Clinical Utility of Serum Bone Turnover Markers in Postmenopausal Osteoporosis Therapy Monitoring: A Systematic Review

OSTEOPOROSIS

Clinical Utility of Serum Bone Turnover Markers in Postmenopausal Osteoporosis Therapy Monitoring: A Systematic Review Thomas Funck-Brentano, MD,* Emmanuel Biver, MD,† Florence Chopin, MD,‡ Beatrice Bouvard, MD,§ Guillaume Coiffier, MD,¶ Jean-Claude Souberbielle, MD,储 Patrick Garnero, PhD,** and Christian Roux, MD, PhD*

Objectives: Serum bone turnover markers (sBTM) are used in clinical practice for patients undergoing postmenopausal osteoporosis therapy. The aim of this study was to systematically analyze the literature on the ability of sBTM to monitor therapy, focusing on the following 5 objectives: (1) pretreatment values and treatment choice; (2) short-term changes and clinical response; (3) sBTM effect on persistence to therapy; (4) sBTM ability to predict fracture risk after withdrawal of therapy; and (5) the prediction of serious adverse effects. Methods: A systematic search on Medline completed manually was performed until November 2010 and was limited to postmenopausal osteoporosis and marketed therapies. Results: Following the PRISMA statement for systematic reviews, 48 studies were selected. Baseline sBTM levels were not able to predict fracture risk reduction with either treatment. There was more evidence for the prediction of fracture risk reduction with bone formation sBTM including PINP than with sCTX. Most of the studies found correlations between sBTM and bone mineral density (BMD) changes under antiresorptive therapies, although inconsistently. The only published study on the impact of sBTM on persistence to therapy showed negative results. There was no evidence that sBTM allow the prediction of adverse effects, especially osteonecrosis of the jaw. Conclusions: sBTM reflect the skeletal effects of anti-osteoporotic treatments. Pretreatment values are not recommended for selecting therapy. Short-term changes are significantly correlated with BMD variation, but there is no published evidence that they predict benefit on fracture risk at the individual level. © 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:157-169 Keywords: bone turnover marker, osteoporosis, postmenopausal/therapy, drug monitoring, medication adherence, collagen type I trimeric cross-linked peptide

*Paris Descartes University, Cochin Hospital, Department of Rheumatology B, Paris, France. †University Hospital of Lille, Department of Rheumatology, Lille, France. ‡University Hospital of St-Etienne, Department of Rheumatology, St-Etienne, France. §University Hospital of Angers, Department of Rheumatology, Angers, France. ¶University Hospital of Rennes, Department of Rheumatology, Rennes, France. 储Paris Descartes University, Necker Hospital, Department of Biology, Paris, France. **INSERM Research Unit 664, Lyon, France. Editorial assistance was funded by an independent grant from Roche. The funding source did not review or comment on the manuscript. The authors received a grant from Roche. Address reprint requests to Christian Roux, MD, PhD, Paris Descartes V University, Department of Rheumatology, Cochin Hospital, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. E-mail: [email protected].

0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2011.01.005

S

erum biochemical bone turnover markers (sBTM) are used in the management of bone diseases including postmenopausal osteoporosis (PMO). They allow a dynamic assessment of bone remodeling, as they reflect bone cell activity. A high bone remodeling, as reflected by a high sBTM level, is associated with accelerated bone loss and thus can be associated with bone fragility in some patients (1). Serum and urinary BTM have been used extensively in clinical trials, as a surrogate endpoint for assessment of treatments effects. Indeed, their rapid and large responses to therapies help assess short-term bone effects from treatments. Among bone resorption markers, serum C-telopeptide cross-link of type 1 collagen (sCTX) is a highly sensitive indicator of bone resorption. Serum CTX is released from 157

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cathepsin K-mediated proteolytic degradation of the ␣1chain C telopeptide of type 1 collagen during osteoclastic resorption and is assessed by ELISA. sBTM assessment has several advantages over urinary markers of type I collagen degradation such as uCTX, uNTX (N-telopeptide of type I collagen), or deoxypyridinoline. First, it does not require urinary creatinine measurement. Second, it is available for standard clinical laboratory as either a manual ELISA (2) or an immunochemiluminescent assay adapted on fully automated platforms, and is more convenient to use than manual assays, with improved analytical performances and higher throughput (3). Third, reference ranges established in large and well-documented populations of healthy premenopausal women are available (4-6). Fourth, sCTX has both a short-term and a long-term within-subject variability, which is approximately twice lower than urinary markers (around 10-15% compared with around 20-30%) (7). However, it must be emphasized that this low within-subject variability can only be obtained when sCTX is measured in morning fasting subjects because food intake markedly decreases sCTX levels and increases its variability (8). The lowest significant change is thus lower with this serum assessment. Usual lowest significant change for serum CTX is close to 30% (9,10). Among bone formation markers, N-terminal and Cterminal propeptides of type I procollagen (PINP and PICP) are cleaved during procollagen extracellular metabolism and are released in the blood. Their serum concentration reflects bone synthesis. The intact form of PINP presents the advantage of not being affected by glomerular filtration rate (11). Most serum PINP and PICP originate from bone and thus reflect its synthesis. Hannon and coworkers have established PINP’s least significant change (P ⬍ 0.05) at 21% (12). It is also the sBTM with the highest signal-to-noise ratio (effect of therapy/fluctuation with placebo) with a bone formation agent far above NTX, free deoxypyridinoline, bone-specific alkaline phosphatase (BSAP), and PICP (13). Osteocalcin is a matrix protein synthesized by osteoblasts and odontoblasts, the function of which has not clearly been identified. It is involved in bone mineralization regulation and possibly acts as a regulator of insulin (14). BSAP is an osteoblastic enzyme involved in the mineralization of osteoid, thereby reflecting osteoblast activity. It has shown higher performance than alkaline phosphatase to reflect bone formation, even in hemodialysis patients (15). Based on results from clinical studies on 1 hand, and technical performance and sBTM assessment practicability on the other hand, several national and international guidelines recommend these markers in the follow-up of patients treated for PMO (16-18). Using a systematic analysis of the literature, this article reviews evidence for this recommendation, answering the following 5 questions:

1. Can sBTM help choosing a treatment? 2. Can early changes in sBTM predict treatment efficacy? 3. Can sBTM improve persistence to treatment? 4. Are sBTM useful in the discussion of drug reintroduction? 5. Can sBTM predict adverse effects from drug therapy?

METHODS Research Method A review of the literature focusing on sBTM and PMO therapy was performed by searching published studies on Medline up to November 2010. The literature search procedure followed the PRISMA recommendations for systematic literature analysis (19). Bone resorption markers we focused on were as follows: serum C- or N-terminal cross-linked telopeptide of type 1 collagen (sCTX or sNTX), and tartrate-resistant acid phosphatase 5b (TRAPc5b). Bone formation markers were as follows: serum bone-specific alkaline phosphatase (bone ALP), serum C-terminal and N-terminal extension peptide of procollagen type I (PICP and PINP), and serum osteocalcin (sOC). For questions 1 to 4, we included only original studies (clinical trials or meta-analysis) focusing directly on 1 and 2: correlation of sBTM pretreatment values or short-term variation and fracture risk or bone mineral density (BMD) variation in therapeutic clinical trials; 3: their impact on persistence to therapy; 4: correlation with fracture risk after drug withdrawal. Most of the studies included several sBTM. The query for this part of the search was as follows: (“fractures, bone”[MH] OR (“osteoporosis, postmenopausal”[MH] OR “osteoporosis”[MH])) AND “female”[MH] AND (“collagen type I ”[MH] OR procollagen [MH] OR “Biological markers”[MH] OR osteocalcin [TW] OR “bone specific alkaline phosphatase” [TW] OR P1NP [TW] OR PINP [TW] OR PICP [TW] OR CTX [TW] OR NTX [TW] OR TRACP [TW]). We limited the search to clinical trials or metaanalysis in English or French. For question 5, we limited our search to bisphosphonates adverse effects: osteonecrosis of the jaw (ONJ) and insufficiency fractures. The query was: “Bisphosphonates/ adverse effects”[MH] AND (osteonecrosis [tw] OR fracture [MH]). After exclusion of duplicates, all references were gathered and screened for eligibility. The remaining articles were fully read for final selection. Exclusion criteria were as follows: reviews, editorials, comments or letters, studies on other topics than PMO therapy, studies without analysis of correlation with BMD or fracture, and studies with only urinary markers.

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Figure 1 Flowchart.

RESULTS Study Selection The results of the literature search are presented in Figure 1. Medline search with the previously described limits found 781 references for questions 1 to 4 and 1029 for question 5. Because of the different ways of referencing biochemical markers of bone remodeling, a hand search was added, giving 5 extra studies, 3 of them not being indexed in PubMed at that time of writing. A total of 48 studies were finally included for the 5 objectives (29 for questions 1 to 4, 19 for question 5). Question 1: Can sBTM Help Choosing a Treatment? To assess whether sBTM could help deciding which initial treatment should be started in PMO, we focused on the 12 studies that provided data on sBTM pretreatment

values and their correlation with either fracture risk or BMD response with therapy. Fracture Risk Four studies focused on the link between pretreatment BTM values and the fracture risk under therapy and are summarized in Table 1. The Fracture Intervention Trial (FIT) study specifically looked at BTMs pretreatment values and fracture risk reduction with alendronate in 6186 patients. Only 562 patients (9%) had morning and fasting sCTX measurement conditions. In this group no correlation between sCTX pretreatment values and fracture risk reduction with alendronate was found. Only high values of PINP when expressed in tertiles showed an association with nonvertebral fracture risk reduction (OR ⫽ 0.54 (95%CI 0.39, 0.74); P ⫽ 0.03) (20,21). In a study of teriparatide (1637 patients), other sBTM than sCTX

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Table 1 Correlation Between Baseline BTM and Fracture Risk Under Therapy Reference

n

BTMs

Analyse

Fractures

Alendronate Bauer et al (20)

6186

BSAP, PINP sCTX

Linear

All fractures at M36 ⫹ M48

Bauer et al (21)

6186

BSAP, PINP

Tertiles

All fractures at M36 ⫹ M48

sCTX

Results No linear correlation with vertebral or nonvertebral fracture. The highest PINP tertile is associated with a decrease in nonvertebral fracture risk. OR ⫽ 0.54 (95%CI 0.39, 0.74) P ⫽ 0.03

Teriparatide Delmas et al (24)

1637

PINP, PICP, BSAP

Linear/Tertiles

All fractures at M18

Treatment is effective whatever the baseline BTM level.

Strontium ranelate Collette et al (25)

4891

BSAP, sCTX

Tertiles

Vertebral fractures at M36

Treatment is effective whatever the baseline BTM level.

BSAP, bone-specific alkaline phosphatase; PINP, serum amino-terminal extension peptide of procollagen type I; PICP, serum carboxyterminal extension peptide of procollagen type I; sOC, serum osteocalcin; sNTX, serum N-telopeptide of type I collagen; sCTX, serum C-terminal cross-linked telopeptide of type 1 collagen; TRAPc5b, serum tartrate-resistant acid phosphatase 5b.

were measured. Delmas and coworkers showed that fracture risk reduction under therapy was independent of pretreatment BTM values (22-24). A recent study with strontium ranelate in 4891 patients showed no differences in fracture risk reduction at 3 years according to baseline sCTX or BSAP tertile levels (25). Bone Mineral Density Correlations between pretreatment sBTM and BMD changes under treatment were found in 8 studies and are summarized in Table 2. These studies include alendronate, PTH, and strontium ranelate therapy. With alendronate, correlations were inconsistent and more often seen with bone formation markers. Baseline sOC was inconsistently associated with BMD variations at different sites in 4 studies (26-29). Baseline BSAP was associated with total body BMD changes at 3 years in a single study on 314 patients (r ⫽ ⫺0262, P ⬍ 0.05), but not with lumbar spine or hip BMD (30,31). Nenonen and coworkers found in a study of 148 patients receiving alendronate 5 mg/d that baseline sCTX and TRAPc5b were correlated with BMD changes at 2 years (r ⫽ ⫺0.19, P ⬍ 0.05, r ⫽ ⫺0.24, P ⬍ 0.01, respectively) (29). However, Ravn and coworkers did not confirm this correlation between alendronate-induced BMD changes and baseline sCTX in a smaller study of only 67 patients (26). In contrast, significant correlations were observed with PTH treatment, including both markers of resorption and formation. Bauer and coworkers showed in a study with PTH analog at 100 ␮g/d in 119 patients that for each standard deviation baseline sCTX increase, there was a 1.4% (0.1, 2.6) lumbar spine BMD increase at 1 year.

This result was not significant at the hip (32). However, baseline sCTX was not assessed in the single study with teriparatide (33). In that study on 520 patients, pretreatment PINP, PICP, and BSAP were associated with treatment-induced BMD changes at the spine at 1 year (r ⫽ 0.41, r ⫽ 0.36, r ⫽ 0.28, P ⬍ 0.05, respectively). PINP was also significantly correlated with spine BMD change under PTH analog treatment. Question 2: Can Early Changes in sBTM Predict Treatment Efficacy? Twenty-four studies were found with correlations between short-term BTM changes and fracture risk reduction or BMD variation. Fracture Risk Correlations between short-term changes in BTM and fracture risk under therapy were found in 5 studies and are summarized in Table 3. Under raloxifene therapy, only formation sBTM were available in 3 publications of the multiple outcomes of raloxifene evaluation (MORE) study. Reginster and coworkers in an analysis on 967 patients found PINP reduction at 1 year to be the most predictive of vertebral fracture risk reduction at 3 years (slope estimate for each % PINP reduction ⫽ 0.0085, P ⬍ 0.001). Each percentage reduction accounted for 27.5% (3.3, 51.1%) of the total new vertebral fracture reduction assessed by radiography (34). Interestingly, sOC and BSAP reduction were also predictive of vertebral fracture risk reduction at 2 or 3

T. Funck-Brentano et al.

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Table 2 Correlation Between Baseline BTM and BMD Changes Reference

n

Alendronate Ravn et al (26)

67

Ravn et al (27)

Dose

BMD

(mg/d) 1-5 to 10-20

M24

1202

2.5-5

M24

Kim et al (28) Nenonen et al (29)

138 148

10 5

M12 M12

Watts et al (30)

314

10

M36

Kyd et al (31) PTH Bauer et al (32)

35

M12

119

5 (␮g/d) 100

Chen et al (33)

520

20-40

M12

Hip: M12 Spine: M18

BTM

Spine BMD

Hip BMD

Total Body BMD

sOC TRAPc5b sCTX PINP sOC BSAP BSAP PAL BSAP

NS NS r ⫽ 0.3a NS NS NS NS NS NS r ⫽ ⫺0.09, (NS) to r ⫽ 0.17c No precision for site NS r ⫽ ⫺0262a — r ⫽ ⫺ 0.24b — — r ⫽ ⫺ 0.19a — — NS — — r ⫽ ⫺0.18a — — NS — — NS NS r ⫽ 0.22a NS NS NS NS NS —

PINP (per SD 1) BSAP sCTX

1.7 (0.5, 3.0) NS 1.4 (0.1, 2.6)

1.2 (0.4, 2.0) 1.6 (0.9, 2.3) NS

— — —

r ⫽ 0.41a r ⫽ 0.36a r ⫽ 0.28a

NS NS NS

— — —

N-midOC sOC sCTX sOC

PINP PICP BSAP

BSAP, bone-specific alkaline phosphatase; PINP, serum amino-terminal extension peptide of procollagen type I; PICP, serum carboxyterminal extension peptide of procollagen type I; sOC, serum osteocalcin; sNTX, serum N-telopeptide of type I collagen; sCTX, serum C-terminal cross-linked telopeptide of type 1 collagen; TRAPc5b, serum tartrate-resistant acid phosphatase 5b. aP ⬍ 0.05. bP ⬍ 0.01. cP ⬍ 0.001.

years in the 3 analyses of the MORE study that included up to 2722 patients (34-36). With antiresorptive drugs, the single study that looked at correlations of short-term changes in sCTX under therapy and fracture risk reduction is the FIT trial with alendronate. In the subgroup of 562 patients (9%) that had standardized assessment of sCTX, no correlation was found with fracture risk (20). In contrast, formation sBTM changes at 1 year were predictive of vertebral fracture (BSAP: OR ⫽ 0.74 [0.63, 0.87]; PINP: OR ⫽ 0.77 [0.66, 0.90]) or hip fracture (BSAP OR ⫽ 0.61 [0.46, 0.80]). A recent study with zoledronic acid (n ⫽ 1132) showed a nonsignificant trend between PINP level expressed in deciles at 1 year (no change from baseline, ie, not in Table 3) and fracture risk at 3 years (37). Serum CTX was also assessed in this study and showed a significant decrease as soon as 10 days after injection. However, no correlation with fracture risk was established since this marker was only measured in half of the patients (n ⫽ 604). A recent study with strontium ranelate on 2373 patients showed no association between 3 months change in sCTX, BSAP, or PINP and fracture risk reduction at 3 years (38). Besides these original studies, Hochberg and coworkers published a meta-analysis in 2002 that focused on the relationship between nonvertebral fractures incidence reduction under antiresorptive treatments and BTM changes at 1 year.

In this meta-analysis, studies with etidronate, tiludronate, alendronate, risedronate, raloxifene, and calcitonin were included, providing data on 2415 women with incident vertebral fractures. Pooled data on formation and resorption markers were compared with fracture risk reduction. The authors concluded that a greater reduction in BTM was associated with a greater reduction in fracture risk. A 70% reduction in resorption BTM at 1 year would reduce risk by 40% at the end of the trial (ranging from 1 to 5 years), and a 50% reduction in formation BTM would reduce risk by 44% (39). No individual data for each BTM, including sCTX or PINP, was available in the article. Bone Mineral Density Correlations between short-term BTM changes and BMD changes are summarized in Table 4. Of the 20 studies that were selected, only 5 focused on sCTX. They showed significant negative correlations between 3- or 6-months sCTX changes and 12- or 36-months lumbar spine or hip BMD changes with risedronate and alendronate treatment (26,29,40,41) except in 1 study in only 15 patients (42). A recent post-hoc analysis on 670 patients undergoing 1 weekly oral bisphosphonate therapy in the Fosamax Actonel Comparison Trial confirmed this negative correlation of 3-month BTM changes with BMD response at 2 years (rang-

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Table 3 Early Changes of BTM and Fracture Risk Reduction Under Therapy Reference

n

Dose

BTM

Raloxifene Reginster et al (34)

967

mg/d 60-120

PINP

⌬BTM

Fractures

M12

VF at M36

M6 ⫹ M12

VF at M24 ⫹ M36

sOC BSAP Bjarnason et al (35)

2722

60-120

BSAP

sOC

RR 1. %2 at M12: slope estimate ⫽ 0.0085b 2. %2 at M12 accounts for 27.5% (3.3, 51.1%) of the total new VF reduction by RXF %2 at M12: slope estimate ⫽ 0.0068a %2 at M12: slope estimate ⫽ 0.0056a Lowest tertile: RR ⫽ 0.38 (0.22, 0.68)a at M6 RR ⫽ 0,42 (0.23, 0.74)a at M12 Lowest tertile: RR ⫽ 0.35 (0.21, 0.6)a at M6 RR ⫽ 0.37 (0.20, 0.60)a at M12 1. % 2 at M24 accounts for 34% (⫺0.7-61%) of the total new VF reduction 2. % 2 at M12: slope estimate ⫽ 0.22a 3. Better predictor than %1FN BMD at M12

Sarkar et al (36)

2503

60-120

sOC

M12 ⫹ M24

VF at M36

Alendronate Bauer et al (20)

3105

mg/d 5-10

BSAP

M12

All fractures at M36 ⫹ M48

1. per SD of 1 year 2 VF: OR ⫽ 0.74 (0.63, 0.87); NVF: NS; HF: OR ⫽ 0.61 (0.46, 0.80) 2. each SD of 1 year 2 accounts for 24% (11-36%) reduction in VF and 38% (13-55%) reduction in HF VF: OR ⫽ 0.77 (0.66, 0.90); NVF: NS; HF: NS NS

M3

All fractures at M36

NS NS NS

PINP sCTX Strontium ranelate Bruyere et al (38)

g/d 2373

2

BSAP PICP sCTX

BSAP, bone-specific alkaline phosphatase; PINP, serum amino-terminal extension peptide of procollagen type I; PICP, serum carboxyterminal extension peptide of procollagen type I; sOC, serum osteocalcin; sNTX, serum N-telopeptide of type I collagen; sCTX, serum C-terminal cross-linked telopeptide of type 1 collagen; TRAPc5b, serum tartrate-resistant acid phosphatase 5b. aP ⬍ 0.05. bP ⬍ 0.001.

ing from r ⫽ ⫺0.10 to ⫺0.25); the strongest correlation was observed with sCTX (r ⫽ ⫺0.19 to ⫺0.25) (40). The proportion of nonresponders, ie, patients having any decrease in BMD at month 24, was lower in the highest tertile of sCTX decrease at 3 months: 10%, as compared with 45% in the lowest tertile. Under PTH treatment, positive correlation was found between 1 or 3 months sCTX changes and lumbar spine BMD changes at 1 year (32). Bone formation markers also showed conflicting results in the selected studies. PINP variation was associated with BMD changes at the spine and hip in a study with 59 patients under clodronate (43), and in 1 post-hoc analysis with risedronate and alendronate. In this study, the highest tertile

reductions were correlated with BMD changes at 2 years at various sites (40). Similar results were found in 2 studies with PTH analogs (32,33). In the opposite, this was not confirmed under risedronate in another small study of 15 patients (42) or under alendronate in the study by Nenonen and coworkers (29). Question 3: Can sBTM Improve Persistence to Treatment? Three clinical studies studied the impact of monitoring PMO therapy with BTM on persistence, 2 of which had to be excluded since urinary NTX were used (44,45).

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Table 4 Correlation Between Short-Term BMT changes and Longer Term BMD Changes Under Therapy References Raloxifene Majima et al (77) Alendronate Garnero et al (78) Braga de Castro Machado et al (79) Ravn et al (27) Kim et al (28) Greenspan et al (80) Watts et al (30)

n

⌬BTM

73 M3

307 M6 26 M6

1202 M6 138 M3 ⫹ M6 120 M6 314 M6

BMD

BTM BSAP sNTX

NS NS

M24 M6

BSAP sOC, PICP, BSAP

⌬ BSAP predict ⌬BMD NS

M24 M12 M30

sOC sOC sOC BSAP BSAP

PINP sOC BSAP sOC N-midOC sOC

r ⫽ ⫺0.16 to ⫺0.25c NS r ⫽ ⫺0.43b NS M12: r ⫽ ⫺0.36c; M24: r ⫽ ⫺0.24a; M36: NS M12: r ⫽ ⫺0.21a; M24: NS; M36: NS NS NS r ⫽ ⫺0.32 (⫺0.51, 0.10)b r ⫽ ⫺0.024 (⫺0.5, 0.1)b NS NS NS NS r ⫽ ⫺0.59 to ⫺0.78c r ⫽ ⫺0.58 to ⫺0.70c

BSAP sCTX

r ⫽ ⫺0.32 to ⫺0.38b r ⫽ ⫺0.73 to ⫺0.77c

sOC BSAP sOC, PICP BSAP

r ⫽ ⫺0.46c NS NS NS

— — — — r ⫽ ⫺40 to ⫺0.54c r ⫽ ⫺0.36b to ⫺0.39c NS r ⫽ ⫺0.49 to ⫺0.53c r ⫽ ⫺0.47c r ⫽ ⫺0.467a NS NS r ⫽ ⫺0.45c r ⫽ ⫺0.36c

M12 ⫹ M24 ⫹ M36

373 M6

M36

148 M6 ⫹ M12

BMD M12

sOC BSAP TRAPc5b sCTX

Ivaska et al (82) Ravn et al (26)

164 M3 67 M3 ⫹ M6 ⫹ M12

Hip BMD

M6 ⫹ M12

PAL Greenspan et al (81) Nenonen et al (29)

Spine BMD

BMD M12 M24

NS NS — —

NS r ⫽ ⫺0.31a NS NS NS NS r ⫽ ⫺0.411c — —

Ravn et al (83) Atmaca et al (84)

212 M6 30 M6

M48 M12

Kyd et al (31) Clodronate Tähtelä et al (43)

35 M6

M12

59 M12

M24

TRAPc5b PINP

r ⫽ ⫺0.36c r ⫽ ⫺0.39c

15 M1

M12

sOC, PINP sCTX

NS

—

323 M3

M12

sCTX

r ⫽ ⫺0.19b

—

Hip M12 Spine M18

PINP PICP

M12

BSAP PINP

r ⫽ 0.26a r ⫽ ⫺0.11 (NS) to r ⫽ 0.39a NS % ⌬BMD per SD1 at M1: 3.8 (2.6, 4.9) at M3: 4.0 (2.9, 5.0) M1: 2.3 (1.0, 3.6) M3: 3.0 (1.8, 4.1) M1: NS M3: 2.6 (1.3, 3.8)

Risedronate Kumm et al (42) Ibandronate Hochberg et al (41) PTH Chen et al (33)

Bauer et al (32)

1637 M1 M3 M6 M12 119 M1 ⫹ M3

BSAP sCTX

NS r ⫽ ⫺0.06 (NS) to r ⫽ 0.17a NS M: 1.2 (0.4, 2.0) M3: M1: M3: M1: M3:

1.3 (0.44, 2.1) 5.7 (2.3, 9.2) 5.8 (2.7, 8.9) NS NS

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Table 4 Continued References Strontium ranelate Bruyere et al (38)

n 2373 M3

⌬BTM

BMD

BTM

M36

BSAP PICP sCTX

Spine BMD Prediction change of BMD by ⫺1% change BTM: P ⬍ 0.001 P ⬍ 0.001 NS

Hip BMD Prediction change of BMD by ⫺1% change BTM: P ⬍ 0.001 P ⬍ 0.001 P ⬍ 0.001

BSAP, bone-specific alkaline phosphatase; PINP, serum amino-terminal extension peptide of procollagen type I; PICP, serum carboxyterminal extension peptide of procollagen type I; sOC, serum osteocalcin; sNTX, serum N-telopeptide of type I collagen; sCTX, serum C-terminal cross-linked telopeptide of type 1 collagen; TRAPc5b, serum tartrate-resistant acid phosphatase 5b. aP ⬍ 0.05. bP ⬍ 0.01. cP ⬍ 0.001.

A recent Asian study tested the impact of sCTX feedback to 596 patients on adherence to monthly ibandronate. One group had information on their 3 months’ sCTX change, and 1 had not. The proportions of adherent patients were comparable in both arms (92.6% vs 96.0%, P ⫽ 0.16), showing no effect of sCTX information on adherence with ibandronate (46). Question 4: Are sBTM Useful in the Discussion of Drug Reintroduction? No study was found that specifically analyzed the fracture risk stratified by sBTM changes after drug withdrawal. The FLEX study compared the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years in 1099 patients. After 5 years of treatment, patients were randomized to either continuing alendronate for 5 additional years or being switched to placebo. In the placebo group, sCTX significantly increased compared with the continuing therapy group, but in ranges that remained below pretreatment levels. Despite this return to increased turnover, the nonvertebral and morphometric vertebral fracture risk remained unchanged in both groups after 5 years (47). Watts and coworkers looked at the effect of discontinuing risedronate 5 mg/d (n ⫽ 398) or placebo (n ⫽ 361) after 3 years (VERT-NA study) on BTM and vertebral fracture risk at 1 year. One year after withdrawal, uNTX and BSAP had returned to the placebo group levels. However, the benefit of prior treatment was sustained with a persistent reduction in vertebral fracture risk (48). Data on later endpoints are needed. Another study focused on the effect of drug withdrawal in postmenopausal hysterectomized osteoporotic women. One year after either estrogen, alendronate, or combination therapy withdrawal taken for the 2 previous years, the effects on BMD, uNTX, and BSAP changes were analyzed. At 1 year, although BTM statistically increased in all groups that discontinued active treatments, BMD only decreased in the group that discontinued estrogen therapy alone but not in the alendronate-treated groups (49).

Thus, no definitive conclusion can be drawn on the use of sBTM in the discussion of drug reintroduction, as far as fracture risk is concerned. Question 5: Can sBTM Predict Adverse Effects from Drug Therapy? BTM monitoring could be an interesting application for the prediction of adverse effects under therapy, thereby helping the decision of a drug discontinuation. The 2 main PMO therapy adverse effects that are reported in the literature are ONJ and subtrochanteric atypical fractures. This section reports studies that tested sBTM as predictors for these adverse effects. It has recently been suggested by Marx and coworkers that serum CTX could predict the risk of ONJ (50). Based on the observations of 30 patients, they suggested that dental surgery should not be performed if sCTX were lower than 150 pg/mL and that a 4- to 6-month drug holiday should be awaited to reach this threshold. In this study, there was no control group and no data on the least significant change based on sCTX coefficient of variability; moreover, a low value of sCTX is a very expected result in all patients receiving an antiresorptive treatment. Since, 2 publications from the same journal have compared sCTX levels of patients under bisphosphonate therapy that developed ONJ, with controls that had no dental event, and found no differences of sCTX levels between groups (51,52). A small pilot study (18 patients with osteoporosis) suggested there might be a correlation between the level of sCTX and clinical severity of ONJ (53). However, these results were only obtained from univariate analysis and no conclusion can thereby be drawn. Indeed, another cross-sectional study on 15 patients with bisphosphonate-induced ONJ found no correlation between sCTX level and the size of the osteonecrotic areas or the number of exposed bone areas (54). A recent review of the literature on this topic indicates that current evidence does not support the use of sBTM to predict the risk of ONJ under bisphosphonate therapy, although data are very limited (55). The American Society for Bone and

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Mineral Research Task Force on Osteonecrosis of the Jaw has criticized Marx and colleagues’ point of view (56) and proposed a report of their task force that does not recommend the use of sBTM (57). Subtrochanteric or shaft atypical femoral fracture is another rare complication described with bisphosphonates therapy (mainly alendronate) for PMO (58-66). It has been suggested in case reports that profound suppression of bone turnover could lead to a lack of repair in microdamage, resulting in pathologic fractures. Giusti and coworkers recently published a review on clinical cases or series of atypical fractures of the femur. BTM were often prescribed but at a variable period after fracture. Bone formation or resorption markers were more often normal (about 70 to 80% of patients), the rest being either low or increased (67). No data on sBTM just before fracture are available. Moreover, some of these cases are reported after a short duration of treatment, and other mechanisms may explain these atypical fractures. Thus, there is no evidence that sBTM is useful in the prediction of complications of anti-osteoporotic drugs during therapy. DISCUSSION There is a large amount of data showing that sBTM assess treatment effects on bone turnover. However, the goal of a treatment is the reduction in fracture risk; current data are available for groups of patients and may not be useful for the physician managing individual patients. Moreover, there are very few data dedicated to sCTX, although this marker is often used by clinicians. A French investigation in 2002 on BTM prescription reported on 309 questionnaires that over 80% of the physicians taking charge of patients with osteoporosis (mainly rheumatologists and endocrinologists) prescribed at least 1 bone formation and 1 bone resorption marker (68). In another investigation conducted in 87 French rheumatologists, 40 (46%) claimed that they assess sCTX or another resorption marker at the time of diagnosis of osteoporosis (unpublished data). PMO therapy includes drugs that can increase bone formation (as teriparatide and PTH), decrease bone resorption (as bisphosphonates, raloxifene, and denosumab (69)), or both (strontium ranelate). One could expect that the choice between these agents may be driven by bone remodeling (ie, a bone-forming agent in the case of a low turnover and an antiresorptive drug in the case of a high turnover). However current data do not support this concept. We did not find any convincing data suggesting that sCTX nor PINP may help in this matter. sBTM response to therapy is rapid and of large magnitude, and easier to assess than other surrogate markers, such as BMD variation. sCTX responds more dramatically than other sBTM to antiresorptive drugs. However, there is no published evidence that the assessment of sCTX alone is able to predict the individual antifracture

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effect of a treatment. Evidence in this matter has been shown with urinary markers (22) or, with bone formation markers, and particularly with PINP under raloxifene (34), alendronate (20), and zoledronate (37). There may be several explanations for that. First of all, in the studies we reviewed for this analysis, sCTX was available only in a limited number of studies, or in subgroups, comprising a relatively low number of subjects. We acknowledge that the fact it is not published does not mean that it is not useful. The second reason may be linked to variability issues. Indeed, sCTX is markedly affected by food intake and subject to a large diurnal variability. The lack of standardization in sample collection (such as FIT with alendronate) is likely to decrease the power of finding significant associations. Conversely, formation BTM, such as BALP and PINP, are very stable and very modestly affected by food intake and diurnal. Serum vitamin D is a determinant of bone turnover, and changes in 25OHD level can influence bone turnover and sCTX level (70,71). In most of the studies, serum 25OHD levels are not available. Moreover, in clinical trials, patients receive calcium and vitamin D, but shortterm serum 25OHD changes were not assessed in parallel with sCTX changes. Fracture risk is driven by various parameters including age, risk of fall, and low BMD. Part of the results may be explained by the heterogeneity of the studied populations. There is no evidence that a single sBTM (such as sCTX) can reflect the same anti-osteoporotic treatment efficacy with respect to patient characteristics, and fracture site (ie, vertebral or nonvertebral). Moreover, the proportion of treatment effect explained by sBTM changes, if any, varies according to the treatment. Maintaining long-term persistence with oral anti-osteoporotic treatments is a challenge (72), as low persistence has been associated with higher fracture risk and health care use. Two major studies on this matter included urinary markers. Briefly, a study with raloxifene showed persistence was greater when patients were monitored by nurses (with or without uNTX) than when not monitored. No overall difference on persistence was observed between patients with or without BTM feedback. However, patients with a positive message were 18% more likely to adhere to therapy than monitored by a nurse visit alone (44). This positive reinforcement effect on persistence was confirmed in another trial with risedronate. However, a negative message had a drastic pejorative impact on persistence, compared with no message at all (45). Studies suggest that persistence can be improved by careful clinical monitoring, either by nurse (44) or by follow-up program (73). There is no evidence that systematic use of BTMs can dramatically improve persistence, and data suggest that a poor BTM response may be a determinant of an early discontinuation (45). It has however to be mentioned that the number of studies on this subject is limited. They were performed in the context of clinical trials characterized by a very high overall

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compliance. Thus the power to detect a difference in persistence between monitored and not monitored subject is limited. This methodology may not be appropriate to assess a role in regular clinical practice. Eastell and coworkers proposed an algorithm using PINP for the monitoring of patients under teriparatide. The authors have chosen this sBTM because of its high signal-to-noise compared with other sBTM in a post-hoc analysis. They suggest using a cutoff of 10 ␮g/L increase at 3 months, above which patients would have positive reinforcement. Below this cutoff, patients would be assessed for adherence to therapy and technical injection problems and should be given a neutral message so that they continue therapy. This interesting algorithm should be validated prospectively in clinical trials before being recommended (13). A similar strategy could also be investigated with antiresorptive therapies, since bone formation markers also demonstrated more evidence of predicting their clinical effects, with smaller variability. Optimal duration of anti-osteoporotic treatment is unknown. Duration of clinical trials and long-term follow-up studies provides information on treatment safety and efficacy and thereby allows recommendations on therapy duration (74). Very long-term treatments must be considered in patients with severe osteoporosis, although concerns arise on potential deleterious effects of bisphosphonates, based on their long-term bone retention and profound effects on bone turnover. Current data with sBTMs do not provide evidence that these markers can be used in the management of treatment duration neither to decide stopping an overall effective treatment nor to decide reintroducing a treatment. In particular, it must be stressed that at the present time there is no indication for sCTX assessment at the time of dental care. Most of these issues were retrospectively investigated in a very limited number of studies with few cases and should thus be revisited in further prospective studies specifically designed to address these important clinical questions. Thus, there is low a level of evidence that sCTX are useful to predict at the individual level PMO treatments’ antifracture efficacy. So the rationale for including sCTX in current guidelines (8-10) is only based on a practical issue, ie, an unmet need in the management of patients with PMO. Indeed, optimal health care must be delivered in this chronic disease, including monitoring treatment to insure optimal response. There is no mean to measure directly bone strength in patients; BMD is a good surrogate measurement of bone strength but because of limited sensitivity to change, no measurement can be performed before 1 to 2 years after beginning treatment. A key point is that patients treated in clinical practice are different than those included in clinical trials and have a number of factors that may influence response to therapy, including comorbid conditions, which are usually exclusion criteria in trials. For instance, in the osteoporosis research field, Dowd and coworkers showed these discrepancies between ordinary patients and study subjects by comparing chart

reviews of 120 patients meeting clinical treatment criteria to the inclusion and exclusion of 4 large multicenter study protocols. Only 21% would have been included in the trial with the most liberal criteria (75). Moreover, a Hawthorne effect (ie, an increase in the expected result produced by the psychological stimulus of being singled out) is well described in clinical studies, which may optimize the results of persistence studies (76). Thus, short-term evidence of the treatment’s effect on the targeted tissue is an issue in chronic disease. Other markers have the same limitations in other chronic diseases. For example, rituximab decreases CD19⫹ CD20⫹ lymphocytes on 1 hand and improves rheumatoid arthritis on the other hand, but the decrease in these counts is not correlated with efficacy. The profound decrease of CRP under anti-IL6 therapy reflects the pharmacological effect of the drug, but this is not used as a predictor of the structural efficacy of this treatment. This stresses the difference between the assessment of a drug’s expected effect on the target tissue and the assessment of the drug’s efficacy on the clinical outcome. CONCLUSIONS In clinical practice, based on a systematic review of the currently available literature, sBTM have shown limited value in the monitoring of PMO therapy. Pretreatment values cannot help decide which treatment should be introduced. Short-term sCTX changes showed no correlation with fracture risk reduction, but this direct relation was hardly ever tested in the literature. Other bone formation markers such as PINP may be better surrogate markers. Prospective studies are needed to affirm its benefit in the monitoring of PMO treatment strategies. Further studies should be performed to investigate if sBTM help identifying patients at risk of fracture after drug discontinuation. Finally, there is actually no scientific indication of monitoring any sBTM to predict osteonecrosis of the jaw or atypical femoral fractures. REFERENCES 1. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000;15(8):1526-36. 2. Rosenquist C, Fledelius C, Christgau S, Pedersen B, Bonde M, Qvist P, et al. Serum CrossLaps One Step ELISA. First application of monoclonal antibodies for measurement in serum of bonerelated degradation products from C-terminal telopeptides of type I collagen. Clin Chem 1998;44(11):2281-9. 3. Garnero P, Borel O, Delmas PD. Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis. Clin Chem 2001;47(4):694-702. 4. Garnero P, Hausherr E, Chapuy MC, Marcelli C, Grandjean H, Muller C, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 1996;11(10):1531-8. 5. Glover S, Gall M, Schoenborn-Kellenberger O, Wagener M, Garnero P, Boonen S, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, pre-menopausal women

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