Higher FSH Level Is Associated With Increased Risk Of Incident Hip Fracture In Older Adults, Independent Of Sex Hormone Levels

Context Higher levels of follicle stimulating hormone (FSH) are associated with bone loss among women during the perimenopausal transition and among older men, independent of estradiol and testosterone levels, but it is unknown whether higher FSH is an independent risk factor for fracture. Objective Determine whether baseline FSH level predicts subsequent hip fracture in older adults. Setting, Design, Participants Using a case-cohort design, we randomly sampled 295 participants stratified by sex from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort, including 25 participants with incident hip fracture within 10 years after baseline. We sampled an additional 230 sex-stratified participants with incident hip fracture. Serum FSH and sex hormone levels were measured at baseline. Robust weighted Cox proportional hazards models were used to determine the relationship between FSH and hip fracture risk. Main Outcome Incident hip fracture Results As no interaction was identified between FSH and sex for the relationship with fracture, men and women were pooled for analysis. Higher levels of FSH were associated with a significantly 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 sex hormone binding globulin levels [HR 1.20 (95% CI 1.01-1.44, p=0.04) per sex-specific SD increase in FSH level]. Conclusions Higher FSH is associated with increased risk of subsequent hip fracture. Our findings support a growing body of evidence for direct pleiotropic effects of FSH on bone, and for a role for FSH in aging and disability independent of sex hormone levels. ### Competing Interest Statement Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: EHK, SKE, SS, VG, TFH, EV, TY, MZ, CJR, AVS, and ALS had support from the National Institutes of Health for the submitted work. SS and VG also had support from Hjartavernd (Icelandic Heart Association) and the Althingi (Icelandic Parliament) for the submitted work. CO has received research support from the Swedish Research Council and grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement, from the Novo Nordisk Foundation, and from the Knut and Alice Wallenberg Foundation; he also has two patents/ patent applications in the field of probiotics and bone health. MZ has patents addressing FSH, FSH formulation, bone, body fat, and neurodegeneration, and MZ and TY have patents addressing luteinizing hormone (LH) and body composition. ALS has received investigator-initiated research grant support from Amgen addressing bone health after bariatric surgery, and grant support from Bone Health Technologies. There are no other relationships or activities that could appear to have influenced the submitted work. ### Funding Statement This study was funded by the National Institute on Aging (NIA, U19AG060917), with additional support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS, R01AR057819, R01AR065645, P30AR075055). The AGES-Reykjavik Study is supported by funding from the NIA (N01AG12100), the NIA Intramural Research program, Hjartavernd (the Icelandic Heart Association), and the Althingi (Icelandic Parliament). EHK has received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, T32DK007418). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Icelandic National Bioethics Committee and the Institutional Review Board of the Intramural Research Program of the National Institute on Aging, National Institutes of Health gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available through collaboration under a data usage agreement with the Icelandic Heart Association. (Based on the informed consent provided by AGES-Reykjavik participants, analyses using the data can only be carried out after approval from the Icelandic data protection authority.)