Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: The OFELY prospective study

The Asp(1211) residue of the (1209)AHDGGR(1214) sequence of the C-terminal cross-linking telopeptide of type I collagen (CTX) can undergo spontaneous post-translational modifications, namely, racemization and isomerization, which result in the formation of four isomers: the native form (a-L) and three age-related forms, that is, an isomerized form (beta-L), a racemized form (alpha-D), and an isomerized/racemized (beta-D) form. Previous studies have suggested that changes in the pattern of type I collagen racemization/isomerization, which can be assessed in vivo by measuring the degradation products of the CTX isoforms, may be associated with alterations of bone structure. The aim of this study was to examine prospectively the value of the different urinary CTX isoforms and their related ratio in the prediction of osteoporotic fractures in 408 healthy untreated postmenopausal women aged 50-89 years (mean, 64 years) who were part of the OFELY cohort. During a median 6.8 years follow-up, 16 incident vertebral fractures and 55 peripheral fractures were recorded in 65 women. The baseline levels of the four CTX isoformrs in women who subsequently had a fracture were compared with those of the 343 women who did not fracture. At baseline, women with fractures had increased levels of ratios of native alpha-L-CTX to age-related isoforms (beta-L, alpha-D, and beta-D) compared with controls (p < 0.01). In logistic regression analysis after adjustment for age, prevalent fractures, and physical activity, women with levels of alpha-L/beta-L, alpha-L/alpha-D, and alpha-L/beta-D-CTX ratios in the highest quartile had a 1.5-to 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 2.0 (1.2-3.5), 1.8 (1.02-2.7), and 1.5 (0.9-2.7), respectively. Adjustment of alpha-L/beta-L and alpha-alpha/alpha-D-CTX ratios by the level of bone turnover assessed by serum bone alkaline phosphatase (ALP)- or femoral neck bone mineral density (BMD) decreased slightly the RR, which remained significant for the alpha-L/beta-L-CTX ratio (RR [95%] CI, 1.8 [1.1-3.2] after adjustment for bone ALP, 1.8 [1.03-3.1] after adjustment for BMD, and 1.7 [0.95-2.9] after adjustment for both bone ALP and BMD). Women with both high alpha-L/beta-L-CTX ratio and high bone ALP had a 50% higher risk of fracture than women with either one of these two risk factors. Similarly, women with both increased CTX ratio and love femoral neck BMD (T score < -2.5) had a higher risk of fracture with an RR (95% CI) of 4.5 (2.0-10.1). In conclusion, increased urinary ratio between native and age-related forms of CTX, reflecting decreased degree of type I collagen racemization/isomerization, is associated with increased fracture risk independently of BMD and partly of bone turnover rate. This suggests that alterations of type I collagen isomerization/racemization that can be detected by changes in urinary CTX ratios may be associated with increased skeletal fragility.