KUOPIO OSTEOPOROSIS RISK FACTORS AND PREVENTION COHORT (OSTPRE) (STUDY 2)

4.2.1 Study population and design

Study 2 of this thesis is based on the 20 years’ postal questionnaire based follow-up of the population of the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort (Figure 6). The first self-administered baseline postal questionnaire was sent to all women aged 47-56 years who were residents of Kuopio Province, Eastern Finland (n= 14 220) in February 1989. A total of 13 100 (92.1%) women responded.

Subsequently the 5 year up in 1994, 10 year up in 1999, 15 year follow-up in 2004, and 20 year follow-follow-up in 2009 were mailed to the 13 100, 12 562, 12 075, and 11 420 women respectively. A total of 11 954 (91.2%), 11 538 (91.8%), 10 926 (90.4%) and 8195 (71.8%) women responded to the 5, 10, 15, and 20 year follow ups respectively. The questionnaires were sent to women who had responded to the baseline inquiry, were alive, and had a valid postal address at that time (Figure 7).

Figure 6: Flow-chart of the Kuopio Osteoporosis risk factors and Prevention cohort (OSTPRE) The study population of the present study included those 8195 women for whom we had complete data on confounders and self-reported HT exposure. Outcome data and register-based exposure data were available for all participants (Figure 7).

Figure 7: Study population of Kuopio Osteoporosis Risk Factors and Prevention Cohort (Study 2)

0 2 000 4 000 6 000 8 000 10 000 12 000 14 000 16 000

1989 1994 1999 2004 2009

Sent 14 220 13 100 12 562 12 075 11 420

Received 13 100 11 954 11 538 10 926 8195

Number of questionnaires

Postal questionnaire sent to all 47-56 year old women who were resident of Kuopio Province in February 1989 (n=14,220)

Returned Baseline questionnaire n= 13,100

Study 2 sample (n=8195)

Baseline questionnaire not obtained (n=1120)

Missing data on any confounder, n=4905

Sensitivity analysis among those with data on education, n= 2383

4.2.2 Exposure data

In examining the association of postmenopausal HT use with risk of AD, data on HT use was collected in two ways; first, reported HT use was taken from self-administered questionnaires over 20 years; second, HT use was ascertained from registers.

Self-reported HT use was recorded as lifetime use in years (and indication of use) at the baseline inquiry in 1989. In all follow-up questionnaires, numbers of months per year of estrogen use were reported and the duration of self-reported estrogen use was calculated on the basis of these questionnaires. Self-reported use of estrogen was categorized into post-menopausal HT based on the use after the onset of the menopause.

In order to exclude the possibility of recall bias in the self-reported questionnaires, we accessed the prescription register data to ascertain HT use. HT was defined from the registry as those preparations having systemic estrogenic properties belonging to the following codes in the ATC classification: G03C (estrogens), G03F (estrogen and progesterone) excluding oral contraceptives. Duration of medication (HT) use was calculated based on prescription purchased data. ATC codes for each purchase history were processed for each individual. Purchase history was used to calculate defined daily dose which could be used to determine exposure period for each drug. The prescription register does not cover drugs used in public nursing homes or during stay in hospitals (Tolppanen et al., 2016).

4.2.3 Outcome data

The main outcome of study 2 was a clinically verified AD diagnosis. These diagnoses from the years 1999-2009 were identified from the Finnish Special Reimbursement Register maintained by the Social Insurance Institution. The contents of the register have been described above. A sensitivity analysis with any dementia as an outcome was also performed.

Dementia diagnoses were extracted from the National Hospital Discharge register using the following ICD-10 codes: F00-03 (F00-Dementia in Alzheimer’s disease; F01-vascular dementia; F02-Dementia in other diseases classified elsewhere; F03-Unspecified dementia) and G30 (Alzheimer’s disease-early/late onset). This register includes all inpatient admissions, as mandated by law. Main and auxiliary diagnosis codes for each admission had been made by the attending physician. All Finnish citizens/long-term residents are covered by tax-supported public health service so the coverage is not restricted by non-medical factors e.g. ability to pay for medications.

4.2.4 Covariables

Data on BMI, menopause status, physical activity, education, smoking, occupation status, alcohol use, and health disorders diagnosed by a physician, and gynecological history were inquired in baseline questionnaires and then repeated in all of the following questionnaires.

A woman was considered postmenopausal if ≥ 12 months had passed since her last natural menstrual cycle; if she had undergone surgical menopause through bilateral oophorectomy with or without hysterectomy; or if the time since menopause and the history of HT use could be clarified from the follow-up questionnaire. BMI was calculated as the ratio of weight in kilograms to height in meters squared. Physical activity was inquired through self-reported data in three ways at baseline and in all follow-up surveys as: leisure time physical activity as well as asking about how

physically demanding their work had been in the last year; ambulatory status as capability and extent of movement, need of aids in movement, and history of joint degeneration; amount of physical activity including winter and summer activities, amount of current regular physical activity and its duration (hours per week).

Data on education was available from a sub-cohort only; these individuals had undergone a bone mineral density measurement (n=2383). History of ever/never smoking was asked in all self-reported questionnaires along with regularity of smoking, number of years of smoking, and number of cigarettes smoked per day. Data on occupation was gathered under 9 different categories but then dichotomized into

“employed” and “unemployed”. Alcohol consumption was inquired as the amount of alcohol beverages consumed during a one-month period and converted into grams of alcohol intake per month.

At baseline, women were asked about the age at menarche, age at menopause, number of pregnancies, number of live births, and abortions. Abortion was inquired in questionnaire as “Number of times to interrupt pregnancies due to abortion/miscarriage”. A history of any gynecological operations (caesarian sections and sterilizations) was also obtained, as well as what, if anything, had been removed in these operations (uterus, ovary, part of both, cervix, or other parts of genitals).

4.3 CARDIOVASCULAR RISK FACTORS, AGING AND DEMENTIA