Bone remodeling markers and bone cancer

Introduction

Bone metastases are frequent and seen in many malignancies, but preferentially occur in patients with breast, prostate, thyroid, kidney, bladder, and lung cancers. Although usually not lethal in themselves, bone metastases often cause refractory pain, hypercalcemia, fractures, neurological symptoms, and, as a result, profound morbidity and a reduction in quality of life [ ]. Over 60% of breast cancer patients with skeletal metastasis have skeletal complications, averaging to four such events per year [ ]. Of note, newer bisphosphonates significantly reduce the rate of skeletal events in cancer patients, particularly when used during early disease stages [ ]. Consequently, there is a clear clinical requirement to identify patients with bone metastases as early as possible, and to develop sensitive and specific means to monitor treatment efficacy and predict outcomes.

The diagnostic approach to metastatic bone disease traditionally focuses on the localization and characterization of the lesion, employing an array of different imaging techniques such as radiographs, CT, MRI, (quantitative) ⁹⁹ Tc bone scans, and positron emission tomography (PET). All of these procedures are of value in case-finding studies, where the goal is to identify patients with established metastatic spread. At earlier stages of the disease process, however, changes in skeletal morphology or radionuclide uptake may be discrete, nonspecific, or completely absent. Also, not all imaging techniques are equally well suited for the monitoring of skeletal disease progression or therapeutic response, particularly in patients with short survival times. Tumor markers such as PSA closely correlate with the extent of neoplastic tissue and may therefore be useful in the clinical monitoring of tumor behavior and treatment response [ ]. With scant exceptions, however, these markers do not provide information specific to the skeleton's involvement.

Under normal conditions, the process of bone remodeling is a balanced, lifelong continuum of resorbing old bone (through the action of osteoclasts) and replacing the removed tissue by an equal amount of newly formed bone (through the action of osteoblasts). The presence of cancer cells within the bone microenvironment greatly perturbs this balance. Thus, most osteolytic cancers are known to secrete cytokines and other factors (such as PTHrP), which induce osteoblasts and osteocytes to release RANKL. This potent cytokine activates osteoclasts to resorb bone, which not only provides space for the tumor to expand into, but also causes, the release of growth factors from the bone matrix, which in turn support and induce further tumor growth [ , ]. Bone formation rates can vary but are usually inadequate to compensate for the tumor-driven escalation in bone resorption. Radiographically, these changes result in predominantly lytic or mixed lytic–sclerotic lesions, as typically seen in breast cancer metastases to bone. In contrast, prostate cancers often cause sclerotic lesions characterized at the cellular level by a relative excess of bone formation compared to bone resorption. However, even the skeletal metastases of prostate cancer are characterized by an increase in the rate of both bone resorption and formation. High bone turnover with excess bone resorption therefore is an archetypal feature of most, if not all bone metastases. The cellular mechanisms associated with bone metastasis are covered in Chapters of Part 1, Section 2 in this volume and have also been reviewed in Refs. [ ].

Biochemical markers of bone turnover ( Fig. 30.1 ) are noninvasive and relatively inexpensive tools that, if applied and interpreted correctly, can be effectively used in assessing changes in bone remodeling associated with metastatic bone disease. Table 30.1 summarizes the biological and technical details of the currently used bone markers. For an in-depth review of the basic biochemistry of bone markers, please refer to Refs. [ ].

This chapter focuses on the clinical application of biochemical markers of bone turnover in metastatic bone disease, with specific emphasis on the clinically important topics of diagnosis, prognosis, and therapeutic response monitoring. For information on the utility of cytokine/osteoclastogenesis-related markers such as RANKL, OPG, and interleukins in metastatic bone disease, please refer to Ref. [ ]. This recent consensus paper also contains information regarding the use of biochemical markers in malignant bone disease.