on nonselective NSAIDs, 19 with COX-2-selective NSAIDs, and 101 with opioids.
While it's not really surprising that opiate analgesics should be linked with increased risk of falls and fractures, another finding in this study proved unexpected: The composite cardiovascular event rate was 77 per 1,000 person-years with nonselective NSAIDs, 88 per 1,000 with COX-2-selective NSAIDs, and 122 with narcotic analgesics.
The patients taking opioids had a 77% greater risk of cardiovascular events and those taking COX-2-selective NSAIDs had a 28% greater risk than did patients on nonselective NSAIDs, according to findings from a multivariate Cox regression analysis. The fracture risk was 4.47-fold greater with narcotic analgesics than with NSAIDs. The GI bleeding risk was 40% lower in the COX-2-selective NSAID group than in the other groups. The all-cause mortality risk was 87% greater in the narcotic analgesic group than with nonselective NSAIDs, while COX-2-selective NSAIDs weren't tied to increased risk (Arch. Intern. Med. 2010;170:1968-78).
This work was funded by the National Institutes of Health, the Geisinger Clinic, and the Clinical and Translational Science Institute. Dr. Cronstein has served as a paid consultant to Allos, Bristol-Myers Squibb, Novartis, and several other pharmaceutical companies.
'You're trading off falls and fractures for MIs,' while hip fracture is significantly deadlier than MI after age 65.
Source DR. CRONSTEIN
SNOWMASS, COLO. – The guideline-endorsed demotion of nonsteroidal anti-inflammatory drugs in favor of narcotic analgesics for chronic pain has led to a marked increase in falls, fractures, and other bad outcomes among elderly arthritis patients.
“The real take-home message here is that current guidelines for the treatment of pain should be revisited,” Dr. Bruce N. Cronstein asserted at the conference.
Since the cyclo-oxygenase-2 (COX-2)-selective NSAID rofecoxib (Vioxx) was taken off the market in late 2004 because of a scandal related to cover-up of an increased risk of myocardial infarction, prescriptions for narcotic analgesics in elderly patients with arthritis have risen sharply. This trend accelerated following the 2007 publication of an American Heart Association scientific statement on the treatment of chronic pain in patients with or at increased risk for heart disease (Circulation 2007;115:1634-42). The AHA guidelines elevated short-term use of narcotic analgesics to first-tier status alongside aspirin, acetaminophen, and tramadol, while demoting both COX-2-selective and nonselective NSAIDs to second-tier status.
Data supporting the unintended consequences of such changes in treatment priorities come from a study by Dr. Cronstein, Dr. Paul R. Esserman professor of medicine at New York University, and his associates. They conducted a nested case-control study of 3,830 elderly patients with osteoarthritis (OA) in the Geisinger Health Plan in Danville, Pa., who had fractures and 11,490 others matched for age and Charlson Comorbidity Index without fractures. In a multivariate analysis, patients on narcotic analgesics had a threefold greater risk of falls or fractures than those on either COX-2-selective or nonselective NSAIDs.
Thus, the use of narcotic analgesics as the sole prescription medication for pain relief in elderly OA patients more than doubled after Vioxx was withdrawn from the market. The patients on narcotic analgesics with or without a COX-2-selective NSAID had a fourfold greater rate of falls or fractures than those on nonselective NSAIDs or COX-2-selective agents.
Dr. Cronstein noted that the AHA guidelines focus on the evidence of increased cardiovascular risk associated with nearly all NSAIDs without considering how the drugs stack up in terms of overall safety – noncardiovascular as well as cardiovascular – compared with the other major analgesic group: narcotic analgesics. And it turns out that the NSAIDs look pretty good in comparison, he added.
“You're trading off falls and fractures for MIs – and it turns out that in patients over age 65, the mortality from hip fracture is significantly greater than it is for MI,” said Dr. Cronstein, who is also director of the Clinical and Translational Science Institute.
He cited a large Medicare study conducted that examined the comparative safety of analgesics in elderly arthritis patients and concluded that narcotic analgesics come up short.
The investigators, at Brigham and Women's Hospital, Boston, sifted through the population of Medicare beneficiaries in Pennsylvania and New Jersey to identify elderly patients with rheumatoid arthritis or osteoarthritis (OA) who were started on a nonselective NSAID, a COX-2-selective NSAID, or a narcotic analgesic during 1999-2005. They came up with 4,280 propensity score–matched patients in each of the three groups.
The composite incidence of fractures of the hip, pelvis, humerus, or radius was 26 per 1,000 person-years in patients on nonselective NSAIDs, 19 with COX-2-selective NSAIDs, and 101 with opioids.
While it's not really surprising that opiate analgesics should be linked with increased risk of falls and fractures, another finding in this study proved unexpected: The composite cardiovascular event rate was 77 per 1,000 person-years with nonselective NSAIDs, 88 per 1,000 with COX-2-selective NSAIDs, and 122 with narcotic analgesics.
The patients taking opioids had a 77% greater risk of cardiovascular events and those taking COX-2-selective NSAIDs had a 28% greater risk than did patients on nonselective NSAIDs, according to findings from a multivariate Cox regression analysis. The fracture risk was 4.47-fold greater with narcotic analgesics than with NSAIDs. The GI bleeding risk was 40% lower in the COX-2-selective NSAID group than in the other groups. The all-cause mortality risk was 87% greater in the narcotic analgesic group than with nonselective NSAIDs, while COX-2-selective NSAIDs weren't tied to increased risk (Arch. Intern. Med. 2010;170:1968-78).
This work was funded by the National Institutes of Health, the Geisinger Clinic, and the Clinical and Translational Science Institute. Dr. Cronstein has served as a paid consultant to Allos, Bristol-Myers Squibb, Novartis, and several other pharmaceutical companies.
'You're trading off falls and fractures for MIs,' while hip fracture is significantly deadlier than MI after age 65.
Source DR. CRONSTEIN
SNOWMASS, COLO. – The guideline-endorsed demotion of nonsteroidal anti-inflammatory drugs in favor of narcotic analgesics for chronic pain has led to a marked increase in falls, fractures, and other bad outcomes among elderly arthritis patients.
“The real take-home message here is that current guidelines for the treatment of pain should be revisited,” Dr. Bruce N. Cronstein asserted at the conference.
Since the cyclo-oxygenase-2 (COX-2)-selective NSAID rofecoxib (Vioxx) was taken off the market in late 2004 because of a scandal related to cover-up of an increased risk of myocardial infarction, prescriptions for narcotic analgesics in elderly patients with arthritis have risen sharply. This trend accelerated following the 2007 publication of an American Heart Association scientific statement on the treatment of chronic pain in patients with or at increased risk for heart disease (Circulation 2007;115:1634-42). The AHA guidelines elevated short-term use of narcotic analgesics to first-tier status alongside aspirin, acetaminophen, and tramadol, while demoting both COX-2-selective and nonselective NSAIDs to second-tier status.
Data supporting the unintended consequences of such changes in treatment priorities come from a study by Dr. Cronstein, Dr. Paul R. Esserman professor of medicine at New York University, and his associates. They conducted a nested case-control study of 3,830 elderly patients with osteoarthritis (OA) in the Geisinger Health Plan in Danville, Pa., who had fractures and 11,490 others matched for age and Charlson Comorbidity Index without fractures. In a multivariate analysis, patients on narcotic analgesics had a threefold greater risk of falls or fractures than those on either COX-2-selective or nonselective NSAIDs.
Thus, the use of narcotic analgesics as the sole prescription medication for pain relief in elderly OA patients more than doubled after Vioxx was withdrawn from the market. The patients on narcotic analgesics with or without a COX-2-selective NSAID had a fourfold greater rate of falls or fractures than those on nonselective NSAIDs or COX-2-selective agents.
Dr. Cronstein noted that the AHA guidelines focus on the evidence of increased cardiovascular risk associated with nearly all NSAIDs without considering how the drugs stack up in terms of overall safety – noncardiovascular as well as cardiovascular – compared with the other major analgesic group: narcotic analgesics. And it turns out that the NSAIDs look pretty good in comparison, he added.
“You're trading off falls and fractures for MIs – and it turns out that in patients over age 65, the mortality from hip fracture is significantly greater than it is for MI,” said Dr. Cronstein, who is also director of the Clinical and Translational Science Institute.
He cited a large Medicare study conducted that examined the comparative safety of analgesics in elderly arthritis patients and concluded that narcotic analgesics come up short.
The investigators, at Brigham and Women's Hospital, Boston, sifted through the population of Medicare beneficiaries in Pennsylvania and New Jersey to identify elderly patients with rheumatoid arthritis or osteoarthritis (OA) who were started on a nonselective NSAID, a COX-2-selective NSAID, or a narcotic analgesic during 1999-2005. They came up with 4,280 propensity score–matched patients in each of the three groups.
The composite incidence of fractures of the hip, pelvis, humerus, or radius was 26 per 1,000 person-years in patients on nonselective NSAIDs, 19 with COX-2-selective NSAIDs, and 101 with opioids.
While it's not really surprising that opiate analgesics should be linked with increased risk of falls and fractures, another finding in this study proved unexpected: The composite cardiovascular event rate was 77 per 1,000 person-years with nonselective NSAIDs, 88 per 1,000 with COX-2-selective NSAIDs, and 122 with narcotic analgesics.
The patients taking opioids had a 77% greater risk of cardiovascular events and those taking COX-2-selective NSAIDs had a 28% greater risk than did patients on nonselective NSAIDs, according to findings from a multivariate Cox regression analysis. The fracture risk was 4.47-fold greater with narcotic analgesics than with NSAIDs. The GI bleeding risk was 40% lower in the COX-2-selective NSAID group than in the other groups. The all-cause mortality risk was 87% greater in the narcotic analgesic group than with nonselective NSAIDs, while COX-2-selective NSAIDs weren't tied to increased risk (Arch. Intern. Med. 2010;170:1968-78).
This work was funded by the National Institutes of Health, the Geisinger Clinic, and the Clinical and Translational Science Institute. Dr. Cronstein has served as a paid consultant to Allos, Bristol-Myers Squibb, Novartis, and several other pharmaceutical companies.
'You're trading off falls and fractures for MIs,' while hip fracture is significantly deadlier than MI after age 65.
Source DR. CRONSTEIN
Expert Analysis from a Symposium Sponsored by the American College of Rheumatology