Osteoporosis

SAN DIEGO – The World Health Organization’s widely used, Web-based fracture risk assessment tool known as FRAX seriously underestimates the risk of major osteoporotic and hip fractures in patients with diabetes, according to a large Canadian study.

This finding indicates diabetes is an independent risk factor for fractures above and beyond the conventional risk factors incorporated in the FRAX tool, which include age, gender, smoking, fracture history, and glucocorticoid use – but not diabetes.

"One implication of our findings is that FRAX should be applied cautiously in clinical situations involving diabetic patients," Lora Giangregorio, Ph.D., said at the annual meeting of the American Society for Bone and Mineral Research.

"Future iterations of the FRAX tool might consider adding diabetes to the list of risk factors," added Dr. Giangregorio of the University of Waterloo (Ontario).

She presented an analysis of a large Manitoba Province–wide database that included 3,518 patients with type 1 or type 2 diabetes and 36,085 nondiabetic controls, all at least 50 years old when they underwent bone mineral density testing during 1987-2008.

The FRAX tool was used to calculate 10-year fracture risk probabilities, and the actual incidence of major osteoporotic or hip fractures was determined through 2008.

The key finding: After the researchers controlled for FRAX fracture probability scores and the use of osteoporotic medications, diabetes was independently associated with a 59% increased fracture rate during an average 10 years of follow-up.

Of note, despite the increased fracture rate documented in diabetic patients in this study, a lower proportion of subjects with diabetes were receiving osteoporotic medications, compared with the nondiabetes population, Dr. Giangregorio observed.

Diabetes was a stronger predictor of hip fracture risk in younger subjects. Indeed, it was independently associated with a 5.3-fold increased risk of hip fracture in individuals younger than age 65, compared with a 2.1-fold increase in those who were older. In contrast, the risk of major osteoporotic fractures in diabetic patients was not related to age.

The fracture probability curves for diabetic and nondiabetic subjects diverged from the beginning of follow-up and continued to separate throughout the study period.

An important area for future research, in Dr. Giangregorio’s view, is the identification of potentially modifiable diabetes-related fracture risk factors. As a hypothetical example, perhaps some diabetes medications are associated with an increase in fractures while others are not.

"Future iterations of the FRAX tool might consider adding diabetes to the list of risk factors."

The study did not differentiate between type 1 and type 2 diabetes. However, in another study presented at the meeting, Dr. Ling Oei of Erasmus University, Rotterdam, the Netherlands, noted that patients with type 2 diabetes are paradoxically at increased risk of osteoporotic fractures even though their bone mineral density is typically normal or even increased.

In a prospective, population-based study of 203 patients with adequately controlled type 2 diabetes, 217 others with inadequately controlled disease, and 3,715 nondiabetic controls, Dr. Oei and coworkers showed that women with inadequately controlled diabetes had significantly higher bone mineral density at both the lumbar spine and femoral neck, compared with women in the other two groups.

After the researchers controlled for age, femoral neck bone mineral density, and body mass index, women with inadequately controlled type 2 diabetes had a 1.6-fold increased risk of fracture during an average 8.2-year follow-up, compared with patients who had adequately controlled type 2 diabetes or patients without diabetes. In other words, inadequate control of type 2 diabetes appears to be a risk factor for fracture in elderly women but not men, according to the Dutch investigators.

Dr. Giangregorio and Dr. Oei reported having no financial conflicts.

SAN DIEGO – The World Health Organization’s widely used, Web-based fracture risk assessment tool known as FRAX seriously underestimates the risk of major osteoporotic and hip fractures in patients with diabetes, according to a large Canadian study.

This finding indicates diabetes is an independent risk factor for fractures above and beyond the conventional risk factors incorporated in the FRAX tool, which include age, gender, smoking, fracture history, and glucocorticoid use – but not diabetes.

"One implication of our findings is that FRAX should be applied cautiously in clinical situations involving diabetic patients," Lora Giangregorio, Ph.D., said at the annual meeting of the American Society for Bone and Mineral Research.

"Future iterations of the FRAX tool might consider adding diabetes to the list of risk factors," added Dr. Giangregorio of the University of Waterloo (Ontario).

She presented an analysis of a large Manitoba Province–wide database that included 3,518 patients with type 1 or type 2 diabetes and 36,085 nondiabetic controls, all at least 50 years old when they underwent bone mineral density testing during 1987-2008.

The FRAX tool was used to calculate 10-year fracture risk probabilities, and the actual incidence of major osteoporotic or hip fractures was determined through 2008.

The key finding: After the researchers controlled for FRAX fracture probability scores and the use of osteoporotic medications, diabetes was independently associated with a 59% increased fracture rate during an average 10 years of follow-up.

Of note, despite the increased fracture rate documented in diabetic patients in this study, a lower proportion of subjects with diabetes were receiving osteoporotic medications, compared with the nondiabetes population, Dr. Giangregorio observed.

Diabetes was a stronger predictor of hip fracture risk in younger subjects. Indeed, it was independently associated with a 5.3-fold increased risk of hip fracture in individuals younger than age 65, compared with a 2.1-fold increase in those who were older. In contrast, the risk of major osteoporotic fractures in diabetic patients was not related to age.

The fracture probability curves for diabetic and nondiabetic subjects diverged from the beginning of follow-up and continued to separate throughout the study period.

An important area for future research, in Dr. Giangregorio’s view, is the identification of potentially modifiable diabetes-related fracture risk factors. As a hypothetical example, perhaps some diabetes medications are associated with an increase in fractures while others are not.

"Future iterations of the FRAX tool might consider adding diabetes to the list of risk factors."

The study did not differentiate between type 1 and type 2 diabetes. However, in another study presented at the meeting, Dr. Ling Oei of Erasmus University, Rotterdam, the Netherlands, noted that patients with type 2 diabetes are paradoxically at increased risk of osteoporotic fractures even though their bone mineral density is typically normal or even increased.

In a prospective, population-based study of 203 patients with adequately controlled type 2 diabetes, 217 others with inadequately controlled disease, and 3,715 nondiabetic controls, Dr. Oei and coworkers showed that women with inadequately controlled diabetes had significantly higher bone mineral density at both the lumbar spine and femoral neck, compared with women in the other two groups.

After the researchers controlled for age, femoral neck bone mineral density, and body mass index, women with inadequately controlled type 2 diabetes had a 1.6-fold increased risk of fracture during an average 8.2-year follow-up, compared with patients who had adequately controlled type 2 diabetes or patients without diabetes. In other words, inadequate control of type 2 diabetes appears to be a risk factor for fracture in elderly women but not men, according to the Dutch investigators.

Dr. Giangregorio and Dr. Oei reported having no financial conflicts.

SAN DIEGO – The World Health Organization’s widely used, Web-based fracture risk assessment tool known as FRAX seriously underestimates the risk of major osteoporotic and hip fractures in patients with diabetes, according to a large Canadian study.

This finding indicates diabetes is an independent risk factor for fractures above and beyond the conventional risk factors incorporated in the FRAX tool, which include age, gender, smoking, fracture history, and glucocorticoid use – but not diabetes.

"One implication of our findings is that FRAX should be applied cautiously in clinical situations involving diabetic patients," Lora Giangregorio, Ph.D., said at the annual meeting of the American Society for Bone and Mineral Research.

"Future iterations of the FRAX tool might consider adding diabetes to the list of risk factors," added Dr. Giangregorio of the University of Waterloo (Ontario).

She presented an analysis of a large Manitoba Province–wide database that included 3,518 patients with type 1 or type 2 diabetes and 36,085 nondiabetic controls, all at least 50 years old when they underwent bone mineral density testing during 1987-2008.

The FRAX tool was used to calculate 10-year fracture risk probabilities, and the actual incidence of major osteoporotic or hip fractures was determined through 2008.

The key finding: After the researchers controlled for FRAX fracture probability scores and the use of osteoporotic medications, diabetes was independently associated with a 59% increased fracture rate during an average 10 years of follow-up.

Of note, despite the increased fracture rate documented in diabetic patients in this study, a lower proportion of subjects with diabetes were receiving osteoporotic medications, compared with the nondiabetes population, Dr. Giangregorio observed.

Diabetes was a stronger predictor of hip fracture risk in younger subjects. Indeed, it was independently associated with a 5.3-fold increased risk of hip fracture in individuals younger than age 65, compared with a 2.1-fold increase in those who were older. In contrast, the risk of major osteoporotic fractures in diabetic patients was not related to age.

The fracture probability curves for diabetic and nondiabetic subjects diverged from the beginning of follow-up and continued to separate throughout the study period.

An important area for future research, in Dr. Giangregorio’s view, is the identification of potentially modifiable diabetes-related fracture risk factors. As a hypothetical example, perhaps some diabetes medications are associated with an increase in fractures while others are not.

"Future iterations of the FRAX tool might consider adding diabetes to the list of risk factors."

The study did not differentiate between type 1 and type 2 diabetes. However, in another study presented at the meeting, Dr. Ling Oei of Erasmus University, Rotterdam, the Netherlands, noted that patients with type 2 diabetes are paradoxically at increased risk of osteoporotic fractures even though their bone mineral density is typically normal or even increased.

In a prospective, population-based study of 203 patients with adequately controlled type 2 diabetes, 217 others with inadequately controlled disease, and 3,715 nondiabetic controls, Dr. Oei and coworkers showed that women with inadequately controlled diabetes had significantly higher bone mineral density at both the lumbar spine and femoral neck, compared with women in the other two groups.

After the researchers controlled for age, femoral neck bone mineral density, and body mass index, women with inadequately controlled type 2 diabetes had a 1.6-fold increased risk of fracture during an average 8.2-year follow-up, compared with patients who had adequately controlled type 2 diabetes or patients without diabetes. In other words, inadequate control of type 2 diabetes appears to be a risk factor for fracture in elderly women but not men, according to the Dutch investigators.

Dr. Giangregorio and Dr. Oei reported having no financial conflicts.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

SAN DIEGO – Denosumab produced progressive increases in bone mineral density at key skeletal sites, along with a sustained reduction in biomarkers of bone turnover, through 8 years in a long-term extension of a clinical trial.

These 8-year continuous treatment data are both highly reassuring and clinically relevant, Dr. Michael McClung observed at the annual meeting of the American Society for Bone and Mineral Research.

"Because the effects of denosumab on inhibiting bone remodeling are actually quite quickly reversible upon discontinuing therapy, long-term treatment with denosumab is anticipated to be important. Furthermore, denosumab, like other antiresorptive agents, is not the cure for osteoporosis and so maintaining bone strength with long-term therapy becomes necessary," according to Dr. McClung, founding director of the Oregon Osteoporosis Center, Portland.

Other investigators presented 5-year denosumab (Prolia) safety and efficacy updates from the ongoing extension of the landmark 7,868-patient phase III Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. The original 3-year results of FREEDOM were instrumental in winning marketing approval of the novel RANK ligand inhibitor for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The FREEDOM trial is being extended to 10 years of denosumab therapy in the original treatment arm and 7 years in placebo-treated patients who crossed over to open-label active therapy.

Dr. McClung reported on the 200 postmenopausal women with osteoporosis or low bone mass who completed a 4-year phase 2 study of denosumab by subcutaneous injection of 60 mg once every 6 months and then enrolled in a 4-year extension study.

During the first 4 years on denosumab, the women showed an average 8% gain in bone mineral density at the lumbar spine and a 5% gain at the total hip. By 8 years, these gains had increased to 17% at the lumbar spine compared with baseline and 7% at the total hip. Reductions in the bone turnover markers, serum C-telopeptide of type I collagen, and bone-specific alkaline phosphatase remained stable throughout the 8 years of treatment, he added.

Also at the meeting, Dr. Steven R. Cummings presented an analysis of years 4 and 5 of the extension of the FREEDOM trial in which he concluded that denosumab significantly reduced the estimated risk of new vertebral fractures by 36% and nonvertebral fractures by 51% compared with placebo.

What’s unusual about his analysis is that there is actually no placebo arm in the extension phase of the trial. For purposes of comparison, he employed a novel "virtual twin" simulation method he and his colleagues created and have subsequently validated (Stat. Med. 2010;29:1127-36). The statistical tool uses data from the initial placebo-controlled phase of the trial to project expected outcomes for a cohort of "virtual twins" had they remained on placebo during the study extension.

Based on the virtual twin method, the projected yearly incidence of nonvertebral fractures in years 4 and 5 was 2.6% in the virtual twins on placebo, compared with 1.3% in the real denosumab-treated group. The projected incidence of new vertebral fractures in the extension phase was 2.2% per year in the virtual twins, compared with 1.4% in women on denosumab, according to Dr. Cummings, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco.

"Long-term treatment with denosumab is anticipated to be important."

He was first author of the landmark core 3-year FREEDOM trial, in which denosumab reduced the risk of new nonvertebral, vertebral, and hip fractures by 20%, 68%, and 40%, respectively, compared with placebo (N. Engl. J. Med. 2009;361:756-65).

Dr. Henry G. Bone presented an updated safety analysis of denosumab through 5 years of the extended FREEDOM trial.

"The bottom line for this report is that through the 4th and 5th years of this program, the long-term extension and crossover data do not indicate any progression of infection or malignancy," said Dr. Bone, head, endocrinology division, St. John Hospital and Medical Center, Detroit.

For example, the denosumab prescribing information cautions that cellulitis and erysipelas occurred more often in the active treatment arm than in placebo-treated controls during the first 3 years of the trial: four cases in year 1 in the denosumab arm, one case in year 2, and eight in year 3, compared with just one case in 3 years of placebo. The trend suggested a potential worsening problem over time with denosumab. But there were only two cases of the serious skin infections in year 4 of denosumab therapy and one in year 5, along with one case during 2 years of therapy in patients crossed over from placebo.

"I think that’s informative about what the long-term trend might be," he commented.

The safety analysis included 2,343 women on the RANK ligand for the full 5 years and 2,207 crossed over to open-label denosumab after 3 years on placebo.

An increased risk of endocarditis is also mentioned in the prescribing information based on three cases that occurred in the first 3 years; however, no further cases have occurred during the extension phase. Moreover, upon closer inspection one of the three cases of endocarditis appears suspect, as it didn’t result in hospitalization or antibiotic therapy.

Malignancy rates have remained similar and stable over time in both study arms, with no evidence of a concentration of cases in any organ system, according to Dr. Bone.

Dr. McClung and Dr. Bone disclosed that they serve as consultants to and are on the speakers bureau of Amgen, which sponsored the clinical trials. Dr. Cummings is also a consultant to the company.

SAN DIEGO – Denosumab produced progressive increases in bone mineral density at key skeletal sites, along with a sustained reduction in biomarkers of bone turnover, through 8 years in a long-term extension of a clinical trial.

These 8-year continuous treatment data are both highly reassuring and clinically relevant, Dr. Michael McClung observed at the annual meeting of the American Society for Bone and Mineral Research.

"Because the effects of denosumab on inhibiting bone remodeling are actually quite quickly reversible upon discontinuing therapy, long-term treatment with denosumab is anticipated to be important. Furthermore, denosumab, like other antiresorptive agents, is not the cure for osteoporosis and so maintaining bone strength with long-term therapy becomes necessary," according to Dr. McClung, founding director of the Oregon Osteoporosis Center, Portland.

Other investigators presented 5-year denosumab (Prolia) safety and efficacy updates from the ongoing extension of the landmark 7,868-patient phase III Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. The original 3-year results of FREEDOM were instrumental in winning marketing approval of the novel RANK ligand inhibitor for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The FREEDOM trial is being extended to 10 years of denosumab therapy in the original treatment arm and 7 years in placebo-treated patients who crossed over to open-label active therapy.

Dr. McClung reported on the 200 postmenopausal women with osteoporosis or low bone mass who completed a 4-year phase 2 study of denosumab by subcutaneous injection of 60 mg once every 6 months and then enrolled in a 4-year extension study.

During the first 4 years on denosumab, the women showed an average 8% gain in bone mineral density at the lumbar spine and a 5% gain at the total hip. By 8 years, these gains had increased to 17% at the lumbar spine compared with baseline and 7% at the total hip. Reductions in the bone turnover markers, serum C-telopeptide of type I collagen, and bone-specific alkaline phosphatase remained stable throughout the 8 years of treatment, he added.

Also at the meeting, Dr. Steven R. Cummings presented an analysis of years 4 and 5 of the extension of the FREEDOM trial in which he concluded that denosumab significantly reduced the estimated risk of new vertebral fractures by 36% and nonvertebral fractures by 51% compared with placebo.

What’s unusual about his analysis is that there is actually no placebo arm in the extension phase of the trial. For purposes of comparison, he employed a novel "virtual twin" simulation method he and his colleagues created and have subsequently validated (Stat. Med. 2010;29:1127-36). The statistical tool uses data from the initial placebo-controlled phase of the trial to project expected outcomes for a cohort of "virtual twins" had they remained on placebo during the study extension.

Based on the virtual twin method, the projected yearly incidence of nonvertebral fractures in years 4 and 5 was 2.6% in the virtual twins on placebo, compared with 1.3% in the real denosumab-treated group. The projected incidence of new vertebral fractures in the extension phase was 2.2% per year in the virtual twins, compared with 1.4% in women on denosumab, according to Dr. Cummings, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco.

"Long-term treatment with denosumab is anticipated to be important."

He was first author of the landmark core 3-year FREEDOM trial, in which denosumab reduced the risk of new nonvertebral, vertebral, and hip fractures by 20%, 68%, and 40%, respectively, compared with placebo (N. Engl. J. Med. 2009;361:756-65).

Dr. Henry G. Bone presented an updated safety analysis of denosumab through 5 years of the extended FREEDOM trial.

"The bottom line for this report is that through the 4th and 5th years of this program, the long-term extension and crossover data do not indicate any progression of infection or malignancy," said Dr. Bone, head, endocrinology division, St. John Hospital and Medical Center, Detroit.

For example, the denosumab prescribing information cautions that cellulitis and erysipelas occurred more often in the active treatment arm than in placebo-treated controls during the first 3 years of the trial: four cases in year 1 in the denosumab arm, one case in year 2, and eight in year 3, compared with just one case in 3 years of placebo. The trend suggested a potential worsening problem over time with denosumab. But there were only two cases of the serious skin infections in year 4 of denosumab therapy and one in year 5, along with one case during 2 years of therapy in patients crossed over from placebo.

"I think that’s informative about what the long-term trend might be," he commented.

The safety analysis included 2,343 women on the RANK ligand for the full 5 years and 2,207 crossed over to open-label denosumab after 3 years on placebo.

An increased risk of endocarditis is also mentioned in the prescribing information based on three cases that occurred in the first 3 years; however, no further cases have occurred during the extension phase. Moreover, upon closer inspection one of the three cases of endocarditis appears suspect, as it didn’t result in hospitalization or antibiotic therapy.

Malignancy rates have remained similar and stable over time in both study arms, with no evidence of a concentration of cases in any organ system, according to Dr. Bone.

Dr. McClung and Dr. Bone disclosed that they serve as consultants to and are on the speakers bureau of Amgen, which sponsored the clinical trials. Dr. Cummings is also a consultant to the company.

SAN DIEGO – Denosumab produced progressive increases in bone mineral density at key skeletal sites, along with a sustained reduction in biomarkers of bone turnover, through 8 years in a long-term extension of a clinical trial.

These 8-year continuous treatment data are both highly reassuring and clinically relevant, Dr. Michael McClung observed at the annual meeting of the American Society for Bone and Mineral Research.

"Because the effects of denosumab on inhibiting bone remodeling are actually quite quickly reversible upon discontinuing therapy, long-term treatment with denosumab is anticipated to be important. Furthermore, denosumab, like other antiresorptive agents, is not the cure for osteoporosis and so maintaining bone strength with long-term therapy becomes necessary," according to Dr. McClung, founding director of the Oregon Osteoporosis Center, Portland.

Other investigators presented 5-year denosumab (Prolia) safety and efficacy updates from the ongoing extension of the landmark 7,868-patient phase III Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. The original 3-year results of FREEDOM were instrumental in winning marketing approval of the novel RANK ligand inhibitor for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The FREEDOM trial is being extended to 10 years of denosumab therapy in the original treatment arm and 7 years in placebo-treated patients who crossed over to open-label active therapy.

Dr. McClung reported on the 200 postmenopausal women with osteoporosis or low bone mass who completed a 4-year phase 2 study of denosumab by subcutaneous injection of 60 mg once every 6 months and then enrolled in a 4-year extension study.

During the first 4 years on denosumab, the women showed an average 8% gain in bone mineral density at the lumbar spine and a 5% gain at the total hip. By 8 years, these gains had increased to 17% at the lumbar spine compared with baseline and 7% at the total hip. Reductions in the bone turnover markers, serum C-telopeptide of type I collagen, and bone-specific alkaline phosphatase remained stable throughout the 8 years of treatment, he added.

Also at the meeting, Dr. Steven R. Cummings presented an analysis of years 4 and 5 of the extension of the FREEDOM trial in which he concluded that denosumab significantly reduced the estimated risk of new vertebral fractures by 36% and nonvertebral fractures by 51% compared with placebo.

What’s unusual about his analysis is that there is actually no placebo arm in the extension phase of the trial. For purposes of comparison, he employed a novel "virtual twin" simulation method he and his colleagues created and have subsequently validated (Stat. Med. 2010;29:1127-36). The statistical tool uses data from the initial placebo-controlled phase of the trial to project expected outcomes for a cohort of "virtual twins" had they remained on placebo during the study extension.

Based on the virtual twin method, the projected yearly incidence of nonvertebral fractures in years 4 and 5 was 2.6% in the virtual twins on placebo, compared with 1.3% in the real denosumab-treated group. The projected incidence of new vertebral fractures in the extension phase was 2.2% per year in the virtual twins, compared with 1.4% in women on denosumab, according to Dr. Cummings, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco.

"Long-term treatment with denosumab is anticipated to be important."

He was first author of the landmark core 3-year FREEDOM trial, in which denosumab reduced the risk of new nonvertebral, vertebral, and hip fractures by 20%, 68%, and 40%, respectively, compared with placebo (N. Engl. J. Med. 2009;361:756-65).

Dr. Henry G. Bone presented an updated safety analysis of denosumab through 5 years of the extended FREEDOM trial.

"The bottom line for this report is that through the 4th and 5th years of this program, the long-term extension and crossover data do not indicate any progression of infection or malignancy," said Dr. Bone, head, endocrinology division, St. John Hospital and Medical Center, Detroit.

For example, the denosumab prescribing information cautions that cellulitis and erysipelas occurred more often in the active treatment arm than in placebo-treated controls during the first 3 years of the trial: four cases in year 1 in the denosumab arm, one case in year 2, and eight in year 3, compared with just one case in 3 years of placebo. The trend suggested a potential worsening problem over time with denosumab. But there were only two cases of the serious skin infections in year 4 of denosumab therapy and one in year 5, along with one case during 2 years of therapy in patients crossed over from placebo.

"I think that’s informative about what the long-term trend might be," he commented.

The safety analysis included 2,343 women on the RANK ligand for the full 5 years and 2,207 crossed over to open-label denosumab after 3 years on placebo.

An increased risk of endocarditis is also mentioned in the prescribing information based on three cases that occurred in the first 3 years; however, no further cases have occurred during the extension phase. Moreover, upon closer inspection one of the three cases of endocarditis appears suspect, as it didn’t result in hospitalization or antibiotic therapy.

Malignancy rates have remained similar and stable over time in both study arms, with no evidence of a concentration of cases in any organ system, according to Dr. Bone.

Dr. McClung and Dr. Bone disclosed that they serve as consultants to and are on the speakers bureau of Amgen, which sponsored the clinical trials. Dr. Cummings is also a consultant to the company.

SAN DIEGO – Postmenopausal women who are being treated for low bone mineral density have nearly a fivefold greater response rate to bisphosphonate therapy if they maintain a serum vitamin D level of 33 ng/mL or higher than they do with a level below that threshold, according to an award-winning study.

Moreover, a multivariate analysis demonstrated that for each 1-ng/mL decrease in serum vitamin D level, the likelihood of a favorable response to bisphosphonate therapy dropped by 5%, Dr. Amanda Carmel reported at the annual meeting of the American Society for Bone and Mineral Research.

This is the first study to identify a threshold level of serum vitamin D that defines improved therapeutic outcomes with bisphosphonates. The identified threshold of 33 ng/mL is higher than recommended as adequate for the general population in the 2010 Institute of Medicine report. The discrepancy suggests that higher vitamin D levels may be required for specific therapeutic outcomes, said Dr. Carmel, whose study earned the 2011 ASBMR Shun-Ichi Harada Young Investigator Award.

The study was based upon a chart review of 210 women (mean age, 66 years) who had been on bisphosphonate therapy for low bone mass or osteoporosis for an average of 5 years. Half were on alendronate (Fosamax), 27% were on risedronate (Actonel), and the rest were on ibandronate (Boniva) or zoledronic acid (Reclast).

In all, 52% of subjects were categorized as bisphosphonate nonresponders on the basis of a T score less than –3 that persisted on dual-energy x-ray absorptiometry scans taken at least 18 months apart, or a greater-than-3% decrease in bone mineral density, or an incident fracture on therapy.

The average serum vitamin D level was 42.1 ng/mL in responders and 32.3% in nonresponders. A level of 33 ng/mL or less was present in 21% of responders and 58% of nonresponders, said Dr. Carmel of Cornell University, New York.

Several audience members expressed skepticism regarding her conclusions. They argued that Dr. Carmel may have mistaken cause and effect. In their view, the most likely explanation for nonresponse to bisphosphonates is poor adherence to medication, and women who are noncompliant with their bisphosphonate are also probably going to be nonadherent to their vitamin D supplementation.

Dr. Carmel replied that she and her colleagues screened for poor compliance by asking women if they were taking their bisphosphonate regularly and excluding those who said they weren’t.

She reported having no financial conflicts.

SAN DIEGO – Postmenopausal women who are being treated for low bone mineral density have nearly a fivefold greater response rate to bisphosphonate therapy if they maintain a serum vitamin D level of 33 ng/mL or higher than they do with a level below that threshold, according to an award-winning study.

Moreover, a multivariate analysis demonstrated that for each 1-ng/mL decrease in serum vitamin D level, the likelihood of a favorable response to bisphosphonate therapy dropped by 5%, Dr. Amanda Carmel reported at the annual meeting of the American Society for Bone and Mineral Research.

This is the first study to identify a threshold level of serum vitamin D that defines improved therapeutic outcomes with bisphosphonates. The identified threshold of 33 ng/mL is higher than recommended as adequate for the general population in the 2010 Institute of Medicine report. The discrepancy suggests that higher vitamin D levels may be required for specific therapeutic outcomes, said Dr. Carmel, whose study earned the 2011 ASBMR Shun-Ichi Harada Young Investigator Award.

The study was based upon a chart review of 210 women (mean age, 66 years) who had been on bisphosphonate therapy for low bone mass or osteoporosis for an average of 5 years. Half were on alendronate (Fosamax), 27% were on risedronate (Actonel), and the rest were on ibandronate (Boniva) or zoledronic acid (Reclast).

In all, 52% of subjects were categorized as bisphosphonate nonresponders on the basis of a T score less than –3 that persisted on dual-energy x-ray absorptiometry scans taken at least 18 months apart, or a greater-than-3% decrease in bone mineral density, or an incident fracture on therapy.

The average serum vitamin D level was 42.1 ng/mL in responders and 32.3% in nonresponders. A level of 33 ng/mL or less was present in 21% of responders and 58% of nonresponders, said Dr. Carmel of Cornell University, New York.

Several audience members expressed skepticism regarding her conclusions. They argued that Dr. Carmel may have mistaken cause and effect. In their view, the most likely explanation for nonresponse to bisphosphonates is poor adherence to medication, and women who are noncompliant with their bisphosphonate are also probably going to be nonadherent to their vitamin D supplementation.

Dr. Carmel replied that she and her colleagues screened for poor compliance by asking women if they were taking their bisphosphonate regularly and excluding those who said they weren’t.

She reported having no financial conflicts.

SAN DIEGO – Postmenopausal women who are being treated for low bone mineral density have nearly a fivefold greater response rate to bisphosphonate therapy if they maintain a serum vitamin D level of 33 ng/mL or higher than they do with a level below that threshold, according to an award-winning study.

Moreover, a multivariate analysis demonstrated that for each 1-ng/mL decrease in serum vitamin D level, the likelihood of a favorable response to bisphosphonate therapy dropped by 5%, Dr. Amanda Carmel reported at the annual meeting of the American Society for Bone and Mineral Research.

This is the first study to identify a threshold level of serum vitamin D that defines improved therapeutic outcomes with bisphosphonates. The identified threshold of 33 ng/mL is higher than recommended as adequate for the general population in the 2010 Institute of Medicine report. The discrepancy suggests that higher vitamin D levels may be required for specific therapeutic outcomes, said Dr. Carmel, whose study earned the 2011 ASBMR Shun-Ichi Harada Young Investigator Award.

The study was based upon a chart review of 210 women (mean age, 66 years) who had been on bisphosphonate therapy for low bone mass or osteoporosis for an average of 5 years. Half were on alendronate (Fosamax), 27% were on risedronate (Actonel), and the rest were on ibandronate (Boniva) or zoledronic acid (Reclast).

In all, 52% of subjects were categorized as bisphosphonate nonresponders on the basis of a T score less than –3 that persisted on dual-energy x-ray absorptiometry scans taken at least 18 months apart, or a greater-than-3% decrease in bone mineral density, or an incident fracture on therapy.

The average serum vitamin D level was 42.1 ng/mL in responders and 32.3% in nonresponders. A level of 33 ng/mL or less was present in 21% of responders and 58% of nonresponders, said Dr. Carmel of Cornell University, New York.

Several audience members expressed skepticism regarding her conclusions. They argued that Dr. Carmel may have mistaken cause and effect. In their view, the most likely explanation for nonresponse to bisphosphonates is poor adherence to medication, and women who are noncompliant with their bisphosphonate are also probably going to be nonadherent to their vitamin D supplementation.

Dr. Carmel replied that she and her colleagues screened for poor compliance by asking women if they were taking their bisphosphonate regularly and excluding those who said they weren’t.

She reported having no financial conflicts.

SAN DIEGO – A novel once-daily oral calcitonin tablet hit all of its efficacy and safety end points in a phase III clinical trial for treatment of postmenopausal osteoporosis.

The oral formulation of recombinant salmon calcitonin, known as Ostora, proved significantly more effective at building bone mineral density than conventional nasal calcitonin in the 18-site, multinational, double-blind, double-placebo ORACAL trial, Dr. Neil Binkley reported at the meeting.

ORACAL involved 565 postmenopausal women with osteoporosis and a mean age of 66 years. They were randomized 4:3:2 to once-daily bedtime therapy with oral calcitonin at 200 mcg, conventional nasal calcitonin at 200 IU, or placebo.

The absolute change in lumbar spine bone mineral density at 48 weeks – the primary study end point – showed a relatively modest 1.5% increase in the oral calcitonin group. But this was significantly greater than the 0.8% increase with the commercially available nasal calcitonin, which in turn was significantly better than the placebo response.

Potential safety issues with the bisphosphonates and other currently available medications have led many osteoporosis patients to decline therapy, while other women stop treatment due to side effects. Calcitonin, in contrast, has a 30-year history of safe prescription use via the intranasal and injectable routes. An oral formulation “might improve convenience and compliance with calcitonin therapy,” observed Dr. Binkley, an endocrinologist at the University of Wisconsin, Madison.

Salmon calcitonin is an analogue of human calcitonin that's 30- to 50-fold more potent in suppressing osteoclast resorption.

In the ORACAL trial, levels of CTx (C-terminal telopeptide), a biomarker of bone resorption, dropped by 30% in the oral calcitonin group at 48 weeks, compared with 11% reductions in the nasal calcitonin and placebo arms.

Only 6.5% of women assigned to oral calcitonin developed anticalcitonin antibodies, compared with 32.5% of those on nasal calcitonin. This suggests delivery of the agent via the gastrointestinal tract is less immunogenic than the nasal mucosa. In any case, the production of antibodies had no apparent impacts on safety or efficacy, the endocrinologist continued.

The side effect picture in the oral and nasal calcitonin groups mirrored that in placebo-treated controls.

Tarsa Therapeutics, which is developing oral calcitonin, plans to file with the Food and Drug Administration for marketing approval later this year and with the European regulatory agency next year. In addition, the company is developing oral calcitonin for the prevention of osteoporosis in postmenopausal women with osteopenia.

SAN DIEGO – A novel once-daily oral calcitonin tablet hit all of its efficacy and safety end points in a phase III clinical trial for treatment of postmenopausal osteoporosis.

The oral formulation of recombinant salmon calcitonin, known as Ostora, proved significantly more effective at building bone mineral density than conventional nasal calcitonin in the 18-site, multinational, double-blind, double-placebo ORACAL trial, Dr. Neil Binkley reported at the meeting.

ORACAL involved 565 postmenopausal women with osteoporosis and a mean age of 66 years. They were randomized 4:3:2 to once-daily bedtime therapy with oral calcitonin at 200 mcg, conventional nasal calcitonin at 200 IU, or placebo.

The absolute change in lumbar spine bone mineral density at 48 weeks – the primary study end point – showed a relatively modest 1.5% increase in the oral calcitonin group. But this was significantly greater than the 0.8% increase with the commercially available nasal calcitonin, which in turn was significantly better than the placebo response.

Potential safety issues with the bisphosphonates and other currently available medications have led many osteoporosis patients to decline therapy, while other women stop treatment due to side effects. Calcitonin, in contrast, has a 30-year history of safe prescription use via the intranasal and injectable routes. An oral formulation “might improve convenience and compliance with calcitonin therapy,” observed Dr. Binkley, an endocrinologist at the University of Wisconsin, Madison.

Salmon calcitonin is an analogue of human calcitonin that's 30- to 50-fold more potent in suppressing osteoclast resorption.

In the ORACAL trial, levels of CTx (C-terminal telopeptide), a biomarker of bone resorption, dropped by 30% in the oral calcitonin group at 48 weeks, compared with 11% reductions in the nasal calcitonin and placebo arms.

Only 6.5% of women assigned to oral calcitonin developed anticalcitonin antibodies, compared with 32.5% of those on nasal calcitonin. This suggests delivery of the agent via the gastrointestinal tract is less immunogenic than the nasal mucosa. In any case, the production of antibodies had no apparent impacts on safety or efficacy, the endocrinologist continued.

The side effect picture in the oral and nasal calcitonin groups mirrored that in placebo-treated controls.

Tarsa Therapeutics, which is developing oral calcitonin, plans to file with the Food and Drug Administration for marketing approval later this year and with the European regulatory agency next year. In addition, the company is developing oral calcitonin for the prevention of osteoporosis in postmenopausal women with osteopenia.

SAN DIEGO – A novel once-daily oral calcitonin tablet hit all of its efficacy and safety end points in a phase III clinical trial for treatment of postmenopausal osteoporosis.

The oral formulation of recombinant salmon calcitonin, known as Ostora, proved significantly more effective at building bone mineral density than conventional nasal calcitonin in the 18-site, multinational, double-blind, double-placebo ORACAL trial, Dr. Neil Binkley reported at the meeting.

ORACAL involved 565 postmenopausal women with osteoporosis and a mean age of 66 years. They were randomized 4:3:2 to once-daily bedtime therapy with oral calcitonin at 200 mcg, conventional nasal calcitonin at 200 IU, or placebo.

The absolute change in lumbar spine bone mineral density at 48 weeks – the primary study end point – showed a relatively modest 1.5% increase in the oral calcitonin group. But this was significantly greater than the 0.8% increase with the commercially available nasal calcitonin, which in turn was significantly better than the placebo response.

Potential safety issues with the bisphosphonates and other currently available medications have led many osteoporosis patients to decline therapy, while other women stop treatment due to side effects. Calcitonin, in contrast, has a 30-year history of safe prescription use via the intranasal and injectable routes. An oral formulation “might improve convenience and compliance with calcitonin therapy,” observed Dr. Binkley, an endocrinologist at the University of Wisconsin, Madison.

Salmon calcitonin is an analogue of human calcitonin that's 30- to 50-fold more potent in suppressing osteoclast resorption.

In the ORACAL trial, levels of CTx (C-terminal telopeptide), a biomarker of bone resorption, dropped by 30% in the oral calcitonin group at 48 weeks, compared with 11% reductions in the nasal calcitonin and placebo arms.

Only 6.5% of women assigned to oral calcitonin developed anticalcitonin antibodies, compared with 32.5% of those on nasal calcitonin. This suggests delivery of the agent via the gastrointestinal tract is less immunogenic than the nasal mucosa. In any case, the production of antibodies had no apparent impacts on safety or efficacy, the endocrinologist continued.

The side effect picture in the oral and nasal calcitonin groups mirrored that in placebo-treated controls.

Tarsa Therapeutics, which is developing oral calcitonin, plans to file with the Food and Drug Administration for marketing approval later this year and with the European regulatory agency next year. In addition, the company is developing oral calcitonin for the prevention of osteoporosis in postmenopausal women with osteopenia.

SAN DIEGO – The risk of hip fracture nearly doubles in the week following a new prescription for a loop diuretic.

In contrast, there is no spike in the risk of hip fracture in the 7 days after a new prescription for other classes of diuretics or for ACE inhibitors, according to an analysis of the Health Improvement Network (THIN) database involving more than 400 U.K. primary care practices.

The short-term jump in risk of hip fracture may be related to the prominent urinary symptoms that often accompany a new prescription for loop diuretics. The resultant rush to the bathroom could increase falls during that initial adjustment period, Dr. Sarah D. Berry speculated.

She reported on 28,703 subjects who experienced a hip fracture and more than 2 million others who did not. She and her coworkers compared the occurrence of new diuretic prescriptions in the 7 days prior to a hip fracture to the occurrence of new diuretic prescriptions in the control period 31–37 days before the fracture.

The adjusted odds ratio of an incident hip fracture was significantly increased by 80% in the 7 days following a new prescription for a loop diuretic. The absolute risk during this week-long window, however, remained low: 2.9 hip fractures per 100,000 new loop diuretic prescriptions, said Dr. Berry of the Hebrew SeniorLife Institute for Aging Research and Beth Israel Deaconess Medical Center, Boston.

Dr. Berry declared having no financial conflicts regarding the study, which was supported by the National Institutes of Health and Hebrew SeniorLife.

SAN DIEGO – The risk of hip fracture nearly doubles in the week following a new prescription for a loop diuretic.

In contrast, there is no spike in the risk of hip fracture in the 7 days after a new prescription for other classes of diuretics or for ACE inhibitors, according to an analysis of the Health Improvement Network (THIN) database involving more than 400 U.K. primary care practices.

The short-term jump in risk of hip fracture may be related to the prominent urinary symptoms that often accompany a new prescription for loop diuretics. The resultant rush to the bathroom could increase falls during that initial adjustment period, Dr. Sarah D. Berry speculated.

She reported on 28,703 subjects who experienced a hip fracture and more than 2 million others who did not. She and her coworkers compared the occurrence of new diuretic prescriptions in the 7 days prior to a hip fracture to the occurrence of new diuretic prescriptions in the control period 31–37 days before the fracture.

The adjusted odds ratio of an incident hip fracture was significantly increased by 80% in the 7 days following a new prescription for a loop diuretic. The absolute risk during this week-long window, however, remained low: 2.9 hip fractures per 100,000 new loop diuretic prescriptions, said Dr. Berry of the Hebrew SeniorLife Institute for Aging Research and Beth Israel Deaconess Medical Center, Boston.

Dr. Berry declared having no financial conflicts regarding the study, which was supported by the National Institutes of Health and Hebrew SeniorLife.

SAN DIEGO – The risk of hip fracture nearly doubles in the week following a new prescription for a loop diuretic.

In contrast, there is no spike in the risk of hip fracture in the 7 days after a new prescription for other classes of diuretics or for ACE inhibitors, according to an analysis of the Health Improvement Network (THIN) database involving more than 400 U.K. primary care practices.

The short-term jump in risk of hip fracture may be related to the prominent urinary symptoms that often accompany a new prescription for loop diuretics. The resultant rush to the bathroom could increase falls during that initial adjustment period, Dr. Sarah D. Berry speculated.

She reported on 28,703 subjects who experienced a hip fracture and more than 2 million others who did not. She and her coworkers compared the occurrence of new diuretic prescriptions in the 7 days prior to a hip fracture to the occurrence of new diuretic prescriptions in the control period 31–37 days before the fracture.

The adjusted odds ratio of an incident hip fracture was significantly increased by 80% in the 7 days following a new prescription for a loop diuretic. The absolute risk during this week-long window, however, remained low: 2.9 hip fractures per 100,000 new loop diuretic prescriptions, said Dr. Berry of the Hebrew SeniorLife Institute for Aging Research and Beth Israel Deaconess Medical Center, Boston.

Dr. Berry declared having no financial conflicts regarding the study, which was supported by the National Institutes of Health and Hebrew SeniorLife.

Mortality risk doubles during the year after hip fracture among women aged 65 years and older, then returns to baseline in many women; but this pattern doesn't apply in all cases, according to a large, prospective cohort study.

Mortality risk in patients who have sustained hip fracture differs bypage, underlying health, and the interval since the injury occurred in this population, said Dr. Erin S. LeBlanc of the center for health research at Kaiser Permanente Northwest Region, Portland, Ore., and her associates.

Previous studies of this issue have had methodological limitations and have yielded inconsistent results. Most have shown increased short-term mortality, but have had mixed findings on long-term mortality. “Our data suggest that previous mixed results…may have been the result of differences in the underlying age and health status of the population being studied,” the researchers said (Arch. Intern. Med. 2011 Sept. 26 [doi:10.1001/archinternmed.2011.447]).

They used data from the SOF (Study of Osteoporotic Fractures) to address these methodological limitations. The subjects were identified before hip fractures occurred, and extensive data on comorbidities allowed adjustment for potential confounders.

The SOF subjects were 5,580 community-dwelling women aged 65 and older who resided in Maryland, Minnesota, Oregon, and Pennsylvania at baseline in 1986–1988. This population included 1,116 women who sustained incident hip fractures during a mean follow-up of 14 years, and 4,464 age-matched control subjects without hip fracture.

Mortality risk was highest in the first year after hip fracture. The rate was 16.9% among cases, versus only 8.4% in controls. This doubling of risk persisted after adjustment to account for factors such as total hip bone mineral density.

Moreover, deaths in the control group were evenly spread throughout the year, whereas those in the case group were concentrated within the first 6 months of the year, with more than half the deaths occurring in the first 3 months. When thestubjects were categorized by age (younger than 70 years, 70–79 years, or 80 years and older), the youngest group showed a fivefold rise in mortality risk during the first year after hip fracture (16.3%), compared with women younger than 70 who did not sustain a hip fracture (3.7%). In contrast, the oldest women showed no increased mortality risk in the year following hip fracture, and the middle group showed an intermediate risk.

In addition, mortality risk remained elevated for years 1–10 in the youngest a group, but it was somewhat lower than the mortality risk in the first year. Imortality risk declined to baseline for the next 10 years in the two older age groups.

“We hypothesize that age influences the risk of death after hip fracture by affecting the baseline death rate in the population. Those who are younger … have a low risk of dying from other causes. Therefore, experiencing a hip fracture may increase their mortality risk compared with nonfracture controls.

“In contrast, octogenarians generally have a relatively high risk of dying from other causes; therefore, experiencing a hip fracture does not result in an increased risk of death during the next year compared with other women their age,” the researchers said.

This study was supported by the U.S. Public Health Service, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Center for Research Resources. No financial conflicts of interest were reported.

Mortality risk doubles during the year after hip fracture among women aged 65 years and older, then returns to baseline in many women; but this pattern doesn't apply in all cases, according to a large, prospective cohort study.

Mortality risk in patients who have sustained hip fracture differs bypage, underlying health, and the interval since the injury occurred in this population, said Dr. Erin S. LeBlanc of the center for health research at Kaiser Permanente Northwest Region, Portland, Ore., and her associates.

Previous studies of this issue have had methodological limitations and have yielded inconsistent results. Most have shown increased short-term mortality, but have had mixed findings on long-term mortality. “Our data suggest that previous mixed results…may have been the result of differences in the underlying age and health status of the population being studied,” the researchers said (Arch. Intern. Med. 2011 Sept. 26 [doi:10.1001/archinternmed.2011.447]).

They used data from the SOF (Study of Osteoporotic Fractures) to address these methodological limitations. The subjects were identified before hip fractures occurred, and extensive data on comorbidities allowed adjustment for potential confounders.

The SOF subjects were 5,580 community-dwelling women aged 65 and older who resided in Maryland, Minnesota, Oregon, and Pennsylvania at baseline in 1986–1988. This population included 1,116 women who sustained incident hip fractures during a mean follow-up of 14 years, and 4,464 age-matched control subjects without hip fracture.

Mortality risk was highest in the first year after hip fracture. The rate was 16.9% among cases, versus only 8.4% in controls. This doubling of risk persisted after adjustment to account for factors such as total hip bone mineral density.

Moreover, deaths in the control group were evenly spread throughout the year, whereas those in the case group were concentrated within the first 6 months of the year, with more than half the deaths occurring in the first 3 months. When thestubjects were categorized by age (younger than 70 years, 70–79 years, or 80 years and older), the youngest group showed a fivefold rise in mortality risk during the first year after hip fracture (16.3%), compared with women younger than 70 who did not sustain a hip fracture (3.7%). In contrast, the oldest women showed no increased mortality risk in the year following hip fracture, and the middle group showed an intermediate risk.

In addition, mortality risk remained elevated for years 1–10 in the youngest a group, but it was somewhat lower than the mortality risk in the first year. Imortality risk declined to baseline for the next 10 years in the two older age groups.

“We hypothesize that age influences the risk of death after hip fracture by affecting the baseline death rate in the population. Those who are younger … have a low risk of dying from other causes. Therefore, experiencing a hip fracture may increase their mortality risk compared with nonfracture controls.

“In contrast, octogenarians generally have a relatively high risk of dying from other causes; therefore, experiencing a hip fracture does not result in an increased risk of death during the next year compared with other women their age,” the researchers said.

This study was supported by the U.S. Public Health Service, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Center for Research Resources. No financial conflicts of interest were reported.

Mortality risk doubles during the year after hip fracture among women aged 65 years and older, then returns to baseline in many women; but this pattern doesn't apply in all cases, according to a large, prospective cohort study.

Mortality risk in patients who have sustained hip fracture differs bypage, underlying health, and the interval since the injury occurred in this population, said Dr. Erin S. LeBlanc of the center for health research at Kaiser Permanente Northwest Region, Portland, Ore., and her associates.

Previous studies of this issue have had methodological limitations and have yielded inconsistent results. Most have shown increased short-term mortality, but have had mixed findings on long-term mortality. “Our data suggest that previous mixed results…may have been the result of differences in the underlying age and health status of the population being studied,” the researchers said (Arch. Intern. Med. 2011 Sept. 26 [doi:10.1001/archinternmed.2011.447]).

They used data from the SOF (Study of Osteoporotic Fractures) to address these methodological limitations. The subjects were identified before hip fractures occurred, and extensive data on comorbidities allowed adjustment for potential confounders.

The SOF subjects were 5,580 community-dwelling women aged 65 and older who resided in Maryland, Minnesota, Oregon, and Pennsylvania at baseline in 1986–1988. This population included 1,116 women who sustained incident hip fractures during a mean follow-up of 14 years, and 4,464 age-matched control subjects without hip fracture.

Mortality risk was highest in the first year after hip fracture. The rate was 16.9% among cases, versus only 8.4% in controls. This doubling of risk persisted after adjustment to account for factors such as total hip bone mineral density.

Moreover, deaths in the control group were evenly spread throughout the year, whereas those in the case group were concentrated within the first 6 months of the year, with more than half the deaths occurring in the first 3 months. When thestubjects were categorized by age (younger than 70 years, 70–79 years, or 80 years and older), the youngest group showed a fivefold rise in mortality risk during the first year after hip fracture (16.3%), compared with women younger than 70 who did not sustain a hip fracture (3.7%). In contrast, the oldest women showed no increased mortality risk in the year following hip fracture, and the middle group showed an intermediate risk.

In addition, mortality risk remained elevated for years 1–10 in the youngest a group, but it was somewhat lower than the mortality risk in the first year. Imortality risk declined to baseline for the next 10 years in the two older age groups.

“We hypothesize that age influences the risk of death after hip fracture by affecting the baseline death rate in the population. Those who are younger … have a low risk of dying from other causes. Therefore, experiencing a hip fracture may increase their mortality risk compared with nonfracture controls.

“In contrast, octogenarians generally have a relatively high risk of dying from other causes; therefore, experiencing a hip fracture does not result in an increased risk of death during the next year compared with other women their age,” the researchers said.

This study was supported by the U.S. Public Health Service, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Center for Research Resources. No financial conflicts of interest were reported.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CT myelogram shows an epidural hematoma and cord compression associated with a vertebral fracture.

Source Courtesy Dr. Victor Jaramillo/Dr. Aravind Pothineni

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CT myelogram shows an epidural hematoma and cord compression associated with a vertebral fracture.

Source Courtesy Dr. Victor Jaramillo/Dr. Aravind Pothineni

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CT myelogram shows an epidural hematoma and cord compression associated with a vertebral fracture.

Source Courtesy Dr. Victor Jaramillo/Dr. Aravind Pothineni

Major Finding: New osteoporotic fractures occurred in 1.6% of men on zoledronic acid and in 4.9% of those on placebo after 2 years of either active treatment or placebo.

Data Source: Multinational, randomized, phase III clinical trial of 1,199 men with primary or secondary osteoporosis.

Disclosures: Dr. Boonen disclosed that he has received research grants from and serves as a consultant to Novartis.

San Diego – Once-yearly intravenous zoledronic acid in men who have osteoporosis reduced their risk of vertebral fractures by 67% over a 2-year period, compared with placebo, in a large, multinational, phase III randomized clinical trial.

“This is the first clear demonstration of antifracture efficacy for an osteoporosis agent in male osteoporosis,” said Dr. Steven Boonen in presenting the study results at the meeting.

“These findings suggest the use of zoledronic acid as a treatment option in male patients, particularly because annual infusions ensure that patients will have the full effect of treatment for at least the next year,” added Dr. Boonen, who is professor of geriatric medicine and head of the gerontology and geriatrics section at Catholic University of Leuven (Belgium).

He reported on 1,199 men (mean age, 66 years) with primary osteoporosis or osteoporosis secondary to hypogonadism who were randomized in a double-blind fashion to a once-yearly 15-minute infusion of 5 mg of zoledronic acid (Reclast) or placebo at 134 centers. At enrollment, 32% of the men had one or more vertebral fractures.

The primary end point of the study was the proportion of subjects with one or more new vertebral fractures during 2 years of follow-up. The rate was 1.6% in men assigned to zoledronic acid and 4.9% in the placebo-treated controls, which translated to a highly significant 67% relative risk reduction. The 12-month rate was 0.9% in the zoledronic acid group vs. 2.8% in controls, for a 68% relative risk reduction.

The incidence of moderate to severe vertebral fractures was similarly reduced by 63% in zoledronic acid recipients, compared with controls.

Men on zoledronic acid had a stable 60% reduction in levels of the bone turnover biomarker CTx, compared with the placebo group, throughout the study, Dr. Boonen said.

At 2 years, bone mineral density was roughly 6% greater at the spine and 2% greater at the total hip in the patients who received zoledronic acid, compared with the controls.

“All of these findings are remarkably similar in magnitude to the risk reductions that have been documented with zoledronic acid in the pivotal fracture trial in postmenopausal osteoporosis,” the geriatrician observed.

The men on zoledronic acid also experienced a smaller height loss, compared with controls (mean, 2.34 vs. 4.49 mm), he said.

No major safety issues arose in the study. Similar numbers of patients in both study arms dropped out of the trial because of adverse events.

At the present time, zoledronic acid's approved indications include treatment to increase bone mass in men with osteoporosis.

Bone mineral density was roughly 6% greater at the spine in the zoledronic acid group.

Source DR. BOONEN

Major Finding: New osteoporotic fractures occurred in 1.6% of men on zoledronic acid and in 4.9% of those on placebo after 2 years of either active treatment or placebo.

Data Source: Multinational, randomized, phase III clinical trial of 1,199 men with primary or secondary osteoporosis.

Disclosures: Dr. Boonen disclosed that he has received research grants from and serves as a consultant to Novartis.

San Diego – Once-yearly intravenous zoledronic acid in men who have osteoporosis reduced their risk of vertebral fractures by 67% over a 2-year period, compared with placebo, in a large, multinational, phase III randomized clinical trial.

“This is the first clear demonstration of antifracture efficacy for an osteoporosis agent in male osteoporosis,” said Dr. Steven Boonen in presenting the study results at the meeting.

“These findings suggest the use of zoledronic acid as a treatment option in male patients, particularly because annual infusions ensure that patients will have the full effect of treatment for at least the next year,” added Dr. Boonen, who is professor of geriatric medicine and head of the gerontology and geriatrics section at Catholic University of Leuven (Belgium).

He reported on 1,199 men (mean age, 66 years) with primary osteoporosis or osteoporosis secondary to hypogonadism who were randomized in a double-blind fashion to a once-yearly 15-minute infusion of 5 mg of zoledronic acid (Reclast) or placebo at 134 centers. At enrollment, 32% of the men had one or more vertebral fractures.

The primary end point of the study was the proportion of subjects with one or more new vertebral fractures during 2 years of follow-up. The rate was 1.6% in men assigned to zoledronic acid and 4.9% in the placebo-treated controls, which translated to a highly significant 67% relative risk reduction. The 12-month rate was 0.9% in the zoledronic acid group vs. 2.8% in controls, for a 68% relative risk reduction.

The incidence of moderate to severe vertebral fractures was similarly reduced by 63% in zoledronic acid recipients, compared with controls.

Men on zoledronic acid had a stable 60% reduction in levels of the bone turnover biomarker CTx, compared with the placebo group, throughout the study, Dr. Boonen said.

At 2 years, bone mineral density was roughly 6% greater at the spine and 2% greater at the total hip in the patients who received zoledronic acid, compared with the controls.

“All of these findings are remarkably similar in magnitude to the risk reductions that have been documented with zoledronic acid in the pivotal fracture trial in postmenopausal osteoporosis,” the geriatrician observed.

The men on zoledronic acid also experienced a smaller height loss, compared with controls (mean, 2.34 vs. 4.49 mm), he said.

No major safety issues arose in the study. Similar numbers of patients in both study arms dropped out of the trial because of adverse events.

At the present time, zoledronic acid's approved indications include treatment to increase bone mass in men with osteoporosis.

Bone mineral density was roughly 6% greater at the spine in the zoledronic acid group.

Source DR. BOONEN

Major Finding: New osteoporotic fractures occurred in 1.6% of men on zoledronic acid and in 4.9% of those on placebo after 2 years of either active treatment or placebo.

Data Source: Multinational, randomized, phase III clinical trial of 1,199 men with primary or secondary osteoporosis.

Disclosures: Dr. Boonen disclosed that he has received research grants from and serves as a consultant to Novartis.

San Diego – Once-yearly intravenous zoledronic acid in men who have osteoporosis reduced their risk of vertebral fractures by 67% over a 2-year period, compared with placebo, in a large, multinational, phase III randomized clinical trial.

“This is the first clear demonstration of antifracture efficacy for an osteoporosis agent in male osteoporosis,” said Dr. Steven Boonen in presenting the study results at the meeting.

“These findings suggest the use of zoledronic acid as a treatment option in male patients, particularly because annual infusions ensure that patients will have the full effect of treatment for at least the next year,” added Dr. Boonen, who is professor of geriatric medicine and head of the gerontology and geriatrics section at Catholic University of Leuven (Belgium).

He reported on 1,199 men (mean age, 66 years) with primary osteoporosis or osteoporosis secondary to hypogonadism who were randomized in a double-blind fashion to a once-yearly 15-minute infusion of 5 mg of zoledronic acid (Reclast) or placebo at 134 centers. At enrollment, 32% of the men had one or more vertebral fractures.

The primary end point of the study was the proportion of subjects with one or more new vertebral fractures during 2 years of follow-up. The rate was 1.6% in men assigned to zoledronic acid and 4.9% in the placebo-treated controls, which translated to a highly significant 67% relative risk reduction. The 12-month rate was 0.9% in the zoledronic acid group vs. 2.8% in controls, for a 68% relative risk reduction.

The incidence of moderate to severe vertebral fractures was similarly reduced by 63% in zoledronic acid recipients, compared with controls.

Men on zoledronic acid had a stable 60% reduction in levels of the bone turnover biomarker CTx, compared with the placebo group, throughout the study, Dr. Boonen said.

At 2 years, bone mineral density was roughly 6% greater at the spine and 2% greater at the total hip in the patients who received zoledronic acid, compared with the controls.

“All of these findings are remarkably similar in magnitude to the risk reductions that have been documented with zoledronic acid in the pivotal fracture trial in postmenopausal osteoporosis,” the geriatrician observed.

The men on zoledronic acid also experienced a smaller height loss, compared with controls (mean, 2.34 vs. 4.49 mm), he said.

No major safety issues arose in the study. Similar numbers of patients in both study arms dropped out of the trial because of adverse events.

At the present time, zoledronic acid's approved indications include treatment to increase bone mass in men with osteoporosis.

Bone mineral density was roughly 6% greater at the spine in the zoledronic acid group.

Source DR. BOONEN