Data source

We conducted a retrospective cohort study using data from the Clinical Practice Research Datalink (CPRD), a large database containing primary care medical records of 6.9% of the United Kingdom (UK) population, representative of the wider population in terms of age and sex distribution [17]. Practices included in CPRD receive training on recording clinical information, with data from a practice being used only when it has reached a certain standard of quality (up-to-standard; UTS). Patient information is recorded using a coded thesaurus of clinical terms (Read codes).

Study population

Separate exposed populations were defined for PMR and GCA, which were not mutually exclusive. Patients with PMR and/or GCA, aged 40 and over, were identified based on the presence of one or more relevant Read codes (Additional file 1: Table S1) documented in the patient’s electronic medical record between 1990 and 2004. Each patient was assigned an index date corresponding to the date of their first recorded disease diagnosis. Those diagnosed with PMR or GCA before the study period or within 3 months of their registration with a practice were considered prevalent cases and excluded [18].

Two control populations were separately defined for PMR and GCA. Controls did not have a diagnosis of any inflammatory conditions (PMR, GCA, gout, ankylosing spondylitis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematous or psoriasis) recorded in their entire electronic medical record up until the end of study. For each exposed patient, four controls were randomly selected matched on age, sex and general practice. The non-exposed patient’s index date was defined as their matched exposed patient’s index date.

Follow-up

The study start date was defined as the date of a patient’s registration with their practice, the date their practice was defined as UTS, the patient’s index date or on January 1, 1990, whichever came latest. The study end date was defined as the earliest of the date of the patient’s death, the date the patient transferred out of the practice, the date of last data collection from that practice, the date of first fracture, or August 31, 2015. Those with less than 12 months UTS data prior to index date and less than 3 years UTS follow-up after the index date were excluded.

Outcome definition

The event of interest was time from index date until first fracture. As we were concerned with fragility fractures, fractures at four sites encompassing the definition for ‘major osteoporotic fracture’ [19] were selected (vertebrae, humerus, wrist and hip); we also included general codes for fragility fracture where site was unspecified. First fracture was identified using Read codes (Additional file 1: Table S1), which have been previously validated in CPRD [20]. In order to ensure this was the first fracture, patients with a Read code for fracture prior to their index date were excluded.

Covariates

We extracted information on patient demographics (age, sex) at their index date, lifestyle-related characteristics (body mass index (BMI), smoking status and alcohol consumption) using the measurement nearest to their index date (ever prior to index and up to 1 year after), comorbidities (summarised using the Charlson comorbidity index [21]) and prescription of medications (glucocorticoid, methotrexate, bisphosphonates and proton pump inhibitors (PPIs)) prior to the outcome for both the exposed and non-exposed. BMI was categorised according to the World Health Organization classification as underweight (<18.5 kg/m²), normal (18.5–25 kg/m²), overweight (25–29.9 kg/m²) or obese (≥ 30 kg/m²). Those with missing information on BMI, smoking and alcohol use were included as a separate category. Information on falls was collected during the study period. Dose and duration of each glucocorticoid prescription was derived from available information using the algorithm described in Additional file 2, which was subsequently used to calculate the average daily dose. Doses of oral glucocorticoid were converted into a prednisolone-equivalent dosage. Where a condition/prescription is present in the record, we assume that the patient received this diagnosis/prescription at the time it was recorded. Where there is no record of a condition/prescription, it is assumed that the patient did not have this condition/prescription.

Statistical analysis

All data summaries and analyses were performed separately for the PMR and GCA cohorts. Demographics and lifestyle-related characteristics were summarised using frequencies and percentages. Incidence rates were expressed as the number of first fractures per 10,000 person years. To assess the association between exposure and time to osteoporotic fracture, Cox proportional hazard models were used to obtain estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), based on robust standard errors to account for matching. Unadjusted estimates were obtained followed by adjustment for age, sex, BMI, alcohol, smoking, Charlson comorbidity index and PPI use. To avoid over-adjustment, models were only adjusted for confounding factors (associated with both the outcome and exposure) which affected estimates by > 10%. Proportionality of hazards assumption was tested throughout using Schoenfeld residuals. Subgroup analyses by sex and age group were performed. The timing of fracture reporting in relation to PMR and GCA diagnosis was then assessed by comparing the absolute rate of fracture at yearly intervals up to 5 years after PMR/GCA diagnosis among the exposed and non-exposed in terms of incidence rate ratios using a Poisson regression model. Analyses were stratified by fracture site. The effect of the use of methotrexate and the cumulative dose of glucocorticoid on the incidence of fracture was evaluated by estimating hazard ratios within those with PMR/GCA, excluding the controls without PMR/GCA from this analysis. Any methotrexate use was compared to none and each quintile of average daily glucocorticoid dose was compared to lowest quintile. The analyses were adjusted as above, with the addition of bisphosphonate use.

Sensitivity analyses were performed, defining the exposure status as a Read code for PMR or GCA, plus two or more prescriptions for glucocorticoids during the study period; hence, patients who did not have two or more glucocorticoid prescriptions were excluded, along with their matched controls.

Patients with GCA may have symptoms of both PMR and GCA, whereas patients with PMR would not be expected to have symptoms of GCA; therefore, additional sensitivity analysis was performed estimating the risk of fracture in the group of patients with PMR diagnosis, excluding those with GCA codes. Finally, analyses considering complete cases only (no missing category for smoking, alcohol use and BMI) were performed as sensitivity analyses and compared to the main results.

All analyses were performed using Stata/MP 14.2 (Stata Corporation, TX, USA).

Basic characteristics

Risk of fracture

Figure 1 shows incidence rate ratio of fracture in the years following PMR and GCA diagnosis compared to controls. For patients with both conditions, the incidence rate ratio of fracture remained significantly increased 5 years post-diagnosis.

Risk by fracture site

Risk by prescriptions

Sensitivity analyses

Restricting analyses to the cases with two or more prescriptions for glucocorticoids did not alter the overall adjusted estimates of fracture significantly (GCA: HR 1.59, 95% CI 1.40–1.81; PMR: HR 1.62, 95% CI 1.53–1.73).

The risk of fracture was similar in PMR-only cases, i.e. when cases with any GCA diagnoses were removed (PMR only: HR 1.61, 95% CI 1.52–1.71).

When analysing complete cases only, results were similar to when including a missing category for smoking, alcohol use and BMI (results not presented).

Strengths and limitations of the study

By utilising CPRD and selecting all incident cases of PMR and GCA during the study period, our findings are generalisable to the wider UK primary care population. Matching cases and controls by age, sex and practice reduces the likelihood of confounding. However, as in any database study, it is possible that residual confounding remains. Furthermore, our methods do not facilitate the identification of asymptomatic or undiagnosed vertebral fractures. Vertebral fractures often do not come to clinical attention [22], and it is theoretically possible that the pain of GCA and/or PMR may mask the presentation of these fractures; both of these factors may result in underestimation of this risk. A number of further limitations of our study are worthy of acknowledgement. First, we relied on General Practitioner diagnoses of GCA and PMR. The diagnosis of GCA has previously been validated in CPRD [23], although PMR has not. Other conditions may be misclassified as PMR, which may explain why 12% of those with a PMR Read code were not treated with two or more glucocorticoid prescriptions. However, a sensitivity analysis which excluded these participants did not change our findings, providing confidence in our estimates. Second, we excluded patients without 3 years of UTS follow-up records after baseline, which may have resulted in the cases being healthier and a potentially bias in our findings towards the null hypothesis. Third, we cannot account for drugs prescribed in secondary care, for example, parenteral osteoporosis treatments and intravenous or intramuscular glucocorticoids. However, in practice, oral glucocorticoids remain the mainstay of treatment, intravenous glucocorticoids are more likely to be prescribed to those already on high oral doses, intramuscular doses are unlikely to be prescribed exclusively in secondary care, and the proportion of patients on parenteral osteoporosis treatment is small. Further, patients with GCA and PMR may have consulted more frequently, resulting in ascertainment bias, particularly relevant to the identification of vertebral fractures which often go undiagnosed [22]. However, adjustment for consultation rate made little difference to the results. Finally, it was not possible to determine the inflammatory burden associated with our conditions of interest. It is theoretically possible that the inflammatory component of GCA is more deleterious to bones than glucocorticoids, and that when glucocorticoids effectively treat high levels of inflammation, the fracture risk incurred by the glucocorticoids themselves is offset.

Comparison with other studies

Previous studies have demonstrated a dose-dependent increase in fracture risk with glucocorticoid dose [3] and these findings were mirrored in our study. However, previous studies of fracture risk in patients treated with glucocorticoids in CPRD suggest a rapid offset of increased risk on treatment cessation, with most excess risk disappearing within 1 year of stopping [3]. In our study, risk persisted for more than 5 years after diagnosis, but we did not compare rates before and after stopping. A previous study using CPRD found a much lower relative risk (1.09) of wrist fracture in glucocorticoid users [3]; higher rates of wrist fractures in our study may have been due to the increased number of falls recorded during the study period. Rossini et al. [13] found that vertebral fractures were more common than fractures at other sites in patients with GCA; however, theirs was an observational study in which patients had radiographs that would have resulted in an increased detection of subclinical fractures in the spine. The previous population study examining fracture risk in GCA found a higher risk of fracture in men than women, which is in contrast to our findings [12]. This may be related to the inclusion of fractures at sites that are typically traumatic, as opposed to fragility fractures. Other studies have found much higher rates of bisphosphonate use; in our study, the proportion of patients prescribed bisphosphonates was half of that in previous prospective primary care cohorts of patients with PMR [24] or prescribed glucocorticoid generally [25], and one-sixth of the proportion of patients with PMR treated with bisphosphonates in secondary care [26]. This might be explained by changes in practice over the dates of study inclusion, although UK guidance in 2002 advocated the use of bisphosphonates in patients treated with > 7.5 mg prednisolone aged 65 and over [27].

The finding that fracture risk in PMR and GCA is similar is surprising given that considerably lower dose glucocorticoids are recommended for PMR than for GCA. If the UK guidelines for typical dosing and duration of glucocorticoid are followed, a patient with PMR would be expected to receive half the cumulative dose of steroids as compared to the cumulative dose a patient with GCA would be expected to receive (2817.5 mg over 15 months compared with 5705 mg over 18 months) [28, 29]. Relatively little is known about ‘real life’ steroid use in PMR and GCA; however, our findings demonstrate that, PMR is, in practice, treated for a longer duration than GCA. Furthermore, in PMR, which is more likely to be treated exclusively by primary care physicians than secondary care specialists (especially in the UK where our study was based), daily doses are also likely to be higher than those recommended; in a UK survey of 1249 randomly selected General Practitioners, over 40% reported initiating doses of 30 mg of prednisolone or more, in excess of the EULAR/ACR recommended starting dose of between 15 and 25 mg [30, 31].