JOURNAL OF BONE AND MINERAL RESEARCH Volume 8, Number 2, 1993 zyxwvutsr Mary Ann Liebert, he., Publishers zyxwvutsrqp Serum Markers of Type I Collagen Formation and Degradation in Metabolic Bone Disease: Correlation with Bone Histomorphometry ERIK F. ERIKSEN,' PEDER CHARLES,' FLEMMING MELSEN,' LEIF MOSEKILDE,' LEILA RISTELI,2 and JUHA RISTELP ABSTRACT Type I collagen makes up more than zyxwvu 90% of bone matrix. Therefore, analysis of antigens related to collagen formation and degradation in bone should provide good and specific estimates of both bone resorption and bone formation rates. In this study we measured serum levels of the pyridinoline cross-linked telopeptide do- main of type I collagen (ICTP) as a marker of bone resorption and serum carboxy-terminal propeptide of type I procollagen (PICP) as a marker of bone formation. Serum levels of the two antigens were correlated to histomorphometric indices of bone resorption and bone formation calculated from iliac crest bone biop- sies in a group of 18 individuals with high- and low-turnover bone disease (myxedema, primary hyperpara- thyroidism, and thyrotoxicosis). After logarithmic transformation the regression of S-ICTP on volume-ref- erent resorption rate (BRs/R/BV) was significant zyxwvu (r zyxwvu = 0.61, p < 0.01, SEM/Y = 56%). S-ICTP also showed a significant regression on the volume-referent cancellous bone balance (r = -0.45, p < 0.05, SEM/Y = 412%). S-PICP was significantly correlated to the mineral appositional rate (r = 0.53, p < 0.05) and volume-ref- erent bone formation rate (r = 0.61, p < 0.01, SEM/Y = 48%). The correlation to bone turnover as ex- pressed in the activation frequency was also highly significant (r = 0.61, p < 0.01, SEM/Y = 51%). No sig- nificant correlation with wall thickness or bone balance was demonstrable per remodeling cycle. Thus, as- says employing antigens that reflect collagen formation and degradation are useful instruments for the eval- uation of rates of bone remodeling in metabolic bone disease. INTRODUCTION YPE I COLLAGEN is the main constituent of bone matrix. T The precursor molecule type I procollagen is synthe- sized intracellularly and contains both amino-terminal and carboxy-terminal trimeric extension domains, known as propeptides (PINP and PICP, respectively). ('-') PICP has a molecular weight around 100,OOO and is therefore not subject to excretion by glomerular filtration. The carboxy- terminal propeptide is split off the collagen molecule be- fore formation of the collagen fibril, and the production rate of this propeptide (S-PICP) therefore reflects the for- mation rate of collagen molecules on a stoichiometric basis. ('-') Since purification of the propeptides is demand- ing with respect to both the chromatographic methods ap- plied and the availability of starting material, only one clinically useful assay for PICP has been established. The degradation pathways and the intermediates of bone collagen digestion are not known in detail. We have recently observed, however, that during collagen type I degradation the carboxy-terminal cross-linked telopeptide region (ICTP) is liberated into the serum as an immuno- logic intact fragment, which resists further degradation. This trimeric antigen constitutes the type I collagen-de- 'Aarhus Bone and Mineral Research Group, University Department of Endocrinology and Metabolism, Aarhus Amtssygehus, 'Departments of Medical Biochemistry and Clinical Chemistry, University of Oulu, Finland. Denmark. 127