Journal of Bone and Mineral Metabolism

, Volume 37, Issue 4, pp 676–684 | Cite as

Quantitation and distribution of metallic elements in sequestra of medication-related osteonecrosis of jaw (MRONJ) using inductively coupled plasma atomic emission spectroscopy and synchrotron radiation X-ray fluorescence analysis

  • Ruri Komiya
  • Takahiro Wada
  • Fumihiko Tsushima
  • Kei Sakamoto
  • Tohru Ikeda
  • Akira Yamaguchi
  • Hiroyuki Harada
  • Motohiro UoEmail author
Original Article


Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive agents like bisphosphonates. Abnormal concentrations of various trace metallic elements contained in bone minerals have been associated with MRONJ. In this study, we focused on trace metallic elements contained in the MRONJ sequestrum; their content and distribution were compared to those in osteomyelitis and non-inflammatory bones using inductively coupled plasma atomic emission spectroscopy (ICP-AES) and synchrotron radiation X-ray fluorescence analysis (SR-XRF). On ICP-AES analyses, various trace elements (Co, Cr, Cu, Fe, K, Mg, Ni, Sb, Ti, V, Pb) were significantly more in MRONJ sequestra than non-inflammatory bones. The Cu content was significantly higher in MRONJ sequestra than osteomyelitis and non-inflammatory bones. The Cu content in MRONJ sequestra was high even after decalcification. Additionally, Cu was distributed along the trabecular structures in decalcified MRONJ specimens, as observed using SR-XRF analysis. Therefore, this study was indicative of the characteristic behavior of Cu in MRONJ.


Medication-related osteonecrosis of the jaw (MRONJ) Trace metallic element Inductively coupled plasma atomic emission spectroscopy (ICP-AES) Synchrotron radiation X-ray fluorescence analysis (SR-XRF) 



The authors would like to thank Ms. Miwako Hamagaki for the preparation of the specimens for elemental analyses. SR-XRF measurements were performed with the approval of the Photon Factory Program Advisory Committee (Proposal no. 2016G018). This work was supported by a Grant-in Aid from the Japan Society for the Promotion of Science (JSPS no. 16H02688).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All patients provided informed consent and the study protocol was approved by the Ethical Committee of Tokyo Medical and Dental University (D2016-002)

Supplementary material

774_2018_975_MOESM1_ESM.doc (54 kb)
Supplementary material 1 (DOC 54 kb)


  1. 1.
    Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaw: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117CrossRefGoogle Scholar
  2. 2.
    Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 72:1938–1956CrossRefGoogle Scholar
  3. 3.
    Coleman R, Woodward E, Brown J, Cameron D, Bell R, Dodwell D, Keane M, Gil M, Davies C, Burkinshaw R, Houston SJ, Grieve RJ, Barrett-Lee PJ, Thorpe H (2011) Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01–04) for women with stage II/III breast cancer. Breast Cancer Res Treat 127:429–438CrossRefGoogle Scholar
  4. 4.
    Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis CG, Boukovinas I, Koloutsos GE, Teleioudis Z, Kitikidou K, Paraskevopoulos P, Zervas K, Antoniades K (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27:5356–5362CrossRefGoogle Scholar
  5. 5.
    Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, Hutchinson M, Lathon PV, Sanchez G, Silver P, Chandra M, McCloskey CA, Staffa JA, Willy M, Selby JV, Go AS (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243–253CrossRefGoogle Scholar
  6. 6.
    Qi WX, Tang LN, He AN, Yao Y, Shen Z (2014) Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 16:403–410CrossRefGoogle Scholar
  7. 7.
    Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F (2015) Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis. J Clin Periodontol 42:922–932CrossRefGoogle Scholar
  8. 8.
    Kim JW, Kong KA, Kim SJ, Choi SK, Cha IH, Kim MR (2013) Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates. Bone 57:201–205CrossRefGoogle Scholar
  9. 9.
    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 65:2397–2410CrossRefGoogle Scholar
  10. 10.
    Lowe NM, Fraser WD, Jackson MJ (2002) Is there a potential therapeutic value of copper and zinc for osteoporosis? Proc Nutr Soc 61:181–185CrossRefGoogle Scholar
  11. 11.
    Koçer G, Nazıroğlu M, Çelik Ö, Önal L, Özçelik D, Koçer M, Sönmez TT (2013) Basic fibroblast growth factor attenuates bisphosphonate-induced oxidative injury but decreases zinc and copper levels in oral epithelium of rat. Biol Trace Elem Res 153:251–256CrossRefGoogle Scholar
  12. 12.
    Sugiyama T, Uo M, Mizoguchi T, Wada T, Omagari D, Komiyama K, Mori Y (2015) Copper accumulation in the sequestrum of medication-related osteonecrosis of the jaw. Bone Rep 3:40–47CrossRefGoogle Scholar
  13. 13.
    Baslé MF, Mauras Y, Audran M, Clochon P, Rebel A, Allain P (1990) Concentration of bone elements in osteoporosis. J Bone Miner Res 5:41–47CrossRefGoogle Scholar
  14. 14.
    Chappard D, Bizot P, Mabilleau G, Hubert L (2016) Aluminum and bone: review of new clinical circumstances associated with Al3+ deposition in the calcified matrix of bone. Morphologie 100:95–105CrossRefGoogle Scholar
  15. 15.
    Newnham RR (1994) Essentiality of boron for healthy bones and joints. Environ Health Perspect 102:83–85Google Scholar
  16. 16.
    Tisato F, Marzano C, Porchia M, Pellei M, Santini C (2010) Copper in diseases and treatments, and copper-based anticancer strategies. Med Res Rev 30:708–749Google Scholar
  17. 17.
    Harvey LJ, McArdle HJ (2008) Biomarkers of copper status: a brief update. Br J Nutr 99:S10–S13CrossRefGoogle Scholar
  18. 18.
    Marquardt ML, Done SL, Sandrock M, Berdon WE, Feldman KW (2012) Copper deficiency presenting as metabolic bone disease in extremely low birth weight, short-gut infants. Pediatrics 130:e1–e4CrossRefGoogle Scholar
  19. 19.
    Qu X, He Z, Qiao H, Zhai Z, Mao Z, Yu Z, Dai K (2018) Serum copper levels are associated with bone mineral density and total fracture. J Orthop Transl 14:34–44Google Scholar
  20. 20.
    Rico H, Roca-Botran C, Hernández ER, Seco C, Paez E, Valencia MJ, Villa LF (2000) The effect of supplemental copper on osteopenia induced by ovariectomy in rats. Menopause 7:413–416CrossRefGoogle Scholar
  21. 21.
    Rest JR (1976) The histological effects of copper and zinc on chick embryo skeletal tissues in organ culture. Br J Nutr 36:243–256CrossRefGoogle Scholar
  22. 22.
    Kaji T, Kawatani R, Takata M, Hoshino T, Miyahara T, Kozuka H, Koizumi F (1988) The effect of cadmium, copper or zinc on formation of embryonic chick bone in tissue culture. Toxicology 50:303–316CrossRefGoogle Scholar
  23. 23.
    Li S, Wang M, Chen X, Li SF, Ling L, Xie HQ (2014) Inhibition of osteogenic differentiation of mesenchymal stem cells by copper supplementation. Cell Prolif 47:81–90CrossRefGoogle Scholar
  24. 24.
    Massie HR, Aiello VR, Shumway ME, Armstrong T (1990) Calcium, iron, copper, boron, collagen, and density changes in bone with aging in C57BL/6 J male mice. Exp Gerontol 25:469–481CrossRefGoogle Scholar
  25. 25.
    World Health Organization (1996) Trace elements in human nutrition and health. World Health Organization, Geneva, pp 123–143. Accessed 15 Oct 2018

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Ruri Komiya
    • 1
  • Takahiro Wada
    • 2
  • Fumihiko Tsushima
    • 1
  • Kei Sakamoto
    • 3
  • Tohru Ikeda
    • 3
  • Akira Yamaguchi
    • 3
    • 4
  • Hiroyuki Harada
    • 1
  • Motohiro Uo
    • 2
    • 5
    Email author
  1. 1.Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Advanced Biomaterials, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  3. 3.Department of Oral Pathology, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  4. 4.Oral Health Science CenterTokyo Dental CollegeTokyoJapan
  5. 5.Department of Materials Engineering, Graduate School of EngineeringThe University of TokyoTokyoJapan

Personalised recommendations