Commentary based on Jovanovich A, Ginsberg C, You Z, et al. FGF23, frailty, and falls in SPRINT. J Am Geriatr Soc 2021;69:467-73.¹

Geriatric Cardiology Take Home Points

• Fibroblast growth factor 23 (FGF23) is a biomarker that is associated with frailty and mortality among community-dwelling older adults.² Levels of FGF23 are higher among individuals with chronic kidney disease (CKD)³ and as such, may help to identify older adults at risk of developing adverse health outcomes and for targeted interventions.
• Among SPRINT participants with CKD, this study found an association between higher FGF23 levels and frailty status. Participants were also about twice as likely to have a fall in the higher quartile FGF23 group compared to the lower quartile FGF23 group; this finding was independent of blood pressure (BP) treatment intensity.
• Subgroup analyses among participants either <75 years old or ≥75 years old showed similar results with respect to the full cohort, namely elevated FGF23 predicted risk of future falls.
• Given the observational nature of this study, causality cannot be determined. However, with more study, FGF23 may prove useful as an early biomarker for frailty as well as a potential intervention target to reduce risk for falls among older adults.

Study Question
FGF23 is a hormone important for phosphate and calcium balance⁴ and is thought to play a role in bone metabolism and muscle weakness. Levels of FGF23 are increased in people with CKD³ and could potentially identify individuals with CKD at risk of developing adverse health outcomes including frailty and falls. The aim of this study was to assess the association between serum FGF23 levels and prevalence of frailty and risk of falls among SPRINT participants with CKD.

Methods
In this cross-sectional and longitudinal observational study, authors examined a pre-planned subgroup of participants with CKD (defined as estimated GFR <60 mL/min/1.73 m²) from the SPRINT trial,⁵ a randomized controlled trial assessing standard (<140 mmHg) versus intensive (<120 mmHg) systolic BP control in reducing adverse cardiovascular events among hypertensive participants. Participants were excluded if they had diabetes mellitus, history of stroke, polycystic kidney disease, proteinuria above 1 g/d, and any solid organ transplant.

FGF23 samples were collected at the baseline study visit. Frailty status was defined as an accumulation of deficits and was evaluated using a 36-item index with the exclusion of the renal component from the original index.⁶ A smaller subgroup was measured with a 37-item index with the addition of a 4-meter walk test. Participants with 30 or more items available for analysis were included and classified as non-frail (≤.10), pre-frail (.10 to ≤.21) or frail (> .21). Staff assessed for falls during quarterly study visits, with falls being defined as a positional change where the individual came to rest on the floor or ground not due to syncope or external force. Other collected variables included: age, sex, race, medical history, smoking status, body mass index (BMI), serum PTH, cholesterol, creatinine, urine albumin, and urine creatinine.

Multinomial logistic regression models were used to assess the association of FGF23 and frailty. Cox proportional hazards models were used to evaluate the association of FGF23 and falls. FGF23 was analyzed both as a continuous measure as well as by quartiles. Analyses were adjusted for demographic variables, cardiovascular disease, kidney function, mineral metabolism markers, and frailty status.

Results
A total of 2,376 participants were included in this study with a mean age of 73 years.

• After adjustment, higher serum FGF23 levels were associated with frailty (OR 1.34 [CI 95%, 1.01-1.77]) but not pre-frailty. Neither sex nor race had an impact on the relationship between FGF23 and frailty.
• There were 102 falls during the 39 months of follow up with falls about twice as likely in the highest FGF23 quartile compared to the lowest quartile (HR 2.32 [CI 95%, 1.26-4.26] in the fully adjusted model). This result was not related to the intensity of BP treatment group (p value for interaction term = 0.8).
• Similar results were seen for subgroup analyses of participants both younger than 75 years and 75 years and older.

Conclusion
This study showed that higher serum FGF23 levels were independently associated with frailty and falls among SPRINT participants with CKD. Standard versus intensive-treatment BP control did not further contribute to fall risk. Similar to the original SPRINT trial that showed an increased risk of hypotension and syncope, but not falls, among older adults stratified to the more intensive BP control group,⁷ this finding continues to support the idea that other factors contribute more to fall risk than intensity of BP management. Further studies are needed to understand the pathophysiology of FGF23, as well as its potential as an intervention target to improve frailty status and decrease fall risk.

References

1. Jovanovich A, Ginsberg C, You Z, et al. FGF23, frailty, and falls in SPRINT. J Am Geriatr Soc 2021;69:467-73.
2. Beben T, Ix JH, Shlipak MG, et al. Fibroblast growth factor-23 and frailty in elderly community-dwelling individuals: the Cardiovascular Health Study. J Am Geriatr Soc 2016;64:270-6.
3. Lu X, Hu MC. Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease. Kidney Dis (Basel) 2017;3:15-23
4. Fukumoto S. FGF23 and bone and mineral metabolism. Handb Exp Pharmacol 2020;262:281-308.
5. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
6. Pajewski NM, Williamson JD, Applegate WB, et al. Characterizing frailty status in the systolic blood pressure intervention trial. J Gerontol A Biol Sci Med Sci 2016;71:649-55.
7. Sink KM, Evans GW, Shorr RI, et al. Syncope, hypotension, and falls in the treatment of hypertension: results from the randomized clinical systolic blood pressure intervention trial. J Am Geriatr Soc 2018;66:679-86.

Clinical Topics: Dyslipidemia, Geriatric Cardiology, Lipid Metabolism, Nonstatins

Keywords: Geriatrics, Accidental Falls, Body Mass Index, Calcium, Creatinine, Frail Elderly, Independent Living, Logistic Models, Blood Pressure, Proportional Hazards Models, Cross-Sectional Studies, Phosphates, Prevalence, Muscle Weakness, Control Groups, Cardiovascular Diseases, Follow-Up Studies, Renal Insufficiency, Chronic, Hypotension, Syncope, Proteinuria, Diabetes Mellitus, Polycystic Kidney Diseases, Stroke, Biomarkers, Hormones, Outcome Assessment, Health Care, Cholesterol, Reference Standards, Albumins

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