DIFFERENT EFFECTS OF BISPHOSPHONATE AND ESTROGEN THERAPY ON FREE AND PEPTIDE-BOUND BONE CROSS-LINKS EXCRETION

We have measured the free and peptide-bound type I collagen cross-link excretions in normal women and in patients with metabolic bone diseas e using the HPLC technique and immunoassays recognizing specifically t he free or peptide-bound forms of pyridinoline (Pyr). After menopause, free deoxypyridinoline free D-Pyr) excretion measured by HPLC without urine hydrolysis and expressed as a fraction of the total excretion w as lower than in premenopausal women (45 +/- 15% vs. 59 +/- 12%, p < 0 .005), whereas the fraction of free Pyr was not changed. In normal pre - and postmenopausal women (n = 43), the fraction of free D-Pyr was ne gatively correlated with bone turnover rate as assessed by the total u rinary excretion of Pyr (r = -0.64, p < 0.001). In patients with a var iety of metabolic bone diseases characterized by increased bone turnov er (osteoporosis, Paget's disease, and hyperthyroidism), the fractions of free Pyr and free D-Pyr were significantly lower than in premenopa usal controls (p < 0.001 for all diseases). After 3 days of intravenou s (iv) treatment with the bisphosphonate pamidronate in patients with Paget's disease and osteoporosis, the urinary excretion of cross-linke d peptides measured by high performance liquid chromatography (HPLC) o r enzyme-linked immunoassay (ELISA) (NTX and CrossLaps(TM)) was marked ly decreased (-52% and -85% for NTX, -71% and -93% for CrossLaps(TM) i n Paget's disease and osteoporosis, respectively). The excretion of to tal cross-links was decreased to a lesser extent after treatment (-25% and -25% for total Pyr, -37% and -45% for total D-Pyr) and, surprisin gly, free cross-links measured either by HPLC without urine hydrolysis or with an ELISA specific for free D-Pyr were unchanged after treatme nt. In contrast to bisphosphonate therapy, estrogen treatment of postm enopausal women decreased not only total and cross-linked peptides but also the free cross-link excretion that was seduced by about 30-40%. The different effects of bisphosphonate and estrogen therapy on the ex cretion of peptide-bound and free cross-link excretion were confirmed by gel filtration of the urine on Sephadex G 25 before and after treat ment. In conclusion, we have shown that increased bone turnover in pat ients with metabolic bone disease could result in a larger increase of the urinary excretion of cross-linked peptides over the increase of f ree cross-links. Bisphosphonate therapy decreased markedly cross-linke d peptides without significant change in free cross-link excretion con trasting with a decrease of both free and peptide-bound cross-links af ter estrogen therapy. These data suggest that these two antiresorptive therapies may affect differently the pattern of bone collagen degrada tion, an intriguing possibility that should be further investigated in vitro.