ASBMR Annual Meeting 2011

SAN DIEGO – Teriparatide is gaining traction as an off-label therapy to speed fracture repair and promote healing of delayed union and nonunion fractures.

At a session expressly devoted to anabolic agents for fracture repair at the annual meeting of the American Society for Bone and Mineral Research, Dr. Robert Marcus said he is aware of numerous anecdotal reports of successful use of teriparatide (Forteo) to accelerate fracture healing and shorten return-to-play time in high-profile professional and elite collegiate athletes.

Although HIPAA regulations prevent him from naming any of the American athletes involved, Dr. Marcus said, HIPAA doesn't apply to the Italian soccer superstar Francesco Totti.

Totti, a prolific goal scorer known as Il Bimbo d’Oro (The Golden Boy) and Il Gladiatore, suffered a serious combined tibia/fibula fracture in the spring of 2006. The injury was expected to keep him out of action for the entire World Cup tournament that summer, and for well beyond. But he was placed on teriparatide almost immediately after the fracture. He played every game of the series, Italy won the 2006 World Cup, and Totti was named to the tournament’s all-star team.

Dr. Marcus, professor of medicine emeritus at Stanford (Calif.) University and a former Eli Lilly employee, made it clear he is not promoting the off-label use of teriparatide to accelerate fracture healing. He recalled that when Eli Lilly approached the Food and Drug Administration with the aim of gaining this additional indication, the agency required as an initial proof-of-concept study a randomized, double-blind, placebo-controlled trial conducted in postmenopausal women with a distal radial fracture incurred within the previous 10 days.

That multicenter study in 102 women with Colles’ fracture showed a highly significantly shorter time to healing with 8 weeks of daily teriparatide at the standard 20-mcg dose used for osteoporosis therapy than with placebo, although the 40-mcg dose unexpectedly proved ineffective (J. Bone Miner. Res. 2010;25:404-14).

But Colles’ fracture isn’t really a good test of the therapy, according to Dr. Marcus, because it doesn’t involve weight-bearing bones. Where an agent for acceleration of fracture repair would really be a boon in young people with, say, tibia fractures caused by motorcycle or skateboarding accidents. Such fractures often fail to heal successfully with conservative treatment in a reasonable time and eventually require surgical fixation and metal hardware, the endocrinologist said.

Dr. Marcus noted that Dr. Susan V. Bukata, an orthopedic oncologist at the University of Rochester (N.Y.), has previously reported on 145 patients with painful delayed/nonunion fractures treated with daily teriparatide at the standard 20-mcg dose. Within 12 weeks of starting therapy, 93% of patients in this retrospective observational series showed full radiographic and clinical healing. Another 4% had partial radiographic union that functioned clinically as a healed fracture. Only 3% of patients remained unimproved after 12 weeks of teriparatide. Dr. Bukata’s series has grown to more than 500 patients treated for delayed/nonunion fractures; the data are now being analyzed.

In order to gain an FDA indication for acceleration of fracture healing, however, it will be essential to conduct a randomized controlled trial involving fractures at clinically appropriate sites. Quantitative assessment of radiographic endpoints with CT and/or MRI will be a must, as will inclusion of functional end points such as pain reduction, muscle strength, ambulation, and return to work or daily activities. The FDA’s concern about osteosarcomas and other bone tumors seen in rats on lifelong very-high-dose teriparatide will be an issue, Dr. Marcus predicted.

Elsewhere at the meeting, Dr. Peter Peichl presented a study that fulfilled many of the requirements of a pivotal trial, albeit using the naturally occurring parathyroid hormone (PTH) containing 84 amino acids rather than its close relative, teriparatide.

The study involved 65 elderly postmenopausal women hospitalized for painful pubic bone fractures to be treated without surgery. In all, 21 patients were randomized to once-daily injection of 100 mcg of PTH. The 44 women who didn’t receive PTH served as controls. All participants received daily calcium and vitamin D supplements.

The 21 patients in the PTH-treated group showed CT-confirmed healing of their pubic bone fractures at a mean of 7.8 weeks, significantly faster than the 12.6 weeks in controls. At 8 weeks, all subjects in the PTH study arm were healed, as were only 4 of 44 controls. In addition, the PTH-treated patients showed bigger and faster improvements on a pain visual analog scale and on the Timed Up and Go functional assessment, reported Dr. Peichl of Evangelical Hospital Vienna.

Dr. Peichl declared having no financial conflicts. Dr. Marcus is a consultant to and on the speaker’s bureau for Eli Lilly.

SAN DIEGO – Teriparatide is gaining traction as an off-label therapy to speed fracture repair and promote healing of delayed union and nonunion fractures.

At a session expressly devoted to anabolic agents for fracture repair at the annual meeting of the American Society for Bone and Mineral Research, Dr. Robert Marcus said he is aware of numerous anecdotal reports of successful use of teriparatide (Forteo) to accelerate fracture healing and shorten return-to-play time in high-profile professional and elite collegiate athletes.

Although HIPAA regulations prevent him from naming any of the American athletes involved, Dr. Marcus said, HIPAA doesn't apply to the Italian soccer superstar Francesco Totti.

Totti, a prolific goal scorer known as Il Bimbo d’Oro (The Golden Boy) and Il Gladiatore, suffered a serious combined tibia/fibula fracture in the spring of 2006. The injury was expected to keep him out of action for the entire World Cup tournament that summer, and for well beyond. But he was placed on teriparatide almost immediately after the fracture. He played every game of the series, Italy won the 2006 World Cup, and Totti was named to the tournament’s all-star team.

Dr. Marcus, professor of medicine emeritus at Stanford (Calif.) University and a former Eli Lilly employee, made it clear he is not promoting the off-label use of teriparatide to accelerate fracture healing. He recalled that when Eli Lilly approached the Food and Drug Administration with the aim of gaining this additional indication, the agency required as an initial proof-of-concept study a randomized, double-blind, placebo-controlled trial conducted in postmenopausal women with a distal radial fracture incurred within the previous 10 days.

That multicenter study in 102 women with Colles’ fracture showed a highly significantly shorter time to healing with 8 weeks of daily teriparatide at the standard 20-mcg dose used for osteoporosis therapy than with placebo, although the 40-mcg dose unexpectedly proved ineffective (J. Bone Miner. Res. 2010;25:404-14).

But Colles’ fracture isn’t really a good test of the therapy, according to Dr. Marcus, because it doesn’t involve weight-bearing bones. Where an agent for acceleration of fracture repair would really be a boon in young people with, say, tibia fractures caused by motorcycle or skateboarding accidents. Such fractures often fail to heal successfully with conservative treatment in a reasonable time and eventually require surgical fixation and metal hardware, the endocrinologist said.

Dr. Marcus noted that Dr. Susan V. Bukata, an orthopedic oncologist at the University of Rochester (N.Y.), has previously reported on 145 patients with painful delayed/nonunion fractures treated with daily teriparatide at the standard 20-mcg dose. Within 12 weeks of starting therapy, 93% of patients in this retrospective observational series showed full radiographic and clinical healing. Another 4% had partial radiographic union that functioned clinically as a healed fracture. Only 3% of patients remained unimproved after 12 weeks of teriparatide. Dr. Bukata’s series has grown to more than 500 patients treated for delayed/nonunion fractures; the data are now being analyzed.

In order to gain an FDA indication for acceleration of fracture healing, however, it will be essential to conduct a randomized controlled trial involving fractures at clinically appropriate sites. Quantitative assessment of radiographic endpoints with CT and/or MRI will be a must, as will inclusion of functional end points such as pain reduction, muscle strength, ambulation, and return to work or daily activities. The FDA’s concern about osteosarcomas and other bone tumors seen in rats on lifelong very-high-dose teriparatide will be an issue, Dr. Marcus predicted.

Elsewhere at the meeting, Dr. Peter Peichl presented a study that fulfilled many of the requirements of a pivotal trial, albeit using the naturally occurring parathyroid hormone (PTH) containing 84 amino acids rather than its close relative, teriparatide.

The study involved 65 elderly postmenopausal women hospitalized for painful pubic bone fractures to be treated without surgery. In all, 21 patients were randomized to once-daily injection of 100 mcg of PTH. The 44 women who didn’t receive PTH served as controls. All participants received daily calcium and vitamin D supplements.

The 21 patients in the PTH-treated group showed CT-confirmed healing of their pubic bone fractures at a mean of 7.8 weeks, significantly faster than the 12.6 weeks in controls. At 8 weeks, all subjects in the PTH study arm were healed, as were only 4 of 44 controls. In addition, the PTH-treated patients showed bigger and faster improvements on a pain visual analog scale and on the Timed Up and Go functional assessment, reported Dr. Peichl of Evangelical Hospital Vienna.

Dr. Peichl declared having no financial conflicts. Dr. Marcus is a consultant to and on the speaker’s bureau for Eli Lilly.

SAN DIEGO – Teriparatide is gaining traction as an off-label therapy to speed fracture repair and promote healing of delayed union and nonunion fractures.

At a session expressly devoted to anabolic agents for fracture repair at the annual meeting of the American Society for Bone and Mineral Research, Dr. Robert Marcus said he is aware of numerous anecdotal reports of successful use of teriparatide (Forteo) to accelerate fracture healing and shorten return-to-play time in high-profile professional and elite collegiate athletes.

Although HIPAA regulations prevent him from naming any of the American athletes involved, Dr. Marcus said, HIPAA doesn't apply to the Italian soccer superstar Francesco Totti.

Totti, a prolific goal scorer known as Il Bimbo d’Oro (The Golden Boy) and Il Gladiatore, suffered a serious combined tibia/fibula fracture in the spring of 2006. The injury was expected to keep him out of action for the entire World Cup tournament that summer, and for well beyond. But he was placed on teriparatide almost immediately after the fracture. He played every game of the series, Italy won the 2006 World Cup, and Totti was named to the tournament’s all-star team.

Dr. Marcus, professor of medicine emeritus at Stanford (Calif.) University and a former Eli Lilly employee, made it clear he is not promoting the off-label use of teriparatide to accelerate fracture healing. He recalled that when Eli Lilly approached the Food and Drug Administration with the aim of gaining this additional indication, the agency required as an initial proof-of-concept study a randomized, double-blind, placebo-controlled trial conducted in postmenopausal women with a distal radial fracture incurred within the previous 10 days.

That multicenter study in 102 women with Colles’ fracture showed a highly significantly shorter time to healing with 8 weeks of daily teriparatide at the standard 20-mcg dose used for osteoporosis therapy than with placebo, although the 40-mcg dose unexpectedly proved ineffective (J. Bone Miner. Res. 2010;25:404-14).

But Colles’ fracture isn’t really a good test of the therapy, according to Dr. Marcus, because it doesn’t involve weight-bearing bones. Where an agent for acceleration of fracture repair would really be a boon in young people with, say, tibia fractures caused by motorcycle or skateboarding accidents. Such fractures often fail to heal successfully with conservative treatment in a reasonable time and eventually require surgical fixation and metal hardware, the endocrinologist said.

Dr. Marcus noted that Dr. Susan V. Bukata, an orthopedic oncologist at the University of Rochester (N.Y.), has previously reported on 145 patients with painful delayed/nonunion fractures treated with daily teriparatide at the standard 20-mcg dose. Within 12 weeks of starting therapy, 93% of patients in this retrospective observational series showed full radiographic and clinical healing. Another 4% had partial radiographic union that functioned clinically as a healed fracture. Only 3% of patients remained unimproved after 12 weeks of teriparatide. Dr. Bukata’s series has grown to more than 500 patients treated for delayed/nonunion fractures; the data are now being analyzed.

In order to gain an FDA indication for acceleration of fracture healing, however, it will be essential to conduct a randomized controlled trial involving fractures at clinically appropriate sites. Quantitative assessment of radiographic endpoints with CT and/or MRI will be a must, as will inclusion of functional end points such as pain reduction, muscle strength, ambulation, and return to work or daily activities. The FDA’s concern about osteosarcomas and other bone tumors seen in rats on lifelong very-high-dose teriparatide will be an issue, Dr. Marcus predicted.

Elsewhere at the meeting, Dr. Peter Peichl presented a study that fulfilled many of the requirements of a pivotal trial, albeit using the naturally occurring parathyroid hormone (PTH) containing 84 amino acids rather than its close relative, teriparatide.

The study involved 65 elderly postmenopausal women hospitalized for painful pubic bone fractures to be treated without surgery. In all, 21 patients were randomized to once-daily injection of 100 mcg of PTH. The 44 women who didn’t receive PTH served as controls. All participants received daily calcium and vitamin D supplements.

The 21 patients in the PTH-treated group showed CT-confirmed healing of their pubic bone fractures at a mean of 7.8 weeks, significantly faster than the 12.6 weeks in controls. At 8 weeks, all subjects in the PTH study arm were healed, as were only 4 of 44 controls. In addition, the PTH-treated patients showed bigger and faster improvements on a pain visual analog scale and on the Timed Up and Go functional assessment, reported Dr. Peichl of Evangelical Hospital Vienna.

Dr. Peichl declared having no financial conflicts. Dr. Marcus is a consultant to and on the speaker’s bureau for Eli Lilly.

SAN DIEGO – Depression and subclinical cardiovascular abnormalities in patients with primary hyperparathyroidism are emerging as two novel indications for parathyroidectomy.

Primary hyperparathyroidism is no longer typically characterized by the classic florid manifestations involving metabolic bone disease, GI disturbances, and nephrolithiasis. In an era of routine serum calcium measurement, most affected patients are largely asymptomatic, or they report nonspecific symptoms involving mood, cognition, and neuromuscular function.

Studies presented at the annual meeting of the American Society for Bone and Mineral Research indicate that clinically significant depression is more frequent and severe in patients with primary hyperparathyroidism, and subclinical cardiovascular abnormalities are more common as well.

Moreover, investigators presented evidence that both conditions respond favorably to parathyroidectomy. The clear implication for clinical practice, according to the presenters, is that assessment for depression as well as a cardiovascular evaluation including carotid ultrasound and an echocardiogram should become part of the routine evaluation of patients with primary hyperparathyroidism (PHP). Positive findings may be an appropriate indication for parathyroidectomy in patients who otherwise don’t meet the surgical criteria.

Depression

Dr. Rachel Espiritu presented a prospective, nonrandomized, case-control study involving 169 patients with PHP and 85 controls with benign, nontoxic forms of thyroid disease. At baseline, 88 PHP patients underwent parathyroidectomy, while the other 81 were observed for the yearlong study period. The controls with benign thyroid disease underwent thyroidectomy at baseline.

The validated Patient Health Questionnaire–9 (PHQ-9) was used to identify subjects with clinically significant depression. All study participants took the test at baseline and at 1, 3, 6, and 12 months. The three groups were similar in terms of history of depression, use of antidepressant medications, and experience with psychotherapy.

Average baseline PHQ-9 scores were significantly higher in the 169 patients with PHP than in controls by a margin of 1.71 points out of the theoretically possible 27. Major depression, as defined by a score of 10 or more, was twice as common in the PHP patients, with a baseline prevalence of 31% compared with 15% in the thyroid disease group. The PHP patients who had a baseline serum calcium of 11 mg/dL or higher had a median PHQ-9 score of 9 compared with 4 in those with a lower calcium level.

Parathyroidectomy resulted in a large, durable reduction in PHQ-9 scores. The scores dropped by an age- and gender-adjusted average of 64% 1 month post surgery, with a 66% reduction at 1 year compared with baseline, reported Dr. Espiritu of the Mayo Clinic, Rochester, Minn.

A PHQ-9 score of 10 or greater was present at baseline in 43% of the parathyroidectomy group. The prevalence plunged to 7% at 1 month post surgery and remained there at 1 year. In contrast, the prevalence of scores of 10-plus remained unchanged over the course of the year in the 81 PHP patients in the observation arm.

PHQ-9 scores also declined following thyroidectomy in the control group. But the reductions were significantly greater in the parathyroidectomy group at every time point.

Dr. Espiritu concluded that a PHQ-9 score of 10 or more or ongoing depression in a patient with PHP warrants consideration of parathyroid surgery.

Cardiovascular Abnormalities

Dr. Marcella Walker reported on 44 patients with mild hyperparathyroidism who underwent carotid ultrasound and echocardiographic studies before postparathyroidectomy and 12 and 24 months afterward.

Selected subclinical cardiovascular abnormalities present at baseline improved and often normalized during the second year of follow-up. Increased carotid stiffness, present in 17 of 44 patients at baseline, normalized in 8 patients and decreased without reaching normal range to a lesser extent in the others. Increased intima-media thickness, present in 32 patients at baseline, declined from an average of 0.99 mm at baseline to 0.97 mm 2 years later.

Diastolic dysfunction, as defined by an abnormal early to late mitral annular velocity ratio, was present in 11 patients at baseline and normalized postsurgically in all cases. Similarly, another indicator of diastolic dysfunction – an elevated intravascular relaxation time – was identified in eight patients preoperatively, all of whom improved to within normal range post parathyroidectomy, according to Dr. Walker of Columbia University, New York.

On the other hand, baseline abnormalities in left ventricular mass index remained unchanged following surgery. Nor was any improvement seen in maximal carotid plaque thickness or carotid plaque number, she noted.

The changes noted in cardiovascular parameters following parathyroidectomy can’t be attributed to reductions in blood pressure or body mass index, as both parameters remained unaltered during the 2-year study period.

No financial conflicts of interest were reported.

SAN DIEGO – Depression and subclinical cardiovascular abnormalities in patients with primary hyperparathyroidism are emerging as two novel indications for parathyroidectomy.

Primary hyperparathyroidism is no longer typically characterized by the classic florid manifestations involving metabolic bone disease, GI disturbances, and nephrolithiasis. In an era of routine serum calcium measurement, most affected patients are largely asymptomatic, or they report nonspecific symptoms involving mood, cognition, and neuromuscular function.

Studies presented at the annual meeting of the American Society for Bone and Mineral Research indicate that clinically significant depression is more frequent and severe in patients with primary hyperparathyroidism, and subclinical cardiovascular abnormalities are more common as well.

Moreover, investigators presented evidence that both conditions respond favorably to parathyroidectomy. The clear implication for clinical practice, according to the presenters, is that assessment for depression as well as a cardiovascular evaluation including carotid ultrasound and an echocardiogram should become part of the routine evaluation of patients with primary hyperparathyroidism (PHP). Positive findings may be an appropriate indication for parathyroidectomy in patients who otherwise don’t meet the surgical criteria.

Depression

Dr. Rachel Espiritu presented a prospective, nonrandomized, case-control study involving 169 patients with PHP and 85 controls with benign, nontoxic forms of thyroid disease. At baseline, 88 PHP patients underwent parathyroidectomy, while the other 81 were observed for the yearlong study period. The controls with benign thyroid disease underwent thyroidectomy at baseline.

The validated Patient Health Questionnaire–9 (PHQ-9) was used to identify subjects with clinically significant depression. All study participants took the test at baseline and at 1, 3, 6, and 12 months. The three groups were similar in terms of history of depression, use of antidepressant medications, and experience with psychotherapy.

Average baseline PHQ-9 scores were significantly higher in the 169 patients with PHP than in controls by a margin of 1.71 points out of the theoretically possible 27. Major depression, as defined by a score of 10 or more, was twice as common in the PHP patients, with a baseline prevalence of 31% compared with 15% in the thyroid disease group. The PHP patients who had a baseline serum calcium of 11 mg/dL or higher had a median PHQ-9 score of 9 compared with 4 in those with a lower calcium level.

Parathyroidectomy resulted in a large, durable reduction in PHQ-9 scores. The scores dropped by an age- and gender-adjusted average of 64% 1 month post surgery, with a 66% reduction at 1 year compared with baseline, reported Dr. Espiritu of the Mayo Clinic, Rochester, Minn.

A PHQ-9 score of 10 or greater was present at baseline in 43% of the parathyroidectomy group. The prevalence plunged to 7% at 1 month post surgery and remained there at 1 year. In contrast, the prevalence of scores of 10-plus remained unchanged over the course of the year in the 81 PHP patients in the observation arm.

PHQ-9 scores also declined following thyroidectomy in the control group. But the reductions were significantly greater in the parathyroidectomy group at every time point.

Dr. Espiritu concluded that a PHQ-9 score of 10 or more or ongoing depression in a patient with PHP warrants consideration of parathyroid surgery.

Cardiovascular Abnormalities

Dr. Marcella Walker reported on 44 patients with mild hyperparathyroidism who underwent carotid ultrasound and echocardiographic studies before postparathyroidectomy and 12 and 24 months afterward.

Selected subclinical cardiovascular abnormalities present at baseline improved and often normalized during the second year of follow-up. Increased carotid stiffness, present in 17 of 44 patients at baseline, normalized in 8 patients and decreased without reaching normal range to a lesser extent in the others. Increased intima-media thickness, present in 32 patients at baseline, declined from an average of 0.99 mm at baseline to 0.97 mm 2 years later.

Diastolic dysfunction, as defined by an abnormal early to late mitral annular velocity ratio, was present in 11 patients at baseline and normalized postsurgically in all cases. Similarly, another indicator of diastolic dysfunction – an elevated intravascular relaxation time – was identified in eight patients preoperatively, all of whom improved to within normal range post parathyroidectomy, according to Dr. Walker of Columbia University, New York.

On the other hand, baseline abnormalities in left ventricular mass index remained unchanged following surgery. Nor was any improvement seen in maximal carotid plaque thickness or carotid plaque number, she noted.

The changes noted in cardiovascular parameters following parathyroidectomy can’t be attributed to reductions in blood pressure or body mass index, as both parameters remained unaltered during the 2-year study period.

No financial conflicts of interest were reported.

SAN DIEGO – Depression and subclinical cardiovascular abnormalities in patients with primary hyperparathyroidism are emerging as two novel indications for parathyroidectomy.

Primary hyperparathyroidism is no longer typically characterized by the classic florid manifestations involving metabolic bone disease, GI disturbances, and nephrolithiasis. In an era of routine serum calcium measurement, most affected patients are largely asymptomatic, or they report nonspecific symptoms involving mood, cognition, and neuromuscular function.

Studies presented at the annual meeting of the American Society for Bone and Mineral Research indicate that clinically significant depression is more frequent and severe in patients with primary hyperparathyroidism, and subclinical cardiovascular abnormalities are more common as well.

Moreover, investigators presented evidence that both conditions respond favorably to parathyroidectomy. The clear implication for clinical practice, according to the presenters, is that assessment for depression as well as a cardiovascular evaluation including carotid ultrasound and an echocardiogram should become part of the routine evaluation of patients with primary hyperparathyroidism (PHP). Positive findings may be an appropriate indication for parathyroidectomy in patients who otherwise don’t meet the surgical criteria.

Depression

Dr. Rachel Espiritu presented a prospective, nonrandomized, case-control study involving 169 patients with PHP and 85 controls with benign, nontoxic forms of thyroid disease. At baseline, 88 PHP patients underwent parathyroidectomy, while the other 81 were observed for the yearlong study period. The controls with benign thyroid disease underwent thyroidectomy at baseline.

The validated Patient Health Questionnaire–9 (PHQ-9) was used to identify subjects with clinically significant depression. All study participants took the test at baseline and at 1, 3, 6, and 12 months. The three groups were similar in terms of history of depression, use of antidepressant medications, and experience with psychotherapy.

Average baseline PHQ-9 scores were significantly higher in the 169 patients with PHP than in controls by a margin of 1.71 points out of the theoretically possible 27. Major depression, as defined by a score of 10 or more, was twice as common in the PHP patients, with a baseline prevalence of 31% compared with 15% in the thyroid disease group. The PHP patients who had a baseline serum calcium of 11 mg/dL or higher had a median PHQ-9 score of 9 compared with 4 in those with a lower calcium level.

Parathyroidectomy resulted in a large, durable reduction in PHQ-9 scores. The scores dropped by an age- and gender-adjusted average of 64% 1 month post surgery, with a 66% reduction at 1 year compared with baseline, reported Dr. Espiritu of the Mayo Clinic, Rochester, Minn.

A PHQ-9 score of 10 or greater was present at baseline in 43% of the parathyroidectomy group. The prevalence plunged to 7% at 1 month post surgery and remained there at 1 year. In contrast, the prevalence of scores of 10-plus remained unchanged over the course of the year in the 81 PHP patients in the observation arm.

PHQ-9 scores also declined following thyroidectomy in the control group. But the reductions were significantly greater in the parathyroidectomy group at every time point.

Dr. Espiritu concluded that a PHQ-9 score of 10 or more or ongoing depression in a patient with PHP warrants consideration of parathyroid surgery.

Cardiovascular Abnormalities

Dr. Marcella Walker reported on 44 patients with mild hyperparathyroidism who underwent carotid ultrasound and echocardiographic studies before postparathyroidectomy and 12 and 24 months afterward.

Selected subclinical cardiovascular abnormalities present at baseline improved and often normalized during the second year of follow-up. Increased carotid stiffness, present in 17 of 44 patients at baseline, normalized in 8 patients and decreased without reaching normal range to a lesser extent in the others. Increased intima-media thickness, present in 32 patients at baseline, declined from an average of 0.99 mm at baseline to 0.97 mm 2 years later.

Diastolic dysfunction, as defined by an abnormal early to late mitral annular velocity ratio, was present in 11 patients at baseline and normalized postsurgically in all cases. Similarly, another indicator of diastolic dysfunction – an elevated intravascular relaxation time – was identified in eight patients preoperatively, all of whom improved to within normal range post parathyroidectomy, according to Dr. Walker of Columbia University, New York.

On the other hand, baseline abnormalities in left ventricular mass index remained unchanged following surgery. Nor was any improvement seen in maximal carotid plaque thickness or carotid plaque number, she noted.

The changes noted in cardiovascular parameters following parathyroidectomy can’t be attributed to reductions in blood pressure or body mass index, as both parameters remained unaltered during the 2-year study period.

No financial conflicts of interest were reported.

SAN DIEGO – Angiotensin-converting enzyme inhibitor therapy may reduce the risk of age-related bone loss in elderly men.

A retrospective analysis of longitudinal data from the prospective Health ABC (Dynamics of Health, Aging and Body Composition Study) found that femoral neck bone mineral density was significantly greater in elderly men on an ACE inhibitor for 5 or more years for treatment of hypertension than in those who were not on long-term ACE inhibitor therapy, Dr. Nahid Rianon reported at the annual meeting of the American Society for Bone and Mineral Research.

This secondary analysis of Health ABC involved 583 men with a mean age of 83 years. At 10-year follow-up, femoral neck bone mineral density was 0.04 g/cm² greater in the 137 subjects on an ACE inhibitor for at least 5 years than in men not on long-term therapy with a drug in this class.

Of note, the same magnitude of improvement in femoral neck bone mineral density was seen after just 5 years of ACE inhibitor therapy. In other words, no further divergence in bone mineral density occurred during years 5-10.

These study findings warrant confirmation in a prospective clinical trial featuring analysis of bone markers, which wasn’t done in Health ABC. Osteoporosis and hypertension are two major age-related chronic diseases that at present are managed separately using different classes of drugs. If ACE inhibitors can be shown to be beneficial in both of these extremely common diseases, management would be considerably simplified, observed Dr. Rianon of the University of Texas, Houston.

The finding that long-term ACE inhibitor therapy appears to prevent age-related bone loss in older men has mechanistic plausibility, the physician continued. These drugs inhibit production of angiotensin II, a hormone that affects bone by binding to the angiotensin-1 and angiotensin-2 receptors expressed in osteoblasts, among other sites. And angiotensin-1 and angiotensin-2 expression appears to promote receptor-activated nuclear factor–kappaB ligand activity, which enhances bone loss.

Health ABC is sponsored by the National Institute on Aging. Dr. Rianon declared having no financial conflicts.

SAN DIEGO – Angiotensin-converting enzyme inhibitor therapy may reduce the risk of age-related bone loss in elderly men.

A retrospective analysis of longitudinal data from the prospective Health ABC (Dynamics of Health, Aging and Body Composition Study) found that femoral neck bone mineral density was significantly greater in elderly men on an ACE inhibitor for 5 or more years for treatment of hypertension than in those who were not on long-term ACE inhibitor therapy, Dr. Nahid Rianon reported at the annual meeting of the American Society for Bone and Mineral Research.

This secondary analysis of Health ABC involved 583 men with a mean age of 83 years. At 10-year follow-up, femoral neck bone mineral density was 0.04 g/cm² greater in the 137 subjects on an ACE inhibitor for at least 5 years than in men not on long-term therapy with a drug in this class.

Of note, the same magnitude of improvement in femoral neck bone mineral density was seen after just 5 years of ACE inhibitor therapy. In other words, no further divergence in bone mineral density occurred during years 5-10.

These study findings warrant confirmation in a prospective clinical trial featuring analysis of bone markers, which wasn’t done in Health ABC. Osteoporosis and hypertension are two major age-related chronic diseases that at present are managed separately using different classes of drugs. If ACE inhibitors can be shown to be beneficial in both of these extremely common diseases, management would be considerably simplified, observed Dr. Rianon of the University of Texas, Houston.

The finding that long-term ACE inhibitor therapy appears to prevent age-related bone loss in older men has mechanistic plausibility, the physician continued. These drugs inhibit production of angiotensin II, a hormone that affects bone by binding to the angiotensin-1 and angiotensin-2 receptors expressed in osteoblasts, among other sites. And angiotensin-1 and angiotensin-2 expression appears to promote receptor-activated nuclear factor–kappaB ligand activity, which enhances bone loss.

Health ABC is sponsored by the National Institute on Aging. Dr. Rianon declared having no financial conflicts.

SAN DIEGO – Angiotensin-converting enzyme inhibitor therapy may reduce the risk of age-related bone loss in elderly men.

A retrospective analysis of longitudinal data from the prospective Health ABC (Dynamics of Health, Aging and Body Composition Study) found that femoral neck bone mineral density was significantly greater in elderly men on an ACE inhibitor for 5 or more years for treatment of hypertension than in those who were not on long-term ACE inhibitor therapy, Dr. Nahid Rianon reported at the annual meeting of the American Society for Bone and Mineral Research.

This secondary analysis of Health ABC involved 583 men with a mean age of 83 years. At 10-year follow-up, femoral neck bone mineral density was 0.04 g/cm² greater in the 137 subjects on an ACE inhibitor for at least 5 years than in men not on long-term therapy with a drug in this class.

Of note, the same magnitude of improvement in femoral neck bone mineral density was seen after just 5 years of ACE inhibitor therapy. In other words, no further divergence in bone mineral density occurred during years 5-10.

These study findings warrant confirmation in a prospective clinical trial featuring analysis of bone markers, which wasn’t done in Health ABC. Osteoporosis and hypertension are two major age-related chronic diseases that at present are managed separately using different classes of drugs. If ACE inhibitors can be shown to be beneficial in both of these extremely common diseases, management would be considerably simplified, observed Dr. Rianon of the University of Texas, Houston.

The finding that long-term ACE inhibitor therapy appears to prevent age-related bone loss in older men has mechanistic plausibility, the physician continued. These drugs inhibit production of angiotensin II, a hormone that affects bone by binding to the angiotensin-1 and angiotensin-2 receptors expressed in osteoblasts, among other sites. And angiotensin-1 and angiotensin-2 expression appears to promote receptor-activated nuclear factor–kappaB ligand activity, which enhances bone loss.

Health ABC is sponsored by the National Institute on Aging. Dr. Rianon declared 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.

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 – Combined daily supplementation with folic acid and vitamins B6 and B12 proved to be a bust for reduction of nonvertebral fracture risk in a large, randomized, double-blind clinical trial conducted in women with known cardiovascular disease or multiple risk factors.

A secondary analysis of fracture outcomes in 5,442 female health professionals over age 42 years who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) showed an overall nonvertebral fracture incidence of 7.6% during an average 7.3 years of treatment and follow-up in the supplementation group and a similar 6.9% rate in placebo-treated controls, Dr. Douglas C. Bauer reported at the annual meeting of the American Society for Bone and Mineral Research.

Participants in WAFACS had known cardiovascular disease or three or more cardiovascular risk factors. The previously reported primary study end points were cardiovascular event rates and all-cause mortality, where supplements had no effect (JAMA 2008;299:2027-36).

The new retrospective secondary analysis of WAFACS was undertaken because some prior observational studies had concluded that elevated homocysteine and low vitamin B12 levels are associated with increased fracture risk. The supplement regimen utilized in the trial was designed to lower homocysteine and boost vitamin B12 levels. It consisted of daily folic acid at 2.5 mg, vitamin B6 at 50 mg, and vitamin B12 at 1 mg.

In all, 80% of participants reported greater than 66% compliance with therapy. Rates of hip, wrist, and total nonspine fractures were similar in both high-compliance subgroups, noted Dr. Bauer of the University of California, San Francisco.

WAFACS was funded by the National Heart, Lung, and Blood Institute. Dr. Bauer reported having no financial conflicts.

SAN DIEGO – Combined daily supplementation with folic acid and vitamins B6 and B12 proved to be a bust for reduction of nonvertebral fracture risk in a large, randomized, double-blind clinical trial conducted in women with known cardiovascular disease or multiple risk factors.

A secondary analysis of fracture outcomes in 5,442 female health professionals over age 42 years who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) showed an overall nonvertebral fracture incidence of 7.6% during an average 7.3 years of treatment and follow-up in the supplementation group and a similar 6.9% rate in placebo-treated controls, Dr. Douglas C. Bauer reported at the annual meeting of the American Society for Bone and Mineral Research.

Participants in WAFACS had known cardiovascular disease or three or more cardiovascular risk factors. The previously reported primary study end points were cardiovascular event rates and all-cause mortality, where supplements had no effect (JAMA 2008;299:2027-36).

The new retrospective secondary analysis of WAFACS was undertaken because some prior observational studies had concluded that elevated homocysteine and low vitamin B12 levels are associated with increased fracture risk. The supplement regimen utilized in the trial was designed to lower homocysteine and boost vitamin B12 levels. It consisted of daily folic acid at 2.5 mg, vitamin B6 at 50 mg, and vitamin B12 at 1 mg.

In all, 80% of participants reported greater than 66% compliance with therapy. Rates of hip, wrist, and total nonspine fractures were similar in both high-compliance subgroups, noted Dr. Bauer of the University of California, San Francisco.

WAFACS was funded by the National Heart, Lung, and Blood Institute. Dr. Bauer reported having no financial conflicts.

SAN DIEGO – Combined daily supplementation with folic acid and vitamins B6 and B12 proved to be a bust for reduction of nonvertebral fracture risk in a large, randomized, double-blind clinical trial conducted in women with known cardiovascular disease or multiple risk factors.

A secondary analysis of fracture outcomes in 5,442 female health professionals over age 42 years who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) showed an overall nonvertebral fracture incidence of 7.6% during an average 7.3 years of treatment and follow-up in the supplementation group and a similar 6.9% rate in placebo-treated controls, Dr. Douglas C. Bauer reported at the annual meeting of the American Society for Bone and Mineral Research.

Participants in WAFACS had known cardiovascular disease or three or more cardiovascular risk factors. The previously reported primary study end points were cardiovascular event rates and all-cause mortality, where supplements had no effect (JAMA 2008;299:2027-36).

The new retrospective secondary analysis of WAFACS was undertaken because some prior observational studies had concluded that elevated homocysteine and low vitamin B12 levels are associated with increased fracture risk. The supplement regimen utilized in the trial was designed to lower homocysteine and boost vitamin B12 levels. It consisted of daily folic acid at 2.5 mg, vitamin B6 at 50 mg, and vitamin B12 at 1 mg.

In all, 80% of participants reported greater than 66% compliance with therapy. Rates of hip, wrist, and total nonspine fractures were similar in both high-compliance subgroups, noted Dr. Bauer of the University of California, San Francisco.

WAFACS was funded by the National Heart, Lung, and Blood Institute. Dr. Bauer reported having no financial conflicts.

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 – Physicians overall are doing a less than stellar job of recognizing glucocorticoid-induced osteoporosis and prescribing bone-protective medications for affected or high-risk patients.

But some specialties are doing significantly better than others.

"While many rheumatologists and endocrinologists are doing a pretty good job, we know that collectively, internationally, this still continues to be a major therapeutic dilemma, and steroids still constitute the most common form of drug-induced osteoporosis," Dr. Kenneth G. Saag declared at the annual meeting of the American Society for Bone and Mineral Research.

He cited a recent as-yet-published study led by University of Alabama epidemiologist Ryan C. Outman, who, together with his coinvestigators, analyzed 106,310 patients in the Medco Pharmacy database who were at high risk for glucocorticoid-induced osteoporosis (GIOP) by virtue of having received more than 90 days of systemic corticosteroid therapy during the study years of 2004-2007.

The primary study outcome was prescription of any form of anti-GIOP medication within 12 months after patients reached the 90-day mark of steroid therapy. The 12-month mark is the point on the therapeutic time line when, according to American College of Rheumatology guidelines, physicians are supposed to initiate bone-protective therapy.

The steroids were prescribed by a total of 53,766 physicians. During the 12-month window, the physicians ordered bone mineral density tests in just 4.6% of the patients, and 23.5% of patients received a prescription for an anti- GIOP medication, according to Dr. Saag, professor of medicine and epidemiology at the University of Alabama, Birmingham.

The results varied by physician specialty. In a multivariate analysis adjusted for patient age, gender, and other potential confounders, endocrinologists were 61% more likely to prescribe anti-GIOP medication for patients having more than 90 days of exposure to systemic steroids than were internists, who served as the reference standard. Rheumatologists were 59% more likely than internists to prescribe therapy.

Nephrologists, pulmonologists, and gastroenterologists were 37%, 34%, and 15%, respectively, more likely to have prescribed bone-protective medications for their at-risk patients than were internists. Dermatologists and physicians in all other specialties who prescribed steroids for longer than 90 days were, collectively, 22% less likely to introduce anti-GIOP therapy than were internists.

Rates of prescription of anti-GIOP medications were particularly low in men of all ages and in premenopausal women. During the 12 months after more than 90 days of exposure to systemic steroids, 36.8% of affected women aged 50 years or older were prescribed bone-protective medication, compared with 11.4% of affected women under age 50 years and 14.7% of men of any age, said Dr. Saag, who was not involved in the study.

"We’ve got a lot of work to do in terms of initiating therapy, but adherence is a big problem, too. Less than half of patients who start on any bone-protective drug are still taking it a year later," he said.

Dr. Saag disclosed that he has received research grants from and serves as a paid consultant to Amgen, Eli Lilly, Merck, and Novartis.

SAN DIEGO – Physicians overall are doing a less than stellar job of recognizing glucocorticoid-induced osteoporosis and prescribing bone-protective medications for affected or high-risk patients.

But some specialties are doing significantly better than others.

"While many rheumatologists and endocrinologists are doing a pretty good job, we know that collectively, internationally, this still continues to be a major therapeutic dilemma, and steroids still constitute the most common form of drug-induced osteoporosis," Dr. Kenneth G. Saag declared at the annual meeting of the American Society for Bone and Mineral Research.

He cited a recent as-yet-published study led by University of Alabama epidemiologist Ryan C. Outman, who, together with his coinvestigators, analyzed 106,310 patients in the Medco Pharmacy database who were at high risk for glucocorticoid-induced osteoporosis (GIOP) by virtue of having received more than 90 days of systemic corticosteroid therapy during the study years of 2004-2007.

The primary study outcome was prescription of any form of anti-GIOP medication within 12 months after patients reached the 90-day mark of steroid therapy. The 12-month mark is the point on the therapeutic time line when, according to American College of Rheumatology guidelines, physicians are supposed to initiate bone-protective therapy.

The steroids were prescribed by a total of 53,766 physicians. During the 12-month window, the physicians ordered bone mineral density tests in just 4.6% of the patients, and 23.5% of patients received a prescription for an anti- GIOP medication, according to Dr. Saag, professor of medicine and epidemiology at the University of Alabama, Birmingham.

The results varied by physician specialty. In a multivariate analysis adjusted for patient age, gender, and other potential confounders, endocrinologists were 61% more likely to prescribe anti-GIOP medication for patients having more than 90 days of exposure to systemic steroids than were internists, who served as the reference standard. Rheumatologists were 59% more likely than internists to prescribe therapy.

Nephrologists, pulmonologists, and gastroenterologists were 37%, 34%, and 15%, respectively, more likely to have prescribed bone-protective medications for their at-risk patients than were internists. Dermatologists and physicians in all other specialties who prescribed steroids for longer than 90 days were, collectively, 22% less likely to introduce anti-GIOP therapy than were internists.

Rates of prescription of anti-GIOP medications were particularly low in men of all ages and in premenopausal women. During the 12 months after more than 90 days of exposure to systemic steroids, 36.8% of affected women aged 50 years or older were prescribed bone-protective medication, compared with 11.4% of affected women under age 50 years and 14.7% of men of any age, said Dr. Saag, who was not involved in the study.

"We’ve got a lot of work to do in terms of initiating therapy, but adherence is a big problem, too. Less than half of patients who start on any bone-protective drug are still taking it a year later," he said.

Dr. Saag disclosed that he has received research grants from and serves as a paid consultant to Amgen, Eli Lilly, Merck, and Novartis.

SAN DIEGO – Physicians overall are doing a less than stellar job of recognizing glucocorticoid-induced osteoporosis and prescribing bone-protective medications for affected or high-risk patients.

But some specialties are doing significantly better than others.

"While many rheumatologists and endocrinologists are doing a pretty good job, we know that collectively, internationally, this still continues to be a major therapeutic dilemma, and steroids still constitute the most common form of drug-induced osteoporosis," Dr. Kenneth G. Saag declared at the annual meeting of the American Society for Bone and Mineral Research.

He cited a recent as-yet-published study led by University of Alabama epidemiologist Ryan C. Outman, who, together with his coinvestigators, analyzed 106,310 patients in the Medco Pharmacy database who were at high risk for glucocorticoid-induced osteoporosis (GIOP) by virtue of having received more than 90 days of systemic corticosteroid therapy during the study years of 2004-2007.

The primary study outcome was prescription of any form of anti-GIOP medication within 12 months after patients reached the 90-day mark of steroid therapy. The 12-month mark is the point on the therapeutic time line when, according to American College of Rheumatology guidelines, physicians are supposed to initiate bone-protective therapy.

The steroids were prescribed by a total of 53,766 physicians. During the 12-month window, the physicians ordered bone mineral density tests in just 4.6% of the patients, and 23.5% of patients received a prescription for an anti- GIOP medication, according to Dr. Saag, professor of medicine and epidemiology at the University of Alabama, Birmingham.

The results varied by physician specialty. In a multivariate analysis adjusted for patient age, gender, and other potential confounders, endocrinologists were 61% more likely to prescribe anti-GIOP medication for patients having more than 90 days of exposure to systemic steroids than were internists, who served as the reference standard. Rheumatologists were 59% more likely than internists to prescribe therapy.

Nephrologists, pulmonologists, and gastroenterologists were 37%, 34%, and 15%, respectively, more likely to have prescribed bone-protective medications for their at-risk patients than were internists. Dermatologists and physicians in all other specialties who prescribed steroids for longer than 90 days were, collectively, 22% less likely to introduce anti-GIOP therapy than were internists.

Rates of prescription of anti-GIOP medications were particularly low in men of all ages and in premenopausal women. During the 12 months after more than 90 days of exposure to systemic steroids, 36.8% of affected women aged 50 years or older were prescribed bone-protective medication, compared with 11.4% of affected women under age 50 years and 14.7% of men of any age, said Dr. Saag, who was not involved in the study.

"We’ve got a lot of work to do in terms of initiating therapy, but adherence is a big problem, too. Less than half of patients who start on any bone-protective drug are still taking it a year later," he said.

Dr. Saag disclosed that he has received research grants from and serves as a paid consultant to Amgen, Eli Lilly, Merck, and Novartis.

SAN DIEGO – Teriparatide has received a boost in status as a preferentially effective treatment for glucocorticoid-induced osteoporosis in the form of a second, confirmatory, randomized double-blind trial demonstrating the anabolic agent achieves substantially greater increases in bone mineral density compared to a bisphosphonate.

One of these studies also included fracture rates as a preplanned secondary endpoint; the trial demonstrated a significant reduction in vertebral fractures with teriparatide (Forteo) as compared to alendronate (Fosamax).

These positive study findings are bolstered by a biologically plausible mechanism of benefit, Dr. Kenneth G. Saag observed at the annual meeting of the American Society for Bone and Mineral Research.

"Based upon the pathogenesis of glucocorticoid-induced osteoporosis [(GIOP)], we think that an anabolic agent makes some sense. It may be beneficial to stimulate osteoblasts to promote new bone formation," said Dr. Saag, professor of medicine and epidemiology at the University of Alabama at Birmingham.

Steroids are known to have apoptosis-mediated deleterious effects on both osteocytes and osteoblasts that lead to decline in bone function and an abrupt increase in fracture risk independent of bone mineral density (BMD). Osteoclasts are also unfavorably impacted due to crosstalk and the indirect effects of sex steroids, insulin-like growth factor, and a modest effect of secondary hyperparathyroidism mediated through altered calcium absorption. In addition, higher-dose steroids have adverse effects upon muscle that can independently lead to a higher fracture rate, the rheumatologist explained.

The FDA has approved alendronate, zoledronic acid (Reclast), and risedronate (Actonel) for treatment GIOP. More recently, raloxifene (Evista) has joined the ranks of agents shown to increase BMD in patients on long-term steroids; this came in the form of a double-blind, placebo-controlled, 12-month study (Ann. Rheum. Dis. 2011;70:778-84).

Subcutaneous daily teriparatide for up to 2 years also has the approval of the Food and Drug Administration for use in adults at high fracture risk because they are on sustained systemic steroid therapy.

There is no definitive study demonstrating that any of these agents actually prevents fractures in patients with GIOP. Nor is it likely such a study will be undertaken. Such trials require large numbers of patients and lengthy follow-up, and pharmaceutical companies have little incentive to mount such a costly project given that the medications are already approved for use in patients on steroids, Dr. Saag noted.

However, data from a study in which Dr. Saag was lead investigator showed that teriparatide-treated patients had significantly fewer vertebral fractures than those assigned to alendronate. The study was a 36-month randomized, double-blind, clinical trial that assessed fracture rates as a preplanned secondary endpoint. The radiographic and clinical vertebral fracture rates in 169 alendronate-treated patients were 7.7% and 2.4%, respectively, compared to 1.7% and 0% in 173 teriparatide-treated patients (P = .007 and .037). No significant difference in nonvertebral fractures was found between the two treatment arms.

The primary study endpoint was the change in BMD from baseline. Here again teriparatide proved significantly more effective than the bisphosphonate, with a mean 11% increase at the lumbar spine, compared to 5.3% with alendronate. Teriparatide-treated patients also had a 5.2% increase in BMD at the total hip and a 6.3% boost at the femoral neck, compared to 2.7% and 3.4%, respectively, with alendronate (Arthritis Rheum. 2009;60:3346-55).

Confirmation of teriparatide’s superior BMD-building effect came from the EuroGIOPs trial presented by Dr. Claus C. Glüer at the ASBMR meeting.

EuroGIOPS was an 18-month, open-label, phase III clinical trial in which 92 men with GIOP were randomized to teriparatide or risedronate. At 6 months the mean increase in lumbar spine BMD was 5.7% in the teriparatide group, compared with 3.3% in the risedronate arm. At 18 months – the primary study endpoint – the teriparatide group averaged a 16.3% BMD increase over baseline, while the risedronate arm had a 3.8% rise.

Intriguingly, new clinical fractures occurred during 18 months of therapy in 5 patients on risedronate and none on teriparatide, a difference that came within a hair of statistical significance (P = .056).

Bone strength as formally measured in terms of anterior bending, axial compression, and axial torsion was also significantly greater in the teriparatide group, according to Dr. Glüer, who is professor of medical physics at the department of diagnostic radiology, University Hospital Schleswig-Holstein in Kiel, Germany.

The 2010 update of the American College of Rheumatology guidelines for the prevention and treatment of GIOP recommend bisphosphonates but not teriparatide for older adults at high risk of fracture who are taking less than 5 mg/day of prednisone for less than 1 month (Arthritis Care Res. 2010;62:1515-26). The ACR guidelines recommend reserving use of teriparatide for high-risk patients – that is, those with a prevalent fracture or a World Health Organization Fracture Risk Assessment Tool (FRAX) score indicative of a greater than 20% 10-year risk of a major osteoporotic fracture – who are on at least 6 mg/day of prednisone for less than 1 month or on any dose of glucocorticoids for longer than 1 month.

Although Dr. Saag was a coauthor of the ACR guidelines, he disagreed with this particular one in light of his own clinical trial findings as well as evidence that BMD loss and fracture risk increase early on after starting steroids, and at lower doses than previously thought problematic. So he was pleased to see a new commentary on the ACR guidelines published by the Professional Practice Committee of the ASBMR. The review recommends teriparatide or any of the bisphosphonates for high-risk patients, period.

Dr. Saag, who wasn’t involved in the ASBMR review, recommended it as useful reading both for its areas of agreement with the ACR guidelines as well as for raising several patient scenarios in which the ASBMR committee believes the ACR recommendations either don’t apply or might be improved upon.

The ASBMR commentary also lays out a research agenda, identifying key areas for future study. For example, what’s the best management strategy in lupus patients and others who may need to be on systemic steroids for a decade or more, given that teriparatide is only FDA approved for 2 years of daily use and the clinical trials of bisphosphonates for GIOPS were only 1 or 2 years long (J. Bone Miner. Res. 2011;26:1989-96).

Dr. Glüer declared having no financial conflicts regarding the Eli Lilly-funded EuroGIOPs trial. Dr. Saag disclosed that he has received research grants from and serves as a paid consultant to Amgen, Eli Lilly, Merck, and Novartis.

SAN DIEGO – Teriparatide has received a boost in status as a preferentially effective treatment for glucocorticoid-induced osteoporosis in the form of a second, confirmatory, randomized double-blind trial demonstrating the anabolic agent achieves substantially greater increases in bone mineral density compared to a bisphosphonate.

One of these studies also included fracture rates as a preplanned secondary endpoint; the trial demonstrated a significant reduction in vertebral fractures with teriparatide (Forteo) as compared to alendronate (Fosamax).

These positive study findings are bolstered by a biologically plausible mechanism of benefit, Dr. Kenneth G. Saag observed at the annual meeting of the American Society for Bone and Mineral Research.

"Based upon the pathogenesis of glucocorticoid-induced osteoporosis [(GIOP)], we think that an anabolic agent makes some sense. It may be beneficial to stimulate osteoblasts to promote new bone formation," said Dr. Saag, professor of medicine and epidemiology at the University of Alabama at Birmingham.

Steroids are known to have apoptosis-mediated deleterious effects on both osteocytes and osteoblasts that lead to decline in bone function and an abrupt increase in fracture risk independent of bone mineral density (BMD). Osteoclasts are also unfavorably impacted due to crosstalk and the indirect effects of sex steroids, insulin-like growth factor, and a modest effect of secondary hyperparathyroidism mediated through altered calcium absorption. In addition, higher-dose steroids have adverse effects upon muscle that can independently lead to a higher fracture rate, the rheumatologist explained.

The FDA has approved alendronate, zoledronic acid (Reclast), and risedronate (Actonel) for treatment GIOP. More recently, raloxifene (Evista) has joined the ranks of agents shown to increase BMD in patients on long-term steroids; this came in the form of a double-blind, placebo-controlled, 12-month study (Ann. Rheum. Dis. 2011;70:778-84).

Subcutaneous daily teriparatide for up to 2 years also has the approval of the Food and Drug Administration for use in adults at high fracture risk because they are on sustained systemic steroid therapy.

There is no definitive study demonstrating that any of these agents actually prevents fractures in patients with GIOP. Nor is it likely such a study will be undertaken. Such trials require large numbers of patients and lengthy follow-up, and pharmaceutical companies have little incentive to mount such a costly project given that the medications are already approved for use in patients on steroids, Dr. Saag noted.

However, data from a study in which Dr. Saag was lead investigator showed that teriparatide-treated patients had significantly fewer vertebral fractures than those assigned to alendronate. The study was a 36-month randomized, double-blind, clinical trial that assessed fracture rates as a preplanned secondary endpoint. The radiographic and clinical vertebral fracture rates in 169 alendronate-treated patients were 7.7% and 2.4%, respectively, compared to 1.7% and 0% in 173 teriparatide-treated patients (P = .007 and .037). No significant difference in nonvertebral fractures was found between the two treatment arms.

The primary study endpoint was the change in BMD from baseline. Here again teriparatide proved significantly more effective than the bisphosphonate, with a mean 11% increase at the lumbar spine, compared to 5.3% with alendronate. Teriparatide-treated patients also had a 5.2% increase in BMD at the total hip and a 6.3% boost at the femoral neck, compared to 2.7% and 3.4%, respectively, with alendronate (Arthritis Rheum. 2009;60:3346-55).

Confirmation of teriparatide’s superior BMD-building effect came from the EuroGIOPs trial presented by Dr. Claus C. Glüer at the ASBMR meeting.

EuroGIOPS was an 18-month, open-label, phase III clinical trial in which 92 men with GIOP were randomized to teriparatide or risedronate. At 6 months the mean increase in lumbar spine BMD was 5.7% in the teriparatide group, compared with 3.3% in the risedronate arm. At 18 months – the primary study endpoint – the teriparatide group averaged a 16.3% BMD increase over baseline, while the risedronate arm had a 3.8% rise.

Intriguingly, new clinical fractures occurred during 18 months of therapy in 5 patients on risedronate and none on teriparatide, a difference that came within a hair of statistical significance (P = .056).

Bone strength as formally measured in terms of anterior bending, axial compression, and axial torsion was also significantly greater in the teriparatide group, according to Dr. Glüer, who is professor of medical physics at the department of diagnostic radiology, University Hospital Schleswig-Holstein in Kiel, Germany.

The 2010 update of the American College of Rheumatology guidelines for the prevention and treatment of GIOP recommend bisphosphonates but not teriparatide for older adults at high risk of fracture who are taking less than 5 mg/day of prednisone for less than 1 month (Arthritis Care Res. 2010;62:1515-26). The ACR guidelines recommend reserving use of teriparatide for high-risk patients – that is, those with a prevalent fracture or a World Health Organization Fracture Risk Assessment Tool (FRAX) score indicative of a greater than 20% 10-year risk of a major osteoporotic fracture – who are on at least 6 mg/day of prednisone for less than 1 month or on any dose of glucocorticoids for longer than 1 month.

Although Dr. Saag was a coauthor of the ACR guidelines, he disagreed with this particular one in light of his own clinical trial findings as well as evidence that BMD loss and fracture risk increase early on after starting steroids, and at lower doses than previously thought problematic. So he was pleased to see a new commentary on the ACR guidelines published by the Professional Practice Committee of the ASBMR. The review recommends teriparatide or any of the bisphosphonates for high-risk patients, period.

Dr. Saag, who wasn’t involved in the ASBMR review, recommended it as useful reading both for its areas of agreement with the ACR guidelines as well as for raising several patient scenarios in which the ASBMR committee believes the ACR recommendations either don’t apply or might be improved upon.

The ASBMR commentary also lays out a research agenda, identifying key areas for future study. For example, what’s the best management strategy in lupus patients and others who may need to be on systemic steroids for a decade or more, given that teriparatide is only FDA approved for 2 years of daily use and the clinical trials of bisphosphonates for GIOPS were only 1 or 2 years long (J. Bone Miner. Res. 2011;26:1989-96).

Dr. Glüer declared having no financial conflicts regarding the Eli Lilly-funded EuroGIOPs trial. Dr. Saag disclosed that he has received research grants from and serves as a paid consultant to Amgen, Eli Lilly, Merck, and Novartis.

SAN DIEGO – Teriparatide has received a boost in status as a preferentially effective treatment for glucocorticoid-induced osteoporosis in the form of a second, confirmatory, randomized double-blind trial demonstrating the anabolic agent achieves substantially greater increases in bone mineral density compared to a bisphosphonate.

One of these studies also included fracture rates as a preplanned secondary endpoint; the trial demonstrated a significant reduction in vertebral fractures with teriparatide (Forteo) as compared to alendronate (Fosamax).

These positive study findings are bolstered by a biologically plausible mechanism of benefit, Dr. Kenneth G. Saag observed at the annual meeting of the American Society for Bone and Mineral Research.

"Based upon the pathogenesis of glucocorticoid-induced osteoporosis [(GIOP)], we think that an anabolic agent makes some sense. It may be beneficial to stimulate osteoblasts to promote new bone formation," said Dr. Saag, professor of medicine and epidemiology at the University of Alabama at Birmingham.

Steroids are known to have apoptosis-mediated deleterious effects on both osteocytes and osteoblasts that lead to decline in bone function and an abrupt increase in fracture risk independent of bone mineral density (BMD). Osteoclasts are also unfavorably impacted due to crosstalk and the indirect effects of sex steroids, insulin-like growth factor, and a modest effect of secondary hyperparathyroidism mediated through altered calcium absorption. In addition, higher-dose steroids have adverse effects upon muscle that can independently lead to a higher fracture rate, the rheumatologist explained.

The FDA has approved alendronate, zoledronic acid (Reclast), and risedronate (Actonel) for treatment GIOP. More recently, raloxifene (Evista) has joined the ranks of agents shown to increase BMD in patients on long-term steroids; this came in the form of a double-blind, placebo-controlled, 12-month study (Ann. Rheum. Dis. 2011;70:778-84).

Subcutaneous daily teriparatide for up to 2 years also has the approval of the Food and Drug Administration for use in adults at high fracture risk because they are on sustained systemic steroid therapy.

There is no definitive study demonstrating that any of these agents actually prevents fractures in patients with GIOP. Nor is it likely such a study will be undertaken. Such trials require large numbers of patients and lengthy follow-up, and pharmaceutical companies have little incentive to mount such a costly project given that the medications are already approved for use in patients on steroids, Dr. Saag noted.

However, data from a study in which Dr. Saag was lead investigator showed that teriparatide-treated patients had significantly fewer vertebral fractures than those assigned to alendronate. The study was a 36-month randomized, double-blind, clinical trial that assessed fracture rates as a preplanned secondary endpoint. The radiographic and clinical vertebral fracture rates in 169 alendronate-treated patients were 7.7% and 2.4%, respectively, compared to 1.7% and 0% in 173 teriparatide-treated patients (P = .007 and .037). No significant difference in nonvertebral fractures was found between the two treatment arms.

The primary study endpoint was the change in BMD from baseline. Here again teriparatide proved significantly more effective than the bisphosphonate, with a mean 11% increase at the lumbar spine, compared to 5.3% with alendronate. Teriparatide-treated patients also had a 5.2% increase in BMD at the total hip and a 6.3% boost at the femoral neck, compared to 2.7% and 3.4%, respectively, with alendronate (Arthritis Rheum. 2009;60:3346-55).

Confirmation of teriparatide’s superior BMD-building effect came from the EuroGIOPs trial presented by Dr. Claus C. Glüer at the ASBMR meeting.

EuroGIOPS was an 18-month, open-label, phase III clinical trial in which 92 men with GIOP were randomized to teriparatide or risedronate. At 6 months the mean increase in lumbar spine BMD was 5.7% in the teriparatide group, compared with 3.3% in the risedronate arm. At 18 months – the primary study endpoint – the teriparatide group averaged a 16.3% BMD increase over baseline, while the risedronate arm had a 3.8% rise.

Intriguingly, new clinical fractures occurred during 18 months of therapy in 5 patients on risedronate and none on teriparatide, a difference that came within a hair of statistical significance (P = .056).

Bone strength as formally measured in terms of anterior bending, axial compression, and axial torsion was also significantly greater in the teriparatide group, according to Dr. Glüer, who is professor of medical physics at the department of diagnostic radiology, University Hospital Schleswig-Holstein in Kiel, Germany.

The 2010 update of the American College of Rheumatology guidelines for the prevention and treatment of GIOP recommend bisphosphonates but not teriparatide for older adults at high risk of fracture who are taking less than 5 mg/day of prednisone for less than 1 month (Arthritis Care Res. 2010;62:1515-26). The ACR guidelines recommend reserving use of teriparatide for high-risk patients – that is, those with a prevalent fracture or a World Health Organization Fracture Risk Assessment Tool (FRAX) score indicative of a greater than 20% 10-year risk of a major osteoporotic fracture – who are on at least 6 mg/day of prednisone for less than 1 month or on any dose of glucocorticoids for longer than 1 month.

Although Dr. Saag was a coauthor of the ACR guidelines, he disagreed with this particular one in light of his own clinical trial findings as well as evidence that BMD loss and fracture risk increase early on after starting steroids, and at lower doses than previously thought problematic. So he was pleased to see a new commentary on the ACR guidelines published by the Professional Practice Committee of the ASBMR. The review recommends teriparatide or any of the bisphosphonates for high-risk patients, period.

Dr. Saag, who wasn’t involved in the ASBMR review, recommended it as useful reading both for its areas of agreement with the ACR guidelines as well as for raising several patient scenarios in which the ASBMR committee believes the ACR recommendations either don’t apply or might be improved upon.

The ASBMR commentary also lays out a research agenda, identifying key areas for future study. For example, what’s the best management strategy in lupus patients and others who may need to be on systemic steroids for a decade or more, given that teriparatide is only FDA approved for 2 years of daily use and the clinical trials of bisphosphonates for GIOPS were only 1 or 2 years long (J. Bone Miner. Res. 2011;26:1989-96).

Dr. Glüer declared having no financial conflicts regarding the Eli Lilly-funded EuroGIOPs trial. Dr. Saag disclosed that he has received research grants from and serves as a paid consultant to Amgen, Eli Lilly, Merck, and Novartis.

SAN DIEGO – Heart failure constitutes a previously unrecognized independent risk factor for major osteoporotic fractures, according to a Canadian cohort study.

"Patients with heart failure have double the 5-year risk of fracture," compared with those without heart failure. And "patients with heart failure have lower bone mineral density at every skeletal site at the time of their first test," compared with those without heart failure. "Finally, neither differences in bone mass nor shared risk factors [are enough] to explain the increased risk," said Dr. Sumit Majumdar at the annual meeting of the American Society for Bone and Mineral Research.

He presented a population-based cohort study that included all Manitobans older than age 50 years who had their first bone mineral density test in 1998-2009. The study earned him the 2011 ASBMR Most Outstanding Clinical Abstract Award.

Overall, 4% of the nearly 46,000 Manitobans who had an initial bone minteral density (BMD) test during the study years were identified as having recent-onset heart failure (that is, heart failure diagnosed within the previous 2 years). There were 2,703 new fractures in the study population during a median 5 years of follow-up. The recent heart failure group had a 10% incidence of major nontraumatic fractures of the upper extremities, vertebrae, and hip during the 5 years following the first BMD test, compared with a 5% incidence in subjects without heart failure.

The median time to first fracture in the heart failure group was 3.6 years. The curves describing fracture incidence started to diverge soon after the first BMD test and continued to widen throughout the maximum 10 years of follow-up, reported Dr. Majumdar, professor of general internal medicine at the University of Alberta, Edmonton.

Patients with heart failure had more of all the standard risk factors for osteoporosis (except weight) than did subjects without heart failure. They were significantly older (mean age, 74 vs. 66 years) and 21% of them had a prior major osteoporotic fracture, compared with 13% of those without heart failure. Some 12% of heart failure patients had been on systemic corticosteroids for longer than 90 days, compared with 4% of those without heart failure.

Moreover, 40% of heart failure patients had osteoporosis at the time of their first BMD measurement (defined as a T score less than –2.5 at any skeletal site), compared with 29% of individuals without heart failure. T scores were significantly lower in the heart failure group at all measured sites.

"A diagnosis of heart failure portends an increased risk of fracture greater than rheumatoid arthritis or prior fracture."

On the other hand, nearly every medication used in treating heart failure has previously been shown to increase BMD and to reduce fracture risk, with the exception of loop diuretics, which reduce BMD.

In addition, osteoporosis and heart failure are common, chronic conditions that share several etiologic risk factors, including older age, postmenopausal status, diabetes, and smoking, he continued.

The unadjusted risk of a major osteoporotic fracture was increased 2.45-fold in patients with heart failure. But upon adjustment in a multivariate analysis for nearly 30 potential confounders including age, sex, osteoporosis-related factors, medications, comorbidities, and total hip BMD, heart failure remained independently associated with a highly significant 28% increased risk of major osteoporotic fractures.

A disturbing finding of the study was that a mere 14% of heart failure patients who experienced an osteoporotic fracture were then placed on a bisphosphonate or other bone-protective therapy. Bisphosphonates had no association with mortality in the heart failure group.

"For clinicians, I think our study means we need to start understanding that a diagnosis of heart failure portends an increased risk of fracture greater than rheumatoid arthritis or prior fracture, in our data. And we need to learn that patients with heart failure are easily diagnosed and need much more attention to their bone health," Dr. Majumdar observed.

This study also opens up research opportunities for bench scientists, as the Manitoba database contains no information on patients’ aldosterone, parathyroid hormone, or vitamin D levels, or indeed on any other variables that might provide a mechanistic explanation for the link between heart failure and osteoporotic fractures.

"Ours is an example of bedside-to-bench research," he said.

In that vein, one audience member noted that increased adrenergic drive is a hallmark of heart failure. He wondered if heart failure patients on beta-blocker therapy had a lower fracture risk. Dr. Majumdar replied that he and his coinvestigators had had the same thought. However, when they specifically compared the nearly 35% of heart failure patients who were on a beta-blocker vs. those who weren’t, they found that fracture rates in the two groups weren’t significantly different.

Dr. Majumdar declared having no relevant financial interests.

SAN DIEGO – Heart failure constitutes a previously unrecognized independent risk factor for major osteoporotic fractures, according to a Canadian cohort study.

"Patients with heart failure have double the 5-year risk of fracture," compared with those without heart failure. And "patients with heart failure have lower bone mineral density at every skeletal site at the time of their first test," compared with those without heart failure. "Finally, neither differences in bone mass nor shared risk factors [are enough] to explain the increased risk," said Dr. Sumit Majumdar at the annual meeting of the American Society for Bone and Mineral Research.

He presented a population-based cohort study that included all Manitobans older than age 50 years who had their first bone mineral density test in 1998-2009. The study earned him the 2011 ASBMR Most Outstanding Clinical Abstract Award.

Overall, 4% of the nearly 46,000 Manitobans who had an initial bone minteral density (BMD) test during the study years were identified as having recent-onset heart failure (that is, heart failure diagnosed within the previous 2 years). There were 2,703 new fractures in the study population during a median 5 years of follow-up. The recent heart failure group had a 10% incidence of major nontraumatic fractures of the upper extremities, vertebrae, and hip during the 5 years following the first BMD test, compared with a 5% incidence in subjects without heart failure.

The median time to first fracture in the heart failure group was 3.6 years. The curves describing fracture incidence started to diverge soon after the first BMD test and continued to widen throughout the maximum 10 years of follow-up, reported Dr. Majumdar, professor of general internal medicine at the University of Alberta, Edmonton.

Patients with heart failure had more of all the standard risk factors for osteoporosis (except weight) than did subjects without heart failure. They were significantly older (mean age, 74 vs. 66 years) and 21% of them had a prior major osteoporotic fracture, compared with 13% of those without heart failure. Some 12% of heart failure patients had been on systemic corticosteroids for longer than 90 days, compared with 4% of those without heart failure.

Moreover, 40% of heart failure patients had osteoporosis at the time of their first BMD measurement (defined as a T score less than –2.5 at any skeletal site), compared with 29% of individuals without heart failure. T scores were significantly lower in the heart failure group at all measured sites.

"A diagnosis of heart failure portends an increased risk of fracture greater than rheumatoid arthritis or prior fracture."

On the other hand, nearly every medication used in treating heart failure has previously been shown to increase BMD and to reduce fracture risk, with the exception of loop diuretics, which reduce BMD.

In addition, osteoporosis and heart failure are common, chronic conditions that share several etiologic risk factors, including older age, postmenopausal status, diabetes, and smoking, he continued.

The unadjusted risk of a major osteoporotic fracture was increased 2.45-fold in patients with heart failure. But upon adjustment in a multivariate analysis for nearly 30 potential confounders including age, sex, osteoporosis-related factors, medications, comorbidities, and total hip BMD, heart failure remained independently associated with a highly significant 28% increased risk of major osteoporotic fractures.

A disturbing finding of the study was that a mere 14% of heart failure patients who experienced an osteoporotic fracture were then placed on a bisphosphonate or other bone-protective therapy. Bisphosphonates had no association with mortality in the heart failure group.

"For clinicians, I think our study means we need to start understanding that a diagnosis of heart failure portends an increased risk of fracture greater than rheumatoid arthritis or prior fracture, in our data. And we need to learn that patients with heart failure are easily diagnosed and need much more attention to their bone health," Dr. Majumdar observed.

This study also opens up research opportunities for bench scientists, as the Manitoba database contains no information on patients’ aldosterone, parathyroid hormone, or vitamin D levels, or indeed on any other variables that might provide a mechanistic explanation for the link between heart failure and osteoporotic fractures.

"Ours is an example of bedside-to-bench research," he said.

In that vein, one audience member noted that increased adrenergic drive is a hallmark of heart failure. He wondered if heart failure patients on beta-blocker therapy had a lower fracture risk. Dr. Majumdar replied that he and his coinvestigators had had the same thought. However, when they specifically compared the nearly 35% of heart failure patients who were on a beta-blocker vs. those who weren’t, they found that fracture rates in the two groups weren’t significantly different.

Dr. Majumdar declared having no relevant financial interests.

SAN DIEGO – Heart failure constitutes a previously unrecognized independent risk factor for major osteoporotic fractures, according to a Canadian cohort study.

"Patients with heart failure have double the 5-year risk of fracture," compared with those without heart failure. And "patients with heart failure have lower bone mineral density at every skeletal site at the time of their first test," compared with those without heart failure. "Finally, neither differences in bone mass nor shared risk factors [are enough] to explain the increased risk," said Dr. Sumit Majumdar at the annual meeting of the American Society for Bone and Mineral Research.

He presented a population-based cohort study that included all Manitobans older than age 50 years who had their first bone mineral density test in 1998-2009. The study earned him the 2011 ASBMR Most Outstanding Clinical Abstract Award.

Overall, 4% of the nearly 46,000 Manitobans who had an initial bone minteral density (BMD) test during the study years were identified as having recent-onset heart failure (that is, heart failure diagnosed within the previous 2 years). There were 2,703 new fractures in the study population during a median 5 years of follow-up. The recent heart failure group had a 10% incidence of major nontraumatic fractures of the upper extremities, vertebrae, and hip during the 5 years following the first BMD test, compared with a 5% incidence in subjects without heart failure.

The median time to first fracture in the heart failure group was 3.6 years. The curves describing fracture incidence started to diverge soon after the first BMD test and continued to widen throughout the maximum 10 years of follow-up, reported Dr. Majumdar, professor of general internal medicine at the University of Alberta, Edmonton.

Patients with heart failure had more of all the standard risk factors for osteoporosis (except weight) than did subjects without heart failure. They were significantly older (mean age, 74 vs. 66 years) and 21% of them had a prior major osteoporotic fracture, compared with 13% of those without heart failure. Some 12% of heart failure patients had been on systemic corticosteroids for longer than 90 days, compared with 4% of those without heart failure.

Moreover, 40% of heart failure patients had osteoporosis at the time of their first BMD measurement (defined as a T score less than –2.5 at any skeletal site), compared with 29% of individuals without heart failure. T scores were significantly lower in the heart failure group at all measured sites.

"A diagnosis of heart failure portends an increased risk of fracture greater than rheumatoid arthritis or prior fracture."

On the other hand, nearly every medication used in treating heart failure has previously been shown to increase BMD and to reduce fracture risk, with the exception of loop diuretics, which reduce BMD.

In addition, osteoporosis and heart failure are common, chronic conditions that share several etiologic risk factors, including older age, postmenopausal status, diabetes, and smoking, he continued.

The unadjusted risk of a major osteoporotic fracture was increased 2.45-fold in patients with heart failure. But upon adjustment in a multivariate analysis for nearly 30 potential confounders including age, sex, osteoporosis-related factors, medications, comorbidities, and total hip BMD, heart failure remained independently associated with a highly significant 28% increased risk of major osteoporotic fractures.

A disturbing finding of the study was that a mere 14% of heart failure patients who experienced an osteoporotic fracture were then placed on a bisphosphonate or other bone-protective therapy. Bisphosphonates had no association with mortality in the heart failure group.

"For clinicians, I think our study means we need to start understanding that a diagnosis of heart failure portends an increased risk of fracture greater than rheumatoid arthritis or prior fracture, in our data. And we need to learn that patients with heart failure are easily diagnosed and need much more attention to their bone health," Dr. Majumdar observed.

This study also opens up research opportunities for bench scientists, as the Manitoba database contains no information on patients’ aldosterone, parathyroid hormone, or vitamin D levels, or indeed on any other variables that might provide a mechanistic explanation for the link between heart failure and osteoporotic fractures.

"Ours is an example of bedside-to-bench research," he said.

In that vein, one audience member noted that increased adrenergic drive is a hallmark of heart failure. He wondered if heart failure patients on beta-blocker therapy had a lower fracture risk. Dr. Majumdar replied that he and his coinvestigators had had the same thought. However, when they specifically compared the nearly 35% of heart failure patients who were on a beta-blocker vs. those who weren’t, they found that fracture rates in the two groups weren’t significantly different.

Dr. Majumdar declared having no relevant financial interests.