FRI675 Higher FSH Level Is Associated With Increased Risk Of Incident Hip Fracture In Older Adults, Independent Of Sex Hormone Levels
Authors: Koh Eileen H , Ewing Susan K , Sigurdsson Sigurdur , Guðnason Vilmundar , Hue Trisha F , Vittinghoff Eric , Zaidi Mone , Rosen Clifford J , Ohlsson Claes , Grahnemo Louise , Tivesten Åsa , Schwartz Ann V , Schafer Anne L 
Published: October 2023

Abstract
Disclosure: E.H. Koh: None. S.K. Ewing: None. S. Sigurdsson: None. V. Guðnason: None. T.F. Hue: None. E. Vittinghoff: None. M. Zaidi: Research Investigator; Self; patents on FSH, bone, body fat and neurodegeneration. Held by Icahn School of Medicine and Mount Sinai. C.J. Rosen: None. C. Ohlsson: None. L. Grahnemo: None. Å. Tivesten: None. A.V. Schwartz: None. A.L. Schafer: None.
Higher levels of follicle stimulating hormone (FSH) are associated with bone loss among women during the perimenopausal transition and among older men, independent of sex hormone levels. In vitro studies have shown bone remodeling via FSH-receptors on bone cells. Furthermore, treating ovariectomized mice with FSH-blocking polyclonal antibodies results in increased bone mineral density. However, it is uncertain whether this association of FSH elevation and bone loss translates to increased fracture risk. To examine the relationship between FSH and incident hip fracture, independent of sex hormone levels, we used a case-cohort design to sample from the AGES-Reykjavik cohort, a longitudinal cohort of 5764 older Icelandic adults designed to assess gene/environment interactions and their relationship to diseases in old age. Baseline visits took place from 2002 and through 2006. We excluded those with prior hip fracture, those whose quantitative computed tomography bone mineral density scan quality was unacceptable, or who were taking sex hormone replacement, sex hormone antagonists, or glucocorticoid medications. We randomly sampled, stratified by sex, 147 women and 148 men to form our subcohort. Our cases were comprised of a random sample, stratified by sex, of 133 women and 122 men (of whom 25 were in the subcohort) who sustained incident hip fracture within 10 years of the baseline visit. Fractures were adjudicated and recorded in the AGES-Reykjavik fracture registry. FSH and sex hormone binding globulin (SHBG) were measured on baseline serum by immunoassay and estradiol and total testosterone by mass spectrometry. Robust weighted Cox proportional hazards models were used to determine the relationship between FSH and subsequent risk of hip fracture, with adjustment for covariates. Among the subcohort, mean age was 76 years. In women, mean ± SD FSH was 64.4 ± 25.5 IU/L with estradiol 5.7 ± 4.2 pg/mL, testosterone 22.5 ± 10.4 ng/dL, and SHBG 74.0 ± 33.8 nmol/L. In men, mean FSH was 12.2 ± 11.9 IU/L with estradiol 21.3 ± 6.9 pg/mL, testosterone 457.9 ± 171.2 ng/dL, and SHBG 52.8 ± 17.5 nmol/L. No interaction was identified between FSH and sex for the relationship with fracture, so men and women were pooled for analysis. Higher levels of FSH were associated with a significant increased risk of incident hip fracture in models adjusted for age and sex [hazard ratio (HR) 1.24 (95% CI 1.04-1.48, p=0.02)] and after further adjustment for estradiol, testosterone, and SHBG levels [HR 1.20 (95% 1.01-1.44, p=0.04)] per sex-specific SD increase in FSH level. Our findings support a growing body of evidence for direct pleiotropic effects of FSH on bone. FSH may contribute to aging and disability independent of sex hormone levels.
Presentation: Friday, June 16, 2023