The effect on cartilage of different forms of application of postmenopausal estrogen therapy: comparison of oral and transdermal therapy Pernille Ravn a, * , Lise Warming a , Stephan Christgau b , Claus Christiansen a a Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark b Nordic Bioscience, Osteopark, Herlev Hovedgade 207, DK-2730 Herlev, Denmark Received 2 June 2003; revised 10 May 2004; accepted 26 July 2004 Available online 27 September 2004 Abstract The effect on urine C-telopeptides of type II collagen (uCTX-II) of oral and transdermal estradiol treatment was compared using samples from two randomized, double-blind, placebo-controlled trials. A total of 171 healthy, Danish postmenopausal women, 45–65 years of age completed the 2-year study periods. The uCTX-II marker assessed cartilage degradation, and this response was compared with the effect on urine C-telopeptides of type I collagen (uCTX-I), considered a specific marker of bone resorption. Doses in the oral estradiol treatment groups (continuous combined therapy) were 1 mg 17-h-estradiol + 1 mg drosperinone or 1 mg 17-h-estradiol + 2 mg drosperinone or 1 mg 17-h-estradiol + 3 mg drosperinone or placebo. Doses in the transdermal estradiol treatment groups (continuous combined therapy) were 45 Ag 17-h-estradiol + 30 levonorgestrel or 45 Ag 17-h-estradiol + 40 Ag levonorgestrel or placebo. The effect of oral and transdermal estradiol therapy on cartilage degradation was reflected as a decrease of 19–30% in uCTX-II ( P = 0.02 and P = 0.003 vs. placebo) after 1 year of treatment. uCTX-I decreased 70% ( P b 0.0001 vs. placebo) reflecting a pronounced effect on bone resorption that was consistent with a 2- year increase in spine and hip BMD of 7–8% and 4–6%, respectively. The results indicate that different regimens of postmenopausal HRT both have an effect on cartilage and bone thus protecting against osteoporosis and osteoarthritis (OA). However, long-term clinical trials are needed to further investigate this issue. D 2004 Elsevier Inc. All rights reserved. Keywords: CTX-I; CTX-II; Cartilage degradation; Postmenopausal women; Estradiol Introduction Osteoarthritis (OA) is a chronic and debilitating disease characterized by degradation of joint cartilage. In the Western world, at least 10% of the population has symptoms of OA, and the condition is one of the leading disabilities in the Western world [1]. Despite the high prevalence of OA, current diagnostic tools for assessing structural damage of affected joints are not very sophisticated. The diagnosis and follow-up on progression relies on assessing radiographic changes such as narrowing of joint space, osteophytes, and sclerosis of subchondral bone [2]. Although efforts have been made to standardize scoring methods for assessing these variables, they remain difficult to quantify, and extended follow-up periods are needed to see significant changes on successive radiographs [2]. With the aim of improving the diagnosis and monitoring of diseases affecting the joint cartilage, we have recently developed an immunoassay for measurement of the urinary concentration of collagen type II C-telopeptide degradation products (uCTX-II) [3]. Type II collagen is almost exclusively localized in cartilage where it is the major structural component of the tissue. Hence, fragments derived from the protein represent a specific marker of cartilage turnover [3]. It has long been recognized that estrogen replacement therapy (ERT) has a significant effect on postmenopausal symptoms [4] and bone turnover [5,6] in postmenopausal women. Furthermore, several studies have suggested that 8756-3282/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2004.07.017 * Corresponding author. Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark. Fax: +45 4468 4220. E-mail address: CCBR _ Ballerup@CCBR.DK (P. Ravn). Bone 35 (2004) 1216 – 1221 www.elsevier.com/locate/bone