The Effect of Bisphosphonates’ Oncologic dose on the Static and Dynamic Bone Parameters of the Temporomandibular Joint’s Condyle (A Randomized Animal Controlled Trial)

Document Type : Original Article


1 Lecturer, Oral Biology Department, Faculty of Dentistry, Cairo University, Egypt

2 Professor, Oral Biology Department, Faculty of Dentistry, Cairo University, Egypt

3 Associate Professor, Oral Biology Department, Faculty of Dentistry, Cairo University, Egypt


The present study was conducted to assess the effect of oncologic dose of bisphosphonate on the condylar temporomandibular joint’s (TMJ’s) static and dynamic bone parameters. Forty adult male albino rats were utilized in the study. Animals were randomly assigned into four groups, each included ten rats that were intraperitoneally injected with saline (control groups I and II), or 0.2 Zoledronic acid (experimental groups I and II). The rats were sacrificed at the end of 6 weeks (groups I) and 12 weeks (groups II). The right side TMJs condyles were used in histological and histomorphometric analysis while the left side condyles were utilized for assessing dynamic bone parameters. Bone volume/ Tissue volume (BV/TV) and trabecular thickness (Tb.Th) were significantly increased in ZOL group II as compared to control and Zoledronic acid (ZOL) group I (p=<0.001) while trabecular separation (Tb.Sp) was markedly increased in ZOL group I as compared to both control and ZOL group II (p=0.001 and 0.012, respectively). The ZOL group II showed a significant increase in mineral apposition rate as compared to the ZOL group I (p < 0.001). Our results demonstrated that oncologic dose of Zoledronic could have a catabolic effect on TMJ’s condyles after six weeks which is reversed after 12 weeks as evidenced by enhanced endochondral and intramembranous ossification.


1. Marieb E.N., Hoehn K., 2007. The Endocrine System. In Human Anatomy & Physiology Eighth Edition; Beauparlant, S., Ed.; Benjamin Cummings. 616–618.
2. Regezi J., Sciubba J., Jordan R., 2016. ‏Oral Pathology: Clinical Pathologic Correlations, 7th edition.; Dolan, J., Ed.; Elsevier. pp.346-369
3. Miller P.D., Watts N.B., 2013. Bisphosphonates. In Osteoporosis: diagnosis and management; Stovall, D.W., Ed.; John Wiley & Sons, Ltd. pp 123–143.
4. Giger E.V, Castagner B., Leroux J.C., 2013. Biomedical applications of bisphosphonates. J Control Release. 167(2), 175–188.
5. Srivastava M., Deal C., 2002. Osteoporosis in Elderly: Prevention and Treatment. Clin Geriatr Med. 18, 529–555.
6. Ivanova S., Vasileva L., Ivanova S., Peikova L., Obreshkova D., 2015. Osteoporosis: therapeutic options. Folia Med. (Plovdiv). 57 (3–4), 181–190.
7. Watts N.B., Diab D.L., 2010. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 95(4), 1555–1565.
8. Ebetino F.H., Hogan A.M.L., Sun S., Tsoumpra M.K., Duan X., Triffitt J.T., Kwaasi A.A., Dunford J.E., Barnett B.L., Oppermann U., Lundy M.W., Boyde A., Kashemirov B.A., McKenna C.E., Russell R.G., 2011. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 49(1), 20–33.
9. Cremers S., Papapoulos S., 2011. Pharmacology of bisphosphonates. Bone. 49(1), 42–49.
10. Russell R.G., Watts N.B., Ebetino F.H., Rogers M.J., 2008. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 19(6), 733–759.
11. Drake M.T., Cremers S.C.L.M., 2010. Bisphosphonate therapeutics in bone disease: the hard and soft data on osteoclast inhibition. Mol Interv. 10(3), 141–152.
12. Powles T., Paterson A., McCloskey E., Schein P., Scheffler B., Tidy A., Ashley S., Smith I., Ottestad L., Kanis J., 2006. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res. 8(2), R13.
13. Graham R., Russell G., 2011. Bisphosphonates: The first 40 years. Bone. 49, 2–19.
14. Nancollas G.H., Tang R., Phipps R.J., Henneman Z., Gulde S., Wu W., 2006. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 38, 617–627.
15. Rogers M.J., Crockett J.C., Coxon F.P., Monkkonen J., 2011. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 49(1), 34–41.
16. Khan S.A., Kanis J.A., Vasikaran S., Kline W.F., Matuszewski B.K., McCloskey E.V., Beneton M.N., Gertz B.J., Sciberras D.G., Holland S.D., Orgee J., Coombes G.M., Rogers S.R., Porras A.G., 1997. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res. 12(10), 1700–1707.
17. Dunford J.E., Thompson K., Coxon F.P., Luckman S.P., Hahn F.M., Poulter C.D., Ebetino F.H., Rogers M.J., 2001. 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. 296(2), 235–242.
18. Gasser J.A., Ingold P., Venturiere A., Shen V., Green J.R., 2008. Long-term protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat. J Bone Miner Res. 23, 544–551.
19. Ralston S., 2015. Bisphosphonates for Osteoporosis. In Medicines for Women; Harrison-Woolrych, M., Ed.; Springer International Publishing: Cham. 345–371.
20. Grey A., Bolland M., Wattie D., Horne A., Gamble G., Reid I.R., 2010. Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J Bone Miner Res. 25(10), 2251–2255. https://doi .org/10.1002/jbmr.103.
21. Black D.M., Delmas P.D., Eastell R., Reid I.R., Boonen S., Cauley J.A., Cosman F., Lakatos P., Leung P.C., Man Z., Mautalen C., Mesenbrink P., Hu H., Caminis J., Tong K., Rosario-Jansen T., Krasnow J., Hue T.F., Sellmeyer D., Eriksen E.F., Cummings S.R., 2007. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 356(18), 1809–1822.
22. Recker R.R., Delmas P.D., Halse J., Reid I.R., Boonen S., García-Hernandez P. a, Supronik J., Lewiecki E.M., Ochoa L., Miller P., Hu H., Mesenbrink P., Hartl F., Gasser J.A., Eriksen E.F., 2008. Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. J Bone Miner Res. 23(1), 6–16.
23. Delmas P.D., Munoz F., Black D.M., Cosman F., Boonen S., Watts N.B., Kendler D., Eriksen E.F., Mesenbrink P.G., Eastell R., 2009. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of pinp with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res. 24(9), 1544–1551.
24. Black D.M., Reid I.R., Boonen S., Bucci-rechtweg C., Cauley J.A., Cosman F., Cummings S.R., Hue T.F., Lippuner K., Lakatos P., Leung P. C., Man Z., Lou R., Martinez M., Tan M., Ruzycky M.E., Su G., Eastell R., 2012. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 27(2), 243–254.
25. Black D.M., Reid I.R., Cauley J.A., Cosman F., Leung P.C., Lakatos P., Lippuner K., Cummings S.R., Hue T.F., Mukhopadhyay A., Tan M., Aftring R.P., Eastell R., 2015. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). Am Soc Bone Miner Res. 30 (5), 934–944.
26. Grey A., Bolland M.J., Wattie D., Horne A., Gamble G., Reid I.R., 2009. The antiresorptive effects of a single dose of zoledronate persist for two years: a randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Meta. 94(2), 538–544.
27. Greenspan S.L., Perera S., Ferchak M.A., Nace D.A., Resnick N.M., 2015. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women a randomized clinical trial. J Am Med Assoc. 175(6), 913–921.
28. Cosman F., Cauley J.A., Eastell R., Boonen S., Palermo L., Reid I.R., Cummings S.R., Black D.M., Hayes H.C., 2014. Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment? J Clin Endocrinol Metab. 99 (December), 4546–4554.
29. Boonen S., Kaufman J.-M., Lippuner K., Zanchetta J., Langdahl B., Rizzoli R., Lipschitz S., Dimai H.P., Witvrouw R., Eriksen E., Brixen K., Russo L., Claessens F., Papanastasiou P., Antunez O., Su G., Bucci-Rechtweg C., Hruska J., Incera E., Vanderschueren D., Orwoll E., 2012. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med. 367(18), 1714–1732. https:// /10.1056 /NEJMoa1204061.
30. Lekamwasam S., Adachi J. D., Agnusdei D., Bilezikian J., Boonen S., Borgström F., Cooper C., Diez Perez A., Eastell R., Hofbauer L.C., Kanis J.A., Langdahl B.L., Lesnyak O., Lorenc R., McCloskey E., Messina O.D., Napoli N., Obermayer-Pietsch B., Ralston S.H., Sambrook P.N., Silverman S., Sosa M., Stepan J., Suppan G., Wahl D.A., Compston J.E., 2012. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos. Int. 23(9), 2257–2276. https ://doi. org/10 .1007/s00198-012-1958-1.
31. Zhao X., Hu X., 2015. Dosing of zoledronic acid with its anti-tumor effects in breast cancer. J Bone Oncol. 4(3), 98–101. https: //doi. org/10.1016 /j.jbo.2015.08.001.
32. Santini D., Vincenzi B., Galluzzo S., Battistoni F., Rocci L., Venditti O., Schiavon G., Angeletti S., Uzzalli F., Caraglia M., 2007. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 13(15), 4482–4486.
33. Wellington K., Goa K.L., Coleman R.E., Dearnaley D.R., Fleisch H., Hotte S.J., 2003. Zoledronic acid a review of its use in the management of bone metastases and hypercalcaemia of malignancy. Drugs. 63(4), 417–437.
34. Wood J., Bonjean K., Ruetz S., Ene A.B., Devy L., Foidart J.M., Castronovo V., Green J.R., Biology T., 2002. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 302(3), 1055–1061. .1124 / jpet. 102.035295.opment.
35. Wang G., Chen J., Ma R., Xu W., Yan C., Niu C., 2018. Effects of zoledronic acid and ibandronate in the treatment of cancer pain in rats with lung cancer combined with bone metastases. Oncol Lett. 16(2), 1696–1700.
36. Walker K., Medhurst S.J., Kidd B.L., Glatt M., Bowes M., Patel S., McNair K., Kesingland A., Green J., Chan O., Fox A.J., Urban L.A., 2002. Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain. Pain. 100(3), 219–229. https:// /https:// .1016/S0304-3959(02)00040-4.
37. Reid I.R., Gamble G.D., Mesenbrink P., Lakatos P., Black D.M., 2010. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab. 95(9), 4380–4387. https:// .1210/jc.2010-0597.
38. Rathbone E.J., Brown J.E., Marshall H.C., Collinson M., Liversedge V., Murden G.A., Cameron D., Bell R., Spensley S., Agrawal R., Jyothirmayi R., Chakraborti P., Yuille F., Coleman R.E., 2013. Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04). J Clin Oncol. 31(21), 2685–2691. https:/ / 10.1200/ JCO.2012.46.4792.
39. Khosla S., Burr D., Cauley J., Dempster D.W., Ebeling P.R., Felsenberg D., Gagel R.F., Gilsanz V., Guise T., Koka S., McCauley L.K., McGowan J., McKee M.D., Mohla S., Pendrys D.G., Raisz L.G., Ruggiero S.L., Shafer D.M., Shum L., Silverman S.L., Van Poznak C.H., Watts N., Woo S.B., Shane E., 2007. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 22, 1479–1491.
40. Reid I.R., 2009. Osteonecrosis of the jaw: who gets it, and why? Bone. 44(1), 4–10.
41. Pacheco V.N., Langie R., Etges A., Ponzoni D., Puricelli E., 2015. Nitrogen containing bisphosphonate therapy: assessment of the alveolar bone structure in rats–a blind randomized controlled trial. Int J Exp Pathol. 96(4), 255–260.
42. Allen M.R., Kubek D.J., Burr D.B., 2010. Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res. 25(1), 98–105.
43. Dempster D.W., Compston J.E., Drezner M.K., Glorieux F.H., Kanis J.A., Malluche H., Meunier P.J., Ott S.M., Recker R.R., Parfitt A.M., 2013. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 28(1), 2–17.
44. Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., Preibisch S., Rueden C., Saalfeld S., Schmid B., Tinevez J.Y., White D.J., Hartenstein V., Eliceiri K., Tomancak P., Cardona A., 2012. Fiji: an open-source platform for biological-image analysis. Nat Methods. 9(7), 676–682.
45. Arganda-Carreras I., Kaynig V., Rueden C., Eliceiri K.W., Schindelin J., Cardona A., Sebastian Seung H., 2017. Trainable weka segmentation: a machine learning tool for microscopy pixel classification. Bioinformatics. 33(15), 2424–2426. https://doi. org/10.1093/ bioinformatics/btx180.
46. Doube M., Kłosowski M.M., Arganda-Carreras I., Cordelières F.P., Dougherty R.P., Jackson J.S., Schmid B., Hutchinson J.R., Shefelbine S.J., 2010. BoneJ: free and extensible bone image analysis in ImageJ. Bone. 47 (6), 1076–1079. :// 1016/j.bone .2010.08.023.
47. Malhan D., Muelke M., Rosch S., Schaefer A.B., Merboth F., Weisweiler D., Heiss C., Arganda-Carreras I., El Khassawna T., 2018. An optimized approach to perform bone histomorphometry. Front Endocrinol (Lausanne). 9, 666. fendo.2018. 00666.
48. Kulak C.A.M., Dempster D.W., 2010. Bone histomorphometry: a concise review for endocrinologists and clinicians. Arq Bras Endocrinol Metabol. 54(2), 87–98.
 49. Parfitt A.M., Mathews C.H., Villanueva A.R., Kleerekoper M., Frame B., Rao D.S., 1983. Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest. 72(4), 1396–1409.
50. Kohno N., Aogi K., Minami H., Nakamura S., Asaga T., Iino Y., Watanabe T., Goessl C., Ohashi Y., Takashima S., 2005. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol. 23(15), 3314–3321. https ://doi. org/10.1200/JCO.2005.05.116.
51. de Barros Silva P.G., Junior A.E.C.F., Teófilo C.R., Barbosa M.C., Lima R.C.P., Sousa F.B., Mota M.R.L., de Albuquerque Ribeiro R., Alves A.P.N.N., 2015. Effect of different doses of zoledronic acid in establishing of bisphosphonate-related osteonecrosis. Arch Oral Biol. 60(9), 1237–1245.
52. Jabbour Z., El-Hakim M., Henderson J.E., Rubens F., 2014. Bisphosphonates inhibit bone remodeling in the jaw bones of rats and delay healing following tooth extractions. Oral Oncol. 50(5), 485–490.
53. Giannasi C., Niada S., Farronato D., Lombardi G., Manfredi B., Farronato G., Brini A.T., 2019. Nitrogen containing bisphosphonates impair the release of bone homeostasis mediators and matrix production by human primary pre-osteoblasts. Int J Med Sci. 16(1), 23-32.
54. Singh A., Gill G., Kaur H., Amhmed M., Jakhu H., 2018. Role of osteopontin in bone remodeling and orthodontic tooth movement: a review. Prog Orthod. 19(1), 18.
55. Pozzi S., Vallet S., Mukherjee S., Cirstea D., Vaghela N., Santo L., Rosen E., Ikeda H., Okawa Y., Kiziltepe T., Schoonmaker J., Xie W., Hideshima T., Weller E., Bouxsein M.L., Munshi N.C., Anderson K.C., Raje N., 2009. High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin Cancer Res. 15(18), 5829–5839.
56. Nyangoga H., Blouin S., Libouban H., Baslé M.F., Chappard D., 2010. A single pretreatment by zoledronic acid converts metastases from osteolytic to osteoblastic in the rat. Microsc Res Tech. 73(8), 733–740.
57. Labrinidis A., Hay S., Liapis V., Findlay D.M., Evdokiou A., 2010. Zoledronic acid protects against osteosarcoma-induced bone destruction but lacks efficacy against pulmonary metastases in a syngeneic rat model. Int J Cancer. 127 (2), 345–354.
58. Haider M.T., Holen I., Dear T.N., Hunter K., Brown H.K., 2014. Modifying the osteoblastic niche with zoledronic acid in vivo-potential implications for breast cancer bone metastasis. Bone. 66(100), 240–250.
59. Camacho-Alonso F., López-Jornet P., Vicente-Hernández A., 2013. Short-term effect of zoledronic acid upon fracture resistance of the mandibular condyle and femoral head in an animal model. Med Oral Patol Oral Cir Bucal. 18(3), e421-6. https: //
60. Allen M.R., Kubek D.J., Burr D.B., 2010. Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res. 25(1), 98–105.
61. Binkley N., Kimmel D., Bruner J., Haffa A., Davidowitz B., Meng C., Schaffer V., Green J., 1998. Zoledronate prevents the development of absolute osteopenia following ovariectomy in adult Rhesus monkeys. J Bone Miner Res. 13(11), 1775–1782.
62. Gonen Z.B., Colpak H.A., Onger M.E., 2019. Effects of bisphosphonate treatment on mandibular condyle tissues of temporomandibular joint: a stereological study. J Stomatol Oral Maxillofac Surg. 120(6), 513–516.
63. Kalder M., Kyvernitakis I., Albert U.S., Baier-Ebert M., Hadji P., 2015. Effects of zoledronic acid versus placebo on bone mineral density and bone texture analysis assessed by the trabecular bone score in premenopausal women with breast cancer treatment-induced bone loss: results of the ProBONE II substudy. Osteoporos. Int. J. Establ. as result Coop. between  Eur Found Osteoporos Natl Osteoporos. Found. USA 26(1), 353–360.
64. Gnant M.F.X., Mlineritsch B., Luschin-Ebengreuth G., Grampp S., Kaessmann H., Schmid M., Menzel C., Piswanger-Soelkner J.C., Galid A., Mittlboeck M., Hausmaninger H., Jakesz R., 2007. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian breast and colorectal cancer study group. J Clin Oncol. 25(7), 820–828.
65. Brufsky A., Harker W.G., Beck J.T., Carroll R., Tan-Chiu E., Seidler C., Hohneker J., Lacerna L., Petrone S., Perez E.A., 2007. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol . 25(7), 829–836.
66. Saad F., 2005. Clinical benefit of zoledronic acid for the prevention of skeletal complications in advanced prostate cancer. Clin Prostate Cancer. 4(1), 31–37.
67. Saad F., Gleason D.M., Murray R., Tchekmedyian S., Venner P., Lacombe L., Chin J.L., Vinholes J.J., Goas J.A., Zheng M., 2004. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 96(11), 879–882.
68. Rosen L.S., Gordon D., Tchekmedyian S., Yanagihara R., Hirsh V., Krzakowski M., Pawlicki M., de Souza P., Zheng M., Urbanowitz G., Reitsma D., Seaman J.J., 2003. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial-the zoledronic acid lung cancer and other solid tumors study group. J Clin Oncol . 21(16), 3150–3157.
69. Coxon F.P., Helfrich M.H., Larijani B., Muzylak M., Dunford J.E., Marshall D., Mckinnon A.D., Nesbitt S.A., Horton M.A., Seabra M.C., Ebetino F.H., Rogers M.J., 2001. Identification of a novel phosphonocarboxylate inhibitor of Rab geranylgeranyl transferase that specifically prevents Rab prenylation in osteoclasts and macrophages. J Biol Chem. 276 (51), 48213–48222.
70. Rogers M.J., Frith J.C., Luckman S.P., Coxon F.P., Benford H.L., Monkkonen J., Auriola S., Chilton K.M., Russell R.G., 1999. Molecular mechanisms of action of bisphosphonates. Bone. 24 (5 Suppl), 73S-79S.
71. Kimachi K., Kajiya H., Nakayama S., 2011. Zoledronic acid inhibits rank expression and migration of osteoclast precursors during osteoclastogenesis. Naunyn-Schmied Arch Pharmacol. 383, 297–308.
72. Kellinsalmi M., Mönkkönen H., Mönkkönen J., Leskelä H.-V., Parikka V., Hämäläinen M., Lehenkari P., 2005. In vitro comparison of clodronate, pamidronate and zoledronic acid effects on rat osteoclasts and human stem cell-derived osteoblasts. Basic Clin. Pharmacol. Toxicol. 97(6), 382–391.
73. Bellido T., Plotkin L.I., 2011. Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone. 49(1), 50–55.
74. Nishikawa M., Akatsu T., Katayama Y., Yasutomo Y., Kado S., Kugal N., Yamamoto M., Nagata N., 1996. Bisphosphonates act on osteoblastic cells and inhibit osteoclast formation in mouse marrow cultures. Bone. 18(1), 9–14.
75. Viereck V., Emons G., Lauck V., Frosch K.H., Blaschke S., Grundker C., Hofbauer L.C., 2002. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun. 291(3), 680–686.
76. Pan B., Farrugia A.N., To L.B., Findlay D.M., Green J., Lynch K., Zannettino A.C.W., 2004. The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res. 19(1), 147–154.
77. Nanci A., 2013. Ten Cate’s Oral Histology: development, structure and function, eighth edi; St Louis: El Sevier Mosby.
78. Teitelbaum S.L., 2007. Osteoclasts: what do they do and how do they do it? Am J Pathol. 170, 427–435.
79. Tyrovola J.B., Spyropoulos M.N., Makou M., Perrea D., 2008. Root resorption and the OPG / RANKL / RANK system : A Mini Review. J Oral Sci. 50, 367–376.
80. Plotkin L.I., Lezcano V., Thostenson J., Weinstein R.S., Manolagas S.C., Bellido T., 2008. Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res. 23(11), 1712–1721.
81. Corrado A., Neve A., Maruotti N., Gaudio A., Marucci A., Cantatore F.P., 2010. Dose-dependent metabolic effect of zoledronate on primary human osteoblastic cell cultures. Clin Exp Rheumatol. 28(6), 873–879.
82. Huang X., Huang S., Guo F., Xu F., Cheng P., Ye Y., Dong Y., Xiang W., Chen A., 2016. Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro. Mol Med Rep. 13(1), 613–622.
83. Zafar S., Coates D.E., Cullinan M.P., Drummond B.K., Milne T., Seymour G.J., 2016. Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts. Clin Oral Investig. 20(8), 2023–2035.
84. Patntirapong S., Singhatanadgit W., Chanruangvanit C., Lavanrattanakul K., Satravaha Y., 2012. Zoledronic acid suppresses mineralization through direct cytotoxicity and osteoblast differentiation inhibition. J Oral Pathol Med. 41(9), 713–720.
85. Hao Y., Wang X., Wang L., Lu Y., Mao Z., Ge S., Dai K., 2015. Zoledronic Acid Suppresses Callus Remodeling but Enhances Callus Strength in an Osteoporotic Rat Model of Fracture Healing. Bone. 81, 702–711.
86. Zhou Q., Zhao Z.N., Cheng J.T., Zhang B., Xu J., Huang F., Zhao R.N., Chen Y.J., 2011. Ibandronate promotes osteogenic differentiation of periodontal ligament stem cells by regulating the expression of micrornas. Biochem Biophys Res Commun. 404(1), 127–132.
87. Greiner S., Kadow‐Romacker A., Lübberstedt M., Schmidmaier G., Wildemann B., 2007. The effect of zoledronic acid incorporated in a poly (d, llactide) implant coating on osteoblasts in vitro. J Biomed Mater Res. Part A, 80(4), 769–775.
88. Idris A.I., Rojas J., Greig I.R., van’t Hof R.J., Ralston S.H., 2008. Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int. 82(3), 191–201.
89. Reinholz G.G., Getz B., Pederson L., Sanders E.S., Subramaniam M., Ingle J.N., Spelsberg T.C., 2000. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res. 60(21), 6001–6007.
90. Strassle B.W., Mark L., Leventhal L., Piesla M.J., Li X.J., Kennedy J.D., Glasson S.S., Whiteside G.T., 2010. Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease. Osteoarthr Cartil. 18(10), 1319–1328
91. Herrak P., Görtz B., Hayer S., Redlich K., Reiter E., Gasser J., Bergmeister H., Kollias G., Smolen J. S., Schett G., 2004. Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis. Arthritis Rheum Off J Am Coll Rheumatol. 50(7), 2327–2337.
Volume 10, Issue 4
December 2020
Pages 297-313
  • Receive Date: 13 August 2020
  • Revise Date: 13 September 2020
  • Accept Date: 29 September 2020
  • First Publish Date: 30 September 2020