Osteoporosis

It may be appropriate to forgo dual-energy x-ray absorptiometry scanning and instead use body mass index to rule out osteoporosis in some obese patients, according to the findings of a large study presented by Dr. Thomas Nelson at the annual European Congress of Rheumatology.

Patients in the study with a BMI greater than 30 kg/m², age younger than 70 years, and few clinical risk factors for osteoporosis had a low prevalence of osteoporosis, compared with the general population, said Dr. Nelson, a rheumatologist at the Royal Lancaster (England) Infirmary.

For example, after correction for risk factors including age, sex, index of deprivation, and a number of clinical risk factors (such as recurrent falls, smoking, rheumatoid arthritis, corticosteroid use, maternal hip fracture, excessive consumption of alcohol, fragility fractures, and secondary osteoporosis), a low BMI in 10,657 patients who were randomly assigned to a reference cohort was found to be an independent predictor of osteoporosis (area under the ROC curve, 0.72 for total hip osteoporosis and 0.67 for lumbar spine osteoporosis).

Use of a BMI threshold "of approximately 30 was found to give 93.6% sensitivity for hip osteoporosis and 90.8% for lumbar spine osteoporosis," Dr. Nelson said.

Thus, a hypothesis was formed that in obese patients, osteoporosis could be excluded without dual-energy x-ray absorptiometry (DXA), and only 6.4% of patients with hip osteoporosis – and 9.2% with lumbar spine osteoporosis – would be missed.

When the hypothesis was applied in a validation cohort of 5,329 patients, hip osteoporosis was seen in 2.7% of obese patients, and lumbar spine osteoporosis was observed in 7.2%, compared with 10.7% and 16.6%, respectively, in the entire cohort.

Among those younger than age 70 years, only 0.7% and 5.4% had hip and lumbar spine osteoporosis, respectively.

Patients in the study were scanned between June 2004 and August 2010. They were randomly assigned to the reference or validation cohorts. The cohorts did not differ in regard to age, sex, BMI, body fat percentage, deprivation, or number of clinical risk factors. About 23% of patients in both groups were obese.

Should the suggestion that DXA scanning is unnecessary for ruling out osteoporosis in obese patients be validated in other populations, the finding could help to minimize radiation exposure, improve convenience, and lower costs for many patients. However, it is plausible that a greater bone mineral density is required by obese patients, compared with nonobese patients, to avoid symptoms and fracture risk associated with osteoporosis, and further research is required in this area, he concluded.

Dr. Nelson had no disclosures to report.

It may be appropriate to forgo dual-energy x-ray absorptiometry scanning and instead use body mass index to rule out osteoporosis in some obese patients, according to the findings of a large study presented by Dr. Thomas Nelson at the annual European Congress of Rheumatology.

Patients in the study with a BMI greater than 30 kg/m², age younger than 70 years, and few clinical risk factors for osteoporosis had a low prevalence of osteoporosis, compared with the general population, said Dr. Nelson, a rheumatologist at the Royal Lancaster (England) Infirmary.

For example, after correction for risk factors including age, sex, index of deprivation, and a number of clinical risk factors (such as recurrent falls, smoking, rheumatoid arthritis, corticosteroid use, maternal hip fracture, excessive consumption of alcohol, fragility fractures, and secondary osteoporosis), a low BMI in 10,657 patients who were randomly assigned to a reference cohort was found to be an independent predictor of osteoporosis (area under the ROC curve, 0.72 for total hip osteoporosis and 0.67 for lumbar spine osteoporosis).

Use of a BMI threshold "of approximately 30 was found to give 93.6% sensitivity for hip osteoporosis and 90.8% for lumbar spine osteoporosis," Dr. Nelson said.

Thus, a hypothesis was formed that in obese patients, osteoporosis could be excluded without dual-energy x-ray absorptiometry (DXA), and only 6.4% of patients with hip osteoporosis – and 9.2% with lumbar spine osteoporosis – would be missed.

When the hypothesis was applied in a validation cohort of 5,329 patients, hip osteoporosis was seen in 2.7% of obese patients, and lumbar spine osteoporosis was observed in 7.2%, compared with 10.7% and 16.6%, respectively, in the entire cohort.

Among those younger than age 70 years, only 0.7% and 5.4% had hip and lumbar spine osteoporosis, respectively.

Patients in the study were scanned between June 2004 and August 2010. They were randomly assigned to the reference or validation cohorts. The cohorts did not differ in regard to age, sex, BMI, body fat percentage, deprivation, or number of clinical risk factors. About 23% of patients in both groups were obese.

Should the suggestion that DXA scanning is unnecessary for ruling out osteoporosis in obese patients be validated in other populations, the finding could help to minimize radiation exposure, improve convenience, and lower costs for many patients. However, it is plausible that a greater bone mineral density is required by obese patients, compared with nonobese patients, to avoid symptoms and fracture risk associated with osteoporosis, and further research is required in this area, he concluded.

Dr. Nelson had no disclosures to report.

It may be appropriate to forgo dual-energy x-ray absorptiometry scanning and instead use body mass index to rule out osteoporosis in some obese patients, according to the findings of a large study presented by Dr. Thomas Nelson at the annual European Congress of Rheumatology.

Patients in the study with a BMI greater than 30 kg/m², age younger than 70 years, and few clinical risk factors for osteoporosis had a low prevalence of osteoporosis, compared with the general population, said Dr. Nelson, a rheumatologist at the Royal Lancaster (England) Infirmary.

For example, after correction for risk factors including age, sex, index of deprivation, and a number of clinical risk factors (such as recurrent falls, smoking, rheumatoid arthritis, corticosteroid use, maternal hip fracture, excessive consumption of alcohol, fragility fractures, and secondary osteoporosis), a low BMI in 10,657 patients who were randomly assigned to a reference cohort was found to be an independent predictor of osteoporosis (area under the ROC curve, 0.72 for total hip osteoporosis and 0.67 for lumbar spine osteoporosis).

Use of a BMI threshold "of approximately 30 was found to give 93.6% sensitivity for hip osteoporosis and 90.8% for lumbar spine osteoporosis," Dr. Nelson said.

Thus, a hypothesis was formed that in obese patients, osteoporosis could be excluded without dual-energy x-ray absorptiometry (DXA), and only 6.4% of patients with hip osteoporosis – and 9.2% with lumbar spine osteoporosis – would be missed.

When the hypothesis was applied in a validation cohort of 5,329 patients, hip osteoporosis was seen in 2.7% of obese patients, and lumbar spine osteoporosis was observed in 7.2%, compared with 10.7% and 16.6%, respectively, in the entire cohort.

Among those younger than age 70 years, only 0.7% and 5.4% had hip and lumbar spine osteoporosis, respectively.

Patients in the study were scanned between June 2004 and August 2010. They were randomly assigned to the reference or validation cohorts. The cohorts did not differ in regard to age, sex, BMI, body fat percentage, deprivation, or number of clinical risk factors. About 23% of patients in both groups were obese.

Should the suggestion that DXA scanning is unnecessary for ruling out osteoporosis in obese patients be validated in other populations, the finding could help to minimize radiation exposure, improve convenience, and lower costs for many patients. However, it is plausible that a greater bone mineral density is required by obese patients, compared with nonobese patients, to avoid symptoms and fracture risk associated with osteoporosis, and further research is required in this area, he concluded.

Dr. Nelson had no disclosures to report.

TAMPA – The treatment of osteoporosis is in flux because of a variety of forces, including a substantial increase in the number of aging patients deemed eligible for treatments, a leading geriatrician said. Just as baby boomers begin reaching senior status, a recently developed tool for assessing people’s fracture risk is increasing the number of patients considered suitable for preventive therapy.

Meanwhile, those therapy options are multiplying, and emerging evidence suggests that one, bisphosphonates, is associated with an increased risk for atypical fractures, although the absolute risk appears to be low, Dr. Barbara Messinger-Rapport, said at the AMDA Dedicated to Long Term Care Medicine annual meeting.

The assessment tool making a difference is the Web-based Fracture Risk Assessment Tool (FRAX), released by the World Health Organization in 2008. FRAX guides clinicians to consider drug therapy for patients with T scores (deviations from healthy bone density) of –2.5 or lower at the femoral neck or spine, a T score between –1.0 and –2.5 as well as a 3% or higher calculated risk for hip fracture over 10 years, or a 20% or greater risk of major osteoporosis-related fracture.

Even if a person’s T score never reaches –2.5, his or her hip fracture risk can climb to 3% or higher, said Dr. Messinger-Rapport, director of the Center for Geriatric Medicine at the Cleveland Clinic and medical director of the Fairfax Health Care Center Nursing Home, also in Cleveland. "This could widen the number of people who could be put on treatment."

Bisphosphonates remain the most-common treatment strategy, but optimal duration of therapy, timing of drug holidays, and how age and gender play into risk for adverse events remains unclear, she said.

A newer option, the monoclonal antibody denosumab (Prolia, Amgen), significantly reduced vertebral fractures compared with a placebo in published studies. Administered as a subcutaneous injection every 6 months, denosumab also may be more convenient than agents requiring infusion, Dr. Messinger-Rapport said.

Higher cost is a consideration, however. Wholesale cost of denosumab is approximately $850/60-mg subcutaneous injection. In contrast, generic alendronate costs $100-$200/year; brand-name oral bisphosphonate costs up to $1,000/year; and zoledronic acid, delivered via intravenous infusion, is approximately $1,100/year, she said.

Denosumab’s impact on clinical care is not yet know, Dr. Messinger-Rapport said. She suggested that clinicians consider this agent in high-risk elders, women or men with osteoporosis, men with prostate cancer with androgen deprivation, patients with metastatic prostate or breast cancer, and possibly patients with renal impairment (denosumab clearance is not renal). Also consider denosumab for patients who cannot tolerate a bisphosphonate either orally or by infusion, she added.

Researchers showed a 68% decrease in vertebral fractures, a 40% decline in hip fractures, and a 20% decrease in nonvertebral fractures with denosumab versus placebo in the FREEDOM study of osteoporotic women treated for 36 months (N. Engl. J. Med. 2009;361:756-65). A similar 62% decrease in vertebral fractures with denosumab, compared with placebo, was observed in a 24-month study of men with androgen deprivation for prostate cancer (N. Engl. J. Med. 2009;361:745-55).

Researchers also have examined reports of atypical femoral fractures associated with bisphosphonate use and found an association. For example, in a study published last year, 17 of 20 atypical femoral fractures occurred in patients taking oral bisphosphonates (N. Engl. J. Med. 2010;363:1848-9). In a New England Journal letter (N. Engl. J. Med. 2010;362:1848-9), the researchers stated that although they found the association, "overall the anti-fracture effects of bisphosphonates far outweigh their potential risks."

More recently, other investigators found an increased risk of subtrochanteric and femoral shaft fractures in women treated for 5 years or more with oral bisphosphonates (JAMA 2011;305:783-9). The authors stated that the absolute risk of the atypical fractures is low, however.

Dr. Messinger-Rapport listed contraindications to bisphosphonates as a prior allergic reaction, vitamin D depletion (less than 30 ng/mL), hypocalcemia, dysphagia, esophageal disorders, and severe gastroesophageal reflux disorder.

A person attending the meeting asked if it is appropriate to continue bisphosphonate therapy after a patient’s T score improves. "Yes, even if the T score only improves by a few percentage points," Dr. Messinger-Rapport replied, because there is a disproportionate benefit in terms of fracture risk reduction.

Dr. Messinger-Rapport disclosed that she is an editorial board member for the National Osteoporosis Foundation.

TAMPA – The treatment of osteoporosis is in flux because of a variety of forces, including a substantial increase in the number of aging patients deemed eligible for treatments, a leading geriatrician said. Just as baby boomers begin reaching senior status, a recently developed tool for assessing people’s fracture risk is increasing the number of patients considered suitable for preventive therapy.

Meanwhile, those therapy options are multiplying, and emerging evidence suggests that one, bisphosphonates, is associated with an increased risk for atypical fractures, although the absolute risk appears to be low, Dr. Barbara Messinger-Rapport, said at the AMDA Dedicated to Long Term Care Medicine annual meeting.

The assessment tool making a difference is the Web-based Fracture Risk Assessment Tool (FRAX), released by the World Health Organization in 2008. FRAX guides clinicians to consider drug therapy for patients with T scores (deviations from healthy bone density) of –2.5 or lower at the femoral neck or spine, a T score between –1.0 and –2.5 as well as a 3% or higher calculated risk for hip fracture over 10 years, or a 20% or greater risk of major osteoporosis-related fracture.

Even if a person’s T score never reaches –2.5, his or her hip fracture risk can climb to 3% or higher, said Dr. Messinger-Rapport, director of the Center for Geriatric Medicine at the Cleveland Clinic and medical director of the Fairfax Health Care Center Nursing Home, also in Cleveland. "This could widen the number of people who could be put on treatment."

Bisphosphonates remain the most-common treatment strategy, but optimal duration of therapy, timing of drug holidays, and how age and gender play into risk for adverse events remains unclear, she said.

A newer option, the monoclonal antibody denosumab (Prolia, Amgen), significantly reduced vertebral fractures compared with a placebo in published studies. Administered as a subcutaneous injection every 6 months, denosumab also may be more convenient than agents requiring infusion, Dr. Messinger-Rapport said.

Higher cost is a consideration, however. Wholesale cost of denosumab is approximately $850/60-mg subcutaneous injection. In contrast, generic alendronate costs $100-$200/year; brand-name oral bisphosphonate costs up to $1,000/year; and zoledronic acid, delivered via intravenous infusion, is approximately $1,100/year, she said.

Denosumab’s impact on clinical care is not yet know, Dr. Messinger-Rapport said. She suggested that clinicians consider this agent in high-risk elders, women or men with osteoporosis, men with prostate cancer with androgen deprivation, patients with metastatic prostate or breast cancer, and possibly patients with renal impairment (denosumab clearance is not renal). Also consider denosumab for patients who cannot tolerate a bisphosphonate either orally or by infusion, she added.

Researchers showed a 68% decrease in vertebral fractures, a 40% decline in hip fractures, and a 20% decrease in nonvertebral fractures with denosumab versus placebo in the FREEDOM study of osteoporotic women treated for 36 months (N. Engl. J. Med. 2009;361:756-65). A similar 62% decrease in vertebral fractures with denosumab, compared with placebo, was observed in a 24-month study of men with androgen deprivation for prostate cancer (N. Engl. J. Med. 2009;361:745-55).

Researchers also have examined reports of atypical femoral fractures associated with bisphosphonate use and found an association. For example, in a study published last year, 17 of 20 atypical femoral fractures occurred in patients taking oral bisphosphonates (N. Engl. J. Med. 2010;363:1848-9). In a New England Journal letter (N. Engl. J. Med. 2010;362:1848-9), the researchers stated that although they found the association, "overall the anti-fracture effects of bisphosphonates far outweigh their potential risks."

More recently, other investigators found an increased risk of subtrochanteric and femoral shaft fractures in women treated for 5 years or more with oral bisphosphonates (JAMA 2011;305:783-9). The authors stated that the absolute risk of the atypical fractures is low, however.

Dr. Messinger-Rapport listed contraindications to bisphosphonates as a prior allergic reaction, vitamin D depletion (less than 30 ng/mL), hypocalcemia, dysphagia, esophageal disorders, and severe gastroesophageal reflux disorder.

A person attending the meeting asked if it is appropriate to continue bisphosphonate therapy after a patient’s T score improves. "Yes, even if the T score only improves by a few percentage points," Dr. Messinger-Rapport replied, because there is a disproportionate benefit in terms of fracture risk reduction.

Dr. Messinger-Rapport disclosed that she is an editorial board member for the National Osteoporosis Foundation.

TAMPA – The treatment of osteoporosis is in flux because of a variety of forces, including a substantial increase in the number of aging patients deemed eligible for treatments, a leading geriatrician said. Just as baby boomers begin reaching senior status, a recently developed tool for assessing people’s fracture risk is increasing the number of patients considered suitable for preventive therapy.

Meanwhile, those therapy options are multiplying, and emerging evidence suggests that one, bisphosphonates, is associated with an increased risk for atypical fractures, although the absolute risk appears to be low, Dr. Barbara Messinger-Rapport, said at the AMDA Dedicated to Long Term Care Medicine annual meeting.

The assessment tool making a difference is the Web-based Fracture Risk Assessment Tool (FRAX), released by the World Health Organization in 2008. FRAX guides clinicians to consider drug therapy for patients with T scores (deviations from healthy bone density) of –2.5 or lower at the femoral neck or spine, a T score between –1.0 and –2.5 as well as a 3% or higher calculated risk for hip fracture over 10 years, or a 20% or greater risk of major osteoporosis-related fracture.

Even if a person’s T score never reaches –2.5, his or her hip fracture risk can climb to 3% or higher, said Dr. Messinger-Rapport, director of the Center for Geriatric Medicine at the Cleveland Clinic and medical director of the Fairfax Health Care Center Nursing Home, also in Cleveland. "This could widen the number of people who could be put on treatment."

Bisphosphonates remain the most-common treatment strategy, but optimal duration of therapy, timing of drug holidays, and how age and gender play into risk for adverse events remains unclear, she said.

A newer option, the monoclonal antibody denosumab (Prolia, Amgen), significantly reduced vertebral fractures compared with a placebo in published studies. Administered as a subcutaneous injection every 6 months, denosumab also may be more convenient than agents requiring infusion, Dr. Messinger-Rapport said.

Higher cost is a consideration, however. Wholesale cost of denosumab is approximately $850/60-mg subcutaneous injection. In contrast, generic alendronate costs $100-$200/year; brand-name oral bisphosphonate costs up to $1,000/year; and zoledronic acid, delivered via intravenous infusion, is approximately $1,100/year, she said.

Denosumab’s impact on clinical care is not yet know, Dr. Messinger-Rapport said. She suggested that clinicians consider this agent in high-risk elders, women or men with osteoporosis, men with prostate cancer with androgen deprivation, patients with metastatic prostate or breast cancer, and possibly patients with renal impairment (denosumab clearance is not renal). Also consider denosumab for patients who cannot tolerate a bisphosphonate either orally or by infusion, she added.

Researchers showed a 68% decrease in vertebral fractures, a 40% decline in hip fractures, and a 20% decrease in nonvertebral fractures with denosumab versus placebo in the FREEDOM study of osteoporotic women treated for 36 months (N. Engl. J. Med. 2009;361:756-65). A similar 62% decrease in vertebral fractures with denosumab, compared with placebo, was observed in a 24-month study of men with androgen deprivation for prostate cancer (N. Engl. J. Med. 2009;361:745-55).

Researchers also have examined reports of atypical femoral fractures associated with bisphosphonate use and found an association. For example, in a study published last year, 17 of 20 atypical femoral fractures occurred in patients taking oral bisphosphonates (N. Engl. J. Med. 2010;363:1848-9). In a New England Journal letter (N. Engl. J. Med. 2010;362:1848-9), the researchers stated that although they found the association, "overall the anti-fracture effects of bisphosphonates far outweigh their potential risks."

More recently, other investigators found an increased risk of subtrochanteric and femoral shaft fractures in women treated for 5 years or more with oral bisphosphonates (JAMA 2011;305:783-9). The authors stated that the absolute risk of the atypical fractures is low, however.

Dr. Messinger-Rapport listed contraindications to bisphosphonates as a prior allergic reaction, vitamin D depletion (less than 30 ng/mL), hypocalcemia, dysphagia, esophageal disorders, and severe gastroesophageal reflux disorder.

A person attending the meeting asked if it is appropriate to continue bisphosphonate therapy after a patient’s T score improves. "Yes, even if the T score only improves by a few percentage points," Dr. Messinger-Rapport replied, because there is a disproportionate benefit in terms of fracture risk reduction.

Dr. Messinger-Rapport disclosed that she is an editorial board member for the National Osteoporosis Foundation.

SAN DIEGO – Contrary to conventional wisdom, primary hyperparathyroidism is not extremely rare among people younger than 30 years, and it presents differently in these patients, compared with those older than 60 years, according to an analysis of data from 335 consecutive patients.

"Since routine calcium screening is not done in younger patients, primary hyperparathyroidism should be considered when nephrolithiasis, GERD [gastroesophageal reflux disease], and bone disease occur in patients younger than 30 years," Dr. Jovenel Cherenfant of the University of Chicago and his colleagues concluded.

To identify differences in hyperparathyroidism among age groups, the researchers reviewed data from 335 consecutive patients who underwent parathyroidectomy at a single center between 1998 and 2009.

The study population included 40 patients younger than 30 years, 155 patients aged 30-60 years, and 140 patients older than 60 years. Approximately 63% were women.

Prior to surgery, calcium and parathyroid hormone levels were significantly higher in patients younger than 30 years, compared with those older than 60 years. Presurgical calcium levels in patients younger than 30 years and those older than 60 years were 11.7 mg/dL and 10.9 mg/dL, respectively. Presurgical parathyroid hormone levels for the older and younger groups were 290 pg/mL and 159 pg/mL, respectively. All levels returned to normal after surgery; the median postoperative calcium and intact parathyroid hormone values for all patients were 9.35 mg/dL and 42.1 pg/mL, respectively, according to the results, which were presented in a poster at the annual meeting of the American Association of Clinical Endocrinologists.

At presentation, 58% of patients younger than 30 years complained of GERD, compared with 26% of those aged 30-60 years and 23% of those older than 60 years.

After the researchers controlled for age, women had a higher prevalence of GERD and osteoporosis, compared with men. Men of all ages were more likely to have a history of kidney stones, compared with women, but kidney stones were more common in younger women, compared with older women (40% of women younger than 30 years vs. 12% of women older than 30 years).

In addition, osteoporosis was significantly more common in patients older than 60 years vs. those younger than 30 years (49% vs. 9%), but 63% of the younger women had osteopenia, vs. 43% of those older than 60 years.

Dr. Cherenfant had no financial conflicts to disclose.

SAN DIEGO – Contrary to conventional wisdom, primary hyperparathyroidism is not extremely rare among people younger than 30 years, and it presents differently in these patients, compared with those older than 60 years, according to an analysis of data from 335 consecutive patients.

"Since routine calcium screening is not done in younger patients, primary hyperparathyroidism should be considered when nephrolithiasis, GERD [gastroesophageal reflux disease], and bone disease occur in patients younger than 30 years," Dr. Jovenel Cherenfant of the University of Chicago and his colleagues concluded.

To identify differences in hyperparathyroidism among age groups, the researchers reviewed data from 335 consecutive patients who underwent parathyroidectomy at a single center between 1998 and 2009.

The study population included 40 patients younger than 30 years, 155 patients aged 30-60 years, and 140 patients older than 60 years. Approximately 63% were women.

Prior to surgery, calcium and parathyroid hormone levels were significantly higher in patients younger than 30 years, compared with those older than 60 years. Presurgical calcium levels in patients younger than 30 years and those older than 60 years were 11.7 mg/dL and 10.9 mg/dL, respectively. Presurgical parathyroid hormone levels for the older and younger groups were 290 pg/mL and 159 pg/mL, respectively. All levels returned to normal after surgery; the median postoperative calcium and intact parathyroid hormone values for all patients were 9.35 mg/dL and 42.1 pg/mL, respectively, according to the results, which were presented in a poster at the annual meeting of the American Association of Clinical Endocrinologists.

At presentation, 58% of patients younger than 30 years complained of GERD, compared with 26% of those aged 30-60 years and 23% of those older than 60 years.

After the researchers controlled for age, women had a higher prevalence of GERD and osteoporosis, compared with men. Men of all ages were more likely to have a history of kidney stones, compared with women, but kidney stones were more common in younger women, compared with older women (40% of women younger than 30 years vs. 12% of women older than 30 years).

In addition, osteoporosis was significantly more common in patients older than 60 years vs. those younger than 30 years (49% vs. 9%), but 63% of the younger women had osteopenia, vs. 43% of those older than 60 years.

Dr. Cherenfant had no financial conflicts to disclose.

SAN DIEGO – Contrary to conventional wisdom, primary hyperparathyroidism is not extremely rare among people younger than 30 years, and it presents differently in these patients, compared with those older than 60 years, according to an analysis of data from 335 consecutive patients.

"Since routine calcium screening is not done in younger patients, primary hyperparathyroidism should be considered when nephrolithiasis, GERD [gastroesophageal reflux disease], and bone disease occur in patients younger than 30 years," Dr. Jovenel Cherenfant of the University of Chicago and his colleagues concluded.

To identify differences in hyperparathyroidism among age groups, the researchers reviewed data from 335 consecutive patients who underwent parathyroidectomy at a single center between 1998 and 2009.

The study population included 40 patients younger than 30 years, 155 patients aged 30-60 years, and 140 patients older than 60 years. Approximately 63% were women.

Prior to surgery, calcium and parathyroid hormone levels were significantly higher in patients younger than 30 years, compared with those older than 60 years. Presurgical calcium levels in patients younger than 30 years and those older than 60 years were 11.7 mg/dL and 10.9 mg/dL, respectively. Presurgical parathyroid hormone levels for the older and younger groups were 290 pg/mL and 159 pg/mL, respectively. All levels returned to normal after surgery; the median postoperative calcium and intact parathyroid hormone values for all patients were 9.35 mg/dL and 42.1 pg/mL, respectively, according to the results, which were presented in a poster at the annual meeting of the American Association of Clinical Endocrinologists.

At presentation, 58% of patients younger than 30 years complained of GERD, compared with 26% of those aged 30-60 years and 23% of those older than 60 years.

After the researchers controlled for age, women had a higher prevalence of GERD and osteoporosis, compared with men. Men of all ages were more likely to have a history of kidney stones, compared with women, but kidney stones were more common in younger women, compared with older women (40% of women younger than 30 years vs. 12% of women older than 30 years).

In addition, osteoporosis was significantly more common in patients older than 60 years vs. those younger than 30 years (49% vs. 9%), but 63% of the younger women had osteopenia, vs. 43% of those older than 60 years.

Dr. Cherenfant had no financial conflicts to disclose.

SAN DIEGO – Bone density and fracture risk continued to improve from baseline in postmenopausal women taking denosumab for osteoporosis, based on data from a 2-year extension of the FREEDOM study in more than 4,000 women.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

These results were the basis of the Food and Drug Administration's approval of denosumab in June 2010.

In the extension study, 2,343 patients from the original treatment group and 2,207 patients in the control group received the denosumab treatment for 2 years (as well as calcium and vitamin D), yielding follow-up data for up to 5 years of drug exposure, said Dr. Cesar Libanati at the meeting.

Women in the long-term group who received denosumab for 5 years showed significant BMD improvements from baseline, of 13.7% in the lumbar spine and 7.0% in the total hip. Women in crossover group showed significant BMD improvements from the start of the extension study, of 7.9% in the lumbar spine and 4.1% in the total hip.

Patients in the crossover group showed significant increase in BMD from the extension study baseline similar to those seen in the long-term patients during their first 2 years of denosumab use, noted Dr. Libanati, clinical research medical director at Amgen Pharmaceuticals, maker of denosumab (Prolia), in Newbury Park, Calif.

During years 4 and 5, the annualized yearly incidence of new vertebral fractures in the long-term patients was steady at 1.4%, compared with 1.1% at the end of the 3-year FREEDOM study. The yearly incidence in the crossover treatment group was 0.9% for their first 2 years of denosumab exposure, compared with 2.5% in the first 2 years of the FREEDOM study.

The yearly incidence of nonvertebral fractures in the long-term patients was 1.4% after 4 years and 1.1% after 5 years.

Denosumab remained well tolerated during the extension study. The adverse event profile was “similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study,” Dr. Libanati said. Long-term patients also maintained the reductions in bone turnover seen during the original FREEDOM study, he added.

SAN DIEGO – Bone density and fracture risk continued to improve from baseline in postmenopausal women taking denosumab for osteoporosis, based on data from a 2-year extension of the FREEDOM study in more than 4,000 women.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

These results were the basis of the Food and Drug Administration's approval of denosumab in June 2010.

In the extension study, 2,343 patients from the original treatment group and 2,207 patients in the control group received the denosumab treatment for 2 years (as well as calcium and vitamin D), yielding follow-up data for up to 5 years of drug exposure, said Dr. Cesar Libanati at the meeting.

Women in the long-term group who received denosumab for 5 years showed significant BMD improvements from baseline, of 13.7% in the lumbar spine and 7.0% in the total hip. Women in crossover group showed significant BMD improvements from the start of the extension study, of 7.9% in the lumbar spine and 4.1% in the total hip.

Patients in the crossover group showed significant increase in BMD from the extension study baseline similar to those seen in the long-term patients during their first 2 years of denosumab use, noted Dr. Libanati, clinical research medical director at Amgen Pharmaceuticals, maker of denosumab (Prolia), in Newbury Park, Calif.

During years 4 and 5, the annualized yearly incidence of new vertebral fractures in the long-term patients was steady at 1.4%, compared with 1.1% at the end of the 3-year FREEDOM study. The yearly incidence in the crossover treatment group was 0.9% for their first 2 years of denosumab exposure, compared with 2.5% in the first 2 years of the FREEDOM study.

The yearly incidence of nonvertebral fractures in the long-term patients was 1.4% after 4 years and 1.1% after 5 years.

Denosumab remained well tolerated during the extension study. The adverse event profile was “similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study,” Dr. Libanati said. Long-term patients also maintained the reductions in bone turnover seen during the original FREEDOM study, he added.

SAN DIEGO – Bone density and fracture risk continued to improve from baseline in postmenopausal women taking denosumab for osteoporosis, based on data from a 2-year extension of the FREEDOM study in more than 4,000 women.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

These results were the basis of the Food and Drug Administration's approval of denosumab in June 2010.

In the extension study, 2,343 patients from the original treatment group and 2,207 patients in the control group received the denosumab treatment for 2 years (as well as calcium and vitamin D), yielding follow-up data for up to 5 years of drug exposure, said Dr. Cesar Libanati at the meeting.

Women in the long-term group who received denosumab for 5 years showed significant BMD improvements from baseline, of 13.7% in the lumbar spine and 7.0% in the total hip. Women in crossover group showed significant BMD improvements from the start of the extension study, of 7.9% in the lumbar spine and 4.1% in the total hip.

Patients in the crossover group showed significant increase in BMD from the extension study baseline similar to those seen in the long-term patients during their first 2 years of denosumab use, noted Dr. Libanati, clinical research medical director at Amgen Pharmaceuticals, maker of denosumab (Prolia), in Newbury Park, Calif.

During years 4 and 5, the annualized yearly incidence of new vertebral fractures in the long-term patients was steady at 1.4%, compared with 1.1% at the end of the 3-year FREEDOM study. The yearly incidence in the crossover treatment group was 0.9% for their first 2 years of denosumab exposure, compared with 2.5% in the first 2 years of the FREEDOM study.

The yearly incidence of nonvertebral fractures in the long-term patients was 1.4% after 4 years and 1.1% after 5 years.

Denosumab remained well tolerated during the extension study. The adverse event profile was “similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study,” Dr. Libanati said. Long-term patients also maintained the reductions in bone turnover seen during the original FREEDOM study, he added.

Major Finding: The difference in the absolute risk of atypical femoral fracture between users and nonusers of bisphosponates was five cases per 10,000 patient-years; the number need to harm was 2,000 for every year of use.

Data Source: A nationwide cohort analysis of data on all 12,777 women aged 55 and older in Sweden who sustained a femoral fracture during 2008, and a population-based, case-control study of a subgroup of 322 of these patients.

Disclosures: This study was funded by the Swedish Research Council. Dr. Schilcher's associate reported ties to Eli Lilly and Amgen, and holds stock in AddBIO, a company that is attempting to commercialize a method for bisphosphonate coating of implants to be inserted in bone and that holds a patent on that method.

The magnitude of the absolute risk for atypical fractures of the femoral shaft among women taking bisphosphonates is small, according to a recent report.

The absolute risk remains small even though there is a high prevalence of use of the drugs in patients who develop such fractures. Moreover, that risk is small enough to be easily outweighed by bisphosphonates' benefit in preventing fractures, said Dr. Jörg Schilcher of Linköping (Sweden) University and his associates.

These findings, which come from nationwide population-based analyses of data on all 12,777 women in Sweden who were aged 55 and older and sustained a femoral fracture in 2008, “should be reassuring for bisphosphonate users,” they noted.

The American Society for Bone and Mineral Research has formed a task force report about the issue, ant the Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

Another population-based study in longtime elderly bisphosphonate users in Ontario recently showed that the absolute risk of atypical fractures was 1 in 1,000 women (JAMA 2011;305:783-9).

The investigators first reviewed the radiographs of all femoral sub-trochanteric and shaft fractures that were treated throughout Sweden that year. They identified the 1,234 cases among older women that resulted from falls.

The researchers then identified 47 cases of typical stress fractures (transverse on the lateral side without intermediate fragments, plus a thickening of the lateral cortex at the fracture site and no involvement of the trochanteric or condylar areas).

A second group of 12 patients had suspected stress fractures with the same characteristics as the fractures in the first group, but either without a thickening of the lateral cortex or with an intermediate fragment.

In a case-control analysis, Dr. Schilcher and his associates compared the use of bisphosphonates between these 59 women and 263 women who were chosen as control subjects and did not have stress fractures but who did have breaks in similar locations.

The prevalence of bisphosphonate use was much higher among the subjects who had atypical stress fractures (78%) than it was among the control subjects (10%). However, the absolute risk of sustaining an atypical fracture while using bisphosphonates was small: five cases per 10,000 patient-years.

This translates to a number needed to harm of 2,000 for every year of use; that is, 2,000 patients would need to use bisphosphonate for one case of drug-related atypical fracture to occur per year, Dr. Schilcher and his colleagues reported (N. Engl. J. Med. 2011;364:1728-37).

Thus, “the benefits of fracture prevention with bisphosphonate use will greatly outweigh the risk of atypical femoral fracture,” they wrote.

The risk of these atypical femoral fractures also appeared to be unrelated to the use of systemic glucocorticoids and other medications that affect bone. “It has been proposed that glucocorticoids and proton pump inhibitors are likely to contribute to the risk of atypical fractures, but our data suggest that this is not the case,” they added.

The risk of atypical femoral fracture also was independent of coexisting conditions and of patient age in this study population.

Previous studies that suggested that bisphosphonates raised the absolute risk of atypical femoral fractures to an unacceptable degree “relied on registry data or hospital records,” whereas this study relied on direct examination and classification of fractures from radiographs.

“The specific radiographie classification is important, since our analysis shows that the rare atypical femoral fracture will be overshadowed by other types of fractures in registry studies, impeding the detection of their association with bisphosphonates,” the investigators noted.

This study was limited in that it did not assess long-term bisphosphonate use or bone density. It also included only women of Northern European ethnicity, so the results may not be generalizable to men and other ethnic groups, they added.

Major Finding: The difference in the absolute risk of atypical femoral fracture between users and nonusers of bisphosponates was five cases per 10,000 patient-years; the number need to harm was 2,000 for every year of use.

Data Source: A nationwide cohort analysis of data on all 12,777 women aged 55 and older in Sweden who sustained a femoral fracture during 2008, and a population-based, case-control study of a subgroup of 322 of these patients.

Disclosures: This study was funded by the Swedish Research Council. Dr. Schilcher's associate reported ties to Eli Lilly and Amgen, and holds stock in AddBIO, a company that is attempting to commercialize a method for bisphosphonate coating of implants to be inserted in bone and that holds a patent on that method.

The magnitude of the absolute risk for atypical fractures of the femoral shaft among women taking bisphosphonates is small, according to a recent report.

The absolute risk remains small even though there is a high prevalence of use of the drugs in patients who develop such fractures. Moreover, that risk is small enough to be easily outweighed by bisphosphonates' benefit in preventing fractures, said Dr. Jörg Schilcher of Linköping (Sweden) University and his associates.

These findings, which come from nationwide population-based analyses of data on all 12,777 women in Sweden who were aged 55 and older and sustained a femoral fracture in 2008, “should be reassuring for bisphosphonate users,” they noted.

The American Society for Bone and Mineral Research has formed a task force report about the issue, ant the Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

Another population-based study in longtime elderly bisphosphonate users in Ontario recently showed that the absolute risk of atypical fractures was 1 in 1,000 women (JAMA 2011;305:783-9).

The investigators first reviewed the radiographs of all femoral sub-trochanteric and shaft fractures that were treated throughout Sweden that year. They identified the 1,234 cases among older women that resulted from falls.

The researchers then identified 47 cases of typical stress fractures (transverse on the lateral side without intermediate fragments, plus a thickening of the lateral cortex at the fracture site and no involvement of the trochanteric or condylar areas).

A second group of 12 patients had suspected stress fractures with the same characteristics as the fractures in the first group, but either without a thickening of the lateral cortex or with an intermediate fragment.

In a case-control analysis, Dr. Schilcher and his associates compared the use of bisphosphonates between these 59 women and 263 women who were chosen as control subjects and did not have stress fractures but who did have breaks in similar locations.

The prevalence of bisphosphonate use was much higher among the subjects who had atypical stress fractures (78%) than it was among the control subjects (10%). However, the absolute risk of sustaining an atypical fracture while using bisphosphonates was small: five cases per 10,000 patient-years.

This translates to a number needed to harm of 2,000 for every year of use; that is, 2,000 patients would need to use bisphosphonate for one case of drug-related atypical fracture to occur per year, Dr. Schilcher and his colleagues reported (N. Engl. J. Med. 2011;364:1728-37).

Thus, “the benefits of fracture prevention with bisphosphonate use will greatly outweigh the risk of atypical femoral fracture,” they wrote.

The risk of these atypical femoral fractures also appeared to be unrelated to the use of systemic glucocorticoids and other medications that affect bone. “It has been proposed that glucocorticoids and proton pump inhibitors are likely to contribute to the risk of atypical fractures, but our data suggest that this is not the case,” they added.

The risk of atypical femoral fracture also was independent of coexisting conditions and of patient age in this study population.

Previous studies that suggested that bisphosphonates raised the absolute risk of atypical femoral fractures to an unacceptable degree “relied on registry data or hospital records,” whereas this study relied on direct examination and classification of fractures from radiographs.

“The specific radiographie classification is important, since our analysis shows that the rare atypical femoral fracture will be overshadowed by other types of fractures in registry studies, impeding the detection of their association with bisphosphonates,” the investigators noted.

This study was limited in that it did not assess long-term bisphosphonate use or bone density. It also included only women of Northern European ethnicity, so the results may not be generalizable to men and other ethnic groups, they added.

Major Finding: The difference in the absolute risk of atypical femoral fracture between users and nonusers of bisphosponates was five cases per 10,000 patient-years; the number need to harm was 2,000 for every year of use.

Data Source: A nationwide cohort analysis of data on all 12,777 women aged 55 and older in Sweden who sustained a femoral fracture during 2008, and a population-based, case-control study of a subgroup of 322 of these patients.

Disclosures: This study was funded by the Swedish Research Council. Dr. Schilcher's associate reported ties to Eli Lilly and Amgen, and holds stock in AddBIO, a company that is attempting to commercialize a method for bisphosphonate coating of implants to be inserted in bone and that holds a patent on that method.

The magnitude of the absolute risk for atypical fractures of the femoral shaft among women taking bisphosphonates is small, according to a recent report.

The absolute risk remains small even though there is a high prevalence of use of the drugs in patients who develop such fractures. Moreover, that risk is small enough to be easily outweighed by bisphosphonates' benefit in preventing fractures, said Dr. Jörg Schilcher of Linköping (Sweden) University and his associates.

These findings, which come from nationwide population-based analyses of data on all 12,777 women in Sweden who were aged 55 and older and sustained a femoral fracture in 2008, “should be reassuring for bisphosphonate users,” they noted.

The American Society for Bone and Mineral Research has formed a task force report about the issue, ant the Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

Another population-based study in longtime elderly bisphosphonate users in Ontario recently showed that the absolute risk of atypical fractures was 1 in 1,000 women (JAMA 2011;305:783-9).

The investigators first reviewed the radiographs of all femoral sub-trochanteric and shaft fractures that were treated throughout Sweden that year. They identified the 1,234 cases among older women that resulted from falls.

The researchers then identified 47 cases of typical stress fractures (transverse on the lateral side without intermediate fragments, plus a thickening of the lateral cortex at the fracture site and no involvement of the trochanteric or condylar areas).

A second group of 12 patients had suspected stress fractures with the same characteristics as the fractures in the first group, but either without a thickening of the lateral cortex or with an intermediate fragment.

In a case-control analysis, Dr. Schilcher and his associates compared the use of bisphosphonates between these 59 women and 263 women who were chosen as control subjects and did not have stress fractures but who did have breaks in similar locations.

The prevalence of bisphosphonate use was much higher among the subjects who had atypical stress fractures (78%) than it was among the control subjects (10%). However, the absolute risk of sustaining an atypical fracture while using bisphosphonates was small: five cases per 10,000 patient-years.

This translates to a number needed to harm of 2,000 for every year of use; that is, 2,000 patients would need to use bisphosphonate for one case of drug-related atypical fracture to occur per year, Dr. Schilcher and his colleagues reported (N. Engl. J. Med. 2011;364:1728-37).

Thus, “the benefits of fracture prevention with bisphosphonate use will greatly outweigh the risk of atypical femoral fracture,” they wrote.

The risk of these atypical femoral fractures also appeared to be unrelated to the use of systemic glucocorticoids and other medications that affect bone. “It has been proposed that glucocorticoids and proton pump inhibitors are likely to contribute to the risk of atypical fractures, but our data suggest that this is not the case,” they added.

The risk of atypical femoral fracture also was independent of coexisting conditions and of patient age in this study population.

Previous studies that suggested that bisphosphonates raised the absolute risk of atypical femoral fractures to an unacceptable degree “relied on registry data or hospital records,” whereas this study relied on direct examination and classification of fractures from radiographs.

“The specific radiographie classification is important, since our analysis shows that the rare atypical femoral fracture will be overshadowed by other types of fractures in registry studies, impeding the detection of their association with bisphosphonates,” the investigators noted.

This study was limited in that it did not assess long-term bisphosphonate use or bone density. It also included only women of Northern European ethnicity, so the results may not be generalizable to men and other ethnic groups, they added.

SAN DIEGO – Bone density and fracture risk continued to improve from baseline in postmenopausal women taking denosumab for osteoporosis, according to data from a 2-year extension of the FREEDOM study in more than 4,000 women.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months.

All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756–65).

The FREEDOM results were the basis of the Food and Drug Administration's approval of denosumab in June 2010. In the extension study, 2,343 patients from the original treatment group and 2,207 patients in the control group received the denosumab treatment for 2 years (as well as calcium and vitamin D), yielding follow-up data for up to 5 years of drug exposure, said Dr. Cesar Libanati at the meeting.

Women in the long-term group who received denosumab for 5 years showed significant BMD improvements from baseline, of 13.7% in the lumbar spine and 7.0% in the total hip. Women in crossover group showed significant BMD improvements from the start of the extension study, of 7.9% in the lumbar spine and 4.1% in the total hip.

Patients in the crossover group showed significant increased in BMD from the extension study baseline similar to those seen in the long-term patients during their first 2 years of denosumab use, noted Dr. Libanati, clinical research medical director at Amgen Pharmaceuticals, maker of denosumab (Prolia), in Newbury Park, Calif.

During years 4 and 5, the annualized yearly incidence of new vertebral fractures in the long-term patients was steady at 1.4%, compared with 1.1% at the end of the 3-year FREEDOM study.

The yearly incidence in the crossover treatment group was 0.9% for their first 2 years of denosumab exposure, compared with 2.5% in the first 2 years of the FREEDOM study.

The yearly incidence of nonvertebral fractures in the long-term patients was 1.4% after 4 years and 1.1% after 5 years.

Nonvertebral fracture data for the crossover patients were not presented.

Denosumab remained well tolerated during the extension study. The adverse event profile was “similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study,” Dr. Libanati said.

Long-term patients also maintained the reductions in bone turnover seen during the original FREEDOM study, he added.

Dr. Libanati is employed by Amgen.

SAN DIEGO – Bone density and fracture risk continued to improve from baseline in postmenopausal women taking denosumab for osteoporosis, according to data from a 2-year extension of the FREEDOM study in more than 4,000 women.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months.

All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756–65).

The FREEDOM results were the basis of the Food and Drug Administration's approval of denosumab in June 2010. In the extension study, 2,343 patients from the original treatment group and 2,207 patients in the control group received the denosumab treatment for 2 years (as well as calcium and vitamin D), yielding follow-up data for up to 5 years of drug exposure, said Dr. Cesar Libanati at the meeting.

Women in the long-term group who received denosumab for 5 years showed significant BMD improvements from baseline, of 13.7% in the lumbar spine and 7.0% in the total hip. Women in crossover group showed significant BMD improvements from the start of the extension study, of 7.9% in the lumbar spine and 4.1% in the total hip.

Patients in the crossover group showed significant increased in BMD from the extension study baseline similar to those seen in the long-term patients during their first 2 years of denosumab use, noted Dr. Libanati, clinical research medical director at Amgen Pharmaceuticals, maker of denosumab (Prolia), in Newbury Park, Calif.

During years 4 and 5, the annualized yearly incidence of new vertebral fractures in the long-term patients was steady at 1.4%, compared with 1.1% at the end of the 3-year FREEDOM study.

The yearly incidence in the crossover treatment group was 0.9% for their first 2 years of denosumab exposure, compared with 2.5% in the first 2 years of the FREEDOM study.

The yearly incidence of nonvertebral fractures in the long-term patients was 1.4% after 4 years and 1.1% after 5 years.

Nonvertebral fracture data for the crossover patients were not presented.

Denosumab remained well tolerated during the extension study. The adverse event profile was “similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study,” Dr. Libanati said.

Long-term patients also maintained the reductions in bone turnover seen during the original FREEDOM study, he added.

Dr. Libanati is employed by Amgen.

SAN DIEGO – Bone density and fracture risk continued to improve from baseline in postmenopausal women taking denosumab for osteoporosis, according to data from a 2-year extension of the FREEDOM study in more than 4,000 women.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months.

All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756–65).

The FREEDOM results were the basis of the Food and Drug Administration's approval of denosumab in June 2010. In the extension study, 2,343 patients from the original treatment group and 2,207 patients in the control group received the denosumab treatment for 2 years (as well as calcium and vitamin D), yielding follow-up data for up to 5 years of drug exposure, said Dr. Cesar Libanati at the meeting.

Women in the long-term group who received denosumab for 5 years showed significant BMD improvements from baseline, of 13.7% in the lumbar spine and 7.0% in the total hip. Women in crossover group showed significant BMD improvements from the start of the extension study, of 7.9% in the lumbar spine and 4.1% in the total hip.

Patients in the crossover group showed significant increased in BMD from the extension study baseline similar to those seen in the long-term patients during their first 2 years of denosumab use, noted Dr. Libanati, clinical research medical director at Amgen Pharmaceuticals, maker of denosumab (Prolia), in Newbury Park, Calif.

During years 4 and 5, the annualized yearly incidence of new vertebral fractures in the long-term patients was steady at 1.4%, compared with 1.1% at the end of the 3-year FREEDOM study.

The yearly incidence in the crossover treatment group was 0.9% for their first 2 years of denosumab exposure, compared with 2.5% in the first 2 years of the FREEDOM study.

The yearly incidence of nonvertebral fractures in the long-term patients was 1.4% after 4 years and 1.1% after 5 years.

Nonvertebral fracture data for the crossover patients were not presented.

Denosumab remained well tolerated during the extension study. The adverse event profile was “similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study,” Dr. Libanati said.

Long-term patients also maintained the reductions in bone turnover seen during the original FREEDOM study, he added.

Dr. Libanati is employed by Amgen.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from the FREEDOM trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of −2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of −2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of −2.5 or less; or were 75 years or older with a femoral neck BMD T score of −2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) in those at risk via baseline femoral neck BMD T score of −2.5 by 6.8% (9.9% vs. 3.1%), and in those with both risk factors by 12.3% (20.1% vs. 8.1%), Dr. Boonen and associates said.

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than −2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of −2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

“It is reassuring to see that the effect is similar across a range of fracture risk. … The FDA-approved indication for denosumab is for 'postmenopausal women at high risk of fracture,' but the FREEDOM trial was not enriched with 'women at high risk,' ” noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. “This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It's clear that women who fracture have decreased survival, so it's logical that preventing fracture would reduce mortality.”

The study was funded by Amgen Inc., from which Dr. Boonen has received renumeration for research, consulting, and lecturing. Four of the study's coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, and Vivus.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from the FREEDOM trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of −2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of −2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of −2.5 or less; or were 75 years or older with a femoral neck BMD T score of −2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) in those at risk via baseline femoral neck BMD T score of −2.5 by 6.8% (9.9% vs. 3.1%), and in those with both risk factors by 12.3% (20.1% vs. 8.1%), Dr. Boonen and associates said.

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than −2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of −2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

“It is reassuring to see that the effect is similar across a range of fracture risk. … The FDA-approved indication for denosumab is for 'postmenopausal women at high risk of fracture,' but the FREEDOM trial was not enriched with 'women at high risk,' ” noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. “This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It's clear that women who fracture have decreased survival, so it's logical that preventing fracture would reduce mortality.”

The study was funded by Amgen Inc., from which Dr. Boonen has received renumeration for research, consulting, and lecturing. Four of the study's coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, and Vivus.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from the FREEDOM trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of −2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of −2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of −2.5 or less; or were 75 years or older with a femoral neck BMD T score of −2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) in those at risk via baseline femoral neck BMD T score of −2.5 by 6.8% (9.9% vs. 3.1%), and in those with both risk factors by 12.3% (20.1% vs. 8.1%), Dr. Boonen and associates said.

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than −2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of −2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

“It is reassuring to see that the effect is similar across a range of fracture risk. … The FDA-approved indication for denosumab is for 'postmenopausal women at high risk of fracture,' but the FREEDOM trial was not enriched with 'women at high risk,' ” noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. “This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It's clear that women who fracture have decreased survival, so it's logical that preventing fracture would reduce mortality.”

The study was funded by Amgen Inc., from which Dr. Boonen has received renumeration for research, consulting, and lecturing. Four of the study's coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, and Vivus.

Prolonged use of oral bisphosphonates is associated with an increased risk of subtrochanteric or femoral shaft fractures in older women. However, the absolute risk for these fractures is low, according to a large population-based study.

“There wasn't good research about what the absolute risk of the fractures was. This study adds that piece,” lead author Laura Y. Park-Wyllie, Pharm.D., said in an interview.

During the 7-year study period, researchers found that women aged 68 years or older who used bisphosphonates for 5 years or longer were 2.74 times more likely to have subtrochanteric or femoral shaft fractures after minimal trauma, compared with women who took the medications transiently (JAMA 2011;305:783-9).

The study also showed that the absolute risk of such atypical fractures was at 1 in 1,000 women.

“If you combine all the information that we have about osteoporosis and the information we have about the risk versus benefits [of bisphosphonates] they would favor the continuation of treatment,” Dr. Park-Wyllie said.

The growing number of reports on the issue and conflicting studies prompted the group to launch the study, said Dr. Park-Wyllie, a research fellow at Li Ka Shing Knowledge Institute of St. Michael's Hospital in Toronto.

The American Society for Bone and Mineral Research recently released a task force report about the issue. The Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

The population-based, nested case-control study examined 205,466 women 68 years or older who were treated with bisphosphonates between April 1, 2002, and March 31, 2008. The women were followed until the first fracture, death, or end of the study. Women with a history of conditions that could affect bone integrity were excluded.

In the group, 716 women (0.35%) had subtrochanteric (411) or femoral shaft fractures (305). Each case was matched with up to five controls – 3,580 total – from the cohort not hospitalized for either type of fracture, according to the study.

When compared with women who had used bisphosphonates transiently during the study period (less than 100 days in total), women who used the medication for 5 years or longer had an increased risk of subtrochanteric or femoral shaft fracture, the authors concluded.

To validate their findings, the investigators also conducted a secondary analysis, examining the risk of typical osteoporotic fractures among women who used bisphosphonates for 5 years or more, compared with women who used the medication transiently. Of the cohort, 9,723 women sustained femoral neck or intertrochanteric region fractures. “As expected, we found that extended bisphosphonate use was associated with a reduced risk of fracture compared with transient use,” the authors wrote.

The absolute risk was estimated from 52,595 women in the cohort with at least 5 years of bisphosphonate therapy. Seventy-one, or 0.13%, sustained subtrochanteric or femoral shaft fractures during the following year and 117 (0.22%) within 2 years.

The authors noted that during their study period (2002–2008) only a small proportion of the cohort received 5 or more years of bisphosphonate therapy. “It is likely that the prevalence of long-term bisphosphonate exposure will increase over time as more women achieve 5 cumulative years of therapy because these drugs are still relatively new and because sustained adherence to bisphosphonates is actively promoted in the community setting,” they wrote.

The study should not deter physicians and patients from the use of bisphosphonates, they said, noting that typical hip fractures were far more common than were subtrochanteric or femoral shaft fractures during the study period (9,723 vs. 716).

One of the coauthors – Muhammad M. Mamdani, Pharm.D. – reported financial relationships with Boehringer Ingelheim, Janssen-Ortho, Novartis, and Pfizer. The study was funded by the Ontario Ministry of Health and Long-Term Care.

Prolonged use of oral bisphosphonates is associated with an increased risk of subtrochanteric or femoral shaft fractures in older women. However, the absolute risk for these fractures is low, according to a large population-based study.

“There wasn't good research about what the absolute risk of the fractures was. This study adds that piece,” lead author Laura Y. Park-Wyllie, Pharm.D., said in an interview.

During the 7-year study period, researchers found that women aged 68 years or older who used bisphosphonates for 5 years or longer were 2.74 times more likely to have subtrochanteric or femoral shaft fractures after minimal trauma, compared with women who took the medications transiently (JAMA 2011;305:783-9).

The study also showed that the absolute risk of such atypical fractures was at 1 in 1,000 women.

“If you combine all the information that we have about osteoporosis and the information we have about the risk versus benefits [of bisphosphonates] they would favor the continuation of treatment,” Dr. Park-Wyllie said.

The growing number of reports on the issue and conflicting studies prompted the group to launch the study, said Dr. Park-Wyllie, a research fellow at Li Ka Shing Knowledge Institute of St. Michael's Hospital in Toronto.

The American Society for Bone and Mineral Research recently released a task force report about the issue. The Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

The population-based, nested case-control study examined 205,466 women 68 years or older who were treated with bisphosphonates between April 1, 2002, and March 31, 2008. The women were followed until the first fracture, death, or end of the study. Women with a history of conditions that could affect bone integrity were excluded.

In the group, 716 women (0.35%) had subtrochanteric (411) or femoral shaft fractures (305). Each case was matched with up to five controls – 3,580 total – from the cohort not hospitalized for either type of fracture, according to the study.

When compared with women who had used bisphosphonates transiently during the study period (less than 100 days in total), women who used the medication for 5 years or longer had an increased risk of subtrochanteric or femoral shaft fracture, the authors concluded.

To validate their findings, the investigators also conducted a secondary analysis, examining the risk of typical osteoporotic fractures among women who used bisphosphonates for 5 years or more, compared with women who used the medication transiently. Of the cohort, 9,723 women sustained femoral neck or intertrochanteric region fractures. “As expected, we found that extended bisphosphonate use was associated with a reduced risk of fracture compared with transient use,” the authors wrote.

The absolute risk was estimated from 52,595 women in the cohort with at least 5 years of bisphosphonate therapy. Seventy-one, or 0.13%, sustained subtrochanteric or femoral shaft fractures during the following year and 117 (0.22%) within 2 years.

The authors noted that during their study period (2002–2008) only a small proportion of the cohort received 5 or more years of bisphosphonate therapy. “It is likely that the prevalence of long-term bisphosphonate exposure will increase over time as more women achieve 5 cumulative years of therapy because these drugs are still relatively new and because sustained adherence to bisphosphonates is actively promoted in the community setting,” they wrote.

The study should not deter physicians and patients from the use of bisphosphonates, they said, noting that typical hip fractures were far more common than were subtrochanteric or femoral shaft fractures during the study period (9,723 vs. 716).

One of the coauthors – Muhammad M. Mamdani, Pharm.D. – reported financial relationships with Boehringer Ingelheim, Janssen-Ortho, Novartis, and Pfizer. The study was funded by the Ontario Ministry of Health and Long-Term Care.

Prolonged use of oral bisphosphonates is associated with an increased risk of subtrochanteric or femoral shaft fractures in older women. However, the absolute risk for these fractures is low, according to a large population-based study.

“There wasn't good research about what the absolute risk of the fractures was. This study adds that piece,” lead author Laura Y. Park-Wyllie, Pharm.D., said in an interview.

During the 7-year study period, researchers found that women aged 68 years or older who used bisphosphonates for 5 years or longer were 2.74 times more likely to have subtrochanteric or femoral shaft fractures after minimal trauma, compared with women who took the medications transiently (JAMA 2011;305:783-9).

The study also showed that the absolute risk of such atypical fractures was at 1 in 1,000 women.

“If you combine all the information that we have about osteoporosis and the information we have about the risk versus benefits [of bisphosphonates] they would favor the continuation of treatment,” Dr. Park-Wyllie said.

The growing number of reports on the issue and conflicting studies prompted the group to launch the study, said Dr. Park-Wyllie, a research fellow at Li Ka Shing Knowledge Institute of St. Michael's Hospital in Toronto.

The American Society for Bone and Mineral Research recently released a task force report about the issue. The Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

The population-based, nested case-control study examined 205,466 women 68 years or older who were treated with bisphosphonates between April 1, 2002, and March 31, 2008. The women were followed until the first fracture, death, or end of the study. Women with a history of conditions that could affect bone integrity were excluded.

In the group, 716 women (0.35%) had subtrochanteric (411) or femoral shaft fractures (305). Each case was matched with up to five controls – 3,580 total – from the cohort not hospitalized for either type of fracture, according to the study.

When compared with women who had used bisphosphonates transiently during the study period (less than 100 days in total), women who used the medication for 5 years or longer had an increased risk of subtrochanteric or femoral shaft fracture, the authors concluded.

To validate their findings, the investigators also conducted a secondary analysis, examining the risk of typical osteoporotic fractures among women who used bisphosphonates for 5 years or more, compared with women who used the medication transiently. Of the cohort, 9,723 women sustained femoral neck or intertrochanteric region fractures. “As expected, we found that extended bisphosphonate use was associated with a reduced risk of fracture compared with transient use,” the authors wrote.

The absolute risk was estimated from 52,595 women in the cohort with at least 5 years of bisphosphonate therapy. Seventy-one, or 0.13%, sustained subtrochanteric or femoral shaft fractures during the following year and 117 (0.22%) within 2 years.

The authors noted that during their study period (2002–2008) only a small proportion of the cohort received 5 or more years of bisphosphonate therapy. “It is likely that the prevalence of long-term bisphosphonate exposure will increase over time as more women achieve 5 cumulative years of therapy because these drugs are still relatively new and because sustained adherence to bisphosphonates is actively promoted in the community setting,” they wrote.

The study should not deter physicians and patients from the use of bisphosphonates, they said, noting that typical hip fractures were far more common than were subtrochanteric or femoral shaft fractures during the study period (9,723 vs. 716).

One of the coauthors – Muhammad M. Mamdani, Pharm.D. – reported financial relationships with Boehringer Ingelheim, Janssen-Ortho, Novartis, and Pfizer. The study was funded by the Ontario Ministry of Health and Long-Term Care.

Major Finding: In women who received zoledronic acid, the rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women.

Data Source: Post-hoc analysis of 3,889 women who received zoledronic acid in the HORIZON pivotal fracture study that compared zoledronic acid infusions against placebo.

Disclosures: HORIZON was supported by Novartis, the company that markets zoledronic acid. Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.

TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug's pivotal trial for fracture prevention.

The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women's baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.

The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.

The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh. It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.

The results support a prior report with similar findings from the Women's Health Initiative on the impact of estrogen or estrogen plus progesterone on fracture risk (JAMA 2003;290:1729-38). However, results from another prior study on the impact of clodronate on fracture risk suggested that osteoporotic women with the highest baseline fracture risk stood to gain the most from bisphosphonate treatment (Osteoporosis Int. 2009;20:811-17).

The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22).

Assessment of the study's primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.

To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zoledronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28).

The modification calculated a woman's baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.

Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women's FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON. During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45 respectively in the low-, intermediate-, and high-risk tertiles. Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.

The researchers then assessed follow-up fracture rates among the low-, intermediate-, and high-risk women who received zoledronic acid. The rate of morphometric vertebral fractures compared with the placebo group fell by 80% in the low-risk tertile of women, by 69% in the intermediate-risk tertile, and by 68% in the high-risk women, differences that were not statistically significant.

The rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women, also nonsignificant differences.

The rate of hip fractures with zoledronic acid treatment compared with placebo fell by 71% in the low-risk women, 41% in intermediate-risk women, and 22% in high-risk women. These between-group differences just missed being statistically significant.

Additional analyses also showed that the zoledronic acid treatment consistently increased bone mineral density, and reduced two biomarkers of osteoporosis, procollagen type I N-propeptide and C-telopeptide cross-linked collagen, compared with the placebo group, regardless of baseline fracture risk, Dr. Cauley said.

It is not necessary to target treatment to women with an especially elevated fracture risk.

Source DR. CAULEY

Major Finding: In women who received zoledronic acid, the rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women.

Data Source: Post-hoc analysis of 3,889 women who received zoledronic acid in the HORIZON pivotal fracture study that compared zoledronic acid infusions against placebo.

Disclosures: HORIZON was supported by Novartis, the company that markets zoledronic acid. Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.

TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug's pivotal trial for fracture prevention.

The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women's baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.

The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.

The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh. It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.

The results support a prior report with similar findings from the Women's Health Initiative on the impact of estrogen or estrogen plus progesterone on fracture risk (JAMA 2003;290:1729-38). However, results from another prior study on the impact of clodronate on fracture risk suggested that osteoporotic women with the highest baseline fracture risk stood to gain the most from bisphosphonate treatment (Osteoporosis Int. 2009;20:811-17).

The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22).

Assessment of the study's primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.

To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zoledronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28).

The modification calculated a woman's baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.

Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women's FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON. During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45 respectively in the low-, intermediate-, and high-risk tertiles. Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.

The researchers then assessed follow-up fracture rates among the low-, intermediate-, and high-risk women who received zoledronic acid. The rate of morphometric vertebral fractures compared with the placebo group fell by 80% in the low-risk tertile of women, by 69% in the intermediate-risk tertile, and by 68% in the high-risk women, differences that were not statistically significant.

The rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women, also nonsignificant differences.

The rate of hip fractures with zoledronic acid treatment compared with placebo fell by 71% in the low-risk women, 41% in intermediate-risk women, and 22% in high-risk women. These between-group differences just missed being statistically significant.

Additional analyses also showed that the zoledronic acid treatment consistently increased bone mineral density, and reduced two biomarkers of osteoporosis, procollagen type I N-propeptide and C-telopeptide cross-linked collagen, compared with the placebo group, regardless of baseline fracture risk, Dr. Cauley said.

It is not necessary to target treatment to women with an especially elevated fracture risk.

Source DR. CAULEY

Major Finding: In women who received zoledronic acid, the rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women.

Data Source: Post-hoc analysis of 3,889 women who received zoledronic acid in the HORIZON pivotal fracture study that compared zoledronic acid infusions against placebo.

Disclosures: HORIZON was supported by Novartis, the company that markets zoledronic acid. Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.

TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug's pivotal trial for fracture prevention.

The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women's baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.

The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.

The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh. It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.

The results support a prior report with similar findings from the Women's Health Initiative on the impact of estrogen or estrogen plus progesterone on fracture risk (JAMA 2003;290:1729-38). However, results from another prior study on the impact of clodronate on fracture risk suggested that osteoporotic women with the highest baseline fracture risk stood to gain the most from bisphosphonate treatment (Osteoporosis Int. 2009;20:811-17).

The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22).

Assessment of the study's primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.

To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zoledronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28).

The modification calculated a woman's baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.

Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women's FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON. During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45 respectively in the low-, intermediate-, and high-risk tertiles. Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.

The researchers then assessed follow-up fracture rates among the low-, intermediate-, and high-risk women who received zoledronic acid. The rate of morphometric vertebral fractures compared with the placebo group fell by 80% in the low-risk tertile of women, by 69% in the intermediate-risk tertile, and by 68% in the high-risk women, differences that were not statistically significant.

The rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women, also nonsignificant differences.

The rate of hip fractures with zoledronic acid treatment compared with placebo fell by 71% in the low-risk women, 41% in intermediate-risk women, and 22% in high-risk women. These between-group differences just missed being statistically significant.

Additional analyses also showed that the zoledronic acid treatment consistently increased bone mineral density, and reduced two biomarkers of osteoporosis, procollagen type I N-propeptide and C-telopeptide cross-linked collagen, compared with the placebo group, regardless of baseline fracture risk, Dr. Cauley said.

It is not necessary to target treatment to women with an especially elevated fracture risk.

Source DR. CAULEY

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).