Clinical Use of Quantitative Computed Tomography (QCT) of the Hip in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions—Part I

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. 18, no. 3, 338e358, 2015 Ó Copyright 2015 by The International Society for Clinical Densitometry 1094-6950/18:338e358/$36.00 http://dx.doi.org/10.1016/j.jocd.2015.06.012

2015 ISCD Position Development Conference

Clinical Use of Quantitative Computed Tomography (QCT) of the Hip in the Management of Osteoporosis in Adults: the 2015 ISCD Official PositionsdPart I Klaus Engelke,*,1,2 Thomas Lang,3 Sundeep Khosla,4 Ling Qin,5 Philippe Zysset,6 William D. Leslie,7,8 John A. Shepherd,3 and John T. Schousboe9,10 1

Institute of Medical Physics, University of Erlangen, Germany; 2Bioclinica, Hamburg, Germany; 3Department of Radiology and Biomedical Imaging, UCSF School of Medicine, San Francisco, CA, USA; 4Center for Clinical and Translational Science, Mayo Clinic College of Medicine, Rochester, MN, USA; 5Bone Quality and Health Center, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, China; 6Institute for Surgical Technology & Biomechanics, University of Bern, Switzerland; 7Department of Medicine, University of Manitoba, Winnipeg, Canada; 8Department of Radiology, University of Manitoba, Winnipeg, Canada; 9Park Nicollet Clinic/ HealthPartners, Minneapolis, MN, USA; and 10Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA

Abstract The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of quantitative computed tomography of the hip. The ISCD task force for quantitative computed tomography reviewed the evidence for clinical applications and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here, we discuss the agreed on ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Parts II and III address the advanced techniques of finite element analysis applied to computed tomography scans and the clinical feasibility of existing techniques for opportunistic screening of osteoporosis using computed tomography scans obtained for other diagnosis such as colonography was addressed. Key Words: Bone mineral density (BMD); Osteoporosis; Position; Proximal femur; Quantitative computed tomography (QCT). in adults and the clinical use of QCT in children (2). The current report targets the adult population. It is split into 3 parts: the clinical use of QCT of the hip (part I), the clinical value of bone strength calculated by QCT-based finite element analysis (FEA) (part II), and the clinical value of advanced methods such as voxel- or tensor-based morphometry or statistical parameter mapping (SPM) (part III). Part III also addresses how to obtain reliable BMD information from computed tomography (CT) scans acquired to address diagnostic questions other than osteoporosis (i.e., CT scans typically performed without an in-scan calibration phantom used in standard QCT applications). QCT of the hip has become an established method. Evidence is supported by many publications addressing technical

Introduction The report of the quantitative computed tomography (QCT) task force addresses the evolving clinical use of QCT and providing evidence on new and updated official International Society for Clinical Densitometry (ISCD) position statements. Earlier reports (1) described the use of bone mineral density (BMD) and of geometric parameters for fracture prediction, diagnosis of osteoporosis, initialization of treatment, and monitoring of age- and treatment-related changes Received 06/25/15; Accepted 06/25/15. *Address correspondence to: Klaus Engelke, PhD, Institute of Medical Physics, University of Erlangen, Henkestr. 91, D 91052 Erlangen, Germany. E-mail: [email protected]

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ISCD 2015 Official Positions - QCT of the Hip issues fracture prediction and longitudinal monitoring (3,4). The overview on CT technology and QCT imaging given in the earlier position article (1) is still up to date. The aim of the QCT task force report is to present a comprehensive review of the available literature, and based on this evidence, propose ISCD official positions for the clinical use of QCT of the hip (part I), of QCT-based FEA (part II) and SPM and for the use of CT scans obtained without an in-scan calibration phantom for BMD assessment (part III). Although a number studies for the forearm in particular using high-resolution peripheral QCT have been published, the inclusion of the forearm was beyond the scope of this position development conference (PDC).

Update on Standard QCT Measurements of the Spine and Hip Since the last position development conference on QCT in adults in 2007, the use of QCT has significantly increased. A large number of QCT studies for the hip and lumbar spine have been published strengthening the evidentiary basis for the clinical utility of QCT. First, the commercially available and Food and Drug Administrationeapproved software QCTPro (Mindways Inc., Austin, TX, USA) is quite widely used by clinical sites for QCT of the spine and CTXA (computed tomography X-ray absorptiometry) of the hip. About 2000e2500 implementations exist worldwide (5,6). CTXA is a technique to simulate dual-energy X-ray absorptiometry (DXA) using projectional data from 3D CT images to estimate areal bone mineral density (aBMD). Second, almost all clinical trials evaluating pharmaceutical treatment for the prevention of new osteoporotic fractures now include QCT in a subset of patients. Experimental software offers advanced analysis options beyond QCTPro such as the Medical Image Analysis Framework (University of Erlangen) (7e12) and software developed by UCSF (13,14), and the Universities of Sheffield (15) and Cambridge (16). These have been used for central analysis although QCTPro including the Bone Investigational Toolkit has also been applied (17e21). In addition, in some studies integral BMD measurements of the lumbar vertebrae and total hip obtained from the FEA software (VirtuOst) developed by ON Diagnostics (Berkeley, CA) have been reported (22). Third, in addition to trabecular BMD of the lumbar vertebrae spine historically measured by QCT, the cortex of the hip has become a focus of major interest and has triggered the increasing application of QCT of the hip in clinical trials (7e13,15,20,21,23,24). A number of in vivo QCT studies of the hip have also reported on prediction (25e28) or discrimination (29e35) of osteoporotic fractures of the hip as well as on age (36e41) and treatment (22e24,42e44) related changes. Some also used QCT of the hip to assess secondary osteoporosis (45). Several of these studies were dedicated specifically to the femoral neck (25,28,36,37,39). In vivo studies using 3D QCT of the hip are summarized in Tables 1e3. The results column lists the most relevant data

339 with respect to the ISCD positions but is usually not fully representative of the results given in the cited publication. The accumulating evidence in the use of QCT of the hip is reflected in new ISCD positions for QCT of the hip. The 2007 ISCD positions for QCT of the spine are further supported by a large number of published studies. Several pharmaceutical and clinical studies employing QCT of the spine have shown that QCT of the spine can be used to monitor BMD changes related to age (52), and disease and treatment (7e9,12,18,20e22,43,53). In addition, a recent prospective study of the AGES-Reykjavik cohort has shown that average trabecular BMD measured in the elliptical volume of interest of 2 vertebral bodies in the segment T12 to L4 (usually L1 and L2) could predict incident vertebral fractures in men and women older than 60 yr.

Projectional DXA-Equivalent Measures of the Hip 3D QCT data sets of the hip can be used to simulate a projectional DXA-like image. In this image, aBMD, bone mineral content (BMC), and area are measured and DXA equivalent hip T-scores can be calculated. Food and Drug Administration approved implementations of this technique for QCTPro from Mindways (CTXA mode) (Fig. 1) (6) and for VirtuOst from ON-Diagnostics (54). A projectional option is also available in the UCSF QCT hip software developed by Lang (40). CTXA DXA equivalent T-scores, and aBMD for the femoral neck have recently been integrated into the WHO Fracture Risk Assessment Tool (FRAX), which calculates 10-yr fracture probability (55). In CTXA, a projection of the CT data is performed before the segmentation of the femur, whereas in VirtuOst, and in the USCF software, the femur is segmented in the 3D QCT data set before the 2D projection. In the case of QCTPro, the true 3D QCT parameters are calculated from a back-projection of the segmented 2D DXA type projection into the 3D data set. Consequently, the QCTPro approach often suffers from an overlap of acetabulum and femoral neck. This is a reason why similar to DXA, the QCTPro hip module suggests that during acquisition the feet should be rotated internally. In the 2 other techniques, the acetabulum is separated from the femoral head and neck before the projectional simulation allowing the advantage of the 3D CT acquisition over the 2D projectional DXA images to be fully exploited. Although a DXA equivalent projectional BMD or T-score measurement from a QCT scan is an alternative if, for example, a DXA scanner is not available, it is usually not advisable to perform a QCT acquisition just with the intention of a projectional analysis because the radiation exposure is significantly higher than in DXA. Of course, for existing CT scans obtained in clinical routine for diagnostic purposes other than osteoporosis (see part III) an additional DXA may no longer be needed. In general, a 2D projection calculated from a 3D QCT data set could provide a DXA equivalent assessment in addition to true 3D QCT parameters; however, independent segmentations of the 3D and the projected 2D data should be carried out.

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Table 1 In Vivo 3D QCT Studies of the Hip Related to Hip Fracture Risk Study duration [yr]

Johannesdottir (25)

4

5

AGES-Reykjavik study; A: hip fx, neck fx, female: age 79.4
6.1 yr; n 5 47, male: age 80.2
5.8 yr; n 5 31, troch fx, female: age 79.7
4.8 yr; n 5 41, male: age 80.1
5.2 yr; n 5 24; B: age-matched control, female: age 79.3
5.2 yr; n 5 187, male: age 79.6
5.1 yr; n 5 111

3D QCT hip: Siemens Sensation 4, 120 kV, 140 mAs, 1-mm slice thickness; aBMD analysis: CTXA using QCT scans; vBMD analysis: QCTPro; BIT option for quadrant analysis

Hip fracture discrimination; 3D QCT: FN aBMD, int vBMD, app Ct.Th

HR (CI) for mid neck VOI; all fx: female: aBMD 1.8 (1.4e2.5); vBMD 1.9 (1.4e2.6); app Ct.Th 1.7 (1.3e2.3), male: aBMD 3.1 (2.1e4.5); vBMD 2.9 (2.1e4.0); app Ct.Th 3.1 (2.2e4.4), neck fx, female: aBMD 1.7 (1.2e2.6); vBMD 1.8 (1.2e2.6); app Ct.Th 1.6 (1.1e2.3), male: aBMD 2.7 (1.7e 4.5); vBMD 2.9 (1.8e4.5); app Ct.Th 3.2 (2.0e5.3), troch fx, female: aBMD 2.1 (1.3e3.2); vBMD 2.4 (1.5e3.8); app Ct.Th 2.0 (1.3e3.1), male: aBMD 4.4 (2.4e8.2); vBMD 3.2 (1.9e5.3); app Ct.Th 3.6 (2.1e6.2)

Black (28)

4

5.5

QCT data of 3374 male of MrOs study; age at baseline 73.5
5.9 yr, 42 hip fx during study period

DXA hip: Hologic QDR 4500W, 3D QCT hip: various scanners, 80 kV, 280 mA, 3 mm slice thickness, vBMD analysis: UCSF

Hip fracture discrimination; DXA: FN aBMD, 3D QCT: FN int, cort, trab vBMD, and vol, CSA

HR (CI) for FN adjusted for age, BMI, clinical site; aBMD 4.1 (2.7e6.4), int vBMD 3.55 (2.3e5.4); int vol ns, trab vBMD 2.2 (1.6e3.2), cort vBMD 1.7 (1.2e2.4); cort vol 1.62 (1.1,2.4), CSA ns

Yang (26)

4

5.5

Random subcohort of MrOs study; A: hip fx, male: age 80.2
5.8 yr; n 5 40, B: control, male: age 79.6
5.1 yr; n 5 210

DXA hip: Hologic QDR 4500W, 3D QCT hip: various scanners, 80 kV, 280 mA, 3 mm slice thickness, vBMD analysis: custom software

Hip fracture discrimination; DXA: aBMD TH, 3D QCT: vBMD, app Ct.Th of various VOIs of the TH

HR (CI) for TH adjusted for age, BMI, clinical site; aBMD 5.2 (2.8e9.7), int vBMD 3.23 (1.8e5.7), trab vBMD 4.9 (2.6e9.5), cort vBMD 2.6 (1.6e4.3)

Case cohort design nested in prospective study

Rianon (27)

6

n.a.

Subcohort of AGESReykjavik study; female: age 76
5 yr; n 5 2682, male: age 76
5 yr; n 5 2110

3D QCT hip: Siemens Sensation 4, 120 kV, 140 mAs, 1-mm slice thickness, vBMD analysis: UCSF

Association with selfreported fracture status; multivariate analysis incl: FN: trab BMD, app Ct.Th, min CSA, LS: trab BMD

OR (CI) for most sig variable in model; female: LS trab vBMD 1.47 (1.02e2.13); FN trab vBMD 1.56 (1.09e 2.27), male: LS trab vBMD 1.92 (1.09e3.45)

Fx status: first-ever vert or wrist fx after 65 yr or hip fx at any age

Reference

Populationb

Technique or devices

Endpoints

Results

Comments Case cohort design nested in prospective study, in multivariable analysis including aBMD and thickness: app Ct.Th in the superoanterior (SA) quadrant was sig in female and male, and remained a sig predictor after adjustment for aBMD

Engelke et al.

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Study typea

n.a

A: hip fx, female: age 75.1
9.0 yr; n 5 50, B: age-matched control, female: age 75.1
9.5 yr; n 5 50

DXA hip: Hologic Discovery, 3D QCT hip: GE Light Speed VCT, 120 kV, 136e160 mAs, 0.625-mm slice thickness, pitch 1, vBMD analysis: custom software

Hip fracture discrimination; DXA: aBMD TH, FN, 3D QCT: vBMD, app Ct.Th of various VOIs of the TH

OR (CI); aBMD: TH 5.5 (2.2e13.9), FN 4.3 (1.9e9.5), int vBMD: TH 3.0 (1.6e5.5), FN 3.4 (1.7e6.6), trab vBMD: TH 4.1 (1.9e9.1), FN 3.7 (1.8e8.0), cort vBMD: TH 3.3 (1.8e6.1), FN 5.5 (2.2e13.5), app Ct.Th: TH 6.9 (2.3e20.6), FN 5.1 (2.1e12.3), ORs remained sig after adjustment for TH or FN aBMD

Prevalent hip fx; QCT performed 23e93 (median 67) d after hip fx

Bousson (29)

6

n.a

Effect study, white female, A: hip fx, female: age 81.6
11.0 yr; n 5 47 B: age-matched control, female: age 73.4
9.1 yr; n 5 60

DXA hip: GE Prodigy, 3D QCT hip: GE Light Speed VCT and Siemens Volume Zoom, 120 kV, 170 mAs, 1e1.25-mm slice thickness, pitch 1, vBMD analysis: MIAF

Hip fracture discrimination; multivariate analysis for QCT variables incl. int, trab, cort vBMD, and app Ct.Th

OR (CI) adjusted for age, height, weight; aBMD: TH 3.0 (1.5e6.2), best QCT model: int vBMD: femoral head 3.1 (1.5e6.4), app Ct.Th: femoral shaft 1.7 (1.0e2.9), 2nd best QCT model:int vBMD: femoral head 2.9 (1.7e4.9), app Ct.Th: FN 1.7 (0.9e3.1),

QCT performed immediately after hip fx and before surgery, DXA performed 12 d (mean) after QCT scan

Cheng (30)

6

n.a

Chinese female, A: atraumatic acute hip fx, female: age 74.7
5.9 yr; n 5 45, B: age-matched control female: age 70.7
4.neck yr; n 5 66

3D QCT hip: GE CT Pro FII and Siemens Volume Zoom, 120 kV, 200 mAs, 3 mm slice thickness, pitch 1, aBMD: UCSF using QCT scans, vBMD analysis: UCSF

Hip fracture discrimination; 3D QCT: int, trab, cort vBMD, app Ct.Th TH; aBMD TH, and FN

OR (CI) adjusted for age, height, weight; aBMD: TH 6.9 (3.2e18.4), FN 4.1 (2.1e8.7). int vBMD: TH 5.6 (2.8e13.6), FN 5.6 (2.7e13.5), trab vBMD: TH 6.8 (3.2e18.3), FN 2.7 (1.5e5.1), cort vBMD: TH 2.5 (1.4e4.5), FN 2.4 (1.3e4.4), app Ct.Th: TH 6.9 (2.3e20.6), FN 5.1 (2.1e12.3)

QCT performed within 48 hours of hip fx

Ito (31)/Nishiyama (32)

6

n.a

Japanese female, A: prevalent neck fx, female: age 80.1
4.5 yr; n 5 20, B: prevalent trochanteric fx, female (age 82.6
5.0); n 5 15, B: age-matched control, female: age 79.2
2.6 yr; n 5 20, C: age-matched non-fx control group, female (age 79.9
3.1) n 5 35

3D QCT hip: Siemens Sensation 4 or Toshiba Aquilion 16, 120 kV, 250 mAs, 0.5 mm slice thickness, vBMD analysis: QCTPro

Hip fracture discrimination BMD group differences and ROC analysis; vBMD including FN and TH measurements

Between group difference in % ( p-value), pooled fractures: vBMD TH: 32.2 (!0.001); FN: 26.3 (!0.001); trochanteric fractures: vBMD TH: 30 (!0.001); FN: 23.8 (!0.001); neck fractures: vBMD TH: 33.3 (!0.001); FN: 28.1 (!0.001); AUC pooled fractures: vBMD 0.87;

FE results are shown in part II Table 1

(Continued)

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Yang (46)

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Table 1 (Continued )

Reference

Study typea

Study duration [yr]

Populationb

Technique or devices

Endpoints

Results

Comments

trochanteric fractures: vBMD 0.83, neck fractures: vBMD 0.86 6

n.a.

A: female with low trauma fresh neck fx, age 70.1
4.3, n 5 10, B: female controls (age, height, weight-matched) no fracture, age 69.6
3.9, n 5 18

3D QCT hip: Technicare PS 1440, 130 kV, 400 mAs, 3 mm slice thickness, vBMD analysis: custom software

Hip fracture discrimination using BMD differences; 3D QCT: neck, trochanter: trab, cort, int vBMD, vol, Hip fracture discrimination using geometrical differences; head width, NAL, neck width

Between group difference: p-value; trab vBMD neck 0.035, trab vBMD trochanter 0.77, int vBMD neck 0.07, head width 0.001, NAL 0.35, neck width 0.025

Low trauma defined as fx resulting from fall from standing height or lower

Lang (35)

6

n.a

Italian female, A: vertebral fx, age 76.1
6.5, n 5 26, B: control, age 71.5
4.4, n 5 45

DXA: PA L-spine, hip: Norland XR-263D, 3D QCT spine: GE 9800, 80 kV, 180 mA, 3-mm slice thickness, 3D QCT hip: GE 9800, 120 kV, 150 mA, 3-mm slice thickness, vBMD analysis: UCSF

Spine fracture discrimination using BMD differences; 3D QCT: spine: trab and cort vBMD L1 þ L2, hip: trab cort int vBMD TH, QCT 10 mm midvertebral slice: trab and int vBMD L1 þ L2, DXA: PA L-spine, hip aBMD

Between group difference: p-value; 3D QCT spine: trab vBMD 0.04, cort vBMD 0.009, 3D QCT hip: trab vBMD 0.07, cort vBMD 0.06, int vBMD ns, QCT 10-mm midvertebral slice: trab vBMD 0.02, int vBMD 0.004, DXA: aBMD PA Lspine 0.008, neck 0.02, troch ns Between group difference: p-value; 3D QCT spine: trab vBMD ns, cort vBMD 0.015, 3D QCT hip: trav and cort neck ns, int neck vBMD 0.025, trab troch ns, cort troch vBMD 0.03, int troch vBMD 0.007, tot hip trab vBMD 0.06, tot hip cort BMD 0.04, tot hip inte BMD 0.007, DXA: aBMD PA L-spine 0.02, troch 0.03

Inconsistent number of patients in the group without fx: lang n 5 45, Guglielmi n 5 51, age, height, and weight means and SDs are identical in both articles

Guglielmi (34)

Control group from above was split into: A, subjects with degenerative changes L1eL4 grade 0, n 5 29, B, subjects with degenerative changes L1eL4 grade 1, n 5 22

Spine fracture (degenerative changes) discrimination using BMD differences; 3D QCT: spine: trab and cort vBMD L1 þ L2, hip: trab cort int vBMD TH, QCT 10-mm midvertebral slice: trab and int vBMD L1 þ L2, DXA: PA L-spine, hip aBMD

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Engelke et al.

Cody (33)

Note: OR and HR are given per SD decrease of corresponding variable. Abbr: aBMD, areal bone mineral density; app, apparent; AUC, areal under the curve; CI, confidence interval; cort, cortical; CSA, cross-sectional area; Ct.Th, cortical thickness; FN, femoral neck; fx, fracture; HR, hazard ratio; int, integral 5 trabecular and cortical; min, minimum; NAL, neck axis length; n.a., not applicable; ns, not significant; OR, odds ratio; SD, standard deviation; sig, significant; TH, total hip; trab, trabecular; troch, trochanter; vBMD: bone mineral density as measured by 3D QCT; vert, vertebral; vol, volume. a Study type: 1: randomized controlled trial, 2: nonrandomized trial with contemporaneous controls, 3: nonrandomized trial with historic controls, 4: cohort study, 5: case-control Study, 6: cross-sectional study, 7: surveillance (e.g., using databases or registries), 8: series of consecutive cases. b A, B, C. denote different study groups.

Amin (47)

6

n.a.

Subcohort of Rochester Epidemiology Project, 314 female (age 61
15), 266 male (age 62
16), A: any prevalent fx (139 female, 104 male), B: op fx (55 female, 28 male), C: no fx (175 female, 162 male)

3D QCT hip: Light Speed QX/I, GE, 2.5-mm slice thickness, aBMD analysis: CTXA, vBMD analysis: QCTPro?

Discrimination of: any fracture & any osteoporotic fracture, TH aBMD, TH vBMD

Age-adjusted ORs, female, any fracture, aBMD: 1.3, p ! 0.05; vBMD: 1.6, p ! 0.05, any osteoporotic fracture, aBMD: 1.5, p ! 0.05; vBMD: 2.0, p ! 0.05; Age-adjusted ORs, male, any fracture, aBMD: 1.4, p ! 0.05; vBMD: 1.6, p ! 0.05, any osteoporotic fracture, aBMD: 2.0, p ! 0.05; vBMD: 3.4, p ! 0.05

Any fx: fx at any skeletal site at age  35. Osteoporotic fracture: low or moderate trauma-induced fx at the proximal femur, spine, distal forearm, or proximal humerus, FE results are shown in part II Table 1

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Methodology A systematic literature search in Medline related to QCT of the femur using the search items: (QCT[All Fields] OR (quantitative[All Fields] AND (computed[All Fields] OR computerized[All Fields]) AND tomograph*[All Fields])) AND (osteoporo*[All Fields] OR osteopen*[All Fields] OR fracture*[All Fields] OR *BMD[All Fields] OR BMC [All Fields] OR densit*[All Fields] OR ‘‘bone mass’’[All Fields] OR structur*[All Fields] OR strength[All Fields] OR size[All Fields] OR bone[All Fields] OR (cortical[All Fields] OR cortex[All Fields]) OR trabecul*[All Fields] OR cancellous[All Fields] OR geometri*[All Fields]) AND hip[All Fields] OR femor*[All Fields] OR femur[All Fields]) identified 1350 entries. We restricted our evaluation to human studies; animal studies were not included in the systematic review. We also did not include measurements in children or orthopedic applications, such as the quantification of BMD near prostheses. We only evaluated measurements at the hip. Official positions for QCT of the spine were presented earlier (1), therefore, the systematic review did not include QCT studies that only presented standard measurements such as BMD and geometry at the spine. Articles in languages other than English were not included in the systematic review but were cited to support the evidence. The methods used to develop and grade the ISCD official positions, are presented in the executive summary that accompanies this article. In brief, all positions were rated by the expert panel on quality of evidence (good, fair, poor), strength of recommendation (A, B, or C), and applicability (worldwide 5 W or variable, according to local requirements 5 L). Good quality is evidence that includes results from well-designed, well-conducted studies in representative populations. Fair quality is evidence sufficient to determine effects on outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies. Poor quality is evidence that is insufficient to assess the effects on outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or information. A is a strong recommendation supported by the evidence, B is a recommendation supported by the evidence, and C is a recommendation supported primarily by expert opinion. In the following, we will present the ISCD official positions for QCT of the hip.

ISCD Official Positions Position on the Use of DXA Versus QCT or QCT-Based Techniques ISCD Official Position Where QCT and DXA are both available and provide comparable information, DXA is preferred to limit radiation exposure.

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Reference

Study Study duration a type [yr] 5

Population

Technique or devices

Endpoints

3D QCT hip: Siemens Longitudinal age-related Subcohort of AGESSensation 4, 120 kV, changes; FN, inf FN, Reykjavik study; 140 mAs, 1 mm slice sup FN, int, trab, app female: age 74
5.2 yr; n 5 300, thickness, aBMD cort vBMD, CSA, app analysis: CTXA using Ct.Th, FN aBMD male: age 74
4.4 yr; n 5 100 QCT images, vBMD analysis: QCTPro; BIT option for quadrant analysis

Results %change (CI) tot neck tot neck tot neck tot neck tot neck sup neck inf neck sup neck inf neck sup neck inf neck sup neck inf neck

male 0.7 0.8 0.2 0.7 0.7 1.6 0.5 2.2 0.4 0.6 0.1 2.4 0.4

Comments

4

Lang (40)

4

5

Nicks (38)

4

n.a.

Subcohort of Rochester Epidemiology Project, female: age 20e97 yr; n 5 358

3D QCT hip: GE Light Age-related changes; Speed QX-I, 120 kV, int, trab, cort vBMD 64 mAs, 2.5-mm slice app Ct.Th in large thickness, pitch 0.75, variety of analysis vBMD analysis: VOIs MIAF, slice thickness extrapolated to 1 mm

%change 20e90 yr int vBMD trab vBMD app cort vBMD int vol trab vol cort vol

neck 45 74 26 þ15 þ26 þ4

troch 41 62 28 þ20 þ25 þ13

intertroch 46 70 23 þ23 þ39 1

Poole (37)

4

n.a.

female: age 20e90 yr; n 5 100

3D QCT hip: Siemens Sensation 64, 120 kV, 160 mAs, 1-mm slice thickness, pitch 1.4, vBMD analysis: QCTPro BIT option was used for FN quadrant analysis

%change, 25e85 yr SP app Ct.Th 76 int vBMD 62 cort vBMD 37 trab vBMD 56 neck vBMD: 35% neck vol: þ15% CTXA neck aBMD: 31%

SA 61 48 23 37

IP 41 36 17 42

Longitudinal age-related changes, TH QCTderived aBMD, trab vBMD, cort/int vol (cvol/ivol)

Age-related changes; VOIs: FN, quadrants in FN, compartments: int, trab, app cort v variables: vBMD, app Ct.Th, FN aBMD from CTXA

int vBMD aBMD CSA CSMI min CSMI max app Ct.Th app Ct.Th int vBMD int vBMD cort vBMD cort vBMD trab vBMD trab vBMD

(0.8,0.5) (1.2,0.5) (0.2,0) (0.9,0.5) (0.9,0.5) (2.1,1.1) (0.7,0.3) (2.7,1.6) (0.6,0.2) (0.3,0.8) (0.1,0.2) (4.5,0.2) (0.8,0)

female 1.1 1.3 0 0.9 0.8 3.3 0.9 3.4 1 1.2 0.4 3 0.4

(1.2,1.0) (1.5,1.0) (0,0.1) (1.0,0.7) (0.9,0.7) (3.8,2.8) (1.0,0.8) (3.8,3.0) (1.2,0.9) (1.4,0.9) (0.5,0.3) (3.8,2.3) (1.3,0.6)

%change (CI), trab vBMD, aBMD, cvol/ivol: all p ! 0.0001, for each gender, aBMD (%): 3.9% (female) vs 6.1% (male), p ! 0.001, trab vBMD (%): 4.8% (female) vs 23.9% (male), p ! 0.0001

FE results are shown in part II Table 2

prox shaft 35 n.a. 16 þ16 n.a. 11

Large slice thickness prevented more accurate cortical measurements, slopes of trab vBMD with age were similar in prepm and pm female, app cort all changes p ! 0.001 vBMD remained % app cort vBMD decreases in sup neck quadrant were 2- to 3-fold greater than in relatively stable in inf quadrant prm female but decreased sig with age after menopause. int volume increased predominantly in prem female IA 15 10 1 3

SP, SA, IP, IA: superior posterior, superior anterior, interior posterior and interior anterior in the neck

Engelke et al.

Volume 18, 2015

Johannesdottir (39)

Subcohort of AGES3D QCT hip: Siemens Sensation 4, 120 kV, Reykjavik study; 140 mAs, 3-mm slice female: age thickness, pitch 1, 77.0
5.11, n 5 112, aBMD analysis: male: age 76.7
5.6, UCSF using QCT n 5 111 images, vBMD software: UCSF

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Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Table 2 In Vivo 3D QCT Studies of the Hip Related to Age- and Gender-Related Changes

Abbr: aBMD, areal bone mineral density; app, apparent; CI, confidence interval; cort, cortical; CSA, cross-sectional area; Ct.Th, cortical thickness; FN, femoral neck; fx, fracture; inf, inferior; int, integral 5 trabecular and cortical; max: maximum; min, minimum; n.a., not applicable; ns, not significant; pm, postmenopausal; prem: premenopausal; prox, proximal; sig, significant; sup, superior; TH, total hip; tot: total; trab, trabecular; troch, trochanter; vBMD, bone mineral density as measured by 3D QCT; VOI, volume of interest. a Study type: 1: randomized controlled trial, 2: nonrandomized trial with contemporaneous controls, 3: nonrandomized trial with historic controls, 4: cohort study, 5: case-control study, 6: cross-sectional study, 7: surveillance (e.g., using databases or registries), 8: series of consecutive cases.

(1) DXA FN aBMD was the same in female and male; (2) pooled analysis (linear regression, 146 men and 136 women) adjusted for FN aBMD: male had larger FN CSA, lower int, trab and cort vBMD than female (all p ! 0.001); (3) 114 male and 114 female matched for FN aBMD, male had larger FN CSA ( p ! 0.001), lower int ( p ! 0.001), lower trab ( p ! 0.001), and lower cort vBMD ( p ! 0.01) than female DXA hip: Lunar Prodigy, Gender differences; FN 3D QCT hip: GE Light aBMD, FN int, trab, Speed QX-I, 120 kV, cort vBMD, CSA 64 mAs, 2.5-mm slice thickness, pitch 0.75, aBMD analysis: Lunar, vBMD analysis: Majo Clinic Subcohort of Rochester Epidemiology Project; female and male 40e90 yr, not on antiosteoporosis therapy, female: age 61.8
12.6, n 5 136, male: age 63.5
13.8, n 5 146 4 Srinivasan (41)

n.a.

4 Kim (36)

n.a.

perm and pm Korean 3D QCT hip: GE Light female: age 45e80 yr; Speed QX-I, 2.5 mm n 5 214 slice thickness, aBMD analysis: CTXA using QCT images, vBMD analysis: QCTPro; BIT option for quadrant analysis

Age-related changes; FN, int, trab, app cort vBMD, CSA, app Ct.Th, buckling ratio (BR), FN aBMD

%change, 50e80 yr aBMD int vBMD trab vBMD neck width app Ct.Th BR

neck 23 31 33 þ12 54 þ240

FEA results are shown in part II Table 2

ISCD 2015 Official Positions - QCT of the Hip

345 Grade: FaireC-W Rationale. According to the ALARA (as low as reasonably achievable; defined in Title 10, Section 20.1003, of the Code of Federal Regulations (10 CFR 20.1003)), DXA is preferred to QCT acquisition due to significant lower radiation exposure, unless QCT or QCT-based techniques provide superior information to DXA. Discussion. Radiation exposure levels for QCT protocols typically used in clinical scans were given in the earlier position article (Table 3 in (1)). Subsequently, the International Commission on Radiation Protection has updated the socalled tissue weighing factors characterizing the tissue sensitivity to ionizing radiation (56). With respect to the previously published values, the effective dose for the hip scan protocol has been reduced by approximately 30% while that for the lumbar spine is about the same. Nevertheless, radiation exposure for QCT of the spine or hip is higher that than that for DXA by about a factor of 50 to 100. Diagnostic procedures using ionizing radiation are associated with a stochastic risk of radiation-induced cancer, which if at all, typically occurs decades after the examination. Thus, in elderly people the benefit-risk ratio of such a diagnostic procedure is much higher than in children or younger adults. There are also ongoing efforts to further decrease exposure levels for a given examination, for example, by using automated exposure control techniques implemented on all newer CT scanners.

Position on the Scan Acquisition for QCT of the Proximal Femur ISCD Official Position QCT acquisition of the proximal femur should extend from the femoral head to the proximal shaft.

Grade: GoodeA-W Rationale. In most in vivo QCT studies of the hip BMD integral, cortical and trabecular BMD (and other assessments) of the total femur were used, analogous to DXA of the combined volume of the neck, trochanter, and intertrochanter. All in vitro studies providing evidence to use QCT to assess the strength of the femur included the complete hip down to the shaft typically cut off a few centimeters below the lesser trochanter. FEA and SPM of the hip require CT scans of the complete hip. Furthermore, for the prediction or discrimination of trochanteric fractures the assessments of the trochanter show higher odds ratios or relative risks compared to those of the neck. Even a CT scan of just the neck, will include the trochanter and a significant portion of the intertrochanter because of the position of the neck relative to the scan plane. Thus, even with respect to radiation exposure there is a rather small advantage, if the scan range is limited to the neck. Landmarks

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Table 3 In Vivo 3D QCT Studies of the Hip Related to Osteoporosis Treatment

Reference Black (48)

Study Study duration [yr] typea 1

1

Bauer (49)

Black (50)

2

Populationb

Technique or devices

Endpoints

Intervention

Results

Comments

Engelke et al.

Volume 18, 2015

Publication does not %change after year 1; 3D A: PTH (1e84) 100-mg BMD changes; DXA: Path study; pm osteoporotic DXA hip: Hologic QDR contain cortical data for QCT hip (similar results daily sc. B: PTH: aBMD TH, 3D QCT: 4500 or Delphi, 3D QCT female (white 93.3% QCT, ALN: alendronate for total hip and neck), alendronate 10 mg daily, vBMD TH and several hip: GE 9800, vBMD other 6.7%), A: PTH, trab BMD: PTH þ8.6%, Publication does not C: PTH(1e84) 100-mg hip sub VOIs analysis: UCSF age 69.4
7.3, n 5 119, contain data on groups B smaller increases in comb sc and alendronate B: ALN, age 70.7
6.8, and C but does contain and ALN; group diff ns, 10 mg daily, all groups: n 5 60, C: PTH þ ALN cortical data for QCT cort BMD: PTH-1.7%, calcium 500 mg/day, vit. (CMB), age 70.2
6.8, comb 0.1%, ALN þ1.2%, D 400 IU/d n 5 59 cort vol: PTH þ3.5%, comb ns, ALN ns; increase sig higher in PTH than in comb and ALN, DXA hip: (comparable to neck): PTH 0.3%, comp 1.9%, ALN 3%; no sign group diff Path study, first year as %change after year 2; 3D Publication only contains Groups A, B, C: previously mentioned, trabecular BMD data for QCT hip (similar results alendronate 10 mg/daily, second year: Group A QCT for total hip and neck), all groups: calcium from year 1 split into trab BMD: PTH/ALN 500 mg/day, vit. D 400 groups A and D in year þ13%, comb/ALN IU/d 2, A: PTH-ALN, age þ11%, ALN/ALN þ4% 68.7
7.4, n 5 59, B: (ns), PTH/placebo þ4% ALN-ALN, age (ns) (i.e., decrease in year 70.7
6.8, n 5 60, C: 2), cort BMD: PTH/ALN CMB-ALN, age -3%, comb/ALN þ1% 70.2
.8, n 5 59, D: (ns), ALN/ALN -2%, PTH/placebo þ3%; placebo, age 70.1
7.3, between gr diff ns, cort n 5 60 vol: PTH/ALN þ6%, comb/ALN þ7%, ALN/ ALN þ6%, PTH/placebo þ1%, DXA hip: PTH/ ALN þ4%, comb/ALN þ3%, ALN/ALN þ3%, PTH/placebo þ0%, PTH/ALN increase sig higher than in other 3 groups

1

1.5

Lewiecki (7)

1

1

Engelke (12)

Fritzpatrick (9)

1

3D QCT performed at one 120 pm female; LS, hip or DXA hip: no info, 3D QCT BMD changes and diff vs A: daily injections of 100- Treatment differences vs site in subset of 120 mg PTH (1e84), B: placebo in %; trab vBMD: hip: no info, vBMD Placebo, DXA: aBMD neck, T-score ! 3 and female, scanner type and placebo FN þ4.5%, troch þ4.3%, analysis: UCSF TH, 3D QCT: trab no fx: or ! 2.5 and model not provided, TH þ4.7%, TH cort vBMD TH, FN, troch; 1e4 vert fx, A: PTH age although vert fx was vBMD 4.7%, cort BMC cort, int vBMD and int 64.4
7.4; B: Placebo primary endpoint, RR þ4.8%, cort vol þ9.0, BMC: TH age: 64.5
7.9 for densitometric DXA: no separate results measurements not in given for QCT subgroup manuscript BMD changes & diff versus A: oral IBN 150 mg/mo, B: Treatment differences vs Boniva IQ trial; pm female; DXA hip: Lunar and Multicenter trial, IBN: placebo, both groups: Placebo; DXA: aBMD Hologic, 3D QCT hip: LS, hip, or neck, 2.0  ibandronate, FE results placebo in %; int vBMD TH, 3D QCT: int, trab, multiple scanner types, T-score  5.0, 89.2% are shown in part II þ2.2% TH, þ1.9% FN, calcium 1000 mg/d, vit cort vBMD, and BMC 120 kV, 170 mAs, white, 9.7% black, A: IBN Table 2 int vBMD þ3.0% troch, D 400 IU/d TH, FN, troch 1e1.25-mm slice group: age 64.8
7.2, all p ! 0.05, in favor of thickness, vBMD 79% completed study, IBN, DXA aBMD analysis: MIAF n 5 47, B. Placebo group: þ2.0% TH ( p ! 0.05), age 63.5
6.0, 78% ns FN completed study, n 5 46 Treatment differences vs BMD changes and diff vs placebo in %; subcort Placebo, Analysis of vBMD þ3.7% TH, additional QCT extended cort vBMD variables: vBMD of þ1.5% TH, all p ! 0.05, subcortical and extended in favor of IBN cortical VOIs

ISCD 2015 Official Positions - QCT of the Hip

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Greenspan (51)

(Continued)

347

Volume 18, 2015

0.8e1 pm female; LS, hip or neck, DXA hip: Lunar and BMD changes and diff vs Ronacaleret: A: Ron1: 100- %change for total hip after Multicenter trial, TPTD: teriparatide, Ron: 2.5  T-score  4.0 mo 10e12, D: int mg QD, B: Ron2: 200Placebo, DXA: aBMD Hologic, 3D QCT hip: ronacaleret, study and no fx, or 2.0 vBMD 0.5% ns, trab mg QD, C: Ron3: 300TH, 3D QCT: int, trab, multiple scanner types, terminated early, Last  T-score  4.0 and vBMD þ2.8%, cort mg QD, D: Ron4: 400cort vBMD and BMC 120 kV, 170 mAs, QCT measurements 1 fx, A: Ron1, age vBMD 1.8%, DXA mg QD, E: ALN: 70-mg TH, FN, troch 1e1.25-mm slice taken 10e12 mo after 65.5
8.0, n 5 50, B: aBMD 1.4%, E: int QD, F: TPTD 20-mg sc thickness, vBMD baseline Ron2, age 63.9
7.2, vBMD þ2.5%, trab QD open lable, G. analysis: MIAF n 5 43, C: Ron3, age vBMD þ3.1%, cort Placebo, All groups: 64.3
7.1, n 5 43, D: vBMD þ2.4%, DXA calcium 500 e660 mg/d, Ron4, age 65.2
7.5, aBMD þ3.1%, F: int vit D 400 IU/d n 5 41, E: ALN, age vBMD þ3.9%, trab 65.0
7.5, n 5 49, F: vBMD þ13.2%, cort TPTD, age 62.9
5.8 vBMD þ0.2% ns, DXA n 5 36, G: Placebo, age aBMD þ3.1%, G: int 63.1
6.7, n 5 42 vBMD 0.2% ns, trab vBMD 0.4% ns, cort vBMD þ1.1%, DXA aBMD þ0.4%

Reference

348

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Table 3 (Continued ) Study Study duration [yr] typea

Populationb

Technique or devices

Endpoints

Intervention

Results

Comments

Treatment differences vs Multicenter trial, Zol: zolodronic acid, placebo in %, TH int although in the two vBMD þ6.0%, trab publications, different vBMD þ10.1%, cort analysis software was vBMD þ1.0% ns, FN used and slightly int vBMD þ4.0%, trab different patient subsets vBMD þ10.7%, cort treatment differences in vBMD þ0.92% ns, Yang’s analysis were DXA aBMD þ5.1% almost identical to TH, 5.1% FN, all sig vs results in Eastell’s placebo unless ns analysis shown on the left. For further subdivision of the neck and results for trochanter and intertrochanter pls see Yang’s publication

1

3

BMD changes and diff vs A: Zol: zolodronic acid Subset of Horizon trial; pm DXA hip: Lunar and 5 mg every 12 mo, B: Placebo; DXA: aBMD Hologic, 3D QCT hip: female; neck, 2.5  TPlacebo, both groups: TH FN, 3D QCT: int, multiple scanner types, score or 1.5  T-score calcium  1000 mg/d, trab, cort vBMD, BMC 80 kV, 280 mAs, 3-mm and 2 mild or one vit D  400 IU/d vol TH, more slice thickness, pitch 1, moderate vert fx, A: Zol, comprehensive analysis vBMD analysis: UCSF age 74.2
5.6, n 5 122, of 3D QCT parameters B: Placebo, age in Yang’s publication 74.3
6.4, n 5 111

Yang (15)

1

3

same as above but Equipment: same as above different subset vBMD analysis: custom A: Zol, age 73.1
5.2, software, University of n 5 94 Sheffield B: Placebo, age 73.4
6.2, n 5 85

Engelke (8)

1

2

BMD changes and diff vs ONO-5334: A: Cat-K1: 50- Treatment differences vs Multicenter trial; groups A Ono Ocean trial, pm female; DXA hip: Lunar and placebo in % C: TH int mg BID, B: Cat-K2: Placebo, DXA: aBMD Hologic, 3D QCT hip: LS or hip 2.5  Tand B showed vBMD þ6.2%, trab 100-mg QD, C: Cat-K3: TH, 3D QCT: int, trab, multiple scanner types, score and no fx, or comparable or lower vBMD þ14.6%, cort 300 mg QD, D: ALN: cort vBMD, BMC vol 120 kV, 170 mAs, 1e 1.0  T-score  2.5 treatment differences vBMD þ2.4%, DXA 70-mg QD, E: placebo, TH 1.25-mm slice thickness, and 1 fx, A. Cat-K1, age compared to group C aBMD þ3.8%, D: TH all groups: calcium pitch 1, vBMD analysis: 65.3
5.1, n 5 27, B. int vBMD þ5.5%, trab 400 mg/d, VitD 400 MIAF Cat-K2, age 65.7
5.0, vBMD þ11.5%, cort IU/d n 5 34, C. Cat-K3, age vBMD þ2.5%, DXA 64.6
5.2, n 5 32, D. aBMD þ4.2%, all ALN, age 65.7
4.4, n 5 30, E. placebo, age p ! 0.01 65.0
4.3, n 5 24

McClung (21)

1

3

Treatment differences vs Multicenter trial, group A: BMD changes and diff vs A: Denosumab: 50 mg Subset of Freedom trial; pm DXA hip: Lunar and QCT-Pro n 5 32, MIAF placebo in %; TH Q6M, B: Placebo, both Placebo, DXA: aBMD Hologic, 3D QCT female; LS or hip n 5 36, group A and B: vBMD: int þ7.8%, trab groups: TH FN, 3D QCT: int, thickness, pitch hip: 2.5  T-score  4.0, QCT-Pro n 5 58, MIAF þ4.7%*, cort ns, TH calcium  1000 mg/d, trab, cort vBMD, BMC multiple scanner types, A: denosumab, age n 5 62, Stradwin BMC: int þ5.2%*, trab vit D  400 IU/d vol TH 120 kV, 170 mAs, 174
5, n 5 32, B: n 5 61, treatment þ8.2%*, cort þ8.7%, 1.25-mm slice 1, vBMD placebo, age 75
6, difference vs placebo for TH vol: int ns, trab analysis: QCTPro n 5 26 TH DXA aBMD 1.4*, cort þ11.1%*, þ7.3%; *: estimated FN vBMD: int þ5.9%, from graphs shown in all sig versus placebo the publications unless ns

Engelke et al.

Volume 18, 2015

Eastell (13)

Equipment: same as previously mentioned, vBMD analysis: MIAF

Poole (16)

Equipment: same as previously mentioned, vBMD analysis: Stradwin

Brixen (20)

Engelke (10)

1

2

3D QCT TH: cort vBMD, BMC, vol, Ct.Th

Treatment differences vs placebo in % TH vBMD: int þ7.9%, trab þ17.7%, sub cort þ8.1%, cort þ5.5%, TH BMC: int þ7.4%, trab þ17.4%, sub cort þ8.0%, cort þ5.0%, TH vol: int ns, trab ns, cort ns, all sig versus placebo unless ns Treatment differences vs placebo in % TH vBMD: cort þ2.1%* TH BMC: cort þ5.6%* TH app CtTh: þ4.1%

Treatment differences vs Multicenter trial, group A: BMD changes and diff vs A: ODN: 50 mg/wk, B: DXA hip: Lunar and pm female; LS, hip, placebo in % TH Placebo, both groups: Placebo, DXA: aBMD Hologic, 3D QCT hip: or neck 1.5  QCT-Pro n 5 84, MIAF vBMD: int þ3.7%, trab calcium to bring total TH, FN, 3D QCT: int, multiple scanner types, T-score  3.5, A: n 5 78, group B: QCTþ4.2%, FN cort vBMD intake to 1200 mg/d, vit trab, cort vBMD, BMC, 120 kV, 170 mAs, ODN, age 63.9
7.3, Pro n 5 90, MIAF ns, app Ct.Th þ6.0%. D  5600 IU/wk and vol TH 1e1.25-mm slice n 5 84, B: placebo, age n 5 80, ODN: cort area þ4.9%, tot thickness, pitch 1, 64.0
6.2, n 5 90 odanacatib vBMD analysis: area ns, TH DXA aBMD QCTPro þ3.3%, FN DXA aBMD þ3.8% Equipment: same as Treatment differences vs previously mentioned, placebo in % TH vBMD: vBMD analysis: MIAF int þ5.4%, trab þ12.2%, sub cort þ6.1%, cort þ2.5%, FN vBMD: int þ4.5%, trab þ9.9%, sub cort þ5.7%, cort þ2.0%, TH BMC: int þ5.4%, cort þ3.6%, FN BMC: int þ4.6%, cort þ3.1%, TH vol: int ns, cort þ1.1%, FN vol: int ns, cort ns; app Ct.Th: ns, all sig vs placebo unless ns

ISCD 2015 Official Positions - QCT of the Hip

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Genant (11)

(Continued)

349

Volume 18, 2015

Reference

350

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Table 3 (Continued ) Study Study duration [yr] typea

Populationb

Technique or devices

Endpoints

Intervention A: RIS: residronate acid 5 mg every 12 mo, B: ALN: alendronate 10 mg daily or 70 mg weekly

Results

Comments

%change after 1 yr, A: TH *: estimated from graphs shown in the int vBMD 0.5%*, trab publications vBMD þ5.3%, DXA aBMD 0.3%, B: TH int vBMD þ0.8%*, trab vBMD þ13.3%*, DXA aBMD þ1.7%

2

1

pm osteoporotic female, A: DXA hip: no details given, BMD changes, DXA: aBMD TH, 3D QCT: 3D QCT hip: no details RIS, age 69.3
7.4, TH int, trab vBMD given, vBMD analysis: n 5 112, B: ALN, age UCSF 67.7
7.8,n 5 119

Borggrefe (17)

4

2

TPTD 20 mg/d sc BMD changes; DXA: DXA hip: Lunar and Subset of EUROFORS aBMD TH, 3D QCT: Hologic, 3D QCT hip: trial, 78 pm female; LS, vBMD TH and several multiple scanner types, hip or neck 2.5  TBIT variables 120 kV, 70e200 mAs, score þ 1 fx 3-mm slice thickness, vBMD analysis: QCTPro Bit

%change after year 2; TH Multicenter trial, subjects were pooled from 3 vBMD: int þ3.0%, trab pretreatment groups: þ5.2%, cort 2.0%, na€ıve and pretreatment DXA aBMD þ4%, TH vBMC: int þ2.2%, trab with and without þ2.6%, cort þ2.3%, TH adequate response CSA: int 0.6% ns, cort þ4.3%

Lian (45)

5

n.a

Between group differences DXA hip: Hologic QDR pm Caucasian female, in DXA/QCT; aBMD: 4500, 3D QCT hip: GE DXA and QCT cohort, TH, neck, trochanter, 9800, 120 kV (GC A: glucocorticoid (GC) L1eL4, QCT: int, trab, group), 80 kV (control group: age 62.8
10.3, cort vBMD and BMC at group), 280 mA, 3-mm n 5 64, treatment for TH, neck, trochanter, slice thickness, vBMD 13.4
12.0 yr, mean volume TH, FN CSA, analysis: UCSF dose 8.02
4.8 mg/day, NAL B: controls no treatment, age 74.6
4.13, n 5 120

QCT, int vBMD (TH, FN, Retrospective combined analysis of cases and troch): all differences controls, which were p ! 0.001, trab vBMD recruited for different (all sites): all differences studies. Study p ! 0.05, cort vBMD population partly (all sites): all differences overlaps with study p ! 0.001, cort vol (all population from sites): all differences Rehman. Cases and p ! 0.005, trab vol (all controls were sig sites): all differences ns, different in age and ysm. CSA and HAL: all FE results shown in part differences ns, DXA; II Table 2 aBMD at TH, FN and trochanter: all differences p ! 0.001

Muschitz (42)

1

0.75

Confors trial; pm female DXA hip: Lunar iDXA, 3D BMD changes; DXA: QCT hip: Philips with 9m TPTD 20 mg/d aBMD TH, 3D QCT: MX8000, 3.2-mm slice sc treatment, A: TPTD TH int, trab vBMD age 78.2
8.9, n 5 42, thickness, vBMD B: TPTD þ RAL age analysis: QCTPro

A: TPTD 20 mg/d sc, B: TPTD 20 mg/d sc þ, RAL 60 mg/d, C: TPTD20 mg/d sc þ, ALN 70 mg/wk

%change after 9 mo; A: TH TPTD: teriparatide, RAL: raloxifen, ALN: int vBMD þ6.0%*, trab alendronate, first DXA vBMD þ4.5%*, cort scan at 9 mo, TH vBMD þ2.8%*, DXA aBMD change from aBMD þ1.4%*, B: TH

Engelke et al.

Volume 18, 2015

Miller (14)

Abbr: aBMD, areal bone mineral density; ALN, alendronate; app, apparent; BMI, body mass index; Cat-K, Cathepsin-K; CI, confidence interval; cort, cortical; CSA, crosssectional area; Ct.Th, cortical thickness; FN, femoral neck; fx, fracture; IBN, ibandronate; inf, inferior; int, integral 5 trabecular and cortical; n.a., not applicable; ns, not significant; perm, perimenopausal; pm, postmenopausal; RAL, raloxifen; RIS, residronate; RR, relative risk; sc, subcutaneous; sig, significant; sup, superior; TH, total hip; tot, total; TPTD, teriparatide; trab, trabecular; troch, trochanter; vBMD, bone mineral density as measured by 3D QCT; ysm, years since menopause; ZOL, zolodronic acid. a Study type: 1: randomized controlled trial, 2: nonrandomized trial with contemporaneous controls, 3: nonrandomized trial with historic controls, 4: cohort study, 5: case-control study, 6: cross-sectional study, 7: surveillance (e.g., using databases or registries), 8: series of consecutive cases. b A, B, C. denote different study groups.

72.4
9.1, n 5 34, C: TPTD þ RAL, age 70.5
8.4, n 5 41

int vBMD þ2.0%*, trab vBMD þ4.5%*, cort vBMD 1.8%*, DXA aBMD 1 þ 0.4%*, C: TH int vBMD þ9.7%*, trab vBMD þ10.8%*, cort vBMD þ6.3%*, DXA aBMD 1 þ 0.4%*, For FN results please see publication

9 mo to BL QCT visit (month 0) was 2.7%; *: estimated from graphs shown in the publications, data for a 12-mo extension phase not shown here

ISCD 2015 Official Positions - QCT of the Hip

351

Fig. 1. Mindways CTXA-hip: a 2D projection similar to a dual-energy X-ray absortiometry image is calculated from the computed tomography data. The true 3D QCT parameters are calculated from a back-projection of the segmented 2D projection into the 3D data set.

for a total femur scans are easier to identify than those for a neck-only scan. Discussion. It is not the intent of this position to state that parameters of the total femur are more important measurements than those of the neck. The position only refers to the CT scan, which should cover the total femur. This is equivalent to DXA, where also the total femur is scanned. The subsequent decision on analysis regions of interest depends on the specific clinical or scientific question. However, precision errors for bone mineral density as measured by 3D QCT (vBMD) measurements in the neck are about twice as high as vBMD measurements of the total femur (see Table 4 and position on age- and treatment-related changes).

Can QCT of the Hip be Used for Fracture Risk Assessment? ISCD Official Position Total femur trabecular BMD measured by QCT predicts hip fractures as well as hip BMD measured by DXA in postmenopausal women and older men.

Grade: FaireB-W Rationale. Age-adjusted standardized risk gradients can be calculated from a variety of cross-sectional studies in which

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Volume 18, 2015

352

Engelke et al. Table 4 Precision of 3D QCT of the Hip vBMD and FEA precision: duplicate 3D QCT scans of the hip with subject repositioning

Reference

Population

Lang (57)

n 5 7 female (age 60
10 yr) GE 9800, 80 kV, 280 mAs, 3-mm slice thickness

Li (58)

n 5 10 female (age 63
2 yr) Philips MX800, 90 kV, 280 mAs, 3-mm slice thickness, repeat scans were 3D registered

VOI

Parameter

tot femur tot femur Neck Neck tot femur tot femur tot femur Neck Neck Neck

int vBMD trab vBMD int vBMD trab vBMD int vBMD trab vBMD cort vBMD int vBMD trab vBMD cort vBMD

Intraoperator reanalysis CVrms [%]

Interoperator reanalysis CVrms [%]

0.4 0.3 3.0 1.8

0.2 0.3 2.5 2.2

Intraoperator reanalysis CVrms [%]

Interoperator reanalysis CVrms [%]

Inter scan CVrms [%] 0.8 0.8 3.3 1.1 0.9 0.8 1.2 1.3 4.5 1.1

vBMD reanalysis precision: repeat analysis of same scan

Yang (26)

16 scans from MrOs population analyzed 3 times each multiple scanners, 90 kV, 280 mA, 3-mm slice thickness

Gerner (59)

30 scans of pm female (age 63
2 yr), multicenter study, multiple scanners, 120 kV, 170 mAs, 1-mm slice thick. Five operators

tot femur tot femur tot Femur neck neck neck tot femur tot femur tot femur neck neck neck

int vBMD trab vBMD cort vBMD int vBMD trab vBMD cort vBMD int vBMD trab vBMD cort vBMD int vBMD trab vBMD cort vBMD

0.6a 0.5a 0.7a 1.2a 1.2a 1.2a 0.9 1.2 1.6 1.7 3.4 2.7

Abbr: cort, cortical; CV, coefficient of variation; int, intergral; pm, post menopausal; trab, trabecular; vBMD, bone mineral density as measured by 3D QCT; VOI, volume of interest. a %CV instead of %CVrms values were reported.

DXA and QCT of the hip have been determined in the same populations (Table 5). In 3 studies (26,30,46), standardized risk gradients for trabecular vBMD of the total hip as measured by 3D QCT were similar to those of DXA total hip aBMD. Discussion. Table 1 summarizes published QCT studies of the hip related to fracture prediction, fracture discrimination, or the comparison of groups with and without fractures. As discussed in more detail in (1), the risk gradient for a given measurement can be obtained from prospective cohort studies with fracture endpoint; however, these studies are sparse for QCT. As an alternative, cross-sectional studies may be used if in these studies an accepted gold standard, that is DXA, is used in parallel with QCT (61). Unfortunately, the predictive power of DXA often varies significantly among cross-sectional studies. To compare cross-

sectional studies and to further relate to the predictive power of DXA previously determined in large prospective cohort studies for QCT, a corrected standardized age-adjusted odds ratio sORcor

ln sRRref ðDXAÞ
lnðsORcor Þ 5 ln sORstudy ðQCTÞ , ln sORstudy ðDXAÞ can be used (62). sORstudy are the standardized age-adjusted odds ratios of the QCT and the DXA measurements for the cross-sectional study and sRRref(DXA) is the accepted standardized risk gradient for DXA obtained from a metaanalysis of multiple cohort studies taken here from Cummings et al (60). As evident from Table 5 in the 3 studies reporting 3D QCT total hip sORcor results (26,30,46) were numerically higher for trabecular than for integral vBMD although the difference

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353

Table 5 Standardized Age-Adjusted Risk Gradients for Hip Fractures for DXA Hip aBMD and 3D QCT vBMD Study Goldstandard: DXA femur Cummings (60),a 3D QCT hip Black (28), MrOsa

Yang (26), case-control design within MrOs Johannesdottir (25), casecontrol design within AGES

Gender

Variable

aBMD Male

Female Male

Yang (46)

Female

Cheng (30)

Female

int vBMD trab vBMD cort vBMD cort vol int vBMD trab vBMD cort vBMD int vBMD app cort thickness int vBMD app cort thickness int vBMD trab vBMD cort vBMD cort BMC app cort thickness int vBMD trab vBMD cort vBMD

Total femur

Neck

2.4 (2.2e2.6) 2.3 1.7 1.4 1.4 2.0 3.0 1.6 2.8 2.4 2.5 2.6 2.2 2.4 3.0 2.0 2.9 2.3 1.6 1.5

2.0 2.5 1.7

1.8 2.2 1.9 1.9 2.8 2.3 2.6 1.6

Note: Using RR values from publication (60) age-adjusted relative risks, hazard ratios, or odds ratios for QCT have been normalized to DXA of the femur for hip fractures according to the procedure described in section ‘‘Can QCT of .’’ Abbr: aBMD, areal bone mineral density; BMD, bone mineral density; cort, cortical; int, intergral; trab, trabecular; vBMD, bone mineral density as measured by 3D QCT. a Prospective studies.

may not have been significant. If the measurements were limited to the neck, the advantage for trabecular vBMD was less evident. In particular, in the only prospective analysis (28) sORcor was higher for integral compared to trabecular vBMD of the neck. Most of the studies listed in Table 5 report weaker fracture risk prediction for cortical vBMD than for integral vBMD. Interestingly, an in vitro study (57) confirmed these results: highest correlations with failure load were found in the total femur for trabecular and in the neck for integral vBMD, correlations with cortical vBMD were weaker in both locations. From a mechanical point of view, one would expect that integral vBMD should have at least the same capability to predict failure load than trabecular vBMD. The spatial resolution of QCT obtainable in vivo with acceptable radiation exposure limits the accuracy of cortical assessments. This may be one reason why integral vBMD predicts fracture better than cortical vBMD (Table 5). There is ongoing effort to improve the cortical segmentation and techniques implemented into the QCT analysis programs vary significantly. Several in vivo and in vitro studies included results of cortical thickness (25,27,29,46,63) or of bone strength parameters that depended on cortical thickness (30,31). In several studies, these parameters showed

high ORs for hip fracture discrimination or high correlations with failure load but most importantly the combination of vBMD and cortical thickness measurements seems to be most powerful (29,63), however, the consideration of cortical measurements in the official ISCD positions is premature.

Can QCT of the Hip be Used to Diagnose Osteoporosis? ISCD Official Position Femoral neck and total hip T-scores calculated from 2D projections of QCT data are equivalent to the corresponding DXA T-scores for diagnosis of osteoporosis in accordance with the WHO criteria.

Grade: FaireB-W Rationale. CTXA and VirtuOst T-scores calculated using the NHANES III reference data are equivalent to DXA T-scores. Other measurements for QCT of the hip, such as BMD assessments cannot be used for a diagnosis of osteoporosis because the exclusive applicability of the WHO diagnostic classification to DXA is inherent to the definition. Thus, the absence of

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354 an equivalent classification for techniques other than DXA does not indicate problems with these techniques but rather an intrinsic limitation of the WHO classification. This limitation is historical because at the time of the formulation of the WHO classification appropriate epidemiological data were only available for DXA. DXA of the hip still is the preferred method because precision data for CTXA and VirtuOst aBMD and T-scores have not been reported and because of higher radiation exposure. Discussion. aBMD of total femur and femoral neck as measured by CTXA are highly correlated (r2 O 0.9) with DXA of the same region (6,64) in studies of predominantly elderly postmenopausal women. In the CASH study, a study of Chinese males (63.8
5.6 yr) and females (62.0
6.8 yr) correlations for total femur (r2 5 0.88) and femoral neck (r2 5 0.81) were somewhat lower (65). Khoo et al (64) published calibration equations to derive equivalent DXA aBMD values from CTXA aBMD values using their population of old women (82.8
2.5 yr). CTXA T-scores were then calculated by comparing the calibrated CTXA aBMD values to young normal reference data from the NHANES III database (66). CTXA and DXA Tscores still differed but correlation were high (total femur: r2 5 0.88; femoral neck r2 5 0.84), and CTXA equivalent T-scores were obtained by another calibration (64). For the femoral neck the calibration from CTXA to DXA Tscore was almost identical in a more recent publication (67). In the CTXA hip module of the QCTPro software, by default CTXA T-Scores are calculated by comparing the measured CTXA aBMD values with the CTXA reference data. Optionally NHANES III reference data can be installed in the CTXA Hip module. In this case, the CTXA T-scores are calibrated to equivalent DXA T-scores using the equations in the Khoo publication (64), but it should be remembered that the aBMD estimates returned by the CTXA Hip module are independent of the installed

Fig. 2. Average T-scores vs age: comparison of CTXA ‘‘equivalent DXA T-scores’’ with Hologic DXA T-scores based on NHANES III reference data (courtesy: Keenan Brown, Mindways Inc). CTXA, computed tomography Xray absorptiometry; DXA, dual-energy X-ray absorptiometry.

Engelke et al. reference data set. Fig. 2 shows the equivalence of the CTXA NHANES III and the Hologic DXA NHANES III T-scores. For the VirtuOst software, good agreement of age-related changes between the procreational BMD measurement and DXA aBMD of the hip has been shown in the Rochester cohort (68). The VirtuOst aBMD algorithm developed in the Rochester cohort was validated in an independent population of 75 community dwelling women and men over age 65 yr also from the Rochester, MN area. Similar to CTXA, VirtuOst and DXA T-scores correlated highly (r2 5 0.93) (69). For the USCF implementation, a good correlation between QCT and DXA aBMD measures (r 5 0.94, SEE 5 0.046 mg/cm2, SEE: standard error of the estimate) has been reported (70).

Can QCT of the Hip Be Used to Monitor Treatment Or Age-Related Changes of BMD? ISCD Official Position Integral and trabecular BMD of the proximal femur measured by QCT can be used to monitor age- and treatment-related BMD changes.

Grade: FaireB-W Rationale. 3D QCT of the hip has been used successfully to assess age-related changes of vBMD in women (36e41) and men. With respect to treatment, 3D QCT of the hip in women has been used successfully to monitor vBMD in prospective treatment studies of alendronate (8,9,22,23,44,48,51,71), ibandronate (7,12), raloxifene (22,23), teriparatide (9,17,22,23), parathyroid hormone (PTH) (44), denosumab (11,16,21), ronacanalerete (9), odanacatib (10,20), ONO-5334 cathsepsin-K (8), and zolodronic acid (13,15). In most of the studies, postmenopausal women were evaluated. DXA of the spine and hip were also used in several of these studies. In men, QCT of the hip has not been used in any treatment studies to date. Precision data required to calculate least significant changes (LSC) and monitoring time interval (MTI), required when monitoring individual patients have been published for 3D QCT of the hip. Discussion. A large number of studies have shown that vBMD as measured by QCT of the hip can monitor age (Table 2) and treatment-related changes (Table 3) at least as well as DXA aBMD of the hip. Although no treatment studies using QCT have been reported in men, the odds that QCT cannot be used to asses corresponding treatment-related changes in men are small. To transfer the result to the individual patient, precision data are required to compute least significant changes and MTIs. Although currently in practice, DXA is the primary method to monitor BMD changes in the hip the

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ISCD 2015 Official Positions - QCT of the Hip use of QCT may particularly be useful if DXA is not performed, for example, if CT scans obtained for other diagnostic purposes will also be used for follow-up measurements. Precision data of vBMD measured with 3D QCT at the hip are summarized in Table 4. Only 2 studies (57,58), both conducted at UCSF, reported precision from duplicate patient measurements with repositioning reflecting the difficulty of obtaining ethical approval for duplicated QCT hip scans. The results from (57) showed that repositioning added about 0.5% to interoperator reanalysis precision results and the results from (58) showed that a 3D registration predominantly improved precision of cortical vBMD, while precision errors of integral and trabecular bone decreased only slightly compared to an independent analysis of the 2 scans. The other 2 studies only reported intraoperator (26) or interoperator (59) reanalysis precision errors, but it seems to be justified to add the 0.5% difference to a plain reanalysis precision error to estimate the precision with repositioning reported previously. The reason is that the QCT analysis is less affected by repositioning than DXA because instead of a projectional image affected by rotation, the full 3D data set is segmented and analyzed. There was agreement across all 4 studies that precision errors for neck measurements were about 50% higher than for total femur measurements. Not surprisingly in higher resolution scans obtained with lower mAs precision errors were slightly higher. The studies from Yang and Engelke used scans from multicenter studies involving different type of equipment and all 4 studies used scans from elderly subjects representative of the osteoporotic population seen in clinical practice. Taken together, the studies show that for total femur vBMD scans an in vivo short-term precision error of 1%e2% and in the neck of 2%e3% can be obtained, values comparable to hip DXA (72). LSC of 2.5% e5% for total femur vBMD and 1% annual change in vBMD translate to a MTI of 2.5e5 yr, and a 1.5% vBMD change to an MTI of 1.7e3.3 yr. These values are also comparable to hip DXA. In the Ages-Reykjavik study 5-yr decreases of total femur trabecular vBMD were about 20% higher in men and about 4 times as high in postmenopausal women compared to decrease in total femur aBMD (40), whereas decreases in the neck were very similar (39). Both studies used the Ages-Reykjavik population but different subcohorts were analyzed. In the Rochester Epidemiology Project QCT data set, between the ages of 20 and 90 yr, integral vBMD decreased by 42%, 38%, and 43% in the neck, trochanter, and intertrochanter, respectively, whereas in the NHANES III study, corresponding decreases for areal BMD were 33%, 28%, and 28% (66). Similar to NHANES III total hip aBMD in the Rochester Epidemiology Project QCT data set decreased by about 30% (68). In another study of Korean women, Kim (36) also reported higher age-related vBMD than aBMD decreases.

355 Thus with comparable LSC and MTI values for total hip vBMD and aBMD and higher age-related vBMD decreases, in particular for trabecular vBMD, QCT is more sensitive to capture age-related changes. A similar conclusion can be drawn with respect to treatment related changes. Although integral vBMD treatment effects of the total femur were mostly comparable to those for aBMD, changes in trabecular vBMD were higher. In conclusion, the ISCD official positions provided here address the application of QCT of the hip. They complement the 2007 ISCD official positions for QCT of the spine and peripheral QCT of the distal radius and tibia. Based on an extensive review evidence supporting the ISCD official positions is presented. It is obvious from the last years that QCT still is an area of rapid development, therefore it is recommended that the evidence be reviewed again, in the not too distant future, and to update these ISCD official positions as new information becomes available.

Acknowledgment We acknowledge the input of A. Brett from Mindways Inc. who served as external expert.

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