qualidade Óssea

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579Arq Bras Endocrinol Metab vol 50 n 4 Agosto 2006

ABSTRACT

Bone quality describes aspects of bone composition and structure thatcontribute to bone strength independently of bone mineral density.These include bone turnover, microarchitecture, mineralisation, micro-damage and the composition of bone matrix and mineral. New tech-niques to assess these components of bone quality are being developedand should produce important insights into determinants of fracture riskin untreated and treated disease. (Arq Bras Endocrinol Metab

2006;50/4:579-585)Keywords: Bone quality; Turnover; Mineralisation; Microarchitecture;Fracture; Bone strength

RESUMO

Qualidade ssea: O Que Significa e Como Mensur-la?A qualidade do osso compreende os aspectos da composio e estru-tura ssea que contribuem para sua fora, independentemente dadensidade mineral ssea, as quais incluem: turnover sseo, microar-quitetura, mineralizao, microdanos e a composio da matriz ssea emineral. Novas tcnicas para avaliar estes componentes da qualidadessea tm sido desenvolvidas e devem proporcionar importantes

avanos para determinao do risco de fraturas nas doenas tratadase no tratadas. (Arq Bras Endocrinol Metab 2006;50/4:579-585)

Descritores: Qualidade ssea; Turnover; Mineralizao; Microarquitetura;Fratura; Fora ssea

WHAT IS BONE QUALITY?

BONE STRENGTH IS DETERMINED by bone mass, geometry and quality.The latter includes several aspects of bone structure and composition,

including bone turnover, microarchitecture, the degree and distribution ofmineralisation, the extent of microdamage and its repair and, finally, the

composition of bone matrix and mineral (figure 1). These components arelargely interdependent, so that a primary abnormality in one will often leadto changes in others. In particular, bone turnover is a major determinantof other components of bone quality and hence its measurement in clini-cal practice is of key importance.

The recent interest in bone quality has arisen from observations thatthe traditional measure of bone strength in clinical practice, namely bonedensitometry, does not always reliably predict fracture risk (1). This hasstimulated the search for other aspects of bone composition and structurethat contribute to bone fragility. This review describes some disease statesin which abnormal bone quality is associated with increased fracture risk,sometimes despite increased bone mineral density. Techniques for themeasurement of bone quality will be discussed together with how these

review article

Bone Quality: What is it and How is itMeasured?

Juliet Compston

University of Cambridge School ofClinical Medicine, Cambridge

CB2 2QQ, UK.

Received in 05/09/06Accepted in 05/27/06


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Bone QualityCompston

580 Arq Bras Endocrinol Metab vol 50 n 4 Agosto 2006

have advanced our understanding of the mechanismsby which bone strength may be improved by thera-peutic intervention.

ASSESSMENT OF BONE QUALITY

In vivo assessment of bone quality is limited to mea-surement of bone turnover and of some aspects ofbone geometry and architecture. However, using bonebiopsy or autopsy specimens, a number of approacheshave been developed that have increased our under-standing of how bone quality contributes to bonestrength in untreated and treated disease (table 1).

Bone turnoverBone turnover is most commonly assessed in clinicalpractice by measurement of biochemical markers ofresorption and formation (table 2). The markers,which are mainly serum based, reflect whole bodyturnover and thus provide assessment predominantly

of cortical bone, which constitutes 8090% of theskeleton. They show considerable variability, bothwithin and between individuals, and may be affectedby diet, so blood or urine specimens should ideally beobtained in the fasting state and at a standard time ofthe day.

Bone turnover can also be assessed by histo-morphometric assessment of bone, using tetracyclinelabelling prior to the biopsy (2). The extent of tetra-cycline-labelled surfaces indicates bone turnover, pro-vided that bone remodelling is in a steady state andthat bone resorption and formation are coupled.

However, bone turnover in iliac crest biopsies may notreflect turnover at other sites, since there are consider-able intra-individual variations in bone turnoverthroughout the skeleton (3). Thus it is not surprisingthat there may be differences between biochemicalmarkers and histomorphometry in their assessment ofbone turnover; in particular, the degree of suppressionof bone turnover by anti-resorptive agents is generallygreater when assessed by the latter technique. Tech-niques such as 18F-fluoride positron electron tomogra-phy and single photon emission computed tomogra-phy gamma camera imaging using technetium labelledbisphosphonate provide new approaches to the assess-ment of regional bone turnover at sites of clinical rel-evance, for example the spine.

Assessment of bone microarchitectureAlterations in bone microarchitecture make an impor-tant contribution to bone strength that may not alwaysbe captured by bone mineral density measurements.Cortical and cancellous architecture are both important

in this respect. In cancellous bone, the size and shapeof trabeculae and their connectivity and orientation(anisotropy) contribute to bone strength whilst in cor-tical bone cortical width, cortical porosity and bonesize are the main determinants. Although some of thesearchitectural features can be assessed in histological sec-tions of bone biopsy specimens using 2-dimensionalapproaches (4), more sophisticated methods have nowbeen developed that enable 3-dimensional visualisationand quantification. These include high-resolution mag-netic resonance imaging (HR-MRI), high resolutionperipheral quantitative computed tomography (HR-

Figure 1. Determinants of bone quality.


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pQCT), micro-CT (CT) and synchrotron radiationCT (5). These are currently research tools and, invivo, can only be applied to the peripheral skeletonalthough technological advances may eventually extendtheir use to the central skeleton.

Changes in bone microarchitecture in untreatedand treated disease states result from the underlyingalterations in bone remodelling. High turnover statesand increased osteoclast activity predispose to trabecu-

lar penetration, loss of connectivity, cortical thinningand increased cortical porosity, whereas low boneturnover states and reduced bone formation are asso-ciated with trabecular thinning and relative preserva-tion of bone microarchitecture.

Assessment of bone mineralisationMineralisation of bone matrix occurs in two phases. Pri-mary mineralisation occurs when the bone mineral isdeposited during the bone remodelling cycle, whereassecondary mineralisation describes the process of furthermineralisation after the remodelling cycle has been com-

pleted. The degree of secondary mineralisation is criti-cally dependent on bone turnover; when this is low,there is more time for mineralisation to proceed where-as in high turnover states, recently formed bone isremoved before there is time for prolonged secondarymineralisation (6). The degree of mineralisation and itsdistribution throughout bone can be measured ex vivoby several methods including microradiography, quan-titative back-scattered electron imaging and spectro-scopic techniques. The degree of mineralisation is cap-tured by bone mineral density measurements, but itscontribution relative to other factors influencing bonemineral density cannot be directly deduced.

Assessment of bone matrix and mineralcompositionRelatively little is known about how bone matrixand mineral composition contribute to bonestrength. Changes in the cross-linking of type 1 col-lagen (7) and post-translational modifications suchas lysyl-hydroxylation, glycosylation and beta-iso-merisation of aspartate residues in carboxyterminaltelopeptides may have significant biomechanical

implications (8,9), as may alterations in the size andstructure of bone mineral. Since collagen structureand mineralisation are so closely associated it is like-ly that when changes occur in one, both are affect-ed (10).

New approaches to studying bone matrix andcomposition include Raman and Fourier transforminfrared spectroscopy, transmission electron micros-copy, and small angle X-ray scattering (SAXS). Thesetechniques can only be applied ex vivo to bone speci-mens; however, assays for the measurement of beta-isomerisation of CTX have recently been developed

and this approach, together with the development ofother biochemical measurements of changes in colla-gen composition in serum or urine, is an importantarea for research in the future.

Assessment of microdamageMicrodamage in bone consists of microcracks andmicrofractures. The relationship between these, ifany, is unknown and although both forms of micro-damage increase with age their effects on bonestrength are unclear (11). Assessment of microdam-age can currently be made only by histological tech-niques.

Table 1. Assessment of bone quality.

Variable Technique

Bone turnover Biochemical markers, histomorphometryBone microarchitecture Histomorphometry, CT, SR-CT, HR-MRI, pQCTBone mineralisation Microradiography, qBSEI, SAXS, spectroscopyMicrodamage Histology, confocal microscopyMatrix/mineral composite FTIR, TEM, SAXS, Raman spectroscopy, biochemistry

CT micro computed tomography; SR synchrotron radiation; HR-MRI magnetic resonanceimaging; pQCT peripheral computed computed tomography; qBSEI quantitativebackscattered electron imaging; FTIR Fourier Transform Infrared; TEM transmission electronmicroscopy; SAXS small angle X-ray scattering

Table 2. Biochemical markers of bone turnover.

Bone formation Bone resorption

Osteocalcin Collagen type 1 telopeptides (Ctx, Ntx)Bone specific alkaline phosphatase DeoxypyridinolineProcollagen type 1 N propeptide (P1NP) Tartarte-resistant acid phosphatase type 5b


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CHANGES IN BONE QUALITY IN BONE DISEASES

Reduced bone strength and increased fracture risk may

be caused by a number of abnormalities in bone qual-ity and may occur despite increased bone mineral den-sity. Examination of these disease states emphasises theinterdependence of the different components of bonequality and the importance of normal bone quality inthe maintenance of bone health.

Changes in bone mineralisationBoth decreased and increased mineralisation may beassociated with increased bone fragility. Osteomalaciais associated with reduced mineralisation of bone,leading to accumulation of osteoid. Osteomalacic

bones are soft and bend easily, resulting in the charac-teristic skeletal deformities that are seen in rickets andin severe cases of adult osteomalacia. Pseudofracturesand pathological fractures may also occur. In contrast,the condition of osteopetrosis is characterised byincreased mineralisation as a result of absent or great-ly reduced osteoclastic activity (figure 2). Osteopetrot-ic bones are stiff and brittle and can absorb little ener-gy before breaking; thus despite greatly increased bonemineral density, fracture risk is increased.

Bone exposed to fluoride provides an example ofa qualitative abnormality of bone mineral that is associ-ated with reduced bone strength. The size and compo-sition of hydroxyapatite crystals is changed as a result ofsubstitution of the hydroxyl group of hydroxyapatite byfluoride; in addition, there may be accumulation ofosteoid and the formation of woven bone (12).

Abnormalities of type 1 collagenOsteogenesis imperfecta is a disease in which there isproduction of abnormal type 1 collagen. Depending

on the genotype, there may be alterations in the bonematrix/mineral composite, decreased mineralisationof bone and abnormal bone modelling and architec-ture; these changes are associated with increased frac-ture risk (13).

Even subtle abnormalities in the structure oftype 1 collagen may adversely affect bone strength andfracture risk. For example, a polymorphism affecting abinding site of the transcription factor Sp1 in the pro-moter region of the collagen type 1A1 gene is associ-ated with reduced spine bone mineral density andincreased fracture risk (14). The increase in fracture

risk cannot be explained solely on the basis of thedecrease in bone mineral density, indicating that theabnormal collagen structure contributes independent-ly to reduced bone strength.

High bone turnoverSeveral high turnover states are associated withincreased fracture risk including postmenopausalosteoporosis, Pagets disease of bone, immobilisation-induced bone loss, post-transplantation bone diseaseand secondary hyperparathyroidism. High boneturnover reduces bone strength both through reduc-tion in bone mass and disruption of bone microarchi-

tecture, an effect that is largely independent of thechanges in bone mass. The degree of mineralisation ofbone is also reduced in high turnover states. Corticalporosity and endosteal resorption increase, resulting inreduced cortical thickness and strength.

In Pagets disease of bone, increased boneturnover and osteoclastic activity are associated withmultiple alterations in bone quality. Bone matrix mayhave a mosaic structure due to the presence of bothwoven and lamellar bone, and mineralisation, architec-ture and geometry may also be abnormal. Post-trans-plantation bone loss affects both cortical and cancel-

lous bone (15), whilst in secondary hyperparathy-roidism bone loss is predominantly cortical. Increasedbone turnover is also likely to contribute to bone lossin the early stages of glucocorticoid therapy, althoughin the longer-term reduced bone turnover and forma-tion predominate. There is evidence that the increasein fracture risk associated with glucocorticoid therapyis to some extent independent of bone mineral densi-ty (16), consistent with a role for altered bone quality.

Low bone turnoverThe effects of low bone turnover on bone strengthhave not been established. In theory, low bone

Figure 2. X-ray of pelvis in a patient with osteopetrosis. Notethe increased radiodensity of bone and disordered microar-chitecture of cortical and cancellous bone.


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turnover might be expected to increase bone fragilityas a result of hypermineralisation, reduced osteocyteviability and accumulation of microdamage (17).

However, whilst over-suppression of bone turnover indogs causes significant accumulation of microdamage,adverse effects on bone strength have not been shown.In humans, adynamic renal bone disease (18,19) isassociated with histological evidence of very low boneturnover, but robust evidence for increased fracturerisk in this condition is lacking. Biochemical markersof bone turnover do not always reflect the suppressionof bone turnover seen histologically and bone mineraldensity may be normal.

Concerns have been expressed about whetherlong-term treatment with potent anti-resorptive agents

for osteoporosis might cause over-suppression of boneturnover and increased bone fragility. Clinical trials indi-cate that anti-fracture efficacy is maintained for up tofive years of treatment; subsequently, the data are lessrobust but studies for up to 7 years of treatment withrisedronate (20) and 10 years with alendronate (21) areconsistent with continued efficacy and have not demon-strated an increase in fracture risk above that expected.

Odvina et al. (22) recently reported the presenceof spontaneous fractures, often with evidence ofimpaired healing, in 9 patients treated with alendronate.Three were also taking hormone replacement therapyand two prednisolone. Bone biopsy in all cases showedcomplete absence of double tetracycline labelling,although biochemical markers of bone turnover werenormal in many cases and only two patients had osteo-porosis as defined by densitometric criteria. Althoughfirm conclusions cannot be drawn from these observa-tional data, these cases raise the possibility that very lowbone turnover may be associated with increased bonefragility despite normal bone mineral density values.

A possible association between osteonecrosis ofthe jaw and bisphosphonate therapy has recently beenreported (23). This condition often presents with anon-healing tooth extraction socket or painful

exposed bone in the mandible or maxilla and is seenmost commonly in individuals with malignant disease.Although not exclusively associated with bisphospho-nate therapy, the increased numbers of cases reportedin such patients has raised the possibility that bisphos-phonates may contribute to osteonecrosis by severalmechanisms including immunosuppression, inhibitionof angiogenesis and suppression of bone turnover. Itshould be emphasised that the majority of cases havebeen described in association with malignant diseasesfor which high doses of intravenous bisphosphonateshave been used.

EFFECTS OF PHARMACOLOGICALINTERVENTIONS ON BONE QUALITY

Bone turnoverThe degree of suppression of bone turnover inducedby anti-resorptive drugs varies, whether measured bybiochemical markers or bone histomorphometry. Themost potent effects are seen with alendronate, zole-dronate and ibandronate, which reduce activation fre-quency in iliac crest bone biopsies by around 7590%(24-26). Risedronate and hormone replacement ther-apy are of intermediate potency, with a reduction ofaround 50% (27,28) and the smallest effect is seenwith raloxifene (approximately 20%) (29). These dif-ferences do not appear to be reflected by variations in

anti-fracture efficacy, at least in the spine. However,different degrees of suppression of bone turnover maybe relevant to anti-fracture efficacy at non-vertebralsites. Thus for weaker anti-resorptive agents such asraloxifene, whilst the modest reduction in boneturnover is sufficient to reduce fractures at cancellousbone sites where high bone turnover has a markedeffect on bone strength, this may not be the case atcortical bone sites where the effects of bone turnoveron bone microarchitecture are less prominent, andwhere larger increases in bone mineral density arerequired to provide protection against fracture (30).

The reduction in bone turnover induced byanti-resorptive agents has been shown to be a majorand independent determinant of fracture reduction, atleast at vertebral sites (31,32). This is attributable tothe major role of high bone turnover in the pathogen-esis of vertebral fracture, which again is independent ofbone mineral density (33) and the consequent preven-tion of microarchitectural changes by anti-resorptivedrugs.

In the case of teriparatide (recombinant humanparathyroid hormone peptide 1-34) activation fre-quency is increased in cancellous bone, but this is asso-ciated with a positive remodelling balance and thus

bone mass increases.

MicroarchitectureBoth anti-resorptive and anabolic interventions affectbone microarchitecture, the changes induced reflect-ing the associated alterations in bone turnover. Anti-resorptive agents preserve existing bone architecture,as demonstrated in iliac crest biopsies using 2-dimen-sional histological techniques in women treated withhormone replacement therapy (34), raloxifene (29) oribandronate (26) and CT in women treated with rise-dronate (35,36). Decreased cortical porosity (37) and


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unchanged cortical thickness (35) have also beenreported in iliac crest bone obtained from womenundergoing treatment with anti-resorptive therapy.

In contrast, teriparatide improves bonemicroarchitecture in both cancellous and corticalbone. Increased connectivity density of cancellousbone and increased cortical thickness have beendemonstrated using CT of iliac crest biopsy speci-mens (38,39). There is also some evidence forincreased periosteal bone apposition, leading to anincrease in bone size.

MineralisationAnti-resorptive therapy increases the degree of miner-alisation of bone as a result of the reduction in bone

turnover. Three years alendronate therapy in post-menopausal women with osteoporosis increased themean degree of mineralisation in iliac bone by around11%, an effect that was seen both in cancellous andcortical bone (40). Similar, although smaller, changeshave been reported in women treated with risedronate(35), hormone replacement therapy (41), and ralox-ifene (44). These changes are associated with increasedhomogeneity of mineralisation.

In postmenopausal women with osteoporosistreated with teriparatide, a small reduction in thedegree of mineralisation of bone has been reported,reflecting the increased bone turnover that resultsfrom this treatment (42).

Bone matrix and mineral compositionLittle is known about the effects of anti-resorptive andanabolic interventions on the bone matrix/mineral com-posite. There is some evidence that age-related changesin the ratio of non-reducible to reducible collagen cross-links and in bone mineral crystallinity are prevented byanti-resorptive therapy; however, the implications ofthese effects, if any, on bone strength are unclear.

The effects of strontium ranelate on bone miner-al structure are of particular interest since strontium is a

bone-seeking element that is taken up mainly by adsorp-tion onto bone mineral, exchanging with a maximum ofone in ten calcium ions in hydroxyapatite (43). Thesechanges in mineral composition do not result in anychange in the degree of mineralisation of bone.

SUMMARY AND CONCLUSIONS

Bone quality comprises a number of components thatcontribute to bone strength but are only partially cap-tured by measurements of bone mineral. Advances in

the assessment of bone quality in recent years haveprovided new insights into bone fragility in bothuntreated and treated bone disease. The translation of

these into clinical practice is an important priority forfuture research and may eventually lead to better pre-diction of fracture risk and an improved understandingof the mechanisms by which pharmacological inter-ventions affect bone strength.

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