Skip to main content

Advertisement

Log in

The utility of bone scintigraphy in the assessment of mandibular metabolism during long-term bisphosphonate administration

  • Original Article
  • Published:
Odontology Aims and scope Submit manuscript

Abstract

The duration of antiresorptive therapy is an important risk factor for medication-related osteonecrosis of the jaw. We performed a pilot study using quantitative analysis by bone scintigraphy to test the hypothesis that mandibular metabolism is affected by long-term bisphosphonate (BP) therapy. Our primary objectives were to assess changes in bone metabolism of the mandible in response to long-term BP therapy and compare the bone metabolism changes of the mandible with other bone sites. We compared the metabolic difference at the site in the mandible unaffected by disease, the humerus and the femur between 14 osteoporosis patients who were being treated with BP (BP group) and 14 patients who were not being treated with BP (control group) using a quantitative analysis and bone scintigraphy. Study endpoints were the mean and maximum bone uptake values (BUVs) quantified using bone scintigraphy images of the mandible, humerus and femur. Quantified images of the site in the mandible unaffected by disease had significantly higher mean and maximum BUVs compared to the controls (mean, 0.74 vs. 0.49, p = 0.019; max., 1.29 vs. 0.85, p = 0.009, respectively). The mean and maximum BUV of femur ROIs in the BP group were significantly lower than those in control patients (mean BUV, 0.23 vs. 0.30, p = 0.039; max. BUV, 0.43 vs. 0.53, p = 0.024, respectively). This is the first report of mandible changes in response to long-term BP treatment, using bone scintigraphy. The results using bone scintigraphy demonstrated that the bone metabolism of the intact mandible is affected by a long-term administration of BP.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. 2010;68:243–53.

    Article  PubMed  Google Scholar 

  2. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125–32.

    Article  PubMed  Google Scholar 

  3. Gabbert TI, Hoffmeister B, Felsenberg D. Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients. J Cancer Res Clin Oncol. 2015;141:749–58.

    Article  PubMed  Google Scholar 

  4. Kwon JW, Park EJ, Jung SY, Sohn HS, Ryu H, Suh HS. A large national cohort study of the association between bisphosphonates and osteonecrosis of the jaw in patients with osteoporosis: a nested case-control study. J Dent Res. 2015;94(9 Suppl):212S–9S.

    Article  PubMed  Google Scholar 

  5. Kimmel DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res. 2007;86:1022–33.

    Article  PubMed  Google Scholar 

  6. Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ. Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells. Bone. 2008;42:848–60.

    Article  PubMed  Google Scholar 

  7. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998;13:581–9.

    Article  PubMed  Google Scholar 

  8. Luckman SP, Coxon FP, Ebetino FH, Russell RG, Rogers MJ. Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure–activity relationships in J774 macrophages. J Bone Miner Res. 1998;13:1668–78.

    Article  PubMed  Google Scholar 

  9. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA. Mechanism of action of alendronate:geranylgeraniol, an intermediate of the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption and kinase activation in vitro. Proc Natl Acad Sci USA. 1999;96:133–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. van Beek E, Pieterman E, Cohen L, Löwik C, Papapoulos S. Papapoulos. Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun. 1999;255:491–4.

    Article  PubMed  Google Scholar 

  11. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ. Structure–activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296:235–42.

    PubMed  Google Scholar 

  12. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. PNAS. 2006;103:7829–34.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Reszka AA, Rodan GA. Bisphosphonate mechanism of action. Curr Rheumatol Rep. 2003;5:65–74.

    Article  PubMed  Google Scholar 

  14. Flanagan AM, Chambers TJ. Dichloromethylenebisphosphonate (Cl2MBP) inhibits bone resorption through injury to osteoclasts that resorb Cl2MBP-coated bone. Bone Miner. 1986;6:33–43.

    Article  Google Scholar 

  15. Ito M, Chokki M, Ogino Y, Satomi Y, Azuma Y, Ohta T, Kiyoki M. Comparison of the cytotoxic effects of bisphosphnates in vitro and in vivo. Calcif Tissue Int. 1998;63:143–7.

    Article  PubMed  Google Scholar 

  16. Breuil V, Cosman F, Stein L, Horbert W, Nieves J, Shen V, Lindsay R, Dempster DW. Human osteoclast formation and activity in vitro: effects of alendronate. J Bone Miner Res. 1998;13:1721–9.

    Article  PubMed  Google Scholar 

  17. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR, Boyce BF. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 1995;10:1478–87.

    Article  PubMed  Google Scholar 

  18. Selander KS, Mönkkönen J, Karhukorpi EK, Härkönen P, Hannuniemi R, Väänänen HK. Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages. Mol Pharmacol. 1996;50:1127–38.

    PubMed  Google Scholar 

  19. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000;27:687–94.

    Article  PubMed  Google Scholar 

  20. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone. 2001;29:185–91.

    Article  PubMed  Google Scholar 

  21. Orriss IR, Key ML, Colston KW, Arnett TR. Inhibition of osteoblast function in vitro by aminobisphosphonates. J Cell Biochem. 2009;106:109–18.

    Article  PubMed  Google Scholar 

  22. Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg. 2009;67:61–70.

    Article  PubMed  Google Scholar 

  23. Bauer DC, Black DM, Garnero P, Hochberg M, Ott S, Orloff J, Thompson DE, Ewing SK, Delmas PD. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res. 2004;19:1250–8.

    Article  PubMed  Google Scholar 

  24. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24:153–61.

    Article  PubMed  Google Scholar 

  25. Bala Y, Farlay D, Chapurlat RD, Boivin G. Modifications of bone material properties in postmenopausal osteoporotic women long-term treated with alendronate. Eur J Endocrinol. 2011;165:647–55.

    Article  PubMed  Google Scholar 

  26. Arlot M, Meunier PJ, Boivin G, Haddock L, Tamayo J, Correa-Rotter R, Jasqui S, Donley DW, Dalsky GP, Martin JS, Eriksen EF. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res. 2005;20:1244–53.

    Article  PubMed  Google Scholar 

  27. Chavassieux P, Meunier PJ, Roux JP, Portero-Muzy N, Pierre M, Chapurlat R. Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women: randomized comparison to alendronate. J Bone Miner Res. 2014;29:618–28.

    Article  PubMed  Google Scholar 

  28. Yamagami Y, Mashiba T, Iwata K, Tanaka M, Nozaki K, Yamamoto T. Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys. Bone. 2013;54:1–7.

    Article  PubMed  Google Scholar 

  29. Carnevale V, Dicembrino F, Frusciante V, Chiodini I, Minisola S, Scillitani A. Different patterns of global and regional skeletal uptake of 99mTc-methylene diphosphonate with age: relevance to the pathogenesis of bone loss. J Nucl Med. 2000;41:1478–83.

    PubMed  Google Scholar 

  30. Zanglis A, Andreopoulos D, Dima M, Baltas G, Baziotis N. Jaw uptake of technetium-99 methylene diphosphonate in patients on biphosphonates: a word of caution. Hell J Nucl Med. 2007;10:177–80.

    PubMed  Google Scholar 

  31. Tryniszewski W, Gadzicki M, Gorska-Chrzastek M, Rysz J, Maziarz Z. Bone metabolism assessment, bone metabolism index designation and the determination of its normal values range in young healthy women. Med Sci Monit. 2011;17:CR563–71.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Termaat MF, Raijmakers PG, Scholten HJ, Bakker FC, Patka P, Haarman HJ. The accuracy of diagnostic imaging for the assessment of chronic osteomyelitis: a systematic review and meta-analysis. J Bone Joint Surg Am. 2005;87:2464–71.

    PubMed  Google Scholar 

  33. Ristow O, Gerngroß C, Schwaiger M, Hohlweg-Majert B, Kehl V, Jansen H, Hahnefeld L, Koerdt S, Otto S, Pautke C. Effect of antiresorptive drugs on bony turnover in the jaw: denosumab compared with bisphosphonates. Br J Oral Maxillofac Surg. 2014;52:308–13.

    Article  PubMed  Google Scholar 

  34. O’Ryan FS, Khoury S, Liao W, Han MM, Hui RL, Baer D, Martin D, Liberty D, Lo JC. Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J Oral Maxillofac Surg. 2009;67:1363–72.

    Article  PubMed  Google Scholar 

  35. Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ, Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou L, Daniels A, Carriere P, Dansey R. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23:1341–7.

    Article  PubMed  Google Scholar 

  36. Morris PG, Hudis C, Carrasquillo J, Larson S, Grewal RK, Van Poznak C. Bone scans, bisphosphonates, and a lack of acute changes within the mandible. J Oral Maxillofac Surg. 2011;69:114–9.

    Article  PubMed  Google Scholar 

  37. Ristow O, Gerngross C, Schwaiger M, Hohlweg-Majert B, Kehl V, Jansen H, Hahnefeld L, Otto S, Pautke C. Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? J Oral Maxillofac Surg. 2014;72:903–10.

    Article  PubMed  Google Scholar 

  38. Ristow O, Gerngross C, Schwaiger M, Hohlweg-Majert B, Ristow M, Koerdt S, Schuster R, Otto S, Pautke C. Does regular zoledronic acid change the bone turnover of the jaw in men with metastatic prostate cancer: a possible clue to the pathogenesis of bisphosphonate related osteonecrosis of the jaw? J Cancer Res Clin Oncol. 2014;140:487–93.

    Article  PubMed  Google Scholar 

  39. Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the. Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007;65:369–76.

    Article  Google Scholar 

  40. Arano Y. Recent advances in 99mTc radiopharmaceuticals. Ann Nucl Med. 2002;16:79–93.

    Article  PubMed  Google Scholar 

  41. Borah B, Ritman EL, Dufresne TE, Jorgensen SM, Liu S, Sacha J, Phipps RJ, Turner RT. The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover. Bone. 2005;37:1–9.

    Article  PubMed  Google Scholar 

  42. Chapurlat RD, Delmas PD. Bone microdamage: a clinical perspective. Osteoporos Int. 2009;20:1299–308.

    Article  PubMed  Google Scholar 

  43. Chapurlat RD, Arlot M, Burt-Pichat B, Chavassieux P, Roux JP, Portero-Muzy N, Delmas PD. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res. 2007;22:1502–9.

    Article  PubMed  Google Scholar 

  44. Patel VC, Lazzarini AM. Bilateral simultaneous femoral diaphyseal fractures in a patient with long-term ibandronate use. Orthopedics. 2010;33:775.

    PubMed  Google Scholar 

  45. Iwata K, Mashiba T, Hitora T, Yamagami Y, Yamamoto T. A large amount of microdamages in the cortical bone around fracture site in a patient of atypical femoral fracture after long-term bisphosphonate therapy. Bone. 2014;64:183–6.

    Article  PubMed  Google Scholar 

  46. Hoefert S, Schmitz I, Tannapfel A, Eufinger H. Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin Oral Investig. 2010;14:271–84.

    Article  PubMed  Google Scholar 

  47. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007;357:905–16.

    Article  PubMed  Google Scholar 

  48. Burr DB, Allen MR. Mandibular necrosis in beagle dogs treated with bisphosphonates. Orthod Craniofac Res. 2009;12:221–8.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Okamoto Y. Accumulation of technetium-99m methylene diphosphonate. Conditions affecting adsorption to hydroxyapatite. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80:115–9.

    Article  PubMed  Google Scholar 

  50. Burr DB, Kubek DJ, Allen MR. Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res. 2010;25:98–105.

    Article  PubMed  Google Scholar 

  51. Uchida K, Nakajima H, Miyazaki T, Yayama T, Kawahara H, Kobayashi S, Tsuchida T, Okazawa H, Fujibayashi Y, Baba H. Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured by 18F-fluoride PET: a prospective study. J Nucl Med. 2009;50:1808–14.

    Article  PubMed  Google Scholar 

  52. Lovy AJ, Koehler SM, Keswani A, Joseph D, Hasija R, Ghillani R. Atypical femur fracture during bisphosphonate drug holiday: a case series. Osteoporos Int. 2015;26:1755–8.

    Article  PubMed  Google Scholar 

  53. Gatti D, Adami S, Viapiana O, Rossini M. The use of bisphosphonates in women: when to use and when to stop. Expert Opin Pharmacother 2015:1–13.

Download references

Acknowledgments

This study was supported by the JSPS KAKENHI, Grant No. 26463011.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yumiko Ohbayashi.

Ethics declarations

The protocols, patient information, and informed consent forms were reviewed and approved by the Kagawa University Ethical Committee (H24–#106).

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ohbayashi, Y., Nakai, F., Iwasaki, A. et al. The utility of bone scintigraphy in the assessment of mandibular metabolism during long-term bisphosphonate administration. Odontology 105, 382–390 (2017). https://doi.org/10.1007/s10266-016-0279-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10266-016-0279-9

Keywords

Navigation