Abdul-Hameed, D., Alassaf, F. (2026). Bone Turnover and the Folate–Homocysteine Pathway in Women Using Combined Oral Contraceptives. , 23(3), 100-106. doi: 10.33899/iraqij.p.2026.170376.1198
Dalal M. Abdul-Hameed; Fawaz A. Alassaf. "Bone Turnover and the Folate–Homocysteine Pathway in Women Using Combined Oral Contraceptives". , 23, 3, 2026, 100-106. doi: 10.33899/iraqij.p.2026.170376.1198
Abdul-Hameed, D., Alassaf, F. (2026). 'Bone Turnover and the Folate–Homocysteine Pathway in Women Using Combined Oral Contraceptives', , 23(3), pp. 100-106. doi: 10.33899/iraqij.p.2026.170376.1198
Abdul-Hameed, D., Alassaf, F. Bone Turnover and the Folate–Homocysteine Pathway in Women Using Combined Oral Contraceptives. , 2026; 23(3): 100-106. doi: 10.33899/iraqij.p.2026.170376.1198

Bone Turnover and the Folate–Homocysteine Pathway in Women Using Combined Oral Contraceptives

Iraqi Journal of Pharmacy
Article 2, Volume 23, Issue 3, September 2026, Pages 100-106    PDF (671.02 K)
Document Type: Research Paper
DOI: 10.33899/iraqij.p.2026.170376.1198
Authors
Dalal M. Abdul-Hameed; Fawaz A. Alassaf*
Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq
Abstract
Background: The metabolic pathways of the folate-homocysteine pathway including folic acid, vitamin B12, and homocysteine are linked to bone quality and skeletal integrity. The impact of combined oral contraceptives (COC) on this metabolic pathway and its interaction with bone turnover markers remains an area of research. Objectives: This study aims to investigate the association of bone turnover markers with folate-homocysteine metabolic pathways in women using COC. Methods: A total of 84 women (42 controls and 42 COCs users) were recruited, blood was withdrawn and serum was separated. Serum folic acid, vitamin B12, homocysteine, and parathyroid hormone were all measured using ELISA technique and bone turnover markers (osteocalcin, bone specific alkaline phosphatase, and C-terminal telopeptide type I collagen) were also measured. Results: The use of COC in women was associated with a significant increase in osteocalcin levels (4.83 ± 1.15 ng/ml) compared to controls (3.38 ± 1.13 ng/ml, p = 0.001), while folic acid levels were also significantly higher in COC users (16.40 ± 4.28 ng/ml) than in controls (12.92 ± 4.09 ng/ml, p = 0.02). Positive correlations of both folic acid and vitamin B12 with bone turnover markers (osteocalcin, bone-specific alkaline phosphatase, and C-terminal telopeptide type I collagen) were demonstrated. Homocysteine showed a positive correlation with bone-specific alkaline phosphatase. Conclusion: Combined oral contraceptives use is associated with alterations in the bone remodeling process and the folate-homocysteine metabolic pathway. The outcomes of the study suggest that folic acid and vitamin B12 may play a role in modulating bone metabolism, highlighting the importance of considering hormonal and nutritional status in the assessment of bone health in women using combined oral contraceptives.
Keywords
Combined oral contraceptives; Bone turnover markers; Bone health; Folic acid; Homocysteine
References
  1. Wang J, Zhang Y, Cao J, Wang Y, Anwar N, Zhang Z, et al. The role of autophagy in bone metabolism and clinical significance. Autophagy 2023;19(9): 2409–2427.
  2. Wu S, Wang L, Zhang X, Cai L, Ke Q, Xu J. Bone turnover markers (β-CTX, PINP, ALP) in osteoporosis: correlation with bone loss and fracture risk stratification. Frontiers in Endocrinology 2026;16: 1628434.
  3. Martiniakova M, Biro R, Kovacova V, Babikova M, Zemanova N, Mondockova V, Omelka R. Current knowledge of bone-derived factor osteocalcin: its role in the management and treatment of diabetes mellitus, osteoporosis, osteopetrosis and inflammatory joint diseases. Journal of Molecular Medicine 2024;102(4):435-52.
  4. Brown JP, Don-Wauchope A, Douville P, Albert C, Vasikaran SD. Current use of bone turnover markers in the management of osteoporosis. Clinical biochemistry 2022;109: 1–10.
  5. Schini M, Vilaca T, Gossiel F, Salam S, Eastell R. Bone Turnover Markers: Basic Biology to Clinical Applications. Endocrine Reviews 2023;44(3): 417–473.
  6. Pignolo RJ. Aging and Bone Metabolism. Comprehensive Physiology 2023;13(1): 4355–4386.
  7. Zou J, Shu M, Chen J, Wusiman M, Ye J, Yang S, et al. Associations of Serum Homocysteine with Bone Mineral Density and Osteoporosis Incidence in Chinese Middle-Aged and Older Adults: A Retrospective Cohort Study. Nutrients 2025;17(1): 192.
  8. Agostini D, Bartolacci A, Rotondo R, De Pandis MF, Battistelli M, Micucci M, et al. Homocysteine, Nutrition, and Gut Microbiota: A Comprehensive Review of Current Evidence and Insights. Nutrients 2025;17(8): 1325.
  9. Zhang Z, Zhang Q, Zhao Z. Correlational Analysis of Hemoglobin, Red Cell Distribution Width and Homocysteine Levels with Bone Mineral Density in Patients with Type 2 Diabetes. Advances in Bioscience and Biotechnology 2025;16, 487-501.
  10. Toussirot E, Compagne C, Vauchy C, Bereau M. Bone health in Parkinson’s disease: a comprehensive review of bone involvement and its pathophysiological mechanisms. Frontiers in Medicine 2026;12: 1737844.
  11. Jiang M, Li G, Yang K, Tao L. Role of vitamins in the development and treatment of osteoporosis. International Journal of Molecular Medicine 2025;56(1): 109.
  12. Ilesanmi-Oyelere BL, Kruger MC. B vitamins and homocysteine as determinants of bone health: A literature review of human studies. Journal of Human Nutrition and Dietetics. 2023;36(3): 1031–1044.
  13. Sharma DK, Cheok TS, Rogers M, Lu VYZ, Solomon LB, Ramasamy B, et al. Relationship between homocysteine levels and bone quality in healthy adults - A systematic review and meta-analysis. Clinical nutrition ESPEN 2025;68: 790–805.
  14. Mohan A, Kumar R, Kumar V, Yadav M. Homocysteine, Vitamin B12 and Folate Level: Possible Risk Factors in the Progression of Chronic Heart and Kidney Disorders. Current Cardiology Reviews 2023;19(4): 66–83.
  15. Ampatzis C, Zervoudis S, Iatrakis G, Mastorakos G. Effect of oral contraceptives on bone mineral density. Acta Endocrinologica (Bucharest) 2022;18(3): 355-360.
  16. Hadji P, Colli E, Regidor PA. Bone health in estrogen-free contraception. Osteoporosis International 2019;30(12): 2391–2400.
  17. Bolamperti S, Villa I, Rubinacci A. Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Research 2022;10: 48.
  18. Cheng CH, Chen LR, Chen KH. Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover. International Journal of Molecular Sciences 2022;23(3): 1376.
  19. Jiang C, Zhu S, Zhan W, Lou L, Li A, Cai J. Comparative analysis of bone turnover markers in bone marrow and peripheral blood: implications for osteoporosis. Journal of Orthopaedic Surgery and Research. 2024;19(1):163.
  20. Liu H, Li B, Liu L, Ying W, Rosen CJ. Weight loss induced bone loss: mechanism of action and clinical implications. Bone Research 2025;13(1): 99.
  21. Dang S, Jain A, Dhanda G, Bhattacharya N, Bhattacharya A, Senapati S. One carbon metabolism and its implication in health and immune functions. Cell Biochemistry and Function 2024;42(1): e3926.
  22. Jin J, Wang Y, Jiang H, Kourkoumelis N, Renaudineau Y, Deng Z. The impact of obesity through fat depots and adipokines on bone homeostasis. AME Medical Journal 2018;3(1): 10.
  23. Martin D, Cooper SB, Tang JCY, Fraser WD, Sale C, Elliott-Sale KJ. Bone metabolic marker concentrations across the menstrual cycle and phases of combined oral contraceptive use. Bone 2021;145: 115864.
  24. Fathi M, Heshmat R, Ebrahimi M, Salimzadeh A, Ostovar A, Fathi A, et al. Association between biomarkers of bone health and osteosarcopenia among Iranian older people: The Bushehr Elderly Health (BEH) program. BMC Geriatrics 2021;.21(1): 654.
  25. Migliorini F, Maffulli N, Spiezia F, Peretti GM, Tingart M, Giorgino R. Potential of biomarkers during pharmacological therapy setting for postmenopausal osteoporosis: a systematic review. Journal of Orthopaedic Surgery and Research 2021;16(1): 351.
  26. Pawlowska E, Szczepanska J, Derwich M, Sobczuk P, Düzgüneş N, Blasiak J. DNA Methylation in Periodontal Disease: A Focus on Folate, Folic Acid, Mitochondria, and Dietary Intervention. International Journal of Molecular Sciences 2025;26(7): 3225.
  27. He T, Jin X, Koh YS, Zhang Q, Zhang C, Liu F. The association of homocysteine, folate, vitamin B12, and vitamin B6 with fracture incidence in older adults: a systematic review and meta-analysis. Annals of Translational Medicine 2021;9(14): 1143.
  28. Van Wijngaarden JP, Doets EL, Szczecińska A, Souverein OW, Duffy ME, Dullemeijer C, et al. Vitamin B12, Folate, Homocysteine, and Bone Health in Adults and Elderly People: A Systematic Review with Meta-Analyses. Journal of Nutrition and Metabolism 2013;2013(1): 486186.
  29. Rondanelli M, Tartara A, Fossari F, Vecchio V, Faliva MA, Naso M, et al. Adequate Intake and Supplementation of B Vitamins, in Particular FolicAcid, can Play a Protective Role in Bone Health. Current Aging Science 2021;15(2): 110–120.
  30. Skalny AV, Aschner M, Tsatsakis A, Rocha JB, Santamaria A, Spandidos DA, Martins AC, Lu R, Korobeinikova TV, Chen W, Chang JS. Role of vitamins beyond vitamin D 3 in bone health and osteoporosis. International journal of molecular medicine 2024 ;53(1):1-21.
  31. Adhish M, Manjubala I. Integrative in-silico and in-vitro analysis of taurine and vitamin B12 in modulating PPARγ and Wnt signaling in hyperhomocysteinemia-induced osteoporosis. Biology Direct 2024;19(1):141.
  32. De Martinis M, Sirufo MM, Nocelli C, Fontanella L, Ginaldi L. Hyperhomocysteinemia is Associated with Inflammation, Bone Resorption, Vitamin B12 and Folate Deficiency and MTHFR C677T Polymorphism in Postmenopausal Women with Decreased Bone Mineral Density. International Journal of Environmental Research and Public Health 2020;17(12): 4260.
  33. Zhao J, Lu Q, Zhang X. Associations of serum vitamin B12 and its biomarkers with musculoskeletal health in middle-aged and older adults. Frontiers in Endocrinology 2024;15: 1387035.
  34. Kositsawat J, Vogrin S, French C, Gebauer M, Candow DG, Duque G, Kirk B. Relationship between plasma homocysteine and bone density, lean mass, muscle strength and physical function in 1480 middle-aged and older adults: data from NHANES. Calcified Tissue International 2023;112(1):45-54.
  35. Orsolini LR, Goldberg TBL, Caldeirão TD, da Silva CC, da Rizzo ACB, Biason TP, et al. Bone impact after two years of low-dose oral contraceptive use during adolescence. PLOS ONE 2023;18(6): e0285885.
  36. Tassi A, Londero AP, Xholli A, Lanzolla G, Bertozzi S, Savelli L, et al. Hormonal Contraception and Bone Metabolism: Emerging Evidence from a Systematic Review and Meta-Analysis of Studies on Post-Pubertal and Reproductive-Age Women. Pharmaceuticals 2025;18(1): 61.
Statistics
Article View: 743
PDF Download: 265


Journal Management System. Powered by iJournalPro.com