Objective: Bone turnover markers (BTMs) predict fracture in older women, whereas data on younger women are lacking. To test the hypothesis that BTMs measured before and after menopause predict fracture risk, we performed a cohort study of 2,305 women.
Methods: Women attended up to nine clinic visits for an average of 7.6 ± 1.6 years; all were aged 42 to 52 years and were premenopausal or early perimenopausal at baseline. Incident fractures were self-reported. Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen (NTX) were measured at baseline. NTX was measured at each annual follow-up. Interval-censored survival models or generalized estimating equations were used to test whether baseline BTMs and changes in NTX, respectively, were associated with fracture risk. Hazard ratios (HRs) or odds ratios were calculated with 95% CIs.
Results: Women who experienced fractures (n = 184) had about a 10% higher baseline median NTX (34.4 vs 31.5 nanomoles of bone collagen equivalents per liter per nanomole of creatinine per liter; P = 0.001), but there was no difference in osteocalcin. A 1-SD decrease in lumbar spine bone mineral density (BMD) measured premenopausally was associated with a higher fracture risk during menopause (HR, 1.50; 95% CI, 1.28-1.68). Women with a baseline NTX greater than the median had a 45% higher risk of fracture, multivariable-adjusted (HR, 1.46; 95% CI, 1.05-2.26). The HR of fracture among women with both the lowest spine BMD (quartile 1) and the highest NTX (quartile 4) at baseline was 2.87 (95% CI, 1.61-6.01), compared with women with lower NTX and higher BMD. Women whose NTX increased more than the median had a higher risk of fracture (odds ratio, 1.51; 95% CI, 1.08-2.10). Women who had baseline NTX greater than the median experienced greater loss of spine and hip BMD.
Conclusions: A higher urinary NTX excretion measured before menopause and across menopause is associated with a higher risk of fracture. Our results are consistent with the pathophysiology of transmenopausal changes in bone strength.
From the 1Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA; 2University of California, Los Angeles, Los Angeles, CA; 3Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA; 4Division of Research, Kaiser Permanente Northern California, Oakland, CA; 5School of Medicine, University of Pittsburgh, Pittsburgh, PA; and 6University of Michigan, Ann Arbor, MI.
Received December 2, 2011; revised and accepted March 1, 2012.
Funding/support: The Study of Women’s Health Across the Nation receivedgrant support from the National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging, the National Institute of Nursing Research, and the NIH Office of Research on Women’s Health (grants NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, and AG012495). Measures of cross-linked N-telopeptide of type I collagenwere funded by the Swiss Precision Diagnostics Development Company Limited Priory (Business Park Bedford, UK) under the direction of Dr. Sarah Johnson. This work was also supported by Department of Defense grant DAMD17-96-6118; NIH grant K24-DK02759 (to J.S.F.); the Iris Cantor-University of California, Los Angeles Women’s Health Center; University of California, Los Angeles Center of Excellence in Women’s Health grant RFP 282-97-0025 (to G.A.G.); and NIH grant RR-1066 (to Massachusetts General Hospital, Boston, MA).
Financial disclosure/conflicts of interest: Dr. Cauley has received research support and consulting fees from Novartis Pharmaceuticals and Merck. Drs. Chang, Crandall, Danielson, Lo, Finkelstein, Greendale, Neer, Prairie, and Ruppert, as well as Ms. Meyn, have no conflicts of interest to report. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging, the National Institute of Nursing Research, the Office of Research on Women’s Health, or the NIH.
Address correspondence to: Jane A. Cauley, DrPH, Department of Epidemiology, University of Pittsburgh, 130 DeSoto Street, Crabtree A510, Pittsburgh, PA 15261. E-mail: firstname.lastname@example.org