Abstract
Background
Bisphosphonate and denosumab are widely used for the treatment of osteoporosis and bone metastasis of cancer to prevent excessive bone resorption. Osteonecrosis of the jaw is a serious adverse effect of bisphosphonate or denosumab referred to as bisphosphonate-related osteonecrosis of the jaw (BRONJ) or denosumab-related osteonecrosis of the jaw (DRONJ), respectively. Since bisphosphonate and denosumab inhibit bone resorption by different mechanism, we evaluated whether these drug types result in different histopathological characteristics related to bone resorption.
Materials and Methods
We histopathologically investigated 10 cases of BRONJ, DRONJ, and suppurative osteomyelitis. Paraffin sections prepared from decalcified dissected jaw bones were used for histopathological observation, second harmonic generation imaging, and bone histomorphometry. The samples were also observed by a scanning electron microscope.
Results
Numerous bone resorption lacunae were observed on the necrotic bone surface in almost all cases of BRONJ; however, such resorption lacunae were limited in DRONJ and suppurative osteomyelitis. Prominent bone resorption lacunae were also confirmed by second harmonic generation imaging and scanning electron microscopy in BRONJ, but not in DRONJ or suppurative osteomyelitis. As determined by bone histomorphometry, the number of bone resorption lacunae and the length of the erosion surface of resorption lacunae were significantly higher in BRONJ group than in the DRONJ and suppurative osteomyelitis groups. These parameters were correlated between the necrotic bones and the vital bones in BRONJ.
Conclusions
Persistent bone resorption lacunae on the necrotic bone surface are unique to BRONJ, providing a basis for distinguishing BRONJ from DRONJ and OM in histopathological diagnosis.
Similar content being viewed by others
References
Fizazi K, Carducci M, Smith M, Damião R, Brown J et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822
Baron R, Ferrari S, Russell RG (2011) Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48:677–692
Rogers MJ, Monkkonen J, Munoz MA (2020) Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone 139:115493
Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC et al (2012) Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11:401–419
Cai G, Laslett LL, Aitken D, Halliday A, Pan F et al (2018) Effect of zoledronic acid and denosumab in patients with low back pain and modic change: a proof-of-principle trial. J Bone Miner Res 33:773–782
Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117
Taylor KH, Middlefell LS, Mizen KD (2010) Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg 48:221–223
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T et al (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update. J Oral Maxillofac Surg 72:1938–1956
Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi 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
McGowan K, McGowan T, Ivanovski S (2018) Risk factors for medication-related osteonecrosis of the jaws: a systematic review. Oral Dis 24:527–536
Hansen T, Kirkpatrick CJ, Walter C, Kunkel M (2006) Increased numbers of osteoclasts expressing cysteine proteinase cathepsin K in patients with infected osteoradionecrosis and bisphosphonate-associated osteonecrosis–a paradoxical observation? Virchows Arch 449:448–454
Hansen T, Kunkel M, Weber A, James Kirkpatrick C et al (2006) Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155–160
Marx RE, Tursun R (2012) Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease. Int J Oral Maxillofac Surg 41:283–289
Favia G, Pilolli GP, Maiorano E (2009) Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone 45:406–413
Koerdt S, Dax S, Grimaldi H, Ristow O, Kuebler AC et al (2014) Histomorphologic characteristics of bisphosphonate-related osteonecrosis of the jaw. J Oral Pathol Med 43:448–453
Hinson AM, Smith CW, Siegel ER, Stack BC Jr et al (2014) Is bisphosphonate-related osteonecrosis of the jaw an infection? A histological and microbiological ten-year summary. Int J Dent 2014:452737
Franco-Pretto E, Pacheco M, Moreno A, Messa O, Gnecco J et al (2014) Bisphosphonate-induced osteonecrosis of the jaws: clinical, imaging, and histopathology findings. Oral Surg Oral Med Oral Pathol Oral Radiol 118:408–417
Kim SM, Eo MY, Kim YS, Lee SK et al (2017) Histochemical observation of bony reversal lines in bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 123:220–228
Gross C, Weber M, Creutzburg K, Mobius P, Preidl R et al (2017) Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis. J Transl Med 15:128
Hoefert S, Yuan A, Munz A, Grimm M, Elayouti A et al (2017) Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ). J Craniomaxillofac Surg 45:570–578
Matsushita Y, Hayashida S, Morishita K, Sakamoto H, Naruse T et al (2016) Denosumab-associated osteonecrosis of the jaw affects osteoclast formation and differentiation: pathological features of two cases. Mol Clin Oncol 4:191–194
Yuan A, Munz A, Reinert S, Hoefert S et al (2020) Histologic analysis of medication-related osteonecrosis of the jaw compared with antiresorptive-exposed bone and other infectious, inflammatory, and necrotic jaw diseases. Oral Surg Oral Med Oral Pathol Oral Radiol 129:133–140
Ren S, Takano H, Abe K (2005) Two types of bone resorption lacunae in the mouse parietal bones as revealed by scanning electron microscopy and histochemistry. Arch Histol Cytol 68:103–113
Weinstein RS, Roberson PK, Manolagas SC (2009) Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 360:53–62
Jain N, Weinstein RS (2009) Giant osteoclasts after long-term bisphosphonate therapy: diagnostic challenges. Nat Rev Rheumatol 5:341–346
Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ et al (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100:1475–1480
Recker RR, Weinstein RS, Chesnut CH, Schimmer RC, Mahoney P et al (2014) Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study. Osteoporos Int 15:231–237
Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S et al (2018) Effects of long-term denosumab on bone histomorphometry and mineralization in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 103:2498–2509
Recknor C, Czerwinski E, Bone HG, Bonnick SL, Binkley N et al (2013) Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol 121:1291–1299
Loyson T, Van Cann T, Schoffski P, Clement PM, Bechter O et al (2018) Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab. Acta Clin Belg 73:100–109
Mamilos A, Spörl S, Spanier G, Ettl T, Brochhausen C et al (2020) The first quantitative histomorphological analyses of bone vitality and inflammation in surgical specimens of patients with medication-related osteonecrosis of the jaw. J Oral Pathol Med 50:76–84
Acknowledgement
We are grateful to Niigata Bone Science Institute, Niigata, Japan, for helping bone histomorphometric analysis.
Funding
This research was supported by a grant for MEXT Private University Branding Project, and Branding Project for Multidisciplinary Research Center for Jaw Disease Fund, Tokyo Dental College.
Author information
Authors and Affiliations
Contributions
KA and AY designed this research. KA, MS, SA, and AY were involved in data interpretation. KA and SI conducted the histological analyses, and SI conducted scanning microscopy analysis. KA, TS, TN, and HM performed clinical analysis of the patients. KA contributed to write the manuscript, and AY edited and reviewed the manuscript. All authors have read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was approved by the Ethics Committee of Tokyo Metropolitan Bokutoh Hospital (approval number: 29-64), Tokyo Dental College (approval number:850), and Ichikawa General Hospital Tokyo Dental College (approval number: I-19-59).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
About this article
Cite this article
Aoki, K., Matsunaga, S., Ito, S. et al. Persistent bone resorption lacunae on necrotic bone distinguish bisphosphonate-related osteonecrosis of jaw from denosumab-related osteonecrosis. J Bone Miner Metab 39, 737–747 (2021). https://doi.org/10.1007/s00774-021-01223-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00774-021-01223-4