Osteoarthritis

LONDON – An investigational nerve growth factor inhibitor, fulranumab, showed promising efficacy and safety as a pain reliever for patients with hip or knee osteoarthritis in 12-week results from a phase II study of 466 patients.

Further study of fulranumab in osteoarthritis had been on hold. The Food and Drug Administration issued a moratorium last December that halted clinical testing of fulranumab and most other investigational agents in the anti–nerve growth factor class, following reports that some of these drugs appeared to trigger episodes of rapid progression of hip or knee osteoarthritis (OA) that led to joint replacement and possible osteonecrosis. The FDA lifted that moratorium on research with fulranumab in cancer pain this month. The moratorium on research involving OA pain remains in place, according to investigators.

Whether or not osteoarthritis progressed rapidly in any patient treated with fulranumab remains unknown. "Cases of joint replacement reported during the entire trial are under investigation, and will be reported in a future publication," Dr. John Thipphawong said at the annual European Congress of Rheumatology.

The safety data Dr. Thipphawong presented for 12 weeks of treatment showed a well-tolerated profile, compared with placebo. Specifically, serious adverse events occurred in 1% of patients treated with fulranumab, compared with 2% of those on placebo. Adverse events led to discontinuation of the assigned drug in 2% of fulranumab recipients and 1% of those on placebo. Adverse events that occurred more often in fulranumab-treated patients were paresthesia, with a 6%-10% rate in the higher fulranumab dosage subgroups, compared with a 3% rate for patients on placebo, and a hypoesthesia rate of 5%-6% in the higher dosage fulranumab subgroups, compared with a 1% rate with placebo. The fulranumab-treated patients also had no significant changes in laboratory values, ECG, or vital signs at 12 weeks after treatment began.

The study enrolled patients with documented hip or knee osteoarthritis who met the diagnostic criteria of the American College of Rheumatology and showed radiographic evidence of the disease, with a Kellgren-Lawrence grade of 2 or greater. All patients also reported moderate to severe pain, with a painscore of at least 5 on a 0-10 numerical rating scale despite treatment with an opioid, a nonsteroidal anti-inflammatory drug, or both.

The study randomized patients to receive fulranumab or placebo once every 4 or 8 weeks as a subcutaneous injection in addition to standard pain medications. The protocol tested five different fulranumab dosages: 1 mg every 4 weeks, 3 mg every 4 weeks, 3 mg every 8 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks. Fulranumab is a fully human, recombinant monoclonal antibody that neutralizes the biological actions of human nerve growth factor. About 78 patients entered each of the five active-treatment arms as well as a placebo arm. The study’s primary efficacy end point was the change in average pain score from baseline to the end of week 12 of the study.

The patients’ average age was 61 years, 58% were women, and two-thirds were white. Their average body mass index was 32 kg/m², and 60% weighed at least 85 kg. Knee OA predominated as the affected joint, in 77% of patients.

At 12 weeks after the start of treatment, average pain reduction with fulranumab significantly surpassed the placebo group in the 3 mg every 4 weeks, 6 mg every 8 weeks, and 10 mg every 8 weeks subgroups. In these three groups, pain scores fell by an average of 3.05, 2.64, and 2.65 points, respectively, compared with an average drop of 1.91 points in the placebo group, reported Dr. Thipphawong, who is senior director of clinical development, Johnson & Johnson Pharmaceutical Research & Development.

The study also included several secondary efficacy measures. The three highest-dosage subgroups, as well as the 3 mg every 8 weeks subgroup, showed statistically significant declines, compared with placebo after 12 weeks in the average levels of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) subscales for pain and global function. For the WOMAC subscales of physical function and stiffness, all five fulranumab dosage subgroups showed significant reductions, compared with placebo.

On the Brief Pain Inventory-Short Form, patients in the 3 mg every 4 weeks and 10 mg every 8 weeks subgroups had significant average reductions, compared with the placebo group for the subscales of pain intensity and pain interference with activities. The three highest-dosage subgroups also produced average drops in patient global assessment of disease status that were statistically significant, compared with the placebo group’s average.

In a separate poster at the meeting, Dr. Thipphawong and his associates also reported that several of the fulranumab subgroups showed statistically significant average improvements, with placebo in several subscale measures on the Short From-36, specifically bodily pain, vitality, and physical component. The four highest-dosage subgroups also had significant average improvements in pain interference with sleep, compared with placebo, and all five fulranumab dosage subgroups had significant average improvements in sleep adequacy, compared with the placebo group.

Dr. Thipphawong and several of his associates are employees of Johnson & Johnson, the company developing fulranumab.

LONDON – An investigational nerve growth factor inhibitor, fulranumab, showed promising efficacy and safety as a pain reliever for patients with hip or knee osteoarthritis in 12-week results from a phase II study of 466 patients.

Further study of fulranumab in osteoarthritis had been on hold. The Food and Drug Administration issued a moratorium last December that halted clinical testing of fulranumab and most other investigational agents in the anti–nerve growth factor class, following reports that some of these drugs appeared to trigger episodes of rapid progression of hip or knee osteoarthritis (OA) that led to joint replacement and possible osteonecrosis. The FDA lifted that moratorium on research with fulranumab in cancer pain this month. The moratorium on research involving OA pain remains in place, according to investigators.

Whether or not osteoarthritis progressed rapidly in any patient treated with fulranumab remains unknown. "Cases of joint replacement reported during the entire trial are under investigation, and will be reported in a future publication," Dr. John Thipphawong said at the annual European Congress of Rheumatology.

The safety data Dr. Thipphawong presented for 12 weeks of treatment showed a well-tolerated profile, compared with placebo. Specifically, serious adverse events occurred in 1% of patients treated with fulranumab, compared with 2% of those on placebo. Adverse events led to discontinuation of the assigned drug in 2% of fulranumab recipients and 1% of those on placebo. Adverse events that occurred more often in fulranumab-treated patients were paresthesia, with a 6%-10% rate in the higher fulranumab dosage subgroups, compared with a 3% rate for patients on placebo, and a hypoesthesia rate of 5%-6% in the higher dosage fulranumab subgroups, compared with a 1% rate with placebo. The fulranumab-treated patients also had no significant changes in laboratory values, ECG, or vital signs at 12 weeks after treatment began.

The study enrolled patients with documented hip or knee osteoarthritis who met the diagnostic criteria of the American College of Rheumatology and showed radiographic evidence of the disease, with a Kellgren-Lawrence grade of 2 or greater. All patients also reported moderate to severe pain, with a painscore of at least 5 on a 0-10 numerical rating scale despite treatment with an opioid, a nonsteroidal anti-inflammatory drug, or both.

The study randomized patients to receive fulranumab or placebo once every 4 or 8 weeks as a subcutaneous injection in addition to standard pain medications. The protocol tested five different fulranumab dosages: 1 mg every 4 weeks, 3 mg every 4 weeks, 3 mg every 8 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks. Fulranumab is a fully human, recombinant monoclonal antibody that neutralizes the biological actions of human nerve growth factor. About 78 patients entered each of the five active-treatment arms as well as a placebo arm. The study’s primary efficacy end point was the change in average pain score from baseline to the end of week 12 of the study.

The patients’ average age was 61 years, 58% were women, and two-thirds were white. Their average body mass index was 32 kg/m², and 60% weighed at least 85 kg. Knee OA predominated as the affected joint, in 77% of patients.

At 12 weeks after the start of treatment, average pain reduction with fulranumab significantly surpassed the placebo group in the 3 mg every 4 weeks, 6 mg every 8 weeks, and 10 mg every 8 weeks subgroups. In these three groups, pain scores fell by an average of 3.05, 2.64, and 2.65 points, respectively, compared with an average drop of 1.91 points in the placebo group, reported Dr. Thipphawong, who is senior director of clinical development, Johnson & Johnson Pharmaceutical Research & Development.

The study also included several secondary efficacy measures. The three highest-dosage subgroups, as well as the 3 mg every 8 weeks subgroup, showed statistically significant declines, compared with placebo after 12 weeks in the average levels of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) subscales for pain and global function. For the WOMAC subscales of physical function and stiffness, all five fulranumab dosage subgroups showed significant reductions, compared with placebo.

On the Brief Pain Inventory-Short Form, patients in the 3 mg every 4 weeks and 10 mg every 8 weeks subgroups had significant average reductions, compared with the placebo group for the subscales of pain intensity and pain interference with activities. The three highest-dosage subgroups also produced average drops in patient global assessment of disease status that were statistically significant, compared with the placebo group’s average.

In a separate poster at the meeting, Dr. Thipphawong and his associates also reported that several of the fulranumab subgroups showed statistically significant average improvements, with placebo in several subscale measures on the Short From-36, specifically bodily pain, vitality, and physical component. The four highest-dosage subgroups also had significant average improvements in pain interference with sleep, compared with placebo, and all five fulranumab dosage subgroups had significant average improvements in sleep adequacy, compared with the placebo group.

Dr. Thipphawong and several of his associates are employees of Johnson & Johnson, the company developing fulranumab.

LONDON – An investigational nerve growth factor inhibitor, fulranumab, showed promising efficacy and safety as a pain reliever for patients with hip or knee osteoarthritis in 12-week results from a phase II study of 466 patients.

Further study of fulranumab in osteoarthritis had been on hold. The Food and Drug Administration issued a moratorium last December that halted clinical testing of fulranumab and most other investigational agents in the anti–nerve growth factor class, following reports that some of these drugs appeared to trigger episodes of rapid progression of hip or knee osteoarthritis (OA) that led to joint replacement and possible osteonecrosis. The FDA lifted that moratorium on research with fulranumab in cancer pain this month. The moratorium on research involving OA pain remains in place, according to investigators.

Whether or not osteoarthritis progressed rapidly in any patient treated with fulranumab remains unknown. "Cases of joint replacement reported during the entire trial are under investigation, and will be reported in a future publication," Dr. John Thipphawong said at the annual European Congress of Rheumatology.

The safety data Dr. Thipphawong presented for 12 weeks of treatment showed a well-tolerated profile, compared with placebo. Specifically, serious adverse events occurred in 1% of patients treated with fulranumab, compared with 2% of those on placebo. Adverse events led to discontinuation of the assigned drug in 2% of fulranumab recipients and 1% of those on placebo. Adverse events that occurred more often in fulranumab-treated patients were paresthesia, with a 6%-10% rate in the higher fulranumab dosage subgroups, compared with a 3% rate for patients on placebo, and a hypoesthesia rate of 5%-6% in the higher dosage fulranumab subgroups, compared with a 1% rate with placebo. The fulranumab-treated patients also had no significant changes in laboratory values, ECG, or vital signs at 12 weeks after treatment began.

The study enrolled patients with documented hip or knee osteoarthritis who met the diagnostic criteria of the American College of Rheumatology and showed radiographic evidence of the disease, with a Kellgren-Lawrence grade of 2 or greater. All patients also reported moderate to severe pain, with a painscore of at least 5 on a 0-10 numerical rating scale despite treatment with an opioid, a nonsteroidal anti-inflammatory drug, or both.

The study randomized patients to receive fulranumab or placebo once every 4 or 8 weeks as a subcutaneous injection in addition to standard pain medications. The protocol tested five different fulranumab dosages: 1 mg every 4 weeks, 3 mg every 4 weeks, 3 mg every 8 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks. Fulranumab is a fully human, recombinant monoclonal antibody that neutralizes the biological actions of human nerve growth factor. About 78 patients entered each of the five active-treatment arms as well as a placebo arm. The study’s primary efficacy end point was the change in average pain score from baseline to the end of week 12 of the study.

The patients’ average age was 61 years, 58% were women, and two-thirds were white. Their average body mass index was 32 kg/m², and 60% weighed at least 85 kg. Knee OA predominated as the affected joint, in 77% of patients.

At 12 weeks after the start of treatment, average pain reduction with fulranumab significantly surpassed the placebo group in the 3 mg every 4 weeks, 6 mg every 8 weeks, and 10 mg every 8 weeks subgroups. In these three groups, pain scores fell by an average of 3.05, 2.64, and 2.65 points, respectively, compared with an average drop of 1.91 points in the placebo group, reported Dr. Thipphawong, who is senior director of clinical development, Johnson & Johnson Pharmaceutical Research & Development.

The study also included several secondary efficacy measures. The three highest-dosage subgroups, as well as the 3 mg every 8 weeks subgroup, showed statistically significant declines, compared with placebo after 12 weeks in the average levels of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) subscales for pain and global function. For the WOMAC subscales of physical function and stiffness, all five fulranumab dosage subgroups showed significant reductions, compared with placebo.

On the Brief Pain Inventory-Short Form, patients in the 3 mg every 4 weeks and 10 mg every 8 weeks subgroups had significant average reductions, compared with the placebo group for the subscales of pain intensity and pain interference with activities. The three highest-dosage subgroups also produced average drops in patient global assessment of disease status that were statistically significant, compared with the placebo group’s average.

In a separate poster at the meeting, Dr. Thipphawong and his associates also reported that several of the fulranumab subgroups showed statistically significant average improvements, with placebo in several subscale measures on the Short From-36, specifically bodily pain, vitality, and physical component. The four highest-dosage subgroups also had significant average improvements in pain interference with sleep, compared with placebo, and all five fulranumab dosage subgroups had significant average improvements in sleep adequacy, compared with the placebo group.

Dr. Thipphawong and several of his associates are employees of Johnson & Johnson, the company developing fulranumab.

Major Finding: The fracture risk for gastric bypass surgery patients was 2.3-fold greater than that for the general population.

Data Source: A retrospective study of 258 patients who underwent bariatric surgery between 1985 and 2004.

Disclosures: Dr. Kennel reported that he and his coinvestigators have no significant financial relationships to report.

BOSTON – Gastric bypass surgery appears to be linked to increased long-term fracture risk, based on a retrospective study of 258 bariatric surgery patients.

“Bariatric surgery results in an increased risk of fractures. We think the important take-home point here is that we need to start looking at the skeleton as one of those key areas for long-term follow-up,” Dr. Kurt Kennel said at the meeting.

The fracture risk for bariatric surgery patients in this study was 2.3 times greater than that for individuals who did not have bariatric surgery, reported Dr. Kennel of the endocrinology department at the Mayo Clinic in Rochester, Minn.

“We have questions about what this means in the long term,” said Dr. Kennel. In this study, the mean time to first fracture was 6 years, with a mean follow-up of 9 years. However, in much of the current literature on bariatric surgery, patients are followed only 1–2 years and the only issues addressed are related to surgery or weight.

“Some issues – like bone, for example – may not show the manifestations of these effects for many years and therefore we may be missing some of those effects,” said Dr. Kennel.

The researchers used data from the Rochester Epidemiology Project to conduct a retrospective study of fracture incidence. REP connects medical records from the Mayo Clinic, local hospitals, and local private practices. The study included data from 258 patients, who underwent a first bariatric surgery between 1985 and 2004 at the Mayo Clinic.

Fractures were expressed in standardized incidence ratios that compare the number of observed fractures to the number of expected fractures by skeletal site.

Expected fracture data were derived by applying age- and sex-specific incidence rates from the local population to the age- and sex-specific person-years of follow-up.

The average age of the bariatric surgery patients was 44 years and most (83%) were female. Following bariatric surgery, 79 patients experienced 132 fractures.

Bariatric surgery patients had an increased risk of fracture at nearly all of the skeletal sites studied, not just in weight-bearing bones.

Also of note, 94% of these patients had undergone gastric bypass procedures. Dr. Kennel attributed this to the time frame used in the study.

Other bariatric surgical procedures – such as adjustable gastric banding and sleeve gastrectomy – are more recent developments. Dr. Kennel acknowledged that different bariatric procedures might yield different fracture risks.

The increased rate of fractures “suggests that structural and biochemical changes in bone that are observed after bariatric surgery are clinically important.

Clinicians should discuss bone health with patients who have undergone or are considering bariatric surgery.”

Major Finding: The fracture risk for gastric bypass surgery patients was 2.3-fold greater than that for the general population.

Data Source: A retrospective study of 258 patients who underwent bariatric surgery between 1985 and 2004.

Disclosures: Dr. Kennel reported that he and his coinvestigators have no significant financial relationships to report.

BOSTON – Gastric bypass surgery appears to be linked to increased long-term fracture risk, based on a retrospective study of 258 bariatric surgery patients.

“Bariatric surgery results in an increased risk of fractures. We think the important take-home point here is that we need to start looking at the skeleton as one of those key areas for long-term follow-up,” Dr. Kurt Kennel said at the meeting.

The fracture risk for bariatric surgery patients in this study was 2.3 times greater than that for individuals who did not have bariatric surgery, reported Dr. Kennel of the endocrinology department at the Mayo Clinic in Rochester, Minn.

“We have questions about what this means in the long term,” said Dr. Kennel. In this study, the mean time to first fracture was 6 years, with a mean follow-up of 9 years. However, in much of the current literature on bariatric surgery, patients are followed only 1–2 years and the only issues addressed are related to surgery or weight.

“Some issues – like bone, for example – may not show the manifestations of these effects for many years and therefore we may be missing some of those effects,” said Dr. Kennel.

The researchers used data from the Rochester Epidemiology Project to conduct a retrospective study of fracture incidence. REP connects medical records from the Mayo Clinic, local hospitals, and local private practices. The study included data from 258 patients, who underwent a first bariatric surgery between 1985 and 2004 at the Mayo Clinic.

Fractures were expressed in standardized incidence ratios that compare the number of observed fractures to the number of expected fractures by skeletal site.

Expected fracture data were derived by applying age- and sex-specific incidence rates from the local population to the age- and sex-specific person-years of follow-up.

The average age of the bariatric surgery patients was 44 years and most (83%) were female. Following bariatric surgery, 79 patients experienced 132 fractures.

Bariatric surgery patients had an increased risk of fracture at nearly all of the skeletal sites studied, not just in weight-bearing bones.

Also of note, 94% of these patients had undergone gastric bypass procedures. Dr. Kennel attributed this to the time frame used in the study.

Other bariatric surgical procedures – such as adjustable gastric banding and sleeve gastrectomy – are more recent developments. Dr. Kennel acknowledged that different bariatric procedures might yield different fracture risks.

The increased rate of fractures “suggests that structural and biochemical changes in bone that are observed after bariatric surgery are clinically important.

Clinicians should discuss bone health with patients who have undergone or are considering bariatric surgery.”

Major Finding: The fracture risk for gastric bypass surgery patients was 2.3-fold greater than that for the general population.

Data Source: A retrospective study of 258 patients who underwent bariatric surgery between 1985 and 2004.

Disclosures: Dr. Kennel reported that he and his coinvestigators have no significant financial relationships to report.

BOSTON – Gastric bypass surgery appears to be linked to increased long-term fracture risk, based on a retrospective study of 258 bariatric surgery patients.

“Bariatric surgery results in an increased risk of fractures. We think the important take-home point here is that we need to start looking at the skeleton as one of those key areas for long-term follow-up,” Dr. Kurt Kennel said at the meeting.

The fracture risk for bariatric surgery patients in this study was 2.3 times greater than that for individuals who did not have bariatric surgery, reported Dr. Kennel of the endocrinology department at the Mayo Clinic in Rochester, Minn.

“We have questions about what this means in the long term,” said Dr. Kennel. In this study, the mean time to first fracture was 6 years, with a mean follow-up of 9 years. However, in much of the current literature on bariatric surgery, patients are followed only 1–2 years and the only issues addressed are related to surgery or weight.

“Some issues – like bone, for example – may not show the manifestations of these effects for many years and therefore we may be missing some of those effects,” said Dr. Kennel.

The researchers used data from the Rochester Epidemiology Project to conduct a retrospective study of fracture incidence. REP connects medical records from the Mayo Clinic, local hospitals, and local private practices. The study included data from 258 patients, who underwent a first bariatric surgery between 1985 and 2004 at the Mayo Clinic.

Fractures were expressed in standardized incidence ratios that compare the number of observed fractures to the number of expected fractures by skeletal site.

Expected fracture data were derived by applying age- and sex-specific incidence rates from the local population to the age- and sex-specific person-years of follow-up.

The average age of the bariatric surgery patients was 44 years and most (83%) were female. Following bariatric surgery, 79 patients experienced 132 fractures.

Bariatric surgery patients had an increased risk of fracture at nearly all of the skeletal sites studied, not just in weight-bearing bones.

Also of note, 94% of these patients had undergone gastric bypass procedures. Dr. Kennel attributed this to the time frame used in the study.

Other bariatric surgical procedures – such as adjustable gastric banding and sleeve gastrectomy – are more recent developments. Dr. Kennel acknowledged that different bariatric procedures might yield different fracture risks.

The increased rate of fractures “suggests that structural and biochemical changes in bone that are observed after bariatric surgery are clinically important.

Clinicians should discuss bone health with patients who have undergone or are considering bariatric surgery.”

Major Finding: During the 5- to 10-year period of extended, continuous treatment with strontium ranelate, postmenopausal women with osteoporosis at baseline had a 21% rate of vertebral fractures and a 14% rate of nonvertebral fractures, significantly less than the 28% and 20% rates, respectively, of fractures in a matched placebo group.

Data Source: Cohort of 233 postmenopausal women with osteoporosis maintained on 2 g/day strontium ranelate for 10 years, compared with a matched control group of 458 women drawn from a pivotal trial of strontium ranelate.

Disclosures: The SOTI and TROPOS trials were funded by Servier, which markets strontium ranelate (Protelos). Dr. Reginster reported financial relationships with Amgen, Analis, Bristol-Myers Squibb, Ebewe, Genévrier, GlaxoSmith-Kline, IBSA, Eli Lilly, Merck Sharp & Dohme, Merckle, Negma, Novartis, Novo Nordisk, NPS Pharmaceuticals, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, Wyeth, UCB, and Zodiac.

LONDON – Strontium ranelate continued to safely and effectively prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis during 5–10 years of continuous treatment, in a “modified” case-control study that included 233 women who maintained daily 2-g/day strontium dosing for 10 years.

“Strontium ranelate should not be considered a second-line alternative to bisphosphonates or to any other [osteoporosis] treatment,” Dr. Jean-Yves Reginster said at the meeting.

Treatment with strontium ranelate “gives you a chance to bring bone turnover back to premenopausal values,” said Dr. Reginster, professor of epidemiology and chairman of the department of public health at the University of Liège in Belgium.

The ability of strontium ranelate to maintain a reduced rate of both vertebral and nonvertebral fractures over 10 years of continuous use in this study marks the first reported evidence of an antiosteoporotic drug exerting an unequivocal antifracture benefit for such a prolonged period.

The only other report on 10-year treatment came from the Fracture Intervention Trial Long Term Extension, which included 1,099 women randomized to alendronate or placebo for 10 years (JAMA 2006;296:2927-38).

Those results showed that 5–10 years of extended alendronate treatment did not result in a reduction of all clinical fractures or nonvertebral fracture, compared with women maintained on placebo during years 5–10, but extended alendronate did reduce the clinical vertebral fracture rate, compared with placebo.

“In our study [of strontium ranelate], we had no placebo group, but we showed that you can reduce fractures over 10 years with this drug.”

Strontium maintained its efficacy over 10 years “probably because of its mechanism of action, a dual action,” Dr. Reginster said in an interview.

“With bisphosphonates you reduce bone resorption. With strontium ranelate you reduce bone resorption by 20%–25%, and you increase bone formation by 20%–25%, so you bring the bone back to what you see in younger women. I think it is a more physiologic approach” than treatment with a bisphosphonate.

In addition, “safety is most important to me when you treat for 10 years. One of the biggest advantages of strontium ranelate is that it is a very safe drug, with little risk of adverse effects over time. I think that calculating the risk/benefit ratio of a drug over time is very important.”

In his report, Dr. Reginster emphasized that the women maintained on the drug for 10 years did not have a single episode of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation, and their adverse-event profile showed better safety than in the original, pivotal trials of strontium ranelate.

He also noted that while the extension included only 233 women on the drug, registry data on about one million patients who have taken the drug also show no reported cases of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation.

The 233 women followed for 10 years on continuous strontium ranelate treatment came from either of the two pivotal, 5-year trials of the drug: the Treatment of Peripheral Osteoporosis Study (TROPOS) (J. Clin. Endocrinol. Met. 2005;90:2816-22), and the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (New. Engl. J. Med. 2004;350:459-68).

They continued to receive 2 g/day strontium ranelate, and 73% of the women completed the full extension period. Their average duration of drug use was 9.8 years, and their average compliance with the regimen was 89%.

During their additional 5 years on the drug, average lumbar spine bone mineral density continued to rise, increasing from about 20% above baseline at the start of the extension to about 27% above baseline at 10 years.

To assess the efficacy of treatment for preventing vertebral and nonvertebral fractures, Dr. Reginster and his associates “rebuilt” a control population by selecting placebo patients from the TROPOS trial who matched the 233 extended-treatment women based on their baseline Fracture Risk Assessment scores.

The researchers matched two TROPOS placebo-group women with each woman in the extension study, assembling a total of 458 controls.

The incidence of vertebral fractures during years 5–10 in the women on strontium ranelate was 21%, compared with a 28% rate in the rebuilt control group, a statistically significant difference.

In addition, the 21% reduction during the 5 to 10- year period was statistically similar to the 19% vertebral fracture rate among women treated during 0–5 years in SOTI.

The incidence of nonvertebral fractures during years 5–10 with strontium ranelate was 14%, significantly less than the 20% rate in the derived placebo group and statistically similar to the 13% rate seen in TROPOS, Dr. Reginster reported.

Major Finding: During the 5- to 10-year period of extended, continuous treatment with strontium ranelate, postmenopausal women with osteoporosis at baseline had a 21% rate of vertebral fractures and a 14% rate of nonvertebral fractures, significantly less than the 28% and 20% rates, respectively, of fractures in a matched placebo group.

Data Source: Cohort of 233 postmenopausal women with osteoporosis maintained on 2 g/day strontium ranelate for 10 years, compared with a matched control group of 458 women drawn from a pivotal trial of strontium ranelate.

Disclosures: The SOTI and TROPOS trials were funded by Servier, which markets strontium ranelate (Protelos). Dr. Reginster reported financial relationships with Amgen, Analis, Bristol-Myers Squibb, Ebewe, Genévrier, GlaxoSmith-Kline, IBSA, Eli Lilly, Merck Sharp & Dohme, Merckle, Negma, Novartis, Novo Nordisk, NPS Pharmaceuticals, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, Wyeth, UCB, and Zodiac.

LONDON – Strontium ranelate continued to safely and effectively prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis during 5–10 years of continuous treatment, in a “modified” case-control study that included 233 women who maintained daily 2-g/day strontium dosing for 10 years.

“Strontium ranelate should not be considered a second-line alternative to bisphosphonates or to any other [osteoporosis] treatment,” Dr. Jean-Yves Reginster said at the meeting.

Treatment with strontium ranelate “gives you a chance to bring bone turnover back to premenopausal values,” said Dr. Reginster, professor of epidemiology and chairman of the department of public health at the University of Liège in Belgium.

The ability of strontium ranelate to maintain a reduced rate of both vertebral and nonvertebral fractures over 10 years of continuous use in this study marks the first reported evidence of an antiosteoporotic drug exerting an unequivocal antifracture benefit for such a prolonged period.

The only other report on 10-year treatment came from the Fracture Intervention Trial Long Term Extension, which included 1,099 women randomized to alendronate or placebo for 10 years (JAMA 2006;296:2927-38).

Those results showed that 5–10 years of extended alendronate treatment did not result in a reduction of all clinical fractures or nonvertebral fracture, compared with women maintained on placebo during years 5–10, but extended alendronate did reduce the clinical vertebral fracture rate, compared with placebo.

“In our study [of strontium ranelate], we had no placebo group, but we showed that you can reduce fractures over 10 years with this drug.”

Strontium maintained its efficacy over 10 years “probably because of its mechanism of action, a dual action,” Dr. Reginster said in an interview.

“With bisphosphonates you reduce bone resorption. With strontium ranelate you reduce bone resorption by 20%–25%, and you increase bone formation by 20%–25%, so you bring the bone back to what you see in younger women. I think it is a more physiologic approach” than treatment with a bisphosphonate.

In addition, “safety is most important to me when you treat for 10 years. One of the biggest advantages of strontium ranelate is that it is a very safe drug, with little risk of adverse effects over time. I think that calculating the risk/benefit ratio of a drug over time is very important.”

In his report, Dr. Reginster emphasized that the women maintained on the drug for 10 years did not have a single episode of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation, and their adverse-event profile showed better safety than in the original, pivotal trials of strontium ranelate.

He also noted that while the extension included only 233 women on the drug, registry data on about one million patients who have taken the drug also show no reported cases of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation.

The 233 women followed for 10 years on continuous strontium ranelate treatment came from either of the two pivotal, 5-year trials of the drug: the Treatment of Peripheral Osteoporosis Study (TROPOS) (J. Clin. Endocrinol. Met. 2005;90:2816-22), and the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (New. Engl. J. Med. 2004;350:459-68).

They continued to receive 2 g/day strontium ranelate, and 73% of the women completed the full extension period. Their average duration of drug use was 9.8 years, and their average compliance with the regimen was 89%.

During their additional 5 years on the drug, average lumbar spine bone mineral density continued to rise, increasing from about 20% above baseline at the start of the extension to about 27% above baseline at 10 years.

To assess the efficacy of treatment for preventing vertebral and nonvertebral fractures, Dr. Reginster and his associates “rebuilt” a control population by selecting placebo patients from the TROPOS trial who matched the 233 extended-treatment women based on their baseline Fracture Risk Assessment scores.

The researchers matched two TROPOS placebo-group women with each woman in the extension study, assembling a total of 458 controls.

The incidence of vertebral fractures during years 5–10 in the women on strontium ranelate was 21%, compared with a 28% rate in the rebuilt control group, a statistically significant difference.

In addition, the 21% reduction during the 5 to 10- year period was statistically similar to the 19% vertebral fracture rate among women treated during 0–5 years in SOTI.

The incidence of nonvertebral fractures during years 5–10 with strontium ranelate was 14%, significantly less than the 20% rate in the derived placebo group and statistically similar to the 13% rate seen in TROPOS, Dr. Reginster reported.

Major Finding: During the 5- to 10-year period of extended, continuous treatment with strontium ranelate, postmenopausal women with osteoporosis at baseline had a 21% rate of vertebral fractures and a 14% rate of nonvertebral fractures, significantly less than the 28% and 20% rates, respectively, of fractures in a matched placebo group.

Data Source: Cohort of 233 postmenopausal women with osteoporosis maintained on 2 g/day strontium ranelate for 10 years, compared with a matched control group of 458 women drawn from a pivotal trial of strontium ranelate.

Disclosures: The SOTI and TROPOS trials were funded by Servier, which markets strontium ranelate (Protelos). Dr. Reginster reported financial relationships with Amgen, Analis, Bristol-Myers Squibb, Ebewe, Genévrier, GlaxoSmith-Kline, IBSA, Eli Lilly, Merck Sharp & Dohme, Merckle, Negma, Novartis, Novo Nordisk, NPS Pharmaceuticals, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, Wyeth, UCB, and Zodiac.

LONDON – Strontium ranelate continued to safely and effectively prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis during 5–10 years of continuous treatment, in a “modified” case-control study that included 233 women who maintained daily 2-g/day strontium dosing for 10 years.

“Strontium ranelate should not be considered a second-line alternative to bisphosphonates or to any other [osteoporosis] treatment,” Dr. Jean-Yves Reginster said at the meeting.

Treatment with strontium ranelate “gives you a chance to bring bone turnover back to premenopausal values,” said Dr. Reginster, professor of epidemiology and chairman of the department of public health at the University of Liège in Belgium.

The ability of strontium ranelate to maintain a reduced rate of both vertebral and nonvertebral fractures over 10 years of continuous use in this study marks the first reported evidence of an antiosteoporotic drug exerting an unequivocal antifracture benefit for such a prolonged period.

The only other report on 10-year treatment came from the Fracture Intervention Trial Long Term Extension, which included 1,099 women randomized to alendronate or placebo for 10 years (JAMA 2006;296:2927-38).

Those results showed that 5–10 years of extended alendronate treatment did not result in a reduction of all clinical fractures or nonvertebral fracture, compared with women maintained on placebo during years 5–10, but extended alendronate did reduce the clinical vertebral fracture rate, compared with placebo.

“In our study [of strontium ranelate], we had no placebo group, but we showed that you can reduce fractures over 10 years with this drug.”

Strontium maintained its efficacy over 10 years “probably because of its mechanism of action, a dual action,” Dr. Reginster said in an interview.

“With bisphosphonates you reduce bone resorption. With strontium ranelate you reduce bone resorption by 20%–25%, and you increase bone formation by 20%–25%, so you bring the bone back to what you see in younger women. I think it is a more physiologic approach” than treatment with a bisphosphonate.

In addition, “safety is most important to me when you treat for 10 years. One of the biggest advantages of strontium ranelate is that it is a very safe drug, with little risk of adverse effects over time. I think that calculating the risk/benefit ratio of a drug over time is very important.”

In his report, Dr. Reginster emphasized that the women maintained on the drug for 10 years did not have a single episode of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation, and their adverse-event profile showed better safety than in the original, pivotal trials of strontium ranelate.

He also noted that while the extension included only 233 women on the drug, registry data on about one million patients who have taken the drug also show no reported cases of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation.

The 233 women followed for 10 years on continuous strontium ranelate treatment came from either of the two pivotal, 5-year trials of the drug: the Treatment of Peripheral Osteoporosis Study (TROPOS) (J. Clin. Endocrinol. Met. 2005;90:2816-22), and the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (New. Engl. J. Med. 2004;350:459-68).

They continued to receive 2 g/day strontium ranelate, and 73% of the women completed the full extension period. Their average duration of drug use was 9.8 years, and their average compliance with the regimen was 89%.

During their additional 5 years on the drug, average lumbar spine bone mineral density continued to rise, increasing from about 20% above baseline at the start of the extension to about 27% above baseline at 10 years.

To assess the efficacy of treatment for preventing vertebral and nonvertebral fractures, Dr. Reginster and his associates “rebuilt” a control population by selecting placebo patients from the TROPOS trial who matched the 233 extended-treatment women based on their baseline Fracture Risk Assessment scores.

The researchers matched two TROPOS placebo-group women with each woman in the extension study, assembling a total of 458 controls.

The incidence of vertebral fractures during years 5–10 in the women on strontium ranelate was 21%, compared with a 28% rate in the rebuilt control group, a statistically significant difference.

In addition, the 21% reduction during the 5 to 10- year period was statistically similar to the 19% vertebral fracture rate among women treated during 0–5 years in SOTI.

The incidence of nonvertebral fractures during years 5–10 with strontium ranelate was 14%, significantly less than the 20% rate in the derived placebo group and statistically similar to the 13% rate seen in TROPOS, Dr. Reginster reported.

DESTIN, FLA. – Opioid rotation is a common and potentially beneficial practice for helping to relieve chronic pain in patients who require ongoing opioid therapy, but there is very little data to guide best practice.

The recommended approach, therefore, is one that focuses on safety, Dr. Perry Fine said at the Congress of Clinical Rheumatology.

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects, or when benefits are inadequate despite dose increases, according to recently published clinical guidelines (J. Pain 2009;10:113-30).

However, it is important to consider a number of factors before making changes in treatment, including demographic, disease-related, and treatment-related factors, as well as comorbidities, concomitant pharmacotherapy, drug sensitivities, and social situation, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

If a decision is made to convert a patient’s treatment, a two-step, safety-focused approach is needed, he said.

Step 1 involves an "automatic safety factor" calculation. That is, the equianalgesic dose of the new opioid should be calculated via an equianalgesic table such as a mu-agonist dose chart, and, with a few exceptions, an automatic dose reduction of 25%-50% should be made, except if the new drug is methadone or transdermal fentanyl.

A 25% reduction for opioids (other than methadone or fentanyl) is adequate in patients with no risk factors and/or if the switch is to a different route of administration of the same drug. A 50% reduction is needed in those receiving a relatively high dose of the current opioid, those who are elderly or frail, and those of Chinese lineage, as the Chinese population has been shown to be at increased risk of poor metabolism of opioid drugs, Dr. Fine said.

If the switch is to methadone, a 75%-90% dose reduction is needed, and if the switch is to transdermal fentanyl, use the reduction that is built into the conversion charts provided in the prescribing information, he advised.

If an oral transmucosal fentanyl citrate formulation is used, start with the lowest dose, he added.

The second safety-focused conversion step involves patient-specific adjustments. The patient should be assessed for pain severity and other medical or psychosocial characteristics, and appropriate additional adjustments should be made to the initial dose of the new opioid. For severe pain, consider a dose increase. If pain is under control, but the patient is experiencing adverse effects, any adjustments to the dose should be minimal.

In patients with specific vulnerabilities such as advanced age, renal insufficiency, or cognitive impairment, an additional 10%-30% dose reduction should be considered, Dr. Fine said.

He used as an example a case involving a patient with mild renal insufficiency who was undergoing a switch from morphine to hydromorphone. The patient had moderate pain, mild confusion, and was on multiple other medications. According to step 1, an automatic 25% reduction in the equianalgesic hydromorphone dose would be calculated. According to step 2, an additional 25% reduction would be taken because of the patient’s decreased renal clearance, cognitive problems, and potential drug-drug interactions. Dosage would then be titrated based on the patient’s response.

It is important that a strategy for frequent assessment of initial response be in place, Dr. Fine said, noting that this may involve regular phone calls to the patient or scheduled office visits. This will allow for improved safety and appropriate titration, he said.

Dr. Fine offered the following examples of initial dose calculation in three common analgesic conversions:

• To convert controlled-release oxycodone (60 mg oral dose twice daily) to controlled-release morphine:

1. Calculate the total oxycodone 24-hour dose (120 mg).

2. Determine the morphine dose equivalency (20 mg oxycodone = 30 mg morphine).

3. Convert the 24-hour oxycodone dose to the morphine dose (120 mg oxycodone = 180 mg morphine).

4. Reduce the morphine dose by 25% (135 mg morphine).

5. Split the total morphine dose to the twice-daily dose (67.5 mg). Because the controlled-release (extended-release) morphine is not provided in this exact dose, give the closest available dose (60 mg, twice daily).

• To convert controlled-release morphine (30 mg oral dose twice daily) to transdermal fentanyl:

1. Calculate the total morphine 24-hour dose (60 mg).

2. Use the prescribing information to determine the oral equivalent dose of transdermal fentanyl (60 mg oral morphine = 25 mcg/hr transdermal fentanyl patch).

3. Prescribe 25 mcg/hr transdermal fentanyl patch to be changed every 3 days. Supply patient with five patches (a 15-day supply); instruct patient on application, and follow-up by phone or in office within 2-3 days.

• To convert methadone (20 mg oral dose three times daily) to extended-release oxymorphone:

1. Calculate the total methadone 24-hour dose (60 mg daily).

2. Use mu-agonist dose chart to calculate oxymorphone dose equivalency to methadone (5 mg methadone = 10 mg oxymorphone).

3. Convert the 24-hour methadone dose to oxymorphone dose (60 mg methadone = 120 mg oxymorphone).

4. Reduce the dose by 50% and split the 50% total calculated oxymorphone dosage to a twice-daily dose. Prescribe oxymorphone ER (30 mg oral dose every 12 hours).

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King (now Pfizer), Meda, and Purdue-Pharma. He also is a consultant for Cephalon and Johnson & Johnson.

DESTIN, FLA. – Opioid rotation is a common and potentially beneficial practice for helping to relieve chronic pain in patients who require ongoing opioid therapy, but there is very little data to guide best practice.

The recommended approach, therefore, is one that focuses on safety, Dr. Perry Fine said at the Congress of Clinical Rheumatology.

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects, or when benefits are inadequate despite dose increases, according to recently published clinical guidelines (J. Pain 2009;10:113-30).

However, it is important to consider a number of factors before making changes in treatment, including demographic, disease-related, and treatment-related factors, as well as comorbidities, concomitant pharmacotherapy, drug sensitivities, and social situation, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

If a decision is made to convert a patient’s treatment, a two-step, safety-focused approach is needed, he said.

Step 1 involves an "automatic safety factor" calculation. That is, the equianalgesic dose of the new opioid should be calculated via an equianalgesic table such as a mu-agonist dose chart, and, with a few exceptions, an automatic dose reduction of 25%-50% should be made, except if the new drug is methadone or transdermal fentanyl.

A 25% reduction for opioids (other than methadone or fentanyl) is adequate in patients with no risk factors and/or if the switch is to a different route of administration of the same drug. A 50% reduction is needed in those receiving a relatively high dose of the current opioid, those who are elderly or frail, and those of Chinese lineage, as the Chinese population has been shown to be at increased risk of poor metabolism of opioid drugs, Dr. Fine said.

If the switch is to methadone, a 75%-90% dose reduction is needed, and if the switch is to transdermal fentanyl, use the reduction that is built into the conversion charts provided in the prescribing information, he advised.

If an oral transmucosal fentanyl citrate formulation is used, start with the lowest dose, he added.

The second safety-focused conversion step involves patient-specific adjustments. The patient should be assessed for pain severity and other medical or psychosocial characteristics, and appropriate additional adjustments should be made to the initial dose of the new opioid. For severe pain, consider a dose increase. If pain is under control, but the patient is experiencing adverse effects, any adjustments to the dose should be minimal.

In patients with specific vulnerabilities such as advanced age, renal insufficiency, or cognitive impairment, an additional 10%-30% dose reduction should be considered, Dr. Fine said.

He used as an example a case involving a patient with mild renal insufficiency who was undergoing a switch from morphine to hydromorphone. The patient had moderate pain, mild confusion, and was on multiple other medications. According to step 1, an automatic 25% reduction in the equianalgesic hydromorphone dose would be calculated. According to step 2, an additional 25% reduction would be taken because of the patient’s decreased renal clearance, cognitive problems, and potential drug-drug interactions. Dosage would then be titrated based on the patient’s response.

It is important that a strategy for frequent assessment of initial response be in place, Dr. Fine said, noting that this may involve regular phone calls to the patient or scheduled office visits. This will allow for improved safety and appropriate titration, he said.

Dr. Fine offered the following examples of initial dose calculation in three common analgesic conversions:

• To convert controlled-release oxycodone (60 mg oral dose twice daily) to controlled-release morphine:

1. Calculate the total oxycodone 24-hour dose (120 mg).

2. Determine the morphine dose equivalency (20 mg oxycodone = 30 mg morphine).

3. Convert the 24-hour oxycodone dose to the morphine dose (120 mg oxycodone = 180 mg morphine).

4. Reduce the morphine dose by 25% (135 mg morphine).

5. Split the total morphine dose to the twice-daily dose (67.5 mg). Because the controlled-release (extended-release) morphine is not provided in this exact dose, give the closest available dose (60 mg, twice daily).

• To convert controlled-release morphine (30 mg oral dose twice daily) to transdermal fentanyl:

1. Calculate the total morphine 24-hour dose (60 mg).

2. Use the prescribing information to determine the oral equivalent dose of transdermal fentanyl (60 mg oral morphine = 25 mcg/hr transdermal fentanyl patch).

3. Prescribe 25 mcg/hr transdermal fentanyl patch to be changed every 3 days. Supply patient with five patches (a 15-day supply); instruct patient on application, and follow-up by phone or in office within 2-3 days.

• To convert methadone (20 mg oral dose three times daily) to extended-release oxymorphone:

1. Calculate the total methadone 24-hour dose (60 mg daily).

2. Use mu-agonist dose chart to calculate oxymorphone dose equivalency to methadone (5 mg methadone = 10 mg oxymorphone).

3. Convert the 24-hour methadone dose to oxymorphone dose (60 mg methadone = 120 mg oxymorphone).

4. Reduce the dose by 50% and split the 50% total calculated oxymorphone dosage to a twice-daily dose. Prescribe oxymorphone ER (30 mg oral dose every 12 hours).

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King (now Pfizer), Meda, and Purdue-Pharma. He also is a consultant for Cephalon and Johnson & Johnson.

DESTIN, FLA. – Opioid rotation is a common and potentially beneficial practice for helping to relieve chronic pain in patients who require ongoing opioid therapy, but there is very little data to guide best practice.

The recommended approach, therefore, is one that focuses on safety, Dr. Perry Fine said at the Congress of Clinical Rheumatology.

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects, or when benefits are inadequate despite dose increases, according to recently published clinical guidelines (J. Pain 2009;10:113-30).

However, it is important to consider a number of factors before making changes in treatment, including demographic, disease-related, and treatment-related factors, as well as comorbidities, concomitant pharmacotherapy, drug sensitivities, and social situation, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

If a decision is made to convert a patient’s treatment, a two-step, safety-focused approach is needed, he said.

Step 1 involves an "automatic safety factor" calculation. That is, the equianalgesic dose of the new opioid should be calculated via an equianalgesic table such as a mu-agonist dose chart, and, with a few exceptions, an automatic dose reduction of 25%-50% should be made, except if the new drug is methadone or transdermal fentanyl.

A 25% reduction for opioids (other than methadone or fentanyl) is adequate in patients with no risk factors and/or if the switch is to a different route of administration of the same drug. A 50% reduction is needed in those receiving a relatively high dose of the current opioid, those who are elderly or frail, and those of Chinese lineage, as the Chinese population has been shown to be at increased risk of poor metabolism of opioid drugs, Dr. Fine said.

If the switch is to methadone, a 75%-90% dose reduction is needed, and if the switch is to transdermal fentanyl, use the reduction that is built into the conversion charts provided in the prescribing information, he advised.

If an oral transmucosal fentanyl citrate formulation is used, start with the lowest dose, he added.

The second safety-focused conversion step involves patient-specific adjustments. The patient should be assessed for pain severity and other medical or psychosocial characteristics, and appropriate additional adjustments should be made to the initial dose of the new opioid. For severe pain, consider a dose increase. If pain is under control, but the patient is experiencing adverse effects, any adjustments to the dose should be minimal.

In patients with specific vulnerabilities such as advanced age, renal insufficiency, or cognitive impairment, an additional 10%-30% dose reduction should be considered, Dr. Fine said.

He used as an example a case involving a patient with mild renal insufficiency who was undergoing a switch from morphine to hydromorphone. The patient had moderate pain, mild confusion, and was on multiple other medications. According to step 1, an automatic 25% reduction in the equianalgesic hydromorphone dose would be calculated. According to step 2, an additional 25% reduction would be taken because of the patient’s decreased renal clearance, cognitive problems, and potential drug-drug interactions. Dosage would then be titrated based on the patient’s response.

It is important that a strategy for frequent assessment of initial response be in place, Dr. Fine said, noting that this may involve regular phone calls to the patient or scheduled office visits. This will allow for improved safety and appropriate titration, he said.

Dr. Fine offered the following examples of initial dose calculation in three common analgesic conversions:

• To convert controlled-release oxycodone (60 mg oral dose twice daily) to controlled-release morphine:

1. Calculate the total oxycodone 24-hour dose (120 mg).

2. Determine the morphine dose equivalency (20 mg oxycodone = 30 mg morphine).

3. Convert the 24-hour oxycodone dose to the morphine dose (120 mg oxycodone = 180 mg morphine).

4. Reduce the morphine dose by 25% (135 mg morphine).

5. Split the total morphine dose to the twice-daily dose (67.5 mg). Because the controlled-release (extended-release) morphine is not provided in this exact dose, give the closest available dose (60 mg, twice daily).

• To convert controlled-release morphine (30 mg oral dose twice daily) to transdermal fentanyl:

1. Calculate the total morphine 24-hour dose (60 mg).

2. Use the prescribing information to determine the oral equivalent dose of transdermal fentanyl (60 mg oral morphine = 25 mcg/hr transdermal fentanyl patch).

3. Prescribe 25 mcg/hr transdermal fentanyl patch to be changed every 3 days. Supply patient with five patches (a 15-day supply); instruct patient on application, and follow-up by phone or in office within 2-3 days.

• To convert methadone (20 mg oral dose three times daily) to extended-release oxymorphone:

1. Calculate the total methadone 24-hour dose (60 mg daily).

2. Use mu-agonist dose chart to calculate oxymorphone dose equivalency to methadone (5 mg methadone = 10 mg oxymorphone).

3. Convert the 24-hour methadone dose to oxymorphone dose (60 mg methadone = 120 mg oxymorphone).

4. Reduce the dose by 50% and split the 50% total calculated oxymorphone dosage to a twice-daily dose. Prescribe oxymorphone ER (30 mg oral dose every 12 hours).

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King (now Pfizer), Meda, and Purdue-Pharma. He also is a consultant for Cephalon and Johnson & Johnson.

LONDON – The reasons why fewer black than white patients undergo knee replacement as a treatment option for end-stage osteoarthritis remain elusive.

According to the findings of a 725-patient study, women and blacks with knee osteoarthritis (OA) were less willing than men or their white counterparts to consider having total knee replacement (TKR) surgery.

Black patients were also found to be less aware of the benefits of joint replacement and had worse expectations of the outcome than did white patients.

Despite a number of sociocultural differences, however, it is not clear why the uptake of TKR differs among ethnic groups.

"We know that joint replacement is an effective – actually the only effective – intervention for end-stage osteoarthritis," said study author Dr. C. Kent Kwoh, who is professor of medicine, epidemiology and clinical and translational science at the University of Pittsburgh and chief of the rheumatology section at VA Pittsburgh Healthcare System.

"The problem is that there have been many studies that have shown there are disparities in joint replacement; [blacks] get hip and knee replacement much less often than do whites," Dr. Kwoh added in an interview during a poster session at the annual European Congress of Rheumatology. "The question is, Why?"

Previous research has shown that even when faced with very severe and painful OA and a physician recommendation for TKR, black patients are less willing than whites to consider this an option.

The present study was in a much larger community-based sample than has been the case in past investigations, said Dr. Kwoh, and it aimed to identify more specific factors and patient attitudes that might influence the decision to undergo TKR.

Using a cross-sectional survey design, the investigators recruited patients aged 50 years or older who had chronic, frequent knee pain and radiographic evidence of OA.

The study population consisted of 234 black and 491 white patients, with mean respective ages of 58 years and 68 years (P less than .0004).

In addition to being younger, black patients tended to have worse knee pain, with higher total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index scores (54 vs. 43), and OA Pain Assessment scores for constant (7 vs. 11) and intermittent (14 vs. 11) pain than white patients (P less than .0004 for all comparisons).

"There were differences in a number of [other] variables [between whites and blacks], such as income, employment status, education, access to insurance, expectations of outcome, trust in the health system, and religiosity, that may impact the choice for joint replacement" Dr. Kwoh observed.

However, putting all of these variables into a multivariate model didn’t seem to fully explain the disparity in TKR acceptance between the two groups.

The adjusted odds ratio for willingness to undergo TKR was 0.38 comparing black vs. white patients (95% confidence interval, 0.19-0.74; P = .005) and 2.52 for male vs. female sex (95% CI, 1.37-4.66; P = .003).

"We’re left a little bit puzzled at this point," Dr. Kwoh admitted. "Our other studies have shown differences in expectations; that is, if you have worse expectations, you were less likely to consider joint replacement."

In that previous work, however, an adjustment of the findings according to patient expectations seemed to take care of the difference in willingness. "In this study, we weren’t able to show that," Dr. Kwoh said. "So maybe there are other, unmeasured confounders that we have to address."

As to where these findings leave the practicing physician who advises patients, Dr. Kwoh noted that patient education is important and that patients really need to have a good understanding of the risks and benefits.

"Joint replacement is effective, we know that it works very well, it has low morbidity and low mortality, and so patients who really need it should avail themselves to it," Dr. Kwoh advised.

Dr. Kwoh stated that he had no conflicts of interest. The study was funded by the University of Pittsburgh Multidisciplinary Clinical Research Center for Rheumatic and Musculoskeletal Diseases.

LONDON – The reasons why fewer black than white patients undergo knee replacement as a treatment option for end-stage osteoarthritis remain elusive.

According to the findings of a 725-patient study, women and blacks with knee osteoarthritis (OA) were less willing than men or their white counterparts to consider having total knee replacement (TKR) surgery.

Black patients were also found to be less aware of the benefits of joint replacement and had worse expectations of the outcome than did white patients.

Despite a number of sociocultural differences, however, it is not clear why the uptake of TKR differs among ethnic groups.

"We know that joint replacement is an effective – actually the only effective – intervention for end-stage osteoarthritis," said study author Dr. C. Kent Kwoh, who is professor of medicine, epidemiology and clinical and translational science at the University of Pittsburgh and chief of the rheumatology section at VA Pittsburgh Healthcare System.

"The problem is that there have been many studies that have shown there are disparities in joint replacement; [blacks] get hip and knee replacement much less often than do whites," Dr. Kwoh added in an interview during a poster session at the annual European Congress of Rheumatology. "The question is, Why?"

Previous research has shown that even when faced with very severe and painful OA and a physician recommendation for TKR, black patients are less willing than whites to consider this an option.

The present study was in a much larger community-based sample than has been the case in past investigations, said Dr. Kwoh, and it aimed to identify more specific factors and patient attitudes that might influence the decision to undergo TKR.

Using a cross-sectional survey design, the investigators recruited patients aged 50 years or older who had chronic, frequent knee pain and radiographic evidence of OA.

The study population consisted of 234 black and 491 white patients, with mean respective ages of 58 years and 68 years (P less than .0004).

In addition to being younger, black patients tended to have worse knee pain, with higher total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index scores (54 vs. 43), and OA Pain Assessment scores for constant (7 vs. 11) and intermittent (14 vs. 11) pain than white patients (P less than .0004 for all comparisons).

"There were differences in a number of [other] variables [between whites and blacks], such as income, employment status, education, access to insurance, expectations of outcome, trust in the health system, and religiosity, that may impact the choice for joint replacement" Dr. Kwoh observed.

However, putting all of these variables into a multivariate model didn’t seem to fully explain the disparity in TKR acceptance between the two groups.

The adjusted odds ratio for willingness to undergo TKR was 0.38 comparing black vs. white patients (95% confidence interval, 0.19-0.74; P = .005) and 2.52 for male vs. female sex (95% CI, 1.37-4.66; P = .003).

"We’re left a little bit puzzled at this point," Dr. Kwoh admitted. "Our other studies have shown differences in expectations; that is, if you have worse expectations, you were less likely to consider joint replacement."

In that previous work, however, an adjustment of the findings according to patient expectations seemed to take care of the difference in willingness. "In this study, we weren’t able to show that," Dr. Kwoh said. "So maybe there are other, unmeasured confounders that we have to address."

As to where these findings leave the practicing physician who advises patients, Dr. Kwoh noted that patient education is important and that patients really need to have a good understanding of the risks and benefits.

"Joint replacement is effective, we know that it works very well, it has low morbidity and low mortality, and so patients who really need it should avail themselves to it," Dr. Kwoh advised.

Dr. Kwoh stated that he had no conflicts of interest. The study was funded by the University of Pittsburgh Multidisciplinary Clinical Research Center for Rheumatic and Musculoskeletal Diseases.

LONDON – The reasons why fewer black than white patients undergo knee replacement as a treatment option for end-stage osteoarthritis remain elusive.

According to the findings of a 725-patient study, women and blacks with knee osteoarthritis (OA) were less willing than men or their white counterparts to consider having total knee replacement (TKR) surgery.

Black patients were also found to be less aware of the benefits of joint replacement and had worse expectations of the outcome than did white patients.

Despite a number of sociocultural differences, however, it is not clear why the uptake of TKR differs among ethnic groups.

"We know that joint replacement is an effective – actually the only effective – intervention for end-stage osteoarthritis," said study author Dr. C. Kent Kwoh, who is professor of medicine, epidemiology and clinical and translational science at the University of Pittsburgh and chief of the rheumatology section at VA Pittsburgh Healthcare System.

"The problem is that there have been many studies that have shown there are disparities in joint replacement; [blacks] get hip and knee replacement much less often than do whites," Dr. Kwoh added in an interview during a poster session at the annual European Congress of Rheumatology. "The question is, Why?"

Previous research has shown that even when faced with very severe and painful OA and a physician recommendation for TKR, black patients are less willing than whites to consider this an option.

The present study was in a much larger community-based sample than has been the case in past investigations, said Dr. Kwoh, and it aimed to identify more specific factors and patient attitudes that might influence the decision to undergo TKR.

Using a cross-sectional survey design, the investigators recruited patients aged 50 years or older who had chronic, frequent knee pain and radiographic evidence of OA.

The study population consisted of 234 black and 491 white patients, with mean respective ages of 58 years and 68 years (P less than .0004).

In addition to being younger, black patients tended to have worse knee pain, with higher total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index scores (54 vs. 43), and OA Pain Assessment scores for constant (7 vs. 11) and intermittent (14 vs. 11) pain than white patients (P less than .0004 for all comparisons).

"There were differences in a number of [other] variables [between whites and blacks], such as income, employment status, education, access to insurance, expectations of outcome, trust in the health system, and religiosity, that may impact the choice for joint replacement" Dr. Kwoh observed.

However, putting all of these variables into a multivariate model didn’t seem to fully explain the disparity in TKR acceptance between the two groups.

The adjusted odds ratio for willingness to undergo TKR was 0.38 comparing black vs. white patients (95% confidence interval, 0.19-0.74; P = .005) and 2.52 for male vs. female sex (95% CI, 1.37-4.66; P = .003).

"We’re left a little bit puzzled at this point," Dr. Kwoh admitted. "Our other studies have shown differences in expectations; that is, if you have worse expectations, you were less likely to consider joint replacement."

In that previous work, however, an adjustment of the findings according to patient expectations seemed to take care of the difference in willingness. "In this study, we weren’t able to show that," Dr. Kwoh said. "So maybe there are other, unmeasured confounders that we have to address."

As to where these findings leave the practicing physician who advises patients, Dr. Kwoh noted that patient education is important and that patients really need to have a good understanding of the risks and benefits.

"Joint replacement is effective, we know that it works very well, it has low morbidity and low mortality, and so patients who really need it should avail themselves to it," Dr. Kwoh advised.

Dr. Kwoh stated that he had no conflicts of interest. The study was funded by the University of Pittsburgh Multidisciplinary Clinical Research Center for Rheumatic and Musculoskeletal Diseases.

LONDON – A single 5-mg infusion of zoledronic acid, a bisphosphonate, in patients with knee osteoarthritis led to significant pain reduction and shrinkage of bone marrow lesions in a randomized, placebo-controlled study with 59 patients.

The zoledronic acid treatment led to an average 15-point drop in pain (on a visual analog scale of 0-100) beyond what occurred in the placebo group, and the active treatment was also linked with an average 170-mm² reduction in maximal bone marrow lesion (BML) area beyond the placebo-treated patients, which was a cut in BML area of about 37%, compared with the starting BML area, Dr. Graeme Jones said at the annual European Congress of Rheumatology. Dr. Jones visualizes BMLs using MRI knee scans.

"This is the first intervention shown to work on BMLs" in patients with osteoarthritis (OA), said Dr. Jones, professor of rheumatology and epidemiology and head of the musculoskeletal unit at the Menzies Research Institute Tasmania, Hobart, Australia.

"This is exciting for treating existing OA. It is one of the first positive structure modification trials," commented Dr. Philip Conaghan, professor and chairman of musculoskeletal medicine at the University of Leeds (England).

"Results from several studies have linked BMLs with pain and cartilage damage in OA patients. The larger the BML, the faster the cartilage loss and the worse the pain," Dr. Jones said in an interview. Based on studies his group has done, about 20% of BMLs that are associated with knee OA spontaneously enlarge over the course of 3 years, another 20% shrink in size, and about 60% remain the same, he said. Their earlier research findings also showed that BMLs are independently linked with fast progression of OA and the need for knee replacement. "If you reduce BMLs, it should produce good outcomes in patients," he said.

"The next step is to show that treatment with zoledronic acid not only reduces BML size but also slows cartilage loss. Sixty patients followed for 12 months were not enough to assess cartilage. We will need about 400 patients followed for 2 years," Dr. Jones added.

Despite not yet having information on cartilage effects, he said that his results so far have convinced him that treatment with zoledronic acid is reasonable for patients with painful knee OA and BMLs.

"I use it off label. Patients need to know it’s off label, and they [therefore] must be willing to pay for it, but I use it. It’s been shown to work, and nothing else works. Zoledronic acid [Reclast] is available, we know about its safety, and it’s been used for a long time to treat osteoporosis and cancers. If you have OA patients with BMLs, this is something to actively consider for them. Patients with OA have very limited treatment options. This can make a large difference in their pain, and it has long-lasting benefit so it can be given once a year," Dr. Jones said.

He recommended an infusion of 5 mg of zoledronic acid for patients who are at least 50 years old with knee OA that fulfills the American College of Rheumatology clinical criteria, and knee BMLs that are visible on an MRI scan of the affected knee. In his experience, 88% of these knee OA patients have BMLs. Dr. Jones noted that he does not use a maximal BML area threshold for initiating treatment, although in his study the average maximal BML area was about 465 mm². About one-third of people aged 50 years or older with no clinical evidence of OA also have BMLs, he noted.

The benefits of zoledronic acid that were seen in his study might be a class effect that may be replicated by treatment with another bisphosphonate, but zoledronic acid is more potent than oral bisphosphonates and hence the drug’s beneficial effect on pain and BML shrinkage may exceed the effect that other bisphosphonates might have, he said.

The pain benefit appeared to start wearing off about a year after the zoledronic acid injection. Dr. Jones said that he has a small number of patients whom he has infused a second time, which produced a second round of pain reduction. He has not yet given any OA patients a third dose of the drug.

The 59 patients who were enrolled in the study had an average age of about 60 years, with an average knee pain score of about 52 on the visual analog scale; all patients had BMLs as seen on MRI scans of their affected knees. In all, 31 patients received a 5-mg infusion of zoledronic acid and 28 patients received a placebo infusion. All patients also continued their conventional pain medication regimens. The zoledronic acid infusion was well tolerated: Although infusion reactions were reported in 90% of the patients who received the drug and in 43% of the placebo patients, serious adverse effects occurred in only 19% of the patients who received zoledronic acid and in 4% of the placebo patients.

The Food and Drug Administration has approved zoledronic acid under a number of brand names to prevent or treat osteoporosis in postmenopausal women or patients who are at risk for osteoporosis because they are taking or have taken corticosteroid therapy; to manage Paget disease; and to prevent chemotherapy-induced bone fractures or fractures in patients with multiple myeloma or cancer that has metastasized to the bones from other locations.

The study was funded by Novartis, which markets zoledronic acid (Reclast). Dr. Jones and Dr. Conaghan said that they had no disclosures.

*Correction, 6/6/2011: An earlier version of this story incorrectly stated that Dr. Jones had no disclosures. Dr. Jones has received speaker fees, travel sponsorship, and research support from Novartis and from several other drug companies.

 

LONDON – A single 5-mg infusion of zoledronic acid, a bisphosphonate, in patients with knee osteoarthritis led to significant pain reduction and shrinkage of bone marrow lesions in a randomized, placebo-controlled study with 59 patients.

The zoledronic acid treatment led to an average 15-point drop in pain (on a visual analog scale of 0-100) beyond what occurred in the placebo group, and the active treatment was also linked with an average 170-mm² reduction in maximal bone marrow lesion (BML) area beyond the placebo-treated patients, which was a cut in BML area of about 37%, compared with the starting BML area, Dr. Graeme Jones said at the annual European Congress of Rheumatology. Dr. Jones visualizes BMLs using MRI knee scans.

"This is the first intervention shown to work on BMLs" in patients with osteoarthritis (OA), said Dr. Jones, professor of rheumatology and epidemiology and head of the musculoskeletal unit at the Menzies Research Institute Tasmania, Hobart, Australia.

"This is exciting for treating existing OA. It is one of the first positive structure modification trials," commented Dr. Philip Conaghan, professor and chairman of musculoskeletal medicine at the University of Leeds (England).

"Results from several studies have linked BMLs with pain and cartilage damage in OA patients. The larger the BML, the faster the cartilage loss and the worse the pain," Dr. Jones said in an interview. Based on studies his group has done, about 20% of BMLs that are associated with knee OA spontaneously enlarge over the course of 3 years, another 20% shrink in size, and about 60% remain the same, he said. Their earlier research findings also showed that BMLs are independently linked with fast progression of OA and the need for knee replacement. "If you reduce BMLs, it should produce good outcomes in patients," he said.

"The next step is to show that treatment with zoledronic acid not only reduces BML size but also slows cartilage loss. Sixty patients followed for 12 months were not enough to assess cartilage. We will need about 400 patients followed for 2 years," Dr. Jones added.

Despite not yet having information on cartilage effects, he said that his results so far have convinced him that treatment with zoledronic acid is reasonable for patients with painful knee OA and BMLs.

"I use it off label. Patients need to know it’s off label, and they [therefore] must be willing to pay for it, but I use it. It’s been shown to work, and nothing else works. Zoledronic acid [Reclast] is available, we know about its safety, and it’s been used for a long time to treat osteoporosis and cancers. If you have OA patients with BMLs, this is something to actively consider for them. Patients with OA have very limited treatment options. This can make a large difference in their pain, and it has long-lasting benefit so it can be given once a year," Dr. Jones said.

He recommended an infusion of 5 mg of zoledronic acid for patients who are at least 50 years old with knee OA that fulfills the American College of Rheumatology clinical criteria, and knee BMLs that are visible on an MRI scan of the affected knee. In his experience, 88% of these knee OA patients have BMLs. Dr. Jones noted that he does not use a maximal BML area threshold for initiating treatment, although in his study the average maximal BML area was about 465 mm². About one-third of people aged 50 years or older with no clinical evidence of OA also have BMLs, he noted.

The benefits of zoledronic acid that were seen in his study might be a class effect that may be replicated by treatment with another bisphosphonate, but zoledronic acid is more potent than oral bisphosphonates and hence the drug’s beneficial effect on pain and BML shrinkage may exceed the effect that other bisphosphonates might have, he said.

The pain benefit appeared to start wearing off about a year after the zoledronic acid injection. Dr. Jones said that he has a small number of patients whom he has infused a second time, which produced a second round of pain reduction. He has not yet given any OA patients a third dose of the drug.

The 59 patients who were enrolled in the study had an average age of about 60 years, with an average knee pain score of about 52 on the visual analog scale; all patients had BMLs as seen on MRI scans of their affected knees. In all, 31 patients received a 5-mg infusion of zoledronic acid and 28 patients received a placebo infusion. All patients also continued their conventional pain medication regimens. The zoledronic acid infusion was well tolerated: Although infusion reactions were reported in 90% of the patients who received the drug and in 43% of the placebo patients, serious adverse effects occurred in only 19% of the patients who received zoledronic acid and in 4% of the placebo patients.

The Food and Drug Administration has approved zoledronic acid under a number of brand names to prevent or treat osteoporosis in postmenopausal women or patients who are at risk for osteoporosis because they are taking or have taken corticosteroid therapy; to manage Paget disease; and to prevent chemotherapy-induced bone fractures or fractures in patients with multiple myeloma or cancer that has metastasized to the bones from other locations.

The study was funded by Novartis, which markets zoledronic acid (Reclast). Dr. Jones and Dr. Conaghan said that they had no disclosures.

*Correction, 6/6/2011: An earlier version of this story incorrectly stated that Dr. Jones had no disclosures. Dr. Jones has received speaker fees, travel sponsorship, and research support from Novartis and from several other drug companies.

 

LONDON – A single 5-mg infusion of zoledronic acid, a bisphosphonate, in patients with knee osteoarthritis led to significant pain reduction and shrinkage of bone marrow lesions in a randomized, placebo-controlled study with 59 patients.

The zoledronic acid treatment led to an average 15-point drop in pain (on a visual analog scale of 0-100) beyond what occurred in the placebo group, and the active treatment was also linked with an average 170-mm² reduction in maximal bone marrow lesion (BML) area beyond the placebo-treated patients, which was a cut in BML area of about 37%, compared with the starting BML area, Dr. Graeme Jones said at the annual European Congress of Rheumatology. Dr. Jones visualizes BMLs using MRI knee scans.

"This is the first intervention shown to work on BMLs" in patients with osteoarthritis (OA), said Dr. Jones, professor of rheumatology and epidemiology and head of the musculoskeletal unit at the Menzies Research Institute Tasmania, Hobart, Australia.

"This is exciting for treating existing OA. It is one of the first positive structure modification trials," commented Dr. Philip Conaghan, professor and chairman of musculoskeletal medicine at the University of Leeds (England).

"Results from several studies have linked BMLs with pain and cartilage damage in OA patients. The larger the BML, the faster the cartilage loss and the worse the pain," Dr. Jones said in an interview. Based on studies his group has done, about 20% of BMLs that are associated with knee OA spontaneously enlarge over the course of 3 years, another 20% shrink in size, and about 60% remain the same, he said. Their earlier research findings also showed that BMLs are independently linked with fast progression of OA and the need for knee replacement. "If you reduce BMLs, it should produce good outcomes in patients," he said.

"The next step is to show that treatment with zoledronic acid not only reduces BML size but also slows cartilage loss. Sixty patients followed for 12 months were not enough to assess cartilage. We will need about 400 patients followed for 2 years," Dr. Jones added.

Despite not yet having information on cartilage effects, he said that his results so far have convinced him that treatment with zoledronic acid is reasonable for patients with painful knee OA and BMLs.

"I use it off label. Patients need to know it’s off label, and they [therefore] must be willing to pay for it, but I use it. It’s been shown to work, and nothing else works. Zoledronic acid [Reclast] is available, we know about its safety, and it’s been used for a long time to treat osteoporosis and cancers. If you have OA patients with BMLs, this is something to actively consider for them. Patients with OA have very limited treatment options. This can make a large difference in their pain, and it has long-lasting benefit so it can be given once a year," Dr. Jones said.

He recommended an infusion of 5 mg of zoledronic acid for patients who are at least 50 years old with knee OA that fulfills the American College of Rheumatology clinical criteria, and knee BMLs that are visible on an MRI scan of the affected knee. In his experience, 88% of these knee OA patients have BMLs. Dr. Jones noted that he does not use a maximal BML area threshold for initiating treatment, although in his study the average maximal BML area was about 465 mm². About one-third of people aged 50 years or older with no clinical evidence of OA also have BMLs, he noted.

The benefits of zoledronic acid that were seen in his study might be a class effect that may be replicated by treatment with another bisphosphonate, but zoledronic acid is more potent than oral bisphosphonates and hence the drug’s beneficial effect on pain and BML shrinkage may exceed the effect that other bisphosphonates might have, he said.

The pain benefit appeared to start wearing off about a year after the zoledronic acid injection. Dr. Jones said that he has a small number of patients whom he has infused a second time, which produced a second round of pain reduction. He has not yet given any OA patients a third dose of the drug.

The 59 patients who were enrolled in the study had an average age of about 60 years, with an average knee pain score of about 52 on the visual analog scale; all patients had BMLs as seen on MRI scans of their affected knees. In all, 31 patients received a 5-mg infusion of zoledronic acid and 28 patients received a placebo infusion. All patients also continued their conventional pain medication regimens. The zoledronic acid infusion was well tolerated: Although infusion reactions were reported in 90% of the patients who received the drug and in 43% of the placebo patients, serious adverse effects occurred in only 19% of the patients who received zoledronic acid and in 4% of the placebo patients.

The Food and Drug Administration has approved zoledronic acid under a number of brand names to prevent or treat osteoporosis in postmenopausal women or patients who are at risk for osteoporosis because they are taking or have taken corticosteroid therapy; to manage Paget disease; and to prevent chemotherapy-induced bone fractures or fractures in patients with multiple myeloma or cancer that has metastasized to the bones from other locations.

The study was funded by Novartis, which markets zoledronic acid (Reclast). Dr. Jones and Dr. Conaghan said that they had no disclosures.

*Correction, 6/6/2011: An earlier version of this story incorrectly stated that Dr. Jones had no disclosures. Dr. Jones has received speaker fees, travel sponsorship, and research support from Novartis and from several other drug companies.

 

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010–2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756–65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of –2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with one or both risk factors.

Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab significantly reduced hip fracture incidence among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of –2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

“Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggest that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction,” Dr. Boonen and his associates concluded.

The study was funded by Amgen. Dr. Boonen has received funding for serving as an investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of his coinvestigators are Amgen employees, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010–2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756–65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of –2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with one or both risk factors.

Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab significantly reduced hip fracture incidence among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of –2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

“Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggest that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction,” Dr. Boonen and his associates concluded.

The study was funded by Amgen. Dr. Boonen has received funding for serving as an investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of his coinvestigators are Amgen employees, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010–2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756–65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of –2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with one or both risk factors.

Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab significantly reduced hip fracture incidence among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of –2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

“Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggest that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction,” Dr. Boonen and his associates concluded.

The study was funded by Amgen. Dr. Boonen has received funding for serving as an investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of his coinvestigators are Amgen employees, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

BOSTON – Healthy individuals do not need to be screened for vitamin D deficiency, according to guidelines from the Endocrine Society.

“That's an important message. So we're recommending screening for those at risk for vitamin D deficiency – those who are obese, African Americans, pregnant and lactating women, patients with malabsorption syndromes, and a whole list that we have provided in the guidelines,” lead author Dr. Michael F. Holick said at the meeting.

Dr. Holick headed a task force appointed by the clinical guidelines subcommittee of the Endocrine Society to formulate evidence-based recommendations on vitamin D deficiency. The subcommittee deemed vitamin D deficiency a priority area in need of practice guidelines.

The task force recommended that those at risk for vitamin D deficiency be screened by measuring serum 25-hydroxyvitamin D levels using a reliable assay. Causes of vitamin D deficiency include obesity, fat malabsorption syndromes, bariatric surgery, nephrotic syndrome, a wide range of medications (anticonvulsants and anti-HIV/AIDS drugs), chronic granuloma-forming disorders, some lymphomas, and primary hyperthyroidism.

The guidelines were released at the meeting and will be published in the July issue of the Journal of Clinical Endocrinology & Metabolism (doi: 10.1210/jc.2011–0385).

The guidelines provide long-awaited recommendations on vitamin D intake and the diagnosis and treatment of vitamin D deficiency.

Physicians have struggled for years to delineate how much vitamin D is necessary for different clinical groups, how to measure it, and how best to supplement deficiencies.

The task force commissioned two systematic reviews of the literature to inform its key recommendations and followed the approach recommended by GRADE, an international group with expertise in development and implementation of evidence-based guidelines.

“All available evidence suggests that children and adults should maintain a blood level of 25(OH)D above 20 ng/mL to prevent rickets and osteomalacia, respectively. However, to maximize vitamin D's effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/mL,” the group wrote.

In the new guidelines, vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L). The task force suggests:

▸ Infants aged 0–1 year require at least 400 IU/day (IU = 25 ng) of vitamin D to maximize bone health.

▸ Children 1 year and older require at least 600 IU/day.

▸ Adults aged 19–50 years require at least 600 IU/day.

▸ Adults aged 50–70 years require at least 600 IU/day.

▸ Adults 70 years and older require 800 IU/day.

▸ Pregnant and lactating women require at least 600 IU/day.

The task force also recommends that obese children and adults and children and adults on certain medications (anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS) be given at least 2-3 times more vitamin D for their age group to satisfy their bodies' vitamin D requirements. Either vitamin D₂ or vitamin D₃ can be used for the treatment and prevention of vitamin D deficiency.

The group recommends that adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for 8 weeks or its equivalent of 6,000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D greater than 30 ng/mL.

This should be followed by maintenance therapy of 1,500-2,000 IU/day.

The task force also recommends vitamin D supplementation for fall prevention. “We know that there is sufficient evidence to give vitamin D for fall prevention. It's well documented that vitamin D is very important for muscle strength,” said Dr. Holick, professor of medicine, physiology and biophysics at Boston University.

However, the group does not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life, because there is insufficient evidence.

The task force noted that most individuals do not get adequate vitamin D for a number of reasons. In particular, “there needs to be an appreciation that unprotected sun exposure is the major source of vitamin D for both children and adults and that in the absence of sun exposure it is difficult, if not impossible, to obtain an adequate amount of vitamin D from dietary sources without supplementation to satisfy the body's requirement. Concerns about melanoma and other types of skin cancer necessitate avoidance of excessive exposure to midday sun,” they wrote.

The guidelines are cosponsored by the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation.

All but one of the authors reported having significant financial relationships with pharmaceutical companies, medical organizations and/or food industry groups.

BOSTON – Healthy individuals do not need to be screened for vitamin D deficiency, according to guidelines from the Endocrine Society.

“That's an important message. So we're recommending screening for those at risk for vitamin D deficiency – those who are obese, African Americans, pregnant and lactating women, patients with malabsorption syndromes, and a whole list that we have provided in the guidelines,” lead author Dr. Michael F. Holick said at the meeting.

Dr. Holick headed a task force appointed by the clinical guidelines subcommittee of the Endocrine Society to formulate evidence-based recommendations on vitamin D deficiency. The subcommittee deemed vitamin D deficiency a priority area in need of practice guidelines.

The task force recommended that those at risk for vitamin D deficiency be screened by measuring serum 25-hydroxyvitamin D levels using a reliable assay. Causes of vitamin D deficiency include obesity, fat malabsorption syndromes, bariatric surgery, nephrotic syndrome, a wide range of medications (anticonvulsants and anti-HIV/AIDS drugs), chronic granuloma-forming disorders, some lymphomas, and primary hyperthyroidism.

The guidelines were released at the meeting and will be published in the July issue of the Journal of Clinical Endocrinology & Metabolism (doi: 10.1210/jc.2011–0385).

The guidelines provide long-awaited recommendations on vitamin D intake and the diagnosis and treatment of vitamin D deficiency.

Physicians have struggled for years to delineate how much vitamin D is necessary for different clinical groups, how to measure it, and how best to supplement deficiencies.

The task force commissioned two systematic reviews of the literature to inform its key recommendations and followed the approach recommended by GRADE, an international group with expertise in development and implementation of evidence-based guidelines.

“All available evidence suggests that children and adults should maintain a blood level of 25(OH)D above 20 ng/mL to prevent rickets and osteomalacia, respectively. However, to maximize vitamin D's effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/mL,” the group wrote.

In the new guidelines, vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L). The task force suggests:

▸ Infants aged 0–1 year require at least 400 IU/day (IU = 25 ng) of vitamin D to maximize bone health.

▸ Children 1 year and older require at least 600 IU/day.

▸ Adults aged 19–50 years require at least 600 IU/day.

▸ Adults aged 50–70 years require at least 600 IU/day.

▸ Adults 70 years and older require 800 IU/day.

▸ Pregnant and lactating women require at least 600 IU/day.

The task force also recommends that obese children and adults and children and adults on certain medications (anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS) be given at least 2-3 times more vitamin D for their age group to satisfy their bodies' vitamin D requirements. Either vitamin D₂ or vitamin D₃ can be used for the treatment and prevention of vitamin D deficiency.

The group recommends that adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for 8 weeks or its equivalent of 6,000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D greater than 30 ng/mL.

This should be followed by maintenance therapy of 1,500-2,000 IU/day.

The task force also recommends vitamin D supplementation for fall prevention. “We know that there is sufficient evidence to give vitamin D for fall prevention. It's well documented that vitamin D is very important for muscle strength,” said Dr. Holick, professor of medicine, physiology and biophysics at Boston University.

However, the group does not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life, because there is insufficient evidence.

The task force noted that most individuals do not get adequate vitamin D for a number of reasons. In particular, “there needs to be an appreciation that unprotected sun exposure is the major source of vitamin D for both children and adults and that in the absence of sun exposure it is difficult, if not impossible, to obtain an adequate amount of vitamin D from dietary sources without supplementation to satisfy the body's requirement. Concerns about melanoma and other types of skin cancer necessitate avoidance of excessive exposure to midday sun,” they wrote.

The guidelines are cosponsored by the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation.

All but one of the authors reported having significant financial relationships with pharmaceutical companies, medical organizations and/or food industry groups.

BOSTON – Healthy individuals do not need to be screened for vitamin D deficiency, according to guidelines from the Endocrine Society.

“That's an important message. So we're recommending screening for those at risk for vitamin D deficiency – those who are obese, African Americans, pregnant and lactating women, patients with malabsorption syndromes, and a whole list that we have provided in the guidelines,” lead author Dr. Michael F. Holick said at the meeting.

Dr. Holick headed a task force appointed by the clinical guidelines subcommittee of the Endocrine Society to formulate evidence-based recommendations on vitamin D deficiency. The subcommittee deemed vitamin D deficiency a priority area in need of practice guidelines.

The task force recommended that those at risk for vitamin D deficiency be screened by measuring serum 25-hydroxyvitamin D levels using a reliable assay. Causes of vitamin D deficiency include obesity, fat malabsorption syndromes, bariatric surgery, nephrotic syndrome, a wide range of medications (anticonvulsants and anti-HIV/AIDS drugs), chronic granuloma-forming disorders, some lymphomas, and primary hyperthyroidism.

The guidelines were released at the meeting and will be published in the July issue of the Journal of Clinical Endocrinology & Metabolism (doi: 10.1210/jc.2011–0385).

The guidelines provide long-awaited recommendations on vitamin D intake and the diagnosis and treatment of vitamin D deficiency.

Physicians have struggled for years to delineate how much vitamin D is necessary for different clinical groups, how to measure it, and how best to supplement deficiencies.

The task force commissioned two systematic reviews of the literature to inform its key recommendations and followed the approach recommended by GRADE, an international group with expertise in development and implementation of evidence-based guidelines.

“All available evidence suggests that children and adults should maintain a blood level of 25(OH)D above 20 ng/mL to prevent rickets and osteomalacia, respectively. However, to maximize vitamin D's effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/mL,” the group wrote.

In the new guidelines, vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L). The task force suggests:

▸ Infants aged 0–1 year require at least 400 IU/day (IU = 25 ng) of vitamin D to maximize bone health.

▸ Children 1 year and older require at least 600 IU/day.

▸ Adults aged 19–50 years require at least 600 IU/day.

▸ Adults aged 50–70 years require at least 600 IU/day.

▸ Adults 70 years and older require 800 IU/day.

▸ Pregnant and lactating women require at least 600 IU/day.

The task force also recommends that obese children and adults and children and adults on certain medications (anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS) be given at least 2-3 times more vitamin D for their age group to satisfy their bodies' vitamin D requirements. Either vitamin D₂ or vitamin D₃ can be used for the treatment and prevention of vitamin D deficiency.

The group recommends that adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for 8 weeks or its equivalent of 6,000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D greater than 30 ng/mL.

This should be followed by maintenance therapy of 1,500-2,000 IU/day.

The task force also recommends vitamin D supplementation for fall prevention. “We know that there is sufficient evidence to give vitamin D for fall prevention. It's well documented that vitamin D is very important for muscle strength,” said Dr. Holick, professor of medicine, physiology and biophysics at Boston University.

However, the group does not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life, because there is insufficient evidence.

The task force noted that most individuals do not get adequate vitamin D for a number of reasons. In particular, “there needs to be an appreciation that unprotected sun exposure is the major source of vitamin D for both children and adults and that in the absence of sun exposure it is difficult, if not impossible, to obtain an adequate amount of vitamin D from dietary sources without supplementation to satisfy the body's requirement. Concerns about melanoma and other types of skin cancer necessitate avoidance of excessive exposure to midday sun,” they wrote.

The guidelines are cosponsored by the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation.

All but one of the authors reported having significant financial relationships with pharmaceutical companies, medical organizations and/or food industry groups.

DESTIN, FLA. – More is not necessarily better when it comes to vitamin D.

“The optimal intake and blood levels are probably much more moderate than many have led us to believe,” Dr. JoAnn E. Manson said.

As a member of the 14-person Institute of Medicine Committee charged with developing a recently published report on dietary reference intakes of vitamin D and calcium, Dr. Manson assisted in a “rigorous comprehensive review” of more than 1,000 studies, and while many researchers and clinicians have argued that people need much higher levels than the 400-800 IU/day intake (depending on age) recommended by the IOM to promote optimal health, the available evidence simply has not borne that out, said Dr. Manson, professor of epidemiology at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, Boston.

Although some IOM report naysayers advocate for levels up to 6,000 IU/day – and the lay press is replete with stories touting vitamin D as a panacea, it is actually very difficult to find any solid data showing increased benefit with higher doses, she said.

In fact, the committee's findings indicate that adequate intake for infants through age 12 months is 400 IU/day, and that the Recommended Dietary Allowance for individuals aged 1-70 years should be at least 600 IU/day, and in those over age 70 years it should be 800 IU/day. The upper intake levels are 1,000 and 1,500 IU/day for those ages 0-6 months and 6-12 months, respectively, 2,500 IU/day for those ages 1–3 years, 3,000 IU/day for those ages 4–8 years, and 4,000 IU/day for those over age 8 years, according to the IOM report (J. Clin. Endocrinol. Metab. 2011;96:53–8).

These minimum levels represent the intake needed to meet the vitamin D requirements of 97.5% of the population, and correspond to a serum 25-hydroxyvitamin D [25(OH)D] level of 20 ng/mL, which the data indicate is the optimal level. At levels above the upper intake level, which correspond to a serum 25-OHD level of about 50 ng/mL, adverse effects have been reported, Dr. Manson said.

Emerging evidence suggests excess intake may be associated with increased all-cause mortality, cancer, cardiovascular disease, falls, and fractures, she noted.

National Health and Nutrition Examination Survey (NHANES) data from 2008 showed that age-adjusted mortality was highest among those with serum 25(OH)D levels below 19 ng/mL in African Americans and below 27.5 ng/mL in the entire cohort, and that mortality decreased with increasing levels – but only to a certain point. At levels in the 50 ng/mL range for African Americans, and above 85 ng/mL in the entire cohort, mortality increased steadily.

Data on the effects of vitamin D on skeletal health, which provided the strongest basis for the IOM committee's report as they were most plentiful and convincing in terms of showing cause and effect (although evidence regarding numerous other diseases such as cancer, diabetes, and more were also considered), also suggest that too much vitamin D can lead to adverse effects. Women's Health Initiative findings, for example, show that adjusted hip fracture rates are highest among those with serum 25(OH)D levels of 19.04 ng/mL and those greater than 28.3 ng/mL, and lowest among those between these levels (Ann. Intern. Med. 2008;149:242–50), she said.

In older men in the Osteoporotic Fractures in Men (MrOS) study, the adjusted risk of hip fractures was shown to be highest in those with serum 25(OH)D levels less than 19 ng/mL (odds ratio 2.36, compared with those with levels greater than 28 ng/mL), with risk declining steadily in those with levels up to 28 ng/mL (J. Bone Miner. Res. 2010;25:545–53).

The skeletal benefits of vitamin D are dependent on adequate calcium intake, which the committee determined is 200 and 260 mg/day for those aged 0–6 and 6–12 months, respectively; 700 mg/day for those aged 1–3 years; 1,000 mg/day for those aged 4–8 years, 19–70 years, and for women aged 19–50 years who are pregnant or lactating; 1,200 mg/day for those aged 51 years and older; and 1,300 mg/day for those aged 9–18 years, and for women aged 14-18 years who are pregnant or lactating.

An Agency for Healthcare Research and Quality report in 2009 showed that three randomized controlled trials indicated no significant effect of vitamin D alone on fracture risk, but that one randomized controlled trial showed a benefit in those who received 800 IU of vitamin D₃ plus 1,200 mg/day of calcium for 2 years (OR of fractures 0.80), she said.

Dr. Manson has funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids.

DESTIN, FLA. – More is not necessarily better when it comes to vitamin D.

“The optimal intake and blood levels are probably much more moderate than many have led us to believe,” Dr. JoAnn E. Manson said.

As a member of the 14-person Institute of Medicine Committee charged with developing a recently published report on dietary reference intakes of vitamin D and calcium, Dr. Manson assisted in a “rigorous comprehensive review” of more than 1,000 studies, and while many researchers and clinicians have argued that people need much higher levels than the 400-800 IU/day intake (depending on age) recommended by the IOM to promote optimal health, the available evidence simply has not borne that out, said Dr. Manson, professor of epidemiology at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, Boston.

Although some IOM report naysayers advocate for levels up to 6,000 IU/day – and the lay press is replete with stories touting vitamin D as a panacea, it is actually very difficult to find any solid data showing increased benefit with higher doses, she said.

In fact, the committee's findings indicate that adequate intake for infants through age 12 months is 400 IU/day, and that the Recommended Dietary Allowance for individuals aged 1-70 years should be at least 600 IU/day, and in those over age 70 years it should be 800 IU/day. The upper intake levels are 1,000 and 1,500 IU/day for those ages 0-6 months and 6-12 months, respectively, 2,500 IU/day for those ages 1–3 years, 3,000 IU/day for those ages 4–8 years, and 4,000 IU/day for those over age 8 years, according to the IOM report (J. Clin. Endocrinol. Metab. 2011;96:53–8).

These minimum levels represent the intake needed to meet the vitamin D requirements of 97.5% of the population, and correspond to a serum 25-hydroxyvitamin D [25(OH)D] level of 20 ng/mL, which the data indicate is the optimal level. At levels above the upper intake level, which correspond to a serum 25-OHD level of about 50 ng/mL, adverse effects have been reported, Dr. Manson said.

Emerging evidence suggests excess intake may be associated with increased all-cause mortality, cancer, cardiovascular disease, falls, and fractures, she noted.

National Health and Nutrition Examination Survey (NHANES) data from 2008 showed that age-adjusted mortality was highest among those with serum 25(OH)D levels below 19 ng/mL in African Americans and below 27.5 ng/mL in the entire cohort, and that mortality decreased with increasing levels – but only to a certain point. At levels in the 50 ng/mL range for African Americans, and above 85 ng/mL in the entire cohort, mortality increased steadily.

Data on the effects of vitamin D on skeletal health, which provided the strongest basis for the IOM committee's report as they were most plentiful and convincing in terms of showing cause and effect (although evidence regarding numerous other diseases such as cancer, diabetes, and more were also considered), also suggest that too much vitamin D can lead to adverse effects. Women's Health Initiative findings, for example, show that adjusted hip fracture rates are highest among those with serum 25(OH)D levels of 19.04 ng/mL and those greater than 28.3 ng/mL, and lowest among those between these levels (Ann. Intern. Med. 2008;149:242–50), she said.

In older men in the Osteoporotic Fractures in Men (MrOS) study, the adjusted risk of hip fractures was shown to be highest in those with serum 25(OH)D levels less than 19 ng/mL (odds ratio 2.36, compared with those with levels greater than 28 ng/mL), with risk declining steadily in those with levels up to 28 ng/mL (J. Bone Miner. Res. 2010;25:545–53).

The skeletal benefits of vitamin D are dependent on adequate calcium intake, which the committee determined is 200 and 260 mg/day for those aged 0–6 and 6–12 months, respectively; 700 mg/day for those aged 1–3 years; 1,000 mg/day for those aged 4–8 years, 19–70 years, and for women aged 19–50 years who are pregnant or lactating; 1,200 mg/day for those aged 51 years and older; and 1,300 mg/day for those aged 9–18 years, and for women aged 14-18 years who are pregnant or lactating.

An Agency for Healthcare Research and Quality report in 2009 showed that three randomized controlled trials indicated no significant effect of vitamin D alone on fracture risk, but that one randomized controlled trial showed a benefit in those who received 800 IU of vitamin D₃ plus 1,200 mg/day of calcium for 2 years (OR of fractures 0.80), she said.

Dr. Manson has funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids.

DESTIN, FLA. – More is not necessarily better when it comes to vitamin D.

“The optimal intake and blood levels are probably much more moderate than many have led us to believe,” Dr. JoAnn E. Manson said.

As a member of the 14-person Institute of Medicine Committee charged with developing a recently published report on dietary reference intakes of vitamin D and calcium, Dr. Manson assisted in a “rigorous comprehensive review” of more than 1,000 studies, and while many researchers and clinicians have argued that people need much higher levels than the 400-800 IU/day intake (depending on age) recommended by the IOM to promote optimal health, the available evidence simply has not borne that out, said Dr. Manson, professor of epidemiology at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, Boston.

Although some IOM report naysayers advocate for levels up to 6,000 IU/day – and the lay press is replete with stories touting vitamin D as a panacea, it is actually very difficult to find any solid data showing increased benefit with higher doses, she said.

In fact, the committee's findings indicate that adequate intake for infants through age 12 months is 400 IU/day, and that the Recommended Dietary Allowance for individuals aged 1-70 years should be at least 600 IU/day, and in those over age 70 years it should be 800 IU/day. The upper intake levels are 1,000 and 1,500 IU/day for those ages 0-6 months and 6-12 months, respectively, 2,500 IU/day for those ages 1–3 years, 3,000 IU/day for those ages 4–8 years, and 4,000 IU/day for those over age 8 years, according to the IOM report (J. Clin. Endocrinol. Metab. 2011;96:53–8).

These minimum levels represent the intake needed to meet the vitamin D requirements of 97.5% of the population, and correspond to a serum 25-hydroxyvitamin D [25(OH)D] level of 20 ng/mL, which the data indicate is the optimal level. At levels above the upper intake level, which correspond to a serum 25-OHD level of about 50 ng/mL, adverse effects have been reported, Dr. Manson said.

Emerging evidence suggests excess intake may be associated with increased all-cause mortality, cancer, cardiovascular disease, falls, and fractures, she noted.

National Health and Nutrition Examination Survey (NHANES) data from 2008 showed that age-adjusted mortality was highest among those with serum 25(OH)D levels below 19 ng/mL in African Americans and below 27.5 ng/mL in the entire cohort, and that mortality decreased with increasing levels – but only to a certain point. At levels in the 50 ng/mL range for African Americans, and above 85 ng/mL in the entire cohort, mortality increased steadily.

Data on the effects of vitamin D on skeletal health, which provided the strongest basis for the IOM committee's report as they were most plentiful and convincing in terms of showing cause and effect (although evidence regarding numerous other diseases such as cancer, diabetes, and more were also considered), also suggest that too much vitamin D can lead to adverse effects. Women's Health Initiative findings, for example, show that adjusted hip fracture rates are highest among those with serum 25(OH)D levels of 19.04 ng/mL and those greater than 28.3 ng/mL, and lowest among those between these levels (Ann. Intern. Med. 2008;149:242–50), she said.

In older men in the Osteoporotic Fractures in Men (MrOS) study, the adjusted risk of hip fractures was shown to be highest in those with serum 25(OH)D levels less than 19 ng/mL (odds ratio 2.36, compared with those with levels greater than 28 ng/mL), with risk declining steadily in those with levels up to 28 ng/mL (J. Bone Miner. Res. 2010;25:545–53).

The skeletal benefits of vitamin D are dependent on adequate calcium intake, which the committee determined is 200 and 260 mg/day for those aged 0–6 and 6–12 months, respectively; 700 mg/day for those aged 1–3 years; 1,000 mg/day for those aged 4–8 years, 19–70 years, and for women aged 19–50 years who are pregnant or lactating; 1,200 mg/day for those aged 51 years and older; and 1,300 mg/day for those aged 9–18 years, and for women aged 14-18 years who are pregnant or lactating.

An Agency for Healthcare Research and Quality report in 2009 showed that three randomized controlled trials indicated no significant effect of vitamin D alone on fracture risk, but that one randomized controlled trial showed a benefit in those who received 800 IU of vitamin D₃ plus 1,200 mg/day of calcium for 2 years (OR of fractures 0.80), she said.

Dr. Manson has funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids.

Updated World Health Organization estimates are showing a downward trend in the incidence of gout in North America among 65-year-olds, but men in that age group on the continent are far more likely to suffer from gout than are men in Africa.

That’s a sampling of the updated data on a host of musculoskeletal disorders worldwide, including rheumatoid arthritis, said Dr. Lyn March at the Annual European Congress of Rheumatology.

She presented a preliminary report from the Musculoskeletal Expert Group that’s part of the new Global Burden of Diseases, Injuries, and Risk Factors Study, which began in the spring of 2007. This is the first major effort since the original Global Burden of Disease in 1990 study to carry out a complete systematic assessment of the data on all diseases and injuries, and to produce comprehensive and comparable estimates of the burden of diseases, injuries, and risk factors for two time periods (1990 and 2005), according to the WHO. The project is due to produce final estimates in the spring, said Dr. March of the Royal North Shore Hospital in Sydney.

Dr. March said the specific aims for the Musculoskeletal Expert Group are to include more population-based self-report data; to develop health-state descriptions for different levels of severity of osteoarthritis, rheumatoid arthritis, back pain, neck pain, gout, and other musculoskeletal disorders; and to update systematic literature reviews of incidence, prevalence, and mortality risk for these conditions. The group will also evaluate bone mineral density (g/cm²) as a risk factor for disability-adjusted life-year (DALY) burden, "which will put the [degenerative] bone condition on the map for policy making," she said.

"The methodology employed in the systematic review, development of lay health state descriptions, and generation of data estimates for calculating [DALYs] will be revealed," Dr. March said.

In 2000, the beginning of what the WHO declared "the Bone and Joint Decade," results from the previous Global Burden of Disease (GBD) study reported that rheumatoid arthritis accounted for 0.3% of global DALYs (a time-based measure that combined years of life lost to premature mortality and years of life lost to time lived in health states of less-than-ideal health). "These data enable, in part, an evaluation of the impact of the Bone and Joint Decade and the setting of the research agenda for the next decade," Dr. March said.

The GBD study investigated the incidence of 109 diseases and injuries and 10 risk factors across eight World Bank regions. In 2000, the WHO reported that osteoarthritis accounted for 1.1% of global DALYs, ranking 19th among all diseases and disorders, and rheumatoid arthritis accounted for 0.3% of DALYs. All musculoskeletal disorders combined had a prevalence of 2.1% of the worldwide population and ranked 12th in DALYs among all disorders, according to Dr. March. Preliminary data from the 2005 study show trends toward increases in the prevalence of osteoarthritis of the knee and hip, rheumatoid arthritis, and other musculoskeletal disease, and slight decreases in low-back pain and gout, she said, noting that the findings will likely have policy implications.

A 2005 update reported that musculoskeletal disorders are more common in developed countries.

Dr. March had no disclosures to report. The study received funding from the Bill and Melinda Gates Foundation and the Australian Commonwealth Government’s Department of Health and Aging.

Updated World Health Organization estimates are showing a downward trend in the incidence of gout in North America among 65-year-olds, but men in that age group on the continent are far more likely to suffer from gout than are men in Africa.

That’s a sampling of the updated data on a host of musculoskeletal disorders worldwide, including rheumatoid arthritis, said Dr. Lyn March at the Annual European Congress of Rheumatology.

She presented a preliminary report from the Musculoskeletal Expert Group that’s part of the new Global Burden of Diseases, Injuries, and Risk Factors Study, which began in the spring of 2007. This is the first major effort since the original Global Burden of Disease in 1990 study to carry out a complete systematic assessment of the data on all diseases and injuries, and to produce comprehensive and comparable estimates of the burden of diseases, injuries, and risk factors for two time periods (1990 and 2005), according to the WHO. The project is due to produce final estimates in the spring, said Dr. March of the Royal North Shore Hospital in Sydney.

Dr. March said the specific aims for the Musculoskeletal Expert Group are to include more population-based self-report data; to develop health-state descriptions for different levels of severity of osteoarthritis, rheumatoid arthritis, back pain, neck pain, gout, and other musculoskeletal disorders; and to update systematic literature reviews of incidence, prevalence, and mortality risk for these conditions. The group will also evaluate bone mineral density (g/cm²) as a risk factor for disability-adjusted life-year (DALY) burden, "which will put the [degenerative] bone condition on the map for policy making," she said.

"The methodology employed in the systematic review, development of lay health state descriptions, and generation of data estimates for calculating [DALYs] will be revealed," Dr. March said.

In 2000, the beginning of what the WHO declared "the Bone and Joint Decade," results from the previous Global Burden of Disease (GBD) study reported that rheumatoid arthritis accounted for 0.3% of global DALYs (a time-based measure that combined years of life lost to premature mortality and years of life lost to time lived in health states of less-than-ideal health). "These data enable, in part, an evaluation of the impact of the Bone and Joint Decade and the setting of the research agenda for the next decade," Dr. March said.

The GBD study investigated the incidence of 109 diseases and injuries and 10 risk factors across eight World Bank regions. In 2000, the WHO reported that osteoarthritis accounted for 1.1% of global DALYs, ranking 19th among all diseases and disorders, and rheumatoid arthritis accounted for 0.3% of DALYs. All musculoskeletal disorders combined had a prevalence of 2.1% of the worldwide population and ranked 12th in DALYs among all disorders, according to Dr. March. Preliminary data from the 2005 study show trends toward increases in the prevalence of osteoarthritis of the knee and hip, rheumatoid arthritis, and other musculoskeletal disease, and slight decreases in low-back pain and gout, she said, noting that the findings will likely have policy implications.

A 2005 update reported that musculoskeletal disorders are more common in developed countries.

Dr. March had no disclosures to report. The study received funding from the Bill and Melinda Gates Foundation and the Australian Commonwealth Government’s Department of Health and Aging.

Updated World Health Organization estimates are showing a downward trend in the incidence of gout in North America among 65-year-olds, but men in that age group on the continent are far more likely to suffer from gout than are men in Africa.

That’s a sampling of the updated data on a host of musculoskeletal disorders worldwide, including rheumatoid arthritis, said Dr. Lyn March at the Annual European Congress of Rheumatology.

She presented a preliminary report from the Musculoskeletal Expert Group that’s part of the new Global Burden of Diseases, Injuries, and Risk Factors Study, which began in the spring of 2007. This is the first major effort since the original Global Burden of Disease in 1990 study to carry out a complete systematic assessment of the data on all diseases and injuries, and to produce comprehensive and comparable estimates of the burden of diseases, injuries, and risk factors for two time periods (1990 and 2005), according to the WHO. The project is due to produce final estimates in the spring, said Dr. March of the Royal North Shore Hospital in Sydney.

Dr. March said the specific aims for the Musculoskeletal Expert Group are to include more population-based self-report data; to develop health-state descriptions for different levels of severity of osteoarthritis, rheumatoid arthritis, back pain, neck pain, gout, and other musculoskeletal disorders; and to update systematic literature reviews of incidence, prevalence, and mortality risk for these conditions. The group will also evaluate bone mineral density (g/cm²) as a risk factor for disability-adjusted life-year (DALY) burden, "which will put the [degenerative] bone condition on the map for policy making," she said.

"The methodology employed in the systematic review, development of lay health state descriptions, and generation of data estimates for calculating [DALYs] will be revealed," Dr. March said.

In 2000, the beginning of what the WHO declared "the Bone and Joint Decade," results from the previous Global Burden of Disease (GBD) study reported that rheumatoid arthritis accounted for 0.3% of global DALYs (a time-based measure that combined years of life lost to premature mortality and years of life lost to time lived in health states of less-than-ideal health). "These data enable, in part, an evaluation of the impact of the Bone and Joint Decade and the setting of the research agenda for the next decade," Dr. March said.

The GBD study investigated the incidence of 109 diseases and injuries and 10 risk factors across eight World Bank regions. In 2000, the WHO reported that osteoarthritis accounted for 1.1% of global DALYs, ranking 19th among all diseases and disorders, and rheumatoid arthritis accounted for 0.3% of DALYs. All musculoskeletal disorders combined had a prevalence of 2.1% of the worldwide population and ranked 12th in DALYs among all disorders, according to Dr. March. Preliminary data from the 2005 study show trends toward increases in the prevalence of osteoarthritis of the knee and hip, rheumatoid arthritis, and other musculoskeletal disease, and slight decreases in low-back pain and gout, she said, noting that the findings will likely have policy implications.

A 2005 update reported that musculoskeletal disorders are more common in developed countries.

Dr. March had no disclosures to report. The study received funding from the Bill and Melinda Gates Foundation and the Australian Commonwealth Government’s Department of Health and Aging.