Osteoarthritis

Strong signals for a correlation between diabetes and osteoarthritis in several epidemiological and experimental studies have led to the concept of a diabetes-induced OA phenotype. If confirmed, knowledge of the phenotype could have a dramatic impact on the prevention and progression of the musculoskeletal disease, according to Dr. Francis Berenbaum, head of the department of rheumatology at Pierre and Marie Curie University in Paris.

An association between diabetes and OA was first noted in the literature in 1961 in a paper that assessed the occurrence of definite radiological OA in 6 anatomical areas of 30 patients with diabetes and 30 matched controls, which showed a statistically significant correlation between diabetes and OA of the feet and knees (Tufts Folia Med. 1961;7:13-9 Dr. Berenbaum reported online ahead of print in the Annals of Rheumatic Diseases.

Since that time, multiple cross-sectional studies have been published, including one that looked at OA patterns in 809 patients with knee or hip-joint replacement and found that bilateral OA occurred more frequently in patients with non-insulin-dependent diabetes (Scand. J. Rheumatol. 2001;30:169-71).

Most recently, a study designed to test the hypothesis that vascular cell adhesion molecule 1 predicts severe knee or hip OA showed an increased prevalence of non-insulin-dependent diabetes among the 60 patients who underwent joint replacement surgery relative to the 852 patients who did not (Arthritis Rheum. 2009;60:2381-9).

Although it cannot be definitively concluded from the collective case-control studies that diabetes is an independent risk factor for OA given the potential for interference with the results by such confounders as age, weight, and level of activity, "taken together, there may be a positive signal for an independent correlation between OA and diabetes," Dr. Berenbaum wrote (Ann Rheum Dis. 2011 [Epub. Doi:10.1136/ard.2010.146399]).

In vitro, in vivo, and human experimental data also point toward an independent association. For example, advanced glycation end products (AGEs) accumulate in diabetic tissues as a result of hyperglycemia and research data have suggested that AGE modification may contribute to the pathogenesis of OA, Dr. Berenbaum noted. "To the best of my knowledge, to date no experimental studies have assessed the level of AGE formation in diabetic cartilage compared to normal cartilage, either in human or animal cartilage," he stated. "However, it seems realistic to consider that an increased concentration of glucose in the diabetic cartilage–matrix environment would lead to the same deleterious result."

With respect to in vivo data, in the streptozotocin-induced diabetes rat model that mimics type I diabetes, "cartilage becomes resistant to the anabolic action of insulin-like growth factor 1 [IGF-1], a condition that is correctable by hypophysectomy, suggesting a metabolic impairment at the tissue level," Dr. Berenbaum wrote.

Diabetes-induced peripheral nerve impairment, which has been described in human experimental data, "could be an added risk factor for OA in patients with diabetes," Dr. Berenbaum hypothesized, given the presence of local and systemic neurological dysfunction in some patients with OA. Similarly, low-grade systemic inflammation has been associated with both cartilage loss and hyperglycemia. As such, he stated, "I propose that an independent hyperglycemia-induced systemic inflammation may also have an impact on the progression of OA."

Given the multiple signs pointing to a correlation between diabetes and OA, "it is time to encourage the scientific community to perform prospective studies devoted to confirm or invalidate this hypothesis," Dr. Berenbaum wrote. Such studies should be designed to provide insight into the mechanisms underlying the interactions between both diseases, he said, noting that "a better knowledge of the specificities of a diabetes-induced OA phenotype compared to the others should lead to a personalized approach of preventive and curative treatments for OA."

Dr. Berenbaum reported having no competing interests to disclose.

Strong signals for a correlation between diabetes and osteoarthritis in several epidemiological and experimental studies have led to the concept of a diabetes-induced OA phenotype. If confirmed, knowledge of the phenotype could have a dramatic impact on the prevention and progression of the musculoskeletal disease, according to Dr. Francis Berenbaum, head of the department of rheumatology at Pierre and Marie Curie University in Paris.

An association between diabetes and OA was first noted in the literature in 1961 in a paper that assessed the occurrence of definite radiological OA in 6 anatomical areas of 30 patients with diabetes and 30 matched controls, which showed a statistically significant correlation between diabetes and OA of the feet and knees (Tufts Folia Med. 1961;7:13-9 Dr. Berenbaum reported online ahead of print in the Annals of Rheumatic Diseases.

Since that time, multiple cross-sectional studies have been published, including one that looked at OA patterns in 809 patients with knee or hip-joint replacement and found that bilateral OA occurred more frequently in patients with non-insulin-dependent diabetes (Scand. J. Rheumatol. 2001;30:169-71).

Most recently, a study designed to test the hypothesis that vascular cell adhesion molecule 1 predicts severe knee or hip OA showed an increased prevalence of non-insulin-dependent diabetes among the 60 patients who underwent joint replacement surgery relative to the 852 patients who did not (Arthritis Rheum. 2009;60:2381-9).

Although it cannot be definitively concluded from the collective case-control studies that diabetes is an independent risk factor for OA given the potential for interference with the results by such confounders as age, weight, and level of activity, "taken together, there may be a positive signal for an independent correlation between OA and diabetes," Dr. Berenbaum wrote (Ann Rheum Dis. 2011 [Epub. Doi:10.1136/ard.2010.146399]).

In vitro, in vivo, and human experimental data also point toward an independent association. For example, advanced glycation end products (AGEs) accumulate in diabetic tissues as a result of hyperglycemia and research data have suggested that AGE modification may contribute to the pathogenesis of OA, Dr. Berenbaum noted. "To the best of my knowledge, to date no experimental studies have assessed the level of AGE formation in diabetic cartilage compared to normal cartilage, either in human or animal cartilage," he stated. "However, it seems realistic to consider that an increased concentration of glucose in the diabetic cartilage–matrix environment would lead to the same deleterious result."

With respect to in vivo data, in the streptozotocin-induced diabetes rat model that mimics type I diabetes, "cartilage becomes resistant to the anabolic action of insulin-like growth factor 1 [IGF-1], a condition that is correctable by hypophysectomy, suggesting a metabolic impairment at the tissue level," Dr. Berenbaum wrote.

Diabetes-induced peripheral nerve impairment, which has been described in human experimental data, "could be an added risk factor for OA in patients with diabetes," Dr. Berenbaum hypothesized, given the presence of local and systemic neurological dysfunction in some patients with OA. Similarly, low-grade systemic inflammation has been associated with both cartilage loss and hyperglycemia. As such, he stated, "I propose that an independent hyperglycemia-induced systemic inflammation may also have an impact on the progression of OA."

Given the multiple signs pointing to a correlation between diabetes and OA, "it is time to encourage the scientific community to perform prospective studies devoted to confirm or invalidate this hypothesis," Dr. Berenbaum wrote. Such studies should be designed to provide insight into the mechanisms underlying the interactions between both diseases, he said, noting that "a better knowledge of the specificities of a diabetes-induced OA phenotype compared to the others should lead to a personalized approach of preventive and curative treatments for OA."

Dr. Berenbaum reported having no competing interests to disclose.

Strong signals for a correlation between diabetes and osteoarthritis in several epidemiological and experimental studies have led to the concept of a diabetes-induced OA phenotype. If confirmed, knowledge of the phenotype could have a dramatic impact on the prevention and progression of the musculoskeletal disease, according to Dr. Francis Berenbaum, head of the department of rheumatology at Pierre and Marie Curie University in Paris.

An association between diabetes and OA was first noted in the literature in 1961 in a paper that assessed the occurrence of definite radiological OA in 6 anatomical areas of 30 patients with diabetes and 30 matched controls, which showed a statistically significant correlation between diabetes and OA of the feet and knees (Tufts Folia Med. 1961;7:13-9 Dr. Berenbaum reported online ahead of print in the Annals of Rheumatic Diseases.

Since that time, multiple cross-sectional studies have been published, including one that looked at OA patterns in 809 patients with knee or hip-joint replacement and found that bilateral OA occurred more frequently in patients with non-insulin-dependent diabetes (Scand. J. Rheumatol. 2001;30:169-71).

Most recently, a study designed to test the hypothesis that vascular cell adhesion molecule 1 predicts severe knee or hip OA showed an increased prevalence of non-insulin-dependent diabetes among the 60 patients who underwent joint replacement surgery relative to the 852 patients who did not (Arthritis Rheum. 2009;60:2381-9).

Although it cannot be definitively concluded from the collective case-control studies that diabetes is an independent risk factor for OA given the potential for interference with the results by such confounders as age, weight, and level of activity, "taken together, there may be a positive signal for an independent correlation between OA and diabetes," Dr. Berenbaum wrote (Ann Rheum Dis. 2011 [Epub. Doi:10.1136/ard.2010.146399]).

In vitro, in vivo, and human experimental data also point toward an independent association. For example, advanced glycation end products (AGEs) accumulate in diabetic tissues as a result of hyperglycemia and research data have suggested that AGE modification may contribute to the pathogenesis of OA, Dr. Berenbaum noted. "To the best of my knowledge, to date no experimental studies have assessed the level of AGE formation in diabetic cartilage compared to normal cartilage, either in human or animal cartilage," he stated. "However, it seems realistic to consider that an increased concentration of glucose in the diabetic cartilage–matrix environment would lead to the same deleterious result."

With respect to in vivo data, in the streptozotocin-induced diabetes rat model that mimics type I diabetes, "cartilage becomes resistant to the anabolic action of insulin-like growth factor 1 [IGF-1], a condition that is correctable by hypophysectomy, suggesting a metabolic impairment at the tissue level," Dr. Berenbaum wrote.

Diabetes-induced peripheral nerve impairment, which has been described in human experimental data, "could be an added risk factor for OA in patients with diabetes," Dr. Berenbaum hypothesized, given the presence of local and systemic neurological dysfunction in some patients with OA. Similarly, low-grade systemic inflammation has been associated with both cartilage loss and hyperglycemia. As such, he stated, "I propose that an independent hyperglycemia-induced systemic inflammation may also have an impact on the progression of OA."

Given the multiple signs pointing to a correlation between diabetes and OA, "it is time to encourage the scientific community to perform prospective studies devoted to confirm or invalidate this hypothesis," Dr. Berenbaum wrote. Such studies should be designed to provide insight into the mechanisms underlying the interactions between both diseases, he said, noting that "a better knowledge of the specificities of a diabetes-induced OA phenotype compared to the others should lead to a personalized approach of preventive and curative treatments for OA."

Dr. Berenbaum reported having no competing interests to disclose.

NATIONAL HARBOR, MD. – Topical diclofenac sodium 1% gel was as well tolerated as placebo, based on data from 1,426 patients with knee osteoarthritis and 783 patients with hand osteoarthritis.

Findings from previous studies have shown that diclofenac sodium 1% gel (DSG) is effective in treating knee and hand osteoarthritis (OA), but safety data were limited, said Dr. John H. Peniston of Feasterville (Pa.) Family Health Clinic.

In this pooled analysis, the researchers reviewed data from patients aged 35 years and older with knee OA and aged 40 years and older with hand OA. The findings were presented in a poster at the annual meeting of the American Academy of Pain Medicine.

In the group with knee OA, 721 patients were randomized to DSG and 705 to a placebo gel. The most common adverse events were application site related; these occurred in 406 (56.3%) of the DSG patients and 340 (48.2%) of the placebo patients. The incidence of gastrointestinal, cardiovascular, hepatic, or renal adverse events (AEs) was similar between the two groups. The only serious AE potentially related to treatment was a deep-vein thrombosis and pulmonary embolism that developed in an 80-year-old woman with multiple cardiovascular–risk factors, the researchers noted. The most common treatment-emergent AE was headache, reported in approximately 15% of patients in each group.

In the group with hand OA, 400 patients were randomized to DSG and 383 to a placebo gel. Application site events were the most common AEs, occurring in 163 (40.8%) of the DSG patients and 139 (36.3%) of the placebo patients. Rates of cardiovascular, gastrointestinal, renal, and hepatic AEs were similar between the groups. Treatment-related gastrointestinal events occurred in two patients in the DSG group and one in the placebo group. None of the cardiovascular or serious AEs in either group were considered treatment-related, the researchers wrote. However, two patients with hand OA in both the active treatment and placebo groups experienced liver-enzyme elevation to three times the upper limit of normal. The most common treatment-emergent AE was headache, reported by 9% of patients in the DSG group and 10% of the placebo group.

"In general, adverse events with diclofenac sodium were mild and resolved without the need for additional treatment, consistent with a favorable tolerability profile," the researchers said.

The clinical trials for DSG were funded by Novartis, and this post hoc analysis was funded by Endo Pharmaceuticals. Dr. Peniston said he had no financial conflicts to disclose, but several study coauthors were employed by either Novartis or Endo.

NATIONAL HARBOR, MD. – Topical diclofenac sodium 1% gel was as well tolerated as placebo, based on data from 1,426 patients with knee osteoarthritis and 783 patients with hand osteoarthritis.

Findings from previous studies have shown that diclofenac sodium 1% gel (DSG) is effective in treating knee and hand osteoarthritis (OA), but safety data were limited, said Dr. John H. Peniston of Feasterville (Pa.) Family Health Clinic.

In this pooled analysis, the researchers reviewed data from patients aged 35 years and older with knee OA and aged 40 years and older with hand OA. The findings were presented in a poster at the annual meeting of the American Academy of Pain Medicine.

In the group with knee OA, 721 patients were randomized to DSG and 705 to a placebo gel. The most common adverse events were application site related; these occurred in 406 (56.3%) of the DSG patients and 340 (48.2%) of the placebo patients. The incidence of gastrointestinal, cardiovascular, hepatic, or renal adverse events (AEs) was similar between the two groups. The only serious AE potentially related to treatment was a deep-vein thrombosis and pulmonary embolism that developed in an 80-year-old woman with multiple cardiovascular–risk factors, the researchers noted. The most common treatment-emergent AE was headache, reported in approximately 15% of patients in each group.

In the group with hand OA, 400 patients were randomized to DSG and 383 to a placebo gel. Application site events were the most common AEs, occurring in 163 (40.8%) of the DSG patients and 139 (36.3%) of the placebo patients. Rates of cardiovascular, gastrointestinal, renal, and hepatic AEs were similar between the groups. Treatment-related gastrointestinal events occurred in two patients in the DSG group and one in the placebo group. None of the cardiovascular or serious AEs in either group were considered treatment-related, the researchers wrote. However, two patients with hand OA in both the active treatment and placebo groups experienced liver-enzyme elevation to three times the upper limit of normal. The most common treatment-emergent AE was headache, reported by 9% of patients in the DSG group and 10% of the placebo group.

"In general, adverse events with diclofenac sodium were mild and resolved without the need for additional treatment, consistent with a favorable tolerability profile," the researchers said.

The clinical trials for DSG were funded by Novartis, and this post hoc analysis was funded by Endo Pharmaceuticals. Dr. Peniston said he had no financial conflicts to disclose, but several study coauthors were employed by either Novartis or Endo.

NATIONAL HARBOR, MD. – Topical diclofenac sodium 1% gel was as well tolerated as placebo, based on data from 1,426 patients with knee osteoarthritis and 783 patients with hand osteoarthritis.

Findings from previous studies have shown that diclofenac sodium 1% gel (DSG) is effective in treating knee and hand osteoarthritis (OA), but safety data were limited, said Dr. John H. Peniston of Feasterville (Pa.) Family Health Clinic.

In this pooled analysis, the researchers reviewed data from patients aged 35 years and older with knee OA and aged 40 years and older with hand OA. The findings were presented in a poster at the annual meeting of the American Academy of Pain Medicine.

In the group with knee OA, 721 patients were randomized to DSG and 705 to a placebo gel. The most common adverse events were application site related; these occurred in 406 (56.3%) of the DSG patients and 340 (48.2%) of the placebo patients. The incidence of gastrointestinal, cardiovascular, hepatic, or renal adverse events (AEs) was similar between the two groups. The only serious AE potentially related to treatment was a deep-vein thrombosis and pulmonary embolism that developed in an 80-year-old woman with multiple cardiovascular–risk factors, the researchers noted. The most common treatment-emergent AE was headache, reported in approximately 15% of patients in each group.

In the group with hand OA, 400 patients were randomized to DSG and 383 to a placebo gel. Application site events were the most common AEs, occurring in 163 (40.8%) of the DSG patients and 139 (36.3%) of the placebo patients. Rates of cardiovascular, gastrointestinal, renal, and hepatic AEs were similar between the groups. Treatment-related gastrointestinal events occurred in two patients in the DSG group and one in the placebo group. None of the cardiovascular or serious AEs in either group were considered treatment-related, the researchers wrote. However, two patients with hand OA in both the active treatment and placebo groups experienced liver-enzyme elevation to three times the upper limit of normal. The most common treatment-emergent AE was headache, reported by 9% of patients in the DSG group and 10% of the placebo group.

"In general, adverse events with diclofenac sodium were mild and resolved without the need for additional treatment, consistent with a favorable tolerability profile," the researchers said.

The clinical trials for DSG were funded by Novartis, and this post hoc analysis was funded by Endo Pharmaceuticals. Dr. Peniston said he had no financial conflicts to disclose, but several study coauthors were employed by either Novartis or Endo.

NEW YORK – Researchers will likely have to wait for months before they find out if they can continue studies on the use of nerve growth factor inhibitors in treating osteoarthritis pain, according to Dr. Nancy E. Lane, Endowed Professor of Medicine and Rheumatology at the University of California, Davis, in Sacramento.

Over the past year, the Food and Drug Administration has put on clinical hold nearly all programs for nerve growth factor inhibitor (anti-NGF) development, particularly those related to treating knee pain in osteoarthritis. The agency requested that pharmaceutical manufacturers halt their trials because of reports that study subjects taking the drugs had developed rapidly progressive hip and knee osteoarthritis requiring total joint replacement. A few of those patients also were reported to have had osteonecrosis. The fate of those studies could be determined later this year, when the FDA meets with the pharmaceutical companies involved in developing NGF inhibitors to discuss the issue, Dr. Lane said at a rheumatology meeting sponsored by New York University.

Dr. Lane, who was an investigator for Pfizer’s anti-NGF drug tanezumab, said the drug makers developing these compounds have been studying the possible causes of the adverse effects. The question remains whether the disease progression was due to reduced pain and increased activity, or if the inhibition of NGF compromised blood flow to the bone, resulting in osteonecrosis, she said. Regardless of whether the anti-NGF trials continue, Dr. Lane said understanding the NGF receptor TrkA and how to inhibit it may "bear fruit in the long term."

NEW YORK – Researchers will likely have to wait for months before they find out if they can continue studies on the use of nerve growth factor inhibitors in treating osteoarthritis pain, according to Dr. Nancy E. Lane, Endowed Professor of Medicine and Rheumatology at the University of California, Davis, in Sacramento.

Over the past year, the Food and Drug Administration has put on clinical hold nearly all programs for nerve growth factor inhibitor (anti-NGF) development, particularly those related to treating knee pain in osteoarthritis. The agency requested that pharmaceutical manufacturers halt their trials because of reports that study subjects taking the drugs had developed rapidly progressive hip and knee osteoarthritis requiring total joint replacement. A few of those patients also were reported to have had osteonecrosis. The fate of those studies could be determined later this year, when the FDA meets with the pharmaceutical companies involved in developing NGF inhibitors to discuss the issue, Dr. Lane said at a rheumatology meeting sponsored by New York University.

Dr. Lane, who was an investigator for Pfizer’s anti-NGF drug tanezumab, said the drug makers developing these compounds have been studying the possible causes of the adverse effects. The question remains whether the disease progression was due to reduced pain and increased activity, or if the inhibition of NGF compromised blood flow to the bone, resulting in osteonecrosis, she said. Regardless of whether the anti-NGF trials continue, Dr. Lane said understanding the NGF receptor TrkA and how to inhibit it may "bear fruit in the long term."

NEW YORK – Researchers will likely have to wait for months before they find out if they can continue studies on the use of nerve growth factor inhibitors in treating osteoarthritis pain, according to Dr. Nancy E. Lane, Endowed Professor of Medicine and Rheumatology at the University of California, Davis, in Sacramento.

Over the past year, the Food and Drug Administration has put on clinical hold nearly all programs for nerve growth factor inhibitor (anti-NGF) development, particularly those related to treating knee pain in osteoarthritis. The agency requested that pharmaceutical manufacturers halt their trials because of reports that study subjects taking the drugs had developed rapidly progressive hip and knee osteoarthritis requiring total joint replacement. A few of those patients also were reported to have had osteonecrosis. The fate of those studies could be determined later this year, when the FDA meets with the pharmaceutical companies involved in developing NGF inhibitors to discuss the issue, Dr. Lane said at a rheumatology meeting sponsored by New York University.

Dr. Lane, who was an investigator for Pfizer’s anti-NGF drug tanezumab, said the drug makers developing these compounds have been studying the possible causes of the adverse effects. The question remains whether the disease progression was due to reduced pain and increased activity, or if the inhibition of NGF compromised blood flow to the bone, resulting in osteonecrosis, she said. Regardless of whether the anti-NGF trials continue, Dr. Lane said understanding the NGF receptor TrkA and how to inhibit it may "bear fruit in the long term."

Adults who underwent total joint replacement of the hip or knee were not significantly more likely to have atherosclerosis, based on data from 5,170 adults with an average age of 76 years. However, women who had a total joint replacement and hand osteoarthritis were significantly more likely to have atherosclerosis. The results were published online on March 1 in the Annals of the Rheumatic Diseases.

In this study, Dr. Helgi Jonsson of the University of Iceland in Reykjavik and colleagues used total joint replacement (TJR) as an indicator of severe osteoarthritis (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.144980]). The study population included 2,195 men and 2,975 women; 539 patients had total joint replacement, including 316 with total hip replacements (THR), 223 with total knee replacements (TKR), and 31 with both hip and knee replacements.

Overall, women who had a joint replacement showed a nonsignificant trend toward increased coronary calcifications and carotid plaques, but no such associations were seen in men. "Apart from marginally increased aortic calcium in women with TKR, there were no statistical differences in those with and without TKR and THR," the researchers noted.

But the researchers saw a significant upward trend in coronary calcifications among women with hand osteoarthritis (HOA). The difference between the average value of women without either TJR or HOA and the women with both TJR and HOA was significant – approximately 10% – for three markers of atherosclerosis: coronary calcium, periventricular white matter hyperintensities, and carotid plaque.

The data were taken from a subset of older patients in the AGES–Reykjavik Study, a population-based study conducted in Iceland.

The results support findings from previous studies suggesting a link between osteoarthritis and atherosclerosis in women, the researchers noted. "We are currently analyzing a number of ‘midlife’ biomarkers and inflammatory markers available from previous visits in the 40-year-long Reykjavik Study in an attempt to clarify this relationship," they said.

The Reykjavik study was funded by the National Institutes of Health, the National Institute on Aging Intramural Research Program, the Icelandic Heart Association, the Icelandic Parliament, the Icelandic Osteoarthritis Fund, and the University of Iceland Research Fund. The researchers had no financial conflicts to disclose.

Adults who underwent total joint replacement of the hip or knee were not significantly more likely to have atherosclerosis, based on data from 5,170 adults with an average age of 76 years. However, women who had a total joint replacement and hand osteoarthritis were significantly more likely to have atherosclerosis. The results were published online on March 1 in the Annals of the Rheumatic Diseases.

In this study, Dr. Helgi Jonsson of the University of Iceland in Reykjavik and colleagues used total joint replacement (TJR) as an indicator of severe osteoarthritis (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.144980]). The study population included 2,195 men and 2,975 women; 539 patients had total joint replacement, including 316 with total hip replacements (THR), 223 with total knee replacements (TKR), and 31 with both hip and knee replacements.

Overall, women who had a joint replacement showed a nonsignificant trend toward increased coronary calcifications and carotid plaques, but no such associations were seen in men. "Apart from marginally increased aortic calcium in women with TKR, there were no statistical differences in those with and without TKR and THR," the researchers noted.

But the researchers saw a significant upward trend in coronary calcifications among women with hand osteoarthritis (HOA). The difference between the average value of women without either TJR or HOA and the women with both TJR and HOA was significant – approximately 10% – for three markers of atherosclerosis: coronary calcium, periventricular white matter hyperintensities, and carotid plaque.

The data were taken from a subset of older patients in the AGES–Reykjavik Study, a population-based study conducted in Iceland.

The results support findings from previous studies suggesting a link between osteoarthritis and atherosclerosis in women, the researchers noted. "We are currently analyzing a number of ‘midlife’ biomarkers and inflammatory markers available from previous visits in the 40-year-long Reykjavik Study in an attempt to clarify this relationship," they said.

The Reykjavik study was funded by the National Institutes of Health, the National Institute on Aging Intramural Research Program, the Icelandic Heart Association, the Icelandic Parliament, the Icelandic Osteoarthritis Fund, and the University of Iceland Research Fund. The researchers had no financial conflicts to disclose.

Adults who underwent total joint replacement of the hip or knee were not significantly more likely to have atherosclerosis, based on data from 5,170 adults with an average age of 76 years. However, women who had a total joint replacement and hand osteoarthritis were significantly more likely to have atherosclerosis. The results were published online on March 1 in the Annals of the Rheumatic Diseases.

In this study, Dr. Helgi Jonsson of the University of Iceland in Reykjavik and colleagues used total joint replacement (TJR) as an indicator of severe osteoarthritis (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.144980]). The study population included 2,195 men and 2,975 women; 539 patients had total joint replacement, including 316 with total hip replacements (THR), 223 with total knee replacements (TKR), and 31 with both hip and knee replacements.

Overall, women who had a joint replacement showed a nonsignificant trend toward increased coronary calcifications and carotid plaques, but no such associations were seen in men. "Apart from marginally increased aortic calcium in women with TKR, there were no statistical differences in those with and without TKR and THR," the researchers noted.

But the researchers saw a significant upward trend in coronary calcifications among women with hand osteoarthritis (HOA). The difference between the average value of women without either TJR or HOA and the women with both TJR and HOA was significant – approximately 10% – for three markers of atherosclerosis: coronary calcium, periventricular white matter hyperintensities, and carotid plaque.

The data were taken from a subset of older patients in the AGES–Reykjavik Study, a population-based study conducted in Iceland.

The results support findings from previous studies suggesting a link between osteoarthritis and atherosclerosis in women, the researchers noted. "We are currently analyzing a number of ‘midlife’ biomarkers and inflammatory markers available from previous visits in the 40-year-long Reykjavik Study in an attempt to clarify this relationship," they said.

The Reykjavik study was funded by the National Institutes of Health, the National Institute on Aging Intramural Research Program, the Icelandic Heart Association, the Icelandic Parliament, the Icelandic Osteoarthritis Fund, and the University of Iceland Research Fund. The researchers had no financial conflicts to disclose.

Chondroitin sulfate slows the progression of knee osteoarthritis, according to findings from a pilot study that used magnetic resonance imaging to assess joint structural changes.

"It’s reassuring to see that the four major x-rays studies are now confirmed by high technology in the assessment of disease progression," said the study’s lead author Dr. Jean-Pierre Pelletier, in an interview. (Osteoarthr. Cartil. 1998;6:39-46), (Osteoarthr. Cartil. 2004;12:269-76), (Arthritis Rheum. 2005;52:779-86), (Arthritis Rheum. 2009;60:524-33).

The randomized, double-blind, placebo-controlled study showed that chondroitin sulfate reduced the cartilage loss volume in 69 patients with knee OA in as early as 6 months. (Ann. Rheum. Dis. 2011 March 1)

The findings show that "[MRI] is a good quantitative technique to find answers in shorter period of time with smaller number of patients," said Dr. Roy D. Altman, professor of medicine at the University of California, Los Angeles, who is not involved with the study.

The effect of disease-modifying drug chondroitin sulfate on cartilage volume loss, bone marrow lesions (BML), and disease symptoms has been controversial (BMJ 2010;341:c4675). However, the authors of this study said that the MRI findings provided additional evidence on the joint structure protective effect of chondroitin sulfate.

Several studies have also shown that MRI can quantitatively and reliably assess the volume and cartilage thickness in addition to joint structural changes in subchondral bone, menisci, and synovium, the authors reported.

"MRI provides you with direct visualization of the cartilage," said Dr. Pelletier, director of the osteoarthritis research unit at the University of Montreal Hospital Research Centre. "And the beauty of MRI is that it not only it provides assessment of progression of change in cartilage, but also in many other tissues of the joint, like the subchondral bone and the synovium.

"In addition, the pronounced reduction in OA cartilage loss found in patients treated with chondroitin sulfate was also associated with a reduction in the size of BML. This finding is most interesting as BML are believed to be associated with the progression of OA cartilage lesions," according to a number of studies, said Dr. Pelletier.

The study also showed that patients who were being treated with NSAIDs in addition to chondroitin sulfate showed a significant reduction in synovial membrane thickness (1.3 plus or minus 0.3 mm in 6 months vs. 1.6 plus or minus 0.3 mm placebo) and a lower incidence of joint swelling, compared with the placebo group (0% in chondroitin sulfate vs. 11.4% in placebo). The finding "is interesting with practical clinical impact, and definitely needs future exploration," the authors wrote.

Researchers recruited 69 patients of both sexes between 40 and 80 years of age from rheumatology clinics in Quebec province. All patients had clinical signs of synovitis.

The study had two phases. For the double-blind phase, the patients were randomly assigned to once-daily placebo or 800 mg of chondroitin sulfate for 6 months. During the following 6 months, or the open-label phase, both groups received 800 mg of chondroitin sulfate daily.

Cartilage volume and BML were assessed by MRI at baseline, 6 months, and 12 months. Synovial membrane thickness was assessed at baseline and 6 months.

Patients who took a daily oral dose of chondroitin sulfate had a significant reduction in cartilage volume loss at 6 months (–2.87%) and 12 months (–3.71%) in the global knee compared to the placebo group (–4.67% at 6 months and -6.12% at 12 months).

There were no differences in BML during the first 6 months. But, at 12 months reduction in BML were observed in the chondroitin sulfate group (–0.57%), especially in the lateral compartment (–0.13%) and the lateral condyle (–0.43). The additional 6-months needed to see the change could suggest that "BML are consequential to cartilage degradation and thus reducing cartilage lesions could lead to fewer BML. Alternatively, BML were shown to be involved in an inflammatory/catabolic process on which chondroitin sulfate could act directly, leading to structural repair," according to the study.

No significant difference in disease symptoms were measured by visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires. "The main aim of the study was not the symptoms. The main goal was to find out whether chondroitin sulfate can reduce progression of knee OA," said Dr. Pelletier.

The study had limitations, including a small sample size. In addition, the system used did not allow the detection of the cartilage in the patella, researchers reported. They added that long-term studies are needed to find the impact of CS in disease symptoms.

Whether the quantitive MRI technique will eventually replace X-ray technology in such studies is unclear, said Dr. Pelletier. "That’s for regulatory bodies to decide," he said. "But it’s quite clear that MRI is the technology of the future. It’s very helpful, because you can truly speed up drug development in the field of OA and with less expense, using smaller number of patients and in a shorter period of time."

Dr. Jean-Pierre Pelletier and Dr. Johanne Martel-Pelletier are consultants for and shareholders in ArthroLab Inc. and ArthroVision Inc. Jean-Pierre Raynauld is a consultant for ArthroVision. Dr. André Beaulieu, Dr. Louis Bassette, and Dr. Frédéric Morin received honoraria from ArthroLab. François Abram is an employee of ArthroVision. Marc Dorais is a consultant for ArthroVision. Dr. Altman had no relevant financial conflicts of interest.

Chondroitin sulfate slows the progression of knee osteoarthritis, according to findings from a pilot study that used magnetic resonance imaging to assess joint structural changes.

"It’s reassuring to see that the four major x-rays studies are now confirmed by high technology in the assessment of disease progression," said the study’s lead author Dr. Jean-Pierre Pelletier, in an interview. (Osteoarthr. Cartil. 1998;6:39-46), (Osteoarthr. Cartil. 2004;12:269-76), (Arthritis Rheum. 2005;52:779-86), (Arthritis Rheum. 2009;60:524-33).

The randomized, double-blind, placebo-controlled study showed that chondroitin sulfate reduced the cartilage loss volume in 69 patients with knee OA in as early as 6 months. (Ann. Rheum. Dis. 2011 March 1)

The findings show that "[MRI] is a good quantitative technique to find answers in shorter period of time with smaller number of patients," said Dr. Roy D. Altman, professor of medicine at the University of California, Los Angeles, who is not involved with the study.

The effect of disease-modifying drug chondroitin sulfate on cartilage volume loss, bone marrow lesions (BML), and disease symptoms has been controversial (BMJ 2010;341:c4675). However, the authors of this study said that the MRI findings provided additional evidence on the joint structure protective effect of chondroitin sulfate.

Several studies have also shown that MRI can quantitatively and reliably assess the volume and cartilage thickness in addition to joint structural changes in subchondral bone, menisci, and synovium, the authors reported.

"MRI provides you with direct visualization of the cartilage," said Dr. Pelletier, director of the osteoarthritis research unit at the University of Montreal Hospital Research Centre. "And the beauty of MRI is that it not only it provides assessment of progression of change in cartilage, but also in many other tissues of the joint, like the subchondral bone and the synovium.

"In addition, the pronounced reduction in OA cartilage loss found in patients treated with chondroitin sulfate was also associated with a reduction in the size of BML. This finding is most interesting as BML are believed to be associated with the progression of OA cartilage lesions," according to a number of studies, said Dr. Pelletier.

The study also showed that patients who were being treated with NSAIDs in addition to chondroitin sulfate showed a significant reduction in synovial membrane thickness (1.3 plus or minus 0.3 mm in 6 months vs. 1.6 plus or minus 0.3 mm placebo) and a lower incidence of joint swelling, compared with the placebo group (0% in chondroitin sulfate vs. 11.4% in placebo). The finding "is interesting with practical clinical impact, and definitely needs future exploration," the authors wrote.

Researchers recruited 69 patients of both sexes between 40 and 80 years of age from rheumatology clinics in Quebec province. All patients had clinical signs of synovitis.

The study had two phases. For the double-blind phase, the patients were randomly assigned to once-daily placebo or 800 mg of chondroitin sulfate for 6 months. During the following 6 months, or the open-label phase, both groups received 800 mg of chondroitin sulfate daily.

Cartilage volume and BML were assessed by MRI at baseline, 6 months, and 12 months. Synovial membrane thickness was assessed at baseline and 6 months.

Patients who took a daily oral dose of chondroitin sulfate had a significant reduction in cartilage volume loss at 6 months (–2.87%) and 12 months (–3.71%) in the global knee compared to the placebo group (–4.67% at 6 months and -6.12% at 12 months).

There were no differences in BML during the first 6 months. But, at 12 months reduction in BML were observed in the chondroitin sulfate group (–0.57%), especially in the lateral compartment (–0.13%) and the lateral condyle (–0.43). The additional 6-months needed to see the change could suggest that "BML are consequential to cartilage degradation and thus reducing cartilage lesions could lead to fewer BML. Alternatively, BML were shown to be involved in an inflammatory/catabolic process on which chondroitin sulfate could act directly, leading to structural repair," according to the study.

No significant difference in disease symptoms were measured by visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires. "The main aim of the study was not the symptoms. The main goal was to find out whether chondroitin sulfate can reduce progression of knee OA," said Dr. Pelletier.

The study had limitations, including a small sample size. In addition, the system used did not allow the detection of the cartilage in the patella, researchers reported. They added that long-term studies are needed to find the impact of CS in disease symptoms.

Whether the quantitive MRI technique will eventually replace X-ray technology in such studies is unclear, said Dr. Pelletier. "That’s for regulatory bodies to decide," he said. "But it’s quite clear that MRI is the technology of the future. It’s very helpful, because you can truly speed up drug development in the field of OA and with less expense, using smaller number of patients and in a shorter period of time."

Dr. Jean-Pierre Pelletier and Dr. Johanne Martel-Pelletier are consultants for and shareholders in ArthroLab Inc. and ArthroVision Inc. Jean-Pierre Raynauld is a consultant for ArthroVision. Dr. André Beaulieu, Dr. Louis Bassette, and Dr. Frédéric Morin received honoraria from ArthroLab. François Abram is an employee of ArthroVision. Marc Dorais is a consultant for ArthroVision. Dr. Altman had no relevant financial conflicts of interest.

Chondroitin sulfate slows the progression of knee osteoarthritis, according to findings from a pilot study that used magnetic resonance imaging to assess joint structural changes.

"It’s reassuring to see that the four major x-rays studies are now confirmed by high technology in the assessment of disease progression," said the study’s lead author Dr. Jean-Pierre Pelletier, in an interview. (Osteoarthr. Cartil. 1998;6:39-46), (Osteoarthr. Cartil. 2004;12:269-76), (Arthritis Rheum. 2005;52:779-86), (Arthritis Rheum. 2009;60:524-33).

The randomized, double-blind, placebo-controlled study showed that chondroitin sulfate reduced the cartilage loss volume in 69 patients with knee OA in as early as 6 months. (Ann. Rheum. Dis. 2011 March 1)

The findings show that "[MRI] is a good quantitative technique to find answers in shorter period of time with smaller number of patients," said Dr. Roy D. Altman, professor of medicine at the University of California, Los Angeles, who is not involved with the study.

The effect of disease-modifying drug chondroitin sulfate on cartilage volume loss, bone marrow lesions (BML), and disease symptoms has been controversial (BMJ 2010;341:c4675). However, the authors of this study said that the MRI findings provided additional evidence on the joint structure protective effect of chondroitin sulfate.

Several studies have also shown that MRI can quantitatively and reliably assess the volume and cartilage thickness in addition to joint structural changes in subchondral bone, menisci, and synovium, the authors reported.

"MRI provides you with direct visualization of the cartilage," said Dr. Pelletier, director of the osteoarthritis research unit at the University of Montreal Hospital Research Centre. "And the beauty of MRI is that it not only it provides assessment of progression of change in cartilage, but also in many other tissues of the joint, like the subchondral bone and the synovium.

"In addition, the pronounced reduction in OA cartilage loss found in patients treated with chondroitin sulfate was also associated with a reduction in the size of BML. This finding is most interesting as BML are believed to be associated with the progression of OA cartilage lesions," according to a number of studies, said Dr. Pelletier.

The study also showed that patients who were being treated with NSAIDs in addition to chondroitin sulfate showed a significant reduction in synovial membrane thickness (1.3 plus or minus 0.3 mm in 6 months vs. 1.6 plus or minus 0.3 mm placebo) and a lower incidence of joint swelling, compared with the placebo group (0% in chondroitin sulfate vs. 11.4% in placebo). The finding "is interesting with practical clinical impact, and definitely needs future exploration," the authors wrote.

Researchers recruited 69 patients of both sexes between 40 and 80 years of age from rheumatology clinics in Quebec province. All patients had clinical signs of synovitis.

The study had two phases. For the double-blind phase, the patients were randomly assigned to once-daily placebo or 800 mg of chondroitin sulfate for 6 months. During the following 6 months, or the open-label phase, both groups received 800 mg of chondroitin sulfate daily.

Cartilage volume and BML were assessed by MRI at baseline, 6 months, and 12 months. Synovial membrane thickness was assessed at baseline and 6 months.

Patients who took a daily oral dose of chondroitin sulfate had a significant reduction in cartilage volume loss at 6 months (–2.87%) and 12 months (–3.71%) in the global knee compared to the placebo group (–4.67% at 6 months and -6.12% at 12 months).

There were no differences in BML during the first 6 months. But, at 12 months reduction in BML were observed in the chondroitin sulfate group (–0.57%), especially in the lateral compartment (–0.13%) and the lateral condyle (–0.43). The additional 6-months needed to see the change could suggest that "BML are consequential to cartilage degradation and thus reducing cartilage lesions could lead to fewer BML. Alternatively, BML were shown to be involved in an inflammatory/catabolic process on which chondroitin sulfate could act directly, leading to structural repair," according to the study.

No significant difference in disease symptoms were measured by visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires. "The main aim of the study was not the symptoms. The main goal was to find out whether chondroitin sulfate can reduce progression of knee OA," said Dr. Pelletier.

The study had limitations, including a small sample size. In addition, the system used did not allow the detection of the cartilage in the patella, researchers reported. They added that long-term studies are needed to find the impact of CS in disease symptoms.

Whether the quantitive MRI technique will eventually replace X-ray technology in such studies is unclear, said Dr. Pelletier. "That’s for regulatory bodies to decide," he said. "But it’s quite clear that MRI is the technology of the future. It’s very helpful, because you can truly speed up drug development in the field of OA and with less expense, using smaller number of patients and in a shorter period of time."

Dr. Jean-Pierre Pelletier and Dr. Johanne Martel-Pelletier are consultants for and shareholders in ArthroLab Inc. and ArthroVision Inc. Jean-Pierre Raynauld is a consultant for ArthroVision. Dr. André Beaulieu, Dr. Louis Bassette, and Dr. Frédéric Morin received honoraria from ArthroLab. François Abram is an employee of ArthroVision. Marc Dorais is a consultant for ArthroVision. Dr. Altman had no relevant financial conflicts of interest.

TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug's pivotal trial for fracture prevention.

The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women's baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.

The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.

The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh.

It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.

The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22).

Assessment of the study's primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.

To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zole-dronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28).

The modification calculated a woman's baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.

Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women's FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON.

During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45, respectively, in the low-, intermediate-, and high-risk tertiles.

Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.

HORIZON was supported by Novartis, the company that markets zoledronic acid. Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.

TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug's pivotal trial for fracture prevention.

The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women's baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.

The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.

The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh.

It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.

The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22).

Assessment of the study's primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.

To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zole-dronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28).

The modification calculated a woman's baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.

Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women's FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON.

During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45, respectively, in the low-, intermediate-, and high-risk tertiles.

Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.

HORIZON was supported by Novartis, the company that markets zoledronic acid. Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.

TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug's pivotal trial for fracture prevention.

The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women's baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.

The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.

The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh.

It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.

The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22).

Assessment of the study's primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.

To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zole-dronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28).

The modification calculated a woman's baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.

Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women's FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON.

During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45, respectively, in the low-, intermediate-, and high-risk tertiles.

Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.

HORIZON was supported by Novartis, the company that markets zoledronic acid. Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, they said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both. However, headaches were much more common with active nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study because of headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers said.

View on the News

Next Step: Assess Fracture Rate

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011;305:826-7).

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, they said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both. However, headaches were much more common with active nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study because of headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers said.

View on the News

Next Step: Assess Fracture Rate

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011;305:826-7).

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide. “Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night. The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to −2.0 at the lumbar spine and higher than −2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, they said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months. At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use. In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both. However, headaches were much more common with active nitroglycerin, and often led to discontinuation of therapy. The number of headaches markedly declined with time, and no subjects dropped out of the second year of the study because of headache.

“The possibility that different preparations, doses, or schedules of administration would reduce the frequency of headaches without diminishing the effects on bone should be explored in future studies,” the researchers said.

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Next Step: Assess Fracture Rate

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011;305:826-7).

Several U.S. public health groups have recently made self-management training for patients with arthritis a priority. But clinicians resist this, despite an evidence-based track record that goes back more than 30 years.

In essence, arthritis self-management consists of arthritis patients using exercise, injury prevention strategies, weight management through healthful eating, disease education, meditation, and other supportive therapies to ease their pain and increase their function.

Both government and rheumatology organizations have been enthusiastic in their support for these measures, as shown by the following:

• The Centers for Disease Control and Prevention has formally supported arthritis self-management training (as well as similar training for patients with other chronic diseases). In addition, the CDC’s arthritis program says that one of its main short-term goals is to "improve and increase self-management attitudes and behaviors among persons with arthritis. ... Without doubt, self-management is a core issue in public health," said Dr. Patience White, a rheumatologist and chief public health officer of the Arthritis Foundation in Atlanta.

• The U.S. Administration on Aging received cash support from the 2009 American Recovery and Reinvestment Act. With that stimulus money, the AoA handed out $27 million in grants to 45 states, Puerto Rico, and the District of Columbia last year to deliver self-management training programs to patients with chronic diseases including those with osteoarthritis (OA) or rheumatoid arthritis (RA).

• In the 2010 report "A National Public Health Agenda for Osteoarthritis," jointly issued by the Arthritis Foundation and the CDC, the first recommendation for action in the report’s 10-item plan is: "Self-management education should be expanded as a community-based intervention for people with symptomatic OA." The American College of Rheumatology has also endorsed self-management training for OA patients in the society’s OA management recommendations (Arthritis Rheum. 2000;43:1905-15), and the Arthritis Foundation has promoted self-management as a key element in managing patients with RA.

• Healthy People 2020, a set of public health targets released in December 2010 by the Department of Health and Human Services, said that one goal for patients with arthritis is to "increase the proportion of adults with doctor-diagnosed arthritis who have had effective, evidence-based arthritis education as an integral part of the management of their condition."

In short, self-management – with its safety and proven modest efficacy – has emerged as an attractive complement to the medical approach for dealing with arthritis.

Data Support Self-Management’s Efficacy

Kate Lorig, Dr.P.H., noted that "we give patients a lot of tools to use so that they can do the things they need to do with less pain."

"What we find is that patients who take the course have statistically significantly less pain," added Dr. Lorig, professor of medicine and director of the Patient Education Research Center at Stanford (Calif.) University in Palo Alto, in an interview. "They have a small to moderate reduction in pain that is similar to what they get from NSAIDs. ... We see people able to do things that they couldn’t before, related to improvements in mobility and depression, and we see improvements in their quality of life."

Dr. Lorig has led a group at Stanford that began developing and testing an arthritis-oriented self-management program in the late 1970s (Arthritis Rheum. 1985;28:680-5). Subsequently the same group developed a more generic chronic disease program (Arthritis Rheum. 2005;53:950-7), and arthritis programs available by mail (Arthritis Rheum. 2009;61:867-75) and over the Internet (Arthritis Rheum. 2008;59:1009-17).

"The individual improvement for each patient can be rather small, but the cost saving [of promoting wide use of self-management training] is high because of the large number of patients," said Dr. White. In addition, although the overall effect size may be small, for a subset of patients the effect is "life changing," she added.

Clinicians’ Indifference

But despite these positive assessments and public health promotions, self-management training for patients with OA or RA remains neglected and unused. Experts widely agree that a scant fraction of U.S. arthritis patients have received self-management training.

According to the Arthritis Foundation’s Dr. White, currently 60,000 U.S. arthritis patients undergo self-management training each year, a number dwarfed by the roughly 50 million Americans who have some form of arthritis. "Very few are in the program, even when it gets megabucks from the government," she said.

The best known and most thoroughly-studied self-management training course for patients with arthritis is the Arthritis Self-Management Program developed by Dr. Lorig and her associates at Stanford University and licensed by Stanford to training sites. The Stanford group also subsequently developed the similar Chronic Disease Self-Management Program. The Stanford programs are the most widely used, and rightly so, said Maura D. Iversen, Sc.D., professor and chairman of the department of physical therapy at Northeastern University in Boston.

The Stanford arthritis program "was the basis for the Arthritis Foundation’s self-help program in the 1980s, and thus many health professionals and patient volunteers used it," Dr. Iversen said in an interview. Writing in a review of self-management last year, Dr. Iversen and her associates said that "self-management programs are now acknowledged as a key element of quality care" for patients with OA, RA, and other chronic diseases. The unaddressed issues today include whether the benefits from self-management training extend long term, and whether any patient attributes are linked with better outcomes following training, they wrote (Ann. Rheum. Dis. 2010;69:955-63).

"There are many ways for patients to get self-help, but from the standpoint of having the data, [the Stanford programs] are the best for both arthritis and chronic disease," said Dr. White.

The Stanford program "is the most popular. It has been well studied and popularized by the Arthritis Foundation and the CDC," said Dr. Daniel H. Solomon, a rheumatologist at Brigham and Women’s Hospital in Boston. But that "most popular" characterization is relative: The program’s popularity drops precipitously inside the offices of many rheumatologists and primary care physicians. Major issues seem to be skepticism about efficacy; questions about the need for formal programs; and a lack of awareness about self-management, time to make a referral, and knowledge about where to refer.

"I doubt many rheumatologists regularly refer patients to such programs. It is hard to argue with such programs, but few rheumatologists view them as beneficial. They are clearly nontoxic, but how beneficial they are can be debated," said Dr. Solomon. Several years ago, he headed a controlled study with 113 patients with OA, RA, or fibromyalgia that failed to find a significant benefit from the arthritis self-management program (J. Rheumatol. 2002;29:362-8). He also coauthored a meta-analysis of 17 other controlled trials of the same program, and found that self-management classes led to small reductions in pain and disability (Arthritis Rheum. 2003;48: 2207-13).

"A self-management course is just one of several tools to promote patient coping," said Dr. Nortin M. Hadler, a rheumatologist and professor of medicine at the University of North Carolina at Chapel Hill. "I believe that almost all rheumatologists are aware that an important part of treating regional joint pain is to have patients exercise and meet with peer groups, but the patient doesn’t need a structured Arthritis Foundation program. They can go the aerobics classes, the YMCA, or a health club."

"As a group, rheumatologists don’t refer their patients to self-management," said rheumatologist Dr. Halsted R. Holman, the Guggenheim Professor of Medicine Emeritus at Stanford and a codeveloper with Dr. Lorig of the Stanford self-management program. In many cases when a rheumatologist or other physician makes the referral, the patient has a hard time finding a nearby program or a program at a convenient time. "It’s mainly access issues," he said.

Another rheumatologist who collaborated on developing the Stanford program agreed. "There are about 7,000 classes given a year in the United States, but the country is big and just because there is a class in a patient’s area doesn’t mean it will be convenient," said Dr. James F. Fries, also a rheumatologist and professor emeritus at Stanford. In addition, "the referral mode has always been lousy." The growing availability of self-management training via the Internet may address the convenience issues and broaden patient uptake, he said in an interview.

Hurdles to Referral

"I’ve never felt any hostility from rheumatologists, and the American College of Rheumatology has never been less than 100% supportive," Dr. Lorig said. "We don’t get a lot of referrals from rheumatologists in most places, but I don’t think it’s the rheumatologists’ fault. We make it exceedingly difficult to refer."

In general, physicians don’t know about self-management programs in their communities – where they’re offered and when – because "the programs have never been closely linked to the medical system. "We have 1,000 license holders [groups that have purchased a license from Stanford to hold arthritis or chronic disease self-management classes] and more than 3,000 trainers," but despite that, doctors don’t know where and when programs are offered. "We all recognize this is a huge problem. We’re now big enough that a national, central referral source is possible, and we will hopefully have one within the next year," she said.

"We also know from our research that people with arthritis who receive a referral or recommendation from their doctor are 18 times more likely to attend a self-management education program," said Teresa J. Brady, Ph.D., a senior behavioral scientist in the CDC’s arthritis program, adding that the No. 1 reason why patients don’t attend a program is that they do not know it exists, and they believe that if it did exist, they would have heard about it from their physician. "As a consequence, we at the CDC’s arthritis program have begun pilot testing a marketing strategy to help health care providers know when and where in their community patients can take training programs."

In recent years, the ways in which patients can take courses has significantly broadened, moving beyond the traditional small-class format to also include courses by mail and the Internet. The National Council on Aging (NCoA) is the technical advisor to the AoA’s grant program for chronic disease self-management training. The NCoA is now developing a Web site where patients and physicians can find all the classes offered in their communities, but Wendy Zenker, vice president of the NCoA’s benefits access group, said she could not provide a target date when the Web site will become operational.

The Arthritis Foundation’s Dr. White agreed that a low referral rate by physicians is a major problem. In general, physicians "don’t refer enough to community services in any form," she said. To help address this, the Arthritis Foundation has recently been working with the American College of Physicians to alert internal medicine physicians about the arthritis self-management program. Yet another issue is the time commitment (2.5 hours a week for 6 weeks) for patients who take a class. "The majority of people don’t complete it," Dr. White said. "The issue is: How do we get people to do it? We don’t have that magic bullet yet."

Dr. White, Dr. Iverson, Dr. Solomon, Dr. Hadler, and Dr. Brady said that they had no disclosures. Dr. Lorig, Dr. Holman, and Dr. Fries said that they receive royalties from the licensing of the Stanford self-management programs and from sales of the teaching texts.

Several U.S. public health groups have recently made self-management training for patients with arthritis a priority. But clinicians resist this, despite an evidence-based track record that goes back more than 30 years.

In essence, arthritis self-management consists of arthritis patients using exercise, injury prevention strategies, weight management through healthful eating, disease education, meditation, and other supportive therapies to ease their pain and increase their function.

Both government and rheumatology organizations have been enthusiastic in their support for these measures, as shown by the following:

• The Centers for Disease Control and Prevention has formally supported arthritis self-management training (as well as similar training for patients with other chronic diseases). In addition, the CDC’s arthritis program says that one of its main short-term goals is to "improve and increase self-management attitudes and behaviors among persons with arthritis. ... Without doubt, self-management is a core issue in public health," said Dr. Patience White, a rheumatologist and chief public health officer of the Arthritis Foundation in Atlanta.

• The U.S. Administration on Aging received cash support from the 2009 American Recovery and Reinvestment Act. With that stimulus money, the AoA handed out $27 million in grants to 45 states, Puerto Rico, and the District of Columbia last year to deliver self-management training programs to patients with chronic diseases including those with osteoarthritis (OA) or rheumatoid arthritis (RA).

• In the 2010 report "A National Public Health Agenda for Osteoarthritis," jointly issued by the Arthritis Foundation and the CDC, the first recommendation for action in the report’s 10-item plan is: "Self-management education should be expanded as a community-based intervention for people with symptomatic OA." The American College of Rheumatology has also endorsed self-management training for OA patients in the society’s OA management recommendations (Arthritis Rheum. 2000;43:1905-15), and the Arthritis Foundation has promoted self-management as a key element in managing patients with RA.

• Healthy People 2020, a set of public health targets released in December 2010 by the Department of Health and Human Services, said that one goal for patients with arthritis is to "increase the proportion of adults with doctor-diagnosed arthritis who have had effective, evidence-based arthritis education as an integral part of the management of their condition."

In short, self-management – with its safety and proven modest efficacy – has emerged as an attractive complement to the medical approach for dealing with arthritis.

Data Support Self-Management’s Efficacy

Kate Lorig, Dr.P.H., noted that "we give patients a lot of tools to use so that they can do the things they need to do with less pain."

"What we find is that patients who take the course have statistically significantly less pain," added Dr. Lorig, professor of medicine and director of the Patient Education Research Center at Stanford (Calif.) University in Palo Alto, in an interview. "They have a small to moderate reduction in pain that is similar to what they get from NSAIDs. ... We see people able to do things that they couldn’t before, related to improvements in mobility and depression, and we see improvements in their quality of life."

Dr. Lorig has led a group at Stanford that began developing and testing an arthritis-oriented self-management program in the late 1970s (Arthritis Rheum. 1985;28:680-5). Subsequently the same group developed a more generic chronic disease program (Arthritis Rheum. 2005;53:950-7), and arthritis programs available by mail (Arthritis Rheum. 2009;61:867-75) and over the Internet (Arthritis Rheum. 2008;59:1009-17).

"The individual improvement for each patient can be rather small, but the cost saving [of promoting wide use of self-management training] is high because of the large number of patients," said Dr. White. In addition, although the overall effect size may be small, for a subset of patients the effect is "life changing," she added.

Clinicians’ Indifference

But despite these positive assessments and public health promotions, self-management training for patients with OA or RA remains neglected and unused. Experts widely agree that a scant fraction of U.S. arthritis patients have received self-management training.

According to the Arthritis Foundation’s Dr. White, currently 60,000 U.S. arthritis patients undergo self-management training each year, a number dwarfed by the roughly 50 million Americans who have some form of arthritis. "Very few are in the program, even when it gets megabucks from the government," she said.

The best known and most thoroughly-studied self-management training course for patients with arthritis is the Arthritis Self-Management Program developed by Dr. Lorig and her associates at Stanford University and licensed by Stanford to training sites. The Stanford group also subsequently developed the similar Chronic Disease Self-Management Program. The Stanford programs are the most widely used, and rightly so, said Maura D. Iversen, Sc.D., professor and chairman of the department of physical therapy at Northeastern University in Boston.

The Stanford arthritis program "was the basis for the Arthritis Foundation’s self-help program in the 1980s, and thus many health professionals and patient volunteers used it," Dr. Iversen said in an interview. Writing in a review of self-management last year, Dr. Iversen and her associates said that "self-management programs are now acknowledged as a key element of quality care" for patients with OA, RA, and other chronic diseases. The unaddressed issues today include whether the benefits from self-management training extend long term, and whether any patient attributes are linked with better outcomes following training, they wrote (Ann. Rheum. Dis. 2010;69:955-63).

"There are many ways for patients to get self-help, but from the standpoint of having the data, [the Stanford programs] are the best for both arthritis and chronic disease," said Dr. White.

The Stanford program "is the most popular. It has been well studied and popularized by the Arthritis Foundation and the CDC," said Dr. Daniel H. Solomon, a rheumatologist at Brigham and Women’s Hospital in Boston. But that "most popular" characterization is relative: The program’s popularity drops precipitously inside the offices of many rheumatologists and primary care physicians. Major issues seem to be skepticism about efficacy; questions about the need for formal programs; and a lack of awareness about self-management, time to make a referral, and knowledge about where to refer.

"I doubt many rheumatologists regularly refer patients to such programs. It is hard to argue with such programs, but few rheumatologists view them as beneficial. They are clearly nontoxic, but how beneficial they are can be debated," said Dr. Solomon. Several years ago, he headed a controlled study with 113 patients with OA, RA, or fibromyalgia that failed to find a significant benefit from the arthritis self-management program (J. Rheumatol. 2002;29:362-8). He also coauthored a meta-analysis of 17 other controlled trials of the same program, and found that self-management classes led to small reductions in pain and disability (Arthritis Rheum. 2003;48: 2207-13).

"A self-management course is just one of several tools to promote patient coping," said Dr. Nortin M. Hadler, a rheumatologist and professor of medicine at the University of North Carolina at Chapel Hill. "I believe that almost all rheumatologists are aware that an important part of treating regional joint pain is to have patients exercise and meet with peer groups, but the patient doesn’t need a structured Arthritis Foundation program. They can go the aerobics classes, the YMCA, or a health club."

"As a group, rheumatologists don’t refer their patients to self-management," said rheumatologist Dr. Halsted R. Holman, the Guggenheim Professor of Medicine Emeritus at Stanford and a codeveloper with Dr. Lorig of the Stanford self-management program. In many cases when a rheumatologist or other physician makes the referral, the patient has a hard time finding a nearby program or a program at a convenient time. "It’s mainly access issues," he said.

Another rheumatologist who collaborated on developing the Stanford program agreed. "There are about 7,000 classes given a year in the United States, but the country is big and just because there is a class in a patient’s area doesn’t mean it will be convenient," said Dr. James F. Fries, also a rheumatologist and professor emeritus at Stanford. In addition, "the referral mode has always been lousy." The growing availability of self-management training via the Internet may address the convenience issues and broaden patient uptake, he said in an interview.

Hurdles to Referral

"I’ve never felt any hostility from rheumatologists, and the American College of Rheumatology has never been less than 100% supportive," Dr. Lorig said. "We don’t get a lot of referrals from rheumatologists in most places, but I don’t think it’s the rheumatologists’ fault. We make it exceedingly difficult to refer."

In general, physicians don’t know about self-management programs in their communities – where they’re offered and when – because "the programs have never been closely linked to the medical system. "We have 1,000 license holders [groups that have purchased a license from Stanford to hold arthritis or chronic disease self-management classes] and more than 3,000 trainers," but despite that, doctors don’t know where and when programs are offered. "We all recognize this is a huge problem. We’re now big enough that a national, central referral source is possible, and we will hopefully have one within the next year," she said.

"We also know from our research that people with arthritis who receive a referral or recommendation from their doctor are 18 times more likely to attend a self-management education program," said Teresa J. Brady, Ph.D., a senior behavioral scientist in the CDC’s arthritis program, adding that the No. 1 reason why patients don’t attend a program is that they do not know it exists, and they believe that if it did exist, they would have heard about it from their physician. "As a consequence, we at the CDC’s arthritis program have begun pilot testing a marketing strategy to help health care providers know when and where in their community patients can take training programs."

In recent years, the ways in which patients can take courses has significantly broadened, moving beyond the traditional small-class format to also include courses by mail and the Internet. The National Council on Aging (NCoA) is the technical advisor to the AoA’s grant program for chronic disease self-management training. The NCoA is now developing a Web site where patients and physicians can find all the classes offered in their communities, but Wendy Zenker, vice president of the NCoA’s benefits access group, said she could not provide a target date when the Web site will become operational.

The Arthritis Foundation’s Dr. White agreed that a low referral rate by physicians is a major problem. In general, physicians "don’t refer enough to community services in any form," she said. To help address this, the Arthritis Foundation has recently been working with the American College of Physicians to alert internal medicine physicians about the arthritis self-management program. Yet another issue is the time commitment (2.5 hours a week for 6 weeks) for patients who take a class. "The majority of people don’t complete it," Dr. White said. "The issue is: How do we get people to do it? We don’t have that magic bullet yet."

Dr. White, Dr. Iverson, Dr. Solomon, Dr. Hadler, and Dr. Brady said that they had no disclosures. Dr. Lorig, Dr. Holman, and Dr. Fries said that they receive royalties from the licensing of the Stanford self-management programs and from sales of the teaching texts.

Several U.S. public health groups have recently made self-management training for patients with arthritis a priority. But clinicians resist this, despite an evidence-based track record that goes back more than 30 years.

In essence, arthritis self-management consists of arthritis patients using exercise, injury prevention strategies, weight management through healthful eating, disease education, meditation, and other supportive therapies to ease their pain and increase their function.

Both government and rheumatology organizations have been enthusiastic in their support for these measures, as shown by the following:

• The Centers for Disease Control and Prevention has formally supported arthritis self-management training (as well as similar training for patients with other chronic diseases). In addition, the CDC’s arthritis program says that one of its main short-term goals is to "improve and increase self-management attitudes and behaviors among persons with arthritis. ... Without doubt, self-management is a core issue in public health," said Dr. Patience White, a rheumatologist and chief public health officer of the Arthritis Foundation in Atlanta.

• The U.S. Administration on Aging received cash support from the 2009 American Recovery and Reinvestment Act. With that stimulus money, the AoA handed out $27 million in grants to 45 states, Puerto Rico, and the District of Columbia last year to deliver self-management training programs to patients with chronic diseases including those with osteoarthritis (OA) or rheumatoid arthritis (RA).

• In the 2010 report "A National Public Health Agenda for Osteoarthritis," jointly issued by the Arthritis Foundation and the CDC, the first recommendation for action in the report’s 10-item plan is: "Self-management education should be expanded as a community-based intervention for people with symptomatic OA." The American College of Rheumatology has also endorsed self-management training for OA patients in the society’s OA management recommendations (Arthritis Rheum. 2000;43:1905-15), and the Arthritis Foundation has promoted self-management as a key element in managing patients with RA.

• Healthy People 2020, a set of public health targets released in December 2010 by the Department of Health and Human Services, said that one goal for patients with arthritis is to "increase the proportion of adults with doctor-diagnosed arthritis who have had effective, evidence-based arthritis education as an integral part of the management of their condition."

In short, self-management – with its safety and proven modest efficacy – has emerged as an attractive complement to the medical approach for dealing with arthritis.

Data Support Self-Management’s Efficacy

Kate Lorig, Dr.P.H., noted that "we give patients a lot of tools to use so that they can do the things they need to do with less pain."

"What we find is that patients who take the course have statistically significantly less pain," added Dr. Lorig, professor of medicine and director of the Patient Education Research Center at Stanford (Calif.) University in Palo Alto, in an interview. "They have a small to moderate reduction in pain that is similar to what they get from NSAIDs. ... We see people able to do things that they couldn’t before, related to improvements in mobility and depression, and we see improvements in their quality of life."

Dr. Lorig has led a group at Stanford that began developing and testing an arthritis-oriented self-management program in the late 1970s (Arthritis Rheum. 1985;28:680-5). Subsequently the same group developed a more generic chronic disease program (Arthritis Rheum. 2005;53:950-7), and arthritis programs available by mail (Arthritis Rheum. 2009;61:867-75) and over the Internet (Arthritis Rheum. 2008;59:1009-17).

"The individual improvement for each patient can be rather small, but the cost saving [of promoting wide use of self-management training] is high because of the large number of patients," said Dr. White. In addition, although the overall effect size may be small, for a subset of patients the effect is "life changing," she added.

Clinicians’ Indifference

But despite these positive assessments and public health promotions, self-management training for patients with OA or RA remains neglected and unused. Experts widely agree that a scant fraction of U.S. arthritis patients have received self-management training.

According to the Arthritis Foundation’s Dr. White, currently 60,000 U.S. arthritis patients undergo self-management training each year, a number dwarfed by the roughly 50 million Americans who have some form of arthritis. "Very few are in the program, even when it gets megabucks from the government," she said.

The best known and most thoroughly-studied self-management training course for patients with arthritis is the Arthritis Self-Management Program developed by Dr. Lorig and her associates at Stanford University and licensed by Stanford to training sites. The Stanford group also subsequently developed the similar Chronic Disease Self-Management Program. The Stanford programs are the most widely used, and rightly so, said Maura D. Iversen, Sc.D., professor and chairman of the department of physical therapy at Northeastern University in Boston.

The Stanford arthritis program "was the basis for the Arthritis Foundation’s self-help program in the 1980s, and thus many health professionals and patient volunteers used it," Dr. Iversen said in an interview. Writing in a review of self-management last year, Dr. Iversen and her associates said that "self-management programs are now acknowledged as a key element of quality care" for patients with OA, RA, and other chronic diseases. The unaddressed issues today include whether the benefits from self-management training extend long term, and whether any patient attributes are linked with better outcomes following training, they wrote (Ann. Rheum. Dis. 2010;69:955-63).

"There are many ways for patients to get self-help, but from the standpoint of having the data, [the Stanford programs] are the best for both arthritis and chronic disease," said Dr. White.

The Stanford program "is the most popular. It has been well studied and popularized by the Arthritis Foundation and the CDC," said Dr. Daniel H. Solomon, a rheumatologist at Brigham and Women’s Hospital in Boston. But that "most popular" characterization is relative: The program’s popularity drops precipitously inside the offices of many rheumatologists and primary care physicians. Major issues seem to be skepticism about efficacy; questions about the need for formal programs; and a lack of awareness about self-management, time to make a referral, and knowledge about where to refer.

"I doubt many rheumatologists regularly refer patients to such programs. It is hard to argue with such programs, but few rheumatologists view them as beneficial. They are clearly nontoxic, but how beneficial they are can be debated," said Dr. Solomon. Several years ago, he headed a controlled study with 113 patients with OA, RA, or fibromyalgia that failed to find a significant benefit from the arthritis self-management program (J. Rheumatol. 2002;29:362-8). He also coauthored a meta-analysis of 17 other controlled trials of the same program, and found that self-management classes led to small reductions in pain and disability (Arthritis Rheum. 2003;48: 2207-13).

"A self-management course is just one of several tools to promote patient coping," said Dr. Nortin M. Hadler, a rheumatologist and professor of medicine at the University of North Carolina at Chapel Hill. "I believe that almost all rheumatologists are aware that an important part of treating regional joint pain is to have patients exercise and meet with peer groups, but the patient doesn’t need a structured Arthritis Foundation program. They can go the aerobics classes, the YMCA, or a health club."

"As a group, rheumatologists don’t refer their patients to self-management," said rheumatologist Dr. Halsted R. Holman, the Guggenheim Professor of Medicine Emeritus at Stanford and a codeveloper with Dr. Lorig of the Stanford self-management program. In many cases when a rheumatologist or other physician makes the referral, the patient has a hard time finding a nearby program or a program at a convenient time. "It’s mainly access issues," he said.

Another rheumatologist who collaborated on developing the Stanford program agreed. "There are about 7,000 classes given a year in the United States, but the country is big and just because there is a class in a patient’s area doesn’t mean it will be convenient," said Dr. James F. Fries, also a rheumatologist and professor emeritus at Stanford. In addition, "the referral mode has always been lousy." The growing availability of self-management training via the Internet may address the convenience issues and broaden patient uptake, he said in an interview.

Hurdles to Referral

"I’ve never felt any hostility from rheumatologists, and the American College of Rheumatology has never been less than 100% supportive," Dr. Lorig said. "We don’t get a lot of referrals from rheumatologists in most places, but I don’t think it’s the rheumatologists’ fault. We make it exceedingly difficult to refer."

In general, physicians don’t know about self-management programs in their communities – where they’re offered and when – because "the programs have never been closely linked to the medical system. "We have 1,000 license holders [groups that have purchased a license from Stanford to hold arthritis or chronic disease self-management classes] and more than 3,000 trainers," but despite that, doctors don’t know where and when programs are offered. "We all recognize this is a huge problem. We’re now big enough that a national, central referral source is possible, and we will hopefully have one within the next year," she said.

"We also know from our research that people with arthritis who receive a referral or recommendation from their doctor are 18 times more likely to attend a self-management education program," said Teresa J. Brady, Ph.D., a senior behavioral scientist in the CDC’s arthritis program, adding that the No. 1 reason why patients don’t attend a program is that they do not know it exists, and they believe that if it did exist, they would have heard about it from their physician. "As a consequence, we at the CDC’s arthritis program have begun pilot testing a marketing strategy to help health care providers know when and where in their community patients can take training programs."

In recent years, the ways in which patients can take courses has significantly broadened, moving beyond the traditional small-class format to also include courses by mail and the Internet. The National Council on Aging (NCoA) is the technical advisor to the AoA’s grant program for chronic disease self-management training. The NCoA is now developing a Web site where patients and physicians can find all the classes offered in their communities, but Wendy Zenker, vice president of the NCoA’s benefits access group, said she could not provide a target date when the Web site will become operational.

The Arthritis Foundation’s Dr. White agreed that a low referral rate by physicians is a major problem. In general, physicians "don’t refer enough to community services in any form," she said. To help address this, the Arthritis Foundation has recently been working with the American College of Physicians to alert internal medicine physicians about the arthritis self-management program. Yet another issue is the time commitment (2.5 hours a week for 6 weeks) for patients who take a class. "The majority of people don’t complete it," Dr. White said. "The issue is: How do we get people to do it? We don’t have that magic bullet yet."

Dr. White, Dr. Iverson, Dr. Solomon, Dr. Hadler, and Dr. Brady said that they had no disclosures. Dr. Lorig, Dr. Holman, and Dr. Fries said that they receive royalties from the licensing of the Stanford self-management programs and from sales of the teaching texts.

The Problem

A 97 year-old independently living female presents with her family because she is having increasing difficulty getting around at home. She has a history of a permanent pacemaker for “cardiac conduction disease,” atrial fibrillation, coronary artery disease, and hypothyroidism. She describes bilateral knee pain moderately severe in intensity, in her left leg greater than her right. She has nocturnal pain that wakes her when she is rolling over in bed. The pain is worse with standing and better with sitting. She denies swelling, redness, or a history of gout. On examination, she has no swelling redness or warmth on either knee, but she has joint line tenderness bilaterally. You review an old knee x-ray that demonstrates medial compartment narrowing bilaterally. You make the diagnosis of osteoarthritis and proceed with conservative measures including topical diclofenac gel, lidocaine patches, stretching exercises, and a prescription for walking as tolerated. She returns several weeks later complaining of ongoing pain somewhat addressed with conservative measures. You elect to do a steroid injection of her left knee, which improves her pain. She calls back 6 weeks later and requests pain medication. She tells you that she had shoulder surgery in the 1990s at which time she received propoxyphene/acetaminophen that has since been removed from the market. She requests a substitute. You consider a narcotic. You decide to review the evidence.

The Question

Compared with NSAIDs, are narcotics safer for older patients and associated with fewer side effects?

The Search

You open PubMed, and enter the terms “analgesics AND arthritis.”

Our Critique

This pharmacoepidemiologic study provides new information for the care of our elderly patients. Limitations of this study include no information on quality of life and no information on BMI, alcohol or tobacco use, or use of over-the-counter medications.

Clinical Decision

You prescribe a coxib (a cyclo-oxygenase-2 inhibitor) and recommend a proton pump inhibitor. In the meantime, the family has moved her to assisted living.

The Evidence

“The Comparative Safety of Analgesics in Older Adults With Arthritis” (Arch. Intern. Med. 2010;170:1968-76).

P Study Cohort: The eligible cohort consisted of Medicare beneficiaries in Pennsylvania and New Jersey who qualified for pharmaceutical assistance programs based on income. Insurance coverage was provided for all medications without restriction. The study cohort consisted of the eligible adults who had recorded diagnoses for osteoarthritis or rheumatoid arthritis on two separate occasions. At the time of the second diagnosis, their first new analgesic prescription was recorded. New use of a nonselective NSAID, coxib, or an opioid was determined by excluding persons who received these drugs in the 180 days before the index date. Eligible subjects also were excluded if they had cancer, used hospice in the proceeding year, or received analgesics from two categories at the same time, either as combination products or as two separate medications. Propensity score matching was used and attempts were made to balance exposure groups upon potential confounders. Potential confounders included a history of medication use related to the diagnoses of cardiovascular disease, osteoporosis, bone fracture, and gastrointestinal, liver, and renal disease.

P Outcome Safety Events: Safety events were defined as all clinically significant on intent health effects related to analgesics. Cardiovascular events included MI, stroke, heart failure, revascularization, and out-of-hospital cardiac death. Gastrointestinal events included upper and lower GI tract bleeding and bowel obstruction. Acute kidney injury included hospitalizations for acute renal failure requiring dialysis. Liver toxic effects included inpatient and outpatient events. Fractures included hip, pelvis, wrist, and humerus but not spine. Trauma diagnoses denoting a fall also were identified.

P Analgesic Exposure: Exposure was categorized based on analgesic class: coxib, opioid, or nonselective NSAID. Medication use came from pharmacy dispensing claims records. Subjects were allowed to enter the analysis only once.

P Results: The final cohort consisted of 12,840 subjects. Almost 85% of subjects were women with a mean age of 80.0 years. Most (80%) had osteoarthritis. Comorbidities were similar across groups. Mean follow-up time was 117 days for NSAIDs, 202 days for coxibs, and 137 days for opioids. Compared with nonselective NSAIDs, more CV events were observed with coxibs (hazard ratio 1.28; 95% confidence interval, 1.01-1.62) and opioids (HR, 1.77; CI, 1.39-2.24). Compared with nonselective NSAID users, a similar risk for GI bleeding was observed for opioid users (HR, 1.07; CI, 0.65-1.76), but a lower risk was observed for coxib users (HR, 0.60; 95% CI, 0.35-1.00). Coxib and nonselective NSAID users had a similar risk for fracture. Fracture risk was elevated with opioid use (HR, 4.47; 95% CI, 3.12-6.41), compared with nonselective NSAID use. Compared with use of nonselective NSAIDs, an increased risk of safety events requiring hospitalization was observed with opioid use (HR, 1.68; 95% CI, 1.37-2.07), but not coxibs (HR, 1.12; CI, 0.91-1.38). Compared with nonselective NSAID users, an increased risk of all-cause mortality was observed among opioid users (HR, 1.87; 95 CI, 1.39-2.53), but not coxib users (HR, 1.16; CI, 0.85-1.57).

The Problem

A 97 year-old independently living female presents with her family because she is having increasing difficulty getting around at home. She has a history of a permanent pacemaker for “cardiac conduction disease,” atrial fibrillation, coronary artery disease, and hypothyroidism. She describes bilateral knee pain moderately severe in intensity, in her left leg greater than her right. She has nocturnal pain that wakes her when she is rolling over in bed. The pain is worse with standing and better with sitting. She denies swelling, redness, or a history of gout. On examination, she has no swelling redness or warmth on either knee, but she has joint line tenderness bilaterally. You review an old knee x-ray that demonstrates medial compartment narrowing bilaterally. You make the diagnosis of osteoarthritis and proceed with conservative measures including topical diclofenac gel, lidocaine patches, stretching exercises, and a prescription for walking as tolerated. She returns several weeks later complaining of ongoing pain somewhat addressed with conservative measures. You elect to do a steroid injection of her left knee, which improves her pain. She calls back 6 weeks later and requests pain medication. She tells you that she had shoulder surgery in the 1990s at which time she received propoxyphene/acetaminophen that has since been removed from the market. She requests a substitute. You consider a narcotic. You decide to review the evidence.

The Question

Compared with NSAIDs, are narcotics safer for older patients and associated with fewer side effects?

The Search

You open PubMed, and enter the terms “analgesics AND arthritis.”

Our Critique

This pharmacoepidemiologic study provides new information for the care of our elderly patients. Limitations of this study include no information on quality of life and no information on BMI, alcohol or tobacco use, or use of over-the-counter medications.

Clinical Decision

You prescribe a coxib (a cyclo-oxygenase-2 inhibitor) and recommend a proton pump inhibitor. In the meantime, the family has moved her to assisted living.

The Evidence

“The Comparative Safety of Analgesics in Older Adults With Arthritis” (Arch. Intern. Med. 2010;170:1968-76).

P Study Cohort: The eligible cohort consisted of Medicare beneficiaries in Pennsylvania and New Jersey who qualified for pharmaceutical assistance programs based on income. Insurance coverage was provided for all medications without restriction. The study cohort consisted of the eligible adults who had recorded diagnoses for osteoarthritis or rheumatoid arthritis on two separate occasions. At the time of the second diagnosis, their first new analgesic prescription was recorded. New use of a nonselective NSAID, coxib, or an opioid was determined by excluding persons who received these drugs in the 180 days before the index date. Eligible subjects also were excluded if they had cancer, used hospice in the proceeding year, or received analgesics from two categories at the same time, either as combination products or as two separate medications. Propensity score matching was used and attempts were made to balance exposure groups upon potential confounders. Potential confounders included a history of medication use related to the diagnoses of cardiovascular disease, osteoporosis, bone fracture, and gastrointestinal, liver, and renal disease.

P Outcome Safety Events: Safety events were defined as all clinically significant on intent health effects related to analgesics. Cardiovascular events included MI, stroke, heart failure, revascularization, and out-of-hospital cardiac death. Gastrointestinal events included upper and lower GI tract bleeding and bowel obstruction. Acute kidney injury included hospitalizations for acute renal failure requiring dialysis. Liver toxic effects included inpatient and outpatient events. Fractures included hip, pelvis, wrist, and humerus but not spine. Trauma diagnoses denoting a fall also were identified.

P Analgesic Exposure: Exposure was categorized based on analgesic class: coxib, opioid, or nonselective NSAID. Medication use came from pharmacy dispensing claims records. Subjects were allowed to enter the analysis only once.

P Results: The final cohort consisted of 12,840 subjects. Almost 85% of subjects were women with a mean age of 80.0 years. Most (80%) had osteoarthritis. Comorbidities were similar across groups. Mean follow-up time was 117 days for NSAIDs, 202 days for coxibs, and 137 days for opioids. Compared with nonselective NSAIDs, more CV events were observed with coxibs (hazard ratio 1.28; 95% confidence interval, 1.01-1.62) and opioids (HR, 1.77; CI, 1.39-2.24). Compared with nonselective NSAID users, a similar risk for GI bleeding was observed for opioid users (HR, 1.07; CI, 0.65-1.76), but a lower risk was observed for coxib users (HR, 0.60; 95% CI, 0.35-1.00). Coxib and nonselective NSAID users had a similar risk for fracture. Fracture risk was elevated with opioid use (HR, 4.47; 95% CI, 3.12-6.41), compared with nonselective NSAID use. Compared with use of nonselective NSAIDs, an increased risk of safety events requiring hospitalization was observed with opioid use (HR, 1.68; 95% CI, 1.37-2.07), but not coxibs (HR, 1.12; CI, 0.91-1.38). Compared with nonselective NSAID users, an increased risk of all-cause mortality was observed among opioid users (HR, 1.87; 95 CI, 1.39-2.53), but not coxib users (HR, 1.16; CI, 0.85-1.57).

The Problem

A 97 year-old independently living female presents with her family because she is having increasing difficulty getting around at home. She has a history of a permanent pacemaker for “cardiac conduction disease,” atrial fibrillation, coronary artery disease, and hypothyroidism. She describes bilateral knee pain moderately severe in intensity, in her left leg greater than her right. She has nocturnal pain that wakes her when she is rolling over in bed. The pain is worse with standing and better with sitting. She denies swelling, redness, or a history of gout. On examination, she has no swelling redness or warmth on either knee, but she has joint line tenderness bilaterally. You review an old knee x-ray that demonstrates medial compartment narrowing bilaterally. You make the diagnosis of osteoarthritis and proceed with conservative measures including topical diclofenac gel, lidocaine patches, stretching exercises, and a prescription for walking as tolerated. She returns several weeks later complaining of ongoing pain somewhat addressed with conservative measures. You elect to do a steroid injection of her left knee, which improves her pain. She calls back 6 weeks later and requests pain medication. She tells you that she had shoulder surgery in the 1990s at which time she received propoxyphene/acetaminophen that has since been removed from the market. She requests a substitute. You consider a narcotic. You decide to review the evidence.

The Question

Compared with NSAIDs, are narcotics safer for older patients and associated with fewer side effects?

The Search

You open PubMed, and enter the terms “analgesics AND arthritis.”

Our Critique

This pharmacoepidemiologic study provides new information for the care of our elderly patients. Limitations of this study include no information on quality of life and no information on BMI, alcohol or tobacco use, or use of over-the-counter medications.

Clinical Decision

You prescribe a coxib (a cyclo-oxygenase-2 inhibitor) and recommend a proton pump inhibitor. In the meantime, the family has moved her to assisted living.

The Evidence

“The Comparative Safety of Analgesics in Older Adults With Arthritis” (Arch. Intern. Med. 2010;170:1968-76).

P Study Cohort: The eligible cohort consisted of Medicare beneficiaries in Pennsylvania and New Jersey who qualified for pharmaceutical assistance programs based on income. Insurance coverage was provided for all medications without restriction. The study cohort consisted of the eligible adults who had recorded diagnoses for osteoarthritis or rheumatoid arthritis on two separate occasions. At the time of the second diagnosis, their first new analgesic prescription was recorded. New use of a nonselective NSAID, coxib, or an opioid was determined by excluding persons who received these drugs in the 180 days before the index date. Eligible subjects also were excluded if they had cancer, used hospice in the proceeding year, or received analgesics from two categories at the same time, either as combination products or as two separate medications. Propensity score matching was used and attempts were made to balance exposure groups upon potential confounders. Potential confounders included a history of medication use related to the diagnoses of cardiovascular disease, osteoporosis, bone fracture, and gastrointestinal, liver, and renal disease.

P Outcome Safety Events: Safety events were defined as all clinically significant on intent health effects related to analgesics. Cardiovascular events included MI, stroke, heart failure, revascularization, and out-of-hospital cardiac death. Gastrointestinal events included upper and lower GI tract bleeding and bowel obstruction. Acute kidney injury included hospitalizations for acute renal failure requiring dialysis. Liver toxic effects included inpatient and outpatient events. Fractures included hip, pelvis, wrist, and humerus but not spine. Trauma diagnoses denoting a fall also were identified.

P Analgesic Exposure: Exposure was categorized based on analgesic class: coxib, opioid, or nonselective NSAID. Medication use came from pharmacy dispensing claims records. Subjects were allowed to enter the analysis only once.

P Results: The final cohort consisted of 12,840 subjects. Almost 85% of subjects were women with a mean age of 80.0 years. Most (80%) had osteoarthritis. Comorbidities were similar across groups. Mean follow-up time was 117 days for NSAIDs, 202 days for coxibs, and 137 days for opioids. Compared with nonselective NSAIDs, more CV events were observed with coxibs (hazard ratio 1.28; 95% confidence interval, 1.01-1.62) and opioids (HR, 1.77; CI, 1.39-2.24). Compared with nonselective NSAID users, a similar risk for GI bleeding was observed for opioid users (HR, 1.07; CI, 0.65-1.76), but a lower risk was observed for coxib users (HR, 0.60; 95% CI, 0.35-1.00). Coxib and nonselective NSAID users had a similar risk for fracture. Fracture risk was elevated with opioid use (HR, 4.47; 95% CI, 3.12-6.41), compared with nonselective NSAID use. Compared with use of nonselective NSAIDs, an increased risk of safety events requiring hospitalization was observed with opioid use (HR, 1.68; 95% CI, 1.37-2.07), but not coxibs (HR, 1.12; CI, 0.91-1.38). Compared with nonselective NSAID users, an increased risk of all-cause mortality was observed among opioid users (HR, 1.87; 95 CI, 1.39-2.53), but not coxib users (HR, 1.16; CI, 0.85-1.57).

CHICAGO — Visceral obesity was associated with low bone mineral density in a study of premenopausal women, indicating that abdominal fat is a risk factor for osteoporosis.

The finding indicates that “obesity does not always protect against osteoporosis,” study investigator Dr. Miriam A. Bredella said in a press briefing at the meeting. “Excessive visceral fat is not only a risk factor for heart disease and diabetes, but also for bone loss.”

The study flies in the face of current thinking that obesity actually protects against osteoporosis. Previous studies suggesting a link between fat and bone health focused primarily on body mass index (BMI), which incorporates muscle and bone mass and subcutaneous fat as well as visceral fat, she said. The present study zeroed in specifically on visceral fat.

Dr. Bredella noted “disturbing pictures emerging from the obesity epidemic, because the number of forearm fractures among young patients has increased dramatically over the last year, and the strongest risk factor in that group … was actually increased body weight.” This finding prompted the investigators to see whether there was a connection between osteoporosis and fat, said Dr. Bredella of Massachusetts General Hospital and Harvard Medical School, both in Boston.

Fifty premenopausal women with a BMI of 19-46 kg/m

The results showed a positive correlation between visceral fat and BM fat (r = 0.28) and an inverse association between visceral fat and BMD (r = −0.31) and between vertebral BM fat and BMD (r = −0.45). These results were statistically significant. There was no correlation between either subcutaneous fat (concentrated around the hips and thighs) or total body fat and either BM fat or BMD. These results reveal the distinctly detrimental effect of abdominal obesity on bone health, Dr. Bredella said.

The study is among the first to explore the relationship between body fat and bone marrow fat, and the dynamic appears to be complex, she said in an interview.

According to recent research, “the amount of fat within your bones could predict if you will develop a fracture independent of bone mineral density,” she noted.

Dr. Bredella had no financial disclosures.

Abdominal CT scanoin an obese womean, shows high visceral adipose tissue.

Source Courtesy Radiological Society of North America

CHICAGO — Visceral obesity was associated with low bone mineral density in a study of premenopausal women, indicating that abdominal fat is a risk factor for osteoporosis.

The finding indicates that “obesity does not always protect against osteoporosis,” study investigator Dr. Miriam A. Bredella said in a press briefing at the meeting. “Excessive visceral fat is not only a risk factor for heart disease and diabetes, but also for bone loss.”

The study flies in the face of current thinking that obesity actually protects against osteoporosis. Previous studies suggesting a link between fat and bone health focused primarily on body mass index (BMI), which incorporates muscle and bone mass and subcutaneous fat as well as visceral fat, she said. The present study zeroed in specifically on visceral fat.

Dr. Bredella noted “disturbing pictures emerging from the obesity epidemic, because the number of forearm fractures among young patients has increased dramatically over the last year, and the strongest risk factor in that group … was actually increased body weight.” This finding prompted the investigators to see whether there was a connection between osteoporosis and fat, said Dr. Bredella of Massachusetts General Hospital and Harvard Medical School, both in Boston.

Fifty premenopausal women with a BMI of 19-46 kg/m

The results showed a positive correlation between visceral fat and BM fat (r = 0.28) and an inverse association between visceral fat and BMD (r = −0.31) and between vertebral BM fat and BMD (r = −0.45). These results were statistically significant. There was no correlation between either subcutaneous fat (concentrated around the hips and thighs) or total body fat and either BM fat or BMD. These results reveal the distinctly detrimental effect of abdominal obesity on bone health, Dr. Bredella said.

The study is among the first to explore the relationship between body fat and bone marrow fat, and the dynamic appears to be complex, she said in an interview.

According to recent research, “the amount of fat within your bones could predict if you will develop a fracture independent of bone mineral density,” she noted.

Dr. Bredella had no financial disclosures.

Abdominal CT scanoin an obese womean, shows high visceral adipose tissue.

Source Courtesy Radiological Society of North America

CHICAGO — Visceral obesity was associated with low bone mineral density in a study of premenopausal women, indicating that abdominal fat is a risk factor for osteoporosis.

The finding indicates that “obesity does not always protect against osteoporosis,” study investigator Dr. Miriam A. Bredella said in a press briefing at the meeting. “Excessive visceral fat is not only a risk factor for heart disease and diabetes, but also for bone loss.”

The study flies in the face of current thinking that obesity actually protects against osteoporosis. Previous studies suggesting a link between fat and bone health focused primarily on body mass index (BMI), which incorporates muscle and bone mass and subcutaneous fat as well as visceral fat, she said. The present study zeroed in specifically on visceral fat.

Dr. Bredella noted “disturbing pictures emerging from the obesity epidemic, because the number of forearm fractures among young patients has increased dramatically over the last year, and the strongest risk factor in that group … was actually increased body weight.” This finding prompted the investigators to see whether there was a connection between osteoporosis and fat, said Dr. Bredella of Massachusetts General Hospital and Harvard Medical School, both in Boston.

Fifty premenopausal women with a BMI of 19-46 kg/m

The results showed a positive correlation between visceral fat and BM fat (r = 0.28) and an inverse association between visceral fat and BMD (r = −0.31) and between vertebral BM fat and BMD (r = −0.45). These results were statistically significant. There was no correlation between either subcutaneous fat (concentrated around the hips and thighs) or total body fat and either BM fat or BMD. These results reveal the distinctly detrimental effect of abdominal obesity on bone health, Dr. Bredella said.

The study is among the first to explore the relationship between body fat and bone marrow fat, and the dynamic appears to be complex, she said in an interview.

According to recent research, “the amount of fat within your bones could predict if you will develop a fracture independent of bone mineral density,” she noted.

Dr. Bredella had no financial disclosures.

Abdominal CT scanoin an obese womean, shows high visceral adipose tissue.

Source Courtesy Radiological Society of North America