Osteoarthritis

PHILADELPHIA — Prophylactic zoledronic acid appears to reduce morbidity associated with bone mineral loss and fractures in patients who have undergone a liver transplant, Dr. Martin Bodingbauer said at the annual meeting of the American Society for Bone and Mineral Research.

Vertebral fractures after liver transplant are linked to substantial morbidity and increased mortality. Fracture rates in the first 12 months after the procedure have been reported to range from 25% to 35%.

“Bone mineral density measurements do not accurately predict the fracture risk of the transplant patients,” said Dr. Bodingbauer of the surgery department at the Medical University of Vienna. The etiology of hepatic osteodystrophy is unclear.

In this preliminary study, 96 patients were randomized at the time of transplant to receive treatment with zoledronic acid (eight 4-mg IV infusions in 12 months) along with calcium (1,000 mg/day) and vitamin D (800 IU/day) supplements, or supplements alone.

Of the 96 patients, 47 were randomized to the treatment group and 49 to the control group. Results at 24 months' follow-up were available for 35 patients in the treatment group and 34 control subjects.

At 24 months, 26% of the treatment group and 46% of the control group either had a fracture or had died—the combined primary end point. The difference between the groups was statistically significant.

Analysis of bone biochemical markers indicated a statistically significant lower rate of bone turnover in the treated patients than in the control group.

In addition, bone mineral density measurements were greater in the treatment patients than in the control subjects.

Eight deaths occurred in the treatment group and 12 among the control subjects—all due to either septicemia or posttransplantation proliferative disorder.

Infection and nausea occurred at similar rates in each group, and both side effects resolved quickly. There were seven discontinuations in each group, mostly due to liver or kidney dysfunction.

Dr. Bodingbauer disclosed that he had no conflicts of interest.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Prophylactic zoledronic acid appears to reduce morbidity associated with bone mineral loss and fractures in patients who have undergone a liver transplant, Dr. Martin Bodingbauer said at the annual meeting of the American Society for Bone and Mineral Research.

Vertebral fractures after liver transplant are linked to substantial morbidity and increased mortality. Fracture rates in the first 12 months after the procedure have been reported to range from 25% to 35%.

“Bone mineral density measurements do not accurately predict the fracture risk of the transplant patients,” said Dr. Bodingbauer of the surgery department at the Medical University of Vienna. The etiology of hepatic osteodystrophy is unclear.

In this preliminary study, 96 patients were randomized at the time of transplant to receive treatment with zoledronic acid (eight 4-mg IV infusions in 12 months) along with calcium (1,000 mg/day) and vitamin D (800 IU/day) supplements, or supplements alone.

Of the 96 patients, 47 were randomized to the treatment group and 49 to the control group. Results at 24 months' follow-up were available for 35 patients in the treatment group and 34 control subjects.

At 24 months, 26% of the treatment group and 46% of the control group either had a fracture or had died—the combined primary end point. The difference between the groups was statistically significant.

Analysis of bone biochemical markers indicated a statistically significant lower rate of bone turnover in the treated patients than in the control group.

In addition, bone mineral density measurements were greater in the treatment patients than in the control subjects.

Eight deaths occurred in the treatment group and 12 among the control subjects—all due to either septicemia or posttransplantation proliferative disorder.

Infection and nausea occurred at similar rates in each group, and both side effects resolved quickly. There were seven discontinuations in each group, mostly due to liver or kidney dysfunction.

Dr. Bodingbauer disclosed that he had no conflicts of interest.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Prophylactic zoledronic acid appears to reduce morbidity associated with bone mineral loss and fractures in patients who have undergone a liver transplant, Dr. Martin Bodingbauer said at the annual meeting of the American Society for Bone and Mineral Research.

Vertebral fractures after liver transplant are linked to substantial morbidity and increased mortality. Fracture rates in the first 12 months after the procedure have been reported to range from 25% to 35%.

“Bone mineral density measurements do not accurately predict the fracture risk of the transplant patients,” said Dr. Bodingbauer of the surgery department at the Medical University of Vienna. The etiology of hepatic osteodystrophy is unclear.

In this preliminary study, 96 patients were randomized at the time of transplant to receive treatment with zoledronic acid (eight 4-mg IV infusions in 12 months) along with calcium (1,000 mg/day) and vitamin D (800 IU/day) supplements, or supplements alone.

Of the 96 patients, 47 were randomized to the treatment group and 49 to the control group. Results at 24 months' follow-up were available for 35 patients in the treatment group and 34 control subjects.

At 24 months, 26% of the treatment group and 46% of the control group either had a fracture or had died—the combined primary end point. The difference between the groups was statistically significant.

Analysis of bone biochemical markers indicated a statistically significant lower rate of bone turnover in the treated patients than in the control group.

In addition, bone mineral density measurements were greater in the treatment patients than in the control subjects.

Eight deaths occurred in the treatment group and 12 among the control subjects—all due to either septicemia or posttransplantation proliferative disorder.

Infection and nausea occurred at similar rates in each group, and both side effects resolved quickly. There were seven discontinuations in each group, mostly due to liver or kidney dysfunction.

Dr. Bodingbauer disclosed that he had no conflicts of interest.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Steroidal and nonsteroidal aromatase inhibitors appear to have very similar effects on bone metabolism, which result in increased bone turnover, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

“Anastrozole, letrozole, and exemestane in this study seem to have similar effects on bone biochemical measurements, and thus bone turnover. … The increase in bone turnover doesn't appear to be significantly different with the steroidal versus nonsteroidal aromatase inhibitors,” said Dr. Eugene McCloskey, a senior clinical lecturer in metabolic bone disease at the University of Sheffield in England.

Aromatase inhibitors have been associated with increased bone turnover, particularly in the setting of adjuvant therapy for breast cancer. Some preclinical studies have suggested that there may be differences between the effect of the steroidal (exemestane) and nonsteroidal (letrozole and anastrozole) aromatase inhibitors on bone turnover.

With the Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) trial, Dr. McCloskey and his colleagues compared the effects of these three aromatase inhibitors on safety parameters such as serum markers of bone formation and resorption, lipid profiles, and adrenal function in healthy postmenopausal women with normal bone mineral density at the spine and hip.

Letrozole (Femara) is made by Novartis Pharmaceutical Corp., exemestane (Aromasin) by Pfizer Inc., and anastrozole (Arimidex) by AstraZeneca. The study was sponsored by AstraZeneca, and Dr. McCloskey disclosed that he has received research grants from the company.

In the study, healthy postmenopausal women were randomized to receive letrozole (2.5 mg/day), exemestane (25 mg/day), or anastrozole (1 mg/day) once daily for 24 weeks. The women were followed for another 12 weeks after the end of therapy. Overall, 102 women were randomized and 96 are included in this analysis (32 on letrozole, 34 on exemestane, and 30 on anastrozole).

The researchers measured changes from baseline bone alkaline phosphatase (a formation marker), serum C-telopeptide crosslinks (a marker of resorption), parathyroid hormone, and propeptide of type I procollagen (a marker of formation).

For bone alkaline phosphatase (ALP) all three drugs showed a trend toward increased levels but only exemestane reached statistical significance. However, there was no statistical difference between the three groups.

There was a nonstatistical increase for all three groups in terms of propeptide of type I procollagen (P1NP) but no statistical difference between the groups.

Serum C-telopeptide crosslinks (CTX) levels were also increased in all three groups but there was no significant difference between the groups.

To look at these formation and resorption marker increases in more detail, the researchers calculated the uncoupling index, which is a measure of the difference between formation and resorption. To do this, they calculated z scores for the resorption marker (CTX) and formation markers (ALP and P1NP). Z scores for formation markers were subtracted from z scores for CTX. The results indicated that resorption generally exceeds formation for all three drugs.

In terms of change in parathyroid hormone (PTH) levels, there was a greater decrease with exemestane than with anastrozole. The difference was statistically significant. It's unclear whether there are any significant differences between these drugs in terms of fracture rates, Dr. McCloskey noted.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Steroidal and nonsteroidal aromatase inhibitors appear to have very similar effects on bone metabolism, which result in increased bone turnover, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

“Anastrozole, letrozole, and exemestane in this study seem to have similar effects on bone biochemical measurements, and thus bone turnover. … The increase in bone turnover doesn't appear to be significantly different with the steroidal versus nonsteroidal aromatase inhibitors,” said Dr. Eugene McCloskey, a senior clinical lecturer in metabolic bone disease at the University of Sheffield in England.

Aromatase inhibitors have been associated with increased bone turnover, particularly in the setting of adjuvant therapy for breast cancer. Some preclinical studies have suggested that there may be differences between the effect of the steroidal (exemestane) and nonsteroidal (letrozole and anastrozole) aromatase inhibitors on bone turnover.

With the Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) trial, Dr. McCloskey and his colleagues compared the effects of these three aromatase inhibitors on safety parameters such as serum markers of bone formation and resorption, lipid profiles, and adrenal function in healthy postmenopausal women with normal bone mineral density at the spine and hip.

Letrozole (Femara) is made by Novartis Pharmaceutical Corp., exemestane (Aromasin) by Pfizer Inc., and anastrozole (Arimidex) by AstraZeneca. The study was sponsored by AstraZeneca, and Dr. McCloskey disclosed that he has received research grants from the company.

In the study, healthy postmenopausal women were randomized to receive letrozole (2.5 mg/day), exemestane (25 mg/day), or anastrozole (1 mg/day) once daily for 24 weeks. The women were followed for another 12 weeks after the end of therapy. Overall, 102 women were randomized and 96 are included in this analysis (32 on letrozole, 34 on exemestane, and 30 on anastrozole).

The researchers measured changes from baseline bone alkaline phosphatase (a formation marker), serum C-telopeptide crosslinks (a marker of resorption), parathyroid hormone, and propeptide of type I procollagen (a marker of formation).

For bone alkaline phosphatase (ALP) all three drugs showed a trend toward increased levels but only exemestane reached statistical significance. However, there was no statistical difference between the three groups.

There was a nonstatistical increase for all three groups in terms of propeptide of type I procollagen (P1NP) but no statistical difference between the groups.

Serum C-telopeptide crosslinks (CTX) levels were also increased in all three groups but there was no significant difference between the groups.

To look at these formation and resorption marker increases in more detail, the researchers calculated the uncoupling index, which is a measure of the difference between formation and resorption. To do this, they calculated z scores for the resorption marker (CTX) and formation markers (ALP and P1NP). Z scores for formation markers were subtracted from z scores for CTX. The results indicated that resorption generally exceeds formation for all three drugs.

In terms of change in parathyroid hormone (PTH) levels, there was a greater decrease with exemestane than with anastrozole. The difference was statistically significant. It's unclear whether there are any significant differences between these drugs in terms of fracture rates, Dr. McCloskey noted.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Steroidal and nonsteroidal aromatase inhibitors appear to have very similar effects on bone metabolism, which result in increased bone turnover, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

“Anastrozole, letrozole, and exemestane in this study seem to have similar effects on bone biochemical measurements, and thus bone turnover. … The increase in bone turnover doesn't appear to be significantly different with the steroidal versus nonsteroidal aromatase inhibitors,” said Dr. Eugene McCloskey, a senior clinical lecturer in metabolic bone disease at the University of Sheffield in England.

Aromatase inhibitors have been associated with increased bone turnover, particularly in the setting of adjuvant therapy for breast cancer. Some preclinical studies have suggested that there may be differences between the effect of the steroidal (exemestane) and nonsteroidal (letrozole and anastrozole) aromatase inhibitors on bone turnover.

With the Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) trial, Dr. McCloskey and his colleagues compared the effects of these three aromatase inhibitors on safety parameters such as serum markers of bone formation and resorption, lipid profiles, and adrenal function in healthy postmenopausal women with normal bone mineral density at the spine and hip.

Letrozole (Femara) is made by Novartis Pharmaceutical Corp., exemestane (Aromasin) by Pfizer Inc., and anastrozole (Arimidex) by AstraZeneca. The study was sponsored by AstraZeneca, and Dr. McCloskey disclosed that he has received research grants from the company.

In the study, healthy postmenopausal women were randomized to receive letrozole (2.5 mg/day), exemestane (25 mg/day), or anastrozole (1 mg/day) once daily for 24 weeks. The women were followed for another 12 weeks after the end of therapy. Overall, 102 women were randomized and 96 are included in this analysis (32 on letrozole, 34 on exemestane, and 30 on anastrozole).

The researchers measured changes from baseline bone alkaline phosphatase (a formation marker), serum C-telopeptide crosslinks (a marker of resorption), parathyroid hormone, and propeptide of type I procollagen (a marker of formation).

For bone alkaline phosphatase (ALP) all three drugs showed a trend toward increased levels but only exemestane reached statistical significance. However, there was no statistical difference between the three groups.

There was a nonstatistical increase for all three groups in terms of propeptide of type I procollagen (P1NP) but no statistical difference between the groups.

Serum C-telopeptide crosslinks (CTX) levels were also increased in all three groups but there was no significant difference between the groups.

To look at these formation and resorption marker increases in more detail, the researchers calculated the uncoupling index, which is a measure of the difference between formation and resorption. To do this, they calculated z scores for the resorption marker (CTX) and formation markers (ALP and P1NP). Z scores for formation markers were subtracted from z scores for CTX. The results indicated that resorption generally exceeds formation for all three drugs.

In terms of change in parathyroid hormone (PTH) levels, there was a greater decrease with exemestane than with anastrozole. The difference was statistically significant. It's unclear whether there are any significant differences between these drugs in terms of fracture rates, Dr. McCloskey noted.

ELSEVIER GLOBAL MEDICAL NEWS

An 81-year-old man presented with severe proximal muscle pain, reduced mobility, and a history of frequent falls as well as knee osteoarthritis, hypertension, and a vertebral wedge collapse nearly 2 decades earlier. Clinical examination revealed ankle swelling and left knee synovitis, as well as bilateral quadriceps muscle wasting and grade 4 or 5 muscle power.

Scintigraphy showed the Lone Ranger sign, with increased uptake in the skull and around the eyes and reduced soft tissue activity. Laboratory evaluations identified and elevated calcium level, at 4.02 mmol/L, and an elevated alkaline phosphate level, at 782 U/L, which suggested severe bone disease.

Diagnosis

The diagnosis, based on scintigraphy and other radiographic investigations, was long-standing parathyroid bone disease complicating primary hyperparathyroidism (Ann. Rheum. Dis. 2006;65:1244).

The scintigraphic findings were characterized as a superscan, in which there is diffuse increased skeletal uptake relating to increased bone turnover and which can appear to be a negative or normal scan. This appearance is more common in metastatic cancer and is quite unusual in hyperparathyroid bone disease, according to Dr. D. John Pradeep of Norfolk and Norwich University Hospital, Norwich, England.

Hyperparathyroidism itself today is usually detected quite early, and a presentation such as this, with extensive bone disease, is quite rare, Dr. Pradeep said in an interview. Aside from the scintigraphic findings, hyperparathyroidism also is characterized by x-ray findings of brown tumors, which are small lytic lesions of the hip.

Further diagnostic evaluation of this patient using ultrasound and Tc-99m sestamibi scanning identified a mass by the left upper pole of the thyroid. The tumor was removed by minimally invasive parathyroidectomy, and histologically was found to be a benign adenoma.

An 81-year-old man presented with severe proximal muscle pain, reduced mobility, and a history of frequent falls as well as knee osteoarthritis, hypertension, and a vertebral wedge collapse nearly 2 decades earlier. Clinical examination revealed ankle swelling and left knee synovitis, as well as bilateral quadriceps muscle wasting and grade 4 or 5 muscle power.

Scintigraphy showed the Lone Ranger sign, with increased uptake in the skull and around the eyes and reduced soft tissue activity. Laboratory evaluations identified and elevated calcium level, at 4.02 mmol/L, and an elevated alkaline phosphate level, at 782 U/L, which suggested severe bone disease.

Diagnosis

The diagnosis, based on scintigraphy and other radiographic investigations, was long-standing parathyroid bone disease complicating primary hyperparathyroidism (Ann. Rheum. Dis. 2006;65:1244).

The scintigraphic findings were characterized as a superscan, in which there is diffuse increased skeletal uptake relating to increased bone turnover and which can appear to be a negative or normal scan. This appearance is more common in metastatic cancer and is quite unusual in hyperparathyroid bone disease, according to Dr. D. John Pradeep of Norfolk and Norwich University Hospital, Norwich, England.

Hyperparathyroidism itself today is usually detected quite early, and a presentation such as this, with extensive bone disease, is quite rare, Dr. Pradeep said in an interview. Aside from the scintigraphic findings, hyperparathyroidism also is characterized by x-ray findings of brown tumors, which are small lytic lesions of the hip.

Further diagnostic evaluation of this patient using ultrasound and Tc-99m sestamibi scanning identified a mass by the left upper pole of the thyroid. The tumor was removed by minimally invasive parathyroidectomy, and histologically was found to be a benign adenoma.

An 81-year-old man presented with severe proximal muscle pain, reduced mobility, and a history of frequent falls as well as knee osteoarthritis, hypertension, and a vertebral wedge collapse nearly 2 decades earlier. Clinical examination revealed ankle swelling and left knee synovitis, as well as bilateral quadriceps muscle wasting and grade 4 or 5 muscle power.

Scintigraphy showed the Lone Ranger sign, with increased uptake in the skull and around the eyes and reduced soft tissue activity. Laboratory evaluations identified and elevated calcium level, at 4.02 mmol/L, and an elevated alkaline phosphate level, at 782 U/L, which suggested severe bone disease.

Diagnosis

The diagnosis, based on scintigraphy and other radiographic investigations, was long-standing parathyroid bone disease complicating primary hyperparathyroidism (Ann. Rheum. Dis. 2006;65:1244).

The scintigraphic findings were characterized as a superscan, in which there is diffuse increased skeletal uptake relating to increased bone turnover and which can appear to be a negative or normal scan. This appearance is more common in metastatic cancer and is quite unusual in hyperparathyroid bone disease, according to Dr. D. John Pradeep of Norfolk and Norwich University Hospital, Norwich, England.

Hyperparathyroidism itself today is usually detected quite early, and a presentation such as this, with extensive bone disease, is quite rare, Dr. Pradeep said in an interview. Aside from the scintigraphic findings, hyperparathyroidism also is characterized by x-ray findings of brown tumors, which are small lytic lesions of the hip.

Further diagnostic evaluation of this patient using ultrasound and Tc-99m sestamibi scanning identified a mass by the left upper pole of the thyroid. The tumor was removed by minimally invasive parathyroidectomy, and histologically was found to be a benign adenoma.

PHILADELPHIA — The increased risk of hip fracture in women with lower bone mineral density mainly reflects an increased risk of nonsevere fracture rather than severe fracture, Jane A. Cauley, Dr.P.H., reported at the annual meeting of the American Society for Bone and Mineral Research.

Dr. Cauley, a professor of epidemiology at the University of Pittsburgh, looked for differences in risk factors for severe and nonsevere hip fractures using data from the longitudinal Study of Osteoporotic Fractures, involving 9,704 women aged 65 years and older.

The women were contacted every 4 months by postcard to determine if a hip fracture had occurred. The average follow-up period was 10.5 years.

Preoperative hip radiographs were obtained for 462 women—249 with femoral neck fractures and 213 with intertrochanteric fractures.

The fractures were rated by a single radiologist using the Garden and Kyle systems.

Most hip fractures were classified as severe. Of the femoral neck fractures, 70% were displaced. Of the intertrochanteric fractures, 72% were unstable.

For femoral neck hip fracture, women who went on to have undisplaced fractures had a femoral neck BMD about 7% lower than did women who had a displaced fracture. Among women in the lowest tertile for femoral neck BMD, 58% had displaced fractures, compared with 83% of women in the highest tertile for BMD.

Although lower femoral neck BMD was associated with a greater risk of both types of fracture, a one-standard-deviation decrease in BMD was associated with a more than threefold increased risk of having an undisplaced fracture. There was only an 86% increase in having a displaced fracture.

For intertrochanteric hip fracture, women who went on to have stable fractures had an intertrochanteric BMD about 7% lower than did women who had an unstable fracture. Among women in the lowest tertile for intertrochanteric BMD, 62% had unstable intertrochanteric fractures compared with about 80% of women with higher BMD, said Dr. Cauley.

Again, while low intertrochanteric BMD was associated with an increased risk of both types of intertrochanteric fractures, women with lower BMD had a threefold increase in the risk of having a stable intertrochanteric fracture, compared with an almost twofold increased risk of having an unstable fracture.

One standard deviation decrease in walking speed was a risk factor for femoral neck displaced and undisplaced fractures. A greater height at the age of 25 and steroid and alcohol use were associated with an increased risk for a femoral neck displaced factor.

Dr. Cauley disclosed that she has received research grants from Pfizer Inc., Novartis Pharmaceuticals Corp., Merck & Co, and Eli Lilly & Co. She also has received consulting fees from Novartis.

PHILADELPHIA — The increased risk of hip fracture in women with lower bone mineral density mainly reflects an increased risk of nonsevere fracture rather than severe fracture, Jane A. Cauley, Dr.P.H., reported at the annual meeting of the American Society for Bone and Mineral Research.

Dr. Cauley, a professor of epidemiology at the University of Pittsburgh, looked for differences in risk factors for severe and nonsevere hip fractures using data from the longitudinal Study of Osteoporotic Fractures, involving 9,704 women aged 65 years and older.

The women were contacted every 4 months by postcard to determine if a hip fracture had occurred. The average follow-up period was 10.5 years.

Preoperative hip radiographs were obtained for 462 women—249 with femoral neck fractures and 213 with intertrochanteric fractures.

The fractures were rated by a single radiologist using the Garden and Kyle systems.

Most hip fractures were classified as severe. Of the femoral neck fractures, 70% were displaced. Of the intertrochanteric fractures, 72% were unstable.

For femoral neck hip fracture, women who went on to have undisplaced fractures had a femoral neck BMD about 7% lower than did women who had a displaced fracture. Among women in the lowest tertile for femoral neck BMD, 58% had displaced fractures, compared with 83% of women in the highest tertile for BMD.

Although lower femoral neck BMD was associated with a greater risk of both types of fracture, a one-standard-deviation decrease in BMD was associated with a more than threefold increased risk of having an undisplaced fracture. There was only an 86% increase in having a displaced fracture.

For intertrochanteric hip fracture, women who went on to have stable fractures had an intertrochanteric BMD about 7% lower than did women who had an unstable fracture. Among women in the lowest tertile for intertrochanteric BMD, 62% had unstable intertrochanteric fractures compared with about 80% of women with higher BMD, said Dr. Cauley.

Again, while low intertrochanteric BMD was associated with an increased risk of both types of intertrochanteric fractures, women with lower BMD had a threefold increase in the risk of having a stable intertrochanteric fracture, compared with an almost twofold increased risk of having an unstable fracture.

One standard deviation decrease in walking speed was a risk factor for femoral neck displaced and undisplaced fractures. A greater height at the age of 25 and steroid and alcohol use were associated with an increased risk for a femoral neck displaced factor.

Dr. Cauley disclosed that she has received research grants from Pfizer Inc., Novartis Pharmaceuticals Corp., Merck & Co, and Eli Lilly & Co. She also has received consulting fees from Novartis.

PHILADELPHIA — The increased risk of hip fracture in women with lower bone mineral density mainly reflects an increased risk of nonsevere fracture rather than severe fracture, Jane A. Cauley, Dr.P.H., reported at the annual meeting of the American Society for Bone and Mineral Research.

Dr. Cauley, a professor of epidemiology at the University of Pittsburgh, looked for differences in risk factors for severe and nonsevere hip fractures using data from the longitudinal Study of Osteoporotic Fractures, involving 9,704 women aged 65 years and older.

The women were contacted every 4 months by postcard to determine if a hip fracture had occurred. The average follow-up period was 10.5 years.

Preoperative hip radiographs were obtained for 462 women—249 with femoral neck fractures and 213 with intertrochanteric fractures.

The fractures were rated by a single radiologist using the Garden and Kyle systems.

Most hip fractures were classified as severe. Of the femoral neck fractures, 70% were displaced. Of the intertrochanteric fractures, 72% were unstable.

For femoral neck hip fracture, women who went on to have undisplaced fractures had a femoral neck BMD about 7% lower than did women who had a displaced fracture. Among women in the lowest tertile for femoral neck BMD, 58% had displaced fractures, compared with 83% of women in the highest tertile for BMD.

Although lower femoral neck BMD was associated with a greater risk of both types of fracture, a one-standard-deviation decrease in BMD was associated with a more than threefold increased risk of having an undisplaced fracture. There was only an 86% increase in having a displaced fracture.

For intertrochanteric hip fracture, women who went on to have stable fractures had an intertrochanteric BMD about 7% lower than did women who had an unstable fracture. Among women in the lowest tertile for intertrochanteric BMD, 62% had unstable intertrochanteric fractures compared with about 80% of women with higher BMD, said Dr. Cauley.

Again, while low intertrochanteric BMD was associated with an increased risk of both types of intertrochanteric fractures, women with lower BMD had a threefold increase in the risk of having a stable intertrochanteric fracture, compared with an almost twofold increased risk of having an unstable fracture.

One standard deviation decrease in walking speed was a risk factor for femoral neck displaced and undisplaced fractures. A greater height at the age of 25 and steroid and alcohol use were associated with an increased risk for a femoral neck displaced factor.

Dr. Cauley disclosed that she has received research grants from Pfizer Inc., Novartis Pharmaceuticals Corp., Merck & Co, and Eli Lilly & Co. She also has received consulting fees from Novartis.

Daily supplementation with calcium and vitamin D boosted bone mineral density by a small but statistically significant amount in children with juvenile rheumatoid arthritis who were not being treated with corticosteroids, according to findings from a randomized, double-blind, placebo-controlled trial.

“Since peak bone mass is achieved no later than the end of the second decade of life, efforts to increase bone mineralization in children with JRA must be started at an early age,” said Dr. Daniel J. Lovell of the Cincinnati Children's Hospital Medical Center and his associates.

The investigators were cautious in their interpretation of the findings, however, concluding that the increase in bone mineral density (BMD) was not enough to provide “strong support” for the use of routine calcium supplementation in children with JRA who are not taking corticosteroids. The 198 children in the study had not received corticosteroids for at least 3 months prior to the 24-month study, and many had normal or nearly normal baseline BMD.

The children, aged 6-18 years (mean age of 12 years), had had JRA for a mean of 6 years. They were randomized to receive two daily oral tablets—either an oral supplement of 1,000 mg calcium (taken as 2,500 mg calcium carbonate) and a tablet containing 400 IU of vitamin D, or a matched placebo tablet and 400 IU of vitamin D, for 24 months.

They underwent dual x-ray absorptiometry at baseline and then every 6 months, and their adherence to the treatment regimen was regularly assessed. They were permitted to continue taking nonsteroidal anti-inflammatory drugs and antirheumatic medications. Patients in both treatment groups had similar levels of physical activity and dietary intake of calcium at baseline and throughout the study.

At baseline, the mean total body BMD was 0.89 gm/cm2 among patients randomized to receive calcium, and 0.87 gm/cm2 among those randomized to receive placebo. At 24 months, the total body BMD had increased to 0.95 gm/cm2 in the calcium group (a 6.7% increase) and 0.92 gm/cm2 (a 5.8% increase) in the placebo group.

Similarly, patients treated with calcium had a higher lumbar spine BMD—and a higher percentage change in lumbar spine BMD—than did control patients. But, “as expected, all patients demonstrated increases in (total body BMD) and lumbar spine BMD,” Dr. Lovell and his associates said (Arthritis Rheum. 2006;54:2235-42).

When the investigators adjusted for baseline differences in BMD and relevant “outcome effect modifiers,” they found significantly higher total body and mean lumbar spine BMD in patients who received calcium.

The increased rate of bone mineralization in the calcium group was seen during the first 18 months only, however. For the last 6 months of the study, BMD increased at a similar rate in both groups, “suggesting that a threshold for the biologic effect of Ca supplementation had been reached,” the investigators said.

And although statistically significant, the increases in BMD were surprisingly small, they said. Based on an earlier small, open study that showed increased bone mineralization with calcium supplementation, the investigators had projected a 10% greater increase in total body BMD in calcium-treated patients.

The “modest response … may be a reflection of the pathogenic mechanisms of JRA-associated osteopenia,” they wrote. “The potency of [inflammatory cytokines] to mediate BMD, and their systemic overproduction in autoimmune diseases such as JRA may be difficult to overcome with oral calcium treatment alone.”

Adherence to the supplementation regimen was “very good overall” in the study—much higher than in other studies—which means that “the effect of calcium supplementation, when used as part of routine clinical care … may therefore be less than the effect seen [here],” they said.

The study did not address the role of calcium supplementation in patients with JRA who require treatment with corticosteroids or who already have significantly decreased BMD, they noted.

Daily supplementation with calcium and vitamin D boosted bone mineral density by a small but statistically significant amount in children with juvenile rheumatoid arthritis who were not being treated with corticosteroids, according to findings from a randomized, double-blind, placebo-controlled trial.

“Since peak bone mass is achieved no later than the end of the second decade of life, efforts to increase bone mineralization in children with JRA must be started at an early age,” said Dr. Daniel J. Lovell of the Cincinnati Children's Hospital Medical Center and his associates.

The investigators were cautious in their interpretation of the findings, however, concluding that the increase in bone mineral density (BMD) was not enough to provide “strong support” for the use of routine calcium supplementation in children with JRA who are not taking corticosteroids. The 198 children in the study had not received corticosteroids for at least 3 months prior to the 24-month study, and many had normal or nearly normal baseline BMD.

The children, aged 6-18 years (mean age of 12 years), had had JRA for a mean of 6 years. They were randomized to receive two daily oral tablets—either an oral supplement of 1,000 mg calcium (taken as 2,500 mg calcium carbonate) and a tablet containing 400 IU of vitamin D, or a matched placebo tablet and 400 IU of vitamin D, for 24 months.

They underwent dual x-ray absorptiometry at baseline and then every 6 months, and their adherence to the treatment regimen was regularly assessed. They were permitted to continue taking nonsteroidal anti-inflammatory drugs and antirheumatic medications. Patients in both treatment groups had similar levels of physical activity and dietary intake of calcium at baseline and throughout the study.

At baseline, the mean total body BMD was 0.89 gm/cm2 among patients randomized to receive calcium, and 0.87 gm/cm2 among those randomized to receive placebo. At 24 months, the total body BMD had increased to 0.95 gm/cm2 in the calcium group (a 6.7% increase) and 0.92 gm/cm2 (a 5.8% increase) in the placebo group.

Similarly, patients treated with calcium had a higher lumbar spine BMD—and a higher percentage change in lumbar spine BMD—than did control patients. But, “as expected, all patients demonstrated increases in (total body BMD) and lumbar spine BMD,” Dr. Lovell and his associates said (Arthritis Rheum. 2006;54:2235-42).

When the investigators adjusted for baseline differences in BMD and relevant “outcome effect modifiers,” they found significantly higher total body and mean lumbar spine BMD in patients who received calcium.

The increased rate of bone mineralization in the calcium group was seen during the first 18 months only, however. For the last 6 months of the study, BMD increased at a similar rate in both groups, “suggesting that a threshold for the biologic effect of Ca supplementation had been reached,” the investigators said.

And although statistically significant, the increases in BMD were surprisingly small, they said. Based on an earlier small, open study that showed increased bone mineralization with calcium supplementation, the investigators had projected a 10% greater increase in total body BMD in calcium-treated patients.

The “modest response … may be a reflection of the pathogenic mechanisms of JRA-associated osteopenia,” they wrote. “The potency of [inflammatory cytokines] to mediate BMD, and their systemic overproduction in autoimmune diseases such as JRA may be difficult to overcome with oral calcium treatment alone.”

Adherence to the supplementation regimen was “very good overall” in the study—much higher than in other studies—which means that “the effect of calcium supplementation, when used as part of routine clinical care … may therefore be less than the effect seen [here],” they said.

The study did not address the role of calcium supplementation in patients with JRA who require treatment with corticosteroids or who already have significantly decreased BMD, they noted.

Daily supplementation with calcium and vitamin D boosted bone mineral density by a small but statistically significant amount in children with juvenile rheumatoid arthritis who were not being treated with corticosteroids, according to findings from a randomized, double-blind, placebo-controlled trial.

“Since peak bone mass is achieved no later than the end of the second decade of life, efforts to increase bone mineralization in children with JRA must be started at an early age,” said Dr. Daniel J. Lovell of the Cincinnati Children's Hospital Medical Center and his associates.

The investigators were cautious in their interpretation of the findings, however, concluding that the increase in bone mineral density (BMD) was not enough to provide “strong support” for the use of routine calcium supplementation in children with JRA who are not taking corticosteroids. The 198 children in the study had not received corticosteroids for at least 3 months prior to the 24-month study, and many had normal or nearly normal baseline BMD.

The children, aged 6-18 years (mean age of 12 years), had had JRA for a mean of 6 years. They were randomized to receive two daily oral tablets—either an oral supplement of 1,000 mg calcium (taken as 2,500 mg calcium carbonate) and a tablet containing 400 IU of vitamin D, or a matched placebo tablet and 400 IU of vitamin D, for 24 months.

They underwent dual x-ray absorptiometry at baseline and then every 6 months, and their adherence to the treatment regimen was regularly assessed. They were permitted to continue taking nonsteroidal anti-inflammatory drugs and antirheumatic medications. Patients in both treatment groups had similar levels of physical activity and dietary intake of calcium at baseline and throughout the study.

At baseline, the mean total body BMD was 0.89 gm/cm2 among patients randomized to receive calcium, and 0.87 gm/cm2 among those randomized to receive placebo. At 24 months, the total body BMD had increased to 0.95 gm/cm2 in the calcium group (a 6.7% increase) and 0.92 gm/cm2 (a 5.8% increase) in the placebo group.

Similarly, patients treated with calcium had a higher lumbar spine BMD—and a higher percentage change in lumbar spine BMD—than did control patients. But, “as expected, all patients demonstrated increases in (total body BMD) and lumbar spine BMD,” Dr. Lovell and his associates said (Arthritis Rheum. 2006;54:2235-42).

When the investigators adjusted for baseline differences in BMD and relevant “outcome effect modifiers,” they found significantly higher total body and mean lumbar spine BMD in patients who received calcium.

The increased rate of bone mineralization in the calcium group was seen during the first 18 months only, however. For the last 6 months of the study, BMD increased at a similar rate in both groups, “suggesting that a threshold for the biologic effect of Ca supplementation had been reached,” the investigators said.

And although statistically significant, the increases in BMD were surprisingly small, they said. Based on an earlier small, open study that showed increased bone mineralization with calcium supplementation, the investigators had projected a 10% greater increase in total body BMD in calcium-treated patients.

The “modest response … may be a reflection of the pathogenic mechanisms of JRA-associated osteopenia,” they wrote. “The potency of [inflammatory cytokines] to mediate BMD, and their systemic overproduction in autoimmune diseases such as JRA may be difficult to overcome with oral calcium treatment alone.”

Adherence to the supplementation regimen was “very good overall” in the study—much higher than in other studies—which means that “the effect of calcium supplementation, when used as part of routine clinical care … may therefore be less than the effect seen [here],” they said.

The study did not address the role of calcium supplementation in patients with JRA who require treatment with corticosteroids or who already have significantly decreased BMD, they noted.

TORONTO — Women with postmenopausal osteoporosis who had previously discontinued oral bisphosphonate therapy because of gastrointestinal intolerance preferred an intravenous, every-3-month regimen of ibandronate over a monthly oral regimen, Dr. E. Michael Lewiecki reported at a world congress on osteoporosis.

Adherence was addressed in a 12-month, open-label multicenter study that included 542 patients with osteoporosis or osteopenia who had stopped daily or weekly treatment with oral alendronate or risedronate because of perceived or actual symptoms such as heartburn and acid reflux. All received supplemental vitamin D (400 IU/day) and elemental calcium (1,000 mg/day).

Patients were given the choice of oral ibandronate, 150 mg once monthly, or 3 mg intravenously every 3 months. The intravenous injection takes 15-30 seconds to complete. A total of 396 (73%) of patients chose the intravenous regimen, while 146 (27%) chose the oral route.

They were permitted to switch treatment groups once during the study if they experienced adverse effects, he noted.

Severity and frequency of gastrointestinal symptoms and other side effects were evaluated with surveys administered at baseline and at months 1, 4, 7, and 10.

Available data indicate that adherence to both regimens at 6 months was high, at 94.5%. Actual duration of study medication intake divided by maximum duration of intake and a threshold of 75% or more was used to define adherence, according to Dr. Lewiecki of New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

Among patients receiving the oral drug, adherence was 87.7%, while adherence was 94.9% among those receiving the intravenous formulation, Dr. Lewiecki wrote in a poster session; the meeting was sponsored by the International Osteoporosis Foundation.

Among patients who chose the intravenous route of administration, 147 (37.1%) had a history of fracture as an adult, compared with 36 (24.7%) of those who chose the oral drug.

Thus far, 26 patients have switched their route of administration. Eleven switched from oral to intravenous ibandronate because of gastrointestinal intolerance, while 15 switched from intravenous to oral for reasons including influenzalike symptoms and injection-site reactions.

By month 4, 28.1% and 36.6% of patients on the oral and intravenous drugs, respectively, reported improvements in gastrointestinal tolerance compared with baseline.

“Based on these findings, it appears that patients who had previously discontinued weekly or daily oral bisphosphonates because of gastrointestinal intolerance prefer intravenous dosing, and that patients with a previous fracture are even more likely to do so than patients without a previous fracture,” Dr. Lewiecki concluded.

TORONTO — Women with postmenopausal osteoporosis who had previously discontinued oral bisphosphonate therapy because of gastrointestinal intolerance preferred an intravenous, every-3-month regimen of ibandronate over a monthly oral regimen, Dr. E. Michael Lewiecki reported at a world congress on osteoporosis.

Adherence was addressed in a 12-month, open-label multicenter study that included 542 patients with osteoporosis or osteopenia who had stopped daily or weekly treatment with oral alendronate or risedronate because of perceived or actual symptoms such as heartburn and acid reflux. All received supplemental vitamin D (400 IU/day) and elemental calcium (1,000 mg/day).

Patients were given the choice of oral ibandronate, 150 mg once monthly, or 3 mg intravenously every 3 months. The intravenous injection takes 15-30 seconds to complete. A total of 396 (73%) of patients chose the intravenous regimen, while 146 (27%) chose the oral route.

They were permitted to switch treatment groups once during the study if they experienced adverse effects, he noted.

Severity and frequency of gastrointestinal symptoms and other side effects were evaluated with surveys administered at baseline and at months 1, 4, 7, and 10.

Available data indicate that adherence to both regimens at 6 months was high, at 94.5%. Actual duration of study medication intake divided by maximum duration of intake and a threshold of 75% or more was used to define adherence, according to Dr. Lewiecki of New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

Among patients receiving the oral drug, adherence was 87.7%, while adherence was 94.9% among those receiving the intravenous formulation, Dr. Lewiecki wrote in a poster session; the meeting was sponsored by the International Osteoporosis Foundation.

Among patients who chose the intravenous route of administration, 147 (37.1%) had a history of fracture as an adult, compared with 36 (24.7%) of those who chose the oral drug.

Thus far, 26 patients have switched their route of administration. Eleven switched from oral to intravenous ibandronate because of gastrointestinal intolerance, while 15 switched from intravenous to oral for reasons including influenzalike symptoms and injection-site reactions.

By month 4, 28.1% and 36.6% of patients on the oral and intravenous drugs, respectively, reported improvements in gastrointestinal tolerance compared with baseline.

“Based on these findings, it appears that patients who had previously discontinued weekly or daily oral bisphosphonates because of gastrointestinal intolerance prefer intravenous dosing, and that patients with a previous fracture are even more likely to do so than patients without a previous fracture,” Dr. Lewiecki concluded.

TORONTO — Women with postmenopausal osteoporosis who had previously discontinued oral bisphosphonate therapy because of gastrointestinal intolerance preferred an intravenous, every-3-month regimen of ibandronate over a monthly oral regimen, Dr. E. Michael Lewiecki reported at a world congress on osteoporosis.

Adherence was addressed in a 12-month, open-label multicenter study that included 542 patients with osteoporosis or osteopenia who had stopped daily or weekly treatment with oral alendronate or risedronate because of perceived or actual symptoms such as heartburn and acid reflux. All received supplemental vitamin D (400 IU/day) and elemental calcium (1,000 mg/day).

Patients were given the choice of oral ibandronate, 150 mg once monthly, or 3 mg intravenously every 3 months. The intravenous injection takes 15-30 seconds to complete. A total of 396 (73%) of patients chose the intravenous regimen, while 146 (27%) chose the oral route.

They were permitted to switch treatment groups once during the study if they experienced adverse effects, he noted.

Severity and frequency of gastrointestinal symptoms and other side effects were evaluated with surveys administered at baseline and at months 1, 4, 7, and 10.

Available data indicate that adherence to both regimens at 6 months was high, at 94.5%. Actual duration of study medication intake divided by maximum duration of intake and a threshold of 75% or more was used to define adherence, according to Dr. Lewiecki of New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

Among patients receiving the oral drug, adherence was 87.7%, while adherence was 94.9% among those receiving the intravenous formulation, Dr. Lewiecki wrote in a poster session; the meeting was sponsored by the International Osteoporosis Foundation.

Among patients who chose the intravenous route of administration, 147 (37.1%) had a history of fracture as an adult, compared with 36 (24.7%) of those who chose the oral drug.

Thus far, 26 patients have switched their route of administration. Eleven switched from oral to intravenous ibandronate because of gastrointestinal intolerance, while 15 switched from intravenous to oral for reasons including influenzalike symptoms and injection-site reactions.

By month 4, 28.1% and 36.6% of patients on the oral and intravenous drugs, respectively, reported improvements in gastrointestinal tolerance compared with baseline.

“Based on these findings, it appears that patients who had previously discontinued weekly or daily oral bisphosphonates because of gastrointestinal intolerance prefer intravenous dosing, and that patients with a previous fracture are even more likely to do so than patients without a previous fracture,” Dr. Lewiecki concluded.

TORONTO — Increased urinary excretion of a biomarker of bone resorption signals the presence and extent of bone metastases in breast cancer patients, Dr. Diana J. Leeming said at a world congress on osteoporosis.

Technetium-99 (99Tc) bone scintigraphy remains the standard method of detecting skeletal metastases in cancer patients. However, this approach is not suitable for close, frequent monitoring because of significant radiation exposure, Dr. Leeming said.

She and her colleagues previously investigated a number of biomarkers to determine if their presence correlated with the number and extent of bone metastases (Cancer Epidemiol. Biomarkers Prev. 2006;15:32-8). Among these were the resorption markers ααCTX and ββCTX; bone-specific alkaline phosphatase (a bone-formation marker); and markers of osteoclastogenesis, such as osteoprotegerin.

They determined that ααCTX—which is the nonisomerized form of the C-telopeptide of collagen type I—correlated most closely with the Soloway score quantification of bone metastases. “We have shown that, for a Soloway score of 1, indicating fewer than six metastases, ααCTX is approximately 200% increased. With a Soloway score of 3, when more than 20 metastases are present, ααCTX is elevated more than 600%,” said Dr. Leeming of Nordic Bioscience A/S, Herlev, Denmark.

The current study included 90 patients with newly diagnosed breast cancer; 45 had bone metastases verified by 99Tc scintigraphy or other imaging studies. The concentration of CTX fragments was measured in morning urine using ELISA (amyloid-β peptide enzyme-linked immunosorbent assay). There were no differences in age or body mass index between patients with and without metastases.

Mean ααCTX in patients without metastases was 0.39 mcg/mmol, a level that correlates with that seen in normal, age-matched healthy controls. For the group with metastases, however, the level was significantly higher, at 1.23 mcg/mmol, according to Dr. Leeming. Analysis also revealed that the presence of one, two, and three metastases was associated with increases of 38%, 57%, and 81% in ααCTX, respectively.

“This suggests that ααCTX may be sufficiently sensitive to detect the first bone metastasis,” she said. Histologic analysis of bone biopsy specimens using cytokeratin and tartrate-resistant acid phosphatase (TRACP) staining confirmed the localized presence of ααCTX and an increased number of osteoclasts near the tumor. The production of CTX is part of a vicious cycle, in which breast cancer cells induce RANK-L (receptor activator of nuclear factor kappa β ligand) in osteoblasts by a number of cytokines, Dr. Leeming explained. This in turn increases the number and survival of osteoclasts, and when osteoclasts resorb bone they release proteins and growth factors from the matrix, further activating cancer cells.

“This high bone remodeling could explain the release of increased levels of ααCTX,” said Dr. Leeming at the meeting, which was sponsored by the International Osteoporosis Foundation.

TORONTO — Increased urinary excretion of a biomarker of bone resorption signals the presence and extent of bone metastases in breast cancer patients, Dr. Diana J. Leeming said at a world congress on osteoporosis.

Technetium-99 (99Tc) bone scintigraphy remains the standard method of detecting skeletal metastases in cancer patients. However, this approach is not suitable for close, frequent monitoring because of significant radiation exposure, Dr. Leeming said.

She and her colleagues previously investigated a number of biomarkers to determine if their presence correlated with the number and extent of bone metastases (Cancer Epidemiol. Biomarkers Prev. 2006;15:32-8). Among these were the resorption markers ααCTX and ββCTX; bone-specific alkaline phosphatase (a bone-formation marker); and markers of osteoclastogenesis, such as osteoprotegerin.

They determined that ααCTX—which is the nonisomerized form of the C-telopeptide of collagen type I—correlated most closely with the Soloway score quantification of bone metastases. “We have shown that, for a Soloway score of 1, indicating fewer than six metastases, ααCTX is approximately 200% increased. With a Soloway score of 3, when more than 20 metastases are present, ααCTX is elevated more than 600%,” said Dr. Leeming of Nordic Bioscience A/S, Herlev, Denmark.

The current study included 90 patients with newly diagnosed breast cancer; 45 had bone metastases verified by 99Tc scintigraphy or other imaging studies. The concentration of CTX fragments was measured in morning urine using ELISA (amyloid-β peptide enzyme-linked immunosorbent assay). There were no differences in age or body mass index between patients with and without metastases.

Mean ααCTX in patients without metastases was 0.39 mcg/mmol, a level that correlates with that seen in normal, age-matched healthy controls. For the group with metastases, however, the level was significantly higher, at 1.23 mcg/mmol, according to Dr. Leeming. Analysis also revealed that the presence of one, two, and three metastases was associated with increases of 38%, 57%, and 81% in ααCTX, respectively.

“This suggests that ααCTX may be sufficiently sensitive to detect the first bone metastasis,” she said. Histologic analysis of bone biopsy specimens using cytokeratin and tartrate-resistant acid phosphatase (TRACP) staining confirmed the localized presence of ααCTX and an increased number of osteoclasts near the tumor. The production of CTX is part of a vicious cycle, in which breast cancer cells induce RANK-L (receptor activator of nuclear factor kappa β ligand) in osteoblasts by a number of cytokines, Dr. Leeming explained. This in turn increases the number and survival of osteoclasts, and when osteoclasts resorb bone they release proteins and growth factors from the matrix, further activating cancer cells.

“This high bone remodeling could explain the release of increased levels of ααCTX,” said Dr. Leeming at the meeting, which was sponsored by the International Osteoporosis Foundation.

TORONTO — Increased urinary excretion of a biomarker of bone resorption signals the presence and extent of bone metastases in breast cancer patients, Dr. Diana J. Leeming said at a world congress on osteoporosis.

Technetium-99 (99Tc) bone scintigraphy remains the standard method of detecting skeletal metastases in cancer patients. However, this approach is not suitable for close, frequent monitoring because of significant radiation exposure, Dr. Leeming said.

She and her colleagues previously investigated a number of biomarkers to determine if their presence correlated with the number and extent of bone metastases (Cancer Epidemiol. Biomarkers Prev. 2006;15:32-8). Among these were the resorption markers ααCTX and ββCTX; bone-specific alkaline phosphatase (a bone-formation marker); and markers of osteoclastogenesis, such as osteoprotegerin.

They determined that ααCTX—which is the nonisomerized form of the C-telopeptide of collagen type I—correlated most closely with the Soloway score quantification of bone metastases. “We have shown that, for a Soloway score of 1, indicating fewer than six metastases, ααCTX is approximately 200% increased. With a Soloway score of 3, when more than 20 metastases are present, ααCTX is elevated more than 600%,” said Dr. Leeming of Nordic Bioscience A/S, Herlev, Denmark.

The current study included 90 patients with newly diagnosed breast cancer; 45 had bone metastases verified by 99Tc scintigraphy or other imaging studies. The concentration of CTX fragments was measured in morning urine using ELISA (amyloid-β peptide enzyme-linked immunosorbent assay). There were no differences in age or body mass index between patients with and without metastases.

Mean ααCTX in patients without metastases was 0.39 mcg/mmol, a level that correlates with that seen in normal, age-matched healthy controls. For the group with metastases, however, the level was significantly higher, at 1.23 mcg/mmol, according to Dr. Leeming. Analysis also revealed that the presence of one, two, and three metastases was associated with increases of 38%, 57%, and 81% in ααCTX, respectively.

“This suggests that ααCTX may be sufficiently sensitive to detect the first bone metastasis,” she said. Histologic analysis of bone biopsy specimens using cytokeratin and tartrate-resistant acid phosphatase (TRACP) staining confirmed the localized presence of ααCTX and an increased number of osteoclasts near the tumor. The production of CTX is part of a vicious cycle, in which breast cancer cells induce RANK-L (receptor activator of nuclear factor kappa β ligand) in osteoblasts by a number of cytokines, Dr. Leeming explained. This in turn increases the number and survival of osteoclasts, and when osteoclasts resorb bone they release proteins and growth factors from the matrix, further activating cancer cells.

“This high bone remodeling could explain the release of increased levels of ααCTX,” said Dr. Leeming at the meeting, which was sponsored by the International Osteoporosis Foundation.

ATLANTA — Anastrozole decreased bone mineral density by an average of 6.1% in the lumbar spine and 7.2% in the hip over the 5 years that postmenopausal breast cancer patients were enrolled in a study presented by Dr. Robert E. Coleman at the annual meeting of the American Society of Clinical Oncology.

Osteoporosis risk appeared limited to women who were osteopenic before starting treatment with anastrozole (Arimidex), an aromatase inhibitor. Less clear was the likelihood of progression to osteopenia in women who started out with normal bone mineral density (BMD).

All the women who became osteoporotic—four treated with anastrozole and one who was treated with tamoxifen—were osteopenic before they began adjuvant hormonal therapy in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.

“No patient with normal bone at baseline became osteoporotic after 5 years of treatment,” Dr. Coleman, a professor of medical oncology at Weston Park Hospital in Sheffield, England, said in his report on a subset of 167 women who were tracked for bone loss.

Among 81 patients tracked in the anastrozole arm of the trial, just 13 had normal BMD after 5 years. All but one had been classified as having normal bone before the study started.

The group of patients identified as osteopenic after 5 years was more mixed, comprising 14 women who entered the study with normal BMD and 21 who were osteopenic at the outset. Dr. Coleman calculated that 17% of patients on anastrozole progressed from normal BMD to osteopenia during the study.

About a third of the anastrozole patients had not reached 5 years of follow-up, however. They were categorized as “not recorded” in Dr. Coleman's analysis.

In a discussion of the trial, Dr. Julie Gralow, of the University of Washington, Seattle, excluded the 27 unrecorded patients, 6 of whom started out with normal BMD, from a recalculation of the data. When she looked only at patients for whom 5-year data were available, she found that 53% of the women who started with normal BMD became osteopenic on anastrozole.

That anastrozole caused bone loss was no surprise to Dr. Coleman and his coinvestigators. The 9,366-patient ATAC trial reported that the aromatase inhibitor was more effective than tamoxifen at preventing breast cancer recurrences and had fewer side effects overall. Fractures were an exception, however, occurring in 11% of women on anastrozole but in only 7.7% of those on tamoxifen (Lancet 2005;365:60-2).

“Anastrozole suppresses postmenopausal estradiol levels by about 97%, so one would anticipate it would have an effect on bone health,” Dr. Coleman said, noting that the bone-loss study was planned when the trial was designed.

Tamoxifen increases estradiol levels and was associated with significantly less bone loss for 86 women in the other arm of the study. Their average BMD loss was just 2.8% in the lumbar spine and 0.7% in the hip.

Despite greater bone loss with anastrozole, he said its “superior efficacy and better overall tolerability, compared with tamoxifen” would continue to give anastrozole the advantage in a risk-benefit analysis.

AstraZeneca provided research funds and honoraria.

ATLANTA — Anastrozole decreased bone mineral density by an average of 6.1% in the lumbar spine and 7.2% in the hip over the 5 years that postmenopausal breast cancer patients were enrolled in a study presented by Dr. Robert E. Coleman at the annual meeting of the American Society of Clinical Oncology.

Osteoporosis risk appeared limited to women who were osteopenic before starting treatment with anastrozole (Arimidex), an aromatase inhibitor. Less clear was the likelihood of progression to osteopenia in women who started out with normal bone mineral density (BMD).

All the women who became osteoporotic—four treated with anastrozole and one who was treated with tamoxifen—were osteopenic before they began adjuvant hormonal therapy in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.

“No patient with normal bone at baseline became osteoporotic after 5 years of treatment,” Dr. Coleman, a professor of medical oncology at Weston Park Hospital in Sheffield, England, said in his report on a subset of 167 women who were tracked for bone loss.

Among 81 patients tracked in the anastrozole arm of the trial, just 13 had normal BMD after 5 years. All but one had been classified as having normal bone before the study started.

The group of patients identified as osteopenic after 5 years was more mixed, comprising 14 women who entered the study with normal BMD and 21 who were osteopenic at the outset. Dr. Coleman calculated that 17% of patients on anastrozole progressed from normal BMD to osteopenia during the study.

About a third of the anastrozole patients had not reached 5 years of follow-up, however. They were categorized as “not recorded” in Dr. Coleman's analysis.

In a discussion of the trial, Dr. Julie Gralow, of the University of Washington, Seattle, excluded the 27 unrecorded patients, 6 of whom started out with normal BMD, from a recalculation of the data. When she looked only at patients for whom 5-year data were available, she found that 53% of the women who started with normal BMD became osteopenic on anastrozole.

That anastrozole caused bone loss was no surprise to Dr. Coleman and his coinvestigators. The 9,366-patient ATAC trial reported that the aromatase inhibitor was more effective than tamoxifen at preventing breast cancer recurrences and had fewer side effects overall. Fractures were an exception, however, occurring in 11% of women on anastrozole but in only 7.7% of those on tamoxifen (Lancet 2005;365:60-2).

“Anastrozole suppresses postmenopausal estradiol levels by about 97%, so one would anticipate it would have an effect on bone health,” Dr. Coleman said, noting that the bone-loss study was planned when the trial was designed.

Tamoxifen increases estradiol levels and was associated with significantly less bone loss for 86 women in the other arm of the study. Their average BMD loss was just 2.8% in the lumbar spine and 0.7% in the hip.

Despite greater bone loss with anastrozole, he said its “superior efficacy and better overall tolerability, compared with tamoxifen” would continue to give anastrozole the advantage in a risk-benefit analysis.

AstraZeneca provided research funds and honoraria.

ATLANTA — Anastrozole decreased bone mineral density by an average of 6.1% in the lumbar spine and 7.2% in the hip over the 5 years that postmenopausal breast cancer patients were enrolled in a study presented by Dr. Robert E. Coleman at the annual meeting of the American Society of Clinical Oncology.

Osteoporosis risk appeared limited to women who were osteopenic before starting treatment with anastrozole (Arimidex), an aromatase inhibitor. Less clear was the likelihood of progression to osteopenia in women who started out with normal bone mineral density (BMD).

All the women who became osteoporotic—four treated with anastrozole and one who was treated with tamoxifen—were osteopenic before they began adjuvant hormonal therapy in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.

“No patient with normal bone at baseline became osteoporotic after 5 years of treatment,” Dr. Coleman, a professor of medical oncology at Weston Park Hospital in Sheffield, England, said in his report on a subset of 167 women who were tracked for bone loss.

Among 81 patients tracked in the anastrozole arm of the trial, just 13 had normal BMD after 5 years. All but one had been classified as having normal bone before the study started.

The group of patients identified as osteopenic after 5 years was more mixed, comprising 14 women who entered the study with normal BMD and 21 who were osteopenic at the outset. Dr. Coleman calculated that 17% of patients on anastrozole progressed from normal BMD to osteopenia during the study.

About a third of the anastrozole patients had not reached 5 years of follow-up, however. They were categorized as “not recorded” in Dr. Coleman's analysis.

In a discussion of the trial, Dr. Julie Gralow, of the University of Washington, Seattle, excluded the 27 unrecorded patients, 6 of whom started out with normal BMD, from a recalculation of the data. When she looked only at patients for whom 5-year data were available, she found that 53% of the women who started with normal BMD became osteopenic on anastrozole.

That anastrozole caused bone loss was no surprise to Dr. Coleman and his coinvestigators. The 9,366-patient ATAC trial reported that the aromatase inhibitor was more effective than tamoxifen at preventing breast cancer recurrences and had fewer side effects overall. Fractures were an exception, however, occurring in 11% of women on anastrozole but in only 7.7% of those on tamoxifen (Lancet 2005;365:60-2).

“Anastrozole suppresses postmenopausal estradiol levels by about 97%, so one would anticipate it would have an effect on bone health,” Dr. Coleman said, noting that the bone-loss study was planned when the trial was designed.

Tamoxifen increases estradiol levels and was associated with significantly less bone loss for 86 women in the other arm of the study. Their average BMD loss was just 2.8% in the lumbar spine and 0.7% in the hip.

Despite greater bone loss with anastrozole, he said its “superior efficacy and better overall tolerability, compared with tamoxifen” would continue to give anastrozole the advantage in a risk-benefit analysis.

AstraZeneca provided research funds and honoraria.

TORONTO — The extension phases of two large trials evaluating strontium ranelate for the prevention of osteoporotic fractures have shown that the efficacy previously seen at 3 years holds up during years 4 and 5, Dr. Jean-Yves Reginster said at a world congress on osteoporosis.

Efficacy of strontium ranelate was confirmed for both vertebral and nonvertebral fractures, Dr. Reginster said.

After 4 years of treatment, patients in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial randomized to receive strontium ranelate had a significant 33% reduction in risk of new vertebral fractures compared with on placebo, said Dr. Reginster of the University of Liège, Belgium. The trial included 1,649 women with postmenopausal osteoporosis whose mean age was 69 years and whose mean lumbar spine bone mineral density T score was −3.6. They were recruited from 72 centers in 11 European countries and Australia. All had had at least one vertebral fracture.

Study patients were randomized to receive 2 g of oral strontium ranelate daily or placebo, and initially were followed for 3 years, at which time treatment was associated with a 41% risk reduction for vertebral fractures (N. Engl. J. Med. 2004;350:459-68).

In the second trial, the Treatment of Peripheral Osteoporosis (TROPOS) study, treatment with 2 g/day strontium ranelate among 5,091 postmenopausal women with osteoporosis was associated with a 16% relative risk reduction for all nonvertebral fractures at 3 years and a 39% reduction for vertebral fractures (J. Clin. Endocrinol. Metab. 2005; 90:2816-22).

At 5 years, the relative risk reduction for nonvertebral fractures was 15%, and for vertebral fractures the risk reduction was 24%.

Patients in this study were older, averaging 76.7 years, Dr. Reginster said. Mean femoral neck T score was −3.1. With regard to safety, no new concerns arose. “Among all patients at the beginning of the trials there was a slight increase in the incidence of deep vein thrombosis, but this vanished over time and was no longer apparent during years 4 and 5,” he said at the meeting, sponsored by the International Osteoporosis Foundation.

After 4 years, patients taking strontium ranelate had a significant 33% reduction in risk. DR. REGINSTER

TORONTO — The extension phases of two large trials evaluating strontium ranelate for the prevention of osteoporotic fractures have shown that the efficacy previously seen at 3 years holds up during years 4 and 5, Dr. Jean-Yves Reginster said at a world congress on osteoporosis.

Efficacy of strontium ranelate was confirmed for both vertebral and nonvertebral fractures, Dr. Reginster said.

After 4 years of treatment, patients in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial randomized to receive strontium ranelate had a significant 33% reduction in risk of new vertebral fractures compared with on placebo, said Dr. Reginster of the University of Liège, Belgium. The trial included 1,649 women with postmenopausal osteoporosis whose mean age was 69 years and whose mean lumbar spine bone mineral density T score was −3.6. They were recruited from 72 centers in 11 European countries and Australia. All had had at least one vertebral fracture.

Study patients were randomized to receive 2 g of oral strontium ranelate daily or placebo, and initially were followed for 3 years, at which time treatment was associated with a 41% risk reduction for vertebral fractures (N. Engl. J. Med. 2004;350:459-68).

In the second trial, the Treatment of Peripheral Osteoporosis (TROPOS) study, treatment with 2 g/day strontium ranelate among 5,091 postmenopausal women with osteoporosis was associated with a 16% relative risk reduction for all nonvertebral fractures at 3 years and a 39% reduction for vertebral fractures (J. Clin. Endocrinol. Metab. 2005; 90:2816-22).

At 5 years, the relative risk reduction for nonvertebral fractures was 15%, and for vertebral fractures the risk reduction was 24%.

Patients in this study were older, averaging 76.7 years, Dr. Reginster said. Mean femoral neck T score was −3.1. With regard to safety, no new concerns arose. “Among all patients at the beginning of the trials there was a slight increase in the incidence of deep vein thrombosis, but this vanished over time and was no longer apparent during years 4 and 5,” he said at the meeting, sponsored by the International Osteoporosis Foundation.

After 4 years, patients taking strontium ranelate had a significant 33% reduction in risk. DR. REGINSTER

TORONTO — The extension phases of two large trials evaluating strontium ranelate for the prevention of osteoporotic fractures have shown that the efficacy previously seen at 3 years holds up during years 4 and 5, Dr. Jean-Yves Reginster said at a world congress on osteoporosis.

Efficacy of strontium ranelate was confirmed for both vertebral and nonvertebral fractures, Dr. Reginster said.

After 4 years of treatment, patients in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial randomized to receive strontium ranelate had a significant 33% reduction in risk of new vertebral fractures compared with on placebo, said Dr. Reginster of the University of Liège, Belgium. The trial included 1,649 women with postmenopausal osteoporosis whose mean age was 69 years and whose mean lumbar spine bone mineral density T score was −3.6. They were recruited from 72 centers in 11 European countries and Australia. All had had at least one vertebral fracture.

Study patients were randomized to receive 2 g of oral strontium ranelate daily or placebo, and initially were followed for 3 years, at which time treatment was associated with a 41% risk reduction for vertebral fractures (N. Engl. J. Med. 2004;350:459-68).

In the second trial, the Treatment of Peripheral Osteoporosis (TROPOS) study, treatment with 2 g/day strontium ranelate among 5,091 postmenopausal women with osteoporosis was associated with a 16% relative risk reduction for all nonvertebral fractures at 3 years and a 39% reduction for vertebral fractures (J. Clin. Endocrinol. Metab. 2005; 90:2816-22).

At 5 years, the relative risk reduction for nonvertebral fractures was 15%, and for vertebral fractures the risk reduction was 24%.

Patients in this study were older, averaging 76.7 years, Dr. Reginster said. Mean femoral neck T score was −3.1. With regard to safety, no new concerns arose. “Among all patients at the beginning of the trials there was a slight increase in the incidence of deep vein thrombosis, but this vanished over time and was no longer apparent during years 4 and 5,” he said at the meeting, sponsored by the International Osteoporosis Foundation.

After 4 years, patients taking strontium ranelate had a significant 33% reduction in risk. DR. REGINSTER

SAN FRANCISCO — “It's a pretty exciting time for drug development in osteoporosis,” Dr. Deborah Sellmeyer said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

While joking that her information was “sourced from Google and rumor and various investment brochures,” Dr. Sellmeyer, director of the Center for Osteoporosis at the university, listed some of the osteoporosis drugs in the pipeline.

A fracture trial for a full-length version of parathyroid hormone (PTH [1-84]) has been completed, and a new drug application (NDA) was submitted to the Food and Drug Administration in July 2005.

Meanwhile, inhaled-powder and oral forms of PTH are in phase I and phase II trials, and at least one PTH analogue is in phase III. “Everyone's looking for the magic combination that will be able to replicate the PTH skeletal effect and get rid of the hypercalcemic effect,” Dr. Sellmeyer said.

Oral calcitonin preparations are in phase I and phase II. And low-dose and ultralow-dose estrogen remain fertile areas of research. The hope is that these preparations will replicate the beneficial bone effects of estrogen while avoiding its harmful vascular effects. While two low-dose patches and one low-dose pill have already been approved for the prevention of osteoporosis and for the treatment of vasomotor symptoms, no fracture data are yet available.

Zoledronic acid, a once-a-year intravenous bisphosphonate, is currently approved for hypercalcemia of malignancy and is now in a phase III trial to determine whether it prevents osteoporotic fractures. This agent is likely to benefit people who cannot tolerate oral bisphosphonates, people in assisted-living situations, and people who have difficulty remembering to take medication.

There are several new selective estrogen receptor modulators under development, with three—lasofoxifene, bazedoxifene, and arzoxifene—in phase III or beyond. An NDA for lasofoxifene was submitted to the FDA in 2004, but the manufacturer apparently received a nonapprovable letter in September 2005, putting the drug in limbo. An NDA for bazedoxifene was submitted in 2006 for the prevention of osteoporosis, and an NDA is planned for 2007 for a combination of bazedoxifene and estrogen for osteoporosis treatment and possible premenopausal use. Results from a phase III trial of arzoxifene are not expected until 2010.

Tibolone is a drug that “likes every steroid receptor it ever met,” in Dr. Sellmeyer's words. Its three metabolites separately have affinities for estrogen, progesterone, and androgen receptors. A recently completed 24-month prevention trial in 90 women showed no difference in vaginal spotting between tibolone and placebo. Interestingly, the women taking placebo experienced a 12% weight gain, while the women taking tibolone experienced no average weight gain. A multinational fracture study involving 4,000 women is expected to conclude sometime in 2006.

It's been known for decades that strontium improves bone mineral density (BMD), but it was never developed for osteoporosis prevention or treatment because it's a nonpatentable chemical element. Recently, however, a proprietary formulation of strontium—strontium ranelate—has shown some promise. A granular form has already been approved for use in Europe and the United Kingdom, and a once-a-day pill finished a phase I trial in September 2005. Strontium ranelate is likely to complicate interpretation of BMD testing, since it has a higher density than calcium.

Denosumab, also known as AMG 162, is a monoclonal antibody that appears to decrease bone resorption. Currently in a phase III fracture trial on postmenopausal women, denosumab will require two subcutaneous injections per year.

Isosorbide mononitrate, long used for the pain of angina, appears to improve several bone markers in postmenopausal women. A BMD trial is currently underway.

β-Blockers constitute another class of drugs that may well have bone effects. Most epidemiologic studies associate use of β-blockers with increases in BMD and decreases in fractures. Randomized trials are needed to determine whether β-blockers actually have a place in osteoporosis prevention or treatment.

Finally, there are several new agents with previously untried mechanisms of action in the pipeline. Among them are selective androgen receptor modulators, cathepsin K inhibitors, and calcilytics. All are in early-phase studies for osteoporosis.

SAN FRANCISCO — “It's a pretty exciting time for drug development in osteoporosis,” Dr. Deborah Sellmeyer said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

While joking that her information was “sourced from Google and rumor and various investment brochures,” Dr. Sellmeyer, director of the Center for Osteoporosis at the university, listed some of the osteoporosis drugs in the pipeline.

A fracture trial for a full-length version of parathyroid hormone (PTH [1-84]) has been completed, and a new drug application (NDA) was submitted to the Food and Drug Administration in July 2005.

Meanwhile, inhaled-powder and oral forms of PTH are in phase I and phase II trials, and at least one PTH analogue is in phase III. “Everyone's looking for the magic combination that will be able to replicate the PTH skeletal effect and get rid of the hypercalcemic effect,” Dr. Sellmeyer said.

Oral calcitonin preparations are in phase I and phase II. And low-dose and ultralow-dose estrogen remain fertile areas of research. The hope is that these preparations will replicate the beneficial bone effects of estrogen while avoiding its harmful vascular effects. While two low-dose patches and one low-dose pill have already been approved for the prevention of osteoporosis and for the treatment of vasomotor symptoms, no fracture data are yet available.

Zoledronic acid, a once-a-year intravenous bisphosphonate, is currently approved for hypercalcemia of malignancy and is now in a phase III trial to determine whether it prevents osteoporotic fractures. This agent is likely to benefit people who cannot tolerate oral bisphosphonates, people in assisted-living situations, and people who have difficulty remembering to take medication.

There are several new selective estrogen receptor modulators under development, with three—lasofoxifene, bazedoxifene, and arzoxifene—in phase III or beyond. An NDA for lasofoxifene was submitted to the FDA in 2004, but the manufacturer apparently received a nonapprovable letter in September 2005, putting the drug in limbo. An NDA for bazedoxifene was submitted in 2006 for the prevention of osteoporosis, and an NDA is planned for 2007 for a combination of bazedoxifene and estrogen for osteoporosis treatment and possible premenopausal use. Results from a phase III trial of arzoxifene are not expected until 2010.

Tibolone is a drug that “likes every steroid receptor it ever met,” in Dr. Sellmeyer's words. Its three metabolites separately have affinities for estrogen, progesterone, and androgen receptors. A recently completed 24-month prevention trial in 90 women showed no difference in vaginal spotting between tibolone and placebo. Interestingly, the women taking placebo experienced a 12% weight gain, while the women taking tibolone experienced no average weight gain. A multinational fracture study involving 4,000 women is expected to conclude sometime in 2006.

It's been known for decades that strontium improves bone mineral density (BMD), but it was never developed for osteoporosis prevention or treatment because it's a nonpatentable chemical element. Recently, however, a proprietary formulation of strontium—strontium ranelate—has shown some promise. A granular form has already been approved for use in Europe and the United Kingdom, and a once-a-day pill finished a phase I trial in September 2005. Strontium ranelate is likely to complicate interpretation of BMD testing, since it has a higher density than calcium.

Denosumab, also known as AMG 162, is a monoclonal antibody that appears to decrease bone resorption. Currently in a phase III fracture trial on postmenopausal women, denosumab will require two subcutaneous injections per year.

Isosorbide mononitrate, long used for the pain of angina, appears to improve several bone markers in postmenopausal women. A BMD trial is currently underway.

β-Blockers constitute another class of drugs that may well have bone effects. Most epidemiologic studies associate use of β-blockers with increases in BMD and decreases in fractures. Randomized trials are needed to determine whether β-blockers actually have a place in osteoporosis prevention or treatment.

Finally, there are several new agents with previously untried mechanisms of action in the pipeline. Among them are selective androgen receptor modulators, cathepsin K inhibitors, and calcilytics. All are in early-phase studies for osteoporosis.

SAN FRANCISCO — “It's a pretty exciting time for drug development in osteoporosis,” Dr. Deborah Sellmeyer said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

While joking that her information was “sourced from Google and rumor and various investment brochures,” Dr. Sellmeyer, director of the Center for Osteoporosis at the university, listed some of the osteoporosis drugs in the pipeline.

A fracture trial for a full-length version of parathyroid hormone (PTH [1-84]) has been completed, and a new drug application (NDA) was submitted to the Food and Drug Administration in July 2005.

Meanwhile, inhaled-powder and oral forms of PTH are in phase I and phase II trials, and at least one PTH analogue is in phase III. “Everyone's looking for the magic combination that will be able to replicate the PTH skeletal effect and get rid of the hypercalcemic effect,” Dr. Sellmeyer said.

Oral calcitonin preparations are in phase I and phase II. And low-dose and ultralow-dose estrogen remain fertile areas of research. The hope is that these preparations will replicate the beneficial bone effects of estrogen while avoiding its harmful vascular effects. While two low-dose patches and one low-dose pill have already been approved for the prevention of osteoporosis and for the treatment of vasomotor symptoms, no fracture data are yet available.

Zoledronic acid, a once-a-year intravenous bisphosphonate, is currently approved for hypercalcemia of malignancy and is now in a phase III trial to determine whether it prevents osteoporotic fractures. This agent is likely to benefit people who cannot tolerate oral bisphosphonates, people in assisted-living situations, and people who have difficulty remembering to take medication.

There are several new selective estrogen receptor modulators under development, with three—lasofoxifene, bazedoxifene, and arzoxifene—in phase III or beyond. An NDA for lasofoxifene was submitted to the FDA in 2004, but the manufacturer apparently received a nonapprovable letter in September 2005, putting the drug in limbo. An NDA for bazedoxifene was submitted in 2006 for the prevention of osteoporosis, and an NDA is planned for 2007 for a combination of bazedoxifene and estrogen for osteoporosis treatment and possible premenopausal use. Results from a phase III trial of arzoxifene are not expected until 2010.

Tibolone is a drug that “likes every steroid receptor it ever met,” in Dr. Sellmeyer's words. Its three metabolites separately have affinities for estrogen, progesterone, and androgen receptors. A recently completed 24-month prevention trial in 90 women showed no difference in vaginal spotting between tibolone and placebo. Interestingly, the women taking placebo experienced a 12% weight gain, while the women taking tibolone experienced no average weight gain. A multinational fracture study involving 4,000 women is expected to conclude sometime in 2006.

It's been known for decades that strontium improves bone mineral density (BMD), but it was never developed for osteoporosis prevention or treatment because it's a nonpatentable chemical element. Recently, however, a proprietary formulation of strontium—strontium ranelate—has shown some promise. A granular form has already been approved for use in Europe and the United Kingdom, and a once-a-day pill finished a phase I trial in September 2005. Strontium ranelate is likely to complicate interpretation of BMD testing, since it has a higher density than calcium.

Denosumab, also known as AMG 162, is a monoclonal antibody that appears to decrease bone resorption. Currently in a phase III fracture trial on postmenopausal women, denosumab will require two subcutaneous injections per year.

Isosorbide mononitrate, long used for the pain of angina, appears to improve several bone markers in postmenopausal women. A BMD trial is currently underway.

β-Blockers constitute another class of drugs that may well have bone effects. Most epidemiologic studies associate use of β-blockers with increases in BMD and decreases in fractures. Randomized trials are needed to determine whether β-blockers actually have a place in osteoporosis prevention or treatment.

Finally, there are several new agents with previously untried mechanisms of action in the pipeline. Among them are selective androgen receptor modulators, cathepsin K inhibitors, and calcilytics. All are in early-phase studies for osteoporosis.