Adv Ther (2019) 36:2811–2824 https://doi.org/10.1007/s12325-019-01063-9 ORIGINAL RESEARCH Algorithm for the Use of Biochemical Markers of Bone Turnover in the Diagnosis, Assessment and Follow-Up of Treatment for Osteoporosis Mattias Lorentzon . Jaime Branco . Maria Luisa Brandi . Olivier Bruyère . Roland Chapurlat . Cyrus Cooper . Bernard Cortet . Adolfo Diez-Perez . Serge Ferrari . Andrea Gasparik . Markus Herrmann . Niklas Rye Jorgensen . John Kanis . Jean-Marc Kaufman . Andrea Laslop . Médéa Locquet . Radmila Matijevic . Eugene McCloskey . Salvatore Minisola . Richard Pikner . Jean-Yves Reginster . René Rizzoli . Pawel Szulc . Mila Vlaskovska . Etienne Cavalier Received: June 21, 2019 / Published online: August 22, 2019  The Author(s) 2019 ABSTRACT guidance to clinicians on how to use BTMs in patient evaluation in postmenopausal osteo- Introduction: Increased biochemical bone porosis, in fracture risk prediction and in the turnover markers (BTMs) measured in serum are monitoring of treatment efficacy and adherence associated with bone loss, increased fracture risk to osteoporosis medication. and poor treatment adherence, but their role in Methods: A working group with clinical scien- clinical practice is presently unclear. The aim of tists and osteoporosis specialists was invited by this consensus group report is to provide the Scientific Advisory Board of European Soci- ety on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskele- Enhanced Digital Features To view enhanced digital tal Diseases (ESCEO). features for this article go to https://doi.org/10.6084/ m9.figshare.9097391. M. Lorentzon J. Branco Geriatric Medicine, Department of Internal Rheumatology Department, Egas Moniz Hospital, Medicine and Clinical Nutrition, Institute of CHLO, Lisbon, Portugal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden M. L. Brandi FirmoLab Fondazione F.I.R.M.O, University of M. Lorentzon Florence, Florence, Italy Region Västra Götaland, Geriatric Medicine Clinic, Sahlgrenska University Hospital, Gothenburg, O. Bruyère Sweden WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Department M. Lorentzon  J. Kanis of Public Health, Epidemiology and Health Mary MacKillop Institute for Health Research, Economics, University of Liège, Liège, Belgium Australian Catholic University, Melbourne, Australia R. Chapurlat  P. Szulc J. Branco INSERM, UMR 1033, Université de Lyon, Hôpital E CEDOC, NOVA Medical School, Medical Sciencies Herriot, 69437 Lyon Cedex 03, France Faculty, NOVA University of Lisbon, Lisbon, Portugal 2812 Adv Ther (2019) 36:2811–2824 Results: Serum bone formation marker PINP clinical utility of BTMs is for monitoring oral and resorption marker bCTX-I are the preferred bisphosphonate therapy. markers for evaluating bone turnover in the clinical setting due to their specificity to bone, Keywords: Algorithm; Bone; Bone biomarker; performance in clinical studies, wide use and CTX; Osteoporosis; P1NP; Rheumatology relatively low analytical variability. BTMs can- not be used to diagnose osteoporosis because of low sensitivity and specificity, but can be of INTRODUCTION value in patient evaluation where high values may indicate the need to investigate some Osteoporosis—Diagnosis and Burden causes of secondary osteoporosis. Assessing of Disease serum levels of bCTX-I and PINP can improve fracture prediction slightly, with a gradient of Osteoporosis is a disease characterized by low risk of about 1.2 per SD increase in the bone bone mineral density (BMD) and deterioration marker in addition to clinical risk factors and of bone microarchitecture, which leads to bone mineral density. For an individual patient, increased risk of fragility fracture [1, 2]. Osteo- BTMs are not useful in projecting bone loss or porotic fractures, especially of the hip and treatment efficacy, but it is recommended that spine, commonly result in disability, increased serum PINP and bCTX-I be used to monitor morbidity and mortality [3]. In 2010, the adherence to oral bisphosphonate treatment. number of fractures in the European Union was Suppression of the BTMs greater than the least estimated at 3.6 million, of which 620,000 were significant change or to levels in the lower half hip fractures [4]. Patients at high fracture risk of the reference interval in young and healthy can be identified by investigating known clini- premenopausal women is closely related to cal risk factors, which can be combined using a treatment adherence. fracture risk calculator such as FRAX, for the Conclusion: In conclusion, the currently avail- calculation of 10-year probability of major able evidence indicates that the principal osteoporotic and hip fracture [5]. A C. Cooper S. Ferrari  R. Rizzoli MRC Lifecourse Epidemiology Unit, University of Service of Bone Diseases, Geneva University Southampton, Southampton, UK Hospital and Faculty of Medicine, 1211 Geneva 14, Switzerland C. Cooper NIHR Southampton Biomedical Research Centre, A. Gasparik University of Southampton and University Hospital Department of Public Health and Health Southampton, Southampton, UK Management, University of Medicine, Pharmacy, Science and Technology of Targu Mures, Targu C. Cooper Mures, Romania NHS Foundation Trust, Southampton, UK M. Herrmann C. Cooper Clinical Institute of Medical and Chemical NIHR Oxford Biomedical Research Centre, Laboratory Diagnostics, Medical University of Graz, University of Oxford, Oxford, UK Graz, Austria B. Cortet N. R. Jorgensen Department of Rheumatology and EA 44090, CHU Department of Clinical Biochemistry, Copenhagen Lille and University of Lille, 59000 Lille, France University Hospital Rigshospitalet, Copenhagen, Denmark A. Diez-Perez Hospital del Mar Institue of Medical Investigation, N. R. Jorgensen Autonomous University of Barcelona and OPEN, Odense Patient Data Explorative Network, Biomedical Research Network on Frailty and Odense University Hospital/Institute of Clinical Healthy Aging (CIBERFES), Madrid, Spain Research, University of Southern Denmark, Odense, Denmark Adv Ther (2019) 36:2811–2824 2813 measurement of BMD using dual-energy X-ray 4–5 months, which fills the resorption cavity absorptiometry (DXA) provides a good surro- with an unmineralized osteoid, a connective gate for bone strength and is used to diagnose tissue rich in collagen. Levels of bone turnover osteoporosis, which in postmenopausal women markers reflect the activity and number of bone- and men aged C 50 years is defined as a BMD forming (osteoblasts) and bone-degrading cells value of - 2.5 standard deviations (T-score) or (osteoclasts), providing an estimate of bone below the mean of the young adult woman resorption and bone formation. Bone turnover [6, 7]. The estimation of fracture risk probability markers can be measured non-invasively in in FRAX can be further refined by adding either blood or urine at a fairly low cost (usually femoral neck BMD to the clinical risk factors in \ €20). the calculation and is recommended in many The most widely used markers are N-termi- clinical guidelines [8]. nal collagen type I extension propeptide (PINP), osteocalcin and bone alkaline phosphatase for Measuring Bone Turnover bone formation and C-terminal cross-linking telopeptide of type I collagen (bCTX-I), N-ter- Bone turnover is necessary to replace damaged minal telopeptide of type I collagen (NTX), bone, for example, containing microcracks, deoxypyridinoline, hydroxyproline or tartrate- with new and healthy bone and to release cal- resistant acid phosphatase isoform 5b (TRAP5b) cium into the circulation to maintain calcium for bone resorption (Table 1) [9]. Post-transla- homeostasis. Bone resorption comprises the tional cleavage of type I collagen during bone 4–6-week process in which osteoclasts excavate matrix formation gives rise to PINP, which bone to cause resorption pits, from which subsequently leaks out into the circulation and degraded bone releases calcium into the can be measured in serum. Osteocalcin is also microenvironment and later the circulation. In produced by osteoblasts during bone formation, a coupled process, bone resorption triggers bone is excreted by the kidneys and is one of the most formation by osteoblasts, a process taking abundant non-collagenous proteins in bone. It J. Kanis R. Matijevic Centre for Metabolic Bone Diseases, University of Clinical Center of Vojvodina, Clinic for Orthopedic Sheffield Medical School, Sheffield, UK Surgery, Novi Sad, Serbia J.-M. Kaufman E. McCloskey Department of Endocrinology, Ghent University Department of Oncology and Metabolism, Centre Hospital, 9000 Ghent, Belgium for Integrated Research in Musculoskeletal Ageing, University of Sheffield, Sheffield, UK A. Laslop Scientific Office, Federal Office for Safety in Health S. Minisola Care, Austrian Agency for Health and Food Safety, Department of Internal Medicine and Medical Vienna, Austria Disciplines, Rome University, Sapienza, Italy M. Locquet R. Pikner Department of Public Health, Epidemiology and Department of Clinical Biochemistry and Bone Health Economics, University of Liège, Liège, Metabolism, Klatovska Hospital, Klatovy, Czech Belgium Republic M. Locquet R. Pikner Belgium WHO Collaborating Centre for Public Department of Clinical Biochemistry and Health Aspects of Musculoskeletal Health and Heamathology, Faculty of Medicine Pilsen, Charles Ageing, Liège, Belgium University Prague, Pilsen, Czech Republic R. Matijevic R. Pikner University of Novi Sad, Faculty of Medicine, Novi Faculty of Health Care Studies, University of West Sad, Serbia Bohemia, Pilsen, Czech Republic 2814 Adv Ther (2019) 36:2811–2824 is also released during bone resorption. Alkaline Table 1 Biochemical bone turnover markers phosphatase (ALP) is secreted from bone to the Measurement medium circulation when the osteoid is mineralized, but only about half of serum ALP levels are derived Bone formation markers from bone, and the other half emanates mainly Bone alkaline phosphatase Serum from the liver. However, there are currently available assays that to a high degree are specific PICP Serum to the circulating bone ALP isoform (BALP). Osteocalcin Serum, urine Each bone marker has distinct features that reflect particular aspects of bone physiology. For PINPa Serum example, TRAP5b reflects the number of osteo- Bone resorption markers clasts and is not secreted in urine and can therefore be useful in assessing bone and min- CTX-Ia Plasma, serum*, urine eral disorder in chronic kidney disease, whilst ICTP Serum measuring bCTX-I in such patients is inappro- NTX Serum, urine priate since the bone marker accumulates in serum if renal function is poor. bCTX-I reflects Trap5b Serum osteoclast activity resulting in bone degradation Biochemical bone turnover markers that can be measured and is useful in evaluating, e.g., glucocorticoid in serum are listed. aDenotes bone turnover markers rec- induced osteoporosis [10], in which bCTX-I ommended by IOF and IFCC increases rapidly and peaks after about a week PICP procollagen type 1 C propeptide, PINP procollagen after glucocorticoids are started. Oral glucocor- type 1N propeptide, CTX-I carboxyterminal cross-linking ticoid treatment also inhibits bone formation, telopeptide of type I collagen, ICTP carboxy-terminal as reflected by a rapid and profound decline in cross-linking telopeptide of type I collagen, NTX amino- serum osteocalcin levels, whereas the decline in terminal cross-linking telopeptide of type I collagen, PINP is considerably smaller [10]. Trap5b tartrate-resistant acid phosphatase 5b [18] Most clinical trials have used bone turnover markers to monitor osteoporosis treatment but the use has not been widely adopted in clinical practice [11–14]. Factors Affecting Levels of Bone Turnover Markers Bone resorption markers, including bCTX-I, show diurnal variations, with the highest blood concentration early in the morning and the lowest at around 2 p.m. Both the levels of bone J.-Y. Reginster resorption and formation markers are sup- WHO Collaborating Centre for Public Health pressed by feeding, but the effect is much larger Aspects of Musculoskeletal Health and Aging, University of Liège, Liège, Belgium for resorption markers (excepted Trap5b), which are suppressed by 20–40%, whilst for- J.-Y. Reginster mation markers are suppressed by \ 10% Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King [15, 16]. A fracture normally results in a rapid Saud University, Riyadh, Kingdom of Saudi Arabia increase in bone resorption markers, which doubles in weeks, followed by more slowly M. Vlaskovska Department of Pharmacology, Medical Faculty, increasing bone formation markers, which Medical University Sofia, 2, Zdrave Str, 1431 Sofia, double in serum levels after about 3 months, Bulgaria but remain elevated for up to a year after frac- ture [17]. Several other factors, including glu- E. Cavalier (&) University of Liège, CHU de Liège, Liège, Belgium cocorticoids, menopausal state, age, gender, e-mail: Etienne.cavalier@chu.ulg.ac.be pregnancy/lactation, aromatase inhibitors, Adv Ther (2019) 36:2811–2824 2815 Table 2 Controllable and uncontrollable sources of pre-analytical variability in biochemical bone turnover markers Effect Recommendation Importance Controllable sources Circadian High BTM concentrations at night and early Collect serum samples in the morning High rhythm morning, lowest in the afternoon (7.30–10.00 h) Food intake Decrease in BTMs, especially bone resorption Collect samples of bone resorption High markers (about 20–40%) after food intake markers after overnight fast Exercise Intense exercise can decrease bone resorption and Ask patient to refrain from intense Low increase bone formation markers exercise the day prior to blood sampling Alcohol Alcohol consumption decreases BTMs Ask patient to refrain from excessive Low intake alcohol intake the day prior to blood sampling Seasonal Higher levels of BTMs in winter In research, take samples in the same Low season or adjust for seasonal variation Medications -oral GC Rapid and dose-dependent decrease in bone Consider dose of oral GC High formation markers, small effect on bone turnover markers -aromatase Increase in BTMs inhibitors Uncontrollable sources Age Postmenopausal women have higher BTMs than Use age-based reference intervals High premenopausal women Bed rest/ Bone resorption markers increase and formation Consider different expected baseline level High immobility markers decrease when evaluating BTMs Ethnicity Small differences. Lower osteocalcin in African Unclear if different reference intervals Low Americans vs. Caucasians are needed for different ethnicities Fracture BTMs increase after fracture, with maximum Limits evaluation in patients with recent High effect 2–12 weeks, but remains elevated up to fracture 52 weeks Menopause BTMs increase at the time of the final menstrual Use reference intervals considering Moderate period menopausal status Selected factors affecting the pre-analytical variation in bone turnover markers (BTMs) [9, 22] GC glucocorticoids 2816 Adv Ther (2019) 36:2811–2824 renal insufficiency, immobility and exercise, topic and to propose recommendations. After have an impact on blood-bone turnover mark- the meeting, members of the writing group ers and should also be considered in their eval- (ML, JYR, JK, EM) drafted the first manuscript uation (Table 2) [18]. with the recommendations. The manuscript was then reviewed and commented on by all Current Recommendations of Use of Bone group participants from the Geneva meeting. Turnover Markers in Clinical Guidelines This article is based on previously conducted studies and does not contain any studies with The use of serum bone formation marker PINP human participants or animals performed by and resorption marker bCTX-I in the investiga- any of the authors. tion of osteoporosis or in monitoring treatment is currently recommended in several guidelines RESULTS AND DISCUSSION around the world, including those issued by the UK National Osteoporosis Guideline Group Preferred Bone Markers (NOGG), by the National Osteoporosis Foun- dation in the US [19–21] and by the Interna- The IOF and International Federation of Clini- tional Osteoporosis Foundation (IOF) [22, 23]. cal Chemistry and Laboratory Medicine recom- mend that the bone formation marker PINP and Aim resorption marker bCTX-I be used as reference markers and measured in serum using stan- The aim of this consensus group report is to dardized assays. These markers were chosen provide guidance, based on the opinion of the based on a number of criteria, including ade- experts of this group, to clinicians on how to quate characterization of the marker, specificity use bone turnover markers in patient evalua- to bone, performance in clinical studies, bio- tion, in fracture risk prediction and in moni- logical and analytical variability, wide avail- toring treatment effect and adherence to oral ability, potential for standardization of bisphosphonates in postmenopausal osteo- methods, sample handling, stability and med- porosis. The results of this report are endorsed ium of measurement (serum vs. urine) [22–24]. by the Scientific Board of the European Society on Clinical and Economic Aspects of Osteo- The Role of Bone Turnover Markers porosis, Osteoarthritis and Musculoskeletal in the Diagnosis of Osteoporosis Diseases (ESCEO). and Patient Evaluation METHODS Osteoporosis is operationally defined by BMD using DXA. There is an inverse relationship An international working group was gathered to between BMD and the serum levels of bone develop recommendations for the use of bone turnover markers, but the correlation is weak to turnover markers in the diagnosis and treat- moderate [25]. In the TRIO study, only 20% of ment of osteoporosis. Specialists in internal postmenopausal women, diagnosed with medicine, endocrinology, rheumatology, reha- osteoporosis using DXA had serum bCTX-I bilitation, geriatrics, clinical biochemistry and above the upper normal range for healthy pre- epidemiology were invited to participate by the menopausal women [26]. Therefore, bone Scientific Advisory Board of European Society turnover markers cannot be used for the diag- on Clinical and Economic Aspects of Osteo- nosis of osteoporosis. However, abnormal levels porosis, Osteoarthritis and Musculoskeletal of bone turnover markers, particularly when Diseases (ESCEO). A 1-day in-person meeting high, can be useful for identifying patients in was held on 5 February 2019 in Geneva to dis- whom further investigations may be needed to cuss the existing scientific literature on the detect secondary causes of osteoporosis (e.g., Adv Ther (2019) 36:2811–2824 2817 primary hyperparathyroidism, thyrotoxicosis, and incident fractures in postmenopausal and malabsorption) or other bone diseases (e.g., older women have found that the higher the osteomalacia, Paget’s diseases, bone metastases, level of bone turnover markers, the greater the multiple myeloma) [27]. fracture risk [18]. With some exceptions, bone resorption markers and bone alkaline phos- Predicting Bone Loss Using Bone Turnover phatase are more strongly associated with frac- Markers tures (all, multiple, spine and hip) than other bone turnover markers [32, 37–39]. Elevated Declining circulating estradiol levels, particularly bone turnover markers increase fracture risk during the menopausal transition, gives rise to independently of BMD in some but not in all increased bone turnover due to an increased studies [18]. The role of serum PINP and bCTX-I number of bone remodelling units with a greater in fracture prediction was investigated in a increase of osteoclastic activity, causing an meta-analysis of six prospective cohorts with imbalance between bone resorption and forma- women and men. The risk of fracture was tion, leading to bone loss. The increased bone increased by 23% [hazard ratio 1.23 (95% CI turnover is reflected by an increase in bone turn- 1.09–1.39)] and 18% [hazard ratio 1.18 (95% CI over markers, which is associated with loss of both 1.05–1.34)] per SD increase in serum PINP and trabecular and cortical bone [28, 29]. Bone turn- bCTX-I, respectively, but these analyses were over marker levels correlate with bone loss on a not adjusted for BMD [40]. In a recent meta- group level, and this correlation can be strength- analysis of nine studies of mostly post- ened by sampling blood on several occasions to menopausal women, bone turnover markers reduce the between-samples variation. However, were weakly associated with fracture risk after the proportion of the variation in BMD change adjustment for confounders, with a gradients of that can be explained by bone turnover markers risk of 1.20 for serum bCTX-I and of 1.28 for remains quite small. Thus, predicting an individ- serum PINP. It was concluded that PINP and ual’s bone loss over time using bone turnover bCTX-I appear to predict fracture risk indepen- markers has proved challenging and cannot be dently of BMD and clinical risk factors [41], but recommended in a clinical setting [30–32]. Since the availability of knowledge of confounding bone loss from the forearm and hip has been variables was very variable. Bone turnover associated with increased risk of fracture, it seems markers’ ability to predict fractures seems to be reasonable to assume that bone turnover markers, stronger over short (within a few years) rather which are associated with bone loss, can predict than long time periods [42, 43], which likely fractures [33, 34]. In addition, bone turnover limits their value and usefulness in long-term markers may affect fracture risk independently of fracture prediction in risk calculators such as BMD. Increased bone turnover can be accompa- FRAX, but makes them more appealing in the nied by a high proportion of newly formed and prediction of short-term or imminent fracture partly mineralized bone, which is weaker than risk. Based on the relatively weak associations mineralized bone, and poor trabecular bone between bone turnover markers and fracture microstructure, because of resorption cavities on risk, uncertainty about the independent ability the trabeculae, trabecular perforations and loss of to predict fractures, the natural variability in the trabecular connectivity, can have a substantial markers, problems with the assays and the negative impact on bone strength, not captured inability to predict fracture over long time with DXA [35, 36]. periods, the Fracture Risk Assessment Tool (FRAX) Position Development Conference members concluded that bone turnover mark- The Role of Bone Turnover Markers ers should not be included in the calculation of in Fracture Risk Prediction the 10-year probability of fracture in the FRAX tool [44]. Most prospective studies investigating the associations between bone turnover markers 2818 Adv Ther (2019) 36:2811–2824 The Use of Bone Turnover Markers and clinically useful, clear definitions of what in the Monitoring of Osteoporosis constitutes an adequate response to treatment Treatment must exist. A blood test prior to and after a certain time post-treatment initiation will be Bisphosphonates required to determine the level of change in the Bisphosphonates, including alendronate, rise- bone turnover markers. Since serum PINP and dronate, zoledronate and ibandronate, are the bCTX-I are responsive to treatment and have most commonly used medications to treat low within-subject variability, their use is rec- osteoporosis [4]. They reduce bone resorption ommended. A commonly proposed approach to by inhibiting osteoclasts, increase BMD and determine if the change in the bone marker is lower the risk of spine, hip and non-vertebral physiologically relevant (and not due to mea- fractures [45–47]. With treatment in recom- surement or sampling error) is to compare the mended doses, bCTX-I is reduced rapidly, by observed change with the least significant approximately 50–80%, reaching maximum change (LSC). Assuming that the change is suppression after about 2 months, whilst PINP normally distributed, a true change would have suppression is slightly smaller and reaches its to be greater than the LSC, which equals nadir after about 6 months [48]. H2 9 1.96 9 intra-individual coefficient of Several clinical trials have reported a rela- variation (CV) = 2.77 9 CV. For example, using tionship between the reduction of bone turn- this approach, serum bCTX-I would need to over markers and the reduction in vertebral and drop from 350 ng/l to 259 ng/l, assuming an nonvertebral fracture risk following anti-re- intra-individual CV of 9.4%, which corresponds sorptive treatment [18]. For example, changes to an LSC of 26%, in a treated patient to confirm in bone turnover markers have been shown to a positive treatment response. In the TRIO explain a considerable proportion, 54–77%, of study, 3-month bisphosphonate treatment the nonvertebral fracture risk reduction with resulted in suppression of PINP and bCTX-I risedronate treatment [49]. The 12-month larger than LSC in 75–94% and 68–73%, decrease in bCTX-I and PINP with alendronate respectively, of the included women. A detec- treatment in the Fracture Intervention Trial was tion level, describing the proportion of patients associated with the reduction of spine fractures taking oral bisphosphonates that show decrea- [50]. However, due to low sensitivity, it has ses (larger than LSC) in each of the markers, been deemed inappropriate to use bone turn- bCTX-I and PINP, was investigated and was over markers to predict an individual patient’s found to be 84% for PINP, 87% for bCTX-I and response to treatment [51]. as high as 94% when measuring both markers Another complicating factor is that the effect [26, 53]. Based on the findings of the TRIO on bone marker suppression varies across the study, the International Osteoporosis Founda- licensed bisphosphonates. For example, in the tion (IOF) and European Calcified Tissue Society TRIO study, alendronate and ibandronate (ECTS) Working Group recently issued a rec- treatment given to postmenopausal osteo- ommendation to monitor oral bisphosphonate porotic women caused a greater suppression of treatment using a baseline and 3-month mea- bCTX-I and NTX-I levels than risedronate [26]. surement of serum bCTX-I and PINP. According A major challenge with oral bisphosphonates to this recommendation, if the decrease is is the poor adherence with less than half of smaller than the LSC, the treating clinician patients taking medication 1 year after treat- should reassess to identify problems with treat- ment initiation [52]. Women adhering to oral ment, which usually relate to poor adherence bisphosphonates have greater reductions in (Fig. 1) [53]. serum bone turnover marker levels and lower Another approach that has been proposed is fracture risk than women with poor adherence to define the target for treatment as suppression [26]. It has therefore been proposed that bone of the bone turnover marker to the lower half of turnover markers can be used to monitor treat- the reference interval in young and healthy ment adherence. For such a task to be successful premenopausal women [54]. This strategy is Adv Ther (2019) 36:2811–2824 2819 Fig. 1 Algorithm proposed by an IOF-ECTS working group for monitoring bisphosphonate treatment adherence using CTX-I and/or PINP [53] complicated by the fact that not all women are to 10 years of treatment [57]. However, when above this interval prior to receiving treatment. treatment is stopped, there is a rebound If bone turnover markers have not been mea- increase in bone turnover markers well above sured prior to starting therapy, the reference pre-treatment levels and accelerated bone loss is interval method could still be used, which seen [58]. During this phase the risk of multiple increases the clinical usefulness of the method. vertebral fractures increases [59, 60]. Pretreat- An analysis from the TRIO study revealed that ment with bisphosphonates reduces this over- the proportion of responders detected using the shoot in bone turnover markers when reference interval approach was very similar to denosumab treatment stops, and starting bis- the one detected using the LSC approach [26]. phosphonate therapy after denosumab cessa- tion is able to attenuate bone loss, but the Denosumab optimal regime for bisphosphonate therapy Denosumab is a human monoclonal antibody after denosumab cessation has not yet been to RANKL, which is administrated subcuta- determined [61]. It is possible that monitoring neously. It is the most potent inhibitor of bone the bone marker response may aid in the use of resorption, as reflected by a very rapid decrease bisphosphonate treatment frequency and dos- to nearly undetectable levels of bone resorption ing when denosumab treatment is stopped. marker bCTX-I within a few days of adminis- Future research is needed to address this tration [55]. Serum PINP is also suppressed by hypothesis. denosumab treatment, but the decrease is not as marked as for bCTX-I and takes up to 3–- Anabolic Treatment 6 months to be complete [56]. Biannual injec- tions of denosumab reduce the risk of hip, Treatment of postmenopausal women with the vertebral and non-vertebral fractures in post- parathyroid hormone analogue teriparatide menopausal women [13]. The effect of deno- causes a rapid, within days, response in bone sumab is more potent than bisphosphonates in formation markers such as PINP, which reach increasing BMD, which continues to rise for up peak levels after 3 months [62, 63]. This increase 2820 Adv Ther (2019) 36:2811–2824 is followed several months later by a consider- induced gains in BMD. Therefore, the use of ably smaller rise also in bone resorption mark- bone turnover markers cannot be recom- ers. The response to teriparatide is dose- mended to monitor osteoporosis treatment dependent and the increase in PINP correlates effect in individual patients. weakly or moderately with increases in BMD, • Adding data on serum bCTX-I and PINP which are considerably larger at bone sites rich levels in postmenopausal women can only in trabecular bone, such as the lumbar spine, improve fracture risk prediction slightly in than those seen with bisphosphonate therapy addition to clinical risk factors and BMD and [64, 65]. Teriparatide is more effective than oral therefore has limited value. risedronate in reducing the risk of vertebral and • Bisphosphonates are the most commonly clinical fractures in postmenopausal with severe used osteoporosis medications, but adher- osteoporosis [66]. A systematic review of the ence to oral bisphosphonates falls below present evidence concluded that there is insuf- 50% within the first year of treatment. ficient evidence to recommend the use of Monitoring PINP and bCTX-I is effective in monitoring bone turnover markers for predict- monitoring treatment adherence and can be ing the effect of teriparatide treatment effect defined as the sufficient suppression of these [67]. markers (by more than the LSC or to the lower half of the reference interval for young and healthy premenopausal women). CONCLUSION Although the use of bone turnover markers has been extensive in clinical trials, prospective ACKNOWLEDGEMENTS cohort studies, case-control studies and at many clinics included in standard patient evaluation The choice of topics, participants, content and for many years, their value in clinical practice is agenda of the Working Groups as well as the not entirely clear. Challenges relating to large writing, editing, submission and reviewing of pre-analytical (diurnal variations, feeding, age, the manuscript are the sole responsibility of the gender, menopausal status, etc.) and analytical ESCEO, without any influence from third variations and use of a multitude of markers in parties. different clinical scenarios have impaired the interpretation of their value and makes recom- Funding. No funding or sponsorship was mendations for their use in the individual received for this study or publication of this patient more difficult. Despite these challenges, article. The resulting recommendations were this working group recommends that the fol- derived independently by the authors, without lowing conclusions can be made, based upon any influence from funding sources. The latter the available evidence: had no role in the process of writing or editing • The bone formation marker serum PINP and the report; any potential conflicts of interest resorption marker serum bCTX-I are the were disclosed by each member of the working preferred markers for evaluating bone turn- group. The ESCEO Working Group was funded over in the clinical setting. by the ESCEO. The ESCEO receives unrestricted • Bone turnover markers cannot be used to educational grants to support its educational diagnose osteoporosis but can be of value in and scientific activities from non-governmental patient evaluation and can improve the organizations, not-for-profit organizations, ability to detect some causes of secondary non-commercial or corporate partners. osteoporosis. • Serum bCTX-I and PINP correlate only mod- Authorship. All named authors meet the erately with bone loss in postmenopausal International Committee of Medical Journal women and with osteoporosis medication- Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of Adv Ther (2019) 36:2811–2824 2821 the work as a whole, and have given their FRAX but has no financial interest. Eugene approval for this version to be published. McCloskey has received departmental research funding from Roche and IDS and is a participant Disclosures. Mattias Lorentzon has received in advisory board for Roche. Jean-Marc Kauf- lecture or consulting fees from Amgen, Lilly, man, Médéa Locquet, Andrea Laslop, Pawel Meda, UCB Pharma, Renapharma, Radius Szulc, Jaime Branco, Adolfo Diez-Perez, Markus Health and Consilient Health. Maria Luisa Herrmann, Niklas Rye Jorgensen, Radmila Brandi has received honoraria from Amgen, Matijevic, Salvatore Minisola, Mila Vlaskovska Bruno Farmaceutici and Kyowa Kirin, academic and Serge Ferrari have nothing to disclose. grants and/or speaker grants from Abiogen, Alexion, Amgen, Bruno Farmaceutici, Eli Lilly, Compliance with Ethics Guidelines. This Kyowa Kirin, MSD, NPS, Servier, Shire and SPA article is based on previously conducted studies and consultation grants from Alexion, Bruno and does not contain any studies with human Farmaceutici, Kyowa Kirin, Servier and Shire. participants or animals performed by any of the Jean-Yves Reginster is a shareholder of the authors Centre Académique de Recherche et d’Expéri- mentation en Santé (CARES SPRL) and is a Open Access. This article is distributed member of the journal’s Editorial Board. René under the terms of the Creative Commons Rizzoli is a Speaker Bureau or Member of Sci- Attribution-NonCommercial 4.0 International entific Advisory Boards for Danone, Echolight, License (http://creativecommons.org/licenses/ Effryx, Mylan, Nestlé, ObsEva, Pfizer, Radius by-nc/4.0/), which permits any non- Health, Sandoz and TEVA/Theramex and is a commercial use, distribution, and reproduction Section Editor of this journal. Cyrus Cooper has in any medium, provided you give appropriate received lecture fees and honoraria from credit to the original author(s) and the source, Amgen, Danone, Eli Lilly, GSK, Kyowa Kirin, provide a link to the Creative Commons license, Medtronic, Merck, Nestlé, Novartis, Pfizer, and indicate if changes were made. Roche, Servier, Shire, Takeda and UCB outside of the submitted work. Roland Chapurlat is on the advisory boards for Pfizer, Amgen, UCB, Ultragenyx and BMS and is a speaker for REFERENCES Amgen, UCB, Abbvie, MSD, Lilly, Janssen, Pfizer and Arrow. Richard Pikner is a speaker and a 1. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd, Khaltaev N. A reference standard for member of advisory boards for Amgen and has the description of osteoporosis. Bone. received honoraria for speaking from Amgen, 2008;42:467–75. Takeda, Roche, DiaSorin, Abbott and Beck- mann-Coulter. Olivier Bruyère has received 2. Lorentzon M, Cummings SR. 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