Frizzled-related protein variants are risk factors for hip osteoarthritis

OBJECTIVE: To examine the association of the Arg200Trp and Arg324Gly variants of FRZB with the risk and phenotype of radiographic osteoarthritis (OA) of the hip and serum levels of Frizzled-related protein (FRP) in a prospective cohort of elderly Caucasian women. METHODS: Radiographic hip OA status of patients was defined by the presence of severe joint space narrowing (JSN) (feature grade>or=3), a summary grade>or=3, or definite osteophytes (grade>or=2) and JSN (grade>or=2) in the same hip. Genotypes were obtained in 569 patients with radiographic OA of the hip and in 1,317 and 4,136 controls for the Arg200Trp and Arg324Gly variants, respectively. Serum FRP levels were measured by enzyme-linked immunosorbent assay. Multivariate logistic regression was performed. RESULTS: The minor allele frequency for the Arg200Trp polymorphism was 0.12 in the control group compared with 0.14 in the group with radiographic OA of the hip (P=0.12), and the minor allele frequency for the Arg324Gly variant was 0.083 in the control group compared with 0.088 in the group with radiographic OA of the hip (P=0.63). The multilocus genotypes available in 1,886 subjects suggested that inheritance of both minor alleles was a risk factor for developing OA characterized by JSN (P<0.01). Patients with radiographic OA of the hip who were homozygous for the Arg200Trp minor allele had higher serum FRP levels than controls who were homozygous for the major allele. CONCLUSION: Our data confirm findings of another study, that a rare haplotype with both Arg200Trp and Arg324Gly FRZB variants contributes to the genetic susceptibility to hip OA among Caucasian women, and that these polymorphisms may contribute to increased serum levels of proteins as biomarkers of OA.     

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.

     

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.

     

Femorotibial subchondral bone area and regional cartilage thickness: A cross‐sectional description in healthy reference cases and various radiographic stages of osteoarthritis in 1,003 knees from the Osteoarthritis Initiative

Objective

To identify structural differences in total subchondral bone area (tAB) and cartilage thickness between healthy reference knees and knees with radiographic osteoarthritis (OA).

Methods

Baseline magnetic resonance images from 1 knee of 1,003 Osteoarthritis Initiative participants were studied: 112 healthy reference knees without radiographic OA, symptoms, or risk factors; 70 preradiographic OA knees (calculated Kellgren/Lawrence [K/L] grade 0/1); and 821 radiographic OA knees (calculated K/L grade ≥2). Means and standard (Z) scores (SD unit differences compared with normal subjects) of the tAB and regional cartilage thickness were assessed in the weight‐bearing femorotibial joint and compared between groups.

Results

In men, tAB was 8.2% larger in preradiographic OA knees and 6.6%, 8.1%, and 8.5% larger in calculated K/L grade 2, 3, and 4 radiographic OA knees, respectively, than in reference knees. In women, the differences were +6.8%, +7.3%, +9.9%, and +8.1%, respectively. The external medial tibia showed the greatest reduction in cartilage thickness (Z scores ?5.1/?5.6 in men/women) with Osteoarthritis Research Society International medial joint space narrowing (JSN) grade 3, and the external lateral tibia (Z scores ?6.0 for both sexes) showed the greatest reduction with lateral JSN grade 3. In all subregions of end‐stage radiographic OA knees, ≥25% of the average normal cartilage thickness was maintained. An overall trend toward thicker cartilage was found in preradiographic OA and calculated K/L grade 2 knees, especially in the external central medial femur.

Conclusion

tABs were larger in preradiographic OA and radiographic OA knees than in healthy reference knees, and the difference did not become larger with higher calculated K/L grades. Specific subregions with substantial cartilage thickening or thinning were identified in pre‐, early, and late radiographic OA.

     

Effect of alignment of the medial tibial plateau and X‐ray beam on apparent progression of osteoarthritis in the standing anteroposterior knee radiograph

Objective

Previous studies of knee osteoarthritis (OA) have yielded variable estimates of the rate of joint space narrowing (JSN) in the standing anteroposterior (AP) radiograph, due largely to longitudinal changes in the alignment of the medial tibial plateau (MTP) and x‐ray beam. To characterize this bias, we examined serial radiographs of subjects with knee OA in population‐based and clinical OA cohorts from 3 locations in the United States and the United Kingdom.

Methods

Radiographic features of knee OA (e.g., osteophytosis, JSN) and MTP alignment in 428 OA knees were evaluated by consensus of 2 readers. Alignment was considered satisfactory if the anterior and posterior margins of the MTP were superimposed within 1 mm. Readers were blinded to subject identity, and films were read in random order. The minimum medial joint space width was also measured manually (standard error of repeated measurements 0.20 mm) in serial knee images.

Results

Only 14% of serial radiographs exhibited alignment of the MTP in both images. In OA knees with satisfactory alignment in both images, the mean rate of JSN over 2–3 years (0.26 mm/year) was significantly larger (P = 0.004) than that in OA knees with misalignment in 1 or both radiographs and was 86% more rapid than the mean JSN in all OA knees. Moreover, the within‐group standard deviation of JSN was significantly smaller among knees with reproduced alignment of the MTP than in knees in which misalignment occurred in 1 or both images (P = 0.006).

Conclusion

Poor standardization of knee positioning in serial standing AP radiographs in previous studies of OA progression has obscured the rate and variability of articular cartilage loss in subjects with knee OA. True JSN (i.e., JSN that is not attributable to longitudinal changes in the alignment of the MTP with the x‐ray beam in serial radiographic examinations) may occur more rapidly, and with less between‐subject variability, than that previously thought to be characteristic of knee OA.

     

A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p

Objective

To describe a large kinship with inherited hip osteoarthritis (OA) and its associated susceptibility locus.

Methods

Four generations of a kinship with familial hip OA were identified and characterized by family history and by clinical, radiographic, and histopathologic examination. In the genome‐wide search for a susceptibility locus, OA cases were defined as those who had undergone total hip replacement associated with a clinical and radiographic diagnosis of hip OA. A genome‐wide scan was performed using a framework set of microsatellite markers with an average spacing of 10 cM.

Results

The hip OA of this family was indistinguishable from that of idiopathic, nonfamilial hip OA. There was no apparent evidence of spondyloepiphyseal dysplasia or other dysplasias usually associated with mutations in collagen genes. The genome‐wide scan revealed a locus on chromosome 16p between 28 cM and 47 cM from the telomere, and this locus met the criteria for suggestive linkage (multipoint allele‐sharing logarithm of odds [LOD] score 2.58, P = 1.6 × 10⁻⁴). Two additional regions with LOD scores of >1.5 were obtained.

Conclusion

We have identified and described the largest kinship with familial hip OA reported to date. Evidence for linkage in this family suggests that a gene for susceptibility to hip OA exists on chromosome 16p. This represents an independent identification of a susceptibility locus previously reported for hip OA in this geographic region.

     

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.

     

Evidence for a role of the genomic region of the gene encoding for the α1 chain of type IX collagen (COL9A1) in hip osteoarthritis: A population‐based study

Objective

Type IX collagen proteoglycan is an important protein in collagen networks and has been implicated in hip osteoarthritis (OA). We studied 2 COL9A1 markers (509‐8B2 and 509‐12B1) in relation to radiographic OA, within the framework of the Rotterdam Study, a population‐based study of 7,983 subjects ages 55 years and older.

Methods

We used 2 different designs, as follows: 1) a linkage study of 83 probands with multiple joints affected with radiographic OA and their 221 siblings, yielding 445 sibpairs who participated in the study, and 2) an association study in a series of 71 patients with radiographic hip OA and 269 controls without radiographic OA. All subjects were characterized for the 2 COL9A1 markers, 509‐8B2 and 509‐12B1. The mean test was used to assess the proportion of alleles shared in concordantly affected and unaffected sibpairs. The chi‐square test was used to compare the allele distributions in patients and controls.

Results

Affected sibpairs with radiographic hip OA shared alleles identical by descent at markers 8B2 and 12B1 significantly more often than expected (mean ± SD 0.66 ± 0.07 and 0.65 ± 0.08, respectively; P < 0.05). No excess sharing for radiographic OA was observed at other joint sites. When comparing the frequency of marker 8B2 and 12B1 alleles in subjects with radiographic OA and controls, the frequency of 8B2 alleles in subjects with radiographic OA differed significantly(P = 0.01) from that in controls.

Conclusion

Our data suggest that susceptibility for hip OA is conferred within or close to the COL9A1 gene in linkage disequilibrium with the COL9A1 509‐8B2 marker.

     

Selection of knee radiographs for trials of structure‐modifying drugs in patients with knee osteoarthritis: A prospective,longitudinal study of lyon schuss knee radiographs with the definition of adequate alignment of the medial tibial plateau

Objective

The quality of medial tibial plateau (MTP) alignment, which is assessed by measuring the distance between the anterior and posterior margins (intermargin distance [IMD]) of the tibial plateau, and the reproducibility of alignment in serial radiographs are suggested to be key elements in determining the accuracy and sensitivity to change in knee radiographs in patients with tibiofemoral osteoarthritis (OA). We evaluated the influence of both MTP alignment and radiograph superimposition on the sensitivity to change in radiographic joint space narrowing (JSN) in knee OA.

Methods

The study group comprised 106 patients with knee pain (73 with OA). Lyon schuss radiographic images of the knee were obtained twice (at baseline [month 0] and 12 months later), using a standardized radiographic procedure. Computerized measurement of the IMD for the assessment of MTP alignment was compared with the grading of MTP alignment by 2 observers using a 5‐point scale (excellent, good, fair, poor, bad). To obtain the rate of JSN, computerized measurement of the joint space width was performed at month 0 and month 12. The sensitivity of the joint space width to change over 1 year was evaluated by the standardized response mean (SRM).

Results

The mean (±SD) IMD was 1.2 ± 0.9 mm. The correlation between scoring and computer measurement of MTP alignment was highly significant. The cutoff value for satisfactory alignment (excellent or good) was an IMD of ≤1.2 mm. In OA knees, the mean (±SD) annual rate of JSN and the SRM were statistically higher in knees with an IMD of ≤1.2 mm at both month 0 and month 12 (0.34 ± 0.50 mm and 0.68, respectively) than in knees with an IMD of >1.2 mm at month 0 and/or month 12.

Conclusion

The quality of MTP alignment at both baseline and the end point highly influences the sensitivity to change in radiographic JSN in knee OA. To obtain relevant data, only radiographs showing an IMD of ≤1.2 mm at both baseline and the end point would have to be analyzed in studies of structure‐modifying OA drugs.

     

Very low prevalence of hip osteoarthritis among Chinese elderly in Beijing,China, compared with whites in the United States: The Beijing osteoarthritis study

Objective

To compare the prevalence of osteoarthritis (OA) of the hip among elderly persons in China and the US.

Methods

We recruited a population‐based sample of 1,506 persons (82% of those enumerated) ages ≥60 years living in Beijing, China. Subjects answered questions about joint symptoms and underwent radiography of the pelvis. Radiographs of the Beijing subjects were intermingled with hip radiographs of white women ages ≥65 years from the Study of Osteoporotic Fractures (SOF) and white men and women ages 60–74 years from the First National Health and Nutrition Examination Survey (NHANES‐I) and were then interpreted. Radiographic hip OA was defined as the presence of 1 of the following 3 findings in either hip: minimum joint space of ≤1.5 mm, definite osteophytes and joint space narrowing, or ≥3 radiographic features of OA. Symptomatic hip OA was defined as both radiographic OA and hip pain.

Results

The crude prevalence of radiographic hip OA in Chinese ages 60–89 years was 0.9% in women and 1.1% in men; it did not increase with age. Chinese women had a lower age‐standardized prevalence of radiographic hip OA compared with white women in the SOF (age‐standardized prevalence ratio 0.07) and the NHANES‐I (prevalence ratio 0.22). Chinese men had a lower prevalence of radiographic hip OA compared with white men of the same age in the NHANES‐I (prevalence ratio 0.19). There were no cases of symptomatic hip OA in the Chinese men and only 1 case in the Chinese women; 35 cases were expected in both sexes.

Conclusion

This is the first population‐based study of hip OA in China to use standardized radiographic methods and definitions. We found that hip OA was 80–90% less frequent than in white persons in the US. Identification of the genetic and environmental factors that underlie these differences may help elucidate the etiology and prevention of hip OA.

     

Changes in proximal femoral mineral geometry precede the onset of radiographic hip osteoarthritis: The study of osteoporotic fractures

Objective

Radiographic hip osteoarthritis (RHOA) is associated with increased hip areal bone mineral density (aBMD). This study was undertaken to examine whether femoral geometry is associated with RHOA independent of aBMD.

Methods

Participants in the Study of Osteoporotic Fractures in whom pelvic radiographs had been obtained at visits 1 and 5 (mean 8.3 years apart) and hip dual x‐ray absorptiometry (DXA) had been performed (2 years after baseline) were included. Prevalent and incident RHOA phenotypes were defined as composite (osteophytes and joint space narrowing [JSN]), atrophic (JSN without osteophytes), or osteophytic (femoral osteophytes without JSN). Analogous definitions of progression were based on minimum joint space and total osteophyte score. Hip DXA scans were assessed using the Hip Structural Analysis program to derive geometric measures, including femoral neck length, width, and centroid position. Relative risks and 95% confidence intervals for prevalent, incident, and progressive RHOA per SD increase in geometric measure were estimated in a hip‐based analysis using multinomial logistic regression with adjustment for age, body mass index, knee height, and total hip aBMD.

Results

In 5,245 women (mean age 72.6 years), a wider femoral neck with a more medial centroid position was associated with prevalent and incident osteophytic and composite RHOA phenotypes (P < 0.05). Increased neck width and centroid position were associated with osteophyte progression (both P < 0.05). No significant geometric associations with atrophic RHOA were found.

Conclusion

Differences in proximal femoral bone geometry and spatial distribution of bone mass occur early in hip OA and predict prevalent, incident, and progressive osteophytic and composite phenotypes, but not the atrophic phenotype. These bone differences may reflect responses to loading occurring early in the natural history of RHOA.

     

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.

     

Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features: Can hip shape tell us anything about the progression of osteoarthritis?

Objective

Few methods exist to measure the progression of osteoarthritis (OA) or to identify people at high risk of developing OA. Striking radiographic changes include deformation of the femoral head and osteophyte growth, which are usually measured semiquantitatively following visual assessment. In this study, an active shape model (ASM) of the proximal femur was used to determine whether morphologic changes to the bone could be quantified and used as a marker of hip OA.

Methods

One hundred ten subjects who had no signs of radiographic hip OA at baseline (Kellgren/Lawrence [K/L] scores 0–1) were selected from the Rotterdam Study cohort of subjects ages ≥55 years. To measure the progression of OA, subjects were followed up with radiographic assessment after 6 years. At the 6‐year followup, 55 subjects had established OA (K/L score 3), and in 12 of these OA subjects, the progression of the disease required a total hip replacement (THR). Age‐ and sex‐matched control subjects had a K/L score of 0 at followup. Using the ASM, subjects were assessed for shape changes in the femoral head and neck before, during, and after the development of radiographic OA. Scores of shape variance, or mode scores, were assigned for 10 modes of variation in each subject, and differences in mode scores were determined.

Results

During followup, significant changes in shape of the proximal femur occurred within the OA group from baseline to followup (P < 0.0001 for mode 1 and P = 0.002 for mode 6) but not within the control group. At baseline (all subjects having K/L scores 0–1), there were significant differences in mode 6 between the OA group and the control group (P = 0.020), and in modes 3 and 6 between the OA subjects who underwent THR and the remaining OA subjects (P = 0.012 and P = 0.019, respectively).

Conclusion

Compared with traditional scoring methods, the ASM can be used more precisely to quantify the deforming effect of OA on the proximal femur and to identify, at an earlier stage of disease, those subjects at highest risk of developing radiographic OA or needing a THR. The ASM may therefore be useful as an imaging biomarker in the assessment of patients with hip OA.

     

Change in joint space width: Hyaline articular cartilage loss or alteration in meniscus?

Objective

To explore the relative contribution of hyaline cartilage morphologic features and the meniscus to the radiographic joint space.

Methods

The Boston Osteoarthritis of the Knee Study is a natural history study of symptomatic knee osteoarthritis (OA). Baseline and 30‐month followup assessments included knee magnetic resonance imaging (MRI) and fluoroscopically positioned weight‐bearing knee radiographs. Cartilage and meniscal degeneration were scored on MRI in the medial and lateral tibiofemoral joints using a semiquantitative grading system. Meniscal position was measured to the nearest millimeter. The dependent variable was joint space narrowing (JSN) on the plain radiograph (possible range 0–3). The predictor variables were MRI cartilage score, meniscal degeneration, and meniscal position measures. We first conducted a cross‐sectional analysis using multivariate regression to determine the relative contribution of meniscal factors and cartilage morphologic features to JSN, adjusting for body mass index (BMI), age, and sex. The same approach was used for change in JSN and change in predictor variables.

Results

We evaluated 264 study participants with knee OA (mean age 66.7 years, 59% men, mean BMI 31.4 kg/m²). The results from the models demonstrated that meniscal position and meniscal degeneration each contributed to prediction of JSN, in addition to the contribution by cartilage morphologic features. For change in medial joint space, both change in meniscal position and change in articular cartilage score contributed substantially to narrowing of the joint space.

Conclusion

The meniscus (both its position and degeneration) accounts for a substantial proportion of the variance explained in JSN, and the change in meniscal position accounts for a substantial proportion of change in JSN.

     

A new marker for osteoarthritis: Cross‐sectional and longitudinal approach

Objective

To investigate the association between urinary concentrations of C‐telopeptide fragments of type II collagen (CTX‐II) and the prevalence and progression of radiographic osteoarthritis (OA) of the knee and hip.

Methods

The study population consisted of a sample of 1,235 men and women ages ≥55 years who were enrolled in the Rotterdam Study (a population‐based cohort study) and who were followed up for a mean of 6.6 years. Prevalent radiographic OA was defined as a Kellgren/Lawrence score ≥2; progression of radiographic OA was defined as a decrease in joint space width.

Results

Subjects with a CTX‐II level in the highest quartile had a 4.2‐fold increased risk of having radiographic OA of the knee (95% confidence interval [95% CI] 2.5–7.0) and of the hip (95% CI 2.2–7.8) compared with subjects with a CTX‐II level in the lowest quartile. We observed a substantially stronger association between CTX‐II levels and radiographic OA for subjects with hip pain (odds ratio [OR] 20.4, 95% CI 2.3–185.2) than for those without hip pain (OR 3.0, 95% CI 1.5–6.0). Subjects with a CTX‐II level in the highest quartile had a 6.0‐fold increased risk for progression of radiographic OA at the knee (95% CI 1.2–30.8) and an 8.4‐fold increased risk for progression of radiographic OA at the hip (95% CI 1.0–72.9). All of these associations were found to be independent of known risk factors for OA, such as age, sex, and body mass index.

Conclusion

This study shows that CTX‐II is associated with both the prevalence and the progression of radiographic OA at the knee and hip. Importantly, this association is independent of known clinical risk factors for OA and seems stronger in subjects with joint pain.

     

Effects of doxycycline on progression of osteoarthritis: Results of a randomized,placebo‐controlled,double‐blind trial

Objective

To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment.

Methods

In this placebo‐controlled trial, obese women (n = 431) ages 45–64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6‐month intervals.

Results

Seventy‐one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean ± SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 ± 0.42 mm versus 0.24 ± 0.54 mm); after 30 months, it was 33% less (0.30 ± 0.60 mm versus 0.45 ± 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a ≥20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a ≥20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase.

Conclusion

Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.

     

Gremlin 1, Frizzled‐related protein,and Dkk‐1 are key regulators of human articular cartilage homeostasis

Objective

The development of osteoarthritis (OA) may be caused by activation of hypertrophic differentiation of articular chondrocytes. Healthy articular cartilage is highly resistant to hypertrophic differentiation, in contrast to other hyaline cartilage subtypes, such as growth plate cartilage. The purpose of this study was to elucidate the molecular mechanism responsible for the difference in the propensity of human articular cartilage and growth plate cartilage to undergo hypertrophic differentiation.

Methods

Whole‐genome gene‐expression microarray analysis of healthy human growth plate and articular cartilage derived from the same adolescent donors was performed. Candidate genes, which were enriched in the articular cartilage, were validated at the messenger RNA (mRNA) and protein levels and examined for their potential to inhibit hypertrophic differentiation in two models. In addition, we studied a possible genetic association with OA.

Results

Pathway analysis demonstrated decreased Wnt signaling in articular cartilage as compared to growth plate cartilage. This was at least partly due to increased expression of the bone morphogenetic protein and Wnt antagonists Gremlin 1, Frizzled‐related protein (FRP), and Dkk‐1 at the mRNA and protein levels in articular cartilage. Supplementation of these proteins diminished terminal hypertrophic differentiation without affecting chondrogenesis in long‐bone explant cultures and chondrogenically differentiating human mesenchymal stem cells. Additionally, we found that single‐nucleotide polymorphism rs12593365, which is located in a genomic control region of GREM1, was significantly associated with a 20% reduced risk of radiographic hip OA in 2 population‐based cohorts.

Conclusion

Taken together, our study identified Gremlin 1, FRP, and Dkk‐1 as natural brakes on hypertrophic differentiation in articular cartilage. As hypertrophic differentiation of articular cartilage may contribute to the development of OA, our findings may open new avenues for therapeutic intervention.

     

The association between hip morphology parameters and nineteen‐year risk of end‐stage osteoarthritis of the hip: A nested case–control study

Objective

Subtle deformities of the hip joint are implicated in the etiology of osteoarthritis (OA) of the hip. Parameters that quantify these deformities may aid understanding of these associations. We undertook this study to examine relationships between such parameters and the 19‐year risk of total hip arthroplasty (THA) for end‐stage OA.

Methods

A new software program designed for measuring morphologic parameters around the hip was developed and validated in a reliability study. THA was the outcome measure for end‐stage OA. A nested case–control study was used with individuals from a cohort of 1,003 women who were recruited at year 1 in 1989 and followed up to year 20 (the Chingford Study). All hips with THA by year 20 and 243 randomly selected control hips were studied. Pelvis radiographs obtained at year 2 were analyzed for variations in hip morphology. Measurements were compared between the THA case group and the control group.

Results

Patients with THA had a higher prevalence of cam deformity than did their respective controls (median alpha angle 62.4° versus 45.8° [P = 0.001]; mean modified triangular index height 28.5 mm versus 26.9 mm [P = 0.001]) as well as a higher prevalence of acetabular dysplasia (mean lateral center edge angle 29.5° versus 34.3° [P = 0.001]; median extrusion index 0.25 versus 0.185 [P = 0.009]). Logistic regression analyses clustering by subject and adjusting for radiographic hip OA at year 2 showed that these morphologic parameters were still significantly associated with THA by year 20. The alpha angle and lateral center edge angle predicted the risk of THA independently when included in the same model.

Conclusion

This investigation describes measurements that predict the risk of THA for end‐stage OA by year 20, independently of the presence of radiographic hip OA at year 2. These measurements can be made on an anteroposterior pelvis radiograph, which is an inexpensive and commonly used clinical method of investigation.

     

One‐year change in radiographic joint space width in patients with unilateral joint space narrowing: Data from the osteoarthritis initiative

Objective

To examine the rate of joint space width (JSW) loss in both knees of patients with unilateral medial joint space narrowing (JSN) at baseline.

Methods

Cases were selected from a pool of 2,678 subjects enrolled in the Osteoarthritis Initiative cohort. Inclusion criteria for the present study were unilateral medial JSN, bilateral frequent knee pain, and body mass index (BMI) ≥25 kg/m². Baseline and 1‐year fixed flexion radiographs of both knees were read (blinded to time point) using an automated algorithm for minimum JSW and JSW at 4 fixed locations in the medial compartment.

Results

Sixty‐seven participants met the inclusion criteria: 43 women and 24 men, with mean ± SD age 60 ± 9 years and mean ± SD BMI 31 ± 4 kg/m². Thirty‐seven subjects (55%) had ≥1 definite tibiofemoral osteophyte. The average progression in no‐JSN knees was comparable with that in JSN knees (approximately ?0.2 mm/year). However, JSW change was more variable in no‐JSN knees, resulting in standardized response means (SRMs; the mean/SD) of approximately ?0.24 in no‐JSN knees versus approximately ?0.41 in JSN knees on average at the 4 fixed locations, and SRMs of ?0.24 and ?0.35, respectively, for minimum JSW. Young age and high BMI were associated with increased progression, especially in JSN knees.

Conclusion

JSN and no‐JSN knees progressed at a comparable rate, but a wider distribution of JSW change in no‐JSN knees resulted in a poorer sensitivity to change in these knees.

     

Trabecular morphometry by fractal signature analysis is a novel marker of osteoarthritis progression

Objective

To evaluate the effectiveness of using subchondral bone texture observed on a radiograph taken at baseline to predict progression of knee osteoarthritis (OA) over a 3‐year period.

Methods

A total of 138 participants in the Prediction of Osteoarthritis Progression study were evaluated at baseline and after 3 years. Fractal signature analysis (FSA) of the medial subchondral tibial plateau was performed on fixed flexion radiographs of 248 nonreplaced knees, using a commercially available software tool. OA progression was defined as a change in joint space narrowing (JSN) or osteophyte formation of 1 grade according to a standardized knee atlas. Statistical analysis of fractal signatures was performed using a new model based on correlating the overall shape of a fractal dimension curve with radius.

Results

Fractal signature of the medial tibial plateau at baseline was predictive of medial knee JSN progression (area under the curve [AUC] 0.75, of a receiver operating characteristic curve) but was not predictive of osteophyte formation or progression of JSN in the lateral compartment. Traditional covariates (age, sex, body mass index, knee pain), general bone mineral content, and joint space width at baseline were no more effective than random variables for predicting OA progression (AUC 0.52–0.58). The predictive model with maximum effectiveness combined fractal signature at baseline, knee alignment, traditional covariates, and bone mineral content (AUC 0.79).

Conclusion

We identified a prognostic marker of OA that is readily extracted from a plain radiograph using FSA. Although the method needs to be validated in a second cohort, our results indicate that the global shape approach to analyzing these data is a potentially efficient means of identifying individuals at risk of knee OA progression.