Osteoporosis

SAN FRANCISCO — People with HIV infection tend to have more risk factors for bone loss than do people without HIV, and antiretroviral medications may be adding to that risk.

The specific role of antiretroviral therapy in bone loss has been controversial: Some studies say there is no association, but others suggest that the drugs do contribute to bone loss. Results of two small but well -conducted studies recently tipped the emphasis toward concern about the differential effects of antiretrovirals on bone mineral density, Dr. Dolores Shoback said at a meeting on HIV management sponsored by the University of California, San Francisco.

One randomized, controlled trial of 71 HIV-infected patients suggested that antiretroviral regimens that contain a protease inhibitor booster have a greater negative impact on spinal bone density than do regimens without a boosted protease inhibitor, said Dr. Shoback, professor of medicine at UCSF.

At baseline, 31% of the patients were osteopenic and 3% were osteoporotic. Bone densities were retested after 48 weeks of combination HIV therapy with a nonnucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside reverse transcriptase inhibitors (NRTIs), or an NNRTI and a boosted protease inhibitor, or two NRTIs and a boosted protease inhibitor. On average, the cohort as a whole lost 4% of lumbar spine bone mineral density and 3% of hip bone density during those 48 weeks (AIDS 2009;23:817-24).

The groups treated with boosted protease inhibitors lost significantly more spinal density—4.4% when combined with an NNRTI and 5.8% when combined with NRTIs—compared with the NNRTI-plus-NRTI arm (1.5%). Changes in hip bone density did not differ significantly by treatment group.

The second study randomized 50 HIV-infected patients to treatment with lopinavir/ritonavir plus zidovudine/lamivudine (ZDV/3TC) or lopinavir/ritonavir plus nevirapine, with bone densities compared at baseline and 2 years. At the start, up to 31% were osteopenic and up to 4% were osteoporotic. The ZDV/3TC group lost 6.3% of bone mineral density in the hip and 5.1% in the spine, compared with smaller losses of 2.3% in the hip and 2.6% in the spine in the nevirapine group. Spinal density decreased mainly in the first year and then stabilized, but hip density continued to fall in the second year (AIDS 2009;23:1367-76).

The investigators speculated that ZDV/3TC increased osteoclastic activity. “I think there probably is, in fact, a signal here,” Dr. Shoback said.

The evidence does not support changing antiretroviral regimens if bone mineral density is low, she added, but physicians should pay attention to nutrition (especially calcium and vitamin D), lifestyle factors, and weight-bearing exercise in patients with HIV.

Ongoing immune activation in HIV infection leads to high levels of cytokines. “There pretty much isn't a cytokine that doesn't have a negative effect on bone,” she said. Also, five of six cross-sectional studies found low levels of hydroxyvitamin D in patients with HIV. Compared with the HIV-negative population, people with HIV have higher rates of smoking and alcohol use, are more likely to be treated with steroids, and are more likely to have periods of immobilization and illness, bouts of weight loss, hypogonadism (in men), and amenorrhea (in women).

Dr. Shoback has been a speaker for Novartis.

HIV patients on antiretroviral regimens with a protease inhibitor booster have shown greater bone loss.

Source DR. SHOBACK

SAN FRANCISCO — People with HIV infection tend to have more risk factors for bone loss than do people without HIV, and antiretroviral medications may be adding to that risk.

The specific role of antiretroviral therapy in bone loss has been controversial: Some studies say there is no association, but others suggest that the drugs do contribute to bone loss. Results of two small but well -conducted studies recently tipped the emphasis toward concern about the differential effects of antiretrovirals on bone mineral density, Dr. Dolores Shoback said at a meeting on HIV management sponsored by the University of California, San Francisco.

One randomized, controlled trial of 71 HIV-infected patients suggested that antiretroviral regimens that contain a protease inhibitor booster have a greater negative impact on spinal bone density than do regimens without a boosted protease inhibitor, said Dr. Shoback, professor of medicine at UCSF.

At baseline, 31% of the patients were osteopenic and 3% were osteoporotic. Bone densities were retested after 48 weeks of combination HIV therapy with a nonnucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside reverse transcriptase inhibitors (NRTIs), or an NNRTI and a boosted protease inhibitor, or two NRTIs and a boosted protease inhibitor. On average, the cohort as a whole lost 4% of lumbar spine bone mineral density and 3% of hip bone density during those 48 weeks (AIDS 2009;23:817-24).

The groups treated with boosted protease inhibitors lost significantly more spinal density—4.4% when combined with an NNRTI and 5.8% when combined with NRTIs—compared with the NNRTI-plus-NRTI arm (1.5%). Changes in hip bone density did not differ significantly by treatment group.

The second study randomized 50 HIV-infected patients to treatment with lopinavir/ritonavir plus zidovudine/lamivudine (ZDV/3TC) or lopinavir/ritonavir plus nevirapine, with bone densities compared at baseline and 2 years. At the start, up to 31% were osteopenic and up to 4% were osteoporotic. The ZDV/3TC group lost 6.3% of bone mineral density in the hip and 5.1% in the spine, compared with smaller losses of 2.3% in the hip and 2.6% in the spine in the nevirapine group. Spinal density decreased mainly in the first year and then stabilized, but hip density continued to fall in the second year (AIDS 2009;23:1367-76).

The investigators speculated that ZDV/3TC increased osteoclastic activity. “I think there probably is, in fact, a signal here,” Dr. Shoback said.

The evidence does not support changing antiretroviral regimens if bone mineral density is low, she added, but physicians should pay attention to nutrition (especially calcium and vitamin D), lifestyle factors, and weight-bearing exercise in patients with HIV.

Ongoing immune activation in HIV infection leads to high levels of cytokines. “There pretty much isn't a cytokine that doesn't have a negative effect on bone,” she said. Also, five of six cross-sectional studies found low levels of hydroxyvitamin D in patients with HIV. Compared with the HIV-negative population, people with HIV have higher rates of smoking and alcohol use, are more likely to be treated with steroids, and are more likely to have periods of immobilization and illness, bouts of weight loss, hypogonadism (in men), and amenorrhea (in women).

Dr. Shoback has been a speaker for Novartis.

HIV patients on antiretroviral regimens with a protease inhibitor booster have shown greater bone loss.

Source DR. SHOBACK

SAN FRANCISCO — People with HIV infection tend to have more risk factors for bone loss than do people without HIV, and antiretroviral medications may be adding to that risk.

The specific role of antiretroviral therapy in bone loss has been controversial: Some studies say there is no association, but others suggest that the drugs do contribute to bone loss. Results of two small but well -conducted studies recently tipped the emphasis toward concern about the differential effects of antiretrovirals on bone mineral density, Dr. Dolores Shoback said at a meeting on HIV management sponsored by the University of California, San Francisco.

One randomized, controlled trial of 71 HIV-infected patients suggested that antiretroviral regimens that contain a protease inhibitor booster have a greater negative impact on spinal bone density than do regimens without a boosted protease inhibitor, said Dr. Shoback, professor of medicine at UCSF.

At baseline, 31% of the patients were osteopenic and 3% were osteoporotic. Bone densities were retested after 48 weeks of combination HIV therapy with a nonnucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside reverse transcriptase inhibitors (NRTIs), or an NNRTI and a boosted protease inhibitor, or two NRTIs and a boosted protease inhibitor. On average, the cohort as a whole lost 4% of lumbar spine bone mineral density and 3% of hip bone density during those 48 weeks (AIDS 2009;23:817-24).

The groups treated with boosted protease inhibitors lost significantly more spinal density—4.4% when combined with an NNRTI and 5.8% when combined with NRTIs—compared with the NNRTI-plus-NRTI arm (1.5%). Changes in hip bone density did not differ significantly by treatment group.

The second study randomized 50 HIV-infected patients to treatment with lopinavir/ritonavir plus zidovudine/lamivudine (ZDV/3TC) or lopinavir/ritonavir plus nevirapine, with bone densities compared at baseline and 2 years. At the start, up to 31% were osteopenic and up to 4% were osteoporotic. The ZDV/3TC group lost 6.3% of bone mineral density in the hip and 5.1% in the spine, compared with smaller losses of 2.3% in the hip and 2.6% in the spine in the nevirapine group. Spinal density decreased mainly in the first year and then stabilized, but hip density continued to fall in the second year (AIDS 2009;23:1367-76).

The investigators speculated that ZDV/3TC increased osteoclastic activity. “I think there probably is, in fact, a signal here,” Dr. Shoback said.

The evidence does not support changing antiretroviral regimens if bone mineral density is low, she added, but physicians should pay attention to nutrition (especially calcium and vitamin D), lifestyle factors, and weight-bearing exercise in patients with HIV.

Ongoing immune activation in HIV infection leads to high levels of cytokines. “There pretty much isn't a cytokine that doesn't have a negative effect on bone,” she said. Also, five of six cross-sectional studies found low levels of hydroxyvitamin D in patients with HIV. Compared with the HIV-negative population, people with HIV have higher rates of smoking and alcohol use, are more likely to be treated with steroids, and are more likely to have periods of immobilization and illness, bouts of weight loss, hypogonadism (in men), and amenorrhea (in women).

Dr. Shoback has been a speaker for Novartis.

HIV patients on antiretroviral regimens with a protease inhibitor booster have shown greater bone loss.

Source DR. SHOBACK

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

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

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

Discussing findings from a recent cross-sectional study involving 340 African Americans with type 2 diabetes, Dr. Buckley said that serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries (J. Clin. Endo. Metab. Jan. 8, 2010; Epub ahead of print PMID:20061416).

“The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African Americans are unknown. Prospective trials are needed,” the investigators wrote.

Recently, a large prospective randomized trial assessed the effects of using calcium supplements on vascular event rates, but it did not involve African Americans. The trial involved 1,471 healthy postmenopausal New Zealand women who were randomized to receive either supplemental calcium or placebo. By 5 years of follow-up, there were a total of 101 myocardial infarctions, strokes, and sudden deaths in 69 women in the supplemental calcium group compared to 54 such events in 42 control subjects (Br. Med. J. 2008; 336:262-6).

The numbers needed to treat (NNT) were “particularly disturbing,” said Dr. Buckley. The NNT for 5 years of supplemental calcium to cause one additional MI than with placebo was 44. The NNT for one stroke was 56. And the NNT to cause one additional cardiovascular event was 29. In contrast, the NNT to prevent one symptomatic fracture was 50.

The vascular event rate was higher in women with high compliance with calcium supplementation. The event rate was also higher during months 30–60 of follow-up, consistent with an initial latent period in which silent vascular damage occurs in advance of climbing cardiovascular event rates.

The vitamin D assay has become one of the most-ordered U.S. lab tests, despite the assay's questionable reliability, its $40-$200 cost, and considerable unresolved debate as to what constitutes an optimal blood level. Medicare is considering changing policy such that vitamin D tests for screening purposes would not be covered, according to Dr. Buckley.

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

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

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

There is intriguing evidence to indicate the optimal level of vitamin D to promote bone health, muscle strength, immunity, and other key functions may vary by race. Data from the National Health and Nutrition Examination Survey show that very few white children ages 1–12 years are vitamin D–deficient using the classic threshold of 15 ng/mL. In contrast, about 10% of non-Hispanic black 1- to 6-year-olds are vitamin D–deficient, as are close to 30% in the 7–12 age bracket (Pediatrics Sept. 2009; e362-70; doi:10-1542/peds.2009-0051).

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

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

Support for this notion comes from studies showing that pushing serum vitamin D levels to 30 ng/mL or higher in whites reduces their parathyroid hormone levels, while pushing levels above 20 ng/mL in African Americans—young or old—does not further decrease parathyroid hormone or increase bone density.

In her own practice, Dr. Buckley generally tries to get patients into the 20- to 29-ng/mL range, while in African Americans and patients with known cardiovascular disease she aims for 15 ng/mL or slightly more, she said. She reserves expedited supplementation—50,000 IU weekly for 8 weeks—mainly for vitamin D–deficient elderly patients at high risk for fracture or fall. That's where there is supporting evidence of benefit. There is no evidence to support supplementation in young or middle-aged patients.

Like many others, Dr. Buckley eagerly awaits fresh guidance in the form of updated recommendations on vitamin D from the Institute of Medicine. That IOM report, due this spring, is expected to recommend an increase in the currently recommended supplemental 400 IU/day for 50- to 70-year-olds not getting sufficient vitamin D from the sun (see related article on p. 1). Her hope is the IOM will address the thorny issues of who should receive supplementation, and how fast it should be done.

Dr. Buckley reported having no relevant financial relationships.

The extra calcium absorption promoted by boosting vitamin D may be taken up by atherosclerotic plaque.

Source DR. BUCKLEY

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

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

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

Discussing findings from a recent cross-sectional study involving 340 African Americans with type 2 diabetes, Dr. Buckley said that serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries (J. Clin. Endo. Metab. Jan. 8, 2010; Epub ahead of print PMID:20061416).

“The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African Americans are unknown. Prospective trials are needed,” the investigators wrote.

Recently, a large prospective randomized trial assessed the effects of using calcium supplements on vascular event rates, but it did not involve African Americans. The trial involved 1,471 healthy postmenopausal New Zealand women who were randomized to receive either supplemental calcium or placebo. By 5 years of follow-up, there were a total of 101 myocardial infarctions, strokes, and sudden deaths in 69 women in the supplemental calcium group compared to 54 such events in 42 control subjects (Br. Med. J. 2008; 336:262-6).

The numbers needed to treat (NNT) were “particularly disturbing,” said Dr. Buckley. The NNT for 5 years of supplemental calcium to cause one additional MI than with placebo was 44. The NNT for one stroke was 56. And the NNT to cause one additional cardiovascular event was 29. In contrast, the NNT to prevent one symptomatic fracture was 50.

The vascular event rate was higher in women with high compliance with calcium supplementation. The event rate was also higher during months 30–60 of follow-up, consistent with an initial latent period in which silent vascular damage occurs in advance of climbing cardiovascular event rates.

The vitamin D assay has become one of the most-ordered U.S. lab tests, despite the assay's questionable reliability, its $40-$200 cost, and considerable unresolved debate as to what constitutes an optimal blood level. Medicare is considering changing policy such that vitamin D tests for screening purposes would not be covered, according to Dr. Buckley.

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

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

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

There is intriguing evidence to indicate the optimal level of vitamin D to promote bone health, muscle strength, immunity, and other key functions may vary by race. Data from the National Health and Nutrition Examination Survey show that very few white children ages 1–12 years are vitamin D–deficient using the classic threshold of 15 ng/mL. In contrast, about 10% of non-Hispanic black 1- to 6-year-olds are vitamin D–deficient, as are close to 30% in the 7–12 age bracket (Pediatrics Sept. 2009; e362-70; doi:10-1542/peds.2009-0051).

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

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

Support for this notion comes from studies showing that pushing serum vitamin D levels to 30 ng/mL or higher in whites reduces their parathyroid hormone levels, while pushing levels above 20 ng/mL in African Americans—young or old—does not further decrease parathyroid hormone or increase bone density.

In her own practice, Dr. Buckley generally tries to get patients into the 20- to 29-ng/mL range, while in African Americans and patients with known cardiovascular disease she aims for 15 ng/mL or slightly more, she said. She reserves expedited supplementation—50,000 IU weekly for 8 weeks—mainly for vitamin D–deficient elderly patients at high risk for fracture or fall. That's where there is supporting evidence of benefit. There is no evidence to support supplementation in young or middle-aged patients.

Like many others, Dr. Buckley eagerly awaits fresh guidance in the form of updated recommendations on vitamin D from the Institute of Medicine. That IOM report, due this spring, is expected to recommend an increase in the currently recommended supplemental 400 IU/day for 50- to 70-year-olds not getting sufficient vitamin D from the sun (see related article on p. 1). Her hope is the IOM will address the thorny issues of who should receive supplementation, and how fast it should be done.

Dr. Buckley reported having no relevant financial relationships.

The extra calcium absorption promoted by boosting vitamin D may be taken up by atherosclerotic plaque.

Source DR. BUCKLEY

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

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

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

Discussing findings from a recent cross-sectional study involving 340 African Americans with type 2 diabetes, Dr. Buckley said that serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries (J. Clin. Endo. Metab. Jan. 8, 2010; Epub ahead of print PMID:20061416).

“The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African Americans are unknown. Prospective trials are needed,” the investigators wrote.

Recently, a large prospective randomized trial assessed the effects of using calcium supplements on vascular event rates, but it did not involve African Americans. The trial involved 1,471 healthy postmenopausal New Zealand women who were randomized to receive either supplemental calcium or placebo. By 5 years of follow-up, there were a total of 101 myocardial infarctions, strokes, and sudden deaths in 69 women in the supplemental calcium group compared to 54 such events in 42 control subjects (Br. Med. J. 2008; 336:262-6).

The numbers needed to treat (NNT) were “particularly disturbing,” said Dr. Buckley. The NNT for 5 years of supplemental calcium to cause one additional MI than with placebo was 44. The NNT for one stroke was 56. And the NNT to cause one additional cardiovascular event was 29. In contrast, the NNT to prevent one symptomatic fracture was 50.

The vascular event rate was higher in women with high compliance with calcium supplementation. The event rate was also higher during months 30–60 of follow-up, consistent with an initial latent period in which silent vascular damage occurs in advance of climbing cardiovascular event rates.

The vitamin D assay has become one of the most-ordered U.S. lab tests, despite the assay's questionable reliability, its $40-$200 cost, and considerable unresolved debate as to what constitutes an optimal blood level. Medicare is considering changing policy such that vitamin D tests for screening purposes would not be covered, according to Dr. Buckley.

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

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

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

There is intriguing evidence to indicate the optimal level of vitamin D to promote bone health, muscle strength, immunity, and other key functions may vary by race. Data from the National Health and Nutrition Examination Survey show that very few white children ages 1–12 years are vitamin D–deficient using the classic threshold of 15 ng/mL. In contrast, about 10% of non-Hispanic black 1- to 6-year-olds are vitamin D–deficient, as are close to 30% in the 7–12 age bracket (Pediatrics Sept. 2009; e362-70; doi:10-1542/peds.2009-0051).

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

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

Support for this notion comes from studies showing that pushing serum vitamin D levels to 30 ng/mL or higher in whites reduces their parathyroid hormone levels, while pushing levels above 20 ng/mL in African Americans—young or old—does not further decrease parathyroid hormone or increase bone density.

In her own practice, Dr. Buckley generally tries to get patients into the 20- to 29-ng/mL range, while in African Americans and patients with known cardiovascular disease she aims for 15 ng/mL or slightly more, she said. She reserves expedited supplementation—50,000 IU weekly for 8 weeks—mainly for vitamin D–deficient elderly patients at high risk for fracture or fall. That's where there is supporting evidence of benefit. There is no evidence to support supplementation in young or middle-aged patients.

Like many others, Dr. Buckley eagerly awaits fresh guidance in the form of updated recommendations on vitamin D from the Institute of Medicine. That IOM report, due this spring, is expected to recommend an increase in the currently recommended supplemental 400 IU/day for 50- to 70-year-olds not getting sufficient vitamin D from the sun (see related article on p. 1). Her hope is the IOM will address the thorny issues of who should receive supplementation, and how fast it should be done.

Dr. Buckley reported having no relevant financial relationships.

The extra calcium absorption promoted by boosting vitamin D may be taken up by atherosclerotic plaque.

Source DR. BUCKLEY

Middle-aged women aren't being routinely assessed for osteoporosis during their ob.gyn. visits, despite this group's increased awareness of the condition, survey results released by the North American Menopause Society showed.

In a poll of 881 women, most of whom were either perimenopausal or postmenopausal, nearly all (98%) said they considered bone strength to be an important health concern. But 45% reported that osteoporosis was not addressed during their last routine ob.gyn. visit, and 26% said they had never discussed osteoporosis with their gynecologist.

Dr. Wulf H. Utian, the honorary founding president and executive director emeritus of the North American Menopause Society (NAMS), said that the survey shows there is more work to be done in raising awareness among ob.gyns. but that the results aren't a cause for concern. “Some important issues don't get attention during the consultation, and that may be a reflection of modern medicine and the limited time that's available,” he said in an interview.

In fact, Dr. Utian said both the public and health care providers have significantly greater awareness of osteoporosis and bone health than they did only a decade ago.

But there are barriers to making bone health a regular part of ob.gyn. care, he said. One issue is a lack of reimbursement for performing bone density testing. In some instances, physicians may not be recommending bone density testing because they think it won't be reimbursed, and they believe they can get an adequate risk assessment without the test.

In other cases, physicians are recommending bone density testing, but patients are rejecting it because they will have to pay out of pocket, Dr. Utian said. In fact, the survey found that even though nearly 63% of women reported that their ob.gyn. had recommended a bone scan, 27% of women surveyed had never had one.

Another barrier is the confusion among physicians about who should get a bone density test. There has been a good deal of variation among the recommendations coming out of various medical organizations, Dr. Utian said, creating a sense of uncertainty. In an effort to spell out more clearly the appropriate diagnosis, prevention, and treatment for postmenopausal osteoporosis, NAMS recently issued a new position statement on osteoporosis in midlife (February 2010, p. 1.).

In the position statement, NAMS recommends the use of the World Health Organization's FRAX (Fracture Risk Assessment) tool as well as increased vitamin D₃ intake. NAMS plans to take the scientific paper, which was issued last month, and translate it into a series of consumer education pieces, he said.

The NAMS survey also points to a possible communication gap between women and their ob.gyns. about the risk factors for osteoporosis. For example, among the women surveyed, 45 women said they had a broken bone in the past 5 years that occurred in a site associated with osteoporosis such as the hip, spine, wrist, collarbone, arm, leg, or pelvis. However, 35 of those women said their ob.gyn. was not aware of the break.

Additionally, while most women surveyed said that their ob.gyns. had told them that broken bones could be a sign of osteoporosis, the women were not as well informed about other possible consequences, including loss of height, dowager's hump, and disability or immobility.

The survey results could indicate that physicians are failing to take an adequate history during routine exams, Dr. Utian said. It also could mean that patients are failing to understand the association between bone fracture and menopause. “In other words, the woman doesn't tie the fact that she's had a fracture with anything that's to do with her visit to the gynecologist,” he said.

Dr. Utian said that all gynecologists who see women in their middle years should routinely ask about risk factors for bone loss and fracture.

Middle-aged women aren't being routinely assessed for osteoporosis during their ob.gyn. visits, despite this group's increased awareness of the condition, survey results released by the North American Menopause Society showed.

In a poll of 881 women, most of whom were either perimenopausal or postmenopausal, nearly all (98%) said they considered bone strength to be an important health concern. But 45% reported that osteoporosis was not addressed during their last routine ob.gyn. visit, and 26% said they had never discussed osteoporosis with their gynecologist.

Dr. Wulf H. Utian, the honorary founding president and executive director emeritus of the North American Menopause Society (NAMS), said that the survey shows there is more work to be done in raising awareness among ob.gyns. but that the results aren't a cause for concern. “Some important issues don't get attention during the consultation, and that may be a reflection of modern medicine and the limited time that's available,” he said in an interview.

In fact, Dr. Utian said both the public and health care providers have significantly greater awareness of osteoporosis and bone health than they did only a decade ago.

But there are barriers to making bone health a regular part of ob.gyn. care, he said. One issue is a lack of reimbursement for performing bone density testing. In some instances, physicians may not be recommending bone density testing because they think it won't be reimbursed, and they believe they can get an adequate risk assessment without the test.

In other cases, physicians are recommending bone density testing, but patients are rejecting it because they will have to pay out of pocket, Dr. Utian said. In fact, the survey found that even though nearly 63% of women reported that their ob.gyn. had recommended a bone scan, 27% of women surveyed had never had one.

Another barrier is the confusion among physicians about who should get a bone density test. There has been a good deal of variation among the recommendations coming out of various medical organizations, Dr. Utian said, creating a sense of uncertainty. In an effort to spell out more clearly the appropriate diagnosis, prevention, and treatment for postmenopausal osteoporosis, NAMS recently issued a new position statement on osteoporosis in midlife (February 2010, p. 1.).

In the position statement, NAMS recommends the use of the World Health Organization's FRAX (Fracture Risk Assessment) tool as well as increased vitamin D₃ intake. NAMS plans to take the scientific paper, which was issued last month, and translate it into a series of consumer education pieces, he said.

The NAMS survey also points to a possible communication gap between women and their ob.gyns. about the risk factors for osteoporosis. For example, among the women surveyed, 45 women said they had a broken bone in the past 5 years that occurred in a site associated with osteoporosis such as the hip, spine, wrist, collarbone, arm, leg, or pelvis. However, 35 of those women said their ob.gyn. was not aware of the break.

Additionally, while most women surveyed said that their ob.gyns. had told them that broken bones could be a sign of osteoporosis, the women were not as well informed about other possible consequences, including loss of height, dowager's hump, and disability or immobility.

The survey results could indicate that physicians are failing to take an adequate history during routine exams, Dr. Utian said. It also could mean that patients are failing to understand the association between bone fracture and menopause. “In other words, the woman doesn't tie the fact that she's had a fracture with anything that's to do with her visit to the gynecologist,” he said.

Dr. Utian said that all gynecologists who see women in their middle years should routinely ask about risk factors for bone loss and fracture.

Middle-aged women aren't being routinely assessed for osteoporosis during their ob.gyn. visits, despite this group's increased awareness of the condition, survey results released by the North American Menopause Society showed.

In a poll of 881 women, most of whom were either perimenopausal or postmenopausal, nearly all (98%) said they considered bone strength to be an important health concern. But 45% reported that osteoporosis was not addressed during their last routine ob.gyn. visit, and 26% said they had never discussed osteoporosis with their gynecologist.

Dr. Wulf H. Utian, the honorary founding president and executive director emeritus of the North American Menopause Society (NAMS), said that the survey shows there is more work to be done in raising awareness among ob.gyns. but that the results aren't a cause for concern. “Some important issues don't get attention during the consultation, and that may be a reflection of modern medicine and the limited time that's available,” he said in an interview.

In fact, Dr. Utian said both the public and health care providers have significantly greater awareness of osteoporosis and bone health than they did only a decade ago.

But there are barriers to making bone health a regular part of ob.gyn. care, he said. One issue is a lack of reimbursement for performing bone density testing. In some instances, physicians may not be recommending bone density testing because they think it won't be reimbursed, and they believe they can get an adequate risk assessment without the test.

In other cases, physicians are recommending bone density testing, but patients are rejecting it because they will have to pay out of pocket, Dr. Utian said. In fact, the survey found that even though nearly 63% of women reported that their ob.gyn. had recommended a bone scan, 27% of women surveyed had never had one.

Another barrier is the confusion among physicians about who should get a bone density test. There has been a good deal of variation among the recommendations coming out of various medical organizations, Dr. Utian said, creating a sense of uncertainty. In an effort to spell out more clearly the appropriate diagnosis, prevention, and treatment for postmenopausal osteoporosis, NAMS recently issued a new position statement on osteoporosis in midlife (February 2010, p. 1.).

In the position statement, NAMS recommends the use of the World Health Organization's FRAX (Fracture Risk Assessment) tool as well as increased vitamin D₃ intake. NAMS plans to take the scientific paper, which was issued last month, and translate it into a series of consumer education pieces, he said.

The NAMS survey also points to a possible communication gap between women and their ob.gyns. about the risk factors for osteoporosis. For example, among the women surveyed, 45 women said they had a broken bone in the past 5 years that occurred in a site associated with osteoporosis such as the hip, spine, wrist, collarbone, arm, leg, or pelvis. However, 35 of those women said their ob.gyn. was not aware of the break.

Additionally, while most women surveyed said that their ob.gyns. had told them that broken bones could be a sign of osteoporosis, the women were not as well informed about other possible consequences, including loss of height, dowager's hump, and disability or immobility.

The survey results could indicate that physicians are failing to take an adequate history during routine exams, Dr. Utian said. It also could mean that patients are failing to understand the association between bone fracture and menopause. “In other words, the woman doesn't tie the fact that she's had a fracture with anything that's to do with her visit to the gynecologist,” he said.

Dr. Utian said that all gynecologists who see women in their middle years should routinely ask about risk factors for bone loss and fracture.

Major Finding: After 5 years, lasofoxifene reduced the risk of vertebral and nonvertebral fractures by 9.3 cases per 1,000 person-years (HR 0.58) and 5.8 cases per 1,000 person-years (HR 0.76), respectively, compared with placebo.

Data Source: The PEARL study, which randomized 8,556 postmenopausal women with osteoporosis to receive lasofoxifene or placebo for 5 years.

Disclosures: Dr. Cummings has received consulting fees from Amgen, Eli Lilly, GlaxoSmithKline, and Organon, lecture fees from Eli Lilly and Novartis, and grant support from Amgen, Pfizer, and Eli Lilly.

The investigational drug lasofoxifene decreased the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis in a large, randomized, placebo-controlled trial.

The nonsteroidal selective estrogen-receptor modulator (SERM) also reduces the risk of ER-positive breast cancer, major coronary heart disease events, and stroke without raising the risk of endometrial cancer or hyperplasia. Like other SERMs, lasofoxifene raises the risk of venous thromboembolism and increases the rate of hot flushes and leg cramps, wrote Dr. Steven R. Cummings of California Pacific Medical Center Research Institute, San Francisco, and his associates in the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) study.

Taken together, these findings seem to indicate that lasofoxifene performs somewhat better than do other SERMs such as raloxifene, and also has advantages over hormone therapy, tamoxifen, and tibolone. However, in an editorial accompanying this report, Dr. Carolyn Becker of the division of endocrinology, diabetes, and hypertension at Brigham and Women's Hospital, Boston, argued that the drug “offers no major clinically important benefits over raloxifene for the skeleton, breast, heart, or reproductive tract.

“Given the plethora of drugs currently available for osteoporosis, studies of new agents should show clear benefits over existing agents,” she wrote. Results of the PEARL study do not do so, Dr. Becker added.

Dr. Cummings and his colleagues performed the international, randomized, placebo-controlled PEARL study in 8,556 women aged 59–80 years who had a bone mineral density T score of −2.5 or less at the lumbar spine or femoral neck. A total of 28% already had at least one vertebral fracture at baseline.

After 5 years of follow-up, women who received 0.5 mg per day of lasofoxifene showed a 42% reduction in relative risk for vertebral fractures and a 24% reduction in relative risk for nonvertebral fractures, compared with those who received placebo. Bone density at the lumbar spine, femoral neck, and total hip improved by about 3% with the active drug, the investigators said (N. Engl. J. Med. 2010;362;686-96).

This decrease in risk of vertebral fractures is comparable with that reported in women taking raloxifene, estrogen therapy, oral bisphosphonates, and tibolone. The decrease in risk of nonvertebral fractures also is similar to that observed in women taking other antiresorptive therapies, and it stands in contrast to raloxifene's inability to reduce this risk, they said.

However, Dr. Becker noted in her editorial that nearly all the reduction in risk for nonvertebral fractures could be attributed to forearm and wrist fractures. “A significant effect in the overall group was not evident until 5 years, and absolute risk reductions were very small.

“On balance, lasofoxifene seems to offer little, if any, advantage over raloxifene as an agent against osteoporosis,” she said (N. Engl. J. Med. 2010;362;752-4).

Lasofoxifene also reduced the risk of ER-positive breast cancer by 85%, compared with placebo. Although this finding is “impressive,” it is similar to the risk reduction reported for raloxifene, Dr. Becker added.

Lasofoxifene was associated with a 32% reduction in relative risk of coronary heart disease events (5.1 cases per 1,000 person-years) and a 36% reduction in relative risk of stroke (2.5 cases per 1,000 person-years), compared with placebo (7.5 and 3.9 cases per 1,000 person-years, respectively), Dr. Cummings and his associates said.

However, Dr. Becker noted that the number of these events was quite small, and there were no differences in rates of fatal stroke. “Although the cardiovascular benefits reported in the PEARL trial seem impressive, one would need to treat 492 patients for 1 year to prevent a single major coronary event,” she said.

The PEARL investigators said that lasofoxifene raised the risk of venous thromboembolism to a similar degree as do raloxifene, tamoxifen, and oral estrogen therapies. Like these agents, lasofoxifene also significantly increased the rate of hot flushes and leg cramps. It did not raise the risk of endometrial cancer or endometrial hyperplasia.

Dr. Becker countered that although the increase in absolute risk of venous thromboembolism was small, lasofoxifene more than doubled the relative risk. In addition, rates of uterine polyps, endometrial hypertrophy, and vaginal candidiasis all were significantly higher than with placebo, she said.

The PEARL study was funded by Pfizer, manufacturer of lasofoxifene. Pfizer submitted a new drug application to the Food and Drug Administration in 2007, and in 2008 an advisory panel voted 9–3 that the benefits of the SERM outweighed this risk in postmenopausal women with osteoporosis. The FDA has not yet issued a decision.

Dr. Becker's financial disclosures are available with the text of the article at www.NEJM.org

Major Finding: After 5 years, lasofoxifene reduced the risk of vertebral and nonvertebral fractures by 9.3 cases per 1,000 person-years (HR 0.58) and 5.8 cases per 1,000 person-years (HR 0.76), respectively, compared with placebo.

Data Source: The PEARL study, which randomized 8,556 postmenopausal women with osteoporosis to receive lasofoxifene or placebo for 5 years.

Disclosures: Dr. Cummings has received consulting fees from Amgen, Eli Lilly, GlaxoSmithKline, and Organon, lecture fees from Eli Lilly and Novartis, and grant support from Amgen, Pfizer, and Eli Lilly.

The investigational drug lasofoxifene decreased the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis in a large, randomized, placebo-controlled trial.

The nonsteroidal selective estrogen-receptor modulator (SERM) also reduces the risk of ER-positive breast cancer, major coronary heart disease events, and stroke without raising the risk of endometrial cancer or hyperplasia. Like other SERMs, lasofoxifene raises the risk of venous thromboembolism and increases the rate of hot flushes and leg cramps, wrote Dr. Steven R. Cummings of California Pacific Medical Center Research Institute, San Francisco, and his associates in the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) study.

Taken together, these findings seem to indicate that lasofoxifene performs somewhat better than do other SERMs such as raloxifene, and also has advantages over hormone therapy, tamoxifen, and tibolone. However, in an editorial accompanying this report, Dr. Carolyn Becker of the division of endocrinology, diabetes, and hypertension at Brigham and Women's Hospital, Boston, argued that the drug “offers no major clinically important benefits over raloxifene for the skeleton, breast, heart, or reproductive tract.

“Given the plethora of drugs currently available for osteoporosis, studies of new agents should show clear benefits over existing agents,” she wrote. Results of the PEARL study do not do so, Dr. Becker added.

Dr. Cummings and his colleagues performed the international, randomized, placebo-controlled PEARL study in 8,556 women aged 59–80 years who had a bone mineral density T score of −2.5 or less at the lumbar spine or femoral neck. A total of 28% already had at least one vertebral fracture at baseline.

After 5 years of follow-up, women who received 0.5 mg per day of lasofoxifene showed a 42% reduction in relative risk for vertebral fractures and a 24% reduction in relative risk for nonvertebral fractures, compared with those who received placebo. Bone density at the lumbar spine, femoral neck, and total hip improved by about 3% with the active drug, the investigators said (N. Engl. J. Med. 2010;362;686-96).

This decrease in risk of vertebral fractures is comparable with that reported in women taking raloxifene, estrogen therapy, oral bisphosphonates, and tibolone. The decrease in risk of nonvertebral fractures also is similar to that observed in women taking other antiresorptive therapies, and it stands in contrast to raloxifene's inability to reduce this risk, they said.

However, Dr. Becker noted in her editorial that nearly all the reduction in risk for nonvertebral fractures could be attributed to forearm and wrist fractures. “A significant effect in the overall group was not evident until 5 years, and absolute risk reductions were very small.

“On balance, lasofoxifene seems to offer little, if any, advantage over raloxifene as an agent against osteoporosis,” she said (N. Engl. J. Med. 2010;362;752-4).

Lasofoxifene also reduced the risk of ER-positive breast cancer by 85%, compared with placebo. Although this finding is “impressive,” it is similar to the risk reduction reported for raloxifene, Dr. Becker added.

Lasofoxifene was associated with a 32% reduction in relative risk of coronary heart disease events (5.1 cases per 1,000 person-years) and a 36% reduction in relative risk of stroke (2.5 cases per 1,000 person-years), compared with placebo (7.5 and 3.9 cases per 1,000 person-years, respectively), Dr. Cummings and his associates said.

However, Dr. Becker noted that the number of these events was quite small, and there were no differences in rates of fatal stroke. “Although the cardiovascular benefits reported in the PEARL trial seem impressive, one would need to treat 492 patients for 1 year to prevent a single major coronary event,” she said.

The PEARL investigators said that lasofoxifene raised the risk of venous thromboembolism to a similar degree as do raloxifene, tamoxifen, and oral estrogen therapies. Like these agents, lasofoxifene also significantly increased the rate of hot flushes and leg cramps. It did not raise the risk of endometrial cancer or endometrial hyperplasia.

Dr. Becker countered that although the increase in absolute risk of venous thromboembolism was small, lasofoxifene more than doubled the relative risk. In addition, rates of uterine polyps, endometrial hypertrophy, and vaginal candidiasis all were significantly higher than with placebo, she said.

The PEARL study was funded by Pfizer, manufacturer of lasofoxifene. Pfizer submitted a new drug application to the Food and Drug Administration in 2007, and in 2008 an advisory panel voted 9–3 that the benefits of the SERM outweighed this risk in postmenopausal women with osteoporosis. The FDA has not yet issued a decision.

Dr. Becker's financial disclosures are available with the text of the article at www.NEJM.org

Major Finding: After 5 years, lasofoxifene reduced the risk of vertebral and nonvertebral fractures by 9.3 cases per 1,000 person-years (HR 0.58) and 5.8 cases per 1,000 person-years (HR 0.76), respectively, compared with placebo.

Data Source: The PEARL study, which randomized 8,556 postmenopausal women with osteoporosis to receive lasofoxifene or placebo for 5 years.

Disclosures: Dr. Cummings has received consulting fees from Amgen, Eli Lilly, GlaxoSmithKline, and Organon, lecture fees from Eli Lilly and Novartis, and grant support from Amgen, Pfizer, and Eli Lilly.

The investigational drug lasofoxifene decreased the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis in a large, randomized, placebo-controlled trial.

The nonsteroidal selective estrogen-receptor modulator (SERM) also reduces the risk of ER-positive breast cancer, major coronary heart disease events, and stroke without raising the risk of endometrial cancer or hyperplasia. Like other SERMs, lasofoxifene raises the risk of venous thromboembolism and increases the rate of hot flushes and leg cramps, wrote Dr. Steven R. Cummings of California Pacific Medical Center Research Institute, San Francisco, and his associates in the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) study.

Taken together, these findings seem to indicate that lasofoxifene performs somewhat better than do other SERMs such as raloxifene, and also has advantages over hormone therapy, tamoxifen, and tibolone. However, in an editorial accompanying this report, Dr. Carolyn Becker of the division of endocrinology, diabetes, and hypertension at Brigham and Women's Hospital, Boston, argued that the drug “offers no major clinically important benefits over raloxifene for the skeleton, breast, heart, or reproductive tract.

“Given the plethora of drugs currently available for osteoporosis, studies of new agents should show clear benefits over existing agents,” she wrote. Results of the PEARL study do not do so, Dr. Becker added.

Dr. Cummings and his colleagues performed the international, randomized, placebo-controlled PEARL study in 8,556 women aged 59–80 years who had a bone mineral density T score of −2.5 or less at the lumbar spine or femoral neck. A total of 28% already had at least one vertebral fracture at baseline.

After 5 years of follow-up, women who received 0.5 mg per day of lasofoxifene showed a 42% reduction in relative risk for vertebral fractures and a 24% reduction in relative risk for nonvertebral fractures, compared with those who received placebo. Bone density at the lumbar spine, femoral neck, and total hip improved by about 3% with the active drug, the investigators said (N. Engl. J. Med. 2010;362;686-96).

This decrease in risk of vertebral fractures is comparable with that reported in women taking raloxifene, estrogen therapy, oral bisphosphonates, and tibolone. The decrease in risk of nonvertebral fractures also is similar to that observed in women taking other antiresorptive therapies, and it stands in contrast to raloxifene's inability to reduce this risk, they said.

However, Dr. Becker noted in her editorial that nearly all the reduction in risk for nonvertebral fractures could be attributed to forearm and wrist fractures. “A significant effect in the overall group was not evident until 5 years, and absolute risk reductions were very small.

“On balance, lasofoxifene seems to offer little, if any, advantage over raloxifene as an agent against osteoporosis,” she said (N. Engl. J. Med. 2010;362;752-4).

Lasofoxifene also reduced the risk of ER-positive breast cancer by 85%, compared with placebo. Although this finding is “impressive,” it is similar to the risk reduction reported for raloxifene, Dr. Becker added.

Lasofoxifene was associated with a 32% reduction in relative risk of coronary heart disease events (5.1 cases per 1,000 person-years) and a 36% reduction in relative risk of stroke (2.5 cases per 1,000 person-years), compared with placebo (7.5 and 3.9 cases per 1,000 person-years, respectively), Dr. Cummings and his associates said.

However, Dr. Becker noted that the number of these events was quite small, and there were no differences in rates of fatal stroke. “Although the cardiovascular benefits reported in the PEARL trial seem impressive, one would need to treat 492 patients for 1 year to prevent a single major coronary event,” she said.

The PEARL investigators said that lasofoxifene raised the risk of venous thromboembolism to a similar degree as do raloxifene, tamoxifen, and oral estrogen therapies. Like these agents, lasofoxifene also significantly increased the rate of hot flushes and leg cramps. It did not raise the risk of endometrial cancer or endometrial hyperplasia.

Dr. Becker countered that although the increase in absolute risk of venous thromboembolism was small, lasofoxifene more than doubled the relative risk. In addition, rates of uterine polyps, endometrial hypertrophy, and vaginal candidiasis all were significantly higher than with placebo, she said.

The PEARL study was funded by Pfizer, manufacturer of lasofoxifene. Pfizer submitted a new drug application to the Food and Drug Administration in 2007, and in 2008 an advisory panel voted 9–3 that the benefits of the SERM outweighed this risk in postmenopausal women with osteoporosis. The FDA has not yet issued a decision.

Dr. Becker's financial disclosures are available with the text of the article at www.NEJM.org

NATIONAL HARBOR, MD. — Bone mineralization was not significantly altered among 17 children receiving chronic proton pump inhibitor therapy, including 12 who were also using inhaled steroids.

Proton pump inhibitors (PPIs) are commonly prescribed for acid suppression in children with gastroesophageal reflux, sometimes for long periods.

A significantly increased risk of bone fracture has been reported in adult patients receiving long-term PPI therapy (JAMA 2006;296:2947-53), and chronic acid suppression has also been shown to impair calcium absorption, thereby promoting bone resorption (Am. J. Med. 2005;118:778-81).

However, this pilot study is believed to be the first to look at bone mineralization or fractures in children on PPIs, Dr. Stephanie Willot said in a poster presentation at the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

The 17 patients (12 boys) had a mean age of 7.8 years (range 0.8-16.7 years). All had severe gastroesophageal reflux secondary to esophageal atresia and had received PPI therapy at a mean dosage of 2.0 mg/kg daily (1.0-3.2 mg/kg) for a mean of 2.6 years (0.6-11.3 years). Twelve of the children were also receiving chronic inhaled steroid therapy for pulmonary disease.

Lumbar spine areal bone mineral density (BMD) was assessed by using dual x-ray absorptiometry and was compared with normative data. Volumetric BMD, a parameter that more accurately assesses BMD in patients with short stature, was also calculated in order to account for differences in bone size, said Dr. Willot of the division of pediatric gastroenterology at Sainte-Justine Hospital, University of Montreal, who conducted the study with colleagues from the division of pediatric endocrinology.

No patient had a history of traumatic fracture. Five patients (29%) had a statural growth delay of less than −2 standard deviations for age. Among the 14 children older than 2 years, 5 (35%) had a body mass index less than the 10th percentile.

No patient had a significantly low BMD, defined in the study as a z score less than −2 standard deviations for age. Although six patients (35%) had a z score BMD of less than −1 standard deviation for age, they all had normal volumetric BMD (ranging from −0.8 to 0.6 standard deviation), as did the other seven children who were older than 4 years of age, Dr. Willot and her associates reported.

In a follow-up interview, Dr. Willot said that, given the small sample size of the study and its cross-sectional nature, its implications are limited to the finding that BMD is not low in children on chronic PPI therapy. “We cannot conclude about the association between PPI and fracture risk. In the future, we would like to follow our cohort to assess BMD in a longitudinal way to establish if z score could decrease during the course of PPI treatment.”

Dr. Willot stated that she had no personal financial disclosures.

NATIONAL HARBOR, MD. — Bone mineralization was not significantly altered among 17 children receiving chronic proton pump inhibitor therapy, including 12 who were also using inhaled steroids.

Proton pump inhibitors (PPIs) are commonly prescribed for acid suppression in children with gastroesophageal reflux, sometimes for long periods.

A significantly increased risk of bone fracture has been reported in adult patients receiving long-term PPI therapy (JAMA 2006;296:2947-53), and chronic acid suppression has also been shown to impair calcium absorption, thereby promoting bone resorption (Am. J. Med. 2005;118:778-81).

However, this pilot study is believed to be the first to look at bone mineralization or fractures in children on PPIs, Dr. Stephanie Willot said in a poster presentation at the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

The 17 patients (12 boys) had a mean age of 7.8 years (range 0.8-16.7 years). All had severe gastroesophageal reflux secondary to esophageal atresia and had received PPI therapy at a mean dosage of 2.0 mg/kg daily (1.0-3.2 mg/kg) for a mean of 2.6 years (0.6-11.3 years). Twelve of the children were also receiving chronic inhaled steroid therapy for pulmonary disease.

Lumbar spine areal bone mineral density (BMD) was assessed by using dual x-ray absorptiometry and was compared with normative data. Volumetric BMD, a parameter that more accurately assesses BMD in patients with short stature, was also calculated in order to account for differences in bone size, said Dr. Willot of the division of pediatric gastroenterology at Sainte-Justine Hospital, University of Montreal, who conducted the study with colleagues from the division of pediatric endocrinology.

No patient had a history of traumatic fracture. Five patients (29%) had a statural growth delay of less than −2 standard deviations for age. Among the 14 children older than 2 years, 5 (35%) had a body mass index less than the 10th percentile.

No patient had a significantly low BMD, defined in the study as a z score less than −2 standard deviations for age. Although six patients (35%) had a z score BMD of less than −1 standard deviation for age, they all had normal volumetric BMD (ranging from −0.8 to 0.6 standard deviation), as did the other seven children who were older than 4 years of age, Dr. Willot and her associates reported.

In a follow-up interview, Dr. Willot said that, given the small sample size of the study and its cross-sectional nature, its implications are limited to the finding that BMD is not low in children on chronic PPI therapy. “We cannot conclude about the association between PPI and fracture risk. In the future, we would like to follow our cohort to assess BMD in a longitudinal way to establish if z score could decrease during the course of PPI treatment.”

Dr. Willot stated that she had no personal financial disclosures.

NATIONAL HARBOR, MD. — Bone mineralization was not significantly altered among 17 children receiving chronic proton pump inhibitor therapy, including 12 who were also using inhaled steroids.

Proton pump inhibitors (PPIs) are commonly prescribed for acid suppression in children with gastroesophageal reflux, sometimes for long periods.

A significantly increased risk of bone fracture has been reported in adult patients receiving long-term PPI therapy (JAMA 2006;296:2947-53), and chronic acid suppression has also been shown to impair calcium absorption, thereby promoting bone resorption (Am. J. Med. 2005;118:778-81).

However, this pilot study is believed to be the first to look at bone mineralization or fractures in children on PPIs, Dr. Stephanie Willot said in a poster presentation at the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

The 17 patients (12 boys) had a mean age of 7.8 years (range 0.8-16.7 years). All had severe gastroesophageal reflux secondary to esophageal atresia and had received PPI therapy at a mean dosage of 2.0 mg/kg daily (1.0-3.2 mg/kg) for a mean of 2.6 years (0.6-11.3 years). Twelve of the children were also receiving chronic inhaled steroid therapy for pulmonary disease.

Lumbar spine areal bone mineral density (BMD) was assessed by using dual x-ray absorptiometry and was compared with normative data. Volumetric BMD, a parameter that more accurately assesses BMD in patients with short stature, was also calculated in order to account for differences in bone size, said Dr. Willot of the division of pediatric gastroenterology at Sainte-Justine Hospital, University of Montreal, who conducted the study with colleagues from the division of pediatric endocrinology.

No patient had a history of traumatic fracture. Five patients (29%) had a statural growth delay of less than −2 standard deviations for age. Among the 14 children older than 2 years, 5 (35%) had a body mass index less than the 10th percentile.

No patient had a significantly low BMD, defined in the study as a z score less than −2 standard deviations for age. Although six patients (35%) had a z score BMD of less than −1 standard deviation for age, they all had normal volumetric BMD (ranging from −0.8 to 0.6 standard deviation), as did the other seven children who were older than 4 years of age, Dr. Willot and her associates reported.

In a follow-up interview, Dr. Willot said that, given the small sample size of the study and its cross-sectional nature, its implications are limited to the finding that BMD is not low in children on chronic PPI therapy. “We cannot conclude about the association between PPI and fracture risk. In the future, we would like to follow our cohort to assess BMD in a longitudinal way to establish if z score could decrease during the course of PPI treatment.”

Dr. Willot stated that she had no personal financial disclosures.

Major Finding: High-dose vitamin D improved pain scores and bone mineral density at the femoral neck in postmenopausal women with hormone receptor–positive breast cancer, but also caused hypercalciuria that required nearly one in five treated patients to be dropped from the study.

Data Source: Placebo-controlled study of 60 patients.

Disclosures: The study was supported by a research grant from AstraZeneca.

SAN ANTONIO — Testosterone undecanoate and high-dose vitamin D show promise for the treatment of aromatase inhibitor–associated musculoskeletal pain in breast cancer patients, according to two double-blind, placebo-controlled, randomized trials presented at the San Antonio Breast Cancer Symposium.

There's a caveat regarding the high-dose vitamin D regimen: Although it improved pain scores and bone mineral density at the femoral neck, it also caused hypercalciuria to such an extent that nearly one in five treated patients had to be dropped from the study at the 2-month mark, according to Dr. Antonella Rastelli of the Siteman Cancer Center at Washington University in St. Louis.

“I think that's actually a point of caution. I'm seeing and hearing that everybody is using vitamin D already. There could be a considerable number of patients who are receiving it for a long time, perhaps 4 or 5 years, while we give an aromatase inhibitor. Down the line, if we don't monitor their urinary calcium excretion, we may see kidney stones,” she warned.

Dr. Rastelli reported on 60 postmenopausal women with hormone receptor–positive breast cancer and low to marginal serum vitamin D levels of 10-29 ng/mL. All had developed significant musculoskeletal pain since going on adjuvant anastrozole at least 8 weeks prior to enrollment. All were placed on oral calcium at 1,000 mg/day and vitamin D₃ at 400 IU/day.

In addition, patients randomized to the active treatment group received vitamin D₂ (ergocalciferol) at 50,000 IU/week for 8 weeks if their baseline serum vitamin D level was 20-29 ng/mL, and for 16 weeks if it was 10-19 ng/mL. Thereafter, they got 50,000 IU once monthly for the balance of the 6-month trial. The control group received placebo on the same schedule.

At 2 months of follow-up, women in the high-dose vitamin D arm had significantly lower pain scores than did controls on both the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire. They also scored significantly better than controls on the Health Assessment Questionnaire–Disability Index domains that specifically assessed ability to climb steps and walk on flat ground.

These benefits were no longer significant at the 4- and 6-month follow-ups, probably because by then the high-dose vitamin D had been switched from weekly to monthly therapy, Dr. Rastelli said.

In future studies, she plans to continue high-dose vitamin D for a longer period in an effort to achieve more lasting benefits. In addition, she is considering using daily cholecalciferol to maintain more stable serum vitamin D levels than is possible with weekly ergocalciferol. She is also interested in broadening the study population to include patients with vitamin D levels that are currently considered normal.

Separately, Dr. Steve N. Birrell reported on 90 postmenopausal women with breast cancer who had been on adjuvant anastrozole for a median of 16 months and were experiencing significant joint pain. They were randomized in a double-blind manner to 3 months of oral testosterone undecanoate at 40 or 80 mg/day, or to placebo.

Eligibility for the trial required that patients have baseline visual analog scale scores in excess of 50 out of a possible 100 for both pain and stiffness. At follow-up assessments at 1 and 3 months, a strong placebo effect was evident, with roughly 40% of controls reporting their pain and stiffness scores had dropped below 50.

However, a significant treatment benefit was seen with high-dose testosterone, with three-quarters of patients on 80 mg/day reporting scores below 50 for both pain and stiffness at 3 months, according to Dr. Birrell, head of the breast cancer unit at Flinders Medical Centre, Adelaide, South Australia.

The safety data were reassuring, with good tolerability of testosterone therapy at both doses. Two testosterone-treated patients developed mild acne, and one experienced mild hirsutism. There was no hint of an increase in serum estradiol levels in connection with testosterone therapy, which is unsurprising in light of the fact that aromatase inhibitors are widely used to block conversion of testosterone to estradiol in athletes who illicitly use anabolic steroids to enhance performance, he noted.

Dr. Birrell's own preclinical studies suggest that testosterone therapy does not impinge upon the anticancer effects of aromatase inhibitor therapy. In fact, there was evidence of a synergistic antiproliferative effect that warrants further study, the surgeon continued.

The biological rationale for testosterone therapy in aromatase inhibitor–associated joint morbidity lies in the premise that affected patients have a reduced ability to convert endogenous testosterone to 5-alpha-dihydrotestosterone. This potent testosterone metabolite appears to be important in reducing the proinflammatory interleukins present in the synovium of patients with inflammatory joint disease, Dr. Birrell explained.

“It's really quite interesting that women on aromatase inhibitors have a significant increase in Sjögren's syndrome, where it has been demonstrated that there is a perturbation in the ability to convert testosterone into activated dihydrotestosterone,” he observed.

Session chair Dr. Charles L. Loprinzi of the Mayo Clinic in Rochester, Minn., commented that he considers both the testosterone and high-dose vitamin D trials to be pilot studies which, although encouraging, don't rise to the level of being practice changing.

Dr. Birrell said that crossover studies of testosterone therapy for aromatase inhibitor–associated joint pain will be difficult to conduct.

“Women on testosterone in this trial were very keen to stay on it,” he noted.

Dr. Birrell's study was also supported by a research grant from AstraZeneca. Dr. Birrell disclosed that he is a stockholder in Chavah Pty Ltd., which is developing novel cancer therapies.

If we don't monitor patients on high–vitamin D regimens for urinary calcium, they may develop kidney stones.

Source DR. RASTELLI

The safety data were reassuring, with good tolerability of testosterone therapy at both doses.

Source DR. BIRRELL

Major Finding: High-dose vitamin D improved pain scores and bone mineral density at the femoral neck in postmenopausal women with hormone receptor–positive breast cancer, but also caused hypercalciuria that required nearly one in five treated patients to be dropped from the study.

Data Source: Placebo-controlled study of 60 patients.

Disclosures: The study was supported by a research grant from AstraZeneca.

SAN ANTONIO — Testosterone undecanoate and high-dose vitamin D show promise for the treatment of aromatase inhibitor–associated musculoskeletal pain in breast cancer patients, according to two double-blind, placebo-controlled, randomized trials presented at the San Antonio Breast Cancer Symposium.

There's a caveat regarding the high-dose vitamin D regimen: Although it improved pain scores and bone mineral density at the femoral neck, it also caused hypercalciuria to such an extent that nearly one in five treated patients had to be dropped from the study at the 2-month mark, according to Dr. Antonella Rastelli of the Siteman Cancer Center at Washington University in St. Louis.

“I think that's actually a point of caution. I'm seeing and hearing that everybody is using vitamin D already. There could be a considerable number of patients who are receiving it for a long time, perhaps 4 or 5 years, while we give an aromatase inhibitor. Down the line, if we don't monitor their urinary calcium excretion, we may see kidney stones,” she warned.

Dr. Rastelli reported on 60 postmenopausal women with hormone receptor–positive breast cancer and low to marginal serum vitamin D levels of 10-29 ng/mL. All had developed significant musculoskeletal pain since going on adjuvant anastrozole at least 8 weeks prior to enrollment. All were placed on oral calcium at 1,000 mg/day and vitamin D₃ at 400 IU/day.

In addition, patients randomized to the active treatment group received vitamin D₂ (ergocalciferol) at 50,000 IU/week for 8 weeks if their baseline serum vitamin D level was 20-29 ng/mL, and for 16 weeks if it was 10-19 ng/mL. Thereafter, they got 50,000 IU once monthly for the balance of the 6-month trial. The control group received placebo on the same schedule.

At 2 months of follow-up, women in the high-dose vitamin D arm had significantly lower pain scores than did controls on both the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire. They also scored significantly better than controls on the Health Assessment Questionnaire–Disability Index domains that specifically assessed ability to climb steps and walk on flat ground.

These benefits were no longer significant at the 4- and 6-month follow-ups, probably because by then the high-dose vitamin D had been switched from weekly to monthly therapy, Dr. Rastelli said.

In future studies, she plans to continue high-dose vitamin D for a longer period in an effort to achieve more lasting benefits. In addition, she is considering using daily cholecalciferol to maintain more stable serum vitamin D levels than is possible with weekly ergocalciferol. She is also interested in broadening the study population to include patients with vitamin D levels that are currently considered normal.

Separately, Dr. Steve N. Birrell reported on 90 postmenopausal women with breast cancer who had been on adjuvant anastrozole for a median of 16 months and were experiencing significant joint pain. They were randomized in a double-blind manner to 3 months of oral testosterone undecanoate at 40 or 80 mg/day, or to placebo.

Eligibility for the trial required that patients have baseline visual analog scale scores in excess of 50 out of a possible 100 for both pain and stiffness. At follow-up assessments at 1 and 3 months, a strong placebo effect was evident, with roughly 40% of controls reporting their pain and stiffness scores had dropped below 50.

However, a significant treatment benefit was seen with high-dose testosterone, with three-quarters of patients on 80 mg/day reporting scores below 50 for both pain and stiffness at 3 months, according to Dr. Birrell, head of the breast cancer unit at Flinders Medical Centre, Adelaide, South Australia.

The safety data were reassuring, with good tolerability of testosterone therapy at both doses. Two testosterone-treated patients developed mild acne, and one experienced mild hirsutism. There was no hint of an increase in serum estradiol levels in connection with testosterone therapy, which is unsurprising in light of the fact that aromatase inhibitors are widely used to block conversion of testosterone to estradiol in athletes who illicitly use anabolic steroids to enhance performance, he noted.

Dr. Birrell's own preclinical studies suggest that testosterone therapy does not impinge upon the anticancer effects of aromatase inhibitor therapy. In fact, there was evidence of a synergistic antiproliferative effect that warrants further study, the surgeon continued.

The biological rationale for testosterone therapy in aromatase inhibitor–associated joint morbidity lies in the premise that affected patients have a reduced ability to convert endogenous testosterone to 5-alpha-dihydrotestosterone. This potent testosterone metabolite appears to be important in reducing the proinflammatory interleukins present in the synovium of patients with inflammatory joint disease, Dr. Birrell explained.

“It's really quite interesting that women on aromatase inhibitors have a significant increase in Sjögren's syndrome, where it has been demonstrated that there is a perturbation in the ability to convert testosterone into activated dihydrotestosterone,” he observed.

Session chair Dr. Charles L. Loprinzi of the Mayo Clinic in Rochester, Minn., commented that he considers both the testosterone and high-dose vitamin D trials to be pilot studies which, although encouraging, don't rise to the level of being practice changing.

Dr. Birrell said that crossover studies of testosterone therapy for aromatase inhibitor–associated joint pain will be difficult to conduct.

“Women on testosterone in this trial were very keen to stay on it,” he noted.

Dr. Birrell's study was also supported by a research grant from AstraZeneca. Dr. Birrell disclosed that he is a stockholder in Chavah Pty Ltd., which is developing novel cancer therapies.

If we don't monitor patients on high–vitamin D regimens for urinary calcium, they may develop kidney stones.

Source DR. RASTELLI

The safety data were reassuring, with good tolerability of testosterone therapy at both doses.

Source DR. BIRRELL

Major Finding: High-dose vitamin D improved pain scores and bone mineral density at the femoral neck in postmenopausal women with hormone receptor–positive breast cancer, but also caused hypercalciuria that required nearly one in five treated patients to be dropped from the study.

Data Source: Placebo-controlled study of 60 patients.

Disclosures: The study was supported by a research grant from AstraZeneca.

SAN ANTONIO — Testosterone undecanoate and high-dose vitamin D show promise for the treatment of aromatase inhibitor–associated musculoskeletal pain in breast cancer patients, according to two double-blind, placebo-controlled, randomized trials presented at the San Antonio Breast Cancer Symposium.

There's a caveat regarding the high-dose vitamin D regimen: Although it improved pain scores and bone mineral density at the femoral neck, it also caused hypercalciuria to such an extent that nearly one in five treated patients had to be dropped from the study at the 2-month mark, according to Dr. Antonella Rastelli of the Siteman Cancer Center at Washington University in St. Louis.

“I think that's actually a point of caution. I'm seeing and hearing that everybody is using vitamin D already. There could be a considerable number of patients who are receiving it for a long time, perhaps 4 or 5 years, while we give an aromatase inhibitor. Down the line, if we don't monitor their urinary calcium excretion, we may see kidney stones,” she warned.

Dr. Rastelli reported on 60 postmenopausal women with hormone receptor–positive breast cancer and low to marginal serum vitamin D levels of 10-29 ng/mL. All had developed significant musculoskeletal pain since going on adjuvant anastrozole at least 8 weeks prior to enrollment. All were placed on oral calcium at 1,000 mg/day and vitamin D₃ at 400 IU/day.

In addition, patients randomized to the active treatment group received vitamin D₂ (ergocalciferol) at 50,000 IU/week for 8 weeks if their baseline serum vitamin D level was 20-29 ng/mL, and for 16 weeks if it was 10-19 ng/mL. Thereafter, they got 50,000 IU once monthly for the balance of the 6-month trial. The control group received placebo on the same schedule.

At 2 months of follow-up, women in the high-dose vitamin D arm had significantly lower pain scores than did controls on both the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire. They also scored significantly better than controls on the Health Assessment Questionnaire–Disability Index domains that specifically assessed ability to climb steps and walk on flat ground.

These benefits were no longer significant at the 4- and 6-month follow-ups, probably because by then the high-dose vitamin D had been switched from weekly to monthly therapy, Dr. Rastelli said.

In future studies, she plans to continue high-dose vitamin D for a longer period in an effort to achieve more lasting benefits. In addition, she is considering using daily cholecalciferol to maintain more stable serum vitamin D levels than is possible with weekly ergocalciferol. She is also interested in broadening the study population to include patients with vitamin D levels that are currently considered normal.

Separately, Dr. Steve N. Birrell reported on 90 postmenopausal women with breast cancer who had been on adjuvant anastrozole for a median of 16 months and were experiencing significant joint pain. They were randomized in a double-blind manner to 3 months of oral testosterone undecanoate at 40 or 80 mg/day, or to placebo.

Eligibility for the trial required that patients have baseline visual analog scale scores in excess of 50 out of a possible 100 for both pain and stiffness. At follow-up assessments at 1 and 3 months, a strong placebo effect was evident, with roughly 40% of controls reporting their pain and stiffness scores had dropped below 50.

However, a significant treatment benefit was seen with high-dose testosterone, with three-quarters of patients on 80 mg/day reporting scores below 50 for both pain and stiffness at 3 months, according to Dr. Birrell, head of the breast cancer unit at Flinders Medical Centre, Adelaide, South Australia.

The safety data were reassuring, with good tolerability of testosterone therapy at both doses. Two testosterone-treated patients developed mild acne, and one experienced mild hirsutism. There was no hint of an increase in serum estradiol levels in connection with testosterone therapy, which is unsurprising in light of the fact that aromatase inhibitors are widely used to block conversion of testosterone to estradiol in athletes who illicitly use anabolic steroids to enhance performance, he noted.

Dr. Birrell's own preclinical studies suggest that testosterone therapy does not impinge upon the anticancer effects of aromatase inhibitor therapy. In fact, there was evidence of a synergistic antiproliferative effect that warrants further study, the surgeon continued.

The biological rationale for testosterone therapy in aromatase inhibitor–associated joint morbidity lies in the premise that affected patients have a reduced ability to convert endogenous testosterone to 5-alpha-dihydrotestosterone. This potent testosterone metabolite appears to be important in reducing the proinflammatory interleukins present in the synovium of patients with inflammatory joint disease, Dr. Birrell explained.

“It's really quite interesting that women on aromatase inhibitors have a significant increase in Sjögren's syndrome, where it has been demonstrated that there is a perturbation in the ability to convert testosterone into activated dihydrotestosterone,” he observed.

Session chair Dr. Charles L. Loprinzi of the Mayo Clinic in Rochester, Minn., commented that he considers both the testosterone and high-dose vitamin D trials to be pilot studies which, although encouraging, don't rise to the level of being practice changing.

Dr. Birrell said that crossover studies of testosterone therapy for aromatase inhibitor–associated joint pain will be difficult to conduct.

“Women on testosterone in this trial were very keen to stay on it,” he noted.

Dr. Birrell's study was also supported by a research grant from AstraZeneca. Dr. Birrell disclosed that he is a stockholder in Chavah Pty Ltd., which is developing novel cancer therapies.

If we don't monitor patients on high–vitamin D regimens for urinary calcium, they may develop kidney stones.

Source DR. RASTELLI

The safety data were reassuring, with good tolerability of testosterone therapy at both doses.

Source DR. BIRRELL

Impaired kidney function was associated with increased bone loss in an analysis of data from the population-based Canadian Multicentre Osteoporosis Study.

Among 635 study participants whose bone mineral density had been tested at baseline and at 5 years' follow-up, estimated creatinine clearance (eCCr) and estimated glomerular filtration rate (eGFR) at baseline were predictive of bone loss at the hip and spine, according to Dr. Sophie A. Jamal of the University of Toronto and her colleagues.

“One way to decrease the economic costs, morbidity, and mortality associated with fractures in patients with [chronic kidney disease] is to identify patients at high risk and target treatments to this group,” Dr. Jamal and her colleagues wrote. The investigators analyzed baseline data to calculate eCCr and eGFR in 191 men and 444 women who were aged at least 50 years.

BMD was measured with dual-energy x-ray absorptiometry at the lumbar spine, femoral neck, and total hip.

Participants also had filled out questionnaires to assess risk factors for fractures and use of medications. The study ran from 2000 to 2005.

“The primary predictor of change in BMD during 5 years was eCCr measured at baseline and stratified into quartiles. Our secondary predictor was eGFR, also stratified into quartiles,” the researchers wrote.

The quartiles represented highest to lowest eCCr (from greater than 101.2 mL/min in the first quartile to less than 68.3 mL/min in the fourth) and eGFR (from greater than 86.3 mL/min to less than 68.5 mL/min) (Am. J. Kidney Dis. 2010;55:291-9 [doi:10.1053/j.ajkd.2009.10.049

“A cross-sectional analysis showed that compared with those in the first quartile, those with more impaired kidney function (in the second, third, and fourth quartiles of eCCr) had lower BMD at the lumbar spine, femoral neck, and total hip at year 5,” Dr. Jamal and her coinvestigators wrote.

Over the long term, they added, “these modest decreases result in substantial bone loss.”

Among the study's limitations were its observational design, its small sample size of all-white community dwellers, and, most importantly, the issue of competing mortality.

“To estimate longitudinal change in BMD, participants had to survive to the second measurement. It is possible that participants with the greatest impairment in kidney function had the most rapid bone loss and died before year 5, and as such, were not included in the analysis,” the researchers wrote.

The authors stated they had no financial conflicts to disclose.

Impaired kidney function was associated with increased bone loss in an analysis of data from the population-based Canadian Multicentre Osteoporosis Study.

Among 635 study participants whose bone mineral density had been tested at baseline and at 5 years' follow-up, estimated creatinine clearance (eCCr) and estimated glomerular filtration rate (eGFR) at baseline were predictive of bone loss at the hip and spine, according to Dr. Sophie A. Jamal of the University of Toronto and her colleagues.

“One way to decrease the economic costs, morbidity, and mortality associated with fractures in patients with [chronic kidney disease] is to identify patients at high risk and target treatments to this group,” Dr. Jamal and her colleagues wrote. The investigators analyzed baseline data to calculate eCCr and eGFR in 191 men and 444 women who were aged at least 50 years.

BMD was measured with dual-energy x-ray absorptiometry at the lumbar spine, femoral neck, and total hip.

Participants also had filled out questionnaires to assess risk factors for fractures and use of medications. The study ran from 2000 to 2005.

“The primary predictor of change in BMD during 5 years was eCCr measured at baseline and stratified into quartiles. Our secondary predictor was eGFR, also stratified into quartiles,” the researchers wrote.

The quartiles represented highest to lowest eCCr (from greater than 101.2 mL/min in the first quartile to less than 68.3 mL/min in the fourth) and eGFR (from greater than 86.3 mL/min to less than 68.5 mL/min) (Am. J. Kidney Dis. 2010;55:291-9 [doi:10.1053/j.ajkd.2009.10.049

“A cross-sectional analysis showed that compared with those in the first quartile, those with more impaired kidney function (in the second, third, and fourth quartiles of eCCr) had lower BMD at the lumbar spine, femoral neck, and total hip at year 5,” Dr. Jamal and her coinvestigators wrote.

Over the long term, they added, “these modest decreases result in substantial bone loss.”

Among the study's limitations were its observational design, its small sample size of all-white community dwellers, and, most importantly, the issue of competing mortality.

“To estimate longitudinal change in BMD, participants had to survive to the second measurement. It is possible that participants with the greatest impairment in kidney function had the most rapid bone loss and died before year 5, and as such, were not included in the analysis,” the researchers wrote.

The authors stated they had no financial conflicts to disclose.

Impaired kidney function was associated with increased bone loss in an analysis of data from the population-based Canadian Multicentre Osteoporosis Study.

Among 635 study participants whose bone mineral density had been tested at baseline and at 5 years' follow-up, estimated creatinine clearance (eCCr) and estimated glomerular filtration rate (eGFR) at baseline were predictive of bone loss at the hip and spine, according to Dr. Sophie A. Jamal of the University of Toronto and her colleagues.

“One way to decrease the economic costs, morbidity, and mortality associated with fractures in patients with [chronic kidney disease] is to identify patients at high risk and target treatments to this group,” Dr. Jamal and her colleagues wrote. The investigators analyzed baseline data to calculate eCCr and eGFR in 191 men and 444 women who were aged at least 50 years.

BMD was measured with dual-energy x-ray absorptiometry at the lumbar spine, femoral neck, and total hip.

Participants also had filled out questionnaires to assess risk factors for fractures and use of medications. The study ran from 2000 to 2005.

“The primary predictor of change in BMD during 5 years was eCCr measured at baseline and stratified into quartiles. Our secondary predictor was eGFR, also stratified into quartiles,” the researchers wrote.

The quartiles represented highest to lowest eCCr (from greater than 101.2 mL/min in the first quartile to less than 68.3 mL/min in the fourth) and eGFR (from greater than 86.3 mL/min to less than 68.5 mL/min) (Am. J. Kidney Dis. 2010;55:291-9 [doi:10.1053/j.ajkd.2009.10.049

“A cross-sectional analysis showed that compared with those in the first quartile, those with more impaired kidney function (in the second, third, and fourth quartiles of eCCr) had lower BMD at the lumbar spine, femoral neck, and total hip at year 5,” Dr. Jamal and her coinvestigators wrote.

Over the long term, they added, “these modest decreases result in substantial bone loss.”

Among the study's limitations were its observational design, its small sample size of all-white community dwellers, and, most importantly, the issue of competing mortality.

“To estimate longitudinal change in BMD, participants had to survive to the second measurement. It is possible that participants with the greatest impairment in kidney function had the most rapid bone loss and died before year 5, and as such, were not included in the analysis,” the researchers wrote.

The authors stated they had no financial conflicts to disclose.

Major Findings: Treatment with teriparatide plus zoledronic acid increased spinal bone mineral density more than either drug alone.

Source of Data: One-year study of 412 postmenopausal women with previously untreated osteoporosis.

Disclosures: The study was sponsored by Novartis, which makes Zometa. Dr. Cosman reported that she has received consulting fees from Novartis and other pharmaceutical companies.

DENVER — Bone mineral density at the spine and hip increased more rapidly and to a greater degree with combined teriparatide and zoledronic acid than with either agent alone in a 1-year study of 412 postmenopausal women with previously untreated osteoporosis.

“Combination therapy could therefore be considered in some patients at high risk for hip and other fractures,” Dr. Felicia Cosman said at the annual meeting of the American Society for Bone and Mineral Research.

Clinical fractures were assessed as part of serious adverse event monitoring and were confirmed using radiographic reports. There were 13 fractures in the zoledronic acid (Zometa) group, 8 in the teriparatide (Forteo) group, and 4 in the combination therapy group.

At 1 year, the increase in spine BMD was 4.4% with zoledronic acid alone, 7.1% with the teriparatide alone, and 7.5% with combination therapy. Spine BMD increased more rapidly with combination therapy, but it eventually caught up to similar levels with teriparatide alone.

Similarly significant increases in total hip BMD occurred in all treatment groups, said Dr. Cosman, medical director of the clinical research center at Helen Hayes Hospital in West Haverstraw, N.Y.

The study included three active treatment groups: 5 mg zoledronic acid at baseline (open arm), 20 mcg daily subcutaneous teriparatide (placebo infusion at baseline), and a combination of the two. All patients received calcium and vitamin D supplements. Average age at baseline was 65 years. The women had a mean spine T score of −2.9, and a mean total hip T score of −1.9. Baseline variables did not differ among the three groups.

The researchers also measured two bone markers: Beta C-terminal telopeptide of type I collagen (CTx) is a marker of bone resorption, and amino-terminal propeptide of type 1 procollagen (P1NP) is a marker of bone formation.

“In the combination group, there is first a small increase and then a brief but modest decline in P1NP, followed by a progressive rise thereafter,” she said. The decline in P1NP for the combination group is not as great as for those on zoledronic acid alone.

For patients on zoledronic acid alone, there was a rapid and robust suppression of beta CTx up to 4 weeks, when the levels trended back toward baseline. There was no change in beta CTx in patients on teriparatide alone for the first month. Then beta CTx levels began to increase, peaking at about 6 months. In the combination group, there was a prominent suppression of beta CTx (bone resorption) similar to that of zoledronic acid over the first 2 months. A gradual increase followed, with levels greater than at baseline for the latter half of the year.

For P1NP, there is a lag in suppression compared with beta CTx with zoledronic acid treatment, followed by prominent suppression with a nadir/plateau at 6 months. For those on teriparatide alone, there is a doubling of baseline P1NP levels by 4 weeks, with levels peaking at about 6 months.

Major Findings: Treatment with teriparatide plus zoledronic acid increased spinal bone mineral density more than either drug alone.

Source of Data: One-year study of 412 postmenopausal women with previously untreated osteoporosis.

Disclosures: The study was sponsored by Novartis, which makes Zometa. Dr. Cosman reported that she has received consulting fees from Novartis and other pharmaceutical companies.

DENVER — Bone mineral density at the spine and hip increased more rapidly and to a greater degree with combined teriparatide and zoledronic acid than with either agent alone in a 1-year study of 412 postmenopausal women with previously untreated osteoporosis.

“Combination therapy could therefore be considered in some patients at high risk for hip and other fractures,” Dr. Felicia Cosman said at the annual meeting of the American Society for Bone and Mineral Research.

Clinical fractures were assessed as part of serious adverse event monitoring and were confirmed using radiographic reports. There were 13 fractures in the zoledronic acid (Zometa) group, 8 in the teriparatide (Forteo) group, and 4 in the combination therapy group.

At 1 year, the increase in spine BMD was 4.4% with zoledronic acid alone, 7.1% with the teriparatide alone, and 7.5% with combination therapy. Spine BMD increased more rapidly with combination therapy, but it eventually caught up to similar levels with teriparatide alone.

Similarly significant increases in total hip BMD occurred in all treatment groups, said Dr. Cosman, medical director of the clinical research center at Helen Hayes Hospital in West Haverstraw, N.Y.

The study included three active treatment groups: 5 mg zoledronic acid at baseline (open arm), 20 mcg daily subcutaneous teriparatide (placebo infusion at baseline), and a combination of the two. All patients received calcium and vitamin D supplements. Average age at baseline was 65 years. The women had a mean spine T score of −2.9, and a mean total hip T score of −1.9. Baseline variables did not differ among the three groups.

The researchers also measured two bone markers: Beta C-terminal telopeptide of type I collagen (CTx) is a marker of bone resorption, and amino-terminal propeptide of type 1 procollagen (P1NP) is a marker of bone formation.

“In the combination group, there is first a small increase and then a brief but modest decline in P1NP, followed by a progressive rise thereafter,” she said. The decline in P1NP for the combination group is not as great as for those on zoledronic acid alone.

For patients on zoledronic acid alone, there was a rapid and robust suppression of beta CTx up to 4 weeks, when the levels trended back toward baseline. There was no change in beta CTx in patients on teriparatide alone for the first month. Then beta CTx levels began to increase, peaking at about 6 months. In the combination group, there was a prominent suppression of beta CTx (bone resorption) similar to that of zoledronic acid over the first 2 months. A gradual increase followed, with levels greater than at baseline for the latter half of the year.

For P1NP, there is a lag in suppression compared with beta CTx with zoledronic acid treatment, followed by prominent suppression with a nadir/plateau at 6 months. For those on teriparatide alone, there is a doubling of baseline P1NP levels by 4 weeks, with levels peaking at about 6 months.

Major Findings: Treatment with teriparatide plus zoledronic acid increased spinal bone mineral density more than either drug alone.

Source of Data: One-year study of 412 postmenopausal women with previously untreated osteoporosis.

Disclosures: The study was sponsored by Novartis, which makes Zometa. Dr. Cosman reported that she has received consulting fees from Novartis and other pharmaceutical companies.

DENVER — Bone mineral density at the spine and hip increased more rapidly and to a greater degree with combined teriparatide and zoledronic acid than with either agent alone in a 1-year study of 412 postmenopausal women with previously untreated osteoporosis.

“Combination therapy could therefore be considered in some patients at high risk for hip and other fractures,” Dr. Felicia Cosman said at the annual meeting of the American Society for Bone and Mineral Research.

Clinical fractures were assessed as part of serious adverse event monitoring and were confirmed using radiographic reports. There were 13 fractures in the zoledronic acid (Zometa) group, 8 in the teriparatide (Forteo) group, and 4 in the combination therapy group.

At 1 year, the increase in spine BMD was 4.4% with zoledronic acid alone, 7.1% with the teriparatide alone, and 7.5% with combination therapy. Spine BMD increased more rapidly with combination therapy, but it eventually caught up to similar levels with teriparatide alone.

Similarly significant increases in total hip BMD occurred in all treatment groups, said Dr. Cosman, medical director of the clinical research center at Helen Hayes Hospital in West Haverstraw, N.Y.

The study included three active treatment groups: 5 mg zoledronic acid at baseline (open arm), 20 mcg daily subcutaneous teriparatide (placebo infusion at baseline), and a combination of the two. All patients received calcium and vitamin D supplements. Average age at baseline was 65 years. The women had a mean spine T score of −2.9, and a mean total hip T score of −1.9. Baseline variables did not differ among the three groups.

The researchers also measured two bone markers: Beta C-terminal telopeptide of type I collagen (CTx) is a marker of bone resorption, and amino-terminal propeptide of type 1 procollagen (P1NP) is a marker of bone formation.

“In the combination group, there is first a small increase and then a brief but modest decline in P1NP, followed by a progressive rise thereafter,” she said. The decline in P1NP for the combination group is not as great as for those on zoledronic acid alone.

For patients on zoledronic acid alone, there was a rapid and robust suppression of beta CTx up to 4 weeks, when the levels trended back toward baseline. There was no change in beta CTx in patients on teriparatide alone for the first month. Then beta CTx levels began to increase, peaking at about 6 months. In the combination group, there was a prominent suppression of beta CTx (bone resorption) similar to that of zoledronic acid over the first 2 months. A gradual increase followed, with levels greater than at baseline for the latter half of the year.

For P1NP, there is a lag in suppression compared with beta CTx with zoledronic acid treatment, followed by prominent suppression with a nadir/plateau at 6 months. For those on teriparatide alone, there is a doubling of baseline P1NP levels by 4 weeks, with levels peaking at about 6 months.

SAN ANTONIO — The largest-ever analysis of osteonecrosis of the jaw occurring in women receiving the antiangiogenesis agent bevacizumab for advanced breast cancer indicates the incidence is less than 1%, even in patients receiving bisphosphonates.

The analysis involved more than 3,500 bevacizumab-treated women with locally recurrent or metastatic breast cancer prospectively followed in large clinical trials.

As such, it provides a much more accurate—and reassuring—risk estimate than the 16% incidence recently reported by Greek investigators in patients on a bisphosphonate plus bevacizumab (Avastin) or another antiangiogenesis agent, sunitinib (Sutent), for various advanced cancers (Oncology 2009;76:209-11).

The Greek report was a retrospective analysis based on 116 bisphosphonate-treated patients, only a subset of whom were on an antiangiogenesis agent, Dr. Valentina Guarneri noted at the San Antonio Breast Cancer Symposium.

In contrast, she reported on 3,560 patients on bevacizumab combined with a taxane or other standard chemotherapy as first-line treatment for locally recurrent or metastatic breast cancer. The women were participants in the open-label ATHENA study or the randomized RIBBON-1 or AVADO trials.

In the randomized trials, the incidence of osteonecrosis of the jaw (ONJ) was 0.3% in patients on bevacizumab and zero with placebo during follow-up of 10-19 months. In ATHENA, the incidence was 0.4% during 13 months of follow-up of more than 2,200 women on bevacizumab.

The incidence of ONJ was higher in bevacizumab-treated patients with prior or current exposure to bisphosphonates, but not close to the 16% figure cited in the small Greek study. In ATHENA, the incidence of ONJ was 2.4% in bevacizumab-treated patients who had been exposed to bisphosphonates and zero in those who had not.

In the two randomized trials, the rate was 0.9% in patients who had been on a bisphosphonate, compared with 0.2% in those who had not, according to Dr. Guarneri of the University of Modena and Reggio Emilia (Italy).

Detailed analysis of all ONJ cases in this series showed that dental/oral hygiene issues—a recent extraction, a loose tooth, maxillary fracture repair—were present in one-third. Thus, dental examination and avoidance of invasive dental procedures are important in patients on intravenous bisphosphonates, regardless of whether they're on bevacizumab, she added.

Disclosures: This study was funded by F. Hoffmann-La Roche Ltd.

SAN ANTONIO — The largest-ever analysis of osteonecrosis of the jaw occurring in women receiving the antiangiogenesis agent bevacizumab for advanced breast cancer indicates the incidence is less than 1%, even in patients receiving bisphosphonates.

The analysis involved more than 3,500 bevacizumab-treated women with locally recurrent or metastatic breast cancer prospectively followed in large clinical trials.

As such, it provides a much more accurate—and reassuring—risk estimate than the 16% incidence recently reported by Greek investigators in patients on a bisphosphonate plus bevacizumab (Avastin) or another antiangiogenesis agent, sunitinib (Sutent), for various advanced cancers (Oncology 2009;76:209-11).

The Greek report was a retrospective analysis based on 116 bisphosphonate-treated patients, only a subset of whom were on an antiangiogenesis agent, Dr. Valentina Guarneri noted at the San Antonio Breast Cancer Symposium.

In contrast, she reported on 3,560 patients on bevacizumab combined with a taxane or other standard chemotherapy as first-line treatment for locally recurrent or metastatic breast cancer. The women were participants in the open-label ATHENA study or the randomized RIBBON-1 or AVADO trials.

In the randomized trials, the incidence of osteonecrosis of the jaw (ONJ) was 0.3% in patients on bevacizumab and zero with placebo during follow-up of 10-19 months. In ATHENA, the incidence was 0.4% during 13 months of follow-up of more than 2,200 women on bevacizumab.

The incidence of ONJ was higher in bevacizumab-treated patients with prior or current exposure to bisphosphonates, but not close to the 16% figure cited in the small Greek study. In ATHENA, the incidence of ONJ was 2.4% in bevacizumab-treated patients who had been exposed to bisphosphonates and zero in those who had not.

In the two randomized trials, the rate was 0.9% in patients who had been on a bisphosphonate, compared with 0.2% in those who had not, according to Dr. Guarneri of the University of Modena and Reggio Emilia (Italy).

Detailed analysis of all ONJ cases in this series showed that dental/oral hygiene issues—a recent extraction, a loose tooth, maxillary fracture repair—were present in one-third. Thus, dental examination and avoidance of invasive dental procedures are important in patients on intravenous bisphosphonates, regardless of whether they're on bevacizumab, she added.

Disclosures: This study was funded by F. Hoffmann-La Roche Ltd.

SAN ANTONIO — The largest-ever analysis of osteonecrosis of the jaw occurring in women receiving the antiangiogenesis agent bevacizumab for advanced breast cancer indicates the incidence is less than 1%, even in patients receiving bisphosphonates.

The analysis involved more than 3,500 bevacizumab-treated women with locally recurrent or metastatic breast cancer prospectively followed in large clinical trials.

As such, it provides a much more accurate—and reassuring—risk estimate than the 16% incidence recently reported by Greek investigators in patients on a bisphosphonate plus bevacizumab (Avastin) or another antiangiogenesis agent, sunitinib (Sutent), for various advanced cancers (Oncology 2009;76:209-11).

The Greek report was a retrospective analysis based on 116 bisphosphonate-treated patients, only a subset of whom were on an antiangiogenesis agent, Dr. Valentina Guarneri noted at the San Antonio Breast Cancer Symposium.

In contrast, she reported on 3,560 patients on bevacizumab combined with a taxane or other standard chemotherapy as first-line treatment for locally recurrent or metastatic breast cancer. The women were participants in the open-label ATHENA study or the randomized RIBBON-1 or AVADO trials.

In the randomized trials, the incidence of osteonecrosis of the jaw (ONJ) was 0.3% in patients on bevacizumab and zero with placebo during follow-up of 10-19 months. In ATHENA, the incidence was 0.4% during 13 months of follow-up of more than 2,200 women on bevacizumab.

The incidence of ONJ was higher in bevacizumab-treated patients with prior or current exposure to bisphosphonates, but not close to the 16% figure cited in the small Greek study. In ATHENA, the incidence of ONJ was 2.4% in bevacizumab-treated patients who had been exposed to bisphosphonates and zero in those who had not.

In the two randomized trials, the rate was 0.9% in patients who had been on a bisphosphonate, compared with 0.2% in those who had not, according to Dr. Guarneri of the University of Modena and Reggio Emilia (Italy).

Detailed analysis of all ONJ cases in this series showed that dental/oral hygiene issues—a recent extraction, a loose tooth, maxillary fracture repair—were present in one-third. Thus, dental examination and avoidance of invasive dental procedures are important in patients on intravenous bisphosphonates, regardless of whether they're on bevacizumab, she added.

Disclosures: This study was funded by F. Hoffmann-La Roche Ltd.

SAN ANTONIO — Denosumab proved superior to zoledronic acid in delaying or preventing complications from bone metastases in breast cancer patients in a large phase III clinical trial.

Denosumab also showed significantly less toxicity than did zoledronic acid (Zometa), the current standard treatment for bone metastases.

Particularly noteworthy was the substantially lower rate of renal toxicity with denosumab; there is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate, Dr. Alison Stopeck noted at the San Antonio Breast Cancer Symposium.

Denosumab is an investigational fully humanized monoclonal antibody targeting RANK ligand (RANKL), the primary mediator of osteoclast formation, function, and survival.

Metastatic cancer cells stimulate RANKL activity, resulting in increased bone resorption and destruction, explained Dr. Stopeck of the University of Arizona Cancer Center, Tucson.

She reported on 2,046 breast cancer patients with confirmed bone metastases.

Participants were randomized double-blind to denosumab at 120 mg given once monthly by subcutaneous injection or to 4 mg of zoledronic acid given intravenously on an individualized dosing schedule governed by serum creatinine level in accord with the product labeling.

The primary study end point was the time to the first on-study skeletal-related event (SRE), consisting of fracture, radiation to bone for pain control, surgery, or spinal cord compression.

There was a highly significant 18% relative risk reduction favoring denosumab. The median time to the first SRE was 26.5 months in the zoledronic acid arm; it has not yet been reached in the denosumab arm.

At 34 months of follow up, 30.7% of patients on denosumab and 36.5% on zoledronic acid had experienced at least one SRE, for a 16% relative reduction with the RANKL inhibitor.

The difference between the two therapies grew in magnitude over time: The relative risk reduction favoring denosumab was 5.6% at 12 months and 11.5% at 18 months, Dr. Stopeck continued.

A total of 608 SREs occurred in the zoledronic acid group, compared with 474 with denosumab, a 23% reduction.

The time to experiencing moderate or severe pain was a secondary study outcome—and the most important end point of all from most patients' perspectives.

A score greater than 4 on the 11-point validated Brief Pain Inventory occurred for the first time at a median 64 days in the zoledronic acid group compared with 88 days in the denosumab arm, translating to a 23% advantage favoring the investigational agent (P = .009).

Flu-like acute phase reactions in conjunction with administration of therapy occurred in 27.3% of patients in the zoledronic acid arm compared with 10.4% on denosumab.

Adverse events related to renal toxicity occurred in 8.5% of the zoledronic acid group and 4.9% with denosumab; severe renal toxicity occurred in 1.5% of the zoledronic acid-treated patients compared to 0.2% of those on denosumab.

Osteonecrosis of the jaw (ONJ) occurred in 1.4% of patients on zoledronic acid and a statistically similar 2.0% of those on denosumab.

More than 80% of cases of ONJ were associated with dental extractions, poor oral hygiene, or use of a dental appliance.

Dr. Theresa Guise, professor of medicine at Indiana University, Indianapolis, commented that it wasn't clear prior to this trial whether ONJ was an adverse event limited to bisphosphonate therapy. These data indicate that it is more globally a side effect associated with inhibiting bone resorption.

Dr. Stopeck said that, interestingly, some cases of ONJ in denosumab-treated patients have turned out to be reversible.

She speculated that this may be a function of the monoclonal antibody's limited duration of activity in bone, in contrast to the bisphosphonates, which remain present in bone for years.

There is great interest in testing denosumab in the adjuvant setting in patients with early stage breast cancer because of theoretic reasons that RANKL inhibition should curb development of breast cancer, according to Dr. Stopeck.

Asked how she will incorporate denosumab into her own clinical practice if the agent receives marketing approval for the treatment of bone metastases, Dr. Stopeck replied, “I'm going to incorporate it rather quickly, assuming the price isn't exorbitant, since it shows better efficacy, it's easier to give by subcutaneous injection, I don't have to monitor the serum creatinine, and it has less toxicity.”

In October, the Food and Drug Administration held up Amgen's application for marketing approval for denosumab pending more information.

In an interview, a company spokesperson said Amgen plans to resubmit to the FDA, and file for marketing approval in Europe sometime in 2010, armed with these updated data from the breast cancer trial, the findings from another phase III trial involving patients with various solid organ cancers or multiple myeloma, and the results of a third phase III trial in men with prostate cancer, which is expected to report results in the first quarter of 2010.

Collectively, the three studies total roughly 6,000 cancer patients.

Disclosures: Dr. Stopeck serves as a consultant to Amgen and Novartis and is on the speakers bureau for Novartis, which markets zoledronic acid.

There is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate.

Source DR. STOPECK

SAN ANTONIO — Denosumab proved superior to zoledronic acid in delaying or preventing complications from bone metastases in breast cancer patients in a large phase III clinical trial.

Denosumab also showed significantly less toxicity than did zoledronic acid (Zometa), the current standard treatment for bone metastases.

Particularly noteworthy was the substantially lower rate of renal toxicity with denosumab; there is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate, Dr. Alison Stopeck noted at the San Antonio Breast Cancer Symposium.

Denosumab is an investigational fully humanized monoclonal antibody targeting RANK ligand (RANKL), the primary mediator of osteoclast formation, function, and survival.

Metastatic cancer cells stimulate RANKL activity, resulting in increased bone resorption and destruction, explained Dr. Stopeck of the University of Arizona Cancer Center, Tucson.

She reported on 2,046 breast cancer patients with confirmed bone metastases.

Participants were randomized double-blind to denosumab at 120 mg given once monthly by subcutaneous injection or to 4 mg of zoledronic acid given intravenously on an individualized dosing schedule governed by serum creatinine level in accord with the product labeling.

The primary study end point was the time to the first on-study skeletal-related event (SRE), consisting of fracture, radiation to bone for pain control, surgery, or spinal cord compression.

There was a highly significant 18% relative risk reduction favoring denosumab. The median time to the first SRE was 26.5 months in the zoledronic acid arm; it has not yet been reached in the denosumab arm.

At 34 months of follow up, 30.7% of patients on denosumab and 36.5% on zoledronic acid had experienced at least one SRE, for a 16% relative reduction with the RANKL inhibitor.

The difference between the two therapies grew in magnitude over time: The relative risk reduction favoring denosumab was 5.6% at 12 months and 11.5% at 18 months, Dr. Stopeck continued.

A total of 608 SREs occurred in the zoledronic acid group, compared with 474 with denosumab, a 23% reduction.

The time to experiencing moderate or severe pain was a secondary study outcome—and the most important end point of all from most patients' perspectives.

A score greater than 4 on the 11-point validated Brief Pain Inventory occurred for the first time at a median 64 days in the zoledronic acid group compared with 88 days in the denosumab arm, translating to a 23% advantage favoring the investigational agent (P = .009).

Flu-like acute phase reactions in conjunction with administration of therapy occurred in 27.3% of patients in the zoledronic acid arm compared with 10.4% on denosumab.

Adverse events related to renal toxicity occurred in 8.5% of the zoledronic acid group and 4.9% with denosumab; severe renal toxicity occurred in 1.5% of the zoledronic acid-treated patients compared to 0.2% of those on denosumab.

Osteonecrosis of the jaw (ONJ) occurred in 1.4% of patients on zoledronic acid and a statistically similar 2.0% of those on denosumab.

More than 80% of cases of ONJ were associated with dental extractions, poor oral hygiene, or use of a dental appliance.

Dr. Theresa Guise, professor of medicine at Indiana University, Indianapolis, commented that it wasn't clear prior to this trial whether ONJ was an adverse event limited to bisphosphonate therapy. These data indicate that it is more globally a side effect associated with inhibiting bone resorption.

Dr. Stopeck said that, interestingly, some cases of ONJ in denosumab-treated patients have turned out to be reversible.

She speculated that this may be a function of the monoclonal antibody's limited duration of activity in bone, in contrast to the bisphosphonates, which remain present in bone for years.

There is great interest in testing denosumab in the adjuvant setting in patients with early stage breast cancer because of theoretic reasons that RANKL inhibition should curb development of breast cancer, according to Dr. Stopeck.

Asked how she will incorporate denosumab into her own clinical practice if the agent receives marketing approval for the treatment of bone metastases, Dr. Stopeck replied, “I'm going to incorporate it rather quickly, assuming the price isn't exorbitant, since it shows better efficacy, it's easier to give by subcutaneous injection, I don't have to monitor the serum creatinine, and it has less toxicity.”

In October, the Food and Drug Administration held up Amgen's application for marketing approval for denosumab pending more information.

In an interview, a company spokesperson said Amgen plans to resubmit to the FDA, and file for marketing approval in Europe sometime in 2010, armed with these updated data from the breast cancer trial, the findings from another phase III trial involving patients with various solid organ cancers or multiple myeloma, and the results of a third phase III trial in men with prostate cancer, which is expected to report results in the first quarter of 2010.

Collectively, the three studies total roughly 6,000 cancer patients.

Disclosures: Dr. Stopeck serves as a consultant to Amgen and Novartis and is on the speakers bureau for Novartis, which markets zoledronic acid.

There is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate.

Source DR. STOPECK

SAN ANTONIO — Denosumab proved superior to zoledronic acid in delaying or preventing complications from bone metastases in breast cancer patients in a large phase III clinical trial.

Denosumab also showed significantly less toxicity than did zoledronic acid (Zometa), the current standard treatment for bone metastases.

Particularly noteworthy was the substantially lower rate of renal toxicity with denosumab; there is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate, Dr. Alison Stopeck noted at the San Antonio Breast Cancer Symposium.

Denosumab is an investigational fully humanized monoclonal antibody targeting RANK ligand (RANKL), the primary mediator of osteoclast formation, function, and survival.

Metastatic cancer cells stimulate RANKL activity, resulting in increased bone resorption and destruction, explained Dr. Stopeck of the University of Arizona Cancer Center, Tucson.

She reported on 2,046 breast cancer patients with confirmed bone metastases.

Participants were randomized double-blind to denosumab at 120 mg given once monthly by subcutaneous injection or to 4 mg of zoledronic acid given intravenously on an individualized dosing schedule governed by serum creatinine level in accord with the product labeling.

The primary study end point was the time to the first on-study skeletal-related event (SRE), consisting of fracture, radiation to bone for pain control, surgery, or spinal cord compression.

There was a highly significant 18% relative risk reduction favoring denosumab. The median time to the first SRE was 26.5 months in the zoledronic acid arm; it has not yet been reached in the denosumab arm.

At 34 months of follow up, 30.7% of patients on denosumab and 36.5% on zoledronic acid had experienced at least one SRE, for a 16% relative reduction with the RANKL inhibitor.

The difference between the two therapies grew in magnitude over time: The relative risk reduction favoring denosumab was 5.6% at 12 months and 11.5% at 18 months, Dr. Stopeck continued.

A total of 608 SREs occurred in the zoledronic acid group, compared with 474 with denosumab, a 23% reduction.

The time to experiencing moderate or severe pain was a secondary study outcome—and the most important end point of all from most patients' perspectives.

A score greater than 4 on the 11-point validated Brief Pain Inventory occurred for the first time at a median 64 days in the zoledronic acid group compared with 88 days in the denosumab arm, translating to a 23% advantage favoring the investigational agent (P = .009).

Flu-like acute phase reactions in conjunction with administration of therapy occurred in 27.3% of patients in the zoledronic acid arm compared with 10.4% on denosumab.

Adverse events related to renal toxicity occurred in 8.5% of the zoledronic acid group and 4.9% with denosumab; severe renal toxicity occurred in 1.5% of the zoledronic acid-treated patients compared to 0.2% of those on denosumab.

Osteonecrosis of the jaw (ONJ) occurred in 1.4% of patients on zoledronic acid and a statistically similar 2.0% of those on denosumab.

More than 80% of cases of ONJ were associated with dental extractions, poor oral hygiene, or use of a dental appliance.

Dr. Theresa Guise, professor of medicine at Indiana University, Indianapolis, commented that it wasn't clear prior to this trial whether ONJ was an adverse event limited to bisphosphonate therapy. These data indicate that it is more globally a side effect associated with inhibiting bone resorption.

Dr. Stopeck said that, interestingly, some cases of ONJ in denosumab-treated patients have turned out to be reversible.

She speculated that this may be a function of the monoclonal antibody's limited duration of activity in bone, in contrast to the bisphosphonates, which remain present in bone for years.

There is great interest in testing denosumab in the adjuvant setting in patients with early stage breast cancer because of theoretic reasons that RANKL inhibition should curb development of breast cancer, according to Dr. Stopeck.

Asked how she will incorporate denosumab into her own clinical practice if the agent receives marketing approval for the treatment of bone metastases, Dr. Stopeck replied, “I'm going to incorporate it rather quickly, assuming the price isn't exorbitant, since it shows better efficacy, it's easier to give by subcutaneous injection, I don't have to monitor the serum creatinine, and it has less toxicity.”

In October, the Food and Drug Administration held up Amgen's application for marketing approval for denosumab pending more information.

In an interview, a company spokesperson said Amgen plans to resubmit to the FDA, and file for marketing approval in Europe sometime in 2010, armed with these updated data from the breast cancer trial, the findings from another phase III trial involving patients with various solid organ cancers or multiple myeloma, and the results of a third phase III trial in men with prostate cancer, which is expected to report results in the first quarter of 2010.

Collectively, the three studies total roughly 6,000 cancer patients.

Disclosures: Dr. Stopeck serves as a consultant to Amgen and Novartis and is on the speakers bureau for Novartis, which markets zoledronic acid.

There is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate.

Source DR. STOPECK