Measurement of urinary excretion of nonisomerized and beta-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget's disease.
OBJECTIVE
We have previously shown that the woven pagetic bone in patients with Paget's disease is characterized by an impaired degree of beta-isomerization of C-telopeptides of type I collagen molecules, which results in a preferential urinary excretion of nonisomerized type I collagen C-telopeptide breakdown products (CTX). The aim of this study was to measure the urinary excretion of nonisomerized (alpha) and beta-isomerized (beta) CTX in patients with Paget's disease treated with a bisphosphonate.


METHODS
We studied 28 patients with active Paget's disease of bone who were a part of a randomized, double-blind, placebo-controlled study comparing the effects of several doses of a single injection of zoledronate, a new potent bisphosphonate. Serum bone alkaline phosphatase (BAP) and type I collagen C-terminal extension propeptide (PICP) and urinary excretion of free deoxypyridinoline (free D-Pyr), N-telopeptide breakdown products (NTX), alphaCTX, and betaCTX were measured at baseline and 5, 10, 30, and 60 days after injection.


RESULTS
At baseline, all markers were significantly increased in the patients compared with a group of 97 sex- and age-matched controls, with a greater increase in BAP (12-fold), NTX (19-fold), and alphaCTX (10-fold) compared with PICP (2.2-fold), free D-Pyr (2.5-fold), and betaCTX (3-fold). The ratio of alphaCTX to betaCTX was about 3-fold higher than in controls (2.1 versus 0.76; P < 0.001). After a single intravenous injection of zoledronate (200 or 400 microg), all markers decreased within 5 days, except for BAP and free D-Pyr, which decreased on day 10. The maximum decrease was greater and occurred faster for NTX, alphaCTX (-55% after 10 days), and betaCTX (-42% after 10 days) than for free D-Pyr (-25% after 30 days). After the initial decrease, the urinary excretion of betaCTX increased between days 10 and 30 and returned to pretreatment levels after 2 months, in contrast to the sustained decrease in alphaCTX and NTX that was maintained up to 60 days. The urinary ratio of alphaCTX to betaCTX decreased significantly between days 10 and 60, and returned to within the normal range in most patients after 2 months of treatment, probably reflecting the progressive replacement of woven bone by a lamellar bone with a higher and normal degree of beta-isomerization of type I collagen, as previously documented by histology.


CONCLUSIONS
The determination of the urinary ratio of alphaCTX to betaCTX could be useful for monitoring the effect of bisphosphonate treatment in restoring bone quality in patients with Paget's disease.
Garnero
P
P
INSERM, Lyon, France.
Gineyts
E
E
Schaffer
A V
AV
Seaman
J
J
Delmas
P D
PD
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001842:Bone and Bones / Q000378:metabolism; D003094:Collagen / Q000097:blood / Q000378:metabolism* / Q000652:urine*; D024042:Collagen Type I; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007536:Isomerism; D008297:Male; D008875:Middle Aged; D010001:Osteitis Deformans / Q000097:blood / Q000188:drug therapy* / Q000652:urine*; D010455:Peptides / Q000097:blood / Q000652:urine*; D014556:Urine / Q000737:chemistry*; D000077211:Zoledronic Acid
D015415:Biomarkers; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000077211:Zoledronic Acid; D003094:Collagen