Pharmacology Journal

Menopause is accompanied by accelerated bone loss, and increasing incidence of fractures. Several studies have shown that hormone replacement therapy (HRT) can reduce bone loss, increase bone mineral density, and decrease the risk of fracture. However, the duration of treatment needed and of the protective effect after treatment is stopped, and the influence of age at which treatment is initiated, are still controversial. We carried out a large, population based, nested case-control study to investigate these issues.

The data used for this study were obtained from the health services database of Lombardia. Lombardia is one of 20 Regions in Italy, with a population of about 9 million inhabitants (about 16% of the population of Italy). The population is entirely covered by the National Health Service (NHS), which has administered this program since 1997. It utilizes an automated system of databases on the use of health services including demographic and administrative data, hospital discharge and outpatient prescription drug benefits. Information is recorded for the NHS and can be linked for each individual using a unique personal identification code.

Procedures aimed to protect personal data were enforced in order to protect privacy and to prevent the identification of individual data. In practice, each identification code was automatically converted to a unique and anonymous code, and the inverse process was prevented by the deletion of the conversion table.

Cohort selection and follow-up

All women aged 45–75 years who received at least one HRT prescription anytime during 1998–2000, were identified from the outpatient prescription drug database. These drugs included all those used in Italy to treat symptoms of menopause (oestrogens or estradiol alone or conjugated with progestin) and modes of administration (ovules, gels, patches and pills).

Each woman accumulated person-years of follow-up from the date of the first recorded prescription of a drug for HRT (index prescription) until the earliest of the dates of death, hospitalization for cancer, cardiovascular disease or fracture, emigration or December 31, 2005.

Eligible women who, in the period from January 1, 1997 to the date of the index prescription, took at least one prescription of HRT or were hospitalized for cancer or cardiovascular disease, and those who did not have at least 6 months of follow-up, were excluded.

Case and control selection

Case patients were all the members of the cohort hospitalized with main cause recorded as fracture (codes 800–829 according to the International Classification of Diseases, 9th Revision) during follow-up. Up to six controls for each case were selected randomly within the cohort after they were matched for age at cohort entry, date of cohort entry and were at risk for the outcome at the time of the matched case event (index date).

Cases and controls who during follow-up were hospitalized for malignancy, severe alcohol misuse, psychosis, or senile dementia were not considered for this study.

Use of HRT and concomitant conditions

The type and the dose of each HRT prescription dispensed to the cases and controls from cohort entry until the index date were retrieved from the outpatient prescription drug database. The conjugated-oestrogen dose equivalent was calculated for each dispensed prescription (0.625 mg of conjugated oestrogens were considered equivalent to 0.625 mg of esterified oestrogens and to 0.05 mg of ethinyl oestrogens), and the resulting defined daily dose units, established as the typical adult’s daily maintenance dose, was calculated for each prescribed drug. For overlapping prescriptions, the individual was assumed to have refilled early and completed the first prescription before starting the second. An indicator of the duration of HRT use during follow-up was constructed by summing up the number of days with medication available and categorized according to the following four approximately equal-sized categories measured in controls: ≤2 months, 2–6 months, 6–20 months and >20 months.

How recently HRT had been used was calculated according to the time interval since last HRT use until the index date. It was categorized into mutually exclusive groups of current, recent, and past use. Current use was defined as HRT use in the period of 6 months before or at the index date, including ongoing treatment at the index date, recent use as exposure in the period of 6–12 months before the index date and past use as exposure in the period of 12 months or more before the index date.

Hospital discharges for thyroid disease (ICD-9: 240–246), diabetes (250), chronic renal failure (585) and connective tissue diseases (710), and prescriptions for corticosteroids for systemic use (H02) and for drugs used for diabetes (ATC code: A10), thyroid therapy (H03), and osteoporosis (e.g. biphosphonates: M05BA, M05BB; calcitonin: H05BA; and raloxifene: G03XC01), experienced by each case and control during follow-up were recorded. Hospital discharges for fracture which occurred from January 1, 1997 until the date of cohort entry were also recorded.

Data analysis

Univariate logistic regression was used to compare cases and controls according to each of the subject’s characteristics measured at cohort entry or during follow-up.

Multivariate logistic regression was then used to estimate OR, and to calculate its 95% CI, for the association between HRT and the risk of fracture. The independent effect of the categories of cumulative duration of HRT use and its combined effect with the categories of how recently HRT had been used (recency) were estimated, respectively, by including in the model only the main term of duration and also the main term of recency and the interaction term between duration and recency. Trend in ORs were tested, when feasible, according to the statistical significance of the regression coefficient of the recoded variables obtained by scoring the corresponding categories. Separate analyses according to three categories of age at cohort entry (45–55, 56–65, and 66–75 years) were carried out. All the models included the following terms: (i) signs suggestive of thyroid disease, diabetes, chronic renal failure, connective tissue diseases and osteoporosis, each categorized as sign presentvs. no signs recorded during follow-up; (ii) duration of corticosteroid use during follow-up categorized as no use, use for less than 6 months, and use for 7 months or more; (iii) history of bone fractures which occurred prior to the date of cohort entry categorized as positive vs. negative history.

Due to the matching procedure, the parameters of both univariate and multivariate logistic models were estimated by maximizing the conditional likelihood function.

The corresponding calculations were carried out using the PHREG procedure of the SAS package [36]. For all hypotheses tested two-tailed P values less than 0.05 were considered to be significant.

Filed under: Drug Safety