Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw

Objectives: To examine the level of saliva total protein and C-terminal telopeptide of type 1 collagen (CTX) in patients who receiving anti-resorptive drugs.

Patients and methods: A study compared in 3 groups (n=8): MRONJ patients, patients receiving anti-resorptive drugs without MRONJ development and participants without drug use. Unstimulated saliva samples were collected and analyzed levels of saliva total protein and CTX. One-way ANOVA was used for statistical analysis with p-value < 0.05.

Results: We found the lowest saliva CTX levels in MRONJ patients. A statistically significant reduction of the saliva CTX levels was found in MRONJ patients compared with at-risk patients (p=0.011).

Conclusion: CTX a bone resorption biomarker, can be detected in saliva. The level of saliva CTX in patients with MRONJ may decrease from the effect of anti-resorptive drugs. This suggests that saliva CTX might be used to predict the risk of MRONJ development in patients who are taking anti-resorptive drugs.

1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61(9): 1115-1117.

2. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg 2014; 72(10): 1938-1956.


3. Kolokythas A, Karras M, Collins E, Flick W, Miloro M, Adami G. Salivary Biomarkers Associated With Bone Deterioration in atients With medication-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2015; 73(9): 1741-1747.

4. Hutcheson A, Cheng A, Kunchar R, Stein B, Sambrook P, Goss A. A C-terminal crosslinking telopeptide test-based protocol for patients on oral bisphosphonates requiring extraction: a prospective single-center controlled study. J Oral Maxillofac Surg 2014;72(8): 1456-1462.

5. Pellegrini GG, Gonzales Chaves MM, Fajardo MA, et al. Salivary bone turnover markers in healthy pre- and postmenopausal women: daily and seasonal rhythm. Clin Oral Investig 2012; 16(2): 651-657.

6. Kim JW, Kong KA, Kim SJ, Choi SK, Cha IH, Kim MR. Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates. Bone 2013; 57(1): 201-205.

7.Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DT. Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev 2013; 26(4): 781-791.

8. Soutome S, Hayashida S, Funahara M, et al. Factors affecting development of medication-related osteonecrosis of the jaw in cancer patients receiving high-dose bisphosphonate or denosumab therapy: Is tooth extraction a risk factor? PLoS One 2018; 13(7): e0201343.

9. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27(32): 5356-5362.

10. Otto S, Schreyer C, Hafner S, et al. Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg 2012; 40(4): 303-309.

11. Otto S, Troltzsch M, Jambrovic V, et al. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development? J Craniomaxillofac Surg 2015; 43(6): 847-854.

12. Potup P Wk, Klainak K, Piyarattanapan C, Pankla S.R. The Association Between Bone Mineral density and Biochemical Bone Turnover Markers in Women at Thapho Diatrict, Pitsanulok Province. Songkla Med J 2014; 32(2): 63-72.

13. Auzina D, Erts R, Lejniece S. Prognostic value of the bone turnover markers in multiple myeloma. Exp Oncol 2017; 39(1): 53-56.

14.Hinge M, Andersen KT, Lund T, et al. Bone healing in multiple myeloma: a prospective evaluation of the impact of first-line anti-myeloma treatment. Haematologica 2016; 101(10): e419-e22.

15. Fehm T, Beck V, Banys M, et al. Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 2009; 112(3): 605-609.

16. Thumbigere-Math V, Michalowicz BS, de Jong EP, et al. Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw. Oral Dis 2015; 21(1): 46-56.

17. Fliefel R, Troltzsch M, Kuhnisch J, Ehrenfeld M, Otto S. Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int J Oral Maxillofac Surg 2015; 44(5): 568-585.

18. Shaila M, Pai GP, Shetty P. Salivary protein concentration, flow rate, buffer capacity and pH estimation: A comparative study among young and elderly subjects, both normal and with gingivitis and periodontitis. J Indian Soc Periodontol 2013; 17(1): 42-46.

19. Henskens YM, van der Velden U, Veerman EC, Nieuw Amerongen AV. Protein, albumin and cystatin concentrations in saliva of healthy subjects and of patients with gingivitis or periodontitis. J Periodontal Res 1993; 28(1): 43-48.

20. Johnson M. Protein Quantitation. Mater Methods 2012; 2: 115

21. Noble JE, Bailey MJ. Quantitation of protein. Methods Enzymol 2009; 463: 73-95.

22.Pongchaiyakul C, Kosulwat V, Charoenkiatkul S, Chailurkit LO, Rajatanavin R. The association of dietary calcium, bone mineral density and biochemical bone turnover markers in rural Thai women. J Med Assoc Thai 2008; 91(3): 295-302.

23. Gursoy UK, Kononen E, Huumonen S, et al. Salivary type I collagen degradation end-products and related matrix metalloproteinases in periodontitis. J Clin Periodontol 2013; 40(1): 18-25.

24. Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 2000; 11 (Suppl 6): S30-44.

25. Glover SJ, Gall M, Schoenborn-Kellenberger O, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res 2009; 24(3): 389-397.

26. Chubb SA. Measurement of C-terminal telopeptide of type I collagen (CTX) in serum. Clin Biochem 2012; 45(12): 928-935.

27. Fleisher KE, Welch G, Kottal S, Craig RG, Saxena D, Glickman RS. Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110(4): 509-516.

28. Miricescu D, Totan A, Calenic B, et al. Salivary biomarkers: relationship between oxidative stress and alveolar bone loss in chronic periodontitis. Acta Odontol Scand 2014; 72(1): 42-47.

29. Marx RE, Cillo JE, Jr., Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65(12): 2397-2410.

30. Thumbigere-Math V, Michalowicz BS, Hughes PJ, et al. Serum markers of bone turnover and angiogenesis in patients with bisphosphonate-related osteonecrosis of the jaw after discontinuation of long-term intravenous bisphosphonate therapy. J Oral Maxillofac Surg 2016; 74(4): 738-746.

Wongla A, Buranaphatthana W, Tachasuttirut K. Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw: Original articles. CM Dent J [Internet]. 2020 Jan 01 [cited 2024 Nov 01];42(1):173-183. Available from: https://www.dent.cmu.ac.th/cmdj/frontend/web/?r=site/viewarticle&id=25

Wongla, A., Buranaphatthana, W. & Tachasuttirut, K. (2020). Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw. CM Dent J, 42(1), 173-183. Retrieved from: https://www.dent.cmu.ac.th/cmdj/frontend/web/?r=site/viewarticle&id=25

Wongla, A., Buranaphatthana Worakanya and Tachasuttirut Kathawut. 2020. "Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw." CM Dent J, 42(1), 173-183. https://www.dent.cmu.ac.th/cmdj/frontend/web/?r=site/viewarticle&id=25

Wongla, A. et al. 2020. 'Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw', CM Dent J, 42(1), 173-183. Retrieved from https://www.dent.cmu.ac.th/cmdj/frontend/web/?r=site/viewarticle&id=25

Wongla, A., Buranaphatthana, W. and Tachasuttirut, K. "Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw", CM Dent J, vol.42, no. 1, pp. 173-183, Jan. 2020.

Wongla Atchara, Buranaphatthana Worakanya, Tachasuttirut Kathawut "Salivary C-terminal Telopeptide Levels in Patients with Medication-related Osteonecrosis of the Jaw." CM Dent J, vol.42, no. 1, Jan. 2020, pp. 173-183, https://www.dent.cmu.ac.th/cmdj/frontend/web/?r=site/viewarticle&id=25