OARSI 2012

BARCELONA – A cartilage transplant procedure known as osteochondral allografting for femoral condyle lesions eased pain and improved function in the majority of patients, with grafts lasting as long as 20 years in more than half the recipients studied, according to Dr. Yadin Levy of Tel Aviv Medical Center, who conducted the study while a research fellow at the Scripps Clinic in La Jolla, Calif.

For this follow-up study, Dr. Levy used data from the Scripps Clinic’s osteochondral allografting (OCA) outcomes program, which has information on 614 OCA knee transplantations in 536 patients. Of these, 122 patients (129 knees) who had undergone OCA transplantation of the femoral condyle and were at least 10 years on from their initial surgery were eligible for this analysis. Most (91%) of these patients had over 10 years of follow-up. The average patient age was 31 years, and 85% were younger than 45 years.

Patients underwent surgery for pathologies including osteochondritis dissecans (45%), traumatic cartilage injury (22.5%), degenerative chondral lesion (15.5%), avascular necrosis (14.7%), and osteochondral fracture (2.3%), he said at the World Congress on Osteoarthritis.

Clinical outcome measures included the modified D’Aubigne and 18-point Postel score, the International Knee Documentation Committee (IKDC), the Knee Society (KS) function score, and subjective patient satisfaction with the outcome of their procedure. Reoperations were recorded by frequency and type, and graft survivorship was also assessed.

A mean follow-up of 14.4 years (2.4-27.5) showed that 24% of knees failed with a mean time to failure of 7.2 +/- 5.2 years.

IKDC pain scores dropped from a mean of 7.0 preoperatively to 3.8 (P less than .001) postoperatively. Function also showed improvement over the follow-up period from a mean IKDC function score of 3.4 preoperatively to 7.2 postoperatively (P less than .001). KS function improved from 65.6 to 82.5 (P less than .001). The vast majority (72%) of patients rated their operation outcome as "extremely satisfied."

With respect to graft survival, results showed that 82% survived intact for 10 years and 66% for 20 years. Patients who were older than 30 years were 3.5 times more likely to fail than patients who were younger (P less than .05). Also, patients who had experienced over two operations were 2.8 times more likely to fail than patients who had undergone one or no previous operations (P less than .05).

"The results demonstrate that this is a good treatment modality for young patients," remarked Dr. Levy.

"Firstly, [OCA] successfully treats the condition and allows the majority of patients to return to their daily activities, and secondly, it postpones the need for arthroplasty or graft removal," he added.

Many short-term follow-up studies exist providing evidence of clinical results, but very few long-term follow-up studies were available that address graft survivorship and durability, he said.

Dr. Levy explained the principle of OCA. "We basically transfer a structured articular cartilage with viable chondrocytes on the surface and underneath the bone, which acts as a scaffold," he said at the congress, sponsored by the Osteoarthritis Research Society International.

The operation is suitable for large and small chondral and osteochondral defects and can be clinically applied for cartilage repair and in complex reconstructions. "In complex reconstruction we are trying to repair the bone underneath the cartilage as well as the cartilage," he said.

"Since there is cartilage wear, the joint surfaces are not smooth and gliding, which will lead to accelerated wear and ultimately to osteoarthritis," Dr. Levy pointed out.

Cartilage problems pose a treatment challenge because the tissue is incapable of self-repair and self-regrowth. Both artificial and biological modalities exist, but according to Dr. Levy, biological treatment modalities, such as OCA, are a viable option before artificial joint replacement especially in young patients for whom there is a high risk of revision.

"ACI [autologous chondrocyte implantation] and OCA are commonly used for large lesions, of more than 4 cm. The advantage of OCA is the ability to perform a single-stage operation for large bone defect," he said.

A major advantage of the method was that, even if the first allograft failed, patients could reconvert to another allograft in the revision surgery, which would again postpone the need for arthroplasty, Dr. Levy added.

Reoperations were conducted in 47% of knees. The number of reoperations was roughly equal for graft-related and non-graft-related reasons: 23% of patients required non-graft-related reoperations including arthroscopy, such as hardware removal, while graft-related reoperations were required by 24% of patients, the majority of which (48%) were OCA revision. "The majority of failures were because of pain and radiographic fragmentation of the allografts," reported Dr. Levy.

In addition, the researchers evaluated predictors for OCA failure using logistical regression analysis. "We found that older patients who had had several pervious surgeries tended to fail more," he said. "This raises the question of whether, in the era of MRI and advanced radiographic assessments, we should treat younger patients with single operations increasing the likelihood of success."

In conclusion, Dr. Levy said that he believed OCA was a very good treatment modality, which many young patients could benefit from. "It can reduce pain, return functional ability and can postpone the need for arthroplasty."

"Ultimately, I would be happy to see [fewer] failures in the short term; however, I believe that we do not fully understand what causes graft failure and this will need further studies," he said.

Dr. Levy has not reported any relevant financial conflicts.

BARCELONA – A cartilage transplant procedure known as osteochondral allografting for femoral condyle lesions eased pain and improved function in the majority of patients, with grafts lasting as long as 20 years in more than half the recipients studied, according to Dr. Yadin Levy of Tel Aviv Medical Center, who conducted the study while a research fellow at the Scripps Clinic in La Jolla, Calif.

For this follow-up study, Dr. Levy used data from the Scripps Clinic’s osteochondral allografting (OCA) outcomes program, which has information on 614 OCA knee transplantations in 536 patients. Of these, 122 patients (129 knees) who had undergone OCA transplantation of the femoral condyle and were at least 10 years on from their initial surgery were eligible for this analysis. Most (91%) of these patients had over 10 years of follow-up. The average patient age was 31 years, and 85% were younger than 45 years.

Patients underwent surgery for pathologies including osteochondritis dissecans (45%), traumatic cartilage injury (22.5%), degenerative chondral lesion (15.5%), avascular necrosis (14.7%), and osteochondral fracture (2.3%), he said at the World Congress on Osteoarthritis.

Clinical outcome measures included the modified D’Aubigne and 18-point Postel score, the International Knee Documentation Committee (IKDC), the Knee Society (KS) function score, and subjective patient satisfaction with the outcome of their procedure. Reoperations were recorded by frequency and type, and graft survivorship was also assessed.

A mean follow-up of 14.4 years (2.4-27.5) showed that 24% of knees failed with a mean time to failure of 7.2 +/- 5.2 years.

IKDC pain scores dropped from a mean of 7.0 preoperatively to 3.8 (P less than .001) postoperatively. Function also showed improvement over the follow-up period from a mean IKDC function score of 3.4 preoperatively to 7.2 postoperatively (P less than .001). KS function improved from 65.6 to 82.5 (P less than .001). The vast majority (72%) of patients rated their operation outcome as "extremely satisfied."

With respect to graft survival, results showed that 82% survived intact for 10 years and 66% for 20 years. Patients who were older than 30 years were 3.5 times more likely to fail than patients who were younger (P less than .05). Also, patients who had experienced over two operations were 2.8 times more likely to fail than patients who had undergone one or no previous operations (P less than .05).

"The results demonstrate that this is a good treatment modality for young patients," remarked Dr. Levy.

"Firstly, [OCA] successfully treats the condition and allows the majority of patients to return to their daily activities, and secondly, it postpones the need for arthroplasty or graft removal," he added.

Many short-term follow-up studies exist providing evidence of clinical results, but very few long-term follow-up studies were available that address graft survivorship and durability, he said.

Dr. Levy explained the principle of OCA. "We basically transfer a structured articular cartilage with viable chondrocytes on the surface and underneath the bone, which acts as a scaffold," he said at the congress, sponsored by the Osteoarthritis Research Society International.

The operation is suitable for large and small chondral and osteochondral defects and can be clinically applied for cartilage repair and in complex reconstructions. "In complex reconstruction we are trying to repair the bone underneath the cartilage as well as the cartilage," he said.

"Since there is cartilage wear, the joint surfaces are not smooth and gliding, which will lead to accelerated wear and ultimately to osteoarthritis," Dr. Levy pointed out.

Cartilage problems pose a treatment challenge because the tissue is incapable of self-repair and self-regrowth. Both artificial and biological modalities exist, but according to Dr. Levy, biological treatment modalities, such as OCA, are a viable option before artificial joint replacement especially in young patients for whom there is a high risk of revision.

"ACI [autologous chondrocyte implantation] and OCA are commonly used for large lesions, of more than 4 cm. The advantage of OCA is the ability to perform a single-stage operation for large bone defect," he said.

A major advantage of the method was that, even if the first allograft failed, patients could reconvert to another allograft in the revision surgery, which would again postpone the need for arthroplasty, Dr. Levy added.

Reoperations were conducted in 47% of knees. The number of reoperations was roughly equal for graft-related and non-graft-related reasons: 23% of patients required non-graft-related reoperations including arthroscopy, such as hardware removal, while graft-related reoperations were required by 24% of patients, the majority of which (48%) were OCA revision. "The majority of failures were because of pain and radiographic fragmentation of the allografts," reported Dr. Levy.

In addition, the researchers evaluated predictors for OCA failure using logistical regression analysis. "We found that older patients who had had several pervious surgeries tended to fail more," he said. "This raises the question of whether, in the era of MRI and advanced radiographic assessments, we should treat younger patients with single operations increasing the likelihood of success."

In conclusion, Dr. Levy said that he believed OCA was a very good treatment modality, which many young patients could benefit from. "It can reduce pain, return functional ability and can postpone the need for arthroplasty."

"Ultimately, I would be happy to see [fewer] failures in the short term; however, I believe that we do not fully understand what causes graft failure and this will need further studies," he said.

Dr. Levy has not reported any relevant financial conflicts.

BARCELONA – A cartilage transplant procedure known as osteochondral allografting for femoral condyle lesions eased pain and improved function in the majority of patients, with grafts lasting as long as 20 years in more than half the recipients studied, according to Dr. Yadin Levy of Tel Aviv Medical Center, who conducted the study while a research fellow at the Scripps Clinic in La Jolla, Calif.

For this follow-up study, Dr. Levy used data from the Scripps Clinic’s osteochondral allografting (OCA) outcomes program, which has information on 614 OCA knee transplantations in 536 patients. Of these, 122 patients (129 knees) who had undergone OCA transplantation of the femoral condyle and were at least 10 years on from their initial surgery were eligible for this analysis. Most (91%) of these patients had over 10 years of follow-up. The average patient age was 31 years, and 85% were younger than 45 years.

Patients underwent surgery for pathologies including osteochondritis dissecans (45%), traumatic cartilage injury (22.5%), degenerative chondral lesion (15.5%), avascular necrosis (14.7%), and osteochondral fracture (2.3%), he said at the World Congress on Osteoarthritis.

Clinical outcome measures included the modified D’Aubigne and 18-point Postel score, the International Knee Documentation Committee (IKDC), the Knee Society (KS) function score, and subjective patient satisfaction with the outcome of their procedure. Reoperations were recorded by frequency and type, and graft survivorship was also assessed.

A mean follow-up of 14.4 years (2.4-27.5) showed that 24% of knees failed with a mean time to failure of 7.2 +/- 5.2 years.

IKDC pain scores dropped from a mean of 7.0 preoperatively to 3.8 (P less than .001) postoperatively. Function also showed improvement over the follow-up period from a mean IKDC function score of 3.4 preoperatively to 7.2 postoperatively (P less than .001). KS function improved from 65.6 to 82.5 (P less than .001). The vast majority (72%) of patients rated their operation outcome as "extremely satisfied."

With respect to graft survival, results showed that 82% survived intact for 10 years and 66% for 20 years. Patients who were older than 30 years were 3.5 times more likely to fail than patients who were younger (P less than .05). Also, patients who had experienced over two operations were 2.8 times more likely to fail than patients who had undergone one or no previous operations (P less than .05).

"The results demonstrate that this is a good treatment modality for young patients," remarked Dr. Levy.

"Firstly, [OCA] successfully treats the condition and allows the majority of patients to return to their daily activities, and secondly, it postpones the need for arthroplasty or graft removal," he added.

Many short-term follow-up studies exist providing evidence of clinical results, but very few long-term follow-up studies were available that address graft survivorship and durability, he said.

Dr. Levy explained the principle of OCA. "We basically transfer a structured articular cartilage with viable chondrocytes on the surface and underneath the bone, which acts as a scaffold," he said at the congress, sponsored by the Osteoarthritis Research Society International.

The operation is suitable for large and small chondral and osteochondral defects and can be clinically applied for cartilage repair and in complex reconstructions. "In complex reconstruction we are trying to repair the bone underneath the cartilage as well as the cartilage," he said.

"Since there is cartilage wear, the joint surfaces are not smooth and gliding, which will lead to accelerated wear and ultimately to osteoarthritis," Dr. Levy pointed out.

Cartilage problems pose a treatment challenge because the tissue is incapable of self-repair and self-regrowth. Both artificial and biological modalities exist, but according to Dr. Levy, biological treatment modalities, such as OCA, are a viable option before artificial joint replacement especially in young patients for whom there is a high risk of revision.

"ACI [autologous chondrocyte implantation] and OCA are commonly used for large lesions, of more than 4 cm. The advantage of OCA is the ability to perform a single-stage operation for large bone defect," he said.

A major advantage of the method was that, even if the first allograft failed, patients could reconvert to another allograft in the revision surgery, which would again postpone the need for arthroplasty, Dr. Levy added.

Reoperations were conducted in 47% of knees. The number of reoperations was roughly equal for graft-related and non-graft-related reasons: 23% of patients required non-graft-related reoperations including arthroscopy, such as hardware removal, while graft-related reoperations were required by 24% of patients, the majority of which (48%) were OCA revision. "The majority of failures were because of pain and radiographic fragmentation of the allografts," reported Dr. Levy.

In addition, the researchers evaluated predictors for OCA failure using logistical regression analysis. "We found that older patients who had had several pervious surgeries tended to fail more," he said. "This raises the question of whether, in the era of MRI and advanced radiographic assessments, we should treat younger patients with single operations increasing the likelihood of success."

In conclusion, Dr. Levy said that he believed OCA was a very good treatment modality, which many young patients could benefit from. "It can reduce pain, return functional ability and can postpone the need for arthroplasty."

"Ultimately, I would be happy to see [fewer] failures in the short term; however, I believe that we do not fully understand what causes graft failure and this will need further studies," he said.

Dr. Levy has not reported any relevant financial conflicts.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – People with knee and hip osteoarthritis tend to overstate their walking disability, but timed walking tests provide an accurate assessment of their lameness, according to a new study.

Dr. Luke Brunton, orthopedic surgeon and researcher at the musculoskeletal research unit at the University of Bristol (England), and his colleagues wanted to find out whether patient self-reports of walking could be used to accurately represent their walking ability. "We found a very poor correlation between self-reports and objective tests," said Dr. Brunton at the World Congress on Osteoarthritis.

He added that "the observers found that patients were performing much more easily than they reported. There was a much better correlation between the observers’ reports and the tests than the patient’s self-reported walking ability."

According to Dr. Brunton, walking impairment in patients with hip and knee OA was particularly important because it was part of the reason for patients’ reduced life span, is linked to social isolation, and has been associated with dementia.

"Questions on walking are very often used to assess function, quality of life, and disability in people with OA. People are commonly asked to self-report on either walking restrictions or distance limitations, however, simply asking patients may not give the whole picture," said Dr. Brunton.

The researchers looked at the correlations between self-reported walking ability and functional tests, and observers’ assessments and the same functional tests of walking ability.

Data from a large U.K. community based cohort study known as the South West and Avon Survey of Health (SASH) cohort were used including demographic and disease-related data.

Self-assessment questions were taken from the commonly used Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne assessment. WOMAC asked, ‘What degree of difficulty have you experienced walking on flat ground in the last week due to your hips or knees?’ while Lequesne asked, "What is the maximum distance you can walk with pain?"

The study involved 806 participants with a mean age of 68 years and body mass index of 28.6 kg/m². They were asked to carry out a timed 6-meter walking test and a "get up and go" test. The latter test times how long patients take to stand up from a sitting position, walk 3 meters, turn around, and sit down again.

In particular, research observers looked at whether patients had any difficulties walking and how far they said they could walk. They correlated these findings with the 6-meter walk and the "get-up and go" test results, and compared this to the correlation between patient self-reports and the same objective tests.

"We tell the observers it doesn’t matter how long the person is taking. The important thing is how easy it is for the patient to complete the test or not," explained Dr. Brunton.

A stronger association was found between observer evaluation of walking ability and the timed walk (ANOVA r2 = 0.58; P less than .001) and "get up and go" tests (ANOVA r2= 0.56; P less than .001), than patient self-reports (SF-36; ANOVA r2 = 0.23; P less than .001 and Lequesne ANOVA r2 = 0.27; P less than .001) with the objective tests. ANOVA r2 is a measure of the statistical correlation between the two variables

"It is notable that the observers were watching the patients actually carry out a test whereas patients were asked generally how well they walked," he continued, admitting it was a very different scenario being assessed. "But if you are only asking patients one question on walking you are assuming that their self-assessment and their functional test should be very similar. We have showed this isn’t the case."

The data showed most people did the test with similar times how they rated their own walking ability.

"You can’t just take a questionnaire but you may need to undertake a functional assessment too. Most clinicians would assess patients themselves rather than relying solely on questionnaires. For research, I think we also need a combination of the two methods," he said.

Dr. Brunton has reported no relevant financial disclosures. The meeting was sponsored by the Osteoarthritis Research Society International.

BARCELONA – People with knee and hip osteoarthritis tend to overstate their walking disability, but timed walking tests provide an accurate assessment of their lameness, according to a new study.

Dr. Luke Brunton, orthopedic surgeon and researcher at the musculoskeletal research unit at the University of Bristol (England), and his colleagues wanted to find out whether patient self-reports of walking could be used to accurately represent their walking ability. "We found a very poor correlation between self-reports and objective tests," said Dr. Brunton at the World Congress on Osteoarthritis.

He added that "the observers found that patients were performing much more easily than they reported. There was a much better correlation between the observers’ reports and the tests than the patient’s self-reported walking ability."

According to Dr. Brunton, walking impairment in patients with hip and knee OA was particularly important because it was part of the reason for patients’ reduced life span, is linked to social isolation, and has been associated with dementia.

"Questions on walking are very often used to assess function, quality of life, and disability in people with OA. People are commonly asked to self-report on either walking restrictions or distance limitations, however, simply asking patients may not give the whole picture," said Dr. Brunton.

The researchers looked at the correlations between self-reported walking ability and functional tests, and observers’ assessments and the same functional tests of walking ability.

Data from a large U.K. community based cohort study known as the South West and Avon Survey of Health (SASH) cohort were used including demographic and disease-related data.

Self-assessment questions were taken from the commonly used Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne assessment. WOMAC asked, ‘What degree of difficulty have you experienced walking on flat ground in the last week due to your hips or knees?’ while Lequesne asked, "What is the maximum distance you can walk with pain?"

The study involved 806 participants with a mean age of 68 years and body mass index of 28.6 kg/m². They were asked to carry out a timed 6-meter walking test and a "get up and go" test. The latter test times how long patients take to stand up from a sitting position, walk 3 meters, turn around, and sit down again.

In particular, research observers looked at whether patients had any difficulties walking and how far they said they could walk. They correlated these findings with the 6-meter walk and the "get-up and go" test results, and compared this to the correlation between patient self-reports and the same objective tests.

"We tell the observers it doesn’t matter how long the person is taking. The important thing is how easy it is for the patient to complete the test or not," explained Dr. Brunton.

A stronger association was found between observer evaluation of walking ability and the timed walk (ANOVA r2 = 0.58; P less than .001) and "get up and go" tests (ANOVA r2= 0.56; P less than .001), than patient self-reports (SF-36; ANOVA r2 = 0.23; P less than .001 and Lequesne ANOVA r2 = 0.27; P less than .001) with the objective tests. ANOVA r2 is a measure of the statistical correlation between the two variables

"It is notable that the observers were watching the patients actually carry out a test whereas patients were asked generally how well they walked," he continued, admitting it was a very different scenario being assessed. "But if you are only asking patients one question on walking you are assuming that their self-assessment and their functional test should be very similar. We have showed this isn’t the case."

The data showed most people did the test with similar times how they rated their own walking ability.

"You can’t just take a questionnaire but you may need to undertake a functional assessment too. Most clinicians would assess patients themselves rather than relying solely on questionnaires. For research, I think we also need a combination of the two methods," he said.

Dr. Brunton has reported no relevant financial disclosures. The meeting was sponsored by the Osteoarthritis Research Society International.

BARCELONA – People with knee and hip osteoarthritis tend to overstate their walking disability, but timed walking tests provide an accurate assessment of their lameness, according to a new study.

Dr. Luke Brunton, orthopedic surgeon and researcher at the musculoskeletal research unit at the University of Bristol (England), and his colleagues wanted to find out whether patient self-reports of walking could be used to accurately represent their walking ability. "We found a very poor correlation between self-reports and objective tests," said Dr. Brunton at the World Congress on Osteoarthritis.

He added that "the observers found that patients were performing much more easily than they reported. There was a much better correlation between the observers’ reports and the tests than the patient’s self-reported walking ability."

According to Dr. Brunton, walking impairment in patients with hip and knee OA was particularly important because it was part of the reason for patients’ reduced life span, is linked to social isolation, and has been associated with dementia.

"Questions on walking are very often used to assess function, quality of life, and disability in people with OA. People are commonly asked to self-report on either walking restrictions or distance limitations, however, simply asking patients may not give the whole picture," said Dr. Brunton.

The researchers looked at the correlations between self-reported walking ability and functional tests, and observers’ assessments and the same functional tests of walking ability.

Data from a large U.K. community based cohort study known as the South West and Avon Survey of Health (SASH) cohort were used including demographic and disease-related data.

Self-assessment questions were taken from the commonly used Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne assessment. WOMAC asked, ‘What degree of difficulty have you experienced walking on flat ground in the last week due to your hips or knees?’ while Lequesne asked, "What is the maximum distance you can walk with pain?"

The study involved 806 participants with a mean age of 68 years and body mass index of 28.6 kg/m². They were asked to carry out a timed 6-meter walking test and a "get up and go" test. The latter test times how long patients take to stand up from a sitting position, walk 3 meters, turn around, and sit down again.

In particular, research observers looked at whether patients had any difficulties walking and how far they said they could walk. They correlated these findings with the 6-meter walk and the "get-up and go" test results, and compared this to the correlation between patient self-reports and the same objective tests.

"We tell the observers it doesn’t matter how long the person is taking. The important thing is how easy it is for the patient to complete the test or not," explained Dr. Brunton.

A stronger association was found between observer evaluation of walking ability and the timed walk (ANOVA r2 = 0.58; P less than .001) and "get up and go" tests (ANOVA r2= 0.56; P less than .001), than patient self-reports (SF-36; ANOVA r2 = 0.23; P less than .001 and Lequesne ANOVA r2 = 0.27; P less than .001) with the objective tests. ANOVA r2 is a measure of the statistical correlation between the two variables

"It is notable that the observers were watching the patients actually carry out a test whereas patients were asked generally how well they walked," he continued, admitting it was a very different scenario being assessed. "But if you are only asking patients one question on walking you are assuming that their self-assessment and their functional test should be very similar. We have showed this isn’t the case."

The data showed most people did the test with similar times how they rated their own walking ability.

"You can’t just take a questionnaire but you may need to undertake a functional assessment too. Most clinicians would assess patients themselves rather than relying solely on questionnaires. For research, I think we also need a combination of the two methods," he said.

Dr. Brunton has reported no relevant financial disclosures. The meeting was sponsored by the Osteoarthritis Research Society International.

BARCELONA – Dramatic weight loss favorably alters mechanical and inflammatory mechanisms that are part of the osteoarthritis disease pathway, according to 18-month findings from a prospective, single-line randomized controlled trial.

Weight loss appears to reduce knee joint compressive loads and the inflammatory markers interleukin-6 (IL-6) and leptin, explained Stephen P. Messier, Ph.D., at the World Congress on Osteoarthritis.

Exercise also plays a role, he stressed. In fact, "the pain data suggest the combination of diet and exercise is the best," because weight loss offsets the slight increase in joint loads and inflammation that is seen with exercise only. The combination packs a one-two punch: Weight loss impacts the mechanisms of OA, while the combination of diet and exercise impacts the clinical aspects of OA.

Dr. Messier, director of the J.B. Snow Biomechanics Laboratory at Wake Forest University, Winston-Salem, N.C., and his colleagues have been looking at the effects of different types of exercise for 20 years. The culmination of this work has resulted in exercise becoming the standard of care in knee OA. "We no longer expect people with knee OA to sit around and do nothing because it hurts. It actually hurts more if they don’t do anything and less if they do," he said

But because many people with OA are obese, Dr. Messier and his colleagues were spurred to investigate the effects of a combination of exercise and weight loss.

They initially carried out investigations with the aim of a 5% weight-loss target, and found clinically significant differences in the patients who followed the diet and exercise program.

But Dr. Messier also found that the 5% weight loss was insufficient to make an impact on the mechanical and physiological pathways. "So we decided to double the weight-loss target to 10%, and we’ve found it has made a difference."

Dr. Messier pointed out that he chose an 18-month over a 6-month program because he wanted this to be a change in lifestyle and something the participants do for the rest of their lives.

Dr. Messier presented primary results from the Intensive Diet and Exercise for Arthritis (IDEA) trial, which involved 454 overweight and obese (body mass index, 27-40.5 kg/m²) adults over age 55 with tibiofemoral OA (Kellgren-Lawrence grade of 2-3). Participants were randomly assigned to three groups: intensive dietary restriction (minimum 1,200 calories for men and 1,100 calories for women), intensive dietary restriction and exercise, or exercise only. More than 85% of participants in each group adhered to their regimen for the full 18-month period.

Exercise involved low- to moderate-intensity walking and resistance training for 3 days per week at 1 hour per day. High-speed motion analysis and musculoskeletal modeling were used to assess biomechanics during exercise and to calculate knee joint loads. Fasting serum concentrations of inflammatory biomarkers also were measured. Results from the three groups were compared at baseline, and at 6 and 18 months combined.

The investigators also conducted a gait analysis with six cameras and a force platform. Participants walked across the platform, and "from this we can determine the loads on the joints," Dr. Messier explained.

Mean weight loss over the 18 months was highest in the diet and exercise group at 11%. For participants on diet alone the loss was 10%, and for exercise alone, 2%.

At the American College of Rheumatology (ACR) meeting in November 2011, the researchers had reported that all three groups reduced pain over the 18 months, with the diet and exercise group reducing pain by approximately 50%. At the study’s end, 4 of 10 (38%) participants in the diet and exercise group reported little or no pain, with pain scores of 0 or 1 on a scale of 0-20, compared with about 2 of 10 for the diet-only and exercise-only groups.

"If you can tell someone you can cut their pain in half without taking drugs, that’s good," he noted.

Walking speed changed in those on the diet and exercise program, showing an increase from 1.20 m/second to 1.34 m/second. Those on diet alone changed from 1.18 meters/second to 1.30 m/second.

Measures of interleukin-6 (IL-6), the primary outcome, decreased significantly in the diet-alone group, with a mean change of –0.43 pg/mL; in the diet and exercise group, the mean change was –0.36 pg/mL; and in the exercise-alone group, it was +0.04 pg/mL (P = .005). Leptin levels also were affected, with changes of –13, –14, and –3 ng/mL in the groups, respectively.

The primary mechanical outcome, knee compressive force, decreased by 174 newtons/step (39.1 pounds/step) in the diet-only group, and by 51 newtons/step (11.5 pounds/step) in the exercise and diet group. Knee compressive force increased by 154 newtons/step (34.6 pounds/step) in the exercise-only group.

The decreases in both mechanical load and inflammation are posited to be the two factors that result in the reduction in pain.

"We spend so much on knee replacements, if we just took some of that money and invested it in prevention it would prevent some of these operations. That’s where I’m going with my research. I want to know how I can relate this to the real world," Dr. Messier said.

Dr. Marcia U. Rezende from the department of orthopedics and trauma at the University of São Paulo (Brazil) General Hospital, said she would make one alteration to the intervention: "Since these patients had knee pain, why not think about cycling rather than walking? It has less force and slower motion, and it is the sort of aerobic exercise that might not increase inflammatory reaction as the walking did. So you would have the aerobic part, the strengthening program, and it would be as effective."

The congress was sponsored by Osteoarthritis Research Society International. The IDEA study was funded by the Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier reported having no relevant conflicts of interest.

BARCELONA – Dramatic weight loss favorably alters mechanical and inflammatory mechanisms that are part of the osteoarthritis disease pathway, according to 18-month findings from a prospective, single-line randomized controlled trial.

Weight loss appears to reduce knee joint compressive loads and the inflammatory markers interleukin-6 (IL-6) and leptin, explained Stephen P. Messier, Ph.D., at the World Congress on Osteoarthritis.

Exercise also plays a role, he stressed. In fact, "the pain data suggest the combination of diet and exercise is the best," because weight loss offsets the slight increase in joint loads and inflammation that is seen with exercise only. The combination packs a one-two punch: Weight loss impacts the mechanisms of OA, while the combination of diet and exercise impacts the clinical aspects of OA.

Dr. Messier, director of the J.B. Snow Biomechanics Laboratory at Wake Forest University, Winston-Salem, N.C., and his colleagues have been looking at the effects of different types of exercise for 20 years. The culmination of this work has resulted in exercise becoming the standard of care in knee OA. "We no longer expect people with knee OA to sit around and do nothing because it hurts. It actually hurts more if they don’t do anything and less if they do," he said

But because many people with OA are obese, Dr. Messier and his colleagues were spurred to investigate the effects of a combination of exercise and weight loss.

They initially carried out investigations with the aim of a 5% weight-loss target, and found clinically significant differences in the patients who followed the diet and exercise program.

But Dr. Messier also found that the 5% weight loss was insufficient to make an impact on the mechanical and physiological pathways. "So we decided to double the weight-loss target to 10%, and we’ve found it has made a difference."

Dr. Messier pointed out that he chose an 18-month over a 6-month program because he wanted this to be a change in lifestyle and something the participants do for the rest of their lives.

Dr. Messier presented primary results from the Intensive Diet and Exercise for Arthritis (IDEA) trial, which involved 454 overweight and obese (body mass index, 27-40.5 kg/m²) adults over age 55 with tibiofemoral OA (Kellgren-Lawrence grade of 2-3). Participants were randomly assigned to three groups: intensive dietary restriction (minimum 1,200 calories for men and 1,100 calories for women), intensive dietary restriction and exercise, or exercise only. More than 85% of participants in each group adhered to their regimen for the full 18-month period.

Exercise involved low- to moderate-intensity walking and resistance training for 3 days per week at 1 hour per day. High-speed motion analysis and musculoskeletal modeling were used to assess biomechanics during exercise and to calculate knee joint loads. Fasting serum concentrations of inflammatory biomarkers also were measured. Results from the three groups were compared at baseline, and at 6 and 18 months combined.

The investigators also conducted a gait analysis with six cameras and a force platform. Participants walked across the platform, and "from this we can determine the loads on the joints," Dr. Messier explained.

Mean weight loss over the 18 months was highest in the diet and exercise group at 11%. For participants on diet alone the loss was 10%, and for exercise alone, 2%.

At the American College of Rheumatology (ACR) meeting in November 2011, the researchers had reported that all three groups reduced pain over the 18 months, with the diet and exercise group reducing pain by approximately 50%. At the study’s end, 4 of 10 (38%) participants in the diet and exercise group reported little or no pain, with pain scores of 0 or 1 on a scale of 0-20, compared with about 2 of 10 for the diet-only and exercise-only groups.

"If you can tell someone you can cut their pain in half without taking drugs, that’s good," he noted.

Walking speed changed in those on the diet and exercise program, showing an increase from 1.20 m/second to 1.34 m/second. Those on diet alone changed from 1.18 meters/second to 1.30 m/second.

Measures of interleukin-6 (IL-6), the primary outcome, decreased significantly in the diet-alone group, with a mean change of –0.43 pg/mL; in the diet and exercise group, the mean change was –0.36 pg/mL; and in the exercise-alone group, it was +0.04 pg/mL (P = .005). Leptin levels also were affected, with changes of –13, –14, and –3 ng/mL in the groups, respectively.

The primary mechanical outcome, knee compressive force, decreased by 174 newtons/step (39.1 pounds/step) in the diet-only group, and by 51 newtons/step (11.5 pounds/step) in the exercise and diet group. Knee compressive force increased by 154 newtons/step (34.6 pounds/step) in the exercise-only group.

The decreases in both mechanical load and inflammation are posited to be the two factors that result in the reduction in pain.

"We spend so much on knee replacements, if we just took some of that money and invested it in prevention it would prevent some of these operations. That’s where I’m going with my research. I want to know how I can relate this to the real world," Dr. Messier said.

Dr. Marcia U. Rezende from the department of orthopedics and trauma at the University of São Paulo (Brazil) General Hospital, said she would make one alteration to the intervention: "Since these patients had knee pain, why not think about cycling rather than walking? It has less force and slower motion, and it is the sort of aerobic exercise that might not increase inflammatory reaction as the walking did. So you would have the aerobic part, the strengthening program, and it would be as effective."

The congress was sponsored by Osteoarthritis Research Society International. The IDEA study was funded by the Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier reported having no relevant conflicts of interest.

BARCELONA – Dramatic weight loss favorably alters mechanical and inflammatory mechanisms that are part of the osteoarthritis disease pathway, according to 18-month findings from a prospective, single-line randomized controlled trial.

Weight loss appears to reduce knee joint compressive loads and the inflammatory markers interleukin-6 (IL-6) and leptin, explained Stephen P. Messier, Ph.D., at the World Congress on Osteoarthritis.

Exercise also plays a role, he stressed. In fact, "the pain data suggest the combination of diet and exercise is the best," because weight loss offsets the slight increase in joint loads and inflammation that is seen with exercise only. The combination packs a one-two punch: Weight loss impacts the mechanisms of OA, while the combination of diet and exercise impacts the clinical aspects of OA.

Dr. Messier, director of the J.B. Snow Biomechanics Laboratory at Wake Forest University, Winston-Salem, N.C., and his colleagues have been looking at the effects of different types of exercise for 20 years. The culmination of this work has resulted in exercise becoming the standard of care in knee OA. "We no longer expect people with knee OA to sit around and do nothing because it hurts. It actually hurts more if they don’t do anything and less if they do," he said

But because many people with OA are obese, Dr. Messier and his colleagues were spurred to investigate the effects of a combination of exercise and weight loss.

They initially carried out investigations with the aim of a 5% weight-loss target, and found clinically significant differences in the patients who followed the diet and exercise program.

But Dr. Messier also found that the 5% weight loss was insufficient to make an impact on the mechanical and physiological pathways. "So we decided to double the weight-loss target to 10%, and we’ve found it has made a difference."

Dr. Messier pointed out that he chose an 18-month over a 6-month program because he wanted this to be a change in lifestyle and something the participants do for the rest of their lives.

Dr. Messier presented primary results from the Intensive Diet and Exercise for Arthritis (IDEA) trial, which involved 454 overweight and obese (body mass index, 27-40.5 kg/m²) adults over age 55 with tibiofemoral OA (Kellgren-Lawrence grade of 2-3). Participants were randomly assigned to three groups: intensive dietary restriction (minimum 1,200 calories for men and 1,100 calories for women), intensive dietary restriction and exercise, or exercise only. More than 85% of participants in each group adhered to their regimen for the full 18-month period.

Exercise involved low- to moderate-intensity walking and resistance training for 3 days per week at 1 hour per day. High-speed motion analysis and musculoskeletal modeling were used to assess biomechanics during exercise and to calculate knee joint loads. Fasting serum concentrations of inflammatory biomarkers also were measured. Results from the three groups were compared at baseline, and at 6 and 18 months combined.

The investigators also conducted a gait analysis with six cameras and a force platform. Participants walked across the platform, and "from this we can determine the loads on the joints," Dr. Messier explained.

Mean weight loss over the 18 months was highest in the diet and exercise group at 11%. For participants on diet alone the loss was 10%, and for exercise alone, 2%.

At the American College of Rheumatology (ACR) meeting in November 2011, the researchers had reported that all three groups reduced pain over the 18 months, with the diet and exercise group reducing pain by approximately 50%. At the study’s end, 4 of 10 (38%) participants in the diet and exercise group reported little or no pain, with pain scores of 0 or 1 on a scale of 0-20, compared with about 2 of 10 for the diet-only and exercise-only groups.

"If you can tell someone you can cut their pain in half without taking drugs, that’s good," he noted.

Walking speed changed in those on the diet and exercise program, showing an increase from 1.20 m/second to 1.34 m/second. Those on diet alone changed from 1.18 meters/second to 1.30 m/second.

Measures of interleukin-6 (IL-6), the primary outcome, decreased significantly in the diet-alone group, with a mean change of –0.43 pg/mL; in the diet and exercise group, the mean change was –0.36 pg/mL; and in the exercise-alone group, it was +0.04 pg/mL (P = .005). Leptin levels also were affected, with changes of –13, –14, and –3 ng/mL in the groups, respectively.

The primary mechanical outcome, knee compressive force, decreased by 174 newtons/step (39.1 pounds/step) in the diet-only group, and by 51 newtons/step (11.5 pounds/step) in the exercise and diet group. Knee compressive force increased by 154 newtons/step (34.6 pounds/step) in the exercise-only group.

The decreases in both mechanical load and inflammation are posited to be the two factors that result in the reduction in pain.

"We spend so much on knee replacements, if we just took some of that money and invested it in prevention it would prevent some of these operations. That’s where I’m going with my research. I want to know how I can relate this to the real world," Dr. Messier said.

Dr. Marcia U. Rezende from the department of orthopedics and trauma at the University of São Paulo (Brazil) General Hospital, said she would make one alteration to the intervention: "Since these patients had knee pain, why not think about cycling rather than walking? It has less force and slower motion, and it is the sort of aerobic exercise that might not increase inflammatory reaction as the walking did. So you would have the aerobic part, the strengthening program, and it would be as effective."

The congress was sponsored by Osteoarthritis Research Society International. The IDEA study was funded by the Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier reported having no relevant conflicts of interest.

BARCELONA – Overweight women who follow a 2.5-year diet and exercise program showed a significant reduction in incident knee osteoarthritis, judging from the findings of a new Dutch study.

Jos Runhaar, a research scientist from the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, presented findings from the first-ever preventive randomized controlled trial on osteoarthritis (OA) at the World Congress on Osteoarthritis.

The already high number of people with OA worldwide is set to rise further with the growing incidence of obesity and an aging population. "Associated financial costs will also rise substantially to reflect this," he said.

Mr. Runhaar pointed out that the research community was already well informed in terms of the course and burden of OA, definitions of disease status, progression, and risk factors but lacked evidence on prevention. "We felt it was time to take the next step and investigate prevention of the disease and associated medical costs in people at risk," he noted.

The Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study aimed to evaluate the preventive effects of a weight-loss program and of oral glucosamine sulphate on incident knee OA. After selection for study criteria, 407 women from the Rotterdam area were randomized to study interventions or placebo. "We selected a high-risk group of women between 50 to 60 years of age, BMI [body mass index] of at least 27, and without any clinical or radiographic signs of knee OA at baseline," said Mr. Runhaar. Half of the knees had a Kellgren-Lawrence (K&L) grade 0 at baseline.

The study assessed the effectiveness of two interventions: a weight-reduction program and oral glucosamine sulphate (1,500 mg/day). At the meeting, Mr. Runhaar presented only the results of the weight-reduction intervention.

The trial involved 200 women who received the weight-reduction intervention and 200 who served as controls, and in both groups half received glucosamine and half placebo.

"It was a pragmatic intervention. It was intended to be a regimen that could be easily implemented in daily life," Mr. Runhaar explained.

The weight-reduction program involved a weekly group session that featured a variety of low-impact sports to re-encourage interest and enjoyment in physical activity, and aimed to maintain this over the long term. "Women were referred to a dietician to develop dietary targets and have motivational discussions," he added.

"The supportive sessions were important because these women generally had inactive lifestyles and poor nutritional habits that were difficult to change, especially by the age of 50-60 years," he said.

Three possible incidence measures were used to represent the primary outcome of incident knee OA after 2.5 years. Participants needed to have a knee OA incidence with a K&L grade of at least 2; incidence of clinical knee OA according to clinical and radiographic American College of Rheumatology criteria; or joint-space narrowing of at least 1.0 mm.

The researchers combined both radiographic and clinical outcomes to ensure they had enough data to provide meaningful results.

After 2.5 years, women who complied with the weight-reduction program showed a mean weight reduction of 1.4 ± 5.5 kg, compared with 0.1 ± 6.3 kg in controls.

Also after 2.5 years of intervention, the researchers saw an incidence of knee OA, adjusted for BMI and K&L grade at baseline, of 22% in all knees, which equated to 36% of all women with one or more knees affected. On an intention-to-treat basis, 25% of the controls had knee OA versus 19% in the weight-reduction group (odds ratio, 0.62; 95% confidence interval, 0.38-1.04). The per-protocol analysis showed a greater difference of 25% incidence of knee OA in the controls versus 10% in the intervention arm (OR, 0.28).

"In the per-protocol analysis, we see the effect of the intervention in women who actually complied with the program. They exercised and followed the diet. This is what happens if you stay with the program. The incidence rate over halved with a statistically significant odds ratio," Mr. Runhaar reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

When asked whether this program really had practical application, he said that only a quarter of women were compliant with the intervention. "It is really difficult to change the habits of these women. This is one possible way of doing it, but we need to look at other ways of getting these women active and on a diet. If we can achieve this, then we are likely to prevent more OA."

Mr. Runhaar reported no relevant financial disclosures.

BARCELONA – Overweight women who follow a 2.5-year diet and exercise program showed a significant reduction in incident knee osteoarthritis, judging from the findings of a new Dutch study.

Jos Runhaar, a research scientist from the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, presented findings from the first-ever preventive randomized controlled trial on osteoarthritis (OA) at the World Congress on Osteoarthritis.

The already high number of people with OA worldwide is set to rise further with the growing incidence of obesity and an aging population. "Associated financial costs will also rise substantially to reflect this," he said.

Mr. Runhaar pointed out that the research community was already well informed in terms of the course and burden of OA, definitions of disease status, progression, and risk factors but lacked evidence on prevention. "We felt it was time to take the next step and investigate prevention of the disease and associated medical costs in people at risk," he noted.

The Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study aimed to evaluate the preventive effects of a weight-loss program and of oral glucosamine sulphate on incident knee OA. After selection for study criteria, 407 women from the Rotterdam area were randomized to study interventions or placebo. "We selected a high-risk group of women between 50 to 60 years of age, BMI [body mass index] of at least 27, and without any clinical or radiographic signs of knee OA at baseline," said Mr. Runhaar. Half of the knees had a Kellgren-Lawrence (K&L) grade 0 at baseline.

The study assessed the effectiveness of two interventions: a weight-reduction program and oral glucosamine sulphate (1,500 mg/day). At the meeting, Mr. Runhaar presented only the results of the weight-reduction intervention.

The trial involved 200 women who received the weight-reduction intervention and 200 who served as controls, and in both groups half received glucosamine and half placebo.

"It was a pragmatic intervention. It was intended to be a regimen that could be easily implemented in daily life," Mr. Runhaar explained.

The weight-reduction program involved a weekly group session that featured a variety of low-impact sports to re-encourage interest and enjoyment in physical activity, and aimed to maintain this over the long term. "Women were referred to a dietician to develop dietary targets and have motivational discussions," he added.

"The supportive sessions were important because these women generally had inactive lifestyles and poor nutritional habits that were difficult to change, especially by the age of 50-60 years," he said.

Three possible incidence measures were used to represent the primary outcome of incident knee OA after 2.5 years. Participants needed to have a knee OA incidence with a K&L grade of at least 2; incidence of clinical knee OA according to clinical and radiographic American College of Rheumatology criteria; or joint-space narrowing of at least 1.0 mm.

The researchers combined both radiographic and clinical outcomes to ensure they had enough data to provide meaningful results.

After 2.5 years, women who complied with the weight-reduction program showed a mean weight reduction of 1.4 ± 5.5 kg, compared with 0.1 ± 6.3 kg in controls.

Also after 2.5 years of intervention, the researchers saw an incidence of knee OA, adjusted for BMI and K&L grade at baseline, of 22% in all knees, which equated to 36% of all women with one or more knees affected. On an intention-to-treat basis, 25% of the controls had knee OA versus 19% in the weight-reduction group (odds ratio, 0.62; 95% confidence interval, 0.38-1.04). The per-protocol analysis showed a greater difference of 25% incidence of knee OA in the controls versus 10% in the intervention arm (OR, 0.28).

"In the per-protocol analysis, we see the effect of the intervention in women who actually complied with the program. They exercised and followed the diet. This is what happens if you stay with the program. The incidence rate over halved with a statistically significant odds ratio," Mr. Runhaar reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

When asked whether this program really had practical application, he said that only a quarter of women were compliant with the intervention. "It is really difficult to change the habits of these women. This is one possible way of doing it, but we need to look at other ways of getting these women active and on a diet. If we can achieve this, then we are likely to prevent more OA."

Mr. Runhaar reported no relevant financial disclosures.

BARCELONA – Overweight women who follow a 2.5-year diet and exercise program showed a significant reduction in incident knee osteoarthritis, judging from the findings of a new Dutch study.

Jos Runhaar, a research scientist from the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, presented findings from the first-ever preventive randomized controlled trial on osteoarthritis (OA) at the World Congress on Osteoarthritis.

The already high number of people with OA worldwide is set to rise further with the growing incidence of obesity and an aging population. "Associated financial costs will also rise substantially to reflect this," he said.

Mr. Runhaar pointed out that the research community was already well informed in terms of the course and burden of OA, definitions of disease status, progression, and risk factors but lacked evidence on prevention. "We felt it was time to take the next step and investigate prevention of the disease and associated medical costs in people at risk," he noted.

The Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study aimed to evaluate the preventive effects of a weight-loss program and of oral glucosamine sulphate on incident knee OA. After selection for study criteria, 407 women from the Rotterdam area were randomized to study interventions or placebo. "We selected a high-risk group of women between 50 to 60 years of age, BMI [body mass index] of at least 27, and without any clinical or radiographic signs of knee OA at baseline," said Mr. Runhaar. Half of the knees had a Kellgren-Lawrence (K&L) grade 0 at baseline.

The study assessed the effectiveness of two interventions: a weight-reduction program and oral glucosamine sulphate (1,500 mg/day). At the meeting, Mr. Runhaar presented only the results of the weight-reduction intervention.

The trial involved 200 women who received the weight-reduction intervention and 200 who served as controls, and in both groups half received glucosamine and half placebo.

"It was a pragmatic intervention. It was intended to be a regimen that could be easily implemented in daily life," Mr. Runhaar explained.

The weight-reduction program involved a weekly group session that featured a variety of low-impact sports to re-encourage interest and enjoyment in physical activity, and aimed to maintain this over the long term. "Women were referred to a dietician to develop dietary targets and have motivational discussions," he added.

"The supportive sessions were important because these women generally had inactive lifestyles and poor nutritional habits that were difficult to change, especially by the age of 50-60 years," he said.

Three possible incidence measures were used to represent the primary outcome of incident knee OA after 2.5 years. Participants needed to have a knee OA incidence with a K&L grade of at least 2; incidence of clinical knee OA according to clinical and radiographic American College of Rheumatology criteria; or joint-space narrowing of at least 1.0 mm.

The researchers combined both radiographic and clinical outcomes to ensure they had enough data to provide meaningful results.

After 2.5 years, women who complied with the weight-reduction program showed a mean weight reduction of 1.4 ± 5.5 kg, compared with 0.1 ± 6.3 kg in controls.

Also after 2.5 years of intervention, the researchers saw an incidence of knee OA, adjusted for BMI and K&L grade at baseline, of 22% in all knees, which equated to 36% of all women with one or more knees affected. On an intention-to-treat basis, 25% of the controls had knee OA versus 19% in the weight-reduction group (odds ratio, 0.62; 95% confidence interval, 0.38-1.04). The per-protocol analysis showed a greater difference of 25% incidence of knee OA in the controls versus 10% in the intervention arm (OR, 0.28).

"In the per-protocol analysis, we see the effect of the intervention in women who actually complied with the program. They exercised and followed the diet. This is what happens if you stay with the program. The incidence rate over halved with a statistically significant odds ratio," Mr. Runhaar reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

When asked whether this program really had practical application, he said that only a quarter of women were compliant with the intervention. "It is really difficult to change the habits of these women. This is one possible way of doing it, but we need to look at other ways of getting these women active and on a diet. If we can achieve this, then we are likely to prevent more OA."

Mr. Runhaar reported no relevant financial disclosures.

BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.

The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.

"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.

The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.

In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.

The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.

Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.

Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."

They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.

Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.

Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.

The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."

Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."

The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.

The meeting was sponsored by the Osteoarthritis Research Society International.

Dr. Eckstein reported ties with Medtronic, Merck Serono, Novartis, Perceptive, Pfizer, Sanofi-Aventis, and Synthes. He founded Chondrometrics in 2003. The study was funded by OAI, a public-private partnership of Novartis Pharma; the University of Pittsburgh’s Pivotal OAI MRI Analyses (POMA) study; the University of California, San Francisco; and the National Institutes of Health.

BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.

The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.

"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.

The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.

In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.

The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.

Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.

Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."

They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.

Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.

Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.

The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."

Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."

The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.

The meeting was sponsored by the Osteoarthritis Research Society International.

Dr. Eckstein reported ties with Medtronic, Merck Serono, Novartis, Perceptive, Pfizer, Sanofi-Aventis, and Synthes. He founded Chondrometrics in 2003. The study was funded by OAI, a public-private partnership of Novartis Pharma; the University of Pittsburgh’s Pivotal OAI MRI Analyses (POMA) study; the University of California, San Francisco; and the National Institutes of Health.

BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.

The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.

"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.

The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.

In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.

The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.

Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.

Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."

They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.

Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.

Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.

The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."

Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."

The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.

The meeting was sponsored by the Osteoarthritis Research Society International.

Dr. Eckstein reported ties with Medtronic, Merck Serono, Novartis, Perceptive, Pfizer, Sanofi-Aventis, and Synthes. He founded Chondrometrics in 2003. The study was funded by OAI, a public-private partnership of Novartis Pharma; the University of Pittsburgh’s Pivotal OAI MRI Analyses (POMA) study; the University of California, San Francisco; and the National Institutes of Health.