The FOCUM human disease model for development of osteoarthritis

In 2016, approximately 1,25 million people in the Netherlands were registered
in primary care with the diagnosis osteoarthritis (OA) of the knees, hips or
hands. At present 1.4% (110 million euro) of the Dutch healthcare cost are due
to OA, of which 71% are made for women. The National Institute for Public
Health and Environment (RIVM) estimated that by 2040 the numbers for OA will
have doubled and that OA becomes the most prevalent disease in the Netherlands.

The prevalence of OA sharply increases in women compared to men after the age
of 50, which suggests a role of menopause. However, the role of menopause is
still diffuse and insufficiently investigated. There are a few pathways that
emerge from literature, which could explain the rise in OA after menopause.
These hypothetical pathways include: fat metabolism, activation of the innate
immune system, collagen content of connective tissues including the
accumulation of Advanced Glycation End products (AGEs), and subchondral bone
remodelling. These pathways undergo changes after menopause and thus underscore
the likelihood for female specific pathways that lead to OA.

Studying the influence of menopause on the development of OA is hampered by the
slow hormonal changes during menopausal transition. Sudden drop in estrogen do
occur after ovariectomy, but is accompanied by a pronounced androgen drop as
well. Other drawbacks of ovariectomy as a human model is the subsequent
hormonal replacement therapy (HRT), the malignancy and its associated
treatments. Currently used animal models (often mice) for menopause are mostly
based on ovariectomy. Apart from the ethical drawbacks, these models are
limited in validity due to the obvious metabolic differences between mice and
humans and differences in changes of sex hormones.

Identifying the female specific pathways in the development of OA is however
crucial to develop novel prevention strategies and therapies for OA. Therefore
we propose an unique and highly innovative human model for sudden menopause:
Females discontinuing Oral Contraceptives Use at Menopausal age (FOCUM). This
model does not have the limitations in generalizability of animal models and
the results are immediately relevant.

The model consists of women who use long-term oral contraceptives (OC) into
their fifties and are willing to stop OC use at short term. This will introduce
a sudden change in hormones, modelling sudden menopause. This allows us to
study the changes that occur immediately after a rapid change in hormones.
Linking these changes to OA outcomes, we will be able to determine which female
specific pathways are activated after sudden menopause that lead to OA. This
will yield potential and promising targets for prevention strategies and
therapies to decrease the disease burden of OA in women at least towards that
in men. The FOCUM model will also be relevant for other menopause-related
diseases like cardiovascular diseases, diabetes, osteoporosis and
tendinopathies.

The primary objective of this study is to develop the FOCUM human disease model
for development of OA. The secondary objective is to identify which changes
after sudden menopause are associated with the development of OA after two
years.

The study design is an observational prospective cohort study with two years
follow-up (pilot study). Participants will be recruited from general practices
and pharmacies. Participants will be invited to the Erasmus MC five times: at
baseline (0 to 30 days before stopping OC use) and at six weeks, six months,
one year and two years after stopping OC use. Each time point of measurement
will contain a questionnaire, a photography of both hands and a sample of blood
by vena puncture. At baseline and two years follow-up other measurements will
be performed: physical examination, X-ray of both hands, MRI of one knee,
DEXA-scan and ultrasonography of one Achilles tendon.

The burden for the participants will be nine hours spread out over two years
and there is a little risk for their health due to the X-rays of the hands and
the DEXA-scans.