Bone markers and their prognostic value in metastatic bone disease: Clinical evidence and future directions

doi:10.1016/j.ctrv.2008.05.001

Cancer Treatment Reviews

Volume 34, Issue 7, November 2008, Pages 629-639

https://doi.org/10.1016/j.ctrv.2008.05.001 Get rights and content

Summary

Background

Bone metastases are prevalent among patients with advanced solid tumors. Metastatic bone disease alters bone homeostasis, resulting in reduced bone integrity and, consequently, increased skeletal complications. Biochemical markers of bone metabolism may meet an unmet need for useful, noninvasive, and sensitive surrogate information for following patients’ skeletal health.

Materials and methods

Data for this review were identified by searches of PubMed, and references from relevant articles using the search terms “bone markers” or individual bone marker nomenclature, “cancer,” and “metastases.” Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English between 1990 and 2007 were included.

Results

Recent retrospective analyses with bisphosphonates, and particularly with zoledronic acid, have shown significant correlations between biochemical markers of bone metabolism levels and clinical outcomes, especially for bone resorption markers. Clinical results for biochemical markers of bone formation and resorption and other emerging markers of bone metabolism including bone sialoprotein, receptor–activator of nuclear factor-κB ligand, osteoprotegerin, and other markers are presented. However, biochemical markers of bone metabolism are not yet an established surrogate endpoint for treatment efficacy.

Conclusions

Biochemical markers of bone metabolism may allow physicians to identify which patients with metastatic bone disease are at high risk for skeletal-related events or death and who may be responding to therapy. Prospective randomized clinical trials are underway to further assess the utility of markers of bone metabolism in patients with bone metastases.

Introduction

Bone is a common site for metastases in patients with solid tumors such as breast, prostate, lung, thyroid, and renal cancers.¹ Approximately 70% of patients with advanced prostate cancer or breast cancer will develop bone metastases, and metastatic disease is often limited to the skeleton in patients with advanced prostate cancer.² Bone metastases have been reported in up to 40% of patients with advanced solid tumors other than breast and prostate cancer.² Moreover, almost all patients with multiple myeloma will develop bone lesions during the course of their disease.² Metastatic bone disease disrupts the normal homeostasis of bone, which is a dynamic process that involves the coupled and balanced osteoclast-mediated osteolysis and osteogenesis by osteoblasts.¹ The resulting increased and unbalanced bone metabolism leads to a loss of bone integrity, which can result in skeletal complications.

Conventional measurements of skeletal health and treatment response in metastatic bone lesions are imprecise and can only detect changes after the damage has occurred. Surrogate assessments that are simple and can rapidly and sensitively detect changes in skeletal health are needed, so that serial measurements may be easily taken to follow patient progress. Biochemical markers of bone resorption and formation may fill this area of clinical need. The ideal marker of bone metabolism would provide both sensitivity to identify patients with bone metastases or patients at high risk for negative clinical outcomes from bone metastases and specificity in monitoring skeletal health. In addition, its clinical variations would be well-defined and reference values established.

The science and clinical utility of biochemical markers of bone metabolism are still evolving; therefore, they are not yet an established surrogate measurement for clinical efficacy. Therefore, the current medical literature was surveyed using PubMed searches, and additional information was gathered from recent conference proceedings and presentations on current use and potential utility of biochemical markers of bone metabolism in the clinical setting. In this review, we present the clinically relevant biochemical markers of bone metabolism and the available evidence for their use in the metastatic bone disease setting.

Section snippets

Mechanisms of bone remodeling and the bone microenvironment

Bone is composed of two basic types: cortical and cancellous (trabecular). Cortical bone comprises the shafts of the long bones in the skeleton and the outer layer of all bones. It constitutes approximately 80% of the total skeletal mass.³ Cancellous bone comprises the inner structure of the vertebrae, pelvis, and the ends of the long bones. It provides a large honeycombed surface area for bone-forming cells and minerals. Although cancellous bone constitutes approximately 20% of the total

Biochemical markers of bone formation and bone resorption

Skeletal health may be evaluated by various measurements such as histomorphometry, bone mineral density, and plain radiographs.11, 12 However, each of these established methodologies has limitations. For example, histomorphometry is an expensive and invasive procedure that measures bone predominantly in the iliac crest and requires a relatively long time to obtain results. Bone mineral densitometry (dual-energy X-ray absorptiometry; e.g., to assess bone mineral density), scintigraphy (e.g., to

Clinical experience with biochemical markers of bone metabolism

Biochemical markers of bone metabolism may provide valuable prognostic information in patients with metastatic bone disease. These patients often have increased bone metabolism as evidenced by increases in both bone formation and resorption marker levels. Patients also often have unbalanced bone metabolism, which results in a loss of bone integrity and increased risk of skeletal complications.¹ For clinical utility, changes in biochemical markers of bone metabolism (bone markers) should

Interpretation of bone marker changes during treatment

Changes in biochemical markers of bone metabolism may provide valuable information for prediction and monitoring of response to therapy. In multiple myeloma, reductions of bone resorption markers have been observed in patients who received a combination of antimyeloma agents with zoledronic acid.74, 81 The reduction of NTX or CTX was greater in patients who responded to thalidomide-based regimens compared with patients who did not respond to treatment.⁸¹ Furthermore, bortezomib, a proteasome

Conclusions

Although biochemical markers of bone metabolism are useful tools to provide insight into the ongoing levels of skeletal metabolism, they are not sufficiently characterized surrogate measurements to definitively predict clinical outcomes in individual patients. However, evidence is accumulating regarding the prognostic value of some biochemical markers of bone metabolism. Elevated NTX levels clearly have negative prognostic implications for SREs and survival in patients with bone lesions from

Conflict of interest statement

Dr. Smith is a consultant to Novartis Oncology, Amgen Oncology, Merck, and GTx, Inc.

Dr. Coleman has received consultancy fees, speaker fees, and research funding from Novartis and has given expert testimony on their behalf.

Dr. Terpos has received an honorarium for participation in an advisory board for Novartis.

Dr. Major has received consultancy fees and participated in advisory boards for Novartis.

Dr. Brown has participated in an advisory board for Novartis.

Dr. Cook has received consultancy

Role of the funding source

Funding for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.

Acknowledgments

The authors thank Tamalette Loh, PhD, ProEd Communications, Inc.^®, for medical editorial assistance with this manuscript. All authors were responsible for the generation of this article, controlling content from inception, analysis and interpretation of data, critically revising for intellectual content, and providing final approval of the submitted version.

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Assessments of serum or urinary levels of bone turnover markers may provide a simpler, more rapid, and more convenient way of detecting changes in skeletal health or bone lesion progression (Coleman et al., 2008). The ideal marker would need to be both sensitive and specific, and several candidate markers, including urinary N-telopeptide of type 1 collagen (uNTX) and bone-specific alkaline phosphatase (bone ALP), have been suggested (Grávalos et al., 2016; Coleman et al., 2008; Coleman et al., 2011). However, research is still required to establish the most appropriate surrogate marker for SREs (Coleman et al., 2011).
As a result of the negative impact of bone metastases on patient quality of life, it is important to identify patients at increased risk of skeletal-related events (SREs). Biochemical markers produced by osteoblasts and osteoclasts may provide an early indicator of treatment response to antiresorptive therapy. We aimed to explore the relationship between change in the urinary bone turnover marker cross-linked N-terminal telopeptide of type 1 collagen (uNTX) at the earliest time of steady state and risk of SREs.
A comprehensive search of eight bibliographic databases and two trial registries was conducted (June 2017). We included randomized controlled trials of adults (≥18 years old) with bone metastases from solid tumors (including breast, lung, prostate) or bone lesions from multiple myeloma that compared denosumab or bisphosphonate(s) with each other or a placebo. Meta-analyses were used to evaluate the relationship between uNTX and SREs. The primary outcomes were based on uNTX at week 13 and SREs in those studies.
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GENERAL AND SUPPORTIVE CAREBone markers and their prognostic value in metastatic bone disease: Clinical evidence and future directions

Summary

Background

Materials and methods

Results

Conclusions

Introduction

Section snippets

Mechanisms of bone remodeling and the bone microenvironment

Biochemical markers of bone formation and bone resorption

Clinical experience with biochemical markers of bone metabolism

Interpretation of bone marker changes during treatment

Conclusions

Conflict of interest statement

Role of the funding source

Acknowledgments

Bone

J Pharm Biomed Anal

Blood Rev

Blood

J Pharm Biomed Anal

Blood

Bone

J Biol Chem

Bone

Bone

Ann Oncol

J Thorac Oncol

Ann Oncol

Ann Oncol

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors

J Natl Cancer Inst

Skeletal complications of malignancy

Cancer

Clinical utility of biochemical markers of bone remodeling

Clin Chem

Identifying genes that regulate bone remodeling as potential therapeutic targets

J Exp Med

[Development, physiology, and cell activity of bone]

Ned Tijdschr Tandheelkd

Bone quality – the material and structural basis of bone strength and fragility

N Engl J Med

Clinical review 165: markers of bone remodeling in metastatic bone disease

J Clin Endocrinol Metab

Molecular mechanism of the life and death of the osteoclast

Ann N Y Acad Sci

[Molecules which are involved in osteoclastic bone resorption: from the aspect of targets of treatment for osteoporosis]

Clin Calcium

[Molecular mechanisms of bone formation and bone-forming factors]

Clin Calcium

Precision and accuracy of measuring changes in bone mineral density by dual-energy X-ray absorptiometry

Osteoporos Int

Markers of bone turnover for the management of patients with bone metastases from prostate cancer

Br J Cancer

A placebo-controlled study of three osteocalcin assays for assessment of prednisolone-induced suppression of bone turnover

J Endocrinol

Bone formation and resorption biological markers in cosmonauts during and after a 180-day space flight (Euromir 95)

Clin Chem

Markers of type I and type III collagen synthesis in serum as indicators of tissue growth during pregnancy

J Clin Endocrinol Metab

Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial

J Bone Miner Res

Bone turnover in elderly men: relationships to change in bone mineral density

BMC Musculoskelet Disord

The roles of annexins and alkaline phosphatase in mineralization process

Acta Biochim Pol

Urinary osteocalcin as a marker of bone metabolism

Clin Chem

Molecular basis and clinical application of biological markers of bone turnover

Endocr Rev

Serum amino-terminal propeptide of type 1 procollagen (P1NP) in prostate cancer: a potential predictor of bone metastases and prognosticator for disease progression and survival

Urol Int

Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma

Prostate

The clinical use of bone resorption markers in patients with malignant bone disease

Cancer

Biochemical markers for assessment of bone metastases in patients with breast cancer

Kaohsiung J Med Sci

Utilisation des marqueurs du remodelage osseux dans l’osteoporose

J Inf Biomed [in French]

GENERAL AND SUPPORTIVE CARE
Bone markers and their prognostic value in metastatic bone disease: Clinical evidence and future directions