Mary Ann Moon

Major Finding: Preadolescent girls (aged 9–12) can develop PCOS, and physicians should suspect the disorder in girls with early-onset pubarche or thelarche as well as those with traditional risk factors including hyperinsulinemia and a family history of PCOS.

Data Source: A cross-sectional retrospective chart study of 58 females aged 9–18 years with PCOS.

Disclosures: No funding sources or financial conflicts of interest were reported.

Polycystic ovary syndrome appears to be manifesting at younger ages than previously thought, a study has shown.

The disorder should be considered and a thorough work-up performed in prepubertal girls who have risk factors suggestive of PCOS, with attention given to hyperinsulinemia and early pubarche and thelarche, said Dr. Jason Bronstein and his associates at New York University.

In what they described as the largest pediatric PCOS study to date, the researchers found “a large subgroup of young PCOS girls with characteristic metabolic derangements at a younger age, suggesting a need for early therapeutic interventions.” Early onset of PCOS does not portend well for future complications such as infertility, metabolic syndrome, and vascular disease. Earlier recognition and treatment of PCOS might reduce morbidity in later adolescence and adulthood, they noted.

The researchers performed a retrospective, cross-sectional chart study of 58 patients from diverse ethnic backgrounds who attended two large, urban tertiary care centers and were diagnosed with PCOS between ages 9 and 18. Fifteen (26%) of these subjects were preadolescents aged 9–12, and 43 (74%) were adolescents aged 13–18 years.

The severity of PCOS was similar between preadolescents and adolescents. Hyperinsulinemia was present in similar proportions of both groups, indicating that metabolic derangement is already present in the youngest girls with PCOS.

However, preadolescent girls were different in that they had significantly earlier pubarche and thelarche than did adolescent girls with PCOS, and the disorder developed much sooner after thelarche in the younger girls. Clinicians should look for early pubarche and thelarche in girls predisposed to PCOS, the investigators said (J. Pediatr. Adolesc. Gynecol. 2011;24:15-20).

The two groups also had similar risk factors. Mothers or other relatives had PCOS in approximately 14% of the study subjects, and there were no significant differences between preadolescents and adolescents in historical risk factors such as gestational age at birth, birth weight, childhood obesity, or family history of obesity, diabetes, or hypertension.

There also were no differences between preadolescents and adolescents in clinical risk factors such as body mass index, acne, hirsutism, alopecia, or hyperandrogenism, and no differences in biochemical risk factors such as serum total testosterone and free testosterone levels, insulin resistance, HDL levels, triglyceride levels, or fasting glucose levels.

“Pediatricians need a high index of suspicion in order to diagnose PCOS in preadolescents. We recommend that pediatricians ascertain risk for PCOS in their patients, including maternal factors, family history, birth weight, metabolic factors, and history of premature pubarche and/or early thelarche,” Dr. Bronstein and his colleagues said.

Major Finding: Preadolescent girls (aged 9–12) can develop PCOS, and physicians should suspect the disorder in girls with early-onset pubarche or thelarche as well as those with traditional risk factors including hyperinsulinemia and a family history of PCOS.

Data Source: A cross-sectional retrospective chart study of 58 females aged 9–18 years with PCOS.

Disclosures: No funding sources or financial conflicts of interest were reported.

Polycystic ovary syndrome appears to be manifesting at younger ages than previously thought, a study has shown.

The disorder should be considered and a thorough work-up performed in prepubertal girls who have risk factors suggestive of PCOS, with attention given to hyperinsulinemia and early pubarche and thelarche, said Dr. Jason Bronstein and his associates at New York University.

In what they described as the largest pediatric PCOS study to date, the researchers found “a large subgroup of young PCOS girls with characteristic metabolic derangements at a younger age, suggesting a need for early therapeutic interventions.” Early onset of PCOS does not portend well for future complications such as infertility, metabolic syndrome, and vascular disease. Earlier recognition and treatment of PCOS might reduce morbidity in later adolescence and adulthood, they noted.

The researchers performed a retrospective, cross-sectional chart study of 58 patients from diverse ethnic backgrounds who attended two large, urban tertiary care centers and were diagnosed with PCOS between ages 9 and 18. Fifteen (26%) of these subjects were preadolescents aged 9–12, and 43 (74%) were adolescents aged 13–18 years.

The severity of PCOS was similar between preadolescents and adolescents. Hyperinsulinemia was present in similar proportions of both groups, indicating that metabolic derangement is already present in the youngest girls with PCOS.

However, preadolescent girls were different in that they had significantly earlier pubarche and thelarche than did adolescent girls with PCOS, and the disorder developed much sooner after thelarche in the younger girls. Clinicians should look for early pubarche and thelarche in girls predisposed to PCOS, the investigators said (J. Pediatr. Adolesc. Gynecol. 2011;24:15-20).

The two groups also had similar risk factors. Mothers or other relatives had PCOS in approximately 14% of the study subjects, and there were no significant differences between preadolescents and adolescents in historical risk factors such as gestational age at birth, birth weight, childhood obesity, or family history of obesity, diabetes, or hypertension.

There also were no differences between preadolescents and adolescents in clinical risk factors such as body mass index, acne, hirsutism, alopecia, or hyperandrogenism, and no differences in biochemical risk factors such as serum total testosterone and free testosterone levels, insulin resistance, HDL levels, triglyceride levels, or fasting glucose levels.

“Pediatricians need a high index of suspicion in order to diagnose PCOS in preadolescents. We recommend that pediatricians ascertain risk for PCOS in their patients, including maternal factors, family history, birth weight, metabolic factors, and history of premature pubarche and/or early thelarche,” Dr. Bronstein and his colleagues said.

Major Finding: Preadolescent girls (aged 9–12) can develop PCOS, and physicians should suspect the disorder in girls with early-onset pubarche or thelarche as well as those with traditional risk factors including hyperinsulinemia and a family history of PCOS.

Data Source: A cross-sectional retrospective chart study of 58 females aged 9–18 years with PCOS.

Disclosures: No funding sources or financial conflicts of interest were reported.

Polycystic ovary syndrome appears to be manifesting at younger ages than previously thought, a study has shown.

The disorder should be considered and a thorough work-up performed in prepubertal girls who have risk factors suggestive of PCOS, with attention given to hyperinsulinemia and early pubarche and thelarche, said Dr. Jason Bronstein and his associates at New York University.

In what they described as the largest pediatric PCOS study to date, the researchers found “a large subgroup of young PCOS girls with characteristic metabolic derangements at a younger age, suggesting a need for early therapeutic interventions.” Early onset of PCOS does not portend well for future complications such as infertility, metabolic syndrome, and vascular disease. Earlier recognition and treatment of PCOS might reduce morbidity in later adolescence and adulthood, they noted.

The researchers performed a retrospective, cross-sectional chart study of 58 patients from diverse ethnic backgrounds who attended two large, urban tertiary care centers and were diagnosed with PCOS between ages 9 and 18. Fifteen (26%) of these subjects were preadolescents aged 9–12, and 43 (74%) were adolescents aged 13–18 years.

The severity of PCOS was similar between preadolescents and adolescents. Hyperinsulinemia was present in similar proportions of both groups, indicating that metabolic derangement is already present in the youngest girls with PCOS.

However, preadolescent girls were different in that they had significantly earlier pubarche and thelarche than did adolescent girls with PCOS, and the disorder developed much sooner after thelarche in the younger girls. Clinicians should look for early pubarche and thelarche in girls predisposed to PCOS, the investigators said (J. Pediatr. Adolesc. Gynecol. 2011;24:15-20).

The two groups also had similar risk factors. Mothers or other relatives had PCOS in approximately 14% of the study subjects, and there were no significant differences between preadolescents and adolescents in historical risk factors such as gestational age at birth, birth weight, childhood obesity, or family history of obesity, diabetes, or hypertension.

There also were no differences between preadolescents and adolescents in clinical risk factors such as body mass index, acne, hirsutism, alopecia, or hyperandrogenism, and no differences in biochemical risk factors such as serum total testosterone and free testosterone levels, insulin resistance, HDL levels, triglyceride levels, or fasting glucose levels.

“Pediatricians need a high index of suspicion in order to diagnose PCOS in preadolescents. We recommend that pediatricians ascertain risk for PCOS in their patients, including maternal factors, family history, birth weight, metabolic factors, and history of premature pubarche and/or early thelarche,” Dr. Bronstein and his colleagues said.

Major Finding: When physicians told patients that they were overweight or obese, patients were much more likely to accurately perceive that they were overweight (94%) or obese (97%), compared with patients who had not been given that information by their physicians (63% and 81%, respectively).

Data Source: A cross-sectional analysis of data from the nationally representative 2005–2008 NHANES study involving 7,790 men and women aged 20–64 years, of whom 5,474 were overweight.

Disclosures: No financial conflicts of interest were reported.

When physicians tell patients directly that they are overweight, it raises the odds that the patients will perceive their weight realistically, will want to lose weight, and will try to lose weight, according to a new report.

However, fewer than half of overweight patients and fewer than two-thirds of obese patients say they have been told by their physicians that they are overweight.

“Physicians need to tell more overweight and obese patients that they are overweight because this may help encourage them to change their behavior to lose weight and lower their risk for many diseases,” said Dr. Robert E. Post of the department of family medicine, Medical University of South Carolina, Charleston, and his associates.

Today's overweight and obese patients are more likely to consider themselves to be of normal weight than their counterparts of 20 years ago were, in part because the current obesity epidemic has made higher weights and larger sizes seem more normal. Patients who don't perceive their weight accurately won't recognize their health risks, the investigators said.

They analyzed data from the 2005–2008 National Health and Nutrition Examination Survey in a cross-sectional study. The study included data for 7,790 men and women aged 20–64 years who constituted a nationally representative sample of the U.S. population.

A total of 5,474 of these subjects qualified as overweight, with a BMI of 25 kg/m

Of the overweight subjects, 45% reported that their physicians had told them they were overweight, as did 66% of the obese subjects. These subjects were much more likely to identify themselves as overweight (94%) or obese (97%) than were overweight subjects whose physicians had not so informed them (63% and 81%, respectively). They also were much more likely to report that they wanted to lose weight and had attempted to lose weight during the preceding year.

However, about 37% of overweight and 19% of obese subjects had not been told they were overweight by their physicians and did not consider themselves to be. In comparison, only 6% of overweight and 3% of obese subjects who had been told by their physicians that they were overweight continued to consider themselves to be of normal weight.

“This speaks strongly to the influence that physicians' words have on their patients,” Dr. Post and his colleagues said (Arch. Intern. Med. 2011;171:316-21).

Extrapolating this finding to the general U.S. adult population, “this equates to more than 74 million overweight individuals, including nearly 23 million obese individuals, who have never been told that they are overweight,” they added.

Telling patients that they are overweight was associated with an eightfold increase in the odds that they would accurately see themselves as overweight and a sixfold increase in the odds that they would accurately see themselves as obese. This recognition is essential because being aware of the problem is the first step in changing behavior to overcome it, the investigators noted.

This study could not assess why physicians fail to identify patients as overweight. It is possible that some patients didn't “hear” this even though their physicians did tell them.

Alternatively, some physicians may not bother to inform patients of weight status because they see patients as lacking in self-control or motivation to change. Some may feel that labeling patients as overweight or obese is simply stating the obvious and won't make much difference.

View on the News

Intervention Is Not an Insult

Some patients may feel insulted when told they are overweight or obese, but “expressing concern rather than judgment, and normalizing the conversation by simply comparing measured weight with standard definitions is likely to be effective,” Dr. Robert B. Baron said.

Saying, “I am concerned about your weight. Today's measurement places you in the overweight (or obese) category, according to our medical definitions,” should minimize the patient's tendency to take offense, he said.

Physicians should inform patients of their weight status in a straightforward manner analogous to telling patients that their blood pressure or cholesterol level is elevated, he noted.

Vitals

DR. BARON is in the department of medicine at the University of California, San Francisco. He reported no financial conflicts of interest. These remarks were taken from his invited commentary that accompanied Dr. Post's report (Arch. Intern. Med. 2011;171: 321-2).

Major Finding: When physicians told patients that they were overweight or obese, patients were much more likely to accurately perceive that they were overweight (94%) or obese (97%), compared with patients who had not been given that information by their physicians (63% and 81%, respectively).

Data Source: A cross-sectional analysis of data from the nationally representative 2005–2008 NHANES study involving 7,790 men and women aged 20–64 years, of whom 5,474 were overweight.

Disclosures: No financial conflicts of interest were reported.

When physicians tell patients directly that they are overweight, it raises the odds that the patients will perceive their weight realistically, will want to lose weight, and will try to lose weight, according to a new report.

However, fewer than half of overweight patients and fewer than two-thirds of obese patients say they have been told by their physicians that they are overweight.

“Physicians need to tell more overweight and obese patients that they are overweight because this may help encourage them to change their behavior to lose weight and lower their risk for many diseases,” said Dr. Robert E. Post of the department of family medicine, Medical University of South Carolina, Charleston, and his associates.

Today's overweight and obese patients are more likely to consider themselves to be of normal weight than their counterparts of 20 years ago were, in part because the current obesity epidemic has made higher weights and larger sizes seem more normal. Patients who don't perceive their weight accurately won't recognize their health risks, the investigators said.

They analyzed data from the 2005–2008 National Health and Nutrition Examination Survey in a cross-sectional study. The study included data for 7,790 men and women aged 20–64 years who constituted a nationally representative sample of the U.S. population.

A total of 5,474 of these subjects qualified as overweight, with a BMI of 25 kg/m

Of the overweight subjects, 45% reported that their physicians had told them they were overweight, as did 66% of the obese subjects. These subjects were much more likely to identify themselves as overweight (94%) or obese (97%) than were overweight subjects whose physicians had not so informed them (63% and 81%, respectively). They also were much more likely to report that they wanted to lose weight and had attempted to lose weight during the preceding year.

However, about 37% of overweight and 19% of obese subjects had not been told they were overweight by their physicians and did not consider themselves to be. In comparison, only 6% of overweight and 3% of obese subjects who had been told by their physicians that they were overweight continued to consider themselves to be of normal weight.

“This speaks strongly to the influence that physicians' words have on their patients,” Dr. Post and his colleagues said (Arch. Intern. Med. 2011;171:316-21).

Extrapolating this finding to the general U.S. adult population, “this equates to more than 74 million overweight individuals, including nearly 23 million obese individuals, who have never been told that they are overweight,” they added.

Telling patients that they are overweight was associated with an eightfold increase in the odds that they would accurately see themselves as overweight and a sixfold increase in the odds that they would accurately see themselves as obese. This recognition is essential because being aware of the problem is the first step in changing behavior to overcome it, the investigators noted.

This study could not assess why physicians fail to identify patients as overweight. It is possible that some patients didn't “hear” this even though their physicians did tell them.

Alternatively, some physicians may not bother to inform patients of weight status because they see patients as lacking in self-control or motivation to change. Some may feel that labeling patients as overweight or obese is simply stating the obvious and won't make much difference.

View on the News

Intervention Is Not an Insult

Some patients may feel insulted when told they are overweight or obese, but “expressing concern rather than judgment, and normalizing the conversation by simply comparing measured weight with standard definitions is likely to be effective,” Dr. Robert B. Baron said.

Saying, “I am concerned about your weight. Today's measurement places you in the overweight (or obese) category, according to our medical definitions,” should minimize the patient's tendency to take offense, he said.

Physicians should inform patients of their weight status in a straightforward manner analogous to telling patients that their blood pressure or cholesterol level is elevated, he noted.

Vitals

DR. BARON is in the department of medicine at the University of California, San Francisco. He reported no financial conflicts of interest. These remarks were taken from his invited commentary that accompanied Dr. Post's report (Arch. Intern. Med. 2011;171: 321-2).

Major Finding: When physicians told patients that they were overweight or obese, patients were much more likely to accurately perceive that they were overweight (94%) or obese (97%), compared with patients who had not been given that information by their physicians (63% and 81%, respectively).

Data Source: A cross-sectional analysis of data from the nationally representative 2005–2008 NHANES study involving 7,790 men and women aged 20–64 years, of whom 5,474 were overweight.

Disclosures: No financial conflicts of interest were reported.

When physicians tell patients directly that they are overweight, it raises the odds that the patients will perceive their weight realistically, will want to lose weight, and will try to lose weight, according to a new report.

However, fewer than half of overweight patients and fewer than two-thirds of obese patients say they have been told by their physicians that they are overweight.

“Physicians need to tell more overweight and obese patients that they are overweight because this may help encourage them to change their behavior to lose weight and lower their risk for many diseases,” said Dr. Robert E. Post of the department of family medicine, Medical University of South Carolina, Charleston, and his associates.

Today's overweight and obese patients are more likely to consider themselves to be of normal weight than their counterparts of 20 years ago were, in part because the current obesity epidemic has made higher weights and larger sizes seem more normal. Patients who don't perceive their weight accurately won't recognize their health risks, the investigators said.

They analyzed data from the 2005–2008 National Health and Nutrition Examination Survey in a cross-sectional study. The study included data for 7,790 men and women aged 20–64 years who constituted a nationally representative sample of the U.S. population.

A total of 5,474 of these subjects qualified as overweight, with a BMI of 25 kg/m

Of the overweight subjects, 45% reported that their physicians had told them they were overweight, as did 66% of the obese subjects. These subjects were much more likely to identify themselves as overweight (94%) or obese (97%) than were overweight subjects whose physicians had not so informed them (63% and 81%, respectively). They also were much more likely to report that they wanted to lose weight and had attempted to lose weight during the preceding year.

However, about 37% of overweight and 19% of obese subjects had not been told they were overweight by their physicians and did not consider themselves to be. In comparison, only 6% of overweight and 3% of obese subjects who had been told by their physicians that they were overweight continued to consider themselves to be of normal weight.

“This speaks strongly to the influence that physicians' words have on their patients,” Dr. Post and his colleagues said (Arch. Intern. Med. 2011;171:316-21).

Extrapolating this finding to the general U.S. adult population, “this equates to more than 74 million overweight individuals, including nearly 23 million obese individuals, who have never been told that they are overweight,” they added.

Telling patients that they are overweight was associated with an eightfold increase in the odds that they would accurately see themselves as overweight and a sixfold increase in the odds that they would accurately see themselves as obese. This recognition is essential because being aware of the problem is the first step in changing behavior to overcome it, the investigators noted.

This study could not assess why physicians fail to identify patients as overweight. It is possible that some patients didn't “hear” this even though their physicians did tell them.

Alternatively, some physicians may not bother to inform patients of weight status because they see patients as lacking in self-control or motivation to change. Some may feel that labeling patients as overweight or obese is simply stating the obvious and won't make much difference.

View on the News

Intervention Is Not an Insult

Some patients may feel insulted when told they are overweight or obese, but “expressing concern rather than judgment, and normalizing the conversation by simply comparing measured weight with standard definitions is likely to be effective,” Dr. Robert B. Baron said.

Saying, “I am concerned about your weight. Today's measurement places you in the overweight (or obese) category, according to our medical definitions,” should minimize the patient's tendency to take offense, he said.

Physicians should inform patients of their weight status in a straightforward manner analogous to telling patients that their blood pressure or cholesterol level is elevated, he noted.

Vitals

DR. BARON is in the department of medicine at the University of California, San Francisco. He reported no financial conflicts of interest. These remarks were taken from his invited commentary that accompanied Dr. Post's report (Arch. Intern. Med. 2011;171: 321-2).

Major Finding: Type 2 diabetes resolved in 93% of patients who underwent gastric bypass surgery, compared with 47% of patients who underwent sleeve gastrectomy.

Data Source: A double-blind, randomized trial comparing gastric bypass surgery, which excludes the duodenum, against sleeve gastrectomy, which does not bypass the duodenum, in 60 patients with poorly controlled type 2 diabetes and a BMI of 25–35 kg/m

Disclosures: No financial conflicts of interest were reported.

For non–morbidly obese patients with poorly controlled type 2 diabetes, gastric bypass surgery with exclusion of the duodenum was much more likely to resolve diabetes than was a simpler, purely restrictive procedure that does not exclude the duodenum, according to a double-blind, randomized trial.

However, the relative safety of the purely restrictive procedure may make it a better first choice than gastric bypass surgery for many patients, the study's authors said.

Diabetes resolved in 28 of 30 (93%) patients who underwent gastric bypass, which prevents contact between ingested food and the duodenum, compared with 14 of 30 (47%) who underwent sleeve gastrectomy, which does not prevent such contact. The study is the first randomized trial to examine surgical treatment's effect on non–morbidly obese patients with a body mass index (BMI) of less than 35 kg/m

Both groups of patients showed significant weight loss and improvement in such metabolic measures as waist circumference, hemoglobin A_1c levels, and insulin levels. But those improvements were more frequent and more extensive in the patients who underwent full gastric bypass.

The findings strongly support the hypothesis that the duodenum plays a large role in the resolution of diabetes following bariatric surgery. “The mechanism seems to relate to postprandial glucose metabolism rather than to an increase in insulin secretion, and is independent of weight reduction,” said Dr. Wei-Jei Lee of Min-Sheng General Hospital, National Taiwan (China) University, and associates (Arch. Surg. 2011; 146:143-8).

In the double-blind study, 60 patients aged 34–58 years were randomly assigned to undergo one of the two operations using standard laparoscopic techniques. The mean BMI was 30.3, and the average age was 45 years. All patients had been seeing an endocrinologist for type 2 diabetes for at least 6 months but continued to have poorly controlled disease, with a mean HbA_1c level of 10% (range, 7.5%–15%).

The primary end point – glycemic control at 12 months without the use of oral hypoglycemic agents or insulin – was achieved by significantly more patients in the gastric bypass group (93%) than in the sleeve gastrectomy group (47%).

“These results corroborate previous reports that gastric bypass may achieve an 80% diabetes mellitus remission and pure restrictive-type procedures may achieve a rate of approximately 50%,” the researchers wrote.

Although weight loss was similar between the two groups, patients who underwent full gastric bypass also showed a smaller waist circumference, lower fasting plasma glucose levels, lower HbA_1c levels, and lower blood lipid levels – in short, a higher rate of remission of the metabolic syndrome (93% vs. 40%). Their blood pressure, insulin levels, and C-peptide levels also were lower than were those in the sleeve gastrectomy group.

There were no deaths or major complications, and minor complications developed in three patients in each group.

However, it is important to note that restrictive procedures such as sleeve gastrectomy or gastric banding are 10-fold safer than the more-complex gastric bypass procedures, the investigators cautioned. In addition, those two restrictive procedures avoid the long-term sequela of micronutrient deficiency that sometimes follows duodenum exclusion. Thus should be considered the first choice for many patients, Dr. Lee and colleagues said.

In contrast, gastric bypass might be a better choice for patients with metabolic syndrome or hyperlipidemia, they noted.

The mechanism by which exclusion of the duodenum and upper jejunum reverses diabetes (the so-called foregut theory) has not been fully explained, and “without data regarding the change in gut hormones, such as glucagon, gastric inhibitory peptide, and glucagon-like peptide 1, we cannot elucidate the underlying mechanisms,” the researchers added.

Given the 1-year follow-up of the study, the study's authors said they also could not confirm the durability of diabetes remission in such patients, or the influence of future changes in weight.

Major Finding: Type 2 diabetes resolved in 93% of patients who underwent gastric bypass surgery, compared with 47% of patients who underwent sleeve gastrectomy.

Data Source: A double-blind, randomized trial comparing gastric bypass surgery, which excludes the duodenum, against sleeve gastrectomy, which does not bypass the duodenum, in 60 patients with poorly controlled type 2 diabetes and a BMI of 25–35 kg/m

Disclosures: No financial conflicts of interest were reported.

For non–morbidly obese patients with poorly controlled type 2 diabetes, gastric bypass surgery with exclusion of the duodenum was much more likely to resolve diabetes than was a simpler, purely restrictive procedure that does not exclude the duodenum, according to a double-blind, randomized trial.

However, the relative safety of the purely restrictive procedure may make it a better first choice than gastric bypass surgery for many patients, the study's authors said.

Diabetes resolved in 28 of 30 (93%) patients who underwent gastric bypass, which prevents contact between ingested food and the duodenum, compared with 14 of 30 (47%) who underwent sleeve gastrectomy, which does not prevent such contact. The study is the first randomized trial to examine surgical treatment's effect on non–morbidly obese patients with a body mass index (BMI) of less than 35 kg/m

Both groups of patients showed significant weight loss and improvement in such metabolic measures as waist circumference, hemoglobin A_1c levels, and insulin levels. But those improvements were more frequent and more extensive in the patients who underwent full gastric bypass.

The findings strongly support the hypothesis that the duodenum plays a large role in the resolution of diabetes following bariatric surgery. “The mechanism seems to relate to postprandial glucose metabolism rather than to an increase in insulin secretion, and is independent of weight reduction,” said Dr. Wei-Jei Lee of Min-Sheng General Hospital, National Taiwan (China) University, and associates (Arch. Surg. 2011; 146:143-8).

In the double-blind study, 60 patients aged 34–58 years were randomly assigned to undergo one of the two operations using standard laparoscopic techniques. The mean BMI was 30.3, and the average age was 45 years. All patients had been seeing an endocrinologist for type 2 diabetes for at least 6 months but continued to have poorly controlled disease, with a mean HbA_1c level of 10% (range, 7.5%–15%).

The primary end point – glycemic control at 12 months without the use of oral hypoglycemic agents or insulin – was achieved by significantly more patients in the gastric bypass group (93%) than in the sleeve gastrectomy group (47%).

“These results corroborate previous reports that gastric bypass may achieve an 80% diabetes mellitus remission and pure restrictive-type procedures may achieve a rate of approximately 50%,” the researchers wrote.

Although weight loss was similar between the two groups, patients who underwent full gastric bypass also showed a smaller waist circumference, lower fasting plasma glucose levels, lower HbA_1c levels, and lower blood lipid levels – in short, a higher rate of remission of the metabolic syndrome (93% vs. 40%). Their blood pressure, insulin levels, and C-peptide levels also were lower than were those in the sleeve gastrectomy group.

There were no deaths or major complications, and minor complications developed in three patients in each group.

However, it is important to note that restrictive procedures such as sleeve gastrectomy or gastric banding are 10-fold safer than the more-complex gastric bypass procedures, the investigators cautioned. In addition, those two restrictive procedures avoid the long-term sequela of micronutrient deficiency that sometimes follows duodenum exclusion. Thus should be considered the first choice for many patients, Dr. Lee and colleagues said.

In contrast, gastric bypass might be a better choice for patients with metabolic syndrome or hyperlipidemia, they noted.

The mechanism by which exclusion of the duodenum and upper jejunum reverses diabetes (the so-called foregut theory) has not been fully explained, and “without data regarding the change in gut hormones, such as glucagon, gastric inhibitory peptide, and glucagon-like peptide 1, we cannot elucidate the underlying mechanisms,” the researchers added.

Given the 1-year follow-up of the study, the study's authors said they also could not confirm the durability of diabetes remission in such patients, or the influence of future changes in weight.

Major Finding: Type 2 diabetes resolved in 93% of patients who underwent gastric bypass surgery, compared with 47% of patients who underwent sleeve gastrectomy.

Data Source: A double-blind, randomized trial comparing gastric bypass surgery, which excludes the duodenum, against sleeve gastrectomy, which does not bypass the duodenum, in 60 patients with poorly controlled type 2 diabetes and a BMI of 25–35 kg/m

Disclosures: No financial conflicts of interest were reported.

For non–morbidly obese patients with poorly controlled type 2 diabetes, gastric bypass surgery with exclusion of the duodenum was much more likely to resolve diabetes than was a simpler, purely restrictive procedure that does not exclude the duodenum, according to a double-blind, randomized trial.

However, the relative safety of the purely restrictive procedure may make it a better first choice than gastric bypass surgery for many patients, the study's authors said.

Diabetes resolved in 28 of 30 (93%) patients who underwent gastric bypass, which prevents contact between ingested food and the duodenum, compared with 14 of 30 (47%) who underwent sleeve gastrectomy, which does not prevent such contact. The study is the first randomized trial to examine surgical treatment's effect on non–morbidly obese patients with a body mass index (BMI) of less than 35 kg/m

Both groups of patients showed significant weight loss and improvement in such metabolic measures as waist circumference, hemoglobin A_1c levels, and insulin levels. But those improvements were more frequent and more extensive in the patients who underwent full gastric bypass.

The findings strongly support the hypothesis that the duodenum plays a large role in the resolution of diabetes following bariatric surgery. “The mechanism seems to relate to postprandial glucose metabolism rather than to an increase in insulin secretion, and is independent of weight reduction,” said Dr. Wei-Jei Lee of Min-Sheng General Hospital, National Taiwan (China) University, and associates (Arch. Surg. 2011; 146:143-8).

In the double-blind study, 60 patients aged 34–58 years were randomly assigned to undergo one of the two operations using standard laparoscopic techniques. The mean BMI was 30.3, and the average age was 45 years. All patients had been seeing an endocrinologist for type 2 diabetes for at least 6 months but continued to have poorly controlled disease, with a mean HbA_1c level of 10% (range, 7.5%–15%).

The primary end point – glycemic control at 12 months without the use of oral hypoglycemic agents or insulin – was achieved by significantly more patients in the gastric bypass group (93%) than in the sleeve gastrectomy group (47%).

“These results corroborate previous reports that gastric bypass may achieve an 80% diabetes mellitus remission and pure restrictive-type procedures may achieve a rate of approximately 50%,” the researchers wrote.

Although weight loss was similar between the two groups, patients who underwent full gastric bypass also showed a smaller waist circumference, lower fasting plasma glucose levels, lower HbA_1c levels, and lower blood lipid levels – in short, a higher rate of remission of the metabolic syndrome (93% vs. 40%). Their blood pressure, insulin levels, and C-peptide levels also were lower than were those in the sleeve gastrectomy group.

There were no deaths or major complications, and minor complications developed in three patients in each group.

However, it is important to note that restrictive procedures such as sleeve gastrectomy or gastric banding are 10-fold safer than the more-complex gastric bypass procedures, the investigators cautioned. In addition, those two restrictive procedures avoid the long-term sequela of micronutrient deficiency that sometimes follows duodenum exclusion. Thus should be considered the first choice for many patients, Dr. Lee and colleagues said.

In contrast, gastric bypass might be a better choice for patients with metabolic syndrome or hyperlipidemia, they noted.

The mechanism by which exclusion of the duodenum and upper jejunum reverses diabetes (the so-called foregut theory) has not been fully explained, and “without data regarding the change in gut hormones, such as glucagon, gastric inhibitory peptide, and glucagon-like peptide 1, we cannot elucidate the underlying mechanisms,” the researchers added.

Given the 1-year follow-up of the study, the study's authors said they also could not confirm the durability of diabetes remission in such patients, or the influence of future changes in weight.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

Of 400 women enrolled, only 243 remained in the study long enough to be included in the analysis: 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the treatment group and 15 in the placebo group discontinued or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years. Those who received active nitroglycerin showed a significant increase of about 7%, compared with women in the placebo group, in that measure.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, the investigators said (JAMA 2011;305:800-7).

Nitroglycerin therapy also was linked with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects was 4% in both groups. However, headaches were much more common with nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study owing to headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers concluded.

This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

View on the News

Proof Is In Fracture Risk

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do.

These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011:305:826-7).

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

Of 400 women enrolled, only 243 remained in the study long enough to be included in the analysis: 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the treatment group and 15 in the placebo group discontinued or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years. Those who received active nitroglycerin showed a significant increase of about 7%, compared with women in the placebo group, in that measure.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, the investigators said (JAMA 2011;305:800-7).

Nitroglycerin therapy also was linked with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects was 4% in both groups. However, headaches were much more common with nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study owing to headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers concluded.

This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

View on the News

Proof Is In Fracture Risk

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do.

These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011:305:826-7).

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

Of 400 women enrolled, only 243 remained in the study long enough to be included in the analysis: 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the treatment group and 15 in the placebo group discontinued or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years. Those who received active nitroglycerin showed a significant increase of about 7%, compared with women in the placebo group, in that measure.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, the investigators said (JAMA 2011;305:800-7).

Nitroglycerin therapy also was linked with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects was 4% in both groups. However, headaches were much more common with nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study owing to headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers concluded.

This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

View on the News

Proof Is In Fracture Risk

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do.

These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011:305:826-7).

Major Finding: Overall 5-year survival was 91.8% with axillary node dissection and 92.5% without it; the 5-year disease-free survival was 82.2% with axillary node dissection and 83.9% without it. The differences were not significant.

Data Source: A phase III noninferiority trial involving 891 women with invasive node-positive breast cancer treated at 115 medical centers.

Disclosures: This study was supported by the National Cancer Institute. No financial conflicts of interest were reported.

Axillary lymph node dissection did not improve overall survival or disease-free survival in women with T1-T2 breast cancer who were found to have limited metastasis on sentinel node dissection.

In the American College of Surgeons Oncology Group's Z0011 trial, survival was nearly identical between women who underwent lumpectomy and sentinel node dissection alone, followed by adjuvant chemotherapy and tangential-field whole-breast irradiation, and women who underwent axillary node dissection when sentinel node biopsy revealed limited metastasis, followed by the same chemotherapy and irradiation.

“The findings from Z0011 document the high rate of locoregional control achieved with modern multimodal therapy, even without axillary lymph node dissection,” said Dr. Armando E. Giuliano of John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, Calif., and his associates.

The results also imply that axillary node dissection is no longer warranted in such patients, because “the only additional information gained … is the number of nodes containing metastases. This prognostic information is unlikely to change systemic therapy decisions and is obtained at the cost of a significant increase in morbidity,” the investigators noted.

Forgoing the standard practice of axillary node dissection when sentinel nodes reveal metastasis constitutes a practice change that “would improve clinical outcomes in thousands of women each year by reducing the complications associated with axillary lymph node dissection and improving quality of life with no diminution in survival,” they concluded.

The need for axillary node dissection when sentinel nodes are found to have metastasis has been called into question for years, and use of this “standard” practice has declined. Until now, “no study has conclusively demonstrated a survival benefit or detriment for omitting axillary node dissection,” they said.

The ACS Oncology Group's Z0011 trial, begun in the late 1990s, was intended to definitively answer that question. The phase III “noninferiority” trial involved 891 women who were followed at 115 centers after undergoing lumpectomy and sentinel node dissection revealing metastasis. These subjects were randomly assigned to undergo standard axillary node dissection (445 patients) or no axillary node dissection (446 patients), followed by whole-breast tangential-field radiation (not third-field nodal irradiation) and whatever adjuvant systemic therapy their treating physicians deemed necessary.

The trial's enrollment was halted early in 2004 “because of concerns regarding the extremely low mortality rate.” It was determined that accrual of more patients would not alter the survival findings, and final follow-up for the analysis was completed in 2010.

After a median of 6 years of follow-up, there were 94 deaths. The 5-year overall survival was 92.5% with sentinel node dissection alone and 91.8% with full axillary node dissection, a nonsignificant difference. The 5-year disease-free survival rate was 83.9% with sentinel node dissection alone and 82.2% with full axillary node dissection, also a nonsignificant difference. These results were consistent across several subgroups of patients, regardless of patient age, tumor size, tumor hormone-receptor status, or which adjuvant therapies were received.

The two study groups did differ significantly in morbidities related to lymph node dissection. The rate of wound infection, axillary seromas, and paresthesias was markedly higher for women who underwent axillary node dissection (70%) than for those who did not (25%). Lymphedema also was more common with axillary node dissection.

“The excellent local and distant outcomes in this study highlight the effects of multiple changes in breast cancer management” in recent years, including “improved imaging, more detailed pathological evaluation, improved planning of surgical and radiation approaches, and more effective systemic therapy,” Dr. Giuliano and his colleagues said (JAMA 2011;305:569-75). They emphasized that this trial did not include patients who had mastectomy, lumpectomy without radiation therapy, partial-breast irradiation, or whole-breast irradiation in the prone position (which would not treat the low axilla). In such patients, “axillary lymph node dissection remains standard practice when sentinel lymph node dissection identifies a positive sentinel lymph node.”

View on The News

A Definitive Answer

The American College of Surgeons Oncology Group Z0011 trial “definitively showed that axillary lymph node dissection is not beneficial,” said Dr. Grant Walter Carlson and Dr. William C. Wood.

Even though 27% of the women who underwent axillary node biopsy were found to have additional lymph nodes containing metastases, the axillary recurrence rates were similar between the two groups.

“Survival was independent of lymph node status and was so good in both groups that longer follow-up has little likelihood of demonstrating any difference between the [two] groups,” they noted. “Taken together, findings from these [and other] investigators provide strong evidence that patients undergoing partial mastectomy, whole-breast irradiation, and systemic therapy for early breast cancer with microscopic sentinel lymph node metastasis can be treated effectively and safely without axillary node dissection.”

DR. CARLSON and DR. WOOD are at Winship Cancer Institute, Emory University, Atlanta. They reported no financial conflicts of interest. These comments were taken from their editorial that accompanied Dr. Giuliano's report (JAMA 2011;305:606-7).

Major Finding: Overall 5-year survival was 91.8% with axillary node dissection and 92.5% without it; the 5-year disease-free survival was 82.2% with axillary node dissection and 83.9% without it. The differences were not significant.

Data Source: A phase III noninferiority trial involving 891 women with invasive node-positive breast cancer treated at 115 medical centers.

Disclosures: This study was supported by the National Cancer Institute. No financial conflicts of interest were reported.

Axillary lymph node dissection did not improve overall survival or disease-free survival in women with T1-T2 breast cancer who were found to have limited metastasis on sentinel node dissection.

In the American College of Surgeons Oncology Group's Z0011 trial, survival was nearly identical between women who underwent lumpectomy and sentinel node dissection alone, followed by adjuvant chemotherapy and tangential-field whole-breast irradiation, and women who underwent axillary node dissection when sentinel node biopsy revealed limited metastasis, followed by the same chemotherapy and irradiation.

“The findings from Z0011 document the high rate of locoregional control achieved with modern multimodal therapy, even without axillary lymph node dissection,” said Dr. Armando E. Giuliano of John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, Calif., and his associates.

The results also imply that axillary node dissection is no longer warranted in such patients, because “the only additional information gained … is the number of nodes containing metastases. This prognostic information is unlikely to change systemic therapy decisions and is obtained at the cost of a significant increase in morbidity,” the investigators noted.

Forgoing the standard practice of axillary node dissection when sentinel nodes reveal metastasis constitutes a practice change that “would improve clinical outcomes in thousands of women each year by reducing the complications associated with axillary lymph node dissection and improving quality of life with no diminution in survival,” they concluded.

The need for axillary node dissection when sentinel nodes are found to have metastasis has been called into question for years, and use of this “standard” practice has declined. Until now, “no study has conclusively demonstrated a survival benefit or detriment for omitting axillary node dissection,” they said.

The ACS Oncology Group's Z0011 trial, begun in the late 1990s, was intended to definitively answer that question. The phase III “noninferiority” trial involved 891 women who were followed at 115 centers after undergoing lumpectomy and sentinel node dissection revealing metastasis. These subjects were randomly assigned to undergo standard axillary node dissection (445 patients) or no axillary node dissection (446 patients), followed by whole-breast tangential-field radiation (not third-field nodal irradiation) and whatever adjuvant systemic therapy their treating physicians deemed necessary.

The trial's enrollment was halted early in 2004 “because of concerns regarding the extremely low mortality rate.” It was determined that accrual of more patients would not alter the survival findings, and final follow-up for the analysis was completed in 2010.

After a median of 6 years of follow-up, there were 94 deaths. The 5-year overall survival was 92.5% with sentinel node dissection alone and 91.8% with full axillary node dissection, a nonsignificant difference. The 5-year disease-free survival rate was 83.9% with sentinel node dissection alone and 82.2% with full axillary node dissection, also a nonsignificant difference. These results were consistent across several subgroups of patients, regardless of patient age, tumor size, tumor hormone-receptor status, or which adjuvant therapies were received.

The two study groups did differ significantly in morbidities related to lymph node dissection. The rate of wound infection, axillary seromas, and paresthesias was markedly higher for women who underwent axillary node dissection (70%) than for those who did not (25%). Lymphedema also was more common with axillary node dissection.

“The excellent local and distant outcomes in this study highlight the effects of multiple changes in breast cancer management” in recent years, including “improved imaging, more detailed pathological evaluation, improved planning of surgical and radiation approaches, and more effective systemic therapy,” Dr. Giuliano and his colleagues said (JAMA 2011;305:569-75). They emphasized that this trial did not include patients who had mastectomy, lumpectomy without radiation therapy, partial-breast irradiation, or whole-breast irradiation in the prone position (which would not treat the low axilla). In such patients, “axillary lymph node dissection remains standard practice when sentinel lymph node dissection identifies a positive sentinel lymph node.”

View on The News

A Definitive Answer

The American College of Surgeons Oncology Group Z0011 trial “definitively showed that axillary lymph node dissection is not beneficial,” said Dr. Grant Walter Carlson and Dr. William C. Wood.

Even though 27% of the women who underwent axillary node biopsy were found to have additional lymph nodes containing metastases, the axillary recurrence rates were similar between the two groups.

“Survival was independent of lymph node status and was so good in both groups that longer follow-up has little likelihood of demonstrating any difference between the [two] groups,” they noted. “Taken together, findings from these [and other] investigators provide strong evidence that patients undergoing partial mastectomy, whole-breast irradiation, and systemic therapy for early breast cancer with microscopic sentinel lymph node metastasis can be treated effectively and safely without axillary node dissection.”

DR. CARLSON and DR. WOOD are at Winship Cancer Institute, Emory University, Atlanta. They reported no financial conflicts of interest. These comments were taken from their editorial that accompanied Dr. Giuliano's report (JAMA 2011;305:606-7).

Major Finding: Overall 5-year survival was 91.8% with axillary node dissection and 92.5% without it; the 5-year disease-free survival was 82.2% with axillary node dissection and 83.9% without it. The differences were not significant.

Data Source: A phase III noninferiority trial involving 891 women with invasive node-positive breast cancer treated at 115 medical centers.

Disclosures: This study was supported by the National Cancer Institute. No financial conflicts of interest were reported.

Axillary lymph node dissection did not improve overall survival or disease-free survival in women with T1-T2 breast cancer who were found to have limited metastasis on sentinel node dissection.

In the American College of Surgeons Oncology Group's Z0011 trial, survival was nearly identical between women who underwent lumpectomy and sentinel node dissection alone, followed by adjuvant chemotherapy and tangential-field whole-breast irradiation, and women who underwent axillary node dissection when sentinel node biopsy revealed limited metastasis, followed by the same chemotherapy and irradiation.

“The findings from Z0011 document the high rate of locoregional control achieved with modern multimodal therapy, even without axillary lymph node dissection,” said Dr. Armando E. Giuliano of John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, Calif., and his associates.

The results also imply that axillary node dissection is no longer warranted in such patients, because “the only additional information gained … is the number of nodes containing metastases. This prognostic information is unlikely to change systemic therapy decisions and is obtained at the cost of a significant increase in morbidity,” the investigators noted.

Forgoing the standard practice of axillary node dissection when sentinel nodes reveal metastasis constitutes a practice change that “would improve clinical outcomes in thousands of women each year by reducing the complications associated with axillary lymph node dissection and improving quality of life with no diminution in survival,” they concluded.

The need for axillary node dissection when sentinel nodes are found to have metastasis has been called into question for years, and use of this “standard” practice has declined. Until now, “no study has conclusively demonstrated a survival benefit or detriment for omitting axillary node dissection,” they said.

The ACS Oncology Group's Z0011 trial, begun in the late 1990s, was intended to definitively answer that question. The phase III “noninferiority” trial involved 891 women who were followed at 115 centers after undergoing lumpectomy and sentinel node dissection revealing metastasis. These subjects were randomly assigned to undergo standard axillary node dissection (445 patients) or no axillary node dissection (446 patients), followed by whole-breast tangential-field radiation (not third-field nodal irradiation) and whatever adjuvant systemic therapy their treating physicians deemed necessary.

The trial's enrollment was halted early in 2004 “because of concerns regarding the extremely low mortality rate.” It was determined that accrual of more patients would not alter the survival findings, and final follow-up for the analysis was completed in 2010.

After a median of 6 years of follow-up, there were 94 deaths. The 5-year overall survival was 92.5% with sentinel node dissection alone and 91.8% with full axillary node dissection, a nonsignificant difference. The 5-year disease-free survival rate was 83.9% with sentinel node dissection alone and 82.2% with full axillary node dissection, also a nonsignificant difference. These results were consistent across several subgroups of patients, regardless of patient age, tumor size, tumor hormone-receptor status, or which adjuvant therapies were received.

The two study groups did differ significantly in morbidities related to lymph node dissection. The rate of wound infection, axillary seromas, and paresthesias was markedly higher for women who underwent axillary node dissection (70%) than for those who did not (25%). Lymphedema also was more common with axillary node dissection.

“The excellent local and distant outcomes in this study highlight the effects of multiple changes in breast cancer management” in recent years, including “improved imaging, more detailed pathological evaluation, improved planning of surgical and radiation approaches, and more effective systemic therapy,” Dr. Giuliano and his colleagues said (JAMA 2011;305:569-75). They emphasized that this trial did not include patients who had mastectomy, lumpectomy without radiation therapy, partial-breast irradiation, or whole-breast irradiation in the prone position (which would not treat the low axilla). In such patients, “axillary lymph node dissection remains standard practice when sentinel lymph node dissection identifies a positive sentinel lymph node.”

View on The News

A Definitive Answer

The American College of Surgeons Oncology Group Z0011 trial “definitively showed that axillary lymph node dissection is not beneficial,” said Dr. Grant Walter Carlson and Dr. William C. Wood.

Even though 27% of the women who underwent axillary node biopsy were found to have additional lymph nodes containing metastases, the axillary recurrence rates were similar between the two groups.

“Survival was independent of lymph node status and was so good in both groups that longer follow-up has little likelihood of demonstrating any difference between the [two] groups,” they noted. “Taken together, findings from these [and other] investigators provide strong evidence that patients undergoing partial mastectomy, whole-breast irradiation, and systemic therapy for early breast cancer with microscopic sentinel lymph node metastasis can be treated effectively and safely without axillary node dissection.”

DR. CARLSON and DR. WOOD are at Winship Cancer Institute, Emory University, Atlanta. They reported no financial conflicts of interest. These comments were taken from their editorial that accompanied Dr. Giuliano's report (JAMA 2011;305:606-7).

Major Finding: Of 58 female patients who were between the ages of 9 and 18 years and were diagnosed with PCOS, 15 (26%) of them were preadolescents aged 9–12 years and 43 (74%) of them were adolescents aged 13–18 years.

Data Source: A cross-sectional retrospective chart study of 58 females aged 9–18 years with PCOS.

Disclosures: No funding sources or financial conflicts of interest were reported.

Polycystic ovary syndrome appears to be manifesting at younger ages than previously thought, a study has shown.

The disorder should be considered and a thorough work-up performed in prepubertal girls who have risk factors suggestive of PCOS, with particular attention given to hyperinsulinemia and early pubarche and thelarche, said Dr. Jason Bronstein and his associates at New York University.

In what they described as the largest pediatric PCOS study to date, the researchers found “a large subgroup of young PCOS girls with characteristic metabolic derangements at a younger age, suggesting a need for early therapeutic interventions.”

Early onset of PCOS does not portend well for future complications such as infertility, metabolic syndrome, and vascular disease.

However, earlier recognition and treatment of PCOS might reduce morbidity in later adolescence and adulthood, they noted.

The investigators performed a retrospective, cross-sectional chart study of 58 patients from diverse ethnic backgrounds who attended two large, urban tertiary care centers and were diagnosed as having PCOS between ages 9 and 18 years. Fifteen (26%) of these subjects were preadolescents aged 9–12 years, and 43 (74%) were adolescents aged 13–18 years.

The severity of PCOS was similar between preadolescents and adolescents. Hyperinsulinemia was present in similar proportions of both groups, indicating that metabolic derangement is already present in the youngest girls with PCOS.

However, preadolescent girls were different in that they had significantly earlier pubarche and thelarche than did adolescent girls with PCOS, and the disorder developed much sooner after thelarche in the younger girls.

Clinicians should look for early pubarche and thelarche in girls predisposed to PCOS, the investigators said (J. Pediatr. Adolesc. Gynecol. 2011;24:15-20).

The two groups also had similar risk factors.

Mothers or other relatives had PCOS in approximately 14% of the study subjects, and there were no significant differences between preadolescents and adolescents in historical risk factors such as gestational age at birth, birth weight, childhood obesity, or family history of obesity, diabetes, or hypertension.

There also were no differences between preadolescents and adolescents in clinical risk factors such as body mass index, acne, hirsutism, alopecia, or hyperandrogenism, and no differences in biochemical risk factors such as serum total testosterone and free testosterone levels, insulin resistance, HDL levels, triglyceride levels, or fasting glucose levels.

These findings show that a high index of suspicion is needed to diagnose PCOS in preadolescents.

'We recommend that pediatricians ascertain risk for PCOS in their patients, including maternal factors, family history, birth weight, metabolic factors, and history of premature pubarche and/or early thelarche,” Dr. Bronstein and his colleagues concluded.

Major Finding: Of 58 female patients who were between the ages of 9 and 18 years and were diagnosed with PCOS, 15 (26%) of them were preadolescents aged 9–12 years and 43 (74%) of them were adolescents aged 13–18 years.

Data Source: A cross-sectional retrospective chart study of 58 females aged 9–18 years with PCOS.

Disclosures: No funding sources or financial conflicts of interest were reported.

Polycystic ovary syndrome appears to be manifesting at younger ages than previously thought, a study has shown.

The disorder should be considered and a thorough work-up performed in prepubertal girls who have risk factors suggestive of PCOS, with particular attention given to hyperinsulinemia and early pubarche and thelarche, said Dr. Jason Bronstein and his associates at New York University.

In what they described as the largest pediatric PCOS study to date, the researchers found “a large subgroup of young PCOS girls with characteristic metabolic derangements at a younger age, suggesting a need for early therapeutic interventions.”

Early onset of PCOS does not portend well for future complications such as infertility, metabolic syndrome, and vascular disease.

However, earlier recognition and treatment of PCOS might reduce morbidity in later adolescence and adulthood, they noted.

The investigators performed a retrospective, cross-sectional chart study of 58 patients from diverse ethnic backgrounds who attended two large, urban tertiary care centers and were diagnosed as having PCOS between ages 9 and 18 years. Fifteen (26%) of these subjects were preadolescents aged 9–12 years, and 43 (74%) were adolescents aged 13–18 years.

The severity of PCOS was similar between preadolescents and adolescents. Hyperinsulinemia was present in similar proportions of both groups, indicating that metabolic derangement is already present in the youngest girls with PCOS.

However, preadolescent girls were different in that they had significantly earlier pubarche and thelarche than did adolescent girls with PCOS, and the disorder developed much sooner after thelarche in the younger girls.

Clinicians should look for early pubarche and thelarche in girls predisposed to PCOS, the investigators said (J. Pediatr. Adolesc. Gynecol. 2011;24:15-20).

The two groups also had similar risk factors.

Mothers or other relatives had PCOS in approximately 14% of the study subjects, and there were no significant differences between preadolescents and adolescents in historical risk factors such as gestational age at birth, birth weight, childhood obesity, or family history of obesity, diabetes, or hypertension.

There also were no differences between preadolescents and adolescents in clinical risk factors such as body mass index, acne, hirsutism, alopecia, or hyperandrogenism, and no differences in biochemical risk factors such as serum total testosterone and free testosterone levels, insulin resistance, HDL levels, triglyceride levels, or fasting glucose levels.

These findings show that a high index of suspicion is needed to diagnose PCOS in preadolescents.

'We recommend that pediatricians ascertain risk for PCOS in their patients, including maternal factors, family history, birth weight, metabolic factors, and history of premature pubarche and/or early thelarche,” Dr. Bronstein and his colleagues concluded.

Major Finding: Of 58 female patients who were between the ages of 9 and 18 years and were diagnosed with PCOS, 15 (26%) of them were preadolescents aged 9–12 years and 43 (74%) of them were adolescents aged 13–18 years.

Data Source: A cross-sectional retrospective chart study of 58 females aged 9–18 years with PCOS.

Disclosures: No funding sources or financial conflicts of interest were reported.

Polycystic ovary syndrome appears to be manifesting at younger ages than previously thought, a study has shown.

The disorder should be considered and a thorough work-up performed in prepubertal girls who have risk factors suggestive of PCOS, with particular attention given to hyperinsulinemia and early pubarche and thelarche, said Dr. Jason Bronstein and his associates at New York University.

In what they described as the largest pediatric PCOS study to date, the researchers found “a large subgroup of young PCOS girls with characteristic metabolic derangements at a younger age, suggesting a need for early therapeutic interventions.”

Early onset of PCOS does not portend well for future complications such as infertility, metabolic syndrome, and vascular disease.

However, earlier recognition and treatment of PCOS might reduce morbidity in later adolescence and adulthood, they noted.

The investigators performed a retrospective, cross-sectional chart study of 58 patients from diverse ethnic backgrounds who attended two large, urban tertiary care centers and were diagnosed as having PCOS between ages 9 and 18 years. Fifteen (26%) of these subjects were preadolescents aged 9–12 years, and 43 (74%) were adolescents aged 13–18 years.

The severity of PCOS was similar between preadolescents and adolescents. Hyperinsulinemia was present in similar proportions of both groups, indicating that metabolic derangement is already present in the youngest girls with PCOS.

However, preadolescent girls were different in that they had significantly earlier pubarche and thelarche than did adolescent girls with PCOS, and the disorder developed much sooner after thelarche in the younger girls.

Clinicians should look for early pubarche and thelarche in girls predisposed to PCOS, the investigators said (J. Pediatr. Adolesc. Gynecol. 2011;24:15-20).

The two groups also had similar risk factors.

Mothers or other relatives had PCOS in approximately 14% of the study subjects, and there were no significant differences between preadolescents and adolescents in historical risk factors such as gestational age at birth, birth weight, childhood obesity, or family history of obesity, diabetes, or hypertension.

There also were no differences between preadolescents and adolescents in clinical risk factors such as body mass index, acne, hirsutism, alopecia, or hyperandrogenism, and no differences in biochemical risk factors such as serum total testosterone and free testosterone levels, insulin resistance, HDL levels, triglyceride levels, or fasting glucose levels.

These findings show that a high index of suspicion is needed to diagnose PCOS in preadolescents.

'We recommend that pediatricians ascertain risk for PCOS in their patients, including maternal factors, family history, birth weight, metabolic factors, and history of premature pubarche and/or early thelarche,” Dr. Bronstein and his colleagues concluded.

Major Finding: Women who were current or past smokers have a modestly higher risk of developing breast cancer than women who never smoked.

Data Source: An updated analysis of data collected on 111,140 subjects followed for 30 years in the Nurses' Health Study.

Disclosures: The Nurses' Health Study was funded by the National Cancer Institute. Dr. Xue and associates reported no relevant financial disclosures.

Smoking raises the risk of breast cancer modestly, a study has shown.

Several measures of smoking – including the current quantity of cigarettes smoked, the past quantity of cigarettes smoked, the age at smoking onset, the duration of smoking, and total pack-years of smoking – correlated with risk of breast cancer in an updated analysis of data from the Nurses' Health Study (NHS).

The strongest association was found in women who began smoking before giving birth for the first time, said Dr. Fei Xue of Brigham and Women's Hospital and Harvard Medical School, Boston, and associates.

There have been numerous previous studies of this issue, but they have yielded a mix of positive, inverse, and null associations. In what the investigators described as “the largest [study] so far on the association between smoking and breast cancer risk,” Dr. Xue and colleagues assessed data on 111,140 women participating in the prospective NHS from 1976 through 2006.

During that time there were 8,772 incident cases of breast cancer.

Women who had ever smoked had a “marginally increased” incidence of the disease compared with those who had never smoked, and the rate appeared to be comparable between current smokers and past smokers. “Every increase of 20 pack-years of smoking after menarche was associated with a marginal increase of incidence of breast cancer after adjusting for other risk factors,” the researchers said.

Breast cancer risk was elevated in women who smoked 25 or more cigarettes per day either currently or in the past, women who began smoking at or before the age of 17, and women who smoked for 20 years or longer. “In most of the previous studies, these smoking measures were not mutually adjusted. In [our] study, we created an index of active smoking that integrates quantity, age at which one started smoking, and duration of smoking.

“The results suggested that, although an elevated risk for light smokers and moderate smokers was not apparent, heavy smokers who started smoking early in life, smoked for a long duration, and smoked a high quantity were at the highest risk of breast cancer, supporting an independent and additive effect from various smoking measures on breast carcinogenesis,” they said (Arch. Intern. Med. 2011;171:125-33).

Starting to smoke before the first birth also was strongly linked with breast cancer. “All previous studies that have separately evaluated smoking before and after the first birth have found a similar pattern, suggesting that smoking before the first birth may be more important to breast carcinogenesis than smoking after the first birth,” Dr. Xue and associates wrote.

“Smoking before menopause was positively associated with breast cancer risk, and there were hints from our results that smoking after menopause might be associated with a slightly decreased breast cancer risk. This difference suggests an antiestrogenic effect of smoking among postmenopausal women that may further reduce theiralready low endogenous estrogen levels.

“Conversely, among premenopausal women, any antiestrogenic effect of smoking may not be strong enough to significantly reduce endogenous estrogen levels, leaving the dominant carcinogenic effect of smoking,” the researchers said.

In contrast to active smoking, passive smoking in childhood or adulthood was not linked with breast cancer risk.

“Our results combined with the evidence from previous prospective cohort studies collectively suggest that passive smoking may not play an important role in the etiology of breast cancer. Nonetheless, we found that regular exposure to passive smoking may magnify the effect of active smoking,” wrote Dr. Xue and colleagues.

Major Finding: Women who were current or past smokers have a modestly higher risk of developing breast cancer than women who never smoked.

Data Source: An updated analysis of data collected on 111,140 subjects followed for 30 years in the Nurses' Health Study.

Disclosures: The Nurses' Health Study was funded by the National Cancer Institute. Dr. Xue and associates reported no relevant financial disclosures.

Smoking raises the risk of breast cancer modestly, a study has shown.

Several measures of smoking – including the current quantity of cigarettes smoked, the past quantity of cigarettes smoked, the age at smoking onset, the duration of smoking, and total pack-years of smoking – correlated with risk of breast cancer in an updated analysis of data from the Nurses' Health Study (NHS).

The strongest association was found in women who began smoking before giving birth for the first time, said Dr. Fei Xue of Brigham and Women's Hospital and Harvard Medical School, Boston, and associates.

There have been numerous previous studies of this issue, but they have yielded a mix of positive, inverse, and null associations. In what the investigators described as “the largest [study] so far on the association between smoking and breast cancer risk,” Dr. Xue and colleagues assessed data on 111,140 women participating in the prospective NHS from 1976 through 2006.

During that time there were 8,772 incident cases of breast cancer.

Women who had ever smoked had a “marginally increased” incidence of the disease compared with those who had never smoked, and the rate appeared to be comparable between current smokers and past smokers. “Every increase of 20 pack-years of smoking after menarche was associated with a marginal increase of incidence of breast cancer after adjusting for other risk factors,” the researchers said.

Breast cancer risk was elevated in women who smoked 25 or more cigarettes per day either currently or in the past, women who began smoking at or before the age of 17, and women who smoked for 20 years or longer. “In most of the previous studies, these smoking measures were not mutually adjusted. In [our] study, we created an index of active smoking that integrates quantity, age at which one started smoking, and duration of smoking.

“The results suggested that, although an elevated risk for light smokers and moderate smokers was not apparent, heavy smokers who started smoking early in life, smoked for a long duration, and smoked a high quantity were at the highest risk of breast cancer, supporting an independent and additive effect from various smoking measures on breast carcinogenesis,” they said (Arch. Intern. Med. 2011;171:125-33).

Starting to smoke before the first birth also was strongly linked with breast cancer. “All previous studies that have separately evaluated smoking before and after the first birth have found a similar pattern, suggesting that smoking before the first birth may be more important to breast carcinogenesis than smoking after the first birth,” Dr. Xue and associates wrote.

“Smoking before menopause was positively associated with breast cancer risk, and there were hints from our results that smoking after menopause might be associated with a slightly decreased breast cancer risk. This difference suggests an antiestrogenic effect of smoking among postmenopausal women that may further reduce theiralready low endogenous estrogen levels.

“Conversely, among premenopausal women, any antiestrogenic effect of smoking may not be strong enough to significantly reduce endogenous estrogen levels, leaving the dominant carcinogenic effect of smoking,” the researchers said.

In contrast to active smoking, passive smoking in childhood or adulthood was not linked with breast cancer risk.

“Our results combined with the evidence from previous prospective cohort studies collectively suggest that passive smoking may not play an important role in the etiology of breast cancer. Nonetheless, we found that regular exposure to passive smoking may magnify the effect of active smoking,” wrote Dr. Xue and colleagues.

Major Finding: Women who were current or past smokers have a modestly higher risk of developing breast cancer than women who never smoked.

Data Source: An updated analysis of data collected on 111,140 subjects followed for 30 years in the Nurses' Health Study.

Disclosures: The Nurses' Health Study was funded by the National Cancer Institute. Dr. Xue and associates reported no relevant financial disclosures.

Smoking raises the risk of breast cancer modestly, a study has shown.

Several measures of smoking – including the current quantity of cigarettes smoked, the past quantity of cigarettes smoked, the age at smoking onset, the duration of smoking, and total pack-years of smoking – correlated with risk of breast cancer in an updated analysis of data from the Nurses' Health Study (NHS).

The strongest association was found in women who began smoking before giving birth for the first time, said Dr. Fei Xue of Brigham and Women's Hospital and Harvard Medical School, Boston, and associates.

There have been numerous previous studies of this issue, but they have yielded a mix of positive, inverse, and null associations. In what the investigators described as “the largest [study] so far on the association between smoking and breast cancer risk,” Dr. Xue and colleagues assessed data on 111,140 women participating in the prospective NHS from 1976 through 2006.

During that time there were 8,772 incident cases of breast cancer.

Women who had ever smoked had a “marginally increased” incidence of the disease compared with those who had never smoked, and the rate appeared to be comparable between current smokers and past smokers. “Every increase of 20 pack-years of smoking after menarche was associated with a marginal increase of incidence of breast cancer after adjusting for other risk factors,” the researchers said.

Breast cancer risk was elevated in women who smoked 25 or more cigarettes per day either currently or in the past, women who began smoking at or before the age of 17, and women who smoked for 20 years or longer. “In most of the previous studies, these smoking measures were not mutually adjusted. In [our] study, we created an index of active smoking that integrates quantity, age at which one started smoking, and duration of smoking.

“The results suggested that, although an elevated risk for light smokers and moderate smokers was not apparent, heavy smokers who started smoking early in life, smoked for a long duration, and smoked a high quantity were at the highest risk of breast cancer, supporting an independent and additive effect from various smoking measures on breast carcinogenesis,” they said (Arch. Intern. Med. 2011;171:125-33).

Starting to smoke before the first birth also was strongly linked with breast cancer. “All previous studies that have separately evaluated smoking before and after the first birth have found a similar pattern, suggesting that smoking before the first birth may be more important to breast carcinogenesis than smoking after the first birth,” Dr. Xue and associates wrote.

“Smoking before menopause was positively associated with breast cancer risk, and there were hints from our results that smoking after menopause might be associated with a slightly decreased breast cancer risk. This difference suggests an antiestrogenic effect of smoking among postmenopausal women that may further reduce theiralready low endogenous estrogen levels.

“Conversely, among premenopausal women, any antiestrogenic effect of smoking may not be strong enough to significantly reduce endogenous estrogen levels, leaving the dominant carcinogenic effect of smoking,” the researchers said.

In contrast to active smoking, passive smoking in childhood or adulthood was not linked with breast cancer risk.

“Our results combined with the evidence from previous prospective cohort studies collectively suggest that passive smoking may not play an important role in the etiology of breast cancer. Nonetheless, we found that regular exposure to passive smoking may magnify the effect of active smoking,” wrote Dr. Xue and colleagues.

For opioid-dependent women who are pregnant, buprenorphine appears to offer an effective, safe, first-line alternative to methadone.

In a randomized clinical trial comparing pregnancy outcomes among women seeking treatment for opioid dependence, infants exposed in utero to buprenorphine developed significantly less severe neonatal abstinence syndrome than did infants exposed in utero to methadone, said Hendrée E. Jones, Ph.D., of Johns Hopkins University, Baltimore, and her associates.

The study involved 175 women aged 18–41 years who were at 6–30 weeks' gestation when they entered treatment for opioid dependence at eight sites in the United States, Austria, and Canada. Eighty-six were randomly assigned to receive oral buprenorphine and 89 to receive oral methadone in a double-blind fashion.

After delivery, their neonates were assessed for signs and symptoms of neonatal abstinence syndrome (NAS) twice a day for at least 10 days.

There were five primary neonatal outcomes. Three of these – percentage of neonates requiring NAS treatment, peak NAS scores, and head circumference – did not differ between the two study groups. However, two of the five primary outcomes – amount of morphine required to treat NAS and length of hospital stay – favored the infants in the buprenorphine group. On average, infants exposed to buprenorphine required 89% less morphine and spent 43% less time in the hospital (10 days vs. 17.5 days) than did infants exposed to methadone.

“The benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy,” they said (N. Engl. J. Med. 2010;363:2320-31).

Despite the comparable or even superior efficacy and safety of buprenorphine, there was one important drawback with the therapy: Women were more likely to discontinue treatment for opioid dependency with buprenorphine (33%) than with methadone (18%).

Most (71%) of the women in the buprenorphine group who discontinued treatment cited “dissatisfaction” with the drug as their reason, while only 13% of those in the methadone group did so.

Future research should focus on reducing this “dissatisfaction” as well as on identifying “subpopulations of pregnant patients who are more likely to have a response to one medication than to the other,” they added.

This study was funded by grants from the National Institute on Drug Abuse. Buprenorphine tablets and the associated placebo were supplied by Reckitt Benckiser Healthcare. Dr. Jones's associates reported ties to numerous drug companies.

For opioid-dependent women who are pregnant, buprenorphine appears to offer an effective, safe, first-line alternative to methadone.

In a randomized clinical trial comparing pregnancy outcomes among women seeking treatment for opioid dependence, infants exposed in utero to buprenorphine developed significantly less severe neonatal abstinence syndrome than did infants exposed in utero to methadone, said Hendrée E. Jones, Ph.D., of Johns Hopkins University, Baltimore, and her associates.

The study involved 175 women aged 18–41 years who were at 6–30 weeks' gestation when they entered treatment for opioid dependence at eight sites in the United States, Austria, and Canada. Eighty-six were randomly assigned to receive oral buprenorphine and 89 to receive oral methadone in a double-blind fashion.

After delivery, their neonates were assessed for signs and symptoms of neonatal abstinence syndrome (NAS) twice a day for at least 10 days.

There were five primary neonatal outcomes. Three of these – percentage of neonates requiring NAS treatment, peak NAS scores, and head circumference – did not differ between the two study groups. However, two of the five primary outcomes – amount of morphine required to treat NAS and length of hospital stay – favored the infants in the buprenorphine group. On average, infants exposed to buprenorphine required 89% less morphine and spent 43% less time in the hospital (10 days vs. 17.5 days) than did infants exposed to methadone.

“The benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy,” they said (N. Engl. J. Med. 2010;363:2320-31).

Despite the comparable or even superior efficacy and safety of buprenorphine, there was one important drawback with the therapy: Women were more likely to discontinue treatment for opioid dependency with buprenorphine (33%) than with methadone (18%).

Most (71%) of the women in the buprenorphine group who discontinued treatment cited “dissatisfaction” with the drug as their reason, while only 13% of those in the methadone group did so.

Future research should focus on reducing this “dissatisfaction” as well as on identifying “subpopulations of pregnant patients who are more likely to have a response to one medication than to the other,” they added.

This study was funded by grants from the National Institute on Drug Abuse. Buprenorphine tablets and the associated placebo were supplied by Reckitt Benckiser Healthcare. Dr. Jones's associates reported ties to numerous drug companies.

For opioid-dependent women who are pregnant, buprenorphine appears to offer an effective, safe, first-line alternative to methadone.

In a randomized clinical trial comparing pregnancy outcomes among women seeking treatment for opioid dependence, infants exposed in utero to buprenorphine developed significantly less severe neonatal abstinence syndrome than did infants exposed in utero to methadone, said Hendrée E. Jones, Ph.D., of Johns Hopkins University, Baltimore, and her associates.

The study involved 175 women aged 18–41 years who were at 6–30 weeks' gestation when they entered treatment for opioid dependence at eight sites in the United States, Austria, and Canada. Eighty-six were randomly assigned to receive oral buprenorphine and 89 to receive oral methadone in a double-blind fashion.

After delivery, their neonates were assessed for signs and symptoms of neonatal abstinence syndrome (NAS) twice a day for at least 10 days.

There were five primary neonatal outcomes. Three of these – percentage of neonates requiring NAS treatment, peak NAS scores, and head circumference – did not differ between the two study groups. However, two of the five primary outcomes – amount of morphine required to treat NAS and length of hospital stay – favored the infants in the buprenorphine group. On average, infants exposed to buprenorphine required 89% less morphine and spent 43% less time in the hospital (10 days vs. 17.5 days) than did infants exposed to methadone.

“The benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy,” they said (N. Engl. J. Med. 2010;363:2320-31).

Despite the comparable or even superior efficacy and safety of buprenorphine, there was one important drawback with the therapy: Women were more likely to discontinue treatment for opioid dependency with buprenorphine (33%) than with methadone (18%).

Most (71%) of the women in the buprenorphine group who discontinued treatment cited “dissatisfaction” with the drug as their reason, while only 13% of those in the methadone group did so.

Future research should focus on reducing this “dissatisfaction” as well as on identifying “subpopulations of pregnant patients who are more likely to have a response to one medication than to the other,” they added.

This study was funded by grants from the National Institute on Drug Abuse. Buprenorphine tablets and the associated placebo were supplied by Reckitt Benckiser Healthcare. Dr. Jones's associates reported ties to numerous drug companies.

The herpes zoster vaccine reduced the incidence of the disease by 55% in real-world clinical practice, according to a recent report.

This finding, from a retrospective cohort study involving more than 303,000 healthy, community-dwelling adults aged 60 and older from diverse backgrounds, confirms and extends the results of clinical trials that found the vaccine effective under idealized conditions.

The cohort study found further benefits that had not been shown before: The herpes zoster vaccine also decreased the rate of ophthalmic herpes, and it was effective in patients with underlying chronic diseases that were feared to interfere with their immune function.

Thus, the benefits of the herpes zoster vaccine extend to the ophthalmic manifestation of the disease, to all races, both genders, and all ages over 60, as well as to patients with chronic illness, said Hung Fu Tseng, Ph.D., of Southern California Kaiser Permanente, Pasadena, and associates.

These results are particularly important given that the public's acceptance of the vaccine has been slow and it is not yet in widespread use. “This vaccine has the potential to annually prevent tens of thousands of cases of herpes zoster and postherpetic neuralgia nationally. To date, herpes zoster vaccine uptake has been poor due to weaknesses in the adult vaccine infrastructure and serious barriers to the vaccine among clinicians and patients.

They assessed the vaccine's effectiveness in 75,761 California patients in the managed care plan who were immunized in 2007–2009, comparing outcomes with those of 227,283 age-matched control subjects who were not vaccinated. A total of 5,434 cases of herpes zoster developed during an average follow-up of 1–2 years.

The incidence of herpes zoster was 6.4 per 1,000 person-years in the vaccinated group, compared with 13 per 1,000 patient-years in the control group. This reflects a 55% reduction in incidence with the vaccine, the investigators wrote. This result showed that “1 episode of herpes zoster would be averted for every 71 patients” vaccinated, they wrote (JAMA 2011;305:160–6).

The vaccine benefit persisted across all subgroups of patients, particularly in the oldest subjects. “Our results support recommendations to offer herpes zoster vaccine to eligible patients of all ages, including the oldest population,” Dr. Tseng and his associates wrote.

“For the oldest group, this could translate into a very large absolute reduction in disease because they bear the greatest burden of herpes zoster and postherpetic neuralgia,” the researchers added.

Effectiveness against ophthalmic herpes is an important finding not reported previously. Ophthalmic involvement is common and can lead to serious vision-threatening sequelae, they noted.

The finding that the vaccine also was effective in patients with chronic underlying disease was “reassuring,” because “these diseases might have interfered with functional immunity and vaccine effectiveness. Control of pain from herpes zoster and postherpetic neuralgia is complicated in these patients because of their underlying conditions and the medications they must take,” the authors wrote.

The study involved only fully insured patients in a single region of the country, limiting its generalizability.

The herpes zoster vaccine reduced the incidence of the disease by 55% in real-world clinical practice, according to a recent report.

This finding, from a retrospective cohort study involving more than 303,000 healthy, community-dwelling adults aged 60 and older from diverse backgrounds, confirms and extends the results of clinical trials that found the vaccine effective under idealized conditions.

The cohort study found further benefits that had not been shown before: The herpes zoster vaccine also decreased the rate of ophthalmic herpes, and it was effective in patients with underlying chronic diseases that were feared to interfere with their immune function.

Thus, the benefits of the herpes zoster vaccine extend to the ophthalmic manifestation of the disease, to all races, both genders, and all ages over 60, as well as to patients with chronic illness, said Hung Fu Tseng, Ph.D., of Southern California Kaiser Permanente, Pasadena, and associates.

These results are particularly important given that the public's acceptance of the vaccine has been slow and it is not yet in widespread use. “This vaccine has the potential to annually prevent tens of thousands of cases of herpes zoster and postherpetic neuralgia nationally. To date, herpes zoster vaccine uptake has been poor due to weaknesses in the adult vaccine infrastructure and serious barriers to the vaccine among clinicians and patients.

They assessed the vaccine's effectiveness in 75,761 California patients in the managed care plan who were immunized in 2007–2009, comparing outcomes with those of 227,283 age-matched control subjects who were not vaccinated. A total of 5,434 cases of herpes zoster developed during an average follow-up of 1–2 years.

The incidence of herpes zoster was 6.4 per 1,000 person-years in the vaccinated group, compared with 13 per 1,000 patient-years in the control group. This reflects a 55% reduction in incidence with the vaccine, the investigators wrote. This result showed that “1 episode of herpes zoster would be averted for every 71 patients” vaccinated, they wrote (JAMA 2011;305:160–6).

The vaccine benefit persisted across all subgroups of patients, particularly in the oldest subjects. “Our results support recommendations to offer herpes zoster vaccine to eligible patients of all ages, including the oldest population,” Dr. Tseng and his associates wrote.

“For the oldest group, this could translate into a very large absolute reduction in disease because they bear the greatest burden of herpes zoster and postherpetic neuralgia,” the researchers added.

Effectiveness against ophthalmic herpes is an important finding not reported previously. Ophthalmic involvement is common and can lead to serious vision-threatening sequelae, they noted.

The finding that the vaccine also was effective in patients with chronic underlying disease was “reassuring,” because “these diseases might have interfered with functional immunity and vaccine effectiveness. Control of pain from herpes zoster and postherpetic neuralgia is complicated in these patients because of their underlying conditions and the medications they must take,” the authors wrote.

The study involved only fully insured patients in a single region of the country, limiting its generalizability.

The herpes zoster vaccine reduced the incidence of the disease by 55% in real-world clinical practice, according to a recent report.

This finding, from a retrospective cohort study involving more than 303,000 healthy, community-dwelling adults aged 60 and older from diverse backgrounds, confirms and extends the results of clinical trials that found the vaccine effective under idealized conditions.

The cohort study found further benefits that had not been shown before: The herpes zoster vaccine also decreased the rate of ophthalmic herpes, and it was effective in patients with underlying chronic diseases that were feared to interfere with their immune function.

Thus, the benefits of the herpes zoster vaccine extend to the ophthalmic manifestation of the disease, to all races, both genders, and all ages over 60, as well as to patients with chronic illness, said Hung Fu Tseng, Ph.D., of Southern California Kaiser Permanente, Pasadena, and associates.

These results are particularly important given that the public's acceptance of the vaccine has been slow and it is not yet in widespread use. “This vaccine has the potential to annually prevent tens of thousands of cases of herpes zoster and postherpetic neuralgia nationally. To date, herpes zoster vaccine uptake has been poor due to weaknesses in the adult vaccine infrastructure and serious barriers to the vaccine among clinicians and patients.

They assessed the vaccine's effectiveness in 75,761 California patients in the managed care plan who were immunized in 2007–2009, comparing outcomes with those of 227,283 age-matched control subjects who were not vaccinated. A total of 5,434 cases of herpes zoster developed during an average follow-up of 1–2 years.

The incidence of herpes zoster was 6.4 per 1,000 person-years in the vaccinated group, compared with 13 per 1,000 patient-years in the control group. This reflects a 55% reduction in incidence with the vaccine, the investigators wrote. This result showed that “1 episode of herpes zoster would be averted for every 71 patients” vaccinated, they wrote (JAMA 2011;305:160–6).

The vaccine benefit persisted across all subgroups of patients, particularly in the oldest subjects. “Our results support recommendations to offer herpes zoster vaccine to eligible patients of all ages, including the oldest population,” Dr. Tseng and his associates wrote.

“For the oldest group, this could translate into a very large absolute reduction in disease because they bear the greatest burden of herpes zoster and postherpetic neuralgia,” the researchers added.

Effectiveness against ophthalmic herpes is an important finding not reported previously. Ophthalmic involvement is common and can lead to serious vision-threatening sequelae, they noted.

The finding that the vaccine also was effective in patients with chronic underlying disease was “reassuring,” because “these diseases might have interfered with functional immunity and vaccine effectiveness. Control of pain from herpes zoster and postherpetic neuralgia is complicated in these patients because of their underlying conditions and the medications they must take,” the authors wrote.

The study involved only fully insured patients in a single region of the country, limiting its generalizability.

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, they said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both. However, headaches were much more common with active nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study because of headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers said.

View on the News

Next Step: Assess Fracture Rate

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011;305:826-7).

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, they said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both. However, headaches were much more common with active nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study because of headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers said.

View on the News

Next Step: Assess Fracture Rate

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011;305:826-7).

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, they said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both. However, headaches were much more common with active nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study because of headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers said.

View on the News

Next Step: Assess Fracture Rate

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011;305:826-7).