Jeff Evans

ARLINGTON, VA. — African Americans may have a lower rate of osteoporosis-related fractures than whites because of adaptations in calcium homeostasis, bone turnover and resorption, and response to parathyroid hormone, Dr. Felicia Cosman said at a conference sponsored by the American Society for Bone and Mineral Research.

It is “very surprising” that at all ages, black individuals have a lower rate of fractures and higher bone mineral density (BMD) than white individuals, even though blacks generally have higher rates of vitamin D deficiency or insufficiency, said Dr. Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital, West Haverstraw, N.Y.

Mean serum levels of 25-hydroxyvitamin D [25(OH)D] are known at all ages and in both genders to be generally lower in blacks than in whites. This is the result of reduced skin production of vitamin D (due to higher melanin content in the skin) and a lower dietary intake of vitamin D, Dr. Cosman said.

An alteration in the vitamin D-endocrine system in blacks was first proposed by Dr. Norman Bell; it was based on evidence that blacks have a greater prevalence of vitamin D deficiency and relative secondary hyperparathyroidism, lower levels of bone turnover, and increased urinary calcium retention as an adaptive means to maintain calcium homeostasis without sacrificing the skeleton (J. Clin. Invest. 1985;76:470–3).

In many studies, parathyroid hormone (PTH) levels are higher, on average, in blacks than in whites. The PTH levels found in blacks occur within the context of low calcium intake in addition to low 25(OH)D levels, which may be related to “real or perceived” lactose intolerance, Dr. Cosman said. As a result of high PTH levels, blacks have generally been measured with higher 1–25dihydroxyvitamin D [1,25(OH)₂D] levels than have whites.

“We would expect that with higher 1,25(OH)₂D levels, you would see greater [dietary] calcium absorption in black individuals compared to whites,” but studies have reported inconsistent data, many of which have shown no significant interracial differences, she said.

One would also expect blacks to have higher bone turnover levels because of high PTH levels, but in general this has not been true, Dr. Cosman said.

However, nearly all studies of the kidney have found that blacks have lower urinary calcium excretion than whites.

In addition, supplementation of 1,25(OH)₂D has been shown to cause a significantly greater decrease in urinary calcium excretion in blacks than in whites. Markers of bone formation also increased more among blacks than among whites, whereas bone resorption indices showed no racial differences (Osteoporos. Int. 2000;11:271–7). In a separate study, administration of PTH also caused blacks to retain urinary calcium to a greater degree than it did in whites, but it did not cause any racial differences in bone formation markers. After receipt of PTH, blacks also did not have as great an increase in bone resorption markers (J. Bone Miner. Res. 1997;12:958–66). This finding directly confirms “the hypothesis that the black skeleton could be resistant to the acute bone resorptive effects of PTH,” she said.

Studies of histomorphometric differences in bone have shown significantly reduced bone formation rates and a longer total bone formation period in blacks, compared with whites. The results of those studies are consistent with evidence that blacks have a lower level of serum osteocalcin—which has been the most sensitive indicator of a racial difference in bone turnover levels—and that blacks respond more slowly to bone remodeling therapies.

“The bottom line message … for these measurements is that in a relative secondary hyperparathyroid state you really expect to see high [bone] turnover,” Dr. Cosman said. “We never see that. We see either the same or, in most cases, lower turnover in blacks.”

ARLINGTON, VA. — African Americans may have a lower rate of osteoporosis-related fractures than whites because of adaptations in calcium homeostasis, bone turnover and resorption, and response to parathyroid hormone, Dr. Felicia Cosman said at a conference sponsored by the American Society for Bone and Mineral Research.

It is “very surprising” that at all ages, black individuals have a lower rate of fractures and higher bone mineral density (BMD) than white individuals, even though blacks generally have higher rates of vitamin D deficiency or insufficiency, said Dr. Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital, West Haverstraw, N.Y.

Mean serum levels of 25-hydroxyvitamin D [25(OH)D] are known at all ages and in both genders to be generally lower in blacks than in whites. This is the result of reduced skin production of vitamin D (due to higher melanin content in the skin) and a lower dietary intake of vitamin D, Dr. Cosman said.

An alteration in the vitamin D-endocrine system in blacks was first proposed by Dr. Norman Bell; it was based on evidence that blacks have a greater prevalence of vitamin D deficiency and relative secondary hyperparathyroidism, lower levels of bone turnover, and increased urinary calcium retention as an adaptive means to maintain calcium homeostasis without sacrificing the skeleton (J. Clin. Invest. 1985;76:470–3).

In many studies, parathyroid hormone (PTH) levels are higher, on average, in blacks than in whites. The PTH levels found in blacks occur within the context of low calcium intake in addition to low 25(OH)D levels, which may be related to “real or perceived” lactose intolerance, Dr. Cosman said. As a result of high PTH levels, blacks have generally been measured with higher 1–25dihydroxyvitamin D [1,25(OH)₂D] levels than have whites.

“We would expect that with higher 1,25(OH)₂D levels, you would see greater [dietary] calcium absorption in black individuals compared to whites,” but studies have reported inconsistent data, many of which have shown no significant interracial differences, she said.

One would also expect blacks to have higher bone turnover levels because of high PTH levels, but in general this has not been true, Dr. Cosman said.

However, nearly all studies of the kidney have found that blacks have lower urinary calcium excretion than whites.

In addition, supplementation of 1,25(OH)₂D has been shown to cause a significantly greater decrease in urinary calcium excretion in blacks than in whites. Markers of bone formation also increased more among blacks than among whites, whereas bone resorption indices showed no racial differences (Osteoporos. Int. 2000;11:271–7). In a separate study, administration of PTH also caused blacks to retain urinary calcium to a greater degree than it did in whites, but it did not cause any racial differences in bone formation markers. After receipt of PTH, blacks also did not have as great an increase in bone resorption markers (J. Bone Miner. Res. 1997;12:958–66). This finding directly confirms “the hypothesis that the black skeleton could be resistant to the acute bone resorptive effects of PTH,” she said.

Studies of histomorphometric differences in bone have shown significantly reduced bone formation rates and a longer total bone formation period in blacks, compared with whites. The results of those studies are consistent with evidence that blacks have a lower level of serum osteocalcin—which has been the most sensitive indicator of a racial difference in bone turnover levels—and that blacks respond more slowly to bone remodeling therapies.

“The bottom line message … for these measurements is that in a relative secondary hyperparathyroid state you really expect to see high [bone] turnover,” Dr. Cosman said. “We never see that. We see either the same or, in most cases, lower turnover in blacks.”

ARLINGTON, VA. — African Americans may have a lower rate of osteoporosis-related fractures than whites because of adaptations in calcium homeostasis, bone turnover and resorption, and response to parathyroid hormone, Dr. Felicia Cosman said at a conference sponsored by the American Society for Bone and Mineral Research.

It is “very surprising” that at all ages, black individuals have a lower rate of fractures and higher bone mineral density (BMD) than white individuals, even though blacks generally have higher rates of vitamin D deficiency or insufficiency, said Dr. Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital, West Haverstraw, N.Y.

Mean serum levels of 25-hydroxyvitamin D [25(OH)D] are known at all ages and in both genders to be generally lower in blacks than in whites. This is the result of reduced skin production of vitamin D (due to higher melanin content in the skin) and a lower dietary intake of vitamin D, Dr. Cosman said.

An alteration in the vitamin D-endocrine system in blacks was first proposed by Dr. Norman Bell; it was based on evidence that blacks have a greater prevalence of vitamin D deficiency and relative secondary hyperparathyroidism, lower levels of bone turnover, and increased urinary calcium retention as an adaptive means to maintain calcium homeostasis without sacrificing the skeleton (J. Clin. Invest. 1985;76:470–3).

In many studies, parathyroid hormone (PTH) levels are higher, on average, in blacks than in whites. The PTH levels found in blacks occur within the context of low calcium intake in addition to low 25(OH)D levels, which may be related to “real or perceived” lactose intolerance, Dr. Cosman said. As a result of high PTH levels, blacks have generally been measured with higher 1–25dihydroxyvitamin D [1,25(OH)₂D] levels than have whites.

“We would expect that with higher 1,25(OH)₂D levels, you would see greater [dietary] calcium absorption in black individuals compared to whites,” but studies have reported inconsistent data, many of which have shown no significant interracial differences, she said.

One would also expect blacks to have higher bone turnover levels because of high PTH levels, but in general this has not been true, Dr. Cosman said.

However, nearly all studies of the kidney have found that blacks have lower urinary calcium excretion than whites.

In addition, supplementation of 1,25(OH)₂D has been shown to cause a significantly greater decrease in urinary calcium excretion in blacks than in whites. Markers of bone formation also increased more among blacks than among whites, whereas bone resorption indices showed no racial differences (Osteoporos. Int. 2000;11:271–7). In a separate study, administration of PTH also caused blacks to retain urinary calcium to a greater degree than it did in whites, but it did not cause any racial differences in bone formation markers. After receipt of PTH, blacks also did not have as great an increase in bone resorption markers (J. Bone Miner. Res. 1997;12:958–66). This finding directly confirms “the hypothesis that the black skeleton could be resistant to the acute bone resorptive effects of PTH,” she said.

Studies of histomorphometric differences in bone have shown significantly reduced bone formation rates and a longer total bone formation period in blacks, compared with whites. The results of those studies are consistent with evidence that blacks have a lower level of serum osteocalcin—which has been the most sensitive indicator of a racial difference in bone turnover levels—and that blacks respond more slowly to bone remodeling therapies.

“The bottom line message … for these measurements is that in a relative secondary hyperparathyroid state you really expect to see high [bone] turnover,” Dr. Cosman said. “We never see that. We see either the same or, in most cases, lower turnover in blacks.”

ARLINGTON, VA. — People who take sufficiently high supplement doses of vitamin D or those who already have adequate levels of vitamin D were found to have a small but significantly reduced risk of specific fractures, falls, and low bone mineral density, according to an Agency for Healthcare Research and Quality report on the effect of vitamin D supplements on bone health outcomes.

Dr. Ann B. Cranney and her associates at the University of Ottawa Evidence-Based Practice Center extensively reviewed the literature on the effects of 25-hydroxyvitamin D (25[OH]D) concentration or vitamin D supplementation. She presented the results of meta-analyses on studies that met eligibility criteria at a conference sponsored by the American Society for Bone and Mineral Research.

It was not possible to quantitatively summarize the results of 10 randomized controlled trials or 31 observational studies that examined the effect of 25(OH)D levels on bone health outcomes in postmenopausal women and older men, so Dr. Cranney and her colleagues categorized the evidence supporting the effect of the vitamin D metabolite as good, fair, or inconsistent. For serum 25(OH)D levels of at least 50–80 nmol/L, there was good evidence of an association with increased bone mineral density in the hip, fair evidence of an inverse association with the risk of hip fracture, and inconsistent evidence of an association with a reduction in falls and functional measures such as grip strength and body sway.

In 74 randomized controlled trials of supplementation with either vitamin D₃ or vitamin D₂, the investigators found that 25(OH)D levels increased more with supplementation with vitamin D₃ than with vitamin D₂. Data collected from 16 randomized controlled trials provided enough information on 25(OH)D levels in both the control and treatment groups at baseline as well as at the end of the study to enable the investigators to determine that supplementation with 700 IU/day or more of vitamin D₃ was associated with a drop in serum parathyroid hormone levels. The investigators also calculated from the trial results that 1 IU vitamin D₃ raises serum 25(OH)D concentration by 0.016 nmol/L.

Trials that used supplements with either vitamin D₃ or vitamin D₂ did not show a significant effect on reducing the risk of fractures overall or on the risk of hip fractures in particular. Also, supplementation with vitamin D plus calcium or vitamin D alone did not have a significant effect on the risk of nonvertebral fractures. But in eight trials, supplements of 700 IU/day or more vitamin D₃ significantly reduced the risk of nonvertebral fractures by 15%.

This risk reduction was primarily driven by two trials of individuals in an institutional setting, who had a 22% reduction in the risk of nonvertebral fractures. Supplements of 700 IU/day or more vitamin D₃ also significantly lowered the risk of hip fractures; trials in an institutional setting, rather than in the community, factored strongly in the overall results, she noted.

The investigators found that participants in trials of vitamin D₃ supplementation that recorded serum 25(OH)D concentrations of 74 nmol/L or higher had a significant 23% lower risk of nonvertebral fractures than did participants of trials that did not achieve a 25(OH)D level of 74 nmol/L.

Vitamin D supplements did not reduce the risk of falls overall in 12 trials. But vitamin D supplements did significantly lowered the risk of a fall by 11% in six trials in which falls were defined or independently ascertained, Dr. Cranney said.

The Agency for Healthcare Research and Quality requested the report on behalf of the National Institutes of Health Office of Dietary Supplements.

ARLINGTON, VA. — People who take sufficiently high supplement doses of vitamin D or those who already have adequate levels of vitamin D were found to have a small but significantly reduced risk of specific fractures, falls, and low bone mineral density, according to an Agency for Healthcare Research and Quality report on the effect of vitamin D supplements on bone health outcomes.

Dr. Ann B. Cranney and her associates at the University of Ottawa Evidence-Based Practice Center extensively reviewed the literature on the effects of 25-hydroxyvitamin D (25[OH]D) concentration or vitamin D supplementation. She presented the results of meta-analyses on studies that met eligibility criteria at a conference sponsored by the American Society for Bone and Mineral Research.

It was not possible to quantitatively summarize the results of 10 randomized controlled trials or 31 observational studies that examined the effect of 25(OH)D levels on bone health outcomes in postmenopausal women and older men, so Dr. Cranney and her colleagues categorized the evidence supporting the effect of the vitamin D metabolite as good, fair, or inconsistent. For serum 25(OH)D levels of at least 50–80 nmol/L, there was good evidence of an association with increased bone mineral density in the hip, fair evidence of an inverse association with the risk of hip fracture, and inconsistent evidence of an association with a reduction in falls and functional measures such as grip strength and body sway.

In 74 randomized controlled trials of supplementation with either vitamin D₃ or vitamin D₂, the investigators found that 25(OH)D levels increased more with supplementation with vitamin D₃ than with vitamin D₂. Data collected from 16 randomized controlled trials provided enough information on 25(OH)D levels in both the control and treatment groups at baseline as well as at the end of the study to enable the investigators to determine that supplementation with 700 IU/day or more of vitamin D₃ was associated with a drop in serum parathyroid hormone levels. The investigators also calculated from the trial results that 1 IU vitamin D₃ raises serum 25(OH)D concentration by 0.016 nmol/L.

Trials that used supplements with either vitamin D₃ or vitamin D₂ did not show a significant effect on reducing the risk of fractures overall or on the risk of hip fractures in particular. Also, supplementation with vitamin D plus calcium or vitamin D alone did not have a significant effect on the risk of nonvertebral fractures. But in eight trials, supplements of 700 IU/day or more vitamin D₃ significantly reduced the risk of nonvertebral fractures by 15%.

This risk reduction was primarily driven by two trials of individuals in an institutional setting, who had a 22% reduction in the risk of nonvertebral fractures. Supplements of 700 IU/day or more vitamin D₃ also significantly lowered the risk of hip fractures; trials in an institutional setting, rather than in the community, factored strongly in the overall results, she noted.

The investigators found that participants in trials of vitamin D₃ supplementation that recorded serum 25(OH)D concentrations of 74 nmol/L or higher had a significant 23% lower risk of nonvertebral fractures than did participants of trials that did not achieve a 25(OH)D level of 74 nmol/L.

Vitamin D supplements did not reduce the risk of falls overall in 12 trials. But vitamin D supplements did significantly lowered the risk of a fall by 11% in six trials in which falls were defined or independently ascertained, Dr. Cranney said.

The Agency for Healthcare Research and Quality requested the report on behalf of the National Institutes of Health Office of Dietary Supplements.

ARLINGTON, VA. — People who take sufficiently high supplement doses of vitamin D or those who already have adequate levels of vitamin D were found to have a small but significantly reduced risk of specific fractures, falls, and low bone mineral density, according to an Agency for Healthcare Research and Quality report on the effect of vitamin D supplements on bone health outcomes.

Dr. Ann B. Cranney and her associates at the University of Ottawa Evidence-Based Practice Center extensively reviewed the literature on the effects of 25-hydroxyvitamin D (25[OH]D) concentration or vitamin D supplementation. She presented the results of meta-analyses on studies that met eligibility criteria at a conference sponsored by the American Society for Bone and Mineral Research.

It was not possible to quantitatively summarize the results of 10 randomized controlled trials or 31 observational studies that examined the effect of 25(OH)D levels on bone health outcomes in postmenopausal women and older men, so Dr. Cranney and her colleagues categorized the evidence supporting the effect of the vitamin D metabolite as good, fair, or inconsistent. For serum 25(OH)D levels of at least 50–80 nmol/L, there was good evidence of an association with increased bone mineral density in the hip, fair evidence of an inverse association with the risk of hip fracture, and inconsistent evidence of an association with a reduction in falls and functional measures such as grip strength and body sway.

In 74 randomized controlled trials of supplementation with either vitamin D₃ or vitamin D₂, the investigators found that 25(OH)D levels increased more with supplementation with vitamin D₃ than with vitamin D₂. Data collected from 16 randomized controlled trials provided enough information on 25(OH)D levels in both the control and treatment groups at baseline as well as at the end of the study to enable the investigators to determine that supplementation with 700 IU/day or more of vitamin D₃ was associated with a drop in serum parathyroid hormone levels. The investigators also calculated from the trial results that 1 IU vitamin D₃ raises serum 25(OH)D concentration by 0.016 nmol/L.

Trials that used supplements with either vitamin D₃ or vitamin D₂ did not show a significant effect on reducing the risk of fractures overall or on the risk of hip fractures in particular. Also, supplementation with vitamin D plus calcium or vitamin D alone did not have a significant effect on the risk of nonvertebral fractures. But in eight trials, supplements of 700 IU/day or more vitamin D₃ significantly reduced the risk of nonvertebral fractures by 15%.

This risk reduction was primarily driven by two trials of individuals in an institutional setting, who had a 22% reduction in the risk of nonvertebral fractures. Supplements of 700 IU/day or more vitamin D₃ also significantly lowered the risk of hip fractures; trials in an institutional setting, rather than in the community, factored strongly in the overall results, she noted.

The investigators found that participants in trials of vitamin D₃ supplementation that recorded serum 25(OH)D concentrations of 74 nmol/L or higher had a significant 23% lower risk of nonvertebral fractures than did participants of trials that did not achieve a 25(OH)D level of 74 nmol/L.

Vitamin D supplements did not reduce the risk of falls overall in 12 trials. But vitamin D supplements did significantly lowered the risk of a fall by 11% in six trials in which falls were defined or independently ascertained, Dr. Cranney said.

The Agency for Healthcare Research and Quality requested the report on behalf of the National Institutes of Health Office of Dietary Supplements.

ARLINGTON, VA. — Inadequate levels of vitamin D may help to explain not only morbidities such as osteoporosis but also less-appreciated effects of vitamin D insufficiency that worsen bodily functions and are commonly thought to be related to aging alone, Dr. Neil Binkley reported at a conference sponsored by the American Society for Bone and Mineral Research.

“I would like to suggest to you that vitamin D inadequacy might be contributing to what we are currently accepting as old age-related morbidity,” said Dr. Binkley, codirector of the University of Wisconsin Osteoporosis Clinical Center and Research Program, Madison.

The prevalence of densitometric osteopenia markedly increases with advancing age, and at any given bone density, age has a “profound impact” on the risk of fracture, he said.

But many other conditions that are affected by vitamin D status have been labeled as “age-related” morbidities, including sarcopenia, falling, overactive bladder, swallowing dysfunction, decreased lung function, macular degeneration, and cognitive decline.

“Always consider that perhaps some of these other age-related morbidities are what are causing this dramatic effect of age on fracture,” Dr. Binkley said.

▸ Sarcopenia. The expression of vitamin D receptors declines in muscle with aging. In muscle, vitamin D also may be involved with calcium transport and actin-myosin interaction.

A study of 1,008 older adults has suggested that vitamin D inadequacy is associated with sarcopenia. After a 3-year follow-up, men and women with baseline 25(OH)D levels less than 25 nmol/L were more than twice as likely to develop sarcopenia (based on either grip strength or muscle mass) than were those with a higher level of 25(OH)D.

▸ Falling. It is not known whether vitamin D status and muscle strength are causally related, but “it is, however, clear that vitamin D status is related to the risk of falling in both older men and older women,” Dr. Binkley said.

The risk of falling is increased by orthopedic disabilities, visual impairment, central or peripheral neurologic dysfunction, and muscle weakness, which may be the main risk factor, he said. A meta-analysis of double-blind, randomized, trials showed that vitamin D reduced the risk of falling by 22% (JAMA 2004;291:1999–2006).

▸ Overactive bladder. Bladder dysfunction also may be associated with muscle weakness, leading to poorer coordination of the muscles used to control urination. Overactive bladder affects 30%–40% of adults older than 75 years of age and two-thirds of nursing home residents; it is defined as urinary urgency with or without incontinence, usually with frequency and nocturia.

In a study of nearly 6,000 community-dwelling women aged 40 years or older, women in the highest quintiles of vitamin D intake had the lowest risk of developing overactive bladder (Neurourol. Urodyn. 2004;23:204–10).

▸ Difficulty swallowing. Up to 40% of individuals older than 60 years have problems swallowing, which can lead to undernutrition, sarcopenia, and aspiration pneumonia. Dysphagia associated with aging classically has been felt to reflect neurologic disease such as Parkinson's or stroke, but more recent work has shown that even normal healthy adults swallow more slowly and generate lower tongue pressures than do younger adults.

“I think it's at least plausible that this decreased muscle function might be causally related to the increased risk of dysphagia observed with advancing age,” Dr. Binkley suggested.

But no research has been conducted on vitamin D status and the risk of dysphagia of aging, he said.

▸ Pulmonary function. Both the forced expiratory volume in the first second after taking a deep breath and forced vital capacity are known to decline with aging; poor results on such tests are associated with substantial morbidity and mortality.

In a study of people in the National Health and Nutrition Examination Survey III (NHANES III) who were aged 60 years or older, both of those measures of lung function were significantly higher among people in the highest quintile of serum 25(OH)D concentration than in individuals in the lowest quintile of the vitamin.

Biologically plausible ways in which vitamin D might protect against a decline in pulmonary function include the possibility of a decline in respiratory muscle function with inadequate levels of vitamin D, lung tissue remodeling, or a reduction in airway inflammation.

▸ Age-related macular degeneration. In a yet-to-be published study involving 7,752 people who participated in NHANES III, the risk of developing age-related macular degeneration declined steadily from the lowest to the highest quintiles of serum 25(OH)D concentration.

▸ Dementia/cognitive decline. In a small case-control study, deficient and extremely low levels of vitamin D were found in significantly more ambulatory women with Alzheimer's disease than in control women of the same age without Alzheimer's or fractures (Bone 1998;23:555–7).

ARLINGTON, VA. — Inadequate levels of vitamin D may help to explain not only morbidities such as osteoporosis but also less-appreciated effects of vitamin D insufficiency that worsen bodily functions and are commonly thought to be related to aging alone, Dr. Neil Binkley reported at a conference sponsored by the American Society for Bone and Mineral Research.

“I would like to suggest to you that vitamin D inadequacy might be contributing to what we are currently accepting as old age-related morbidity,” said Dr. Binkley, codirector of the University of Wisconsin Osteoporosis Clinical Center and Research Program, Madison.

The prevalence of densitometric osteopenia markedly increases with advancing age, and at any given bone density, age has a “profound impact” on the risk of fracture, he said.

But many other conditions that are affected by vitamin D status have been labeled as “age-related” morbidities, including sarcopenia, falling, overactive bladder, swallowing dysfunction, decreased lung function, macular degeneration, and cognitive decline.

“Always consider that perhaps some of these other age-related morbidities are what are causing this dramatic effect of age on fracture,” Dr. Binkley said.

▸ Sarcopenia. The expression of vitamin D receptors declines in muscle with aging. In muscle, vitamin D also may be involved with calcium transport and actin-myosin interaction.

A study of 1,008 older adults has suggested that vitamin D inadequacy is associated with sarcopenia. After a 3-year follow-up, men and women with baseline 25(OH)D levels less than 25 nmol/L were more than twice as likely to develop sarcopenia (based on either grip strength or muscle mass) than were those with a higher level of 25(OH)D.

▸ Falling. It is not known whether vitamin D status and muscle strength are causally related, but “it is, however, clear that vitamin D status is related to the risk of falling in both older men and older women,” Dr. Binkley said.

The risk of falling is increased by orthopedic disabilities, visual impairment, central or peripheral neurologic dysfunction, and muscle weakness, which may be the main risk factor, he said. A meta-analysis of double-blind, randomized, trials showed that vitamin D reduced the risk of falling by 22% (JAMA 2004;291:1999–2006).

▸ Overactive bladder. Bladder dysfunction also may be associated with muscle weakness, leading to poorer coordination of the muscles used to control urination. Overactive bladder affects 30%–40% of adults older than 75 years of age and two-thirds of nursing home residents; it is defined as urinary urgency with or without incontinence, usually with frequency and nocturia.

In a study of nearly 6,000 community-dwelling women aged 40 years or older, women in the highest quintiles of vitamin D intake had the lowest risk of developing overactive bladder (Neurourol. Urodyn. 2004;23:204–10).

▸ Difficulty swallowing. Up to 40% of individuals older than 60 years have problems swallowing, which can lead to undernutrition, sarcopenia, and aspiration pneumonia. Dysphagia associated with aging classically has been felt to reflect neurologic disease such as Parkinson's or stroke, but more recent work has shown that even normal healthy adults swallow more slowly and generate lower tongue pressures than do younger adults.

“I think it's at least plausible that this decreased muscle function might be causally related to the increased risk of dysphagia observed with advancing age,” Dr. Binkley suggested.

But no research has been conducted on vitamin D status and the risk of dysphagia of aging, he said.

▸ Pulmonary function. Both the forced expiratory volume in the first second after taking a deep breath and forced vital capacity are known to decline with aging; poor results on such tests are associated with substantial morbidity and mortality.

In a study of people in the National Health and Nutrition Examination Survey III (NHANES III) who were aged 60 years or older, both of those measures of lung function were significantly higher among people in the highest quintile of serum 25(OH)D concentration than in individuals in the lowest quintile of the vitamin.

Biologically plausible ways in which vitamin D might protect against a decline in pulmonary function include the possibility of a decline in respiratory muscle function with inadequate levels of vitamin D, lung tissue remodeling, or a reduction in airway inflammation.

▸ Age-related macular degeneration. In a yet-to-be published study involving 7,752 people who participated in NHANES III, the risk of developing age-related macular degeneration declined steadily from the lowest to the highest quintiles of serum 25(OH)D concentration.

▸ Dementia/cognitive decline. In a small case-control study, deficient and extremely low levels of vitamin D were found in significantly more ambulatory women with Alzheimer's disease than in control women of the same age without Alzheimer's or fractures (Bone 1998;23:555–7).

ARLINGTON, VA. — Inadequate levels of vitamin D may help to explain not only morbidities such as osteoporosis but also less-appreciated effects of vitamin D insufficiency that worsen bodily functions and are commonly thought to be related to aging alone, Dr. Neil Binkley reported at a conference sponsored by the American Society for Bone and Mineral Research.

“I would like to suggest to you that vitamin D inadequacy might be contributing to what we are currently accepting as old age-related morbidity,” said Dr. Binkley, codirector of the University of Wisconsin Osteoporosis Clinical Center and Research Program, Madison.

The prevalence of densitometric osteopenia markedly increases with advancing age, and at any given bone density, age has a “profound impact” on the risk of fracture, he said.

But many other conditions that are affected by vitamin D status have been labeled as “age-related” morbidities, including sarcopenia, falling, overactive bladder, swallowing dysfunction, decreased lung function, macular degeneration, and cognitive decline.

“Always consider that perhaps some of these other age-related morbidities are what are causing this dramatic effect of age on fracture,” Dr. Binkley said.

▸ Sarcopenia. The expression of vitamin D receptors declines in muscle with aging. In muscle, vitamin D also may be involved with calcium transport and actin-myosin interaction.

A study of 1,008 older adults has suggested that vitamin D inadequacy is associated with sarcopenia. After a 3-year follow-up, men and women with baseline 25(OH)D levels less than 25 nmol/L were more than twice as likely to develop sarcopenia (based on either grip strength or muscle mass) than were those with a higher level of 25(OH)D.

▸ Falling. It is not known whether vitamin D status and muscle strength are causally related, but “it is, however, clear that vitamin D status is related to the risk of falling in both older men and older women,” Dr. Binkley said.

The risk of falling is increased by orthopedic disabilities, visual impairment, central or peripheral neurologic dysfunction, and muscle weakness, which may be the main risk factor, he said. A meta-analysis of double-blind, randomized, trials showed that vitamin D reduced the risk of falling by 22% (JAMA 2004;291:1999–2006).

▸ Overactive bladder. Bladder dysfunction also may be associated with muscle weakness, leading to poorer coordination of the muscles used to control urination. Overactive bladder affects 30%–40% of adults older than 75 years of age and two-thirds of nursing home residents; it is defined as urinary urgency with or without incontinence, usually with frequency and nocturia.

In a study of nearly 6,000 community-dwelling women aged 40 years or older, women in the highest quintiles of vitamin D intake had the lowest risk of developing overactive bladder (Neurourol. Urodyn. 2004;23:204–10).

▸ Difficulty swallowing. Up to 40% of individuals older than 60 years have problems swallowing, which can lead to undernutrition, sarcopenia, and aspiration pneumonia. Dysphagia associated with aging classically has been felt to reflect neurologic disease such as Parkinson's or stroke, but more recent work has shown that even normal healthy adults swallow more slowly and generate lower tongue pressures than do younger adults.

“I think it's at least plausible that this decreased muscle function might be causally related to the increased risk of dysphagia observed with advancing age,” Dr. Binkley suggested.

But no research has been conducted on vitamin D status and the risk of dysphagia of aging, he said.

▸ Pulmonary function. Both the forced expiratory volume in the first second after taking a deep breath and forced vital capacity are known to decline with aging; poor results on such tests are associated with substantial morbidity and mortality.

In a study of people in the National Health and Nutrition Examination Survey III (NHANES III) who were aged 60 years or older, both of those measures of lung function were significantly higher among people in the highest quintile of serum 25(OH)D concentration than in individuals in the lowest quintile of the vitamin.

Biologically plausible ways in which vitamin D might protect against a decline in pulmonary function include the possibility of a decline in respiratory muscle function with inadequate levels of vitamin D, lung tissue remodeling, or a reduction in airway inflammation.

▸ Age-related macular degeneration. In a yet-to-be published study involving 7,752 people who participated in NHANES III, the risk of developing age-related macular degeneration declined steadily from the lowest to the highest quintiles of serum 25(OH)D concentration.

▸ Dementia/cognitive decline. In a small case-control study, deficient and extremely low levels of vitamin D were found in significantly more ambulatory women with Alzheimer's disease than in control women of the same age without Alzheimer's or fractures (Bone 1998;23:555–7).

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day because of a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels, but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000 IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published. This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]₂D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment. Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day because of a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels, but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000 IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published. This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]₂D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment. Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day because of a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels, but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000 IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published. This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]₂D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment. Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

ARLINGTON, VA. — Fish oil capsules and multivitamin tablets that contain 10 mcg of vitamin D₃ provide the same increase in stored levels of the vitamin when taken daily during a 4-week period, Kristin Holvik reported at a conference sponsored by the American Society for Bone and Mineral Research.

Even though many types of vitamin supplements are available to patients, little is known about whether the bioavailability of vitamin D₃ (cholecalciferol) differs when it is sequestered in fat-containing capsules as opposed to solid tablets, noted Ms. Holvik, a Ph.D. student at the Institute of General Practice and Community Medicine at the University of Oslo.

In a randomized trial, 55 healthy young adults (34 females and 21 males) received 28 days of supplementation with either fish oil capsules or multivitamin tablets, each of which was taken once daily and contained 10 mcg vitamin D₃ (an amount equivalent to 400 IU).

The participants completed a self-administered questionnaire about diet and sun exposure and had a nonfasting venous blood sample drawn at the beginning and end of the study, which took place in Oslo in late winter 2005, according to Ms. Holvik. She won an ASBMR Young Investigator Award for her research, which she presented during a poster session at the conference.

Serum 25-hydroxyvitamin D levels in individuals who took fish oil capsules increased from an average of 48.5 nmol/L to 80.4 nmol/L at the end of the study. Multivitamin users had a similar rise in serum 25-hydroxyvitamin D levels from a mean of 40.3 nmol/L to 76.5 nmol/L. On average, the participants were aged about 28 years and had a body mass index of about 24 kg/m2.

ARLINGTON, VA. — Fish oil capsules and multivitamin tablets that contain 10 mcg of vitamin D₃ provide the same increase in stored levels of the vitamin when taken daily during a 4-week period, Kristin Holvik reported at a conference sponsored by the American Society for Bone and Mineral Research.

Even though many types of vitamin supplements are available to patients, little is known about whether the bioavailability of vitamin D₃ (cholecalciferol) differs when it is sequestered in fat-containing capsules as opposed to solid tablets, noted Ms. Holvik, a Ph.D. student at the Institute of General Practice and Community Medicine at the University of Oslo.

In a randomized trial, 55 healthy young adults (34 females and 21 males) received 28 days of supplementation with either fish oil capsules or multivitamin tablets, each of which was taken once daily and contained 10 mcg vitamin D₃ (an amount equivalent to 400 IU).

The participants completed a self-administered questionnaire about diet and sun exposure and had a nonfasting venous blood sample drawn at the beginning and end of the study, which took place in Oslo in late winter 2005, according to Ms. Holvik. She won an ASBMR Young Investigator Award for her research, which she presented during a poster session at the conference.

Serum 25-hydroxyvitamin D levels in individuals who took fish oil capsules increased from an average of 48.5 nmol/L to 80.4 nmol/L at the end of the study. Multivitamin users had a similar rise in serum 25-hydroxyvitamin D levels from a mean of 40.3 nmol/L to 76.5 nmol/L. On average, the participants were aged about 28 years and had a body mass index of about 24 kg/m2.

ARLINGTON, VA. — Fish oil capsules and multivitamin tablets that contain 10 mcg of vitamin D₃ provide the same increase in stored levels of the vitamin when taken daily during a 4-week period, Kristin Holvik reported at a conference sponsored by the American Society for Bone and Mineral Research.

Even though many types of vitamin supplements are available to patients, little is known about whether the bioavailability of vitamin D₃ (cholecalciferol) differs when it is sequestered in fat-containing capsules as opposed to solid tablets, noted Ms. Holvik, a Ph.D. student at the Institute of General Practice and Community Medicine at the University of Oslo.

In a randomized trial, 55 healthy young adults (34 females and 21 males) received 28 days of supplementation with either fish oil capsules or multivitamin tablets, each of which was taken once daily and contained 10 mcg vitamin D₃ (an amount equivalent to 400 IU).

The participants completed a self-administered questionnaire about diet and sun exposure and had a nonfasting venous blood sample drawn at the beginning and end of the study, which took place in Oslo in late winter 2005, according to Ms. Holvik. She won an ASBMR Young Investigator Award for her research, which she presented during a poster session at the conference.

Serum 25-hydroxyvitamin D levels in individuals who took fish oil capsules increased from an average of 48.5 nmol/L to 80.4 nmol/L at the end of the study. Multivitamin users had a similar rise in serum 25-hydroxyvitamin D levels from a mean of 40.3 nmol/L to 76.5 nmol/L. On average, the participants were aged about 28 years and had a body mass index of about 24 kg/m2.

ARLINGTON, VA. — African Americans may have a lower rate of osteoporosis-related fractures than whites because of adaptations in calcium homeostasis, bone turnover and resorption, and response to parathyroid hormone, Dr. Felicia Cosman said at a conference sponsored by the American Society for Bone and Mineral Research.

It is “very surprising” that at all ages, black individuals have a lower rate of fractures and higher bone mineral density (BMD) than white individuals, even though blacks generally have higher rates of vitamin D deficiency or insufficiency, said Dr. Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital, West Haverstraw, N.Y.

Mean serum levels of 25-hydroxyvitamin D [25(OH)D] are known at all ages and in both genders to be generally lower in blacks than in whites. This is the result of reduced skin production of vitamin D (due to higher melanin content in the skin) and a lower dietary intake of vitamin D, Dr. Cosman said.

An alteration in the vitamin D-endocrine system in blacks was first proposed by Dr. Norman Bell; it was based on evidence that blacks have a greater prevalence of vitamin D deficiency and relative secondary hyperparathyroidism, lower levels of bone turnover, and increased urinary calcium retention as an adaptive means to maintain calcium homeostasis without sacrificing the skeleton (J. Clin. Invest. 1985;76:470–3).

In many studies, parathyroid hormone (PTH) levels are higher, on average, in blacks than in whites. The PTH levels found in blacks occur within the context of low calcium intake in addition to low 25(OH)D levels, which may be related to “real or perceived” lactose intolerance, Dr. Cosman said.

As a consequence of high PTH levels, blacks have generally been measured with higher 1–25dihydroxyvitamin D [1,25(OH)₂D] levels than have whites.

“We would expect that with higher 1,25(OH)₂D levels, you would see greater [dietary] calcium absorption in black individuals compared to whites,” but studies have reported inconsistent data, many of which have shown no significant interracial differences, she said.

One also would expect blacks to have higher bone turnover levels because of high PTH levels, but in general this has not been true, Dr. Cosman said.

However, nearly all studies of the kidney have found that blacks have lower urinary calcium excretion than whites.

In addition, supplementation of 1,25(OH)₂D has been shown to cause a significantly greater decrease in urinary calcium excretion in blacks than in whites. Markers of bone formation also increased more among blacks than among whites, whereas bone resorption indices showed no racial differences (Osteoporos. Int. 2000;11:271–7). In a separate study, administration of PTH also caused blacks to retain urinary calcium to a greater degree than it did in whites, but it did not cause any racial differences in bone formation markers. After receipt of PTH, blacks also did not have as great an increase in bone resorption markers. This finding directly confirms “the hypothesis that the black skeleton could be resistant to the acute bone resorptive effects of PTH,” she said.

Studies of histomorphometric differences in bone have shown significantly reduced bone formation rates and a longer total bone formation period in blacks, compared with whites. The results of those studies are consistent with evidence that blacks have a lower level of serum osteocalcin—which has been the most sensitive indicator of a racial difference in bone turnover levels—and that blacks respond more slowly to bone remodeling therapies.

“The bottom line message … for these measurements is that in a relative secondary hyperparathyroid state you really expect to see high [bone] turnover,” Dr. Cosman said. “We never see that. We see either the same or, in most cases, lower turnover in blacks.”

ARLINGTON, VA. — African Americans may have a lower rate of osteoporosis-related fractures than whites because of adaptations in calcium homeostasis, bone turnover and resorption, and response to parathyroid hormone, Dr. Felicia Cosman said at a conference sponsored by the American Society for Bone and Mineral Research.

It is “very surprising” that at all ages, black individuals have a lower rate of fractures and higher bone mineral density (BMD) than white individuals, even though blacks generally have higher rates of vitamin D deficiency or insufficiency, said Dr. Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital, West Haverstraw, N.Y.

Mean serum levels of 25-hydroxyvitamin D [25(OH)D] are known at all ages and in both genders to be generally lower in blacks than in whites. This is the result of reduced skin production of vitamin D (due to higher melanin content in the skin) and a lower dietary intake of vitamin D, Dr. Cosman said.

An alteration in the vitamin D-endocrine system in blacks was first proposed by Dr. Norman Bell; it was based on evidence that blacks have a greater prevalence of vitamin D deficiency and relative secondary hyperparathyroidism, lower levels of bone turnover, and increased urinary calcium retention as an adaptive means to maintain calcium homeostasis without sacrificing the skeleton (J. Clin. Invest. 1985;76:470–3).

In many studies, parathyroid hormone (PTH) levels are higher, on average, in blacks than in whites. The PTH levels found in blacks occur within the context of low calcium intake in addition to low 25(OH)D levels, which may be related to “real or perceived” lactose intolerance, Dr. Cosman said.

As a consequence of high PTH levels, blacks have generally been measured with higher 1–25dihydroxyvitamin D [1,25(OH)₂D] levels than have whites.

“We would expect that with higher 1,25(OH)₂D levels, you would see greater [dietary] calcium absorption in black individuals compared to whites,” but studies have reported inconsistent data, many of which have shown no significant interracial differences, she said.

One also would expect blacks to have higher bone turnover levels because of high PTH levels, but in general this has not been true, Dr. Cosman said.

However, nearly all studies of the kidney have found that blacks have lower urinary calcium excretion than whites.

In addition, supplementation of 1,25(OH)₂D has been shown to cause a significantly greater decrease in urinary calcium excretion in blacks than in whites. Markers of bone formation also increased more among blacks than among whites, whereas bone resorption indices showed no racial differences (Osteoporos. Int. 2000;11:271–7). In a separate study, administration of PTH also caused blacks to retain urinary calcium to a greater degree than it did in whites, but it did not cause any racial differences in bone formation markers. After receipt of PTH, blacks also did not have as great an increase in bone resorption markers. This finding directly confirms “the hypothesis that the black skeleton could be resistant to the acute bone resorptive effects of PTH,” she said.

Studies of histomorphometric differences in bone have shown significantly reduced bone formation rates and a longer total bone formation period in blacks, compared with whites. The results of those studies are consistent with evidence that blacks have a lower level of serum osteocalcin—which has been the most sensitive indicator of a racial difference in bone turnover levels—and that blacks respond more slowly to bone remodeling therapies.

“The bottom line message … for these measurements is that in a relative secondary hyperparathyroid state you really expect to see high [bone] turnover,” Dr. Cosman said. “We never see that. We see either the same or, in most cases, lower turnover in blacks.”

ARLINGTON, VA. — African Americans may have a lower rate of osteoporosis-related fractures than whites because of adaptations in calcium homeostasis, bone turnover and resorption, and response to parathyroid hormone, Dr. Felicia Cosman said at a conference sponsored by the American Society for Bone and Mineral Research.

It is “very surprising” that at all ages, black individuals have a lower rate of fractures and higher bone mineral density (BMD) than white individuals, even though blacks generally have higher rates of vitamin D deficiency or insufficiency, said Dr. Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital, West Haverstraw, N.Y.

Mean serum levels of 25-hydroxyvitamin D [25(OH)D] are known at all ages and in both genders to be generally lower in blacks than in whites. This is the result of reduced skin production of vitamin D (due to higher melanin content in the skin) and a lower dietary intake of vitamin D, Dr. Cosman said.

An alteration in the vitamin D-endocrine system in blacks was first proposed by Dr. Norman Bell; it was based on evidence that blacks have a greater prevalence of vitamin D deficiency and relative secondary hyperparathyroidism, lower levels of bone turnover, and increased urinary calcium retention as an adaptive means to maintain calcium homeostasis without sacrificing the skeleton (J. Clin. Invest. 1985;76:470–3).

In many studies, parathyroid hormone (PTH) levels are higher, on average, in blacks than in whites. The PTH levels found in blacks occur within the context of low calcium intake in addition to low 25(OH)D levels, which may be related to “real or perceived” lactose intolerance, Dr. Cosman said.

As a consequence of high PTH levels, blacks have generally been measured with higher 1–25dihydroxyvitamin D [1,25(OH)₂D] levels than have whites.

“We would expect that with higher 1,25(OH)₂D levels, you would see greater [dietary] calcium absorption in black individuals compared to whites,” but studies have reported inconsistent data, many of which have shown no significant interracial differences, she said.

One also would expect blacks to have higher bone turnover levels because of high PTH levels, but in general this has not been true, Dr. Cosman said.

However, nearly all studies of the kidney have found that blacks have lower urinary calcium excretion than whites.

In addition, supplementation of 1,25(OH)₂D has been shown to cause a significantly greater decrease in urinary calcium excretion in blacks than in whites. Markers of bone formation also increased more among blacks than among whites, whereas bone resorption indices showed no racial differences (Osteoporos. Int. 2000;11:271–7). In a separate study, administration of PTH also caused blacks to retain urinary calcium to a greater degree than it did in whites, but it did not cause any racial differences in bone formation markers. After receipt of PTH, blacks also did not have as great an increase in bone resorption markers. This finding directly confirms “the hypothesis that the black skeleton could be resistant to the acute bone resorptive effects of PTH,” she said.

Studies of histomorphometric differences in bone have shown significantly reduced bone formation rates and a longer total bone formation period in blacks, compared with whites. The results of those studies are consistent with evidence that blacks have a lower level of serum osteocalcin—which has been the most sensitive indicator of a racial difference in bone turnover levels—and that blacks respond more slowly to bone remodeling therapies.

“The bottom line message … for these measurements is that in a relative secondary hyperparathyroid state you really expect to see high [bone] turnover,” Dr. Cosman said. “We never see that. We see either the same or, in most cases, lower turnover in blacks.”

WASHINGTON — High temperature and humidity appear to increase the risk of recurrent gout attacks independently of other known risk factors, Yuqing Q. Zhang, D.Sc., reported at the annual meeting of the American College of Rheumatology.

“Although the pathophysiology of gout is well understood and efficacious clinical therapies are available, many patients with gout still suffer from recurrent gout attacks” that are brought on by certain risk factors, said Dr. Zhang of Boston University.

Decreases in intravascular volume as a result of perspiration in hot and humid weather can result in high serum uric acid levels because of a reduction in uric acid excretion, Dr. Zhang said.

Only a handful of studies have examined the relationship between risk factors for dehydration and the risk of gout attack recurrence.

Dr. Zhang and his colleagues enrolled 197 patients with a median 5-year history of gout through an online advertisement.

The patients answered a “hazard period” questionnaire on a Web site that asked about risk factors for gout attacks during the 2-day period prior to their report of an attack.

They also filled out a control period questionnaire every 3 months for 1 year to provide data about time intervals during which gout attacks did not occur.

The questionnaires asked about use of dehydrating medication (such as diuretics), alcohol use, food intake (especially foods rich in purine or with little purine), and details of gout attacks when they occurred.

The Weather Underground Web site (www.wunderground.com

As temperature during the 2 days prior to a gout attack increased from the lowest quintile (0–53°F) to the highest quintile (87–105°F), the relative risk of a gout attack doubled.

The dose-response relationship between temperature and recurrent gout attacks seemed to suggest a threshold effect such that when the temperature reached 85°F, the risk of recurrent gout attacks increased dramatically, according to Dr. Zhang.

The relationship between the level of humidity during the 2 days prior to a gout attack and the risk of recurrent attacks followed the pattern for temperature very closely.

High humidity appeared to be the strongest predictor for recurrent gout attacks, but very cold and dry weather also slightly increased the risk of recurrent attacks.

The findings remained significant after controlling for medication use (especially diuretics), alcohol consumption, and purine-rich food intake.

Recurrent gout attacks were not associated with barometric pressure or precipitation.

“In hot and humid weather, subjects with gout may need to increase fluid intake to counteract volume depletion and to prevent a recurrent gout attack,” Dr. Zhang concluded.

WASHINGTON — High temperature and humidity appear to increase the risk of recurrent gout attacks independently of other known risk factors, Yuqing Q. Zhang, D.Sc., reported at the annual meeting of the American College of Rheumatology.

“Although the pathophysiology of gout is well understood and efficacious clinical therapies are available, many patients with gout still suffer from recurrent gout attacks” that are brought on by certain risk factors, said Dr. Zhang of Boston University.

Decreases in intravascular volume as a result of perspiration in hot and humid weather can result in high serum uric acid levels because of a reduction in uric acid excretion, Dr. Zhang said.

Only a handful of studies have examined the relationship between risk factors for dehydration and the risk of gout attack recurrence.

Dr. Zhang and his colleagues enrolled 197 patients with a median 5-year history of gout through an online advertisement.

The patients answered a “hazard period” questionnaire on a Web site that asked about risk factors for gout attacks during the 2-day period prior to their report of an attack.

They also filled out a control period questionnaire every 3 months for 1 year to provide data about time intervals during which gout attacks did not occur.

The questionnaires asked about use of dehydrating medication (such as diuretics), alcohol use, food intake (especially foods rich in purine or with little purine), and details of gout attacks when they occurred.

The Weather Underground Web site (www.wunderground.com

As temperature during the 2 days prior to a gout attack increased from the lowest quintile (0–53°F) to the highest quintile (87–105°F), the relative risk of a gout attack doubled.

The dose-response relationship between temperature and recurrent gout attacks seemed to suggest a threshold effect such that when the temperature reached 85°F, the risk of recurrent gout attacks increased dramatically, according to Dr. Zhang.

The relationship between the level of humidity during the 2 days prior to a gout attack and the risk of recurrent attacks followed the pattern for temperature very closely.

High humidity appeared to be the strongest predictor for recurrent gout attacks, but very cold and dry weather also slightly increased the risk of recurrent attacks.

The findings remained significant after controlling for medication use (especially diuretics), alcohol consumption, and purine-rich food intake.

Recurrent gout attacks were not associated with barometric pressure or precipitation.

“In hot and humid weather, subjects with gout may need to increase fluid intake to counteract volume depletion and to prevent a recurrent gout attack,” Dr. Zhang concluded.

WASHINGTON — High temperature and humidity appear to increase the risk of recurrent gout attacks independently of other known risk factors, Yuqing Q. Zhang, D.Sc., reported at the annual meeting of the American College of Rheumatology.

“Although the pathophysiology of gout is well understood and efficacious clinical therapies are available, many patients with gout still suffer from recurrent gout attacks” that are brought on by certain risk factors, said Dr. Zhang of Boston University.

Decreases in intravascular volume as a result of perspiration in hot and humid weather can result in high serum uric acid levels because of a reduction in uric acid excretion, Dr. Zhang said.

Only a handful of studies have examined the relationship between risk factors for dehydration and the risk of gout attack recurrence.

Dr. Zhang and his colleagues enrolled 197 patients with a median 5-year history of gout through an online advertisement.

The patients answered a “hazard period” questionnaire on a Web site that asked about risk factors for gout attacks during the 2-day period prior to their report of an attack.

They also filled out a control period questionnaire every 3 months for 1 year to provide data about time intervals during which gout attacks did not occur.

The questionnaires asked about use of dehydrating medication (such as diuretics), alcohol use, food intake (especially foods rich in purine or with little purine), and details of gout attacks when they occurred.

The Weather Underground Web site (www.wunderground.com

As temperature during the 2 days prior to a gout attack increased from the lowest quintile (0–53°F) to the highest quintile (87–105°F), the relative risk of a gout attack doubled.

The dose-response relationship between temperature and recurrent gout attacks seemed to suggest a threshold effect such that when the temperature reached 85°F, the risk of recurrent gout attacks increased dramatically, according to Dr. Zhang.

The relationship between the level of humidity during the 2 days prior to a gout attack and the risk of recurrent attacks followed the pattern for temperature very closely.

High humidity appeared to be the strongest predictor for recurrent gout attacks, but very cold and dry weather also slightly increased the risk of recurrent attacks.

The findings remained significant after controlling for medication use (especially diuretics), alcohol consumption, and purine-rich food intake.

Recurrent gout attacks were not associated with barometric pressure or precipitation.

“In hot and humid weather, subjects with gout may need to increase fluid intake to counteract volume depletion and to prevent a recurrent gout attack,” Dr. Zhang concluded.

WASHINGTON — Treatment of early rheumatoid arthritis with an intensive methotrexate dosing strategy may provide a better overall clinical outcome than would a conventional approach with the drug, Dr. Johannes W.J. Bijlsma reported at the annual meeting of the American College of Rheumatology.

Management of early rheumatoid arthritis with intensive methotrexate treatment not only produced a higher remission rate than did conventional methotrexate treatment, but was relatively easy to administer in clinical practice, said Dr. Bijlsma of University Medical Center Utrecht (the Netherlands).

In a multicenter, randomized trial, a significantly greater percentage of 148 intensively treated patients went into clinical remission during 2 years of follow-up than did 151 conventionally-treated patients (51% vs. 39%, respectively).

Clinical remission was defined as having no swollen joints, plus meeting two of the three following criteria for at least 6 months: three or fewer tender joints; an erythrocyte sedimentation rate of 20 mm or less in the first hour; and a visual analog scale score of general well-being of 20 mm or less.

The average time to remission in the intensive treatment group was 11 months, compared with 14 months in the conventional treatment group, while the duration of remission for the two groups was 11 months and 9 months, respectively. Both findings were statistically significant; radiographic joint damage was similarly low in both groups, reported Dr. Bijlsma.

Adverse events also occurred at similar rates between the groups.

Conventional treatment consisted of one outpatient visit every 3 months in which the dose of methotrexate was increased by 5 mg/week if the number of swollen joints rose. The investigators could reduce the dose of methotrexate by 2.5 mg/week when patients went into remission.

Patients who received intensive treatment had one outpatient visit every 4 weeks. Their dosing regimen was individually tailored by a computer program that used a predefined set of criteria, noted Dr. Bijlsma.

The investigators increased the methotrexate dose if there was 20% or less improvement in the number of swollen joints, and if there was 20% or less improvement in two of the three previously mentioned criteria.

The dose decreased when the patients had no swollen joints for 3 or more months and had greater than 20% improvement in at least two of the three variables. If a patient in either group reached 30 mg/week methotrexate without a response based on the criteria, the patients then received methotrexate subcutaneously. Those who continued to show no response also received cyclosporine, reported Dr. Bijlsma.

Dosing in the intensive drug regimen was tailored by a computer program. DR. BIJLSMA

ELSEVIER GLOBAL MEDICAL NEWS

WASHINGTON — Treatment of early rheumatoid arthritis with an intensive methotrexate dosing strategy may provide a better overall clinical outcome than would a conventional approach with the drug, Dr. Johannes W.J. Bijlsma reported at the annual meeting of the American College of Rheumatology.

Management of early rheumatoid arthritis with intensive methotrexate treatment not only produced a higher remission rate than did conventional methotrexate treatment, but was relatively easy to administer in clinical practice, said Dr. Bijlsma of University Medical Center Utrecht (the Netherlands).

In a multicenter, randomized trial, a significantly greater percentage of 148 intensively treated patients went into clinical remission during 2 years of follow-up than did 151 conventionally-treated patients (51% vs. 39%, respectively).

Clinical remission was defined as having no swollen joints, plus meeting two of the three following criteria for at least 6 months: three or fewer tender joints; an erythrocyte sedimentation rate of 20 mm or less in the first hour; and a visual analog scale score of general well-being of 20 mm or less.

The average time to remission in the intensive treatment group was 11 months, compared with 14 months in the conventional treatment group, while the duration of remission for the two groups was 11 months and 9 months, respectively. Both findings were statistically significant; radiographic joint damage was similarly low in both groups, reported Dr. Bijlsma.

Adverse events also occurred at similar rates between the groups.

Conventional treatment consisted of one outpatient visit every 3 months in which the dose of methotrexate was increased by 5 mg/week if the number of swollen joints rose. The investigators could reduce the dose of methotrexate by 2.5 mg/week when patients went into remission.

Patients who received intensive treatment had one outpatient visit every 4 weeks. Their dosing regimen was individually tailored by a computer program that used a predefined set of criteria, noted Dr. Bijlsma.

The investigators increased the methotrexate dose if there was 20% or less improvement in the number of swollen joints, and if there was 20% or less improvement in two of the three previously mentioned criteria.

The dose decreased when the patients had no swollen joints for 3 or more months and had greater than 20% improvement in at least two of the three variables. If a patient in either group reached 30 mg/week methotrexate without a response based on the criteria, the patients then received methotrexate subcutaneously. Those who continued to show no response also received cyclosporine, reported Dr. Bijlsma.

Dosing in the intensive drug regimen was tailored by a computer program. DR. BIJLSMA

ELSEVIER GLOBAL MEDICAL NEWS

WASHINGTON — Treatment of early rheumatoid arthritis with an intensive methotrexate dosing strategy may provide a better overall clinical outcome than would a conventional approach with the drug, Dr. Johannes W.J. Bijlsma reported at the annual meeting of the American College of Rheumatology.

Management of early rheumatoid arthritis with intensive methotrexate treatment not only produced a higher remission rate than did conventional methotrexate treatment, but was relatively easy to administer in clinical practice, said Dr. Bijlsma of University Medical Center Utrecht (the Netherlands).

In a multicenter, randomized trial, a significantly greater percentage of 148 intensively treated patients went into clinical remission during 2 years of follow-up than did 151 conventionally-treated patients (51% vs. 39%, respectively).

Clinical remission was defined as having no swollen joints, plus meeting two of the three following criteria for at least 6 months: three or fewer tender joints; an erythrocyte sedimentation rate of 20 mm or less in the first hour; and a visual analog scale score of general well-being of 20 mm or less.

The average time to remission in the intensive treatment group was 11 months, compared with 14 months in the conventional treatment group, while the duration of remission for the two groups was 11 months and 9 months, respectively. Both findings were statistically significant; radiographic joint damage was similarly low in both groups, reported Dr. Bijlsma.

Adverse events also occurred at similar rates between the groups.

Conventional treatment consisted of one outpatient visit every 3 months in which the dose of methotrexate was increased by 5 mg/week if the number of swollen joints rose. The investigators could reduce the dose of methotrexate by 2.5 mg/week when patients went into remission.

Patients who received intensive treatment had one outpatient visit every 4 weeks. Their dosing regimen was individually tailored by a computer program that used a predefined set of criteria, noted Dr. Bijlsma.

The investigators increased the methotrexate dose if there was 20% or less improvement in the number of swollen joints, and if there was 20% or less improvement in two of the three previously mentioned criteria.

The dose decreased when the patients had no swollen joints for 3 or more months and had greater than 20% improvement in at least two of the three variables. If a patient in either group reached 30 mg/week methotrexate without a response based on the criteria, the patients then received methotrexate subcutaneously. Those who continued to show no response also received cyclosporine, reported Dr. Bijlsma.

Dosing in the intensive drug regimen was tailored by a computer program. DR. BIJLSMA

ELSEVIER GLOBAL MEDICAL NEWS

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day based on a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000-IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published (Am. J. Clin. Nutr. 2004;80:1689S-96S). This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

“It's one thing to say high doses of vitamin D are bad, but it's also very important to recognize how high we are talking about. What dose are we talking about?” he asked. “At least in animals, these doses are way off the curve in terms of anything we've been talking about.”

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]2D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment.

Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

In support of a UL of 10,000 IU/day, Dr. Vieth noted that a colleague has used 1,250 mcg/day vitamin D₃ “for some time,” and induced 25(OH)D levels of up to 643 nmol/L without hypercalcemia. Others also have used vitamin D several times higher than the current upper limit of 2,000 IU/day. Sunshine also can safely provide a dose of 10,000 IU/day to an adult, he said.

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day based on a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000-IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published (Am. J. Clin. Nutr. 2004;80:1689S-96S). This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

“It's one thing to say high doses of vitamin D are bad, but it's also very important to recognize how high we are talking about. What dose are we talking about?” he asked. “At least in animals, these doses are way off the curve in terms of anything we've been talking about.”

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]2D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment.

Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

In support of a UL of 10,000 IU/day, Dr. Vieth noted that a colleague has used 1,250 mcg/day vitamin D₃ “for some time,” and induced 25(OH)D levels of up to 643 nmol/L without hypercalcemia. Others also have used vitamin D several times higher than the current upper limit of 2,000 IU/day. Sunshine also can safely provide a dose of 10,000 IU/day to an adult, he said.

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day based on a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000-IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published (Am. J. Clin. Nutr. 2004;80:1689S-96S). This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

“It's one thing to say high doses of vitamin D are bad, but it's also very important to recognize how high we are talking about. What dose are we talking about?” he asked. “At least in animals, these doses are way off the curve in terms of anything we've been talking about.”

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]2D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment.

Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

In support of a UL of 10,000 IU/day, Dr. Vieth noted that a colleague has used 1,250 mcg/day vitamin D₃ “for some time,” and induced 25(OH)D levels of up to 643 nmol/L without hypercalcemia. Others also have used vitamin D several times higher than the current upper limit of 2,000 IU/day. Sunshine also can safely provide a dose of 10,000 IU/day to an adult, he said.

BOSTON — Live births occurred in 70% of heart transplant recipients who became pregnant after surgery, according to a review of 36 patients with 60 singleton pregnancies reported to the National Transplantation Pregnancy Registry.

Of 42 live-born children, 36 were healthy and developing well at the time of follow-up. Three children were receiving medical management for cardiomyopathy, the same diagnosis for which their mothers received transplants. Among the other three children, one underwent a hypospadias repair, one was treated for attention-deficit hyperactivity disorder, and one died from a traumatic injury, Lisa A. Coscia reported during a poster session at the 2006 World Transplant Congress.

These 42 children were born at a mean gestational age of 37 weeks (5 were premature) and with a mean birth weight of 2.67 kg. A cesarean section was performed in 14 deliveries. Neonatal complications developed in 11 cases.

In the 18 unsuccessful pregnancies, 11 fetuses were aborted spontaneously and 5 for therapeutic reasons. One woman had an ectopic pregnancy and another had a stillborn delivery, according to Ms. Coscia, a registered nurse in the department of surgery at Temple University, Philadelphia.

The 36 patients conceived their pregnancies a mean of 5 years after their transplants, although this ranged from as little as 0.2 years to as much as 15 years. They had an average age of 28 years at conception, ranging from 18 to 39 years.

During pregnancy, hypertension was the most common comorbidity (43%) among the women, followed by infections (14%), preeclampsia (11%), and gestational diabetes (3%).

Nine of the mothers (25%) died after pregnancy, although all of the deaths occurred more than 2 years post partum. These deaths were attributed to cardiac arrest (two), acute rejection (two), and in one patient each, vasculopathy, atherosclerosis, sepsis, lymphoma, and noncompliance. The other 27 mothers (75%) had adequate graft function at follow-up.

According to data collected by the U.S. Organ Procurement and Transplantation Network, the 5-year Kaplan-Meier patient survival rate for heart transplants performed in women between 1997 and 2004 (pregnancies not considered) is just over 69%.

The possibility of maternal death unrelated to pregnancy should be included during prepregnancy counseling, Ms. Coscia advised in her poster at the congress, which was sponsored by the American Society of Transplant Surgeons, the American Society of Transplantation, and the Transplantation Society.

BOSTON — Live births occurred in 70% of heart transplant recipients who became pregnant after surgery, according to a review of 36 patients with 60 singleton pregnancies reported to the National Transplantation Pregnancy Registry.

Of 42 live-born children, 36 were healthy and developing well at the time of follow-up. Three children were receiving medical management for cardiomyopathy, the same diagnosis for which their mothers received transplants. Among the other three children, one underwent a hypospadias repair, one was treated for attention-deficit hyperactivity disorder, and one died from a traumatic injury, Lisa A. Coscia reported during a poster session at the 2006 World Transplant Congress.

These 42 children were born at a mean gestational age of 37 weeks (5 were premature) and with a mean birth weight of 2.67 kg. A cesarean section was performed in 14 deliveries. Neonatal complications developed in 11 cases.

In the 18 unsuccessful pregnancies, 11 fetuses were aborted spontaneously and 5 for therapeutic reasons. One woman had an ectopic pregnancy and another had a stillborn delivery, according to Ms. Coscia, a registered nurse in the department of surgery at Temple University, Philadelphia.

The 36 patients conceived their pregnancies a mean of 5 years after their transplants, although this ranged from as little as 0.2 years to as much as 15 years. They had an average age of 28 years at conception, ranging from 18 to 39 years.

During pregnancy, hypertension was the most common comorbidity (43%) among the women, followed by infections (14%), preeclampsia (11%), and gestational diabetes (3%).

Nine of the mothers (25%) died after pregnancy, although all of the deaths occurred more than 2 years post partum. These deaths were attributed to cardiac arrest (two), acute rejection (two), and in one patient each, vasculopathy, atherosclerosis, sepsis, lymphoma, and noncompliance. The other 27 mothers (75%) had adequate graft function at follow-up.

According to data collected by the U.S. Organ Procurement and Transplantation Network, the 5-year Kaplan-Meier patient survival rate for heart transplants performed in women between 1997 and 2004 (pregnancies not considered) is just over 69%.

The possibility of maternal death unrelated to pregnancy should be included during prepregnancy counseling, Ms. Coscia advised in her poster at the congress, which was sponsored by the American Society of Transplant Surgeons, the American Society of Transplantation, and the Transplantation Society.

BOSTON — Live births occurred in 70% of heart transplant recipients who became pregnant after surgery, according to a review of 36 patients with 60 singleton pregnancies reported to the National Transplantation Pregnancy Registry.

Of 42 live-born children, 36 were healthy and developing well at the time of follow-up. Three children were receiving medical management for cardiomyopathy, the same diagnosis for which their mothers received transplants. Among the other three children, one underwent a hypospadias repair, one was treated for attention-deficit hyperactivity disorder, and one died from a traumatic injury, Lisa A. Coscia reported during a poster session at the 2006 World Transplant Congress.

These 42 children were born at a mean gestational age of 37 weeks (5 were premature) and with a mean birth weight of 2.67 kg. A cesarean section was performed in 14 deliveries. Neonatal complications developed in 11 cases.

In the 18 unsuccessful pregnancies, 11 fetuses were aborted spontaneously and 5 for therapeutic reasons. One woman had an ectopic pregnancy and another had a stillborn delivery, according to Ms. Coscia, a registered nurse in the department of surgery at Temple University, Philadelphia.

The 36 patients conceived their pregnancies a mean of 5 years after their transplants, although this ranged from as little as 0.2 years to as much as 15 years. They had an average age of 28 years at conception, ranging from 18 to 39 years.

During pregnancy, hypertension was the most common comorbidity (43%) among the women, followed by infections (14%), preeclampsia (11%), and gestational diabetes (3%).

Nine of the mothers (25%) died after pregnancy, although all of the deaths occurred more than 2 years post partum. These deaths were attributed to cardiac arrest (two), acute rejection (two), and in one patient each, vasculopathy, atherosclerosis, sepsis, lymphoma, and noncompliance. The other 27 mothers (75%) had adequate graft function at follow-up.

According to data collected by the U.S. Organ Procurement and Transplantation Network, the 5-year Kaplan-Meier patient survival rate for heart transplants performed in women between 1997 and 2004 (pregnancies not considered) is just over 69%.

The possibility of maternal death unrelated to pregnancy should be included during prepregnancy counseling, Ms. Coscia advised in her poster at the congress, which was sponsored by the American Society of Transplant Surgeons, the American Society of Transplantation, and the Transplantation Society.