ABSTRACT
Purpose: After the age of fifty years, the incidence of osteoarthritis (OA) increases rapidly in women, suggesting an effect of menopause on the development of OA. Because it is still unclear how menopause precisely influences the development of OA, we aim to investigate this in a novel human model: the Females discontinuing Oral Contraceptives Use at Menopausal age (FOCUM) model. This model consists of women between fifty and sixty years of age, who are currently using a combined oral contraceptive (OC) and aim to stop OC use at short term. When these women stop using OC, a rapid change in hormones is expected, modelling a “sudden menopause”. Therefore, this model provides an opportunity to study changes occurring during menopausal transition. Because the FOCUM model is new, it is unknown if women want to participate, are willing to stop OC use shortly, and will not start hormone replacement after stopping OC use. Therefore, we aim to investigate the feasibility of the FOCUM study. We define the study to be feasible when: 1) 50 participants are included within one year and received their baseline measurements (including questionnaires, blood samples and Magnetic Resonance Imaging (MRI) assessments), 2) the loss of follow-up at 6 weeks is less than 5%, and 3) no hormone replacement therapy is used by the participants at 6 weeks follow-up. Methods: For the inclusion of participants, pharmacies in and nearby Rotterdam were invited to participate. Pharmacies were asked to search in their information systems to identify all possible eligible subjects, based on age and OC use. All eligible subjects received an invitation letter with information about the study. Interested subjects were contacted by the researchers for more information. Inclusion criteria were: 1) woman, 2) between 50 and 60 years of age, 3) currently using a combined OC (with Anatomical Therapeutic Chemical (ATC) code G03AA or G03AB), and 4) started OC use before the age of 45. Exclusion criteria were: 1) already known with osteoarthritis (self-reported or registered by their general practitioner), 2) already known with another inflammatory rheumatic condition, 3) having a contra-indication for MRI assessment, 4) having a terminal or mental illness, and 5) not being able to give informed consent. In this study, measurements are performed at baseline, just before stopping OC use (T0 = 0 to 30 days), and after (T1 = 6 weeks;T2 = 6 months;T3 = 1 year;T4 = 2 years) stopping OC use. At every time point, a digital questionnaire is filled in and a blood sample is drawn. At T0 and T4, also an MRI of one of the knees is performed. Results: In January 2020, invitations were sent to 106 pharmacies of which 48 were willing to participate. Due to COVID restrictions, the first invitations to possible eligible subjects were sent in July 2020. Until April 2021, a total of 1037 invitation letters were sent. 206 subjects replied positively, of which 175 were screened by the researchers. After screening for in- and exclusion criteria, 85 subjects were eligible. The most common reason why subjects were not eligible, was because they did not use their OC anymore. Eventually, 54 subjects gave informed consent and were all seen for their baseline measurements between August 2020 and July 2021. All baseline questionnaires, blood samples and MRI assessments were available. At 6 weeks follow-up, all 54 subjects were still participating in the study. From one participant the blood sample has not been drawn at 6 weeks follow-up and one participant started hormone replacement therapy after baseline measurements (see flowchart 1). [Formula presented] Conclusions: We reached the number of 54 participants within one year, which is more than the initially targeted number of 50. All baseline measurements, including questionnaires, blood samples and MRI assessments, have been collected from these 54 participants. At 6 weeks follow-up, there was no loss of follow-up, of one participant no blood sample was available and one participant started hormone replacement therapy. Therefore, we conclude that the FOCUM study is feasible. The next step will be to investigate differences in cardiometabolic and inflammatory biomarkers, joint complaints and structural OA features between baseline and follow-up measurements.
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.