ORIGINAL RESEARCH

Algorithm for the Useof BiochemicalMarkers of BoneTurnoverin the Diagnosis,Assessmentand Follow-Upof Treatmentfor Osteoporosis

Mattias Lorentzon . Jaime Branco . Maria Luisa Brandi

. Olivier Bruyere . Roland Chapurlat . Cyrus Cooper .

Bernard Cortet . Adolfo Diez-Perez . Serge Ferrari .

Andrea Gasparik . Markus Herrmann . Niklas Rye Jor-

gensen . John Kanis . Jean-Marc Kaufman . An-

drea Laslop . Medea Locquet . Radmila Matijevic .

Eugene McCloskey . Salvatore Minisola .

Richard Pikner . Jean-Yves Reginster . Rene Rizzoli .

Pawel Szulc . Mila Vlaskovska . Etienne Cavalier

Received: June 21, 2019� The Author(s) 2019

ABSTRACT

Introduction: Increased biochemical boneturnover markers (BTMs) measured in serum areassociated with bone loss, increased fracture riskand poor treatment adherence, but their role inclinical practice is presently unclear. The aim ofthis consensus group report is to provide guid-ance to clinicians on how to use BTMs inpatient evaluation in postmenopausal osteo-porosis, in fracture risk prediction and in themonitoring of treatment efficacy and adherenceto osteoporosis medication.Methods: A working group with clinical scien-tists and osteoporosis specialists was invited bythe Scientific Advisory Board of European Soci-ety on Clinical and Economic Aspects ofOsteoporosis, Osteoarthritis and Musculoskele-tal Diseases (ESCEO).Results: Serum bone formation marker PINPand resorption marker bCTX-I are the preferredmarkers for evaluating bone turnover in theclinical setting due to their specificity to bone,performance in clinical studies, wide use andrelatively low analytical variability. BTMs can-not be used to diagnose osteoporosis because oflow sensitivity and specificity, but can be ofvalue in patient evaluation where high valuesmay indicate the need to investigate some

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M. LorentzonGeriatric Medicine, Department of InternalMedicine and Clinical Nutrition, Institute ofMedicine, Sahlgrenska Academy, University ofGothenburg, Gothenburg, Sweden

M. LorentzonRegion Vastra Gotaland, Geriatric Medicine Clinic,Sahlgrenska University Hospital, Gothenburg,Sweden

M. Lorentzon � J. KanisMary MacKillop Institute for Health Research,Australian Catholic University, Melbourne,Australia

J. BrancoCEDOC, NOVA Medical School, Medical ScienciesFaculty, NOVA University of Lisbon, Lisbon,Portugal

J. BrancoRheumatology Department, Egas Moniz Hospital,CHLO, Lisbon, Portugal

M. L. BrandiFirmoLab Fondazione F.I.R.M.O, University ofFlorence, Florence, Italy

O. BruyereWHO Collaborating Centre for Public Heath Aspectsof Musculoskeletal Health and Aging, Departmentof Public Health, Epidemiology and HealthEconomics, University of Liege, Liege, Belgium

R. Chapurlat � P. SzulcINSERM, UMR 1033, Universite de Lyon, Hopital EHerriot, 69437 Lyon Cedex 03, France

C. CooperMRC Lifecourse Epidemiology Unit, University ofSouthampton, Southampton, UK

C. CooperNIHR Southampton Biomedical Research Centre,University of Southampton and University HospitalSouthampton, Southampton, UK

C. CooperNHS Foundation Trust, Southampton, UK

C. CooperNIHR Oxford Biomedical Research Centre,University of Oxford, Oxford, UK

B. CortetDepartment of Rheumatology and EA 44090, CHULille and University of Lille, 59000 Lille, France

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https://doi.org/10.1007/s12325-019-01063-9

causes of secondary osteoporosis. Assessing serum levels of bCTX-I and PINP can improvefracture prediction slightly, with a gradient ofrisk of about 1.2 per SD increase in the bonemarker in addition to clinical risk factors andbone mineral density. For an individual patient,BTMs are not useful in projecting bone loss ortreatment efficacy, but it is recommended thatserum PINP and bCTX-I be used to monitoradherence to oral bisphosphonate treatment.Suppression of the BTMs greater than the leastsignificant change or to levels in the lower halfof the reference interval in young and healthypremenopausal women is closely related totreatment adherence.Conclusion: In conclusion, the currently avail-able evidence indicates that the principal clini-cal utility of BTMs is for monitoring oralbisphosphonate therapy.

Keywords: Algorithm; Bone; Bone biomarker;CTX; Osteoporosis; P1NP; Rheumatology

INTRODUCTION

Osteoporosis—Diagnosis and Burdenof Disease

Osteoporosis is a disease characterized by lowbone mineral density (BMD) and deteriorationof bone microarchitecture, which leads toincreased risk of fragility fracture [1, 2]. Osteo-porotic fractures, especially of the hip andspine, commonly result in disability, increasedmorbidity and mortality [3]. In 2010, thenumber of fractures in the European Union wasestimated at 3.6 million, of which 620,000 werehip fractures [4]. Patients at high fracture riskcan be identified by investigating known clini-cal risk factors, which can be combined using afracture risk calculator such as FRAX, for thecalculation of 10-year probability of majorosteoporotic and hip fracture [5]. A measure-ment of BMD using dual-energy X-ray absorp-tiometry (DXA) provides a good surrogate forbone strength and is used to diagnose osteo-porosis, which in postmenopausal women andmen aged C 50 years is defined as a BMD valueof - 2.5 standard deviations (T-score) or below

A. Diez-PerezHospital del Mar Institue of Medical Investigation,Autonomous University of Barcelona andBiomedical Research Network on Frailty andHealthy Aging (CIBERFES), Madrid, Spain

S. Ferrari � R. RizzoliService of Bone Diseases, Geneva UniversityHospital and Faculty of Medicine, 1211 Geneva 14,Switzerland

A. GasparikDepartment of Public Health and HealthManagement, University of Medicine, Pharmacy,Science and Technology of Targu Mures, TarguMures, Romania

M. HerrmannClinical Institute of Medical and ChemicalLaboratory Diagnostics, Medical University of Graz,Graz, Austria

N. R. JorgensenDepartment of Clinical Biochemistry, CopenhagenUniversity Hospital Rigshospitalet, Copenhagen,Denmark

N. R. JorgensenOPEN, Odense Patient Data Explorative Network,Odense University Hospital/Institute of ClinicalResearch, University of Southern Denmark, Odense,Denmark

J. KanisCentre for Metabolic Bone Diseases, University ofSheffield Medical School, Sheffield, UK

J.-M. KaufmanDepartment of Endocrinology, Ghent UniversityHospital, 9000 Ghent, Belgium

A. LaslopScientific Office, Federal Office for Safety in HealthCare, Austrian Agency for Health and Food Safety,Vienna, Austria

M. LocquetDepartment of Public Health, Epidemiology andHealth Economics, University of Liege, Liege,Belgium

M. LocquetBelgium WHO Collaborating Centre for PublicHealth Aspects of Musculoskeletal Health andAgeing, Liege, Belgium

R. MatijevicUniversity of Novi Sad, Faculty of Medicine, NoviSad, Serbia

R. MatijevicClinical Center of Vojvodina, Clinic for OrthopedicSurgery, Novi Sad, Serbia

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the mean of the young adult woman [6, 7]. Theestimation of fracture risk probability in FRAXcan be further refined by adding femoral neckBMD to the clinical risk factors in the calcula-tion and is recommended in many clinicalguidelines [8].

Measuring Bone Turnover

Bone turnover is necessary to replace damagedbone, for example, containing microcracks,with new and healthy bone and to release cal-cium into the circulation to maintain calciumhomeostasis. Bone resorption comprises the4–6-week process in which osteoclasts excavatebone to cause resorption pits, from whichdegraded bone releases calcium into the

microenvironment and later the circulation. Ina coupled process, bone resorption triggers boneformation by osteoblasts, a process taking 4–-5 months, which fills the resorption cavity withan unmineralized osteoid, a connective tissuerich in collagen. Levels of bone turnover mark-ers reflect the activity and number of bone-forming (osteoblasts) and bone-degrading cells(osteoclasts), providing an estimate of boneresorption and bone formation. Bone turnovermarkers can be measured non-invasively ineither blood or urine at a fairly low cost (usually\ €20).

The most widely used markers are N-termi-nal collagen type I extension propeptide (PINP),osteocalcin and bone alkaline phosphatase forbone formation and C-terminal cross-linkingtelopeptide of type I collagen (bCTX-I), N-ter-minal telopeptide of type I collagen (NTX),deoxypyridinoline, hydroxyproline or tartrate-resistant acid phosphatase isoform 5b (TRAP5b)for bone resorption (Table 1) [9]. Post-transla-tional cleavage of type I collagen during bonematrix formation gives rise to PINP, whichsubsequently leaks out into the circulation andcan be measured in serum. Osteocalcin is alsoproduced by osteoblasts during bone formation,is excreted by the kidneys and is one of the mostabundant non-collagenous proteins in bone. Itis also released during bone resorption. Alkalinephosphatase (ALP) is secreted from bone to thecirculation when the osteoid is mineralized, butonly about half of serum ALP levels are derivedfrom bone, and the other half emanates mainlyfrom the liver. However, there are currentlyavailable assays that to a high degree are specificto the circulating bone ALP isoform (BALP).

Each bone marker has distinct features thatreflect particular aspects of bone physiology. Forexample, TRAP5b reflects the number of osteo-clasts and is not secreted in urine and cantherefore be useful in assessing bone and min-eral disorder in chronic kidney disease, whilstmeasuring bCTX-I in such patients is inappro-priate since the bone marker accumulates inserum if renal function is poor. bCTX-I reflectsosteoclast activity resulting in bone degradationand is useful in evaluating, e.g., glucocorticoidinduced osteoporosis [10], in which bCTX-Iincreases rapidly and peaks after about a week

E. McCloskeyDepartment of Oncology and Metabolism, Centrefor Integrated Research in Musculoskeletal Ageing,University of Sheffield, Sheffield, UK

S. MinisolaDepartment of Internal Medicine and MedicalDisciplines, Rome University, Sapienza, Italy

R. PiknerDepartment of Clinical Biochemistry and BoneMetabolism, Klatovska Hospital, Klatovy, CzechRepublic

R. PiknerDepartment of Clinical Biochemistry andHeamathology, Faculty of Medicine Pilsen, CharlesUniversity Prague, Pilsen, Czech Republic

R. PiknerFaculty of Health Care Studies, University of WestBohemia, Pilsen, Czech Republic

J.-Y. ReginsterWHO Collaborating Centre for Public HealthAspects of Musculoskeletal Health and Aging,University of Liege, Liege, Belgium

J.-Y. ReginsterChair for Biomarkers of Chronic Diseases,Biochemistry Department, College of Science, KingSaud University, Riyadh, Kingdom of Saudi Arabia

M. VlaskovskaDepartment of Pharmacology, Medical Faculty,Medical University Sofia, 2, Zdrave Str, 1431 Sofia,Bulgaria

E. Cavalier (&)University of Liege, CHU de Liege, Liege, Belgiume-mail: Etienne.cavalier@chu.ulg.ac.be

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after glucocorticoids are started. Oral glucocor-ticoid treatment also inhibits bone formation,as reflected by a rapid and profound decline inserum osteocalcin levels, whereas the decline inPINP is considerably smaller [10].

Most clinical trials have used bone turnovermarkers to monitor osteoporosis treatment butthe use has not been widely adopted in clinicalpractice [11–14].

Factors Affecting Levels of Bone TurnoverMarkers

Bone resorption markers, including bCTX-I,show diurnal variations, with the highest bloodconcentration early in the morning and thelowest at around 2 p.m. Both the levels of boneresorption and formation markers are sup-pressed by feeding, but the effect is much largerfor resorption markers (excepted Trap5b),which are suppressed by 20–40%, whilst for-mation markers are suppressed by \ 10%[15, 16]. A fracture normally results in a rapidincrease in bone resorption markers, whichdoubles in weeks, followed by more slowlyincreasing bone formation markers, whichdouble in serum levels after about 3 months,but remain elevated for up to a year after frac-ture [17]. Several other factors, including glu-cocorticoids, menopausal state, age, gender,pregnancy/lactation, aromatase inhibitors,renal insufficiency, immobility and exercise,have an impact on blood-bone turnover mark-ers and should also be considered in their eval-uation (Table 2) [18].

Current Recommendations of Use of BoneTurnover Markers in Clinical Guidelines

The use of serum bone formation marker PINPand resorption marker bCTX-I in the investiga-tion of osteoporosis or in monitoring treatmentis currently recommended in several guidelinesaround the world, including those issued by theUK National Osteoporosis Guideline Group(NOGG), by the National Osteoporosis Foun-dation in the US [19–21] and by the Interna-tional Osteoporosis Foundation (IOF) [22, 23].

Aim

The aim of this consensus group report is toprovide guidance, based on the opinion of theexperts of this group, to clinicians on how touse bone turnover markers in patient evalua-tion, in fracture risk prediction and in moni-toring treatment effect and adherence to oralbisphosphonates in postmenopausal osteo-porosis. The results of this report are endorsedby the Scientific Board of the European Societyon Clinical and Economic Aspects of Osteo-porosis, Osteoarthritis and MusculoskeletalDiseases (ESCEO).

METHODS

An international working group was gathered todevelop recommendations for the use of boneturnover markers in the diagnosis and

Table 1 Biochemical bone turnover markers

Measurement medium

Bone formation markers

Bone alkaline phosphatase Serum

PICP Serum

Osteocalcin Serum, urine

PINPa Serum

Bone resorption markers

CTX-Ia Plasma, serum*, urine

ICTP Serum

NTX Serum, urine

Trap5b Serum

Biochemical bone turnover markers that can be measuredin serum are listed. aDenotes bone turnover markers rec-ommended by IOF and IFCCPICP procollagen type 1 C propeptide, PINP procollagentype 1N propeptide, CTX-I carboxyterminal cross-linkingtelopeptide of type I collagen, ICTP carboxy-terminalcross-linking telopeptide of type I collagen, NTX amino-terminal cross-linking telopeptide of type I collagen,Trap5b tartrate-resistant acid phosphatase 5b [18]

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treatment of osteoporosis. Specialists in internalmedicine, endocrinology, rheumatology, reha-bilitation, geriatrics, clinical biochemistry andepidemiology were invited to participate by the

Scientific Advisory Board of European Societyon Clinical and Economic Aspects of Osteo-porosis, Osteoarthritis and MusculoskeletalDiseases (ESCEO). A 1-day in-person meeting

Table 2 Controllable and uncontrollable sources of pre-analytical variability in biochemical bone turnover markers

Effect Recommendation Importance

Controllable sources

Circadian

rhythm

High BTM concentrations at night and early

morning, lowest in the afternoon

Collect serum samples in the morning

(7.30–10.00 h)

High

Food intake Decrease in BTMs, especially bone resorption

markers (about 20–40%) after food intake

Collect samples of bone resorption

markers after overnight fast

High

Exercise Intense exercise can decrease bone resorption and

increase bone formation markers

Ask patient to refrain from intense

exercise the day prior to blood

sampling

Low

Alcohol

intake

Alcohol consumption decreases BTMs Ask patient to refrain from excessive

alcohol intake the day prior to blood

sampling

Low

Seasonal Higher levels of BTMs in winter In research, take samples in the same

season or adjust for seasonal variation

Low

Medications

-oral GC Rapid and dose-dependent decrease in bone

formation markers, small effect on bone

turnover markers

Consider dose of oral GC High

-aromatase

inhibitors

Increase in BTMs

Uncontrollable sources

Age Postmenopausal women have higher BTMs than

premenopausal women

Use age-based reference intervals High

Bed rest/

immobility

Bone resorption markers increase and formation

markers decrease

Consider different expected baseline level

when evaluating BTMs

High

Ethnicity Small differences. Lower osteocalcin in African

Americans vs. Caucasians

Unclear if different reference intervals

are needed for different ethnicities

Low

Fracture BTMs increase after fracture, with maximum

effect 2–12 weeks, but remains elevated up to

52 weeks

Limits evaluation in patients with recent

fracture

High

Menopause BTMs increase at the time of the final menstrual

period

Use reference intervals considering

menopausal status

Moderate

Selected factors affecting the pre-analytical variation in bone turnover markers (BTMs) [9, 22]GC glucocorticoids

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was held on 5 February 2019 in Geneva to dis-cuss the existing scientific literature on thetopic and to propose recommendations. Afterthe meeting, members of the writing group(ML, JYR, JK, EM) drafted the first manuscriptwith the recommendations. The manuscriptwas then reviewed and commented on by allgroup participants from the Geneva meeting.This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

RESULTS AND DISCUSSION

Preferred Bone Markers

The IOF and International Federation of Clini-cal Chemistry and Laboratory Medicine recom-mend that the bone formation marker PINP andresorption marker bCTX-I be used as referencemarkers and measured in serum using stan-dardized assays. These markers were chosenbased on a number of criteria, including ade-quate characterization of the marker, specificityto bone, performance in clinical studies, bio-logical and analytical variability, wide avail-ability, potential for standardization ofmethods, sample handling, stability and med-ium of measurement (serum vs. urine) [22–24].

The Role of Bone Turnover Markersin the Diagnosis of Osteoporosisand Patient Evaluation

Osteoporosis is operationally defined by BMDusing DXA. There is an inverse relationshipbetween BMD and the serum levels of boneturnover markers, but the correlation is weak tomoderate [25]. In the TRIO study, only 20% ofpostmenopausal women, diagnosed withosteoporosis using DXA had serum bCTX-Iabove the upper normal range for healthy pre-menopausal women [26]. Therefore, boneturnover markers cannot be used for the diag-nosis of osteoporosis. However, abnormal levelsof bone turnover markers, particularly whenhigh, can be useful for identifying patients in

whom further investigations may be needed todetect secondary causes of osteoporosis (e.g.,primary hyperparathyroidism, thyrotoxicosis,malabsorption) or other bone diseases (e.g.,osteomalacia, Paget’s diseases, bone metastases,multiple myeloma) [27].

Predicting Bone Loss Using Bone TurnoverMarkers

Declining circulating estradiol levels, particu-larly during the menopausal transition, givesrise to increased bone turnover due to anincreased number of bone remodelling unitswith a greater increase of osteoclastic activity,causing an imbalance between bone resorptionand formation, leading to bone loss. Theincreased bone turnover is reflected by anincrease in bone turnover markers, which isassociated with loss of both trabecular and cor-tical bone [28, 29]. Bone turnover marker levelscorrelate with bone loss on a group level, andthis correlation can be strengthened by sam-pling blood on several occasions to reduce thebetween-samples variation. However, the pro-portion of the variation in BMD change thatcan be explained by bone turnover markersremains quite small. Thus, predicting an indi-vidual’s bone loss over time using bone turn-over markers has proved challenging andcannot be recommended in a clinical setting[30–32]. Since bone loss from the forearm andhip has been associated with increased risk offracture, it seems reasonable to assume thatbone turnover markers, which are associatedwith bone loss, can predict fractures [33, 34]. Inaddition, bone turnover markers may affectfracture risk independently of BMD. Increasedbone turnover can be accompanied by a highproportion of newly formed and partly miner-alized bone, which is weaker than mineralizedbone, and poor trabecular bone microstructure,because of resorption cavities on the trabeculae,trabecular perforations and loss of trabecularconnectivity, can have a substantial negativeimpact on bone strength, not captured withDXA [35, 36].

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The Role of Bone Turnover Markersin Fracture Risk Prediction

Most prospective studies investigating theassociations between bone turnover markersand incident fractures in postmenopausal andolder women have found that the higher thelevel of bone turnover markers, the greater thefracture risk [18]. With some exceptions, boneresorption markers and bone alkaline phos-phatase are more strongly associated with frac-tures (all, multiple, spine and hip) than otherbone turnover markers [32, 37–39]. Elevatedbone turnover markers increase fracture riskindependently of BMD in some but not in allstudies [18]. The role of serum PINP and bCTX-Iin fracture prediction was investigated in ameta-analysis of six prospective cohorts withwomen and men. The risk of fracture wasincreased by 23% [hazard ratio 1.23 (95% CI1.09–1.39)] and 18% [hazard ratio 1.18 (95% CI1.05–1.34)] per SD increase in serum PINP andbCTX-I, respectively, but these analyses werenot adjusted for BMD [40]. In a recent meta-analysis of nine studies of mostly post-menopausal women, bone turnover markerswere weakly associated with fracture risk afteradjustment for confounders, with a gradients ofrisk of 1.20 for serum bCTX-I and of 1.28 forserum PINP. It was concluded that PINP andbCTX-I appear to predict fracture risk indepen-dently of BMD and clinical risk factors [41], butthe availability of knowledge of confoundingvariables was very variable. Bone turnovermarkers’ ability to predict fractures seems to bestronger over short (within a few years) ratherthan long time periods [42, 43], which likelylimits their value and usefulness in long-termfracture prediction in risk calculators such asFRAX, but makes them more appealing in theprediction of short-term or imminent fracturerisk. Based on the relatively weak associationsbetween bone turnover markers and fracturerisk, uncertainty about the independent abilityto predict fractures, the natural variability in themarkers, problems with the assays and theinability to predict fracture over long timeperiods, the Fracture Risk Assessment Tool(FRAX) Position Development Conferencemembers concluded that bone turnover

markers should not be included in the calcula-tion of the 10-year probability of fracture in theFRAX tool [44].

The Use of Bone Turnover Markersin the Monitoring of OsteoporosisTreatment

BisphosphonatesBisphosphonates, including alendronate, rise-dronate, zoledronate and ibandronate, are themost commonly used medications to treatosteoporosis [4]. They reduce bone resorptionby inhibiting osteoclasts, increase BMD andlower the risk of spine, hip and non-vertebralfractures [45–47]. With treatment in recom-mended doses, bCTX-I is reduced rapidly, byapproximately 50–80%, reaching maximumsuppression after about 2 months, whilst PINPsuppression is slightly smaller and reaches itsnadir after about 6 months [48].

Several clinical trials have reported a rela-tionship between the reduction of bone turn-over markers and the reduction in vertebral andnonvertebral fracture risk following anti-re-sorptive treatment [18]. For example, changesin bone turnover markers have been shown toexplain a considerable proportion, 54–77%, ofthe nonvertebral fracture risk reduction withrisedronate treatment [49]. The 12-monthdecrease in bCTX-I and PINP with alendronatetreatment in the Fracture Intervention Trial wasassociated with the reduction of spine fractures[50]. However, due to low sensitivity, it hasbeen deemed inappropriate to use bone turn-over markers to predict an individual patient’sresponse to treatment [51].

Another complicating factor is that the effecton bone marker suppression varies across thelicensed bisphosphonates. For example, in theTRIO study, alendronate and ibandronatetreatment given to postmenopausal osteo-porotic women caused a greater suppression ofbCTX-I and NTX-I levels than risedronate [26].

A major challenge with oral bisphosphonatesis the poor adherence with less than half ofpatients taking medication 1 year after treat-ment initiation [52]. Women adhering to oralbisphosphonates have greater reductions in

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serum bone turnover marker levels and lowerfracture risk than women with poor adherence[26]. It has therefore been proposed that boneturnover markers can be used to monitor treat-ment adherence. For such a task to be successfuland clinically useful, clear definitions of whatconstitutes an adequate response to treatmentmust exist. A blood test prior to and after acertain time post-treatment initiation will berequired to determine the level of change in thebone turnover markers. Since serum PINP andbCTX-I are responsive to treatment and havelow within-subject variability, their use is rec-ommended. A commonly proposed approach todetermine if the change in the bone marker isphysiologically relevant (and not due to mea-surement or sampling error) is to compare theobserved change with the least significantchange (LSC). Assuming that the change isnormally distributed, a true change would haveto be greater than the LSC, which equalsH2 9 1.96 9 intra-individual coefficient ofvariation (CV) = 2.77 9 CV. For example, usingthis approach, serum bCTX-I would need todrop from 350 ng/l to 259 ng/l, assuming anintra-individual CV of 9.4%, which correspondsto an LSC of 26%, in a treated patient to confirma positive treatment response. In the TRIOstudy, 3-month bisphosphonate treatmentresulted in suppression of PINP and bCTX-Ilarger than LSC in 75–94% and 68–73%,respectively, of the included women. A detec-tion level, describing the proportion of patientstaking oral bisphosphonates that show decrea-ses (larger than LSC) in each of the markers,bCTX-I and PINP, was investigated and wasfound to be 84% for PINP, 87% for bCTX-I andas high as 94% when measuring both markers[26, 53]. Based on the findings of the TRIOstudy, the International Osteoporosis Founda-tion (IOF) and European Calcified Tissue Society(ECTS) Working Group recently issued a rec-ommendation to monitor oral bisphosphonatetreatment using a baseline and 3-month mea-surement of serum bCTX-I and PINP. Accordingto this recommendation, if the decrease issmaller than the LSC, the treating clinicianshould reassess to identify problems with treat-ment, which usually relate to poor adherence(Fig. 1) [53].

Another approach that has been proposed isto define the target for treatment as suppressionof the bone turnover marker to the lower half ofthe reference interval in young and healthypremenopausal women [54]. This strategy iscomplicated by the fact that not all women areabove this interval prior to receiving treatment.If bone turnover markers have not been mea-sured prior to starting therapy, the referenceinterval method could still be used, whichincreases the clinical usefulness of the method.An analysis from the TRIO study revealed thatthe proportion of responders detected using thereference interval approach was very similar tothe one detected using the LSC approach [26].

DenosumabDenosumab is a human monoclonal antibodyto RANKL, which is administrated subcuta-neously. It is the most potent inhibitor of boneresorption, as reflected by a very rapid decreaseto nearly undetectable levels of bone resorptionmarker bCTX-I within a few days of adminis-tration [55]. Serum PINP is also suppressed bydenosumab treatment, but the decrease is not asmarked as for bCTX-I and takes up to 3–-6 months to be complete [56]. Biannual injec-tions of denosumab reduce the risk of hip,vertebral and non-vertebral fractures in post-menopausal women [13]. The effect of deno-sumab is more potent than bisphosphonates inincreasing BMD, which continues to rise for upto 10 years of treatment [57]. However, whentreatment is stopped, there is a reboundincrease in bone turnover markers well abovepre-treatment levels and accelerated bone loss isseen [58]. During this phase the risk of multiplevertebral fractures increases [59, 60]. Pretreat-ment with bisphosphonates reduces this over-shoot in bone turnover markers whendenosumab treatment stops, and starting bis-phosphonate therapy after denosumab cessa-tion is able to attenuate bone loss, but theoptimal regime for bisphosphonate therapyafter denosumab cessation has not yet beendetermined [61]. It is possible that monitoringthe bone marker response may aid in the use ofbisphosphonate treatment frequency and dos-ing when denosumab treatment is stopped.

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Future research is needed to address thishypothesis.

Anabolic Treatment

Treatment of postmenopausal women with theparathyroid hormone analogue teriparatidecauses a rapid, within days, response in boneformation markers such as PINP, which reachpeak levels after 3 months [62, 63]. This increaseis followed several months later by a consider-ably smaller rise also in bone resorption mark-ers. The response to teriparatide is dose-dependent and the increase in PINP correlatesweakly or moderately with increases in BMD,which are considerably larger at bone sites richin trabecular bone, such as the lumbar spine,than those seen with bisphosphonate therapy[64, 65]. Teriparatide is more effective than oralrisedronate in reducing the risk of vertebral andclinical fractures in postmenopausal with severeosteoporosis [66]. A systematic review of thepresent evidence concluded that there is insuf-ficient evidence to recommend the use ofmonitoring bone turnover markers for predict-ing the effect of teriparatide treatment effect[67].

CONCLUSION

Although the use of bone turnover markers hasbeen extensive in clinical trials, prospectivecohort studies, case-control studies and at manyclinics included in standard patient evaluationfor many years, their value in clinical practice isnot entirely clear. Challenges relating to largepre-analytical (diurnal variations, feeding, age,gender, menopausal status, etc.) and analyticalvariations and use of a multitude of markers indifferent clinical scenarios have impaired theinterpretation of their value and makes recom-mendations for their use in the individualpatient more difficult. Despite these challenges,this working group recommends that the fol-lowing conclusions can be made, based uponthe available evidence:

• The bone formation marker serum PINP andresorption marker serum bCTX-I are thepreferred markers for evaluating bone turn-over in the clinical setting.

• Bone turnover markers cannot be used todiagnose osteoporosis but can be of value inpatient evaluation and can improve the

Fig. 1 Algorithm proposed by an IOF-ECTS working group for monitoring bisphosphonate treatment adherence usingCTX-I and/or PINP [53]

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ability to detect some causes of secondaryosteoporosis.

• Serum bCTX-I and PINP correlate only mod-erately with bone loss in postmenopausalwomen and with osteoporosis medication-induced gains in BMD. Therefore, the use ofbone turnover markers cannot be recom-mended to monitor osteoporosis treatmenteffect in individual patients.

• Adding data on serum bCTX-I and PINPlevels in postmenopausal women can onlyimprove fracture risk prediction slightly inaddition to clinical risk factors and BMD andtherefore has limited value.

• Bisphosphonates are the most commonlyused osteoporosis medications, but adher-ence to oral bisphosphonates falls below50% within the first year of treatment.Monitoring PINP and bCTX-I is effective inmonitoring treatment adherence and can bedefined as the sufficient suppression of thesemarkers (by more than the LSC or to thelower half of the reference interval for youngand healthy premenopausal women).

ACKNOWLEDGEMENTS

The choice of topics, participants, content andagenda of the Working Groups as well as thewriting, editing, submission and reviewing ofthe manuscript are the sole responsibility of theESCEO, without any influence from thirdparties.

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle. The resulting recommendations werederived independently by the authors, withoutany influence from funding sources. The latterhad no role in the process of writing or editingthe report; any potential conflicts of interestwere disclosed by each member of the workinggroup. The ESCEO Working Group was fundedby the ESCEO. The ESCEO receives unrestrictededucational grants to support its educationaland scientific activities from non-governmentalorganizations, not-for-profit organizations,non-commercial or corporate partners.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Mattias Lorentzon has receivedlecture or consulting fees from Amgen, Lilly,Meda, UCB Pharma, Renapharma, RadiusHealth and Consilient Health. Maria LuisaBrandi has received honoraria from Amgen,Bruno Farmaceutici and Kyowa Kirin, academicgrants and/or speaker grants from Abiogen,Alexion, Amgen, Bruno Farmaceutici, Eli Lilly,Kyowa Kirin, MSD, NPS, Servier, Shire and SPAand consultation grants from Alexion, BrunoFarmaceutici, Kyowa Kirin, Servier and Shire.Jean-Yves Reginster is a shareholder of theCentre Academique de Recherche et d’Experi-mentation en Sante (CARES SPRL) and is amember of the journal’s Editorial Board. ReneRizzoli is a Speaker Bureau or Member of Sci-entific Advisory Boards for Danone, Echolight,Effryx, Mylan, Nestle, ObsEva, Pfizer, RadiusHealth, Sandoz and TEVA/Theramex and is aSection Editor of this journal. Cyrus Cooper hasreceived lecture fees and honoraria fromAmgen, Danone, Eli Lilly, GSK, Kyowa Kirin,Medtronic, Merck, Nestle, Novartis, Pfizer,Roche, Servier, Shire, Takeda and UCB outsideof the submitted work. Roland Chapurlat is onthe advisory boards for Pfizer, Amgen, UCB,Ultragenyx and BMS and is a speaker forAmgen, UCB, Abbvie, MSD, Lilly, Janssen, Pfizerand Arrow. Richard Pikner is a speaker and amember of advisory boards for Amgen and hasreceived honoraria for speaking from Amgen,Takeda, Roche, DiaSorin, Abbott and Beck-mann-Coulter. Olivier Bruyere has receivedresearch grants from Biophytis, IBSA, MEDA,Servier and SMB and consulting or lecture feesfrom Amgen, Biophytis, IBSA, MEDA, Servier,SMB, TRB Chemedica and UCB. Andrea Gas-parik has received speaker fees from Eli Lilly andRichter Gedeon. Etienne Cavalier is a consul-tant for IDS, Diasorin, Biomerieux and Fujire-bio. Bernard Cortet has received fees foroccasional interventions as an expert or speakerfor Amgen, Expanscience, Ferring, Lilly,

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Medtronic, MSD, Mylan, Novartis, Roche Diag-nostics and UCB. John Kanis reports grants fromAmgen, Eli Lilly and Radius Health, consultingfees from Theramex, and is the architect ofFRAX� but has no financial interest. EugeneMcCloskey has received departmental researchfunding from Roche and IDS and is a participantin advisory board for Roche. Jean-Marc Kauf-man, Medea Locquet, Andrea Laslop, PawelSzulc, Jaime Branco, Adolfo Diez-Perez, MarkusHerrmann, Niklas Rye Jorgensen, RadmilaMatijevic, Salvatore Minisola, Mila Vlaskovskaand Serge Ferrari have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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