Barbara Rutledge

Management of patients with recurrent Group A β-hemolytic streptococcal infections should include screening the patient's family and intimate contacts in order to identify and treat bacterial carriers, according to Dr. Jack Sobel and his colleagues.

Dr. Sobel of Wayne State University School of Medicine, Detroit, and his associates described two cases of recurrent vulvovaginal infections in adult women caused by Group A β-hemolytic streptococcus (GAS), a pathogenic organism. GAS vulvovaginitis has rarely been reported in adult women. GAS colonization can occur in the vagina, but is more likely in the nasopharynx, perineum, anus, and skin, the investigators wrote (Clin. Infect. Dis. 2007;44:43–5).

Both women reported a history of recurrent episodes of vulvovaginal Streptococcus pyogenes infections presenting with pruritus, vaginal discharge, and erythema. The infections resolved after antibacterial therapy but recurred in a short time.

Screening of the patients' families showed that the husbands were gastrointestinal/perianal carriers of S. pyogenes. For each couple, bacterial typing showed the index strain and carrier strain to be identical.

Reinfection was hypothesized to occur through sexual transmission or contamination of the sheets and mattress from perianal shedding of S. pyogenes.

Antibacterial treatment was given to the women and their male partners. Following eradication of bacterial carriage in the male partner, vaginitis recurrence was finally resolved.

“Carriage or exposure to a carrier is an important pathogenic factor in recurrent GAS infection, although it is often ignored,” wrote the study authors.

They reported no conflicts of interest.

Management of patients with recurrent Group A β-hemolytic streptococcal infections should include screening the patient's family and intimate contacts in order to identify and treat bacterial carriers, according to Dr. Jack Sobel and his colleagues.

Dr. Sobel of Wayne State University School of Medicine, Detroit, and his associates described two cases of recurrent vulvovaginal infections in adult women caused by Group A β-hemolytic streptococcus (GAS), a pathogenic organism. GAS vulvovaginitis has rarely been reported in adult women. GAS colonization can occur in the vagina, but is more likely in the nasopharynx, perineum, anus, and skin, the investigators wrote (Clin. Infect. Dis. 2007;44:43–5).

Both women reported a history of recurrent episodes of vulvovaginal Streptococcus pyogenes infections presenting with pruritus, vaginal discharge, and erythema. The infections resolved after antibacterial therapy but recurred in a short time.

Screening of the patients' families showed that the husbands were gastrointestinal/perianal carriers of S. pyogenes. For each couple, bacterial typing showed the index strain and carrier strain to be identical.

Reinfection was hypothesized to occur through sexual transmission or contamination of the sheets and mattress from perianal shedding of S. pyogenes.

Antibacterial treatment was given to the women and their male partners. Following eradication of bacterial carriage in the male partner, vaginitis recurrence was finally resolved.

“Carriage or exposure to a carrier is an important pathogenic factor in recurrent GAS infection, although it is often ignored,” wrote the study authors.

They reported no conflicts of interest.

Management of patients with recurrent Group A β-hemolytic streptococcal infections should include screening the patient's family and intimate contacts in order to identify and treat bacterial carriers, according to Dr. Jack Sobel and his colleagues.

Dr. Sobel of Wayne State University School of Medicine, Detroit, and his associates described two cases of recurrent vulvovaginal infections in adult women caused by Group A β-hemolytic streptococcus (GAS), a pathogenic organism. GAS vulvovaginitis has rarely been reported in adult women. GAS colonization can occur in the vagina, but is more likely in the nasopharynx, perineum, anus, and skin, the investigators wrote (Clin. Infect. Dis. 2007;44:43–5).

Both women reported a history of recurrent episodes of vulvovaginal Streptococcus pyogenes infections presenting with pruritus, vaginal discharge, and erythema. The infections resolved after antibacterial therapy but recurred in a short time.

Screening of the patients' families showed that the husbands were gastrointestinal/perianal carriers of S. pyogenes. For each couple, bacterial typing showed the index strain and carrier strain to be identical.

Reinfection was hypothesized to occur through sexual transmission or contamination of the sheets and mattress from perianal shedding of S. pyogenes.

Antibacterial treatment was given to the women and their male partners. Following eradication of bacterial carriage in the male partner, vaginitis recurrence was finally resolved.

“Carriage or exposure to a carrier is an important pathogenic factor in recurrent GAS infection, although it is often ignored,” wrote the study authors.

They reported no conflicts of interest.

TAMPA — Vitamin D deficiency is highly prevalent, even in patients whose 25-hydroxyvitamin D levels are within the “normal” range, Dr. Robert P. Heaney said at the annual meeting of the International Society for Clinical Densitometry.

That's because the reference range for serum 25-hydroxyvitamin D (25[OH]D) levels is too low, said Dr. Heaney of Creighton University, Omaha, Neb. “Within the reference range, there is malabsorption of calcium and preventable fractures. These are as much expressions of nutritional deficiency as are the bleeding gums of scurvy.”

The Institute of Medicine reevaluated the nutrient intake recommendations for bone-related nutrients, including vitamin D, in the mid-1990s. The role of vitamin D intake in preventing rickets had long been recognized, and it was known that vitamin D was necessary for calcium absorption. Ten years ago, the unknowns were the vitamin D intake for optimal calcium absorption, possible links between vitamin D and other diseases, and how to determine whether a patient's intake was sufficient.

“We've learned a lot since then,” said Dr. Heaney. “We know that 25(OH)D is the functional status indicator, and we know that at levels below 20 nmol/L or 8 ng/mL, we get rickets and osteomalacia.”

The controversy lies in deciding where the normal range of serum 25(OH)D should be for optimal bone health. Although the low end of the reference range may vary from 38 to 50 nmol/L, an individual is at risk for osteoporosis at serum 25(OH)D levels below 80 nmol/L, according to Dr. Heaney, who argues that normal levels of serum 25(OH)D begin at 80 nmol/L. At levels between 20 and 80 nmol/L, increased bone remodeling, reduced calcium absorption, increased risk of falls, and increased risk of fractures occur.

Individuals might have inadequate vitamin D status even when serum 25(OH)D levels are well within the reference range. A study Dr. Heaney and colleagues conducted assessed serum 25(OH)D levels and calcium absorption in 34 healthy, postmenopausal women. The study showed that women whose serum 25(OH)D levels were at the lower end of the reference range had lower calcium absorption than women with higher levels. The study was conducted over 2 consecutive years in Omaha, in early spring, when serum vitamin D levels would be at their lowest levels.

Participants were given oral 500-mg calcium supplements, and calcium absorption and serum 25(OH)D levels were measured. One year, the participants were predosed with vitamin D supplementation, and the other year, they were not (Am. Coll. Nutr. 2003;22:142–6).

Vitamin D supplementation resulted in an increase in serum 25(OH)D from 50 to 83 nmol/L. Both of those values are considered to be within the reference range, but the two levels had different effects on calcium absorption efficiency.

At the lower serum 25(OH)D level of 50 nmol/L, calcium absorption efficiency was 22%, compared with 37% at the higher serum 25(OH)D level. Higher serum 25(OH)D levels were also associated with higher serum calcium concentrations and decreased serum parathyroid hormone levels.

Other studies have shown higher bone mineral density levels, decreased risk of fractures, or decreased risk of falling with levels of serum 25(OH)D above 80 nmol/L.

“Within the range of 25(OH)D levels commonly encountered, calcium absorption rises as 25(OH)D rises,” said Dr. Heaney. “Raising serum 25(OH)D levels from 50 to [about] 80 nmol/L improves calcium absorption, raises [bone mineral density], and reduces both fall and fracture risk.”

Sources of vitamin D are not equivalent. The high-dose (50,000 IU) vitamin D supplement that is available by prescription is ergocalciferol, or D2, which is less potent than cholecalciferol, or D3. Over-the-counter preparations of vitamin D in the form of cholecalciferol are available at lower doses.

A typical over-the-counter vitamin D supplement might contain 400 IU, but supplementation to increase serum 25(OH)D levels within an effective range usually requires much higher doses. Intake of 1,000 IU of vitamin D raises serum 25(OH)D by approximately 15–25 nmol/L.

In studies conducted by Dr. Heaney, dosages of 5,000–10,000 IU/day for a 4- to 5-month period in healthy adults have not caused elevated calcium levels in serum or urine. Vitamin D dosages in that range produce serum 25(OH)D levels comparable to those seen in outdoor workers at summer's end.

Vitamin D intoxication should not be an issue unless the individual has regular dosages in excess of 10,000 IU per day.

“Our conclusion is that the safe upper limit level ought to be 10,000 IU per day,” said Dr. Heaney. “I don't think many people would ever need that much, but it is nice to know that there is a therapeutic margin of safety.”

TAMPA — Vitamin D deficiency is highly prevalent, even in patients whose 25-hydroxyvitamin D levels are within the “normal” range, Dr. Robert P. Heaney said at the annual meeting of the International Society for Clinical Densitometry.

That's because the reference range for serum 25-hydroxyvitamin D (25[OH]D) levels is too low, said Dr. Heaney of Creighton University, Omaha, Neb. “Within the reference range, there is malabsorption of calcium and preventable fractures. These are as much expressions of nutritional deficiency as are the bleeding gums of scurvy.”

The Institute of Medicine reevaluated the nutrient intake recommendations for bone-related nutrients, including vitamin D, in the mid-1990s. The role of vitamin D intake in preventing rickets had long been recognized, and it was known that vitamin D was necessary for calcium absorption. Ten years ago, the unknowns were the vitamin D intake for optimal calcium absorption, possible links between vitamin D and other diseases, and how to determine whether a patient's intake was sufficient.

“We've learned a lot since then,” said Dr. Heaney. “We know that 25(OH)D is the functional status indicator, and we know that at levels below 20 nmol/L or 8 ng/mL, we get rickets and osteomalacia.”

The controversy lies in deciding where the normal range of serum 25(OH)D should be for optimal bone health. Although the low end of the reference range may vary from 38 to 50 nmol/L, an individual is at risk for osteoporosis at serum 25(OH)D levels below 80 nmol/L, according to Dr. Heaney, who argues that normal levels of serum 25(OH)D begin at 80 nmol/L. At levels between 20 and 80 nmol/L, increased bone remodeling, reduced calcium absorption, increased risk of falls, and increased risk of fractures occur.

Individuals might have inadequate vitamin D status even when serum 25(OH)D levels are well within the reference range. A study Dr. Heaney and colleagues conducted assessed serum 25(OH)D levels and calcium absorption in 34 healthy, postmenopausal women. The study showed that women whose serum 25(OH)D levels were at the lower end of the reference range had lower calcium absorption than women with higher levels. The study was conducted over 2 consecutive years in Omaha, in early spring, when serum vitamin D levels would be at their lowest levels.

Participants were given oral 500-mg calcium supplements, and calcium absorption and serum 25(OH)D levels were measured. One year, the participants were predosed with vitamin D supplementation, and the other year, they were not (Am. Coll. Nutr. 2003;22:142–6).

Vitamin D supplementation resulted in an increase in serum 25(OH)D from 50 to 83 nmol/L. Both of those values are considered to be within the reference range, but the two levels had different effects on calcium absorption efficiency.

At the lower serum 25(OH)D level of 50 nmol/L, calcium absorption efficiency was 22%, compared with 37% at the higher serum 25(OH)D level. Higher serum 25(OH)D levels were also associated with higher serum calcium concentrations and decreased serum parathyroid hormone levels.

Other studies have shown higher bone mineral density levels, decreased risk of fractures, or decreased risk of falling with levels of serum 25(OH)D above 80 nmol/L.

“Within the range of 25(OH)D levels commonly encountered, calcium absorption rises as 25(OH)D rises,” said Dr. Heaney. “Raising serum 25(OH)D levels from 50 to [about] 80 nmol/L improves calcium absorption, raises [bone mineral density], and reduces both fall and fracture risk.”

Sources of vitamin D are not equivalent. The high-dose (50,000 IU) vitamin D supplement that is available by prescription is ergocalciferol, or D2, which is less potent than cholecalciferol, or D3. Over-the-counter preparations of vitamin D in the form of cholecalciferol are available at lower doses.

A typical over-the-counter vitamin D supplement might contain 400 IU, but supplementation to increase serum 25(OH)D levels within an effective range usually requires much higher doses. Intake of 1,000 IU of vitamin D raises serum 25(OH)D by approximately 15–25 nmol/L.

In studies conducted by Dr. Heaney, dosages of 5,000–10,000 IU/day for a 4- to 5-month period in healthy adults have not caused elevated calcium levels in serum or urine. Vitamin D dosages in that range produce serum 25(OH)D levels comparable to those seen in outdoor workers at summer's end.

Vitamin D intoxication should not be an issue unless the individual has regular dosages in excess of 10,000 IU per day.

“Our conclusion is that the safe upper limit level ought to be 10,000 IU per day,” said Dr. Heaney. “I don't think many people would ever need that much, but it is nice to know that there is a therapeutic margin of safety.”

TAMPA — Vitamin D deficiency is highly prevalent, even in patients whose 25-hydroxyvitamin D levels are within the “normal” range, Dr. Robert P. Heaney said at the annual meeting of the International Society for Clinical Densitometry.

That's because the reference range for serum 25-hydroxyvitamin D (25[OH]D) levels is too low, said Dr. Heaney of Creighton University, Omaha, Neb. “Within the reference range, there is malabsorption of calcium and preventable fractures. These are as much expressions of nutritional deficiency as are the bleeding gums of scurvy.”

The Institute of Medicine reevaluated the nutrient intake recommendations for bone-related nutrients, including vitamin D, in the mid-1990s. The role of vitamin D intake in preventing rickets had long been recognized, and it was known that vitamin D was necessary for calcium absorption. Ten years ago, the unknowns were the vitamin D intake for optimal calcium absorption, possible links between vitamin D and other diseases, and how to determine whether a patient's intake was sufficient.

“We've learned a lot since then,” said Dr. Heaney. “We know that 25(OH)D is the functional status indicator, and we know that at levels below 20 nmol/L or 8 ng/mL, we get rickets and osteomalacia.”

The controversy lies in deciding where the normal range of serum 25(OH)D should be for optimal bone health. Although the low end of the reference range may vary from 38 to 50 nmol/L, an individual is at risk for osteoporosis at serum 25(OH)D levels below 80 nmol/L, according to Dr. Heaney, who argues that normal levels of serum 25(OH)D begin at 80 nmol/L. At levels between 20 and 80 nmol/L, increased bone remodeling, reduced calcium absorption, increased risk of falls, and increased risk of fractures occur.

Individuals might have inadequate vitamin D status even when serum 25(OH)D levels are well within the reference range. A study Dr. Heaney and colleagues conducted assessed serum 25(OH)D levels and calcium absorption in 34 healthy, postmenopausal women. The study showed that women whose serum 25(OH)D levels were at the lower end of the reference range had lower calcium absorption than women with higher levels. The study was conducted over 2 consecutive years in Omaha, in early spring, when serum vitamin D levels would be at their lowest levels.

Participants were given oral 500-mg calcium supplements, and calcium absorption and serum 25(OH)D levels were measured. One year, the participants were predosed with vitamin D supplementation, and the other year, they were not (Am. Coll. Nutr. 2003;22:142–6).

Vitamin D supplementation resulted in an increase in serum 25(OH)D from 50 to 83 nmol/L. Both of those values are considered to be within the reference range, but the two levels had different effects on calcium absorption efficiency.

At the lower serum 25(OH)D level of 50 nmol/L, calcium absorption efficiency was 22%, compared with 37% at the higher serum 25(OH)D level. Higher serum 25(OH)D levels were also associated with higher serum calcium concentrations and decreased serum parathyroid hormone levels.

Other studies have shown higher bone mineral density levels, decreased risk of fractures, or decreased risk of falling with levels of serum 25(OH)D above 80 nmol/L.

“Within the range of 25(OH)D levels commonly encountered, calcium absorption rises as 25(OH)D rises,” said Dr. Heaney. “Raising serum 25(OH)D levels from 50 to [about] 80 nmol/L improves calcium absorption, raises [bone mineral density], and reduces both fall and fracture risk.”

Sources of vitamin D are not equivalent. The high-dose (50,000 IU) vitamin D supplement that is available by prescription is ergocalciferol, or D2, which is less potent than cholecalciferol, or D3. Over-the-counter preparations of vitamin D in the form of cholecalciferol are available at lower doses.

A typical over-the-counter vitamin D supplement might contain 400 IU, but supplementation to increase serum 25(OH)D levels within an effective range usually requires much higher doses. Intake of 1,000 IU of vitamin D raises serum 25(OH)D by approximately 15–25 nmol/L.

In studies conducted by Dr. Heaney, dosages of 5,000–10,000 IU/day for a 4- to 5-month period in healthy adults have not caused elevated calcium levels in serum or urine. Vitamin D dosages in that range produce serum 25(OH)D levels comparable to those seen in outdoor workers at summer's end.

Vitamin D intoxication should not be an issue unless the individual has regular dosages in excess of 10,000 IU per day.

“Our conclusion is that the safe upper limit level ought to be 10,000 IU per day,” said Dr. Heaney. “I don't think many people would ever need that much, but it is nice to know that there is a therapeutic margin of safety.”

MENDOZA, ARGENTINA – Two promising pharmacotherapies are currently in clinical trials for treatment of cocaine dependence: disulfiram and a vaccine consisting of a cocaine-cholera toxin complex, Dr. Thomas Kosten said at the Sixth World Congress of Depressive Disorders.

Cocaine blocks the reuptake of dopamine, and after chronic abuse it causes a reduction in the number of postsynaptic dopamine receptors and eventually leads to damage of dopamine-responsive cells in the brain, said Dr. Kosten, professor of psychiatry and neuroscience at Baylor College of Medicine, Houston.

Neuroimaging studies show visible changes in the brain after abuse of amphetamines or cocaine, with a noticeable decrease in the number of dopamine-responding cells. Changes persist even after cocaine use has stopped.

“We have done these imaging studies out to 18 months after stopping cocaine and have shown no restoration in function,” he said. “It appears that these may be very long-term and relatively irreversible changes.”

Disulfiram (Antabuse) may improve this dopamine-deficient state, particularly in people with genetically low levels of the enzyme dopamine beta-hydroxylase, which converts dopamine to norepinephrine. Norepinephrine is associated with withdrawal symptoms, and dopamine is associated with reward from normal activities as well as from drug abuse. Disulfiram inhibits dopamine beta-hydroxylase, causing cells to release dopamine rather than norepinephrine. In seven placebo-controlled, double-blind studies involving more than 700 patients, disulfiram produced considerably better results than did placebo: up to 55% of urine samples were cocaine free in the disulfiram group, compared with about 40% in the placebo group.

“This is an effect size equivalent to what's seen in antidepressants for treating depression or standard antipsychotic agents for treating schizophrenia,” Dr. Kosten said.

The increased amount of dopamine appears to change the acute effects induced by cocaine. Ordinarily, someone smoking cocaine will get euphoria followed by increased craving for cocaine, but disulfiram markedly reduces the craving induced after cocaine is given.

Several minutes after the euphoria abates, the individual is likely to experience cocaine-induced dysphoria, with feelings of nervousness and paranoia that may last for more than an hour. Disulfiram has the dual effect of diminishing the craving and enhancing the negative feelings associated with cocaine use, he said.

Some people experience significantly more nervousness and paranoia when taking disulfiram with cocaine. Genetic mapping has suggested that people who experience disulfiram-induced dysphoria have a dominant mutation in a gene leading to the synthesis of dopamine beta-hydroxylase, a mutation that results in abnormally low enzyme levels. Thus, the dual action of disulfiram has therapeutic implications, particularly in abusers with abnormally low levels of dopamine beta-hydroxylase, who showed the best response to disulfiram treatment, Dr. Kosten said.

The vaccine approach targets the drug itself rather than the receptor. The cocaine molecule is too small to provoke an immunologic response on its own, so the vaccine consists of a complex of cocaine attached to the cholera toxin molecule. Antibodies generated to the cocaine-cholera toxin complex bind to cocaine, trapping it in the bloodstream and preventing its entry into the brain.

Several clinical trials have been conducted, and the vaccine appears to be safe and well tolerated. The most effective dosage is a high dose of the vaccine given five times over a period of 3 months. High levels of antibodies are necessary for a therapeutic effect. The vaccine blockade can be overridden, but three- to fourfold higher levels of cocaine are required for the drug user to feel the “normal” response to cocaine, Dr. Kosten said.

In clinical trials, about 75% of subjects appeared to have an effective antibody response. Subjects who received the vaccine had a significantly higher proportion of cocaine-free urines, compared with baseline, than did subjects who received placebo.

“We will move into phase III [Food and Drug Administration] approval studies in the next year or so, with the hope that this vaccine might be available in 2 or 3 years,” he said.

Dr. Kosten reported no conflicts of interest. He does not hold stock in Celtic Pharma, the company developing the vaccine. His studies have been supported by the National Institute on Drug Abuse.

Celtic Pharma has supplied vaccine and has conducted independent monitoring of the clinical trials for potential FDA submission.

MENDOZA, ARGENTINA – Two promising pharmacotherapies are currently in clinical trials for treatment of cocaine dependence: disulfiram and a vaccine consisting of a cocaine-cholera toxin complex, Dr. Thomas Kosten said at the Sixth World Congress of Depressive Disorders.

Cocaine blocks the reuptake of dopamine, and after chronic abuse it causes a reduction in the number of postsynaptic dopamine receptors and eventually leads to damage of dopamine-responsive cells in the brain, said Dr. Kosten, professor of psychiatry and neuroscience at Baylor College of Medicine, Houston.

Neuroimaging studies show visible changes in the brain after abuse of amphetamines or cocaine, with a noticeable decrease in the number of dopamine-responding cells. Changes persist even after cocaine use has stopped.

“We have done these imaging studies out to 18 months after stopping cocaine and have shown no restoration in function,” he said. “It appears that these may be very long-term and relatively irreversible changes.”

Disulfiram (Antabuse) may improve this dopamine-deficient state, particularly in people with genetically low levels of the enzyme dopamine beta-hydroxylase, which converts dopamine to norepinephrine. Norepinephrine is associated with withdrawal symptoms, and dopamine is associated with reward from normal activities as well as from drug abuse. Disulfiram inhibits dopamine beta-hydroxylase, causing cells to release dopamine rather than norepinephrine. In seven placebo-controlled, double-blind studies involving more than 700 patients, disulfiram produced considerably better results than did placebo: up to 55% of urine samples were cocaine free in the disulfiram group, compared with about 40% in the placebo group.

“This is an effect size equivalent to what's seen in antidepressants for treating depression or standard antipsychotic agents for treating schizophrenia,” Dr. Kosten said.

The increased amount of dopamine appears to change the acute effects induced by cocaine. Ordinarily, someone smoking cocaine will get euphoria followed by increased craving for cocaine, but disulfiram markedly reduces the craving induced after cocaine is given.

Several minutes after the euphoria abates, the individual is likely to experience cocaine-induced dysphoria, with feelings of nervousness and paranoia that may last for more than an hour. Disulfiram has the dual effect of diminishing the craving and enhancing the negative feelings associated with cocaine use, he said.

Some people experience significantly more nervousness and paranoia when taking disulfiram with cocaine. Genetic mapping has suggested that people who experience disulfiram-induced dysphoria have a dominant mutation in a gene leading to the synthesis of dopamine beta-hydroxylase, a mutation that results in abnormally low enzyme levels. Thus, the dual action of disulfiram has therapeutic implications, particularly in abusers with abnormally low levels of dopamine beta-hydroxylase, who showed the best response to disulfiram treatment, Dr. Kosten said.

The vaccine approach targets the drug itself rather than the receptor. The cocaine molecule is too small to provoke an immunologic response on its own, so the vaccine consists of a complex of cocaine attached to the cholera toxin molecule. Antibodies generated to the cocaine-cholera toxin complex bind to cocaine, trapping it in the bloodstream and preventing its entry into the brain.

Several clinical trials have been conducted, and the vaccine appears to be safe and well tolerated. The most effective dosage is a high dose of the vaccine given five times over a period of 3 months. High levels of antibodies are necessary for a therapeutic effect. The vaccine blockade can be overridden, but three- to fourfold higher levels of cocaine are required for the drug user to feel the “normal” response to cocaine, Dr. Kosten said.

In clinical trials, about 75% of subjects appeared to have an effective antibody response. Subjects who received the vaccine had a significantly higher proportion of cocaine-free urines, compared with baseline, than did subjects who received placebo.

“We will move into phase III [Food and Drug Administration] approval studies in the next year or so, with the hope that this vaccine might be available in 2 or 3 years,” he said.

Dr. Kosten reported no conflicts of interest. He does not hold stock in Celtic Pharma, the company developing the vaccine. His studies have been supported by the National Institute on Drug Abuse.

Celtic Pharma has supplied vaccine and has conducted independent monitoring of the clinical trials for potential FDA submission.

MENDOZA, ARGENTINA – Two promising pharmacotherapies are currently in clinical trials for treatment of cocaine dependence: disulfiram and a vaccine consisting of a cocaine-cholera toxin complex, Dr. Thomas Kosten said at the Sixth World Congress of Depressive Disorders.

Cocaine blocks the reuptake of dopamine, and after chronic abuse it causes a reduction in the number of postsynaptic dopamine receptors and eventually leads to damage of dopamine-responsive cells in the brain, said Dr. Kosten, professor of psychiatry and neuroscience at Baylor College of Medicine, Houston.

Neuroimaging studies show visible changes in the brain after abuse of amphetamines or cocaine, with a noticeable decrease in the number of dopamine-responding cells. Changes persist even after cocaine use has stopped.

“We have done these imaging studies out to 18 months after stopping cocaine and have shown no restoration in function,” he said. “It appears that these may be very long-term and relatively irreversible changes.”

Disulfiram (Antabuse) may improve this dopamine-deficient state, particularly in people with genetically low levels of the enzyme dopamine beta-hydroxylase, which converts dopamine to norepinephrine. Norepinephrine is associated with withdrawal symptoms, and dopamine is associated with reward from normal activities as well as from drug abuse. Disulfiram inhibits dopamine beta-hydroxylase, causing cells to release dopamine rather than norepinephrine. In seven placebo-controlled, double-blind studies involving more than 700 patients, disulfiram produced considerably better results than did placebo: up to 55% of urine samples were cocaine free in the disulfiram group, compared with about 40% in the placebo group.

“This is an effect size equivalent to what's seen in antidepressants for treating depression or standard antipsychotic agents for treating schizophrenia,” Dr. Kosten said.

The increased amount of dopamine appears to change the acute effects induced by cocaine. Ordinarily, someone smoking cocaine will get euphoria followed by increased craving for cocaine, but disulfiram markedly reduces the craving induced after cocaine is given.

Several minutes after the euphoria abates, the individual is likely to experience cocaine-induced dysphoria, with feelings of nervousness and paranoia that may last for more than an hour. Disulfiram has the dual effect of diminishing the craving and enhancing the negative feelings associated with cocaine use, he said.

Some people experience significantly more nervousness and paranoia when taking disulfiram with cocaine. Genetic mapping has suggested that people who experience disulfiram-induced dysphoria have a dominant mutation in a gene leading to the synthesis of dopamine beta-hydroxylase, a mutation that results in abnormally low enzyme levels. Thus, the dual action of disulfiram has therapeutic implications, particularly in abusers with abnormally low levels of dopamine beta-hydroxylase, who showed the best response to disulfiram treatment, Dr. Kosten said.

The vaccine approach targets the drug itself rather than the receptor. The cocaine molecule is too small to provoke an immunologic response on its own, so the vaccine consists of a complex of cocaine attached to the cholera toxin molecule. Antibodies generated to the cocaine-cholera toxin complex bind to cocaine, trapping it in the bloodstream and preventing its entry into the brain.

Several clinical trials have been conducted, and the vaccine appears to be safe and well tolerated. The most effective dosage is a high dose of the vaccine given five times over a period of 3 months. High levels of antibodies are necessary for a therapeutic effect. The vaccine blockade can be overridden, but three- to fourfold higher levels of cocaine are required for the drug user to feel the “normal” response to cocaine, Dr. Kosten said.

In clinical trials, about 75% of subjects appeared to have an effective antibody response. Subjects who received the vaccine had a significantly higher proportion of cocaine-free urines, compared with baseline, than did subjects who received placebo.

“We will move into phase III [Food and Drug Administration] approval studies in the next year or so, with the hope that this vaccine might be available in 2 or 3 years,” he said.

Dr. Kosten reported no conflicts of interest. He does not hold stock in Celtic Pharma, the company developing the vaccine. His studies have been supported by the National Institute on Drug Abuse.

Celtic Pharma has supplied vaccine and has conducted independent monitoring of the clinical trials for potential FDA submission.

Acquired resistance against activated protein C may play a key role in increasing the risk of thrombosis in patients with systemic lupus erythematosus, reported Dr. Eelco Meesters of Slotervaart Hospital in Amsterdam and colleagues.

Compared with the general population, patients with systemic lupus erythematosus (SLE) experience a higher incidence of venous thromboembolism, but the underlying mechanism leading to increased risk has not been well defined. Predicting which SLE patients are at greatest risk has been challenging. “An APC [activated protein C] resistance assay may provide an important tool for risk stratification,” wrote Dr. Meesters, “but this assumption needs to be tested in prospective studies.”

Dr. Meesters and colleagues hypothesized that molecular cross talk between inflammatory pathways and coagulation pathways could be a mechanism underlying the increased risk of arterial and venous thrombosis in patients with SLE. They designed a case-control study to examine the profiles of markers of inflammation, endothelial cell condition, and blood coagulation in patients with SLE versus healthy individuals without SLE, matched for age and gender (Blood Coagul. Fibrinolysis 2007;18:21–8).

In the study, 25 women with SLE (mean age 41.7 years) were matched with 25 healthy women (mean age 41.4 years). As expected, the SLE patients had significantly higher levels of chronic inflammatory mediators, such as C-reactive protein and interleukin-6, and had higher erythrocyte sedimentation rates, compared with controls. Levels of soluble vascular cell adhesion molecule (VCAM)-1 were significantly higher in SLE patients than in controls, but the two groups showed no significant differences in E-selectin or von Willebrand's factor, both markers of endothelial cell activation. Cases and controls were comparable in leukocyte count, hemoglobin level, and cholesterol levels, including total cholesterol, HDL cholesterol, and LDL cholesterol.

The two groups showed significant differences in protein S, a glycoprotein that plays a key role in coagulation. Protein S circulates in human plasma in both a bound state and a free state. In the bound state, protein S interacts in the complement pathway, forming a tight complex with C4b-binding protein. In the free state, protein S functions as an essential cofactor of APC, facilitating the inactivation of coagulation factors Va and VIIIa. Genetic deficiencies in protein S increase the risk of thrombosis, with venous thromboembolism being the primary clinical manifestation of the genetic disorder.

Free protein S levels were significantly lower in SLE patients, compared with controls (68% plus or minus 19 vs. 90% plus or minus 16; P <.001), although total protein S levels were comparable in the two groups (107% plus or minus 30 vs. 113% plus or minus 19), ruling out the possibility of a genetic deficiency in protein S in SLE patients.

One likely explanation of the low levels of free protein S in SLE patients compared with controls is that the SLE patients had elevated levels of C4b-binding protein, as previous studies had demonstrated. Higher levels of C4b-binding protein would lead to a greater proportion of total protein S sequestered in the bound form. Thus, the effect on the coagulation pathway would be a decrease in the amount of free protein S available to function as an APC cofactor in anticoagulant activities.

APC resistance, defined as a poor response to the anticoagulant activity of APC, leads to a hypercoagulable state that puts the individual at increased risk for venous thromboembolism. APC resistance can be genetic, resulting from factor V Leiden mutation, or acquired. Resistance to APC was measured using both an endogenous thrombin potential-based (ETP-based) assay and an activated partial thromboplastin time-based (aPTT-based) assay. With each assay, normalized APC sensitivity ratios were significantly different between the cases and controls, indicating APC resistance in the SLE patients.

“Apparently this increased APC resistance is due to acquired factors in the plasma from SLE patients,” wrote Dr. Meesters. “The combination of a lowered free protein S level, subsequent to inflammatory activity and raised C4b-binding protein, and to antiphospholipid antibodies, are most probably responsible for this acquired thrombophilic phenotype.”

Acquired resistance against activated protein C may play a key role in increasing the risk of thrombosis in patients with systemic lupus erythematosus, reported Dr. Eelco Meesters of Slotervaart Hospital in Amsterdam and colleagues.

Compared with the general population, patients with systemic lupus erythematosus (SLE) experience a higher incidence of venous thromboembolism, but the underlying mechanism leading to increased risk has not been well defined. Predicting which SLE patients are at greatest risk has been challenging. “An APC [activated protein C] resistance assay may provide an important tool for risk stratification,” wrote Dr. Meesters, “but this assumption needs to be tested in prospective studies.”

Dr. Meesters and colleagues hypothesized that molecular cross talk between inflammatory pathways and coagulation pathways could be a mechanism underlying the increased risk of arterial and venous thrombosis in patients with SLE. They designed a case-control study to examine the profiles of markers of inflammation, endothelial cell condition, and blood coagulation in patients with SLE versus healthy individuals without SLE, matched for age and gender (Blood Coagul. Fibrinolysis 2007;18:21–8).

In the study, 25 women with SLE (mean age 41.7 years) were matched with 25 healthy women (mean age 41.4 years). As expected, the SLE patients had significantly higher levels of chronic inflammatory mediators, such as C-reactive protein and interleukin-6, and had higher erythrocyte sedimentation rates, compared with controls. Levels of soluble vascular cell adhesion molecule (VCAM)-1 were significantly higher in SLE patients than in controls, but the two groups showed no significant differences in E-selectin or von Willebrand's factor, both markers of endothelial cell activation. Cases and controls were comparable in leukocyte count, hemoglobin level, and cholesterol levels, including total cholesterol, HDL cholesterol, and LDL cholesterol.

The two groups showed significant differences in protein S, a glycoprotein that plays a key role in coagulation. Protein S circulates in human plasma in both a bound state and a free state. In the bound state, protein S interacts in the complement pathway, forming a tight complex with C4b-binding protein. In the free state, protein S functions as an essential cofactor of APC, facilitating the inactivation of coagulation factors Va and VIIIa. Genetic deficiencies in protein S increase the risk of thrombosis, with venous thromboembolism being the primary clinical manifestation of the genetic disorder.

Free protein S levels were significantly lower in SLE patients, compared with controls (68% plus or minus 19 vs. 90% plus or minus 16; P <.001), although total protein S levels were comparable in the two groups (107% plus or minus 30 vs. 113% plus or minus 19), ruling out the possibility of a genetic deficiency in protein S in SLE patients.

One likely explanation of the low levels of free protein S in SLE patients compared with controls is that the SLE patients had elevated levels of C4b-binding protein, as previous studies had demonstrated. Higher levels of C4b-binding protein would lead to a greater proportion of total protein S sequestered in the bound form. Thus, the effect on the coagulation pathway would be a decrease in the amount of free protein S available to function as an APC cofactor in anticoagulant activities.

APC resistance, defined as a poor response to the anticoagulant activity of APC, leads to a hypercoagulable state that puts the individual at increased risk for venous thromboembolism. APC resistance can be genetic, resulting from factor V Leiden mutation, or acquired. Resistance to APC was measured using both an endogenous thrombin potential-based (ETP-based) assay and an activated partial thromboplastin time-based (aPTT-based) assay. With each assay, normalized APC sensitivity ratios were significantly different between the cases and controls, indicating APC resistance in the SLE patients.

“Apparently this increased APC resistance is due to acquired factors in the plasma from SLE patients,” wrote Dr. Meesters. “The combination of a lowered free protein S level, subsequent to inflammatory activity and raised C4b-binding protein, and to antiphospholipid antibodies, are most probably responsible for this acquired thrombophilic phenotype.”

Acquired resistance against activated protein C may play a key role in increasing the risk of thrombosis in patients with systemic lupus erythematosus, reported Dr. Eelco Meesters of Slotervaart Hospital in Amsterdam and colleagues.

Compared with the general population, patients with systemic lupus erythematosus (SLE) experience a higher incidence of venous thromboembolism, but the underlying mechanism leading to increased risk has not been well defined. Predicting which SLE patients are at greatest risk has been challenging. “An APC [activated protein C] resistance assay may provide an important tool for risk stratification,” wrote Dr. Meesters, “but this assumption needs to be tested in prospective studies.”

Dr. Meesters and colleagues hypothesized that molecular cross talk between inflammatory pathways and coagulation pathways could be a mechanism underlying the increased risk of arterial and venous thrombosis in patients with SLE. They designed a case-control study to examine the profiles of markers of inflammation, endothelial cell condition, and blood coagulation in patients with SLE versus healthy individuals without SLE, matched for age and gender (Blood Coagul. Fibrinolysis 2007;18:21–8).

In the study, 25 women with SLE (mean age 41.7 years) were matched with 25 healthy women (mean age 41.4 years). As expected, the SLE patients had significantly higher levels of chronic inflammatory mediators, such as C-reactive protein and interleukin-6, and had higher erythrocyte sedimentation rates, compared with controls. Levels of soluble vascular cell adhesion molecule (VCAM)-1 were significantly higher in SLE patients than in controls, but the two groups showed no significant differences in E-selectin or von Willebrand's factor, both markers of endothelial cell activation. Cases and controls were comparable in leukocyte count, hemoglobin level, and cholesterol levels, including total cholesterol, HDL cholesterol, and LDL cholesterol.

The two groups showed significant differences in protein S, a glycoprotein that plays a key role in coagulation. Protein S circulates in human plasma in both a bound state and a free state. In the bound state, protein S interacts in the complement pathway, forming a tight complex with C4b-binding protein. In the free state, protein S functions as an essential cofactor of APC, facilitating the inactivation of coagulation factors Va and VIIIa. Genetic deficiencies in protein S increase the risk of thrombosis, with venous thromboembolism being the primary clinical manifestation of the genetic disorder.

Free protein S levels were significantly lower in SLE patients, compared with controls (68% plus or minus 19 vs. 90% plus or minus 16; P <.001), although total protein S levels were comparable in the two groups (107% plus or minus 30 vs. 113% plus or minus 19), ruling out the possibility of a genetic deficiency in protein S in SLE patients.

One likely explanation of the low levels of free protein S in SLE patients compared with controls is that the SLE patients had elevated levels of C4b-binding protein, as previous studies had demonstrated. Higher levels of C4b-binding protein would lead to a greater proportion of total protein S sequestered in the bound form. Thus, the effect on the coagulation pathway would be a decrease in the amount of free protein S available to function as an APC cofactor in anticoagulant activities.

APC resistance, defined as a poor response to the anticoagulant activity of APC, leads to a hypercoagulable state that puts the individual at increased risk for venous thromboembolism. APC resistance can be genetic, resulting from factor V Leiden mutation, or acquired. Resistance to APC was measured using both an endogenous thrombin potential-based (ETP-based) assay and an activated partial thromboplastin time-based (aPTT-based) assay. With each assay, normalized APC sensitivity ratios were significantly different between the cases and controls, indicating APC resistance in the SLE patients.

“Apparently this increased APC resistance is due to acquired factors in the plasma from SLE patients,” wrote Dr. Meesters. “The combination of a lowered free protein S level, subsequent to inflammatory activity and raised C4b-binding protein, and to antiphospholipid antibodies, are most probably responsible for this acquired thrombophilic phenotype.”

Reduced use of benzodiazepines in elderly patients does not necessarily result in a lower incidence of hip fracture, according to a study by Anita Wagner, Pharm.D., of the department of ambulatory care and prevention at Harvard Medical School, Boston, and her colleagues.

The researchers found no significant difference in the incidence of hip fracture over a 3-year period between elderly Medicaid recipients in New York, where benzodiazepine use decreased sharply during the study period, and in New Jersey, where benzodiazepine use remained constant.

“Benzodiazepines may not actually be associated with hip fractures, or at least not to the extent reported in some studies,” Dr. Wagner and her colleagues wrote (Ann. Intern. Med. 2007;146:96–103).

The Prescription Drug Improvement and Modernization Act that went into effect in January 2006 further restricted benzodiazepine prescription coverage for Medicare recipients. Federal policy makers may have expected that reduced benzodiazepine access would decrease hip fracture risk and improve quality of life in the elderly.

Earlier data had suggested benzodiazepine use might raise the risk of hip fracture in elderly patients, with postural imbalance associated with benzodiazepine use, possibly leading to more falls and hip fractures in a population already at risk for hip fracture. But studies seeking to document a direct link have yielded conflicting results.

Since 1989, physicians in New York have been required to use serially numbered, triplicate forms for benzodiazepine prescriptions, with the third copy to be forwarded by the pharmacy to the state health authorities.

The study compared the risk of hip fractures in 1988 cohorts of 51,529 elderly Medicaid recipients in New York and 42,029 recipients in New Jersey, where the prescription policy was unchanged.

In New York, the change in prescription policy led to an abrupt decline in the drug's use, decreasing from about 40% of Medicaid enrollees each month in the 12-month period before the policy change to about 15% during the 21 months after the policy change. The drug's use in New Jersey Medicaid enrollees did not change significantly.

In New York, a total of 199 hip fractures occurred in female benzodiazepine recipients over the 33-month study period, with an increase in hazard rate from 53 per 100,000 enrollees before the policy change to 72 per 100,000 enrollees after the policy change.

In New Jersey, 135 hip fractures occurred in female benzodiazepine recipients in the study period, with a similar increase in hazard rate from 42 per 100,000 enrollees to 58 per 100,000 enrollees.

A total of 30 hip fractures in male benzodiazepine recipients in New York occurred over the study period, with the hazard rate increasing from 38 per 100,000 enrollees before the policy change to 54 per 100,000 enrollees after the policy change.

New Jersey results were similar, with a total of 27 hip fractures among male benzodiazepine recipients and an increase in hazard rate from 48 per 100,000 enrollees before the policy change in New York to 52 per 100,000 enrollees. In each case, hazard rates among benzodiazepine nonrecipients were similar.

Reduced use of benzodiazepines in elderly patients does not necessarily result in a lower incidence of hip fracture, according to a study by Anita Wagner, Pharm.D., of the department of ambulatory care and prevention at Harvard Medical School, Boston, and her colleagues.

The researchers found no significant difference in the incidence of hip fracture over a 3-year period between elderly Medicaid recipients in New York, where benzodiazepine use decreased sharply during the study period, and in New Jersey, where benzodiazepine use remained constant.

“Benzodiazepines may not actually be associated with hip fractures, or at least not to the extent reported in some studies,” Dr. Wagner and her colleagues wrote (Ann. Intern. Med. 2007;146:96–103).

The Prescription Drug Improvement and Modernization Act that went into effect in January 2006 further restricted benzodiazepine prescription coverage for Medicare recipients. Federal policy makers may have expected that reduced benzodiazepine access would decrease hip fracture risk and improve quality of life in the elderly.

Earlier data had suggested benzodiazepine use might raise the risk of hip fracture in elderly patients, with postural imbalance associated with benzodiazepine use, possibly leading to more falls and hip fractures in a population already at risk for hip fracture. But studies seeking to document a direct link have yielded conflicting results.

Since 1989, physicians in New York have been required to use serially numbered, triplicate forms for benzodiazepine prescriptions, with the third copy to be forwarded by the pharmacy to the state health authorities.

The study compared the risk of hip fractures in 1988 cohorts of 51,529 elderly Medicaid recipients in New York and 42,029 recipients in New Jersey, where the prescription policy was unchanged.

In New York, the change in prescription policy led to an abrupt decline in the drug's use, decreasing from about 40% of Medicaid enrollees each month in the 12-month period before the policy change to about 15% during the 21 months after the policy change. The drug's use in New Jersey Medicaid enrollees did not change significantly.

In New York, a total of 199 hip fractures occurred in female benzodiazepine recipients over the 33-month study period, with an increase in hazard rate from 53 per 100,000 enrollees before the policy change to 72 per 100,000 enrollees after the policy change.

In New Jersey, 135 hip fractures occurred in female benzodiazepine recipients in the study period, with a similar increase in hazard rate from 42 per 100,000 enrollees to 58 per 100,000 enrollees.

A total of 30 hip fractures in male benzodiazepine recipients in New York occurred over the study period, with the hazard rate increasing from 38 per 100,000 enrollees before the policy change to 54 per 100,000 enrollees after the policy change.

New Jersey results were similar, with a total of 27 hip fractures among male benzodiazepine recipients and an increase in hazard rate from 48 per 100,000 enrollees before the policy change in New York to 52 per 100,000 enrollees. In each case, hazard rates among benzodiazepine nonrecipients were similar.

Reduced use of benzodiazepines in elderly patients does not necessarily result in a lower incidence of hip fracture, according to a study by Anita Wagner, Pharm.D., of the department of ambulatory care and prevention at Harvard Medical School, Boston, and her colleagues.

The researchers found no significant difference in the incidence of hip fracture over a 3-year period between elderly Medicaid recipients in New York, where benzodiazepine use decreased sharply during the study period, and in New Jersey, where benzodiazepine use remained constant.

“Benzodiazepines may not actually be associated with hip fractures, or at least not to the extent reported in some studies,” Dr. Wagner and her colleagues wrote (Ann. Intern. Med. 2007;146:96–103).

The Prescription Drug Improvement and Modernization Act that went into effect in January 2006 further restricted benzodiazepine prescription coverage for Medicare recipients. Federal policy makers may have expected that reduced benzodiazepine access would decrease hip fracture risk and improve quality of life in the elderly.

Earlier data had suggested benzodiazepine use might raise the risk of hip fracture in elderly patients, with postural imbalance associated with benzodiazepine use, possibly leading to more falls and hip fractures in a population already at risk for hip fracture. But studies seeking to document a direct link have yielded conflicting results.

Since 1989, physicians in New York have been required to use serially numbered, triplicate forms for benzodiazepine prescriptions, with the third copy to be forwarded by the pharmacy to the state health authorities.

The study compared the risk of hip fractures in 1988 cohorts of 51,529 elderly Medicaid recipients in New York and 42,029 recipients in New Jersey, where the prescription policy was unchanged.

In New York, the change in prescription policy led to an abrupt decline in the drug's use, decreasing from about 40% of Medicaid enrollees each month in the 12-month period before the policy change to about 15% during the 21 months after the policy change. The drug's use in New Jersey Medicaid enrollees did not change significantly.

In New York, a total of 199 hip fractures occurred in female benzodiazepine recipients over the 33-month study period, with an increase in hazard rate from 53 per 100,000 enrollees before the policy change to 72 per 100,000 enrollees after the policy change.

In New Jersey, 135 hip fractures occurred in female benzodiazepine recipients in the study period, with a similar increase in hazard rate from 42 per 100,000 enrollees to 58 per 100,000 enrollees.

A total of 30 hip fractures in male benzodiazepine recipients in New York occurred over the study period, with the hazard rate increasing from 38 per 100,000 enrollees before the policy change to 54 per 100,000 enrollees after the policy change.

New Jersey results were similar, with a total of 27 hip fractures among male benzodiazepine recipients and an increase in hazard rate from 48 per 100,000 enrollees before the policy change in New York to 52 per 100,000 enrollees. In each case, hazard rates among benzodiazepine nonrecipients were similar.

Insulin resistance may be an independent risk factor for spontaneous abortion in women who undergo treatment for infertility, Dr. Li Tian of Beijing University and colleagues reported.

The researchers examined the incidence of spontaneous abortion among ethnic Chinese patients who became pregnant following assisted reproductive technology (ART) treatment at the Reproductive Medicine Centre of Beijing University. The study population consisted of 107 patients who successfully conceived, among 327 women who underwent in vitro fertilization or intracytoplasmic sperm injection at the clinic from June 2003 to July 2005 (J. Clin. Endocrinol. Metab. 2007 Jan. 23 [Epubl doi:10.1210/jc.2006–1123]).

All patients undergoing ART treatment were tested for insulin resistance before initiating pituitary suppression with a gonadotropin-releasing hormone agonist prior to follicle-stimulating hormone/human chorionic gonadotropin stimulation. Insulin resistance was defined using a homeostasis model, and calculated as the product of fasting insulin and fasting glucose concentrations, divided by 22.5. Patients with an insulin resistance index of greater than 4.5 were considered to have insulin resistance.

The mean age of the study population was 30.8 years (range: 21–39 years), and mean body mass index (BMI) was 22 (range: 16–33). Nineteen women were considered obese, with a BMI of 25 or greater, and 13 women had polycystic ovarian syndrome (PCOS). None of the women had type 2 diabetes, but 23 patients were considered insulin resistant.

Nineteen patients (17.8%) experienced spontaneous abortion. Eleven of 23 patients with insulin resistance (47.8%) had spontaneous abortion, compared with 8 of 84 patients without insulin resistance (9.5%). Overall, patients with insulin resistance had a greater than eightfold increased risk of spontaneous abortion, compared to patients without insulin resistance (odds ratio, 8.32).

In logistic regression analysis, advanced age (35 years or older), high BMI (25 or greater), and PCOS were all factors positively associated with increased risk of spontaneous abortion, but none was associated with significantly increased odds ratios. Only insulin resistance was significantly associated with increased risk of spontaneous abortion, and the association remained significant after controlling for possible confounding effects of advanced age, high BMI, and PCOS.

“Increased insulin resistance may be an independent risk factor for spontaneous abortion after ART treatment,” concluded the study authors. “Patients with high insulin resistance should be advised before ART treatment regarding the need of weight reduction or taking metformin, in order to reduce their risk of spontaneous abortion.”

The authors reported no conflicts of interest.

Insulin resistance may be an independent risk factor for spontaneous abortion in women who undergo treatment for infertility, Dr. Li Tian of Beijing University and colleagues reported.

The researchers examined the incidence of spontaneous abortion among ethnic Chinese patients who became pregnant following assisted reproductive technology (ART) treatment at the Reproductive Medicine Centre of Beijing University. The study population consisted of 107 patients who successfully conceived, among 327 women who underwent in vitro fertilization or intracytoplasmic sperm injection at the clinic from June 2003 to July 2005 (J. Clin. Endocrinol. Metab. 2007 Jan. 23 [Epubl doi:10.1210/jc.2006–1123]).

All patients undergoing ART treatment were tested for insulin resistance before initiating pituitary suppression with a gonadotropin-releasing hormone agonist prior to follicle-stimulating hormone/human chorionic gonadotropin stimulation. Insulin resistance was defined using a homeostasis model, and calculated as the product of fasting insulin and fasting glucose concentrations, divided by 22.5. Patients with an insulin resistance index of greater than 4.5 were considered to have insulin resistance.

The mean age of the study population was 30.8 years (range: 21–39 years), and mean body mass index (BMI) was 22 (range: 16–33). Nineteen women were considered obese, with a BMI of 25 or greater, and 13 women had polycystic ovarian syndrome (PCOS). None of the women had type 2 diabetes, but 23 patients were considered insulin resistant.

Nineteen patients (17.8%) experienced spontaneous abortion. Eleven of 23 patients with insulin resistance (47.8%) had spontaneous abortion, compared with 8 of 84 patients without insulin resistance (9.5%). Overall, patients with insulin resistance had a greater than eightfold increased risk of spontaneous abortion, compared to patients without insulin resistance (odds ratio, 8.32).

In logistic regression analysis, advanced age (35 years or older), high BMI (25 or greater), and PCOS were all factors positively associated with increased risk of spontaneous abortion, but none was associated with significantly increased odds ratios. Only insulin resistance was significantly associated with increased risk of spontaneous abortion, and the association remained significant after controlling for possible confounding effects of advanced age, high BMI, and PCOS.

“Increased insulin resistance may be an independent risk factor for spontaneous abortion after ART treatment,” concluded the study authors. “Patients with high insulin resistance should be advised before ART treatment regarding the need of weight reduction or taking metformin, in order to reduce their risk of spontaneous abortion.”

The authors reported no conflicts of interest.

Insulin resistance may be an independent risk factor for spontaneous abortion in women who undergo treatment for infertility, Dr. Li Tian of Beijing University and colleagues reported.

The researchers examined the incidence of spontaneous abortion among ethnic Chinese patients who became pregnant following assisted reproductive technology (ART) treatment at the Reproductive Medicine Centre of Beijing University. The study population consisted of 107 patients who successfully conceived, among 327 women who underwent in vitro fertilization or intracytoplasmic sperm injection at the clinic from June 2003 to July 2005 (J. Clin. Endocrinol. Metab. 2007 Jan. 23 [Epubl doi:10.1210/jc.2006–1123]).

All patients undergoing ART treatment were tested for insulin resistance before initiating pituitary suppression with a gonadotropin-releasing hormone agonist prior to follicle-stimulating hormone/human chorionic gonadotropin stimulation. Insulin resistance was defined using a homeostasis model, and calculated as the product of fasting insulin and fasting glucose concentrations, divided by 22.5. Patients with an insulin resistance index of greater than 4.5 were considered to have insulin resistance.

The mean age of the study population was 30.8 years (range: 21–39 years), and mean body mass index (BMI) was 22 (range: 16–33). Nineteen women were considered obese, with a BMI of 25 or greater, and 13 women had polycystic ovarian syndrome (PCOS). None of the women had type 2 diabetes, but 23 patients were considered insulin resistant.

Nineteen patients (17.8%) experienced spontaneous abortion. Eleven of 23 patients with insulin resistance (47.8%) had spontaneous abortion, compared with 8 of 84 patients without insulin resistance (9.5%). Overall, patients with insulin resistance had a greater than eightfold increased risk of spontaneous abortion, compared to patients without insulin resistance (odds ratio, 8.32).

In logistic regression analysis, advanced age (35 years or older), high BMI (25 or greater), and PCOS were all factors positively associated with increased risk of spontaneous abortion, but none was associated with significantly increased odds ratios. Only insulin resistance was significantly associated with increased risk of spontaneous abortion, and the association remained significant after controlling for possible confounding effects of advanced age, high BMI, and PCOS.

“Increased insulin resistance may be an independent risk factor for spontaneous abortion after ART treatment,” concluded the study authors. “Patients with high insulin resistance should be advised before ART treatment regarding the need of weight reduction or taking metformin, in order to reduce their risk of spontaneous abortion.”

The authors reported no conflicts of interest.

Postmenopausal women who discontinue alendronate after 5 years of treatment may experience a moderate decline in bone mineral density but are not at a significantly higher risk for fracture compared with those who continue alendronate for an additional 5 years, reported Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues.

“For many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low [bone mineral density], may benefit by continuing beyond 5 years,” Dr. Black wrote (JAMA 2006;296:2927–38).

This conclusion was based on findings from a 5-year extension of the Fracture Intervention Trial (FIT), a randomized, placebo-controlled trial designed to evaluate the effect of daily alendronate on bone mineral density (BMD) and fracture risk in postmenopausal women with low BMD.

The FIT Long-Term Extension (FLEX) study was open to women who had been assigned to the alendronate treatment arm in FIT and who had completed at least 3 years of alendronate treatment. Women with a total hip BMD of less than 0.515 g/cm2 (T score less than −3.5) at baseline were ineligible to participate in FLEX.

Participants were randomly assigned to receive daily treatment with 10 mg alendronate (30%), 5 mg alendronate (30%), or placebo (40%). The primary end point was total hip BMD.

Of 1,099 women participating in FLEX, 437 were assigned to placebo, 329 were assigned to 5 mg alendronate, and 333 were assigned to 10 mg alendronate.

After 5 years, total hip BMD declined 3.38% from baseline in the placebo group and 1.02% in the combination of the two alendronate groups. The combined alendronate group experienced a mean 5.26% increase from FLEX baseline in lumbar spine BMD compared with a mean 1.52% increase in the placebo group.

The treatment groups did not significantly differ in adverse events or other safety parameters during the study.

Notably, mean BMD levels remained at or above FIT baseline levels in all treatment groups after 5 years.

Postmenopausal women who discontinue alendronate after 5 years of treatment may experience a moderate decline in bone mineral density but are not at a significantly higher risk for fracture compared with those who continue alendronate for an additional 5 years, reported Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues.

“For many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low [bone mineral density], may benefit by continuing beyond 5 years,” Dr. Black wrote (JAMA 2006;296:2927–38).

This conclusion was based on findings from a 5-year extension of the Fracture Intervention Trial (FIT), a randomized, placebo-controlled trial designed to evaluate the effect of daily alendronate on bone mineral density (BMD) and fracture risk in postmenopausal women with low BMD.

The FIT Long-Term Extension (FLEX) study was open to women who had been assigned to the alendronate treatment arm in FIT and who had completed at least 3 years of alendronate treatment. Women with a total hip BMD of less than 0.515 g/cm2 (T score less than −3.5) at baseline were ineligible to participate in FLEX.

Participants were randomly assigned to receive daily treatment with 10 mg alendronate (30%), 5 mg alendronate (30%), or placebo (40%). The primary end point was total hip BMD.

Of 1,099 women participating in FLEX, 437 were assigned to placebo, 329 were assigned to 5 mg alendronate, and 333 were assigned to 10 mg alendronate.

After 5 years, total hip BMD declined 3.38% from baseline in the placebo group and 1.02% in the combination of the two alendronate groups. The combined alendronate group experienced a mean 5.26% increase from FLEX baseline in lumbar spine BMD compared with a mean 1.52% increase in the placebo group.

The treatment groups did not significantly differ in adverse events or other safety parameters during the study.

Notably, mean BMD levels remained at or above FIT baseline levels in all treatment groups after 5 years.

Postmenopausal women who discontinue alendronate after 5 years of treatment may experience a moderate decline in bone mineral density but are not at a significantly higher risk for fracture compared with those who continue alendronate for an additional 5 years, reported Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues.

“For many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low [bone mineral density], may benefit by continuing beyond 5 years,” Dr. Black wrote (JAMA 2006;296:2927–38).

This conclusion was based on findings from a 5-year extension of the Fracture Intervention Trial (FIT), a randomized, placebo-controlled trial designed to evaluate the effect of daily alendronate on bone mineral density (BMD) and fracture risk in postmenopausal women with low BMD.

The FIT Long-Term Extension (FLEX) study was open to women who had been assigned to the alendronate treatment arm in FIT and who had completed at least 3 years of alendronate treatment. Women with a total hip BMD of less than 0.515 g/cm2 (T score less than −3.5) at baseline were ineligible to participate in FLEX.

Participants were randomly assigned to receive daily treatment with 10 mg alendronate (30%), 5 mg alendronate (30%), or placebo (40%). The primary end point was total hip BMD.

Of 1,099 women participating in FLEX, 437 were assigned to placebo, 329 were assigned to 5 mg alendronate, and 333 were assigned to 10 mg alendronate.

After 5 years, total hip BMD declined 3.38% from baseline in the placebo group and 1.02% in the combination of the two alendronate groups. The combined alendronate group experienced a mean 5.26% increase from FLEX baseline in lumbar spine BMD compared with a mean 1.52% increase in the placebo group.

The treatment groups did not significantly differ in adverse events or other safety parameters during the study.

Notably, mean BMD levels remained at or above FIT baseline levels in all treatment groups after 5 years.

Insulin resistance may play a role in the pathogenesis of latent autoimmune diabetes in adults, reported Dr. Sofia Carlsson of Karolinska Institutet, Stockholm, and the Stockholm Centre of Public Health, and colleagues.

In their population-based study, the researchers found that increased age, body mass index (BMI) of 30 kg/m2 or higher, and physical inactivity were equally significant risk factors for type 2 diabetes and for latent autoimmune diabetes in adults (LADA). “The association that we see between these factors and LADA suggests a role for insulin resistance in the development of LADA,” they wrote (Diabetologia 2007;50:55–8).

The researchers looked at incident cases of diabetes identified in two surveys conducted as part of the Nord-Trøndelag Health Study, a prospective, population-based study open to all residents, aged 20 years or older, of the Norwegian county of Nord-Trøndelag. Similar surveys were conducted from 1984 to 1986 (baseline) and from 1995 to 1997 (follow-up). The surveys included a clinical examination and questionnaires on health and lifestyle factors.

The first survey enrolled 76,885 subjects, or 90.3% of the eligible population, and the second survey enrolled 65,258 subjects, or 71.3% of the eligible population. Data were available for a cohort of 38,800 men and women who participated in both surveys and were initially free of diabetes.

Patients who reported diabetes only in the follow-up survey were given further tests. Patients underwent measurements of fasting blood glucose, fasting C-peptide, and antibodies against glutamic acid decarboxylase (GAD). Anti-GAD antibody results were expressed as an index value relative to a standard serum, with a value greater than 0.08 defined as positive.

Patients who were treated with insulin within 6 months of diagnosis and who were either anti-GAD positive or who had fasting C-peptide levels less than 150 pmol/L were classified as having type 1 diabetes. Patients who were anti-GAD positive and who had not been treated with insulin within 12 months of diagnosis were classified as having LADA. Patients who were anti-GAD negative and had not been treated with insulin within 12 months of diagnosis were classified as having type 2 diabetes.

During the 11-year period between the first and second surveys, 18 patients developed type 1 diabetes, 81 patients developed LADA, and 738 patients developed type 2 diabetes.

The risk of developing LADA or type 2 diabetes, but not type 1 diabetes, increased progressively with age. The relative risks of developing diabetes for subjects aged 60 or older, versus subjects in the 18− to 39-year age group, were 6.78 for type 2 diabetes and 5.62 for LADA. In addition, physical inactivity was associated with development of type 2 diabetes and LADA.

A BMI of 30 kg/m2 or higher was associated with significantly increased risks of LADA (relative risk 15.37) and type 2 diabetes (relative risk 15.0), but not of type 1 diabetes (relative risk 1.16). “In our population, 70% of the cases of LADA could be attributed to overweight,” wrote the authors. “If these results are confirmed in other populations, they imply that we can expect increasing rates of LADA to result from the current obesity epidemic and demographic transition.”

Insulin resistance may play a role in the pathogenesis of latent autoimmune diabetes in adults, reported Dr. Sofia Carlsson of Karolinska Institutet, Stockholm, and the Stockholm Centre of Public Health, and colleagues.

In their population-based study, the researchers found that increased age, body mass index (BMI) of 30 kg/m2 or higher, and physical inactivity were equally significant risk factors for type 2 diabetes and for latent autoimmune diabetes in adults (LADA). “The association that we see between these factors and LADA suggests a role for insulin resistance in the development of LADA,” they wrote (Diabetologia 2007;50:55–8).

The researchers looked at incident cases of diabetes identified in two surveys conducted as part of the Nord-Trøndelag Health Study, a prospective, population-based study open to all residents, aged 20 years or older, of the Norwegian county of Nord-Trøndelag. Similar surveys were conducted from 1984 to 1986 (baseline) and from 1995 to 1997 (follow-up). The surveys included a clinical examination and questionnaires on health and lifestyle factors.

The first survey enrolled 76,885 subjects, or 90.3% of the eligible population, and the second survey enrolled 65,258 subjects, or 71.3% of the eligible population. Data were available for a cohort of 38,800 men and women who participated in both surveys and were initially free of diabetes.

Patients who reported diabetes only in the follow-up survey were given further tests. Patients underwent measurements of fasting blood glucose, fasting C-peptide, and antibodies against glutamic acid decarboxylase (GAD). Anti-GAD antibody results were expressed as an index value relative to a standard serum, with a value greater than 0.08 defined as positive.

Patients who were treated with insulin within 6 months of diagnosis and who were either anti-GAD positive or who had fasting C-peptide levels less than 150 pmol/L were classified as having type 1 diabetes. Patients who were anti-GAD positive and who had not been treated with insulin within 12 months of diagnosis were classified as having LADA. Patients who were anti-GAD negative and had not been treated with insulin within 12 months of diagnosis were classified as having type 2 diabetes.

During the 11-year period between the first and second surveys, 18 patients developed type 1 diabetes, 81 patients developed LADA, and 738 patients developed type 2 diabetes.

The risk of developing LADA or type 2 diabetes, but not type 1 diabetes, increased progressively with age. The relative risks of developing diabetes for subjects aged 60 or older, versus subjects in the 18− to 39-year age group, were 6.78 for type 2 diabetes and 5.62 for LADA. In addition, physical inactivity was associated with development of type 2 diabetes and LADA.

A BMI of 30 kg/m2 or higher was associated with significantly increased risks of LADA (relative risk 15.37) and type 2 diabetes (relative risk 15.0), but not of type 1 diabetes (relative risk 1.16). “In our population, 70% of the cases of LADA could be attributed to overweight,” wrote the authors. “If these results are confirmed in other populations, they imply that we can expect increasing rates of LADA to result from the current obesity epidemic and demographic transition.”

Insulin resistance may play a role in the pathogenesis of latent autoimmune diabetes in adults, reported Dr. Sofia Carlsson of Karolinska Institutet, Stockholm, and the Stockholm Centre of Public Health, and colleagues.

In their population-based study, the researchers found that increased age, body mass index (BMI) of 30 kg/m2 or higher, and physical inactivity were equally significant risk factors for type 2 diabetes and for latent autoimmune diabetes in adults (LADA). “The association that we see between these factors and LADA suggests a role for insulin resistance in the development of LADA,” they wrote (Diabetologia 2007;50:55–8).

The researchers looked at incident cases of diabetes identified in two surveys conducted as part of the Nord-Trøndelag Health Study, a prospective, population-based study open to all residents, aged 20 years or older, of the Norwegian county of Nord-Trøndelag. Similar surveys were conducted from 1984 to 1986 (baseline) and from 1995 to 1997 (follow-up). The surveys included a clinical examination and questionnaires on health and lifestyle factors.

The first survey enrolled 76,885 subjects, or 90.3% of the eligible population, and the second survey enrolled 65,258 subjects, or 71.3% of the eligible population. Data were available for a cohort of 38,800 men and women who participated in both surveys and were initially free of diabetes.

Patients who reported diabetes only in the follow-up survey were given further tests. Patients underwent measurements of fasting blood glucose, fasting C-peptide, and antibodies against glutamic acid decarboxylase (GAD). Anti-GAD antibody results were expressed as an index value relative to a standard serum, with a value greater than 0.08 defined as positive.

Patients who were treated with insulin within 6 months of diagnosis and who were either anti-GAD positive or who had fasting C-peptide levels less than 150 pmol/L were classified as having type 1 diabetes. Patients who were anti-GAD positive and who had not been treated with insulin within 12 months of diagnosis were classified as having LADA. Patients who were anti-GAD negative and had not been treated with insulin within 12 months of diagnosis were classified as having type 2 diabetes.

During the 11-year period between the first and second surveys, 18 patients developed type 1 diabetes, 81 patients developed LADA, and 738 patients developed type 2 diabetes.

The risk of developing LADA or type 2 diabetes, but not type 1 diabetes, increased progressively with age. The relative risks of developing diabetes for subjects aged 60 or older, versus subjects in the 18− to 39-year age group, were 6.78 for type 2 diabetes and 5.62 for LADA. In addition, physical inactivity was associated with development of type 2 diabetes and LADA.

A BMI of 30 kg/m2 or higher was associated with significantly increased risks of LADA (relative risk 15.37) and type 2 diabetes (relative risk 15.0), but not of type 1 diabetes (relative risk 1.16). “In our population, 70% of the cases of LADA could be attributed to overweight,” wrote the authors. “If these results are confirmed in other populations, they imply that we can expect increasing rates of LADA to result from the current obesity epidemic and demographic transition.”

Postmenopausal women who discontinue alendronate after 5 years of treatment may experience a moderate decline in bone mineral density but are not at a significantly higher risk for fracture compared with those who continue alendronate for an additional 5 years, reported Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues.

“For many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low [bone mineral density], may benefit by continuing beyond 5 years,” Dr. Black wrote (JAMA 2006;296:2927–38).

This conclusion was based on findings from a 5-year extension of the Fracture Intervention Trial (FIT), a randomized, placebo-controlled trial designed to evaluate the effect of daily alendronate on bone mineral density (BMD) and fracture risk in postmenopausal women with low BMD. The FIT Long-Term Extension (FLEX) study was open to women who had been assigned to the alendronate treatment arm in FIT and who had completed at least 3 years of alendronate treatment. Women with a total hip BMD of less than 0.515 g/cm

Participants were randomly assigned to receive daily treatment with 10 mg alendronate (30%), 5 mg alendronate (30%), or placebo (40%). The primary study end point was total hip BMD.

Of 1,099 women participating in FLEX, 437 were assigned to placebo, 329 were assigned to 5 mg alendronate, and 333 were assigned to 10 mg alendronate.

The treatment groups did not significantly differ in adverse events or other safety parameters during the study, and no cases of osteonecrosis were observed.

After 5 years, total hip bone mineral density declined 3.38% (0.22) from baseline values in the placebo group and 1.02% (0.18) in the combination of the two alendronate groups for a mean difference of 2.36% (95% CI: 1.81%–2.90%; P less than .001). The combined alendronate group experienced a mean 5.26% (0.24) increase from FLEX baseline in lumbar spine BMD compared with a mean 1.52% (0.29) increase in the placebo group (mean difference of 3.74%; 95% CI: 3.03%–4.45%, P less than .001). Notably, mean BMD levels remained at or above FIT baseline levels in all treatment groups after 5 years.

The two alendronate groups did not differ significantly in their incidence of total clinical fractures or nonvertebral fractures.

However, the risk of clinical vertebral fractures was significantly higher in the placebo group (5.3%) than in the combined alendronate group (2.4%).

Postmenopausal women who discontinue alendronate after 5 years of treatment may experience a moderate decline in bone mineral density but are not at a significantly higher risk for fracture compared with those who continue alendronate for an additional 5 years, reported Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues.

“For many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low [bone mineral density], may benefit by continuing beyond 5 years,” Dr. Black wrote (JAMA 2006;296:2927–38).

This conclusion was based on findings from a 5-year extension of the Fracture Intervention Trial (FIT), a randomized, placebo-controlled trial designed to evaluate the effect of daily alendronate on bone mineral density (BMD) and fracture risk in postmenopausal women with low BMD. The FIT Long-Term Extension (FLEX) study was open to women who had been assigned to the alendronate treatment arm in FIT and who had completed at least 3 years of alendronate treatment. Women with a total hip BMD of less than 0.515 g/cm

Participants were randomly assigned to receive daily treatment with 10 mg alendronate (30%), 5 mg alendronate (30%), or placebo (40%). The primary study end point was total hip BMD.

Of 1,099 women participating in FLEX, 437 were assigned to placebo, 329 were assigned to 5 mg alendronate, and 333 were assigned to 10 mg alendronate.

The treatment groups did not significantly differ in adverse events or other safety parameters during the study, and no cases of osteonecrosis were observed.

After 5 years, total hip bone mineral density declined 3.38% (0.22) from baseline values in the placebo group and 1.02% (0.18) in the combination of the two alendronate groups for a mean difference of 2.36% (95% CI: 1.81%–2.90%; P less than .001). The combined alendronate group experienced a mean 5.26% (0.24) increase from FLEX baseline in lumbar spine BMD compared with a mean 1.52% (0.29) increase in the placebo group (mean difference of 3.74%; 95% CI: 3.03%–4.45%, P less than .001). Notably, mean BMD levels remained at or above FIT baseline levels in all treatment groups after 5 years.

The two alendronate groups did not differ significantly in their incidence of total clinical fractures or nonvertebral fractures.

However, the risk of clinical vertebral fractures was significantly higher in the placebo group (5.3%) than in the combined alendronate group (2.4%).

Postmenopausal women who discontinue alendronate after 5 years of treatment may experience a moderate decline in bone mineral density but are not at a significantly higher risk for fracture compared with those who continue alendronate for an additional 5 years, reported Dennis M. Black, Ph.D., of the University of California, San Francisco, and his colleagues.

“For many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low [bone mineral density], may benefit by continuing beyond 5 years,” Dr. Black wrote (JAMA 2006;296:2927–38).

This conclusion was based on findings from a 5-year extension of the Fracture Intervention Trial (FIT), a randomized, placebo-controlled trial designed to evaluate the effect of daily alendronate on bone mineral density (BMD) and fracture risk in postmenopausal women with low BMD. The FIT Long-Term Extension (FLEX) study was open to women who had been assigned to the alendronate treatment arm in FIT and who had completed at least 3 years of alendronate treatment. Women with a total hip BMD of less than 0.515 g/cm

Participants were randomly assigned to receive daily treatment with 10 mg alendronate (30%), 5 mg alendronate (30%), or placebo (40%). The primary study end point was total hip BMD.

Of 1,099 women participating in FLEX, 437 were assigned to placebo, 329 were assigned to 5 mg alendronate, and 333 were assigned to 10 mg alendronate.

The treatment groups did not significantly differ in adverse events or other safety parameters during the study, and no cases of osteonecrosis were observed.

After 5 years, total hip bone mineral density declined 3.38% (0.22) from baseline values in the placebo group and 1.02% (0.18) in the combination of the two alendronate groups for a mean difference of 2.36% (95% CI: 1.81%–2.90%; P less than .001). The combined alendronate group experienced a mean 5.26% (0.24) increase from FLEX baseline in lumbar spine BMD compared with a mean 1.52% (0.29) increase in the placebo group (mean difference of 3.74%; 95% CI: 3.03%–4.45%, P less than .001). Notably, mean BMD levels remained at or above FIT baseline levels in all treatment groups after 5 years.

The two alendronate groups did not differ significantly in their incidence of total clinical fractures or nonvertebral fractures.

However, the risk of clinical vertebral fractures was significantly higher in the placebo group (5.3%) than in the combined alendronate group (2.4%).

Reduced use of benzodiazepines in elderly patients does not necessarily result in a lower incidence of hip fracture, according to a study by Anita Wagner, Pharm.D., of the department of ambulatory care and prevention at Harvard Medical School, Boston, and her colleagues.

The researchers found no significant difference in the incidence of hip fracture over a 3-year period between elderly Medicaid recipients in New York, where benzodiazepine use decreased sharply during the study period, and in New Jersey, where benzodiazepine use remained constant.

“Benzodiazepines may not actually be associated with hip fractures, or at least not to the extent reported in some studies,” Dr. Wagner and her colleagues wrote (Ann. Intern. Med. 2007;146:96–103).

The Prescription Drug Improvement and Modernization Act that went into effect in January 2006 further restricted benzodiazepine prescription coverage for Medicare recipients. Federal policy makers may have expected that reduced benzodiazepine access would decrease hip fracture risk and thereby improve quality of life in the elderly.

“According to our analyses, this expectation may not be justified,” Dr. Wagner and her associates concluded.

Earlier studies had suggested that benzodiazepine use might increase the risk of hip fracture in elderly patients, with postural imbalance associated with benzodiazepine use possibly leading to more falls and hip fractures in a population already at risk for hip fracture. But studies seeking to document a direct link have yielded conflicting results.

Since 1989, physicians in New York have been required to use serially numbered, triplicate forms for benzodiazepine prescriptions, with the third copy to be forwarded by the pharmacy to the state health authorities.

The study compared the risk of hip fractures in 1988 cohorts of 51,529 elderly Medicaid recipients in New York and 42,029 in New Jersey, where the prescription policy was unchanged.

In New York, the change in prescription policy led to an abrupt decline in benzodiazepine use, decreasing from about 40% of Medicaid enrollees each month in the 12-month period before the policy change to about 15% during the 21 months after the policy change. Benzodiazepine use among New Jersey Medicaid enrollees did not change significantly.

In New York, a total of 199 hip fractures occurred in female benzodiazepine recipients over the 33-month study period, with an increase in hazard rate from 53 per 100,000 enrollees before the policy change to 72 per 100,000 enrollees after the policy change.

In New Jersey, 135 hip fractures occurred in female benzodiazepine recipients in the study period, with a similar increase in hazard rate from 42 per 100,000 enrollees to 58 per 100,000 enrollees. A total of 30 hip fractures in male benzodiazepine recipients in New York occurred over the study period, with the hazard rate increasing from 38 per 100,000 enrollees before the policy change to 54 per 100,000 enrollees after the policy change. New Jersey results were similar, with a total of 27 hip fractures among male benzodiazepine recipients and an increase in hazard rate from 48 per 100,000 enrollees before the policy change in New York to 52 per 100,000 enrollees. In each case, hazard rates among benzodiazepine nonrecipients were similar.

No evidence suggests that the study results were skewed by disproportionate reductions in benzodiazepine use among different patient subgroups. After the policy change, there was no significant increase in the prevalence of higher-dose benzodiazepine prescriptions, and the increase in nonbenzodiazepine sedatives was modest.

The most likely explanation for the lack of decrease in hip fractures following decreased benzodiazepine use is simply that benzodiazepine use does not increase the risk of hip fracture in the elderly, Dr. Wagner and her colleagues wrote.

Reduced use of benzodiazepines in elderly patients does not necessarily result in a lower incidence of hip fracture, according to a study by Anita Wagner, Pharm.D., of the department of ambulatory care and prevention at Harvard Medical School, Boston, and her colleagues.

The researchers found no significant difference in the incidence of hip fracture over a 3-year period between elderly Medicaid recipients in New York, where benzodiazepine use decreased sharply during the study period, and in New Jersey, where benzodiazepine use remained constant.

“Benzodiazepines may not actually be associated with hip fractures, or at least not to the extent reported in some studies,” Dr. Wagner and her colleagues wrote (Ann. Intern. Med. 2007;146:96–103).

The Prescription Drug Improvement and Modernization Act that went into effect in January 2006 further restricted benzodiazepine prescription coverage for Medicare recipients. Federal policy makers may have expected that reduced benzodiazepine access would decrease hip fracture risk and thereby improve quality of life in the elderly.

“According to our analyses, this expectation may not be justified,” Dr. Wagner and her associates concluded.

Earlier studies had suggested that benzodiazepine use might increase the risk of hip fracture in elderly patients, with postural imbalance associated with benzodiazepine use possibly leading to more falls and hip fractures in a population already at risk for hip fracture. But studies seeking to document a direct link have yielded conflicting results.

Since 1989, physicians in New York have been required to use serially numbered, triplicate forms for benzodiazepine prescriptions, with the third copy to be forwarded by the pharmacy to the state health authorities.

The study compared the risk of hip fractures in 1988 cohorts of 51,529 elderly Medicaid recipients in New York and 42,029 in New Jersey, where the prescription policy was unchanged.

In New York, the change in prescription policy led to an abrupt decline in benzodiazepine use, decreasing from about 40% of Medicaid enrollees each month in the 12-month period before the policy change to about 15% during the 21 months after the policy change. Benzodiazepine use among New Jersey Medicaid enrollees did not change significantly.

In New York, a total of 199 hip fractures occurred in female benzodiazepine recipients over the 33-month study period, with an increase in hazard rate from 53 per 100,000 enrollees before the policy change to 72 per 100,000 enrollees after the policy change.

In New Jersey, 135 hip fractures occurred in female benzodiazepine recipients in the study period, with a similar increase in hazard rate from 42 per 100,000 enrollees to 58 per 100,000 enrollees. A total of 30 hip fractures in male benzodiazepine recipients in New York occurred over the study period, with the hazard rate increasing from 38 per 100,000 enrollees before the policy change to 54 per 100,000 enrollees after the policy change. New Jersey results were similar, with a total of 27 hip fractures among male benzodiazepine recipients and an increase in hazard rate from 48 per 100,000 enrollees before the policy change in New York to 52 per 100,000 enrollees. In each case, hazard rates among benzodiazepine nonrecipients were similar.

No evidence suggests that the study results were skewed by disproportionate reductions in benzodiazepine use among different patient subgroups. After the policy change, there was no significant increase in the prevalence of higher-dose benzodiazepine prescriptions, and the increase in nonbenzodiazepine sedatives was modest.

The most likely explanation for the lack of decrease in hip fractures following decreased benzodiazepine use is simply that benzodiazepine use does not increase the risk of hip fracture in the elderly, Dr. Wagner and her colleagues wrote.

Reduced use of benzodiazepines in elderly patients does not necessarily result in a lower incidence of hip fracture, according to a study by Anita Wagner, Pharm.D., of the department of ambulatory care and prevention at Harvard Medical School, Boston, and her colleagues.

The researchers found no significant difference in the incidence of hip fracture over a 3-year period between elderly Medicaid recipients in New York, where benzodiazepine use decreased sharply during the study period, and in New Jersey, where benzodiazepine use remained constant.

“Benzodiazepines may not actually be associated with hip fractures, or at least not to the extent reported in some studies,” Dr. Wagner and her colleagues wrote (Ann. Intern. Med. 2007;146:96–103).

The Prescription Drug Improvement and Modernization Act that went into effect in January 2006 further restricted benzodiazepine prescription coverage for Medicare recipients. Federal policy makers may have expected that reduced benzodiazepine access would decrease hip fracture risk and thereby improve quality of life in the elderly.

“According to our analyses, this expectation may not be justified,” Dr. Wagner and her associates concluded.

Earlier studies had suggested that benzodiazepine use might increase the risk of hip fracture in elderly patients, with postural imbalance associated with benzodiazepine use possibly leading to more falls and hip fractures in a population already at risk for hip fracture. But studies seeking to document a direct link have yielded conflicting results.

Since 1989, physicians in New York have been required to use serially numbered, triplicate forms for benzodiazepine prescriptions, with the third copy to be forwarded by the pharmacy to the state health authorities.

The study compared the risk of hip fractures in 1988 cohorts of 51,529 elderly Medicaid recipients in New York and 42,029 in New Jersey, where the prescription policy was unchanged.

In New York, the change in prescription policy led to an abrupt decline in benzodiazepine use, decreasing from about 40% of Medicaid enrollees each month in the 12-month period before the policy change to about 15% during the 21 months after the policy change. Benzodiazepine use among New Jersey Medicaid enrollees did not change significantly.

In New York, a total of 199 hip fractures occurred in female benzodiazepine recipients over the 33-month study period, with an increase in hazard rate from 53 per 100,000 enrollees before the policy change to 72 per 100,000 enrollees after the policy change.

In New Jersey, 135 hip fractures occurred in female benzodiazepine recipients in the study period, with a similar increase in hazard rate from 42 per 100,000 enrollees to 58 per 100,000 enrollees. A total of 30 hip fractures in male benzodiazepine recipients in New York occurred over the study period, with the hazard rate increasing from 38 per 100,000 enrollees before the policy change to 54 per 100,000 enrollees after the policy change. New Jersey results were similar, with a total of 27 hip fractures among male benzodiazepine recipients and an increase in hazard rate from 48 per 100,000 enrollees before the policy change in New York to 52 per 100,000 enrollees. In each case, hazard rates among benzodiazepine nonrecipients were similar.

No evidence suggests that the study results were skewed by disproportionate reductions in benzodiazepine use among different patient subgroups. After the policy change, there was no significant increase in the prevalence of higher-dose benzodiazepine prescriptions, and the increase in nonbenzodiazepine sedatives was modest.

The most likely explanation for the lack of decrease in hip fractures following decreased benzodiazepine use is simply that benzodiazepine use does not increase the risk of hip fracture in the elderly, Dr. Wagner and her colleagues wrote.