EC Dental Science

Bisphosphonates (BPs) are drugs known since long time which now occupy a prominent position among therapeutic options for the prevention and treatment of various forms of bone diseases characterized by increased bone turnover. Although all have a similar bone tropism they have marked difference in the potency, mechanism of action and clinical tolerability. The overall clinical experience demonstrates that all BPs are very well tolerated when dosed and administered appropriately. Once absorbed, BPs bind to the bone mineral phase and are retained buried in the bone for extended period of time which vary from weeks, months up to years depending of the chemical structure of the various BPs. Despite good clinical tolerability, the widespread use of these drugs has also shown an increasing incidence of cases of osteonecrosis of the jaw (ONJ). ONJ is a severe pathology affecting the jaw bones of some patients treated for a long time with BPs. However, not all BPs have the same degree of risk, which is related to the different chemical structure, mechanism of action, and affinity for bone hydroxyapatite.

 Keywords: Bisphosphonates; BRONJ; Bone Turnover; Necrosis; Osteomyelitis

1. Serrano AJ., et al. “Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis”. Gynecological Endocrinology 12 (2013): 1005-1014.
2. Marx RE. “Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic”. Journal of Oral and Maxillofacial Surgery 9 (2003): 1115-1117.
3. Takahiko Shibahara. “Antiresorptive agent-related osteonecrosis of the jaw (ARONJ): A twist of fate in the bone”. Tohoku Journal of Experimental Medicine 2 (2019): 75-86.
4. Ruggiero SL., et al. “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”. Journal of Oral and Maxillofacial Surgery 10 (2014): 1938-1956.
5. Mavrokokki T., et al. “Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia”. Journal of Oral and Maxillofacial Surgery 3 (2007): 415-423.
6. Khan AA., et al. “Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the international task force on ONJ”. Journal of Clinical Densitometry 1 (2017): 8-24.
7. Yoneda T., et al. “Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons”. Journal of Bone and Mineral Metabolism 4 (2010): 365-383.
8. Matsumoto T and Endo I. “RANKL as a target for the treatment of osteoporosis”. Journal of Bone and Mineral Metabolism 1 (2021): 91-105.
9. Urade M., et al. “Nationwide survey for bisphosphonate-related osteo- necrosis of the jaws in Japan”. Journal of Oral and Maxillofacial Surgery 11 (2011): e364-371.
10. Shibahara T., et al. “National survey on bisphosphonate-related osteonecrosis of the jaws in Japan”. Journal of Oral and Maxillofacial Surgery 10 (2018): 2105-2112.
11. Aljohani S., et al. “What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review”. Journal of Cranio-Maxillofacial Surgery 9 (2017): 1493-1502.
12. Then C., et al. “Incidence and risk factors of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients having undergone autologous stem cell transplantation”. Onkologie11 (2012): 658-664.
13. Felicia Cosman., et al. “Romosozumab Treatment in Postmenopausal Women with Osteoporosis”. New England Journal of Medicine 16 (2016): 1532-1543.
14. Hoefert S., et al. “BP-associated avascular necrosis (AN) of the jaws: Histological findings [abstract]”. Bone 38 (2006): 76.
15. De Luca A., et al. “Pharmacokinetic evaluation of zoledronic acid”. Expert Opinion on Drug Metabolism and Toxicology 7 (2011): 911-918.
16. Nancollas GH., et al. “Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite”. Bone5 (2006): 617-627.
17. Warnke PH., et al. “Innate immunity in human bone”. Bone 3 (2006): 400-408.
18. Kazuhiro Shima., et al. “Inflammatory effects of nitrogen-containing bisphosphonates (N-BPs): Modulation by Non-N-BPs”. Biological and Pharmaceutical Bulletin 1 (2017): 25-33.
19. Vescovi P. “Bisphosphonates and osteonecrosis: an open matter”. Clinical Cases in Mineral and Bone Metabolism 3 (2012): 142-144.
20. Khan AA., et al. “International Task Force on Osteonecrosis of the J. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus”. Journal of Bone and Mineral Research 1 (2015): 3-23.
21. Kos M., et al. “Pamidronate enhances bacterial adhesion to bone hydroxyapatite. Another puzzle in the pathology of bisphosphonate-related osteonecrosis of the jaw?” Journal of Oral and Maxillofacial Surgery 6 (2013): 1010-1016.
22. Sabrina Crépin., et al. “Osteonecrosis of the jaw induced by clodronate, an alkylbiphosphonate: case report and literature review”. European Journal of Clinical Pharmacology 6 (2010): 547-554.
23. Amir H Montazeri., et al. “Oral sodium clodronate induced osteonecrosis of the jaw in a patient with myeloma”. European Journal of Haematology 1 (2007): 69-71.
24. Yakugaku Zasshi. “Basic studies on the mechanis prevention, and treatment of osteonecrosis of the jaw induced by bisphosphonates”. Yakugaku Zasshi1 (2020): 63-79.