Hip fracture risk in patients with Cushing's syndrome: a population-based cohort study

Cushing's syndrome causes bone loss, yet the risk of hip fractures remains poorly defined. In this nationwide cohort, patients showed a modestly increased risk of hip fracture, particularly soon after diagnosis. These results underscore the importance of early osteoporosis screening and timely fracture prevention strategies.

Glucocorticoid-induced osteoporosis is a common complication of Cushing's syndrome (CS). While the increased risk for vertebral fractures is well-established, evidence regarding hip fracture risk is limited. This study investigates the association between endogenous CS and hip fracture risk and examines the effect of remission on this risk.

A nationwide retrospective matched-cohort study was conducted using the Clalit Health Services database in Israel, including patients diagnosed with endogenous CS between 2000 and 2023. Patients with CS were matched 1:5 to controls based on age, sex, socioeconomic status, and body mass index. The primary outcome was the first diagnosis of hip fractures following the diagnosis of CS. Patients with a history of hip fractures prior to CS diagnosis were excluded.

The study included 606 patients with CS and 2,988 matched controls, with a mean age at diagnosis of 47.8 ± 17.1 years; 65.3% were female. Follow-up durations were 14.0 ± 6.5 years for patients with CS and 14.5 ± 6.5 years for controls. Hip fractures occurred in 3.9% of patients with CS and 2.5% of matched controls, corresponding to a modest association in competing risk analysis (HR 1.57, 95% CI 1.0-2.5; p = 0.05). The risk was higher among patients with Cushing's disease (CD) (HR 2.2, 95% CI 1.07-4.75; p = 0.03) but not in those with an adrenal source (HR 1.3, 95% CI 0.6-2.8). Analysis by remission status showed that hip fractures occurred in 4.3% of patients without remission and 3.6% of those in remission, with no significant difference between groups (HR 1.14, 95% CI 0.4-3.0). In multivariate analysis, older age at CS diagnosis and pre-existing osteoporosis were independently associated with an increased risk of hip fracture.

Endogenous Cushing's syndrome may be associated with an increased hip fracture risk, particularly in CD, driven mainly by older age at diagnosis and pre-existing osteoporosis, with no significant risk reduction after remission. These findings underscore the need for early fracture risk assessment and targeted osteoporosis management in patients with CS.