Clinical AspectsBiochemical markers of bone turnover in Paget’s disease of bone
Introduction
Biochemical markers of bone turnover have been used for many years in the diagnosis and monitoring of treatment for Paget’s disease of bone.3 The standard biochemical markers that have been used are total alkaline phosphatase as a marker of bone formation and urinary hydroxyproline as a marker of bone resorption. These markers perform very well and have provided useful information about the effects of drug treatment on Paget’s disease.
A number of new markers have recently been introduced and may be useful in the setting of milder forms of Paget’s disease. Bone isoform of alkaline phosphatase is now available by immunoassay (enzyme-linked immunosorbent assay [ELISA] and immunoradiometric assay [IRMA]) and by wheat-germ lectin precipitation. The bone isoform performs better than total alkaline phosphatase in milder forms of Paget’s disease. Osteocalcin generally tends not to be elevated in Paget’s disease and responds poorly to treatment and so is not suitable in this condition. It is not clear why osteocalcin is not elevated, but it may be that the molecule is incorporated into the normal bone matrix rather than leaking back into the circulation. Several bone resorption markers based on the pyridinium cross-links of collagen are now available as immunoassays. These include immunoactive free deoxypyridinoline (Pyrlinks D), N-telopeptide of type I collagen (Osteomark), and C-telopeptides of type I collagen (Crosslaps). These assays are useful in the monitoring of Paget’s disease and the telopeptide assays (Osteomark and Crosslaps) show particularly impressive responses to treatment.1, 8 It is not clear why the telopeptide markers are more responsive than the free cross-link markers, but may relate to the renal handling of the different cross-link forms. For example, the telopeptide forms may undergo some metabolism and cleavage of the amino acids, resulting in the production of free cross-links within the kidney. This process may be more efficient in low turnover states when enzymes are not saturated.2
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Diagnosis of Paget’s disease
Bone radiographs and isotope bone scans are the most widely used tests in the diagnosis of Paget’s disease. However, raised alkaline phosphatase is often a trigger for investigating a patient for this condition. In patients with symptomatic Paget’s disease about 85% have elevations of total alkaline phosphatase. Normal levels of bone alkaline phosphatase are particularly common in patients with monostotic disease, which comprises about 15% of patients.3 Bone alkaline phosphatase is particularly
Monitoring of drug therapy
The decrease in bone resorption markers occurs within the first few days of starting bisphosphonate or calcitonin therapy, and decrease in bone formation markers occurs a few weeks later. The decrease in bone resorption markers tends to exceed that of bone formation markers. The mean decrease in patients with Paget’s disease is about 50% and the decrease may continue once the treatment has stopped.
Prolonged biochemical remission in Paget’s disease is associated with three features7:
- 1.
Milder
Limitations of biochemical markers
There are some limitations of using biochemical markers of bone turnover in Paget’s disease and these do always go hand in hand with the improvements seen. For example, pain is often relieved before there is biochemical remission. Some lytic wedge lesions that occur in the long bones may progress despite biochemical remission.5 It is therefore important in the follow-up of patients with lytic lesions that annual X-rays are performed as well as biochemical marker measurements. Some investigators
Conclusions
Biochemical markers of bone turnover are useful in both diagnosis and monitoring of therapy in Paget’s disease of bone. There is much experience with the use of total alkaline phosphatase and urinary hydroxyproline and, for many patients, these older markers are very useful and have the advantage of being inexpensive. For patients with milder disease, a more bone-specific marker, such as bone alkaline phosphatase or telopeptides of type I collagen, may prove more sensitive. These markers are
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