New developments in biological markers of bone metabolism in osteoporosis

doi:10.1016/j.bone.2014.05.016

Bone

Volume 66, September 2014, Pages 46-55

https://doi.org/10.1016/j.bone.2014.05.016 Get rights and content

Highlights

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Serum periostin may reflect periosteal metabolism.
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Periostin, sclerostin and sphingosine-1-phosphate are associated with fracture risk.
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Circulating microRNAs are a novel class of biomarker in osteoporosis.

Abstract

Over the last 15 years several biological markers of bone turnover have been developed with increased specificity and sensitivity. In osteoporosis clinical studies, the IOF and IFCC organizations have recently recommended the measurements of serum type I collagen N-propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) as markers of bone formation and bone resorption, respectively. However these markers have some limitations including a lack of specificity for bone tissue, their inability to reflect osteocyte activity or periosteal apposition. In addition they do not allow the investigation of bone tissue quality an important determinant of skeletal fragility. To address these limitations, new developments in markers of bone metabolism have been recently achieved. These include assays for periostin, a matricellular protein preferentially localized in the periosteal tissue, sphingosine 1-phosphate, a lipid mediator which acts mainly on osteoclastogenesis and the osteocyte factors such as sclerostin and FGF-23. Recent studies have shown an association between the circulating levels of these biological markers and fracture risk in postmenopausal women or elderly men, although data require confirmation in additional prospective studies. Finally, recent studies suggest that the measurements of circulating microRNAs may represent a novel class of early biological markers in osteoporosis. It is foreseen that with the use of genomics and proteomics, new markers will be developed to ultimately improve the management of patients with osteoporosis.

Introduction

Bone metabolism is characterized by an intimate cooperation of bone cells including osteoblasts, osteoclasts and osteocytes in order to maintain a regulated amount of bone tissue and the integrity of bone structure. In metabolic bone diseases such as osteoporosis, bone metabolism is altered, leading to bone loss, often accompanied by changes in the microarchitecture, leading to bone fragility. The development of serum and urinary assays for biochemical markers reflecting either enzymatic activities of osteoblasts and osteoclasts or breakdown products of bone tissue has been of high value to investigate the complex pathways of bone metabolism and their alterations in bone diseases, especially in osteoporosis. They have also helped the clinicians to identify patients at high risk for fracture and to monitor the efficacy of anti-resorptive therapies and bone-forming agents. In the last few years novel biological markers have been developed and studies suggest that they may be valuable research tools for investigating the mechanisms of bone metabolism, to assess the activity of osteocytes and some of them may be of value for the management of patients with osteoporosis. The aim of this paper is to review these novel developments in biological markers of bone metabolism in osteoporosis.

Section snippets

Established biochemical markers of bone metabolism

The structure, biology and clinical utility of conventional biochemical markers in different diseases including osteoporosis has been reviewed in several recent review papers [1], [2], [3]. At present, the most specific and sensitive markers of bone formation are serum total osteocalcin; the bone isoenzyme of alkaline phosphatase (bone ALP); and the procollagen type I N-terminal propeptide (PINP), which reflects the rate of synthesis of the main constituent of bone tissue. For the evaluation of

New biological markers of bone metabolism

Novel markers can be classified in different groups as shown on Table 1 and their involvement in bone cell biology is described on Fig. 1. These include the measurements of some non-collagenous proteins, osteoclastic enzymes other than TRACP5b, osteocyte-secreted factors, molecules involved in the coupling between osteoclast–osteoblasts, and circulating microRNAs. In this paper we will discuss in more details the most promising candidate in each category and their clinical relevance for the

Conclusion

During the last 5 years new developments have been achieved in the field of biological markers of bone metabolism, especially with the investigation of the clinical utility of serum sclerostin in osteoporosis and other metabolic bone diseases. Clinical data on these novel markers remain however limited and sometimes are controversial. The next years will be important to confirm the potential clinical utility of some of these biological markers and it is likely than novel candidates will be

Disclosure

P. Garnero is an employee of Cisbio Bioassays.

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ReviewNew developments in biological markers of bone metabolism in osteoporosis

Highlights

Abstract

Introduction

Section snippets

Established biochemical markers of bone metabolism

New biological markers of bone metabolism

Conclusion

Disclosure

Clin Biochem

Bone

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Joint Bone Spine

Maturitas

Maturitas

Clin Biochem

Dev Cell

Bone

J Biol Chem

J Biol Chem

Bone

Bone

J Biol Chem

Bone turnover markers: use in osteoporosis

Nat Rev Rheumatol

Blood biochemical markers of bone turnover: pre-analytical and technical aspects of sample collection and handling

Clin Chem Lab Med

Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards

Osteoporos Int

The periosteum—a surface for all seasons

Osteoporos Int

Heterogeneity of human bone

J Bone Miner Res

The multiple facets of periostin in bone metabolism

Osteoporos Int

Periostin and transforming factor β-induced protein (TGFβIp) are both expressed by osteoblasts and osteoclasts

Cell Biol Int

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Proc Natl Acad Sci U S A

Zoledronate effects on systemic and jaw osteopenias in ovariectomized periostin-deficient mice

PLoS One

Periostin: novel diagnostic and therapeutic target for cancer

Histol Histopathol

Periostin: a novel serum marker of cortical bone formation

J Bone Miner Res

Serum periostin is associated with fracture risk in postmenopausal women: a 7 years prospective analysis of the OFELY study

J Clin Endocrinol Metab

Cathepsin K inhibitors: a novel target but promising approach in the treatment of osteoporosis

Curr Drug Targets

Human osteoclast cathepsin K is processed intracellularly prior to attachment and bone resorption

J Bone Miner Res

Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget's disease

Clin Lab

Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction

Arthritis Res Ther

Cathepsin K predicts femoral neck bone mineral density change in non osteoporotic peri- and early postmenopausal women

Menopause

Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans

Drug Metab Dispos

RANKL and OPG regulation of bone remodeling in health and disease

Endocr Rev

Changes of serum soluble receptor activator for nuclear factor-κB ligand after glucocorticoid therapy reflect regulation of its expression by osteoblasts

J Clin Endocrinol Metab

Assessment of OPG/RANK/RANKL gene expression levels in peripheral blood mononuclear cells (PBMC) after treatment with strontium ranelate and ibandronate in patients with postmenopausal osteoporosis

J Clin Endocrinol Metab

Relationship between serum RANKL and RANKL in bone

Osteoporos Int

The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma

N Engl J Med

Increased dickkopf-1 (Dkk-1) expression in breast cancer bone metastases

Br J Cancer

Dickkopf-1 is a master regulator of joint remodeling

Nat Med

Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women

Arthritis Rheum

Opposite relationships between circulating Dkk-1 and cartilage breakdown in patients with rheumatoid arthritis and knee osteoarthritis

Ann Rheum Dis

Review
New developments in biological markers of bone metabolism in osteoporosis