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Rev ew Art c e

Biochemical Markers of Bone Turnover Part II: Clinical Applications in the Management of Osteoporosis

Markus J SeibelANZAC Research Institute, The University of Sydney, Concord Campus, Sydney, NSW 2139, AustraliaFor correspondence: Professor Markus J. Seibel e-mail: [email protected]

AbstractW t t e age ng popu at on n most countr es, sor ers o one an m nera meta o sm are ecom ng ncreas ng y re evantto every ay c n ca pract ce. Consequent y, t e nterest n, an t e nee or e ect ve measures to e use n t e screen ng,diagnosis and follow-up of such pathologies have markedly grown. Together with clinical and imaging techniques, biochemicaltests p ay an mportant ro e n t e assessment an erent a agnos s o meta o c one sease. T ese oc em ca n cesare non- nvas ve, comparat ve y nexpens ve an , w en app e an nterprete correct y, e p u too s n t e agnost c antherapeutic assessment of metabolic bone disease.

T s secon part o t e two part ser es rev ews t e current ev ence regar ng t e c n ca use o oc em ca mar ers o oneremodelling in the management of osteoporosis.

Introduction

Part I of this review, published late last year, provided anoverv ew o t e as c oc em stry o one mar ers, ansources of non-specic variability. This second part of theseries will review the current evidence regarding the clinicaluse o oc em ca mar ers o one remo e ng n onedisease. Most of this article will deal with the use of bonemarkers in osteoporosis, as this is the major clinical applicationat t e t me o wr t ng. Ot er con t ons suc as Pagets or metastat c one sease, n w c one mar ers may e useclinically, are only briey mentioned towards the end of thisrev ew; t ese top cs ave een rev ewe recent y y Ro manan W n e an y Se e .

Menopause and AgeingOnce somat c growt su s es, t e serum an ur naryconcentrations of most bone markers return to a level much

below those seen during normal puberty and growth. Thissta sat on usua y occurs ur ng t e 3 eca e an n ea t ymen, eve s o pract ca y a mar ers rema n more or essunchanged until 70 years of age. After that, a slight increases usua y seen n ot ormat on an resorpt on mar ers. -

In contrast, menopause s assoc ate w t a su stant aacceleration in bone turn over, mirrored by a 50-100% increase

n ot mar ers o one ormat on an resorpt on. , , - In

early postmenopausal women, this increase in bone turnover can e attenuate y ora ca c um supp ementat on. - Long-term treatment o women w t oestrogen was s own toreduce resorption markers such as deoxypyridinoline (DPD)and N-telopeptide (NTX) to premeno pausal levels. , , , , -

A prospect ve stu y cover ng t e per meno pausa trans t onin healthy women suggests that changes in bone turnover occur during the late premenopause with a decrease in boneormat on, w c on y ater s o owe y a r se n one

resorpt on. It s now w e y accepte t at t e acce eraterate of bone loss seen after the menopause is mainly dueto an m a ance n one turnover an an ncrease n oneresorpt on. , Stu es emp oy ng spec c one mar ersindicate that bone turnover continues to be increased (and to

be associated with bone loss) during late menopause. - Insome postmenopausa women, ut part cu ar y n t e veryelderly, - this increase in bone turnover is often, but notalways found to due to vitamin D and/ or calcium deciencyan secon ary yperpara t yro sm.

OsteoporosisBone Turnover n Osteoporos sOsteoporos s s a eterogeneous sease. It s t ere ore not

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surprising that in untreated patients with this disorder, ratesof bone turnover tend to vary over a wide range. Althoughmost cross-sect ona stu es s ow acce erate one turnover in a certain proportion of postmenopausal osteoporoticwomen, there is usually broad overlap between diseased and

ea t y popu at ons. - , - In t s context, t s mportantto ear n m n t at researc stu es usua y nc u e g yselective patient populations, which may not alwaysrepresent t e popu at on seen n t e typ ca c n ca sett ng.Us ng a popu at on- ase ata set, an t ere ore avo ngthis selection bias, we have previously shown that none of the major biochemical markers of bone turnover providesu c ent agnost c n ormat on to e use u n t e screen ngfor vertebral osteopenia or osteoporosis. However, another

population-based study showed that urinary levels of NTXcou scr m nate etween o er n v ua s w t norma

p one ens ty, osteopen a an osteo poros s. Aga n, t sassociation did not hold true for men at the level of the spine.

In retrospect ve popu at on- ase stu es, A esson an co-workers have demonstrated that previous fractures wereassociated with abnormal bone turnover. , , , After adjust-ment or age an one m nera ens ty BMD , womenwith fractures occurring within six years prior to the studywere characterised by lower serum levels of osteocalcin andcar oxyterm na proco agen type I propept e PICP , utnorma rates o one resorpt on. In anot er nvest gat on, t esame authors found decreased serum levels of osteocalcin,an e evate ur nary concentrat ons o co a gen cross n s ne er y women at t e t me o a m ss on or a new y susta nehip fracture.

Ta en toget er, t ese ata suggest t at a ong-term m a anceof bone metabolism may lead to increased fragility. Together with the fact that high bone turnover may be sustained for ong per o s an one oss may ncrease w t age, t esen ngs may prov e a rat ona e or es gn ng more e ect ve

intervention strategies. However, other factors such as agesee a ove , me cat on, , , - mmo sat on, , t yrounct on, co-mor ty an t e racture tse , , o

inuence bone metabolism and therefore need to be considered

in the inter pretation of biochemical data and their use inn v ua pat ents. C ear y, none o t e oc em ca mar ers

of bone turnover has proven useful as a single diagnosticindex of osteoporosis.

Bone Turnover an Bone LossBone mass, rates of bone loss, and the risk of osteoporoticractures are nterre ate , an ot ow one mass an rapone oss ave een s own to e n e pen ent pre ctors o

future fracture risk. The rate of bone loss is determined by anumber of factors, one of which appears to be the rate of bone

remodelling. Earlier observations demonstrated that boneformation and bone resorption increase shortly after naturalmenopause, a p ase t at n most women s a so assoc ate w tsigni cantly accelerated bone loss. , , - Similar observationshave been made in ovariectomised, pre menopausal wo menan n castrate men, , n cat ng t at t e w t rawa oen o genous sex stero n uces ot g one turnover anrapid bone loss. Conversely, markers of bone meta bolismreturn to premenopausa eve s ur ng or mone rep acementt erapy HRT . , , , , - Ot er oc em ca stu es suggestthat high rates of bone turnover may be sustained well intoadvanced ages. , , , , However, it is unclear whether thisapp es to a women.

Most longitudinal studies support the notion that individualsw t g rates o one turnover ose one at a aster ratet an su ects w t norma or ow one turnover. , , , -

Following a small group of early postmenopausal women,

C r st ansen an co eagues emonstrate t at t e com nemeasurement o serum tota a a ne p osp atase, osteoca c n,fasting urinary calcium, hydroxyproline or DPD can predict60-70% of the variability in bone loss. , These studies alsos owe t at t e corre at on etween ase ne mar ers o oneturnover and the subsequent rate of postmenopausal boneloss is possibly consistent over a period of at least twelveyears. , Less opt m st c est mates were reporte y ot er groups us ng erent com nat ons o mar ers. , For example, a study in elderly women demonstrated that urinary

NTX, serum osteoca c n an serum parat yro ormonetoget er exp a ne on y 43% o t e var a ty o one oss atthe hip. Markers of bone resorption seemed to be stronger

predictors of future bone loss than markers of bone formation,an corre at ons were stronger n e er y t an n younger women. - In a retrospective study of 354 women (meanobservation period: 13 years), Ross and Knowlton showeda cont nuous re at ons p etween t e measure eve s ovar ous one turnover mar ers an t e r s o rap oneloss at the calcaneus: the odds of rapid bone loss (>2.2% /year ou e or eac stan ar ev at on SD ncrease nserum one spec c a a ne p osp a tase BSAP , serumosteocalcin, urinary free pyridinoline (PYD) or DPD. In

a study of 227 early postmenopausal women treated withca c um a one or HRT p us ca c um, C esnut et a . an Rosenet al. reported that women with high baseline rates of boneresorption were at higher risk of losing bone than women withnorma turnover rates. , F gure 1 . D erent resu ts werereporte y Keen et a ., w o n a our-year prospec t ve stu ywere unable to detect any correlation between rates of boneturn over an c anges n um ar or p BMD. Ot er groupsargue t at ue to t e g egree o var a ty n ur narymarkers of bone turnover, predicting either bone density or changes therein for an individual patient from a single marker

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Figure 1. Assoc at on etween rates o one resorpt on an bone loss in untreated early postmenopausal women. High

baseline rates of bone resorption (urinary NTX stratied byquartiles, x-axis) are associated with a higher risk of boneoss % c ange n um ar BMD a ter 1 year, y-ax s . W en

compare to women on HRT, t e re at ve r s RR o oneoss n untreate women n t e g est quart e Q4 o

baseline urinary NTX (>67 Bone Collagen Equivalents) was17.3 (CI: 2.5-119). The RR (CI) in the three lower quartileswere Q1: 1.4 (0.8-2.5), Q2: 2.5 (1.0-6.1) and Q3: 3.8 (1.6-9.1 , emonstrat ng a re at ve y at gra ent o r s . From:Rosen et a . w t perm ss on o t e J C n En ocr no Meta1997;82:1904-10. 1997, The Endocrine Society.

measurement may not be possible. , Vestergaard andcolleagues showed that serum osteocalcin, BSAP and

y roxypro ne are poor pre ctors o um ar an p oneoss n n v ua per menopausa women.

Ta en toget er, t ere s ev ence t at rates o oneremo e ng are asso c ate w t one oss. However, t estrength of this association seems to depend on a number of factors, such as menopausal age, skeletal site and gender.Bone remo e ng mar ers are no su st tute or n v ua

bone mass measurements, or for a careful assessment of the patients personal and family history.

Bone Turnover an Fracture R sBone turnover is an independent predictor of fracture risk.Ear er post- oc ana ys s o ata rom c n ca tr a s suggestet at n untreate osteoporot c women, verte ra racture ratesincrease as a direct function of either increased bone turn over or of decreased vertebral BMD. Thus, at a given level of verte ra BMD, t e rate o verte ra ractures ncreases w tthe rate of bone turnover. When bone turnover is normal,however, the main determinant of vertebral fractures isverte ra BMD.

Using the large population-based sample of the Rotterdamstudy (7983 individuals, 60% women aged 55 years and over),van Dae e et a . s owe t at women w t ncrease ur naryDPD levels had an increased risk of hip fracture. The relativerisk per SD increase in urinary DPD was 3.0 (95% condencenterva CI 1.3-8.6 . Interest ng y, part o t s assoc at on

appeare to e re ate to sa ty at ase ne. However,when the data were corrected for disability, a relative risk of 1.9 95% CI 0.6-5.6 rema ne . T s num er s very s m ar to t e ncrease n racture r s ca cu ate or 1 SD ecrease nBMD at the lumbar spine. Later analyses of the same studyrevealed that low serum osteocalcin concentrations were alsoassoc ate w t an ncrease r s o p racture o s rat o(OR) : 3.1; 95% CI 1.0-9.2).

In a ve-year o ow-up o t e same popu at on, Wee eta . ater s owe t at an ncrease n ase ne ur nary DPDabove the premenopausal mean value was associated with

an ncrease uture r s o osteoporot c ractures. A typeso non-verte ra ractures, ut espec a y ractures o t e p(OR 5-6) and the upper humerus (OR 3-5) were associatedwith urinary levels of DPD above the premenopausal mean,n epen ent o one m nera ens ty an sa ty. Fracture

risk increased dramatically when elevated rates of boneresorption were combined with low BMD.

S m ar resu ts ave een pu s e or t e Frenc EPIDOSstudy. The relative fracture risks as dened by either BMD or mar er measurements were s m ar RR ~2 to t ose reporteear er y van Dae e. Aga n, com ne measure ments o p

bone density and of bone resorption markers increased the predictive power for hip fractures (RR 5-6). Thus, in elderlywomen, t e re at ve r s o p racture seems to e g estin individuals with both low hip BMD and high rates of boneresorption.

A neste case contro stu y rom t e same group ater suggested that levels of serum under-carboxy lated osteocalcinucOC , ut not o tota osteoca c n, were pre ct ve o uture p ractures OR 2.0; 95% CI: 1.2-3.2 . T ese ata con rm

and extend previous reports, which suggest that increased

serum levels of ucOC are predictive of hip fractures in elderly,nst tut ona se women. - T ese ear er resu ts, owever,

may merely indicate an association between poor nutritionalstatus and hip fracture risk among institutionalised subjects,an not a genera o og ca mec an sm poss y re evantto a more represen tat ve samp ng o t e popu at on. T esignicance of vitamin K deciency to the under-carboxylationo osteo ca c n a een emon strate ear er y Pr ce et a .,an su sequent c n ca stu es s owe t at overt v tam n K deciency may lead to a disproportionate increase in ucOC inthe circulation. , In addition, vitamin K levels have been


one Turnover Markers

rinary NTX by quartile. Q1 lowest, Q4 highest

*signicantly different from baseline, p


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shown to be lower in women with osteo porotic fractures thanin healthy individuals. Although measure ment of ucOCmay e use u n prov ng an ntegrate assessment o t efactors that are responsible for the gamma-carboxylationof osteocalcin, such as vitamins K and D, the underlying

oc em ca mec an sms y w c ucOC cou e assoc atew t mpa re one meta o sm are, as yet, un nown.

In anot er prospect ve stu y rom Swe en, ow serum eve so ot t e car oxy term na propept e an te opept e otype I collagen were associated with an increased risk of hipfracture, independent of age and BMD. Thus, increased rateso one resorpt on or ecrease rates o one ormat on seemto be associated with future osteoporotic fractures.

Recent y, Me er an co eagues emonstrate n a case-co ortcontro stu y o 151 e er y men o owe prospect ve y over 6.3 years that accelerated bone resorption was associated

w t ncrease r s o osteoporot c racture, n epen ent oBMD. Com n ng measurements o BMD an one turnover improved fracture prediction in elderly men. (Figure 2).

Figure 2. Fracture r s an one turnover n men. Inc ence o

any osteoporot c racture accor ng to serum car oxyterm nacrosslinked telopeptide of type I collagen (S-ICTP) levelsand femoral neck BMD. Case-cohort control study of 151o er men rom t e Du o Ep em o og ca Stu y DOESo owe prospect ve y over 6.3 years. From Me er et a .

Repro uce rom J Bone M ner Res 2005;20:579-87 w t permission of the American Society for Bone and MineralResearch.

Prospective data from the Australian FREE study of 1112ra e er y men an women n cate t at g one turnover s a so an n epen ent pre ctor o a cause morta ty. T s

association appeared to be mainly manifested in deaths fromcardiovascular causes. (Figure 3).

Figure 3. High bone turnover is associated with all causemortality in the frail elderly. In a prospective analysis of 1112frail persons (79% female, mean age 86 years) recruitedinto the Australian FREE Study, g one turnover was ann epen ent pre ctor o a cause morta ty. T s assoc at on

appeared to be mainly manifested in deaths from cardiovascular causes. Upper panel: Age- and sex-adjusted mortality curves

by serum carboxyterminal crosslinked telopeptide, a boneresorpt on mar er. Lower pane : Age- an sex-a ustemorta ty curves y serum PINP, a one ormat on mar er.From: Sambrook et al. Reproduced from J Bone Miner Res2006;21:549-55 with permission of the American Society for Bone and Mineral Research.

In summary, data from several independent and large prospect ve stu es n cate t at n ot postmenopausawomen an ea t y men, ncrease rates o one resorpt onare associated with an increased risk of vertebral and non-vertebral fractures, independent of BMD, age and disability.

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In t e uture, mar ers o one turnover, n com nat on w tot er r s actors or osteoporot c racture, may e use todene fracture risk and intervention thresholds.

Pretreatment Bone Turnover an T erapeut c E ectFrom both a theoretical and clinical point of view, it isconceivable that intervention strategies may differ between

pat ents w t acce erate , norma or even a norma y ow bone turnover at the time of diagnosis; hence, a patient presenting with high rates of bone resorption may benet

rom ant resorpt ve t erapy, w ereas n an n v ua w tow one turnover, a st mu ator o one ormat on may y e

better long-term results. So, are pretreatment bone marker measurements e p u n gu ng t e se ect on o t erapyor n v ua pat ents? Some stu es ave s own t at n

osteoporotic patients treated with sub cutaneous calcitonin,increases in lumbar (but not necessarily in hip) BMD weres gn cant y greater n n v ua s w t g t an w t norma

or low base line rates of bone turnover.-

Similar results werelater reported for short term Alendronate treatment, althoughone report w t an equa y sma num er o su ects suggestst at c anges n BMD ur ng treatment w t A en ronate areindependent of pre-therapeutic bone turnover rates.

C esnut et a . an Rosen et a . emonstrate n 227 womentreated with either calcium alone or a combination of HRT

plus calcium, that individuals within the highest quartile for ase ne measures o one turnover a so exper ence t e

greatest gain in BMD after six and twelve months of treatmentwith HRT and calcium. , In this study, baseline urinary NTXan serum osteoca c n s owe t e g est pre ct ve va uesor a c ange n sp na BMD a ter one year o e t er HRT or

calcium. In reverse, those women showing a gain in BMDa ter one year o HRT a s gn cant y g er ase ne rateso one resorpt on as eterm ne y ur nary NTX t an non-responders or subjects losing bone during HRT (Figure 1).This observation is in agreement with the hypothesis thatc anges n one turnover a ects t e r s o verte ra racturesonly if bone turnover is signicantly accelerated, whilemore subtle changes appear to be without major effect. Incontrast, Stevenson et a . n a t ree-year prospect ve stu y

on t e e ect o HRT on sp ne an p BMD were una e todistinguish between responders and non-responders by meanso e t er ase ne or o ow-up measures o one turnover.Bot groups s owe t e same pretreatment va ues o oneformation and resorption, and the change in bone markers inresponse to HRT was identical in the affected and unaffectedgroups.

Post-hoc analyses of the Risedronate clinical phase III programs s ow t at t e re uct on n racture r s ur ng oneand three years of Risedronate treatment is similar in patients

w t ase ne ur nary DPD e ow or a ove t e premenopausame an e w t norma or acce erate one resorpt on .

(Figure 4). However, the number of patients needing treatmentto avo one racture ur ng one an t ree years o treatmentw t R se ronate s s gn cant y ower n pat ents w televated baseline bone turnover as compared to patients withlow baseline bone turnover. Thus, although the reduction in

overa racture r s seems to occur n epen ent o ase ne bone turnover, patient stratication by pretreatment boneresorption rates seems to make some sense from a pharmaco-econom c po nt o v ew.

Figure 4. Pretreatment bone turnover and change of non-verte ra racture r s n response to r se ronate treatment.Post- oc ana ys s o a su set o t e r se ronate p aseIII c n ca programs us ng ur nary DPD as an n ex o

pretreatment bone resorption (PBR). A total of 1593 womenwith postmenopausal osteo porosis were pooled, in similar

proport ons, rom t e r se ronate mu t nat ona an NortAmer can VERT, an rom t e r se ronate HIP tr a s.Pat ents rom treatment an p ace o groups were strat e

by the DPD premeno pausal normative median. The guresshow the cumulative incidence of new vertebral fractures bytreatment group. The dotted lines represent patients with a

ase ne one resorpt on rate e ow or equa to t e normat vemean NM). From: Seibel et al. Reproduced from J Bone Miner Res 2004;19:323-9 with permission of the American Societyor Bone an M nera Researc .




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A similar post-hoc analysis of the Fracture InterventionTrial (FIT), examining the inuence of pretreatment boneturnover on t e ant - racture e cacy o a y a en ronatein postmenopausal women found that the non-spine fractureefcacy of alendronate was signicantly greater among bothosteoporot c an non-osteoporot c women w t g er ase neeve s o t e one ormat on mar er am noterm na propept e

of type I collagen PINP). However, no such association waso serve or verte ra ractures, an c anges n ot BSAPan t e car oxyterm na cross n e te eopept e CTX-I) were not associated with fracture outcomes at any site.

(Figure 5).

Figure 5. Pretreatment bone turnover and reduction in non-verte ra racture r s n response to a en ronate treatmentFracture Inter vent on Tr a . Osteoporot c women treate

with alendronate are represented by dotted lines and the placebo group by solid lines. The analysis was performed by tertile of pretreatment serum PINP levels. The p valuere ers to compar sons etween a en ronate versus p ace ogroups w t n eac tert e. From: Bauer et a . Repro ucerom J Bone M ner Res 2006;21:292-9 w t perm ss on o t e

American Society for Bone and Mineral Research.

Taken together, it remains unclear whether there is a clinicallyrelevant relationship between bone turnover at baseline andt e response to ant resorpt ve treatment. Drugs even o t esame class may differ in this respect.

Bone Turnover Markers and Therapeutic MonitoringBisphosphonates, raloxifene, denosumab, strontium ranelate,

oestrogens, ca c um, ca c ton n an ter parat e a mproveBMD to varying degrees. In contrast, the effects of theseanti-osteoporotic drugs on bone turnover differ greatly:

sp osp onates F gure 6 , oestrogens, enosuma F gure 7 ,ca c ton n an ra ox ene ten to re uce one resorpt on an

bone formation in a dose dependent manner. - Strontiumrane ate, n contrast, as on y su t e e ects on one turnover,s ow ng a s g t re uct on n one resorpt on mar ers an amild increase in bone formation markers. (Figure 8). Finally,teriparatide strongly increases both bone formation and, after acerta n gap per o , one resorpt on mar ers. - F gure 9 .

Figure 6. Change in markers of bone turnover followingtreatment with intravenous zoledronate. Patients wereinjected with varying doses of zoledronate as shown in theegen . O note, a s ng e ose o 4 mg zo e ronate resu te n

a suppress on o one turnover mar ers or up to 12 mont s,w t out any s gns o recovery at t at t me po nt. Newer atasuggest that this suppression may last up to 18 months. From:Reid et al. N Engl J Med 2002;346:653-61. Copyright 2002 Massachusetts Medical Society. All rights reserved.


Seibel M

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Figure 7a. Change in markers of bone turnover followinga 3-mont y os ng o sc. Denosuma . Pat ents rece ve 3-mont y sc. n ect on o vary ng oses o enosuma AMG162 , as s own n t e egen . Percentage c ange rom ase nein serum levels of CTX-I (upper panel) and in BSAP (lower

panel) are shown. A small rise in CTX-I levels can be seen withthe 6 mg dose. The formation marker BSAP decreases with

a e ay, ut ex ts no ma or ose-t me epen ent c anges.Figure 7b. C ange n mar ers o one turnover o ow ng a6-monthly dosing of sc. Denosumab. The percentage changefrom baseline in serum levels of CTX-I in patients with 6-monthly injections of denosumab. In the group of patientstreate w t 14 mg enosuma , a pronounce r se n CTX-Ieve can e seen e ore t e next ose s a m n stere . From

McC ung et a . , N Eng J Me 2006;354:821-31. Copyr g t 2006 Massachusetts Medical Society. All rights reserved.

Figure 8. Change in markers of bone turnover during treatmentwith oral strontium ranelate.The graph shows the differencesin biochemical markers between the strontium treated and

p ace o groups over t me. For eac mar er upper pane :BSAP; ower pane : CTX-I , an t me po nt, mean SE va uesof the placebo group were subtracted from the mean (SE)values of the strontium ranelate group. Absolute changes inmarker levels were small: maximum change in BSAP: + 2.5ng mL n t e treate group at 24 mont s; max mum c ange nCTX-I: -400 pmo L n t e treate group at 6 mont s. FromMeun er et a . N Eng J Me 2004;350:459-68. Copyr g t 2004 Massachusetts Medical Society. All rights reserved.



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Figure 9. Change in markers of bone turnover during therapyw t a y s.c. ter parat e an or a en ronate. Pat entsrece ve ter parat e, a en ronate or a com nat on o otagents. Teriparatide results in an increase of both boneformation and resorption markers, with an earlier responsein bone formation markers. As expected, alendronateea s to a suppress on o t ese n ces. T e net resu t o

com ne treatment w t ter parat e an a en ronate was asuppress on o one turnover. From B ac et a . N Eng JMed 2003;349:1207-15. Copyright 2003 MassachusettsMedical Society. All rights reserved.

Most sp osp onates, ra ox ene, stront um rane ate,oestrogens and teriparatide have also been shown to reducethe risk of osteoporotic fractures. However, the observedre uct on n racture r s s on y part y exp a ne y t e

ocumente c anges n BMD, w t t e re uct on n racturerisk being much greater than predicted from improvements inBMD on y. - Hence, t as een est mate t at c anges nBMD exp a n on y 4% to 28% o t e re uct on n verte rafracture risk attributed to antiresorptive treatments. - It istherefore likely that changes in other determinants of bone

strength, including the rate of bone turnover and its changesduring antiresorptive therapy, may be better predictors of ant - racture e cacy. In act, severa stu es con rme t atshort-term reductions in bone turnover were associated with areduction in ver tebral and/or non-vertebral fracture risk inwomen treate w t HRT, ra ox ene , , r se ronate,a en ronate a n an ronate.

T e re at ons p etween s x an 12 mont s c anges n oneturnover mar ers an verte ra racture r s a ter t ree yearsof raloxifene treatment in postmenopausal women clearlyfavours bone turnover markers as the better predictor of outcome. A ecrease o 9.3 pg mL n serum osteoca c nafter one year of raloxifene treatment was associated withan OR for new vertebral fractures after 3 years of 0.69CI 0.54-0.88, p=0.003 . S m ar y, or a ecrease o 5.91 g L n

BSAP t e OR was 0.75 CI 0.62-0.92, p=0.005 . Important y,these relationships remained after adjustment for baseline

verte ra racture status an BMD. Two su sequent ana ysesnc u ng postmenopausa women w t osteoporos s rom

the same cohort (MORE trial) extended and conrmed theseresu ts s ow ng t at ot , one year percentage c anges nserum PINP and osteocalcin are able to predict the reductionin vertebral fracture risk after three years of treatment. ,

Two stu es ave nvest gate t e c ange n one turnover markers and fracture risk in bisphosphonate treated

postmenopausa women. , Post- oc ana yses o ata romt e VERT stu es nc u ng postmenopausa women w t atleast one vertebral fracture demonstrated that reductions inurinary CTX-I (by 60%) and NTX-I (by 51%) at three to sixmont s o r se ronate treatment were s gn cant y assoc atewith the reduction in vertebral and non-vertebral fracture risk after three years. The change in bone resorption markersexp a ne 50-60% o t e r se ronate-re ate racture r sre uct on or ot verte ra an non-verte ra ractures. Bauer et al. reported that in alendronate-treated women, greater re uct ons n one turnover were assoc ate w t ewer osteoporot c ractures. In t e r stu y, eac SD re uct on nthe change in BSAP at one year was associated with fewer

spine (OR 0.74; CI: 0.63, 0.87), non-spine (relative hazardRH 0.89; CI: 0.78, 1.00 an p ractures RH 0.61; CI:

0.46, 0.78). Furthermore, alendronate-treated women withat least a 30% reduction in BSAP had a lower risk of non-sp ne RH 0.72; CI: 0.55, 0.92 an p ractures RH 0.26;CI: 0.08, 0.83 re at ve to t ose w t re uct ons


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racture r s w t a ar greater e ect on racture re uct ont an as een attr ute to treatment- n uce c anges nBMD. These data suggest that biochemical markers of boneturnover are use u too s to eva uate t erapeut c e ects a ter a re at ve y s ort per o o t me, an t at ser a measurementsof bone markers may help to decide whether or not a patientresponds to a specic antiresorptive treatment. Whether

c anges n one turnover ur ng treatment w t agents suc asstrontium ranelate, denosumab or teriparatide predict fractureoutcomes is presently not clear.

Mon tor ng Pat ent Comp ance Us ng Bone Mar ersLong-term compliance with treatment for osteoporosis isusua y poor. Severa stu es reporte t at up to 50% o

postmenopausa women were not a erent to t e r treatmentafter one to ve years of HRT. - A major cause of non-compliance were unwanted side-effects or fear of side-effects,nconven ence cause y me cat on, an g rug costs. .

Hence, monitoring patients on antiresorptive medication isan eminent part of patient management in order to improvea erence an pers stence to t erapy, an u t mate y treatmente ect veness.

B oc em ca mar ers o one turnover ave een a vocateto facilitate follow-up of patients receiving antiresorptivetreatments or osteoporos s. As one turnover mar ers, n

part cu ar n ces o one resorpt on, ecrease rap y a ter initiation of treatment within three to six months, they mightrepresent useful surrogate markers for monitoring patient

comp ance. On y ew ata, owever, are ava a e to supportthis theoretical approach. Using a decision analysis model,Chapurlat et al. compared two strategies of follow-up:a treatment o a woman w t out spec c mon tor ng, an

b) treatment of this woman with measurement of a serummarker of bone resorption after three months of treatment,w t c ange o treatment response to treatment as assesse

y t s mar er was not sat s actory. T s stu y suggeststhat monitoring osteoporotic women with measurementsof bone markers early during the treatment course mayncrease e ect veness o treatment w t greater qua ty

adjusted life years than no follow-up. In another study of 75 postmenopausal women treated with raloxifene, Cloweset a . exam ne w et er mon tor ng nurse-mon tor ng or marker-monitoring) enhances adherence and persistence withantiresorptive therapy, and whether presenting informationon t e oc em ca response to t erapy prov e a t ona

ene t. Surv va ana yses s owe t at n t e group e ngmonitored, cumulative adherence to therapy increased by57% compare w t no mon tor ng; a so, t ere was a tren or t e mon tore group to pers st w t t erapy or onger per o sof time. However, presentation of results of effects on NTX-I levels did not improve compliance to therapy compared

w t nurse-mon tor ng a one. Nevert e ess, resu ts rom t eIMPACT stu y n postmeno pausa women on r se ronate aveshown that a reinforcement mes sage based on bone marker response n uences pers stence w t ong-term treatment. In

pat ents n w om a ver a ee ac on t e c ange o ur nary NTX-I was provided, one-year persistence was higher thanin non-reinforced subjects. Interestingly, the message given

to pat ents w t a one turnover mar er response cons eregood was associated with signicant improvement in

persistence, whereas the information given to those with a poor resorpt on mar er response e to a ower pers stence.Anot er arge stu y nvest gat ng pat ent comp ance us ngmeasurements of urinary CTX-I is under way and should giveurt er ev ence w et er mon tor ng osteoporos s treatment

us ng one turnover mar ers s ou e encourage n c n ca practice.

Other Conditions

An abundance of experimental and clinical studies havedemonstrated that markers of bone formation and resorptionare use u too s n t e assessment o t e s e eta response toa great var ety o n uences. For examp e, mar ers o oneturnover may reect changes in bone metabo lism induced

y oop orectomy, , yperparat yro sm, , Pagetssease, p ys ca exerc se, mmo sat on, , a co o-

lism, smoking, vitamin D deciency, , , , chronicinammatory bowel disease, , chronic starvation,t yro sor ers, , as we as t e p armaco og ca e ectsof gluco corticosteroids, , , androgens, , , gonadotropin-releasing hormone agonists, warfarin, growth hormoneor nsu n- e growt actors. Bone turnover mar ers mayn use u n t e agnos s an management o certa n o t e

above conditions, but in most cases have not been rigorouslyexam ne .

The situation is somewhat different in cancer: as bonemetastases profoundly perturb normal bone remodelling,

oc em ca mar ers o one turnover ave een s own toreect these tumour-induced changes in bone remodellingand may therefore be useful in the diagnosis, follow-up and

prognos s o pat ents w t ma gnant one sease. ,

F gure 10 . Most mar ers o one turn over, part cu ar y t oseof bone resorption, are elevated in patients with established

one metastases recent y rev ewe . W e t s may n catea ro e o one mar ers as agnost c too s n cancer pat ents,available evidence does not provide any nal conclusionsas to the accuracy and validity of the presently usedmar ers n t e ear y agnos s o one metastases.

Markers of bone resorption respond promptly and pro oun y to sp osp onate an ant -neop ast c t erapy,an t s response appears to e assoc ate w t a avoura e




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clinical outcome in patients with bone metastases. -

Recent evidence indicates that the aim of bisphosphonatet erapy s ou e to norma se ncrease rates o oneremodelling. , However, it remains unknown whether theuse of bone markers in the routine clinical setting has any

e ne ene c a e ects on overa outcome n cancer pat ents.In part cu ar, no stu y as a resse t e quest on w et er

patients with bone metastases should be treated accordingto t e r rate o one turnover, an w at t e treatment goa sare n t s respect. W e t s un e y t at one turnover markers have sufcient diagnostic or prognostic value to beused in isolation, the combination of these markers with other

agnost c tec n ques may e t e way orwar to mprove t eclinical assessment of patients with bone seeking cancers.

Figure 10. Probability of survival according to serum BoneSialoprotein (BSP) values in patients with multiple myeloma.Patients were stratied by serum BSP concentrations at

ase ne so ne: serum BSP 21 ng mL . In a mu t var ate Cox proport onaanalysis, serum BSP (p = 0.012) and monoclonal protein (p= 0.028) were the only predictors of survival in this patientgroup. From Woitge H et al. Br J Cancer 2001;84:344-51w t perm ss on Macm an Pu s ers Lt , copyr g t 2001.

Although the above mentioned studies represent only a smallse ect on o t e ava a e terature, t ey a emonstratethat markers of bone turnover are extremely helpful toolsin evaluating the physio logy and pathophysiology of bonemeta o sm, an n e uc at ng t e pat ogenes s o onedisease.

Compet ng Interests : None ec are .

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