Osteoporosis

ADELPHI, MD. – Data on the safety and effectiveness of bisphosphonate drugs for the long-term treatment of osteoporosis is lacking and direly needed, according to a joint Food and Drug Administration advisory committee meeting.

Specifically, the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-6 on Sept. 9 that labeling for these drugs should be changed to clarify the duration of use for this drug class.

The agency convened the joint meeting to evaluate particular concerns about the long-term use bisphosphonate drugs, given reports of atypical subtrochanteric and femoral fractures, jaw osteonecrosis, and esophageal cancer associated with bisphosphonate use.

The labels of bisphosphonate drugs – alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) – already include "important limitation of use" information. This labeling states that the optimal duration of treatment (for an individual drug) has not been determined and that all patients on bisphosphonate therapy should be periodically reassessed for the necessity of continued therapy.

While the panel voted to clarify the label language, they were emphatic that much more data are needed to establish the long-term efficacy and safety of bisphosphonates in general and with special regard to atypical fractures, jaw osteonecrosis, and esophageal cancer.

The two committees also were asked to assess the strength of data on the long-term use of bisphosphonates; the overall risks and benefits of continuous long-term use (3-5 years or more); whether restricting the duration of use or implementing a drug holiday would be beneficial; which outcomes require further evidence; and how should this data be obtained.

The expert consensus is that existing data – some of which go out to roughly 10 years for one drug – do not address the efficacy of the long-term use of bisphosphonates. They recommended that (in no particular order) additional data are needed with regard to the occurrence of atypical fractures, osteonecrosis of the jaw, esophageal cancer, osteoporotic fracture reduction efficacy with long-term (at least 3-5 years) continuous bisphosphonate use, and the effect of a "drug holiday" on drug safety and effectiveness.

Osteoporosis currently affects approximately 10 million Americans, according to the American Society for Bone and Mineral Research. An additional 34 million have low bone mass, which may progress to osteoporosis.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver, but none were given at this meeting.

ADELPHI, MD. – Data on the safety and effectiveness of bisphosphonate drugs for the long-term treatment of osteoporosis is lacking and direly needed, according to a joint Food and Drug Administration advisory committee meeting.

Specifically, the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-6 on Sept. 9 that labeling for these drugs should be changed to clarify the duration of use for this drug class.

The agency convened the joint meeting to evaluate particular concerns about the long-term use bisphosphonate drugs, given reports of atypical subtrochanteric and femoral fractures, jaw osteonecrosis, and esophageal cancer associated with bisphosphonate use.

The labels of bisphosphonate drugs – alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) – already include "important limitation of use" information. This labeling states that the optimal duration of treatment (for an individual drug) has not been determined and that all patients on bisphosphonate therapy should be periodically reassessed for the necessity of continued therapy.

While the panel voted to clarify the label language, they were emphatic that much more data are needed to establish the long-term efficacy and safety of bisphosphonates in general and with special regard to atypical fractures, jaw osteonecrosis, and esophageal cancer.

The two committees also were asked to assess the strength of data on the long-term use of bisphosphonates; the overall risks and benefits of continuous long-term use (3-5 years or more); whether restricting the duration of use or implementing a drug holiday would be beneficial; which outcomes require further evidence; and how should this data be obtained.

The expert consensus is that existing data – some of which go out to roughly 10 years for one drug – do not address the efficacy of the long-term use of bisphosphonates. They recommended that (in no particular order) additional data are needed with regard to the occurrence of atypical fractures, osteonecrosis of the jaw, esophageal cancer, osteoporotic fracture reduction efficacy with long-term (at least 3-5 years) continuous bisphosphonate use, and the effect of a "drug holiday" on drug safety and effectiveness.

Osteoporosis currently affects approximately 10 million Americans, according to the American Society for Bone and Mineral Research. An additional 34 million have low bone mass, which may progress to osteoporosis.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver, but none were given at this meeting.

ADELPHI, MD. – Data on the safety and effectiveness of bisphosphonate drugs for the long-term treatment of osteoporosis is lacking and direly needed, according to a joint Food and Drug Administration advisory committee meeting.

Specifically, the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-6 on Sept. 9 that labeling for these drugs should be changed to clarify the duration of use for this drug class.

The agency convened the joint meeting to evaluate particular concerns about the long-term use bisphosphonate drugs, given reports of atypical subtrochanteric and femoral fractures, jaw osteonecrosis, and esophageal cancer associated with bisphosphonate use.

The labels of bisphosphonate drugs – alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) – already include "important limitation of use" information. This labeling states that the optimal duration of treatment (for an individual drug) has not been determined and that all patients on bisphosphonate therapy should be periodically reassessed for the necessity of continued therapy.

While the panel voted to clarify the label language, they were emphatic that much more data are needed to establish the long-term efficacy and safety of bisphosphonates in general and with special regard to atypical fractures, jaw osteonecrosis, and esophageal cancer.

The two committees also were asked to assess the strength of data on the long-term use of bisphosphonates; the overall risks and benefits of continuous long-term use (3-5 years or more); whether restricting the duration of use or implementing a drug holiday would be beneficial; which outcomes require further evidence; and how should this data be obtained.

The expert consensus is that existing data – some of which go out to roughly 10 years for one drug – do not address the efficacy of the long-term use of bisphosphonates. They recommended that (in no particular order) additional data are needed with regard to the occurrence of atypical fractures, osteonecrosis of the jaw, esophageal cancer, osteoporotic fracture reduction efficacy with long-term (at least 3-5 years) continuous bisphosphonate use, and the effect of a "drug holiday" on drug safety and effectiveness.

Osteoporosis currently affects approximately 10 million Americans, according to the American Society for Bone and Mineral Research. An additional 34 million have low bone mass, which may progress to osteoporosis.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver, but none were given at this meeting.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class – Merck’s Fosamax (alendronate), Warner Chilcott’s Actonel (risedronate), Novartis’ Reclast (zoledronic acid), and Roche’s Boniva (ibandronate) – currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA’s Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency’s Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss’ view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA’s Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs’ sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class – Merck’s Fosamax (alendronate), Warner Chilcott’s Actonel (risedronate), Novartis’ Reclast (zoledronic acid), and Roche’s Boniva (ibandronate) – currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA’s Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency’s Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss’ view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA’s Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs’ sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class – Merck’s Fosamax (alendronate), Warner Chilcott’s Actonel (risedronate), Novartis’ Reclast (zoledronic acid), and Roche’s Boniva (ibandronate) – currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA’s Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency’s Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss’ view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA’s Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs’ sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There's a lot of controversy surrounding the Institute of Medicine's (IOM) November 2010 report, “Dietary Reference Intakes for Calcium and Vitamin D,” which updated 1997 guidelines.

Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

There is uncertainty about the cutoff level of serum vitamin D that's considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a “sufficient” serum level should be in the 30- to 32-ng/mL range, she said. “It takes most people about 1,200 IU/day to reach that” serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused “a lot of consternation,” she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

“It's almost a moot point because you wouldn't give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial,” Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels.

The concern was sparked by the committee's interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was not significantly different than in patients with a serum level greater than 32 ng/mL.

“I'm really not sure that there is a higher mortality,” Dr. Sellmeyer said. “I think there is enough evidence to suggest that we probably ought to be a little more in the 30- to 40-ng/mL range.”

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day if they are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day at older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It's important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. “We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day,” she said. “Those [are the patients who] can get into trouble.”

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women's Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction or vascular calcification (Circulation 2007; 115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ 2008;336:262-6). The investigators in that study reanalyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19: 342:d2040). There were significant differences in the comparison groups in the reanalysis, including differences in personal history of MI, Dr. Sellmeyer noted.

“Whether this truly represents an increased risk or not is unclear,” Dr. Sellmeyer said.

Another study by some of the same investigators “got a ton of press” even though it was a relatively small meta-analysis, she added.

The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010; 341:c3691).

“It's really hard to know at this point” whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said.

“I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial.”

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, “but for a lot of people it doesn't matter,” she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

Most people need about 1,200 IU per day of vitamin D to reach 'sufficient' serum levels of 30-32 ng/mL.

Source DR. SELLMEYER

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There's a lot of controversy surrounding the Institute of Medicine's (IOM) November 2010 report, “Dietary Reference Intakes for Calcium and Vitamin D,” which updated 1997 guidelines.

Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

There is uncertainty about the cutoff level of serum vitamin D that's considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a “sufficient” serum level should be in the 30- to 32-ng/mL range, she said. “It takes most people about 1,200 IU/day to reach that” serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused “a lot of consternation,” she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

“It's almost a moot point because you wouldn't give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial,” Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels.

The concern was sparked by the committee's interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was not significantly different than in patients with a serum level greater than 32 ng/mL.

“I'm really not sure that there is a higher mortality,” Dr. Sellmeyer said. “I think there is enough evidence to suggest that we probably ought to be a little more in the 30- to 40-ng/mL range.”

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day if they are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day at older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It's important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. “We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day,” she said. “Those [are the patients who] can get into trouble.”

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women's Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction or vascular calcification (Circulation 2007; 115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ 2008;336:262-6). The investigators in that study reanalyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19: 342:d2040). There were significant differences in the comparison groups in the reanalysis, including differences in personal history of MI, Dr. Sellmeyer noted.

“Whether this truly represents an increased risk or not is unclear,” Dr. Sellmeyer said.

Another study by some of the same investigators “got a ton of press” even though it was a relatively small meta-analysis, she added.

The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010; 341:c3691).

“It's really hard to know at this point” whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said.

“I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial.”

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, “but for a lot of people it doesn't matter,” she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

Most people need about 1,200 IU per day of vitamin D to reach 'sufficient' serum levels of 30-32 ng/mL.

Source DR. SELLMEYER

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There's a lot of controversy surrounding the Institute of Medicine's (IOM) November 2010 report, “Dietary Reference Intakes for Calcium and Vitamin D,” which updated 1997 guidelines.

Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

There is uncertainty about the cutoff level of serum vitamin D that's considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a “sufficient” serum level should be in the 30- to 32-ng/mL range, she said. “It takes most people about 1,200 IU/day to reach that” serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused “a lot of consternation,” she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

“It's almost a moot point because you wouldn't give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial,” Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels.

The concern was sparked by the committee's interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was not significantly different than in patients with a serum level greater than 32 ng/mL.

“I'm really not sure that there is a higher mortality,” Dr. Sellmeyer said. “I think there is enough evidence to suggest that we probably ought to be a little more in the 30- to 40-ng/mL range.”

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day if they are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day at older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It's important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. “We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day,” she said. “Those [are the patients who] can get into trouble.”

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women's Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction or vascular calcification (Circulation 2007; 115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ 2008;336:262-6). The investigators in that study reanalyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19: 342:d2040). There were significant differences in the comparison groups in the reanalysis, including differences in personal history of MI, Dr. Sellmeyer noted.

“Whether this truly represents an increased risk or not is unclear,” Dr. Sellmeyer said.

Another study by some of the same investigators “got a ton of press” even though it was a relatively small meta-analysis, she added.

The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010; 341:c3691).

“It's really hard to know at this point” whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said.

“I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial.”

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, “but for a lot of people it doesn't matter,” she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

Most people need about 1,200 IU per day of vitamin D to reach 'sufficient' serum levels of 30-32 ng/mL.

Source DR. SELLMEYER

SAN FRANCISCO – Talking to patients after they start an antiresorptive drug for osteoporosis is better than laboratory testing to convince them to stay on therapy, according to Dr. Douglas C. Bauer.

Bone mineral density testing determines the need for antiresorptive medication, but it's less helpful in monitoring the effects of treatment or adherence to therapy than is talking to patients. A test showing bone loss in the first year of treatment can confuse patients and does not necessarily mean they are not responding to treatment, said Dr. Bauer, professor of medicine and of epidemiology and biostatistics at the University of California, San Francisco.

Besides, most of the patients who stop osteoporosis therapy within 3 years do so within the first few months of treatment, so annual bone density testing is unlikely to improve adherence, he added.

Biochemical markers of bone turnover eventually may become the standard for monitoring treatment, “but we're not there yet,” he said at the meeting, sponsored by the university.

Studies have shown that follow-up discussions after a patient starts antiresorptive medication is the factor that improves adherence, not measuring bone density or bone turnover markers.

Dr. Bauer said he tells patients not to expect routine follow-up bone density testing and asks about and encourages adherence at every patient visit. If a patient develops a fracture while on therapy or is considering a drug holiday after 5 years on alendronate, then he said he considers ordering follow-up bone mineral density testing. “There's a caveat: This may not be the right algorithm for tertiary care centers with severe or complex patients,” said Dr. Bauer.

Although bone mineral density measurements are very precise, small differences in position or “noise” in the measures can produce apparent changes that are not clinically meaningful. To assess whether a change in bone density is “real,” he recommended a useful equation called the “least significant change” equation: Multiply the coefficient of variations by three; if the sum is less than 4.5%, then the change may be due to chance.

For example, if the coefficient of variations in hip bone density is 1.5%, the least significant change is 4.5%. If a patient lost 3% in bone density, there is approximately a 10% chance that there was no change in bone density, he said.

“A somewhat more fundamental question is not just whether the measurements [are] real, but are they meaningful?” Dr. Bauer said.

Analyses of data from the Fracture Intervention Trial (FIT) show that patients on alendronate who lost up to 4% in total hip bone density in the 1-2 years of treatment still had 53% fewer vertebral fractures compared with their counterparts on placebo who lost similar amounts of bone density. Patients who lost up to 4% in spine density had 60% fewer vertebral fractures compared with their counterparts on placebo (Osteoporos. Int. 2005;16:842-8).

Then there's the “regression to the mean” argument that patients with an unusual response in the first year of antiresorptive therapy will develop a more typical response if treatment is continued, he said. A separate analysis of FIT data showed that 92% of patients who lost up to 4% of hip bone density in the first year of therapy gained a mean of nearly 5% in bone density in the second year of treatment (JAMA 2000;283:1318-21).

A more recent analysis of annual bone mineral density data in FIT showed that variation in the change in bone density over a 3-year period was mainly measurement-related, within-person variation.

Treatment-related, between-person variation played a much smaller role (BMJ 2009;338:b2266).

That helps explain how patients can “lose” bone density but still have fewer fractures, Dr. Bauer said. “It's reassuring that 98% on alendronate gained more than 0.02 g/cm

Antiresorptive therapy decreases biochemical markers of bone turnover, but there is a lot of biologic variability and no clear threshold for efficacy. Biochemical marker measurements could be used to identify nonadherence to treatment, but “it's cheaper just to ask,” he said.

In a study of 2,382 osteoporotic women starting a year of risedronate therapy, the women were randomized to get bone turnover markers measured at weeks 13 and 25 or to routine visits without marker measurements. The results showed no difference in adherence rates between the groups (J. Clin. Endocrinol. Metab. 2007;92:1296-304). In the marker measurement group, the adherence rate was 225% worse than in the control group if the marker results suggested a “bad” response to therapy (less than a 30% decrease in marker levels).

“That was unexpected,” Dr. Bauer said. “Bone turnover markers by themselves are not helpful for increasing adherence” to therapy.

A separate randomized study of 75 women starting raloxifene treatment for low bone density randomized them to no monitoring; nurse visits at months 3, 6, and 9; or nurse visits plus bone turnover marker measurements. The nurse visits improved adherence to therapy compared with no monitoring, but biomarker measurements did not add anything to the nurse visits (J. Clin. Endocrinol. Metab. 2004;89:1117-1123). In general, approximately 30%-40% of patients stop taking antiresorptive drugs within 1 year, he said.

Dr. Bauer said he has received research funding from Amgen, Novartis, and Procter & Gamble.

Biochemical marker measurements could identify nonadherence, but 'it's cheaper just to ask.'

Source DR. BAUER

SAN FRANCISCO – Talking to patients after they start an antiresorptive drug for osteoporosis is better than laboratory testing to convince them to stay on therapy, according to Dr. Douglas C. Bauer.

Bone mineral density testing determines the need for antiresorptive medication, but it's less helpful in monitoring the effects of treatment or adherence to therapy than is talking to patients. A test showing bone loss in the first year of treatment can confuse patients and does not necessarily mean they are not responding to treatment, said Dr. Bauer, professor of medicine and of epidemiology and biostatistics at the University of California, San Francisco.

Besides, most of the patients who stop osteoporosis therapy within 3 years do so within the first few months of treatment, so annual bone density testing is unlikely to improve adherence, he added.

Biochemical markers of bone turnover eventually may become the standard for monitoring treatment, “but we're not there yet,” he said at the meeting, sponsored by the university.

Studies have shown that follow-up discussions after a patient starts antiresorptive medication is the factor that improves adherence, not measuring bone density or bone turnover markers.

Dr. Bauer said he tells patients not to expect routine follow-up bone density testing and asks about and encourages adherence at every patient visit. If a patient develops a fracture while on therapy or is considering a drug holiday after 5 years on alendronate, then he said he considers ordering follow-up bone mineral density testing. “There's a caveat: This may not be the right algorithm for tertiary care centers with severe or complex patients,” said Dr. Bauer.

Although bone mineral density measurements are very precise, small differences in position or “noise” in the measures can produce apparent changes that are not clinically meaningful. To assess whether a change in bone density is “real,” he recommended a useful equation called the “least significant change” equation: Multiply the coefficient of variations by three; if the sum is less than 4.5%, then the change may be due to chance.

For example, if the coefficient of variations in hip bone density is 1.5%, the least significant change is 4.5%. If a patient lost 3% in bone density, there is approximately a 10% chance that there was no change in bone density, he said.

“A somewhat more fundamental question is not just whether the measurements [are] real, but are they meaningful?” Dr. Bauer said.

Analyses of data from the Fracture Intervention Trial (FIT) show that patients on alendronate who lost up to 4% in total hip bone density in the 1-2 years of treatment still had 53% fewer vertebral fractures compared with their counterparts on placebo who lost similar amounts of bone density. Patients who lost up to 4% in spine density had 60% fewer vertebral fractures compared with their counterparts on placebo (Osteoporos. Int. 2005;16:842-8).

Then there's the “regression to the mean” argument that patients with an unusual response in the first year of antiresorptive therapy will develop a more typical response if treatment is continued, he said. A separate analysis of FIT data showed that 92% of patients who lost up to 4% of hip bone density in the first year of therapy gained a mean of nearly 5% in bone density in the second year of treatment (JAMA 2000;283:1318-21).

A more recent analysis of annual bone mineral density data in FIT showed that variation in the change in bone density over a 3-year period was mainly measurement-related, within-person variation.

Treatment-related, between-person variation played a much smaller role (BMJ 2009;338:b2266).

That helps explain how patients can “lose” bone density but still have fewer fractures, Dr. Bauer said. “It's reassuring that 98% on alendronate gained more than 0.02 g/cm

Antiresorptive therapy decreases biochemical markers of bone turnover, but there is a lot of biologic variability and no clear threshold for efficacy. Biochemical marker measurements could be used to identify nonadherence to treatment, but “it's cheaper just to ask,” he said.

In a study of 2,382 osteoporotic women starting a year of risedronate therapy, the women were randomized to get bone turnover markers measured at weeks 13 and 25 or to routine visits without marker measurements. The results showed no difference in adherence rates between the groups (J. Clin. Endocrinol. Metab. 2007;92:1296-304). In the marker measurement group, the adherence rate was 225% worse than in the control group if the marker results suggested a “bad” response to therapy (less than a 30% decrease in marker levels).

“That was unexpected,” Dr. Bauer said. “Bone turnover markers by themselves are not helpful for increasing adherence” to therapy.

A separate randomized study of 75 women starting raloxifene treatment for low bone density randomized them to no monitoring; nurse visits at months 3, 6, and 9; or nurse visits plus bone turnover marker measurements. The nurse visits improved adherence to therapy compared with no monitoring, but biomarker measurements did not add anything to the nurse visits (J. Clin. Endocrinol. Metab. 2004;89:1117-1123). In general, approximately 30%-40% of patients stop taking antiresorptive drugs within 1 year, he said.

Dr. Bauer said he has received research funding from Amgen, Novartis, and Procter & Gamble.

Biochemical marker measurements could identify nonadherence, but 'it's cheaper just to ask.'

Source DR. BAUER

SAN FRANCISCO – Talking to patients after they start an antiresorptive drug for osteoporosis is better than laboratory testing to convince them to stay on therapy, according to Dr. Douglas C. Bauer.

Bone mineral density testing determines the need for antiresorptive medication, but it's less helpful in monitoring the effects of treatment or adherence to therapy than is talking to patients. A test showing bone loss in the first year of treatment can confuse patients and does not necessarily mean they are not responding to treatment, said Dr. Bauer, professor of medicine and of epidemiology and biostatistics at the University of California, San Francisco.

Besides, most of the patients who stop osteoporosis therapy within 3 years do so within the first few months of treatment, so annual bone density testing is unlikely to improve adherence, he added.

Biochemical markers of bone turnover eventually may become the standard for monitoring treatment, “but we're not there yet,” he said at the meeting, sponsored by the university.

Studies have shown that follow-up discussions after a patient starts antiresorptive medication is the factor that improves adherence, not measuring bone density or bone turnover markers.

Dr. Bauer said he tells patients not to expect routine follow-up bone density testing and asks about and encourages adherence at every patient visit. If a patient develops a fracture while on therapy or is considering a drug holiday after 5 years on alendronate, then he said he considers ordering follow-up bone mineral density testing. “There's a caveat: This may not be the right algorithm for tertiary care centers with severe or complex patients,” said Dr. Bauer.

Although bone mineral density measurements are very precise, small differences in position or “noise” in the measures can produce apparent changes that are not clinically meaningful. To assess whether a change in bone density is “real,” he recommended a useful equation called the “least significant change” equation: Multiply the coefficient of variations by three; if the sum is less than 4.5%, then the change may be due to chance.

For example, if the coefficient of variations in hip bone density is 1.5%, the least significant change is 4.5%. If a patient lost 3% in bone density, there is approximately a 10% chance that there was no change in bone density, he said.

“A somewhat more fundamental question is not just whether the measurements [are] real, but are they meaningful?” Dr. Bauer said.

Analyses of data from the Fracture Intervention Trial (FIT) show that patients on alendronate who lost up to 4% in total hip bone density in the 1-2 years of treatment still had 53% fewer vertebral fractures compared with their counterparts on placebo who lost similar amounts of bone density. Patients who lost up to 4% in spine density had 60% fewer vertebral fractures compared with their counterparts on placebo (Osteoporos. Int. 2005;16:842-8).

Then there's the “regression to the mean” argument that patients with an unusual response in the first year of antiresorptive therapy will develop a more typical response if treatment is continued, he said. A separate analysis of FIT data showed that 92% of patients who lost up to 4% of hip bone density in the first year of therapy gained a mean of nearly 5% in bone density in the second year of treatment (JAMA 2000;283:1318-21).

A more recent analysis of annual bone mineral density data in FIT showed that variation in the change in bone density over a 3-year period was mainly measurement-related, within-person variation.

Treatment-related, between-person variation played a much smaller role (BMJ 2009;338:b2266).

That helps explain how patients can “lose” bone density but still have fewer fractures, Dr. Bauer said. “It's reassuring that 98% on alendronate gained more than 0.02 g/cm

Antiresorptive therapy decreases biochemical markers of bone turnover, but there is a lot of biologic variability and no clear threshold for efficacy. Biochemical marker measurements could be used to identify nonadherence to treatment, but “it's cheaper just to ask,” he said.

In a study of 2,382 osteoporotic women starting a year of risedronate therapy, the women were randomized to get bone turnover markers measured at weeks 13 and 25 or to routine visits without marker measurements. The results showed no difference in adherence rates between the groups (J. Clin. Endocrinol. Metab. 2007;92:1296-304). In the marker measurement group, the adherence rate was 225% worse than in the control group if the marker results suggested a “bad” response to therapy (less than a 30% decrease in marker levels).

“That was unexpected,” Dr. Bauer said. “Bone turnover markers by themselves are not helpful for increasing adherence” to therapy.

A separate randomized study of 75 women starting raloxifene treatment for low bone density randomized them to no monitoring; nurse visits at months 3, 6, and 9; or nurse visits plus bone turnover marker measurements. The nurse visits improved adherence to therapy compared with no monitoring, but biomarker measurements did not add anything to the nurse visits (J. Clin. Endocrinol. Metab. 2004;89:1117-1123). In general, approximately 30%-40% of patients stop taking antiresorptive drugs within 1 year, he said.

Dr. Bauer said he has received research funding from Amgen, Novartis, and Procter & Gamble.

Biochemical marker measurements could identify nonadherence, but 'it's cheaper just to ask.'

Source DR. BAUER

The science supporting vitamin D supplementation in lupus patients is catching up to the recommendation that all patients with the autoimmune disease increase their intake of the fat-soluble secosteroids.

Findings from a new study by Dr. Suzan Abou-Raya, professor of geriatric medicine at the University of Alexandria (Egypt), and her associates demonstrate that there is a high prevalence of vitamin D deficiency associated with an increased inflammatory burden and thrombophilic state in patients with systemic lupus erythematosus (SLE). The findings also suggest that oral vitamin D supplementation ameliorates chronic inflammatory and hemostatic markers in this patient group.

The use of supplementary calcium and vitamin D is routinely recommended for SLE patients to help minimize the bone loss and increased risk of developing osteoporosis associated with the disease and its treatment. Beyond supporting bone and mineral hemostasis, “vitamin D is now recognized as having additional pleiotropic roles,” according to Dr. Abou-Raya. “We've learned that it has potent immunomodulatory properties that have promoted its potential use in the treatment of autoimmune conditions, including lupus.”

The study was designed to evaluate vitamin D status in lupus patients and to assess changes in disease-related inflammatory and hemostatic markers before and after vitamin D supplementation.

To do this, Dr. Abou-Raya and her fellow researchers conducted a randomized, placebo-controlled trial comprising 148 males and premenopausal females who fulfilled the ACR (American College of Rheumatology) classification criteria for SLE. Also enrolled in the study were 75 lupus-free adults who served as controls and who matched the cases in age, sex, ethnicity, and body mass index.

Individuals with other inflammatory disorders and those taking supplemental vitamin D at the time of the study were excluded from participation.

Study patients were randomized in a 1:1 fashion to receive either 2,000 IU per day of oral cholecalciferol (vitamin D₃) or placebo for 6 months together with standard SLE treatment, Dr. Abou-Raya said.

Before and after 6 months of vitamin D supplementation, the investigators evaluated disease activity using the SLE disease activity index (SLEDAI), levels of serum 25-hydroxyvitamin D (25[OH]D) via DiaSorin's Liaison immunoassay, levels of proinflammatory cytokines interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor (TNF)–alpha, C-reactive protein (CRP), and the hemostatic markers fibrinogen and von Willebrand factor (vWF).

Individuals with 25(OH)D levels of 10-30 ng/mL were classified as having vitamin D insufficiency and those with levels lower than 10 ng/mL were considered vitamin D deficient, she noted.

With respect to baseline demographics, the mean age of the SLE patients was 38.8 years and the mean disease duration was 5.2 years. The mean baseline vitamin D level in the SLE patients was 19.8 ng/mL, which was significantly lower than the mean 28.7 ng/mL in the control group, Dr. Abou-Raya reported. The baseline levels of the inflammatory and hemostatic markers were significantly higher in the SLE patients. “The overall prevalence of vitamin D insufficiency and deficiency, respectively, was 69% and 39%,” she said.

At 6 months, “there was a significant decrease in levels of inflammatory and hemostatic makers in lupus patients who were supplemented with vitamin D” compared with patients who were given placebo together with ongoing therapy, Dr. Abou-Raya reported at the annual European Congress of Rheumatology in London.

After multivariate adjustment, the investigators observed a negative correlation between vitamin D levels and IL-1, IL-6, IL-18, TNF-alpha, CRP, fibrinogen, and vWF, “and lower vitamin D levels were associated with significantly higher SLEDAI scores,” she said.

The results suggest that hypovitaminosis D contributes to a chronic inflammatory and thrombophilic state in SLE patients, said Dr. Abou-Raya. “The findings support the routine recommendation for oral vitamin D supplementation in these patients,” she said.

Dr. Abou-Raya disclosed having no financial conflicts of interest related to her presentation.

The science supporting vitamin D supplementation in lupus patients is catching up to the recommendation that all patients with the autoimmune disease increase their intake of the fat-soluble secosteroids.

Findings from a new study by Dr. Suzan Abou-Raya, professor of geriatric medicine at the University of Alexandria (Egypt), and her associates demonstrate that there is a high prevalence of vitamin D deficiency associated with an increased inflammatory burden and thrombophilic state in patients with systemic lupus erythematosus (SLE). The findings also suggest that oral vitamin D supplementation ameliorates chronic inflammatory and hemostatic markers in this patient group.

The use of supplementary calcium and vitamin D is routinely recommended for SLE patients to help minimize the bone loss and increased risk of developing osteoporosis associated with the disease and its treatment. Beyond supporting bone and mineral hemostasis, “vitamin D is now recognized as having additional pleiotropic roles,” according to Dr. Abou-Raya. “We've learned that it has potent immunomodulatory properties that have promoted its potential use in the treatment of autoimmune conditions, including lupus.”

The study was designed to evaluate vitamin D status in lupus patients and to assess changes in disease-related inflammatory and hemostatic markers before and after vitamin D supplementation.

To do this, Dr. Abou-Raya and her fellow researchers conducted a randomized, placebo-controlled trial comprising 148 males and premenopausal females who fulfilled the ACR (American College of Rheumatology) classification criteria for SLE. Also enrolled in the study were 75 lupus-free adults who served as controls and who matched the cases in age, sex, ethnicity, and body mass index.

Individuals with other inflammatory disorders and those taking supplemental vitamin D at the time of the study were excluded from participation.

Study patients were randomized in a 1:1 fashion to receive either 2,000 IU per day of oral cholecalciferol (vitamin D₃) or placebo for 6 months together with standard SLE treatment, Dr. Abou-Raya said.

Before and after 6 months of vitamin D supplementation, the investigators evaluated disease activity using the SLE disease activity index (SLEDAI), levels of serum 25-hydroxyvitamin D (25[OH]D) via DiaSorin's Liaison immunoassay, levels of proinflammatory cytokines interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor (TNF)–alpha, C-reactive protein (CRP), and the hemostatic markers fibrinogen and von Willebrand factor (vWF).

Individuals with 25(OH)D levels of 10-30 ng/mL were classified as having vitamin D insufficiency and those with levels lower than 10 ng/mL were considered vitamin D deficient, she noted.

With respect to baseline demographics, the mean age of the SLE patients was 38.8 years and the mean disease duration was 5.2 years. The mean baseline vitamin D level in the SLE patients was 19.8 ng/mL, which was significantly lower than the mean 28.7 ng/mL in the control group, Dr. Abou-Raya reported. The baseline levels of the inflammatory and hemostatic markers were significantly higher in the SLE patients. “The overall prevalence of vitamin D insufficiency and deficiency, respectively, was 69% and 39%,” she said.

At 6 months, “there was a significant decrease in levels of inflammatory and hemostatic makers in lupus patients who were supplemented with vitamin D” compared with patients who were given placebo together with ongoing therapy, Dr. Abou-Raya reported at the annual European Congress of Rheumatology in London.

After multivariate adjustment, the investigators observed a negative correlation between vitamin D levels and IL-1, IL-6, IL-18, TNF-alpha, CRP, fibrinogen, and vWF, “and lower vitamin D levels were associated with significantly higher SLEDAI scores,” she said.

The results suggest that hypovitaminosis D contributes to a chronic inflammatory and thrombophilic state in SLE patients, said Dr. Abou-Raya. “The findings support the routine recommendation for oral vitamin D supplementation in these patients,” she said.

Dr. Abou-Raya disclosed having no financial conflicts of interest related to her presentation.

The science supporting vitamin D supplementation in lupus patients is catching up to the recommendation that all patients with the autoimmune disease increase their intake of the fat-soluble secosteroids.

Findings from a new study by Dr. Suzan Abou-Raya, professor of geriatric medicine at the University of Alexandria (Egypt), and her associates demonstrate that there is a high prevalence of vitamin D deficiency associated with an increased inflammatory burden and thrombophilic state in patients with systemic lupus erythematosus (SLE). The findings also suggest that oral vitamin D supplementation ameliorates chronic inflammatory and hemostatic markers in this patient group.

The use of supplementary calcium and vitamin D is routinely recommended for SLE patients to help minimize the bone loss and increased risk of developing osteoporosis associated with the disease and its treatment. Beyond supporting bone and mineral hemostasis, “vitamin D is now recognized as having additional pleiotropic roles,” according to Dr. Abou-Raya. “We've learned that it has potent immunomodulatory properties that have promoted its potential use in the treatment of autoimmune conditions, including lupus.”

The study was designed to evaluate vitamin D status in lupus patients and to assess changes in disease-related inflammatory and hemostatic markers before and after vitamin D supplementation.

To do this, Dr. Abou-Raya and her fellow researchers conducted a randomized, placebo-controlled trial comprising 148 males and premenopausal females who fulfilled the ACR (American College of Rheumatology) classification criteria for SLE. Also enrolled in the study were 75 lupus-free adults who served as controls and who matched the cases in age, sex, ethnicity, and body mass index.

Individuals with other inflammatory disorders and those taking supplemental vitamin D at the time of the study were excluded from participation.

Study patients were randomized in a 1:1 fashion to receive either 2,000 IU per day of oral cholecalciferol (vitamin D₃) or placebo for 6 months together with standard SLE treatment, Dr. Abou-Raya said.

Before and after 6 months of vitamin D supplementation, the investigators evaluated disease activity using the SLE disease activity index (SLEDAI), levels of serum 25-hydroxyvitamin D (25[OH]D) via DiaSorin's Liaison immunoassay, levels of proinflammatory cytokines interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor (TNF)–alpha, C-reactive protein (CRP), and the hemostatic markers fibrinogen and von Willebrand factor (vWF).

Individuals with 25(OH)D levels of 10-30 ng/mL were classified as having vitamin D insufficiency and those with levels lower than 10 ng/mL were considered vitamin D deficient, she noted.

With respect to baseline demographics, the mean age of the SLE patients was 38.8 years and the mean disease duration was 5.2 years. The mean baseline vitamin D level in the SLE patients was 19.8 ng/mL, which was significantly lower than the mean 28.7 ng/mL in the control group, Dr. Abou-Raya reported. The baseline levels of the inflammatory and hemostatic markers were significantly higher in the SLE patients. “The overall prevalence of vitamin D insufficiency and deficiency, respectively, was 69% and 39%,” she said.

At 6 months, “there was a significant decrease in levels of inflammatory and hemostatic makers in lupus patients who were supplemented with vitamin D” compared with patients who were given placebo together with ongoing therapy, Dr. Abou-Raya reported at the annual European Congress of Rheumatology in London.

After multivariate adjustment, the investigators observed a negative correlation between vitamin D levels and IL-1, IL-6, IL-18, TNF-alpha, CRP, fibrinogen, and vWF, “and lower vitamin D levels were associated with significantly higher SLEDAI scores,” she said.

The results suggest that hypovitaminosis D contributes to a chronic inflammatory and thrombophilic state in SLE patients, said Dr. Abou-Raya. “The findings support the routine recommendation for oral vitamin D supplementation in these patients,” she said.

Dr. Abou-Raya disclosed having no financial conflicts of interest related to her presentation.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There’s a lot of controversy surrounding the Institute of Medicine’s (IOM) November 2010 report, "Dietary Reference Intakes for Calcium and Vitamin D," which updated 1997 guidelines. Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

(c) Mary Hope/iStockphoto

There is uncertainty about the cutoff level of serum vitamin D that’s considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a "sufficient" serum level should be in the 30-32 ng/mL range, she said. "It takes most people about 1,200 IU/day to reach that" serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused "a lot of consternation," she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

"It’s almost a moot point because you wouldn’t give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial," Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels. The concern was sparked by the committee’s interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve to mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was statistically not significantly different than in patients with a serum level greater than 32 ng/mL.

"I’m really not sure that there is a higher mortality," Dr. Sellmeyer said. "I think there is enough evidence to suggest that we probably ought to be a little more in the 30-40 ng/mL range."

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day for those who are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day in older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It’s important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. "We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day," she said. "Those [are the patients who] can get into trouble."

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women’s Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction (MI) or vascular calcification (Circulation 2007;115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ. 2008;336:262-6). The investigators in that study re-analyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19:342:d2040).

There were significant differences in the comparison groups in the re-analysis, including differences in personal history of MI, Dr. Sellmeyer noted. "Whether this truly represents an increased risk or not is unclear," she said.

Another study by some of the same investigators "got a ton of press" even though it was a relatively small meta-analysis, she added. The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010;341:c3691).

"It’s really hard to know at this point" whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said. "I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial."

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, "but for a lot of people it doesn’t matter," she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There’s a lot of controversy surrounding the Institute of Medicine’s (IOM) November 2010 report, "Dietary Reference Intakes for Calcium and Vitamin D," which updated 1997 guidelines. Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

(c) Mary Hope/iStockphoto

There is uncertainty about the cutoff level of serum vitamin D that’s considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a "sufficient" serum level should be in the 30-32 ng/mL range, she said. "It takes most people about 1,200 IU/day to reach that" serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused "a lot of consternation," she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

"It’s almost a moot point because you wouldn’t give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial," Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels. The concern was sparked by the committee’s interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve to mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was statistically not significantly different than in patients with a serum level greater than 32 ng/mL.

"I’m really not sure that there is a higher mortality," Dr. Sellmeyer said. "I think there is enough evidence to suggest that we probably ought to be a little more in the 30-40 ng/mL range."

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day for those who are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day in older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It’s important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. "We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day," she said. "Those [are the patients who] can get into trouble."

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women’s Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction (MI) or vascular calcification (Circulation 2007;115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ. 2008;336:262-6). The investigators in that study re-analyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19:342:d2040).

There were significant differences in the comparison groups in the re-analysis, including differences in personal history of MI, Dr. Sellmeyer noted. "Whether this truly represents an increased risk or not is unclear," she said.

Another study by some of the same investigators "got a ton of press" even though it was a relatively small meta-analysis, she added. The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010;341:c3691).

"It’s really hard to know at this point" whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said. "I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial."

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, "but for a lot of people it doesn’t matter," she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There’s a lot of controversy surrounding the Institute of Medicine’s (IOM) November 2010 report, "Dietary Reference Intakes for Calcium and Vitamin D," which updated 1997 guidelines. Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

(c) Mary Hope/iStockphoto

There is uncertainty about the cutoff level of serum vitamin D that’s considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a "sufficient" serum level should be in the 30-32 ng/mL range, she said. "It takes most people about 1,200 IU/day to reach that" serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused "a lot of consternation," she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

"It’s almost a moot point because you wouldn’t give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial," Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels. The concern was sparked by the committee’s interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve to mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was statistically not significantly different than in patients with a serum level greater than 32 ng/mL.

"I’m really not sure that there is a higher mortality," Dr. Sellmeyer said. "I think there is enough evidence to suggest that we probably ought to be a little more in the 30-40 ng/mL range."

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day for those who are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day in older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It’s important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. "We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day," she said. "Those [are the patients who] can get into trouble."

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women’s Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction (MI) or vascular calcification (Circulation 2007;115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ. 2008;336:262-6). The investigators in that study re-analyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19:342:d2040).

There were significant differences in the comparison groups in the re-analysis, including differences in personal history of MI, Dr. Sellmeyer noted. "Whether this truly represents an increased risk or not is unclear," she said.

Another study by some of the same investigators "got a ton of press" even though it was a relatively small meta-analysis, she added. The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010;341:c3691).

"It’s really hard to know at this point" whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said. "I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial."

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, "but for a lot of people it doesn’t matter," she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.

One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.

A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.

The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.

"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.

These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.

"We need more effective treatments," he said.

Anti-Sclerostin Antibodies

Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.

An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.

"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.

Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.

Odanacatib

Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.

Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.

"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.

Nitroglycerin

Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.

Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.

Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.

Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.

Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.

Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.

SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.

One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.

A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.

The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.

"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.

These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.

"We need more effective treatments," he said.

Anti-Sclerostin Antibodies

Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.

An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.

"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.

Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.

Odanacatib

Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.

Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.

"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.

Nitroglycerin

Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.

Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.

Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.

Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.

Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.

Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.

SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.

One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.

A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.

The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.

"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.

These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.

"We need more effective treatments," he said.

Anti-Sclerostin Antibodies

Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.

An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.

"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.

Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.

Odanacatib

Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.

Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.

"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.

Nitroglycerin

Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.

Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.

Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.

Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.

Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.

Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.

SAN FRANCISCO – Vertebroplasty worked no better than sham surgery to reduce pain and disability from vertebral fracture, according to data from recent randomized, controlled trials that put nonsurgical therapies firmly in the first line of treatment.

Osteoporotic vertebral fractures should be treated aggressively with antiresorptive or anabolic therapy for at least 6-12 weeks before considering surgery, Dr. Douglas C. Bauer said at a meeting on osteoporosis sponsored by the University of California, San Francisco. Optimize medical therapy, physical therapy, and other options that might be appropriate such as adding calcitonin or referring the patient for a facet joint injection, he said.

Even after all that, clinicians should consider kyphoplasty before resorting to vertebroplasty, said Dr. Bauer, who is professor of medicine and of epidemiology and biostatistics at the university.

Findings from one unblinded, randomized trial suggests that kyphoplasty may reduce pain and disability, compared with conservative care initially, though the difference in results is less apparent 1 year after surgery.

Despite data from numerous uncontrolled studies suggesting that vertebroplasty also lessens pain and improves function, findings from two well-designed controlled trials "raised a brouhaha" and surprised investigators by showing vertebroplasty to have no benefit, "suggesting that a very commonly done procedure is not helpful," he said. It’s unclear whether the uncontrolled trial results were due to an extended placebo effect or some other factor.

In kyphoplasty, surgeons insert a balloon device to reduce the cervical fracture, remove the balloon, and replace it with cement. Vertebroplasty injects cement only, without the balloon, and does not attempt to increase vertebral height. Both are minimally invasive surgeries that usually are performed under general anesthesia but can be done using local anesthesia, often with conscious sedation.

The unblinded trial of kyphoplasty randomized 149 patients to kyphoplasty and 151 to usual nonsurgical care. "The patients were typical of who we see with vertebral fracture," Dr. Bauer noted. The primary results showed that 1 month after surgery, scores on the Short Form-36 (SF-36) Physical Component Summary had increased from 26 at baseline in both groups to 27 in the kyphoplasty group and 33 in the control group, a significant difference between groups (Lancet 2009;373:1016-24).

Follow-up continued out to 3, 6, and 12 months after surgery, and results were significantly better in the kyphoplasty group at all time points for the SF-36 Physical Component, patient-reported Visual Analog Scale (VAS) scores for back pain, and the number of days of limited activity in the previous 2 weeks.

Although statistically significant, some of the differences between groups were more clinically significant than others. The self-reported VAS pain scores, for example, differed between groups by only 1 point on a 10-point scale at 12 months. The kyphoplasty group, however, enjoyed an average of 60 fewer days of limited activity during those 12 months, compared with the control group, which "patients may be most interested in," he said.

At 24 months, only the difference in pain scores remained statistically significant between groups (J. Bone Miner. Res. 2011;26:1627-37).

More trials of kyphoplasty are needed before the surgery becomes widespread, Dr. Bauer said.

A separate uncontrolled trial that randomized 202 patients to vertebroplasty or usual care similarly found statistically greater improvements in the vertebroplasty group in VAS pain scores at 1 month (a decrease of 5 points) and 1 year (a 6-point drop), compared with usual care (a 3- and 4-point drop, respectively). Patients in the surgery arm also reported less narcotic use (Lancet 2010;376:1085-92).

The two well-designed controlled trials of vertebroplasty contradict other findings, however. Patients were taken to the operating room before randomization. The control group received sham surgery that included needle insertions in their backs and the breaking of a vial of chemicals to disperse a chemical smell. Outcomes assessors were blinded to randomization.

In one study of 71 patients, scores for back pain decreased significantly in both the real and sham surgery groups, but outcomes did not differ significantly between groups at any time point out to 6 months (New Engl. J. Med. 2009;361:557-68).

In the other study of 131 patients, both groups showed immediate improvements in disability and pain scores but no outcomes differed significantly between groups at 1 month (New Engl. J. Med. 2009;361:569-79).

While it’s conceivable that the benefits reported for vertebroplasty and kyphoplasty in uncontrolled studies are due to an extended placebo effect, the likelihood that the placebo effect would last for as much as 24 months of follow-up is unclear, Dr. Bauer said.

Some have suggested that the sham-surgery studies included a harder-to-treat population by accepting patients with vertebral fractures up to 1 year in duration, but a subsequent analysis of data limited to fractures of less than 6 weeks duration found no change in the overall results.

Case series have shown that anesthetic or steroid injections alone can reduce vertebral fracture pain, which may explain the improvement in pain scores in both the real and sham-surgery groups in the vertebroplasty trials, he suggested.

There also may be a difference between the two surgeries that produce different results from kyphoplasty or vertebroplasty. Randomized, controlled trials comparing the two are underway.

Further research is needed on optimal patient selection, on whether the surgeries prevent kyphosis, and on long-term outcomes, Dr. Bauer said.

The 700,000 vertebral compression fractures in the United States each year hospitalize more than 150,000 people.

Dr. Bauer has received research funding from Amgen and Novartis.

SAN FRANCISCO – Vertebroplasty worked no better than sham surgery to reduce pain and disability from vertebral fracture, according to data from recent randomized, controlled trials that put nonsurgical therapies firmly in the first line of treatment.

Osteoporotic vertebral fractures should be treated aggressively with antiresorptive or anabolic therapy for at least 6-12 weeks before considering surgery, Dr. Douglas C. Bauer said at a meeting on osteoporosis sponsored by the University of California, San Francisco. Optimize medical therapy, physical therapy, and other options that might be appropriate such as adding calcitonin or referring the patient for a facet joint injection, he said.

Even after all that, clinicians should consider kyphoplasty before resorting to vertebroplasty, said Dr. Bauer, who is professor of medicine and of epidemiology and biostatistics at the university.

Findings from one unblinded, randomized trial suggests that kyphoplasty may reduce pain and disability, compared with conservative care initially, though the difference in results is less apparent 1 year after surgery.

Despite data from numerous uncontrolled studies suggesting that vertebroplasty also lessens pain and improves function, findings from two well-designed controlled trials "raised a brouhaha" and surprised investigators by showing vertebroplasty to have no benefit, "suggesting that a very commonly done procedure is not helpful," he said. It’s unclear whether the uncontrolled trial results were due to an extended placebo effect or some other factor.

In kyphoplasty, surgeons insert a balloon device to reduce the cervical fracture, remove the balloon, and replace it with cement. Vertebroplasty injects cement only, without the balloon, and does not attempt to increase vertebral height. Both are minimally invasive surgeries that usually are performed under general anesthesia but can be done using local anesthesia, often with conscious sedation.

The unblinded trial of kyphoplasty randomized 149 patients to kyphoplasty and 151 to usual nonsurgical care. "The patients were typical of who we see with vertebral fracture," Dr. Bauer noted. The primary results showed that 1 month after surgery, scores on the Short Form-36 (SF-36) Physical Component Summary had increased from 26 at baseline in both groups to 27 in the kyphoplasty group and 33 in the control group, a significant difference between groups (Lancet 2009;373:1016-24).

Follow-up continued out to 3, 6, and 12 months after surgery, and results were significantly better in the kyphoplasty group at all time points for the SF-36 Physical Component, patient-reported Visual Analog Scale (VAS) scores for back pain, and the number of days of limited activity in the previous 2 weeks.

Although statistically significant, some of the differences between groups were more clinically significant than others. The self-reported VAS pain scores, for example, differed between groups by only 1 point on a 10-point scale at 12 months. The kyphoplasty group, however, enjoyed an average of 60 fewer days of limited activity during those 12 months, compared with the control group, which "patients may be most interested in," he said.

At 24 months, only the difference in pain scores remained statistically significant between groups (J. Bone Miner. Res. 2011;26:1627-37).

More trials of kyphoplasty are needed before the surgery becomes widespread, Dr. Bauer said.

A separate uncontrolled trial that randomized 202 patients to vertebroplasty or usual care similarly found statistically greater improvements in the vertebroplasty group in VAS pain scores at 1 month (a decrease of 5 points) and 1 year (a 6-point drop), compared with usual care (a 3- and 4-point drop, respectively). Patients in the surgery arm also reported less narcotic use (Lancet 2010;376:1085-92).

The two well-designed controlled trials of vertebroplasty contradict other findings, however. Patients were taken to the operating room before randomization. The control group received sham surgery that included needle insertions in their backs and the breaking of a vial of chemicals to disperse a chemical smell. Outcomes assessors were blinded to randomization.

In one study of 71 patients, scores for back pain decreased significantly in both the real and sham surgery groups, but outcomes did not differ significantly between groups at any time point out to 6 months (New Engl. J. Med. 2009;361:557-68).

In the other study of 131 patients, both groups showed immediate improvements in disability and pain scores but no outcomes differed significantly between groups at 1 month (New Engl. J. Med. 2009;361:569-79).

While it’s conceivable that the benefits reported for vertebroplasty and kyphoplasty in uncontrolled studies are due to an extended placebo effect, the likelihood that the placebo effect would last for as much as 24 months of follow-up is unclear, Dr. Bauer said.

Some have suggested that the sham-surgery studies included a harder-to-treat population by accepting patients with vertebral fractures up to 1 year in duration, but a subsequent analysis of data limited to fractures of less than 6 weeks duration found no change in the overall results.

Case series have shown that anesthetic or steroid injections alone can reduce vertebral fracture pain, which may explain the improvement in pain scores in both the real and sham-surgery groups in the vertebroplasty trials, he suggested.

There also may be a difference between the two surgeries that produce different results from kyphoplasty or vertebroplasty. Randomized, controlled trials comparing the two are underway.

Further research is needed on optimal patient selection, on whether the surgeries prevent kyphosis, and on long-term outcomes, Dr. Bauer said.

The 700,000 vertebral compression fractures in the United States each year hospitalize more than 150,000 people.

Dr. Bauer has received research funding from Amgen and Novartis.

SAN FRANCISCO – Vertebroplasty worked no better than sham surgery to reduce pain and disability from vertebral fracture, according to data from recent randomized, controlled trials that put nonsurgical therapies firmly in the first line of treatment.

Osteoporotic vertebral fractures should be treated aggressively with antiresorptive or anabolic therapy for at least 6-12 weeks before considering surgery, Dr. Douglas C. Bauer said at a meeting on osteoporosis sponsored by the University of California, San Francisco. Optimize medical therapy, physical therapy, and other options that might be appropriate such as adding calcitonin or referring the patient for a facet joint injection, he said.

Even after all that, clinicians should consider kyphoplasty before resorting to vertebroplasty, said Dr. Bauer, who is professor of medicine and of epidemiology and biostatistics at the university.

Findings from one unblinded, randomized trial suggests that kyphoplasty may reduce pain and disability, compared with conservative care initially, though the difference in results is less apparent 1 year after surgery.

Despite data from numerous uncontrolled studies suggesting that vertebroplasty also lessens pain and improves function, findings from two well-designed controlled trials "raised a brouhaha" and surprised investigators by showing vertebroplasty to have no benefit, "suggesting that a very commonly done procedure is not helpful," he said. It’s unclear whether the uncontrolled trial results were due to an extended placebo effect or some other factor.

In kyphoplasty, surgeons insert a balloon device to reduce the cervical fracture, remove the balloon, and replace it with cement. Vertebroplasty injects cement only, without the balloon, and does not attempt to increase vertebral height. Both are minimally invasive surgeries that usually are performed under general anesthesia but can be done using local anesthesia, often with conscious sedation.

The unblinded trial of kyphoplasty randomized 149 patients to kyphoplasty and 151 to usual nonsurgical care. "The patients were typical of who we see with vertebral fracture," Dr. Bauer noted. The primary results showed that 1 month after surgery, scores on the Short Form-36 (SF-36) Physical Component Summary had increased from 26 at baseline in both groups to 27 in the kyphoplasty group and 33 in the control group, a significant difference between groups (Lancet 2009;373:1016-24).

Follow-up continued out to 3, 6, and 12 months after surgery, and results were significantly better in the kyphoplasty group at all time points for the SF-36 Physical Component, patient-reported Visual Analog Scale (VAS) scores for back pain, and the number of days of limited activity in the previous 2 weeks.

Although statistically significant, some of the differences between groups were more clinically significant than others. The self-reported VAS pain scores, for example, differed between groups by only 1 point on a 10-point scale at 12 months. The kyphoplasty group, however, enjoyed an average of 60 fewer days of limited activity during those 12 months, compared with the control group, which "patients may be most interested in," he said.

At 24 months, only the difference in pain scores remained statistically significant between groups (J. Bone Miner. Res. 2011;26:1627-37).

More trials of kyphoplasty are needed before the surgery becomes widespread, Dr. Bauer said.

A separate uncontrolled trial that randomized 202 patients to vertebroplasty or usual care similarly found statistically greater improvements in the vertebroplasty group in VAS pain scores at 1 month (a decrease of 5 points) and 1 year (a 6-point drop), compared with usual care (a 3- and 4-point drop, respectively). Patients in the surgery arm also reported less narcotic use (Lancet 2010;376:1085-92).

The two well-designed controlled trials of vertebroplasty contradict other findings, however. Patients were taken to the operating room before randomization. The control group received sham surgery that included needle insertions in their backs and the breaking of a vial of chemicals to disperse a chemical smell. Outcomes assessors were blinded to randomization.

In one study of 71 patients, scores for back pain decreased significantly in both the real and sham surgery groups, but outcomes did not differ significantly between groups at any time point out to 6 months (New Engl. J. Med. 2009;361:557-68).

In the other study of 131 patients, both groups showed immediate improvements in disability and pain scores but no outcomes differed significantly between groups at 1 month (New Engl. J. Med. 2009;361:569-79).

While it’s conceivable that the benefits reported for vertebroplasty and kyphoplasty in uncontrolled studies are due to an extended placebo effect, the likelihood that the placebo effect would last for as much as 24 months of follow-up is unclear, Dr. Bauer said.

Some have suggested that the sham-surgery studies included a harder-to-treat population by accepting patients with vertebral fractures up to 1 year in duration, but a subsequent analysis of data limited to fractures of less than 6 weeks duration found no change in the overall results.

Case series have shown that anesthetic or steroid injections alone can reduce vertebral fracture pain, which may explain the improvement in pain scores in both the real and sham-surgery groups in the vertebroplasty trials, he suggested.

There also may be a difference between the two surgeries that produce different results from kyphoplasty or vertebroplasty. Randomized, controlled trials comparing the two are underway.

Further research is needed on optimal patient selection, on whether the surgeries prevent kyphosis, and on long-term outcomes, Dr. Bauer said.

The 700,000 vertebral compression fractures in the United States each year hospitalize more than 150,000 people.

Dr. Bauer has received research funding from Amgen and Novartis.

SAN FRANCISCO – Evidence continues to mount that thiazolidinediones decrease bone density and increase fracture risk in patients with diabetes, but so far there are no randomized studies to show that adding an antiresorptive drug would protect bone health in this setting.

Bisphosphonates, denosumab, and parathyroid hormone have not been tested in human studies to see if they could reduce fracture risk in patients with diabetes who are taking thiazolidinediones, but randomized studies in mice suggest significant bone benefits from adding a bisphosphonate, Dr. Jonathan Graf said at a conference on osteoporosis sponsored by the University of California, San Francisco.

For now, however, recommendations call for avoiding thiazolidinediones in patients with diabetes who have a high risk of fracture. A patient’s risk should be assessed by using the online FRAX tool and assessing the history for other risk factors for fracture that are not covered by FRAX, said Dr. Graf, a rheumatologist at San Francisco General Hospital.

If you do decide to use a thiazolidinedione to treat diabetes in someone at high risk for fracture, the detrimental effects on bone might be mitigated by using a lower dose. At least two thiazolidinediones – rosiglitazone and pioglitazone – are available in lower-dose formulations in combination with metformin, and the combinations provide the same level of diabetes control as higher-dose glitazone monotherapy, he said.

Preliminary data also suggest that combining lower doses of thiazolidinediones with an incretin drug may provide diabetes control while mitigating adverse effects on bone, he added. Incretins may even promote bone formation, some evidence suggests.

"There is not a lot of evidence out there to steer you one way or the other" in these management choices, but the evidence of damaging effects of thiazolidinediones on bone is becoming nearly overwhelming, he said.

In a prospective cohort study of 84,339 men and women with diabetes, the risk of fracture was 28% higher in patients on thiazolidinediones than in patients taking sulfonylureas, and the risk increased with cumulative exposure to thiazolidinediones. In men, pioglitazone increased fracture risk but rosiglitazone did not (Arch. Intern. Med. 2009;169:1395-1402).

A separate cohort study of 20,964 Medicare beneficiaries over age 65 years with diabetes found a statistical trend toward higher risk of peripheral fractures in both men and women on thiazolidinedione monotherapy compared with treatment with sulfonylureas or metformin (J. Clin. Endocrinol. Metab. 2009;94:2792-98).

Previous trials have suggested that the fracture risk is higher in women than in men. A meta-analysis of 10 trials and 2 observational studies containing a total of 45,484 patients with diabetes reported a doubling of fracture risk in women but not in men on thiazolidinediones, compared with controls (Can. Med. Assoc. J. 2009;180:32-9). In a separate analysis of a claims database, thiazolidinedione therapy doubled the risk of limb fracture in women (Am. J. Manag. Care 2009;15:491-6).

Thiazolidinedione therapy and the duration of therapy in older patients were associated with significant increases in nonvertebral fractures, including more than a fourfold increased risk of hip or femur fracture, a tripling in risk of forearm fracture, and a doubling in risk of humerus fracture, an observational study found (Arch. Intern. Med. 2008;168:820-5).

The 4-year fracture rate in patients on rosiglitazone doubled in both pre- and postmenopausal women but not in men compared with other diabetes treatments in A Diabetes Outcome Progression Trial (ADOPT), a randomized, double-blind study of about 3,600 patients. The fracture rate was 15% on rosiglitazone, 8% on glyburide, and 7% on metformin (Diab. Care 2008;31:845-51). At least three separate studies found significantly increased bone loss in women within weeks of starting thiazolidinediones, especially in postmenopausal women.

Thiazolidinediones are agonists to peroxisome proliferator-activated receptor gamma, which helps regulate bone formation. Thiazolidinediones decrease insulin-like growth factor 1 expression (which decreases bone formation), decrease osteoblastogenesis, and promote osteoblast differentiation.

"Just like glucocorticoids, they have several mechanisms that affect bone," he said.

Dr. Graf reported that he has no conflicts of interest.

SAN FRANCISCO – Evidence continues to mount that thiazolidinediones decrease bone density and increase fracture risk in patients with diabetes, but so far there are no randomized studies to show that adding an antiresorptive drug would protect bone health in this setting.

Bisphosphonates, denosumab, and parathyroid hormone have not been tested in human studies to see if they could reduce fracture risk in patients with diabetes who are taking thiazolidinediones, but randomized studies in mice suggest significant bone benefits from adding a bisphosphonate, Dr. Jonathan Graf said at a conference on osteoporosis sponsored by the University of California, San Francisco.

For now, however, recommendations call for avoiding thiazolidinediones in patients with diabetes who have a high risk of fracture. A patient’s risk should be assessed by using the online FRAX tool and assessing the history for other risk factors for fracture that are not covered by FRAX, said Dr. Graf, a rheumatologist at San Francisco General Hospital.

If you do decide to use a thiazolidinedione to treat diabetes in someone at high risk for fracture, the detrimental effects on bone might be mitigated by using a lower dose. At least two thiazolidinediones – rosiglitazone and pioglitazone – are available in lower-dose formulations in combination with metformin, and the combinations provide the same level of diabetes control as higher-dose glitazone monotherapy, he said.

Preliminary data also suggest that combining lower doses of thiazolidinediones with an incretin drug may provide diabetes control while mitigating adverse effects on bone, he added. Incretins may even promote bone formation, some evidence suggests.

"There is not a lot of evidence out there to steer you one way or the other" in these management choices, but the evidence of damaging effects of thiazolidinediones on bone is becoming nearly overwhelming, he said.

In a prospective cohort study of 84,339 men and women with diabetes, the risk of fracture was 28% higher in patients on thiazolidinediones than in patients taking sulfonylureas, and the risk increased with cumulative exposure to thiazolidinediones. In men, pioglitazone increased fracture risk but rosiglitazone did not (Arch. Intern. Med. 2009;169:1395-1402).

A separate cohort study of 20,964 Medicare beneficiaries over age 65 years with diabetes found a statistical trend toward higher risk of peripheral fractures in both men and women on thiazolidinedione monotherapy compared with treatment with sulfonylureas or metformin (J. Clin. Endocrinol. Metab. 2009;94:2792-98).

Previous trials have suggested that the fracture risk is higher in women than in men. A meta-analysis of 10 trials and 2 observational studies containing a total of 45,484 patients with diabetes reported a doubling of fracture risk in women but not in men on thiazolidinediones, compared with controls (Can. Med. Assoc. J. 2009;180:32-9). In a separate analysis of a claims database, thiazolidinedione therapy doubled the risk of limb fracture in women (Am. J. Manag. Care 2009;15:491-6).

Thiazolidinedione therapy and the duration of therapy in older patients were associated with significant increases in nonvertebral fractures, including more than a fourfold increased risk of hip or femur fracture, a tripling in risk of forearm fracture, and a doubling in risk of humerus fracture, an observational study found (Arch. Intern. Med. 2008;168:820-5).

The 4-year fracture rate in patients on rosiglitazone doubled in both pre- and postmenopausal women but not in men compared with other diabetes treatments in A Diabetes Outcome Progression Trial (ADOPT), a randomized, double-blind study of about 3,600 patients. The fracture rate was 15% on rosiglitazone, 8% on glyburide, and 7% on metformin (Diab. Care 2008;31:845-51). At least three separate studies found significantly increased bone loss in women within weeks of starting thiazolidinediones, especially in postmenopausal women.

Thiazolidinediones are agonists to peroxisome proliferator-activated receptor gamma, which helps regulate bone formation. Thiazolidinediones decrease insulin-like growth factor 1 expression (which decreases bone formation), decrease osteoblastogenesis, and promote osteoblast differentiation.

"Just like glucocorticoids, they have several mechanisms that affect bone," he said.

Dr. Graf reported that he has no conflicts of interest.

SAN FRANCISCO – Evidence continues to mount that thiazolidinediones decrease bone density and increase fracture risk in patients with diabetes, but so far there are no randomized studies to show that adding an antiresorptive drug would protect bone health in this setting.

Bisphosphonates, denosumab, and parathyroid hormone have not been tested in human studies to see if they could reduce fracture risk in patients with diabetes who are taking thiazolidinediones, but randomized studies in mice suggest significant bone benefits from adding a bisphosphonate, Dr. Jonathan Graf said at a conference on osteoporosis sponsored by the University of California, San Francisco.

For now, however, recommendations call for avoiding thiazolidinediones in patients with diabetes who have a high risk of fracture. A patient’s risk should be assessed by using the online FRAX tool and assessing the history for other risk factors for fracture that are not covered by FRAX, said Dr. Graf, a rheumatologist at San Francisco General Hospital.

If you do decide to use a thiazolidinedione to treat diabetes in someone at high risk for fracture, the detrimental effects on bone might be mitigated by using a lower dose. At least two thiazolidinediones – rosiglitazone and pioglitazone – are available in lower-dose formulations in combination with metformin, and the combinations provide the same level of diabetes control as higher-dose glitazone monotherapy, he said.

Preliminary data also suggest that combining lower doses of thiazolidinediones with an incretin drug may provide diabetes control while mitigating adverse effects on bone, he added. Incretins may even promote bone formation, some evidence suggests.

"There is not a lot of evidence out there to steer you one way or the other" in these management choices, but the evidence of damaging effects of thiazolidinediones on bone is becoming nearly overwhelming, he said.

In a prospective cohort study of 84,339 men and women with diabetes, the risk of fracture was 28% higher in patients on thiazolidinediones than in patients taking sulfonylureas, and the risk increased with cumulative exposure to thiazolidinediones. In men, pioglitazone increased fracture risk but rosiglitazone did not (Arch. Intern. Med. 2009;169:1395-1402).

A separate cohort study of 20,964 Medicare beneficiaries over age 65 years with diabetes found a statistical trend toward higher risk of peripheral fractures in both men and women on thiazolidinedione monotherapy compared with treatment with sulfonylureas or metformin (J. Clin. Endocrinol. Metab. 2009;94:2792-98).

Previous trials have suggested that the fracture risk is higher in women than in men. A meta-analysis of 10 trials and 2 observational studies containing a total of 45,484 patients with diabetes reported a doubling of fracture risk in women but not in men on thiazolidinediones, compared with controls (Can. Med. Assoc. J. 2009;180:32-9). In a separate analysis of a claims database, thiazolidinedione therapy doubled the risk of limb fracture in women (Am. J. Manag. Care 2009;15:491-6).

Thiazolidinedione therapy and the duration of therapy in older patients were associated with significant increases in nonvertebral fractures, including more than a fourfold increased risk of hip or femur fracture, a tripling in risk of forearm fracture, and a doubling in risk of humerus fracture, an observational study found (Arch. Intern. Med. 2008;168:820-5).

The 4-year fracture rate in patients on rosiglitazone doubled in both pre- and postmenopausal women but not in men compared with other diabetes treatments in A Diabetes Outcome Progression Trial (ADOPT), a randomized, double-blind study of about 3,600 patients. The fracture rate was 15% on rosiglitazone, 8% on glyburide, and 7% on metformin (Diab. Care 2008;31:845-51). At least three separate studies found significantly increased bone loss in women within weeks of starting thiazolidinediones, especially in postmenopausal women.

Thiazolidinediones are agonists to peroxisome proliferator-activated receptor gamma, which helps regulate bone formation. Thiazolidinediones decrease insulin-like growth factor 1 expression (which decreases bone formation), decrease osteoblastogenesis, and promote osteoblast differentiation.

"Just like glucocorticoids, they have several mechanisms that affect bone," he said.

Dr. Graf reported that he has no conflicts of interest.

Issues around screening and treatment of vitamin D deficiency have been very controversial in recent years. The Endocrine Society recently published an evidence-based guideline aimed at helping determine who should be screened and receive vitamin D replacement.

Conclusions

The Institute of Medicine recently endorsed the historical definition of vitamin D deficiency as a 25-hydroxy vitamin D level of less than 20 ng/ml, insufficiency as 21-29 ng/ml, and sufficiency as 30-100 ng/ml.

It is estimated that at least 20%, if not a large majority, of community-dwelling seniors in the United States are vitamin D deficient, based on the IOM definition, with a high proportion of younger adults and children also likely to be vitamin D deficient. These estimates are supported by numerous epidemiologic studies in varied populations.

The principal source of vitamin D is exposure to natural sunlight. Dark skin pigmentation and sunscreens with an SPF greater than 30 reduce solar vitamin D synthesis dramatically.

Only a few foods, such as salmon, tuna, and shitake mushrooms, are naturally rich in vitamin D, so vitamin D supplementation is added to a variety of foods in the U.S. and Canada.

Obesity is associated with reduction in vitamin D levels.

Vitamin D deficiency is problematic in patients with intestinal malabsorption, including those with bariatric surgeries. Nephrotic syndrome causes increased urinary loss of bound vitamin D.

Multiple medications including corticosteroids, azole antifungals, HIV drugs, and anticonvulsants cause enhanced vitamin D catabolism and increase the risk for vitamin D deficiency.

Patients with lymphomas, granuloma-forming disorders, such as sarcoidosis, certain fungal infections, and tuberculosis have extra-renal metabolism of 25-hydroxy vitamin D to 1,25(OH)D₂ and are at high risk for vitamin D deficiency. They also are at risk of hypercalcemia with vitamin D replacement to sufficiency.

Vitamin D deficiency results in abnormal calcium/phosphate and bone metabolism at intestinal, renal and bone levels.

Implementation

• Prevention: Vitamin D2 or vitamin D3 should be used for the prevention and treatment of vitamin D deficiency.

A dose of at least 600 IU daily of vitamin D is suggested for adults 19-65 years of age, including women who are pregnant and lactating, to maximize bone and muscular function.

At least 800 IU of vitamin D daily is suggested for persons 65 years and older to maximize bone and muscle function and to reduce the risk for falls and associated fractures. The data for this dosing recommendation is stronger than that supporting dosing in younger adults.

Obese adults and those taking anticonvulsants and other medications known to interfere with vitamin D should take doses of vitamin D that are two to three times the dose of their age-matched peers.

These daily allowances may not be sufficient to raise the blood level of 25-OH vitamin D to 30 ng/ml in all persons.

The maximum daily dose of vitamin D which should be taken by adults not under the supervision of a physician, or being treated specifically for vitamin D deficiency is 4000 IU daily.

• Screening: Vitamin D screening should be restricted to patients at increased risk for deficiency. This would include patients with osteoporosis, those with malabsorption syndromes, patients taking medications interfering with vitamin D, those with chronic kidney disease and older adults. The primary circulating form of vitamin D is 25-hydroxy vitamin D and is the recommended test for assessment of deficiency in nearly all patients.

Only patients with chronic kidney disease, and other specific conditions in which vitamin D and phosphate metabolism is altered should be evaluated by 1,25(OH)D₂ level.

• Treatment: Adults who are vitamin D deficient should be treated with 50,000 IU of vitamin D2 [or D3] weekly for 8 weeks with a goal of achieving 25-OH vitamin D levels of 30 ng/ml or above, followed by maintenance therapy to maintain these levels. Alternative dosing strategies are reviewed in the full text guideline.

Evaluation for a cause of vitamin D malabsorption should be considered in patients who are adherent to replacement therapy but in whom the 25-OH vitamin D level does not increase.

Obese patients, those taking medications affecting vitamin D metabolism and those with malabsorption of vitamin D should be treated with replacement doses two- to threefold higher (6,000-10,000 IU daily) to replete their deficiency. They also require higher doses for maintenance therapy.

Patients with extrarenal production of 1,25(OH)D₂ and primary hyperparathyroidism should have serial monitoring of 25-OH vitamin D and calcium during replacement to minimize the risk for hypercalcemia.

Vitamin D receptors are located in many tissues and many potential pleiotropic effects of vitamin D have been noted by researchers, but the data to date are insufficient for firm clinical conclusions about the magnitude of these effects. A number of other questions remain unanswered regarding vitamin D and its effects.

Reference

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline (J. Clin. Endocrinol. Metab. 2011;96:1911-30).

Dr. Golden is professor of medicine and public health and Dr. Hopkins is program director for the internal medicine/pediatrics combined residency program at the University of Arkansas, Little Rock. 

Issues around screening and treatment of vitamin D deficiency have been very controversial in recent years. The Endocrine Society recently published an evidence-based guideline aimed at helping determine who should be screened and receive vitamin D replacement.

Conclusions

The Institute of Medicine recently endorsed the historical definition of vitamin D deficiency as a 25-hydroxy vitamin D level of less than 20 ng/ml, insufficiency as 21-29 ng/ml, and sufficiency as 30-100 ng/ml.

It is estimated that at least 20%, if not a large majority, of community-dwelling seniors in the United States are vitamin D deficient, based on the IOM definition, with a high proportion of younger adults and children also likely to be vitamin D deficient. These estimates are supported by numerous epidemiologic studies in varied populations.

The principal source of vitamin D is exposure to natural sunlight. Dark skin pigmentation and sunscreens with an SPF greater than 30 reduce solar vitamin D synthesis dramatically.

Only a few foods, such as salmon, tuna, and shitake mushrooms, are naturally rich in vitamin D, so vitamin D supplementation is added to a variety of foods in the U.S. and Canada.

Obesity is associated with reduction in vitamin D levels.

Vitamin D deficiency is problematic in patients with intestinal malabsorption, including those with bariatric surgeries. Nephrotic syndrome causes increased urinary loss of bound vitamin D.

Multiple medications including corticosteroids, azole antifungals, HIV drugs, and anticonvulsants cause enhanced vitamin D catabolism and increase the risk for vitamin D deficiency.

Patients with lymphomas, granuloma-forming disorders, such as sarcoidosis, certain fungal infections, and tuberculosis have extra-renal metabolism of 25-hydroxy vitamin D to 1,25(OH)D₂ and are at high risk for vitamin D deficiency. They also are at risk of hypercalcemia with vitamin D replacement to sufficiency.

Vitamin D deficiency results in abnormal calcium/phosphate and bone metabolism at intestinal, renal and bone levels.

Implementation

• Prevention: Vitamin D2 or vitamin D3 should be used for the prevention and treatment of vitamin D deficiency.

A dose of at least 600 IU daily of vitamin D is suggested for adults 19-65 years of age, including women who are pregnant and lactating, to maximize bone and muscular function.

At least 800 IU of vitamin D daily is suggested for persons 65 years and older to maximize bone and muscle function and to reduce the risk for falls and associated fractures. The data for this dosing recommendation is stronger than that supporting dosing in younger adults.

Obese adults and those taking anticonvulsants and other medications known to interfere with vitamin D should take doses of vitamin D that are two to three times the dose of their age-matched peers.

These daily allowances may not be sufficient to raise the blood level of 25-OH vitamin D to 30 ng/ml in all persons.

The maximum daily dose of vitamin D which should be taken by adults not under the supervision of a physician, or being treated specifically for vitamin D deficiency is 4000 IU daily.

• Screening: Vitamin D screening should be restricted to patients at increased risk for deficiency. This would include patients with osteoporosis, those with malabsorption syndromes, patients taking medications interfering with vitamin D, those with chronic kidney disease and older adults. The primary circulating form of vitamin D is 25-hydroxy vitamin D and is the recommended test for assessment of deficiency in nearly all patients.

Only patients with chronic kidney disease, and other specific conditions in which vitamin D and phosphate metabolism is altered should be evaluated by 1,25(OH)D₂ level.

• Treatment: Adults who are vitamin D deficient should be treated with 50,000 IU of vitamin D2 [or D3] weekly for 8 weeks with a goal of achieving 25-OH vitamin D levels of 30 ng/ml or above, followed by maintenance therapy to maintain these levels. Alternative dosing strategies are reviewed in the full text guideline.

Evaluation for a cause of vitamin D malabsorption should be considered in patients who are adherent to replacement therapy but in whom the 25-OH vitamin D level does not increase.

Obese patients, those taking medications affecting vitamin D metabolism and those with malabsorption of vitamin D should be treated with replacement doses two- to threefold higher (6,000-10,000 IU daily) to replete their deficiency. They also require higher doses for maintenance therapy.

Patients with extrarenal production of 1,25(OH)D₂ and primary hyperparathyroidism should have serial monitoring of 25-OH vitamin D and calcium during replacement to minimize the risk for hypercalcemia.

Vitamin D receptors are located in many tissues and many potential pleiotropic effects of vitamin D have been noted by researchers, but the data to date are insufficient for firm clinical conclusions about the magnitude of these effects. A number of other questions remain unanswered regarding vitamin D and its effects.

Reference

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline (J. Clin. Endocrinol. Metab. 2011;96:1911-30).

Dr. Golden is professor of medicine and public health and Dr. Hopkins is program director for the internal medicine/pediatrics combined residency program at the University of Arkansas, Little Rock. 

Issues around screening and treatment of vitamin D deficiency have been very controversial in recent years. The Endocrine Society recently published an evidence-based guideline aimed at helping determine who should be screened and receive vitamin D replacement.

Conclusions

The Institute of Medicine recently endorsed the historical definition of vitamin D deficiency as a 25-hydroxy vitamin D level of less than 20 ng/ml, insufficiency as 21-29 ng/ml, and sufficiency as 30-100 ng/ml.

It is estimated that at least 20%, if not a large majority, of community-dwelling seniors in the United States are vitamin D deficient, based on the IOM definition, with a high proportion of younger adults and children also likely to be vitamin D deficient. These estimates are supported by numerous epidemiologic studies in varied populations.

The principal source of vitamin D is exposure to natural sunlight. Dark skin pigmentation and sunscreens with an SPF greater than 30 reduce solar vitamin D synthesis dramatically.

Only a few foods, such as salmon, tuna, and shitake mushrooms, are naturally rich in vitamin D, so vitamin D supplementation is added to a variety of foods in the U.S. and Canada.

Obesity is associated with reduction in vitamin D levels.

Vitamin D deficiency is problematic in patients with intestinal malabsorption, including those with bariatric surgeries. Nephrotic syndrome causes increased urinary loss of bound vitamin D.

Multiple medications including corticosteroids, azole antifungals, HIV drugs, and anticonvulsants cause enhanced vitamin D catabolism and increase the risk for vitamin D deficiency.

Patients with lymphomas, granuloma-forming disorders, such as sarcoidosis, certain fungal infections, and tuberculosis have extra-renal metabolism of 25-hydroxy vitamin D to 1,25(OH)D₂ and are at high risk for vitamin D deficiency. They also are at risk of hypercalcemia with vitamin D replacement to sufficiency.

Vitamin D deficiency results in abnormal calcium/phosphate and bone metabolism at intestinal, renal and bone levels.

Implementation

• Prevention: Vitamin D2 or vitamin D3 should be used for the prevention and treatment of vitamin D deficiency.

A dose of at least 600 IU daily of vitamin D is suggested for adults 19-65 years of age, including women who are pregnant and lactating, to maximize bone and muscular function.

At least 800 IU of vitamin D daily is suggested for persons 65 years and older to maximize bone and muscle function and to reduce the risk for falls and associated fractures. The data for this dosing recommendation is stronger than that supporting dosing in younger adults.

Obese adults and those taking anticonvulsants and other medications known to interfere with vitamin D should take doses of vitamin D that are two to three times the dose of their age-matched peers.

These daily allowances may not be sufficient to raise the blood level of 25-OH vitamin D to 30 ng/ml in all persons.

The maximum daily dose of vitamin D which should be taken by adults not under the supervision of a physician, or being treated specifically for vitamin D deficiency is 4000 IU daily.

• Screening: Vitamin D screening should be restricted to patients at increased risk for deficiency. This would include patients with osteoporosis, those with malabsorption syndromes, patients taking medications interfering with vitamin D, those with chronic kidney disease and older adults. The primary circulating form of vitamin D is 25-hydroxy vitamin D and is the recommended test for assessment of deficiency in nearly all patients.

Only patients with chronic kidney disease, and other specific conditions in which vitamin D and phosphate metabolism is altered should be evaluated by 1,25(OH)D₂ level.

• Treatment: Adults who are vitamin D deficient should be treated with 50,000 IU of vitamin D2 [or D3] weekly for 8 weeks with a goal of achieving 25-OH vitamin D levels of 30 ng/ml or above, followed by maintenance therapy to maintain these levels. Alternative dosing strategies are reviewed in the full text guideline.

Evaluation for a cause of vitamin D malabsorption should be considered in patients who are adherent to replacement therapy but in whom the 25-OH vitamin D level does not increase.

Obese patients, those taking medications affecting vitamin D metabolism and those with malabsorption of vitamin D should be treated with replacement doses two- to threefold higher (6,000-10,000 IU daily) to replete their deficiency. They also require higher doses for maintenance therapy.

Patients with extrarenal production of 1,25(OH)D₂ and primary hyperparathyroidism should have serial monitoring of 25-OH vitamin D and calcium during replacement to minimize the risk for hypercalcemia.

Vitamin D receptors are located in many tissues and many potential pleiotropic effects of vitamin D have been noted by researchers, but the data to date are insufficient for firm clinical conclusions about the magnitude of these effects. A number of other questions remain unanswered regarding vitamin D and its effects.

Reference

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline (J. Clin. Endocrinol. Metab. 2011;96:1911-30).

Dr. Golden is professor of medicine and public health and Dr. Hopkins is program director for the internal medicine/pediatrics combined residency program at the University of Arkansas, Little Rock.