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A customized protocol to assess bone quality in the metacarpal head, metacarpal shaft and distal radius:… Feehan, Lynne; Buie, Helen; Li, Linda; McKay, Heather Dec 24, 2013

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RESEARCH ARTICLE Open AccessA customized protocol to assess bone quality inthe metacarpal head, metacarpal shaft and distalradius: a high resolution peripheral quantitativecomputed tomography precision studyLynne Feehan1,4,5*, Helen Buie2, Linda Li1,4 and Heather McKay3,5AbstractBackground: High Resolution-Peripheral Quantitative Computed Tomography (HR-pQCT) is an emergingtechnology for evaluation of bone quality in Rheumatoid Arthritis (RA). However, there are limitations with standardHR-pQCT imaging protocols for examination of regions of bone commonly affected in RA. We developed acustomized protocol for evaluation of volumetric bone mineral density (vBMD) and microstructure at the metacarpalhead (MH), metacarpal shaft (MS) and ultra-ultra-distal (UUD) radius; three sites commonly affected in RA. The purposewas to evaluate short-term measurement precision for bone density and microstructure at these sites.Methods: 12 non-RA participants, individuals likely to have no pre-existing bone damage, consented to participate[8 females, aged 23 to 71 y [median (IQR): 44 (28) y]. The custom protocol includes more comfortable/stable positioningand adapted cortical segmentation and direct transformation analysis methods. Dominant arm MH, MS and UUD radiusscans were completed on day one; repeated twice (with repositioning) three to seven days later. Short-term precisionfor repeated measures was explored using intraclass correlational coefficient (ICC), mean coefficient of variation (CV%),root mean square coefficient of variation (RMSCV%) and least significant change (LSC%95).Results: Bone density and microstructure precision was excellent: ICCs varied from 0.88 (MH2 trabecular number) to .99(MS3 polar moment of inertia); CV% varied from< 1 (MS2 vBMD) to 6 (MS3 marrow space diameter); RMSCV% variedfrom< 1 (MH2 full bone vBMD) to 7 (MS3 marrow space diameter); and LSC% 95varied from 2 (MS2 full bone vBMD to21 (MS3 marrow space diameter). Cortical porosity measures were the exception; RMSCV% varying from 19 (MS3) to 42(UUD). No scans were stopped for discomfort. 5% (5/104) were repeated due to motion during imaging. 8% (8/104) offinal images had motion artifact graded > 3 on 5 point scale.Conclusion: In our facility, this custom protocol extends the potential for in vivo HR-pQCT imaging to assess, with highprecision, regional differences in bone quality at three sites commonly affected in RA. Our methods are easy to adoptand we recommend other users of HR-pQCT consider this protocol for further evaluations of its precision and feasibilityin their imaging facilities.Keywords: HR-pQCT, Bone microstructure, Volumetric bone mineral density, Precision, Metacarpal head, Metacarpalshaft, Ultra-ultra-distal radius, Early rheumatoid arthritis* Correspondence: lynne.feehan@gmail.com1Department of Physical Therapy, Faculty of Medicine, University of BritishColumbia (UBC), Vancouver, BC, Canada4Arthritis Research Centre of Canada, Richmond, BC, CanadaFull list of author information is available at the end of the article© 2013 Feehan 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.Feehan et al. BMC Musculoskeletal Disorders 2013, 14:367http://www.biomedcentral.com/1471-2474/14/367BackgroundDespite marked improvements in the clinical managementof systemic inflammatory joint-disease in early rheumatoidarthritis (RA), people with RA remain at risk for developingunderlying systemic inflammatory mediated bone-changes[1-4]. Changes can include progressive periarticular bonethinning (osteopenia) and development of resorptive bone le-sions (erosions) [5,6]. Periarticular bone damage, most com-monly seen in the bone near the metacarpal phalangeal andwrist joints, can contribute to the development of hand de-formities and profound functional limitations in people livingwith RA [6,7]. Additionally, systemic extra-articular inflam-matory bone changes contribute to a two-fold increase infracture risk with aging in people living with RA [8-11].Currently, radiography and several clinical imagingsystems, such as magnetic resonance imaging (MRI),computed tomography (CT), ultrasonography (US), dual-energy X-ray absorptiometry (DXA) and digital X-rayradiogrammetry (DXR) are used clinically to monitorbone changes in RA [12-17]. While these tools are usefulfor capturing later macro-structural joint and bone damagethat occurs in RA, their abilities to identify the earlier bonemicrostructural bone changes are poor. Thus, there is anurgent need for new imaging technologies and methodsto be developed that can reliably identify and characterizethese early changes before permanent macro structuralbone damage occurs. This is especially important given thatearly microstructural changes are potentially modifiableif they are reliably identified and treated early.High Resolution Peripheral Quantitative CT (HR-pQCT;SCANCO Medical AG, Brüttisellen, Switzerland) is apromising imaging technology capable of imaging finebone internal ‘micro’ detail at a resolution similar tothe thickness of a human hair (75 to 100 microns) [18].Thus, HR-pQCT imaging is a promising tool for evaluatingthe changes in bone quality that accompany RA. However,research that uses this tool in RA is limited and just emer-ging [19-32]. Further, it is not possible to compare andsynthesize findings from studies in RA that used HR pQCTas image location, acquisition and evaluation proceduresare not standardized and vary widely [33].There are a number of possibilities for these inconsisten-cies with the primary reason related to applying standardprotocols developed specifically for one region of interest(ROI) to another ROI without consideration of the tech-nical limitations for doing this. Secondly, although a posi-tioning device is available to support standard positioningof the arm, this device is not designed to position andstabilize the hand during imaging near the metacarpalphalangeal or wrist joint regions. Thirdly, standardsemi-automated image evaluation protocols cannot reliablyseparate (segment) cortical and trabecular bone compart-ments in the periarticular metacarpal head and very distalradius bone regions that have very thin cortical shells.This is notable as these regions are commonly affected ininflammatory arthritis [34]. Finally, standard image evalu-ation protocols were not designed to evaluate regions thatare comprised primarily of compact lamellar cortical bonesuch as found in the extra-articular metacarpal mid-shaftregion which is also commonly affected in inflammatoryarthritis [3,35,36].Recently, HR pQCT semi-automated image analysiscapabilities were advanced to allow more accurate seg-mentation of the cortical bone compartment [37,38].This relatively new approach was developed to evaluateregions of bone with a thin cortical shell and thereforeovercomes some of the limitations associated with thestandard imaging protocols. In addition, direct transform-ation image analyses methods developed for microCTanalyses ex vivo were recently adapted to evaluate corticalbone density, morphometry and porosity in vivo, using HR-pQCT [38-41]. Importantly, these advances permit evalu-ation of several micro-structural and macro-structural boneparameters within the integral, trabecular and cortical bonecompartments that could not previously be assessedusing standard HR-pQCT evaluation protocol, in vivo.There is a need, however, to assess the precision of adaptedsemi-automated cortical compartment segmentation andadapted direct transformation image analyses methods forHR-pQCT assessment in vivo, generally and at bone sitescommonly affected by RA (e.g. periarticular distal radiusand metacarpal head regions and extra-articular metacarpalmid-shaft region).Therefore, the purpose of this study was to determinethe short term precision of an HR-pQCT imaging protocol,in vivo customized for the hand and distal radius. Thenovel features of this protocol include: 1) comfortable posi-tioning and better stabilization of the head, trunk and upperarm, 2) standardized positioning of the hand and forearmusing a custom-made positioning device, and 3) adaptedsemi-automated cortical segmentation and direct trans-formation image analyses methods that permit assessmentof integral, cortical and trabecular bone macro- and micro-structural morphometry and bone mineral density atthe Metacarpal Head (MH), Metacarpal Shaft (MS) andthe Ultra-Ultra-Distal (UUD) radius bone regions. Weuse the term Ultra-Ultra-Distal (UUD) radius to differentiatethe more distal periarticular distal radius location examinedin our study, from the standard ultra-distal radius scan loca-tion [42]. Our secondary objectives were to explore partici-pant tolerance to the novel positioning protocol as well asrates for re-scanning due to motion during imaging andexcessive image motion artifact (e.g. graded > 3 on themanufacturer 5 point rating scale) in the final images [43].MethodsThis precision study was conducted in a medical imagingresearch centre setting and received academic institutionalFeehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 2 of 12http://www.biomedcentral.com/1471-2474/14/367ethical approval from the University of British Columbia,Vancouver Canada. Community-dwelling adults wererecruited from a large urban metropolitan setting. Par-ticipants received no financial remuneration for partici-pation and provided informed consent to participate.With the exception of a physician diagnosis of inflam-matory arthritis, participants were not screened for anyother self-reported health (e.g. diabetes, osteoporosis)or lifestyle (e.g. smoking, alcohol consumption, physicalinactivity) condition that may have affected their bonehealth. We specifically excluded individuals with a diagnosisof inflammatory arthritis as we were not be able to de-termine a priori if they may already have underlyingmacro-structural bone damage in the regions of bonewe were examining. Participants were also excluded ifthey: 1) had any physical condition that would preventthem from sitting motionless with their arm in thescanner supported by a positioning device for up to 6minutes, 2) had metal or surgical implants in the hand orforearm of interest, 3) were pregnant or possibly pregnant,4) had sustained a fracture in their dominant arm hand orforearm in the previous 12 months, and 5) were unable toread or understand the consent form.Prior to scanning we assessed height (cm) using awall mounted stadiometer (SECA corp. Chino, CA)and weight (kg) using a medical grade digital floorscale (Tanita Corporation of America, Inc. ArlingtonHeights, Ill) using standard techniques. We derivedbody mass index (BMI) as wt/ht2 (kg/m2) [44]. Follow-ing these anthropometric measures, the hand and fore-arm were positioned in a custom-made positioningdevice made of rigid thermoplastic splinting material.The forearm was aligned parallel to the long axis of thesplint and the metacarpal phalangeal joints positionedin 0 degrees of flexion. The splint-supported hand andforearm were then positioned within a holder that wasmodified from manufacturer specifications to suit thehand (Scanco Medical AG, Switzerland). The hand andforearm were then stabilized with additional strapping(Figure 1A). Participants were positioned to face theimaging system. Pillows were placed behind partici-pants’ hips and in front of them so that the participantcould lean forward and rest on the pillows with theiropposite arm, upper body and head comfortably sup-ported. The holder, with the arm correctly positionedwithin it, was then placed inside the HR pQCT unit forscan acquisition (Figure 1B).A single trained operator (author LF) performed allscans using standard in vivo imaging parameters (82 μmnominal isotropic resolution, 60 kVp effective energy,900 μA current, and 100 ms integration time). The traininginvolved a rigorous and standardized training protocol de-veloped by the facility for the safe operation of the scanner.Manufacturer specifications for the scanner define that forevery 110 slices acquired the measurement time is 2.8minutes with an effective dose of 3 μSv at distal extremitysites. This estimate of effective dose is based on a weightedcomputed tomography dose index (CTDIw) of 6.1 mGyand a local dose of 3.2 mGy using standard HR-pQCTin vivo image acquisition parameters [45]. A trained oper-ator also performed daily density calibrations and weeklygeometry calibrations of the HR-pQCT imaging systemusing the manufacturer’s calibration phantom.Three scans of the dominant arm were completed inseries during a single scanning session. The ROIs includedthe metacarpal head (MH), metacarpal mid-shaft (MS) andultra-ultra-distal (UUD) radius sites. To assess short-termprecision with repositioning, we acquired two additionalseries of three scans with repositioning between each series.The additional two series were completed during a singlescanning session, three to seven days after the initial scans.Prior to each scan, we performed a 150 mm length scoutview of the hand and distal forearm which is the maximumavailable length for a scout view. The reference line for theradius scan was located at the medial edge of the distal ra-dius; the scan region was 1 mm proximal to this referenceline and extended 9.02 mm (110 slices) proximally. For themetacarpal head scan, the reference line was the tip of themost distal second or third metacarpal head; the scanstarted 2 mm distal to this reference line and extended18.04 mm (220 slices) proximally. For the metacarpal shaftscan, the reference line was half (50%) the total length ofthe metacarpal shaft assessed on the scout view. The meta-carpal shaft scan region of interest extended from 4.5 mmdistal to the reference line to 9.02 mm (110 slices) proximalto the reference line (Figure 2 A, B, C).The operator visually assessed all images for motionartifact at the completion of the three-scan series. If mo-tion artifact was apparent in only one image the operatorrepeated the scan. If there was motion artifact in two ormore of the scans across the series, the operator repeatedthe scan at one site only. Our image order of priority wasthe distal radius followed by the metacarpal head.Images were then independently analysed by 1 of 2trained and experienced operators, one of whom wasthe same person as the image acquisition operator in thisstudy (first author LF), the other a study research assist-ance. Before conducting any image analysis in this study,each operator was required to obtain an intra-rater reliabil-ity coefficient (Pearson R) of ≥ 0.90 for measures of UUDtrabecular bone fraction from at least 10 images assessedtwice by the same operator within 7 to 10 days [46].Prior to analysis, each image was graded visually formotion artifact using the 5-point manufacture gradingsystem [47]. We included images graded 3 or less by bothoperators for final data analysis [43]; any disagreement wasresolved by consensus. Image analyses were conductedbased on operator availability; operators did not use imageFeehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 3 of 12http://www.biomedcentral.com/1471-2474/14/367registration to evaluate repeated scans. Operators wereblinded to previous image analyses data; we allowed atleast 10 days between image analyses of a repeated scan inany individual by the same operator. Both operatorsassessed the same numbers of scan images.Using the manufacturer evaluation software (V 6.0), theoperator analyzed five sub-regions of interest [1 - UUDradius (110 slices); 2 - MH2 & MH3 (110 slices); 2 - MS2and MS3 (110 slices)] (Figure 2, A,B,C). They performedsemi-automated contouring of the periosteal bone surfaceand segmented bone from surrounding soft tissue usingstandard manufacturer evaluation script protocols [48].The operator extracted cortical and trabecular regionsusing the semi-automated segmentation method [37,38],but applied a modified boundary condition for analysis ofthe metacarpal head.Following initial segmentation, the operator mademinor adjustments to endosteal and periosteal contoursas needed [39]. This step included a visual inspection ofthe computer generated lines for delineation of the cor-tical region segmentation in all slices, making minormanual corrections to any deviations from accurate peri-osteal or endosteal surface delineation (Figure 2, D,E,F).Manual correction at this step was rarely indicated; usuallyonly required for the correction of the endosteal edgedelineation in a limited number of slices in any image.The most common reason for the need for any manualcorrection was in instances when there were very lar-ger intra-cortical pores or large bi-cortical breaks cre-ated by vascular channels. These manual adjustmentprocedures have been described in further detail byBurghardt et al., [38].The operator then ran a series of evaluation scripts usingthe manufacturer evaluation software for assessmentof the full, cortical and trabecular bone regions usingdirect transformation image analyses scripts adapted fromstandard microCT evaluation scripts recently developed forcortical bone and described in more detail by NishiyamaKK et al. [40], and Liu XS et al., [41]. These adopted directtransformation evaluation scripts for HR-pQCT arenow included in current upgrades of manufacturerevaluation software.For the periarticular UUD Radius, MH2 and MH3regions we examined apparent volumetric bone min-eral density (vBMD) for the full (vBMDfull - mgHA/cm3),cortical (vBMDCort - mgHA/cm3) and trabecular(vBMDTrab - mgHA/cm3) bone regions. We also ex-amined selected microstructural morphometric boneparameters, including: Cortical bone: thickness (CtTh - mm) and porosity(CtPo - %).Figure 1 Custom image acquisition positioning. A) Shows the standardized positioning of the hand and forearm (left or right) in a custom-madeinsert (top) with additional stabilization and placement in a modified manufacturer ex-vivo holder (bottom). B) Shows the modified positioning forimaging with an individual seated on a chair facing scanner with their head, upper body and opposite arm resting on pillows with the hand to bescanned in the holder and positioned inside the scanner for scanning.Feehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 4 of 12http://www.biomedcentral.com/1471-2474/14/367 Trabecular bone: volume fraction (BV/TVtrab - %),number (TbN – 1/mm), thickness (TbTh - mm) andseparation (TbSp - mm).At the extra-articular MS2 and MS3 mid-shaft siteswe examined full and cortical bone apparent volu-metric BMD (vBMDfull & vBMDcort - mgHA/cm3), aswell as, cortical bone material bone mineral density(vTMDcort - mgHA/cm3). In addition we examined thefollowing selected micro- and macro-structural mor-phometric parameters: Full bone: volume (BVfull - mm3), volume fraction(BV/TV full - %), section modulus – major direction(SMfull - mm3), polar moment of inertia(pMOIfull - mm4), and marrow space diameter(MSdia - mm). Cortical bone: thickness (CtTh - mm), porosity(CtPo - %), volume (BVcort - mm3), volume fraction(BV/TVcort - %), section modulus – major direction(SMcort - mm3), polar moment of inertia(pMOIcort - mm4).Direct transformation evaluation methods applied toimages acquired using HR-pQCT, in vivo tend to over-estimate some trabecular bone outcomes (TbTh, TbSpand BV/TVtrab) [49,50]. Therefore, the standard manu-facturer HR-pQCT evaluation script applies a correctionfactor to these parameters to adjust for known differences.We also applied this correction factor to variables acquiredat the UUD Radius, MH2 and MH3 sites so as to directlycompare our data with values acquired using standardimage evaluation methods at other bone regions [41].Trabecular bone volume fraction (BV/TVtrab_s) was de-rived using a standard approach [trabecular bone appar-ent volumetric bone mineral density (vBMDtrab) dividedby 1200 mg/cm3)]. Trabecular thickness (TbThs) andtrabecular separation (TbSps) were derived using a standardFigure 2 Scan locations and cortical segmentation. Top Row (A,B,C) shows the reference line, scan location and Region of Interest (ROI)analyses overlaid on a 150 mm scout view for the Ultra-Ultra-Distal Radius (A), Metacarpal Head (B) and Metacarpal Shaft (C) scans. Bottom Row(D,E,F) shows examples of semi-automated cortical compartment segmentation in one HR-pQCT slice for the UUD radius (D), Metacarpal Head(E) and Metacarpal shaft (F) ROIs.Feehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 5 of 12http://www.biomedcentral.com/1471-2474/14/367approach; BV/TVs and 1 – BV/TVs divided by TbN, re-spectively. Standard evaluation of HR-pQCT images usesdirect transformation methods to determine trabecularnumber (TbN) and full bone and trabecular bone apparentvolumetric bone mineral density (vBMDfull and vBMDtrab).Therefore we did not apply conversion factors to thesevariables.We assessed short-term precision of repeated measureswith repositioning using intraclass correlational coefficient(ICC), mean coefficient of variation (CV%), root meansquare coefficient of variation (RMSCV%) and leastsignificant change (LSC%95) [51]. Participant toleranceto the imaging protocol and rates of excessive imagemotion artifact were assessed by percentage of scan re-acquisition due to discomfort or motion during imagingand percentage of final images graded as higher than 3 on a5 point scale respectively [47,52,53].Results12 individuals (8 females) participated. Participants wereaged 23 to 71 years [Median (IQR): 44 (28) y]. Participants’BMI varied from 19 to 30 kg/m2 [Median (IQR): 24(4.5) kg/m2] (Table 1). Of the 108 potential scans, 104were completed (96%). The four scans not completedincluded 2 MH and MS scans not done in one participantduring the second session as the participant was not feelingwell and did not want to re-schedule. Of the 104 completedscans, none needed to be stopped due to discomfort duringthe scanning session. Whereas, 5 of the 104 completedscans (5%; 3 MH, 1 UUD, 1 MS) were repeated at the timeof acquisition due to motion artifact detected by the oper-ator at the time of imaging. Of 104 final images acquired,we excluded 8 (8%; 3 UUD, 3 MH, 2 MS) from the finalimage analyses due to motion artifact graded higher than3. Notably, of the 8 images excluded from the final ana-lyses, 4 images (1 UUD, 2 MH, 1 MS) were from the sameparticipant (71 y.o. male) who had a resting hand tremorthat was not detected at the time of screening [43,53,54].This left 96 images available for final analyses.For the final repeated measures analyses we were ableto analyze imaging data at the UUD region for 11 of the12 participants as data from one participant was excludeddue to motion artifact in 2 of the 3 UUD images. For themetacarpal head and shaft regions, we analyzed data from10 of the 12 participants. One participant’s MH and MSrepeated measures data was missing because these scanswere not completed during the follow up session. Aswell, one other participant’s MH and another partici-pant’s MS data were excluded due to motion artifact in2 of 3 images.Precision for measures of volumetric BMD andmacro- and microstructural bone morphometry wasvery high at all five sub-ROIs [51,55]. ICCs varied from0.88 (MH2 - TbN) to .99 (MS3 - pMOIcort). CV% variedfrom < 1 (MS2 - vBMDcort) to 6 (MS3 – Msdia). RMSCV%varied from < 1 (MH2- vBMDfull) to 7 (MS3- MSdia)and LSC%95 varied from 2 (MS2 - vTMDcort) to 21(MS2 - MSdia). The exceptions were the poor measureswe report for cortical porosity at all three measurementsites [RMSCV% varying from 19 (MS3) to 42 (UUD)](Tables 2,3,4).Across all regions, vBMD measurement precision wasbetter than precision for measures of microstructuralmorphology; RMSCV% for VBMD varied from < 1 to 4compared with microstructural morphology which variedfrom < 1 to 7. At the periarticular UUD radius and the sec-ond and third MH sites, precision was better for trabecularbone microstructural morphology (RMSCV%: < 1 to 4)compared to measures of cortical thickness (RMSCV%:3 to 7). At the extra-articular second and third MS sitesthe precision for measures of full and cortical bonedensity as well as macro- and microstructural morph-ometry (RMSCV%: < 1 to 3) was better than precisionfor measures of marrow space diameter (RMSCV%: 5 to 7)(Tables 2,3,4).DiscussionThis study extends the literature that uses in HR pQCTto examine ‘‘bone quality” in vivo in a novel way usingcustomized image acquisition and analyses protocols toassess bone parameters in the distal forearm and hand.We deliberately focus upon these regions of interestgiven they are sites where trabecular and cortical bone iscommonly affected in individuals living with RA. Wedemonstrated that our custom HR-pQCT imaging proto-col, in vivo is a precise means to assess integral, corticaland trabecular bone density and macro- and microstructure(with the exception of cortical porosity) at the MH, MS andUUD radius in our imaging facility.Some distinguishing features of our custom image ac-quisition methods are; 1) more comfortable and stablepositioning of the head, trunk and arm during imaging,Table 1 Participant demographicsFemales (n = 8) Males (n = 4) All (n = 12)Age (years): median (IQR); min-max 44 (n/a); 23-62 45 (n/a); 23-71 44 (28); 23-71Height (cm): median (IQR); min-max 165 (n/a); 158-174 185 (n/a); 175-195 173 (18.5); 158-195Weight (kg): median (IQR); min-max 64 (n/a); 63-76 77 (n/a); 64-94 65 (12.5); 55-94BMI (kg/m2): median (IQR); min-max 24 (n/a); 19-30 21 (n/a); 19-24 24 (4.5); 19-30Feehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 6 of 12http://www.biomedcentral.com/1471-2474/14/367and 2) standardized positioning and stabilization of themetacarpal phalangeal and wrist joints in a custom-madepositioning device. These are important advantages as betterstabilization during imaging reduces the potential for partici-pant motion during scanning as well as the degree of mo-tion artifact in final images. Notably, the percentage of scansrepeated due to motion identified at the time of scanning(scan re-acquisition: 5% vs. 29%) as well as percentage of im-ages graded higher than 3 (Poor Image Quality: 8% vs. 20%)was markedly lower than previously reported values forthese parameters using the standard HR-pQCT distalradius protocol [47,54]. Moreover, standardized positioningallows more consistent visual land-marking to locate thescan ROI. This negates the need for the operator to usecomputer assisted image registration methods to evaluaterepeated images of the same bone regions in either shortterm follow up or longer term prospective studies [54].Using adapted semi-automated cortical segmentationmethods ensured the operator was able to reliably extractthe cortical bone compartment in all the regions of bonewe examined. This is an important finding, especiallygiven the challenges presented by very thin and highlyporous cortical shells in the periarticular distal radiusand metacarpal head regions (Figure 3). Reliable andTable 2 Summary of the results for Ultra-Ultra-Distal (UUD) radius region of interest (n = 11)Variables Mean (SD) ICC(0.000-1.000)Mean coefficientof variation (CV%)Root mean squareCV (RMSCV%)Least significantchange% (LSC%95)Density(Apparent)Full Bone (mgHA/cm3) vBMDfull D & S 362 (102) 0.986 2.3 3.2 8.8Cortical density(mgHA/cm3)vBMDcort D 944 (189) 0.962 3.5 3.7 10.4Trabecular density(mgHA/cm3)vBMDtrab D & S 272 (69) 0.993 1.3 1.6 4.5CorticalboneThickness (mm) CtTh D 0.59 (0.20) 0.959 5.9 7.3 20.2Porosity (%) CtPo D 1.3 (0.7) 0.320 34.0 41.7 115.6TrabecularboneBone volumeFraction (%)BV/TVtrab D 37 (7) 0.990 1.7 2.0 5.7BV/TVtrabs S 23 (6)Number (1/mm) TbN D & S 2.4 (0.3) 0.908 3.1 4.3 12.1Thickness (mm) TbTh D 0.22 (0.02) 0.956 0.79 4.5 12.6TbThs S 0.10 (0.01)Separation (mm) TbSp D 0.38 (0.07) 0.932 3.4 1.1 3.0TbSps S 0.34 (0.07)D = Direct Transformation Method; S (Grey fill) = Derived Standard Clinical Equivalent.Table 3 Summary of results for the Metacarpal Head (MH) 2 & 3 regions of interest (n = 10)Variables Mean (SD) ICC (0.000-1.000) Meancoefficientof variation(CV%)Root meansquare CV(RMSCV%)Leastsignificantchange%(LSC%95)MH3 MH2 MH3 MH2 MH3 MH2 MH3 MH2 MH3 MH2Density(Apparent)Full bone (mgHA/cm3) vBMDfull D & S 438 (89) 434 (82) 0.997 0.998 0.83 0.57 1.0 0.78 2.8 2.2Cortical (mgHA/cm3) vBMDcort D 743 (106) 751 (101) 0.975 0.975 1.5 1.3 2.1 1.6 6.0 4.5Trabecular (mgHA/cm3) vBMDtrab D & S 387 (79) 378 (73) 0.996 0.997 0.8 0.7 1.2 1.0 3.2 2.9Cortical bone Thickness (mm) CtTh D 0.39 (0.07) 0.39 (0.06) 0.933 0.973 4.8 1.6 6.17 2.7 17.1 7.4Porosity (%) CtPo D 1.2 (0.7) 1.2 (0.4) 0.153 0.727 23.2 17.0 33.2 22.2 92.1 61.4Trabecular bone Volume fraction (%) BV/TVtrab D 46 (5) 46 (6) 0.984 0.984 1.2 1.3 1.5 1.6 4.3 4.5BV/TVtrabs S 26 (13) 26 (13)Number (1/mm) TbN D & S 2.6 (0.24) 2.5 (0.23) 0.904 0.884 2.1 2.2 2.5 2.8 6.9 7.7Thickness (mm) TbTh D 0.23 (0.02) 0.24 (0.02) 0.978 0.978 0.74 1.1 3.9 3.5 10.8 9.8TbThs S 0.11 (0.03) 0.11 (0.03)Separation (mm) TbSp D 0.34 (0.05) 0.34 (0.06) 0.928 0.944 3.0 3.0 1.1 1.3 3.0 3.5TbSps S 0.27 (0.05) 0.29 (0.05)D = Direct Transformation Method; S (Grey fill) = Derived Standard Clinical Equivalent.Feehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 7 of 12http://www.biomedcentral.com/1471-2474/14/367Table 4 Summary of results for Metacarpal Shaft (MS) 2 & 3 regions of interest (n = 10)Variables Mean (SD) ICC (0.000-1.000) Meancoefficientof variation(CV%)Root meansquare CV(RMSCV%)Leastsignificantchange%(LSC%95)MS3 MS2 MS3 MS2 MS3 MS2 MS3 MS2 MS3 MS2Density (Apparent) Full bone (mgHA/cm3) vBMDfull 1181 (207) 1230 (180) 0.994 0.981 0.88 1.8 1.2 2.9 3.3 7.9Cortical (mgHA/cm3) vBMDcort 1482 (173) 1492 (172) 0.993 0.996 0.83 0.49 1.0 0.80 2.8 2.2Density (Material) Cortical (mgHA/cm3) vTMDcort 1568 (194) 1564 (199) 0.996 0.997 0.57 0.66 0.72 1.0 2.0 2.8Cortical bone Thickness (mm) CtTh 1.8 (0.37) 2.0 (0.34) 0.989 0.989 1.5 1.7 1.9 1.9 5.3 5.1Porosity (%) CtPo 0.29 (0.31) 0.31 (0.22) 0.790 0.949 16.7 29.0 18.8 36.0 52.2 99.7Volume (mm3) BVcort 374 (101) 412 (109) 0.998 0.998 0.97 0.93 1.3 1.1 3.6 3.1Section modulus-major (mm3) SMcort 55 (20) 61 (23) 0.998 0.997 1.2 1.4 1.4 1.7 3.9 4.9Polar moment of inertia (mm4) pMOIcort 476 (234) 535 (256) 0.999 0.998 0.87 1.9 1 2.0 2.8 5.6Full bone Volume (mm3) BVfull 475 (120) 499 (126) 0.997 0.997 0.77 0.97 1.0 1.1 2.8 3.1Volume fraction (%) BV/TVfull 76 (9) 80 (7) 0.991 0.976 0.71 1.2 0.82 1.5 2.3 4.2Marrow space diameter (mm) MSdia 2.6 (0.87) 2.6 (0.73) 0.961 0.979 5.7 3.9 7.4 4.9 20.5 13.6Section modulus – major (mm3) SMfull 52 (20) 58 (23) 0.997 0.998 1.4 1.1 1.7 1.5 4.6 4.0Polar moment of inertia (mm4) pMOIfull 444 (232) 498 (254) 0.998 0.998 1.3 1.7 1.6 1.8 4.3 5.1Figure 3 Cortical compartment 3-dimentional reconstructed images. 3-D reconstructed images of segmented cortical compartments fromthe same HR-pQCT images of the ultra-ultra-distal radius region in three participants (top row - 23 y.o. female, middle row - 50 y.o. male, bottomrow - 67 y.o. female) using the standard clinical evaluation protocol (left) compared to our semi-automated cortical segmentation protocol (right).The images on the right also show shaded areas of cortical porosity identified with the adapted direct transformation cortical evaluation script.Feehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 8 of 12http://www.biomedcentral.com/1471-2474/14/367more accurate cortical bone segmentation methodsadd to the unique ability of HR-pQCT imaging, in vivo toevaluate the independent contribution of trabecular andcortical bone compartment density and microstructuralparameters to integral bone strength [56-58].We demonstrated that adapted direct transformationimage analysis methods traditionally used in microCTimaging were also able to precisely assess many aspectsof integral, trabecular and cortical bone density, macro-and microstructure that are not currently assessedusing standard HR-pQCT evaluation methods, in vivo(cortical porosity was the exception). By including derivedstandard evaluation equivalent values for trabecular bonevolume fraction, thickness and spacing, users are also ableto compare outcomes with normative or other values re-ported at standard distal radius and tibia scan sites [59].Importantly, precision for bone density, macro- andmicrostructure at the MH, MS and UUD radius regions wereport in our imaging facility was comparable to previouslyreported values for distal radius and metacarpal head bonemicrostructure and bone mineral density measurementprecision using HR pQCT [21,53]. To our knowledge, ourstudy is the first to assess HR-pQCT’s ability to preciselyevaluate bone density, bone macro- and microstructureat the very distal periarticular UUD radius site, in vivo.Our findings align with estimates of HR-pQCT precisionerror, in vivo at the standard radius site [RMSCV%;vBMD, < 1–2; microstructure, 1–6] and a site more proximalto the standard distal radius location [RMSCV% <1 – 2;microstructure <1-7] [42,60]. As well as HR-pQCT micro-structure precision (CV%, < 1–6) at the UUD radius sitein cadaver bone ex vivo (similar to the site we assessed)[61]. This is notable as motion artifact is not an issuewhen assessing tissue, ex vivo.The metacarpal mid-shaft region provides a unique op-portunity to use HR-pQCT imaging to examine corticalbone density and morphometry in vivo in the shaft regionof long bone that macro-structurally has a relatively thick(approximately 2 mm) cortical compartment that is com-prised primarily of lamellar compact cortical bone. To ourknowledge, no other study has examined the precisionof HR pQCT for in vivo measures in the mid-shaft regionof a long bone. It is encouraging that, with the exceptionof marrow space diameter and cortical porosity, thatapparent and material volumetric bone mineral density, aswell as, several macro- and microstructure parameters inthis novel mid-shaft region can be assessed with very highprecision (RMSCV% < 2) using HR-pQCT, in vivo. De-velopment of novel approaches for evaluation of corticalbone quality is key given the important contribution ofcortical bone to overall bone strength and fracture risk,as well as, differences in the rate and mechanisms forcortical and trabecular bone turnover with aging andmany chronic diseases [57,62-65].A few others have examined measurement precisionof metacarpal head microstructure in those with RA[21,26,30,31]. Fouque-Aubert et al. [21], used standardimage methods to assess HR-pQCT density and reportedmicrostructure measurement precision in vivo at themetacarpal head in people living with RA comparedwith Non-RA controls. They found no notable differencein vBMD measurement precision between those with RAand controls (CV% < 2). These values align exactly withthe CV we report for vBMD at the metacarpal head.Fouque-Aubert et al. [21], also found no differences betweenthose with RA and controls for measurement precision ofstandard trabecular microstructural parameters (CV variedfrom 3 to 7%), with the exception of trabecular separation(CV of 13% in RA participants versus 6% in controls).Comparably, the CV for standard and other additionalmicrostructural parameters we examined at the meta-carpal head varied from 1 to 5%. As our protocol aimedto control motion artifact due to robust stabilization ofthe measured part, standardize positioning of the handand wrist joints and enhance accuracy of segmentation ofthe very thin cortical bone compartment – these factorstaken together may account for improved cortical and tra-becular bone microstructure measurement precision at themetacarpal head in this study compared to the standardimaging protocols reported previously [21].Cortical porosity is difficult to assess reliably and thisheld true for all regions of bone examined in our study.Relatively low precision for cortical porosity measured atthe standard radius (RMSCV; 13%) [38], and a moreproximal distal radius site (RMSCV; 6 +/− 8%) have beenreported previously [42]. Precision for cortical porosity atthe MH, MS and UUD radius sites we examined were evenpoorer (RMSCV, 19 - 42%). There are a number of factorsthat might explain this. First, is the current 82 μm imagevoxel resolution of HR-pQCT, in vivo. Thus, it is difficult toresolve pore diameters smaller than this within the intra-cortical bone region, particularly in regions of bone withvery thin cortical shells [66,67]. Second, on the endostealsurface of the cortical-trabecular bone interface, corticalpores are difficult to distinguish from marrow space [39].One clear solution is enhanced image resolution in vivo.Indeed, as better image resolution continues to evolveand newer methods of cortical porosity evaluation aredeveloped more precise methods to assess porosity inregions of thin or more compact cortical bone locationswill become available [68,69].We acknowledge that our study has limitations. Thisstudy was conducted in a small cohort of health adultsin a single imaging facility, using imaging operators withextensive experience with in vivo image acquisition andanalyses using HR-pQCT. As such, the precision of thiscustom protocol in our facility cannot be generalized toother imaging facilities that utilize HR-pQCT imagingFeehan et al. BMC Musculoskeletal Disorders 2013, 14:367 Page 9 of 12http://www.biomedcentral.com/1471-2474/14/367that are not familiar with, or trained in, the image acqui-sition and analyses protocols used in this study. Furtherstudies, ideally from multiple centres, are required tofurther define the precision and feasibility for this proto-col. We also could not explore inter-rater reliability asnone of the images in this study were evaluated by bothimage analyses operators. However, and notably, the effectof any measurement error associated with individual varia-tions in image analyses was likely negligible given the highmeasurement precision demonstrated in this study. As well,we excluded people living with inflammatory arthritis inthis precision study as we wanted to explore the utilityof our custom HR-pQCT protocol for identifying andcharacterizing early microstructural bone changes inbone prior to permanent macro-structural damage oc-curring. This was an a priori decision as we were unableto determine if a person diagnosed with inflammatoryarthritis may or may not already have underlying bonechanges in the regions of bone commonly affected byRA. As such, our findings for measurement precision in themetacarpal head and UUD radius periarticular regions can-not be generalized to individuals living with more advancedRA where macro-structural changes from resorptive bonelesions (erosions) may already be present or where position-ing may be affected by the presence of hand deformities.We also did not apply newly available cortical bone porosityimage analyses procedures so we do not know if they wouldenhance the precision of cortical porosity measures at theMH, MS or UUD radius [68,69].In summary, we demonstrated excellent precision formeasures of bone density and many macro- and micro-structural parameters at the MH, MS and UUD radiususing a customized HR-pQCT protocol in our facility. Thenovel image acquisition protocol was well tolerated by allthe participants and provided excellent stabilization ofthe forearm and hand during imaging resulting in alow percentage of final images with excessive motionartifact. The novel image acquisition protocol reflects anumber of other practical advantages over the standarddistal radius image acquisition protocol and can be easilyadopted by HR-pQCT users. Additionally, the adaptedsemi-automatic cortical segmentation and direct transform-ation image evaluation methods used in this study are alsoavailable to other HR-pQCT users through the most recentmanufacturer image evaluation software upgrades.ConclusionIn our facility, this custom protocol extends the potentialfor using in vivo HR pQCT imaging technology to as-sess, with high precision, integral, trabecular and cor-tical bone density and microstructure at sites in thedistal forearm and hand most commonly affected inrheumatoid arthritis. As such, we recommend that thiscustomized protocol be considered by other HR-pQCTusers for further evaluations of its precision and feasi-bility in their imaging facility.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsLF conceived the study and design, managed and participated in the imageacquisition and analyses, contributed to the data analysis and interpretationand drafted all versions of the manuscript. HB was involved in thedevelopment and implementation of the adapted image analyses protocols.LL and HM contributed to the study design, interpretation of the data andediting of manuscript drafts. All authors read and approved the finalmanuscript.AcknowledgmentsWe thank Eric Sayre, PhD. Arthritis Research Centre of Canada, Richmond, BC,Canada for his assistance with the statistical analyses.Author details1Department of Physical Therapy, Faculty of Medicine, University of BritishColumbia (UBC), Vancouver, BC, Canada. 2The Bone Imaging Laboratory,University of Calgary, Calgary, AB, Canada. 3Departments of Orthopedics andFamily Medicine, Faculty of Medicine, UBC, Vancouver, BC, Canada. 4ArthritisResearch Centre of Canada, Richmond, BC, Canada. 5Centre for Hip Healthand Mobility, Faculty of Medicine, UBC, Vancouver, BC, Canada.Received: 21 August 2013 Accepted: 18 December 2013Published: 24 December 2013References1. Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor E,Wakefield RJ, O’Connor PJ, Emery P: An explanation for the apparentdissociation between clinical remission and continued structuraldeterioration in rheumatoid arthritis. Arthritis Rheum 2008, 58:2958–2967.2. 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