Osteoporosis

Annual infusions of zoledronic acid significantly decreased the risk of new morphometric vertebral fractures by 67% in men who had osteoporosis, according to an industry-sponsored clinical trial published online Oct. 31 in the New England Journal of Medicine.

In a 2-year double-blind study conducted in Europe, South America, Africa, and Australia, 553 men with osteoporosis were randomly assigned to receive once-yearly infusions of 5 mg zoledronic acid and 574 were assigned to receive placebo infusions. Only the active drug produced significant and sustained increases in bone mineral density at the lumbar spine, total hip, and femoral neck, and it did so across all levels of serum testosterone, said Dr. Steven Boonen of the Center for Metabolic Bone diseases and the division of geriatric medicine, University Hospitals Leuven (Belgium), and his associates.

Only 1.6% of the men receiving zoledronic acid developed new vertebral fractures, compared with 4.9% of those receiving placebo, a difference that corresponded with an absolute risk reduction of 3.3 percentage points and a relative risk reduction of 67%. This reduction is similar to that seen in women with osteoporosis who receive zoledronic acid, suggesting that the antifracture effect of the drug is independent of patient sex, the investigators said (N. Engl. J. Med. 2012 Oct. 31 [doi:10.1056/NEJMoa1204061]).

Now that an effective treatment has been identified for men with osteoporosis, public health efforts to detect the disease and prevent fractures in the male population, which have been inadequate to date, can be stepped up, Dr. Boonen and his colleagues added.

This study was funded by Novartis Pharma, maker of zoledronic acid. The authors reported numerous ties to industry sources.

Annual infusions of zoledronic acid significantly decreased the risk of new morphometric vertebral fractures by 67% in men who had osteoporosis, according to an industry-sponsored clinical trial published online Oct. 31 in the New England Journal of Medicine.

In a 2-year double-blind study conducted in Europe, South America, Africa, and Australia, 553 men with osteoporosis were randomly assigned to receive once-yearly infusions of 5 mg zoledronic acid and 574 were assigned to receive placebo infusions. Only the active drug produced significant and sustained increases in bone mineral density at the lumbar spine, total hip, and femoral neck, and it did so across all levels of serum testosterone, said Dr. Steven Boonen of the Center for Metabolic Bone diseases and the division of geriatric medicine, University Hospitals Leuven (Belgium), and his associates.

Only 1.6% of the men receiving zoledronic acid developed new vertebral fractures, compared with 4.9% of those receiving placebo, a difference that corresponded with an absolute risk reduction of 3.3 percentage points and a relative risk reduction of 67%. This reduction is similar to that seen in women with osteoporosis who receive zoledronic acid, suggesting that the antifracture effect of the drug is independent of patient sex, the investigators said (N. Engl. J. Med. 2012 Oct. 31 [doi:10.1056/NEJMoa1204061]).

Now that an effective treatment has been identified for men with osteoporosis, public health efforts to detect the disease and prevent fractures in the male population, which have been inadequate to date, can be stepped up, Dr. Boonen and his colleagues added.

This study was funded by Novartis Pharma, maker of zoledronic acid. The authors reported numerous ties to industry sources.

Annual infusions of zoledronic acid significantly decreased the risk of new morphometric vertebral fractures by 67% in men who had osteoporosis, according to an industry-sponsored clinical trial published online Oct. 31 in the New England Journal of Medicine.

In a 2-year double-blind study conducted in Europe, South America, Africa, and Australia, 553 men with osteoporosis were randomly assigned to receive once-yearly infusions of 5 mg zoledronic acid and 574 were assigned to receive placebo infusions. Only the active drug produced significant and sustained increases in bone mineral density at the lumbar spine, total hip, and femoral neck, and it did so across all levels of serum testosterone, said Dr. Steven Boonen of the Center for Metabolic Bone diseases and the division of geriatric medicine, University Hospitals Leuven (Belgium), and his associates.

Only 1.6% of the men receiving zoledronic acid developed new vertebral fractures, compared with 4.9% of those receiving placebo, a difference that corresponded with an absolute risk reduction of 3.3 percentage points and a relative risk reduction of 67%. This reduction is similar to that seen in women with osteoporosis who receive zoledronic acid, suggesting that the antifracture effect of the drug is independent of patient sex, the investigators said (N. Engl. J. Med. 2012 Oct. 31 [doi:10.1056/NEJMoa1204061]).

Now that an effective treatment has been identified for men with osteoporosis, public health efforts to detect the disease and prevent fractures in the male population, which have been inadequate to date, can be stepped up, Dr. Boonen and his colleagues added.

This study was funded by Novartis Pharma, maker of zoledronic acid. The authors reported numerous ties to industry sources.

Increased calcium intake is associated with a reduced risk for primary hyperparathyroidism in women, according to an analysis of data from the Nurses’ Health Study published on Oct. 18.

In what the researchers called the first prospective study to assess the link between hyperparathyroidism and calcium intake, Dr. Julie M. Paik of Brigham and Women’s Hospital in Boston and her colleagues looked at 58,354 women from the Nurses’ Health Study I, an ongoing, prospective cohort study that began in 1976. Participants in the study complete questionnaires every 2 years.

Dietary intake was assessed using the food frequency questionnaire, which asked about participants’ average intake of more than 130 individual food items and 22 beverages during the previous year.

The survey also asked about calcium supplements, vitamin D supplements, and multivitamins, with calcium intake determined by the brand, type, and frequency of use.

Only cases of primary hyperparathyroidism diagnosed between the date on which the 1986 questionnaire was returned and May 31, 2008, were included in the study.

Overall, during 1,475,978 person-years of follow-up, there were 277 cases of incident primary hyperparathyroidism.

After the data were adjusted for age, women in the highest quintile of dietary intake had a relative risk for developing hyperparathyroidism of 0.61, compared with women in the lowest quintile (95% confidence interval, 0.42-0.90; P = .03), the investigators reported (BMJ 2012;345:e6390).

Further adjustments for body mass index, race, smoking, calcium supplement use, intake of vitamin D, dietary intake of vitamin A and protein, alcohol intake, and diuretic use only strengthened the effect: The relative risk among the highest quintile of intake was 0.56, by this calculation, compared with patients in the lowest intake category (95% CI, 0.37-0.86; P = .009).

The authors also looked at supplemental calcium intake, although "because of an insufficient number of cases of primary hyperparathyroidism among the different categories of supplemental calcium use in the earlier time periods, our analysis on the relation between supplemental calcium intake and primary hyperparathyroidism began in 1994 with follow-up until 2008," wrote Dr. Paik and her coinvestigators.

In this analysis, which included 985,628 person-years of follow-up, there were a total of 257 cases of incident primary hyperparathyroidism.

When the findings were adjusted for age, "the relative risk for women taking more than 500 mg/day of calcium supplements compared with those not taking calcium supplements was 0.69 (95% CI, 0.50-0.94; P less than .001)," wrote the authors.

As with dietary intake, the protective effect was only strengthened in multivariable analysis, including adjustment for dietary calcium: The higher-intake group’s risk was 0.41, compared with the lower-intake group (95% CI, 0.29-0.60; P less than .001).

The authors conceded that the study population was exclusively female and almost entirely white, making the findings not necessarily generalizable to men or to women of other races.

Additionally, "although the food frequency questionnaires have been well validated, calcium intake was not perfectly assessed in this study," they wrote.

"However, because of the prospective design, any misclassification would be random with respect to case status, and therefore would probably underestimate the magnitude of the inverse association between calcium intake and risk of primary hyperparathyroidism."

The study investigators stated that they had no relevant financial disclosures. The study was supported by grants from the National Institutes of Health.

Increased calcium intake is associated with a reduced risk for primary hyperparathyroidism in women, according to an analysis of data from the Nurses’ Health Study published on Oct. 18.

In what the researchers called the first prospective study to assess the link between hyperparathyroidism and calcium intake, Dr. Julie M. Paik of Brigham and Women’s Hospital in Boston and her colleagues looked at 58,354 women from the Nurses’ Health Study I, an ongoing, prospective cohort study that began in 1976. Participants in the study complete questionnaires every 2 years.

Dietary intake was assessed using the food frequency questionnaire, which asked about participants’ average intake of more than 130 individual food items and 22 beverages during the previous year.

The survey also asked about calcium supplements, vitamin D supplements, and multivitamins, with calcium intake determined by the brand, type, and frequency of use.

Only cases of primary hyperparathyroidism diagnosed between the date on which the 1986 questionnaire was returned and May 31, 2008, were included in the study.

Overall, during 1,475,978 person-years of follow-up, there were 277 cases of incident primary hyperparathyroidism.

After the data were adjusted for age, women in the highest quintile of dietary intake had a relative risk for developing hyperparathyroidism of 0.61, compared with women in the lowest quintile (95% confidence interval, 0.42-0.90; P = .03), the investigators reported (BMJ 2012;345:e6390).

Further adjustments for body mass index, race, smoking, calcium supplement use, intake of vitamin D, dietary intake of vitamin A and protein, alcohol intake, and diuretic use only strengthened the effect: The relative risk among the highest quintile of intake was 0.56, by this calculation, compared with patients in the lowest intake category (95% CI, 0.37-0.86; P = .009).

The authors also looked at supplemental calcium intake, although "because of an insufficient number of cases of primary hyperparathyroidism among the different categories of supplemental calcium use in the earlier time periods, our analysis on the relation between supplemental calcium intake and primary hyperparathyroidism began in 1994 with follow-up until 2008," wrote Dr. Paik and her coinvestigators.

In this analysis, which included 985,628 person-years of follow-up, there were a total of 257 cases of incident primary hyperparathyroidism.

When the findings were adjusted for age, "the relative risk for women taking more than 500 mg/day of calcium supplements compared with those not taking calcium supplements was 0.69 (95% CI, 0.50-0.94; P less than .001)," wrote the authors.

As with dietary intake, the protective effect was only strengthened in multivariable analysis, including adjustment for dietary calcium: The higher-intake group’s risk was 0.41, compared with the lower-intake group (95% CI, 0.29-0.60; P less than .001).

The authors conceded that the study population was exclusively female and almost entirely white, making the findings not necessarily generalizable to men or to women of other races.

Additionally, "although the food frequency questionnaires have been well validated, calcium intake was not perfectly assessed in this study," they wrote.

"However, because of the prospective design, any misclassification would be random with respect to case status, and therefore would probably underestimate the magnitude of the inverse association between calcium intake and risk of primary hyperparathyroidism."

The study investigators stated that they had no relevant financial disclosures. The study was supported by grants from the National Institutes of Health.

Increased calcium intake is associated with a reduced risk for primary hyperparathyroidism in women, according to an analysis of data from the Nurses’ Health Study published on Oct. 18.

In what the researchers called the first prospective study to assess the link between hyperparathyroidism and calcium intake, Dr. Julie M. Paik of Brigham and Women’s Hospital in Boston and her colleagues looked at 58,354 women from the Nurses’ Health Study I, an ongoing, prospective cohort study that began in 1976. Participants in the study complete questionnaires every 2 years.

Dietary intake was assessed using the food frequency questionnaire, which asked about participants’ average intake of more than 130 individual food items and 22 beverages during the previous year.

The survey also asked about calcium supplements, vitamin D supplements, and multivitamins, with calcium intake determined by the brand, type, and frequency of use.

Only cases of primary hyperparathyroidism diagnosed between the date on which the 1986 questionnaire was returned and May 31, 2008, were included in the study.

Overall, during 1,475,978 person-years of follow-up, there were 277 cases of incident primary hyperparathyroidism.

After the data were adjusted for age, women in the highest quintile of dietary intake had a relative risk for developing hyperparathyroidism of 0.61, compared with women in the lowest quintile (95% confidence interval, 0.42-0.90; P = .03), the investigators reported (BMJ 2012;345:e6390).

Further adjustments for body mass index, race, smoking, calcium supplement use, intake of vitamin D, dietary intake of vitamin A and protein, alcohol intake, and diuretic use only strengthened the effect: The relative risk among the highest quintile of intake was 0.56, by this calculation, compared with patients in the lowest intake category (95% CI, 0.37-0.86; P = .009).

The authors also looked at supplemental calcium intake, although "because of an insufficient number of cases of primary hyperparathyroidism among the different categories of supplemental calcium use in the earlier time periods, our analysis on the relation between supplemental calcium intake and primary hyperparathyroidism began in 1994 with follow-up until 2008," wrote Dr. Paik and her coinvestigators.

In this analysis, which included 985,628 person-years of follow-up, there were a total of 257 cases of incident primary hyperparathyroidism.

When the findings were adjusted for age, "the relative risk for women taking more than 500 mg/day of calcium supplements compared with those not taking calcium supplements was 0.69 (95% CI, 0.50-0.94; P less than .001)," wrote the authors.

As with dietary intake, the protective effect was only strengthened in multivariable analysis, including adjustment for dietary calcium: The higher-intake group’s risk was 0.41, compared with the lower-intake group (95% CI, 0.29-0.60; P less than .001).

The authors conceded that the study population was exclusively female and almost entirely white, making the findings not necessarily generalizable to men or to women of other races.

Additionally, "although the food frequency questionnaires have been well validated, calcium intake was not perfectly assessed in this study," they wrote.

"However, because of the prospective design, any misclassification would be random with respect to case status, and therefore would probably underestimate the magnitude of the inverse association between calcium intake and risk of primary hyperparathyroidism."

The study investigators stated that they had no relevant financial disclosures. The study was supported by grants from the National Institutes of Health.

MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.

Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).

The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.

Patrice Wendling/IMNG Medical Media

The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.

This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.

On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).

The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.

The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.

At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.

Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).

During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.

A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.

"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.

During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.

One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.

"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."

The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.

MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.

Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).

The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.

Patrice Wendling/IMNG Medical Media

The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.

This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.

On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).

The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.

The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.

At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.

Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).

During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.

A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.

"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.

During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.

One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.

"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."

The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.

MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.

Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).

The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.

Patrice Wendling/IMNG Medical Media

The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.

This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.

On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).

The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.

The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.

At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.

Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).

During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.

A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.

"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.

During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.

One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.

"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."

The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.

Combined estrogen and progestin should not be used for the prevention of osteoporosis or other chronic conditions in postmenopausal women, according to recommendations issued by the U.S. Preventive Services Task Force.

Hormone therapy currently has Food and Drug Administration approval for use in the prevention of osteoporosis in postmenopausal women.

The task force, an independent body of volunteer experts that advises the Department of Health and Human Services, issued the recommendations Oct. 22 as an update of its 2005 statement on hormone therapy for prevention of disease in postmenopausal women.

Using the most recent scientific evidence available, including long-term follow-up data from the Women's Health Initiative (WHI) studies of hormone therapy use in postmenopausal women, the task force reached the same conclusions as it had in 2005, advising against combined estrogen and progestin for prevention of chronic conditions, and also against the use of estrogen alone for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.

The task force emphasized that hormone therapy was still indicated for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It additionally made clear that its recommendation against hormone therapy for disease prevention does not apply to women younger than 50 years of age who have undergone surgical menopause.

Prior to the WHI studies, a series of government-funded trials that began in the 1990s, with follow-up ending in 2010, hormones had been widely used for the prevention of bone disease in postmenopausal women. Both estrogen and combined estrogen and progestin are known to reduce fracture risk.

However, both forms of hormone therapy were shown during the WHI studies to also increase the risk of serious adverse events, to the point where the trials were stopped early. In one randomized, placebo-controlled trial, estrogen alone was associated with a significantly higher risk of stroke, deep vein thrombosis, and gallbladder disease, while combined therapy was associated with an increased risk of stroke, invasive breast cancer, dementia, gallbladder disease, deep vein thrombosis, and pulmonary embolism.

Reproductive endocrinologist Jan L. Shifren of the department of obstetrics and gynecology and reproductive biology at Harvard Medical School and director of the menopause program at Massachusetts General Hospital, both in Boston, said in an interview that the task force’s updated position largely reflected the current consensus of the ob.gyn. community, "which is that HT should not be used to prevent the diseases of aging."

The task force was "very careful to point out that they are not saying HT should not be used for the treatment of vasomotor symptoms or vaginal atrophy. It’s not that hormones aren’t indicated; they’re just not indicated for prevention. They remain an appropriate treatment for otherwise healthy, very symptomatic women at the menopause transition," said Dr. Shifren, who is not a task force member.

FDA-approved indications for hormone therapy in postmenopausal women include treatment of menopausal symptoms and prevention of osteoporosis. A black box warning indicates that estrogen with or without progestin should be prescribed at the lowest effective dose and for the shortest time possible. The task force’s findings were based on the dosages and formulations used in the WHI trials: oral conjugated equine estrogen (0.625 mg/day plus medroxyprogesterone acetate, 2.5 mg/day) or estrogen 0.625 mg/day alone.

Dr. Shifren said that there are some practitioners "who believe that hormone therapy could still be appropriate for the prevention of osteoporosis in people who absolutely cannot tolerate any other therapy. But what I would argue is that it is incredibly rare that there is a patient who can’t tolerate one of the very many other FDA-approved treatments for the prevention of osteoporosis."

The task force members declared no relevant financial conflicts of interest.

Combined estrogen and progestin should not be used for the prevention of osteoporosis or other chronic conditions in postmenopausal women, according to recommendations issued by the U.S. Preventive Services Task Force.

Hormone therapy currently has Food and Drug Administration approval for use in the prevention of osteoporosis in postmenopausal women.

The task force, an independent body of volunteer experts that advises the Department of Health and Human Services, issued the recommendations Oct. 22 as an update of its 2005 statement on hormone therapy for prevention of disease in postmenopausal women.

Using the most recent scientific evidence available, including long-term follow-up data from the Women's Health Initiative (WHI) studies of hormone therapy use in postmenopausal women, the task force reached the same conclusions as it had in 2005, advising against combined estrogen and progestin for prevention of chronic conditions, and also against the use of estrogen alone for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.

The task force emphasized that hormone therapy was still indicated for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It additionally made clear that its recommendation against hormone therapy for disease prevention does not apply to women younger than 50 years of age who have undergone surgical menopause.

Prior to the WHI studies, a series of government-funded trials that began in the 1990s, with follow-up ending in 2010, hormones had been widely used for the prevention of bone disease in postmenopausal women. Both estrogen and combined estrogen and progestin are known to reduce fracture risk.

However, both forms of hormone therapy were shown during the WHI studies to also increase the risk of serious adverse events, to the point where the trials were stopped early. In one randomized, placebo-controlled trial, estrogen alone was associated with a significantly higher risk of stroke, deep vein thrombosis, and gallbladder disease, while combined therapy was associated with an increased risk of stroke, invasive breast cancer, dementia, gallbladder disease, deep vein thrombosis, and pulmonary embolism.

Reproductive endocrinologist Jan L. Shifren of the department of obstetrics and gynecology and reproductive biology at Harvard Medical School and director of the menopause program at Massachusetts General Hospital, both in Boston, said in an interview that the task force’s updated position largely reflected the current consensus of the ob.gyn. community, "which is that HT should not be used to prevent the diseases of aging."

The task force was "very careful to point out that they are not saying HT should not be used for the treatment of vasomotor symptoms or vaginal atrophy. It’s not that hormones aren’t indicated; they’re just not indicated for prevention. They remain an appropriate treatment for otherwise healthy, very symptomatic women at the menopause transition," said Dr. Shifren, who is not a task force member.

FDA-approved indications for hormone therapy in postmenopausal women include treatment of menopausal symptoms and prevention of osteoporosis. A black box warning indicates that estrogen with or without progestin should be prescribed at the lowest effective dose and for the shortest time possible. The task force’s findings were based on the dosages and formulations used in the WHI trials: oral conjugated equine estrogen (0.625 mg/day plus medroxyprogesterone acetate, 2.5 mg/day) or estrogen 0.625 mg/day alone.

Dr. Shifren said that there are some practitioners "who believe that hormone therapy could still be appropriate for the prevention of osteoporosis in people who absolutely cannot tolerate any other therapy. But what I would argue is that it is incredibly rare that there is a patient who can’t tolerate one of the very many other FDA-approved treatments for the prevention of osteoporosis."

The task force members declared no relevant financial conflicts of interest.

Combined estrogen and progestin should not be used for the prevention of osteoporosis or other chronic conditions in postmenopausal women, according to recommendations issued by the U.S. Preventive Services Task Force.

Hormone therapy currently has Food and Drug Administration approval for use in the prevention of osteoporosis in postmenopausal women.

The task force, an independent body of volunteer experts that advises the Department of Health and Human Services, issued the recommendations Oct. 22 as an update of its 2005 statement on hormone therapy for prevention of disease in postmenopausal women.

Using the most recent scientific evidence available, including long-term follow-up data from the Women's Health Initiative (WHI) studies of hormone therapy use in postmenopausal women, the task force reached the same conclusions as it had in 2005, advising against combined estrogen and progestin for prevention of chronic conditions, and also against the use of estrogen alone for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.

The task force emphasized that hormone therapy was still indicated for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It additionally made clear that its recommendation against hormone therapy for disease prevention does not apply to women younger than 50 years of age who have undergone surgical menopause.

Prior to the WHI studies, a series of government-funded trials that began in the 1990s, with follow-up ending in 2010, hormones had been widely used for the prevention of bone disease in postmenopausal women. Both estrogen and combined estrogen and progestin are known to reduce fracture risk.

However, both forms of hormone therapy were shown during the WHI studies to also increase the risk of serious adverse events, to the point where the trials were stopped early. In one randomized, placebo-controlled trial, estrogen alone was associated with a significantly higher risk of stroke, deep vein thrombosis, and gallbladder disease, while combined therapy was associated with an increased risk of stroke, invasive breast cancer, dementia, gallbladder disease, deep vein thrombosis, and pulmonary embolism.

Reproductive endocrinologist Jan L. Shifren of the department of obstetrics and gynecology and reproductive biology at Harvard Medical School and director of the menopause program at Massachusetts General Hospital, both in Boston, said in an interview that the task force’s updated position largely reflected the current consensus of the ob.gyn. community, "which is that HT should not be used to prevent the diseases of aging."

The task force was "very careful to point out that they are not saying HT should not be used for the treatment of vasomotor symptoms or vaginal atrophy. It’s not that hormones aren’t indicated; they’re just not indicated for prevention. They remain an appropriate treatment for otherwise healthy, very symptomatic women at the menopause transition," said Dr. Shifren, who is not a task force member.

FDA-approved indications for hormone therapy in postmenopausal women include treatment of menopausal symptoms and prevention of osteoporosis. A black box warning indicates that estrogen with or without progestin should be prescribed at the lowest effective dose and for the shortest time possible. The task force’s findings were based on the dosages and formulations used in the WHI trials: oral conjugated equine estrogen (0.625 mg/day plus medroxyprogesterone acetate, 2.5 mg/day) or estrogen 0.625 mg/day alone.

Dr. Shifren said that there are some practitioners "who believe that hormone therapy could still be appropriate for the prevention of osteoporosis in people who absolutely cannot tolerate any other therapy. But what I would argue is that it is incredibly rare that there is a patient who can’t tolerate one of the very many other FDA-approved treatments for the prevention of osteoporosis."

The task force members declared no relevant financial conflicts of interest.

MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.

At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.

Patrice Wendling/IMNG Medical Media

The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.

The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.

The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.

"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.

The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.

Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.

Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.

Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.

At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.

At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.

Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.

Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.

Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.

The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.

During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."

Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."

She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."

Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.

MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.

At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.

Patrice Wendling/IMNG Medical Media

The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.

The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.

The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.

"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.

The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.

Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.

Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.

Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.

At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.

At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.

Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.

Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.

Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.

The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.

During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."

Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."

She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."

Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.

MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.

At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.

Patrice Wendling/IMNG Medical Media

The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.

The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.

The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.

"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.

The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.

Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.

Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.

Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.

At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.

At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.

Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.

Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.

Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.

The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.

During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."

Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."

She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."

Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.

MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.

At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.

Patrice Wendling/IMNG Medical Media

Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.

AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.

The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.

The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.

"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.

"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."

The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.

The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.

At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.

Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.

Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.

"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.

"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."

Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.

Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.

The most common adverse event with AMG 785 in the phase II trial was injection site reaction (9.8%). No fatal adverse events were reported. The maximum tolerated dose has not been identified, with the monthly 210-mg dose to be carried forward into subsequent phase III trials, Dr. McClung said.

The trial was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner Chilcott.

CORRECTION 10/19/12: The headline for this story misstated the name of the investigational drug. The headline should read "Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena."

MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.

At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.

Patrice Wendling/IMNG Medical Media

Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.

AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.

The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.

The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.

"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.

"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."

The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.

The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.

At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.

Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.

Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.

"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.

"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."

Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.

Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.

The most common adverse event with AMG 785 in the phase II trial was injection site reaction (9.8%). No fatal adverse events were reported. The maximum tolerated dose has not been identified, with the monthly 210-mg dose to be carried forward into subsequent phase III trials, Dr. McClung said.

The trial was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner Chilcott.

CORRECTION 10/19/12: The headline for this story misstated the name of the investigational drug. The headline should read "Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena."

MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.

At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.

Patrice Wendling/IMNG Medical Media

Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.

AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.

The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.

The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.

"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.

"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."

The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.

The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.

At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.

Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.

Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.

"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.

"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."

Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.

Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.

The most common adverse event with AMG 785 in the phase II trial was injection site reaction (9.8%). No fatal adverse events were reported. The maximum tolerated dose has not been identified, with the monthly 210-mg dose to be carried forward into subsequent phase III trials, Dr. McClung said.

The trial was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner Chilcott.

CORRECTION 10/19/12: The headline for this story misstated the name of the investigational drug. The headline should read "Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena."

Adding everolimus to exemestane for the treatment of estrogen receptor–positive advanced breast cancer that is refractory to nonsteroidal aromatase inhibitors has beneficial effects on bone turnover and breast cancer progression in bone, according to an exploratory analysis of data from the BOLERO-2 trial.

Additional exploratory analyses demonstrate that everolimus (Afinitor) is well tolerated among postmenopausal women – including the elderly.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been implicated in resistance to standard endocrine therapy for estrogen receptor–positive breast cancer. Previously reported data from the double-blind, placebo-controlled phase III BOLERO-2 trial showed a significant clinical benefit with respect to the primary end point of progression-free survival when everolimus was added to the steroidal aromatase inhibitor exemestane (Aromasin).

The new findings were presented during poster sessions at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

To evaluate the bone-related effects of everolimus, investigators analyzed bone turnover marker levels and breast cancer progression in bone in BOLERO-2 patients who had bone metastases at baseline, including 184 patients who received placebo and 370 who received exemestane.

They found that active treatment with everolimus and exemestane was associated with improved levels of bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal cross-linking telopeptide of type 1 collagen at 6- and 12-week follow-up.

The levels of each of these markers had increased at both time points in those receiving placebo, but had decreased in those receiving everolimus, Dr. Lowell L. Hart, a hematologist/oncologist in group practice in Fort Myers, Fla., and his colleagues reported (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 102]).

Also, the cumulative incidence rate of breast cancer progressive disease in bone was lower in those who received everolimus, compared with those who received placebo (3.03% vs. 6.16% at day 60), they said, noting that this trend continued beyond 6 months.

Bone-related adverse events among the patients included in this analysis were grade 1/2, and occurred at a similar frequency in both groups (2.9% for the placebo group and 3.8% for the treatment group).

The safety and tolerability of everolimus were also evaluated in two additional exploratory analyses. In one, everolimus treatment was shown at a median of 12.5 months’ follow-up to be generally well tolerated among 492 postmenopausal women in the treatment group for the study.

Notable adverse events of all grades in those patients, compared with the 238 patients in the placebo group, included stomatitis (59% vs. 12%), rash (39% vs. 7%), pneumonitis (16% vs. 0%), and hyperglycemia (14% vs. less than 1%). Notable grade 3/4 events were stomatitis (8% vs. less than 1%), anemia (7% vs. less than 1%), hyperglycemia (5% vs. less than 1%), pneumonitis (3% vs. 0), and rash (1% vs. 0), reported Dr. Alejandra T. Perez, director of the breast cancer center at Memorial Cancer Institute in Hollywood, Fla.

The adverse events were manageable when patients were treated appropriately, Dr. Perez said (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 103]).

For example, the study protocol permitted dose reduction or interruptions for the management of adverse events, and a look at the antitumor effects of treatment showed that results were consistent in those who received time-averaged doses less than 7.5 mg/day and those who received time-averaged doses greater than 7.5 mg/day (hazard ratios, 0.4 vs. 0.45, respectively). Those who developed stomatitis were treated with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics, and those with noninfectious pneumonitis were treated using a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment.

Among the subset of study participants aged 65 years and older, the incidences of adverse events were similar or marginally lower than in the entire population, according to Dr. Hope S. Rugo of the University of California, San Francisco, and her colleagues.

For example, stomatitis occurred in 52% of those aged 65 and older who received everolimus, rash occurred in 32%, pneumonitis occurred in 15%, and hyperglycemia occurred in 13%. Grade 3/4 adverse events among those aged 70 years or older and reported only in those receiving everolimus included fatigue in 10%, anemia in 10%, hyperglycemia in 9%, stomatitis in 8%, dyspnea in 7%, pneumonitis in 5%, neutropenia in 3%, and hypertension in 3% (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 104]).

Adding everolimus to exemestane was well tolerated both in the overall population and among elderly patients, and grade 3/4 adverse events were uncommon and manageable, Dr. Rugo noted. No new safety signals emerged.

Dr. Perez added that knowledge of adverse event management strategies is essential for optimizing tolerability and patient outcomes.

BOLERO-2 trial participants were postmenopausal women with estrogen receptor–positive breast cancer who relapsed or progressed on a nonsteroidal aromatase inhibitor. They were randomized to receive a 10-mg oral daily dose of everolimus plus 25 mg of exemestane once daily, or placebo and 25 mg of exemestane daily; treatment with everolimus conferred a median 4.2-month progression-free survival advantage, more than doubling the median progression-free survival from 3.2 months in the placebo group to 7.8 months in the treatment group. Based on these findings, the U.S. Food and Drug Administration approved the drug for this indication in July, making it the first mTOR inhibitor approved for advanced hormone receptor–positive breast cancer.

BOLERO-2 was sponsored by Novartis Pharmaceuticals. Dr. Rugo reported receiving research funding from Merck, Novartis, and Pfizer. Dr. Hart and Dr. Perez reported having no relevant financial disclosures.

Adding everolimus to exemestane for the treatment of estrogen receptor–positive advanced breast cancer that is refractory to nonsteroidal aromatase inhibitors has beneficial effects on bone turnover and breast cancer progression in bone, according to an exploratory analysis of data from the BOLERO-2 trial.

Additional exploratory analyses demonstrate that everolimus (Afinitor) is well tolerated among postmenopausal women – including the elderly.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been implicated in resistance to standard endocrine therapy for estrogen receptor–positive breast cancer. Previously reported data from the double-blind, placebo-controlled phase III BOLERO-2 trial showed a significant clinical benefit with respect to the primary end point of progression-free survival when everolimus was added to the steroidal aromatase inhibitor exemestane (Aromasin).

The new findings were presented during poster sessions at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

To evaluate the bone-related effects of everolimus, investigators analyzed bone turnover marker levels and breast cancer progression in bone in BOLERO-2 patients who had bone metastases at baseline, including 184 patients who received placebo and 370 who received exemestane.

They found that active treatment with everolimus and exemestane was associated with improved levels of bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal cross-linking telopeptide of type 1 collagen at 6- and 12-week follow-up.

The levels of each of these markers had increased at both time points in those receiving placebo, but had decreased in those receiving everolimus, Dr. Lowell L. Hart, a hematologist/oncologist in group practice in Fort Myers, Fla., and his colleagues reported (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 102]).

Also, the cumulative incidence rate of breast cancer progressive disease in bone was lower in those who received everolimus, compared with those who received placebo (3.03% vs. 6.16% at day 60), they said, noting that this trend continued beyond 6 months.

Bone-related adverse events among the patients included in this analysis were grade 1/2, and occurred at a similar frequency in both groups (2.9% for the placebo group and 3.8% for the treatment group).

The safety and tolerability of everolimus were also evaluated in two additional exploratory analyses. In one, everolimus treatment was shown at a median of 12.5 months’ follow-up to be generally well tolerated among 492 postmenopausal women in the treatment group for the study.

Notable adverse events of all grades in those patients, compared with the 238 patients in the placebo group, included stomatitis (59% vs. 12%), rash (39% vs. 7%), pneumonitis (16% vs. 0%), and hyperglycemia (14% vs. less than 1%). Notable grade 3/4 events were stomatitis (8% vs. less than 1%), anemia (7% vs. less than 1%), hyperglycemia (5% vs. less than 1%), pneumonitis (3% vs. 0), and rash (1% vs. 0), reported Dr. Alejandra T. Perez, director of the breast cancer center at Memorial Cancer Institute in Hollywood, Fla.

The adverse events were manageable when patients were treated appropriately, Dr. Perez said (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 103]).

For example, the study protocol permitted dose reduction or interruptions for the management of adverse events, and a look at the antitumor effects of treatment showed that results were consistent in those who received time-averaged doses less than 7.5 mg/day and those who received time-averaged doses greater than 7.5 mg/day (hazard ratios, 0.4 vs. 0.45, respectively). Those who developed stomatitis were treated with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics, and those with noninfectious pneumonitis were treated using a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment.

Among the subset of study participants aged 65 years and older, the incidences of adverse events were similar or marginally lower than in the entire population, according to Dr. Hope S. Rugo of the University of California, San Francisco, and her colleagues.

For example, stomatitis occurred in 52% of those aged 65 and older who received everolimus, rash occurred in 32%, pneumonitis occurred in 15%, and hyperglycemia occurred in 13%. Grade 3/4 adverse events among those aged 70 years or older and reported only in those receiving everolimus included fatigue in 10%, anemia in 10%, hyperglycemia in 9%, stomatitis in 8%, dyspnea in 7%, pneumonitis in 5%, neutropenia in 3%, and hypertension in 3% (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 104]).

Adding everolimus to exemestane was well tolerated both in the overall population and among elderly patients, and grade 3/4 adverse events were uncommon and manageable, Dr. Rugo noted. No new safety signals emerged.

Dr. Perez added that knowledge of adverse event management strategies is essential for optimizing tolerability and patient outcomes.

BOLERO-2 trial participants were postmenopausal women with estrogen receptor–positive breast cancer who relapsed or progressed on a nonsteroidal aromatase inhibitor. They were randomized to receive a 10-mg oral daily dose of everolimus plus 25 mg of exemestane once daily, or placebo and 25 mg of exemestane daily; treatment with everolimus conferred a median 4.2-month progression-free survival advantage, more than doubling the median progression-free survival from 3.2 months in the placebo group to 7.8 months in the treatment group. Based on these findings, the U.S. Food and Drug Administration approved the drug for this indication in July, making it the first mTOR inhibitor approved for advanced hormone receptor–positive breast cancer.

BOLERO-2 was sponsored by Novartis Pharmaceuticals. Dr. Rugo reported receiving research funding from Merck, Novartis, and Pfizer. Dr. Hart and Dr. Perez reported having no relevant financial disclosures.

Adding everolimus to exemestane for the treatment of estrogen receptor–positive advanced breast cancer that is refractory to nonsteroidal aromatase inhibitors has beneficial effects on bone turnover and breast cancer progression in bone, according to an exploratory analysis of data from the BOLERO-2 trial.

Additional exploratory analyses demonstrate that everolimus (Afinitor) is well tolerated among postmenopausal women – including the elderly.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been implicated in resistance to standard endocrine therapy for estrogen receptor–positive breast cancer. Previously reported data from the double-blind, placebo-controlled phase III BOLERO-2 trial showed a significant clinical benefit with respect to the primary end point of progression-free survival when everolimus was added to the steroidal aromatase inhibitor exemestane (Aromasin).

The new findings were presented during poster sessions at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

To evaluate the bone-related effects of everolimus, investigators analyzed bone turnover marker levels and breast cancer progression in bone in BOLERO-2 patients who had bone metastases at baseline, including 184 patients who received placebo and 370 who received exemestane.

They found that active treatment with everolimus and exemestane was associated with improved levels of bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal cross-linking telopeptide of type 1 collagen at 6- and 12-week follow-up.

The levels of each of these markers had increased at both time points in those receiving placebo, but had decreased in those receiving everolimus, Dr. Lowell L. Hart, a hematologist/oncologist in group practice in Fort Myers, Fla., and his colleagues reported (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 102]).

Also, the cumulative incidence rate of breast cancer progressive disease in bone was lower in those who received everolimus, compared with those who received placebo (3.03% vs. 6.16% at day 60), they said, noting that this trend continued beyond 6 months.

Bone-related adverse events among the patients included in this analysis were grade 1/2, and occurred at a similar frequency in both groups (2.9% for the placebo group and 3.8% for the treatment group).

The safety and tolerability of everolimus were also evaluated in two additional exploratory analyses. In one, everolimus treatment was shown at a median of 12.5 months’ follow-up to be generally well tolerated among 492 postmenopausal women in the treatment group for the study.

Notable adverse events of all grades in those patients, compared with the 238 patients in the placebo group, included stomatitis (59% vs. 12%), rash (39% vs. 7%), pneumonitis (16% vs. 0%), and hyperglycemia (14% vs. less than 1%). Notable grade 3/4 events were stomatitis (8% vs. less than 1%), anemia (7% vs. less than 1%), hyperglycemia (5% vs. less than 1%), pneumonitis (3% vs. 0), and rash (1% vs. 0), reported Dr. Alejandra T. Perez, director of the breast cancer center at Memorial Cancer Institute in Hollywood, Fla.

The adverse events were manageable when patients were treated appropriately, Dr. Perez said (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 103]).

For example, the study protocol permitted dose reduction or interruptions for the management of adverse events, and a look at the antitumor effects of treatment showed that results were consistent in those who received time-averaged doses less than 7.5 mg/day and those who received time-averaged doses greater than 7.5 mg/day (hazard ratios, 0.4 vs. 0.45, respectively). Those who developed stomatitis were treated with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics, and those with noninfectious pneumonitis were treated using a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment.

Among the subset of study participants aged 65 years and older, the incidences of adverse events were similar or marginally lower than in the entire population, according to Dr. Hope S. Rugo of the University of California, San Francisco, and her colleagues.

For example, stomatitis occurred in 52% of those aged 65 and older who received everolimus, rash occurred in 32%, pneumonitis occurred in 15%, and hyperglycemia occurred in 13%. Grade 3/4 adverse events among those aged 70 years or older and reported only in those receiving everolimus included fatigue in 10%, anemia in 10%, hyperglycemia in 9%, stomatitis in 8%, dyspnea in 7%, pneumonitis in 5%, neutropenia in 3%, and hypertension in 3% (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 104]).

Adding everolimus to exemestane was well tolerated both in the overall population and among elderly patients, and grade 3/4 adverse events were uncommon and manageable, Dr. Rugo noted. No new safety signals emerged.

Dr. Perez added that knowledge of adverse event management strategies is essential for optimizing tolerability and patient outcomes.

BOLERO-2 trial participants were postmenopausal women with estrogen receptor–positive breast cancer who relapsed or progressed on a nonsteroidal aromatase inhibitor. They were randomized to receive a 10-mg oral daily dose of everolimus plus 25 mg of exemestane once daily, or placebo and 25 mg of exemestane daily; treatment with everolimus conferred a median 4.2-month progression-free survival advantage, more than doubling the median progression-free survival from 3.2 months in the placebo group to 7.8 months in the treatment group. Based on these findings, the U.S. Food and Drug Administration approved the drug for this indication in July, making it the first mTOR inhibitor approved for advanced hormone receptor–positive breast cancer.

BOLERO-2 was sponsored by Novartis Pharmaceuticals. Dr. Rugo reported receiving research funding from Merck, Novartis, and Pfizer. Dr. Hart and Dr. Perez reported having no relevant financial disclosures.

Home-based and group exercise programs are the interventions that most significantly reduce falls among elderly community-dwelling patients, according to an update published online Sept. 11 in the Cochrane Database of Systematic Reviews.

Home safety interventions also reduce falling, especially among elderly people at highest risk and especially when the interventions are performed by occupational therapists.

In contrast, walking programs, vitamin D supplementation, hormone replacement therapy, adjustment of medication regimens, nutritional therapy, cognitive behavioral therapy, vision improvement interventions, and withdrawal of psychotropic drugs do not decrease falls. And interventions such as footwear assessment, foot and ankle exercises, cataract surgery, pacemaker insertion, and patient education only appear to benefit select patient populations, Dr. Lesley D. Gillespie of the University of Otago, Dunedin, New Zealand, and associates wrote (Cochrane Database Syst. Rev. 2012 [doi: 10.1002/14651858.CD007146.pub3]).

Copyright thinkstockphotos.com

The investigators performed a systematic review of the literature and meta-analysis of 159 randomized clinical trials assessing interventions aimed at reducing falls among the elderly, to update the existing Cochrane Review of the subject that was published in 2009. The update includes 51 new trials that were performed after the publication of that initial Cochrane Review.

These clinical trials were conducted in 21 countries, and included 79,193 participants aged 60 years and older. The median sample size was 230 study subjects (range, 10-9,940 subjects), and 70% of the participants were women.

The effects of each intervention on both the rate of falls (the number of falls per person per year) and the risk of falling (the number of people who fell once or more during follow-up) were assessed for each intervention.

Fifty-nine trials specifically examined the effectiveness of various exercise programs in preventing falls, including gait training, balance training, functional training, muscle strength/resistance training, 3-D training (constant, repetitive movement through all three spatial planes), tai chi, and general physical activity such as walking.

Programs that contained more than one of these components were the most successful. Both home-based and group programs achieved a statistically significant reduction in both the rate of falls and the risk of falling. However, resistance training was associated with an increase in adverse events such as musculoskeletal injury and bursitis.

Tai chi alone significantly reduced the risk of falling, but the decrease in the rate of falls was of borderline significance only.

General activity such as walking did not reduce the rate or the risk of falling.

Medication interventions generally were ineffective at reducing falls, the researchers said.

Even though four new clinical trials involving nearly 6,000 patients examined vitamin D supplementation (with or without calcium), the treatment reduced falls only in those patients who had low serum levels of vitamin D at baseline. The vitamin D analogues calcitriol and alfacalcidol were associated with increased hypercalcemia.

Other medical interventions that were as ineffective included hormone therapy; the gradual withdrawal of psychotropic medications used to improve sleep, reduce anxiety, or treat depression; the adjustment of current medication regimens; and nutritional supplementation. The exception to this finding was a single program in which family physicians were given education by a clinical pharmacist, feedback on their prescribing practices, and financial incentives; their subsequent review and modification of elderly patients’ medication regimens did significantly reduce falls.

Surgical interventions to reduce falls included cataract surgery to improve vision and cardiac pacemaker insertion to decrease dizzy spells. A first cataract operation reduced the rate of falls but not the risk of falling, and subsequent cataract operations did not affect falls. Pacemakers cut the rate of falls in only the subgroup of patients who had cardioinhibitory carotid sinus hypersensitivity that induced sudden changes in heart rate and blood pressure, and they did not decrease the risk of falling in any patient group.

Other, nonsurgical interventions to improve vision actually increased the rate of falls and the risk of falling. One trial found that patients given vision assessment, eye examinations, new eyeglasses, referral for expedited treatment of any ophthalmologic problems, mobility training, and canes actually had higher rates of falls and higher risks of falling than did control subjects. Another trial showed that replacing multifocal eyeglasses with single-lens distance glasses for activities that involved walking and standing failed to reduce the rate or risk of falls overall, and actually increased outdoor falls among the frailer patients.

Interventions that addressed environmental issues or provided assistive technology produced mixed results. Assessing the safety of the home environment and making modifications prevented falls, especially in patients at highest risk of falling, such as those with severe visual impairment. A post hoc analysis showed that these interventions were significantly more effective when performed by an occupational therapist rather than other personnel.

However, providing walking aids such as canes, or communication enhancers such as hearing aids and personal alarm systems, did not decrease falls.

Similarly, changes in footwear were effective in some cases but not in others. The use of balance-enhancing insoles cut the rate of falls but not the risk of falls, and was beneficial primarily to patients who had disabling foot pain. The use of an antislip device on outdoor shoes decreased falls only in adverse weather conditions.

The evidence for or against patient education was inconclusive because of insufficient data at this time.

"As the majority of trials specifically excluded older people who were cognitively impaired, the results of this review may not be applicable to this important group of people at risk [for falling]," Dr. Gillespie and associates said.

Similarly, their review excluded trials involving patients with Parkinson’s disease and recovering stroke patients, "as we felt the results of interventions for those neurological conditions were not necessarily applicable to older people as a whole," they added.

No financial conflicts of interest were reported.

Home-based and group exercise programs are the interventions that most significantly reduce falls among elderly community-dwelling patients, according to an update published online Sept. 11 in the Cochrane Database of Systematic Reviews.

Home safety interventions also reduce falling, especially among elderly people at highest risk and especially when the interventions are performed by occupational therapists.

In contrast, walking programs, vitamin D supplementation, hormone replacement therapy, adjustment of medication regimens, nutritional therapy, cognitive behavioral therapy, vision improvement interventions, and withdrawal of psychotropic drugs do not decrease falls. And interventions such as footwear assessment, foot and ankle exercises, cataract surgery, pacemaker insertion, and patient education only appear to benefit select patient populations, Dr. Lesley D. Gillespie of the University of Otago, Dunedin, New Zealand, and associates wrote (Cochrane Database Syst. Rev. 2012 [doi: 10.1002/14651858.CD007146.pub3]).

Copyright thinkstockphotos.com

The investigators performed a systematic review of the literature and meta-analysis of 159 randomized clinical trials assessing interventions aimed at reducing falls among the elderly, to update the existing Cochrane Review of the subject that was published in 2009. The update includes 51 new trials that were performed after the publication of that initial Cochrane Review.

These clinical trials were conducted in 21 countries, and included 79,193 participants aged 60 years and older. The median sample size was 230 study subjects (range, 10-9,940 subjects), and 70% of the participants were women.

The effects of each intervention on both the rate of falls (the number of falls per person per year) and the risk of falling (the number of people who fell once or more during follow-up) were assessed for each intervention.

Fifty-nine trials specifically examined the effectiveness of various exercise programs in preventing falls, including gait training, balance training, functional training, muscle strength/resistance training, 3-D training (constant, repetitive movement through all three spatial planes), tai chi, and general physical activity such as walking.

Programs that contained more than one of these components were the most successful. Both home-based and group programs achieved a statistically significant reduction in both the rate of falls and the risk of falling. However, resistance training was associated with an increase in adverse events such as musculoskeletal injury and bursitis.

Tai chi alone significantly reduced the risk of falling, but the decrease in the rate of falls was of borderline significance only.

General activity such as walking did not reduce the rate or the risk of falling.

Medication interventions generally were ineffective at reducing falls, the researchers said.

Even though four new clinical trials involving nearly 6,000 patients examined vitamin D supplementation (with or without calcium), the treatment reduced falls only in those patients who had low serum levels of vitamin D at baseline. The vitamin D analogues calcitriol and alfacalcidol were associated with increased hypercalcemia.

Other medical interventions that were as ineffective included hormone therapy; the gradual withdrawal of psychotropic medications used to improve sleep, reduce anxiety, or treat depression; the adjustment of current medication regimens; and nutritional supplementation. The exception to this finding was a single program in which family physicians were given education by a clinical pharmacist, feedback on their prescribing practices, and financial incentives; their subsequent review and modification of elderly patients’ medication regimens did significantly reduce falls.

Surgical interventions to reduce falls included cataract surgery to improve vision and cardiac pacemaker insertion to decrease dizzy spells. A first cataract operation reduced the rate of falls but not the risk of falling, and subsequent cataract operations did not affect falls. Pacemakers cut the rate of falls in only the subgroup of patients who had cardioinhibitory carotid sinus hypersensitivity that induced sudden changes in heart rate and blood pressure, and they did not decrease the risk of falling in any patient group.

Other, nonsurgical interventions to improve vision actually increased the rate of falls and the risk of falling. One trial found that patients given vision assessment, eye examinations, new eyeglasses, referral for expedited treatment of any ophthalmologic problems, mobility training, and canes actually had higher rates of falls and higher risks of falling than did control subjects. Another trial showed that replacing multifocal eyeglasses with single-lens distance glasses for activities that involved walking and standing failed to reduce the rate or risk of falls overall, and actually increased outdoor falls among the frailer patients.

Interventions that addressed environmental issues or provided assistive technology produced mixed results. Assessing the safety of the home environment and making modifications prevented falls, especially in patients at highest risk of falling, such as those with severe visual impairment. A post hoc analysis showed that these interventions were significantly more effective when performed by an occupational therapist rather than other personnel.

However, providing walking aids such as canes, or communication enhancers such as hearing aids and personal alarm systems, did not decrease falls.

Similarly, changes in footwear were effective in some cases but not in others. The use of balance-enhancing insoles cut the rate of falls but not the risk of falls, and was beneficial primarily to patients who had disabling foot pain. The use of an antislip device on outdoor shoes decreased falls only in adverse weather conditions.

The evidence for or against patient education was inconclusive because of insufficient data at this time.

"As the majority of trials specifically excluded older people who were cognitively impaired, the results of this review may not be applicable to this important group of people at risk [for falling]," Dr. Gillespie and associates said.

Similarly, their review excluded trials involving patients with Parkinson’s disease and recovering stroke patients, "as we felt the results of interventions for those neurological conditions were not necessarily applicable to older people as a whole," they added.

No financial conflicts of interest were reported.

Home-based and group exercise programs are the interventions that most significantly reduce falls among elderly community-dwelling patients, according to an update published online Sept. 11 in the Cochrane Database of Systematic Reviews.

Home safety interventions also reduce falling, especially among elderly people at highest risk and especially when the interventions are performed by occupational therapists.

In contrast, walking programs, vitamin D supplementation, hormone replacement therapy, adjustment of medication regimens, nutritional therapy, cognitive behavioral therapy, vision improvement interventions, and withdrawal of psychotropic drugs do not decrease falls. And interventions such as footwear assessment, foot and ankle exercises, cataract surgery, pacemaker insertion, and patient education only appear to benefit select patient populations, Dr. Lesley D. Gillespie of the University of Otago, Dunedin, New Zealand, and associates wrote (Cochrane Database Syst. Rev. 2012 [doi: 10.1002/14651858.CD007146.pub3]).

Copyright thinkstockphotos.com

The investigators performed a systematic review of the literature and meta-analysis of 159 randomized clinical trials assessing interventions aimed at reducing falls among the elderly, to update the existing Cochrane Review of the subject that was published in 2009. The update includes 51 new trials that were performed after the publication of that initial Cochrane Review.

These clinical trials were conducted in 21 countries, and included 79,193 participants aged 60 years and older. The median sample size was 230 study subjects (range, 10-9,940 subjects), and 70% of the participants were women.

The effects of each intervention on both the rate of falls (the number of falls per person per year) and the risk of falling (the number of people who fell once or more during follow-up) were assessed for each intervention.

Fifty-nine trials specifically examined the effectiveness of various exercise programs in preventing falls, including gait training, balance training, functional training, muscle strength/resistance training, 3-D training (constant, repetitive movement through all three spatial planes), tai chi, and general physical activity such as walking.

Programs that contained more than one of these components were the most successful. Both home-based and group programs achieved a statistically significant reduction in both the rate of falls and the risk of falling. However, resistance training was associated with an increase in adverse events such as musculoskeletal injury and bursitis.

Tai chi alone significantly reduced the risk of falling, but the decrease in the rate of falls was of borderline significance only.

General activity such as walking did not reduce the rate or the risk of falling.

Medication interventions generally were ineffective at reducing falls, the researchers said.

Even though four new clinical trials involving nearly 6,000 patients examined vitamin D supplementation (with or without calcium), the treatment reduced falls only in those patients who had low serum levels of vitamin D at baseline. The vitamin D analogues calcitriol and alfacalcidol were associated with increased hypercalcemia.

Other medical interventions that were as ineffective included hormone therapy; the gradual withdrawal of psychotropic medications used to improve sleep, reduce anxiety, or treat depression; the adjustment of current medication regimens; and nutritional supplementation. The exception to this finding was a single program in which family physicians were given education by a clinical pharmacist, feedback on their prescribing practices, and financial incentives; their subsequent review and modification of elderly patients’ medication regimens did significantly reduce falls.

Surgical interventions to reduce falls included cataract surgery to improve vision and cardiac pacemaker insertion to decrease dizzy spells. A first cataract operation reduced the rate of falls but not the risk of falling, and subsequent cataract operations did not affect falls. Pacemakers cut the rate of falls in only the subgroup of patients who had cardioinhibitory carotid sinus hypersensitivity that induced sudden changes in heart rate and blood pressure, and they did not decrease the risk of falling in any patient group.

Other, nonsurgical interventions to improve vision actually increased the rate of falls and the risk of falling. One trial found that patients given vision assessment, eye examinations, new eyeglasses, referral for expedited treatment of any ophthalmologic problems, mobility training, and canes actually had higher rates of falls and higher risks of falling than did control subjects. Another trial showed that replacing multifocal eyeglasses with single-lens distance glasses for activities that involved walking and standing failed to reduce the rate or risk of falls overall, and actually increased outdoor falls among the frailer patients.

Interventions that addressed environmental issues or provided assistive technology produced mixed results. Assessing the safety of the home environment and making modifications prevented falls, especially in patients at highest risk of falling, such as those with severe visual impairment. A post hoc analysis showed that these interventions were significantly more effective when performed by an occupational therapist rather than other personnel.

However, providing walking aids such as canes, or communication enhancers such as hearing aids and personal alarm systems, did not decrease falls.

Similarly, changes in footwear were effective in some cases but not in others. The use of balance-enhancing insoles cut the rate of falls but not the risk of falls, and was beneficial primarily to patients who had disabling foot pain. The use of an antislip device on outdoor shoes decreased falls only in adverse weather conditions.

The evidence for or against patient education was inconclusive because of insufficient data at this time.

"As the majority of trials specifically excluded older people who were cognitively impaired, the results of this review may not be applicable to this important group of people at risk [for falling]," Dr. Gillespie and associates said.

Similarly, their review excluded trials involving patients with Parkinson’s disease and recovering stroke patients, "as we felt the results of interventions for those neurological conditions were not necessarily applicable to older people as a whole," they added.

No financial conflicts of interest were reported.

HOUSTON – Intravenous pamidronate for management of bone hyperresorption in ventilator-dependent patients doesn’t adversely affect renal function, even in those with chronic kidney disease, according to a single-center retrospective study.

"This stands in contrast to prevailing concerns about bisphosphonate therapy to manage bone hyperresorption in chronically critically ill patients, many of whom have chronic kidney disease," Dr. Rifka C. Schulman reported at the annual meeting of the Endocrine Society.

"It is hoped that these results will remove barriers to more aggressive management of metabolic bone disease in chronic critical illness, which may have salutary downstream effects on morbidity and mortality," declared Dr. Schulman of the Mount Sinai School of Medicine in New York.

She presented a retrospective observational study of 315 patients admitted to the Mount Sinai Hospital respiratory care unit with ventilator-dependent chronic critical illness after surviving a bout of acute critical illness. In all, 115 received 30-90 mg of intravenous pamidronate (Aredia) infused over 4 hours, with dosing based on body weight. The other 200 patients did not receive pamidronate. All participants got calcitriol, calcium carbonate, and ergocalciferol to help protect their bones.

The study population consisted of 204 patients with either no or stage 1-2 chronic kidney disease, 41 with stage 3 CKD, 33 with stage 4 disease, and 37 with stage 5 CKD who were on hemodialysis.

The primary study end points were change in glomerular filtration rate and creatinine level following pamidronate administration. Importantly, none of the pamidronate-treated patients showed a 25% or greater reduction in GFR immediately after or at 7 or 14 days post infusion, regardless of their CKD status or dose received.

The group with no or only mild CKD showed no change in median GFR between baseline and day 7 post infusion. Those with stage 3 CKD had a median 4% drop in GFR. So did those with stage 4 disease. Patients with stage 5 CKD had a median 9% reduction in GFR on day 7. Among controls, those with stage 0-3 CKD had no change in median GFR, while those with stage 4 or stage 5 disease averaged a 6% increase in GFR during 7 days. These small fluctuations in renal function aren’t clinically meaningful, according to Dr. Schulman.

Creatinine levels rose between baseline and day 7 in lockstep with CKD status, but to the same extent in pamidronate-treated patients and controls. For example, creatinine climbed by 6.7% and 18.2%, respectively, in pamidronate-treated patients with stage 4 and stage 5 CKD, and by 8.8% and 20.8% in stage 4 and 5 controls.

She observed that metabolic bone disease involving bone hyperresorption with elevated levels of the bone turnover biomarker N-telopeptide is present in more than 90% of patients with chronic critical illness. Contributing factors include immobilization, inflammation, neuroendocrine abnormalities, low vitamin D levels and secondary hyperparathyroidism, and the use of high-dose corticosteroids and other medications with an adverse impact on bone.

Bone loss during critical illness is challenging to reverse. It predisposes to osteoporosis, fractures, and poor quality of life in patients who recover from chronic critical illness. That’s why Dr. Schulman and her coinvestigators favor turning to pamidronate when patients have a 24-hour urine N-telopeptide of 70 nmol BCE/mmol creatinine or a serum level in excess of 40 nmol BCE/L.

The study was supported by a grant from Select Medical. Dr. Schulman reported having no financial conflicts.

HOUSTON – Intravenous pamidronate for management of bone hyperresorption in ventilator-dependent patients doesn’t adversely affect renal function, even in those with chronic kidney disease, according to a single-center retrospective study.

"This stands in contrast to prevailing concerns about bisphosphonate therapy to manage bone hyperresorption in chronically critically ill patients, many of whom have chronic kidney disease," Dr. Rifka C. Schulman reported at the annual meeting of the Endocrine Society.

"It is hoped that these results will remove barriers to more aggressive management of metabolic bone disease in chronic critical illness, which may have salutary downstream effects on morbidity and mortality," declared Dr. Schulman of the Mount Sinai School of Medicine in New York.

She presented a retrospective observational study of 315 patients admitted to the Mount Sinai Hospital respiratory care unit with ventilator-dependent chronic critical illness after surviving a bout of acute critical illness. In all, 115 received 30-90 mg of intravenous pamidronate (Aredia) infused over 4 hours, with dosing based on body weight. The other 200 patients did not receive pamidronate. All participants got calcitriol, calcium carbonate, and ergocalciferol to help protect their bones.

The study population consisted of 204 patients with either no or stage 1-2 chronic kidney disease, 41 with stage 3 CKD, 33 with stage 4 disease, and 37 with stage 5 CKD who were on hemodialysis.

The primary study end points were change in glomerular filtration rate and creatinine level following pamidronate administration. Importantly, none of the pamidronate-treated patients showed a 25% or greater reduction in GFR immediately after or at 7 or 14 days post infusion, regardless of their CKD status or dose received.

The group with no or only mild CKD showed no change in median GFR between baseline and day 7 post infusion. Those with stage 3 CKD had a median 4% drop in GFR. So did those with stage 4 disease. Patients with stage 5 CKD had a median 9% reduction in GFR on day 7. Among controls, those with stage 0-3 CKD had no change in median GFR, while those with stage 4 or stage 5 disease averaged a 6% increase in GFR during 7 days. These small fluctuations in renal function aren’t clinically meaningful, according to Dr. Schulman.

Creatinine levels rose between baseline and day 7 in lockstep with CKD status, but to the same extent in pamidronate-treated patients and controls. For example, creatinine climbed by 6.7% and 18.2%, respectively, in pamidronate-treated patients with stage 4 and stage 5 CKD, and by 8.8% and 20.8% in stage 4 and 5 controls.

She observed that metabolic bone disease involving bone hyperresorption with elevated levels of the bone turnover biomarker N-telopeptide is present in more than 90% of patients with chronic critical illness. Contributing factors include immobilization, inflammation, neuroendocrine abnormalities, low vitamin D levels and secondary hyperparathyroidism, and the use of high-dose corticosteroids and other medications with an adverse impact on bone.

Bone loss during critical illness is challenging to reverse. It predisposes to osteoporosis, fractures, and poor quality of life in patients who recover from chronic critical illness. That’s why Dr. Schulman and her coinvestigators favor turning to pamidronate when patients have a 24-hour urine N-telopeptide of 70 nmol BCE/mmol creatinine or a serum level in excess of 40 nmol BCE/L.

The study was supported by a grant from Select Medical. Dr. Schulman reported having no financial conflicts.

HOUSTON – Intravenous pamidronate for management of bone hyperresorption in ventilator-dependent patients doesn’t adversely affect renal function, even in those with chronic kidney disease, according to a single-center retrospective study.

"This stands in contrast to prevailing concerns about bisphosphonate therapy to manage bone hyperresorption in chronically critically ill patients, many of whom have chronic kidney disease," Dr. Rifka C. Schulman reported at the annual meeting of the Endocrine Society.

"It is hoped that these results will remove barriers to more aggressive management of metabolic bone disease in chronic critical illness, which may have salutary downstream effects on morbidity and mortality," declared Dr. Schulman of the Mount Sinai School of Medicine in New York.

She presented a retrospective observational study of 315 patients admitted to the Mount Sinai Hospital respiratory care unit with ventilator-dependent chronic critical illness after surviving a bout of acute critical illness. In all, 115 received 30-90 mg of intravenous pamidronate (Aredia) infused over 4 hours, with dosing based on body weight. The other 200 patients did not receive pamidronate. All participants got calcitriol, calcium carbonate, and ergocalciferol to help protect their bones.

The study population consisted of 204 patients with either no or stage 1-2 chronic kidney disease, 41 with stage 3 CKD, 33 with stage 4 disease, and 37 with stage 5 CKD who were on hemodialysis.

The primary study end points were change in glomerular filtration rate and creatinine level following pamidronate administration. Importantly, none of the pamidronate-treated patients showed a 25% or greater reduction in GFR immediately after or at 7 or 14 days post infusion, regardless of their CKD status or dose received.

The group with no or only mild CKD showed no change in median GFR between baseline and day 7 post infusion. Those with stage 3 CKD had a median 4% drop in GFR. So did those with stage 4 disease. Patients with stage 5 CKD had a median 9% reduction in GFR on day 7. Among controls, those with stage 0-3 CKD had no change in median GFR, while those with stage 4 or stage 5 disease averaged a 6% increase in GFR during 7 days. These small fluctuations in renal function aren’t clinically meaningful, according to Dr. Schulman.

Creatinine levels rose between baseline and day 7 in lockstep with CKD status, but to the same extent in pamidronate-treated patients and controls. For example, creatinine climbed by 6.7% and 18.2%, respectively, in pamidronate-treated patients with stage 4 and stage 5 CKD, and by 8.8% and 20.8% in stage 4 and 5 controls.

She observed that metabolic bone disease involving bone hyperresorption with elevated levels of the bone turnover biomarker N-telopeptide is present in more than 90% of patients with chronic critical illness. Contributing factors include immobilization, inflammation, neuroendocrine abnormalities, low vitamin D levels and secondary hyperparathyroidism, and the use of high-dose corticosteroids and other medications with an adverse impact on bone.

Bone loss during critical illness is challenging to reverse. It predisposes to osteoporosis, fractures, and poor quality of life in patients who recover from chronic critical illness. That’s why Dr. Schulman and her coinvestigators favor turning to pamidronate when patients have a 24-hour urine N-telopeptide of 70 nmol BCE/mmol creatinine or a serum level in excess of 40 nmol BCE/L.

The study was supported by a grant from Select Medical. Dr. Schulman reported having no financial conflicts.

HOUSTON – Denosumab continued to achieve reduced fractures rates, progressively rising bone mineral density, and sustained reduction in bone turnover biomarkers through 6 years of continuous use in the ongoing 7-year extension of the landmark FREEDOM trial.

FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was the pivotal phase III, double-blind, placebo-controlled, 3-year randomized trial that led to marketing approval of denosumab (Prolia) at 60 mg subcutaneously every 6 months for treatment of postmenopausal osteoporosis (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM extension study is evaluating the long-term safety and efficacy of denosumab for an additional 7 years. Thus, participants who were in the active treatment arm of the original study will receive denosumab for a total of 10 years, whereas patients who crossed over to denosumab after 3 years on placebo will be on the novel RANKL (receptor-activated nuclear factor–kappaB ligand) inhibitor for 7 years.

At the conference, Dr. Henry G. Bone presented updated study results through 6 years. In all, 4,550 postmenopausal women from the original randomized trial were enrolled in the extension and have been followed for an additional 3 years.

In the original FREEDOM trial, 3 years of denosumab resulted in a 10.1% increase in BMD in the lumbar spine, compared with baseline. With an additional 3 years of open-label therapy, this figure has increased to 15.1%. The gain in the crossover group paralleled that seen with active therapy in the original trial; that is, after 6 years – the last 3 on open-label denosumab – those patients had a 9.4% increase over baseline in lumbar spine BMD, reported Dr. Bone, chief of the endocrinology department at St. John Hospital and Medical Center, Detroit, and director of the Michigan Bone and Mineral Clinic.

Total hip BMD rose from a 5.7% increase over baseline after 3 years of denosumab to a 7.5% increase after 6 years. The crossover group had a 4.8% increase at this site after 3 years of active therapy.

During the first 3 years of the FREEDOM trial, new vertebral fractures occurred in 2.3% of the denosumab group, compared with 7.2% of placebo-treated controls. During the subsequent 3 years of open-label therapy, the original denosumab cohort had a 3.5% incidence of new vertebral fractures. Because it would have been unethical to have a placebo arm during those second 3 years, statistical modeling using a method known as "virtual twins" was used to project outcomes had the original control group remained on placebo. Their expected rate of new vertebral fractures during the first 3 years of the extension study was 6.3%.

The incidence of nonvertebral fractures during the 3-year, double-blind phase of FREEDOM was 8.0% in the placebo arm and significantly lower, at 6.5%, in the denosumab group. During the second 3-year period of denosumab therapy, the incidence was 3.8%.

"It’s interesting that the nonvertebral fracture rate in the second 3 years is actually quite a bit lower than in the first 3 years, suggesting there may be an additional benefit of long treatment," Dr. Bone said.

The projected rate of new nonvertebral fractures during years 4-6 in the "virtual twins" was 7.5%.

Turning to safety issues, the endocrinologist said that there were two adjudicated cases of osteonecrosis of the jaw during 6 years of denosumab therapy, and two more in the control group that occurred after crossover to active treatment. There has been one documented case of atypical femoral fracture during 6 consecutive years on denosumab. There has been one serious skin infection in the control group after they were crossed to 3 years of denosumab, and several more during years 4-6 in the long-term extension group.

The FREEDOM study extension is sponsored by Amgen. The presenter is a consultant to and on the speakers bureau for the company.

HOUSTON – Denosumab continued to achieve reduced fractures rates, progressively rising bone mineral density, and sustained reduction in bone turnover biomarkers through 6 years of continuous use in the ongoing 7-year extension of the landmark FREEDOM trial.

FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was the pivotal phase III, double-blind, placebo-controlled, 3-year randomized trial that led to marketing approval of denosumab (Prolia) at 60 mg subcutaneously every 6 months for treatment of postmenopausal osteoporosis (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM extension study is evaluating the long-term safety and efficacy of denosumab for an additional 7 years. Thus, participants who were in the active treatment arm of the original study will receive denosumab for a total of 10 years, whereas patients who crossed over to denosumab after 3 years on placebo will be on the novel RANKL (receptor-activated nuclear factor–kappaB ligand) inhibitor for 7 years.

At the conference, Dr. Henry G. Bone presented updated study results through 6 years. In all, 4,550 postmenopausal women from the original randomized trial were enrolled in the extension and have been followed for an additional 3 years.

In the original FREEDOM trial, 3 years of denosumab resulted in a 10.1% increase in BMD in the lumbar spine, compared with baseline. With an additional 3 years of open-label therapy, this figure has increased to 15.1%. The gain in the crossover group paralleled that seen with active therapy in the original trial; that is, after 6 years – the last 3 on open-label denosumab – those patients had a 9.4% increase over baseline in lumbar spine BMD, reported Dr. Bone, chief of the endocrinology department at St. John Hospital and Medical Center, Detroit, and director of the Michigan Bone and Mineral Clinic.

Total hip BMD rose from a 5.7% increase over baseline after 3 years of denosumab to a 7.5% increase after 6 years. The crossover group had a 4.8% increase at this site after 3 years of active therapy.

During the first 3 years of the FREEDOM trial, new vertebral fractures occurred in 2.3% of the denosumab group, compared with 7.2% of placebo-treated controls. During the subsequent 3 years of open-label therapy, the original denosumab cohort had a 3.5% incidence of new vertebral fractures. Because it would have been unethical to have a placebo arm during those second 3 years, statistical modeling using a method known as "virtual twins" was used to project outcomes had the original control group remained on placebo. Their expected rate of new vertebral fractures during the first 3 years of the extension study was 6.3%.

The incidence of nonvertebral fractures during the 3-year, double-blind phase of FREEDOM was 8.0% in the placebo arm and significantly lower, at 6.5%, in the denosumab group. During the second 3-year period of denosumab therapy, the incidence was 3.8%.

"It’s interesting that the nonvertebral fracture rate in the second 3 years is actually quite a bit lower than in the first 3 years, suggesting there may be an additional benefit of long treatment," Dr. Bone said.

The projected rate of new nonvertebral fractures during years 4-6 in the "virtual twins" was 7.5%.

Turning to safety issues, the endocrinologist said that there were two adjudicated cases of osteonecrosis of the jaw during 6 years of denosumab therapy, and two more in the control group that occurred after crossover to active treatment. There has been one documented case of atypical femoral fracture during 6 consecutive years on denosumab. There has been one serious skin infection in the control group after they were crossed to 3 years of denosumab, and several more during years 4-6 in the long-term extension group.

The FREEDOM study extension is sponsored by Amgen. The presenter is a consultant to and on the speakers bureau for the company.

HOUSTON – Denosumab continued to achieve reduced fractures rates, progressively rising bone mineral density, and sustained reduction in bone turnover biomarkers through 6 years of continuous use in the ongoing 7-year extension of the landmark FREEDOM trial.

FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was the pivotal phase III, double-blind, placebo-controlled, 3-year randomized trial that led to marketing approval of denosumab (Prolia) at 60 mg subcutaneously every 6 months for treatment of postmenopausal osteoporosis (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM extension study is evaluating the long-term safety and efficacy of denosumab for an additional 7 years. Thus, participants who were in the active treatment arm of the original study will receive denosumab for a total of 10 years, whereas patients who crossed over to denosumab after 3 years on placebo will be on the novel RANKL (receptor-activated nuclear factor–kappaB ligand) inhibitor for 7 years.

At the conference, Dr. Henry G. Bone presented updated study results through 6 years. In all, 4,550 postmenopausal women from the original randomized trial were enrolled in the extension and have been followed for an additional 3 years.

In the original FREEDOM trial, 3 years of denosumab resulted in a 10.1% increase in BMD in the lumbar spine, compared with baseline. With an additional 3 years of open-label therapy, this figure has increased to 15.1%. The gain in the crossover group paralleled that seen with active therapy in the original trial; that is, after 6 years – the last 3 on open-label denosumab – those patients had a 9.4% increase over baseline in lumbar spine BMD, reported Dr. Bone, chief of the endocrinology department at St. John Hospital and Medical Center, Detroit, and director of the Michigan Bone and Mineral Clinic.

Total hip BMD rose from a 5.7% increase over baseline after 3 years of denosumab to a 7.5% increase after 6 years. The crossover group had a 4.8% increase at this site after 3 years of active therapy.

During the first 3 years of the FREEDOM trial, new vertebral fractures occurred in 2.3% of the denosumab group, compared with 7.2% of placebo-treated controls. During the subsequent 3 years of open-label therapy, the original denosumab cohort had a 3.5% incidence of new vertebral fractures. Because it would have been unethical to have a placebo arm during those second 3 years, statistical modeling using a method known as "virtual twins" was used to project outcomes had the original control group remained on placebo. Their expected rate of new vertebral fractures during the first 3 years of the extension study was 6.3%.

The incidence of nonvertebral fractures during the 3-year, double-blind phase of FREEDOM was 8.0% in the placebo arm and significantly lower, at 6.5%, in the denosumab group. During the second 3-year period of denosumab therapy, the incidence was 3.8%.

"It’s interesting that the nonvertebral fracture rate in the second 3 years is actually quite a bit lower than in the first 3 years, suggesting there may be an additional benefit of long treatment," Dr. Bone said.

The projected rate of new nonvertebral fractures during years 4-6 in the "virtual twins" was 7.5%.

Turning to safety issues, the endocrinologist said that there were two adjudicated cases of osteonecrosis of the jaw during 6 years of denosumab therapy, and two more in the control group that occurred after crossover to active treatment. There has been one documented case of atypical femoral fracture during 6 consecutive years on denosumab. There has been one serious skin infection in the control group after they were crossed to 3 years of denosumab, and several more during years 4-6 in the long-term extension group.

The FREEDOM study extension is sponsored by Amgen. The presenter is a consultant to and on the speakers bureau for the company.