{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:15:58Z","timestamp":1788243358128,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background: Fibroblast growth factor 23 (FGF23) and \u03b1-Klotho are key regulators of mineral metabolism and bone homeostasis; however, their combined diagnostic value in postmenopausal osteoporosis remains incompletely understood. This study investigated the associations of serum FGF23, \u03b1-Klotho, and the FGF23\/\u03b1-Klotho ratio with bone mineral density (BMD), bone turnover markers, and their diagnostic performance for postmenopausal osteoporosis. Methods: This cross-sectional study included 165 women divided into three groups: premenopausal healthy controls (n = 55), postmenopausal non-osteoporotic women (n = 55), and postmenopausal women with osteoporosis (n = 55). Serum FGF23 and \u03b1-Klotho concentrations were measured by enzyme-linked immunosorbent assay. Bone mineral density was assessed by dual-energy X-ray absorptiometry. Correlation analyses, age- and BMI-adjusted partial correlations, multivariable linear and logistic regression analyses, receiver operating characteristic (ROC) analyses, and incremental diagnostic models were performed. Diagnostic ROC and incremental model analyses were restricted to postmenopausal women (n = 110). Results: Serum FGF23 concentrations and the FGF23\/\u03b1-Klotho ratio increased progressively across the study groups, whereas \u03b1-Klotho levels decreased (all p &lt; 0.001). FGF23 was inversely correlated with lumbar spine, femoral neck, and total hip BMD and T-scores (all p &lt; 0.001), whereas \u03b1-Klotho demonstrated positive correlations with all BMD parameters (all p &lt; 0.001). These associations remained significant after adjustment for age and BMI. In multivariable linear regression analyses, the FGF23\/\u03b1-Klotho ratio showed the strongest independent association with skeletal T-scores (standardized \u03b2 = \u22120.379 to \u22120.404; all p &lt; 0.001). Multivariable logistic regression identified lower 25-hydroxyvitamin D, higher parathyroid hormone, higher FGF23, and lower \u03b1-Klotho as independent factors associated with osteoporosis. In analyses restricted to postmenopausal women, the FGF23\/\u03b1-Klotho ratio showed the highest numerical discriminative performance for osteoporosis (AUC = 0.832, 95% CI: 0.755\u20130.901), followed by \u03b1-Klotho (AUC = 0.793) and FGF23 (AUC = 0.697). The ratio significantly outperformed FGF23 alone (\u0394AUC = 0.135, p = 0.001), whereas its performance did not differ significantly from that of \u03b1-Klotho (\u0394AUC = 0.038, p = 0.270). Adding FGF23 and \u03b1-Klotho to age, BMI, and 25-hydroxyvitamin D increased the AUC from 0.743 to 0.882. Conclusions: Serum FGF23 and \u03b1-Klotho are independently associated with bone mineral density and are linked to bone turnover markers in postmenopausal women. The FGF23\/\u03b1-Klotho ratio showed the highest numerical discriminative performance among the evaluated biomarkers, although its performance was not significantly different from that of \u03b1-Klotho alone. The combined assessment of FGF23 and \u03b1-Klotho provided additional discriminatory information beyond the measured clinical variables. Given the cross-sectional design and lack of external validation, these findings should be considered exploratory and require validation in prospective independent cohorts.<\/jats:p>","DOI":"10.3390\/jcm15176716","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:45:13Z","timestamp":1788241513000},"page":"6716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The FGF23\/\u03b1-Klotho Axis in Postmenopausal Osteoporosis: Associations with Bone Mineral Density and Diagnostic Discrimination"],"prefix":"10.3390","volume":"15","author":[{"given":"Mete Hakan","family":"Karalok","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Istanbul Atlas University, Istanbul 34408, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4735-4091","authenticated-orcid":false,"given":"Naile Fevziye","family":"Misirlioglu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Istanbul Ni\u015fanta\u015f\u0131 University, Istanbul 34398, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oznur Dundar","family":"Akin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Istanbul Atlas University, Istanbul 34408, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafize","family":"Uzun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Istanbul Atlas University, Istanbul 34408, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.ecl.2024.08.008","article-title":"Postmenopausal Osteoporosis: A Review of Latest Guidelines","volume":"53","author":"Subarajan","year":"2024","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_2","first-page":"e48582","article-title":"A Comprehensive Review on Postmenopausal Osteoporosis in Women","volume":"15","author":"Charde","year":"2023","journal-title":"Cureus"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1080\/13697137.2021.1951206","article-title":"Osteoporosis and fractures in women: The burden of disease","volume":"25","author":"Lorentzon","year":"2022","journal-title":"Climacteric"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Leszczy\u0144ska, D., Szatko, A., Tobo\u0142a, A., Karo\u0144, K., Misiorowski, W., Glinicki, P., and Zgliczy\u0144ski, W. (2025). Novel aspects of biochemical assessment of bone remodeling and mineralization. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1702413"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wu, S., Wang, L., Zhang, X., Cai, L., Ke, Q., and Xu, J. (2026). Bone turnover markers (\u03b2-CTX, PINP, ALP) in osteoporosis: Correlation with bone loss and fracture risk stratification. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1628434"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mollica, M.V., Cianciolo, G., Santoro, C., Fimognari, F., Baraldi, O., Di Nunzio, M., Greco, R., Hu, L., Di Dalmazi, G., and Zavatta, G. (2026). Combination of Biomarkers and Novel Diagnostic Tools in the Management of Osteoporosis in Chronic Kidney Disease: An Update. J. Clin. Med., 15.","DOI":"10.3390\/jcm15124712"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/S2213-8587(17)30184-5","article-title":"Use of bone turnover markers in postmenopausal osteoporosis","volume":"5","author":"Eastell","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_8","first-page":"50","article-title":"Contribution of bone mineral density and bone turnover markers to the estimation of risk of osteoporotic fracture in postmenopausal women","volume":"4","author":"Garnero","year":"2004","journal-title":"J. Musculoskelet. Neuronal. Interact."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1210\/endrev\/bnac031","article-title":"Bone Turnover Markers: Basic Biology to Clinical Applications","volume":"44","author":"Schini","year":"2023","journal-title":"Endocr. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.yexcr.2012.02.027","article-title":"Role of FGF23 in vitamin D and phosphate metabolism: Implications in chronic kidney disease","volume":"318","author":"Quarles","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sirikul, W., Siri-Angkul, N., Chattipakorn, N., and Chattipakorn, S.C. (2022). Fibroblast Growth Factor 23 and Osteoporosis: Evidence from Bench to Bedside. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052500"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/MNH.0000000000000467","article-title":"Fibroblast growth factor 23 and \u03b1-Klotho co-dependent and independent functions","volume":"28","author":"Quarles","year":"2019","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jiang, J., Liu, Q., Mao, Y., Wang, N., Lin, W., Li, L., Liang, J., Chen, G., Huang, H., and Wen, J. (2023). Klotho reduces the risk of osteoporosis in postmenopausal women: A cross-sectional study of the National Health and Nutrition Examination Survey (NHANES). BMC Endocr. Disord., 23.","DOI":"10.1186\/s12902-023-01380-9"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.mce.2016.05.008","article-title":"Update on FGF23 and Klotho signaling","volume":"432","author":"Erben","year":"2016","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7536614","DOI":"10.1155\/2021\/7536614","article-title":"Understanding the Stony Bridge between Osteoporosis and Vascular Calcification: Impact of the FGF23\/Klotho axis","volume":"2021","author":"Wei","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_16","first-page":"497","article-title":"The relationship between fibroblast growth factor 23 and osteoporosis in postmenopausal women","volume":"104","author":"Celik","year":"2013","journal-title":"Minerva Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1055\/a-2168-5089","article-title":"The Relationship Between Serum Fibroblast Growth Factor 23 and Klotho Protein and Low Bone Mineral Density in Middle-Aged and Elderly Patients with End-Stage Renal Disease","volume":"56","author":"Huang","year":"2024","journal-title":"Horm. Metab. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1097\/GME.0000000000001276","article-title":"The relationship between serum fibroblast growth factor 23, Klotho, and lumbar spine bone mineral density in northern Chinese postmenopausal women","volume":"26","author":"Han","year":"2019","journal-title":"Menopause"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1007\/s40520-023-02483-y","article-title":"Association between serum soluble \u03b1-klotho and bone mineral density (BMD) in middle-aged and older adults in the United States: A population-based cross-sectional study","volume":"35","author":"Zhang","year":"2023","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s00223-004-0291-x","article-title":"Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women","volume":"77","author":"Mullin","year":"2005","journal-title":"Calcif. Tissue Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1359\/jbmr.2002.17.10.1744","article-title":"Klotho gene polymorphisms associated with bone density of aged postmenopausal women","volume":"17","author":"Kawano","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1007\/BF01622200","article-title":"Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Synopsis of a WHO report","volume":"4","author":"Kanis","year":"1994","journal-title":"WHO Study Group. Osteoporos. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/S0140-6736(18)32112-3","article-title":"Osteoporosis","volume":"393","author":"Compston","year":"2019","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00198-018-4704-5","article-title":"European guidance for the diagnosis and management of osteoporosis in postmenopausal women","volume":"30","author":"Kanis","year":"2019","journal-title":"Osteoporos. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/S0140-6736(23)02800-3","article-title":"Optimising health after early menopause","volume":"403","author":"Mishra","year":"2024","journal-title":"Lancet"},{"key":"ref_26","first-page":"9","article-title":"Primary osteoporosis in postmenopausal women","volume":"1","author":"Ji","year":"2015","journal-title":"Chronic Dis. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.maturitas.2009.08.003","article-title":"Premature menopause or early menopause: Long-term health consequences","volume":"65","author":"Shuster","year":"2010","journal-title":"Maturitas"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1210\/endrev\/bnag006","article-title":"Management of Postmenopausal Osteoporosis","volume":"47","author":"Reid","year":"2026","journal-title":"Endocr. Rev."},{"key":"ref_29","unstructured":"World Health Organization (1994). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ. Tech. Rep. Ser., 843, 1\u2013129."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s43465-023-01019-w","article-title":"Osteoporosis: Investigations and Monitoring","volume":"57","author":"Panchagnula","year":"2023","journal-title":"Indian J. Orthop."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R19","DOI":"10.1530\/EJE-17-0585","article-title":"Diagnosis of endocrine disease: Bone turnover markers: Are they clinically useful?","volume":"178","author":"Eastell","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16033","DOI":"10.1038\/nrdp.2016.33","article-title":"Primary hyperparathyroidism","volume":"2","author":"Bilezikian","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1002\/jbmr.4677","article-title":"Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop","volume":"37","author":"Bilezikian","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6120","DOI":"10.1074\/jbc.C500457200","article-title":"Regulation of fibroblast growth factor-23 signaling by klotho","volume":"281","author":"Kurosu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"754","DOI":"10.31729\/jnma.3604","article-title":"Correlates of Biochemical Markers of Bone turnover among Post-Menopausal Women","volume":"56","author":"Khadka","year":"2018","journal-title":"JNMA J. Nepal Med. Assoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s40618-014-0158-6","article-title":"Alpha Klotho and phosphate homeostasis","volume":"37","author":"Bian","year":"2014","journal-title":"J. Endocrinol. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1053\/j.ajkd.2010.12.027","article-title":"Role of Klotho in aging, phosphate metabolism, and CKD","volume":"58","author":"John","year":"2011","journal-title":"Am. J. Kidney Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1007\/s00198-019-04996-7","article-title":"High FGF23 levels are associated with impaired trabecular bone microarchitecture in patients with osteoporosis","volume":"30","author":"Rupp","year":"2019","journal-title":"Osteoporos. Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/164_2019_330","article-title":"FGF23 and Bone and Mineral Metabolism","volume":"262","author":"Fukumoto","year":"2020","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s11154-011-9199-8","article-title":"The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis","volume":"13","author":"Haussler","year":"2012","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18760","DOI":"10.1038\/s41598-025-04024-1","article-title":"Serum alpha-klotho levels associate with bone mineral density in chronic kidney disease patients from NHANES 2011 to 2016","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1002\/jbmr.2750","article-title":"Associations of FGF23 With Change in Bone Mineral Density and Fracture Risk in Older Individuals","volume":"31","author":"Isakova","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrendo.2009.196","article-title":"The FGF23-Klotho axis: Endocrine regulation of phosphate homeostasis","volume":"5","author":"Razzaque","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1359\/JBMR.0301264","article-title":"FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis","volume":"19","author":"Shimada","year":"2004","journal-title":"J. Bone Miner. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e18551","DOI":"10.1111\/jcmm.18551","article-title":"Fibroblast growth factor 23-mediated regulation of osteoporosis: Assessed via Mendelian randomization and in vitro study","volume":"28","author":"Zhang","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"92","DOI":"10.36150\/2499-6564-N819","article-title":"A Review on Klotho: FGF23 Mediated Pathway Integration and Aging","volume":"73","author":"Devi","year":"2025","journal-title":"J. Gerontol. Geriatr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"eAO0412","DOI":"10.31744\/einstein_journal\/2024AO0412","article-title":"Blood concentrations of \u03b1-Klotho and FGF-23 exhibit no correlation with bone mineral density in elderly individuals","volume":"22","author":"Sawada","year":"2024","journal-title":"Einstein"},{"key":"ref_48","first-page":"50","article-title":"FGF23-Klotho axis in patients with rheumatoid arthritis","volume":"38","author":"Robledo","year":"2020","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s11255-019-02079-4","article-title":"Relationship between cFGF23\/Klotho ratio and phosphate levels in patients with chronic kidney disease","volume":"51","author":"Liu","year":"2019","journal-title":"Int. Urol. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1007\/s00198-018-4598-2","article-title":"FGF23-klotho axis, bone fractures, and arterial stiffness in dialysis: A case-control study","volume":"29","author":"Desbiens","year":"2018","journal-title":"Osteoporos. Int."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/17\/6716\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:54:04Z","timestamp":1788242044000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/17\/6716"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,29]]},"references-count":50,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcm15176716"],"URL":"https:\/\/doi.org\/10.3390\/jcm15176716","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,29]]}}}