EC Dental Science

Bisphosphonates (BPs) are compounds which reduce the rate of bone turnover and affect the activity of several bone cells like the osteoclasts, osteoblasts and osteocytes. BPs have been used for the treatment of bone diseases characterised by high turnover (Paget’s disease of bone, hypercalcemia of malignancy) and osteoporosis by reducing the turnover rate and increasing the bone density. BPs are avidly absorbed by the bone and, on a special way, by the area subjected to remodeling either for physiological needings or as consequence of inflammatory conditions. Bisphosphonates bind to the bone mineral and are retained buried in the bone for extended period of time which vary from weeks, months up to years. The capability to prevent the bone loss has also stimulated investigations on the potential use in the field of dentistry where the BPs can be used systemically or by local application.

Keywords: Bisphosphonates; Dentistry; Bone Remodeling; Periodontal Disease; Implantology

1. Fleisch H., et al. “The influence of pyrophosphate analogues ((diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo”. Calcified Tissue Research 2 (1962): 10-10A.
2. Schenk R., et al. “Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl₂MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats”. Calcified Tissue Research 11 (1973): 196-214.
3. Manolagas SC and Parfit MA. “What old means to bone”. Trends in endocrinology and Metabolism 21 (2010): 369-374.
4. Clarke B. “Normal Bone Anatomy and Physiology”. Clinical Journal of the American Society of Nephrology 3 (2008): S132-S139.
5. Parfitt AM. “Misconceptions(2): Turnover is always higher in cancellous than in cortical bone”. Bone6 (2002): 807-809.
6. Manolagas S. “Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis”. Endocrine Reviews 21 (2000): 115-137.
7. Russell RGG and Fleisch H. “Pyrophosphate and Diphosphonates in Skeletal Metabolism”. Clinical Orthopaedics and Related Research 108 (1975): 241-263.
8. Russell RGG. “Bisphosphonates: Mode of Action and Pharmacology”. Pediatrics2 (2007): S150-S162.
9. Francis MD., et al. “NE-58095: a diphosphonate which prevents bone erosion and preserves joint architecture in experimental arthritis”. International Journal of Tissue Reactions5 (1989): 239-252.
10. Dunn CJ., et al. “Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates”. The Journal of Pharmacology and Experimental Therapeutics 266 (1993): 1691-1698.
11. Cocco R., et al. “Effects of Clodronate on synovial fluid levels of some inflammatory mediators, after intra-articular administration to patients with synovitis secondary to knee osteoarthritis”. Bollettino della Società Italiana di Biologia Sperimentale11-12 (1999): 71-76.
12. Laslett LL., et al. “Zoledronic acid reduces Knee pain and bone marrow lesions over 1 year: a randomised controlled trial”. Annals of the Rheumatic Diseases8 (2012): 1322-1328.
13. Le Goff B., et al. “Alternative use of Bisphosphonate therapy for rheumatic disease”. Current Pharmaceutical Design27 (2010): 3045-3052.
14. Breuil V and Euller-Ziegler L. “Bisphosphonate therapy in rheumatoid arthritis”. Joint Bone Spine4 (2006): 349-354.
15. Corrado A., et al. “Extra-skeletal effects of Bisphosphonates”. Joint Bone Spine1 (2007): 32-816.
16. Toussirot E and Wendling D. “Antiinflammatory treatment with bisphosphonates in ankylosing spondylitis”. Current Opinion in Rheumatology4 (2007): 340-345.
17. Maksymowych WP., et al. “An open study of pamidronate in the treatment of refractory ankylosing spondylitis”. The Journal of Rheumatology4 (1998): 714-777.
18. Lacativa PG and Farias ML. “Osteoporosis and inflammation”. Arquivos Brasileiros de Endocrinologia and Metabologia 54 (2010): 123-132.
19. Ryan ME., et al. “Potential of tetracyclines to modify cartilage breakdown in osteoarthritis”. Current Opinion in Rheumatology3 (1996): 238-247.
20. Kivelä-Rajamäki M., et al. “Levels and molecular forms of MMP-7 (matrilysin-1) and MMP-8 (collagenase-2) in diseased human peri-implant sulcular fluid”. Journal of Periodontal Research 38 (2003): 583-590.
21. Mian M., et al. “Effects of bisphosphonate derivatives on macrophage function”. Pharmacology5 (1994): 336-342.
22. Hyvonen PM and Kowolik MJ. “Influence of dichloromethylene bisphosphonate on the in vitro phagocytosis of hydroxyapatite particles by rat peritoneal exudate cells: an electron microscopic and chemiluminescence study”. Annals of the Rheumatic Diseases 51 (1992): 203-209.
23. Felix R., et al. “Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells”. Calcified Tissue International5 (1981): 549-552.
24. Ohya K., et al. “Effect of bisphosphonates on prostaglandin synthesis by rat cells and mouse calvaria in culture”. Clinical Science4 (1985) :403-411.
25. Listgarten MA. “Nature of periodontal diseases: pathogenic mechanism”. Journal of Periodontal Research 22 (1987): 172-178.
26. Kodama H., et al. “Essential role of Macrophage Colony-Stimulating Factor in the osteoclast differentiation supported by stromal cells”. Journal of Experimental Medicine5 (1991): 1291-1294.
27. Crotti T., et al. “Receptor activator NF kappaB ligand (RANKL) and osteoprotegerine (OPG) protein expression in peridontitis”. Journal of Periodontal Research6 (2003): 380-387.
28. Deo V and Bhongade ML. “Pathogenesis of periodontitis: role of cytokines in host response”. Dentistry Today9 (2010): 60-62.
29. Kanzaki H., et al. “Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor kappaB ligand upregulation via prostaglandin E2 synthesis”. Journal of Bone and Mineral Research2 (2002): 210-220.
30. Fleisch H and Russell RGG. “A review of the physiological and pharmacological effects of pyrophosphate and diphosphonates on bone and teeth”. Journal of Dental Research2 (1972): 324-332.
31. Herforth A., et al. “Clinical studies on the reduction of dental calculus formation by the use of a percent HEDP containing toothpaste”. Deutsche zahnarztliche Zeitschrift9 (1977): 757-759.
32. Nixon GA., et al. “Preliminary safety assessment of Disodium Etidronate as an additive to experimental oral hygiene products”. Toxicology and Applied Pharmacology 22 (1972): 661-671.
33. Tenenbaum HC., et al. “Bisphosphonates and Periodontics: potential applications for regulation of bone mass in the periodontium and other therapeutic/diagnostic uses”. Journal of Periodontology7 (2002): 813-822.
34. Brunsvold MA., et al. “Effects of a Bisphosphonate on experimental periodontitis in monkeys”. Journal of Periodontology10 (1992): 825-830.
35. Weinreb M., et al. “Histomorphometrical analysis of the effects of the bisphosphonate Alendronate on bone loss caused by experimental periodontitis in monkeys”. Journal of Periodontal Research1 (1994): 35-40.
36. Reddy MS., et al. “Alendronate treatment of naturally-occurring periodontitis in beagle dogs”. Journal of Periodontal Research 66 (1995): 211-217.
37. Shoji K., et al. “Inhibitory effects of a bisphosphonate ( Risedronate) on experimental periodontitis in rats”. Journal of Periodontal4 (1995): 277-284.
38. Mitsuta T., et al. “Effects of topical administration of Clodronate on alveolar bone resorption in rats with experimental periodontitis”. Journal of Periodontal Research5 (2002): 479-486.
39. Sharma A and Pradeep AR. “Clinical efficacy of 1% Alendronate gel as a local drug delivery system in the treatment of chronic periodontitis: a randomised, controlled clinical trial”. Journal of Periodontal Research1 (2012): 11-18.
40. Jin Chen., et al. “Effectiveness of alendronate as an adjunct to scaling and root planing in the treatment of periodontitis: a meta-analysis of randomized controlled clinical trials”. Journal of Periodontal and Implant Science6 (2016): 382-395.
41. Jeffcoat MK., et al. “Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis”. The International Academy of Periodontology3 (2007): 70-76.
42. Pradeep AR., et al. “Local drug delivery of alendronate gel for the treatment of patients with chronic periodontitis with diabetes mellitus: a double-masked controlled clinical trial”. Journal of Periodontal10 (2012): 1322-1328.
43. Helmi M., et al. “Annual alveolar bone loss in older adults taking oral bisphosphonate: a retrospective cohort study”. BMC Oral Health 19 (2019): 260-267.
44. Zohaib Akram., et al. “Efficacy of bisphosphonate as an adjunct to nonsurgical periodontal therapy in the management of periodontal disease: a systematic review”. British Journal of Clinical Pharmacology3 (2017): 444-454.
45. Yaffe A., et al. “Regional accelerated phenomenon in the mandible following mucoperiosteal flap surgery”. Journal of Periodontology1 (1994): 79-83.
46. Yaffe A., et al. “The effects of bisphosphonate on alveolar bone resorption following mucoperiosteal flap surgery in the mandible of rats”. Journal of Periodontology11 (1995): 999-1003.
47. Yaffe A., et al. “Local delivery of an amino bisphosphonate prevents the resorptive phase of alveolar bone following mucoperiosteal flap surgery in rats”. Journal of Periodontology 68 (1997): 884-889.
48. Binderman I., et al. “Effectiveness of local delivery of Alendronate in reducing alveolar bone loss following periodontal surgery in rats”. Journal of Periodontology8 (2000): 1236-1240.
49. Saito M., et al. “Interleukin 1 beta and prostaglandin E are involved in the response of periodontal cells to mechanical stress in vivo and in vitro”. American Journal of Orthodontics and Dentofacial Orthopedics3 (1991): 226-240.
50. Mönkkönen J., et al. “Clodronate (dichloromethylene bisphosphonate) inhibits LPS-stimulated IL-6 and TNF production by RAW 264 cells”. Life Sciences14 (1994): 229-234.
51. Yamasaki K., et al. “Prostaglandin as a mediator of bone resorption induced by experimental tooth movement in rats”. Journal of Dental Research10 (1980): 1635-1642.
52. Igarashi K., et al. “Anchorage and retentive effects of a bisphosphonate (AHBuBP) on tooth movements in rats”. American Journal of Orthodontics and Dentofacial Orthopedics3 (1994): 279-893.
53. Liu L., et al. “Effects of local administration of Clodronate on orthodontic tooth movement and root resorption in rats”. European Journal of Orthodontics 26 (2004): 469-473.
54. Adachi H., et al. “Effects of topical administration of a bisphosphonate (Risedronate) on orthodontic tooth movements in rats”. Journal of Dental Research8 (1994): 1478-1486.
55. Meraw SJ and Reeve CM. “Qualitative analysis of peripheral peri-implant bone and influence of Alendronate sodium on early bone regeneration”. Journal of Periodontology10 (1999): 1228-1233.
56. Von Knoch F., et al. “Anabolic effects of bisphosphonates on peri-implant bone stock”. Biomaterials24 (2007): 3549-3559.
57. Wermelin K., et al. “Stainless steel screws with bisphosphonates gave stronger fixation and more surrounding bone. Histomorphometry in rats”. Bone2 (2008): 365-371.
58. Abtahi J., et al. “Effect of local vs. systemic bisphosphonate delivery on dental implant fixation in a model of osteonecrosis of the jaw”. Journal of Dental Research3 (2013): 279-283.
59. Abtahi J., et al. “A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants”. Bone5 (2012): 1148-1151.
60. Berardi D., et al. “Potential applications of bisphosphonates in dental surgical implants”. International Journal of Immunopathology and Pharmacology3 (2007): 455-465.
61. Zuffetti F., et al. “Clinical application of bisphosphonates in implant dentistry: histomorphometric evaluation”. International Journal of Periodontics and Restorative Dentistry1 (2009): 31-39.
62. Abtahi J., et al. “Bisphosphonate coating might improve fixation of dental implants in the maxilla: a pilot study”. International Journal of Oral and Maxillofacial Surgery7 (2010): 673-677.
63. Javed F and Almas K. “Osseointegration of Dental Implants in Patients Undergoing Bisphosphonate Treatment: A Literature Review”. Journal of Periodontology 81 (2010): 479-484.