Ammann, P.

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BONE QUALITY SEMINARS: ULTRASTRUCTUREBone strength and ultrastructureP. AmmannPublished online: 2 April 2009# International Osteoporosis Foundation and National Osteoporosis Foundation 2009IntroductionBone is programmed to withstand low-energy trauma andrepeated stimuli such as walking, running, and jumping to anextent. The ability of bone to withstand physiological stress isgoverned by not only its determinants including mass,geometry, and microarchitecture but also intrinsic bone tissuequality. Intrinsic bone tissue quality is governed by the degreeof mineralization and matrix characteristics such as collagenfiber orientation and chemical structure, both of which help tocharacterize the bone ultrastructure, and while the exact rolesthese determinants play are poorly understood, they appear tobe crucial for the overall understanding of bone mechanicalproperties. These determinants are affected by bone remodel-ing and may therefore be considered as targets of nutritional,hormonal, and therapeutic intervention and activity. If we areto understand how bone adapts to a loss of mass and respondsto pathophysiological alteration or to treatment, all suchaffected contituents need to be considered systematically,including intrinsic bone tissue quality.Measurement of bone mechanical propertiesBiomechanical tests of resistance to fracture provide anobjective measure of overall bone quality. They are invasiveand performed only in animal models but are of majorimportance in the understanding of pathophysiologicalalteration of bone strength. In the animal model,biomechanical properties of both intact cortical andtrabecular bone are investigated by axial compression ofvertebral bodies and proximal tibiae. Purely cortical boneis tested by flexion, whereby force is applied at eitherthree or four points. The load/deflection curve is thenused to measure or extrapolate stiffness (the slope of thelinear portion of the curve) and maximal load (load atpoint of fracture). The departure from linearity represent-ing the separation between elastic (linear) deformationand plastic (nonlinear) deformation is defined as the yieldpoint. The areas under these curves represent the energiesabsorbed during elastic and plastic deformation.Measurement of intrinsic bone tissue qualityVarious techniques are available for assessing and quanti-fying intrinsic bone tissue quality at both the level of thebone structural units (BSU) by microindentation and atlamella level by nanoindentation. They both give an overallreading of intrinsic quality as influenced by the mineral andorganic components, but only nanoindentation selectivelyevaluates the influence of each. Microindentation is used tomeasure microhardness at the BSU or tissue level in termsof resistance to indentation at a defined load over a definedtime period. Nanoindentation measures hardness at thelevel of the individual lamella. The nanoindentation methodinvolves fixing the loading and unloading rates in order toobtain a force displacement curve, which can then beemployed to derive biomechanical parameters such asmicrohardness and Young's elastic modulus. Microindenta-tion uses a set load for a set time, with only the depth,Osteoporos Int (2009) 20:1081–1083DOI 10.1007/s00198-009-0866-5Data presented at the Third Meeting on Bone Quality, France, 24–25June 2008: Bone Ultrastructure.P. Ammann (*)Division of Bone Diseases [WHO Collaborating Center forOsteoporosis Prevention],Department of Rehabilitation and Geriatrics,Geneva University Hospitals and Faculty of Medicine,CH-1211 Geneva, Switzerlande-mail: patrick.ammann@hcuge.chimprint, and hence the diameter of the residual imprint varyingwith the test material. The dimensions of this residual imprintare used to calculate microhardness (kg/mm2), without theability to distinguish between the elastic and plasticcomponents. In the following discussion, results wereobtained using nanoindentation.Relation between bone strength parametersand parameters determined using nanoindentationIn the absence of treatment, ex vivo studies show anexcellent correlation between proximal femur bone mineraldensity (BMD) and the maximal load obtained usingflexion tests of femoral neck and vertebral compressiontests. BMD predicts 66% to 74% of maximal load variance.As a ratio between hydroxyapatite mineral content and scansurface, BMD incorporates bone dimensions in addition tomineral quantity. Indeed, the proficiency of BMD inpredicting bone strength is due, at least in part, to itsincorporation of bone size. In rats, vertebral BMD predicts60% of the variance of maximal load. Including themodulus (elastic tissue properties) improves the predictionto 71.5% and hardness (plastic tissue properties) to 95%.This indicates that combining BMD and tissue qualityallows for a reliable prediction of bone strength. There is asignificant relation between energy measured by compres-sion testing of the rat vertebra and dissipated energymeasured at the tissue level by nanoindentation. Thisdemonstrates that the determination of energy is dominatedby the tissue quality, characterizing its plasticity. Incontrast, there is no relation between stiffness measuredby compression testing of the rat vertebra and modulusmeasured at the tissue level by nanoindentation. Thisdemonstrates that the determination of stiffness is dominat-ed by the geometry of the bone rather than by tissue quality.These different studies clearly demonstrate the crucial roleof intrinsic bone tissue quality in the determination of bonestrength alongside geometry and microarchitecture.The alteration of bone strength and the respective roleof intrinsic bone tissue qualityBone is a heterogeneous tissue made up of a mineralcomponent (hydroxyapatite) and an organic (mostly collag-enous) component. Each component is theoretically capableof influencing the intrinsic quality of bone tissue. Thedegree of mineralization remains the more studied aspect ofbone tissue to date. Studies of the organic component havefocused on collagen fiber orientation and maturity. Theinvolvement of these parameters in tissue quality isespecially evident in osteogenesis imperfecta where fiberdisorganization leads to the high fracture risk. Diseasesresulting in the formation of woven bone (disorganizationof the collagen matrix), such as Paget's, are also associatedwith decreased strength. Preliminary studies are revealingthe importance of the intrinsic bone tissue quality. Theyhave shown tissue to be heterogeneous throughout thedifferent phases of bone remodeling. They also have foundevidence of changes in response to protein intake, hormoneimpregnation, and osteoporosis treatments.Intrinsic bone tissue quality: effect of estrogen deficiencyAt the level of the femoral neck, ovariectomy resulted in anearly decrease of the mechanical properties, followed by arecovery. The initial decrease was explained by a decreasedbone mass, an alteration of microarchitecture and ofintrinsic bone tissue quality. This was followed by acompensatory increase of the external diameter of thefemoral neck, which alone explains the recovery ofmaximal load in ovariectomized rats. This effect ongeometry is related to an increase in circulating IGF-Iobserved following ovariectomy. These observations high-light the importance of the geometry as a derminant of bonestrength.Intrinsic bone tissue quality: effect of protein intakeAn isocaloric reduction of protein intake in rats impairsboth cortical and trabecular intrinsic bone tissue qualitywithout necessarily needing remodeling of the bone tissueinvolved. A recovery of material quality was also observedfollowing protein supplementation in rats fed a low caseindiet. A Fourier transform infrared imaging analysis showsan increased maturation of bone collagen cross-links asindicated by an improvement of Pyr/deH-DHLNL collagencross-link ratio in rats given protein supplements. This wasobserved in areas of the bone not subject to boneremodeling. Altogether, the supplementation of proteinrestores bone mechanical properties by preventing furtherBMD losses, increasing cortical thickness, and restoringintrinsic bone tissue quality. Thus, protein intake candirectly influence the bone matrix quality and be crucialfor the determination of overall bone mechanical properties.Intrinsic bone tissue quality: effects of osteoporosistreatmentsIn OVX rats, bone mechanical properties are improved bybisphosphonates, selective estrogen receptor modulator(SERM), and parathyroid hormone (PTH) treament. Inhib-itors of bone resorption prevent bone loss and thedegradation of microarchitecture; in contrast, PTH increasesbone mass. Intrinsic bone tissue quality was improved1082 Osteoporos Int (2009) 20:1081–1083following treatments with inhibitors of bone resorption:SERM>bisphosphonates, but not in PTH-treated rats. Thispositive effect was in relation to the level of mineralizationachieved in bisphosphonate-treated rats, while in SERM-treated rats the origin of the improvement is yet to beelucidated. This underlines the selective effect of osteopo-rosis treatments on the different determinants of bonestrength. Other works have shown the response of intrinsicbone tissue quality to strontium ranelate treatment, withsignificant increases in both elastic and plastic parametersto even higher values than those observed in sham controls.Strontium ranelate treatment improves trabecular andcortical intrinsic bone tissue quality. This novel property,namely, the improvement of the intrinsic quality of bonetissue that is newly formed in response to strontiumranelate, may lead to a decrease in the development and/or propagation of microcracks. Such an effect on intrinsicbone tissue quality may signify a new target for developersof treatments for osteoporosis.ConclusionThe direct measurement of bone strength provides anobjective measurement of bone quality and integrates allthe effects of the different determinants. Mechanicalproperty determinants, such as geometry, microarchitecture,and intrinsic bone tissue quality, are influenced selectivelyby the different available treatments and nutritional andhormonal status. A recent study clearly indicated thatintrinsic bone tissue quality plays a major role. It is alteredby estrogen deficiency and low protein intake and partiallyrestored by protein renutrition, bisphosphonates, andSERMs but not by PTH. The most effective treatment,however, was strontium ranelate which increased intrinsicbone tissue quality significantly, even compared to thecontrol animals. This highlights the prominent role playedby intrinsic bone tissue quality in determining bonestrength, which may thus become a new target fordevelopers of anti-osteoporotic therapies.Further Reading1. Ammann P, Badoud I, Barraud S, Dayer R, Rizzoli R (2007)Strontium ranelate treatment improves trabecular and corticalintrinsic bone tissue quality, a determinant of bone strength.J Bone Miner Res 22:1419–14252. Ammann P, Rizzoli R, Meyer JM, Bonjour JP (1996) Bone densityand shape as determinants of bone strength in igf-i and/orpamidronate-treated ovariectomized rats. Osteoporos Int 6:219–2273. Ammann P, Rizzoli R, Muller K, Slosman D, Bonjour JP (1993)Igf-i and pamidronate increase bone mineral density in ovariec-tomized adult rats. Am J Physiol 265:E770–E7764. Ammann P, Shen V, Robin B, Mauras Y, Bonjour JP, Rizzoli R(2004) Strontium ranelate improves bone resistance by increasingbone mass and improving architecture in intact female rats. J BoneMiner Res 19:2012–20205. Bagi CM, Ammann P, Rizzoli R, Miller SC (1997) Effect ofestrogen deficiency on cancellous and cortical bone structure andstrength of the femoral neck in rats. Calcif Tissue Int 61:336–3446. Boivin G, Meunier PJ (2003) The mineralization of bone tissue: aforgotten dimension in osteoporosis research. Osteoporos Int 14(Suppl 3):S19–S247. Bonjour JP, Ammann P, Rizzoli R (1999) Importance ofpreclinical studies in the development of drugs for treatment ofosteoporosis: a review related to the 1998 who guidelines.Osteoporos Int 9:379–3938. Bourrin S, Ammann P, Bonjour JP, Rizzoli R (2000) Dietaryprotein restriction lowers plasma insulin-like growth factor i (igf-i),impairs cortical bone formation, and induces osteoblastic resistanceto igf-i in adult female rats. Endocrinology 141:3149–31559. Dalen N, Hellstrom LG, Jacobson B (1976) Bone mineral contentand mechanical strength of the femoral neck. Acta Orthop Scand47:503–50810. Granhed H, Jonson R, Hansson T (1989) Mineral content andstrength of lumbar vertebrae. A cadaver study. Acta Orthop Scand60:105–10911. Hengsberger S, Ammann P, Legros B, Rizzoli R, Zysset P (2005)Intrinsic bone tissue properties in adult rat vertebrae: modulationby dietary protein. Bone 36:134–14112. Turner CH (2002) Biomechanics of bone: determinants of skeletalfragility and bone quality. Osteoporos Int 13:97–104Osteoporos Int (2009) 20:1081–1083 1083

Bone strength and ultrastructure

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Bone strength and ultrastructure

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