Accelerated menopausal changes as disease model for development of osteoarthritis, focum

Abstract

Purpose: After the age of fifty years, the percentage of females with degenerative disorders, including osteoarthritis (OA), increases rapidly It has been suggested that menopause, and the change in hormones during menopausal transition, influences the development of these disorders During menopausal transition, not only the hormone levels change, but also metabolism and inflammatory responses Investigating the influence of menopausal changes, including protein change, on the development of degenerative disorders is difficult, because these changes occur slowly However, identifying these changes is crucial to develop novel female-specific prevention strategies and therapies for these disorders Therefore, we propose the use of an unique and novel human model to investigate the influence of menopause on the development of degenerative disorders by modelling a “sudden menopause”, in which we expect that menopausal-related changes will occur faster: the Females discontinuing Oral Contraceptives Use at Menopausal age (FOCUM) model This model does not have the limitations in generalizability of animal models Nor does it have the limitations of subsequent hormonal support, malignancy and its associated treatments that are pertinent to human models with a sudden menopause caused by ovariectomy The aim of our study is to develop the FOCUM model as a disease model for the development of OA We want to identify when changes, especially in proteins, occur after a “sudden menopause” and which of these changes are associated with the development of OA after two years Furthermore, we want to explore if the model can also be used to learn more about the development of cardiovascular diseases, diabetes, osteoporosis and tendinopathies In this abstract we will report on the feasibility of our inclusion Our aim is to include 50 female participants from the general population in and nearby Rotterdam within one year Methods: Our study design is a pilot observational prospective cohort study with two years of follow-up Our main questions for this pilot study are: will the inclusion of participants be feasible and what are the important time points to find changes in proteins? Females between 50 and 60 years of age, who are currently using a combined oral contraceptive and started oral contraceptive use before the age of 45, are recruited from pharmacies and (if necessary) general practices In general, females are advised to stop oral contraceptive use at the age of 52 Females who are willing to stop oral contraceptive use at short term are invited to participate Different measurements are performed before (T0 = 0 to 30 days) and after (T1 = 6 weeks;T2 = 6 months;T3 = 1 year;T4 = 2 years) stopping oral contraceptive use At every time point of measurements a questionnaire is filled in, a normal photograph of both hands is taken and a sample of blood is drawn to measure hormones, proteins, glucose, cholesterol, DNA-methylation and immunological aspects of cells At the first and final time point of measurements, also a physical examination, an radiograph of both hands, an MRI scan of one knee, a DXA-scan, and an ultrasound tissue characterization of one Achilles tendon are performed To establish which time points of measurements are most relevant to find changes in proteins after hormone change, we will examine changes in serum levels of approximately 150 different inflammation and cardiometabolic related proteins by using the Olink-technology at different time points of measurements At the first stage of this study, we will use the Principal Component Analysis on the change in protein levels over time Thereafter, we will test for the association between principal components and hormone change At the second stage of this study, we will relate these principal components to various OA outcomes Results: In January 2020, we sent invitations to 108 local pharmacies to participate in this study At that time, a total of 55 pharmacies were willing to participate The participating pharmacies were asked to search in their own information system to identify all possible eligible subjects, based on age and oral contraceptive use, and to send an invitation letter in their name to these subjects Unfortunately, due to COVID restrictions we started sending these invitation letters by the end of June 2020, four months later than planned Until now, we have sent 534 invitations from 26 pharmacies to possible eligible subjects A total of 107 females replied positively and gave permission to provide them more information about the study After giving information and screening for in- and exclusion criteria, we now have 25 eligible participants who gave informed consent Of them, 16 participants have had their first (baseline) measurements of 2,5 hours at the Erasmus MC With the 29 participating pharmacies left, we expect to reach the targeted number of 50 inclusions by February 2021 and to report about the first stage of this study Conclusions: At this time, we have included half of our study population So the inclusion of 50 female participants for this study within one year seems to be feasible By performing different measurements before and after stopping oral contraceptive use, we will be able to investigate when and which menopausal changes occur and which of these changes can be related to OA With this model we hope to learn more about the influence of menopause on the development of OA, but also of cardiovascular diseases, diabetes, osteoporosis and tendinopathies, in order to develop new prevention strategies and therapies for these diseases