Calcium and Vitamin D Are No Longer Boring

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.