Osteoarthritis

PHILADELPHIA — Denosumab, an investigational antibody in phase III studies as a treatment to maintain bone density and cut bone metastases, has so far shown better safety than intravenous bisphosphonates, the main comparator drugs.

Results are available from more than 4,500 patients who were treated with denosumab for any indication, including both bone metastases and as osteoporosis treatment, and there have been no cases of renal toxicity and one case of symptomatic hypocalcemia, Dr. Allan Lipton said at a conference on skeletal complications of malignancy. In contrast, both renal toxicity and hypocalcemia have been safety issues for intravenous bisphosphonates, said Dr. Lipton, professor of medicine at Hershey (Pa.) Medical Center.

Denosumab is being developed by Amgen, which sponsored all of the clinical studies. Dr. Lipton is a consultant to and has received honoraria from Amgen.

Compared with bisphosphonates, denosumab also seems to cause fewer acute-phase reactions with flu-like symptoms. In a phase II study of 255 patients with bone metastases from breast cancer led by Dr. Lipton, patients treated with denosumab had an 8% incidence of a flu-like, acute-phase reaction during the first 3 days after treatment start, vs. a 33% rate in patients randomized to treatment with an intravenous bisphosphonate. During the first month after treatment started, acute-phase reactions occurred in 26% of the denosumab patients and 49% of those on an intravenous bisphosphonate.

Denosumab is a fully human monoclonal antibody that binds to and blocks the ligand that stimulates osteoclast-mediated bone resorption. In this way, the drug cuts the rate of bone resorption, and may also have other actions that interfere with bone metastasis.

Reports from two phase II studies of denosumab for treating patients with bone metastases from solid tumors showed that the drug was at least as effective as an intravenous bisphosphonate for reducing a plasma marker of bone resorption. These results, as well as findings from osteoporosis treatment studies, have led to several phase III trials in patients with bone metastases where denosumab's efficacy is again being compared with intravenous bisphosphonates. An additional phase III study is looking at denosumab's ability to prevent bone metastases compared with placebo, Dr. Lipton said at the meeting, jointly sponsored by the Paget Foundation and the University of Michigan.

The dosage used in most of the phase III studies is 120 mg subcutaneously every 4 weeks. In phase II studies, this dosage was more effective for suppressing skeletal-related events than 30 mg subcutaneously every 4 weeks, but the 120-mg dose avoided the asymptomatic hypocalcemia seen in patients getting 180 mg subcutaneously every 4 weeks, Dr. Lipton said.

PHILADELPHIA — Denosumab, an investigational antibody in phase III studies as a treatment to maintain bone density and cut bone metastases, has so far shown better safety than intravenous bisphosphonates, the main comparator drugs.

Results are available from more than 4,500 patients who were treated with denosumab for any indication, including both bone metastases and as osteoporosis treatment, and there have been no cases of renal toxicity and one case of symptomatic hypocalcemia, Dr. Allan Lipton said at a conference on skeletal complications of malignancy. In contrast, both renal toxicity and hypocalcemia have been safety issues for intravenous bisphosphonates, said Dr. Lipton, professor of medicine at Hershey (Pa.) Medical Center.

Denosumab is being developed by Amgen, which sponsored all of the clinical studies. Dr. Lipton is a consultant to and has received honoraria from Amgen.

Compared with bisphosphonates, denosumab also seems to cause fewer acute-phase reactions with flu-like symptoms. In a phase II study of 255 patients with bone metastases from breast cancer led by Dr. Lipton, patients treated with denosumab had an 8% incidence of a flu-like, acute-phase reaction during the first 3 days after treatment start, vs. a 33% rate in patients randomized to treatment with an intravenous bisphosphonate. During the first month after treatment started, acute-phase reactions occurred in 26% of the denosumab patients and 49% of those on an intravenous bisphosphonate.

Denosumab is a fully human monoclonal antibody that binds to and blocks the ligand that stimulates osteoclast-mediated bone resorption. In this way, the drug cuts the rate of bone resorption, and may also have other actions that interfere with bone metastasis.

Reports from two phase II studies of denosumab for treating patients with bone metastases from solid tumors showed that the drug was at least as effective as an intravenous bisphosphonate for reducing a plasma marker of bone resorption. These results, as well as findings from osteoporosis treatment studies, have led to several phase III trials in patients with bone metastases where denosumab's efficacy is again being compared with intravenous bisphosphonates. An additional phase III study is looking at denosumab's ability to prevent bone metastases compared with placebo, Dr. Lipton said at the meeting, jointly sponsored by the Paget Foundation and the University of Michigan.

The dosage used in most of the phase III studies is 120 mg subcutaneously every 4 weeks. In phase II studies, this dosage was more effective for suppressing skeletal-related events than 30 mg subcutaneously every 4 weeks, but the 120-mg dose avoided the asymptomatic hypocalcemia seen in patients getting 180 mg subcutaneously every 4 weeks, Dr. Lipton said.

PHILADELPHIA — Denosumab, an investigational antibody in phase III studies as a treatment to maintain bone density and cut bone metastases, has so far shown better safety than intravenous bisphosphonates, the main comparator drugs.

Results are available from more than 4,500 patients who were treated with denosumab for any indication, including both bone metastases and as osteoporosis treatment, and there have been no cases of renal toxicity and one case of symptomatic hypocalcemia, Dr. Allan Lipton said at a conference on skeletal complications of malignancy. In contrast, both renal toxicity and hypocalcemia have been safety issues for intravenous bisphosphonates, said Dr. Lipton, professor of medicine at Hershey (Pa.) Medical Center.

Denosumab is being developed by Amgen, which sponsored all of the clinical studies. Dr. Lipton is a consultant to and has received honoraria from Amgen.

Compared with bisphosphonates, denosumab also seems to cause fewer acute-phase reactions with flu-like symptoms. In a phase II study of 255 patients with bone metastases from breast cancer led by Dr. Lipton, patients treated with denosumab had an 8% incidence of a flu-like, acute-phase reaction during the first 3 days after treatment start, vs. a 33% rate in patients randomized to treatment with an intravenous bisphosphonate. During the first month after treatment started, acute-phase reactions occurred in 26% of the denosumab patients and 49% of those on an intravenous bisphosphonate.

Denosumab is a fully human monoclonal antibody that binds to and blocks the ligand that stimulates osteoclast-mediated bone resorption. In this way, the drug cuts the rate of bone resorption, and may also have other actions that interfere with bone metastasis.

Reports from two phase II studies of denosumab for treating patients with bone metastases from solid tumors showed that the drug was at least as effective as an intravenous bisphosphonate for reducing a plasma marker of bone resorption. These results, as well as findings from osteoporosis treatment studies, have led to several phase III trials in patients with bone metastases where denosumab's efficacy is again being compared with intravenous bisphosphonates. An additional phase III study is looking at denosumab's ability to prevent bone metastases compared with placebo, Dr. Lipton said at the meeting, jointly sponsored by the Paget Foundation and the University of Michigan.

The dosage used in most of the phase III studies is 120 mg subcutaneously every 4 weeks. In phase II studies, this dosage was more effective for suppressing skeletal-related events than 30 mg subcutaneously every 4 weeks, but the 120-mg dose avoided the asymptomatic hypocalcemia seen in patients getting 180 mg subcutaneously every 4 weeks, Dr. Lipton said.

BARCELONA — Patients who use high-dose glucocorticoids can maintain or improve their bone mineral density with risedronate prophylaxis, Dr. Chi Chiu Mok reported at the annual European Congress of Rheumatology.

“The [American College of Rheumatology] recommends the first-line use of bisphosphonates in patients with T scores below -1 who are expected to use corticosteroids for more than 3 months,” said Dr. Mok of the department of medicine at Tuen Mun Hospital, Hong Kong.

“Multiple clinical trials have confirmed the efficacy of bisphosphonates in the prevention and treatment of glucocorticoid-induced bone loss, and sometimes have demonstrated antifracture efficacy. But most [of these trials] recruited patients taking a relatively small dose of steroids,” an equivalent of 7.5 mg/week of prednisolone or more.

Dr. Mok and colleagues randomized 120 patients with conditions requiring 0.5 mg/kg per day prednisolone (or an equivalent glucocorticoid dose) for 6 weeks or more to 1,000 mg/day calcium plus 5 mg/day risedronate (Actonel) or placebo for 6 months. Mean age was 43 years, and 30% were postmenopausal.

At the end of the double-blind trial, risedronate patients had a significantly greater change in bone mineral density (BMD) at the lumbar spine (0.9%) than did placebo-treated patients (−0.5%). This was significant even after adjusting for baseline BMD, age, gender, body mass index, and cumulative steroid dosage. Risedronate patients maintained BMD in the hip and the whole body overall. Placebo patients lost BMD in both measurements.

Steroid-naive patients, who accounted for about 60% of all patients, had similar results. The maximum dosage of prednisolone given during the trial averaged 0.7 mg/kg per day.

Sanofi Aventis provided free daily-dosed risedronate, but did not otherwise fund the trial. Dr. Mok said that no investigators had conflicts of interest with Sanofi Aventis.

Overall, 51 risedronate- and 52 placebo-treated patients completed the trial. Withdrawals mainly occurred because of the daily drug protocol, but several patients died from their underlying medical condition; two withdrawals occurred in the risedronate group because of adverse events (one skin rash and one dyspepsia).

No patients had preexisting vertebral or hip fractures, although about 50% of the patients were osteopenic. The trial was not powered to test the antifracture efficacy of risedronate.

“Risedronate should be considered for primary prevention of bone mineral loss during periods of high-dose glucocorticoid therapy,” Dr. Mok concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Patients who use high-dose glucocorticoids can maintain or improve their bone mineral density with risedronate prophylaxis, Dr. Chi Chiu Mok reported at the annual European Congress of Rheumatology.

“The [American College of Rheumatology] recommends the first-line use of bisphosphonates in patients with T scores below -1 who are expected to use corticosteroids for more than 3 months,” said Dr. Mok of the department of medicine at Tuen Mun Hospital, Hong Kong.

“Multiple clinical trials have confirmed the efficacy of bisphosphonates in the prevention and treatment of glucocorticoid-induced bone loss, and sometimes have demonstrated antifracture efficacy. But most [of these trials] recruited patients taking a relatively small dose of steroids,” an equivalent of 7.5 mg/week of prednisolone or more.

Dr. Mok and colleagues randomized 120 patients with conditions requiring 0.5 mg/kg per day prednisolone (or an equivalent glucocorticoid dose) for 6 weeks or more to 1,000 mg/day calcium plus 5 mg/day risedronate (Actonel) or placebo for 6 months. Mean age was 43 years, and 30% were postmenopausal.

At the end of the double-blind trial, risedronate patients had a significantly greater change in bone mineral density (BMD) at the lumbar spine (0.9%) than did placebo-treated patients (−0.5%). This was significant even after adjusting for baseline BMD, age, gender, body mass index, and cumulative steroid dosage. Risedronate patients maintained BMD in the hip and the whole body overall. Placebo patients lost BMD in both measurements.

Steroid-naive patients, who accounted for about 60% of all patients, had similar results. The maximum dosage of prednisolone given during the trial averaged 0.7 mg/kg per day.

Sanofi Aventis provided free daily-dosed risedronate, but did not otherwise fund the trial. Dr. Mok said that no investigators had conflicts of interest with Sanofi Aventis.

Overall, 51 risedronate- and 52 placebo-treated patients completed the trial. Withdrawals mainly occurred because of the daily drug protocol, but several patients died from their underlying medical condition; two withdrawals occurred in the risedronate group because of adverse events (one skin rash and one dyspepsia).

No patients had preexisting vertebral or hip fractures, although about 50% of the patients were osteopenic. The trial was not powered to test the antifracture efficacy of risedronate.

“Risedronate should be considered for primary prevention of bone mineral loss during periods of high-dose glucocorticoid therapy,” Dr. Mok concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Patients who use high-dose glucocorticoids can maintain or improve their bone mineral density with risedronate prophylaxis, Dr. Chi Chiu Mok reported at the annual European Congress of Rheumatology.

“The [American College of Rheumatology] recommends the first-line use of bisphosphonates in patients with T scores below -1 who are expected to use corticosteroids for more than 3 months,” said Dr. Mok of the department of medicine at Tuen Mun Hospital, Hong Kong.

“Multiple clinical trials have confirmed the efficacy of bisphosphonates in the prevention and treatment of glucocorticoid-induced bone loss, and sometimes have demonstrated antifracture efficacy. But most [of these trials] recruited patients taking a relatively small dose of steroids,” an equivalent of 7.5 mg/week of prednisolone or more.

Dr. Mok and colleagues randomized 120 patients with conditions requiring 0.5 mg/kg per day prednisolone (or an equivalent glucocorticoid dose) for 6 weeks or more to 1,000 mg/day calcium plus 5 mg/day risedronate (Actonel) or placebo for 6 months. Mean age was 43 years, and 30% were postmenopausal.

At the end of the double-blind trial, risedronate patients had a significantly greater change in bone mineral density (BMD) at the lumbar spine (0.9%) than did placebo-treated patients (−0.5%). This was significant even after adjusting for baseline BMD, age, gender, body mass index, and cumulative steroid dosage. Risedronate patients maintained BMD in the hip and the whole body overall. Placebo patients lost BMD in both measurements.

Steroid-naive patients, who accounted for about 60% of all patients, had similar results. The maximum dosage of prednisolone given during the trial averaged 0.7 mg/kg per day.

Sanofi Aventis provided free daily-dosed risedronate, but did not otherwise fund the trial. Dr. Mok said that no investigators had conflicts of interest with Sanofi Aventis.

Overall, 51 risedronate- and 52 placebo-treated patients completed the trial. Withdrawals mainly occurred because of the daily drug protocol, but several patients died from their underlying medical condition; two withdrawals occurred in the risedronate group because of adverse events (one skin rash and one dyspepsia).

No patients had preexisting vertebral or hip fractures, although about 50% of the patients were osteopenic. The trial was not powered to test the antifracture efficacy of risedronate.

“Risedronate should be considered for primary prevention of bone mineral loss during periods of high-dose glucocorticoid therapy,” Dr. Mok concluded.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Several novel treatments for osteoporosis are under investigation, and one might even provide a cure, Dr. Steven R. Cummings said at a meeting sponsored by the University of California, San Francisco.

“Several of these treatments are based on fundamental biology, on biological mechanisms of bone formation and bone resorption,” Dr. Cummings, director of the San Francisco coordinating center of the California Pacific Medical Center Research Institute, said. “[I expect] these to make a big difference in practice within the next 5 years.”

One treatment involves sclerostin, which is produced by osteocytes, the most common and longest-lived cellular component of bone. Residing in microscopic cavities within bones, osteocytes are 100 times more numerous than osteoblasts and osteoclasts combined. Their job appears to be to sense strain in the bone and to communicate the need for bone building to the osteoblasts.

Sclerostin is not found in any other cell. It powerfully inhibits bone formation by interacting with mesenchymal stem cells—the precursors of osteoblasts—and reducing osteoblast formation. Sclerostin is produced by a gene called SOST, and individuals with mutations in that gene have sclerosteosis, a congenital disease characterized by extremely high bone mass, often leading to intracranial pressure and death.

In one study, female rats that were ovariectomized lost 12% of bone mass. But when given a monoclonal antibody to SOST, their vertebral bone mineral density (BMD) rose by 26% and their leg BMD by 16% over 5 weeks.

“This is a promising treatment, extremely potent, very specific to bone that has, I think, the potential to be a cure for osteoporosis,” Dr. Cummings said. “Human data might be available in the course of the next year.”

Then there is denosumab, an antibody that binds to the RankL receptor on the surface of osteoclasts. Blocking those receptors inhibits the development and activity of osteoclasts and decreases bone resorption.

Given by injection every 6 months, denosumab significantly increased spine and hip BMD, compared with alendronate and placebo in human phase II trials. Phase III trials are underway.

A third potential treatment is to be found in b-blockers. Osteoblasts have been observed in close proximity to sympathetic nerves, and they also possess beta-2 receptors. b-Blockers increase osteoblast activity in vivo. Mice treated with propranolol show increased bone mass. In one study, women taking b-blockers experienced a 28% reduction in the risk of hip fracture.

“Observational data, especially in the case of b-blockers, is difficult to believe enthusiastically,” Dr. Cummings said. “I don't think right now you should alter your clinical decisions about when you use b-blockers.”

Finally, high levels of the amino acid homocysteine appear to result in cardiovascular disease, dementia, blindness, and osteoporosis. Homocysteine appears to bind to and alter cross-links between collagen fibers. Even high-normal levels have been associated with an increased risk of fracture. Treatment with folic acid and vitamin B₁₂ reduces homocysteine levels.

At least one study has shown a large effect of the supplements in reducing fracture risk post stroke. In a randomized controlled trial, 628 patients were given daily doses of 5 mg folate and 1,500 mcg mecobalamin (a vitamin B₁₂ analog) or placebo for 2 years. After adjustment, the patients taking supplements experienced an 80% reduction in the risk of hip fracture (JAMA 2005;293:1082–8).

“This is so dramatic that it's hard to believe,” said Dr. Cummings. He added that he eagerly awaits further research.

Dr. Cummings receives research support and consulting fees from Eli Lilly & Co., Pfizer, and Novartis, and is a consultant to Merck.

Given by injection every 6 months, denosumab significantly increased spine and hip BMD. DR. CUMMINGS

SAN FRANCISCO — Several novel treatments for osteoporosis are under investigation, and one might even provide a cure, Dr. Steven R. Cummings said at a meeting sponsored by the University of California, San Francisco.

“Several of these treatments are based on fundamental biology, on biological mechanisms of bone formation and bone resorption,” Dr. Cummings, director of the San Francisco coordinating center of the California Pacific Medical Center Research Institute, said. “[I expect] these to make a big difference in practice within the next 5 years.”

One treatment involves sclerostin, which is produced by osteocytes, the most common and longest-lived cellular component of bone. Residing in microscopic cavities within bones, osteocytes are 100 times more numerous than osteoblasts and osteoclasts combined. Their job appears to be to sense strain in the bone and to communicate the need for bone building to the osteoblasts.

Sclerostin is not found in any other cell. It powerfully inhibits bone formation by interacting with mesenchymal stem cells—the precursors of osteoblasts—and reducing osteoblast formation. Sclerostin is produced by a gene called SOST, and individuals with mutations in that gene have sclerosteosis, a congenital disease characterized by extremely high bone mass, often leading to intracranial pressure and death.

In one study, female rats that were ovariectomized lost 12% of bone mass. But when given a monoclonal antibody to SOST, their vertebral bone mineral density (BMD) rose by 26% and their leg BMD by 16% over 5 weeks.

“This is a promising treatment, extremely potent, very specific to bone that has, I think, the potential to be a cure for osteoporosis,” Dr. Cummings said. “Human data might be available in the course of the next year.”

Then there is denosumab, an antibody that binds to the RankL receptor on the surface of osteoclasts. Blocking those receptors inhibits the development and activity of osteoclasts and decreases bone resorption.

Given by injection every 6 months, denosumab significantly increased spine and hip BMD, compared with alendronate and placebo in human phase II trials. Phase III trials are underway.

A third potential treatment is to be found in b-blockers. Osteoblasts have been observed in close proximity to sympathetic nerves, and they also possess beta-2 receptors. b-Blockers increase osteoblast activity in vivo. Mice treated with propranolol show increased bone mass. In one study, women taking b-blockers experienced a 28% reduction in the risk of hip fracture.

“Observational data, especially in the case of b-blockers, is difficult to believe enthusiastically,” Dr. Cummings said. “I don't think right now you should alter your clinical decisions about when you use b-blockers.”

Finally, high levels of the amino acid homocysteine appear to result in cardiovascular disease, dementia, blindness, and osteoporosis. Homocysteine appears to bind to and alter cross-links between collagen fibers. Even high-normal levels have been associated with an increased risk of fracture. Treatment with folic acid and vitamin B₁₂ reduces homocysteine levels.

At least one study has shown a large effect of the supplements in reducing fracture risk post stroke. In a randomized controlled trial, 628 patients were given daily doses of 5 mg folate and 1,500 mcg mecobalamin (a vitamin B₁₂ analog) or placebo for 2 years. After adjustment, the patients taking supplements experienced an 80% reduction in the risk of hip fracture (JAMA 2005;293:1082–8).

“This is so dramatic that it's hard to believe,” said Dr. Cummings. He added that he eagerly awaits further research.

Dr. Cummings receives research support and consulting fees from Eli Lilly & Co., Pfizer, and Novartis, and is a consultant to Merck.

Given by injection every 6 months, denosumab significantly increased spine and hip BMD. DR. CUMMINGS

SAN FRANCISCO — Several novel treatments for osteoporosis are under investigation, and one might even provide a cure, Dr. Steven R. Cummings said at a meeting sponsored by the University of California, San Francisco.

“Several of these treatments are based on fundamental biology, on biological mechanisms of bone formation and bone resorption,” Dr. Cummings, director of the San Francisco coordinating center of the California Pacific Medical Center Research Institute, said. “[I expect] these to make a big difference in practice within the next 5 years.”

One treatment involves sclerostin, which is produced by osteocytes, the most common and longest-lived cellular component of bone. Residing in microscopic cavities within bones, osteocytes are 100 times more numerous than osteoblasts and osteoclasts combined. Their job appears to be to sense strain in the bone and to communicate the need for bone building to the osteoblasts.

Sclerostin is not found in any other cell. It powerfully inhibits bone formation by interacting with mesenchymal stem cells—the precursors of osteoblasts—and reducing osteoblast formation. Sclerostin is produced by a gene called SOST, and individuals with mutations in that gene have sclerosteosis, a congenital disease characterized by extremely high bone mass, often leading to intracranial pressure and death.

In one study, female rats that were ovariectomized lost 12% of bone mass. But when given a monoclonal antibody to SOST, their vertebral bone mineral density (BMD) rose by 26% and their leg BMD by 16% over 5 weeks.

“This is a promising treatment, extremely potent, very specific to bone that has, I think, the potential to be a cure for osteoporosis,” Dr. Cummings said. “Human data might be available in the course of the next year.”

Then there is denosumab, an antibody that binds to the RankL receptor on the surface of osteoclasts. Blocking those receptors inhibits the development and activity of osteoclasts and decreases bone resorption.

Given by injection every 6 months, denosumab significantly increased spine and hip BMD, compared with alendronate and placebo in human phase II trials. Phase III trials are underway.

A third potential treatment is to be found in b-blockers. Osteoblasts have been observed in close proximity to sympathetic nerves, and they also possess beta-2 receptors. b-Blockers increase osteoblast activity in vivo. Mice treated with propranolol show increased bone mass. In one study, women taking b-blockers experienced a 28% reduction in the risk of hip fracture.

“Observational data, especially in the case of b-blockers, is difficult to believe enthusiastically,” Dr. Cummings said. “I don't think right now you should alter your clinical decisions about when you use b-blockers.”

Finally, high levels of the amino acid homocysteine appear to result in cardiovascular disease, dementia, blindness, and osteoporosis. Homocysteine appears to bind to and alter cross-links between collagen fibers. Even high-normal levels have been associated with an increased risk of fracture. Treatment with folic acid and vitamin B₁₂ reduces homocysteine levels.

At least one study has shown a large effect of the supplements in reducing fracture risk post stroke. In a randomized controlled trial, 628 patients were given daily doses of 5 mg folate and 1,500 mcg mecobalamin (a vitamin B₁₂ analog) or placebo for 2 years. After adjustment, the patients taking supplements experienced an 80% reduction in the risk of hip fracture (JAMA 2005;293:1082–8).

“This is so dramatic that it's hard to believe,” said Dr. Cummings. He added that he eagerly awaits further research.

Dr. Cummings receives research support and consulting fees from Eli Lilly & Co., Pfizer, and Novartis, and is a consultant to Merck.

Given by injection every 6 months, denosumab significantly increased spine and hip BMD. DR. CUMMINGS

The Food and Drug Administration will seek data for an “in-depth evaluation” of atrial fibrillation for the entire bisphosphonate class of drugs as well as continue to monitor any spontaneous postmarketing reports of the heart rhythm disorder, agency officials announced on Oct. 1.

FDA is not recommending at this point that physicians alter their prescribing choices or that patients change their medications.

The review encompasses products approved primarily to treat osteoporosis, slow bone turnover in Paget's disease, and treat bone metastases in cancer patients—specifically alendronate (Fosamax and Fosamax Plus D), risedronate (Actonel and Actonel with Calcium), ibandronate (Boniva), zoledronic acid (Reclast and Zometa), pamidronate (Aredia), and etidronate.

The evaluation follows publication of two studies describing increased rates of serious atrial fibrillation in older women treated with zoledronic acid or alendronate for osteoporosis (N. Engl. J. Med. 2007;356:1809–33 and N. Engl. J. Med. 2007;356:1895–6). In those studies, researchers found that more women who received one of the bisphosphonates developed serious atrial fibrillation versus those receiving placebo, according to the FDA announcement, which noted that overall rates of atrial fibrillation were not statistically different between the studies' active treatment and placebo arms.

Upon reviewing its postmarketing reports of atrial fibrillation in association with both oral and intravenous bisphosphonates, the agency did not find a “population of bisphosphonates users at increased risk” for the atrial fibrillation. And since atrial fibrillation is a common disorder in patients over age 65 years—the same population that was studied in the New England Journal of Medicine articles—the FDA cautioned that it is “unclear how these data … should be interpreted.”

Further, the FDA's recent review and approval of zoledronic acid included data on possible associations with atrial fibrillation, the agency said.

Those reviews found that most incidents occurred more than a month after infusion of the drug, which is administered once yearly to treat postmenopausal osteoporosis.

The in-depth review may take up to 12 months, according to the FDA. This is the agency's second “early communication” of a drug safety review, part of FDA's efforts to be more transparent in oversight of postmarketing drug safety. The first communication, which was released in August, addressed the proton pump inhibitors omeprazole and esomeprazole.

This newspaper and “The Pink Sheet” are published by Elsevier.

The Food and Drug Administration will seek data for an “in-depth evaluation” of atrial fibrillation for the entire bisphosphonate class of drugs as well as continue to monitor any spontaneous postmarketing reports of the heart rhythm disorder, agency officials announced on Oct. 1.

FDA is not recommending at this point that physicians alter their prescribing choices or that patients change their medications.

The review encompasses products approved primarily to treat osteoporosis, slow bone turnover in Paget's disease, and treat bone metastases in cancer patients—specifically alendronate (Fosamax and Fosamax Plus D), risedronate (Actonel and Actonel with Calcium), ibandronate (Boniva), zoledronic acid (Reclast and Zometa), pamidronate (Aredia), and etidronate.

The evaluation follows publication of two studies describing increased rates of serious atrial fibrillation in older women treated with zoledronic acid or alendronate for osteoporosis (N. Engl. J. Med. 2007;356:1809–33 and N. Engl. J. Med. 2007;356:1895–6). In those studies, researchers found that more women who received one of the bisphosphonates developed serious atrial fibrillation versus those receiving placebo, according to the FDA announcement, which noted that overall rates of atrial fibrillation were not statistically different between the studies' active treatment and placebo arms.

Upon reviewing its postmarketing reports of atrial fibrillation in association with both oral and intravenous bisphosphonates, the agency did not find a “population of bisphosphonates users at increased risk” for the atrial fibrillation. And since atrial fibrillation is a common disorder in patients over age 65 years—the same population that was studied in the New England Journal of Medicine articles—the FDA cautioned that it is “unclear how these data … should be interpreted.”

Further, the FDA's recent review and approval of zoledronic acid included data on possible associations with atrial fibrillation, the agency said.

Those reviews found that most incidents occurred more than a month after infusion of the drug, which is administered once yearly to treat postmenopausal osteoporosis.

The in-depth review may take up to 12 months, according to the FDA. This is the agency's second “early communication” of a drug safety review, part of FDA's efforts to be more transparent in oversight of postmarketing drug safety. The first communication, which was released in August, addressed the proton pump inhibitors omeprazole and esomeprazole.

This newspaper and “The Pink Sheet” are published by Elsevier.

The Food and Drug Administration will seek data for an “in-depth evaluation” of atrial fibrillation for the entire bisphosphonate class of drugs as well as continue to monitor any spontaneous postmarketing reports of the heart rhythm disorder, agency officials announced on Oct. 1.

FDA is not recommending at this point that physicians alter their prescribing choices or that patients change their medications.

The review encompasses products approved primarily to treat osteoporosis, slow bone turnover in Paget's disease, and treat bone metastases in cancer patients—specifically alendronate (Fosamax and Fosamax Plus D), risedronate (Actonel and Actonel with Calcium), ibandronate (Boniva), zoledronic acid (Reclast and Zometa), pamidronate (Aredia), and etidronate.

The evaluation follows publication of two studies describing increased rates of serious atrial fibrillation in older women treated with zoledronic acid or alendronate for osteoporosis (N. Engl. J. Med. 2007;356:1809–33 and N. Engl. J. Med. 2007;356:1895–6). In those studies, researchers found that more women who received one of the bisphosphonates developed serious atrial fibrillation versus those receiving placebo, according to the FDA announcement, which noted that overall rates of atrial fibrillation were not statistically different between the studies' active treatment and placebo arms.

Upon reviewing its postmarketing reports of atrial fibrillation in association with both oral and intravenous bisphosphonates, the agency did not find a “population of bisphosphonates users at increased risk” for the atrial fibrillation. And since atrial fibrillation is a common disorder in patients over age 65 years—the same population that was studied in the New England Journal of Medicine articles—the FDA cautioned that it is “unclear how these data … should be interpreted.”

Further, the FDA's recent review and approval of zoledronic acid included data on possible associations with atrial fibrillation, the agency said.

Those reviews found that most incidents occurred more than a month after infusion of the drug, which is administered once yearly to treat postmenopausal osteoporosis.

The in-depth review may take up to 12 months, according to the FDA. This is the agency's second “early communication” of a drug safety review, part of FDA's efforts to be more transparent in oversight of postmarketing drug safety. The first communication, which was released in August, addressed the proton pump inhibitors omeprazole and esomeprazole.

This newspaper and “The Pink Sheet” are published by Elsevier.

An annual intravenous infusion of zoledronic acid reduced the rate of new clinical fractures and improved survival in patients who had recently undergone surgery for a hip fracture, according to Dr. Kenneth W. Lyles and associates in the HORIZON Recurrent Fracture Trial.

The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study, supported by Novartis, is an international clinical trial that compared the potent bisphosphonate with placebo in 2,127 patients followed for a mean of 2 years, the investigators reported on the New England Journal of Medicine Web site. “No other controlled clinical trial has previously shown efficacy of any osteoporosis medication for reducing the recurrence of fracture in patients who already had a broken hip,” Dr. Karim Calis and Dr. Frank Pucino wrote in an editorial accompanying the report.

All subjects sustained a hip fracture after minimal trauma and underwent surgical repair, then received their first intravenous infusion within 90 days. They received daily oral calcium and vitamin D supplements, and were allowed concomitant therapy with nasal calcitonin, selective estrogen receptor modulators, hormone therapy, tibolone, or external hip protectors. A total of 1,065 patients were randomly assigned to IV zoledronic acid and 1,062 to IV placebo once yearly. Mean age was 74 years.

A total of 424 new clinical fractures occurred during follow-up. The rate was 8.6% with zoledronic acid and 13.9% with placebo, for a reduction in relative risk of 35%, said Dr. Lyles, of Duke University Medical Center, Durham, N.C. A total of 242 subjects died. Mortality was 9.6% with zoledronic acid and 13.3% with placebo, for a significant 28% relative risk reduction.

Bone mineral density (BMD) at the hip increased 2.6% at 1 year, 4.7% at 2 years, and 5.5% at 3 years in the zoledronic acid group. In the placebo group it fell 1.0%, 0.7%, and 0.9%, respectively. BMD at the femoral neck increased 0.8%, 2.2%, and 3.6% in the zoledronic acid group. It declined in the placebo group 1.0%, 0.7%, and 0.9%. All differences were significant (N. Engl. J. Med. 2007 Sept. 17 [Epub doi:10.1056/NEJMoa074941]).

Rates of overall adverse events and serious adverse events were similar. There were no differences in frequencies of cardiovascular adverse effects nor in rates of renal toxic effects. There were no cases of osteonecrosis of the jaw, which research suggested might be tied to zoledronic acid. There was no evidence of delayed bone healing, either.

In their comment, Dr. Calis and Dr. Pucino, both of the National Institutes of Health, Bethesda, Md., wrote, “Zoledronic acid appears to offer several advantages over other potential therapies, with one important caveat: Although the risk-benefit pendulum has now swung in favor of treatment, additional long-term safety data are essential,” (N. Engl. J. Med. 2007 Sept. 17 [Epub10.10565/N EJMe078192]). Future studies should compare treatment with other therapies and address physical function, quality of life, and cost-effectiveness, they added.

ELSEVIER GLOBAL MEDICAL NEWS

An annual intravenous infusion of zoledronic acid reduced the rate of new clinical fractures and improved survival in patients who had recently undergone surgery for a hip fracture, according to Dr. Kenneth W. Lyles and associates in the HORIZON Recurrent Fracture Trial.

The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study, supported by Novartis, is an international clinical trial that compared the potent bisphosphonate with placebo in 2,127 patients followed for a mean of 2 years, the investigators reported on the New England Journal of Medicine Web site. “No other controlled clinical trial has previously shown efficacy of any osteoporosis medication for reducing the recurrence of fracture in patients who already had a broken hip,” Dr. Karim Calis and Dr. Frank Pucino wrote in an editorial accompanying the report.

All subjects sustained a hip fracture after minimal trauma and underwent surgical repair, then received their first intravenous infusion within 90 days. They received daily oral calcium and vitamin D supplements, and were allowed concomitant therapy with nasal calcitonin, selective estrogen receptor modulators, hormone therapy, tibolone, or external hip protectors. A total of 1,065 patients were randomly assigned to IV zoledronic acid and 1,062 to IV placebo once yearly. Mean age was 74 years.

A total of 424 new clinical fractures occurred during follow-up. The rate was 8.6% with zoledronic acid and 13.9% with placebo, for a reduction in relative risk of 35%, said Dr. Lyles, of Duke University Medical Center, Durham, N.C. A total of 242 subjects died. Mortality was 9.6% with zoledronic acid and 13.3% with placebo, for a significant 28% relative risk reduction.

Bone mineral density (BMD) at the hip increased 2.6% at 1 year, 4.7% at 2 years, and 5.5% at 3 years in the zoledronic acid group. In the placebo group it fell 1.0%, 0.7%, and 0.9%, respectively. BMD at the femoral neck increased 0.8%, 2.2%, and 3.6% in the zoledronic acid group. It declined in the placebo group 1.0%, 0.7%, and 0.9%. All differences were significant (N. Engl. J. Med. 2007 Sept. 17 [Epub doi:10.1056/NEJMoa074941]).

Rates of overall adverse events and serious adverse events were similar. There were no differences in frequencies of cardiovascular adverse effects nor in rates of renal toxic effects. There were no cases of osteonecrosis of the jaw, which research suggested might be tied to zoledronic acid. There was no evidence of delayed bone healing, either.

In their comment, Dr. Calis and Dr. Pucino, both of the National Institutes of Health, Bethesda, Md., wrote, “Zoledronic acid appears to offer several advantages over other potential therapies, with one important caveat: Although the risk-benefit pendulum has now swung in favor of treatment, additional long-term safety data are essential,” (N. Engl. J. Med. 2007 Sept. 17 [Epub10.10565/N EJMe078192]). Future studies should compare treatment with other therapies and address physical function, quality of life, and cost-effectiveness, they added.

ELSEVIER GLOBAL MEDICAL NEWS

An annual intravenous infusion of zoledronic acid reduced the rate of new clinical fractures and improved survival in patients who had recently undergone surgery for a hip fracture, according to Dr. Kenneth W. Lyles and associates in the HORIZON Recurrent Fracture Trial.

The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study, supported by Novartis, is an international clinical trial that compared the potent bisphosphonate with placebo in 2,127 patients followed for a mean of 2 years, the investigators reported on the New England Journal of Medicine Web site. “No other controlled clinical trial has previously shown efficacy of any osteoporosis medication for reducing the recurrence of fracture in patients who already had a broken hip,” Dr. Karim Calis and Dr. Frank Pucino wrote in an editorial accompanying the report.

All subjects sustained a hip fracture after minimal trauma and underwent surgical repair, then received their first intravenous infusion within 90 days. They received daily oral calcium and vitamin D supplements, and were allowed concomitant therapy with nasal calcitonin, selective estrogen receptor modulators, hormone therapy, tibolone, or external hip protectors. A total of 1,065 patients were randomly assigned to IV zoledronic acid and 1,062 to IV placebo once yearly. Mean age was 74 years.

A total of 424 new clinical fractures occurred during follow-up. The rate was 8.6% with zoledronic acid and 13.9% with placebo, for a reduction in relative risk of 35%, said Dr. Lyles, of Duke University Medical Center, Durham, N.C. A total of 242 subjects died. Mortality was 9.6% with zoledronic acid and 13.3% with placebo, for a significant 28% relative risk reduction.

Bone mineral density (BMD) at the hip increased 2.6% at 1 year, 4.7% at 2 years, and 5.5% at 3 years in the zoledronic acid group. In the placebo group it fell 1.0%, 0.7%, and 0.9%, respectively. BMD at the femoral neck increased 0.8%, 2.2%, and 3.6% in the zoledronic acid group. It declined in the placebo group 1.0%, 0.7%, and 0.9%. All differences were significant (N. Engl. J. Med. 2007 Sept. 17 [Epub doi:10.1056/NEJMoa074941]).

Rates of overall adverse events and serious adverse events were similar. There were no differences in frequencies of cardiovascular adverse effects nor in rates of renal toxic effects. There were no cases of osteonecrosis of the jaw, which research suggested might be tied to zoledronic acid. There was no evidence of delayed bone healing, either.

In their comment, Dr. Calis and Dr. Pucino, both of the National Institutes of Health, Bethesda, Md., wrote, “Zoledronic acid appears to offer several advantages over other potential therapies, with one important caveat: Although the risk-benefit pendulum has now swung in favor of treatment, additional long-term safety data are essential,” (N. Engl. J. Med. 2007 Sept. 17 [Epub10.10565/N EJMe078192]). Future studies should compare treatment with other therapies and address physical function, quality of life, and cost-effectiveness, they added.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Investigational bone imaging techniques hold the promise of providing clinically useful information about bone structure in three dimensions unattainable with dual-energy x-ray absorptiometry, Mary L. Bouxsein, Ph.D., said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

While dual-energy x-ray absorptiometry (DXA) measurements show moderate to strong correlations with whole bone strength, the technique cannot distinguish specific attributes of three-dimensional geometry, cortical versus cancellous density, trabecular architecture, or intrinsic properties of the bone matrix.

However, there are some exciting newer techniques, although they are currently in the research phase, said Dr. Bouxsein of Harvard Medical School, Boston.

She highlighted the advantages and limitations of five promising novel imaging techniques:

▸ Hip strength analysis (HSA). This technique uses image data from 2-D DXA to derive 3-D geometry. Developed in the early 1980s, HSA uses data from the attenuation profile of the x-ray beam to calculate such things as cortical thickness and bone strength. But HSA makes several assumptions, most notably that there is constant mineral density in the bone and that the neck and shaft of bones are circular.

“This makes a lot of sense in measurements of long bone, and that was where it was first developed,” Dr. Bouxsein said. “Now where I think the challenge comes in … applying this exact same technique to measurement of the femoral neck. … It would be a big challenge to extract properties of the cortex using this direct method.”

One attraction of HSA is that it requires no new data collection, since researchers can reanalyze old DXA scans with this new technique. However, there is much more attention currently being focused on techniques that are truly three-dimensional.

▸ Quantitative computed tomography (QCT). With QCT, standard CT images are made with a bone-density “phantom” in the viewing area. This allows a quantitative measure of bone density in the final image and gives a 3-D view of bone geometry as well as an isolated look at the trabecular and cortical compartments.

The technique's precision, currently at about 2%–6%, is a bit worse than DXA, Dr. Bouxsein said. The radiation dose is higher than DXA, although still low enough to be acceptable for longitudinal studies.

The resolution is on the order of 300 mcm by 1 mm, somewhat too low to resolve individual trabecular elements, which measure about 100–300 mcm in the adult spine.

Studies have shown that QCT does show age- and treatment-related effects and is useful at both axial and peripheral sites. On the other hand, there are no prospective fracture data (although some are coming), reference data are limited, analysis methods are not yet standardized, and marrow fat can influence QCT measurements, with an increase in marrow fat resulting in an apparent decrease in trabecular bone mineral density (BMD).

▸ High-resolution peripheral quantitative CT (pQCT). This technique has become available within the past 2 years. It uses specialized equipment and can measure the peripheral skeleton, including the distal radius and distal tibia.

It has a voxel size of just 82 mcm

The technique's precision is quite good, with short-term reproducibility of 0.7%–1.3% for density and 0.9%–5.1% for microarchitecture. Because it's a peripheral technique, the patient receives a relatively low dose of radiation, and because it uses dedicated equipment, measurements are standardized. Using pQCT, researchers have been able to discriminate among osteopenic women with and without a history of fragility fracture, even when their BMDs are quite similar.

On the other hand, pQCT can't be used to measure central sites, and access is quite limited, with only about 10 machines in the world, including three in the United States. Clinical studies have so far been limited.

▸ High-resolution MRI (HR-MRI). This technique for trabecular bone uses standard clinical scanners and allows physicians to conduct virtual bone biopsies. The technique discriminates patients with a history of fragility fracture from controls, uses nonionizing radiation, and may be useful for monitoring response to treatment.

At the moment, HR-MRI can only be used at peripheral sites, although there is some potential for its use at the hip, Dr. Bouxsein noted.

Its resolution is a bit too low, at just about 100–300 mcm, but that is expected to improve with higher magnetic-field strengths.

Its short-term reproducibility, meanwhile, has been measured at a disappointing 3%–8%. Finally, the HR-MRI technique has been the subject of only limited clinical studies.

▸ Finite element analysis (FEA). Dr. Bouxsein said she was particularly excited about this technique, which is a standard engineering technique that has been used for decades to measure the mechanical properties of airliners and other complex structures. FEA for bone can provide multiple strength metrics.

In measuring bone strength, FEA integrates material and structural information from 3-D QCT to create a computer model of an individual patient's bone. That model is then subjected to virtual stresses and strains.

In vitro, FEA has been shown to predict both femoral and vertebral strength better than BMD measurements alone. But only a small number of clinical studies have been conducted.

The overall state of these promising techniques for noninvasive assessment of bone strength are useful “certainly for clinical research, certainly for clinical trials, [but] certainly not for clinical practice,” said Dr. Bouxsein.

“We don't have T scores or an absolute prediction of fracture risk. We don't yet have good evidence that we can use these to monitor therapy. We need several more years to figure out which one of these, if any, will make their way into clinical practice. [But] we've certainly learned a lot about the pathophysiology of this disease,” she added.

SAN FRANCISCO — Investigational bone imaging techniques hold the promise of providing clinically useful information about bone structure in three dimensions unattainable with dual-energy x-ray absorptiometry, Mary L. Bouxsein, Ph.D., said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

While dual-energy x-ray absorptiometry (DXA) measurements show moderate to strong correlations with whole bone strength, the technique cannot distinguish specific attributes of three-dimensional geometry, cortical versus cancellous density, trabecular architecture, or intrinsic properties of the bone matrix.

However, there are some exciting newer techniques, although they are currently in the research phase, said Dr. Bouxsein of Harvard Medical School, Boston.

She highlighted the advantages and limitations of five promising novel imaging techniques:

▸ Hip strength analysis (HSA). This technique uses image data from 2-D DXA to derive 3-D geometry. Developed in the early 1980s, HSA uses data from the attenuation profile of the x-ray beam to calculate such things as cortical thickness and bone strength. But HSA makes several assumptions, most notably that there is constant mineral density in the bone and that the neck and shaft of bones are circular.

“This makes a lot of sense in measurements of long bone, and that was where it was first developed,” Dr. Bouxsein said. “Now where I think the challenge comes in … applying this exact same technique to measurement of the femoral neck. … It would be a big challenge to extract properties of the cortex using this direct method.”

One attraction of HSA is that it requires no new data collection, since researchers can reanalyze old DXA scans with this new technique. However, there is much more attention currently being focused on techniques that are truly three-dimensional.

▸ Quantitative computed tomography (QCT). With QCT, standard CT images are made with a bone-density “phantom” in the viewing area. This allows a quantitative measure of bone density in the final image and gives a 3-D view of bone geometry as well as an isolated look at the trabecular and cortical compartments.

The technique's precision, currently at about 2%–6%, is a bit worse than DXA, Dr. Bouxsein said. The radiation dose is higher than DXA, although still low enough to be acceptable for longitudinal studies.

The resolution is on the order of 300 mcm by 1 mm, somewhat too low to resolve individual trabecular elements, which measure about 100–300 mcm in the adult spine.

Studies have shown that QCT does show age- and treatment-related effects and is useful at both axial and peripheral sites. On the other hand, there are no prospective fracture data (although some are coming), reference data are limited, analysis methods are not yet standardized, and marrow fat can influence QCT measurements, with an increase in marrow fat resulting in an apparent decrease in trabecular bone mineral density (BMD).

▸ High-resolution peripheral quantitative CT (pQCT). This technique has become available within the past 2 years. It uses specialized equipment and can measure the peripheral skeleton, including the distal radius and distal tibia.

It has a voxel size of just 82 mcm

The technique's precision is quite good, with short-term reproducibility of 0.7%–1.3% for density and 0.9%–5.1% for microarchitecture. Because it's a peripheral technique, the patient receives a relatively low dose of radiation, and because it uses dedicated equipment, measurements are standardized. Using pQCT, researchers have been able to discriminate among osteopenic women with and without a history of fragility fracture, even when their BMDs are quite similar.

On the other hand, pQCT can't be used to measure central sites, and access is quite limited, with only about 10 machines in the world, including three in the United States. Clinical studies have so far been limited.

▸ High-resolution MRI (HR-MRI). This technique for trabecular bone uses standard clinical scanners and allows physicians to conduct virtual bone biopsies. The technique discriminates patients with a history of fragility fracture from controls, uses nonionizing radiation, and may be useful for monitoring response to treatment.

At the moment, HR-MRI can only be used at peripheral sites, although there is some potential for its use at the hip, Dr. Bouxsein noted.

Its resolution is a bit too low, at just about 100–300 mcm, but that is expected to improve with higher magnetic-field strengths.

Its short-term reproducibility, meanwhile, has been measured at a disappointing 3%–8%. Finally, the HR-MRI technique has been the subject of only limited clinical studies.

▸ Finite element analysis (FEA). Dr. Bouxsein said she was particularly excited about this technique, which is a standard engineering technique that has been used for decades to measure the mechanical properties of airliners and other complex structures. FEA for bone can provide multiple strength metrics.

In measuring bone strength, FEA integrates material and structural information from 3-D QCT to create a computer model of an individual patient's bone. That model is then subjected to virtual stresses and strains.

In vitro, FEA has been shown to predict both femoral and vertebral strength better than BMD measurements alone. But only a small number of clinical studies have been conducted.

The overall state of these promising techniques for noninvasive assessment of bone strength are useful “certainly for clinical research, certainly for clinical trials, [but] certainly not for clinical practice,” said Dr. Bouxsein.

“We don't have T scores or an absolute prediction of fracture risk. We don't yet have good evidence that we can use these to monitor therapy. We need several more years to figure out which one of these, if any, will make their way into clinical practice. [But] we've certainly learned a lot about the pathophysiology of this disease,” she added.

SAN FRANCISCO — Investigational bone imaging techniques hold the promise of providing clinically useful information about bone structure in three dimensions unattainable with dual-energy x-ray absorptiometry, Mary L. Bouxsein, Ph.D., said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

While dual-energy x-ray absorptiometry (DXA) measurements show moderate to strong correlations with whole bone strength, the technique cannot distinguish specific attributes of three-dimensional geometry, cortical versus cancellous density, trabecular architecture, or intrinsic properties of the bone matrix.

However, there are some exciting newer techniques, although they are currently in the research phase, said Dr. Bouxsein of Harvard Medical School, Boston.

She highlighted the advantages and limitations of five promising novel imaging techniques:

▸ Hip strength analysis (HSA). This technique uses image data from 2-D DXA to derive 3-D geometry. Developed in the early 1980s, HSA uses data from the attenuation profile of the x-ray beam to calculate such things as cortical thickness and bone strength. But HSA makes several assumptions, most notably that there is constant mineral density in the bone and that the neck and shaft of bones are circular.

“This makes a lot of sense in measurements of long bone, and that was where it was first developed,” Dr. Bouxsein said. “Now where I think the challenge comes in … applying this exact same technique to measurement of the femoral neck. … It would be a big challenge to extract properties of the cortex using this direct method.”

One attraction of HSA is that it requires no new data collection, since researchers can reanalyze old DXA scans with this new technique. However, there is much more attention currently being focused on techniques that are truly three-dimensional.

▸ Quantitative computed tomography (QCT). With QCT, standard CT images are made with a bone-density “phantom” in the viewing area. This allows a quantitative measure of bone density in the final image and gives a 3-D view of bone geometry as well as an isolated look at the trabecular and cortical compartments.

The technique's precision, currently at about 2%–6%, is a bit worse than DXA, Dr. Bouxsein said. The radiation dose is higher than DXA, although still low enough to be acceptable for longitudinal studies.

The resolution is on the order of 300 mcm by 1 mm, somewhat too low to resolve individual trabecular elements, which measure about 100–300 mcm in the adult spine.

Studies have shown that QCT does show age- and treatment-related effects and is useful at both axial and peripheral sites. On the other hand, there are no prospective fracture data (although some are coming), reference data are limited, analysis methods are not yet standardized, and marrow fat can influence QCT measurements, with an increase in marrow fat resulting in an apparent decrease in trabecular bone mineral density (BMD).

▸ High-resolution peripheral quantitative CT (pQCT). This technique has become available within the past 2 years. It uses specialized equipment and can measure the peripheral skeleton, including the distal radius and distal tibia.

It has a voxel size of just 82 mcm

The technique's precision is quite good, with short-term reproducibility of 0.7%–1.3% for density and 0.9%–5.1% for microarchitecture. Because it's a peripheral technique, the patient receives a relatively low dose of radiation, and because it uses dedicated equipment, measurements are standardized. Using pQCT, researchers have been able to discriminate among osteopenic women with and without a history of fragility fracture, even when their BMDs are quite similar.

On the other hand, pQCT can't be used to measure central sites, and access is quite limited, with only about 10 machines in the world, including three in the United States. Clinical studies have so far been limited.

▸ High-resolution MRI (HR-MRI). This technique for trabecular bone uses standard clinical scanners and allows physicians to conduct virtual bone biopsies. The technique discriminates patients with a history of fragility fracture from controls, uses nonionizing radiation, and may be useful for monitoring response to treatment.

At the moment, HR-MRI can only be used at peripheral sites, although there is some potential for its use at the hip, Dr. Bouxsein noted.

Its resolution is a bit too low, at just about 100–300 mcm, but that is expected to improve with higher magnetic-field strengths.

Its short-term reproducibility, meanwhile, has been measured at a disappointing 3%–8%. Finally, the HR-MRI technique has been the subject of only limited clinical studies.

▸ Finite element analysis (FEA). Dr. Bouxsein said she was particularly excited about this technique, which is a standard engineering technique that has been used for decades to measure the mechanical properties of airliners and other complex structures. FEA for bone can provide multiple strength metrics.

In measuring bone strength, FEA integrates material and structural information from 3-D QCT to create a computer model of an individual patient's bone. That model is then subjected to virtual stresses and strains.

In vitro, FEA has been shown to predict both femoral and vertebral strength better than BMD measurements alone. But only a small number of clinical studies have been conducted.

The overall state of these promising techniques for noninvasive assessment of bone strength are useful “certainly for clinical research, certainly for clinical trials, [but] certainly not for clinical practice,” said Dr. Bouxsein.

“We don't have T scores or an absolute prediction of fracture risk. We don't yet have good evidence that we can use these to monitor therapy. We need several more years to figure out which one of these, if any, will make their way into clinical practice. [But] we've certainly learned a lot about the pathophysiology of this disease,” she added.

The intravenous bisphosphonate zoledronic acid (Reclast) has been approved as the first treatment for postmenopausal osteoporosis that is administered once a year.

The approved dosage of zoledronic acid is a single 5-mg infusion given intravenously, over no less than 15 minutes, annually. The approval was announced in August by the drug's manufacturer, Novartis Pharmaceuticals Corporation.

The 5-mg formulation of intravenous zoledronic acid was first approved earlier this year as a treatment for Paget disease. Zoledronic acid has been available in a 4-mg formulation (Zometa) for oncology indications, which is still available and should not be used in a patient taking Reclast.

Like other bisphosphonates, zoledronic acid inhibits osteoclast-mediated bone resorption. Daily, weekly, or monthly dosing schedules for oral bisphosphonate drugs previously have been approved by the Food and Drug Administration. An injectable form of the bisphosphonate ibandronate (Boniva) is approved for use every 3 months for postmenopausal osteoporosis.

The average wholesale acquisition price for each zoledronic acid 5-mg dose is $1,041.00, but the retail price may vary, a Novartis spokesperson said.

Approval for the osteoporosis indication was based on a 3-year, international study of more than 7,700 women with postmenopausal osteoporosis, the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial.

The study, which was published in May, found that women who received an annual 5-mg intravenous infusion of zoledronic acid had a 70% lower risk of vertebral fractures over a 3-year period, compared with women who were taking placebo.

Vertebral fracture occurred in 3.3% of the zoledronic acid group and 10.9% of the placebo group (N. Engl. J. Med. 2007;356:1809-22).

Hip fracture occurred in 1.4% of the zoledronic acid group and 2.5% of the placebo group, which represented a 41% reduction in the risk of hip fracture with active treatment.

Compared with placebo, zoledronic acid treatment also was associated with a significant reduction in nonvertebral fractures, clinical fractures, and clinical vertebral fractures, and significant improvements in bone mineral density and bone metabolism markers. These differences between groups were all statistically significant.

“Given the relatively poor adherence to oral bisphosphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk,” the study authors concluded.

The study was supported by Novartis, and two authors were from Novartis.

“This is the first study where we have evidence for [a reduction in] spine, hip, and non-vertebral fractures all in the same trial,” Dr. Nelson B. Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, said in an interview. Dr. Watts, one of the investigators in the trial, said that based on these efficacy data, he ranks this drug with the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), which also have been shown to reduce the risks of these three significant fracture types.

Dr. Watts disclosed that he is a consultant to Novartis.

He attributes part of the drug's effectiveness to compliance. “Once the patients receive the dose, they have at least a year's worth of drug on board,” he said, noting that one of the problems with treating silent diseases like osteoporosis is that a substantial proportion of patients stop taking the drug within 6-7 months of starting treatment for the disease.

Dr. Watts said that about one-third of patients have an acute phase response, with a fever, muscle aches, and other flu-like symptoms, but if they are premedicated with acetaminophen or ibuprofen, they are less likely to have those symptoms, or the symptoms, if they occur, are less severe.

This is also a first-dose phenomenon, so whether patients do or do not have these symptoms with the first dose, they are unlikely to experience the symptoms with subsequent doses, he added.

The intravenous bisphosphonate zoledronic acid (Reclast) has been approved as the first treatment for postmenopausal osteoporosis that is administered once a year.

The approved dosage of zoledronic acid is a single 5-mg infusion given intravenously, over no less than 15 minutes, annually. The approval was announced in August by the drug's manufacturer, Novartis Pharmaceuticals Corporation.

The 5-mg formulation of intravenous zoledronic acid was first approved earlier this year as a treatment for Paget disease. Zoledronic acid has been available in a 4-mg formulation (Zometa) for oncology indications, which is still available and should not be used in a patient taking Reclast.

Like other bisphosphonates, zoledronic acid inhibits osteoclast-mediated bone resorption. Daily, weekly, or monthly dosing schedules for oral bisphosphonate drugs previously have been approved by the Food and Drug Administration. An injectable form of the bisphosphonate ibandronate (Boniva) is approved for use every 3 months for postmenopausal osteoporosis.

The average wholesale acquisition price for each zoledronic acid 5-mg dose is $1,041.00, but the retail price may vary, a Novartis spokesperson said.

Approval for the osteoporosis indication was based on a 3-year, international study of more than 7,700 women with postmenopausal osteoporosis, the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial.

The study, which was published in May, found that women who received an annual 5-mg intravenous infusion of zoledronic acid had a 70% lower risk of vertebral fractures over a 3-year period, compared with women who were taking placebo.

Vertebral fracture occurred in 3.3% of the zoledronic acid group and 10.9% of the placebo group (N. Engl. J. Med. 2007;356:1809-22).

Hip fracture occurred in 1.4% of the zoledronic acid group and 2.5% of the placebo group, which represented a 41% reduction in the risk of hip fracture with active treatment.

Compared with placebo, zoledronic acid treatment also was associated with a significant reduction in nonvertebral fractures, clinical fractures, and clinical vertebral fractures, and significant improvements in bone mineral density and bone metabolism markers. These differences between groups were all statistically significant.

“Given the relatively poor adherence to oral bisphosphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk,” the study authors concluded.

The study was supported by Novartis, and two authors were from Novartis.

“This is the first study where we have evidence for [a reduction in] spine, hip, and non-vertebral fractures all in the same trial,” Dr. Nelson B. Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, said in an interview. Dr. Watts, one of the investigators in the trial, said that based on these efficacy data, he ranks this drug with the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), which also have been shown to reduce the risks of these three significant fracture types.

Dr. Watts disclosed that he is a consultant to Novartis.

He attributes part of the drug's effectiveness to compliance. “Once the patients receive the dose, they have at least a year's worth of drug on board,” he said, noting that one of the problems with treating silent diseases like osteoporosis is that a substantial proportion of patients stop taking the drug within 6-7 months of starting treatment for the disease.

Dr. Watts said that about one-third of patients have an acute phase response, with a fever, muscle aches, and other flu-like symptoms, but if they are premedicated with acetaminophen or ibuprofen, they are less likely to have those symptoms, or the symptoms, if they occur, are less severe.

This is also a first-dose phenomenon, so whether patients do or do not have these symptoms with the first dose, they are unlikely to experience the symptoms with subsequent doses, he added.

The intravenous bisphosphonate zoledronic acid (Reclast) has been approved as the first treatment for postmenopausal osteoporosis that is administered once a year.

The approved dosage of zoledronic acid is a single 5-mg infusion given intravenously, over no less than 15 minutes, annually. The approval was announced in August by the drug's manufacturer, Novartis Pharmaceuticals Corporation.

The 5-mg formulation of intravenous zoledronic acid was first approved earlier this year as a treatment for Paget disease. Zoledronic acid has been available in a 4-mg formulation (Zometa) for oncology indications, which is still available and should not be used in a patient taking Reclast.

Like other bisphosphonates, zoledronic acid inhibits osteoclast-mediated bone resorption. Daily, weekly, or monthly dosing schedules for oral bisphosphonate drugs previously have been approved by the Food and Drug Administration. An injectable form of the bisphosphonate ibandronate (Boniva) is approved for use every 3 months for postmenopausal osteoporosis.

The average wholesale acquisition price for each zoledronic acid 5-mg dose is $1,041.00, but the retail price may vary, a Novartis spokesperson said.

Approval for the osteoporosis indication was based on a 3-year, international study of more than 7,700 women with postmenopausal osteoporosis, the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial.

The study, which was published in May, found that women who received an annual 5-mg intravenous infusion of zoledronic acid had a 70% lower risk of vertebral fractures over a 3-year period, compared with women who were taking placebo.

Vertebral fracture occurred in 3.3% of the zoledronic acid group and 10.9% of the placebo group (N. Engl. J. Med. 2007;356:1809-22).

Hip fracture occurred in 1.4% of the zoledronic acid group and 2.5% of the placebo group, which represented a 41% reduction in the risk of hip fracture with active treatment.

Compared with placebo, zoledronic acid treatment also was associated with a significant reduction in nonvertebral fractures, clinical fractures, and clinical vertebral fractures, and significant improvements in bone mineral density and bone metabolism markers. These differences between groups were all statistically significant.

“Given the relatively poor adherence to oral bisphosphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk,” the study authors concluded.

The study was supported by Novartis, and two authors were from Novartis.

“This is the first study where we have evidence for [a reduction in] spine, hip, and non-vertebral fractures all in the same trial,” Dr. Nelson B. Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, said in an interview. Dr. Watts, one of the investigators in the trial, said that based on these efficacy data, he ranks this drug with the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), which also have been shown to reduce the risks of these three significant fracture types.

Dr. Watts disclosed that he is a consultant to Novartis.

He attributes part of the drug's effectiveness to compliance. “Once the patients receive the dose, they have at least a year's worth of drug on board,” he said, noting that one of the problems with treating silent diseases like osteoporosis is that a substantial proportion of patients stop taking the drug within 6-7 months of starting treatment for the disease.

Dr. Watts said that about one-third of patients have an acute phase response, with a fever, muscle aches, and other flu-like symptoms, but if they are premedicated with acetaminophen or ibuprofen, they are less likely to have those symptoms, or the symptoms, if they occur, are less severe.

This is also a first-dose phenomenon, so whether patients do or do not have these symptoms with the first dose, they are unlikely to experience the symptoms with subsequent doses, he added.

A new assessment index based on six easily accessible variables effectively predicts the risk of nonvertebral fractures in postmenopausal osteoporotic women, a study has shown.

Because of its efficacy and clinical convenience, the new tool can be used to help in the identification and management of high-risk patients, reported lead investigator Dr. Christian Roux of Université de Paris Descartes, and colleagues.

The effect of a given osteoporosis treatment on nonvertebral fracture risk is a potential determinant of treatment choice. As such, the assessment of nonvertebral fracture risk in postmenopausal women with osteoporosis has important management implications, the authors wrote. Because risk assessment in this population can be difficult, in that multiple variables such as type and mechanism of fracture can impact an individual's risk profile, the investigators sought to identify significant predictive factors from which to develop a clinical useful fracture-risk-assessment tool.

Toward this end, they analyzed 3 years of follow-up data from 2,546 postmenopausal osteoporotic women who had been in the placebo groups of three multicenter, randomized controlled trials of the biphosphonate risendronate.

At baseline, the mean age of the study participants was 72 years, the mean femoral T score was −2.5, and 60% and 53% had prevalent vertebral and nonvertebral fractures, respectively.

All of the participants received 1,000 mg of calcium daily and up to 500 IU of vitamin D daily if baseline serum hydroxyvitamin D was less than 16 ng/mL (Ann. Rheum. Dis. 2007;66:931–35).

During the 3-year follow up, 222 nonvertebral fractures were observed in 206 patients. Of 14 variables included in logistic regression analysis of the fracture group, 6 emerged as independent predictors of nonvertebral fracture risk: age, height, prior nonvertebral fracture, number of prevalent vertebral fractures, femoral neck T score, and serum 25-hydroxyvitamin D, the authors reported.

With respect to vitamin D, “In the 48 patients who had a baseline serum hydroxyvitamin D less than 16 ng/mL, the incidence of nonvertebral fractures was 14.58%,” compared with 8.25% among the patients whose baseline measure was 16 ng/mL or higher, the authors wrote.

“Although patients received supplements of calcium and vitamin D, the low baseline level of 25-hydroxyvitamin D was still a significant risk factor for fracture, which may be related to a long-term effect of sarcopenia due to vitamin D deficiency,” they stated.

Based on the odds ratios for fracture associated with each of these variables, the investigators calculated fracture-risk index values for intervals within each variable, adjusting the minimal possible index contribution for each variable to zero (see index value chart).

For example, the risk index value for patients younger than 65 years is 0, while the index value for patients 80 years or older is 0.8.

The area under the receiver operating characteristic (ROC) curve for the final model based on the six predictors was 0.66. To minimize the absolute difference between sensitivity and specificity in the ROC curve, the investigators selected a cut-off value of 0.086 (or 8.6% nonvertebral fracture risk at baseline) for the predicted probability of nonvertebral fracture.

According to the model, patients with an index value of 2.1 or higher belong to a subgroup at high risk for nonvertebral fracture, the authors wrote.

In the 998 women from the original study population with an index value of at least 2.1, “the incidence of nonvertebral fractures was 13.2%, 1.5 times higher than the average of the population,” they noted.

One of the study's primary limitations is the lack of information on falls, which was not available.

This “ignored parameter” can be of crucial importance in explaining the fractures and may be useful in explaining the low value of the ROC curve, according to the researchers.

Still, the study findings suggest that “among osteoporotic women, a proportion of patients with a high risk of nonvertebral fractures can be selected and an index is a convenient tool for this selection in clinical practice,” the authors concluded.

ELSEVIER GLOBAL MEDICAL NEWS

A new assessment index based on six easily accessible variables effectively predicts the risk of nonvertebral fractures in postmenopausal osteoporotic women, a study has shown.

Because of its efficacy and clinical convenience, the new tool can be used to help in the identification and management of high-risk patients, reported lead investigator Dr. Christian Roux of Université de Paris Descartes, and colleagues.

The effect of a given osteoporosis treatment on nonvertebral fracture risk is a potential determinant of treatment choice. As such, the assessment of nonvertebral fracture risk in postmenopausal women with osteoporosis has important management implications, the authors wrote. Because risk assessment in this population can be difficult, in that multiple variables such as type and mechanism of fracture can impact an individual's risk profile, the investigators sought to identify significant predictive factors from which to develop a clinical useful fracture-risk-assessment tool.

Toward this end, they analyzed 3 years of follow-up data from 2,546 postmenopausal osteoporotic women who had been in the placebo groups of three multicenter, randomized controlled trials of the biphosphonate risendronate.

At baseline, the mean age of the study participants was 72 years, the mean femoral T score was −2.5, and 60% and 53% had prevalent vertebral and nonvertebral fractures, respectively.

All of the participants received 1,000 mg of calcium daily and up to 500 IU of vitamin D daily if baseline serum hydroxyvitamin D was less than 16 ng/mL (Ann. Rheum. Dis. 2007;66:931–35).

During the 3-year follow up, 222 nonvertebral fractures were observed in 206 patients. Of 14 variables included in logistic regression analysis of the fracture group, 6 emerged as independent predictors of nonvertebral fracture risk: age, height, prior nonvertebral fracture, number of prevalent vertebral fractures, femoral neck T score, and serum 25-hydroxyvitamin D, the authors reported.

With respect to vitamin D, “In the 48 patients who had a baseline serum hydroxyvitamin D less than 16 ng/mL, the incidence of nonvertebral fractures was 14.58%,” compared with 8.25% among the patients whose baseline measure was 16 ng/mL or higher, the authors wrote.

“Although patients received supplements of calcium and vitamin D, the low baseline level of 25-hydroxyvitamin D was still a significant risk factor for fracture, which may be related to a long-term effect of sarcopenia due to vitamin D deficiency,” they stated.

Based on the odds ratios for fracture associated with each of these variables, the investigators calculated fracture-risk index values for intervals within each variable, adjusting the minimal possible index contribution for each variable to zero (see index value chart).

For example, the risk index value for patients younger than 65 years is 0, while the index value for patients 80 years or older is 0.8.

The area under the receiver operating characteristic (ROC) curve for the final model based on the six predictors was 0.66. To minimize the absolute difference between sensitivity and specificity in the ROC curve, the investigators selected a cut-off value of 0.086 (or 8.6% nonvertebral fracture risk at baseline) for the predicted probability of nonvertebral fracture.

According to the model, patients with an index value of 2.1 or higher belong to a subgroup at high risk for nonvertebral fracture, the authors wrote.

In the 998 women from the original study population with an index value of at least 2.1, “the incidence of nonvertebral fractures was 13.2%, 1.5 times higher than the average of the population,” they noted.

One of the study's primary limitations is the lack of information on falls, which was not available.

This “ignored parameter” can be of crucial importance in explaining the fractures and may be useful in explaining the low value of the ROC curve, according to the researchers.

Still, the study findings suggest that “among osteoporotic women, a proportion of patients with a high risk of nonvertebral fractures can be selected and an index is a convenient tool for this selection in clinical practice,” the authors concluded.

ELSEVIER GLOBAL MEDICAL NEWS

A new assessment index based on six easily accessible variables effectively predicts the risk of nonvertebral fractures in postmenopausal osteoporotic women, a study has shown.

Because of its efficacy and clinical convenience, the new tool can be used to help in the identification and management of high-risk patients, reported lead investigator Dr. Christian Roux of Université de Paris Descartes, and colleagues.

The effect of a given osteoporosis treatment on nonvertebral fracture risk is a potential determinant of treatment choice. As such, the assessment of nonvertebral fracture risk in postmenopausal women with osteoporosis has important management implications, the authors wrote. Because risk assessment in this population can be difficult, in that multiple variables such as type and mechanism of fracture can impact an individual's risk profile, the investigators sought to identify significant predictive factors from which to develop a clinical useful fracture-risk-assessment tool.

Toward this end, they analyzed 3 years of follow-up data from 2,546 postmenopausal osteoporotic women who had been in the placebo groups of three multicenter, randomized controlled trials of the biphosphonate risendronate.

At baseline, the mean age of the study participants was 72 years, the mean femoral T score was −2.5, and 60% and 53% had prevalent vertebral and nonvertebral fractures, respectively.

All of the participants received 1,000 mg of calcium daily and up to 500 IU of vitamin D daily if baseline serum hydroxyvitamin D was less than 16 ng/mL (Ann. Rheum. Dis. 2007;66:931–35).

During the 3-year follow up, 222 nonvertebral fractures were observed in 206 patients. Of 14 variables included in logistic regression analysis of the fracture group, 6 emerged as independent predictors of nonvertebral fracture risk: age, height, prior nonvertebral fracture, number of prevalent vertebral fractures, femoral neck T score, and serum 25-hydroxyvitamin D, the authors reported.

With respect to vitamin D, “In the 48 patients who had a baseline serum hydroxyvitamin D less than 16 ng/mL, the incidence of nonvertebral fractures was 14.58%,” compared with 8.25% among the patients whose baseline measure was 16 ng/mL or higher, the authors wrote.

“Although patients received supplements of calcium and vitamin D, the low baseline level of 25-hydroxyvitamin D was still a significant risk factor for fracture, which may be related to a long-term effect of sarcopenia due to vitamin D deficiency,” they stated.

Based on the odds ratios for fracture associated with each of these variables, the investigators calculated fracture-risk index values for intervals within each variable, adjusting the minimal possible index contribution for each variable to zero (see index value chart).

For example, the risk index value for patients younger than 65 years is 0, while the index value for patients 80 years or older is 0.8.

The area under the receiver operating characteristic (ROC) curve for the final model based on the six predictors was 0.66. To minimize the absolute difference between sensitivity and specificity in the ROC curve, the investigators selected a cut-off value of 0.086 (or 8.6% nonvertebral fracture risk at baseline) for the predicted probability of nonvertebral fracture.

According to the model, patients with an index value of 2.1 or higher belong to a subgroup at high risk for nonvertebral fracture, the authors wrote.

In the 998 women from the original study population with an index value of at least 2.1, “the incidence of nonvertebral fractures was 13.2%, 1.5 times higher than the average of the population,” they noted.

One of the study's primary limitations is the lack of information on falls, which was not available.

This “ignored parameter” can be of crucial importance in explaining the fractures and may be useful in explaining the low value of the ROC curve, according to the researchers.

Still, the study findings suggest that “among osteoporotic women, a proportion of patients with a high risk of nonvertebral fractures can be selected and an index is a convenient tool for this selection in clinical practice,” the authors concluded.

ELSEVIER GLOBAL MEDICAL NEWS

MONTREAL — The decreased reliance on brute force and manual labor for human survival during the past few thousand years has taken a toll on bone density, anthropologist Christopher B. Ruff, Ph.D., said at the 17th Scientific Meeting of the International Bone and Mineral Society.

This conclusion comes from a review of archaeological samples of human long bones, reported Dr. Ruff of the center for functional anatomy and evolution, Johns Hopkins University, Baltimore. The modern human genus essentially originated about 2 million years ago. Using cross sections of long bones as a measurement of bone strength reveals that, between 2 million and 8,000 years ago, bone strength relative to body size in humans steadily diminished. Extrapolating the trend to modern times reveals modern humans have bone strength about 30% below what would be expected if the trend had continued. “There are many different possible explanations for this, but my preferred explanation is an environmental one relating to mechanical loading and muscle activity effects,” said Dr. Ruff. Over time but especially in the past few thousand years, modern advances have meant brute force and manual labor are less important for survival. This trend demonstrates how important mechanical loading is for bone strength. The price, of course, is today's increased incidence of osteoporotic fractures.

Archaeological samples also shed light on normal growth and developmental patterns in bone. “Patterns of growth and development are very ancient,” said Dr. Ruff. Computed tomography of the bones of 31 children of various ages who died more than a million years ago reveals a pattern of periosteal expansion, followed, around adolescence, by endosteal expansion and then contraction. Studies of modern tennis players who began practicing the sport at different ages reveal that the same pattern of bone growth persists today.

In addition to revealing these patterns of bone growth, archaeological samples also allow for identifying differences between males and females. For instance, marked endosteal contraction occurs in late adolescence in the female femur but is less apparent in the upper limbs; endosteal contraction occurs equally in upper and lower limbs in men. Both systemic factors, such as hormones, and mechanical factors, such as differences in body size, account for these differences, said Dr. Ruff.

Comparing humans to other species reveals an important difference: Although primates, who use all four limbs for locomotion, have similar bone strength in their upper and lower limbs, bipedal humans have stronger lower limbs than upper limbs. This difference starts to develop after about 1 year of age, because humans are generally quadrupedal in their first year of life. Recognizing this helps archaeologists identify when humans first relied primarily on their lower limbs for locomotion. It also reveals that differences between child and adult skeletons and the growth patterns that lead from one to the other have been maintained for at least 2 million years.

During the past 2 million years, patterns of bone growth and development have remained remarkably stable in humans, allowing for the use of archaeological samples to better understand the bones of modern man. “Archaeological samples tend to be more homogeneous genetically and environmentally, so you get a cleaner signal,” said Dr. Ruff. “They are [from] very similar populations with similar diets, similar activity levels. Skeletal material is available for all ages, as opposed to autopsy samples, where it's very difficult to find younger individuals, and [archaeological samples] can serve as a useful baseline for comparison with really modern samples.”

There are disadvantages to using archaeological samples, however. These include the need to rely on cross-sectional study designs, the potential bias inherent in only being able to study the skeletons that have survived this long, and the inability to reliably determine the sex of the skeletons of humans who died before adolescence or in old age.

MONTREAL — The decreased reliance on brute force and manual labor for human survival during the past few thousand years has taken a toll on bone density, anthropologist Christopher B. Ruff, Ph.D., said at the 17th Scientific Meeting of the International Bone and Mineral Society.

This conclusion comes from a review of archaeological samples of human long bones, reported Dr. Ruff of the center for functional anatomy and evolution, Johns Hopkins University, Baltimore. The modern human genus essentially originated about 2 million years ago. Using cross sections of long bones as a measurement of bone strength reveals that, between 2 million and 8,000 years ago, bone strength relative to body size in humans steadily diminished. Extrapolating the trend to modern times reveals modern humans have bone strength about 30% below what would be expected if the trend had continued. “There are many different possible explanations for this, but my preferred explanation is an environmental one relating to mechanical loading and muscle activity effects,” said Dr. Ruff. Over time but especially in the past few thousand years, modern advances have meant brute force and manual labor are less important for survival. This trend demonstrates how important mechanical loading is for bone strength. The price, of course, is today's increased incidence of osteoporotic fractures.

Archaeological samples also shed light on normal growth and developmental patterns in bone. “Patterns of growth and development are very ancient,” said Dr. Ruff. Computed tomography of the bones of 31 children of various ages who died more than a million years ago reveals a pattern of periosteal expansion, followed, around adolescence, by endosteal expansion and then contraction. Studies of modern tennis players who began practicing the sport at different ages reveal that the same pattern of bone growth persists today.

In addition to revealing these patterns of bone growth, archaeological samples also allow for identifying differences between males and females. For instance, marked endosteal contraction occurs in late adolescence in the female femur but is less apparent in the upper limbs; endosteal contraction occurs equally in upper and lower limbs in men. Both systemic factors, such as hormones, and mechanical factors, such as differences in body size, account for these differences, said Dr. Ruff.

Comparing humans to other species reveals an important difference: Although primates, who use all four limbs for locomotion, have similar bone strength in their upper and lower limbs, bipedal humans have stronger lower limbs than upper limbs. This difference starts to develop after about 1 year of age, because humans are generally quadrupedal in their first year of life. Recognizing this helps archaeologists identify when humans first relied primarily on their lower limbs for locomotion. It also reveals that differences between child and adult skeletons and the growth patterns that lead from one to the other have been maintained for at least 2 million years.

During the past 2 million years, patterns of bone growth and development have remained remarkably stable in humans, allowing for the use of archaeological samples to better understand the bones of modern man. “Archaeological samples tend to be more homogeneous genetically and environmentally, so you get a cleaner signal,” said Dr. Ruff. “They are [from] very similar populations with similar diets, similar activity levels. Skeletal material is available for all ages, as opposed to autopsy samples, where it's very difficult to find younger individuals, and [archaeological samples] can serve as a useful baseline for comparison with really modern samples.”

There are disadvantages to using archaeological samples, however. These include the need to rely on cross-sectional study designs, the potential bias inherent in only being able to study the skeletons that have survived this long, and the inability to reliably determine the sex of the skeletons of humans who died before adolescence or in old age.

MONTREAL — The decreased reliance on brute force and manual labor for human survival during the past few thousand years has taken a toll on bone density, anthropologist Christopher B. Ruff, Ph.D., said at the 17th Scientific Meeting of the International Bone and Mineral Society.

This conclusion comes from a review of archaeological samples of human long bones, reported Dr. Ruff of the center for functional anatomy and evolution, Johns Hopkins University, Baltimore. The modern human genus essentially originated about 2 million years ago. Using cross sections of long bones as a measurement of bone strength reveals that, between 2 million and 8,000 years ago, bone strength relative to body size in humans steadily diminished. Extrapolating the trend to modern times reveals modern humans have bone strength about 30% below what would be expected if the trend had continued. “There are many different possible explanations for this, but my preferred explanation is an environmental one relating to mechanical loading and muscle activity effects,” said Dr. Ruff. Over time but especially in the past few thousand years, modern advances have meant brute force and manual labor are less important for survival. This trend demonstrates how important mechanical loading is for bone strength. The price, of course, is today's increased incidence of osteoporotic fractures.

Archaeological samples also shed light on normal growth and developmental patterns in bone. “Patterns of growth and development are very ancient,” said Dr. Ruff. Computed tomography of the bones of 31 children of various ages who died more than a million years ago reveals a pattern of periosteal expansion, followed, around adolescence, by endosteal expansion and then contraction. Studies of modern tennis players who began practicing the sport at different ages reveal that the same pattern of bone growth persists today.

In addition to revealing these patterns of bone growth, archaeological samples also allow for identifying differences between males and females. For instance, marked endosteal contraction occurs in late adolescence in the female femur but is less apparent in the upper limbs; endosteal contraction occurs equally in upper and lower limbs in men. Both systemic factors, such as hormones, and mechanical factors, such as differences in body size, account for these differences, said Dr. Ruff.

Comparing humans to other species reveals an important difference: Although primates, who use all four limbs for locomotion, have similar bone strength in their upper and lower limbs, bipedal humans have stronger lower limbs than upper limbs. This difference starts to develop after about 1 year of age, because humans are generally quadrupedal in their first year of life. Recognizing this helps archaeologists identify when humans first relied primarily on their lower limbs for locomotion. It also reveals that differences between child and adult skeletons and the growth patterns that lead from one to the other have been maintained for at least 2 million years.

During the past 2 million years, patterns of bone growth and development have remained remarkably stable in humans, allowing for the use of archaeological samples to better understand the bones of modern man. “Archaeological samples tend to be more homogeneous genetically and environmentally, so you get a cleaner signal,” said Dr. Ruff. “They are [from] very similar populations with similar diets, similar activity levels. Skeletal material is available for all ages, as opposed to autopsy samples, where it's very difficult to find younger individuals, and [archaeological samples] can serve as a useful baseline for comparison with really modern samples.”

There are disadvantages to using archaeological samples, however. These include the need to rely on cross-sectional study designs, the potential bias inherent in only being able to study the skeletons that have survived this long, and the inability to reliably determine the sex of the skeletons of humans who died before adolescence or in old age.

MONTREAL — Antiresorptive drugs reduce the risk of low-trauma, nonvertebral fractures in women over 50, and women with a prevalent fracture or frank osteoporosis have most to gain from these drugs, according to a study presented at the annual meeting of the International Bone and Mineral Society.

Dr. Suzanne Morin, of McGill University, Montreal, and colleagues obtained data from the Canadian Multicentre Osteoporosis Study (CaMos), in which more than 6,000 women over age 50 were randomly selected from across Canada. Demographics, medical history, and bone mineral density (BMD) were collected.

The researchers conducted a case-control analysis of the data. Women with self-reported incident low-trauma fractures, excluding fractures of the head, hands, feet or vertebrae, were matched with controls with respect to time in study, age, prevalent osteoporosis, prevalent vertebral deformity, prior clinical low-trauma fracture, and baseline BMD availability; 477 cases and 1,377 controls were included. Among cases, 37% were current users of antiresorptive agents (estrogen, bisphosphonates, selective estrogen receptor modulators [SERMs], and calcitonin) versus 41% of controls. Antiresorptive drug use was tied to an adjusted odds ratio of 0.68 for risk of a low-trauma fracture. Among those with a prevalent fracture or a BMD indicative of osteoporosis, OR was 0.58, versus 0.88 for women with neither of these risk factors.

MONTREAL — Antiresorptive drugs reduce the risk of low-trauma, nonvertebral fractures in women over 50, and women with a prevalent fracture or frank osteoporosis have most to gain from these drugs, according to a study presented at the annual meeting of the International Bone and Mineral Society.

Dr. Suzanne Morin, of McGill University, Montreal, and colleagues obtained data from the Canadian Multicentre Osteoporosis Study (CaMos), in which more than 6,000 women over age 50 were randomly selected from across Canada. Demographics, medical history, and bone mineral density (BMD) were collected.

The researchers conducted a case-control analysis of the data. Women with self-reported incident low-trauma fractures, excluding fractures of the head, hands, feet or vertebrae, were matched with controls with respect to time in study, age, prevalent osteoporosis, prevalent vertebral deformity, prior clinical low-trauma fracture, and baseline BMD availability; 477 cases and 1,377 controls were included. Among cases, 37% were current users of antiresorptive agents (estrogen, bisphosphonates, selective estrogen receptor modulators [SERMs], and calcitonin) versus 41% of controls. Antiresorptive drug use was tied to an adjusted odds ratio of 0.68 for risk of a low-trauma fracture. Among those with a prevalent fracture or a BMD indicative of osteoporosis, OR was 0.58, versus 0.88 for women with neither of these risk factors.

MONTREAL — Antiresorptive drugs reduce the risk of low-trauma, nonvertebral fractures in women over 50, and women with a prevalent fracture or frank osteoporosis have most to gain from these drugs, according to a study presented at the annual meeting of the International Bone and Mineral Society.

Dr. Suzanne Morin, of McGill University, Montreal, and colleagues obtained data from the Canadian Multicentre Osteoporosis Study (CaMos), in which more than 6,000 women over age 50 were randomly selected from across Canada. Demographics, medical history, and bone mineral density (BMD) were collected.

The researchers conducted a case-control analysis of the data. Women with self-reported incident low-trauma fractures, excluding fractures of the head, hands, feet or vertebrae, were matched with controls with respect to time in study, age, prevalent osteoporosis, prevalent vertebral deformity, prior clinical low-trauma fracture, and baseline BMD availability; 477 cases and 1,377 controls were included. Among cases, 37% were current users of antiresorptive agents (estrogen, bisphosphonates, selective estrogen receptor modulators [SERMs], and calcitonin) versus 41% of controls. Antiresorptive drug use was tied to an adjusted odds ratio of 0.68 for risk of a low-trauma fracture. Among those with a prevalent fracture or a BMD indicative of osteoporosis, OR was 0.58, versus 0.88 for women with neither of these risk factors.