Does hand osteoarthritis predict future hip or knee osteoarthritis?

Objective

To evaluate the risk of future hip or knee osteoarthritis (OA) in subjects with hand OA at baseline and to evaluate whether the concurrent presence of hand OA, other risk factors for OA, or an OA biomarker (type II collagen C‐telopeptide degradation product [CTX‐II]) further increases the risk.

Methods

Radiographs of the hands (baseline) and the hips and knees (baseline and 6.6 years later) were obtained in a randomly selected subset of participants in the Rotterdam Study who were ages 55 years and older. Radiographs were scored for the presence of OA using the Kellgren/Lawrence (K/L) system. A total of 1,235 subjects without OA of the hip/knee (K/L score 0–1) at baseline were included in the study. CTX‐II levels were measured at baseline. The independent risk of future hip/knee OA in subjects with hand OA at baseline was assessed by logistic regression, as stratified for age, sex, body mass index, family history of OA, and heavy workload.

Results

Overall 12.1% of the participants (19.7% of those with hand OA versus 10.0% of those without) developed hip or knee OA (odds ratio [OR] 2.1 [95% confidence interval (95% CI) 1.3–3.1]). Subjects with hand OA had an increased risk of future hip OA (OR 3.0 [95% CI 1.6–5.4]), which was further increased in those with a family history of OA. Subjects with hand OA had an OR of 1.6 [95% CI 1.0–2.8) for the future development of knee OA, which was further increased in those who were overweight. Concurrent hand OA and high levels of CTX‐II further increased the risk of having hip or knee OA at followup (OR 4.2 [95% CI 2.3–7.8]).

Conclusion

The presence of hand OA at baseline showed an increased risk of future hip/knee OA (higher for hip OA than for knee OA). The concurrent presence of hand OA and other OA risk factors or high CTX‐II levels further increased the risk of future hip/knee OA.

     

Is there an association between the use of different types of nonsteroidal antiinflammatory drugs and radiologic progression of osteoarthritis?: The rotterdam study

Objective

To investigate the influence of the use of various types of nonsteroidal antiinflammatory drugs (NSAIDs) on progression of osteoarthritis (OA) of the hip and knee.

Methods

In 1,695 subjects (2,514 hips) and 635 subjects (874 knees) ages 55 years and older from the Rotterdam Study, radiographs of the hip and knee at baseline and followup (mean followup time 6.6 years) were evaluated. Radiologic OA (ROA) progression was defined as a minimum increase of 1 in the Kellgren/Lawrence grade or incident joint replacement at followup. The associations between the different types of NSAIDs and progression of ROA were assessed using multivariate logistic regression analysis.

Results

Those subjects who were receiving diclofenac >180 days had a 2.4‐fold increased risk (95% confidence interval [95% CI] 1.0–6.2) of progression of hip ROA and a 3.2‐fold increased risk (95% CI 1.0–9.9) of knee ROA, compared with those considered short‐term users (diclofenac for 1–30 days). These associations were adjusted for age, sex, body mass index, baseline ROA, followup time, and defined daily dosage.

Conclusion

These data suggest that diclofenac may induce accelerated progression of hip and knee ROA. Whether this occurs because of a true deleterious effect on cartilage or because of excessive mechanical loading on a hip following pain relief remains to be investigated.

     

A longitudinal analysis of urinary biochemical markers and bone mineral density in STR/Ort mice as a model of spontaneous osteoarthritis

Objective

To investigate the longitudinal changes both in the urinary concentrations of biochemical markers and in bone mineral density (BMD) during disease progression in the STR/Ort mouse model of osteoarthritis (OA).

Methods

Male STR/Ort mice were studied, with CBA mice used as nonarthritic controls. Radiographic evaluation and grading of the knee and measurements of urinary C‐terminal crosslinking telopeptide of type II collagen (CTX‐II), pyridinoline (Pyr), and deoxypyridinoline were performed between 8 weeks and 40 weeks of age. The BMD of the femoral shaft was measured from 20 weeks to 40 weeks of age and adjusted for body weight. Histologic evaluation and grading were performed at 40 weeks of age. STR/Ort mice were divided into 2 subgroups (STR OA and STR non‐OA) based on histologic grading.

Results

No significant differences between STR/Ort and CBA mice were observed for any biochemical marker or BMD at any time point. Urinary CTX‐II levels and BMD in the STR OA subgroup were higher than those in the STR non‐OA subgroup before radiographic changes of OA were apparent. Higher urinary Pyr levels in the STR OA subgroup were observed at the advanced stage of OA.

Conclusion

Urinary CTX‐II could be a useful marker in the early diagnosis and predicting the progression of OA, and urinary Pyr may be a potential marker to assess the severity of OA at an advanced stage. An increase in BMD prior to the establishment of radiographic OA may be related to the induction of OA.

     

Urinary type II collagen helical peptide (HELIX‐II) as a new biochemical marker of cartilage degradation in patients with osteoarthritis and rheumatoid arthritis

Objective

Type II collagen, which consists of a large helical domain and telopeptides at each end, is the most abundant protein of cartilage matrix. The aim of this study was to develop a biochemical marker reflecting the degradation of the helical region of type II collagen and to evaluate its clinical performance in patients with osteoarthritis (OA) and rheumatoid arthritis (RA).

Methods

We developed a competitive polyclonal antibody–based enzyme‐linked immunosorbent assay (ELISA) using the 622–632 peptide derived from the sequence of the α1 chain of human type II collagen (HELIX‐II) as immunogen and standard. We measured urinary levels of HELIX‐II peptide and C‐terminal crosslinking telopeptide of type II collagen (CTX‐II) in 90 patients with knee OA (73% women; mean ± SD age 63.0 ± 8.0 years, mean ± SD disease duration 6.1 ± 6.8 years), 89 patients with early RA (disease duration ≤3 years) (79% women; mean ± SD age 48.7 ± 11.6 years), 25 patients with Paget's disease of bone (HELIX‐II only), and 162 healthy controls. In RA patients, we investigated the relationships between baseline urinary HELIX‐II and CTX‐II levels and the progression of joint destruction as measured by the changes in the total Sharp score (average from 2 independent readers) over 1 year.

Results

The intraassay and interassay variations of the HELIX‐II ELISA were lower than 13% and 15%, respectively. The HELIX‐II ELISA showed no significant cross‐reactivity with human intact or denatured type II collagen, with the homologous peptides from human type I or type III collagens, or with HELIX‐II peptides elongated (by 1 amino acid) or shortened (by 1 or 2 amino acids) at the C‐terminal end, indicating that the HELIX‐II ELISA recognized a neoepitope from the α1 chain of type II collagen. Median urinary HELIX‐II levels were increased in patients with knee OA (by 56%; P < 0.0001) or early RA (by 123%; P < 0.0001) compared with those in age‐ and sex‐matched healthy controls. Baseline urinary HELIX‐II levels in the highest tertile were associated with an increased risk of radiographic progression in RA (increase in the total Sharp score ≥0.5 units/year), with an odds ratio (OR) of 5.9 (95% confidence interval [95% CI] 2.0–17.2) after adjustment for serum C‐reactive protein (CRP) levels and baseline joint damage. Patients with increased levels of both urinary HELIX‐II and CTX‐II had the highest risk of progression (OR 17.5 [95% CI 3.1–99]).

Conclusion

The HELIX‐II ELISA is specific for type II collagen degradation, has adequate technical performance, and can distinguish patients with knee OA or RA from healthy controls. Elevated HELIX‐II levels are associated with increased risk of radiographic progression in RA independently of CRP levels, baseline joint damage, and urinary CTX‐II levels. The HELIX‐II ELISA should be useful for the clinical investigation of patients with arthritis and for identifying RA patients at higher risk of progression.

     

Biomarkers of incident radiographic knee osteoarthritis: Do they vary by chronic knee symptoms?

Objective

To explore the ability of osteoarthritis (OA)–related biomarkers to predict incident radiographic knee OA in a large sample of African American and Caucasian men and women.

Methods

Baseline levels of serum cartilage oligomeric matrix protein (COMP), hyaluronan (HA), high‐sensitivity C‐reactive protein (hsCRP), and keratan sulfate (KS) and baseline and followup radiographs were available for 353 knees without baseline osteophyte formation and for 446 knees without baseline joint space narrowing (JSN). Cox models estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for incident knee OA for a 1‐unit increase in the ln of each biomarker, with adjustment for age, race, sex, body mass index, and knee OA of the contralateral limb. Report of chronic knee symptoms was explored as a modifier of the association.

Results

The hazard of incident knee osteophytes (HR 2.16 [95% CI 1.39–3.37]) and incident JSN (HR 1.82 [95% CI 1.15–2.89]) increased with higher baseline ln(COMP) levels. The hazard of incident knee JSN increased with higher ln(HA) levels (HR 1.46 [95% CI 1.14–1.87]). Baseline ln(hsCRP) and ln(KS) did not predict incident knee outcomes. HRs per unit increase in ln(COMP), ln(HA), and ln(KS) were higher among knees with chronic symptoms than among those without symptoms.

Conclusion

Higher baseline ln(COMP) and ln(HA) levels were associated with incident knee OA over an average followup period of 6.3 years. These results represent detection of a molecular stage of OA prior to radiographic manifestations. Further exploration is needed to determine how chronic knee symptoms modify the biomarker–incident knee OA association.

     

Association of 25‐hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: The osteoporotic fractures in men study

Objective

To examine the cross‐sectional association of serum levels of 25‐hydroxyvitamin D, or 25(OH)D, with prevalent radiographic hip osteoarthritis (OA) in elderly men.

Methods

In a cohort of 1,104 elderly men from the Osteoporotic Fractures in Men Study, 25(OH)D serum levels were determined by mass spectrometry, followed by pelvic radiographs ∼4.6 years later. Categories of vitamin D levels were defined as follows: deficiency as ≤15 ng/ml, insufficiency as 15.1–30 ng/ml, and sufficiency as >30 ng/ml. Radiographs were assessed for severity of hip OA using a summary grade of 0–4 for individual features of hip OA. Logistic regression was used to assess associations of serum 25(OH)D levels with prevalent radiographic hip OA; covariates included age, clinic site, season at the time of blood withdrawal, self‐reported hip pain for >30 days, timed 6‐meter walk, presence of at least 1 coexisting condition, and self‐rated health status.

Results

Men with radiographic hip OA had a slower 6‐meter walking time (P < 0.0001), reported more hip pain (P = 0.0001), had a lower vitamin D level (P = 0.0002), and had a higher prevalence of vitamin D insufficiency (P = 0.002) and vitamin D deficiency (P = 0.012) compared with controls. Higher 25(OH)D levels were associated with a lower prevalence of radiographic hip OA (odds ratio [OR] 1.39 per 1 SD decrease in 25[OH]D, 95% confidence interval [95% CI] 1.11–1.74) after adjusting for age, season, and clinic site. Men with vitamin D insufficiency had an increased likelihood of prevalent radiographic hip OA (OR 2.19, 95% CI 1.21–3.97) compared with men with sufficient levels of 25(OH)D, and in men with vitamin D deficiency, there was a tendency toward an increased likelihood of radiographic hip OA (OR 1.99, 95% CI 0.83–4.74).

Conclusion

Men with vitamin D deficiencies are twice as likely to have prevalent radiographic hip OA, and therefore vitamin D therapy to augment skeletal health in the elderly is warranted.

     

Varus–valgus alignment in the progression of patellofemoral osteoarthritis

Objective

To test the hypotheses that lateral patellofemoral (PF) osteoarthritis (OA) progression is more common than medial PF OA progression, that varus alignment increases the likelihood of medial PF OA progression, and that valgus alignment increases the likelihood of lateral PF OA progression.

Methods

Patients with knee OA were recruited from the community. Inclusion criteria were definite osteophyte presence (i.e., Kellgren/Lawrence radiographic grade ≥2) in 1 or both knees and at least some difficulty with knee‐requiring activity. Varus–valgus alignment (the angle formed by the intersection of the mechanical axes of the femur and tibia) was measured on a full‐limb radiograph at baseline. To assess PF OA progression, weight‐bearing skyline views of the PF compartment were obtained at baseline and at 18‐month followup. Knees with the highest grade of PF narrowing at baseline were excluded from analysis. Logistic regression and generalized estimating equations were used; odds ratios (ORs) were adjusted for age, sex, and body mass index.

Results

Lateral PF OA progression, which occurred in 120 (30%) of 397 knees, was more common than was medial PF OA progression, which occurred in 60 knees (15%). Varus (versus nonvarus) alignment increased the odds of PF OA progression isolated to the medial PF compartment (adjusted OR 1.85, 95% confidence interval [95% CI] 1.00–3.44). Valgus alignment increased the odds of PF OA progression isolated to the lateral compartment (adjusted OR 1.64, 95% CI 1.01–2.66).

Conclusion

Lateral PF OA progression was more common than medial progression, and varus–valgus alignment influenced the likelihood of PF OA progression in a compartment‐specific manner. Interventions that address the stress imposed by alignment on the PF compartments may delay PF OA progression and should be developed.

     

Association of the risk of osteoarthritis with high innate production of interleukin‐1β and low innate production of interleukin‐10 ex vivo,upon lipopolysaccharide stimulation

Objective

In a sibpair study of osteoarthritis (OA) patients, we investigated whether, upon stimulation with lipopolysaccharide (LPS), variations in the innate ex vivo production of interleukin‐1β (IL‐1β), IL‐1 receptor antagonist (IL‐1Ra), IL‐10, and tumor necrosis factor α (TNFα) in whole‐blood assays contribute to the risk of OA.

Methods

Data from 305 patients with OA at multiple sites (hand, knee, hip, and spine), whose median age was 60 years (range 43–79 years), were compared with those from 137 controls. OA was defined in accordance with the American College of Rheumatology criteria. Whole‐blood samples were stimulated with LPS (10 ng/ml). In the supernatants, cytokines were measured by enzyme‐linked immunosorbent assay. Odds ratios (ORs) were used as measures of the relative risk of OA in relation to quartiles of IL‐1β, IL‐1Ra, TNFα, and IL‐10 production. The ORs were adjusted for sex and age, and 95% confidence intervals (95% CIs) were computed using robust standard errors to take into account the intrafamily effect.

Results

Subjects in the highest quartile of IL‐1β and IL‐1Ra had an increased risk of OA (OR 3.3, 95% CI 1.4–7.9 and OR 8.0, 95% CI 3.7–17.4, respectively), while subjects in the lowest quartile of IL‐10 had a 3‐fold increased risk of OA (OR 3.1, 95% CI 1.5–6.5). High innate ex vivo production of TNFα was not associated with an increased risk of OA.

Conclusion

Subjects with a high innate ex vivo production of IL‐1β and IL‐1Ra and low innate ex vivo production of IL‐10 have an increased risk of OA. These results suggest that a proportion of the genetic susceptibility to OA may be encoded for by variations in innate cytokine activity.

     

Risk factors for symptomatic knee osteoarthritis fifteen to twenty‐two years after meniscectomy

Objective

To evaluate the influence of age, sex, body mass index (BMI), extent of meniscal resection, cartilage status, and knee load on the development of radiographically evident osteoarthritis (OA) of the knee and knee symptoms after meniscal resection.

Methods

We evaluated 317 patients with no cruciate ligament injury (mean ± SD age 54 ± 11 years) who had undergone meniscal resection 15–22 years earlier (followup rate 70%), with radiographic and clinical examination. The Knee injury and Osteoarthritis Outcome Score was used to quantify knee‐related symptoms. Sixty‐eight unoperated subjects identified from national population records were included as a reference group.

Results

Symptomatic radiographic OA (corresponding to Kellgren/Lawrence grade ≥2) was present in 83 of 305 operated knees (27%) and 7 of 68 control knees (10%) (relative risk 2.6, 95% confidence interval [95% CI] 1.3–6.1). Patients who had undergone total meniscectomy and subjects with obesity (BMI ≥30) had a greater likelihood of tibiofemoral radiographic OA than those who had undergone partial meniscal resection and those with a BMI <25, respectively. Furthermore, degenerative meniscal tear, intraoperative cartilage changes, and lateral meniscectomy were associated with radiographic OA more frequently than were longitudinal tear, absence of cartilage changes, and medial meniscectomy, respectively. Symptomatic tibiofemoral or patellofemoral radiographic OA was associated with obesity, female sex, and degenerative meniscal tear.

Conclusion

Contributing risk factors for OA development after meniscal resection are similar to risk factors for common knee OA. Systemic factors and local biomechanical factors interact. Obesity, female sex, and preexisting early‐stage OA are features associated with poor self‐reported and radiographic outcome. Partial meniscal resection is associated with less radiographic OA over time than is total meniscectomy.

     

Estrogen receptor α gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women

Objective

Genetic influences have been shown to play an important role in the etiology of osteoarthritis (OA), but the genes involved are ill‐defined. We studied the association between polymorphisms in the estrogen receptor α (ERα) gene and the prevalence of radiographic OA of the knee.

Methods

The study group comprised 1,483 men and women from the Rotterdam Study. Direct molecular haplotyping was used to determine the relationship between 2 polymorphisms in the ERα gene (the Pvu II and Xba I restriction fragment–length polymorphisms). Radiographs of the knee were evaluated according to the Kellgren/Lawrence (K/L) score, along with separate scores for osteophytosis and joint space narrowing.

Results

Three different haplotype alleles were identified: px (54%), PX (34%), and Px (12%). Allele PX was associated with an increased prevalence of radiographic knee OA (K/L score ≥2). The prevalence of radiographic OA was 22% among subjects without allele PX, 24% among those carrying 1 copy, and 35% among subjects carrying 2 copies. The corresponding odds ratios, after adjustment for confounding factors, were 1.3 (95% confidence interval [95% CI] 0.9–1.7) for heterozygotes and 2.2 (95% CI 1.5–3.4) for homozygotes. Separate analyses for men and women showed similar risk estimates. The association appeared to be driven by osteophytosis and is somewhat consistent with the association observed in previous studies of these polymorphisms in relation to OA.

Conclusion

This study shows that polymorphisms in the ERα gene are associated with radiographic OA of the knee, and in particular with osteophytosis, in both elderly men and elderly women.

     

Association of the frizzled‐related protein gene with symptomatic osteoarthritis at multiple sites

Objective

To confirm the association of 2 variants of the Frizzled‐related protein gene (FRZB) with osteoarthritis (OA) of the hip, and to investigate whether these variants also associate with other heritable generalized OA phenotypes.

Methods

An association analysis of 2 variants (R200W and R324G) of FRZB was performed in a random sample of 1,369 subjects (ages 55–70 years) from a population‐based cohort (the Rotterdam Study) scored for radiographic characteristics of OA in the hip, hand, spine, and knee and in a patient population of Caucasian probands (ages 40–70 years) and their siblings selected for the presence of primary symptomatic OA at multiple sites.

Results

The allele frequency of the 2 variants was not significantly different between subjects with hip radiographic OA (ROA) and controls. The frequency of the G allele of the R324G variant was significantly increased in subjects with generalized ROA from the Rotterdam Study (0.10) and in subjects from the Genetics, osteoARthritis and Progression study (0.11) compared with that in controls from the Rotterdam Study (0.08). Carriers of this G allele had increased susceptibility for generalized ROA (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 0.9–1.9, P = 0.10) or familial symptomatic OA at multiple sites (OR 1.6, 95% CI 1.1–2.3, P = 0.02).

Conclusion

Our results confirm that the R324G variant of the FRZB gene is involved in OA and indicate a role of this variant in several generalized OA phenotypes. A more extended OA phenotype may indeed be expected from genetic variation in an essential pathway of skeletal development such as Wnt signaling.

     

Type I collagen α1 Sp1 transcription factor binding site polymorphism is associated with reduced risk of hip osteoarthritis defined by severe joint space narrowing in elderly women

Objective

A common G/T substitution at an Sp1 binding site in intron 1 of the COL1A1 gene has been reported to be associated with reduced bone mineral density and increased risk of osteoporotic fracture. The purpose of this study was to examine whether there is an association between COL1A1 Sp1 polymorphism and radiographic osteoarthritis (OA) of the hip in elderly women in the Study of Osteoporotic Fractures.

Methods

Radiographic hip OA status of subjects was defined by the presence of 1 of the following criteria in either hip: a joint space narrowing (JSN) score of ≥3, a Croft summary grade of ≥3, or both definite (score ≥2) osteophytes and JSN in the same hip. Cases of radiographic OA of the hip were further subdivided into those with JSN score ≥3 and those with a femoral osteophyte score ≥2 and JSN score ≤2. The COL1A1 Sp1 polymorphism was genotyped using allele‐specific kinetic polymerase chain reaction in 4,746 women. Multivariate logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results

Radiographic OA of the hip was present in 571 women (12%). Of these patients, 325 (57%) had severe JSN (score ≥3), and 131 (23%) had moderate or moderate‐to‐severe femoral osteophytosis (score ≥2). There was no association of the T/T genotype with either radiographic hip OA or radiographic hip OA characterized by osteophytosis. For radiographic OA of the hip characterized by moderate‐to‐severe JSN, the odds of disease were significantly reduced among subjects with the T/T compared with the G/G genotype (OR 0.30, 95% CI 0.11–0.81, P = 0.02) and did not change after adjustment for potential confounders (OR 0.36, 95% CI 0.13–0.99, P = 0.048).

Conclusion

The T/T genotype of the COL1A1 Sp1 polymorphism was associated with a reduced risk of radiographic OA of the hip characterized by JSN. This association should be confirmed in other populations to determine if mechanistic studies are warranted.

     

Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis

Objective

Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor β signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)–like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large‐joint OA in humans.

Methods

Ten tag single‐nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA.

Results

A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta‐analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12–1.34), P < 7.5 × 10⁻⁶. For hip OA, the OR was 1.22 (95% CI 1.09–1.36), P < 4.0 × 10^–4. No evidence for heterogeneity was found (I² = 0%).

Conclusion

Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA.

     

Does knee osteoarthritis differentially modulate proprioceptive acuity in the frontal and sagittal planes of the knee?

Objective

Impaired proprioception may alter joint loading and contribute to the progression of knee osteoarthritis (OA). Although frontal plane loading at the knee contributes to OA, proprioception and its modulation with OA in this direction have not been examined. The aim of this study was to assess knee proprioceptive acuity in the frontal and sagittal planes in patients with knee OA and healthy subjects. We hypothesized that proprioceptive acuity in both planes of movement will be decreased in patients with OA.

Methods

The study group comprised 13 patients with knee OA and 14 healthy age‐matched subjects. Proprioceptive acuity was assessed in varus, valgus, flexion, and extension using threshold to detection of passive movement (TDPM) tests. Repeated‐measures analysis of variance was used to assess differences in TDPM values between the 2 groups and across movement directions. Linear regression analyses were performed to assess the correlation of the TDPM between and within planes of movement.

Results

The TDPM was significantly higher (P < 0.05) in the group with knee OA compared with the control group for all directions tested, indicating reduced proprioceptive acuity. Differences in the TDPM between groups were consistent across all movement directions, with mean differences as follows: for valgus, 0.94° (95% confidence interval [95% CI] 0.20–1.65°); for varus, 0.92° (95% CI 0.18–1.68°); for extension, 0.93° (95% CI 0.19–1.66°); for flexion, 1.11° (95% CI 0.38–1.85°). The TDPM measures across planes of movement were only weakly correlated, especially in the group with knee OA.

Conclusion

Consistent differences in the TDPM between the group of patients with knee OA and the control group across all movement directions suggest a global, not direction‐specific, reduction in sensation in patients with knee OA.

     

Bone marrow abnormalities on magnetic resonance imaging are associated with type II collagen degradation in knee osteoarthritis: A three‐month longitudinal study

Objective

Using radiography to assess the efficacy of a disease‐modifying osteoarthritis (OA) drug on joint structure is challenging. Subchondral bone marrow abnormalities determined by magnetic resonance imaging (MRI) and urinary excretion of C‐terminal crosslinking telopeptide of type II collagen (CTX‐II) have recently been shown to be predictors of radiographic progression in patients with knee OA, suggesting that these may represent valuable biomarkers with increased sensitivity compared with findings on radiography. The aims of this investigation were to analyze, in patients with knee OA, whether the values associated with these 2 OA biomarkers can change within 3 months, and to investigate the relationships between bone marrow abnormalities and CTX‐II.

Methods

Knee MRI scans were obtained in 377 patients with painful knee OA (76% women, mean age 63 years, mean disease duration 6.6 years) at both baseline and 3 months. The femoral and tibial condyles and the patella were divided into 8 sites for the scoring of bone marrow abnormalities. A bone marrow abnormality was defined as an area of increased signal on T2‐weighted images of the subchondral bone. All scans were reviewed centrally and scored by a single trained radiologist using a validated 4‐point scoring method. Fasting urine and serum samples were also collected from all patients at baseline, month 1, month 2, and month 3, in order to measure the levels of urinary CTX‐II and serum CTX‐I, a biochemical marker of bone resorption.

Results

At baseline, 82% of patients had MRI evidence of bone marrow abnormalities. Bone marrow abnormality scores correlated significantly with CTX‐II levels (P < 0.0001). Within 3 months, the bone marrow abnormality score decreased in 37 patients (9.8%), increased in 71 patients (18.8%), and did not change in the majority of patients (71.4%). Patients with baseline urinary CTX‐II levels in the highest tertile had a relative risk of 2.4 (95% confidence interval 1.1–5.0) of worsening bone marrow abnormalities at 3 months compared with patients with levels in the lowest tertile, after adjustment for age, sex, and body mass index. In patients who showed a decrease in the bone marrow abnormality score at 3 months, urinary CTX‐II levels decreased significantly (mean −75 ng/mmole creatinine), whereas levels increased (mean +23 ng/mmole creatinine) in patients showing an increase in the bone marrow abnormality score (P = 0.01 between the 2 groups). No significant association between bone marrow abnormalities and serum CTX‐I was observed.

Conclusion

In patients with painful knee OA, bone marrow abnormalities on MRI can change within only 3 months in ∼30% of patients. Reduction in the extent of bone marrow abnormalities is associated with a decrease in cartilage degradation.

     

Knee laxity after staircase exercise predicts radiographic disease progression in medial compartment knee osteoarthritis

Objective

To evaluate whether increased laxity of the knee during daily physical activities such as stair climbing is associated with progression of knee joint osteoarthritis (OA).

Methods

During the years 2001–2003, 136 patients with bilateral primary medial compartment knee joint OA were enrolled in this prospective study. Baseline data collected were body mass index (BMI), muscle power, radiographic joint space width, mechanical axis on standing radiography, and anteroposterior (AP) knee laxity before and after physical exercise. After 8 years of followup, 84 patients were reexamined to assess radiographic changes. Radiographic disease progression was defined as progression of >1 grade on the Kellgren/Lawrence scale.

Results

AP knee laxity increased significantly after stair climbing. Patients with OA progression and those without progression did not differ significantly in age, sex, baseline quadriceps muscle strength, mechanical axis, joint space width, and AP knee laxity before exercise. The 2 groups of patients did, however, differ significantly in baseline BMI and change in AP knee laxity due to exercise. The risk of progression of knee OA increased 4.15‐fold with each millimeter of increase in the change in AP knee laxity due to exercise and 1.24‐fold with each point increase in the BMI.

Conclusion

Our results indicate that patients with OA progression have significantly greater changes in knee joint laxity during physical activities and a higher BMI than patients without OA progression. These findings suggest that larger changes in knee laxity during repetitive physical activities and a higher BMI play significant roles in the progression of knee OA.

     

Impact of type of meniscal tear on radiographic and symptomatic knee osteoarthritis: A sixteen‐year followup of meniscectomy with matched controls

Objective

To investigate long‐term radiographic and patient‐relevant outcome of isolated limited meniscectomy with regard to type of meniscal tear and extent of surgical resection.

Methods

We studied 155 patients with intact cruciate ligaments (mean ± SD age 54 ± 12 years) who had undergone meniscectomy an average of 16 ± 1 years earlier. The patients were examined using standardized radiography and validated self‐administered questionnaires. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used to quantify knee‐related symptoms, and the definition of a symptomatic knee was determined. We used 68 control subjects matched for age, sex, and body mass index to calculate the relative risks (RRs).

Results

Radiographic tibiofemoral osteoarthritis (OA) (Kellgren/Lawrence grade ≥2) was present in 66 index knees (43%), of which 39 (59%) were considered to be symptomatic according to the KOOS. In total, 77 patients (50%) had a symptomatic index knee. In a multivariate model, degenerative meniscal tears were associated with both radiographic OA (P = 0.030) and combined radiographic and symptomatic OA (P ≤ 0.015). The RRs for combined radiographic and symptomatic OA after degenerative and traumatic types of meniscal tear were 7.0 (95% confidence interval [95% CI] 2.1–23.5) and 2.7 (95% CI 0.9–7.7), respectively, compared with matched controls.

Conclusion

An isolated meniscal tear treated by limited meniscectomy is associated with a high risk of radiographic and symptomatic tibiofemoral OA at 16‐year followup. Factors associated with worse outcome were degenerative meniscal lesions and extensive resections. We suggest that degenerative meniscal tears may be associated with incipient OA, and that the meniscal tear signals the first symptom of the disease.

     

Association of biomarkers with pre–radiographically defined and radiographically defined knee osteoarthritis in a population‐based study

Objective

To evaluate 10 biomarkers in magnetic resonance imaging (MRI)–determined, pre–radiographically defined osteoarthritis (pre‐ROA) and radiographically defined OA (ROA) in a population‐based cohort of subjects with symptomatic knee pain.

Methods

Two hundred one white subjects with knee pain, ages 40–79 years, were classified into OA subgroups according to MRI‐based cartilage (MRC) scores (range 0–4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0–4): no OA (MRC score 0, K/L grade <2), pre‐ROA (MRC score ≥1, K/L grade <2), or ROA (MRC score ≥1, K/L grade ≥2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C‐telopeptide of type II collagen (uCTX‐II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N‐telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C‐propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index.

Results

The risk of ROA versus no OA increased with increasing levels of uCTX‐II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35–7.21), uC2C (OR 2.13, 95% CI 1.04–4.37), and uC1,2C (OR 2.07, 95% CI 1.06–4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30–0.94). The risk of pre‐ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05–4.01) and uC1,2C (OR 2.06, 95% CI 1.12–3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTX‐II][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34–9.03) and a risk of pre‐ROA versus no OA of 2.56 (95% CI 1.03–6.40).

Conclusion

Different cartilage degradation markers are associated with pre‐ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.

     

Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: Findings from the multicenter osteoarthritis study and the osteoarthritis initiative

Objective

To study the effect of valgus malalignment on knee osteoarthritis (OA) incidence and progression.

Methods

We measured the mechanical axis from long limb radiographs from the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI) to define limbs with valgus malalignment (mechanical axis of ≥1.1° valgus) and examined the effect of valgus alignment versus neutral alignment (neither varus nor valgus) on OA structural outcomes. Posteroanterior radiographs and knee magnetic resonance (MR) images were obtained at the time of the long limb radiograph and at followup examinations. Lateral progression was defined as an increase in joint space narrowing (on a semiquantitative scale) in knees with OA, and incidence was defined as new lateral narrowing in knees without radiographic OA. We defined lateral cartilage damage and progressive meniscal damage as increases in cartilage or meniscus scores at followup on the Whole‐Organ Magnetic Resonance Imaging Score scale (for the MOST) or the Boston Leeds Osteoarthritis Knee Score scale (for the OAI). We used logistic regression with adjustment for age, sex, body mass index, and Kellgren/Lawrence grade, as well as generalized estimating equations, to evaluate the effect of valgus alignment versus neutral alignment on disease outcomes. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results

We studied 5,053 knees (881 valgus) of subjects in the MOST cohort and 5,953 knees (1,358 valgus) of subjects in the OAI cohort. In both studies, all strata of valgus malalignment, including 1.1° to 3° valgus, were associated with an increased risk of lateral disease progression. In knees without radiographic OA, valgus alignment >3° was associated with incidence (e.g., in the MOST, adjusted OR 2.5 [95% CI 1.0–5.9]). Valgus alignment >3° was also associated with cartilage damage on MR imaging in knees without OA (e.g., in the OAI, adjusted OR 5.9 [95% CI 1.1–30.3]).We found a strong relationship of valgus malalignment with progressive lateral meniscal damage.

Conclusion

Valgus malalignment increases the risk of knee OA radiographic progression and incidence as well as the risk of lateral cartilage damage. It may cause these effects, in part, by increasing the risk of meniscal damage.