Skip to main content

Advertisement

SpringerLink
Log in

Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

In this prospective study, serum levels of 12 possible biomarkers were compared between osteonecrosis of the jaw (ONJ) and control groups, before and after dentoalveolar surgery. The results suggest that patients with abnormal serum levels of specific biomarkers should be monitored closely for the prevention and early diagnosis of ONJ.

Introduction

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is an adverse effect of long-term bisphosphonate therapy. This study aimed to identify bone biomarkers for ONJ risk assessment and diagnosis.

Methods

This prospective study included patients with histories of bisphosphonate therapy without current ONJ who were in need of dentoalveolar surgery of the jaw area. Serum levels of 12 possible bone markers, selected based on their involvement in ONJ pathogenesis, were compared between ONJ and control groups before dentoalveolar surgery (T0), at 8 postoperative weeks (T1), and at 4 months after diagnosis(T2).

Results

Seventy-six patients who met the inclusion criteria were included in the study; 33 were assigned to the ONJ group, and 43 patients without ONJ signs or symptoms after dentoalveolar surgery were assigned to the control group. In the ONJ group, at both T0 and T1, the mean tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) levels were significantly lower and the mean Dickkopf-related protein 1 (DKK1) levels were significantly higher than the corresponding values for the control group. Linear mixed model analysis revealed significant group effects over time for serum TRACP 5b and DKK1 after adjusting for demographic, pharmacological, and diagnostic variables. Lower serum levels of TRACP 5b under a specified cut-off value (≤ 2.899 U/L) at T0 indicated a 20.40-fold increased risk of ONJ development.

Conclusion

Patients with abnormally low serum levels of TRACP 5b and high serum levels of DKK1 should be monitored closely before and after dentoalveolar surgery for the prevention and early diagnosis of ONJ.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F, Association American, of Oral and Maxillofacial Surgeons, (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 72(10):1938–1956

    Article  PubMed  Google Scholar 

  2. Moraschini V, de Almeida DCF, Figueredo CM, Calasans-Maia MD (2019) Association between biomarkers and medication-related osteonecrosis of the jaws: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 127(6):504–515. https://doi.org/10.1016/j.oooo.2019.02.014

    Article  PubMed  Google Scholar 

  3. Pouso AL, Pérez-Sayáns M, Palanca SG, Petronacci CMC, Sebastián JVB, García AG (2019) Biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw: a systematic review. Med Oral Patol Oral Cir Bucal Ed Inglesa 24(1):5

    Google Scholar 

  4. Dal Pra KJ, Lemos CA, Okamoto R, Soubhia AM, Pellizzer EP (2017) Efficacy of the C-terminal telopeptide test in predicting the development of bisphosphonate-related osteonecrosis of the jaw: a systematic review. Int J Oral Maxillofac Surg 46(2):151–156. https://doi.org/10.1016/j.ijom.2016.10.009

    Article  Google Scholar 

  5. Awad ME, Sun C, Jernigan J, Elsalanty M (2019) Serum C-terminal cross-linking telopeptide level as a predictive biomarker of osteonecrosis after dentoalveolar surgery in patients receiving bisphosphonate therapy: Systematic review and meta-analysis. J Am Dent Assoc 150(8):664-675 e668. https://doi.org/10.1016/j.adaj.2019.03.006

    Article  PubMed  PubMed Central  Google Scholar 

  6. Koh AJ, Demiralp B, Neiva KG, Hooten J, Nohutcu RM, Shim H, Datta NS, Taichman RS, McCauley LK (2005) Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology 146(11):4584–4596. https://doi.org/10.1210/en.2005-0333

    Article  CAS  PubMed  Google Scholar 

  7. Martin TJ, Sims NA (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11(2):76–81. https://doi.org/10.1016/j.molmed.2004.12.004

    Article  CAS  PubMed  Google Scholar 

  8. Karsdal MA, Martin TJ, Bollerslev J, Christiansen C, Henriksen K (2007) Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res 22(4):487–494. https://doi.org/10.1359/jbmr.070109

    Article  CAS  PubMed  Google Scholar 

  9. Subramanian G, Cohen HV, Quek SY (2011) A model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw and teriparatide’s potential role in its resolution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112(6):744–753. https://doi.org/10.1016/j.tripleo.2011.04.020

    Article  PubMed  Google Scholar 

  10. Reid IR, Cornish J (2012) Epidemiology and pathogenesis of osteonecrosis of the jaw. Nat Rev Rheumatol 8(2):90–96. https://doi.org/10.1038/nrrheum.2011.181

    Article  CAS  Google Scholar 

  11. Cremers S, Farooki A (2011) Biochemical markers of bone turnover in osteonecrosis of the jaw in patients with osteoporosis and advanced cancer involving the bone. Ann N Y Acad Sci 1218(1):80–87. https://doi.org/10.1111/j.1749-6632.2010.05770.x

    Article  CAS  PubMed  Google Scholar 

  12. Henriksen K, Tanko LB, Qvist P, Delmas PD, Christiansen C, Karsdal MA (2007) Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases. Osteoporos Int 18(5):681–685. https://doi.org/10.1007/s00198-006-0286-8

    Article  CAS  PubMed  Google Scholar 

  13. Karsdal MA, Henriksen K, Sorensen MG et al (2005) Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol 166(2):467–476. https://doi.org/10.1016/S0002-9440(10)62269-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rissanen JP, Suominen MI, Peng ZQ, Halleen JM (2008) Secreted tartrate-resistant acid phosphatase 5b is a marker of osteoclast number in human osteoclast cultures and the rat ovariectomy model. Calcif Tissue Int 82(2):108–115. https://doi.org/10.1007/s00223-007-9091-4

    Article  CAS  PubMed  Google Scholar 

  15. Janckila AJ, Yam LT (2009) Biology and clinical significance of tartrate-resistant acid phosphatases: new perspectives on an old enzyme. Calcif Tissue Int 85(6):465–483. https://doi.org/10.1007/s00223-009-9309-8

    Article  CAS  PubMed  Google Scholar 

  16. Hofbauer LC, Neubauer A, Heufelder AE (2001) Receptor activator of nuclear factor-κB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 92(3):460–470

    Article  CAS  PubMed  Google Scholar 

  17. Kim JW, Cha IH, Kim SJ, Kim MR (2016) Biomarkers for bisphosphonate-related osteonecrosis of the jaw. Clin Implant Dent Relat Res 18(2):281–291. https://doi.org/10.1111/cid.12297

    Article  PubMed  Google Scholar 

  18. Kim JW, Tatad JCI, Landayan MEA, Kim SJ, Kim MR (2015) Animal model for medication-related osteonecrosis of the jaw with precedent metabolic bone disease. Bone 81:442–448. https://doi.org/10.1016/j.bone.2015.08.012

    Article  CAS  PubMed  Google Scholar 

  19. Khan AA, Morrison A, Hanley DA et al (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30(1):3–23. https://doi.org/10.1002/jbmr.2405

    Article  PubMed  Google Scholar 

  20. Szulc P, Delmas PD (2008) Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis. Osteoporos Int 19(12):1683–1704. https://doi.org/10.1007/s00198-008-0660-9

    Article  CAS  PubMed  Google Scholar 

  21. Coleman R, Costa L, Saad F et al (2011) Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol 80(3):411–432. https://doi.org/10.1016/j.critrevonc.2011.02.005

    Article  PubMed  Google Scholar 

  22. Marx RE, Cillo JE, Ulloa JJ (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65(12):2397–2410. https://doi.org/10.1016/j.joms.2007.08.003

    Article  PubMed  Google Scholar 

  23. Nicolatou-Galitis O, Papadopoulou E, Vardas E et al (2020) Alveolar bone histological necrosis observed prior to extractions in patients, who received bone-targeting agents. Oral Dis 26(5):955–966. https://doi.org/10.1111/odi.13294

    Article  PubMed  Google Scholar 

  24. Ristow O, Ruckschloss T, Moratin J et al (2021) Wound closure and alveoplasty after preventive tooth extractions in patients with antiresorptive intake-a randomized pilot trial. Oral Dis 27(3):532–546. https://doi.org/10.1111/odi.13556

    Article  PubMed  Google Scholar 

  25. Otto S, Troltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, Ehrenfeld M, Pautke C (2015) Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Craniomaxillofac Surg 43(6):847–854. https://doi.org/10.1016/j.jcms.2015.03.039

    Article  PubMed  Google Scholar 

  26. Hasegawa T, Kawakita A, Ueda N, Funahara R, Tachibana A, Kobayashi M, Kondou E, Takeda D, Kojima Y, Sato SJOI (2017) A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? Osteoporosis Int 28(8):2465–2473

    Article  CAS  Google Scholar 

  27. Lazarovici TS, Mesilaty-Gross S, Vered I, Pariente C, Kanety H, Givol N, Yahalom R, Taicher S, Yarom N (2010) Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. J Oral Maxillofac Surg 68(9):2241–2247. https://doi.org/10.1016/j.joms.2010.05.043

    Article  PubMed  Google Scholar 

  28. Lee CY, Suzuki JB (2010) CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part II: a prospective clinical study. Implant Dentistry 19(1):29–38

    Article  CAS  PubMed  Google Scholar 

  29. Hannon RA, Clowes JA, Eagleton AC, Al Hadari A, Eastell R, Blumsohn A (2004) Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption. Bone 34(1):187–194. https://doi.org/10.1016/j.bone.2003.04.002

    Article  CAS  PubMed  Google Scholar 

  30. Chao TY, Wu YY, Janckila AJ (2010) Tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) as a serum maker for cancer with bone metastasis. Clin Chim Acta 411(21–22):1553–1564. https://doi.org/10.1016/j.cca.2010.06.027

    Article  CAS  PubMed  Google Scholar 

  31. Halleen JM, Tiitinen SL, Ylipahkala H, Fagerlund KM, Vaananen HK (2006) Tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of bone resorption. Clin Lab 52(9–10):499–509

    CAS  PubMed  Google Scholar 

  32. Baron R, Rawadi G (2007) Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148(6):2635–2643. https://doi.org/10.1210/en.2007-0270

    Article  CAS  PubMed  Google Scholar 

  33. Ott SM (2005) Sclerostin and Wnt signaling–the pathway to bone strength. J Clin Endocrinol Metab 90(12):6741–6743. https://doi.org/10.1210/jc.2005-2370

    Article  CAS  PubMed  Google Scholar 

  34. Ke HZ, Richards WG, Li X, Ominsky MS (2012) Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 33(5):747–783. https://doi.org/10.1210/er.2011-1060

    Article  CAS  PubMed  Google Scholar 

  35. Gatti D, Viapiana O, Adami S, Idolazzi L, Fracassi E, Rossini M (2012) Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin. Bone 50(3):739–742. https://doi.org/10.1016/j.bone.2011.11.028

    Article  CAS  PubMed  Google Scholar 

  36. Marshall MJ, Evans SF, Sharp CA, Powell DE, McCarthy HS, Davie MW (2009) Increased circulating Dickkopf-1 in Paget’s disease of bone. Clin Biochem 42(10–11):965–969. https://doi.org/10.1016/j.clinbiochem.2009.04.007

    Article  CAS  PubMed  Google Scholar 

  37. Ramli FF, Chin KY (2020) A review of the potential application of osteocyte-related biomarkers, fibroblast growth factor-23, sclerostin, and Dickkopf-1 in predicting osteoporosis and fractures. Diagnostics (Basel) 10(3). https://doi.org/10.3390/diagnostics10030145

  38. Memon AR, Butler JS, O’Riordan MV, Guerin E, Dimitrov BD, Harty JA (2013) Comparison of serum Dkk1 (Dickkopf-1) and bone mineral density in patients on bisphosphonate treatment vs no treatment. J Clin Densitom 16(1):118–124. https://doi.org/10.1016/j.jocd.2012.07.003

    Article  PubMed  Google Scholar 

  39. Vasconcelos AC, de Azambuja B-C, Figueiredo MA, Salum FG, Lopes TG, Cherubini K (2013) Laboratory methods and biomarkers in the evaluation of bisphosphonate effects on body tissues: a literature review. J Oral Pathol Med 42(8):577–586. https://doi.org/10.1111/jop.12031

    Article  CAS  PubMed  Google Scholar 

  40. Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J, Viniou N, Yataganas X, Goldman JM, Rahemtulla A (2003) Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 102(3):1064–1069. https://doi.org/10.1182/blood-2003-02-0380

    Article  CAS  PubMed  Google Scholar 

  41. Rogers A, Eastell R (2005) Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 90(11):6323–6331. https://doi.org/10.1210/jc.2005-0794

    Article  CAS  PubMed  Google Scholar 

  42. Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29(2):155–192. https://doi.org/10.1210/er.2007-0014

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2020R1A2C4001842).

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Research Institute for Intractable Osteonecrosis of the Jaw, College of Medicine, Ewha Womans University, Anyangcheon-ro 1071, Yangcheon-gu, Seoul, 07985, Republic of Korea

    Jung-Hyun Park, Sura Cho, Sun-Jong Kim & Jin-Woo Kim

  2. Department of Laboratory Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea

    Tae-Dong Jeong

  3. Department of Hemato‐Oncology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea

    Yeung-Chul Mun

Authors
  1. Jung-Hyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sura Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sun-Jong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tae-Dong Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yeung-Chul Mun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Woo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin-Woo Kim.

Ethics declarations

Ethics approval

This study was approved by the Institutional Bioethics Review Board of Ewha Womans University, Mokdong Hospital (IRB No. EUMC2018-01–046-003).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Conflict of interest

None.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, JH., Cho, S., Kim, SJ. et al. Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study. Osteoporos Int 33, 367–377 (2022). https://doi.org/10.1007/s00198-021-06137-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-021-06137-5

Keywords

Search

Navigation