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Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from… Hunt, Michael A; Pollock, Courtney L; Kraus, Virginia B; Saxne, Tore; Peters, Sue; Huebner, Janet L; Sayre, Eric C; Cibere, Jolanda Mar 27, 2013

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RESEARCH ARTICLE Open AccessRelationships amongst osteoarthritis biomarkers,dynamic knee joint load, and exercise: resultsfrom a randomized controlled pilot studyMichael A Hunt1,2*, Courtney L Pollock1, Virginia Byers Kraus3, Tore Saxne4, Sue Peters1, Janet L Huebner3,Eric C Sayre2 and Jolanda Cibere2,5AbstractBackground: Little is known about the relationships of circulating levels of biomarkers of cartilage degradationwith biomechanical outcomes relevant to knee osteoarthritis (OA) or biomarker changes followingnon-pharmacological interventions. The objectives of this exploratory, pilot study were to: 1) examinerelationships between biomarkers of articular cartilage degradation and synthesis with measures of knee jointload during walking, and 2) examine changes in these biomarkers following 10 weeks of strengthening exercises.Methods: Seventeen (8 male, 9 female; 66.1 +/- 11.3 years of age) individuals with radiographically-confirmedmedial tibiofemoral OA participated. All participants underwent a baseline testing session where serum and urinesamples were collected, followed by a three-dimensional motion analysis. Motion analysis was used to calculate theexternal knee adduction moment (KAM) peak value and impulse. Following baseline testing, participants wererandomized to either 10 weeks of: 1) physiotherapist-supervised lower limb muscle strengthening exercises, or2) no exercises (control). Identical follow-up testing was conducted 11 weeks after baseline. Biomarkers included:urinary C-telopeptide of type II collagen (uCTX-II) and type II collagen cleavage neoepitope (uC2C), serum cartilageoligomeric matrix protein (sCOMP), serum hyaluronic acid (sHA) and serum C-propeptide of type II procollagen(sCPII). Linear regression analysis was used to examine relationships between measures of the KAM and biomarkerconcentrations as baseline, as well as between-group differences following the intervention.Results: KAM impulse predicted significant variation in uCTX-II levels at baseline (p = 0.04), though not whencontrolling for disease severity and walking speed (p = 0.33). KAM impulse explained significant variation in the ratiouCTX-II;sCPII even when controlling for additional variables (p = 0.04). Following the intervention, changes in sCOMPwere significantly greater in the exercise group compared to controls (p = 0.04). On average those in the controlgroup experienced a slight increase in sCOMP and uCTX-II, while those in the exercise group experienced areduction. No other significant findings were observed.Conclusions: This research provides initial evidence of a potential relationship between uCTX-II and knee joint loadmeasures in patients with medial tibiofemoral knee OA. However, this relationship became non-significant aftercontrolling for disease severity and walking speed, suggesting further research is necessary. It also appears thatsCOMP is amenable to change following a strengthening intervention, suggesting a potential beneficial role ofexercise on cartilage structure.Trial registration: Clinicaltrials.gov NCT01241812* Correspondence: michael.hunt@ubc.ca1Department of Physical Therapy, University of British Columbia, Vancouver,BC, Canada2Arthritis Research Centre of Canada, Vancouver, BC, CanadaFull list of author information is available at the end of the article© 2013 Hunt et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Hunt et al. BMC Musculoskeletal Disorders 2013, 14:115http://www.biomedcentral.com/1471-2474/14/115BackgroundOsteoarthritis (OA) is a common chronic health conditionresulting in significant personal and economic burdens. Inthe absence of a cure, the main areas of research to-datehave centred on developing treatments that can improvesymptoms of pain and physical dysfunction as well asimproving methods to diagnose the disease and to monitorprogression. Most commonly affecting the knee, much ofthe current literature in these two research areas has beenconducted in populations with knee OA.Plain radiographs remain the most commonly usedclinical method of assessing joint structure for the purposesof OA diagnosis and classification of severity. Magneticresonance imaging (MRI) has also been used to assesschanges in the morphology of the bone and cartilage tosupplement radiographical findings [1]. Though theseapproaches are reliable and well-established clinically, theiruse for the monitoring of changes in cartilage over time islimited by the fact that these changes take place over longperiods of time and simply detail soft tissue damage thathas already occurred [2]. Indeed, a recent systematic reviewshowed greater responsiveness of radiographic joint spacewidth measurements in studies using follow-up periods ofgreater than 2 years [3]. Given that significant changes insymptoms and joint structure can occur over the course of2 years, coupled with the fact that most non-surgicaland non-pharmacological interventions are conductedover months instead of years, improved methods ofassessing changes in cartilage structure and outcomesfollowing shorter-terms treatments over shorter periods oftime are needed.Joint tissue-related biomarkers in the blood and urinehave been used to further the understanding of the patho-genesis of knee OA. Many biomarkers are produced duringthe synthesis or degradation of articular cartilage and arefound in different concentrations based on the presenceand severity of knee OA [4,5]. For example, the biomarkersC-propeptide of type II procollagen (CPII), hyaluronic acid(HA), and cartilage oligomeric matrix protein (COMP) inserum, as well as C-telopeptide of type II collagen (CTX-II)and type II collagen cleavage neopeptide (C2C) in the urinehave all been shown to be elevated based on the presenceand severity of knee OA [6]. Importantly, given that theirconcentrations reflect processes directly implicated in thesynthesis or degradation of articular cartilage, analysis ofbiomarker concentrations may represent an effectivemethod of assessing cartilage structure over shorter periodsof time than conventional methods such as radiography orMRI. However, much is still unknown about these bio-markers, including factors involved in their production andresponses to non-pharmacological interventions.Excessive joint loading is a recognized risk factor forbreakdown of articular cartilage based on early in vitrostudies [7]. These findings have been supported by later gaitanalysis studies showing a significantly higher rate of kneeOA progression over six years in people with high baselinepeak external knee adduction moment (KAM) values [8] –a valid and reliable measure of medial compartment kneejoint load during walking [9-11] – as well as a relationshipbetween knee cartilage volume loss over twelve monthsand the baseline KAM impulse [12] – the time integral ofthe KAM during stance [13]. A link between joint load andbiomarker concentrations has also been reported. Piscoyaet al. [14] have shown increases in COMP production inresponse to dynamic mechanical load in cartilage explants,and acute bouts of moderately intense physical activity havebeen shown to temporarily increase the concentration ofsCOMP in healthy individuals [15] as well as those withknee OA [16,17]. However, the relationships between othercartilage biomarkers and measures of everyday joint load-ing, such as the KAM, are less well known. Further, theeffects of common non-pharmacological interventions onbiomarker concentrations are also not known.Given the paucity of research on the relationships ofOA biomarkers with joint loading and changes followingexercise, the purpose of the present exploratory, pilotstudy was to address these two knowledge gaps in asample of individuals with knee OA. Specifically, theprimary objective of this study was to determine therelationships between different biomarker concentra-tions and knee joint load, as measured by the KAM.The secondary objective was to examine changes inbiomarker concentrations following a 10-week musclestrengthening intervention.MethodsParticipantsCommunity-based volunteers over the age of 50 yearswere recruited through advertisements in local newspa-pers. All had OA in at least one knee according to theAmerican College of Rheumatology classification criteria[18] and reported average knee pain >3/10 on most daysof the previous month. All participants had varus align-ment and OA predominantly in the medial tibiofemoralcompartment. Exclusion criteria included: history ofknee replacement surgery or high tibial osteotomy; anyknee surgery or corticosteroid injections within the pre-vious 6 months; currently participating in, or intentionto begin structured lower limb strengthening exerciseswithin the next 3 months; inability to complete exercisesat home or attend 5 visits with the study physiotherapist;and, BMI > 35 to reduce soft tissue artifact of markermovement during quantitative gait analysis. For thispilot study, our aim was to recruit between 15 and 20individuals. This study was approved by the ClinicalResearch Ethics Board of the University of BritishColumbia and all participants provided written informedconsent prior to enrollment.Hunt et al. BMC Musculoskeletal Disorders 2013, 14:115 Page 2 of 8http://www.biomedcentral.com/1471-2474/14/115ProcedureA pilot 10-week, randomized, assessor-blinded, controlledtrial was conducted (Figure 1). Interested participantsunderwent an initial phone screening based on the above-mentioned inclusion and exclusion criteria. Next, standingposteroanterior radiographs were obtained and assessed forradiographic severity using the Kellgren and Lawrence (KL)classification system [19], and measured for lower limbalignment using published regression equations for short-film radiographs [20]. Those meeting all inclusion criteriawere invited to attend a baseline testing session in ourlaboratory. In cases of bilateral symptoms and radiographicExcluded (n=31)Too far to travel/ unable to attend (n=8)Other pain/ pathology (n=7)BMI >35 (n=5)Knee pain <3/10 (n=5)Recent exercise treatment (n=4)Previous HTO (n=1)Receiving injections (n=1)Assessed for eligibility by phone (n=56)Assessed for eligibility by x-ray (n=25)Enrollment:PatientsExcluded (n=8)No longer interested (n=4)Did not meet OA inclusion criteria (n=2)Scheduled for surgery (n=1)Presence of hip OA not identified from phone screen (n=1)Assessed for eligibility by physical screening (n=17)Excluded (n=0)Allocation:PatientsRandomized (n = 17)Allocated to control group (n=8)Allocated to strengthening intervention (n=9)Allocation:PhysiotherapistsPhysiotherapist (n=1)Treatment phase5 x Individual treatment sessions plus home exercises 4 x per week Continued with usual activities–noexercise treatmentLost to week 11 assessment (n=0)Week 11Assessment:Lost to week 11 assessment (n=1)- hospitalized due to fall (n=1)Analysis:PatientsAnalyzed (n=9) Analyzed (n=7)Figure 1 Study participant flowchart.Hunt et al. BMC Musculoskeletal Disorders 2013, 14:115 Page 3 of 8http://www.biomedcentral.com/1471-2474/14/115degeneration, the knee reported to be the most painful wasdetermined to be the study limb. Upon completion of datacollection, participants were randomly allocated toeither the exercise or no exercise (control) group.Randomization was conducted by an investigator notinvolved with outcome assessment using sealed andconsecutively numbered opaque envelopes containingthe group allocation information according to acomputer-generated random number.InterventionsThose randomized to the exercise group received a setof 6 exercises designed to strengthen the hip abductors(standing and side lying hip abduction), quadriceps(standing lunges, mini-squats, seated knee extension),and hamstrings (flexion to 90 degrees while maintainingstanding balance on the contralateral limb – with handsupport if required) muscle groups. When applicable,additional resistance was provided using ankle cuff weightsto achieve sufficient exercise intensity for participants tocomplete 3 sets of 10 repetitions for each exercise (definedas the largest weight that the participant could successfullyand safely use to complete the 3 sets). Exercises wereperformed a minimum of 4 days per week at homefor 10 weeks, and exercise performance and safe progres-sion of resistance was monitored across five visits with thestudy physiotherapist (MAH) at weeks 1, 2, 3, 5, and 8 ofthe intervention. Adherence was quantified as the numberof home exercise days completed (maximum of 40 days) aswell as the number of physiotherapy visits (maximum of 5visits), converted to a percentage.Those in the control group did not receive anyadditional intervention for the 10-week duration ofthe study and were instructed to maintain theirusual clinical management for knee OA.Outcome measuresOutcome assessment was conducted at baseline and atfollow-up (11 weeks) by an assessor blinded to group allo-cation. Each assessment session included the collection ofblood and urine, three dimensional gait analysis, andstrength assessment. All outcome measurements werecompleted within a 2-hour period at the same facility.1) Biomarker assessmentsSerum and urine samples were collected following a30 minute rest period in which the participantremained seated. All samples were processed andimmediately stored at –20°C, then transferred withinone week to a –80°C freezer until analysis. Analyseswere conducted at two sites by investigators withprevious biomarkers analysis experience [4]. Serumconcentrations of CPII (IBEX, Montreal, Canada)were analyzed using an enzyme-linkedimmunosorbent assay (ELISA) designed to detectthe carboxy-propeptide that is released from type IIcollagen following new procollagen synthesis. SerumHA (Corgenix, Broomfield, USA) was analyzed by asandwich ELISA utilizing HA binding protein as thecapture molecule. Serum COMP was analyzed usinga sandwich ELISA that uses antibodies directedagainst known antigenic determinants of humanCOMP (AnaMar, Lund, Sweden). CTX-II (IDS,Bolton, UK) in the urine was quantified using anELISA based on a sequence found exclusively inhuman type II collagen. Urinary C2C was measuredusing an ELISA (IBEX, Montreal, Canada) thatmeasures the carboxy-terminus of the primary typeII collagen cleavage generated by collagenases.Urinary CTX-II and C2C were corrected forcreatinine excretion levels quantified by ELISA(Quidel, San Diego, USA). Intra-assay coefficients ofvariation were as follows: sCPII, 4.7%; sHA, 5.4%;sCOMP 2.8%; uCTXII, 2.8%; uC2C, 3.5%. Allsamples yielded measurable concentrations for all 5biomarkers. All analyses were conducted induplicate and blinded to treatment status.2) Knee joint loading during walkingParticipants underwent three-dimensional gaitanalysis while walking barefoot and at a self-selectedspeed. Reflective markers were positioned over lowerlimb anatomical landmarks during walking as well asover the medial femoral epicondyles and medialmalleoli during an initial static standing trial used todetermine joint centre locations. Kinematic datawere collected using 8 high-speed digital videocameras (Motion Analysis Corp., Santa Rosa, CA)sampling at 120 Hz. Kinetic data were sampled at1200 Hz using 2 floor-mounted force platforms(Advanced Mechanical Technology Inc., Watertown,MA) positioned in the middle of the walkway andsynchronized with the cameras. Net joint momentswere calculated using commercially availablesoftware (Orthotrak, Motion Analysis Corp., SantaRosa, CA). The peak KAM (maximum value duringstance) was identified, and the KAM impulse(positive area under the KAM-time curve) wascalculated, for each trial and averaged across a totalof 5 trials with clean force platform strikes by thestudy limb.3) Other measuresIsometric muscle strength was assessed usingdynamometry. Isometric knee extension and flexionstrength was measured using an isokineticdynamometer (Biodex, Shirley, NY) while theparticipant was seated and the knee placed in 40degrees of flexion. Isometric hip abduction strengthwas measured using a handheld dynamometerHunt et al. BMC Musculoskeletal Disorders 2013, 14:115 Page 4 of 8http://www.biomedcentral.com/1471-2474/14/115(Hoggan Health, West Jordan, UT) placed over thelateral femoral epicondyle. For each muscle group,participants performed three repetitions of maximalvoluntary isometric contractions for five secondseach. The maximum force production across thethree trials was averaged and converted to a torqueby multiplying by the lever arm, then normalized tobody mass (Nm/kg). Participants randomized to theexercise groups completed a weekly diary to recordadherence to the home exercise program.Statistical analysisBiomarker data were log-transformed and used asdependent variables in linear regression models with jointload (either peak KAM or KAM impulse) used as the inde-pendent variable to predict variance in each biomarker,while controlling for age and sex [21], with additionalmodels also controlling for KL grade and walking speed.Group membership (exercise or no exercise) was added inregression models to predict change in log biomarker levelswhile adjusting for age and sex, using intention-to-treatprinciples. Finally, changes in KAM peak and impulse aswell as muscle strength were analyzed using repeatedmeasures analysis of variance for descriptive purposes as anindication of the biomechanical and functional effects ofthe intervention.ResultsSeventeen participants (8 males, 9 females; mean (SD)age = 66.1 (11.3) years, BMI = 27.0 (4.5) kg/m2) were en-rolled in the study. Ten participants had mild OA (KL 2),five had moderate OA (KL 3), and two had severe OA (KL4). Baseline demographic and clinical data were similarbetween the two groups. Sixteen participants (five malesand four females from the exercise group and three malesand five females from the control group) returned for thefollow-up assessment a mean (SD) of 76.3 (5.3) days afterthe baseline assessment. Blinding of group allocation to theassessor was maintained for all participants. The time ofsample collection was consistent between baseline andfollow-up for each participant with the mean (SD) diffe-rence being 20 (21) minutes (maximum= 65 minutes).Most (13/17) participants provided samples and underwentbiomechanical testing in the morning prior to 11:00 am.Attendance at the supervised physiotherapy sessions washigh in the exercise group with participants attending amean (SD) of 91% (14%) of the sessions. Home exerciseadherence rates were also high with a mean (SD) of 83%(17%) of the exercise days completed.Across all participants at baseline, and while adjusting forage and sex, KAM impulse predicted significant variationin uCTX-II levels (β = 1.19, 95% CI = 0.16, 2.21; p = 0.05) aswell as the uCTX-II:sCPII ratio (β = 1.50, 95% CI = 0.72,2.28; p < 0.01). However, when KL grade and walking speedwere added to the regression models, the relationship withuCTX-II became non-significant (β = 0.58, 95% CI = -0.53,1.68, p = 0.33), while the significant relationship withuCTX-II:sCPII remained (β = 1.11, 95% CI = 0.15, 2.07;p = 0.04). In contrast, peak KAM was not able to explainany significant amount of variation in any biomarker orratio when accounting for age and sex or when adding KLgrade and walking speed to the models (p > 0.34). Noother significant findings were found for either measure ofKAM in any biomarker regression model.When comparing changes between groups followingthe intervention (Table 1), significantly greater reductionsin sCOMP (β = 0.16, 95% CI = 0.02, 0.30; p = 0.04) as wellas slightly greater, non-significant reductions in uCTX-II(β = 0.33, 95% CI = 0.04, 0.71; p = 0.11) were observed inthe exercise group compared to those in the control group.No other significant between-group differences existed inany single biomarker outcome or biomarker ratio. Finally,no significant between-group differences were observed inany gait or strength outcome (p > 0.11).DiscussionThis pilot study provides new information regarding thecharacteristics of articular cartilage biomarkers relevantto the study and treatment of knee OA. Specifically, thisstudy provides the first data detailing the relationshipbetween multiple OA biomarkers and a measure ofdynamic knee joint load – a potential mechanism of OAbiomarker production – as well as changes in biomarkerconcentrations following exercise. Both study objectivestaken together, these data provide some support to furtherexplore the utility of uCTX-II and sCOMP as biomarkersrelevant to knee OA.Previous animal studies have shown a direct relationshipbetween load magnitude and articular cartilage degradation[22]. The data from the present study provide some evi-dence that higher musculoskeletal loading can be associatedwith increased circulating levels of uCTX-II, though acausative relationship cannot be claimed based on thecurrent data. Furthermore, recent evidence suggests thatuCTX-II levels may arise from bone as well as cartilage[23]; however, higher loading applied to the bone wouldpresumably increase uCTX-II levels under the same mech-anism as uCTX-II derived from cartilage. Though theKAM is a well-accepted and valid measure of medialcompartment joint load [10] with significant relationshipswith many clinical outcomes specific to knee OA in themedial compartment [8,24-29], it does not represent thetotal load within the knee joint [30] nor does it account forany potential changes in joint contact force that may resultfrom increased muscle activity [31]. Further, though asignificant relationship was observed between KAMimpulse and uCTX-II at baseline, this relationship becamenon-significant when adjusting for disease severity andHunt et al. BMC Musculoskeletal Disorders 2013, 14:115 Page 5 of 8http://www.biomedcentral.com/1471-2474/14/115walking speed, and no relationship was found when exam-ining the peak KAM value. Although dynamic knee jointload may play a role in the production of biomarkers – inparticular, uCTX-II – it is not the only factor involved inthis process and evaluation of a single component of overalljoint load (KAM) does not necessarily represent the forcesexperienced by the cartilage in their entirety. It is clear thatmore research needs to be done to understand better therelationship between knee joint biomechanics and OAbiomarkers.The second objective of this study was to examinechanges in biomarker concentrations following an exerciseintervention. Results provide some evidence of a beneficialrole of exercise on joint integrity at the cartilage level. Spe-cifically, those in the exercise group demonstrated reducedmean sCOMP levels following the intervention comparedto those in the control group. Previous studies have shownreductions in sCOMP following a single muscle strength-ening session [32], though increases in sCOMP levelsimmediately following moderate exercise have also beenreported [17]. Given that no significant between-groupdifferences in muscle strength or KAM were observed, it isunlikely that the reductions in sCOMP were due to reduc-tions in joint load. Indeed, baseline results from this studydid not provide evidence of a relationship betweendynamic joint load during walking and sCOMP levels. Thisis in contrast to uCTX-II and may suggest that productionof uCTX-II and sCOMP occurs due to different mecha-nisms. This hypothesis cannot be tested using the currentstudy design or data and requires further research.Though the current results provide new information,this study does have some limitations. First, the smallsample size in this pilot study may have reduced statisticalpower and the ability to make more definitive conclusions.Nevertheless, despite the small sample size, we did findsome statistically significant results. Also, the biomarkerconcentrations measured in this study represent systemiclevels that could theoretically have arisen from any num-ber of joints in the body. However, the normal turnover oftype II collagen in the body is relatively low, suggestingthat significant changes in systemic levels may be expectedto be due to pathological turnover from a single joint [33].Table 1 Mean (SD) values for KAM and strength outcomes as well as for log-transformed, unadjusted biomarker levelsand ratios of degradation to synthesis (sCPII) at baseline and follow-up for each groupBaseline data (n = 17) Follow-up data (n = 16) Between-group changesExercise No exercise Exercise No exercise Difference p-valueGait outcomesPeak KAM (%BW*ht) 3.75 (0.91) 3.38 (0.78) 3.70 (0.91) 3.21 (0.95) 0.04 (-0.64, 0.72) 0.91KAM impulse (%BW*ht*sec) 1.13 (0.40) 1.32 (0.41) 1.01 (0.35) 1.24 (0.55) –0.05 (–0.23, 0.32) 0.72Walking speed (m/s) 1.18 (0.23) 1.03 (0.17) 1.28 (0.18) 1.04 (0.16) 0.08 (–0.02, 0.18) 0.11Strength outcomesKnee extension torque (Nm/kg) 1.25 (0.34) 0.98 (0.25) 1.35 (0.39) 0.97 (0.23) 0.10 (–0.25, 0.06) 0.19Knee flexion torque (Nm/kg) 1.06 (0.33) 0.82 (0.29) 1.12 (0.35) 0.70 (0.48) 0.18 (–0.41, 0.06) 0.12Hip abduction torque (Nm/kg) 0.78 (0.19) 0.59 (0.26) 0.87 (0.28) 0.69 (0.13) –0.02 (–0.14, 0.18) 0.77Urinary markersuCTX-II (log ng/mmol creatinine) 5.40 (0.81) 5.97 (0.57) 5.32 (0.93) 6.25 (0.68) –0.33 (–0.71, 0.04) 0.11uC2C (log μg/mmol creatinine) 2.45 (0.68) 2.46 (0.76) 2.57 (0.81) 2.71 (0.58) –0.10 (–0.35, 0.16) 0.73Serum markerssHA (log U/L) 3.47 (0.93) 3.80 (0.96) 3.26 (1.13) 4.21 (0.86) –0.79 (–1.67, 0.08) 0.10sCOMP (log U/L) 2.20 (0.21) 2.26 (0.17) 2.11 (0.24) 2.36 (0.13) –0.16 (–0.30,–0.02) 0.04sCPII (log U/L) 6.56 (0.19) 6.44 (0.53) 6.50 (0.36) 6.71 (0.40) –0.34 (–0.94, 0.24) 0.27RatiosuCTX-II:sCPII –1.16 (0.74) –0.46 (0.49) –1.18 (0.97) –0.46 (0.81) 0.01 (–0.63, 0.66) 0.97uC2C:sCPII –4.11 (0.69) –3.98 (1.19) –3.93 (0.98) –4.01 (0.73) 0.22 (–0.59, 1.03) 0.61sHA:sCPII –3.09 (0.99) –2.64 (0.87) –3.24 (1.37) –2.50 (0.77) –0.45 (–1.43, 0.53) 0.39Group comparisons (exercise – no exercise) denote the difference in mean change (95% CIs). Between-group mean differences for gait and strength data areunadjusted, while biomarker data for each log-transformed biomarker and ratio using linear regression modeling while adjusting for age and sex. Note thatnegative log-transformed values indicate that the absolute ratio was less than 1.0, with greater negative values indicating a smaller ratio of the degradationbiomarker to the synthesis biomarker sCPII. Thus, improvements in the ratio of degradation to synthesis would be reflected in smaller negative valuesat follow-up.Hunt et al. BMC Musculoskeletal Disorders 2013, 14:115 Page 6 of 8http://www.biomedcentral.com/1471-2474/14/115Finally, we chose a BMI cut-off of 35 kg/m2 to decreaseskin movement artifact during walking, as is commonlyused in motion analysis studies measuring the KAM[34-36] to maximize gait data accuracy. However, giventhat many people with knee OA are overweight or obese,the results of this study cannot necessarily be generalizedto the entire knee OA population, and our findings mustbe viewed in light of this limitation.ConclusionsThis study provides initial evidence of a potential relation-ship between loading in the knee joint during walking andcirculating levels of biomarkers associated with articularcartilage degradation, specifically uCTX-II. A beneficialeffect of strengthening exercises on cartilage health asevidenced by reduced levels of circulating sCOMP was alsoconcluded from the results, though the mechanism of thisfinding is unknown. Further research with more subjectsand a longer intervention period would provide verificationof these findings and enhance our understanding of theutility of biomarkers in the diagnosis of knee OA as well astheir potential as outcome measures following treatment.Competing interestsTS is a cofounder and minor shareholder in AnaMar. JC has receivedresearch grants from Centocor Research & Development Inc and fromAmgen Inc. No other authors have declared a conflict of interest with thiswork.Authors’ contributionsMAH conceived the study and was assisted in study design by JC. CLP wasthe blinded assessor for all outcome measurements. TS, VBK, and JLH wereinvolved in the analysis of samples for biomarker concentrations. SP was theunblinded research coordinator involved in recruitment and groupallocation. ECS performed the statistical analysis. MAH drafted the manuscriptwhile all other authors provided critical revision of the article for importantintellectual content and gave final approval of the manuscript.AcknowledgementsThis study was funded by a grant from the Canadian Arthritis Network. Thestudy sponsor had no involvement in study design, in the collection, analysisand interpretation of data, in the writing of the manuscript, or in thedecision to submit the manuscript for publication.Author details1Department of Physical Therapy, University of British Columbia, Vancouver,BC, Canada. 2Arthritis Research Centre of Canada, Vancouver, BC, Canada.3Duke School of Medicine, Durham, NC, USA. 4Department of ClinicalSciences, Section of Rheumatology, Lund University, Lund, Sweden.5Department of Medicine, University of British Columbia, Vancouver, BC,Canada.Received: 23 May 2012 Accepted: 14 March 2013Published: 27 March 2013References1. Hunter DJ: Advanced imaging in osteoarthritis. Bull Hosp Jt Dis 2008,66:251–260.2. 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Heiden T, Lloyd D, Ackland T: Knee joint kinematics, kinetic and muscleco-contraction in knee osteoarthritis patient gait. Clin Biomech 2009,24:833–841.32. Helmark IC URM, Borglum J, Rothe A, Petersen MCH, Andersen O, LangbergH, Kjaer M: Exercise increases interleukin-10 levels both intraarticularluand peri-synovially in patients with knee osteoarthritis: a randomizedcontrolled trial. Arthritis Res Ther 2010, 12:R126.33. Mobasheri A, Henrotin Y: Biomarkers of osteoarthritis: a review of recentresearch progress on soluble biochemical markers, published patentsand areas for future development. Recent Patents on Biomarkers 2011,1:25–43.34. Henriksen M, Simonsen E, Alkjaer T, Lund H, Graven-Nielsen T, Danneskiold-Samsoe B, Bliddal H: Increased knee joint loads during walking - Aconsequence of pain relief in knee osteoarthritis. Knee 2006, 13:445–450.35. Bennell KL, Hunt MA, Wrigley TV, Hunter DJ, McManus FJ, Hodges PW, Li L,Hinman RS: Hip strengthening reduces symptoms but not knee load inpeople with medial knee osteoarthritis and varus malalignment: arandomised controlled trial. Osteoarthr Cartil 2010, 18:621–628.36. Mundermann A, Dyrby C, Andriacchi T: Secondary gait changes in patientswith medial compartment knee osteoarthritis: increased load at theankle, knee, and hip during walking. Arthritis Rheum 2005, 52:2835–2844.doi:10.1186/1471-2474-14-115Cite this article as: Hunt et al.: Relationships amongst osteoarthritisbiomarkers, dynamic knee joint load, and exercise: results from arandomized controlled pilot study. BMC Musculoskeletal Disorders 201314:115.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitHunt et al. BMC Musculoskeletal Disorders 2013, 14:115 Page 8 of 8http://www.biomedcentral.com/1471-2474/14/115

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