Osteoporosis

CHICAGO – Older adults who undergo Roux-en-Y gastric bypass are at risk for lessened bone mineral density for at least 2 years after their surgery and should be monitored appropriately for osteoporosis or fragility fractures, according to investigators from Massachusetts General Hospital in Boston.

Two years postoperatively, vertebral bone mineral density (BMD) in 30 patients was about 7% lower on quantitative computed tomography (QCT) and 6% lower on dual-energy x-ray absorptiometry (DXA) – both methods were used to ensure accuracy – when compared with 20 well-matched, morbidly obese controls. Total hip BMD was 6% lower on QCT and 10% lower on DXA. Femoral neck BMD was about 6% lower by both measures.

Biomarkers of bone turnover remained markedly elevated in surgery patients, as well, but unchanged in controls (C-telopeptide 0.65 ng/mL vs. 0.3 ng/mL; amino-terminal propeptide of type I collagen 65 ng/mL vs. 40 ng/mL). The findings were all statistically significant.

The groups started to separate early on BMD, and there’s concern that bone loss will continue for more than 2 years after surgery. Preoperatively, most Roux-en-Y gastric bypass patients have a higher than normal BMD, "so even a loss of 10% over 2 years is not going to put most of them in the osteopenic or osteoporotic range. The caveat now is that we are [offering surgery] to older patients and adolescents. Elderly patients are starting with lower bone mass, so there are concerns about [post-op] skeletal fragility. The oldest patient in our study was 72. She became osteoporotic after surgery because her bone density was low to begin with," said lead investigator Dr. Elaine W. Yu, an endocrinologist at Massachusetts General.

"In adolescents, there are implications for achieving peak bone mass. Even if you have a normal bone density 2 years after surgery, what’s going to happen in 10 years, 20 years?" she asked.

In short, "people should pay attention to bone density and bone loss and discuss this as one of the potential negative effects of bariatric surgery. For patients at risk, you should definitely consider serial bone density monitoring and osteoporosis therapy if needed," she said at the joint meeting of the International Society of Endocrinology and the Endocrine Society.

At baseline, both subjects and controls were about 47 years old and 270 pounds, with a mean a mean body mass index of 45 kg/m². About 85% were women. The study excluded patients with histories of bone disorders or use of bone-affecting medications.

Surgery patients lost a mean of about 85 pounds in the first 6 months; their weight loss then stabilized, but they continued to lose bone. Controls stayed about the same weight.

The findings can’t be explained by post-op calcium or vitamin D depletion. "These subjects were aggressively supplemented with both," and both groups maintained normal levels throughout the study. Also, there were no statistical differences in parathyroid hormone levels between the groups.

"Our theory is that there are changes in gut hormones after gastric bypass that have direct effects on bone, like ghrelin," Dr. Yu said.

The National Institutes of Health funded the work. Dr. Yu is a consultant for Amgen.

[email protected]

CHICAGO – Older adults who undergo Roux-en-Y gastric bypass are at risk for lessened bone mineral density for at least 2 years after their surgery and should be monitored appropriately for osteoporosis or fragility fractures, according to investigators from Massachusetts General Hospital in Boston.

Two years postoperatively, vertebral bone mineral density (BMD) in 30 patients was about 7% lower on quantitative computed tomography (QCT) and 6% lower on dual-energy x-ray absorptiometry (DXA) – both methods were used to ensure accuracy – when compared with 20 well-matched, morbidly obese controls. Total hip BMD was 6% lower on QCT and 10% lower on DXA. Femoral neck BMD was about 6% lower by both measures.

Biomarkers of bone turnover remained markedly elevated in surgery patients, as well, but unchanged in controls (C-telopeptide 0.65 ng/mL vs. 0.3 ng/mL; amino-terminal propeptide of type I collagen 65 ng/mL vs. 40 ng/mL). The findings were all statistically significant.

The groups started to separate early on BMD, and there’s concern that bone loss will continue for more than 2 years after surgery. Preoperatively, most Roux-en-Y gastric bypass patients have a higher than normal BMD, "so even a loss of 10% over 2 years is not going to put most of them in the osteopenic or osteoporotic range. The caveat now is that we are [offering surgery] to older patients and adolescents. Elderly patients are starting with lower bone mass, so there are concerns about [post-op] skeletal fragility. The oldest patient in our study was 72. She became osteoporotic after surgery because her bone density was low to begin with," said lead investigator Dr. Elaine W. Yu, an endocrinologist at Massachusetts General.

"In adolescents, there are implications for achieving peak bone mass. Even if you have a normal bone density 2 years after surgery, what’s going to happen in 10 years, 20 years?" she asked.

In short, "people should pay attention to bone density and bone loss and discuss this as one of the potential negative effects of bariatric surgery. For patients at risk, you should definitely consider serial bone density monitoring and osteoporosis therapy if needed," she said at the joint meeting of the International Society of Endocrinology and the Endocrine Society.

At baseline, both subjects and controls were about 47 years old and 270 pounds, with a mean a mean body mass index of 45 kg/m². About 85% were women. The study excluded patients with histories of bone disorders or use of bone-affecting medications.

Surgery patients lost a mean of about 85 pounds in the first 6 months; their weight loss then stabilized, but they continued to lose bone. Controls stayed about the same weight.

The findings can’t be explained by post-op calcium or vitamin D depletion. "These subjects were aggressively supplemented with both," and both groups maintained normal levels throughout the study. Also, there were no statistical differences in parathyroid hormone levels between the groups.

"Our theory is that there are changes in gut hormones after gastric bypass that have direct effects on bone, like ghrelin," Dr. Yu said.

The National Institutes of Health funded the work. Dr. Yu is a consultant for Amgen.

[email protected]

CHICAGO – Older adults who undergo Roux-en-Y gastric bypass are at risk for lessened bone mineral density for at least 2 years after their surgery and should be monitored appropriately for osteoporosis or fragility fractures, according to investigators from Massachusetts General Hospital in Boston.

Two years postoperatively, vertebral bone mineral density (BMD) in 30 patients was about 7% lower on quantitative computed tomography (QCT) and 6% lower on dual-energy x-ray absorptiometry (DXA) – both methods were used to ensure accuracy – when compared with 20 well-matched, morbidly obese controls. Total hip BMD was 6% lower on QCT and 10% lower on DXA. Femoral neck BMD was about 6% lower by both measures.

Biomarkers of bone turnover remained markedly elevated in surgery patients, as well, but unchanged in controls (C-telopeptide 0.65 ng/mL vs. 0.3 ng/mL; amino-terminal propeptide of type I collagen 65 ng/mL vs. 40 ng/mL). The findings were all statistically significant.

The groups started to separate early on BMD, and there’s concern that bone loss will continue for more than 2 years after surgery. Preoperatively, most Roux-en-Y gastric bypass patients have a higher than normal BMD, "so even a loss of 10% over 2 years is not going to put most of them in the osteopenic or osteoporotic range. The caveat now is that we are [offering surgery] to older patients and adolescents. Elderly patients are starting with lower bone mass, so there are concerns about [post-op] skeletal fragility. The oldest patient in our study was 72. She became osteoporotic after surgery because her bone density was low to begin with," said lead investigator Dr. Elaine W. Yu, an endocrinologist at Massachusetts General.

"In adolescents, there are implications for achieving peak bone mass. Even if you have a normal bone density 2 years after surgery, what’s going to happen in 10 years, 20 years?" she asked.

In short, "people should pay attention to bone density and bone loss and discuss this as one of the potential negative effects of bariatric surgery. For patients at risk, you should definitely consider serial bone density monitoring and osteoporosis therapy if needed," she said at the joint meeting of the International Society of Endocrinology and the Endocrine Society.

At baseline, both subjects and controls were about 47 years old and 270 pounds, with a mean a mean body mass index of 45 kg/m². About 85% were women. The study excluded patients with histories of bone disorders or use of bone-affecting medications.

Surgery patients lost a mean of about 85 pounds in the first 6 months; their weight loss then stabilized, but they continued to lose bone. Controls stayed about the same weight.

The findings can’t be explained by post-op calcium or vitamin D depletion. "These subjects were aggressively supplemented with both," and both groups maintained normal levels throughout the study. Also, there were no statistical differences in parathyroid hormone levels between the groups.

"Our theory is that there are changes in gut hormones after gastric bypass that have direct effects on bone, like ghrelin," Dr. Yu said.

The National Institutes of Health funded the work. Dr. Yu is a consultant for Amgen.

[email protected]

CHICAGO – Serum osteocalcin is the first bone turnover marker to recover after intravenous bisphosphonate therapy in children with primary osteoporosis, secondary osteoporosis, or osteogenesis imperfecta, making it a good indicator that it’s time to consider a second round of treatment, according to investigators from Children’s Mercy Hospitals and Clinics in Kansas City, Mo.

In a review of 104 children followed for up to 5 years, they found that the benefits of IV bisphosphonates – for children, usually two or three 2-day courses about 4 months apart – remain durable for up to 3 years. After an initial decrease, serum osteocalcin starts to return to baseline 1 year after the start of treatment (P = 0.007); improvements in lumbar spine bone mineral density z scores on dual energy x-ray absorptiometry (DXA) start to plateau at about 2 years and then reverse after 3 years (P less than 0.0001). Decreases in urine N-telopeptide, a bone resorption marker, plateau at 2-3 years, then start to increase after 3 years (P less than 0.0001). Serum bone-specific alkaline phosphatase, a marker of bone formation like osteocalcin, continues to decrease for about 4.8-5 years (P less than 0.0001).

Although alkaline phosphatase, urine N-telopeptide, and lumbar z scores had begun to recover by the end of follow-up, they were still significantly improved over baseline. For instance, baseline lumbar z scores, more than two standard deviations below normal before treatment, were 1.31 standard deviations below normal at last follow up (P = 0.002).

However, after initial improvement, there was no statistically significant change in serum osteocalcin from baseline; the mean baseline value was 52.7 ng/mL, and mean value at last follow up was 54.5 ng/mL (P = 0.48).

"Osteocalcin is the first marker to increase within the first year after start of bisphosphonate therapy. The results of the study," perhaps the first to define the drug holiday window for bisphosphonates in children, "provide a framework [for] when to anticipate reinitiation of bisphosphonate therapy," the investigators concluded at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"After 3 years, we should consider reinitiation of bisphosphonates in these children," said lead investigator Dr. Naziya Tahseen of the department of pediatric endocrinology at Children’s Mercy Hospitals and Clinics.

The subjects’ mean age was 11.6 years, 61 (58.7%) were girls, 67 (64.4%) were in puberty, and 75 (72.1%) were ambulatory; 59 (56.7%) children had primary or secondary osteoporosis, 26 (25%) had osteopenia, and 19 (18.3%) osteogenesis imperfecta. Lab values were followed every 4 months, with DXA scans repeated every 6-12 months.

Overall, children did better if they were ambulatory, but puberty status and gender had no effect.

The investigators had no relevant disclosures, and no outside funding was used for the project.

[email protected]

CHICAGO – Serum osteocalcin is the first bone turnover marker to recover after intravenous bisphosphonate therapy in children with primary osteoporosis, secondary osteoporosis, or osteogenesis imperfecta, making it a good indicator that it’s time to consider a second round of treatment, according to investigators from Children’s Mercy Hospitals and Clinics in Kansas City, Mo.

In a review of 104 children followed for up to 5 years, they found that the benefits of IV bisphosphonates – for children, usually two or three 2-day courses about 4 months apart – remain durable for up to 3 years. After an initial decrease, serum osteocalcin starts to return to baseline 1 year after the start of treatment (P = 0.007); improvements in lumbar spine bone mineral density z scores on dual energy x-ray absorptiometry (DXA) start to plateau at about 2 years and then reverse after 3 years (P less than 0.0001). Decreases in urine N-telopeptide, a bone resorption marker, plateau at 2-3 years, then start to increase after 3 years (P less than 0.0001). Serum bone-specific alkaline phosphatase, a marker of bone formation like osteocalcin, continues to decrease for about 4.8-5 years (P less than 0.0001).

Although alkaline phosphatase, urine N-telopeptide, and lumbar z scores had begun to recover by the end of follow-up, they were still significantly improved over baseline. For instance, baseline lumbar z scores, more than two standard deviations below normal before treatment, were 1.31 standard deviations below normal at last follow up (P = 0.002).

However, after initial improvement, there was no statistically significant change in serum osteocalcin from baseline; the mean baseline value was 52.7 ng/mL, and mean value at last follow up was 54.5 ng/mL (P = 0.48).

"Osteocalcin is the first marker to increase within the first year after start of bisphosphonate therapy. The results of the study," perhaps the first to define the drug holiday window for bisphosphonates in children, "provide a framework [for] when to anticipate reinitiation of bisphosphonate therapy," the investigators concluded at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"After 3 years, we should consider reinitiation of bisphosphonates in these children," said lead investigator Dr. Naziya Tahseen of the department of pediatric endocrinology at Children’s Mercy Hospitals and Clinics.

The subjects’ mean age was 11.6 years, 61 (58.7%) were girls, 67 (64.4%) were in puberty, and 75 (72.1%) were ambulatory; 59 (56.7%) children had primary or secondary osteoporosis, 26 (25%) had osteopenia, and 19 (18.3%) osteogenesis imperfecta. Lab values were followed every 4 months, with DXA scans repeated every 6-12 months.

Overall, children did better if they were ambulatory, but puberty status and gender had no effect.

The investigators had no relevant disclosures, and no outside funding was used for the project.

[email protected]

CHICAGO – Serum osteocalcin is the first bone turnover marker to recover after intravenous bisphosphonate therapy in children with primary osteoporosis, secondary osteoporosis, or osteogenesis imperfecta, making it a good indicator that it’s time to consider a second round of treatment, according to investigators from Children’s Mercy Hospitals and Clinics in Kansas City, Mo.

In a review of 104 children followed for up to 5 years, they found that the benefits of IV bisphosphonates – for children, usually two or three 2-day courses about 4 months apart – remain durable for up to 3 years. After an initial decrease, serum osteocalcin starts to return to baseline 1 year after the start of treatment (P = 0.007); improvements in lumbar spine bone mineral density z scores on dual energy x-ray absorptiometry (DXA) start to plateau at about 2 years and then reverse after 3 years (P less than 0.0001). Decreases in urine N-telopeptide, a bone resorption marker, plateau at 2-3 years, then start to increase after 3 years (P less than 0.0001). Serum bone-specific alkaline phosphatase, a marker of bone formation like osteocalcin, continues to decrease for about 4.8-5 years (P less than 0.0001).

Although alkaline phosphatase, urine N-telopeptide, and lumbar z scores had begun to recover by the end of follow-up, they were still significantly improved over baseline. For instance, baseline lumbar z scores, more than two standard deviations below normal before treatment, were 1.31 standard deviations below normal at last follow up (P = 0.002).

However, after initial improvement, there was no statistically significant change in serum osteocalcin from baseline; the mean baseline value was 52.7 ng/mL, and mean value at last follow up was 54.5 ng/mL (P = 0.48).

"Osteocalcin is the first marker to increase within the first year after start of bisphosphonate therapy. The results of the study," perhaps the first to define the drug holiday window for bisphosphonates in children, "provide a framework [for] when to anticipate reinitiation of bisphosphonate therapy," the investigators concluded at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"After 3 years, we should consider reinitiation of bisphosphonates in these children," said lead investigator Dr. Naziya Tahseen of the department of pediatric endocrinology at Children’s Mercy Hospitals and Clinics.

The subjects’ mean age was 11.6 years, 61 (58.7%) were girls, 67 (64.4%) were in puberty, and 75 (72.1%) were ambulatory; 59 (56.7%) children had primary or secondary osteoporosis, 26 (25%) had osteopenia, and 19 (18.3%) osteogenesis imperfecta. Lab values were followed every 4 months, with DXA scans repeated every 6-12 months.

Overall, children did better if they were ambulatory, but puberty status and gender had no effect.

The investigators had no relevant disclosures, and no outside funding was used for the project.

[email protected]

CHICAGO – Serum osteocalcin is the first bone turnover marker to recover after intravenous bisphosphonate therapy in children with primary osteoporosis, secondary osteoporosis, or osteogenesis imperfecta, making it a good indicator that it’s time to consider a second round of treatment, according to investigators from Children’s Mercy Hospitals and Clinics in Kansas City, Mo.

In a review of 104 children followed for up to 5 years, they found that the benefits of IV bisphosphonates – for children, usually two or three 2-day courses about 4 months apart – remain durable for up to 3 years. After an initial decrease, serum osteocalcin starts to return to baseline 1 year after the start of treatment (P = 0.007); improvements in lumbar spine bone mineral density z scores on dual energy x-ray absorptiometry (DXA) start to plateau at about 2 years and then reverse after 3 years (P less than 0.0001). Decreases in urine N-telopeptide, a bone resorption marker, plateau at 2-3 years, then start to increase after 3 years (P less than 0.0001). Serum bone-specific alkaline phosphatase, a marker of bone formation like osteocalcin, continues to decrease for about 4.8-5 years (P less than 0.0001).

Although alkaline phosphatase, urine N-telopeptide, and lumbar z scores had begun to recover by the end of follow-up, they were still significantly improved over baseline. For instance, baseline lumbar z scores, more than two standard deviations below normal before treatment, were 1.31 standard deviations below normal at last follow up (P = 0.002).

However, after initial improvement, there was no statistically significant change in serum osteocalcin from baseline; the mean baseline value was 52.7 ng/mL, and mean value at last follow up was 54.5 ng/mL (P = 0.48).

"Osteocalcin is the first marker to increase within the first year after start of bisphosphonate therapy. The results of the study," perhaps the first to define the drug holiday window for bisphosphonates in children, "provide a framework [for] when to anticipate reinitiation of bisphosphonate therapy," the investigators concluded at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"After 3 years, we should consider reinitiation of bisphosphonates in these children," said lead investigator Dr. Naziya Tahseen of the department of pediatric endocrinology at Children’s Mercy Hospitals and Clinics.

The subjects’ mean age was 11.6 years, 61 (58.7%) were girls, 67 (64.4%) were in puberty, and 75 (72.1%) were ambulatory; 59 (56.7%) children had primary or secondary osteoporosis, 26 (25%) had osteopenia, and 19 (18.3%) osteogenesis imperfecta. Lab values were followed every 4 months, with DXA scans repeated every 6-12 months.

Overall, children did better if they were ambulatory, but puberty status and gender had no effect.

The investigators had no relevant disclosures, and no outside funding was used for the project.

[email protected]

CHICAGO – Serum osteocalcin is the first bone turnover marker to recover after intravenous bisphosphonate therapy in children with primary osteoporosis, secondary osteoporosis, or osteogenesis imperfecta, making it a good indicator that it’s time to consider a second round of treatment, according to investigators from Children’s Mercy Hospitals and Clinics in Kansas City, Mo.

In a review of 104 children followed for up to 5 years, they found that the benefits of IV bisphosphonates – for children, usually two or three 2-day courses about 4 months apart – remain durable for up to 3 years. After an initial decrease, serum osteocalcin starts to return to baseline 1 year after the start of treatment (P = 0.007); improvements in lumbar spine bone mineral density z scores on dual energy x-ray absorptiometry (DXA) start to plateau at about 2 years and then reverse after 3 years (P less than 0.0001). Decreases in urine N-telopeptide, a bone resorption marker, plateau at 2-3 years, then start to increase after 3 years (P less than 0.0001). Serum bone-specific alkaline phosphatase, a marker of bone formation like osteocalcin, continues to decrease for about 4.8-5 years (P less than 0.0001).

Although alkaline phosphatase, urine N-telopeptide, and lumbar z scores had begun to recover by the end of follow-up, they were still significantly improved over baseline. For instance, baseline lumbar z scores, more than two standard deviations below normal before treatment, were 1.31 standard deviations below normal at last follow up (P = 0.002).

However, after initial improvement, there was no statistically significant change in serum osteocalcin from baseline; the mean baseline value was 52.7 ng/mL, and mean value at last follow up was 54.5 ng/mL (P = 0.48).

"Osteocalcin is the first marker to increase within the first year after start of bisphosphonate therapy. The results of the study," perhaps the first to define the drug holiday window for bisphosphonates in children, "provide a framework [for] when to anticipate reinitiation of bisphosphonate therapy," the investigators concluded at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"After 3 years, we should consider reinitiation of bisphosphonates in these children," said lead investigator Dr. Naziya Tahseen of the department of pediatric endocrinology at Children’s Mercy Hospitals and Clinics.

The subjects’ mean age was 11.6 years, 61 (58.7%) were girls, 67 (64.4%) were in puberty, and 75 (72.1%) were ambulatory; 59 (56.7%) children had primary or secondary osteoporosis, 26 (25%) had osteopenia, and 19 (18.3%) osteogenesis imperfecta. Lab values were followed every 4 months, with DXA scans repeated every 6-12 months.

Overall, children did better if they were ambulatory, but puberty status and gender had no effect.

The investigators had no relevant disclosures, and no outside funding was used for the project.

[email protected]

CHICAGO – Serum osteocalcin is the first bone turnover marker to recover after intravenous bisphosphonate therapy in children with primary osteoporosis, secondary osteoporosis, or osteogenesis imperfecta, making it a good indicator that it’s time to consider a second round of treatment, according to investigators from Children’s Mercy Hospitals and Clinics in Kansas City, Mo.

In a review of 104 children followed for up to 5 years, they found that the benefits of IV bisphosphonates – for children, usually two or three 2-day courses about 4 months apart – remain durable for up to 3 years. After an initial decrease, serum osteocalcin starts to return to baseline 1 year after the start of treatment (P = 0.007); improvements in lumbar spine bone mineral density z scores on dual energy x-ray absorptiometry (DXA) start to plateau at about 2 years and then reverse after 3 years (P less than 0.0001). Decreases in urine N-telopeptide, a bone resorption marker, plateau at 2-3 years, then start to increase after 3 years (P less than 0.0001). Serum bone-specific alkaline phosphatase, a marker of bone formation like osteocalcin, continues to decrease for about 4.8-5 years (P less than 0.0001).

Although alkaline phosphatase, urine N-telopeptide, and lumbar z scores had begun to recover by the end of follow-up, they were still significantly improved over baseline. For instance, baseline lumbar z scores, more than two standard deviations below normal before treatment, were 1.31 standard deviations below normal at last follow up (P = 0.002).

However, after initial improvement, there was no statistically significant change in serum osteocalcin from baseline; the mean baseline value was 52.7 ng/mL, and mean value at last follow up was 54.5 ng/mL (P = 0.48).

"Osteocalcin is the first marker to increase within the first year after start of bisphosphonate therapy. The results of the study," perhaps the first to define the drug holiday window for bisphosphonates in children, "provide a framework [for] when to anticipate reinitiation of bisphosphonate therapy," the investigators concluded at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"After 3 years, we should consider reinitiation of bisphosphonates in these children," said lead investigator Dr. Naziya Tahseen of the department of pediatric endocrinology at Children’s Mercy Hospitals and Clinics.

The subjects’ mean age was 11.6 years, 61 (58.7%) were girls, 67 (64.4%) were in puberty, and 75 (72.1%) were ambulatory; 59 (56.7%) children had primary or secondary osteoporosis, 26 (25%) had osteopenia, and 19 (18.3%) osteogenesis imperfecta. Lab values were followed every 4 months, with DXA scans repeated every 6-12 months.

Overall, children did better if they were ambulatory, but puberty status and gender had no effect.

The investigators had no relevant disclosures, and no outside funding was used for the project.

[email protected]

CHICAGO – Postmenopausal women on denosumab for 8 years straight showed a continued near-linear increase in bone mineral density at the lumbar spine as well as persistent reduction of bone turnover markers and a sustained low incidence of new vertebral and nonvertebral fractures in the ongoing FREEDOM open-label extension study.

Moreover, no new safety signals have emerged during 5 years of additional denosumab (Prolia) on top of an initial 3 years occurring in the pivotal, phase III, randomized, double-blind, placebo-controlled FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial.

Importantly, the overall risk of adverse events has not increased over time, and rates of malignancies, serious infections, eczema, hypocalcemia, and other adverse events in denosumab-treated patients remain comparable to rates seen in placebo-treated controls in the earlier double-blind phase, Dr. E. Michael Lewiecki reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"The benefit/risk profile for denosumab remains favorable," declared Dr. Lewiecki, director of the New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

The FREEDOM open-label extension is designed to assess the efficacy and safety of up to 10 years of denosumab therapy. Dr. Lewiecki presented the latest update, based on 8 years of treatment, or 5 years for patients in the original placebo arm who later elected to crossover to denosumab upon completing the 3-year double-blind phase. His report included 2,243 women on denosumab at 60 mg by subcutaneous injection every 6 months continuously for 8 years and another 2,207 on the drug for 5 years.

Five cases of osteonecrosis of the jaw have occurred in the long-term therapy group, as well as three cases among those who crossed over to the drug. In addition, there has been one atypical femoral fracture during 8 consecutive years on denosumab and one case in the crossover group.

Impressively, lumbar spine bone mineral density (BMD) has increased by 18.4% over baseline with 8 years of denosumab and by 13.7% with 5 years of active therapy.

"The near-linear slope of increase is unchanged over the course of the study. A similar slope is seen in the crossover group," the endocrinologist observed.

Total hip BMD increased by 8.3% with 8 years of denosumab and 4.9% with 5 years of therapy.

In the pivotal phase III FREEDOM trial, 3 years of denosumab reduced the risk of vertebral fractures by 68% compared to placebo, hip fractures by 40%, and nonvertebral fractures by 20% (N. Engl. J. Med. 2009;361:756-65).

The yearly incidence of new vertebral fractures was 0.7%-1.1% in denosumab-treated patients during years 1-3 and 1.1%-1.3% annually in open-label years 4-8. The annual incidence of new nonvertebral fractures in the denosumab group was 2.1%-2.6% in the first 3 years of double-blind therapy and has trended lower since then: 1.5% in year 4, 1.2% in year 5, 1.8% in year 6, 1.6% in year 7, and 0.7% in year 8.

"There’s a suggestion of a further reduction in the risk of nonvertebral fractures out to the 8-year time point. It’ll be fascinating to look at the data for years 9 and 10 to see if that’s just a statistical aberrance or that very low risk of nonvertebral fractures persists," Dr. Lewiecki commented.

Levels of the bone turnover markers serum C-terminal telopeptide of type 1 collagen and procollagen type 1 N-terminal propeptide quickly dropped upon initiation of denosumab and have remained low through 8 years.

Asked about the mechanism underlying the continued linear increase in lumbar spine BMD seen through 8 years of denosumab, in sharp contrast to the bisphosphonates, where BMD plateaus, Dr. Lewiecki confessed that "Many of us are scratching our heads about this and trying to come up with an explanation."

"I don’t know the reason why, but there are several hypotheses worth considering," he continued. "One is that the effects on cortical bone appear to be different with denosumab than with bisphosphonates. We see a reduction in cortical porosity and a larger improvement in bone mineral density at cortical skeletal sites. Secondly, there’s a possible parathyroid hormone effect that may play a role here: There is a larger and longer-lasting increase in parathyroid hormone with denosumab as compared with bisphosphonates. And finally, there’s animal data in monkeys showing ongoing bone modeling taking place with denosumab; it’s possible that may also play a role."

Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor-kappa B (RANK) ligand.

The FREEDOM study is supported by Amgen. Dr. Lewiecki reported serving as a consultant to that company as well as to AgNovos Healthcare, Lilly, Merck, and Radius Health.

[email protected]

CHICAGO – Postmenopausal women on denosumab for 8 years straight showed a continued near-linear increase in bone mineral density at the lumbar spine as well as persistent reduction of bone turnover markers and a sustained low incidence of new vertebral and nonvertebral fractures in the ongoing FREEDOM open-label extension study.

Moreover, no new safety signals have emerged during 5 years of additional denosumab (Prolia) on top of an initial 3 years occurring in the pivotal, phase III, randomized, double-blind, placebo-controlled FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial.

Importantly, the overall risk of adverse events has not increased over time, and rates of malignancies, serious infections, eczema, hypocalcemia, and other adverse events in denosumab-treated patients remain comparable to rates seen in placebo-treated controls in the earlier double-blind phase, Dr. E. Michael Lewiecki reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"The benefit/risk profile for denosumab remains favorable," declared Dr. Lewiecki, director of the New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

The FREEDOM open-label extension is designed to assess the efficacy and safety of up to 10 years of denosumab therapy. Dr. Lewiecki presented the latest update, based on 8 years of treatment, or 5 years for patients in the original placebo arm who later elected to crossover to denosumab upon completing the 3-year double-blind phase. His report included 2,243 women on denosumab at 60 mg by subcutaneous injection every 6 months continuously for 8 years and another 2,207 on the drug for 5 years.

Five cases of osteonecrosis of the jaw have occurred in the long-term therapy group, as well as three cases among those who crossed over to the drug. In addition, there has been one atypical femoral fracture during 8 consecutive years on denosumab and one case in the crossover group.

Impressively, lumbar spine bone mineral density (BMD) has increased by 18.4% over baseline with 8 years of denosumab and by 13.7% with 5 years of active therapy.

"The near-linear slope of increase is unchanged over the course of the study. A similar slope is seen in the crossover group," the endocrinologist observed.

Total hip BMD increased by 8.3% with 8 years of denosumab and 4.9% with 5 years of therapy.

In the pivotal phase III FREEDOM trial, 3 years of denosumab reduced the risk of vertebral fractures by 68% compared to placebo, hip fractures by 40%, and nonvertebral fractures by 20% (N. Engl. J. Med. 2009;361:756-65).

The yearly incidence of new vertebral fractures was 0.7%-1.1% in denosumab-treated patients during years 1-3 and 1.1%-1.3% annually in open-label years 4-8. The annual incidence of new nonvertebral fractures in the denosumab group was 2.1%-2.6% in the first 3 years of double-blind therapy and has trended lower since then: 1.5% in year 4, 1.2% in year 5, 1.8% in year 6, 1.6% in year 7, and 0.7% in year 8.

"There’s a suggestion of a further reduction in the risk of nonvertebral fractures out to the 8-year time point. It’ll be fascinating to look at the data for years 9 and 10 to see if that’s just a statistical aberrance or that very low risk of nonvertebral fractures persists," Dr. Lewiecki commented.

Levels of the bone turnover markers serum C-terminal telopeptide of type 1 collagen and procollagen type 1 N-terminal propeptide quickly dropped upon initiation of denosumab and have remained low through 8 years.

Asked about the mechanism underlying the continued linear increase in lumbar spine BMD seen through 8 years of denosumab, in sharp contrast to the bisphosphonates, where BMD plateaus, Dr. Lewiecki confessed that "Many of us are scratching our heads about this and trying to come up with an explanation."

"I don’t know the reason why, but there are several hypotheses worth considering," he continued. "One is that the effects on cortical bone appear to be different with denosumab than with bisphosphonates. We see a reduction in cortical porosity and a larger improvement in bone mineral density at cortical skeletal sites. Secondly, there’s a possible parathyroid hormone effect that may play a role here: There is a larger and longer-lasting increase in parathyroid hormone with denosumab as compared with bisphosphonates. And finally, there’s animal data in monkeys showing ongoing bone modeling taking place with denosumab; it’s possible that may also play a role."

Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor-kappa B (RANK) ligand.

The FREEDOM study is supported by Amgen. Dr. Lewiecki reported serving as a consultant to that company as well as to AgNovos Healthcare, Lilly, Merck, and Radius Health.

[email protected]

CHICAGO – Postmenopausal women on denosumab for 8 years straight showed a continued near-linear increase in bone mineral density at the lumbar spine as well as persistent reduction of bone turnover markers and a sustained low incidence of new vertebral and nonvertebral fractures in the ongoing FREEDOM open-label extension study.

Moreover, no new safety signals have emerged during 5 years of additional denosumab (Prolia) on top of an initial 3 years occurring in the pivotal, phase III, randomized, double-blind, placebo-controlled FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial.

Importantly, the overall risk of adverse events has not increased over time, and rates of malignancies, serious infections, eczema, hypocalcemia, and other adverse events in denosumab-treated patients remain comparable to rates seen in placebo-treated controls in the earlier double-blind phase, Dr. E. Michael Lewiecki reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"The benefit/risk profile for denosumab remains favorable," declared Dr. Lewiecki, director of the New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

The FREEDOM open-label extension is designed to assess the efficacy and safety of up to 10 years of denosumab therapy. Dr. Lewiecki presented the latest update, based on 8 years of treatment, or 5 years for patients in the original placebo arm who later elected to crossover to denosumab upon completing the 3-year double-blind phase. His report included 2,243 women on denosumab at 60 mg by subcutaneous injection every 6 months continuously for 8 years and another 2,207 on the drug for 5 years.

Five cases of osteonecrosis of the jaw have occurred in the long-term therapy group, as well as three cases among those who crossed over to the drug. In addition, there has been one atypical femoral fracture during 8 consecutive years on denosumab and one case in the crossover group.

Impressively, lumbar spine bone mineral density (BMD) has increased by 18.4% over baseline with 8 years of denosumab and by 13.7% with 5 years of active therapy.

"The near-linear slope of increase is unchanged over the course of the study. A similar slope is seen in the crossover group," the endocrinologist observed.

Total hip BMD increased by 8.3% with 8 years of denosumab and 4.9% with 5 years of therapy.

In the pivotal phase III FREEDOM trial, 3 years of denosumab reduced the risk of vertebral fractures by 68% compared to placebo, hip fractures by 40%, and nonvertebral fractures by 20% (N. Engl. J. Med. 2009;361:756-65).

The yearly incidence of new vertebral fractures was 0.7%-1.1% in denosumab-treated patients during years 1-3 and 1.1%-1.3% annually in open-label years 4-8. The annual incidence of new nonvertebral fractures in the denosumab group was 2.1%-2.6% in the first 3 years of double-blind therapy and has trended lower since then: 1.5% in year 4, 1.2% in year 5, 1.8% in year 6, 1.6% in year 7, and 0.7% in year 8.

"There’s a suggestion of a further reduction in the risk of nonvertebral fractures out to the 8-year time point. It’ll be fascinating to look at the data for years 9 and 10 to see if that’s just a statistical aberrance or that very low risk of nonvertebral fractures persists," Dr. Lewiecki commented.

Levels of the bone turnover markers serum C-terminal telopeptide of type 1 collagen and procollagen type 1 N-terminal propeptide quickly dropped upon initiation of denosumab and have remained low through 8 years.

Asked about the mechanism underlying the continued linear increase in lumbar spine BMD seen through 8 years of denosumab, in sharp contrast to the bisphosphonates, where BMD plateaus, Dr. Lewiecki confessed that "Many of us are scratching our heads about this and trying to come up with an explanation."

"I don’t know the reason why, but there are several hypotheses worth considering," he continued. "One is that the effects on cortical bone appear to be different with denosumab than with bisphosphonates. We see a reduction in cortical porosity and a larger improvement in bone mineral density at cortical skeletal sites. Secondly, there’s a possible parathyroid hormone effect that may play a role here: There is a larger and longer-lasting increase in parathyroid hormone with denosumab as compared with bisphosphonates. And finally, there’s animal data in monkeys showing ongoing bone modeling taking place with denosumab; it’s possible that may also play a role."

Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor-kappa B (RANK) ligand.

The FREEDOM study is supported by Amgen. Dr. Lewiecki reported serving as a consultant to that company as well as to AgNovos Healthcare, Lilly, Merck, and Radius Health.

[email protected]

CHICAGO – Women with breast cancer and bone metastasis can safely scale back the frequency of their zoledronic acid infusions from every 4 weeks to every 12 weeks without a loss in efficacy*, according to results of the phase III OPTIMIZE 2 trial.

Notably, the dreaded bisphosphonate side effect of osteonecrosis of the jaw was seen in two patients in the monthly arm, but none of those in the every-3-month treatment arm.

The findings apply only to breast cancer patients who’ve completed at least 1 year of monthly zoledronic acid therapy, according to study author Dr. Gabriel N. Hortobagyi, a professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

In an interview with us at the 50th anniversary of the American Society of Clinical Oncology, this past ASCO president said that the findings from this late-breaking abstract study will have implications for the costs of cancer care and possibly for patients with other cancers.

Dr. Hortobagyi reported consultant or advisory roles and research funding with Novartis, the study sponsor. Several coauthors are employees of or have leadership positions with Novartis.

[email protected]

Correction, 5/31/2014: An earlier version of this article misstated the duration of their zoledronic acid infusion treatments.

CHICAGO – Women with breast cancer and bone metastasis can safely scale back the frequency of their zoledronic acid infusions from every 4 weeks to every 12 weeks without a loss in efficacy*, according to results of the phase III OPTIMIZE 2 trial.

Notably, the dreaded bisphosphonate side effect of osteonecrosis of the jaw was seen in two patients in the monthly arm, but none of those in the every-3-month treatment arm.

The findings apply only to breast cancer patients who’ve completed at least 1 year of monthly zoledronic acid therapy, according to study author Dr. Gabriel N. Hortobagyi, a professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

In an interview with us at the 50th anniversary of the American Society of Clinical Oncology, this past ASCO president said that the findings from this late-breaking abstract study will have implications for the costs of cancer care and possibly for patients with other cancers.

Dr. Hortobagyi reported consultant or advisory roles and research funding with Novartis, the study sponsor. Several coauthors are employees of or have leadership positions with Novartis.

[email protected]

Correction, 5/31/2014: An earlier version of this article misstated the duration of their zoledronic acid infusion treatments.

CHICAGO – Women with breast cancer and bone metastasis can safely scale back the frequency of their zoledronic acid infusions from every 4 weeks to every 12 weeks without a loss in efficacy*, according to results of the phase III OPTIMIZE 2 trial.

Notably, the dreaded bisphosphonate side effect of osteonecrosis of the jaw was seen in two patients in the monthly arm, but none of those in the every-3-month treatment arm.

The findings apply only to breast cancer patients who’ve completed at least 1 year of monthly zoledronic acid therapy, according to study author Dr. Gabriel N. Hortobagyi, a professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

In an interview with us at the 50th anniversary of the American Society of Clinical Oncology, this past ASCO president said that the findings from this late-breaking abstract study will have implications for the costs of cancer care and possibly for patients with other cancers.

Dr. Hortobagyi reported consultant or advisory roles and research funding with Novartis, the study sponsor. Several coauthors are employees of or have leadership positions with Novartis.

[email protected]

Correction, 5/31/2014: An earlier version of this article misstated the duration of their zoledronic acid infusion treatments.

ALBUQUERQUE – Postmenopausal women who reported a history of nonmelanoma skin cancer were almost 16% more likely to sustain a lower arm fracture than were women without a skin cancer history, according to a large, prospective, longitudinal study.

Women with prior nonmelanoma skin cancers (NMSCs) also were more likely to suffer a subsequent hip fracture, although the association did not reach statistical significance, said Eric Anderson of the dermatology department at Stanford (Calif.) University School of Medicine.

"These results suggest that prior history of NMSC is associated with an increased risk of subsequent bone fracture, contrary to our hypothesis," noted Mr. Anderson. He presented the findings at the annual meeting of the Society for Investigational Dermatology.

Nonmelanoma skin cancer has been correlated with decreased fracture risk in at least one small cohort study, Mr. Anderson said (Osteoporos. Int. 2007;18:687-92). However, patients with NMSC also have been shown to wear more sunscreen and limit their sun exposure after diagnosis, which might lower their vitamin D levels and increase their fracture risk, Mr. Anderson noted (Cancer Causes Control 2012;23:133-40).

To better clarify the relationship between NMSC and fracture risk, Mr. Anderson and his associates compared prospective data from 4,289 women with self-reported NMSC and 67,470 women who did not report a history of NMSC at baseline. The participants were from the Womens Health Initiative, a prospective longitudinal cohort study of postmenopausal women aged 50-79 years who were enrolled at 40 centers in the United States. Participants were followed for more than 10 years, and new spine, hip, and lower arm fractures were recorded, Mr. Anderson said.

In age-adjusted Cox proportional hazards models, women with a history of NMSC were 1.55 times more likely to sustain a hip fracture (95% confidence interval, 1.31-1.85; P < 0.0001), 1.29 times more likely to suffer a spine fracture (95% CI, 1.10-1.51; P = 0.0018), and 1.28 times more likely to sustain a lower arm fracture (95% CI, 1.13-1.45; P < 0.0001) than were women who did not report a history of NMSC at baseline, Mr. Anderson and his associates reported.

After adjusting for sun exposure, sunscreen use, vitamin D intake, physical activity, and other risk factors for fracture, only lower arm fracture remained statistically significant (hazard ratio, 1.16; 95% CI, 1.31-1.85; P = 0.02), although hip fracture was borderline significant (HR, 1.18; 95% CI, 0.99-1.41; P = 0.06), the investigators reported. Baseline hip bone marrow density was not associated with risk of NMSC in a subgroup analysis of 4,267 women with available data, Mr. Anderson said.

"We’re inclined to believe that this increased fracture risk may be due to sun exposure avoidance after NMSC diagnosis," said Mr. Anderson. He added that, in future studies, the investigators would compare serum vitamin D levels between participants with and without a history of NMSC, and explore temporal relationships between diagnosis of NMSC and fracture occurrence.

The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.

ALBUQUERQUE – Postmenopausal women who reported a history of nonmelanoma skin cancer were almost 16% more likely to sustain a lower arm fracture than were women without a skin cancer history, according to a large, prospective, longitudinal study.

Women with prior nonmelanoma skin cancers (NMSCs) also were more likely to suffer a subsequent hip fracture, although the association did not reach statistical significance, said Eric Anderson of the dermatology department at Stanford (Calif.) University School of Medicine.

"These results suggest that prior history of NMSC is associated with an increased risk of subsequent bone fracture, contrary to our hypothesis," noted Mr. Anderson. He presented the findings at the annual meeting of the Society for Investigational Dermatology.

Nonmelanoma skin cancer has been correlated with decreased fracture risk in at least one small cohort study, Mr. Anderson said (Osteoporos. Int. 2007;18:687-92). However, patients with NMSC also have been shown to wear more sunscreen and limit their sun exposure after diagnosis, which might lower their vitamin D levels and increase their fracture risk, Mr. Anderson noted (Cancer Causes Control 2012;23:133-40).

To better clarify the relationship between NMSC and fracture risk, Mr. Anderson and his associates compared prospective data from 4,289 women with self-reported NMSC and 67,470 women who did not report a history of NMSC at baseline. The participants were from the Womens Health Initiative, a prospective longitudinal cohort study of postmenopausal women aged 50-79 years who were enrolled at 40 centers in the United States. Participants were followed for more than 10 years, and new spine, hip, and lower arm fractures were recorded, Mr. Anderson said.

In age-adjusted Cox proportional hazards models, women with a history of NMSC were 1.55 times more likely to sustain a hip fracture (95% confidence interval, 1.31-1.85; P < 0.0001), 1.29 times more likely to suffer a spine fracture (95% CI, 1.10-1.51; P = 0.0018), and 1.28 times more likely to sustain a lower arm fracture (95% CI, 1.13-1.45; P < 0.0001) than were women who did not report a history of NMSC at baseline, Mr. Anderson and his associates reported.

After adjusting for sun exposure, sunscreen use, vitamin D intake, physical activity, and other risk factors for fracture, only lower arm fracture remained statistically significant (hazard ratio, 1.16; 95% CI, 1.31-1.85; P = 0.02), although hip fracture was borderline significant (HR, 1.18; 95% CI, 0.99-1.41; P = 0.06), the investigators reported. Baseline hip bone marrow density was not associated with risk of NMSC in a subgroup analysis of 4,267 women with available data, Mr. Anderson said.

"We’re inclined to believe that this increased fracture risk may be due to sun exposure avoidance after NMSC diagnosis," said Mr. Anderson. He added that, in future studies, the investigators would compare serum vitamin D levels between participants with and without a history of NMSC, and explore temporal relationships between diagnosis of NMSC and fracture occurrence.

The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.

ALBUQUERQUE – Postmenopausal women who reported a history of nonmelanoma skin cancer were almost 16% more likely to sustain a lower arm fracture than were women without a skin cancer history, according to a large, prospective, longitudinal study.

Women with prior nonmelanoma skin cancers (NMSCs) also were more likely to suffer a subsequent hip fracture, although the association did not reach statistical significance, said Eric Anderson of the dermatology department at Stanford (Calif.) University School of Medicine.

"These results suggest that prior history of NMSC is associated with an increased risk of subsequent bone fracture, contrary to our hypothesis," noted Mr. Anderson. He presented the findings at the annual meeting of the Society for Investigational Dermatology.

Nonmelanoma skin cancer has been correlated with decreased fracture risk in at least one small cohort study, Mr. Anderson said (Osteoporos. Int. 2007;18:687-92). However, patients with NMSC also have been shown to wear more sunscreen and limit their sun exposure after diagnosis, which might lower their vitamin D levels and increase their fracture risk, Mr. Anderson noted (Cancer Causes Control 2012;23:133-40).

To better clarify the relationship between NMSC and fracture risk, Mr. Anderson and his associates compared prospective data from 4,289 women with self-reported NMSC and 67,470 women who did not report a history of NMSC at baseline. The participants were from the Womens Health Initiative, a prospective longitudinal cohort study of postmenopausal women aged 50-79 years who were enrolled at 40 centers in the United States. Participants were followed for more than 10 years, and new spine, hip, and lower arm fractures were recorded, Mr. Anderson said.

In age-adjusted Cox proportional hazards models, women with a history of NMSC were 1.55 times more likely to sustain a hip fracture (95% confidence interval, 1.31-1.85; P < 0.0001), 1.29 times more likely to suffer a spine fracture (95% CI, 1.10-1.51; P = 0.0018), and 1.28 times more likely to sustain a lower arm fracture (95% CI, 1.13-1.45; P < 0.0001) than were women who did not report a history of NMSC at baseline, Mr. Anderson and his associates reported.

After adjusting for sun exposure, sunscreen use, vitamin D intake, physical activity, and other risk factors for fracture, only lower arm fracture remained statistically significant (hazard ratio, 1.16; 95% CI, 1.31-1.85; P = 0.02), although hip fracture was borderline significant (HR, 1.18; 95% CI, 0.99-1.41; P = 0.06), the investigators reported. Baseline hip bone marrow density was not associated with risk of NMSC in a subgroup analysis of 4,267 women with available data, Mr. Anderson said.

"We’re inclined to believe that this increased fracture risk may be due to sun exposure avoidance after NMSC diagnosis," said Mr. Anderson. He added that, in future studies, the investigators would compare serum vitamin D levels between participants with and without a history of NMSC, and explore temporal relationships between diagnosis of NMSC and fracture occurrence.

The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.

LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.

The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.

How common are atypical femoral fractures?

"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.

"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."

"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.

However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.

Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).

There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.

Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.

What are atypical hip fractures?

Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.

"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.

There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.

The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).

The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."

Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.

What should clinicians do if AFF is suspected?

"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.

In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.

In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.

Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.

In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."

Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."

Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.

Atypical femoral fracture register planned

"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.

"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.

Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.

LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.

The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.

How common are atypical femoral fractures?

"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.

"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."

"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.

However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.

Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).

There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.

Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.

What are atypical hip fractures?

Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.

"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.

There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.

The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).

The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."

Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.

What should clinicians do if AFF is suspected?

"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.

In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.

In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.

Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.

In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."

Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."

Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.

Atypical femoral fracture register planned

"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.

"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.

Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.

LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.

The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.

How common are atypical femoral fractures?

"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.

"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."

"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.

However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.

Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).

There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.

Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.

What are atypical hip fractures?

Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.

"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.

There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.

The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).

The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."

Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.

What should clinicians do if AFF is suspected?

"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.

In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.

In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.

Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.

In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."

Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."

Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.

Atypical femoral fracture register planned

"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.

"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.

Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.

In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).

Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.

Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."

Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."

Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D₃ and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D₃ and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.

The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).

Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.

Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.

Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.

"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."

"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."

Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."

Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.

[email protected]

SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.

In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).

Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.

Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."

Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."

Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D₃ and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D₃ and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.

The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).

Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.

Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.

Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.

"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."

"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."

Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."

Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.

[email protected]

SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.

In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).

Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.

Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."

Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."

Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D₃ and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D₃ and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.

The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).

Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.

Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.

Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.

"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."

"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."

Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."

Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.

[email protected]