BACKGROUND: Hip fractures are mainly caused by accidental falls and trips, which magnify forces in well-defined areas of the proximal femur. Unfortunately, the same areas are at risk of rapid bone loss with ageing, since they are relatively stress-shielded during walking and sitting. Focal osteoporosis in those areas may contribute to fracture, and targeted 3D measurements might enhance hip fracture prediction. In the FEMCO case-control clinical study, Cortical Bone Mapping (CBM) was applied to clinical computed tomography (CT) scans to define 3D cortical and trabecular bone defects in patients with acute hip fracture compared to controls. Direct measurements of trabecular bone volume were then made in biopsies of target regions removed at operation. METHODS: The sample consisted of CT scans from 313 female and 40 male volunteers (158 with proximal femoral fracture, 145 age-matched controls and 50 fallers without hip fracture). Detailed Cortical Bone Maps (c.5580 measurement points on the unfractured hip) were created before registering each hip to an average femur shape to facilitate statistical parametric mapping (SPM). Areas where cortical and trabecular bone differed from controls were visualised in 3D for location, magnitude and statistical significance. Measures from the novel regions created by the SPM process were then tested for their ability to classify fracture versus control by comparison with traditional CT measures of areal Bone Mineral Density (aBMD). In women we used the surgical classification of fracture location ('femoral neck' or 'trochanteric') to discover whether focal osteoporosis was specific to fracture type. To explore whether the focal areas were osteoporotic by histological criteria, we used micro CT to measure trabecular bone parameters in targeted biopsies taken from the femoral heads of 14 cases. RESULTS: Hip fracture patients had distinct patterns of focal osteoporosis that determined fracture type, and CBM measures classified fracture type better than aBMD parameters. CBM measures however improved only minimally on aBMD for predicting any hip fracture and depended on the inclusion of trabecular bone measures alongside cortical regions. Focal osteoporosis was confirmed on biopsy as reduced sub-cortical trabecular bone volume. CONCLUSION: Using 3D imaging methods and targeted bone biopsy, we discovered focal osteoporosis affecting trabecular and cortical bone of the proximal femur, among men and women with hip fracture.

BOTNAR Research Institute Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford UK

Department of Engineering University of Cambridge Cambridge UK

Department of Medicine University of Cambridge and Addenbrooke's Hospital Hills Road Cambridge UK

Department of Orthopaedics Faculty of Medicine Charles University and Bulovka Hospital Prague Czech Republic

Department of Orthopaedics Norfolk and Norwich University Hospital Norwich UK

Department of Radiology Homolka Hospital Prague Czech Republic

Faculty of Medicine 1 Charles University and Institute of Rheumatology Prague Czech Republic

Medicine for the Elderly Addenbrooke's Hospital Hills Road Cambridge UK

See more in PubMed

Parker M., Johansen A. Hip fracture. BMJ. 2006;333:27–30. PubMed PMC

Clinical Guideline (CG124) Excellence NIfHaC. 2011. The management of hip fracture in adults. ed. London.

Pulkkinen P., Gluer C.C., Jamsa T. Investigation of differences between hip fracture types: a worthy strategy for improved risk assessment and fracture prevention. Bone. 2011;49:600–604. PubMed

Moja L., Piatti A., Pecoraro V. Timing matters in hip fracture surgery: patients operated within 48 hours have better outcomes. A meta-analysis and meta-regression of over 190,000 patients. PLoS One. 2012;7 PubMed PMC

Juszczyk M.M., Cristofolini L., Salva M., Zani L., Schileo E., Viceconti M. Accurate in vitro identification of fracture onset in bones: failure mechanism of the proximal human femur. J. Biomech. 2013;46:158–164. PubMed

Schileo E., Balistreri L., Grassi L., Cristofolini L., Taddei F. To what extent can linear finite element models of human femora predict failure under stance and fall loading configurations? J. Biomech. 2014;47:3531–3538. PubMed

de Bakker P.M., Manske S.L., Ebacher V., Oxland T.R., Cripton P.A., Guy P. During sideways falls proximal femur fractures initiate in the superolateral cortex: evidence from high-speed video of simulated fractures. J. Biomech. 2009;42:1917–1925. PubMed

Mayhew P.M., Thomas C.D., Clement J.G. Relation between age, femoral neck cortical stability, and hip fracture risk. Lancet. 2005;366:129–135. PubMed

Issever A.S., Burghardt A., Patel V. A micro-computed tomography study of the trabecular bone structure in the femoral head. J. Musculoskelet. Neuronal Interact. 2003;3:176–184. PubMed

Jenkins P.J., Ramaesh R., Pankaj P. A micro-architectural evaluation of osteoporotic human femoral heads to guide implant placement in proximal femoral fractures. Acta Orthop. 2013;84:453–459. PubMed PMC

Carballido-Gamio J., Harnish R., Saeed I. Proximal femoral density distribution and structure in relation to age and hip fracture risk in women. J. Bone Miner. Res. 2013;28:537–546. PubMed PMC

Nicolella D.P., Bredbenner T.L. Development of a parametric finite element model of the proximal femur using statistical shape and density modelling. Comput. Methods Biomech. Biomed. Engin. 2012;15:101–110. PubMed PMC

Treece G.M., Poole K.E., Gee A.H. Imaging the femoral cortex: thickness, density and mass from clinical CT. Med. Image Anal. 2012;16:952–965. PubMed PMC

Treece G.M., Gee A.H., Mayhew P.M., Poole K.E. High resolution cortical bone thickness measurement from clinical CT data. Med. Image Anal. 2010;14:276–290. PubMed PMC

Carballido-Gamio J., Nicolella D.P. Computational anatomy in the study of bone structure. Curr. Osteoporos. Rep. 2013;11:237–245. PubMed

Carballido-Gamio J., Harnish R., Saeed I. Structural patterns of the proximal femur in relation to age and hip fracture risk in women. Bone. 2013;57:290–299. PubMed PMC

Poole K.E., Treece G.M., Mayhew P.M. Cortical thickness mapping to identify focal osteoporosis in patients with hip fracture. PLoS One. 2012;7 PubMed PMC

Nawathe S., Akhlaghpour H., Bouxsein M.L., Keaveny T.M. Microstructural failure mechanisms in the human proximal femur for sideways fall loading. J. Bone Miner. Res. 2014;29:507–515. PubMed

Bessho M., Ohnishi I., Matsumoto T. Prediction of proximal femur strength using a CT-based nonlinear finite element method: differences in predicted fracture load and site with changing load and boundary conditions. Bone. 2009;45:226–231. PubMed

Treece G.M., Gee A.H., Tonkin C. Predicting hip fracture type with cortical bone mapping (CBM) in the osteoporotic fractures in men (MrOS) study. J. Bone Miner. Res. 2015 PubMed PMC

Seeherman H.J., Li X.J., Smith E., Parkington J., Li R., Wozney J.M. Intraosseous injection of rhBMP-2/calcium phosphate matrix improves bone structure and strength in the proximal aspect of the femur in chronic ovariectomized nonhuman primates. J. Bone Joint Surg. Am. 2013;95:36–47. PubMed

Cann C.E., Adams J.E., Brown J.K., Brett A.D. CTXA hip–an extension of classical DXA measurements using quantitative CT. PLoS One. 2014;9 PubMed PMC

Treece G.M., Gee A.H. Independent measurement of femoral cortical thickness and cortical bone density using clinical CT. Med. Image Anal. 2015;20:249–264. PubMed

Poole K.E., Mayhew P.M., Rose C.M. Changing structure of the femoral neck across the adult female lifespan. J. Bone Miner. Res. 2010;25:482–491. PubMed

McEniery C.M., McDonnell B.J., So A. Aortic calcification is associated with aortic stiffness and isolated systolic hypertension in healthy individuals. Hypertension. 2009;53:524–531. PubMed

Muller M.E. Classification and international AO-documentation of femur fractures. Unfallheilkunde. 1980;83:251–259. PubMed

Poole K.E., Treece G.M., Gee A.H. Denosumab rapidly increases cortical bone in key locations of the femur: A 3D bone mapping study in women with osteoporosis. J. Bone Miner. Res. 2015;30:46–54. PubMed

Whitmarsh T., Fritscher K.D., Humbert L. A statistical model of shape and bone mineral density distribution of the proximal femur for fracture risk assessment. Medical image computing and computer-assisted intervention; MICCAI International Conference on Medical Image Computing and Computer-Assisted Intervention; 2011. pp. 393–400. PubMed

Whitmarsh T., Humbert L., De Craene M., Del Rio Barquero L.M., Frangi A.F. Reconstructing the 3D shape and bone mineral density distribution of the proximal femur from dual-energy X-ray absorptiometry. IEEE Trans. Med. Imaging. 2011;30:2101–2114. PubMed

Friston K.J., Holmes A.P., Worsley K.J., Poline J.-P., Frith C.D., Frackowiak R.S.J. Statistical parametric maps in functional imaging: A general linear approach. Hum. Brain Mapp. 1994;2:189–210.

Worsley K., Taylor J., Carbonell F. NeuroImage Organization for Human Brain Mapping 2009 Annual Meeting. 2009. SurfStat: a Matlab toolbox for the statistical analysis of univariate and multivariate surface and volumetric data using linear mixed effects models and random field theory; pp. 47–S102.

Gee A.H., Treece G.M. Systematic misregistration and the statistical analysis of surface data. Med. Image Anal. 2014;18:385–393. PubMed

Andrade A., Paradis A.L., Rouquette S., Poline J.B. Ambiguous results in functional neuroimaging data analysis due to covariate correlation. NeuroImage. 1999;10:483–486. PubMed

Poline J., Kherif F., Pallier C., Penny W. Contrasts and classical inference. In: Friston K.J., Ashburner J.T., Kiebel S., Nichols T., Penny W.D., editors. Statistical Parametric Mapping: The Analysis of Functional Brain Images. Academic Press; 2007. pp. 126–139.

Doube M., Klosowski M.M., Arganda-Carreras I. BoneJ: Free and extensible bone image analysis in ImageJ. Bone. 2010;47:1076–1079. PubMed PMC

Schwartzbaum J., Ahlbom A., Feychting M. Berkson's bias reviewed. Eur. J. Epidemiol. 2003;18:1109–1112. PubMed

Thomas C.D., Mayhew P.M., Power J. Femoral neck trabecular bone: loss with aging and role in preventing fracture. J. Bone Miner. Res. 2009;24:1808–1818. PubMed

Huber M.B., Carballido-Gamio J., Bauer J.S. Proximal femur specimens: automated 3D trabecular bone mineral density analysis at multidetector CT–correlation with biomechanical strength measurement. Radiology. 2008;247:472–481. PubMed

Bousson V.D., Adams J., Engelke K. In vivo discrimination of hip fracture with quantitative computed tomography: results from the prospective European Femur Fracture Study (EFFECT) J. Bone Miner. Res. 2011;26:881–893. PubMed

Johannesdottir F., Poole K.E., Reeve J. Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study. Bone. 2011;48:1268–1276. PubMed PMC

Issever A.S., Walsh A., Lu Y., Burghardt A., Lotz J.C., Majumdar S. Micro-computed tomography evaluation of trabecular bone structure on loaded mice tail vertebrae. Spine. 2003;28:123–128. PubMed

Milovanovic P., Djonic D., Marshall R.P. Micro-structural basis for particular vulnerability of the superolateral neck trabecular bone in the postmenopausal women with hip fractures. Bone. 2012;50:63–68. PubMed

Chiba K., Burghardt A.J., Osaki M., Majumdar S. Heterogeneity of bone microstructure in the femoral head in patients with osteoporosis: an ex vivo HR-pQCT study. Bone. 2013;56:139–146. PubMed PMC

Homminga J., McCreadie B.R., Ciarelli T.E., Weinans H., Goldstein S.A., Huiskes R. Cancellous bone mechanical properties from normals and patients with hip fractures differ on the structure level, not on the bone hard tissue level. Bone. 2002;30:759–764. PubMed

Albright F., Reifenstein J.E.C. 1st ed. Baltimore, USA; The Williams and Wilkins Company: 1948. The Parathyroid Glands and Metabolic Bone Disease – Selected Studies.

Duboeuf F., Hans D., Schott A.M. Different morphometric and densitometric parameters predict cervical and trochanteric hip fracture: the EPIDOS Study. J. Bone Miner. Res. 1997;12:1895–1902. PubMed

Poole K.E., Treece G.M., Ridgway G.R., Mayhew P.M., Borggrefe J., Gee A.H. Targeted regeneration of bone in the osteoporotic human femur. PLoS One. 2011;6 PubMed PMC

Allison S.J., Poole K.E., Treece G.M. The influence of high-impact exercise on cortical and trabecular bone mineral content and 3D distribution across the proximal femur in older men: a randomized controlled unilateral intervention. J. Bone Miner. Res. 2015;30:1709–1716. PubMed

Pickhardt P.J., Pooler B.D., Lauder T., del Rio A.M., Bruce R.J., Binkley N. Opportunistic screening for osteoporosis using abdominal computed tomography scans obtained for other indications. Ann. Intern. Med. 2013;158:588–595. PubMed PMC

Kopperdahl D.L., Aspelund T., Hoffmann P.F. Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans. J. Bone Miner. Res. 2014;29:570–580. PubMed PMC

Keaveny T.M., McClung M.R., Genant H.K. Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. J. Bone Miner. Res. 2014;29:158–165. PubMed PMC

Black D.M., Bouxsein M.L., Marshall L.M. Proximal femoral structure and the prediction of hip fracture in men: a large prospective study using QCT. J. Bone Miner. Res. 2008;23:1326–1333. PubMed PMC

Lang T.F., Sigurdsson S., Karlsdottir G. Age-related loss of proximal femoral strength in elderly men and women: the age gene/environment susceptibility study — Reykjavik. Bone. 2012;50:743–748. PubMed PMC

Li W., Kornak J., Harris T. Identify fracture-critical regions inside the proximal femur using statistical parametric mapping. Bone. 2009;44:596–602. PubMed PMC

Cauley J.A., Chalhoub D., Kassem A.M., Fuleihan G.E. Geographic and ethnic disparities in osteoporotic fractures. Nat. Rev. Endocrinol. 2014 PubMed

Whitmarsh T., Fritscher K.D., Humbert L. Hip fracture discrimination from dual-energy X-ray absorptiometry by statistical model registration. Bone. 2012;51:896–901. PubMed