Drug Criteria & Outcomes: Bad to the (jaw) bone:
Drug Criteria & Outcomes
Bad to the (jaw) bone:
Avoiding ADRs in cancer patients receiving IV bisphosphonates
By Brandy Puet, PharmD Candidate, Auburn (AL) University
Physician, dentist collaboration necessary
The recent appearance of osteonecrosis of the jaw in cancer patients receiving intravenous (IV) bisphosphonates is a painful reminder of the condition that struck match factory workers over a hundred years ago.
In the mid-1800s to early 1900s, cases of osteonecrosis of the jaw began to appear in workers who were involved in the production of matches dipped in white phosphorus throughout Europe and the United States. At least 150 cases were reported from 15 different match factories in the U.S during this time period. These workers suffered from pain, an odorous discharge, and often disfigurement. Lacking the modern advantage of antibiotics, this condition was fatal in approximately 20% of cases.1
Today, bisphosphonate induced osteonecrosis appears to be linked to nitrogen-containing bisphosphonates, with a 2-12 % incidence occurring in patients taking these medications.2 The only bisphosphonates in the U.S. not containing a nitrogen moiety are Didronel (etidronate disodium) and Skelid (tiludronate disodium).3 Aredia (pamidronate disodium) and Zometa (zoledronic acid) -- the main bisphosphonates used in cancer patients -- are responsible for the majority of cases of osteonecrosis, with zolendronic acid having a higher incidence.3,4 In a review by Marx et. al. of 119 patients with osteonecrosis, approximately 97% of patients were receiving either zoledronate or pamidronate.5 Another review by Woo et. al. involving 368 cases of bisphosphonate-associated osteonecrosis revealed that 94% of these patients had been treated with IV bisphosphonates (mainly zoledronic acid and pamidronate).3
Adverse drug reactions surface
Despite the fact that bisphosphonates have been in use for over 30 years, with an indication for IV use in bone metastasis for over ten years, the occurrence of osteonecrosis was not reported until 2003.4,6 In 2004, oncologists and maxillofacial surgeons were warned of the adverse drug reaction (ADR) by letters sent out by Novartis, the manufacturer of the two main causative agents. Dental health professionals were not warned of this potential ADR until May of 2005.6 Now that healthcare professionals are becoming aware of the connection between osteonecrosis and bisphosphonate use, reports are likely to increase.
Intravenous bisphosphonates are highly advantageous in the treatment of cancer patients, treating and preventing complications in these patients such as pain, fractures, spinal cord compression, and hypercalcemia of malignancy. Cancer patients receiving intravenous bisphosphonates are those patients with hypercalcemia of malignancy, those with prostate, lung, or breast cancer with or at risk of bone metastases, and those with multiple myeloma.3-6 Bisphosphonates act by osteoclast inhibition and apoptosis, thus hindering resorption of bone. They are also suspected to have antiangiogenic properties.4,6
How does a drug that prevents fractures also cause osteonecrosis? The exact pathophysiology behind this is unclear. One theory stresses the importance of the body being able to remodel its bones after the daily stress put on them. The jaw especially undergoes constant use and abuse resulting in the collection of microfractures. The body's normal response is to use its osteoblasts and osteoclasts to repair these microfractures. The osteoblasts perform their normal function of bone mineralization; however, due to the bisphosphonate concentration in the bone, the osteoclasts are unable to remove the damaged bone. If you add in the possible antiangiogenic properties, which will take away much needed blood flow to the bone to heal, the main result is a bone that cannot repair itself. Add in patients who are immunosuppressed and unable to fight off the millions of bacteria that live in the mouth and who are undergoing such treatments as chemotherapy, the end result is a perfect atmosphere for osteonecrosis of the bone to occur.4
Dental procedure may proceed onset
Although bisphosphonate induced osteonecrosis can present spontaneously, its presentation typically occurs after a dental procedure such as an extraction or after a recent dental infection.3,6 This is likely due to an inability of the bone to heal from the procedure and concomitant bacterial invasion. In the review by Woo et. al., 60% of cases were related to dental procedures.3 In a web based survey performed by the International Myeloma Foundation, 81% of patients with myeloma and 69% of patients with breast cancer who had osteonecrosis of the jaw had a history of recent dental problems such as infection or a recent tooth extraction.7 In most cases, the initial presentation is an area of exposed bone in the maxilla or mandible. Some patients are otherwise asymptomatic; others may complain of pain. Other symptoms are a nonhealing dental procedure site, ulcer, purulent discharge, and inflammation and swelling of the gums. In later stages, other sites may become affected and surrounding teeth may become loosened. Some patients may only complain of pain with no evidence of exposed bone.4,6,8
Many of the risks of bisphosphonate induced osteonecrosis have already been alluded to in this article. The main risks are associated with the specific type of bisphosphonate (nitrogen containing), the intravenous route of the bisphosphonate, the type of patient (cancer), inappropriate dental hygiene, and dental procedures.4 Other risk factors involve the use of other medications that affect the bone such as corticosteroids and medications that lead to bacterial invasion of the osteonecrotic site such as immunosuppressants.8 A longer duration of bisphosphonate use also increases a patient's risk. 6
Of all these risk factors, the most preventable are those associated with dental care. Patients are at an increased risk if they have dental disease, dental surgery (including extractions), oral trauma, periodontitis, or poor dental hygiene.9 Bisphosphonate induced osteonecrosis is comparable to osteoradionecrosis (bone necrosis caused by radiation). Patients receiving head and neck radiation are referred to a dentist to take care of any dental problems before the procedure to decrease the risk of osteoradionecrosis. Cancer patients receiving IV bisphosphonates should be no different.10 Upon dental evaluation, current infections can be treated and future risky procedures can be prevented by planning ahead and performing those procedures before bisphosphonate therapy.2,5,6,8-10 If dental referral cannot be made before bisphosphonate therapy is initiated due to the urgency of the patient's condition, patients should still seek a dental evaluation as soon as possible.
Patient education recommended
Patients should be counseled about the risk of osteonecrosis, and the importance of good dental hygiene and regular checkups should be stressed. It is important that patients also understand the importance of making their dentist aware that they are receiving IV bisphosphonates. If dentists are aware of a patient's bisphosphonate use, they will know to try to avoid procedures that may be risky in this type of patient. Physician and dentist collaboration is necessary to provide optimal care for cancer patients taking bisphosphonates. Pharmacists can also play a role by helping other health professionals become aware of this adverse drug reaction and by encouraging appropriate dental care when involved in the distribution of these medications to the patient.
For those patients on IV bisphosphonate therapy whose condition necessitates a dental procedure such as an extraction, it is debatable whether or not to discontinue the bisphosphonate therapy before and after the procedure. There is no evidence that discontinuing the bisphosphonate around the time of the procedure decreases the risk of osteonecrosis. It is even debatable if bisphosphonates should be discontinued in cancer patients once osteonecrosis has already occurred.2,3,5,8,9 Debate exists because much is unknown about how long it takes to decrease osteoclast suppression once discontinuing bisphosphonate treatment, and bisphosphonates may significantly improve a cancer patient's quality of life. Due to a current lack of evidence based medicine on this subject, careful consideration of the necessity of the bisphosphonate treatment and collaboration between the dentist or oral surgeon and the physician will determine the decision to continue or discontinue bisphosphonate therapy.
May not respond to standard treatments
Despite its resemblance to a more familiar from of jaw necrosis, osteoradionecrosis, bisphosphonate-induced osteonecrosis is not as likely to have a response to standard treatments such as surgical debridement and hyperbaric oxygen. Bisphosphonate-induced osteonecrosis is typically treated with oral rinses and antibiotic treatment, with surgical removal of bone being a last line option.3-6,10
Although osteonecrosis is most prevalent in cancer patients receiving IV bisphosphonates, a small percentage of the millions of patients receiving oral bisphosphonates for osteoporosis have also developed osteonecrosis of the jaw. Cases reported to drug companies producing these agents report 170 cases with Fosamax (alendronate), 20 with Actonel (risedronate), and one with Boniva (ibandronate) as of early 2006. This is a small number considering the millions of patients receiving oral bisphosphonates for osteoporosis. Despite the small risk in patients receiving oral bisphosphonates, patients should also be referred for dental evaluation before treatment is initiated and have current dental problems treated before initiation of therapy. These patients should also be made aware of the risk of osteonecrosis and encouraged to maintain proper oral hygiene.11 In contrast to patients receiving IV bisphosphonates, dental surgeries are not contraindicated in patients receiving oral bisphosphonates; however, some dental health professionals are recommending discontinuing the oral bisphosphonate around the time of the procedure.
Drop drugs before, after dental surgery
The American Association of Oral and Maxillofacial Surgeons (AAOMS) recently released a position paper that recommends discontinuing oral bisphosphonate therapy three months before and three months after a dental surgery if the patient has been on a bisphosphonate for greater than three years or has been receiving corticosteroids concomitantly. AAOMS also suggests that discontinuing oral bisphosphonates for 6 -12 months after the occurrence of osteonecrosis improves patient outcomes.12
Due to the importance of bisphosphonate therapy, the most valuable step healthcare professionals can take is prevention of adverse drug reactions. Healthcare professionals from the Mayo Clinic have already arisen to this challenge through recommendations made in their guidelines for bisphosphonate use in multiple myeloma patients. In these guidelines, "proactive communication" between the physician and the dental health professional is encouraged and prescribing of pamidronate over zoledronic acid is recommended due to a higher incidence of osteonecrosis in patients receiving zoledronic acid.13 Healthcare professionals from other institutions can become involved in preventing bisphosphonate ADRs by developing guidelines for appropriate bisphosphonate use and educating other healthcare professionals. Guidelines and education should stress the importance of collaboration of healthcare professionals, patient awareness, and appropriate monitoring.
References
- Donoghue AM. Bisphosphonates and osteonecrosis: analogy to phossy jaw. Med J Aust 2005 Aug; 183(3): 163-164.
- Ashcroft J. Bisphosphonates and phossy-jaw: breathing new life into an old problem. Lancet Oncol 2006 June; 7: 447-9.
- Woo S, Hellstein JW, Kalmar JR. Systemic Review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006 May; 144: 753-61.
- Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 2006 June; 7:508-14.
- Marx RE, Sawatari Y, Fortin M, et al. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005; 63: 1567-75.
- Ruggiero S, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Oct; 102(4):433-41.
- Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005 Jul; 353(1): 99-102.
- Mehrotra B, Ruggiero S. Bisphosphonate complications including osteonecrosis of the jaw. Hematology Am Soc Hematol Educ Program 2006:356-60.
- Bilezikian JP. Osteonecrosis of the jaw-Do bisphosphonates pose a risk? N Engl J Med 2006 Nov; 355(22)2278-81.
- Ruggiero SL, Bhoomi M, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 2004 May;62(5):527-34.
- American Dental Association. Expert Panel Recommendations: Dental Management of Patients on Oral Bisphosphonate Therapy: Report of the Council on Scientific Affairs 2006: 1-13.
- American Association of Oral and Maxillofacial Surgeons. Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws 2006 Sept: 1-17.
- Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo Clinic Consensus Statement for the Use of Bisphosphonates in Multiple Myeloma. Mayo Clin Proc 2006 Aug; 81 (8): 1047-53.
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