We have recently developed image processing techniques for measuring the cortical thicknesses of skeletal structures in vivo, with resolution surpassing that of the underlying computed tomography system. The resulting thickness maps can be analysed across cohorts by statistical parametric mapping. Applying these methods to the proximal femurs of osteoporotic women, we discover targeted and apparently synergistic effects of pharmaceutical osteoporosis therapy and habitual mechanical load in enhancing bone thickness

Borggrefe, Jan

Gee, Andrew H

Mayhew, Paul M

Poole, Kenneth ES

Ridgway, Gerard R

Treece, Graham M

PLoS ONE

English

PubMed

Kenneth E S Poole

Graham M Treece

Gerard R Ridgway

Paul M Mayhew

Jan Borggrefe

Andrew H Gee

Directory of Open Access Journals

Targeted regeneration of bone in the osteoporotic human femur.

Kenneth E. S. Poole

Graham M. Treece

Gerard R. Ridgway

Paul M. Mayhew

Andrew H. Gee

CiteSeerX

Targeted regeneration of bone in the osteoporotic human femur

Poole, KES

Treece, GM

Ridgway, GR

Mayhew, PM

Borggrefe, J

Gee, AH

UCL Discovery

Targeted Regeneration of Bone in the OsteoporoticHuman FemurKenneth E. S. Poole1 *, Graham M. Treece , Gerard R. Ridgway , Paul M. Mayhew , Jan Borggrefe ,2 3 1 4Andrew H. Gee21Department of Medicine, University of Cambridge, Cambridge, United Kingdom, 2Department of Engineering, University of Cambridge, Cambridge, United Kingdom,3Institute of Neurology, University College London, London, United Kingdom, 4Department of Diagnostic Radiology, University of Schleswig Holstein, Kiel, GermanyAbstractWe have recently developed image processing techniques for measuring the cortical thicknesses of skeletal structures invivo, with resolution surpassing that of the underlying computed tomography system. The resulting thickness maps can beanalysed across cohorts by statistical parametric mapping. Applying these methods to the proximal femurs of osteoporoticwomen, we discover targeted and apparently synergistic effects of pharmaceutical osteoporosis therapy and habitualmechanical load in enhancing bone thickness.Citation: Poole KES, Treece GM, Ridgway GR, Mayhew PM, Borggrefe J, et al. (2011) Targeted Regeneration of Bone in the Osteoporotic Human Femur. PLoSONE 6(1): e16190. doi:10.1371/journal.pone.0016190Editor: Sudha Agarwal, Ohio State University, United States of AmericaReceived September 15, 2010; Accepted December 16, 2010; Published January 14, 2011Copyright:  2011 Poole et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Funding: This work was supported by an Arthritis Research UK Clinician Scientist Fellowship award to KESP (The FEMCO study, ARC17822, http://www.arthritisresearchuk.org/) and by the Cambridge Biomedical Research Centre (National Institute for Health Research), an institutional award that supports PMM. Thefunders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: KESP and GMT are inventors on a related Great Britain patent application GB0917524.1, "Image data processing systems." This does notalter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.* E-mail: kp254@nhs.netIntroductionThe femur, with its complex load bearing properties andeventual fragility, has been a key anatomical site of study forbiologists, engineers and anthropologists across several centuries[1,2,3]. Indeed, the seminal concept of ‘functional adaptation’,whereby deformation is sensed by bone cells and transduced intobiological signals to optimise skeletal architecture, was based onobservations of proximal femoral structure [1,3,4]. This idea haslong been used to inform orthopaedic practice, and it is in thistradition that we here address an open question in human bonebiology: where, precisely, is bone regenerated in response toosteoporosis therapy? With annual hip fracture rates predicted toexceed six million by 2050, and the distribution of cortical bone inthe proximal femur believed to be the key determinant of fractureresistance [5,6], this question is of scientific, social and economicimportance. The established clinical intervention to stimulate newbone formation is parathyroid hormone (PTH), administered bydaily subcutaneous injection [7]. Invasive animal studies point to asynergistic effect of PTH and localised mechanical stress on bonecells [8], but the more limited experimental techniques applicableto living human beings have, to date, revealed only grossdifferences in response between heavily loaded sites like the femurand lightly loaded sites like the radius [7].Further insight has been hampered by the limited resolution ofwhole-body computed tomography (CT) systems and the per-ceived futility of using such systems to pinpoint tiny changes incortical bone distribution. Now, however, a new CT imageprocessing technique [9] allows us to display cortical thickness as acolour map over the bone surface (Fig. 1a), with several thousandindependent measurements across each proximal femur andsufficient sensitivity to detect even small changes (,30 microns)when expressed systematically by a suitably sized cohort. By makingreasonableassumptions,thattheactual corticaldensity doesnot varydramatically for a given subject at a given time, and that the imagingblur is roughly Gaussian in shape, thickness can be measured tosuper-resolution accuracy, except at the femoral head where theproximity of the acetabulum is problematic. The methodology hasbeen validated against gold standard thickness measurementsobtained from micro-CT scans of cadaveric femurs [9].MethodsHere, we use this technique to map the small changes in corticalbone distribution stimulated by pharmaceutical treatment forosteoporosis. In one branch of the EUROFORS study [10], 69women with severe osteoporosis were treated with recombinanthuman PTH (hPTH-(1-34)) for 24 months, with quantitative CTscans at baseline and 24 months. All data from this cohort wasanalysed in the present study, with the exception of those femurscompromised by metalwork and those where one or both of theCT scans did not extend as far as the lesser trochanter. Thisyielded 119 femurs from 65 women (mean age 67.566.8 years).Participants were from twelve investigative centres in Germanyand Spain [11]. Institutional Review Board approval was obtainedfrom each of the clinical study sites, and written informed consentfor EUROFORS (ClinicalTrials.gov ID NCT00191425) and theQCT sub-study were obtained from each participant. The presentanalysis was approved by Cambridgeshire 4 research ethicscommittee (LREC07/H0305/61).Analysis of the 238 thickness maps followed established practicewithin the neuroimaging community, who have pioneeredtechniques for statistical inference from dense, spatially correlateddata. To account for variations in inter-subject morphology, eachPLoS ONE | www.plosone.org 1 January 2011 | Volume 6 | Issue 1 | e16190map was spatially realigned with a canonical femur surface using aB-spline free-form deformation [12] calculated by the iterativeclosest point registration algorithm [13]. The spatially normalizedmaps were then smoothed with a 10 mm full-width-half-maximumfilter. Thickness changes were summarised for each subject bysubtracting the baseline maps from the 24-month maps andaveraging the left and right responses where both were available.This resulted in 65 summarised response maps, 54 derived fromaveraged left-right data and 11 from single femurs. Formalinference was accomplished by statistical parametric mapping[14], as implemented in the SurfStat package [15]. The modelfitted to the summarised data comprised a constant term and arandom-effect term for left-right averaging: this allows for unequalvariances between the averaged and unaveraged data. T-statisticswere calculated to test the significance of the constant term,corresponding to positive thickness change. Random field theorythen furnished P-values, corrected for multiple comparisons tocontrol the overall image-wise chance of false positives.Results and DiscussionBaseline measurements reveal the anatomical distribution ofcortical thickness seen in advanced osteoporosis (Fig. 2a). Thenonuniformly thin cortex is of clinical relevance, since fracturescommonly traverse the neck (Fig. 1c) or split the trochantericregion during sideways falls (Fig. 1d) [5]. The variation in thicknesspartly reflects femoral growth, with thick bone of the inferomedialaspect preserved into late adulthood by lifelong functionaladaptation to stress, and a thin cortex apparent superiorly. Inother areas, such as the trochanters and their connecting crest,thin cortices overlie predominantly trabecular bone near bony sitesof muscle and tendon insertion (entheses). Following hPTH-(1-34)treatment, and in striking contrast to the expected ageing effects[5], the percentage change map (Fig. 2b) shows marked corticalthickening. Figure 2c shows corrected P-maps for positivethickness change, based on the magnitude of peaks (sensitive tofocal effects) and on the extent of connected clusters exceeding anFigure 1. Visualising the femur in health and trauma. (a) A cortical thickness map of a healthy adult male femur with thick (blue/green) cortexat sites of high load during walking, (b) cortical and trabecular bone. Typical fractures in the (c) femoral neck and (d) inter-trochanteric regions.doi:10.1371/journal.pone.0016190.g001Regeneration of Bone in Osteoporotic Human FemursPLoS ONE | www.plosone.org 2 January 2011 | Volume 6 | Issue 1 | e16190uncorrected P-value threshold of 0.001 (sensitive to distributedeffects).New bone is targeted to regions that predictably encounter highstress during normal locomotion, namely the infero-medialjunction of the cortex with the load-bearing calcar femorale, andthe head-neck junction of the superior cortex. Both these sites arecommonly involved in fracture. No regions of statisticallysignificant thinning are apparent. Foci of new bone are alsoevident at the entheses of powerful locomotion muscles; on thegreater and lesser trochanters at the attachment sites of the gluteusmedius and psoas, and at the inter-trochanteric insertion of thequadratus femoris.Parathyroid hormone is an established clinical intervention tostimulate new bone formation in human osteoporosis. Previousstudies have shown that hPTH-(1-34) treatment in postmenopaus-al women with osteoporosis increases cortical thickness at variousskeletal sites, but this is the first to demonstrate the precise regionaleffects at one of the key sites of fragility fracture, the human hip.hPTH-(1-34) is also known to increase porosity (at least early intreatment) and reduce the mineral density, since new bonestimulated by the drug is relatively under-mineralised compared toolder bone [16]. The cortical thickness measurement is robust toany consequent changes to the average cortical density, since theaverage density value is estimated independently in each data set.It is equally robust to any regional changes in the quality of the CTdata, since the extent of the imaging blur is estimated at everymeasurement location.Intriguingly, both load and PTH act rapidly on the entombed’load sensing’ osteocytes to profoundly reduce secretion of a keymolecular inhibitor of bone formation, sclerostin [17]. Releasedfrom inhibition, the osteoblasts (surface targets of sclerostin) canthen secrete new bone matrix. Fig. 2b suggests a possiblesynergistic effect of habitual load and PTH in the human proximalfemur, since peak effects are seen at sites that are highly stressed byFigure 2. Cortical thickness maps showing severe osteoporosis and the increase in thickness following hPTH-(1-34) treatment. (a)Medial, superior and posterior views of the average pre-treatment cortical thickness map in advanced osteoporosis showing remnants of thicker,highly loaded bone (blue/green) at A) the inferomedial cortex and B) the calcar femorale regions. Elsewhere there is thin, sub-millimetre cortex (pink/red) at key fracture sites including C) the subcapital superior neck region. Also labelled are the insertion sites of key muscles of locomotion; D) gluteusmedius, E) psoas major and F) quadratus femoris (on the inter-trochanteric crest). (b) Post-treatment percentage change and (c) statistical significancemaps which together indicate regeneration of bone at A), B), C), D), E) and F).doi:10.1371/journal.pone.0016190.g002Regeneration of Bone in Osteoporotic Human FemursPLoS ONE | www.plosone.org 3 January 2011 | Volume 6 | Issue 1 | e16190walking. In the light of this, we ask whether hPTH-(1-34)treatment for osteoporosis might be more effective if combinedwith enhanced skeletal loading. Cortical thickness mapping is theideal tool to answer this and other open questions in bone biology.AcknowledgmentsWe thank the contributing investigators of the EUROFORS study.Author ContributionsConceived and designed the experiments: KESP GMT AHG. Performedthe experiments: KESP GMT AHG. Analyzed the data: KESP GMTGRR AHG. Contributed reagents/materials/analysis tools: KESP GMTGRR PMM JB AHG. Wrote the paper: KESP GMT GRR PMM JBAHG.References1. Roux W (1885) Beitrage zur Morphologie der funktionnellen Anspassung. ArchAnat Physiol Anat Abt 9: 120–158.2. Lovejoy CO, Suwa G, Spurlock L, Asfaw B, White TD (2009) The pelvis andfemur of Ardipithecus ramidus: the emergence of upright walking. Science 326:71e71–76.3. Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K (2001) Anabolism.Low mechanical signals strengthen long bones. Nature 412: 603–604.4. Huiskes R, Ruimerman R, van Lenthe GH, Janssen JD (2000) Effects ofmechanical forces on maintenance and adaptation of form in trabecular bone.Nature 405: 704–706.5. Mayhew PM, Thomas CD, Clement JG, Loveridge N, Beck TJ, et al. (2005)Relation between age, femoral neck cortical stability, and hip fracture risk.Lancet 366: 129–135.6. Burr DB (2010) Cortical bone: a target for fracture prevention? Lancet 375:1672–1673.7. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, et al. (2001) Effectof parathyroid hormone (1-34) on fractures and bone mineral density inpostmenopausal women with osteoporosis. N Engl J Med 344: 1434–1441.8. Roberts MD, Santner TJ, Hart RT (2009) Local bone formation due tocombined mechanical loading and intermittent hPTH-(1-34) treatment and itscorrelation to mechanical signal distributions. J Biomech 42: 2431–2438.9. Treece GM, Gee AH, Mayhew PM, Poole KE (2010) High resolution corticalbone thickness measurement from clinical CT data. Med Image Anal 14:276–290.10. Eastell R, Nickelsen T, Marin F, Barker C, Hadji P, et al. (2009) Sequentialtreatment of severe postmenopausal osteoporosis after teriparatide: final resultsof the randomized, controlled European Study of Forsteo (EUROFORS). J BoneMiner Res 24: 726–736.11. Borggrefe J, Graeff C, Nickelsen TN, Marin F, Gluer CC (2009) QuantitativeComputed Tomography Assessment of the Effects of 24 months of TeriparatideTreatment on 3-D Femoral Neck Bone Distribution, Geometry and BoneStrength: Results from the EUROFORS Study. J Bone Miner Res 25: 472–481.12. Rueckert D, Frangi AF, Schnabel JA (2003) Automatic construction of 3-Dstatistical deformation models of the brain using nonrigid registration. IEEETrans Med Imaging 22: 1014–1025.13. Besl PJ, McKay ND (1992) A Method for Registration of 3-D Shapes. IEEETrans Pattern Anal Mach Intell 14: 239–256.14. Friston KJ, Holmes AP, Worsley KJ, Poline J-P, Frith CD, et al. (1994) Statisticalparametric maps in functional imaging: A general linear approach. HumanBrain Mapping 2: 189–210.15. Worsley K, Taylor J, Carbonell F, Chung M, Duerden E, et al. (2009) SurfStat:A Matlab toolbox for the statistical analysis of univariate and multivariatesurface and volumetric data using linear mixed effects models and random fieldtheory. NeuroImage Organization for Human Brain Mapping 2009 AnnualMeeting 47: S102.16. Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, et al. (2003) Effects ofintermittent parathyroid hormone administration on bone mineralizationdensity in iliac crest biopsies from patients with osteoporosis: a paired studybefore and after treatment. J Clin Endocrinol Metab 88: 1150–1156.17. O’Brien CA, Plotkin LI, Galli C, Goellner JG, Gortazar AR, et al. (2008)Control of Bone Mass and Remodeling by PTH Receptor Signaling inOsteocytes. PLoS ONE 3: e2942.Regeneration of Bone in Osteoporotic Human FemursPLoS ONE | www.plosone.org 4 January 2011 | Volume 6 | Issue 1 | e16190

(1885) Beitrage zur Morphologie der funktionnellen Anspassung.

A Method for Registration of 3-D Shapes.

Anabolism. Low mechanical signals strengthen long bones.

Automatic construction of 3-D statistical deformation models of the brain using nonrigid registration.

Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes.

Cortical bone: a target for fracture prevention?

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment.

Effects of mechanical forces on maintenance and adaptation of form in trabecular bone.

High resolution cortical bone thickness measurement from clinical CT data.

Local bone formation due to combined mechanical loading and intermittent hPTH-(1-34) treatment and its correlation to mechanical signal distributions.

Quantitative Computed Tomography Assessment of the Effects of 24 months of Teriparatide Treatment on 3-D Femoral Neck Bone Distribution, Geometry and Bone Strength: Results from the EUROFORS Study.

Relation between age, femoral neck cortical stability, and hip fracture risk.

Sequential treatment of severe postmenopausal osteoporosis after teriparatide: final results of the randomized, controlled European Study of Forsteo (EUROFORS).

Statistical parametric maps in functional imaging: A general linear approach.

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. NeuroImage Organization for Human Brain Mapping

The pelvis and femur of Ardipithecus ramidus: the emergence of upright walking.

Targeted Regeneration of Bone in the Osteoporotic Human Femur

Apollo (Cambridge)

Targeted Regeneration of Bone in the OsteoporoticHuman FemurKenneth E. S. Poole1 *, Graham M. Treece , Gerard R. Ridgway , Paul M. Mayhew , Jan Borggrefe ,2 3 1 4Andrew H. Gee21Department of Medicine, University of Cambridge, Cambridge, United Kingdom, 2Department of Engineering, University of Cambridge, Cambridge, United Kingdom,3 Institute of Neurology, University College London, London, United Kingdom, 4Department of Diagnostic Radiology, University of Schleswig Holstein, Kiel, GermanyAbstractWe have recently developed image processing techniques for measuring the cortical thicknesses of skeletal structures invivo, with resolution surpassing that of the underlying computed tomography system. The resulting thickness maps can beanalysed across cohorts by statistical parametric mapping. Applying these methods to the proximal femurs of osteoporoticwomen, we discover targeted and apparently synergistic effects of pharmaceutical osteoporosis therapy and habitualmechanical load in enhancing bone thickness.Citation: Poole KES, Treece GM, Ridgway GR, Mayhew PM, Borggrefe J, et al. (2011) Targeted Regeneration of Bone in the Osteoporotic Human Femur. PLoSONE 6(1): e16190. doi:10.1371/journal.pone.0016190Editor: Sudha Agarwal, Ohio State University, United States of AmericaReceived September 15, 2010; Accepted December 16, 2010; Published January 14, 2011Copyright:  2011 Poole et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Funding: This work was supported by an Arthritis Research UK Clinician Scientist Fellowship award to KESP (The FEMCO study, ARC17822, http://www.arthritisresearchuk.org/) and by the Cambridge Biomedical Research Centre (National Institute for Health Research), an institutional award that supports PMM. Thefunders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: KESP and GMT are inventors on a related Great Britain patent application GB0917524.1, "Image data processing systems." This does notalter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.* E-mail: kp254@nhs.netIntroductionThe femur, with its complex load bearing properties andeventual fragility, has been a key anatomical site of study forbiologists, engineers and anthropologists across several centuries[1,2,3]. Indeed, the seminal concept of ‘functional adaptation’,whereby deformation is sensed by bone cells and transduced intobiological signals to optimise skeletal architecture, was based onobservations of proximal femoral structure [1,3,4]. This idea haslong been used to inform orthopaedic practice, and it is in thistradition that we here address an open question in human bonebiology: where, precisely, is bone regenerated in response toosteoporosis therapy? With annual hip fracture rates predicted toexceed six million by 2050, and the distribution of cortical bone inthe proximal femur believed to be the key determinant of fractureresistance [5,6], this question is of scientific, social and economicimportance. The established clinical intervention to stimulate newbone formation is parathyroid hormone (PTH), administered bydaily subcutaneous injection [7]. Invasive animal studies point to asynergistic effect of PTH and localised mechanical stress on bonecells [8], but the more limited experimental techniques applicableto living human beings have, to date, revealed only grossdifferences in response between heavily loaded sites like the femurand lightly loaded sites like the radius [7].Further insight has been hampered by the limited resolution ofwhole-body computed tomography (CT) systems and the per-ceived futility of using such systems to pinpoint tiny changes incortical bone distribution. Now, however, a new CT imageprocessing technique [9] allows us to display cortical thickness as acolour map over the bone surface (Fig. 1a), with several thousandindependent measurements across each proximal femur andsufficient sensitivity to detect even small changes (,30 microns)when expressed systematically by a suitably sized cohort. By makingreasonable assumptions, that the actual cortical density does not varydramatically for a given subject at a given time, and that the imagingblur is roughly Gaussian in shape, thickness can be measured tosuper-resolution accuracy, except at the femoral head where theproximity of the acetabulum is problematic. The methodology hasbeen validated against gold standard thickness measurementsobtained from micro-CT scans of cadaveric femurs [9].MethodsHere, we use this technique to map the small changes in corticalbone distribution stimulated by pharmaceutical treatment forosteoporosis. In one branch of the EUROFORS study [10], 69women with severe osteoporosis were treated with recombinanthuman PTH (hPTH-(1-34)) for 24 months, with quantitative CTscans at baseline and 24 months. All data from this cohort wasanalysed in the present study, with the exception of those femurscompromised by metalwork and those where one or both of theCT scans did not extend as far as the lesser trochanter. Thisyielded 119 femurs from 65 women (mean age 67.566.8 years).Participants were from twelve investigative centres in Germanyand Spain [11]. Institutional Review Board approval was obtainedfrom each of the clinical study sites, and written informed consentfor EUROFORS (ClinicalTrials.gov ID NCT00191425) and theQCT sub-study were obtained from each participant. The presentanalysis was approved by Cambridgeshire 4 research ethicscommittee (LREC07/H0305/61).Analysis of the 238 thickness maps followed established practicewithin the neuroimaging community, who have pioneeredtechniques for statistical inference from dense, spatially correlateddata. To account for variations in inter-subject morphology, eachPLoS ONE | www.plosone.org 1 January 2011 | Volume 6 | Issue 1 | e16190map was spatially realigned with a canonical femur surface using aB-spline free-form deformation [12] calculated by the iterativeclosest point registration algorithm [13]. The spatially normalizedmaps were then smoothed with a 10 mm full-width-half-maximumfilter. Thickness changes were summarised for each subject bysubtracting the baseline maps from the 24-month maps andaveraging the left and right responses where both were available.This resulted in 65 summarised response maps, 54 derived fromaveraged left-right data and 11 from single femurs. Formalinference was accomplished by statistical parametric mapping[14], as implemented in the SurfStat package [15]. The modelfitted to the summarised data comprised a constant term and arandom-effect term for left-right averaging: this allows for unequalvariances between the averaged and unaveraged data. T-statisticswere calculated to test the significance of the constant term,corresponding to positive thickness change. Random field theorythen furnished P-values, corrected for multiple comparisons tocontrol the overall image-wise chance of false positives.Results and DiscussionBaseline measurements reveal the anatomical distribution ofcortical thickness seen in advanced osteoporosis (Fig. 2a). Thenonuniformly thin cortex is of clinical relevance, since fracturescommonly traverse the neck (Fig. 1c) or split the trochantericregion during sideways falls (Fig. 1d) [5]. The variation in thicknesspartly reflects femoral growth, with thick bone of the inferomedialaspect preserved into late adulthood by lifelong functionaladaptation to stress, and a thin cortex apparent superiorly. Inother areas, such as the trochanters and their connecting crest,thin cortices overlie predominantly trabecular bone near bony sitesof muscle and tendon insertion (entheses). Following hPTH-(1-34)treatment, and in striking contrast to the expected ageing effects[5], the percentage change map (Fig. 2b) shows marked corticalthickening. Figure 2c shows corrected P-maps for positivethickness change, based on the magnitude of peaks (sensitive tofocal effects) and on the extent of connected clusters exceeding anFigure 1. Visualising the femur in health and trauma. (a) A cortical thickness map of a healthy adult male femur with thick (blue/green) cortexat sites of high load during walking, (b) cortical and trabecular bone. Typical fractures in the (c) femoral neck and (d) inter-trochanteric regions.doi:10.1371/journal.pone.0016190.g001Regeneration of Bone in Osteoporotic Human FemursPLoS ONE | www.plosone.org 2 January 2011 | Volume 6 | Issue 1 | e16190uncorrected P-value threshold of 0.001 (sensitive to distributedeffects).New bone is targeted to regions that predictably encounter highstress during normal locomotion, namely the infero-medialjunction of the cortex with the load-bearing calcar femorale, andthe head-neck junction of the superior cortex. Both these sites arecommonly involved in fracture. No regions of statisticallysignificant thinning are apparent. Foci of new bone are alsoevident at the entheses of powerful locomotion muscles; on thegreater and lesser trochanters at the attachment sites of the gluteusmedius and psoas, and at the inter-trochanteric insertion of thequadratus femoris.Parathyroid hormone is an established clinical intervention tostimulate new bone formation in human osteoporosis. Previousstudies have shown that hPTH-(1-34) treatment in postmenopaus-al women with osteoporosis increases cortical thickness at variousskeletal sites, but this is the first to demonstrate the precise regionaleffects at one of the key sites of fragility fracture, the human hip.hPTH-(1-34) is also known to increase porosity (at least early intreatment) and reduce the mineral density, since new bonestimulated by the drug is relatively under-mineralised compared toolder bone [16]. The cortical thickness measurement is robust toany consequent changes to the average cortical density, since theaverage density value is estimated independently in each data set.It is equally robust to any regional changes in the quality of the CTdata, since the extent of the imaging blur is estimated at everymeasurement location.Intriguingly, both load and PTH act rapidly on the entombed’load sensing’ osteocytes to profoundly reduce secretion of a keymolecular inhibitor of bone formation, sclerostin [17]. Releasedfrom inhibition, the osteoblasts (surface targets of sclerostin) canthen secrete new bone matrix. Fig. 2b suggests a possiblesynergistic effect of habitual load and PTH in the human proximalfemur, since peak effects are seen at sites that are highly stressed byFigure 2. Cortical thickness maps showing severe osteoporosis and the increase in thickness following hPTH-(1-34) treatment. (a)Medial, superior and posterior views of the average pre-treatment cortical thickness map in advanced osteoporosis showing remnants of thicker,highly loaded bone (blue/green) at A) the inferomedial cortex and B) the calcar femorale regions. Elsewhere there is thin, sub-millimetre cortex (pink/red) at key fracture sites including C) the subcapital superior neck region. Also labelled are the insertion sites of key muscles of locomotion; D) gluteusmedius, E) psoas major and F) quadratus femoris (on the inter-trochanteric crest). (b) Post-treatment percentage change and (c) statistical significancemaps which together indicate regeneration of bone at A), B), C), D), E) and F).doi:10.1371/journal.pone.0016190.g002Regeneration of Bone in Osteoporotic Human FemursPLoS ONE | www.plosone.org 3 January 2011 | Volume 6 | Issue 1 | e16190walking. In the light of this, we ask whether hPTH-(1-34)treatment for osteoporosis might be more effective if combinedwith enhanced skeletal loading. Cortical thickness mapping is theideal tool to answer this and other open questions in bone biology.AcknowledgmentsWe thank the contributing investigators of the EUROFORS study.Author ContributionsConceived and designed the experiments: KESP GMT AHG. Performedthe experiments: KESP GMT AHG. Analyzed the data: KESP GMTGRR AHG. Contributed reagents/materials/analysis tools: KESP GMTGRR PMM JB AHG. Wrote the paper: KESP GMT GRR PMM JBAHG.References1. Roux W (1885) Beitrage zur Morphologie der funktionnellen Anspassung. ArchAnat Physiol Anat Abt 9: 120–158.2. Lovejoy CO, Suwa G, Spurlock L, Asfaw B, White TD (2009) The pelvis andfemur of Ardipithecus ramidus: the emergence of upright walking. Science 326:71e71–76.3. Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K (2001) Anabolism.Low mechanical signals strengthen long bones. Nature 412: 603–604.4. Huiskes R, Ruimerman R, van Lenthe GH, Janssen JD (2000) Effects ofmechanical forces on maintenance and adaptation of form in trabecular bone.Nature 405: 704–706.5. Mayhew PM, Thomas CD, Clement JG, Loveridge N, Beck TJ, et al. (2005)Relation between age, femoral neck cortical stability, and hip fracture risk.Lancet 366: 129–135.6. Burr DB (2010) Cortical bone: a target for fracture prevention? Lancet 375:1672–1673.7. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, et al. (2001) Effectof parathyroid hormone (1-34) on fractures and bone mineral density inpostmenopausal women with osteoporosis. N Engl J Med 344: 1434–1441.8. Roberts MD, Santner TJ, Hart RT (2009) Local bone formation due tocombined mechanical loading and intermittent hPTH-(1-34) treatment and itscorrelation to mechanical signal distributions. J Biomech 42: 2431–2438.9. Treece GM, Gee AH, Mayhew PM, Poole KE (2010) High resolution corticalbone thickness measurement from clinical CT data. Med Image Anal 14:276–290.10. Eastell R, Nickelsen T, Marin F, Barker C, Hadji P, et al. (2009) Sequentialtreatment of severe postmenopausal osteoporosis after teriparatide: final resultsof the randomized, controlled European Study of Forsteo (EUROFORS). J BoneMiner Res 24: 726–736.11. Borggrefe J, Graeff C, Nickelsen TN, Marin F, Gluer CC (2009) QuantitativeComputed Tomography Assessment of the Effects of 24 months of TeriparatideTreatment on 3-D Femoral Neck Bone Distribution, Geometry and BoneStrength: Results from the EUROFORS Study. J Bone Miner Res 25: 472–481.12. Rueckert D, Frangi AF, Schnabel JA (2003) Automatic construction of 3-Dstatistical deformation models of the brain using nonrigid registration. IEEETrans Med Imaging 22: 1014–1025.13. Besl PJ, McKay ND (1992) A Method for Registration of 3-D Shapes. IEEETrans Pattern Anal Mach Intell 14: 239–256.14. Friston KJ, Holmes AP, Worsley KJ, Poline J-P, Frith CD, et al. (1994) Statisticalparametric maps in functional imaging: A general linear approach. HumanBrain Mapping 2: 189–210.15. Worsley K, Taylor J, Carbonell F, Chung M, Duerden E, et al. (2009) SurfStat:A Matlab toolbox for the statistical analysis of univariate and multivariatesurface and volumetric data using linear mixed effects models and random fieldtheory. NeuroImage Organization for Human Brain Mapping 2009 AnnualMeeting 47: S102.16. Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, et al. (2003) Effects ofintermittent parathyroid hormone administration on bone mineralizationdensity in iliac crest biopsies from patients with osteoporosis: a paired studybefore and after treatment. J Clin Endocrinol Metab 88: 1150–1156.17. O’Brien CA, Plotkin LI, Galli C, Goellner JG, Gortazar AR, et al. (2008)Control of Bone Mass and Remodeling by PTH Receptor Signaling inOsteocytes. PLoS ONE 3: e2942.Regeneration of Bone in Osteoporotic Human FemursPLoS ONE | www.plosone.org 4 January 2011 | Volume 6 | Issue 1 | e16190

Targeted regeneration of bone in the osteoporotic human femur.

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UCL Discovery

Apollo (Cambridge)