Elsevier

Clinical Biochemistry

Volume 30, Issue 8, December 1997, Pages 573-593
Clinical Biochemistry

Review
Biochemical Markers of Bone Metabolism: An Overview

https://doi.org/10.1016/S0009-9120(97)00113-6Get rights and content

Abstract

Objectives: An overview of biochemical markers of bone metabolism is presented along with indications for their clinical utilization.

Design and Methods: The structure, cyclical metabolism, and hormone regulation of bone is reflected by markers of resorption, formation and/or turnover. Markers of resorption representing degradation of type 1 collagen, include N-telopeptides, C-telopeptides, hydroxyproline, and the collagen crosslinks pyridinoline and deoxypyridinoline; acid phosphatase, a marker of osteoclast activity, and urinary calcium are also indicators of bone resorption. Bone formation markers indicate osteoblast activity; bone-specific alkaline phosphatase and the N-terminal and C-terminal extension peptides of procollagen reflect formation of organic matrix in bone. Osteocalcin, produced by osteoblasts but also released during osteoclastic degradation, may indicate either formation when resorption and formation are coupled or turnover when they are uncoupled.

Results: Bone markers respond to intervention more rapidly than techniques such bone mineral density. Resorption markers respond approximately 1 to 3 months after intervention; markers of formation respond later, after 6 to 9 months. Bone markers may add useful information for assessing fracture risk and for monitoring osteoporosis, Paget’s disease of bone, cancer metastasis, and metabolic disease. Various therapeutic interventions may affect release of some bone markers.

Conclusion: Bone disease has high prevalence in adults so bone markers will become even more important for assessing fracture risk and monitoring therapy as populations age. Characteristics of bone markers are dependent on biology and the assay used. Substantial work remains in characterizing existing assays, identifying better markers and performing the clinical studies to define which bone markers should be measured and when.

Introduction

Diseases of the bone, in particular osteoporosis, represent a major healthcare problem affecting approximately one-half of all women and one-fourth of all men over age 50, at an estimated annual cost of over 10 billion dollars in the United States alone. As the median age of populations increase, the diagnosis, treatment, and monitoring of osteoporosis and other skeletal diseases will become an even more prominent healthcare issue.

Bone metabolism is a dynamic and continuous remodeling process that is normally maintained in a tightly coupled balance between resorption of old or injured bone and formation of new bone. On a microscopic level, bone metabolism always occurs on the surface of bone at focused sites, each of which is termed a bone metabolism unit (or bone remodeling unit [BMU]). Global bone metabolism represents the cumulative behavior of many BMUs such that defects in the organization of bone formation or any imbalance to the side of bone resorption can result in substantial changes in functional integrity over time. Changes can occur rapidly when the rate of turnover is increased.

The tools available to healthcare providers for diagnosing and monitoring diseases of bone provide important information, but clearly have limitations. Histomorphometry provides critical information regarding the activation frequency of BMUs and the rate of bone turnover [1]. However, this technique is generally limited to biopsy of the iliac crest in adults, so the accuracy of assessment at other skeletal sites can be compromised 1, 2. Monitoring calcium accretion rates can be useful for the quantitative assessment of bone loss during menopause, but may not be accurate in elderly women [2]. Use of ultrasound for assessment is under active investigation at present and is attractive because it shows promise for assessing the quantity and quality of bone [3].

Bone density measurement is a most important tool because this technology provides a sensitive means for diagnosing decreased bone mass and predicting fracture [3]. Assessing bone density by dual energy x-ray absorptometry (DEXA) is perhaps most useful, having an accuracy exceeding 95%, and a precision in the range of 1% [3].

Criteria for the diagnosis of osteoporosis is based on bone density measurements. According to criteria developed by the World Health Organization, normal bone mass is defined as bone density within 1 standard deviation (SD) of the young adult mean (YAM); increased bone loss, or osteopenia, is bone mass between 1 and 2.5 SD below the YAM; osteoporosis is defined as bone mass ≥ 2.5 SDs below the YAM. Individuals with decreased bone mass and a previous fracture are at 25-fold greater risk of subsequent fracture compared to the normal population [3]. Although bone density measurements are obviously extremely important clinically, the technology is limited because at least 2–3 years are required before the efficacy of any intervention can be measured reliably [1]. Therefore, a more immediate measure of metabolic status is desirable.

Biochemical markers of bone metabolism can provide more real-time assessment of bone resorption, formation, and turnover. Although bone biochemistry has been a subject of active research for many years, clinical measurement of biochemical bone markers has been a relatively recent development in the clinical arena. Here an overview of available biochemical markers of bone metabolism will be presented. Elucidating the possible role of these markers in the care of patients with bone disease will be a primary focus.

Section snippets

Cells Involved in Bone Metabolism

Osteoclasts and osteoblasts are the biological machinery that carry out bone metabolism at the fundamental BMU site. Osteoclasts function to resorb existing bone and are active early in the bone remodeling cycle. Osteoclasts are derived from fusion of cells of monocyte lineage and are usually multinucleated with apical and basolateral poles that differ both morphologically and functionally. The osteoclast’s apical pole has a fenestrated membrane that is oriented toward the bone matrix and is

Bone Cycle

All adult human bone is derived from previously existing bone via a tightly coupled remodeling process termed the bone remodeling cycle. As indicated in Fig. 1, the bone cycle proceeds in one direction only, in a well-coordinated, carefully orchestrated process controlled by hormones and other factors via mechanisms which are incompletely understood at present.

As indicated in Fig. 1, bone remodeling always begins in the quiescent phase. After activation is initiated, osteoclasts are attracted

Basic Bone Structure and Composition

There are two basic types bone in the human skeleton, each having a different role and function. The first type is cortical bone which comprises about 80% of the skeleton. Cortical bone is well-suited for mechanical, structural and protective functions because it is 80–90% calcified and, therefore, dense. Cortical bone is the major component of long bones and comprises the outside protective surfaces of all bones. The metabolic activity of cortical bone is relatively low.

The second type of

Regulation of Bone Metabolism

Bone metabolism is regulated by complex interaction of a wide variety of hormones and factors. Although the literature on this topic is extensive, elucidation of the exact function, role, and mechanism of each hormone and factor is largely incomplete. Investigation into the basic regulation of bone metabolism is an area of active research.

The role of several factors involved in the activation, proliferation, and control of osteoblast progenitor cells has been clarified in part. Fibroblast

Osteoporosis

According to the World Health Organization, osteoporosis is “a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequential increase in fracture risk” [29]. There are two basic forms of osteoporosis based on whether the disease is the primary disorder or secondary to another identifiable medical condition or treatment.

Primary osteoporosis can be divided into three basic subtypes termed: idiopathic juvenile

Specific Markers of Bone Metabolism

Based on the phases of the bone cycle, markers of bone metabolism may be conveniently classified either as indicators of bone formation, bone resorption, or overall bone turnover. Markers of bone formation assess either osteoblastic synthetic activity or postrelease metabolism of procollagen. Resorption markers reflect osteoclast activity and/or collagen degradation. Bone turnover can theoretically be assessed by comparing the amount of substances that are released during resorption with the

Alkaline Phosphatase (ALP)

ALP is associated with the plasma membrane of cells. Although the exact function of this enzyme is unknown, it has broad tissue distribution and appears to be involved in the transport of substances from the intracellular compartment across the membrane to extracellular region. In bone, ALP may also be involved in the breakdown of pyrophosphate, a potent inhibitor of calcium phosphate deposition at the extracellular level [36]. Mechanistically, the enzyme may be clipped off the membrane and

Urinary Calcium

Fasting urine calcium concentration, in either a 24-hour sample or in a spot or first morning specimen corrected for creatinine, has been used for assessing skeletal loss [71]. Although clearly among the least expensive of bone markers, urinary calcium lacks diagnostic sensitivity and specificity because levels can be substantially affected by factors including diet, renal function and handling, and excesses in hormones including PTH and estrogen [71]. Perhaps one clinical application for urine

Interpretation of Results

The ideal bone marker would have zero day-to-day biologic variability and the assay would have negligible imprecision. Lacking this ideal, all biochemical markers are subject to variability that is represented by inter-individual differences, day-to-day, and diurnal biological differences as well as the analytic variability that is characteristic of the assay. As with other biochemical markers, interpretation of data must be done with caution if the results are not presented in normalized

Clinical Studies Involving Markers of Bone Metabolism

Table 2 lists studies that examined bone markers in a number of diseases, in patients receiving various therapies. The studies listed in Table 2 and discussed here are not intended to be exhaustive, but rather are representative of activity in the field. As with literature dealing with any biochemical marker, it is important that the reader pay close attention to the technology utilized for measurement, as the characteristics of any bone marker can differ significantly depending on how the

Conclusion

Biochemical markers of bone formation and resorption provide a new and potentially important clinical tool for the assessment and monitoring of bone metabolism. Compared to the standard clinical tool of bone mineral density which requires 2–3 years to show a significant response with initiation or removal of therapy, resorption markers respond more quickly, within approximately 3 months; formation markers respond some months later. As the most prevalent bone diseases affect men and women

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