Kerri Wachter

DENVER — The investigational agent denosumab continued to increase bone mineral density in osteoporotic postmenopausal women during 6 years of continuous use, based on the results of an extension of a phase II study including 412 women.

“Over a period of 6 years, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women,” Dr. Paul Miller said at the annual meeting of the American Society for Bone and Mineral Research.

These findings support earlier ones involving shorter follow-up of twice-yearly injections of denosumab in over 7,000 osteoporotic postmenopausal women.

The 93 patients on denosumab 60 mg for 6 years had a continued increase in spine BMD, with a mean cumulative increase from baseline in spine BMD of 13%. In addition, the reduction in resorption, as measured by serum C-telopeptide (CTX) levels, was sustained and plateaued over the course of continuous denosumab treatment.

The study was sponsored by Amgen Inc., which is developing the drug. Dr. Miller reported significant financial relationships with several pharmaceutical companies that make osteoporosis treatments, including Amgen.

In the parent trial, 412 women were randomized to receive denosumab, open-label oral alendronate (70 mg/wk), or placebo. All participants took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU). The 2-year data were published in Bone in 2008 (43:222-9).

At the end of the first 2 years, patients were reallocated. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. The placebo group was maintained. In the extension phase of the study, all patients received denosumab 60 mg every 6 months for 2 more years.

The 16 patients who had been on placebo for 4 years and were switched to denosumab 60 mg every 6 months for the last 2 years had gains in spine BMD that were comparable to those observed in the first 2 years of the trial for patients on denosumab 60 mg every 6 months. Similar results were obtained for hip BMD. Patients on denosumab for 6 years had an average cumulative hip BMD increase of 6%.

“The forearm data … are interesting because forearm BMD increased in the denosumab groups, unlike the other antiresorptive agents that have consistently shown a decrease,” said Dr. Miller, whose group practice in Lakewood, Colo., specializes in treatment of osteoporosis.

In an earlier trial of denosumab, results show a significant decrease in the risk of fractures during 36 months of twice-yearly injections in 7,868 postmenopausal women with osteoporosis, compared with placebo injections (N. Engl. J. Med. 2009 [doi:10.1056/NEJM0a0809493]). The study was funded by Amgen.

Earlier this year, the Food and Drug Administration's Advisory Committee for Reproductive Health Drugs voted that the benefits of denosumab to treat osteoporosis in postmenopausal women outweighed its risks, but the committee did not support use of the drug to prevent osteoporosis.

Amgen was seeking approval of the human IgG2 monoclonal antibody to treat and prevent bone loss in women with breast cancer receiving hormone ablation therapy and to treat and prevent bone loss in men with prostate cancer receiving androgen deprivation therapy.

The committee declined to support most of those uses, primarily because of concerns about long-term safety. Its members did vote 9-4 that the benefits outweighed the risks in treating bone loss in prostate cancer.

The panel voted unanimously that denosumab's benefits outweighed its risks in postmenopausal women, but because of questions about its long-term impact on bone turnover and immunogenicity, suggested that the drug should be limited to those at high risk for fracture or with a history of fracture.

Sherry Boschert and Alicia Ault contributed to this report.

DENVER — The investigational agent denosumab continued to increase bone mineral density in osteoporotic postmenopausal women during 6 years of continuous use, based on the results of an extension of a phase II study including 412 women.

“Over a period of 6 years, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women,” Dr. Paul Miller said at the annual meeting of the American Society for Bone and Mineral Research.

These findings support earlier ones involving shorter follow-up of twice-yearly injections of denosumab in over 7,000 osteoporotic postmenopausal women.

The 93 patients on denosumab 60 mg for 6 years had a continued increase in spine BMD, with a mean cumulative increase from baseline in spine BMD of 13%. In addition, the reduction in resorption, as measured by serum C-telopeptide (CTX) levels, was sustained and plateaued over the course of continuous denosumab treatment.

The study was sponsored by Amgen Inc., which is developing the drug. Dr. Miller reported significant financial relationships with several pharmaceutical companies that make osteoporosis treatments, including Amgen.

In the parent trial, 412 women were randomized to receive denosumab, open-label oral alendronate (70 mg/wk), or placebo. All participants took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU). The 2-year data were published in Bone in 2008 (43:222-9).

At the end of the first 2 years, patients were reallocated. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. The placebo group was maintained. In the extension phase of the study, all patients received denosumab 60 mg every 6 months for 2 more years.

The 16 patients who had been on placebo for 4 years and were switched to denosumab 60 mg every 6 months for the last 2 years had gains in spine BMD that were comparable to those observed in the first 2 years of the trial for patients on denosumab 60 mg every 6 months. Similar results were obtained for hip BMD. Patients on denosumab for 6 years had an average cumulative hip BMD increase of 6%.

“The forearm data … are interesting because forearm BMD increased in the denosumab groups, unlike the other antiresorptive agents that have consistently shown a decrease,” said Dr. Miller, whose group practice in Lakewood, Colo., specializes in treatment of osteoporosis.

In an earlier trial of denosumab, results show a significant decrease in the risk of fractures during 36 months of twice-yearly injections in 7,868 postmenopausal women with osteoporosis, compared with placebo injections (N. Engl. J. Med. 2009 [doi:10.1056/NEJM0a0809493]). The study was funded by Amgen.

Earlier this year, the Food and Drug Administration's Advisory Committee for Reproductive Health Drugs voted that the benefits of denosumab to treat osteoporosis in postmenopausal women outweighed its risks, but the committee did not support use of the drug to prevent osteoporosis.

Amgen was seeking approval of the human IgG2 monoclonal antibody to treat and prevent bone loss in women with breast cancer receiving hormone ablation therapy and to treat and prevent bone loss in men with prostate cancer receiving androgen deprivation therapy.

The committee declined to support most of those uses, primarily because of concerns about long-term safety. Its members did vote 9-4 that the benefits outweighed the risks in treating bone loss in prostate cancer.

The panel voted unanimously that denosumab's benefits outweighed its risks in postmenopausal women, but because of questions about its long-term impact on bone turnover and immunogenicity, suggested that the drug should be limited to those at high risk for fracture or with a history of fracture.

Sherry Boschert and Alicia Ault contributed to this report.

DENVER — The investigational agent denosumab continued to increase bone mineral density in osteoporotic postmenopausal women during 6 years of continuous use, based on the results of an extension of a phase II study including 412 women.

“Over a period of 6 years, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women,” Dr. Paul Miller said at the annual meeting of the American Society for Bone and Mineral Research.

These findings support earlier ones involving shorter follow-up of twice-yearly injections of denosumab in over 7,000 osteoporotic postmenopausal women.

The 93 patients on denosumab 60 mg for 6 years had a continued increase in spine BMD, with a mean cumulative increase from baseline in spine BMD of 13%. In addition, the reduction in resorption, as measured by serum C-telopeptide (CTX) levels, was sustained and plateaued over the course of continuous denosumab treatment.

The study was sponsored by Amgen Inc., which is developing the drug. Dr. Miller reported significant financial relationships with several pharmaceutical companies that make osteoporosis treatments, including Amgen.

In the parent trial, 412 women were randomized to receive denosumab, open-label oral alendronate (70 mg/wk), or placebo. All participants took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU). The 2-year data were published in Bone in 2008 (43:222-9).

At the end of the first 2 years, patients were reallocated. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. The placebo group was maintained. In the extension phase of the study, all patients received denosumab 60 mg every 6 months for 2 more years.

The 16 patients who had been on placebo for 4 years and were switched to denosumab 60 mg every 6 months for the last 2 years had gains in spine BMD that were comparable to those observed in the first 2 years of the trial for patients on denosumab 60 mg every 6 months. Similar results were obtained for hip BMD. Patients on denosumab for 6 years had an average cumulative hip BMD increase of 6%.

“The forearm data … are interesting because forearm BMD increased in the denosumab groups, unlike the other antiresorptive agents that have consistently shown a decrease,” said Dr. Miller, whose group practice in Lakewood, Colo., specializes in treatment of osteoporosis.

In an earlier trial of denosumab, results show a significant decrease in the risk of fractures during 36 months of twice-yearly injections in 7,868 postmenopausal women with osteoporosis, compared with placebo injections (N. Engl. J. Med. 2009 [doi:10.1056/NEJM0a0809493]). The study was funded by Amgen.

Earlier this year, the Food and Drug Administration's Advisory Committee for Reproductive Health Drugs voted that the benefits of denosumab to treat osteoporosis in postmenopausal women outweighed its risks, but the committee did not support use of the drug to prevent osteoporosis.

Amgen was seeking approval of the human IgG2 monoclonal antibody to treat and prevent bone loss in women with breast cancer receiving hormone ablation therapy and to treat and prevent bone loss in men with prostate cancer receiving androgen deprivation therapy.

The committee declined to support most of those uses, primarily because of concerns about long-term safety. Its members did vote 9-4 that the benefits outweighed the risks in treating bone loss in prostate cancer.

The panel voted unanimously that denosumab's benefits outweighed its risks in postmenopausal women, but because of questions about its long-term impact on bone turnover and immunogenicity, suggested that the drug should be limited to those at high risk for fracture or with a history of fracture.

Sherry Boschert and Alicia Ault contributed to this report.

DENVER — Significant predictors of receiving a bisphosphonate prescription within 90 days of a fracture for women are a low bone mineral density score after a fracture, being aged 65–74 years, and oral corticosteroid use, according to the results of a study of 2,000 women.

Women with a bone mineral density (BMD) T score of −2.5 or less in the 90 days after a fracture were almost five times as likely to receive a bisphosphonate prescription than women with higher T scores, Carl Asche, Ph.D., said in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

Women who were aged 65–74 years at the time of fracture were almost twice as likely to receive a prescription, compared with woman younger than 65. Similarly, women taking oral corticosteroids also were more likely to receive a bisphosphonate prescription, wrote Dr. Asche of the pharmacotherapy department at the University of Utah, Salt Lake City.

With use of electronic health records from Geisinger Health System from Jan. 1, 2000, to June 30, 2007, women 50 years of age and older who had had a fracture were included. They also had to have continuous electronic health record activity for at least 365 days before and 365 days after the index date (the date of the fracture). Women were excluded if they had a diagnosis of osteoporosis, a bone mineral density score of −2.5 or less at the time of the fracture, a fracture in the 6 months prior to the index date, or a diagnosis of conditions known to impact bone density and quality.

They considered age, race, body mass index (BMI), BMD score 90 days after the fracture, smoking status, Charlson comorbidity index, oral corticosteroid use, and rheumatoid arthritis to be potential predictors of bisphosphonate prescription—alendronate (Fosamax), ibandron-ate (Boniva), or risedronate (Actonel).

A total of 2,000 women met the inclusion criteria, but less than 10% (188) received a prescription for a bisphosphonate within 90 days of fracture. “Very few women aged [over] 50 receive treatment with an oral bisphosphonate after having a fracture, leaving them potentially vulnerable to future fractures,” he noted.

Obese patients (BMI 30–39.9 kg/m

The study was supported by the Alliance for Better Bone Health—Procter & Gamble Pharmaceuticals and Sanofi-Aventis U.S., which co-promote Actonel. Dr. Asche reported that he has a significant financial relationship with Sanofi-Aventis U.S.

DENVER — Significant predictors of receiving a bisphosphonate prescription within 90 days of a fracture for women are a low bone mineral density score after a fracture, being aged 65–74 years, and oral corticosteroid use, according to the results of a study of 2,000 women.

Women with a bone mineral density (BMD) T score of −2.5 or less in the 90 days after a fracture were almost five times as likely to receive a bisphosphonate prescription than women with higher T scores, Carl Asche, Ph.D., said in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

Women who were aged 65–74 years at the time of fracture were almost twice as likely to receive a prescription, compared with woman younger than 65. Similarly, women taking oral corticosteroids also were more likely to receive a bisphosphonate prescription, wrote Dr. Asche of the pharmacotherapy department at the University of Utah, Salt Lake City.

With use of electronic health records from Geisinger Health System from Jan. 1, 2000, to June 30, 2007, women 50 years of age and older who had had a fracture were included. They also had to have continuous electronic health record activity for at least 365 days before and 365 days after the index date (the date of the fracture). Women were excluded if they had a diagnosis of osteoporosis, a bone mineral density score of −2.5 or less at the time of the fracture, a fracture in the 6 months prior to the index date, or a diagnosis of conditions known to impact bone density and quality.

They considered age, race, body mass index (BMI), BMD score 90 days after the fracture, smoking status, Charlson comorbidity index, oral corticosteroid use, and rheumatoid arthritis to be potential predictors of bisphosphonate prescription—alendronate (Fosamax), ibandron-ate (Boniva), or risedronate (Actonel).

A total of 2,000 women met the inclusion criteria, but less than 10% (188) received a prescription for a bisphosphonate within 90 days of fracture. “Very few women aged [over] 50 receive treatment with an oral bisphosphonate after having a fracture, leaving them potentially vulnerable to future fractures,” he noted.

Obese patients (BMI 30–39.9 kg/m

The study was supported by the Alliance for Better Bone Health—Procter & Gamble Pharmaceuticals and Sanofi-Aventis U.S., which co-promote Actonel. Dr. Asche reported that he has a significant financial relationship with Sanofi-Aventis U.S.

DENVER — Significant predictors of receiving a bisphosphonate prescription within 90 days of a fracture for women are a low bone mineral density score after a fracture, being aged 65–74 years, and oral corticosteroid use, according to the results of a study of 2,000 women.

Women with a bone mineral density (BMD) T score of −2.5 or less in the 90 days after a fracture were almost five times as likely to receive a bisphosphonate prescription than women with higher T scores, Carl Asche, Ph.D., said in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

Women who were aged 65–74 years at the time of fracture were almost twice as likely to receive a prescription, compared with woman younger than 65. Similarly, women taking oral corticosteroids also were more likely to receive a bisphosphonate prescription, wrote Dr. Asche of the pharmacotherapy department at the University of Utah, Salt Lake City.

With use of electronic health records from Geisinger Health System from Jan. 1, 2000, to June 30, 2007, women 50 years of age and older who had had a fracture were included. They also had to have continuous electronic health record activity for at least 365 days before and 365 days after the index date (the date of the fracture). Women were excluded if they had a diagnosis of osteoporosis, a bone mineral density score of −2.5 or less at the time of the fracture, a fracture in the 6 months prior to the index date, or a diagnosis of conditions known to impact bone density and quality.

They considered age, race, body mass index (BMI), BMD score 90 days after the fracture, smoking status, Charlson comorbidity index, oral corticosteroid use, and rheumatoid arthritis to be potential predictors of bisphosphonate prescription—alendronate (Fosamax), ibandron-ate (Boniva), or risedronate (Actonel).

A total of 2,000 women met the inclusion criteria, but less than 10% (188) received a prescription for a bisphosphonate within 90 days of fracture. “Very few women aged [over] 50 receive treatment with an oral bisphosphonate after having a fracture, leaving them potentially vulnerable to future fractures,” he noted.

Obese patients (BMI 30–39.9 kg/m

The study was supported by the Alliance for Better Bone Health—Procter & Gamble Pharmaceuticals and Sanofi-Aventis U.S., which co-promote Actonel. Dr. Asche reported that he has a significant financial relationship with Sanofi-Aventis U.S.

DENVER — Women who are encouraged to self-schedule their dual-energy x-ray absorptiometry scans via mailed brochures and letters undergo more scans than do those in usual practice, but it is still not a silver bullet strategy for identifying women who have osteoporosis.

In study of 3,734 women, mailings of an educational osteoporosis brochure and a letter providing the opportunity to self-schedule increased the percentage of women receiving dual-energy x-ray absorptiometry (DXA) scans by 13% versus routine care, Dr. Amy Warriner and her coinvestigators reported in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

The study involved 28 primary care physicians at the University of Alabama at Birmingham. The researchers identified women aged 65 years or older who had not had a DXA scan in the previous 4 years, and were under the care of a university primary care provider.

The participating providers were randomized to provide or not to provide an intervention.

Intervention-group physicians mailed brochures containing information about osteoporosis and fracture risk. The brochures were created using patient feedback from focus groups. Each mailing included a letter providing patients with the opportunity to self-schedule a DXA scan. Two mailings were sent to each woman.

In all, 665 women were randomized into the intervention group and 3,069 into the control group.

A total of 115 women in the intervention group were determined by their primary care providers not to be medically appropriate for DXA testing. Brochures and letters were mailed to the remaining 550 women.

In the intervention group, 19% of women received DXA scans. Half of these were self-scheduled and half were scheduled by the provider.

In comparison, only 6% of women in the control group had DXA scans. DXA scan self-scheduling and receipt was 13% better with a mailing intervention when compared with normal practice, the researchers noted.

“However, more potent strategies will still be needed to further improve DXA screening rates,” wrote Dr. Warriner, professor of medicine in the division of endocrinology and metabolism at the university.

The study was funded in part by Procter & Gamble, which comarkets the osteoporosis drug risedronate (Actonel).

Dr. Warriner reported that she has a significant financial relationship with Amgen Inc., which is developing the osteoporosis drug denosumab.

Her coinvestigators reported significant financial relationships with a number of pharmaceutical companies that make osteoporosis drugs.

DENVER — Women who are encouraged to self-schedule their dual-energy x-ray absorptiometry scans via mailed brochures and letters undergo more scans than do those in usual practice, but it is still not a silver bullet strategy for identifying women who have osteoporosis.

In study of 3,734 women, mailings of an educational osteoporosis brochure and a letter providing the opportunity to self-schedule increased the percentage of women receiving dual-energy x-ray absorptiometry (DXA) scans by 13% versus routine care, Dr. Amy Warriner and her coinvestigators reported in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

The study involved 28 primary care physicians at the University of Alabama at Birmingham. The researchers identified women aged 65 years or older who had not had a DXA scan in the previous 4 years, and were under the care of a university primary care provider.

The participating providers were randomized to provide or not to provide an intervention.

Intervention-group physicians mailed brochures containing information about osteoporosis and fracture risk. The brochures were created using patient feedback from focus groups. Each mailing included a letter providing patients with the opportunity to self-schedule a DXA scan. Two mailings were sent to each woman.

In all, 665 women were randomized into the intervention group and 3,069 into the control group.

A total of 115 women in the intervention group were determined by their primary care providers not to be medically appropriate for DXA testing. Brochures and letters were mailed to the remaining 550 women.

In the intervention group, 19% of women received DXA scans. Half of these were self-scheduled and half were scheduled by the provider.

In comparison, only 6% of women in the control group had DXA scans. DXA scan self-scheduling and receipt was 13% better with a mailing intervention when compared with normal practice, the researchers noted.

“However, more potent strategies will still be needed to further improve DXA screening rates,” wrote Dr. Warriner, professor of medicine in the division of endocrinology and metabolism at the university.

The study was funded in part by Procter & Gamble, which comarkets the osteoporosis drug risedronate (Actonel).

Dr. Warriner reported that she has a significant financial relationship with Amgen Inc., which is developing the osteoporosis drug denosumab.

Her coinvestigators reported significant financial relationships with a number of pharmaceutical companies that make osteoporosis drugs.

DENVER — Women who are encouraged to self-schedule their dual-energy x-ray absorptiometry scans via mailed brochures and letters undergo more scans than do those in usual practice, but it is still not a silver bullet strategy for identifying women who have osteoporosis.

In study of 3,734 women, mailings of an educational osteoporosis brochure and a letter providing the opportunity to self-schedule increased the percentage of women receiving dual-energy x-ray absorptiometry (DXA) scans by 13% versus routine care, Dr. Amy Warriner and her coinvestigators reported in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

The study involved 28 primary care physicians at the University of Alabama at Birmingham. The researchers identified women aged 65 years or older who had not had a DXA scan in the previous 4 years, and were under the care of a university primary care provider.

The participating providers were randomized to provide or not to provide an intervention.

Intervention-group physicians mailed brochures containing information about osteoporosis and fracture risk. The brochures were created using patient feedback from focus groups. Each mailing included a letter providing patients with the opportunity to self-schedule a DXA scan. Two mailings were sent to each woman.

In all, 665 women were randomized into the intervention group and 3,069 into the control group.

A total of 115 women in the intervention group were determined by their primary care providers not to be medically appropriate for DXA testing. Brochures and letters were mailed to the remaining 550 women.

In the intervention group, 19% of women received DXA scans. Half of these were self-scheduled and half were scheduled by the provider.

In comparison, only 6% of women in the control group had DXA scans. DXA scan self-scheduling and receipt was 13% better with a mailing intervention when compared with normal practice, the researchers noted.

“However, more potent strategies will still be needed to further improve DXA screening rates,” wrote Dr. Warriner, professor of medicine in the division of endocrinology and metabolism at the university.

The study was funded in part by Procter & Gamble, which comarkets the osteoporosis drug risedronate (Actonel).

Dr. Warriner reported that she has a significant financial relationship with Amgen Inc., which is developing the osteoporosis drug denosumab.

Her coinvestigators reported significant financial relationships with a number of pharmaceutical companies that make osteoporosis drugs.

DENVER — People on long-term glucocorticoids have a significant risk for fracture at relatively high bone mineral density T scores. As a result, physicians need to rethink their management of this population.

“In glucocorticoid osteoporosis, the fracture risk seems to take off quite dramatically somewhere around T scores of −1.5,” Dr. Philip Sambrook said during a clinical roundtable session on glucocorticoid-induced osteoporosis at the annual meeting of the American Society for Bone and Mineral Research. “Most of the guidelines around the world are now suggesting that the intervention threshold [for those on glucocorticoids] should be [a T score of] about −1.5.”

Patients on glucocorticoids typically have midline fractures of the vertebrae, where the bone just collapses in the middle of the vertebra.

“This is different from the anterior wedge fracture that occurs most commonly in postmenopausal women with osteoporosis,” noted Dr. Nancy Lane, who also participated in the roundtable session. This is because there are some differences in how bones become fragile in the presence of glucocorticoids. “A number of studies have shown that patients on glucocorticoids, for the most part, tend to fracture at bone densities that are greater than [those of] postmenopausal women with osteoporosis.”

Dr. Lane and her colleagues have followed bone density in mice that were exposed to moderate doses of glucocorticoids. They found that most of the bone loss occurred very quickly. At roughly a month (28 days), there was a 20% loss in trabecular vertebral bone mineral density (BMD) as measured by quantitative CT, a 3-D means of assessing bone volume. However, during days 28–56 there was little additional loss of bone mass. “Upon giving the mice glucocorticoids, we found that bone resorption went up very quickly,” said Dr. Lane, who is the director of the center for healthy aging at the University of California, Davis. By day 7, there was nearly a doubling in bone turnover as measured by CTx, a C-terminal telopeptide of type I collagen, which is a serum marker of bone resorption.

In addition, they found very little change in serum levels of osteocalcin (a biomarker of bone formation) for the first 7 days. Osteocalcin levels then began to decline. “It looks like glucocorticoids also change osteocyte gene expression,” she said.

Thus, with glucocorticoids, bone formation goes down and bone resorption goes up. “I always say that bone doesn't have a chance in the presence of glucocorticoids,” said Dr. Lane.

Dr. Sambrook, who heads the bone and joint group at the Kolling Institute of Medical Research of Royal North Shore Hospital in Sydney, presented cases that “really illustrate the type of patients that we often struggle with.”

Patient No. 1

A 66-year-old woman was recently diagnosed with polymyalgia rheumatica. She had been started on 25 mg/day prednisone and the disease activity lessened in response. Her history included chronic atopic dermatitis and hypothyroidism. She had no other medical problems. There was no family history of hip fracture. She did not smoke or drink. She had a slightly early menopause but had not used hormone therapy. She reported consuming one or two servings of dairy products daily. She also considered herself to be physically active, although she had no formal exercise program.

As part of her work-up, she had a spine x-ray, which showed a vertebral deformity (compression). BMD measurements showed modest osteopenia (T scores of −1.5 at the spine and −1.6 at the hip). She had normal levels of calcium and parathyroid hormone (PTH). Her vitamin D level was equivocal, however. Her thyroid function was normal.

This patient had modest osteopenia at the time of her diagnosis. Once she was started on glucocorticoids, her T scores could have fallen rapidly and then stabilized over time, without treatment for bone loss, said Dr. Sambrook. “As she becomes established on glucocorticoids, she will perhaps not lose that much bone,” but she's at risk of fracture.

So, when clinical trial data are interpreted, it's important to keep two clinical scenarios in mind: prevention (when initial rapid loss of bone is to be avoided) and treatment (when the patient is on chronic glucocorticoids and may not be losing a lot of bone but is still at risk for fracture).

“Most of us would believe that vitamin D [plus] calcium is an adjunctive therapy,” said Dr. Sambrook. The data appear to back that up. In a 1996 trial, patients with glucocorticoid osteoporosis were randomized to 50,000 U/week of vitamin D plus 1,000 mg/day of calcium, or placebo. Both groups lost bone at the spine quite rapidly, although there was a trend for patients on vitamin D and calcium to do slightly better (J. Rheumatol. 1996;23:995–1000).

Bisphosphonates do appear to improve bone density in these patients. In another study, researchers demonstrated that daily alendronate increases bone density in patients who receive glucocorticoid therapy, compared with those on placebo (N. Engl. J. Med. 1998;339:292–9). Similar results have been demonstrated with etidronate, risedronate, and zoledronic acid.

Dr. Sambrook recommended that the patient receive calcium and vitamin D supplementation. Also, “we would primarily give her bisphosphonates until prednisone is discontinued” and possibly beyond, depending on her overall fracture risk after prednisone treatment. It's also important to think about trying to minimize the dose of prednisone.

The woman returned for x-ray of the spine 2 years later. Her bone density was stable, although she had developed mild esophageal symptoms. On endoscopy, these were attributed to esophagitis. She was still taking low-dose prednisone, so she was switched to a different bisphosphonate.

Patient No. 2

A 24-year-old woman has had systemic lupus erythematosus for 3 years, and the disease has become severe over that time. Her SLE complications have included encephalitis, vasculitis, renal involvement, and deep vein thrombosis. She had no family history of osteoporosis. She did not consume much dietary calcium, although she claimed to get adequate sun exposure. She had been on an oral contraceptive since the age of 17. Her appetite and weight were average and stable.

At the time of her presentation, she had been on prednisone for 6 months, with dosages averaging 25–50 mg daily. However, the recent onset of renal complications required increasing the dose to 75 mg daily. She was also taking an antimalaria drug. Her vitamin D level was equivocal and needed to be addressed. She had normal calcium and PTH levels and normal thyroid function. However, her spine T score was −1.4 and her hip T score was −1.0.

The concern to Dr. Sambrook was the effect of bisphosphonates on the fetal development. Although the patient was not pregnant at the start of therapy, she might have become so intentionally or unintentionally. Bisphosphonates are classified as pregnancy category C drugs by the U.S. Food and Drug Administration, meaning that they are contraindicated in pregnancy.

“The reports that have been published so far have generally not identified any developmental or bone density abnormalities,” in association with prenatal exposure to bisphosphonates, Dr. Sambrook noted. Some reports have identified lower birth weight, lower gestational age at birth, and higher rates of spontaneous abortion with exposure to bisphosphonates.

“These have to be interpreted in context. These women are already ill—otherwise they wouldn't be on steroids—and that's going to affect those types of outcomes,” he cautioned.

In animal studies, in which pregnant animals have been subjected to 10 times the recommended human bisphosphonate dose, maternal toxicity, growth retardation, and fetal loss have been reported. “But these are very high doses. What do we see in real life?” Dr. Sambrook asked.

In a study from Canada published this year, researchers followed 21 women who were exposed to bisphosphonates either during or less than 3 months before pregnancy, and then compared them with matched control women. Outcomes were similar between the two groups, suggesting that preconceptional and first-trimester use of bisphosphonates may not pose substantial fetal risks (Bone 2009;44:428–30).

“These data are fairly reassuring in terms of the safety in patients treated prior to becoming pregnant or … if they become pregnant while on bisphosphonates,” he said. However, bisphosphonates should be stopped as soon as it's known that a patient is pregnant, if not prior to her becoming pregnant.

One approach to managing this patient is to simply watch her and measure BMD in 12 months. Another is to use a bisphosphonate in conjunction with vitamin D and calcium supplementation. Risedronate might be the better choice, given its quicker onset and offset of action, he said.

“As long as she stayed on prednisone, I might not be as aggressive as with postmenopausal women,” Dr. Sambrook noted. If the prednisone dose was decreased, he said that he might consider stopping bisphosphonate treatment.

Dr. Lane and Dr. Sambrook both reported significant financial relationships with several pharmaceutical companies.

Dual-energy x-ray absorptiometry provides “areal” BMD (g/cm

Source ©Elsevier

DENVER — People on long-term glucocorticoids have a significant risk for fracture at relatively high bone mineral density T scores. As a result, physicians need to rethink their management of this population.

“In glucocorticoid osteoporosis, the fracture risk seems to take off quite dramatically somewhere around T scores of −1.5,” Dr. Philip Sambrook said during a clinical roundtable session on glucocorticoid-induced osteoporosis at the annual meeting of the American Society for Bone and Mineral Research. “Most of the guidelines around the world are now suggesting that the intervention threshold [for those on glucocorticoids] should be [a T score of] about −1.5.”

Patients on glucocorticoids typically have midline fractures of the vertebrae, where the bone just collapses in the middle of the vertebra.

“This is different from the anterior wedge fracture that occurs most commonly in postmenopausal women with osteoporosis,” noted Dr. Nancy Lane, who also participated in the roundtable session. This is because there are some differences in how bones become fragile in the presence of glucocorticoids. “A number of studies have shown that patients on glucocorticoids, for the most part, tend to fracture at bone densities that are greater than [those of] postmenopausal women with osteoporosis.”

Dr. Lane and her colleagues have followed bone density in mice that were exposed to moderate doses of glucocorticoids. They found that most of the bone loss occurred very quickly. At roughly a month (28 days), there was a 20% loss in trabecular vertebral bone mineral density (BMD) as measured by quantitative CT, a 3-D means of assessing bone volume. However, during days 28–56 there was little additional loss of bone mass. “Upon giving the mice glucocorticoids, we found that bone resorption went up very quickly,” said Dr. Lane, who is the director of the center for healthy aging at the University of California, Davis. By day 7, there was nearly a doubling in bone turnover as measured by CTx, a C-terminal telopeptide of type I collagen, which is a serum marker of bone resorption.

In addition, they found very little change in serum levels of osteocalcin (a biomarker of bone formation) for the first 7 days. Osteocalcin levels then began to decline. “It looks like glucocorticoids also change osteocyte gene expression,” she said.

Thus, with glucocorticoids, bone formation goes down and bone resorption goes up. “I always say that bone doesn't have a chance in the presence of glucocorticoids,” said Dr. Lane.

Dr. Sambrook, who heads the bone and joint group at the Kolling Institute of Medical Research of Royal North Shore Hospital in Sydney, presented cases that “really illustrate the type of patients that we often struggle with.”

Patient No. 1

A 66-year-old woman was recently diagnosed with polymyalgia rheumatica. She had been started on 25 mg/day prednisone and the disease activity lessened in response. Her history included chronic atopic dermatitis and hypothyroidism. She had no other medical problems. There was no family history of hip fracture. She did not smoke or drink. She had a slightly early menopause but had not used hormone therapy. She reported consuming one or two servings of dairy products daily. She also considered herself to be physically active, although she had no formal exercise program.

As part of her work-up, she had a spine x-ray, which showed a vertebral deformity (compression). BMD measurements showed modest osteopenia (T scores of −1.5 at the spine and −1.6 at the hip). She had normal levels of calcium and parathyroid hormone (PTH). Her vitamin D level was equivocal, however. Her thyroid function was normal.

This patient had modest osteopenia at the time of her diagnosis. Once she was started on glucocorticoids, her T scores could have fallen rapidly and then stabilized over time, without treatment for bone loss, said Dr. Sambrook. “As she becomes established on glucocorticoids, she will perhaps not lose that much bone,” but she's at risk of fracture.

So, when clinical trial data are interpreted, it's important to keep two clinical scenarios in mind: prevention (when initial rapid loss of bone is to be avoided) and treatment (when the patient is on chronic glucocorticoids and may not be losing a lot of bone but is still at risk for fracture).

“Most of us would believe that vitamin D [plus] calcium is an adjunctive therapy,” said Dr. Sambrook. The data appear to back that up. In a 1996 trial, patients with glucocorticoid osteoporosis were randomized to 50,000 U/week of vitamin D plus 1,000 mg/day of calcium, or placebo. Both groups lost bone at the spine quite rapidly, although there was a trend for patients on vitamin D and calcium to do slightly better (J. Rheumatol. 1996;23:995–1000).

Bisphosphonates do appear to improve bone density in these patients. In another study, researchers demonstrated that daily alendronate increases bone density in patients who receive glucocorticoid therapy, compared with those on placebo (N. Engl. J. Med. 1998;339:292–9). Similar results have been demonstrated with etidronate, risedronate, and zoledronic acid.

Dr. Sambrook recommended that the patient receive calcium and vitamin D supplementation. Also, “we would primarily give her bisphosphonates until prednisone is discontinued” and possibly beyond, depending on her overall fracture risk after prednisone treatment. It's also important to think about trying to minimize the dose of prednisone.

The woman returned for x-ray of the spine 2 years later. Her bone density was stable, although she had developed mild esophageal symptoms. On endoscopy, these were attributed to esophagitis. She was still taking low-dose prednisone, so she was switched to a different bisphosphonate.

Patient No. 2

A 24-year-old woman has had systemic lupus erythematosus for 3 years, and the disease has become severe over that time. Her SLE complications have included encephalitis, vasculitis, renal involvement, and deep vein thrombosis. She had no family history of osteoporosis. She did not consume much dietary calcium, although she claimed to get adequate sun exposure. She had been on an oral contraceptive since the age of 17. Her appetite and weight were average and stable.

At the time of her presentation, she had been on prednisone for 6 months, with dosages averaging 25–50 mg daily. However, the recent onset of renal complications required increasing the dose to 75 mg daily. She was also taking an antimalaria drug. Her vitamin D level was equivocal and needed to be addressed. She had normal calcium and PTH levels and normal thyroid function. However, her spine T score was −1.4 and her hip T score was −1.0.

The concern to Dr. Sambrook was the effect of bisphosphonates on the fetal development. Although the patient was not pregnant at the start of therapy, she might have become so intentionally or unintentionally. Bisphosphonates are classified as pregnancy category C drugs by the U.S. Food and Drug Administration, meaning that they are contraindicated in pregnancy.

“The reports that have been published so far have generally not identified any developmental or bone density abnormalities,” in association with prenatal exposure to bisphosphonates, Dr. Sambrook noted. Some reports have identified lower birth weight, lower gestational age at birth, and higher rates of spontaneous abortion with exposure to bisphosphonates.

“These have to be interpreted in context. These women are already ill—otherwise they wouldn't be on steroids—and that's going to affect those types of outcomes,” he cautioned.

In animal studies, in which pregnant animals have been subjected to 10 times the recommended human bisphosphonate dose, maternal toxicity, growth retardation, and fetal loss have been reported. “But these are very high doses. What do we see in real life?” Dr. Sambrook asked.

In a study from Canada published this year, researchers followed 21 women who were exposed to bisphosphonates either during or less than 3 months before pregnancy, and then compared them with matched control women. Outcomes were similar between the two groups, suggesting that preconceptional and first-trimester use of bisphosphonates may not pose substantial fetal risks (Bone 2009;44:428–30).

“These data are fairly reassuring in terms of the safety in patients treated prior to becoming pregnant or … if they become pregnant while on bisphosphonates,” he said. However, bisphosphonates should be stopped as soon as it's known that a patient is pregnant, if not prior to her becoming pregnant.

One approach to managing this patient is to simply watch her and measure BMD in 12 months. Another is to use a bisphosphonate in conjunction with vitamin D and calcium supplementation. Risedronate might be the better choice, given its quicker onset and offset of action, he said.

“As long as she stayed on prednisone, I might not be as aggressive as with postmenopausal women,” Dr. Sambrook noted. If the prednisone dose was decreased, he said that he might consider stopping bisphosphonate treatment.

Dr. Lane and Dr. Sambrook both reported significant financial relationships with several pharmaceutical companies.

Dual-energy x-ray absorptiometry provides “areal” BMD (g/cm

Source ©Elsevier

DENVER — People on long-term glucocorticoids have a significant risk for fracture at relatively high bone mineral density T scores. As a result, physicians need to rethink their management of this population.

“In glucocorticoid osteoporosis, the fracture risk seems to take off quite dramatically somewhere around T scores of −1.5,” Dr. Philip Sambrook said during a clinical roundtable session on glucocorticoid-induced osteoporosis at the annual meeting of the American Society for Bone and Mineral Research. “Most of the guidelines around the world are now suggesting that the intervention threshold [for those on glucocorticoids] should be [a T score of] about −1.5.”

Patients on glucocorticoids typically have midline fractures of the vertebrae, where the bone just collapses in the middle of the vertebra.

“This is different from the anterior wedge fracture that occurs most commonly in postmenopausal women with osteoporosis,” noted Dr. Nancy Lane, who also participated in the roundtable session. This is because there are some differences in how bones become fragile in the presence of glucocorticoids. “A number of studies have shown that patients on glucocorticoids, for the most part, tend to fracture at bone densities that are greater than [those of] postmenopausal women with osteoporosis.”

Dr. Lane and her colleagues have followed bone density in mice that were exposed to moderate doses of glucocorticoids. They found that most of the bone loss occurred very quickly. At roughly a month (28 days), there was a 20% loss in trabecular vertebral bone mineral density (BMD) as measured by quantitative CT, a 3-D means of assessing bone volume. However, during days 28–56 there was little additional loss of bone mass. “Upon giving the mice glucocorticoids, we found that bone resorption went up very quickly,” said Dr. Lane, who is the director of the center for healthy aging at the University of California, Davis. By day 7, there was nearly a doubling in bone turnover as measured by CTx, a C-terminal telopeptide of type I collagen, which is a serum marker of bone resorption.

In addition, they found very little change in serum levels of osteocalcin (a biomarker of bone formation) for the first 7 days. Osteocalcin levels then began to decline. “It looks like glucocorticoids also change osteocyte gene expression,” she said.

Thus, with glucocorticoids, bone formation goes down and bone resorption goes up. “I always say that bone doesn't have a chance in the presence of glucocorticoids,” said Dr. Lane.

Dr. Sambrook, who heads the bone and joint group at the Kolling Institute of Medical Research of Royal North Shore Hospital in Sydney, presented cases that “really illustrate the type of patients that we often struggle with.”

Patient No. 1

A 66-year-old woman was recently diagnosed with polymyalgia rheumatica. She had been started on 25 mg/day prednisone and the disease activity lessened in response. Her history included chronic atopic dermatitis and hypothyroidism. She had no other medical problems. There was no family history of hip fracture. She did not smoke or drink. She had a slightly early menopause but had not used hormone therapy. She reported consuming one or two servings of dairy products daily. She also considered herself to be physically active, although she had no formal exercise program.

As part of her work-up, she had a spine x-ray, which showed a vertebral deformity (compression). BMD measurements showed modest osteopenia (T scores of −1.5 at the spine and −1.6 at the hip). She had normal levels of calcium and parathyroid hormone (PTH). Her vitamin D level was equivocal, however. Her thyroid function was normal.

This patient had modest osteopenia at the time of her diagnosis. Once she was started on glucocorticoids, her T scores could have fallen rapidly and then stabilized over time, without treatment for bone loss, said Dr. Sambrook. “As she becomes established on glucocorticoids, she will perhaps not lose that much bone,” but she's at risk of fracture.

So, when clinical trial data are interpreted, it's important to keep two clinical scenarios in mind: prevention (when initial rapid loss of bone is to be avoided) and treatment (when the patient is on chronic glucocorticoids and may not be losing a lot of bone but is still at risk for fracture).

“Most of us would believe that vitamin D [plus] calcium is an adjunctive therapy,” said Dr. Sambrook. The data appear to back that up. In a 1996 trial, patients with glucocorticoid osteoporosis were randomized to 50,000 U/week of vitamin D plus 1,000 mg/day of calcium, or placebo. Both groups lost bone at the spine quite rapidly, although there was a trend for patients on vitamin D and calcium to do slightly better (J. Rheumatol. 1996;23:995–1000).

Bisphosphonates do appear to improve bone density in these patients. In another study, researchers demonstrated that daily alendronate increases bone density in patients who receive glucocorticoid therapy, compared with those on placebo (N. Engl. J. Med. 1998;339:292–9). Similar results have been demonstrated with etidronate, risedronate, and zoledronic acid.

Dr. Sambrook recommended that the patient receive calcium and vitamin D supplementation. Also, “we would primarily give her bisphosphonates until prednisone is discontinued” and possibly beyond, depending on her overall fracture risk after prednisone treatment. It's also important to think about trying to minimize the dose of prednisone.

The woman returned for x-ray of the spine 2 years later. Her bone density was stable, although she had developed mild esophageal symptoms. On endoscopy, these were attributed to esophagitis. She was still taking low-dose prednisone, so she was switched to a different bisphosphonate.

Patient No. 2

A 24-year-old woman has had systemic lupus erythematosus for 3 years, and the disease has become severe over that time. Her SLE complications have included encephalitis, vasculitis, renal involvement, and deep vein thrombosis. She had no family history of osteoporosis. She did not consume much dietary calcium, although she claimed to get adequate sun exposure. She had been on an oral contraceptive since the age of 17. Her appetite and weight were average and stable.

At the time of her presentation, she had been on prednisone for 6 months, with dosages averaging 25–50 mg daily. However, the recent onset of renal complications required increasing the dose to 75 mg daily. She was also taking an antimalaria drug. Her vitamin D level was equivocal and needed to be addressed. She had normal calcium and PTH levels and normal thyroid function. However, her spine T score was −1.4 and her hip T score was −1.0.

The concern to Dr. Sambrook was the effect of bisphosphonates on the fetal development. Although the patient was not pregnant at the start of therapy, she might have become so intentionally or unintentionally. Bisphosphonates are classified as pregnancy category C drugs by the U.S. Food and Drug Administration, meaning that they are contraindicated in pregnancy.

“The reports that have been published so far have generally not identified any developmental or bone density abnormalities,” in association with prenatal exposure to bisphosphonates, Dr. Sambrook noted. Some reports have identified lower birth weight, lower gestational age at birth, and higher rates of spontaneous abortion with exposure to bisphosphonates.

“These have to be interpreted in context. These women are already ill—otherwise they wouldn't be on steroids—and that's going to affect those types of outcomes,” he cautioned.

In animal studies, in which pregnant animals have been subjected to 10 times the recommended human bisphosphonate dose, maternal toxicity, growth retardation, and fetal loss have been reported. “But these are very high doses. What do we see in real life?” Dr. Sambrook asked.

In a study from Canada published this year, researchers followed 21 women who were exposed to bisphosphonates either during or less than 3 months before pregnancy, and then compared them with matched control women. Outcomes were similar between the two groups, suggesting that preconceptional and first-trimester use of bisphosphonates may not pose substantial fetal risks (Bone 2009;44:428–30).

“These data are fairly reassuring in terms of the safety in patients treated prior to becoming pregnant or … if they become pregnant while on bisphosphonates,” he said. However, bisphosphonates should be stopped as soon as it's known that a patient is pregnant, if not prior to her becoming pregnant.

One approach to managing this patient is to simply watch her and measure BMD in 12 months. Another is to use a bisphosphonate in conjunction with vitamin D and calcium supplementation. Risedronate might be the better choice, given its quicker onset and offset of action, he said.

“As long as she stayed on prednisone, I might not be as aggressive as with postmenopausal women,” Dr. Sambrook noted. If the prednisone dose was decreased, he said that he might consider stopping bisphosphonate treatment.

Dr. Lane and Dr. Sambrook both reported significant financial relationships with several pharmaceutical companies.

Dual-energy x-ray absorptiometry provides “areal” BMD (g/cm

Source ©Elsevier

Radiographs are no longer de rigeur in making the diagnosis of knee osteoarthritis, according to guidelines released by the European League Against Rheumatism last month. Clinical signs, symptoms, and risk factors are sufficient to make the diagnosis.

Yet x-rays and other imaging modalities continue to have a role in osteoarthritis, according to Dr. Ali Guermazi and Dr. David J. Hunter. At present, imaging should primarily be used in research rather than in clinical practice (where its use should be limited to ruling out other likely diagnoses), they agreed.

Imaging conveys information about the pathophysiology of OA and has provided insight into symptoms and progression, said Dr. Hunter, chief of the research division of New England Baptist Hospital in Boston. Ultimately, “it will help to define the best treatments for osteoarthritis,” he added. Imaging has the potential to “have wider clinical application, when we have an opportunity to intervene in earlier arthritis through modifying joint structural changes.”

Yet, there continues to be “widespread use of different imaging modalities in the clinical setting, where it's clear there is osteoarthritis.” Dr. Hunter estimated that 60%–70% of patients who present to him in the clinic have an MRI on CD with them. “It doesn't change the diagnosis or what I'm going to do for them, so I'm not sure that there's much rationale for having that at present.”

Each imaging modality has a role to play when assessing the pathophysiology of the whole joint. “Some of that role is complementary, but much of it is unique to that particular modality. … Each has its strengths and weaknesses.”

Dr. Guermazi and Dr. Hunter shared their thoughts on how various imaging modalities can further understanding of the pathophysiology of OA.

Radiograph

An x-ray is typically used only to rule out other diagnoses, said Dr. Hunter. These could include rheumatoid arthritis, gout, intra-articular loose bodies, and trauma. “These would be reasons to think about doing additional imaging.”

X-ray is still the most widely used imaging modality because it's relatively inexpensive, it's available, and it's relatively easy to interpret. X-rays are useful primarily for outlining the two-dimensional geometry of the bones. “You infer from the x-ray what the joint space is, and from that, the health and integrity of the cartilage, but it's an indirect inference and you really can't make any direct representations of other tissues,” Dr. Hunter said.

In addition, x-ray evaluates features that don't contribute to pain, which is the primary symptom of OA, said Dr. Guermazi, director of the quantitative imaging center and section chief of musculoskeletal imaging at Boston University. “If we look at joint space narrowing, thinking that this is the cartilage measure, [x-ray is] useless for many reasons. Arthritis is defined clinically as pain. Cartilage can't be painful because there are no nerves in it.”

Synovitis, effusions, and bone marrow lesions, however, can all be painful. “The only features that are not painful are the ones we are looking at on a radiograph, which are cartilage [inferred from the joint space narrowing] and osteophytes.”

Dr. Hunter noted that the imaging community is divided about whether the best way to monitor the structural progression of underlying disease is to measure joint space on x-ray or to measure other features—such as the cartilage itself—on an MRI.

MRI

The main strength of MRI as a research tool is its ability to provide information on many tissues in the joint. “On MRI, you're able to … see changes in the curvature of the bone, lesions within the bone [which demonstrate where focal loading is occurring, and] alterations within the cartilage itself. … You can see inflammation within the joint [such as synovitis or an effusion], the ligaments, and the muscle,” said Dr. Hunter.

“The more we're learning about osteoarthritis, the more we're realizing that much of the reason why a person has pain [and] functional limitation—and much of the reason why the joint progresses—has a lot more to do with the tissues in the joint other than cartilage,” Dr. Hunter said. “Bone marrow lesions, synovitis, and effusions appear to account for the majority of the reason why a person has pain. MRIs provide a lot of insight there,” he said.

Beyond the local-tissue reasons for a person to have symptoms, there is also some local alteration in the neurophysiology. “The communication between different nerve pathways that leads to sensitization of nerves occurs both peripherally and centrally, “Dr. Hunter said.

“If we are focused on symptomatic response, it's helpful to think about the contribution of all of those factors.” Nerve endings are present in specific tissues, particularly the bone and synovium.

In MRI, gadolinium contrast can be given intravenously or intra-articularly, said Dr. Guermazi. Intravenous contrast is useful for evaluating synovitis and differentiating it from effusions. Intra-articular contrast is useful for evaluating cartilage and meniscal lesions.

Among the several downsides of MRI are its cost and the time needed to acquire the images and to interpret them. MRIs of the knee or hip are acquired with the patient in a lying down or supine position; however, physiologically, the knee is probably best understood when those joints are bearing weight.

CT

CT is widely available and generally less expensive than MRI. Unlike dual-energy x-ray absorptiometry, CT imaging can provide information about volumetric density of the bone via changes in the periarticular density, Dr. Hunter said.

The chosen modality may depend on the joint to be imaged, said Dr. Guermazi. In the case of OA of the facet joints, osteophytosis and bone are better viewed with CT than MRI. However, much other information is lost. Although meniscal and anterior/posterior cruciate ligament lesions can be seen on contrast CT, bone marrow lesions cannot.

Ultrasound

“Intra-articular steroids appear to reduce the extent of inflammation in joints. That can be appreciated on ultrasound,” said Dr. Hunter. Ultrasound can also be used to guide the injection of corticosteroids. “Some of the therapies that are being developed are likely to be intra-articular, and ultrasound may be helpful in guiding the needle to the right spot.”

Ultrasound also is being used in some clinical trials to visualize synovitis, according to Dr. Guermazi. “I think it's promising, especially if you use Doppler and can see vascularity.” Doppler ultrasound can be used to identify and monitor active synovitis, after treatment.

Ultrasound is also able to assess the effect of biologic drugs—currently in testing for OA—on synovitis.

Ultrasound is inexpensive, but “it's very operator dependent,” said Dr. Guermazi. “Ultrasound tends to be used more widely outside the United States, where MRI may not be so readily available.”

Ultrasound allows visualization of ligaments, muscles, and tendons, but not bone, and it can visualize only tissues close to the skin and near the probe.

Therapy

Research into potential OA therapies now focuses on tissues that are likely to play a role symptomatically and structurally, rather than just concentrating on cartilage. Just as bBiologic drugs have made huge inroads in RA, “we're right at the cusp of that” with OA, said Dr. Guermazi. When “therapies do become available, the ability to identify OA in the early stages will be very important.”

X-rays can supply information about the structural progression of underlying disease, as evidenced by the osteophytic changes, subchondral bone sclerosis, and absence of joint space seen in an anteroposterior radiograph of the left knee in a 65-year-old woman with secondary arthritis at 9 years after treated fractures (at left). A lateral view (at right) confirms severe tibiofemoral OA and shows severe patellofemoral OA with large posterior femoral condyles (arrowhead) and tibial plateaus (arrow) not seen on the anteroposterior view.

Sagittal fat-suppressed proton density-weighted MRI shows diffuse cartilage loss of the lateral central weight-bearing tibia and femur. Also seen are a central lateral femur bone marrow lesion (arrow) and a small tibiofibular ganglion cyst (arrowhead).

CT can visualize volumetric density. Medial narrowing plus subchondral medial tibiofemoral bone sclerosis (arrows) and cystic changes are seen on coronal reformatted CT.

Source Images courtesy Dr. Ali Guermazi

Radiographs are no longer de rigeur in making the diagnosis of knee osteoarthritis, according to guidelines released by the European League Against Rheumatism last month. Clinical signs, symptoms, and risk factors are sufficient to make the diagnosis.

Yet x-rays and other imaging modalities continue to have a role in osteoarthritis, according to Dr. Ali Guermazi and Dr. David J. Hunter. At present, imaging should primarily be used in research rather than in clinical practice (where its use should be limited to ruling out other likely diagnoses), they agreed.

Imaging conveys information about the pathophysiology of OA and has provided insight into symptoms and progression, said Dr. Hunter, chief of the research division of New England Baptist Hospital in Boston. Ultimately, “it will help to define the best treatments for osteoarthritis,” he added. Imaging has the potential to “have wider clinical application, when we have an opportunity to intervene in earlier arthritis through modifying joint structural changes.”

Yet, there continues to be “widespread use of different imaging modalities in the clinical setting, where it's clear there is osteoarthritis.” Dr. Hunter estimated that 60%–70% of patients who present to him in the clinic have an MRI on CD with them. “It doesn't change the diagnosis or what I'm going to do for them, so I'm not sure that there's much rationale for having that at present.”

Each imaging modality has a role to play when assessing the pathophysiology of the whole joint. “Some of that role is complementary, but much of it is unique to that particular modality. … Each has its strengths and weaknesses.”

Dr. Guermazi and Dr. Hunter shared their thoughts on how various imaging modalities can further understanding of the pathophysiology of OA.

Radiograph

An x-ray is typically used only to rule out other diagnoses, said Dr. Hunter. These could include rheumatoid arthritis, gout, intra-articular loose bodies, and trauma. “These would be reasons to think about doing additional imaging.”

X-ray is still the most widely used imaging modality because it's relatively inexpensive, it's available, and it's relatively easy to interpret. X-rays are useful primarily for outlining the two-dimensional geometry of the bones. “You infer from the x-ray what the joint space is, and from that, the health and integrity of the cartilage, but it's an indirect inference and you really can't make any direct representations of other tissues,” Dr. Hunter said.

In addition, x-ray evaluates features that don't contribute to pain, which is the primary symptom of OA, said Dr. Guermazi, director of the quantitative imaging center and section chief of musculoskeletal imaging at Boston University. “If we look at joint space narrowing, thinking that this is the cartilage measure, [x-ray is] useless for many reasons. Arthritis is defined clinically as pain. Cartilage can't be painful because there are no nerves in it.”

Synovitis, effusions, and bone marrow lesions, however, can all be painful. “The only features that are not painful are the ones we are looking at on a radiograph, which are cartilage [inferred from the joint space narrowing] and osteophytes.”

Dr. Hunter noted that the imaging community is divided about whether the best way to monitor the structural progression of underlying disease is to measure joint space on x-ray or to measure other features—such as the cartilage itself—on an MRI.

MRI

The main strength of MRI as a research tool is its ability to provide information on many tissues in the joint. “On MRI, you're able to … see changes in the curvature of the bone, lesions within the bone [which demonstrate where focal loading is occurring, and] alterations within the cartilage itself. … You can see inflammation within the joint [such as synovitis or an effusion], the ligaments, and the muscle,” said Dr. Hunter.

“The more we're learning about osteoarthritis, the more we're realizing that much of the reason why a person has pain [and] functional limitation—and much of the reason why the joint progresses—has a lot more to do with the tissues in the joint other than cartilage,” Dr. Hunter said. “Bone marrow lesions, synovitis, and effusions appear to account for the majority of the reason why a person has pain. MRIs provide a lot of insight there,” he said.

Beyond the local-tissue reasons for a person to have symptoms, there is also some local alteration in the neurophysiology. “The communication between different nerve pathways that leads to sensitization of nerves occurs both peripherally and centrally, “Dr. Hunter said.

“If we are focused on symptomatic response, it's helpful to think about the contribution of all of those factors.” Nerve endings are present in specific tissues, particularly the bone and synovium.

In MRI, gadolinium contrast can be given intravenously or intra-articularly, said Dr. Guermazi. Intravenous contrast is useful for evaluating synovitis and differentiating it from effusions. Intra-articular contrast is useful for evaluating cartilage and meniscal lesions.

Among the several downsides of MRI are its cost and the time needed to acquire the images and to interpret them. MRIs of the knee or hip are acquired with the patient in a lying down or supine position; however, physiologically, the knee is probably best understood when those joints are bearing weight.

CT

CT is widely available and generally less expensive than MRI. Unlike dual-energy x-ray absorptiometry, CT imaging can provide information about volumetric density of the bone via changes in the periarticular density, Dr. Hunter said.

The chosen modality may depend on the joint to be imaged, said Dr. Guermazi. In the case of OA of the facet joints, osteophytosis and bone are better viewed with CT than MRI. However, much other information is lost. Although meniscal and anterior/posterior cruciate ligament lesions can be seen on contrast CT, bone marrow lesions cannot.

Ultrasound

“Intra-articular steroids appear to reduce the extent of inflammation in joints. That can be appreciated on ultrasound,” said Dr. Hunter. Ultrasound can also be used to guide the injection of corticosteroids. “Some of the therapies that are being developed are likely to be intra-articular, and ultrasound may be helpful in guiding the needle to the right spot.”

Ultrasound also is being used in some clinical trials to visualize synovitis, according to Dr. Guermazi. “I think it's promising, especially if you use Doppler and can see vascularity.” Doppler ultrasound can be used to identify and monitor active synovitis, after treatment.

Ultrasound is also able to assess the effect of biologic drugs—currently in testing for OA—on synovitis.

Ultrasound is inexpensive, but “it's very operator dependent,” said Dr. Guermazi. “Ultrasound tends to be used more widely outside the United States, where MRI may not be so readily available.”

Ultrasound allows visualization of ligaments, muscles, and tendons, but not bone, and it can visualize only tissues close to the skin and near the probe.

Therapy

Research into potential OA therapies now focuses on tissues that are likely to play a role symptomatically and structurally, rather than just concentrating on cartilage. Just as bBiologic drugs have made huge inroads in RA, “we're right at the cusp of that” with OA, said Dr. Guermazi. When “therapies do become available, the ability to identify OA in the early stages will be very important.”

X-rays can supply information about the structural progression of underlying disease, as evidenced by the osteophytic changes, subchondral bone sclerosis, and absence of joint space seen in an anteroposterior radiograph of the left knee in a 65-year-old woman with secondary arthritis at 9 years after treated fractures (at left). A lateral view (at right) confirms severe tibiofemoral OA and shows severe patellofemoral OA with large posterior femoral condyles (arrowhead) and tibial plateaus (arrow) not seen on the anteroposterior view.

Sagittal fat-suppressed proton density-weighted MRI shows diffuse cartilage loss of the lateral central weight-bearing tibia and femur. Also seen are a central lateral femur bone marrow lesion (arrow) and a small tibiofibular ganglion cyst (arrowhead).

CT can visualize volumetric density. Medial narrowing plus subchondral medial tibiofemoral bone sclerosis (arrows) and cystic changes are seen on coronal reformatted CT.

Source Images courtesy Dr. Ali Guermazi

Radiographs are no longer de rigeur in making the diagnosis of knee osteoarthritis, according to guidelines released by the European League Against Rheumatism last month. Clinical signs, symptoms, and risk factors are sufficient to make the diagnosis.

Yet x-rays and other imaging modalities continue to have a role in osteoarthritis, according to Dr. Ali Guermazi and Dr. David J. Hunter. At present, imaging should primarily be used in research rather than in clinical practice (where its use should be limited to ruling out other likely diagnoses), they agreed.

Imaging conveys information about the pathophysiology of OA and has provided insight into symptoms and progression, said Dr. Hunter, chief of the research division of New England Baptist Hospital in Boston. Ultimately, “it will help to define the best treatments for osteoarthritis,” he added. Imaging has the potential to “have wider clinical application, when we have an opportunity to intervene in earlier arthritis through modifying joint structural changes.”

Yet, there continues to be “widespread use of different imaging modalities in the clinical setting, where it's clear there is osteoarthritis.” Dr. Hunter estimated that 60%–70% of patients who present to him in the clinic have an MRI on CD with them. “It doesn't change the diagnosis or what I'm going to do for them, so I'm not sure that there's much rationale for having that at present.”

Each imaging modality has a role to play when assessing the pathophysiology of the whole joint. “Some of that role is complementary, but much of it is unique to that particular modality. … Each has its strengths and weaknesses.”

Dr. Guermazi and Dr. Hunter shared their thoughts on how various imaging modalities can further understanding of the pathophysiology of OA.

Radiograph

An x-ray is typically used only to rule out other diagnoses, said Dr. Hunter. These could include rheumatoid arthritis, gout, intra-articular loose bodies, and trauma. “These would be reasons to think about doing additional imaging.”

X-ray is still the most widely used imaging modality because it's relatively inexpensive, it's available, and it's relatively easy to interpret. X-rays are useful primarily for outlining the two-dimensional geometry of the bones. “You infer from the x-ray what the joint space is, and from that, the health and integrity of the cartilage, but it's an indirect inference and you really can't make any direct representations of other tissues,” Dr. Hunter said.

In addition, x-ray evaluates features that don't contribute to pain, which is the primary symptom of OA, said Dr. Guermazi, director of the quantitative imaging center and section chief of musculoskeletal imaging at Boston University. “If we look at joint space narrowing, thinking that this is the cartilage measure, [x-ray is] useless for many reasons. Arthritis is defined clinically as pain. Cartilage can't be painful because there are no nerves in it.”

Synovitis, effusions, and bone marrow lesions, however, can all be painful. “The only features that are not painful are the ones we are looking at on a radiograph, which are cartilage [inferred from the joint space narrowing] and osteophytes.”

Dr. Hunter noted that the imaging community is divided about whether the best way to monitor the structural progression of underlying disease is to measure joint space on x-ray or to measure other features—such as the cartilage itself—on an MRI.

MRI

The main strength of MRI as a research tool is its ability to provide information on many tissues in the joint. “On MRI, you're able to … see changes in the curvature of the bone, lesions within the bone [which demonstrate where focal loading is occurring, and] alterations within the cartilage itself. … You can see inflammation within the joint [such as synovitis or an effusion], the ligaments, and the muscle,” said Dr. Hunter.

“The more we're learning about osteoarthritis, the more we're realizing that much of the reason why a person has pain [and] functional limitation—and much of the reason why the joint progresses—has a lot more to do with the tissues in the joint other than cartilage,” Dr. Hunter said. “Bone marrow lesions, synovitis, and effusions appear to account for the majority of the reason why a person has pain. MRIs provide a lot of insight there,” he said.

Beyond the local-tissue reasons for a person to have symptoms, there is also some local alteration in the neurophysiology. “The communication between different nerve pathways that leads to sensitization of nerves occurs both peripherally and centrally, “Dr. Hunter said.

“If we are focused on symptomatic response, it's helpful to think about the contribution of all of those factors.” Nerve endings are present in specific tissues, particularly the bone and synovium.

In MRI, gadolinium contrast can be given intravenously or intra-articularly, said Dr. Guermazi. Intravenous contrast is useful for evaluating synovitis and differentiating it from effusions. Intra-articular contrast is useful for evaluating cartilage and meniscal lesions.

Among the several downsides of MRI are its cost and the time needed to acquire the images and to interpret them. MRIs of the knee or hip are acquired with the patient in a lying down or supine position; however, physiologically, the knee is probably best understood when those joints are bearing weight.

CT

CT is widely available and generally less expensive than MRI. Unlike dual-energy x-ray absorptiometry, CT imaging can provide information about volumetric density of the bone via changes in the periarticular density, Dr. Hunter said.

The chosen modality may depend on the joint to be imaged, said Dr. Guermazi. In the case of OA of the facet joints, osteophytosis and bone are better viewed with CT than MRI. However, much other information is lost. Although meniscal and anterior/posterior cruciate ligament lesions can be seen on contrast CT, bone marrow lesions cannot.

Ultrasound

“Intra-articular steroids appear to reduce the extent of inflammation in joints. That can be appreciated on ultrasound,” said Dr. Hunter. Ultrasound can also be used to guide the injection of corticosteroids. “Some of the therapies that are being developed are likely to be intra-articular, and ultrasound may be helpful in guiding the needle to the right spot.”

Ultrasound also is being used in some clinical trials to visualize synovitis, according to Dr. Guermazi. “I think it's promising, especially if you use Doppler and can see vascularity.” Doppler ultrasound can be used to identify and monitor active synovitis, after treatment.

Ultrasound is also able to assess the effect of biologic drugs—currently in testing for OA—on synovitis.

Ultrasound is inexpensive, but “it's very operator dependent,” said Dr. Guermazi. “Ultrasound tends to be used more widely outside the United States, where MRI may not be so readily available.”

Ultrasound allows visualization of ligaments, muscles, and tendons, but not bone, and it can visualize only tissues close to the skin and near the probe.

Therapy

Research into potential OA therapies now focuses on tissues that are likely to play a role symptomatically and structurally, rather than just concentrating on cartilage. Just as bBiologic drugs have made huge inroads in RA, “we're right at the cusp of that” with OA, said Dr. Guermazi. When “therapies do become available, the ability to identify OA in the early stages will be very important.”

X-rays can supply information about the structural progression of underlying disease, as evidenced by the osteophytic changes, subchondral bone sclerosis, and absence of joint space seen in an anteroposterior radiograph of the left knee in a 65-year-old woman with secondary arthritis at 9 years after treated fractures (at left). A lateral view (at right) confirms severe tibiofemoral OA and shows severe patellofemoral OA with large posterior femoral condyles (arrowhead) and tibial plateaus (arrow) not seen on the anteroposterior view.

Sagittal fat-suppressed proton density-weighted MRI shows diffuse cartilage loss of the lateral central weight-bearing tibia and femur. Also seen are a central lateral femur bone marrow lesion (arrow) and a small tibiofibular ganglion cyst (arrowhead).

CT can visualize volumetric density. Medial narrowing plus subchondral medial tibiofemoral bone sclerosis (arrows) and cystic changes are seen on coronal reformatted CT.

Source Images courtesy Dr. Ali Guermazi

Probiotics do not appear to reduce the incidence of respiratory tract infections, though they may help reduce the severity and duration of these infections, based on a review of 14 published randomized clinical trials.

“The majority of RCTs [randomized clinical trials] included in this review indicate that the incidence of RTIs [respiratory tract infections] does not appear to be considerably influenced by prophylactic administration of probiotics, although probiotics may have a beneficial role in reducing the severity and duration of subsequent RTIs,” wrote Dr. Evridiki K. Vouloumanou of the Alfa Institute of Biomedical Sciences, Athens, and colleagues.

The study appears in the September issue of the International Journal of Antimicrobial Agents (2009;34.e1-197e.10; [doi:10.1016/j.ijantimicag.2008.11.005]).

Ten of the 14 trials showed no difference in the incidence of RTIs between patients on probiotics and those on placebo. In four of the trials, the incidence of RTIs was significantly lower in those on probiotics.

The authors reviewed RCTs exploring the use of probiotics to prevent or ameliorate RTIs that they identified through a literature search. Databases included PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and SCOPUS. The researchers searched for available trials up to Feb. 5, 2008. They identified 14 studies with 3,580 participants that met their quality criteria (Jadad score greater than 2).

Upper RTIs in the studies included common cold, acute otitis media, tonsillitis/tonsillopharyngitis, sinusitis, and recurrent sinusitis. Lower RTIs included bronchitis and pneumonia. Probiotics used in the trials included Lactobacillus spp., a strain of Bifidobacterium longum, combinations of Lactobacillus and Bifidobacterium species, and a nonpathogenic strain of Enterococcus faecalis. Six of the trials involved healthy children or infants, six included healthy adults, one involved children with RTI, and one involved adults with RTI.

“A significant reduction regarding the severity of symptoms of RTIs associated with probiotic treatment was found in five of six RCTs that provided relevant data,” they wrote. There was no difference in symptom severity in the remaining trial. In addition, three of nine RCTs reported a significant difference in favor of the probiotics groups. However, the other six showed no difference.

In six RCTs, no adverse events were noted that could be attributed to the probiotics. In three RCTs, adverse events of minor severity included nausea, bloating, and diarrhea. In one RCT the development of dyspepsia prompted reduction in the amount of probiotic daily intake. The authors said that they had no conflicts of interest.

Probiotics do not appear to reduce the incidence of respiratory tract infections, though they may help reduce the severity and duration of these infections, based on a review of 14 published randomized clinical trials.

“The majority of RCTs [randomized clinical trials] included in this review indicate that the incidence of RTIs [respiratory tract infections] does not appear to be considerably influenced by prophylactic administration of probiotics, although probiotics may have a beneficial role in reducing the severity and duration of subsequent RTIs,” wrote Dr. Evridiki K. Vouloumanou of the Alfa Institute of Biomedical Sciences, Athens, and colleagues.

The study appears in the September issue of the International Journal of Antimicrobial Agents (2009;34.e1-197e.10; [doi:10.1016/j.ijantimicag.2008.11.005]).

Ten of the 14 trials showed no difference in the incidence of RTIs between patients on probiotics and those on placebo. In four of the trials, the incidence of RTIs was significantly lower in those on probiotics.

The authors reviewed RCTs exploring the use of probiotics to prevent or ameliorate RTIs that they identified through a literature search. Databases included PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and SCOPUS. The researchers searched for available trials up to Feb. 5, 2008. They identified 14 studies with 3,580 participants that met their quality criteria (Jadad score greater than 2).

Upper RTIs in the studies included common cold, acute otitis media, tonsillitis/tonsillopharyngitis, sinusitis, and recurrent sinusitis. Lower RTIs included bronchitis and pneumonia. Probiotics used in the trials included Lactobacillus spp., a strain of Bifidobacterium longum, combinations of Lactobacillus and Bifidobacterium species, and a nonpathogenic strain of Enterococcus faecalis. Six of the trials involved healthy children or infants, six included healthy adults, one involved children with RTI, and one involved adults with RTI.

“A significant reduction regarding the severity of symptoms of RTIs associated with probiotic treatment was found in five of six RCTs that provided relevant data,” they wrote. There was no difference in symptom severity in the remaining trial. In addition, three of nine RCTs reported a significant difference in favor of the probiotics groups. However, the other six showed no difference.

In six RCTs, no adverse events were noted that could be attributed to the probiotics. In three RCTs, adverse events of minor severity included nausea, bloating, and diarrhea. In one RCT the development of dyspepsia prompted reduction in the amount of probiotic daily intake. The authors said that they had no conflicts of interest.

Probiotics do not appear to reduce the incidence of respiratory tract infections, though they may help reduce the severity and duration of these infections, based on a review of 14 published randomized clinical trials.

“The majority of RCTs [randomized clinical trials] included in this review indicate that the incidence of RTIs [respiratory tract infections] does not appear to be considerably influenced by prophylactic administration of probiotics, although probiotics may have a beneficial role in reducing the severity and duration of subsequent RTIs,” wrote Dr. Evridiki K. Vouloumanou of the Alfa Institute of Biomedical Sciences, Athens, and colleagues.

The study appears in the September issue of the International Journal of Antimicrobial Agents (2009;34.e1-197e.10; [doi:10.1016/j.ijantimicag.2008.11.005]).

Ten of the 14 trials showed no difference in the incidence of RTIs between patients on probiotics and those on placebo. In four of the trials, the incidence of RTIs was significantly lower in those on probiotics.

The authors reviewed RCTs exploring the use of probiotics to prevent or ameliorate RTIs that they identified through a literature search. Databases included PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and SCOPUS. The researchers searched for available trials up to Feb. 5, 2008. They identified 14 studies with 3,580 participants that met their quality criteria (Jadad score greater than 2).

Upper RTIs in the studies included common cold, acute otitis media, tonsillitis/tonsillopharyngitis, sinusitis, and recurrent sinusitis. Lower RTIs included bronchitis and pneumonia. Probiotics used in the trials included Lactobacillus spp., a strain of Bifidobacterium longum, combinations of Lactobacillus and Bifidobacterium species, and a nonpathogenic strain of Enterococcus faecalis. Six of the trials involved healthy children or infants, six included healthy adults, one involved children with RTI, and one involved adults with RTI.

“A significant reduction regarding the severity of symptoms of RTIs associated with probiotic treatment was found in five of six RCTs that provided relevant data,” they wrote. There was no difference in symptom severity in the remaining trial. In addition, three of nine RCTs reported a significant difference in favor of the probiotics groups. However, the other six showed no difference.

In six RCTs, no adverse events were noted that could be attributed to the probiotics. In three RCTs, adverse events of minor severity included nausea, bloating, and diarrhea. In one RCT the development of dyspepsia prompted reduction in the amount of probiotic daily intake. The authors said that they had no conflicts of interest.

Multiple-session early psychological interventions are no better at reducing posttraumatic stress disorder symptoms than no intervention at all and might even increase symptoms in some individuals, a review of 11 randomized controlled studies shows.

“There was no evidence that a multiple session intervention aimed at everyone following a traumatic event was effective. There was a trend that just failed to reach significance for no intervention to result in less self-reported PTSD symptoms at 3 to 6-month follow-up than a multiple session intervention,” wrote Neil P. Roberts, D.Clin.Psy., of the Traumatic Stress Service at Cardiff and Vale National Health Services (Wales), and coauthors. The results were published online in the Cochrane Database of Systemic Reviews (doi:10.1002/14651858.CD006869.pub2).

The researchers conducted searches of computerized databases and select journals, and they contacted key individuals in the field.

Any randomized controlled trial was eligible for the review. The researchers focused on multiple-session early psychologic interventions intended to prevent symptoms of traumatic stress that were initiated within 3 months of the event.

Potential intervention categories included cognitive-behavioral therapy (CBT), trauma-focused CBT, trauma-focused group CBT, nontrauma-focused group CBT, stress management/relaxation, eye movement desensitization and reprocessing, other psychological interventions, education, provision of information, stepped care, and interventions aimed at enhancing positive coping skills and improving overall well-being.

The researchers limited studies to those that compared a psychological intervention versus waiting list/usual care control or psychological intervention versus an other psychological intervention. The primary outcome was the rate of PTSD among those subjected to trauma, as measured by a standard classification system. Commonly used PTSD measures include the Impact of Event Scale and the Post-traumatic Diagnostic Scale.

The final review included 11 studies, involving 914 participants. Nine studies (775 participants)—two conducted in the United States, two in Australia, two in Sweden, and one each in Canada, France, and the Netherlands—provided data for the final analysis.

Traumatic events included traffic accidents, armed robbery/violence, traumatic childbirth, physical trauma, diagnosis of childhood cancer, and a range of other civilian traumatic experiences. The studies evaluated individual counseling, interpersonal counseling, adapted debriefing, CBT, counseling/collaborative care, and integrated CBT/family therapy. The average number of sessions attended by those who completed therapy was six.

The results “suggest that at this time there is little evidence to support the use of psychological intervention for routine use following traumatic events and that some multiple-session interventions … may have an adverse effect on some individuals,” the researchers wrote.

Multiple-session early psychological interventions are no better at reducing posttraumatic stress disorder symptoms than no intervention at all and might even increase symptoms in some individuals, a review of 11 randomized controlled studies shows.

“There was no evidence that a multiple session intervention aimed at everyone following a traumatic event was effective. There was a trend that just failed to reach significance for no intervention to result in less self-reported PTSD symptoms at 3 to 6-month follow-up than a multiple session intervention,” wrote Neil P. Roberts, D.Clin.Psy., of the Traumatic Stress Service at Cardiff and Vale National Health Services (Wales), and coauthors. The results were published online in the Cochrane Database of Systemic Reviews (doi:10.1002/14651858.CD006869.pub2).

The researchers conducted searches of computerized databases and select journals, and they contacted key individuals in the field.

Any randomized controlled trial was eligible for the review. The researchers focused on multiple-session early psychologic interventions intended to prevent symptoms of traumatic stress that were initiated within 3 months of the event.

Potential intervention categories included cognitive-behavioral therapy (CBT), trauma-focused CBT, trauma-focused group CBT, nontrauma-focused group CBT, stress management/relaxation, eye movement desensitization and reprocessing, other psychological interventions, education, provision of information, stepped care, and interventions aimed at enhancing positive coping skills and improving overall well-being.

The researchers limited studies to those that compared a psychological intervention versus waiting list/usual care control or psychological intervention versus an other psychological intervention. The primary outcome was the rate of PTSD among those subjected to trauma, as measured by a standard classification system. Commonly used PTSD measures include the Impact of Event Scale and the Post-traumatic Diagnostic Scale.

The final review included 11 studies, involving 914 participants. Nine studies (775 participants)—two conducted in the United States, two in Australia, two in Sweden, and one each in Canada, France, and the Netherlands—provided data for the final analysis.

Traumatic events included traffic accidents, armed robbery/violence, traumatic childbirth, physical trauma, diagnosis of childhood cancer, and a range of other civilian traumatic experiences. The studies evaluated individual counseling, interpersonal counseling, adapted debriefing, CBT, counseling/collaborative care, and integrated CBT/family therapy. The average number of sessions attended by those who completed therapy was six.

The results “suggest that at this time there is little evidence to support the use of psychological intervention for routine use following traumatic events and that some multiple-session interventions … may have an adverse effect on some individuals,” the researchers wrote.

Multiple-session early psychological interventions are no better at reducing posttraumatic stress disorder symptoms than no intervention at all and might even increase symptoms in some individuals, a review of 11 randomized controlled studies shows.

“There was no evidence that a multiple session intervention aimed at everyone following a traumatic event was effective. There was a trend that just failed to reach significance for no intervention to result in less self-reported PTSD symptoms at 3 to 6-month follow-up than a multiple session intervention,” wrote Neil P. Roberts, D.Clin.Psy., of the Traumatic Stress Service at Cardiff and Vale National Health Services (Wales), and coauthors. The results were published online in the Cochrane Database of Systemic Reviews (doi:10.1002/14651858.CD006869.pub2).

The researchers conducted searches of computerized databases and select journals, and they contacted key individuals in the field.

Any randomized controlled trial was eligible for the review. The researchers focused on multiple-session early psychologic interventions intended to prevent symptoms of traumatic stress that were initiated within 3 months of the event.

Potential intervention categories included cognitive-behavioral therapy (CBT), trauma-focused CBT, trauma-focused group CBT, nontrauma-focused group CBT, stress management/relaxation, eye movement desensitization and reprocessing, other psychological interventions, education, provision of information, stepped care, and interventions aimed at enhancing positive coping skills and improving overall well-being.

The researchers limited studies to those that compared a psychological intervention versus waiting list/usual care control or psychological intervention versus an other psychological intervention. The primary outcome was the rate of PTSD among those subjected to trauma, as measured by a standard classification system. Commonly used PTSD measures include the Impact of Event Scale and the Post-traumatic Diagnostic Scale.

The final review included 11 studies, involving 914 participants. Nine studies (775 participants)—two conducted in the United States, two in Australia, two in Sweden, and one each in Canada, France, and the Netherlands—provided data for the final analysis.

Traumatic events included traffic accidents, armed robbery/violence, traumatic childbirth, physical trauma, diagnosis of childhood cancer, and a range of other civilian traumatic experiences. The studies evaluated individual counseling, interpersonal counseling, adapted debriefing, CBT, counseling/collaborative care, and integrated CBT/family therapy. The average number of sessions attended by those who completed therapy was six.

The results “suggest that at this time there is little evidence to support the use of psychological intervention for routine use following traumatic events and that some multiple-session interventions … may have an adverse effect on some individuals,” the researchers wrote.

DENVER — Women who are encouraged to self-schedule dual-energy x-ray absorptiometry scans via mailed brochures and letters undergo more scans than do those in usual practice, but it is still not a silver bullet strategy for identifying women with osteoporosis.

In study of 3,734 women, mailings of an educational osteoporosis brochure and a letter providing the opportunity to self-schedule increased the percentage of women receiving dual-energy x-ray absorptiometry (DXA) scans by 13% versus routine care, Dr. Amy Warriner and her coinvestigators reported in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

The study involved 28 primary care physicians at the University of Alabama at Birmingham. The researchers identified women aged 65 years or older who had not had a DXA scan in the past 4 years, and were under the care of a university primary care provider.

The participating providers were randomized to provide an intervention or not. Intervention-group physicians mailed brochures containing information about osteoporosis and fracture risk. The brochures were created using patient feedback from focus groups. Each mailing included a letter providing patients with the opportunity to self-schedule a DXA scan. Two mailings were sent to each woman.

In all, 665 women were randomized into the intervention group and 3,069 into the control group. A total of 115 women in the intervention group were determined by their primary care provider not to be medically appropriate for DXA testing. Brochures and letters were mailed to the remaining 550 women.

In the intervention group, 19% of women received DXA scans. Half of these were self-scheduled and half were scheduled by the provider. In comparison, only 6% of women in the control group had DXA scans. DXA scan self-scheduling and receipt was 13% better with a mailing intervention when compared with normal practice. “However, more potent strategies will still be needed to further improve DXA screening rates,” wrote Dr. Warriner, professor of medicine in the division of endocrinology and metabolism at the university.

The study was funded in part by Procter & Gamble, which comarkets the osteoporosis drug risedronate (Actonel). Dr. Warriner reported a significant financial relationship with Amgen Inc., which is developing the osteoporosis drug denosumab. Her coinvestigators reported significant financial relationships with a number of pharmaceutical companies that make osteoporosis drugs.

DENVER — Women who are encouraged to self-schedule dual-energy x-ray absorptiometry scans via mailed brochures and letters undergo more scans than do those in usual practice, but it is still not a silver bullet strategy for identifying women with osteoporosis.

In study of 3,734 women, mailings of an educational osteoporosis brochure and a letter providing the opportunity to self-schedule increased the percentage of women receiving dual-energy x-ray absorptiometry (DXA) scans by 13% versus routine care, Dr. Amy Warriner and her coinvestigators reported in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

The study involved 28 primary care physicians at the University of Alabama at Birmingham. The researchers identified women aged 65 years or older who had not had a DXA scan in the past 4 years, and were under the care of a university primary care provider.

The participating providers were randomized to provide an intervention or not. Intervention-group physicians mailed brochures containing information about osteoporosis and fracture risk. The brochures were created using patient feedback from focus groups. Each mailing included a letter providing patients with the opportunity to self-schedule a DXA scan. Two mailings were sent to each woman.

In all, 665 women were randomized into the intervention group and 3,069 into the control group. A total of 115 women in the intervention group were determined by their primary care provider not to be medically appropriate for DXA testing. Brochures and letters were mailed to the remaining 550 women.

In the intervention group, 19% of women received DXA scans. Half of these were self-scheduled and half were scheduled by the provider. In comparison, only 6% of women in the control group had DXA scans. DXA scan self-scheduling and receipt was 13% better with a mailing intervention when compared with normal practice. “However, more potent strategies will still be needed to further improve DXA screening rates,” wrote Dr. Warriner, professor of medicine in the division of endocrinology and metabolism at the university.

The study was funded in part by Procter & Gamble, which comarkets the osteoporosis drug risedronate (Actonel). Dr. Warriner reported a significant financial relationship with Amgen Inc., which is developing the osteoporosis drug denosumab. Her coinvestigators reported significant financial relationships with a number of pharmaceutical companies that make osteoporosis drugs.

DENVER — Women who are encouraged to self-schedule dual-energy x-ray absorptiometry scans via mailed brochures and letters undergo more scans than do those in usual practice, but it is still not a silver bullet strategy for identifying women with osteoporosis.

In study of 3,734 women, mailings of an educational osteoporosis brochure and a letter providing the opportunity to self-schedule increased the percentage of women receiving dual-energy x-ray absorptiometry (DXA) scans by 13% versus routine care, Dr. Amy Warriner and her coinvestigators reported in a poster presented at the annual meeting of the American Society for Bone Mineral Research.

The study involved 28 primary care physicians at the University of Alabama at Birmingham. The researchers identified women aged 65 years or older who had not had a DXA scan in the past 4 years, and were under the care of a university primary care provider.

The participating providers were randomized to provide an intervention or not. Intervention-group physicians mailed brochures containing information about osteoporosis and fracture risk. The brochures were created using patient feedback from focus groups. Each mailing included a letter providing patients with the opportunity to self-schedule a DXA scan. Two mailings were sent to each woman.

In all, 665 women were randomized into the intervention group and 3,069 into the control group. A total of 115 women in the intervention group were determined by their primary care provider not to be medically appropriate for DXA testing. Brochures and letters were mailed to the remaining 550 women.

In the intervention group, 19% of women received DXA scans. Half of these were self-scheduled and half were scheduled by the provider. In comparison, only 6% of women in the control group had DXA scans. DXA scan self-scheduling and receipt was 13% better with a mailing intervention when compared with normal practice. “However, more potent strategies will still be needed to further improve DXA screening rates,” wrote Dr. Warriner, professor of medicine in the division of endocrinology and metabolism at the university.

The study was funded in part by Procter & Gamble, which comarkets the osteoporosis drug risedronate (Actonel). Dr. Warriner reported a significant financial relationship with Amgen Inc., which is developing the osteoporosis drug denosumab. Her coinvestigators reported significant financial relationships with a number of pharmaceutical companies that make osteoporosis drugs.

DENVER — Significant predictors of receiving a bisphosphonate prescription within 90 days of a fracture for women are a low bone mineral density score after a fracture, being aged 65-74 years, and oral cortico-steroid use, according to the results of a study of 2,000 women.

Women with a bone mineral density (BMD) T-score of −2.5 or less in the 90 days after a fracture were almost five times as likely to receive a bisphosphonate prescription than women with higher T-scores, according to a poster presented by Carl Asche, Ph.D., at the annual meeting of the American Society for Bone Mineral Research.

Women who were aged 65-74 years at the time of fracture were almost twice as likely to receive a prescription, compared with woman younger than 65. Similarly, women taking oral corticosteroids also were more likely to receive a bisphosphonate prescription, wrote Dr. Asche of the pharmacotherapy department at the University of Utah, Salt Lake City.

Using electronic health records from Geisinger Health System from Jan. 1, 2000, to June 30, 2007, women aged 50 years and older who had had a fracture were included. They also had to have continuous electronic health record activity for at least 365 days before and after the index date (the date of the fracture). Women were excluded if they had a diagnosis of osteoporosis, a bone mineral density score of −2.5 or less at the time of the fracture, a fracture in the 6 months prior to the index date, or a diagnosis of conditions known to impact bone density and quality.

The reseachers considered age, race, body mass index (BMI), BMD score 90 days after the fracture, smoking status, Charlson comorbidity index, oral corticosteroid use, and rheumatoid arthritis to be potential predictors of bisphosphonate prescription—alendronate (Fosamax), ibandronate (Boniva), or risedronate (Actonel).

A total of 2,000 women met the inclusion criteria, but less than 10% (188) received a prescription for a bisphosphonate within 90 days of fracture. “Very few women aged [over] 50 receive treatment with an oral bisphosphonate after having a fracture, leaving them potentially vulnerable to future fractures,” Dr. Asche noted.

Obese patients (BMI 30-39.9 kg/m

One limitation of the study is that it was not possible to determine if the fractures were fragility related or primarily due to an injury.

The study was supported by the Alliance for Better Bone Health—Procter & Gamble Pharmaceuticals and Sanofi-Aventis U.S., which copromote Actonel. Dr. Asche reported that he has a significant financial relationship with Sanofi-Aventis U.S.

Source ELSEVIER GLOBAL MEDICAL NEWS

DENVER — Significant predictors of receiving a bisphosphonate prescription within 90 days of a fracture for women are a low bone mineral density score after a fracture, being aged 65-74 years, and oral cortico-steroid use, according to the results of a study of 2,000 women.

Women with a bone mineral density (BMD) T-score of −2.5 or less in the 90 days after a fracture were almost five times as likely to receive a bisphosphonate prescription than women with higher T-scores, according to a poster presented by Carl Asche, Ph.D., at the annual meeting of the American Society for Bone Mineral Research.

Women who were aged 65-74 years at the time of fracture were almost twice as likely to receive a prescription, compared with woman younger than 65. Similarly, women taking oral corticosteroids also were more likely to receive a bisphosphonate prescription, wrote Dr. Asche of the pharmacotherapy department at the University of Utah, Salt Lake City.

Using electronic health records from Geisinger Health System from Jan. 1, 2000, to June 30, 2007, women aged 50 years and older who had had a fracture were included. They also had to have continuous electronic health record activity for at least 365 days before and after the index date (the date of the fracture). Women were excluded if they had a diagnosis of osteoporosis, a bone mineral density score of −2.5 or less at the time of the fracture, a fracture in the 6 months prior to the index date, or a diagnosis of conditions known to impact bone density and quality.

The reseachers considered age, race, body mass index (BMI), BMD score 90 days after the fracture, smoking status, Charlson comorbidity index, oral corticosteroid use, and rheumatoid arthritis to be potential predictors of bisphosphonate prescription—alendronate (Fosamax), ibandronate (Boniva), or risedronate (Actonel).

A total of 2,000 women met the inclusion criteria, but less than 10% (188) received a prescription for a bisphosphonate within 90 days of fracture. “Very few women aged [over] 50 receive treatment with an oral bisphosphonate after having a fracture, leaving them potentially vulnerable to future fractures,” Dr. Asche noted.

Obese patients (BMI 30-39.9 kg/m

One limitation of the study is that it was not possible to determine if the fractures were fragility related or primarily due to an injury.

The study was supported by the Alliance for Better Bone Health—Procter & Gamble Pharmaceuticals and Sanofi-Aventis U.S., which copromote Actonel. Dr. Asche reported that he has a significant financial relationship with Sanofi-Aventis U.S.

Source ELSEVIER GLOBAL MEDICAL NEWS

DENVER — Significant predictors of receiving a bisphosphonate prescription within 90 days of a fracture for women are a low bone mineral density score after a fracture, being aged 65-74 years, and oral cortico-steroid use, according to the results of a study of 2,000 women.

Women with a bone mineral density (BMD) T-score of −2.5 or less in the 90 days after a fracture were almost five times as likely to receive a bisphosphonate prescription than women with higher T-scores, according to a poster presented by Carl Asche, Ph.D., at the annual meeting of the American Society for Bone Mineral Research.

Women who were aged 65-74 years at the time of fracture were almost twice as likely to receive a prescription, compared with woman younger than 65. Similarly, women taking oral corticosteroids also were more likely to receive a bisphosphonate prescription, wrote Dr. Asche of the pharmacotherapy department at the University of Utah, Salt Lake City.

Using electronic health records from Geisinger Health System from Jan. 1, 2000, to June 30, 2007, women aged 50 years and older who had had a fracture were included. They also had to have continuous electronic health record activity for at least 365 days before and after the index date (the date of the fracture). Women were excluded if they had a diagnosis of osteoporosis, a bone mineral density score of −2.5 or less at the time of the fracture, a fracture in the 6 months prior to the index date, or a diagnosis of conditions known to impact bone density and quality.

The reseachers considered age, race, body mass index (BMI), BMD score 90 days after the fracture, smoking status, Charlson comorbidity index, oral corticosteroid use, and rheumatoid arthritis to be potential predictors of bisphosphonate prescription—alendronate (Fosamax), ibandronate (Boniva), or risedronate (Actonel).

A total of 2,000 women met the inclusion criteria, but less than 10% (188) received a prescription for a bisphosphonate within 90 days of fracture. “Very few women aged [over] 50 receive treatment with an oral bisphosphonate after having a fracture, leaving them potentially vulnerable to future fractures,” Dr. Asche noted.

Obese patients (BMI 30-39.9 kg/m

One limitation of the study is that it was not possible to determine if the fractures were fragility related or primarily due to an injury.

The study was supported by the Alliance for Better Bone Health—Procter & Gamble Pharmaceuticals and Sanofi-Aventis U.S., which copromote Actonel. Dr. Asche reported that he has a significant financial relationship with Sanofi-Aventis U.S.

Source ELSEVIER GLOBAL MEDICAL NEWS

DENVER — The investigational agent denosumab continued to increase bone mineral density in osteoporotic postmenopausal women during 6 years of continuous use, based on the results of an extension of a phase II study including 412 women.

“Over a period of 6 years, continuous treatment with denosumab resulted in progressive gains in [bone mineral density] in postmenopausal women,” Dr. Paul Miller said at the annual meeting of the American Society for Bone and Mineral Research.

The 93 patients on denosumab 60 mg for 6 years had a continued increase in spine bone mineral density (BMD), with a mean cumulative increase from baseline in spine BMD of 13%. In addition, the reduction in resorption, as measured by serum C-telopeptide (CTX) levels, was sustained and plateaued over the course of continuous denosumab treatment.

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density.

The study was sponsored by Amgen Inc., which is developing the drug. Dr. Miller reported significant financial relationships with several pharmaceutical companies that make osteoporosis treatments, including Amgen.

In the parent trial, 412 women were randomized to receive denosumab, open-label oral alendronate (70 mg/wk), or placebo. Denosumab was given subcutaneously either every 3 months (at 6 mg, 14 mg, or 30 mg) or every 6 months (at 14 mg, 60 mg, 100 mg, or 210 mg). All participants took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU).

Postmenopausal women up to 80 years of age were eligible if they had a bone mineral density T score from −1.8 to −4.0 at the lumbar spine or from −1.8 to −3.5 at either the femoral neck or total hip. An upper limit of −1.8 was selected to include subjects with both osteopenia and osteoporosis. The 2-year data were published in Bone in 2008 (43:222-9).

At the end of the first 2 years, patients were reallocated. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. Patients originally randomized to denosumab 6 mg or 14 mg (every 3 months) or 14 mg, 60 mg, and 100 mg (every 6 months) received denosumab 60 mg every 6 months for the next 2 years. This is the dose selected for phase III trials.

Patients originally randomized to denosumab 210 mg every 6 months received placebo for the next 2 years. Patients randomized to denosumab 30 mg every 3 months first received placebo for 12 months and then were subsequently re-treated with denosumab 60 mg every 6 months for the next 12 months. Alendronate patients discontinued alendronate therapy at this time. The placebo group was maintained.

In the extension phase of the study, all patients received denosumab 60 mg every 6 months for 2 more years. Measurements of bone mineral density of the lumbar spine, total hip, and femoral neck were performed by dual-energy x-ray absorptiometry throughout the trial.

The 16 patients who had been on placebo for 4 years and were switched to denosumab 60 mg every 6 months for the last 2 years had gains in spine BMD that were comparable to those observed in the first 2 years of the trial for patients on denosumab 60 mg every 6 months. Similar results were obtained for hip BMD. Patients on denosumab for 6 years had an average cumulative hip BMD increase of 6%.

“The forearm data … are interesting because forearm BMD increased in the denosumab groups, unlike the other antiresorptive agents that have consistently shown a decrease,” said Dr. Miller, whose group practice in Lakewood, Colo., specializes in the treatment of osteoporosis.

The adverse events seen during the extension were similar to those seen in the parent study.

DENVER — The investigational agent denosumab continued to increase bone mineral density in osteoporotic postmenopausal women during 6 years of continuous use, based on the results of an extension of a phase II study including 412 women.

“Over a period of 6 years, continuous treatment with denosumab resulted in progressive gains in [bone mineral density] in postmenopausal women,” Dr. Paul Miller said at the annual meeting of the American Society for Bone and Mineral Research.

The 93 patients on denosumab 60 mg for 6 years had a continued increase in spine bone mineral density (BMD), with a mean cumulative increase from baseline in spine BMD of 13%. In addition, the reduction in resorption, as measured by serum C-telopeptide (CTX) levels, was sustained and plateaued over the course of continuous denosumab treatment.

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density.

The study was sponsored by Amgen Inc., which is developing the drug. Dr. Miller reported significant financial relationships with several pharmaceutical companies that make osteoporosis treatments, including Amgen.

In the parent trial, 412 women were randomized to receive denosumab, open-label oral alendronate (70 mg/wk), or placebo. Denosumab was given subcutaneously either every 3 months (at 6 mg, 14 mg, or 30 mg) or every 6 months (at 14 mg, 60 mg, 100 mg, or 210 mg). All participants took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU).

Postmenopausal women up to 80 years of age were eligible if they had a bone mineral density T score from −1.8 to −4.0 at the lumbar spine or from −1.8 to −3.5 at either the femoral neck or total hip. An upper limit of −1.8 was selected to include subjects with both osteopenia and osteoporosis. The 2-year data were published in Bone in 2008 (43:222-9).

At the end of the first 2 years, patients were reallocated. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. Patients originally randomized to denosumab 6 mg or 14 mg (every 3 months) or 14 mg, 60 mg, and 100 mg (every 6 months) received denosumab 60 mg every 6 months for the next 2 years. This is the dose selected for phase III trials.

Patients originally randomized to denosumab 210 mg every 6 months received placebo for the next 2 years. Patients randomized to denosumab 30 mg every 3 months first received placebo for 12 months and then were subsequently re-treated with denosumab 60 mg every 6 months for the next 12 months. Alendronate patients discontinued alendronate therapy at this time. The placebo group was maintained.

In the extension phase of the study, all patients received denosumab 60 mg every 6 months for 2 more years. Measurements of bone mineral density of the lumbar spine, total hip, and femoral neck were performed by dual-energy x-ray absorptiometry throughout the trial.

The 16 patients who had been on placebo for 4 years and were switched to denosumab 60 mg every 6 months for the last 2 years had gains in spine BMD that were comparable to those observed in the first 2 years of the trial for patients on denosumab 60 mg every 6 months. Similar results were obtained for hip BMD. Patients on denosumab for 6 years had an average cumulative hip BMD increase of 6%.

“The forearm data … are interesting because forearm BMD increased in the denosumab groups, unlike the other antiresorptive agents that have consistently shown a decrease,” said Dr. Miller, whose group practice in Lakewood, Colo., specializes in the treatment of osteoporosis.

The adverse events seen during the extension were similar to those seen in the parent study.

DENVER — The investigational agent denosumab continued to increase bone mineral density in osteoporotic postmenopausal women during 6 years of continuous use, based on the results of an extension of a phase II study including 412 women.

“Over a period of 6 years, continuous treatment with denosumab resulted in progressive gains in [bone mineral density] in postmenopausal women,” Dr. Paul Miller said at the annual meeting of the American Society for Bone and Mineral Research.

The 93 patients on denosumab 60 mg for 6 years had a continued increase in spine bone mineral density (BMD), with a mean cumulative increase from baseline in spine BMD of 13%. In addition, the reduction in resorption, as measured by serum C-telopeptide (CTX) levels, was sustained and plateaued over the course of continuous denosumab treatment.

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density.

The study was sponsored by Amgen Inc., which is developing the drug. Dr. Miller reported significant financial relationships with several pharmaceutical companies that make osteoporosis treatments, including Amgen.

In the parent trial, 412 women were randomized to receive denosumab, open-label oral alendronate (70 mg/wk), or placebo. Denosumab was given subcutaneously either every 3 months (at 6 mg, 14 mg, or 30 mg) or every 6 months (at 14 mg, 60 mg, 100 mg, or 210 mg). All participants took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU).

Postmenopausal women up to 80 years of age were eligible if they had a bone mineral density T score from −1.8 to −4.0 at the lumbar spine or from −1.8 to −3.5 at either the femoral neck or total hip. An upper limit of −1.8 was selected to include subjects with both osteopenia and osteoporosis. The 2-year data were published in Bone in 2008 (43:222-9).

At the end of the first 2 years, patients were reallocated. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. Patients originally randomized to denosumab 6 mg or 14 mg (every 3 months) or 14 mg, 60 mg, and 100 mg (every 6 months) received denosumab 60 mg every 6 months for the next 2 years. This is the dose selected for phase III trials.

Patients originally randomized to denosumab 210 mg every 6 months received placebo for the next 2 years. Patients randomized to denosumab 30 mg every 3 months first received placebo for 12 months and then were subsequently re-treated with denosumab 60 mg every 6 months for the next 12 months. Alendronate patients discontinued alendronate therapy at this time. The placebo group was maintained.

In the extension phase of the study, all patients received denosumab 60 mg every 6 months for 2 more years. Measurements of bone mineral density of the lumbar spine, total hip, and femoral neck were performed by dual-energy x-ray absorptiometry throughout the trial.

The 16 patients who had been on placebo for 4 years and were switched to denosumab 60 mg every 6 months for the last 2 years had gains in spine BMD that were comparable to those observed in the first 2 years of the trial for patients on denosumab 60 mg every 6 months. Similar results were obtained for hip BMD. Patients on denosumab for 6 years had an average cumulative hip BMD increase of 6%.

“The forearm data … are interesting because forearm BMD increased in the denosumab groups, unlike the other antiresorptive agents that have consistently shown a decrease,” said Dr. Miller, whose group practice in Lakewood, Colo., specializes in the treatment of osteoporosis.

The adverse events seen during the extension were similar to those seen in the parent study.