J Korean Assoc Oral Maxillofac Surg.  2023 Apr;49(2):75-85. 10.5125/jkaoms.2023.49.2.75.

Clinical significance of drug cessation on medication-related

• Mustakim KR
• Eo MY
• Lee JY
• Seo MH
• Kim SM

• KMID: 2542213
• DOI: http://doi.org/10.5125/jkaoms.2023.49.2.75

Abstract

Objectives
Suspending bisphosphonates (BPs) to reduce the risk and severity of medication-related osteonecrosis of the jaw (MRONJ) remains controversial. In this study, we quantitatively evaluated the clinical significance of BP suspension before surgery in osteoporosis patients with MRONJ.
Materials and Methods
We analyzed 24 osteoporosis patients with MRONJ who were treated from 2012 to 2020 at Seoul National University Dental Hospital and compared the treatment outcomes of those who suspended BPs with those who did not. The number of surgical interventions, follow-up panoramic radiographs for relative bone density measurement, and laboratory blood tests including white blood cells, erythrocyte sedimentation rate, absolute neutrophil count, hemoglobin, hematocrit, and alkaline phosphatase were analyzed. ANOVA, Student’s t-test, and Mann–Whitney U tests were used to compare results. Fisher’s exact test was used to discover the association between treatment outcome and BP suspension, and Pearson’s correlation test was used to measure the statistical relationship between the changes in serum inflammatory markers.
Results
The number of interventions was significantly higher in the non-drug suspension group due to recurrence (P<0.05). The relative bone density in patients who suspended BPs was significantly different over time (P<0.05), with the highest density at one-year follow-up. Fisher’s exact test shows an association between successful treatment outcomes and BP suspension. The alkaline phosphatase and erythrocyte sedimentation rate levels decreased significantly in the BP-suspended group, and a positive correlation was found between these elevated markers.
Conclusion
A significant increase in bone density throughout follow-up and a lower number of interventions were found in the BP suspension group compared to the non-drug suspension group. Also, BP suspension decreased inflammatory markers in the serum after surgery, resulting in good treatment outcomes. BP suspension is a prognostic factor for MRONJ and should be implemented before surgery.

Keyword

Bisphosphonate-related osteonecrosis of the jaw; Bone density; Drug holiday; Inflammatory marker; Osteoporosis

Figure

• 

  Fig. 1 The method used in the study to quantify relative bone density using Fiji ImageJ software (ver1.53c; NIH).

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  Fig. 2 The chart shows the comparison of relative bone density changes between groups in the examined time periods. The box plots show high relative bone density in the drug suspension group for every time period, indicating bone healing. On the contrary, recurrence and more frequent surgical interventions were predominant in the non-drug suspension group. In this case, the box plots of the non-drug suspension group show various levels of relative bone density. When comparing the two groups at every time period, significant differences in relative bone density levels can be observed mainly in T2-T0 and T3-T0 (P<0.05). (BP: bisphosphonate, T0: immediately postoperatively, T1: 3-month follow-up, T2: 6-month follow-up, T3: 1-year follow-up)

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  Fig. 3 Representative cases of medication-related osteonecrosis of the jaws (MRONJ) from the two groups, non-suspension (A-E) and BP suspension (F-J), showing the bone healing progress of two female patients who received oral alendronate 70 mg/week and developed stage 3 MRONJ on the anterior mandible. In the preoperative panoramic radiographs of both patients (A, F), the yellow arrowheads indicate lesion extension. The immediate postoperative panoramic radiographs of both patients (B, G). The three-month follow-up panoramic radiograph revealed signs of pathologic fracture at the base of the mandible in patients who did not suspend BPs (C, blue arrowheads) compared to patients who suspended BPs three months before surgery (H). The six-month follow-up panoramic radiographs revealed extensive expansion of the recurred lesion in patients who did not suspend BPs (D) compared to the patients who suspended BPs, which showed the bone healing process (I). The one-year follow-up panoramic radiograph of a patient who did not suspend BPs (E) and a patient who suspended BPs revealed good and almost complete bone healing on the left anterior mandible (blue arrowheads) (J).

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  Fig. 4 Scatterplot matrix that shows a moderate degree of positive correlation (r=0.474, P<0.05) between the changes of preoperative and postoperative erythrocyte sedimentation rate (ESR) and alkaline phosphatase (ALP) in all patients. The changes in ALP were occurred in tandem with the changes in ESR.

Reference

References

1. Johnston CB, Dagar M. 2020; Osteoporosis in older adults. Med Clin North Am. 104:873–84. https://doi.org/10.1016/j.mcna.2020.06.004. DOI: 10.1016/j.mcna.2020.06.004. PMID: 32773051.

2. Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. 2022; American Association of Oral and Maxillofacial Surgeons' position paper on medication-related osteonecrosis of the jaws-2022 update. J Oral Maxillofac Surg. 80:920–43. https://doi.org/10.1016/j.joms.2022.02.008. DOI: 10.1016/j.joms.2022.02.008. PMID: 35300956.

3. Kim TH, Seo WG, Koo CH, Lee JH. 2016; Evaluation of the predisposing factors and involved outcome of surgical treatment in bisphosphonate-related osteonecrosis of the jaw cases including bone biopsies. J Korean Assoc Oral Maxillofac Surg. 42:193–204. https://doi.org/10.5125/jkaoms.2016.42.4.193. DOI: 10.5125/jkaoms.2016.42.4.193. PMID: 27595086. PMCID: PMC5009193.

4. Coskun Benlidayi I, Guzel R. 2013; Oral bisphosphonate related osteonecrosis of the jaw: a challenging adverse effect. ISRN Rheumatol. 2013:215034. https://doi.org/10.1155/2013/215034. DOI: 10.1155/2013/215034. PMID: 23762600. PMCID: PMC3671545.

5. Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, et al. 2017; Antiresorptive agent-related osteonecrosis of the jaw: position paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. J Bone Miner Metab. 35:6–19. https://doi.org/10.1007/s00774-016-0810-7. DOI: 10.1007/s00774-016-0810-7. PMID: 28035494.

6. Jeong HG, Hwang JJ, Lee JH, Kim YH, Na JY, Han SS. 2017; Risk factors of osteonecrosis of the jaw after tooth extraction in osteoporotic patients on oral bisphosphonates. Imaging Sci Dent. 47:45–50. https://doi.org/10.5624/isd.2017.47.1.45. DOI: 10.5624/isd.2017.47.1.45. PMID: 28361029. PMCID: PMC5370245.

7. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. 2014; ; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 72:1938–56. https://doi.org/10.1016/j.joms.2014.04.031. DOI: 10.1016/j.joms.2014.04.031. PMID: 25234529.

8. Kim KM, Rhee Y, Kwon YD, Kwon TG, Lee JK, Kim DY. 2015; Medication related osteonecrosis of the jaw: 2015 position statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons. J Bone Metab. 22:151–65. https://doi.org/10.11005/jbm.2015.22.4.151. DOI: 10.11005/jbm.2015.22.4.151. PMID: 26713306. PMCID: PMC4691589.

9. Anagnostis P, Paschou SA, Mintziori G, Ceausu I, Depypere H, Lambrinoudaki I, et al. 2017; Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement. Maturitas. 101:23–30. https://doi.org/10.1016/j.maturitas.2017.04.008. DOI: 10.1016/j.maturitas.2017.04.008. PMID: 28539165.

10. Marx RE, Cillo JE Jr, Ulloa JJ. 2007; Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg. 65:2397–410. https://doi.org/10.1016/j.joms.2007.08.003. DOI: 10.1016/j.joms.2007.08.003. PMID: 18022461.

11. Damm DD, Jones DM. 2013; Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen Dent. 61:33–8. PMID: 23928436.

12. Wutzl A, Pohl S, Sulzbacher I, Seemann R, Lauer G, Ewers R, et al. 2012; Factors influencing surgical treatment of bisphosphonate-related osteonecrosis of the jaws. Head Neck. 34:194–200. https://doi.org/10.1002/hed.21708. DOI: 10.1002/hed.21708. PMID: 21400630.

13. Kang MH, Lee DK, Kim CW, Song IS, Jun SH. 2018; Clinical characteristics and recurrence-related factors of medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg. 44:225–31. https://doi.org/10.5125/jkaoms.2018.44.5.225. DOI: 10.5125/jkaoms.2018.44.5.225. PMID: 30402414. PMCID: PMC6209697.

14. Kim YH, Lee HK, Song SI, Lee JK. 2014; Drug holiday as a prognostic factor of medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg. 40:206–10. https://doi.org/10.5125/jkaoms.2014.40.5.206. DOI: 10.5125/jkaoms.2014.40.5.206. PMID: 25368832. PMCID: PMC4217272.

15. Ramaglia L, Guida A, Iorio-Siciliano V, Cuozzo A, Blasi A, Sculean A. 2018; Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol. Clin Oral Investig. 22:597–615. https://doi.org/10.1007/s00784-017-2325-6. DOI: 10.1007/s00784-017-2325-6. PMID: 29332231.

16. Ottesen C, Schiodt M, Gotfredsen K. 2020; Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): a systematic review. Heliyon. 6:e03795. https://doi.org/10.1016/j.heliyon.2020.e03795. DOI: 10.1016/j.heliyon.2020.e03795. PMID: 32373730. PMCID: PMC7191576.

17. Morishita K, Soutome S, Otsuru M, Hayashida S, Murata M, Sasaki M, et al. 2022; Relationship between drug holiday of the antiresorptive agents and surgical outcome of medication-related osteonecrosis of the jaw in osteoporosis patients. Sci Rep. 12:11545. https://doi.org/10.1038/s41598-022-15720-7. DOI: 10.1038/s41598-022-15720-7. PMID: 35799050. PMCID: PMC9263140.

18. Ruggiero SL. 2015; Diagnosis and staging of medication-related osteonecrosis of the jaw. Oral Maxillofac Surg Clin North Am. 27:479–87. https://doi.org/10.1016/j.coms.2015.06.008. DOI: 10.1016/j.coms.2015.06.008. PMID: 26293329.

19. Reich W, Bilkenroth U, Schubert J, Wickenhauser C, Eckert AW. 2015; Surgical treatment of bisphosphonate-associated osteonecrosis: prognostic score and long-term results. J Craniomaxillofac Surg. 43:1809–22. https://doi.org/10.1016/j.jcms.2015.07.035. DOI: 10.1016/j.jcms.2015.07.035. PMID: 26321065.

20. Ihan Hren N, Miljavec M. 2008; Spontaneous bone healing of the large bone defects in the mandible. Int J Oral Maxillofac Surg. 37:1111–6. https://doi.org/10.1016/j.ijom.2008.07.008. DOI: 10.1016/j.ijom.2008.07.008. PMID: 18760900.

21. Park MS, Eo MY, Myoung H, Kim SM, Lee JH. 2019; Early diagnosis of jaw osteomyelitis by easy digitalized panoramic analysis. Maxillofac Plast Reconstr Surg. 41:6. https://doi.org/10.1186/s40902-019-0188-2. DOI: 10.1186/s40902-019-0188-2. PMID: 30800645. PMCID: PMC6358629.

22. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. 2004; Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 62:527–34. https://doi.org/10.1016/j.joms.2004.02.004. DOI: 10.1016/j.joms.2004.02.004. PMID: 15122554.

23. Cauley JA. 2015; Estrogen and bone health in men and women. Steroids. 99(Pt A):11–5. https://doi.org/10.1016/j.steroids.2014.12.010. DOI: 10.1016/j.steroids.2014.12.010. PMID: 25555470.

24. Kwon YD, Lee CY, Hong SO, Lee YA, Ohe JY, Kim DY. 2016; Bisphosphonate related osteonecrosis of the jaws (BRONJ) in osteoporotic males. Springerplus. 5:1468. https://doi.org/10.1186/s40064-016-3138-9. DOI: 10.1186/s40064-016-3138-9. PMID: 27652043. PMCID: PMC5007241.

25. Shibahara T. 2019; Antiresorptive agent-related osteonecrosis of the jaw (ARONJ): a twist of fate in the bone. Tohoku J Exp Med. 247:75–86. https://doi.org/10.1620/tjem.247.75. DOI: 10.1620/tjem.247.75. PMID: 30713280.

26. Wang JY, Huo L, Yu RQ, Rao NJ, Lu WW, Zheng LW. 2019; Skeletal site-specific response of jawbones and long bones to surgical interventions in rats treated with zoledronic acid. Biomed Res Int. 2019:5138175. https://doi.org/10.1155/2019/5138175. DOI: 10.1155/2019/5138175. PMID: 31930124. PMCID: PMC6942746.

27. Schoenhof R, Munz A, Yuan A, ElAyouti A, Boesmueller H, Blumenstock G, et al. 2021; Microarchitecture of medication-related osteonecrosis of the jaw (MRONJ); a retrospective micro-CT and morphometric analysis. J Craniomaxillofac Surg. 49:508–17. https://doi.org/10.1016/j.jcms.2021.02.018. DOI: 10.1016/j.jcms.2021.02.018. PMID: 33707134.

28. Mercer E, Norton T, Woo S, Treister N, Dodson TB, Solomon DH. 2013; Ninety-one osteoporosis patients affected with bisphosphonate-related osteonecrosis of the jaw: a case series. Calcif Tissue Int. 93:241–8. https://doi.org/10.1007/s00223-013-9747-1. DOI: 10.1007/s00223-013-9747-1. PMID: 23756612. PMCID: PMC3744621.

29. Kim J, Shin JY, Lee J, Song HJ, Choi NK, Park BJ. 2015; Comparison of the prescribing pattern of bisphosphonate and raloxifene in Korean women with osteoporosis: from a national health insurance claims database. PLoS One. 10:e0127970. https://doi.org/10.1371/journal.pone.0127970. DOI: 10.1371/journal.pone.0127970. PMID: 26030300. PMCID: PMC4451256.

30. Figueiredo MA, Medeiros FB, Ortega KL. 2020; Osteonecrosis of the jaw in a patient under treatment of osteoporosis with oral bisphosphonate. Autops Case Rep. 11:e2020186. https://doi.org/10.4322/acr.2020.186. DOI: 10.4322/acr.2020.186. PMID: 33968812. PMCID: PMC8020591.

31. Kim HY, Lee SJ, Kim SM, Myoung H, Hwang SJ, Choi JY, et al. 2017; Extensive surgical procedures result in better treatment outcomes for bisphosphonate-related osteonecrosis of the jaw in patients with osteoporosis. J Oral Maxillofac Surg. 75:1404–13. https://doi.org/10.1016/j.joms.2016.12.014. DOI: 10.1016/j.joms.2016.12.014. PMID: 28039736.

32. Mücke T, Koschinski J, Deppe H, Wagenpfeil S, Pautke C, Mitchell DA, et al. 2011; Outcome of treatment and parameters influencing recurrence in patients with bisphosphonate-related osteonecrosis of the jaws. J Cancer Res Clin Oncol. 137:907–13. https://doi.org/10.1007/s00432-010-0953-1. DOI: 10.1007/s00432-010-0953-1. PMID: 20927569.

33. Okuyama K, Hayashida S, Rokutanda S, Kawakita A, Soutome S, Sawada S, et al. 2021; Surgical strategy for medication-related osteonecrosis of the jaw (MRONJ) on maxilla: a multicenter retrospective study. J Dent Sci. 16:885–90. DOI: 10.1016/j.jds.2020.12.007. PMID: 34141102. PMCID: PMC8189890.

34. Wongratwanich P, Shimabukuro K, Konishi M, Nagasaki T, Ohtsuka M, Suei Y, et al. 2021; Do various imaging modalities provide potential early detection and diagnosis of medication-related osteonecrosis of the jaw? A review. Dentomaxillofac Radiol. 50:20200417. https://doi.org/10.1259/dmfr.20200417. DOI: 10.1259/dmfr.20200417. PMID: 33411572. PMCID: PMC8404513.

35. Seo MH, Eo MY, Myoung H, Kim SM, Lee JH. 2020; The effects of pentoxifylline and tocopherol in jaw osteomyelitis. J Korean Assoc Oral Maxillofac Surg. 46:19–27. https://doi.org/10.5125/jkaoms.2020.46.1.19. DOI: 10.5125/jkaoms.2020.46.1.19. PMID: 32158677. PMCID: PMC7049758.

36. Lapić I, Padoan A, Bozzato D, Plebani M. 2020; Erythrocyte sedimentation rate and C-reactive protein in acute inflammation. Am J Clin Pathol. 153:14–29. https://doi.org/10.1093/ajcp/aqz142. DOI: 10.1093/ajcp/aqz142. PMID: 31598629.

37. Hawkins D, Abrahamse H. 2007; How should an increase in alkaline phosphatase activity be interpreted? Laser Chem. 2007:049608. https://doi.org/10.1155/2007/49608. DOI: 10.1155/2007/49608.

38. Kim SM, Eo MY, Cho YJ, Kim YS, Lee SK. 2017; Wound healing protein profiles in the postoperative exudate of bisphosphonate-related osteonecrosis of mandible. Eur Arch Otorhinolaryngol. 274:3485–95. https://doi.org/10.1007/s00405-017-4657-x. DOI: 10.1007/s00405-017-4657-x. PMID: 28647850.

39. Koth VS, Figueiredo MA, Salum FG, Cherubini K. 2017; Interrelationship of clinical, radiographic and haematological features in patients under bisphosphonate therapy. Dentomaxillofac Radiol. 46:20160260. https://doi.org/10.1259/dmfr.20160260. DOI: 10.1259/dmfr.20160260. PMID: 28107028. PMCID: PMC5595000.

40. Choi SY, An CH, Kim SY, Kwon TG. 2013; Bone turnover and inflammatory markers of bisphosphonate-related osteonecrosis of the jaw in female osteoporosis patients. J Oral Maxillofac Surg Med Pathol. 25:123–8. https://doi.org/10.1016/j.ajoms.2012.06.007. DOI: 10.1016/j.ajoms.2012.06.007.

41. Thumbigere-Math V, Michalowicz BS, Hughes PJ, Basi DL, Tsai ML, Swenson KK, et al. 2016; 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. 74:738–46. https://doi.org/10.1016/j.joms.2015.09.028. DOI: 10.1016/j.joms.2015.09.028. PMID: 26501428. PMCID: PMC4909718.

42. Webber M, Krishnan A, Thomas NG, Cheung BM. 2010; Association between serum alkaline phosphatase and C-reactive protein in the United States National Health and Nutrition Examination Survey 2005-2006. Clin Chem Lab Med. 48:167–73. https://doi.org/10.1515/cclm.2010.052. DOI: 10.1515/CCLM.2010.052. PMID: 19958209.

43. Seo MS, Shim JY, Lee YJ. 2019; Relationship between serum alkaline phosphatase level, C-reactive protein and leukocyte counts in adults aged 60 years or older. Scand J Clin Lab Invest. 79:233–7. https://doi.org/10.1080/00365513.2019.1585567. DOI: 10.1080/00365513.2019.1585567. PMID: 30888211.

44. Taniguchi N, Osaki M, Onuma K, Ishikawa M, Ryoke K, Kodani I, et al. 2020; Bisphosphonate-induced reactive oxygen species inhibit proliferation and migration of oral fibroblasts: a pathogenesis of bisphosphonate-related osteonecrosis of the jaw. J Periodontol. 91:947–55. DOI: 10.1002/JPER.19-0385. PMID: 31863459.

45. Liu D, Du J, Sun J, Li M. 2021; Parathyroid hormone-related protein inhibits nitrogen-containing bisphosphonate-induced apoptosis of human periodontal ligament fibroblasts by activating MKP1 phosphatase. Bioengineered. 12:1997–2006. https://doi.org/10.1080/21655979.2021.1928930. DOI: 10.1080/21655979.2021.1928930. PMID: 34024253. PMCID: PMC8806876.

46. Lee SS, Kim SM, Kim YS, Lee SK. 2020; Extensive protein expression changes induced by pamidronate in RAW 264.7 cells as determined by IP-HPLC. PeerJ. 8:e9202. https://doi.org/10.7717/peerj.9202. DOI: 10.7717/peerj.9202. PMID: 32509464. PMCID: PMC7246033.

47. Hess DR. 2004; Retrospective studies and chart reviews. Respir Care. 49:1171–4. PMID: 15447798.

48. Gearing RE, Mian IA, Barber J, Ickowicz A. 2006; A methodology for conducting retrospective chart review research in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 15:126–34. PMID: 18392182. PMCID: PMC2277255.