Changhai Ding

Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study

CONTEXT IL-1, IL-6, and TNF-alpha play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. OBJECTIVE Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. METHODS A total of 168 randomly selected subjects (mean 63 yr, range 52-78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: -0.18 to -0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-alpha, and the urinary PYR/Cr ratio were measured on both occasions. RESULTS The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-alpha, as well as change in hs-CRP (beta: -0.41%/U, 95% confidence interval -0.68%, -0.15%) and IL-6 (beta: -0.62%/U, 95% confidence interval -1.01%, -0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-alpha (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men. CONCLUSIONS Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.

Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults

OBJECTIVE The role of inflammation in osteoarthritis (OA) pathogenesis is unclear, and the associations between inflammatory cytokines and cartilage loss have not been reported. We determined the associations between serum levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), knee radiographic OA (ROA) and cartilage loss over 2.9 years in older adults. METHODS A total of 172 randomly selected subjects (mean 63 years, range 52-78, 47% female) were studied at baseline and approximately 3 (range 2.6-3.3) years later. IL-6 and TNF-α were assessed by radioimmunoassay. T1-weighted fat-suppressed magnetic resonance imaging of the right knee was performed at baseline and follow-up to determine knee cartilage volume. Knee ROA of both knees was assessed at baseline. RESULTS At baseline, quartiles of IL-6 and TNF-α were associated with increased prevalence of medial tibiofemoral joint space narrowing (OARSI grade ≥ 1) in multivariate analyses [odds ratio (OR): 1.42 and 1.47 per quartile, respectively, both P<0.05]. Longitudinally, baseline IL-6 predicted loss of both medial and lateral tibial cartilage volume (β: -1.19% and -1.35% per annum per quartile, P<0.05 and P<0.01, respectively), independently of TNF-α. Change in IL-6 was associated with increased loss of medial and lateral tibial cartilage volume (β: -1.18% and -1.06% per annum per quartile, both P<0.05) and change in TNF-α was also negatively associated with change in medial cartilage volume (β: -1.27% per annum per quartile, P<0.05). CONCLUSIONS Serum levels of IL-6 and TNF-α are associated with knee cartilage loss in older people suggesting low level inflammation plays a role in the pathogenesis of knee OA.

A prospective study of the associations between 25-hydroxy-vitamin D, sarcopenia progression and physical activity in older adults.

Objective  Low 25‐hydroxyvitamin D (25OHD) levels may be associated with both sarcopenia (the age‐related decline in muscle mass and function) and low physical activity (PA). Our objective was to describe prospective associations between 25OHD, muscle parameters, and PA in community‐dwelling older adults.

Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: The Tasmanian older adult cohort study

OBJECTIVE To determine the associations between serum levels of vitamin D, sunlight exposure, and knee cartilage loss cross-sectionally and longitudinally in older adults. METHODS A total of 880 randomly selected subjects (mean age 61 years [range 51-79 years], 50% women) were studied at baseline, and 353 of these subjects were studied 2.9 years later. Serum levels of 25-hydroxyvitamin D (25[OH]D) were assessed by radioimmunoassay, and sunlight exposure was assessed by questionnaire. T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine knee cartilage volume and defects. Knee radiographic osteoarthritis (OA) and knee pain were also assessed. RESULTS The mean 25(OH)D serum level was 52.8 nmoles/liter at baseline (range 13-119 nmoles/liter). Winter sunlight exposure and serum 25(OH)D level were both positively associated with medial and lateral tibial cartilage volume, and a serum 25(OH)D level<50 nmoles/liter was associated with increased medial tibiofemoral joint space narrowing (all P<0.05). Longitudinally, baseline serum 25(OH)D level predicted change in both medial and lateral tibial cartilage volume (beta=+0.04% per annum per nmole/liter for both; P<0.05), and change in serum 25(OH)D level was positively associated with change in medial tibial cartilage volume. These associations were consistent in subjects with radiographic OA and knee pain and/or in women, but not in men or in subjects without radiographic OA or knee pain. CONCLUSION Sunlight exposure and serum 25(OH)D levels are both associated with decreased knee cartilage loss (assessed by radiograph or MRI). This is best observed using the whole range of 25(OH)D levels rather than predefined cut points and implies that achieving vitamin D sufficiency may prevent and/or retard cartilage loss in knee OA.

Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study

Objective To determine the association between inflammatory markers and change in knee pain over 5 years. Methods A total of 149 randomly selected subjects (mean 63 years, range 52–78; 46% female) was studied. Serum levels of high sensitivity C-reactive protein (hs-CRP), tumour necrosis factor alpha (TNF–α) and interleukin (IL)-6 were measured at baseline and 2.7 years later. Knee pain was recorded using the Western Ontario and McMasters osteoarthritis index questionnaire at baseline and 5 years later. Knee radiographic osteoarthritis of both knees was assessed at baseline, and knee bone marrow lesions, joint effusion and cartilage defects were determined using T1 or T2-weighted fat saturated MRI. Results After adjustment for confounding variables, baseline hs-CRP was positively associated with change in total knee pain (β=0.33 per mg/l, p=0.032), as well as change in the pain at night in bed (β=0.12 per ml/pg, p=0.010) and while sitting/lying (β=0.12 per ml/pg, p=0.002). Change in hs-CRP was also associated with change in knee pain at night and when sitting/lying (both p<0.05). Baseline TNFα and IL-6 were associated with change in pain while standing (β=0.06 per ml/pg, p=0.033; β=0.16 per ml/pg, p=0.035, respectively), and change in TNFα was positively associated with change in total knee pain (β=0.66 ml/pg, p=0.020) and change in pain while standing (β=0.26 ml/pg, p=0.002). Adjustment for radiographic osteoarthritis or MRI-detected structural abnormalities led to no or minor attenuation of these associations. Conclusion Systemic inflammation is an independent predictor of worsening knee pain over 5 years.

Knee Articular Cartilage Development in Children: A Longitudinal Study of the Effect of Sex, Growth, Body Composition, and Physical Activity

The aim of this study was to describe the effect of sex, growth, Tanner stage, and physical activity on knee articular cartilage volume development. A total of 74 randomly selected male and female children aged 9–18 y were measured on two occasions at an average interval of 1.6 y (range 1.3–1.9). Articular cartilage volume was determined at the patella, medial tibial, and lateral tibial compartments by processing images acquired in the sagittal plane using T1-weighted fat saturation magnetic resonance. Height, weight, and BMI were measured while Tanner stage and physical activity were assessed by questionnaire. Articular cartilage volume increased at all sites peaking in Tanner stage two. Males gained articular cartilage faster than females at all sites (patella +233 μL/y, 95% CI −7, +473, medial tibial +350 μL/y, 95% CI +118, +582, lateral tibial +256 μL/y, 95% CI +22, +488). In both sexes, articular cartilage volume accrual at tibial but not patella sites correlated significantly with height change but not weight change. Overweight children did not differ significantly from normal children in articular cartilage volume either cross-sectionally or longitudinally. The most consistent physical activity association was with average intensity of sport with those above the median gaining approximately twice as much as those below the median at tibial (p < 0.05) but not patella sites. In conclusion, most children gain articular cartilage during growth, but there is wide variation in the amount of articular cartilage accrual. In particular, younger children, males, and those undertaking more vigorous sports have substantially higher accrual rates. These results provide novel data on articular cartilage development in humans. The long-term significance of these results with regard to osteoarthritis of the knee in later life remains hypothetical.

Association between age and knee structural change: a cross sectional MRI based study

Objective: To describe the associations between age, knee cartilage morphology, and bone size in adults. Methods: A cross sectional convenience sample of 372 male and female subjects (mean age 45 years, range 26–61) was studied. Knee measures included a cartilage defect five site score (0–4 respectively) and prevalence (defect score of ⩾2 at any site), cartilage volume and thickness, and bone surface area and/or volume. These were determined at the patellar, medial, and lateral tibial and femoral sites using T1 weighted fat saturation MRI. Height, weight, and radiographic osteoarthritis (ROA) were measured by standard protocols. Results: In multivariate analysis, age was significantly associated with knee cartilage defect scores (β = +0.016 to +0.073/year, all p<0.01) and prevalence (OR = 1.05–1.10/year, all p<0.05) in all compartments. Additionally, age was negatively associated with knee cartilage thickness at all sites (β = −0.013 to −0.035 mm/year, all p<0.05), and with patellar (β = −11.5 μl/year, p<0.01) but not tibial cartilage volume. Lastly, age was significantly positively associated with medial and lateral tibial surface bone area (β = +3.0 to +4.7 mm2/year, all p<0.05) and patellar bone volume (β = +34.4 μl/year, p<0.05). Associations between age and tibiofemoral cartilage defect score, cartilage thickness, and bone size decreased in magnitude after adjustment for ROA, suggesting these changes are directly relevant to OA. Conclusion: The most consistent knee structural changes with increasing age are increase in cartilage defect severity and prevalence, cartilage thinning, and increase in bone size with inconsistent change in cartilage volume. Longitudinal studies are needed to determine which of these changes are primary and confirm their relevance to knee OA.

Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults

IntroductionThere are conflicting data on the natural history and clinical significance of bone marrow lesions (BMLs). The aims of this study were to describe the natural history of MRI-detected BMLs at the knee using a quantitative measure and examine the association of BMLs with pain, function and stiffness scores, and total knee replacement (TKR) surgery.MethodsA total of 395 older males and females were randomly selected from the general population (mean age 63 years, range 52 to 79) and measured at baseline and approximately 2.7 years later. BMLs were determined using T2-weighted fat saturation MRI by measuring the maximum area of the lesion. Reproducibility was excellent (intraclass correlation coefficient (ICC): 0.97). Pain, function, and stiffness were assessed by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores. X-ray was used to assess radiographic osteoarthritis (ROA) at baseline.ResultsAt baseline, 43% (n = 168/395) had a BML. Of these 25% decreased in size and 24% increased. Of the remaining sample (n = 227), 7% developed a new BML. In a multivariable model, a change in BML size was associated with a change in pain and function scores (β = 1.13 to 2.55 per 1 SD increase, all P < 0.05), only in those participants without ROA. Lastly, baseline BML severity predicted TKR surgery (odds ratio (OR) 2.10/unit, P = 0.019).ConclusionsIn a population based sample, BMLs (assessed by measuring maximal area) were not static, with similar proportions both worsening and improving. A change in BML size was associated with changes in pain in those without established ROA. This finding suggests that fluctuating knee pain may be attributable to BMLs in those participants with early stage disease. Baseline BMLs also predicted TKR surgery. These findings suggest therapeutic interventions aimed at altering the natural history of BMLs should be considered.

Circulating C reactive protein in osteoarthritis: a systematic review and meta-analysis

Background There is emerging evidence that the development and progression of osteoarthritis (OA) is associated with inflammation. C reactive protein (CRP), a systemic marker for inflammation, may be elevated in OA patients but the evidence is conflicting. Objective To systematically review the literature for the relationship between serum CRP levels measured by a high sensitivity method (high sensitive CRP (hs-CRP)) and OA, as well as the correlation between circulating CRP levels and OA phenotypes. Methods MEDLINE, EMBASE and CINAHL databases were systematically searched from January 1992 to December 2012. Studies were included when they met the inclusion criteria and data from studies were extracted. Two independent reviewers assessed study quality using a modified Newcastle-Ottawa Quality Assessment Scale. Meta-analyses were performed to pool available data from included studies. Results 32 studies met the inclusion criteria. Serum hs-CRP levels in OA were modestly but statistically significantly higher than controls (mean difference=1.19 mg/L, 95% CI 0.64 to 1.73, p<0.001) with significant heterogeneity between studies. Levels were significantly associated with pain (r=0.14, 95% CI 0.09 to 0.20, p<0.001) and decreased physical function (r=0.25, 95% CI 0.13 to 0.39, p<0.001). No significant associations were found between hs-CRP levels and radiographic OA. Conclusions Low-grade systemic inflammation may play a greater role in symptoms rather than radiographic changes in OA.

Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume

We conducted a longitudinal study (duration 2 years), including 294 individuals (mean age 45 years, 58% female), in order to examine associations between meniscal extrusion, knee structure, radiographic changes and risk factors for osteoarthritis (OA) in a largely non-osteoarthritic cohort. Meniscal extrusion, tibiofemoral cartilage defect score and cartilage volume, and tibial plateau bone area were determined using T1-weighted fat-saturated magnetic resonance imaging. At baseline the presence of medial meniscal extrusion was significantly associated with body mass index (odds ratio [OR] per kg/m2 = 1.13, 95% confidence interval [CI] = 1.02–1.25), past knee injury (positive versus negative history: OR = 3.73, 95% CI = 1.16–11.97), medial tibial bone area (OR per cm2 = 1.37, 95% CI = 1.02–1.85), and osteophytes (OR per grade = 4.89, 95% CI = 1.59–15.02). Two-year longitudinal data revealed that medial meniscal extrusion at baseline was associated with a greater rate of loss of medial tibiofemoral cartilage volume (extrusion versus no extrusion: -1.4%/year; P < 0.05) and greater risk for increased medial femoral cartilage defects (OR = 2.59, 95% CI = 1.14–5.86) and lateral tibial cartilage defects (OR = 2.64, 95% CI = 1.03–6.76). However, the latter two associations became nonsignificant after adjustment for tibial bone area and osteophytes. This study suggests that increasing body mass index and bone size, past knee injury, and osteophytes may be causally related to meniscal extrusion. Most importantly, meniscal extrusion at baseline is associated with greater loss of knee cartilage over 2 years, and this seems to be mediated mostly by subchondral bone changes, suggesting extrusion represents one pathway between bone expansion and cartilage loss.