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Tibolone Inhibits Bone Resorption Without Secondary Positive Effects on Cartilage Degradation MA Karsdal*, I Byrjalsen, DJ Leeming and C Christiansen

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Tibolone Inhibits Bone Resorption Without Secondary Positive Effects on Cartilage Degradation MA Karsdal*, I Byrjalsen, DJ Leeming and C Christiansen BMC Musculoskeletal Disorders BioMed Central Research article Open Access Tibolone inhibits bone resorption without secondary positive effects on cartilage degradation MA Karsdal*, I Byrjalsen, DJ Leeming and C Christiansen Address: Nordic Bioscience A/S, Herlev, Denmark Email: MA Karsdal* - [email protected]; I Byrjalsen - [email protected]; DJ Leeming - [email protected]; C Christiansen - [email protected] * Corresponding author Published: 18 November 2008 Received: 30 April 2008 Accepted: 18 November 2008 BMC Musculoskeletal Disorders 2008, 9:153 doi:10.1186/1471-2474-9-153 This article is available from: http://www.biomedcentral.com/1471-2474/9/153 © 2008 Karsdal et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Osteoarthritis is associated with increased bone resorption and increased cartilage degradation in the subchondral bone and joint. The objective of the present study was to determine whether Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties, would have similar dual actions on both bone and cartilage turnover, as reported previously with some SERMS and HRT. Methods: This study was a secondary analysis of ninety-one healthy postmenopausal women aged 52–75 yrs entered a 2-yr double blind, randomized, placebo-controlled study of treatment with either 1.25 mg/day (n = 36), or 2.5 mg/day Tibolone (n = 35), or placebo (n = 20), (J Clin Endocrinol Metab. 1996 Jul;81(7):2419–22) Second void morning urine samples were collected at baseline, and at 3, 6, 12, and 24 months. Urine CrossLaps® ELISA (CTX-I) and Urine CartiLaps® ELISA (CTX-II) was investigated as markers of bone resorption and cartilage degradation, respectively. Results: Tibolone significantly (P < 0.001) suppressed bone resorption by approximately 60%. In contrast, no effect was observed on cartilage degradation. Conclusion: These data suggest uncoupling of the bone and cartilage effects of the synthetic steroid, Tibolone. Bone resorption was significantly decreased, whereas cartilage degradation was unchanged. These effects are in contrast to those observed some SERMs with effects on both bone and cartilage degradation. These effects may in part be described by the complicated pharmacology of Tibolone on testosterone, estrogen and progesterone receptors. Background The relationship between bone and cartilage degradation Osteoarthritis (OA) is the most common form of arthritis in OA is a complex. A apparent co-existence between the [1]. One hallmark of the disease is progressive degenera- two processes exists [2,3], although the cellular and tion of articular cartilage, generation of osteophytes and molecular mechanism remains to be further investigated subsequent joint space narrowing. This progression of dis- and identified [4]. Several groups have demonstrated an ease may involve both bone and cartilage parameters, accelerated incidence of OA in women following meno- which in some instances may be tightly coupled. pause [5,6] which in part may be caused by increased Page 1 of 8 (page number not for citation purposes) BMC Musculoskeletal Disorders 2008, 9:153 http://www.biomedcentral.com/1471-2474/9/153 bone resorption [7,8]. Studies investigating gender and levels has been shown to predict structural progression of age as risk factors of developing OA indicate that OA osteoarthritis under several clinical settings [27]. increases with age and women are at a higher risk than men [9]., which supports the notion that sex hormones As several lines of evidence suggest a tight coupling are related to the incidence of OA. In addition, pre-clinical between bone and cartilage turnover [28], and protective studies in monkeys [10] and rats [11] have shown that effects of estrogens and some SERMs [28], the objective of estrogen depletion results in increased bone turnover, the present study was to determine whether Tibolone, a leading to altered subchondral bone structure and synthetic steroid with estrogenic, androgenic, and pro- decreased articular cartilage integrity. gestogenic properties, would have similar dual actions on both bone and cartilage turnover. In clinical settings a number of studies have provided evi- dence for the coupling between bone and cartilage degra- Methods dation. A selective estrogen-receptor modulator (SERM) This study is a secondary analysis of the effects published was shown to protect against both bone and cartilage deg- previously [21]. Ninety-one healthy postmenopausal radation, by restoring turnover of both compartments to women aged 52–75 yrs entered a 2-yr double blind, rand- pre-menopausal level during a 12 month period [12]. In omized, placebo-controlled study of treatment with either similar context, cartilage degradation was assessed in 384 1.25 mg/day (n = 36), or 2.5 mg/day tibolone (n = 35), or postmenopausal women, and was found to be signifi- placebo (n = 20) as previously described [21]. Second cantly lower in women using hormone replacement ther- void morning urine samples were collected at baseline, apy (HRT) compared to control [6,12], and the cartilage and at 3, 6, 12, and 24 months. The biochemical marker degradation was significantly higher in postmenopausal CTX-II was measured in urine by Urine CartiLaps® ELISA women when compared to an age-matched group of pre- (Nordic Bioscience A/S) as marker of cartilage degrada- menopausal women [6]. tion. Tibolone is a synthetic steroid [(7-α,l7-α & 17-hydroxy-7- As described in the original publication, [21], after being methyl-l9-norpregn-5(1O)-en-20-yn-3-one, Org OD 14, introduced thoroughly about the trial, participants gave Livial, Organon, The Netherlands] with a combination of their informed consent to participate (Helsinki Declara- estrogenic, androgenic, and progestogenic properties, is tion II). The study was approved by the ethical committee capable of relieving climacteric symptoms [13-15] with of Copenhagen County, Denmark. almost no stimulatory effect on the endometrium [16]. Tibolone is metabolized in the intestine and liver into 3 Statistical analysis active metabolites: 3α- and 3β-hydroxy metabolites and To assess longitudinal changes, the values were calculated Δ4-7alpha-methylnorethisterone. The first two metabo- for each person and expressed as the percentage of the ini- lites bind to estrogen receptors, primarily ERα receptors, tial baseline value. The data of the creatinine-corrected and have estrogenic effects on bone, thermoregulatory values of CTXI and CTXII, and the relative changes were centers in the central nervous system, and the vagina [17- logarithmically transformed to obtain normality and sym- 19]. The Δ4-7alpha-methylnorethisterone metabolite metry of variances. The trapezoidal method was applied binds to the progesterone and androgen receptors. Tibo- for calculation of the time-averaged mean change from lone is primarily used to treat women with climacteric baseline. Analysis of variance (ANOVA) was used for com- complaints for whom bleeding is unacceptable, or who parison of baseline data between treatment groups. The have experienced side-effects during conventional HRT. two-tailed Student's t-test was applied for pairwise com- The estrogenic characteristics of tibolone imply an estro- parison of data from the active treatment groups with pla- gen-like effect on bone as well, which have been docu- cebo. mented and characterized previously [20,21]. For all tests p < 0.05 was considered significant. All statis- Bone and cartilage degradation can be assed by biochem- tical calculations were performed using the SAS software ical markers. Bone resorption by osteoclasts is for the package (release 9.1, SAS Institute Inc., Cary, NC, USA). major part mediated by the protease cathespin K, which results in the specific degradation fragment of collagen Results type I, CTX-I [22,23]. CTX-I fragments have been used as Table 1 shows the baseline demographic data of the par- a surrogate measure of bone resorption for in vitro, pre- ticipants within each treatment group who completed the clinical and clinical studies [22,24]. With respect to carti- 2-year study protocol as published previously [21]. The lage degradation, CTX-II, is a matrix metalloprotease group receiving 2.5 mg of tibolone was of slightly higher (MMP) generated fragment of collagen type II which is height (p = 0.04). In all other aspects of age, weight, BMI, predominately found in articular cartilage [25,26]. CTX-II years since menopause, and the biochemical markers of Page 2 of 8 (page number not for citation purposes) BMC Musculoskeletal Disorders 2008, 9:153 http://www.biomedcentral.com/1471-2474/9/153 Table 1: Values shown are mean (SD) or ageometric mean (± 1 SD range) Placebo 1.25 mg 2.5 mg (n = 13) (n = 29) (n = 28) Age (yrs) 68.3 (6.0) 66.5 (7.0) 64.0 (6.7) YSM (yrs) 20 (6.2) 19.6 (6.1) 17.5 (6.5) Height (cm) 158.5 (5.3) 159.7 (5.9) 162.9 (6.1) Weight (kg) 61.8 (6.8) 62.5 (9.5) 61.1 (6.8) BMI (kg/m2) 24.7 (3.2) 24.5 (3.4) 23.1 (2.8) aCTXI (μg/mmol) 0.26 (0.18–0.37) 0.32 (0.21–0.49) 0.31 (0.22–0.45) aCTXII (μg/mmol) 0.13 (0.08–0.26) 0.17 (0.09–0.32) 0.13 (0.07–0.24) urinary CTX-I and CTX-II there were no significant differ- cartilage degradation that may have become statistical sig- ences among the groups. nificant if more samples had been available was observed. These data indicate that the tight coupling between bone The effect of tibolone on bone resorption and cartilage metabolism can be disassociated under Bone resorption was investigated by measurement of uri- some circumstances. This uncoupling is an important dif- nary CTX-I during the 2 years of therapy every 3rd month ference compared to that other estrogen like molecules in the groups receiving 2.5 mg or 1.25 mg of tibolone, or and SERMS that have displayed protective effects on both placebo.
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