With the ageing population in most countries, disorders of bone and mineral metabolism are becoming increasingly relevant to every day clinical practice. Consequently, the interest in, and the need for effective measures to be used in the screening, diagnosis and follow-up of such pathologies has markedly grown. Together with clinical and imaging techniques, biochemical tests play an important role in the assessment and differential diagnosis of metabolic bone disease.

In recent years, the isolation and characterisation of cellular and extracellular components of the skeletal matrix have resulted in the development of molecular markers that are considered to reflect either bone formation or bone resorption. These biochemical indices are non-invasive, comparatively inexpensive and, when applied and interpreted correctly, helpful tools in the diagnostic and therapeutic assessment of metabolic bone disease.

Part I of this article provides an overview of the basic biochemistry of bone markers, and sources of non-specific variability. Part II (to be published in a subsequent issue of this journal) will review the current evidence regarding the clinical use of biochemical markers of bone remodelling in metabolic and metastatic bone disease.

Biochemical Markers of Bone Turnover Part I: Biochemistry and Variability

Biochemical Markers of Bone Metabolism: An Overview

Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study.

We measured serum bone alkaline phosphatase (B-ALP) with a new immunoradiometric assay (IRMA) in a large sample of healthy controls comprising 173 women and 180 men, 20-88 yr of age, and in patients with metabolic bone disease. Using serum samples from patients with liver disease and patients with Paget's disease with elevated total alkaline phosphatase (T-ALP) as a source of, respectively, liver and bone isoenzymes, we determined a liver cross-reactivity of the IRMA of 16% that was confirmed by electrophoresis of the circulating alkaline phosphatase isoenzymes. The IRMA was linear for serial sample dilutions, the recovery ranged from 89-110%, and the intra- and interassay variations were below 7% and 9%, respectively. B-ALP increased linearly with age in both sexes, and the mean B-ALP serum levels were not significantly different for women and men (11.3 +/- 4.8 ng/mL for women; 11.0 +/- 4.0 ng/mL for men). The increase in B-ALP after the menopause was significantly higher than that in T-ALP (+77% vs. +24%; P < 0.001). When the values of postmenopausal women were expressed as the SD from the mean of premenopausal women, the mean Z scores were 2.2 +/- 1.8 for B-ALP and 0.9 +/- 1.3 for T-ALP (P < 0.001 between the two). Serum B-ALP was increased from control values in patients with Paget's disease (n = 57; mean, 171.8 +/- 135.6 ng/mL; P < 0.001), in patients with primary hyperparathyroidism (n = 18; mean, 17.2 +/- 5.9 ng/mL; P < 0.001), and in patients with chronic renal failure on hemodialysis (n = 83; mean, 36.6 +/- 35.7 ng/mL; P < 0.001). In patients with Paget's disease, B-ALP was highly correlated with T-ALP (r2 = 0.94; P < 0.001), and the decrease in its serum level was larger than that in T-ALP after treatment with the bisphosphonate pamidronate (-58% vs. -43%; P < 0.03). In patients with various liver diseases, B-ALP was slightly increased, but stayed within the normal range (mean +/- 2 SD) until T-ALP did not exceed 4.5 mu katal/L. We conclude that this new IRMA for B-ALP is reliable, has a low cross-reactivity with the liver isoenzyme, and appears to be more sensitive than T-ALP for the clinical investigation of patients with osteoporosis and other metabolic bone diseases.

Assessment of the serum levels of bone alkaline phosphatase with a new immunoradiometric assay in patients with metabolic bone disease

We measured iliac bone formation rates on all surfaces after double tetracycline labeling, serum levels of type 1 procollagen carboxy-terminal extension peptide (pColl-I-C), and serum levels of total alkaline phosphatase activity (TAP) in four normal subjects and in 44 patients with various forms of metabolic bone disease. In three patients with enzymatic evidence of liver disease both biochemical serum markers were disproportionately raised. In a patient with idiopathic axial osteosclerosis serum pColl-I-C was selectively increased by more than ten-fold. In the remaining 44 subjects pColl-I-C and TAP levels correlated significantly with each other (r = 0.70) and both showed the same directional changes and broadly similar correlations with iliac bone formation rate expressed in different ways. In general, pColl-I-C levels correlated better with cancellous bone formation rates and TAP levels cortical bone formation rates. There was a modest improvement in prediction of bone formation rate with multiple regression using both markers. In 15 patients with typical uncomplicated postmenopausal osteoporosis, neither biochemical marker, singly or jointly, correlated significantly with any expression of bone formation rate. Disadvantages to the use of pColl-I-C as a marker include a significant contribution to the serum level from type 1 collagen biosynthesis in tissues other than bone, and (probably) variable metabolic clearance. For both biochemical markers the most consistently high correlations (r = 0.77-0.79) were found with total bone formation rate for the entire biopsy core volume, which is the best estimate available from a biopsy of formation rate at the bone organ level of organization in vivo. The core volume as a referent also allows the amount of bone formed on cortical, endocortical, and cancellous surfaces to be compared. Measurement of serum pColl-I-C levels merits further study as a noninvasive index of bone metabolism. Differences between normal and abnormal subjects in the relationships between a variety of biochemical markers and a variety of histologic indices have the potential for providing insight into the pathogenesis of osteoporosis.

Procollagen type I carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with Iliac bone formation rates and comparison with total alkaline phosphatase.

We describe two new methods for the separation and quantification of the bone and liver isoenzymes of alkaline phosphatase (EC 3.1.3.1) in plasma. In the first, we use wheat-germ lectin to precipitate the bone isoenzyme. About 80% of this, but minimal liver isoenzyme, is precipitated. The activity of the bone isoenzyme is calculated from measuring the alkaline phosphatase activity in the precipitate, that of liver alkaline phosphatase by subtracting the activity of the bone isoenzyme from total alkaline phosphatase activity. The liver fraction will also contain biliary, intestinal, and placental alkaline phosphatase if these are present in the original plasma, but correction for such activity is readily made. In the second method, samples are separated on cellulose acetate membranes that, before electrophoresis, have been soaked in buffer containing wheat-germ lectin. The bone isoenzyme is retarded and clearly separated from the liver fraction, allowing these isoenzymes to be quantified by densitometry. Both methods are rapid, reproducible, and suitable for use in the diagnostic laboratory.

Two new methods for separating and quantifying bone and liver alkaline phosphatase isoenzymes in plasma.

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Two new methods for separating and quantifying bone and liver alkaline phosphatase isoenzymes in plasma.