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Abstract

Bone metastases occur frequently in patients with advanced solid tumors and can create serious clinical problems that are commonly referred to as skeletal-related events. Although bisphosphonates, especially zoledronic acid, have emerged as an integral determinant of managing metastatic bone disease, their application remains a challenge because of the lack of standardized measures and their side effects. Since factors derived from bone metabolism are potentially useful to measure the efficacy of zoledronic acid, several clinical trials have investigated these bone markers with respect to their monitoring values. The results suggest that a greater decline in bone marker levels is associated with a more reduced incidence of skeletal-related events and a better improvement of symptoms. This review summarizes the available evidence on the clinical use of bone markers in monitoring zoledronic acid in various cancers with bone metastases including breast, prostate and lung cancer.

Keywords

Bone markers Zoledronic acid Bone metastases Malignant tumor

Introduction

Bone is the most common metastatic site for many solid tumors, with spread to this location occurring in 65-70% of patients with advanced breast cancer (BC) or prostate cancer (PC) and in 15-30% of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid or kidney cancer (1 –3). Without bone-targeted therapies, bone metastases (BMs) can cause a wide range of signs and symptoms that influence quality of life (QoL) or even shorten survival (4). Furthermore, the resulting poor performance status could preclude adequate treatment of primary solid tumors.

The third-generation bisphosphonate (BP) zoledronic acid (ZOL), an inhibitor of bone resorption, is the mainstay of the treatment of patients with BMs and the only agent that has demonstrated direct and indirect antitumor activity from preclinical evaluation to clinical practice (5 –8). However, long-term use of ZOL seems to be associated with a number of side effects including renal impairment (10.7-15.2%) (9 –11), hypocalcemia (30-40%) (12, 13) and osteonecrosis of the jaw (ONJ) (3-10%) (14, 15). It is believed that these adverse effects are both time dependent and dose dependent. The exact assessment of ZOL's activity is crucial for maximizing its pharmacological effects and avoiding the side effects emerging after prolonged use.

Bone markers in serum or urine may be useful tools for diagnosing BMs and predicting skeletal-related events (SREs) (16 –18). Recent studies have also noted that some bone markers may monitor the efficacy of BP therapy on BMs in cancer patients, although the search for biomarkers has just begun. Because the currently used imaging methods generally report accumulated effects, other assessments for BP, including SRE analyses, bone pain measures and QoL measures, are basically clinical and bone markers are showing broad prospects in this area. The following review gives an overview of the clinical use of bone markers in the measurement of ZOL depending on the available evidence.

Search Methods

Eligible studies were identified by searching the PubMed and Cochrane databases for relevant reports before March 2013 using different combinations of the following search criteria: “bone markers”, “bone metastases” and “zoledronic acid”. Data on the predictive value of bone markers for the occurrence of adverse effects and for the response to treatment with ZOL were recorded and their prognostic value was also evaluated. Only English-literature data and the most recent or the most complete studies were used. Meeting abstracts, unpublished reports, and review articles were not considered. We identified 118 articles from the search. After independent review, 28 publications dealing with response to ZOL in BM patients were considered eligible for inclusion.

Biology of BM and ZOL in Cancer Patients

To better demonstrate the predictive value of biomarkers, knowledge of the events that lead to BM and the mechanism of ZOL is required.

Similar to the metastatic process in other organs, BM formation is a highly selective, multi-step process involving complex interactions between tumor and host cells, which is clearly explained by “the seed-and-soil hypothesis” (19): the highly vascular bone and a growth-supportive interaction between the disseminated cells (the “seed”) and the bone microenviroment (the “soil”) account for the predilection of metastasis for those sites (20, 21). Upon invasion into the bone, tumor cells secrete factors that stimulate both osteoblast and osteoclast activation. For example, in many cases of osteolytic metastases particularly from BC and non-small cell lung cancer (NSCLC), tumor cells generally upregulate the expression of osteoclastogenesis inducers including parathyroid hormone-related peptide, matrix metallopeptidase 1, interleukin 11, and C-X-C chemokine receptor 4, which increase bone degradation and make osteoblasts secrete collagen fibrils that become mineralized (22). In osteoblastic metastases, on the other hand, factors including bone morphogenetic proteins, platelet-derived growth factor, fibroblast growth factor and endothelin 1 stimulate osteoblast activation and then resorption of bone. The excess activity of these mature osteoclasts and osteoblasts subsequently results in release of bone-stored insulin-like growth factor-1 and transforming growth factor beta; the former appears to play an important role in stimulating tumor cell growth and directed migration into bone (22). All of these cause disequilibrium in the remodeling process, leading to a pathological “vicious cycle”.

To inhibit the above cycle, BPs act by binding to bone surfaces and stimulating osteoclast apoptosis in 2 ways: by acting through toxic metabolites, preventing isoprenylation of small GTP-binding proteins, or by inhibiting farnesyl pyrophosphate synthase (23). Having the highest activity among all evaluated BPs, ZOL also inhibits the activity of farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway, resulting in inhibited angiogenesis, cell invasion, homing of tumor cells to bone marrow, cell adhesion, bone resorption, and cell proliferation directly and indirectly (24 –26). Moreover, ZOL can activate innate and adaptive immune responses against cancer cells, promote cancer cell apoptosis, and produce synergistic anticancer effects with concurrently or sequentially administered cancer therapies. However, when the osteoblast-osteoclast homeostatic cycle as a result of ZOL therapy takes place along with the antiangiogenic effects of ZOL on endothelial cells, adverse effects, especially ONJ, may occur (27).

During these processes, the inhibition of osteoclast-mediated bone resorption, and in response the osteoclast-mediated bone resorption by ZOL is reflected by changes in the levels of markers of bone remodeling, including bone formation markers, such as bone-specific alkaline phosphatase (BAP), and markers of bone resorption, such as C- and N-terminal cross-linked telopeptides of type I collagen (CTx and NTx). Although many of them could also change in response to other metabolic processes, in patients with BM, acute changes in these marker levels typically indicate alterations in skeletal homeostasis. For these reasons, biomarkers of bone remodeling may be an ideal tool to evaluate patient response to ZOL.

Bone Markers that Monitor Response to ZOL

Bone formation markers

Byproducts of osteogenesis or osteoblast-secreted factors can provide insight into the ongoing levels of bone formation with ZOL. It has been found that the markers of bone formation – propeptide of type I collagen, BAP, and osteocalcin (OC) – decrease gradually over 3 to 6 months and then remain low (28).

BAP

BAP, an isoform of alkaline phosphatase secreted by osteoblasts into the blood, is a specific marker for osteogenesis, and concentrations are elevated in metastatic bone disease, Paget's disease, and osteomalacia. Recent publications have pointed to the fact that BAP may be an excellent choice due to its different concentrations before and after BPs in patients with BMs especially from PC. Lein et al (29) assessed the usefulness of serial bone markers in men with metastatic PC who were treated with ZOL and found BAP levels to have decreased after 12 weeks in patients without bone progression. Izumi et al (30) showed that an increase in BAP at 3 months after starting ZOL treatment resulted in a significant increase in the risk of SREs in PC patients with BM (p=0.004). In a study of 26 patients with at least one site of BM secondary to NSCLC, lower and declining concentrations of BAP were observed after ZOL treatment at all time points (31). However, it must be underlined that BAP may either reflect osteoblastic activity in BM or increase as an indicator of bone formation to repair bone lesions that respond to treatment; in other words, an increase in BAP may be either a negative or positive prognostic biomarker depending on the situation (1, 31).

OC

OC is a noncollagenous marker of late bone formation, appearing during the mineralization phase, and its presence in serum is also thought to be an index of osteoblastic activity (32). Serum OC levels not only seem to be decreased in some BM patients (32) but also to be significantly affected by ZOL (33). However, OC possesses limited specificity in monitoring response to ZOL for its co-existence in bone, calcified cartilage and various tumor patterns.

Propeptides of type I collagen

Type I collagen constitutes approximately 90% of the bone matrix and is synthesized as a procollagen that has amino-terminal (PINP) and carboxy-terminal (PICP) propeptides. PINP and PICP are mediated by osteoblasts, and before fibril formation are cleaved off and released into the circulation in equimolar amounts. Therefore, PINP and PICP are considered representative markers of ongoing type I collagen synthesis and early bone formation, and their concentrations increase during osteoblast proliferation (34).

Serum and urinary levels of PINP and PICP may have detective or predictive value in BM patients (35 –37), and some studies propose PINP as a better monitoring marker than PICP. For example, in a prospective, multicenter trial with 52 patients with BM from PC treated with ZOL (4 mg every 4 weeks for 15 months), Jung et al (38) found that patients who died within the follow-up period had significantly higher concentrations of PINP than surviving patients. The Cox regression models with clinical data and bone markers confirmed that PINP was most predictive for mortality risk in addition to the occurrence of SREs and the continuation of treatment with ZOL (p<0.05). The result was in agreement with studies by Lein et al (29, 39), who also suggested there was a strong association between increasing concentrations of PINP and SREs after ZOL in PC patients with BM. However, serum PINP has limited bone specificity, as several factors (such as diurnal variation, gender, menopausal status, etc.) can affect its levels.

Bone resorption markers

By products of osteolysis or osteoclast-secreted factors can provide insight into the ongoing levels of bone resorption with ZOL. It has been found that ZOL induces a rapid decrease of bone resorption markers with a nadir reached within a few days (40).

CTx and NTx

Being the carboxy-terminal and amino-terminal peptides, respectively, of mature type I collagen with the cross-links attached, CTx and NTx are excreted into the circulation and urine during osteoclast-mediated bone resorption. Recent studies have suggested that NTx and CTx levels may both be sensitive indicators of BM development from prostate, breast or lung cancer (41 –44). Moreover, both react promptly and profoundly to ZOL. Recent data from phase II/III trials for ZOL in patients with BMs from solid tumors confirm that patients with elevated NTx levels have an increased risk of SREs and reduced survival compared with patients who have normal NTx (39, 44, 45). Normalization of NTx has been associated with a significantly lower risk of death and SREs compared with persistently elevated NTx levels (46 –49). However, in a phase III trial of 501 patients with BMs from BC, castration-resistant PC, NSCLC or other solid tumors treated with ZOL over 12 months, Lipton et al (50) found that less than 10% of patients with normal baseline NTx (n=501) developed elevated NTx levels before an SRE or death, with the prognostic factors identified in these analyses being mostly similar across NTx groups. Therefore, whether NTx is a useful tool for monitoring the effect of ZOL or only one of several factors influencing the SRE risk is still unknown. Anyhow, normal NTx levels should not be interpreted as reflecting a reduced need for bone-directed therapy.

Since urinary CTx measurements have poor precision at concentrations lower than 200 mg/L, serum or plasma samples are often used. Thus far it has been found that elevated CTx levels may predict subsequent SREs, and, conversely, normalization of excretion rates is associated with a reduction in SREs and improvement of symptoms after BP treatment including ZOL (29, 31, 33). However, further prospective trials are needed for confirmation.

TRACP isoform 5b

TRACP 5b is produced exclusively by activated osteoclasts and has been found to be another specific marker of osteoclastic activity and response to ZOL treatment (51, 52). This has been confirmed in animal models (53, 54). In humans, Mountzios et al (55) reported that a decrease in TRACP 5b levels after treatment with ZOL for 6 months tended to correlate with a decreased incidence of SREs (HR=0.396, 95% CI=0.14-1.10, p=0.076). However, the authors also found that an increase in serum TRACP 5b levels after treatment with ZOL was not associated with an increased incidence of SREs. In view of this conflicting evidence, the role of TRACP 5b as a predictive factor in patients with BM is still under examination.

C-terminal telopeptide of type I collagen (ICTP)

Another bone degradation marker for detection and prediction of BM is ICTP. Generated through a distinct collagenolytic pathway to CTx and released into the circulation after enzymatic degradation of type I collagen, ICTP correlates well with bone resorption levels in patients with BM. In other words, ICTP provides a reliable marker for diagnosing BM. Recently several studies have shown that serum ICTP levels may be useful in the assessment of BPs (30, 38, 39). However, clinicians should be aware that ICTP accumulates in the circulation in renal failure and further studies are still needed for confirmation.

Markers of osteoclastogenesis

The balance between osteoblastic and osteoclastic activity in bone is essentially determined by osteoclastogenesis. There are 3 proteins regulating this process: receptor activator of nuclear factor kappa-B (RANK), its ligand (RANKL), and osteoprotegerin (OPG). Among them, OPG, the endogenous soluble RANKL decoy receptor, appears particularly promising, for several studies have shown serum OPG concentrations to be elevated in patients with BM and to decrease after BP treatment (55, 56). However, its utility in clinical practice is still being evaluated.

Interpretation of Bone Marker Changes in Patients Developing ONJ after ZOL Treatment

Several reports have been published highlighting the adverse event profile of ZOL, though BPs are not always associated with permanent systemic side effects because of their selective action. We know from many randomized clinical trials in the literature that renal impairment, hypocalcemia or ONJ are possible events following long-term use of ZOL. Among them, ONJ is studied most widely for its palliative management and poor response rate. Although no agreement has been reached regarding the mechanism of BP-related ONJ, it is well recognized that the overall effect is reduced bone turnover, which can be evaluated by measuring biomarkers that indicate the levels of bone resorption and bone formation. CTx may serve as a possible risk assessment marker for ONJ. For example, using a stepwise logistic regression analysis, Lazarovici et al (57) found a five to six fold greater risk of the development of BP-related ONJ in patients whose serum CTx values were <150 pg/mL. This is convincing evidence that serum CTx values can be a useful predictive tool in the risk assessment of BP-related ONJ development, as had been suggested by Marx et al (58). However, there are still few data on the relationship between levels of bone turnover markers and the risk of ONJ in patients with advanced cancer involving the bone. Recent uncontrolled analysis has shown several limitations: many of the patients analyzed had progressive skeletal metastatic disease, which could elevate the levels of bone markers (58). Therefore, prospective controlled studies investigating the levels of biomarkers of bone turnover in patients who develop ONJ are needed.

Conclusion

In patients with BM, assessing the effect of ZOL is an important aspect of clinical monitoring. Based on current evidence, several bone biomarkers hold some promise in this setting, for they can be measured easily, relatively noninvasively and inexpensively, and they can provide information on the status of BMs. However, the suggestion that bone markers provide additional predictive information, both at baseline and during treatment, beyond traditional assessments requires further investigation and validation in prospective trials. The potential utility of bone markers in evaluation of the adverse events of ZOL is as yet not clear. In addition, it should be noted that important challenges remain for their translation into practice. For example, the technology used for measuring various biomarkers has not been standardized. Day-to-day variability occurs in bone biomarker levels, and assay results can vary considerably between laboratories even if they use identical methodology. Therefore, improvements in biotechnology along with better comprehension of the bone metastatic microenvironment are expected to assist clinicians in monitoring and optimizing therapies targeted to the bone microenvironment. Bone markers will begin to play a larger role in monitoring efficacy in patients with BM receiving ZOL.

Footnotes

Abbreviations

Financial Support: The authors received no funding support and disclosed no financial interests.

Conflict of Interest Statement: None.

References

Brown

J.E.

, Cook

R.J.

, Major

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005; 97: 59–69.

Coleman

R.E.

Skeletal complications of malignancy. Cancer 1997; 80: 1588–94.

Lipton

Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention. J Support Oncol 2004; 2: 205–13.

Mundy

G.R.

Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002; 2: 584–93.

Okamoto

, Kawamura

, Li

Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylationindependent manners. J Thorac Oncol 2012; 7: 873–82.

Tamura

, Shomori

, Nakabayashi

, Fujii

, Ryoke

, Ito

Zoledronic acid, a third-generation bisphosphonate, inhibits cellular growth and induces apoptosis in oral carcinoma cell lines. Oncol Rep 2011; 25: 1139–43.

Coleman

R.E.

, Winter

M.C.

, Cameron

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 2010; 102: 1099–105.

Yasuda

, Fujii

, Yuasa

Possible improvement of survival with use of zoledronic acid in patients with bone metastases from renal cell carcinoma. Int J Clin Oncol 2012 Sep 11 [Epub ahead of print].

Rosen

L.S.

, Gordon

, Tchekmedyian

Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial – the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003; 21: 3150–7.

10.

Rosen

L.S.

, Gordon

, Kaminski

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma and breast carcinoma: a randomized, double-blind, multicenter comparative trial. Cancer 2003; 98: 1735–44.

11.

Saad

, Gleason

D.M.

, Murray

A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–68.

12.

Zuradelli

, Masci

, Biancofiore

High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid. Oncologist 2009; 14: 548–56.

13.

Chennuru

, Koduri

, Baumann

M.A.

Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid. Intern Med J 2008; 38: 635–7.

14.

Durie

B.G.

, Katz

, Crowley

Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353: 99–102.

15.

Vahtsevanos

, Kyrgidis

, Verrou

Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27: 5356–62.

16.

Huang

, Ouyang

Biochemical-markers for the diagnosis of bone metastasis: a clinical review. Cancer Epidemiol 2012; 36: 94–8.

17.

Mountzios

, Ramfidis

, Terpos

, Syrigos

K.N.

Prognostic significance of bone markers in patients with lung cancer metastatic to the skeleton: a review of published data. Clin Lung Cancer 2011; 12: 341–9.

18.

Coleman

, Brown

, Terpos

Bone markers and their prognostic value in metastatic bone disease: clinical evidence and future directions. Cancer Treat Rev 2008; 34: 629–39.

19.

Paget

The distribution of secondary growths in cancer of the breast. Lancet 1889; 1: 571–3.

20.

Michigami

, Shimizu

, Williams

P.J.

Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4) beta(1)-integrin enhances production of osteoclast-stimulating activity. Blood 2000; 96: 1953–60.

21.

Chiang

A.C.

, Massagué

Molecular basis of metastasis. N Engl J Med 2008; 359: 2814–23.

22.

Sterling

J.A.

, Edwards

J.R.

, Martin

T.J.

, Mundy

G.R.

Advances in the biology of bone metastasis: how the skeleton affects tumor behavior. Bone 2011; 48: 6–15.

23.

Drake

M.T.

, Clarke

B.L.

, Khosla

Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008; 83: 1032–45.

24.

Russell

R.G.

Bisphosphonates: mode of action and pharmacology. Pediatrics 2007; 119: S150–62.

25.

Stresing

, Fournier

P.G.

, Bellahcène

Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone 2011; 48: 259–66.

26.

Benzaïd

, Mönkkönen

, Stresing

High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res 2011; 71: 4562–72.

27.

Saracino

, Canuto

R.A.

, Maggiora

Exposing human epithelial cells to zole- dronic acid can mediate osteonecrosis of jaw: an in vitro model. J Oral Pathol Med 2012; 41: 788–92.

28.

Ott

S.M.

What is the optimal duration of bisphosphonate therapy?

Cleve Clin J Med 2011; 78: 619–30.

29.

Lein

, Wirth

, Miller

Serial markers of bone turnover in men with metastatic prostate cancer treated with zoledronic acid for detection of bone metastases progression. Eur Urol 2007; 52: 1381–7.

30.

Izumi

, Mizokami

, Itai

Increases in bone turnover marker levels at an early phase after starting zoledronic acid predicts skeletal-related events in patients with prostate cancer with bone metastasis. BJU Int 2012; 109: 394–400.

31.

Francini

, Pascucci

, Bargagli

Effects of intravenous zoledronic acid and oral ibandronate on early changes in markers of bone turnover in patients with bone metastases from non-small cell lung cancer. Int J Clin Oncol 2011; 16: 264–9.

32.

Karapanagiotou

E.M.

, Terpos

, Dilana

K.D.

Serum bone turnover markers may be involved in the metastatic potential of lung cancer patients. Med Oncol 2010; 27: 332–8.

33.

Generali

, Dovio

, Tampellini

Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases. Br J Cancer 2008; 98: 1753–8.

34.

Koizumi

, Yonese

, Fukui

, Ogata

The serum level of the amino-terminal propeptide of type I procollagen is a sensitive marker for prostate cancer metastasis to bone. BJU Int 2001; 87: 348–51.

35.

Klepzig

, Jonas

, Oremek

G.M.

Procollagen type I amino-terminal propeptide: a marker for bone metastases in prostate carcinoma. Anticancer Res 2009; 29: 671–3.

36.

Zissimopoulos

, Stellos

, Matthaios

Type I collagen biomarkers in the diagnosis of bone metastases in breast cancer, lung cancer, urinary bladder cancer and prostate cancer. Comparison to CEA, CA15-3, PSA and bone scintigraphy. J BUON 2009; 14: 463–72.

37.

Dean-Colomb

, Hess

K.R.

, Young

Elevated serum P1NP predicts development of bone metastasis and survival in early-stage breast cancer. Breast Cancer Res Treat 2013; 137: 631–6.

38.

Jung

, Miller

, Wirth

, Albrecht

, Lein

Bone turnover markers as predictors of mortality risk in prostate cancer patients with bone metastases following treatment with zoledronic acid. Eur Urol 2011; 59: 604–12.

39.

Lein

, Miller

, Wirth

Bone turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid. Prostate 2009; 69: 624–32.

40.

Cremers

, Farooki

Biochemical markers of bone turnover in osteonecrosis of the jaw in patients with osteoporosis and advanced cancer involving the bone. Ann N Y Acad Sci 2011; 1218: 80–7.

41.

Tamiya

, Tokunaga

, Okada

Prospective study of urinary and serum cross-linked n-telopeptide of type I collagen (NTx) for diagnosis of bone metastasis in patients with lung cancer. Clin Lung Cancer 2012 Dec 28 [Epub ahead of print].

42.

Tamiya

, Kobayashi

, Morimura

Clinical significance of the serum crosslinked N-telopeptide of type I collagen as a prognostic marker for non-small-cell lung cancer. Clin Lung Cancer 2013; 14: 50–4.

43.

López-Carrizosa

M.C.

, Samper-Ots

P.M.

, Pérez

A.R.

Serum C-telopeptide levels predict the incidence of skeletal-related events in cancer patients with secondary bone metastases. Clin Transl Oncol 2010; 12: 568–73.

44.

Pectasides

, Nikolaou

, Farmakis

Clinical value of bone remodelling markers in patients with bone metastases treated with zoledronic acid. Anticancer Res 2005; 25: 1457–63.

45.

Lipton

, Cook

R.J.

, Major

, Smith

M.R.

, Coleman

R.E.

Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity. Oncologist 2007; 12: 1035–43.

46.

Lipton

, Cook

, Saad

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 2008; 113: 193–201.

47.

Hirsh

, Major

P.P.

, Lipton

Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 2008; 3: 228–36.

48.

Kaira

, Murakami

, Kaira

N-telopeptide of type I collagen is useful for monitoring therapeutic response in non-small cell lung cancer patients with bone metastases. Int J Clin Oncol 2010; 15: 484–8.

49.

Zhao

, Xu

, Zhang

Prognostic and predictive value of clinical and biochemical factors in breast cancer patients with bone metastases receiving “metronomic” zoledronic acid. BMC Cancer 2011; 11: 403.

50.

Lipton

, Cook

, Brown

, Body

J.J.

, Smith

, Coleman

Skeletal-related events and clinical outcomes in patients with bone metastases and normal levels of osteolysis: exploratory analyses. Clin Oncol (R Coll Radiol) 2013; 25: 217–26.

51.

Ohashi

, Ichimura

, Mochizuki

The mechanism of TRACP 5b maturation. Rinsho Byori 2007; 55: 325–9.

52.

Fagerlund

K.M.

, Janckila

A.J.

, Ylipahkala

Clinical performance of six different serum tartrate-resistant acid phosphatase assays for monitoring alendronate treatment. Clin Lab 2008; 54: 347–54.

53.

Quinn

J.E.

, Brown

L.G.

, Zhang

, Keller

E.T.

, Vessella

R.L.

, Corey

Comparison of Fc-osteoprotegerin and zoledronic acid activities suggests that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms. Prostate Cancer Prostatic Dis 2005; 8: 253–9.

54.

Hung

T.T.

, Chan

, Russell

P.J.

, Power

C.A.

Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model. PLoS One 2011; 6: e19389.

55.

Mountzios

, Terpos

, Syrigos

Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid. Transl Res 2010; 155: 247–55.

56.

Mountzios

, Dimopoulos

M.A.

, Bamias

Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton. Acta Oncol 2007; 46: 221–9.

57.

Lazarovici

T.S.

, Mesilaty-Gross

, Vered

Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. J Oral Maxillofac Surg 2010; 68: 2241–7.

58.

Marx

R.E.

, Cillo

J.E.

, Ulloa

J.J.

Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65: 2397–410.

Bone Markers for Monitoring Efficacy in Patients with Bone Metastases Receiving Zoledronic Acid: A Review of Published Data

Abstract

Keywords

Introduction

Search Methods

Biology of BM and ZOL in Cancer Patients

Bone Markers that Monitor Response to ZOL

Bone formation markers

BAP

OC

Propeptides of type I collagen

Bone resorption markers

CTx and NTx

TRACP isoform 5b

C-terminal telopeptide of type I collagen (ICTP)

Markers of osteoclastogenesis

Interpretation of Bone Marker Changes in Patients Developing ONJ after ZOL Treatment

Conclusion

Footnotes

Abbreviations

References