(281) Leuprolide and Fracture Risk in Patients with Central Precocious Puberty

Friday, August 26, 2022

8:00 AM – 6:00 PM CEST

Location: Hall C

Publication Number: 612

Presenting Author(s)

Yandong Qiang, MD, PhD
– US Food and Drug Administration, Silver Spring, Maryland, United States

Co-Author(s)

Talia Menzin
– Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA, Boston, MA, United States
Christian Hampp, PhD, FISPE
– Regeneron Pharmaceuticals, Tarrytown, New York, United States
Hye Seung Lee
– U.S. FOOD & DRUG ADMINISTRATION, United States
Shannon Sullivian, MD, PhD
– Medical Officer, US FDA, Silver Spring, MD, United States
Yueqin Zhao, PhD
– US Food and Drug Administration, United States
Ting-Ying Huang
– Harvard Medical School and Harvard Pilgrim Health Care Institute, United States

Background: Fractures have been reported in patients with central precocious puberty (CPP) after childhood leuprolide use.

Objectives: To study the relationship between leuprolide and fracture

Methods: We identified 3 cohorts of patients ≤10 years in 12 Data Partners in the FDA Sentinel System from 2000 to 2018. The leuprolide exposed cohort included patients with a CPP diagnosis during the 183 days before (baseline) leuprolide initiation (index date). The 1st leuprolide unexposed cohort was patients diagnosed with CPP, indexed on median time from the first CPP diagnosis to exposure summarized from the leuprolide exposed cohort. The 2nd unexposed cohort was individuals with no baseline CPP diagnosis, indexed on the first well visit. All 3 cohorts had no baseline long-acting GnRH agonist use. With variable ratio matching (1: ≤10) on continuous age and calendar month of the index date, we compared the risk of the first fracture in the leuprolide exposed cohort with the unexposed cohort with CPP and cohort without CPP for males and females separately. To assess the impact of differentially truncated follow-up time due to conditioning on matched sets, we conducted a post hoc stratified conditional analysis on age and calendar month of index event.

Results: During the study period, there were 2,845 female and 439 male leuprolide users. The mean ages were 8 (SD=1.7) and 9 (SD=1.8) years, respectively. The mean duration of cumulative leuprolide use was 327 (max=3,749) days in females and 330 (max=1,941) days in males. On average, the leuprolide users were followed ~1,000 days from leuprolide initiation (max=6,046 in females; 4,834 in males).
There were 63 leuprolide exposed females who had fracture in 8,124 person-years (PY) of follow-up and 751 unexposed females with CPP who had fracture over 77,552 PY. Leuprolide exposed females were 25% (Hazard Ratio [HR]=0.75, 95% Confidence Interval 0.57-1.00) less likely to have fracture than the unexposed females with CPP. Compared to the 830 fractures in 83,495 PY among females without CPP, the risk of fracture was 34% less (HR=0.66, 0.50-0.87) in the leuprolide exposed females.
Among males, there were 19 fractures in those exposed to leuprolide during 1,226 PY and 114 fractures in the unexposed males with CPP over 9,299 PY (HR =1.28, 0.75-2.20). Compared to 172 fractures during 12,238 PY in the matched males without CPP , the HR was 1.07 (0.64-1.77).
In the post hoc analysis, the HR was 0.80 (0.62-1.05) compared to the unexposed females with CPP and 0.70 (0.54-0.91) compared to the females without CPP. The HRs for fracture were 1.27 (0.76-2.12) and 1.17 (0.72-1.91) when compared to unexposed males with CPP and males without CPP, respectively.

Conclusions: Results from this study provided no evidence for an increased risk of fracture following leuprolide use.