|Year : 2013 | Volume
| Issue : 2 | Page : 39-43
Bisphosphonates: An update to the general dentist
Varun Dahiya1, Pradeep Shukla1, Shivangi Gupta2
1 Department of Periodontics and Implantology, D.J. College of Dental Sciences and Research, Modinagar, Uttar Pradesh, India
2 P.G. Student, D.J. College of Dental Sciences and Research, Modinagar, Uttar Pradesh, India
|Date of Web Publication||5-Jun-2013|
D.J. College of Dental sciences and Research, Modinagar, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Bisphosphonates (BP), included under host modulation therapy are drugs that inhibit bone resorption and commonly prescribed to prevent skeletal related changes in malignant diseases of bone and bone diseases such as osteoporosis. The sudden rise of this group of drugs is unfortunately because of the serious complication of osteonecrosis of jaws called Bisphosphonate related osteonecrosis of jaws which leads to many dental related complications. This literature review is undertaken to review the general recommendations to the dentist and clinical implications of BP's. The implications of BP's use in dentistry are still being determined.
Keywords: Bisphosphonates, bisphosphonate related osteonecrosis of jaws, bone resorption, osteonecrosis
|How to cite this article:|
Dahiya V, Shukla P, Gupta S. Bisphosphonates: An update to the general dentist. Dent Hypotheses 2013;4:39-43
| Introduction|| |
Gem diphosphonates and diphosphonates - other correct names of bisphosphonates (BP) are not used now-a-days. Pyrophosphate compounds, which are used as anti-tartar agent in toothpastes are linked to BP. 
| Structure|| |
BP are a group of drugs characterized by a phosphorus-carbon-phosphorus backbone. 
Due to this structure the drugs are unable to be hydrolyzed and are responsible for their long activity. The carbon is bonded to a hydroxyl (-OH) group on one side which, in turn, is responsible for binding to hydroxyapatite, a major element of bone. The carbon in the backbone also is bonded to two side chains. 
Because of the replacement of carbon for oxygen in the molecule, BP's are completely resistant to hydrolytic breakdown, hence they accumulate in bone matrix and have extremely long half-life. 
In addition, nitrogen substitution in the backbone carbon of BP's increases potency and perhaps toxicity. Only nitrogen containing BP's have been to produce osteonecrosis of jaws.
BP accumulates in bone cells (osteoclasts) and after ingesting drugs, they render the osteoclasts inactive. 
| Susceptibility of Jaws to Osteonecrosis|| |
High concentration of BP's was found in alveolar bone of jaws due to high turnover rates and perhaps there is more occurrence.  Thin mucosa and periosteum separate the jaw bones from microbiologically diverse oral environment. The condition is known as lingual mandibular sequestration. Bone necrosis occurs as minor trauma causes local damage to thin mucosa and periosteum.
Secondly, no more than 2 mm of periodontal connective tissue separates teeth from bone, infections have easy access to underlying bone. 
| Frequency of Use|| |
According to Grant M, Hadji P, of approximately 250,000 Americans with metastatic bone cancer, at any given time, approximately half take intravenous (IV) bisphosphonate, either pamidronate or zolendronate, usually once monthly.
Greatest number of these patients have metastatic breast cancer with fewer having myeloma, prostate cancer, lung cancer.
Recently, Zolendronate has been studied for prevention of bone metastases in patient with breast cancer.
According to Merck and co., to date hundreds of millions of prescriptions worldwide have been given for oral BP's for treatment of osteoporosis.
IV BP are now used once quarterly in case of ibandronate or once yearly, in case of zolendronate for treatment of osteoporosis.
| Uses of BP|| |
BP were introduced since 19 th century, and the first synthesis was in 1865 in Germany. 
The BP are prescribed for a number of diseases. Osteoporosis is the most common disease of bone metabolism. As aging occurs, imbalance occurs between osteoblasts and osteoclasts and this imbalance causes the bone to lose its density. 
BP are very useful in the management of osteoporosis. They cause an increase in bone mineral density and reduce the frequency of fractures. 
Another disease in which osteoclasts cause the body harm is cancer. When someone has metastatic cancer, the cancer cells secrete the substance receptor activator of nuclear factor kappa B ligand. Paget's disease is another disease in which osteoclasts cause the body harm.
Although, the cause of this disease is not fully understood, a virus is suspected. 
| Clinical Applications|| |
- Reduction of bone loss associated with periodontal disease.
- Bone scanning.
- Inhibiting bone resorption.
- Inhibition of calcification, e.g., heterotopic bone formation, and dental calculus.
- Reduce the activity of cancer cells.
- Prevention of postmenopausal bone loss.
- Hypercalcemia associated with malignancy and osteolysis.
- Metastatic bone disease.
| Currently Available BP|| |
Currently, there are two main types of BP : n0 itrogen containing and non-nitrogen containing. Most of the BP available today are used for inhibition of bone resorption in the treatment of bone diseases [Table 1].
| Complications|| |
The most common complication associated with Bisphosphonate is osteonecrosis of jaws. Bisphosphonate related osteonecrosis of jaws (BRONJ) is associated with the presence of exposed bone in the oral cavity for more than 8 weeks after Bisphosphonate intake and not undergone any radiation therapy. The risk of BRONJ with use of oral BP is very low as compared with IV BP, currently about 1%.  BRONJ from oral BP occur after at least 3 years of drug use  while IV form can take as little as 1 year for the drug to saturate bone, resulting in much higher incidence of BRONJ. 
| Clinical Presentation of Bronj|| |
The characteristic clinical presentation of BON bisphosphonate induced osteonecrosis includes pain, swelling and infection, loosening of teeth, exposed bone.  Symptoms may occur in the bone or at the site of a previous tooth extraction.  However, BON also may remain asymptomatic for weeks or months, and may be evident only after the finding of exposed bone in the jaw [Figure 1]a and b.
|Figure 1: (a) Exposed bone, representing oral bisphosphonate-induced osteonecrosis. (b) Mandibular torus with exposed bone in a patient who received fosamax for 6 years|
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Recommendations for the dental management of patients taking IV BP have been developed,  while for the management of patients taking oral BP no specific guidelines exist.
The risk of development of BON appears to be very low and is likely to occur in approximately 0.7 per 100,000 person.  BON is more commonly associated with dental procedures that traumatize bone, such as dental extractions. ,,
Older age (greater than 65 years), oral glucocorticoid use for chronic conditions, periodontitis and prolonged use of BP have been associated with an increased risk of developing BON. ,,
| Recommendations for Management of Patients|| |
The practitioner should guide the patient taking oral BP that
The risk of developing BON is not very high considered to be 0.07 cases per 100,000 person-years' exposure.
According to the consensus, regular dental checkups is the best way to minimize the risk.
To identify the patients at increased risk of developing BON, no validated diagnostic techniques are available.
Discontinuation of Bisphosphonate therapy may not eliminate the risk of developing BON.
Information about these drugs are constantly evolving, therefore, keeping up to date is essential. However, it is important not to ignore or overreact to the risks of BP.
A proper medical history can help in managing the patients.
Using a consent form for patients who are taking BP gives the dentist and patient an opportunity to talk about the drug and its possible side effects.
Oral and maxillofacial surgery
Surgical intervention may be the only alternative treatment modality remained, when dental and/or periodontal disease treatment has failed. Patients who are undergoing invasive surgical procedures should be informed of the risk, albeit small, of developing BON. Alternative treatment plans consists of endodontics instead of extraction and bridges.
If extractions or surgery are unavoidable, conservative surgical technique with primary tissue closure should be used, when possible. Immediately before and after surgical procedures involving bone, the patient should be advised chlorhexidine mouth-rinses [Table 2].
|Table 2: Management recommendations of patients after dental procedure Antibiotics that may be used to treat unexpected pain, purulence or active sequestration after a dental procedure|
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Endodontic treatment is preferable to surgical manipulation. Routine endodontic technique should be used. Treatment beyond the apex is not recommended.
Prosthodontics and restorative dentistry
Routine restorative procedures can be carried out. Malocclusion or masticatory forces does not increase the risk of developing BON. All prosthodontic appliances in patients taking an oral bisphosphonate should be adjusted for fit as needed.
Periodontal disease management
Regardless of the untoward effects of bisphosphonate, these drugs may be beneficial in host modulation therapy for management of periodontal diseases. Patients with destructive periodontal diseases receiving oral bisphosphonate therapy should receive appropriate forms of nonsurgical therapy, combined with a prolonged phase of initial therapy for observation.
Implant placement and maintenance
Recently, rehabilitation of patients with dental implants for edentulous areas or for hopeless tooth prognosis has been successful. Therefore, treatment plans for patients taking BP should be considered cautiously, since implant placement requires the preparation of the osteotomy site. The patient may be at increased risk of developing BON when extensive implant placement or guided bone regeneration to augment the deficient alveolar ridge before implant placement is necessary.
For patients with peri-implantitis, appropriate forms of nonsurgical therapy combined with a prolonged phase of initial therapy should be considered for patients with peri-implantitis. If the disease does not resolve, surgical contouring of soft tissues around the implant(s) may be appropriate and if necessary, bone re-contouring may be undertaken.
| References|| |
|1.||Marx RE. Oral and intravenous bisphosphonate-induced osteonecrosis of the jaws: history, etiology, prevention, and treatment. Hanover Park, Il Quintessence 2007;1-150. |
|2.||Graham JW. Bisphosphonates and orthodontics: Clinical implications. J Clin Orthod 2006;40:425-8. |
|3.||Stadeker WJ. Bisphosphonates 101: An Update for the General Dentistry. Inside Dental Hygiene. Available from: http://idh.cdeworld.com/courses/4443-bisphosphonates-101-an-update. [Last accessed on 2013 Apr 23]. |
|4.||Wynn RL. Oral bisphosphonates and osteonecrosis of the jaw. Gen Dent 2007;55:8-10. |
|5.||Bagan J, Scully C, Sabater V, Jimenez Y. Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): A concise update. Oral Oncol 2009;45:551-4. |
|6.||Woo SB, Hellstein JW, Kalmar JR. Narrative corrected review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-61. |
|7.||Menschutkin K Bisphosphonates in Medical practice: Actions, side effects and indications. Ann Chem Pharm 1865;133:317. |
|8.||Leite AF, Figueiredo PT, Melo NS, Acevedo AC, Cavalcanti MG, Paula LM, et al. Bisphosphonate-associated osteonecrosis of the jaws, report of a case and literature review. Oral Sur Oral Med Pathol Oral Radiol Endod 2006;102:14-21. |
|9.||Grbic JT, Landesberg R, Lin SQ, Mesenbrink P, Reid IR, Leung PC, et al. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial. J Am Dent Assoc 2008;139:32-40. |
|10.||Ruggiero SL, Drew SJ. Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res 2007;86:1013-21. |
|11.||Gittens SA, Bansal G, Zemicke RF, Uludag H. Advanced Drug Discovery Reviews. Vol.57. Oxford: Elsevier; 2005. p. 1011. |
|12.||American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: Expert panel recommendations. J Am Dent Assoc 2006;137:1144-50. |
|13.||Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007;65:2397-410. |
|14.||Koka S, Clarke BL, Amin S, Gertz M, Ruggiero SL. Oral bisphosphonate therapy and osteonecrosis of the jaw: What to tell the concerned patient. Int J Prosthodont 2007;20:115-22. |
|15.||Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658-68. |
|16.||American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: Expert panel recommendations. J Am Dent Assoc 2006;8:1144-50. |
|17.||Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM, et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract 2006;2:7-14. |
|18.||American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006;137:1144-50. |
|19.||Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34. |
|20.||Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: An emerging oral complication of supportive cancer therapy. Cancer 2005;104:83-93. |
|21.||Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567-75. |
|22.||Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-301. |
|23.||Bagan JV, Jimenez Y, Murillo J, Hernandez S, Poveda R, Sanchis JM, et al. Jaw osteonecrosis associated with bisphosphonates: Multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 2006;42:327-9. |
[Table 1], [Table 2]