Markers of bone turnover in bone metastases

Bone metastases are a frequent complication of cancer disease. The evaluation of metastatic bone disease is crucial for the primary cancer staging because it will influence the therapeutic decision. The diagnosis of bone metastases usually relies on skeletal X-ray and bone scintigraphy. This latter technique is a sensitive diagnostic tool but lacks specificity. Moreover, the assessment of efficacy in the treatment of bone metastasis is difficult because the increased radionucleotide uptake does not always reflect an active metastatic area but may correspond to a bone reconstruction in patients responding to treatment. Markers of bone remodeling could help the clinician in the diagnosis and follow-up of bone metastases.

A common feature of both types of bone metastases (lytic or sclerotic) is an alteration of bone remodeling activity. The rate of formation or degradation of the bone matrix can be assessed either by measuring a prominent enzymatic activity of the bone forming or resorbing cells or by measuring bone matrix components released into the circulation during formation or resorption. They have been separated into markers of formation and resorption, but when both events are coupled and in balance, either of these markers will reflect the overall rate of bone turnover. These markers are of unequal specificity and sensitivity, and some of them have not been fully investigated yet in bone metastases. None of these markers is disease specific.

Several studies of breast carcinoma showed increased levels of pyridinium cross-links in patients with bone metastases. However, in most studies, breast carcinoma patients without evidence of metastatic bone disease excreted pyridinium cross-links at a much higher rate than healthy controls. Similar findings have been observed with other types of primary cancer including lung, prostate, kidney, throat, and digestive carcinoma. Markers of bone formation had a low sensitivity in the diagnosis of bone metastasis, but they could be useful for prostate carcinoma, in which studies have shown that all patients without bone metastasis had normal value of bone alkaline phosphatase. Bone markers can be used for the follow-up of treatment, especially bisphosphonates therapy. Bisphosphonate infusion induces a large decrease of pyridinium cross-link level. Some studies suggest that a high level of resorption markers after treatment could reflect a resistance to the treatment. Moreover, some studies have shown that level of pyridinium cross-links before treatment could be a predictive factor of the response in multiple myeloma and prostate carcinoma.

Bone markers have improved greatly in terms of sensitivity and specificity and could be useful for an early diagnosis of bone metastases. However, the clinical value of the use of bone markers in the diagnosis of bone metastasis has not been clearly shown yet with the possible exception of BPAL in prostate carcinoma. When bone is the only site of metastases, bone markers may be useful for monitoring patients with bone metastases. Markers of bone resorption are sensitive to changes in bone turnover induced by treatment. Bone resorption markers may be particularly useful for the follow-up of bisphosphonate treatment, which is increasingly used in the management of bone metastases.