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OsteoNecrosis from Medications

There are several significant articles about jaw bone death in patients taking certain drugs to reduce bone resorption. The problem arises more frequently when the drugs are used for cancer treatment or the treatment of metastasis to the bone and is more severe and frequent with the drugs that are given by injection rather than by oral pill form.

The American Academy of Oral Medicine issued a position paper based on the review of some distinguished dental scholars, many of whom I know and trust from personal contact with them in the decades I was active with the AAOM. You may click on the link below to read their paper from the American Dental Association Journal.

Managing the care of patients with bisphosphonate-associated osteonecrosis An American Academy of Oral Medicine position paper

US Pharmacology also posted a recent paper which is copied below, detailing the problem and which drugs are currently involved.

Bisphosphonate-Associated Osteonecrosis of the Jaws: Impact on Oral Health

Mea A. Weinberg, DMD, MSD, RPh
Clinical Associate Professor of Periodontics
New York University College of Dentistry
New York, New York

Vol. No: 31:05 Posted: 5/15/2006

US Pharm. 2006;5:62-69.

Osteonecrosis of the jaws (ONJ) is a serious oral condition that has been reported more frequently by dentists and physicians in the last few years in cancer patients receiving chemotherapy, radiation, corticosteroids, or other cancer treatment regimens concomitant with the use of bisphosphonates. These patients may also present with comorbid conditions such as anemia, infections, and preexisting oral disease. Although the original published reports of ONJ involved intravenous bisphosphonates, currently some cases with oral bisphosphonates are occurring. Patients with ONJ usually present with oral signs and symptoms of painful, exposed, and necrotic bone, primarily of the mandible and to a lesser extent the maxilla, after dental treatment. This article reviews the development of osteonecrosis of the jaws, potential risk/precipitating factors, the pharmacology of bisphosphonates, and potential preventive measures for this oral complication.

Background
Introduced in the mid-1990s, bisphosphonates were prescribed as an alternative to hormone replacement therapies for osteoporosis and to treat osteolytic tumors and possibly slow tumor development. In 1996, Fosamax (alendronate) was the first bisphosphonate drug approved for osteoporosis (in which low bone mass and reduced bone strength lead to fractures of the spine, wrist, and hip) in postmenopausal women (and later, in men); it was approved later on for treatment of Paget's disease (in which normal bone is replaced with poor-quality bone).

The first studies on the actions of bisphosphonates to block calcification and bone destruction were published in the 1960s. Didronel (etidronate) was first used over 20 years ago to treat patients with osteoporosis, but they developed osteomalacia and clinical studies were stopped. In the United States, Didronel is not approved for treatment of osteoporosis.

In 2005, the Food and Drug Administration approved Boniva (ibandronate sodium) as the first once-a-month tablet for postmenopausal osteoporosis. Studies showed that it significantly reduced the risk of new vertebral fractures and increased bone mineral density. 1 In January 2006, the FDA approved Boniva injection, the first injectable medication for treatment of postmenopausal osteoporosis. Injectables were developed for individuals having difficulty with oral bisphosphonate dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill. Additionally, the injectable product is administered once every three months by a physician so that monitoring is possible.

The FDA has notified the dental/medical community to the potential problem of osteonecrosis of the jaws (also referred to as avascular or aseptic necrosis)--primarily of the mandible but also cases of the maxilla--occurring in association with bisphosphonates. The first reported cases were associated with intravenous bisphosphonates used to control hypercalcemia in metastatic bone disease2 but there are also anecdotal unpublished reports of oral bisphosphonates causing ONJ.

Drug Properties
Bisphosphonates are synthetic analogues of pyrophosphates, identified in the 1960s as substances present in blood and urine that prevent the formation and aggregation of calcium phosphate crystal.3 Pyrophosphates are used in tartar control toothpastes to inhibit the formation of tartar (calculus)--a hard calcium deposit on the tooth. Bisphosphonates were developed because pyrophosphates were rapidly metabolized in the body. Figure 1 shows the basic chemical structure of bisphosphonates.

Bisphosphonate

Bisphosphonates are not metabolized; only about 3% of the drug is absorbed after an oral dose.4 Within 24 hours, about half the absorbed dose is excreted in the urine and the rest is distributed to bone, from which it is slowly eliminated.

 

Mechanism of Action

The function of bisphosphonates is still relatively unclear. Bisphosphonates bind and accumulate in bone and remain there for months after therapy is discontinued. They are potent inhibitors of normal and abnormal osteoclastic bone resorption that results in metastatic bone disease.5 They also reduce the local release of factors that stimulate tumor growth (antitumor effect).6 Bisphosphonates are known to inhibit osteoclast attachment to bone, to induce apoptosis (programmed cell death) of osteoclasts, and to inhibit differentiation of bone marrow precursor cells into osteoclasts; they may also contribute to inhibition of bone resorption and increase in bone mass.3 Although they block bone resorption, formation continues for about six to 12 months, after which formation stops. Thus, the mineral is more densely packed so that the bone density will increase even though the bone volume does not.

Bisphosphonates also act on osteoblasts to inhibit osteoclast activity and osteoclastic function, an integral part of the normal turnover and maintenance of bone. Osteoclastic function is so severely impaired that osteocytes are not replaced and the capillary network in the bone is not maintained. This results in avascular bone necrosis. The net effect is that physiologic bone deposition and remodeling are severely compromised in cancer patients receiving bisphosphonates.7 The length of drug exposure may play a role in the development of ONJ.8 Patients taking bisphosphonates for more than six months are at the highest risk for ONJ.9

Formulations and Indications
Table 1 lists the oral and parenteral bisphosphonate products currently available in the U.S. Bisphosphonates are indicated for both the treatment and prevention of osteoporosis and in cancers metastatic to bone (skeletal complications of malignancy).6 See Table 2.

8_1741_18_1741_2


Alendronate and risedronate are oral preparations used to treat osteoporosis. Zoledronic acid, pamidronate, and ibandronate are the only intravenous bisphosphonates that are indicated for treatment of hypercalcemia of malignancy, such as squamous cell carcinoma of the head and neck, breast cancer, prostate cancer, multiple myeloma, and renal cancer. The incidence of hypercalcemia in cancer patients is about 20% to 30%; the prognosis is very poor, and many patients die. The first-generation oral bisphosphonates, such as alendronate and risedronate, are not useful in the treatment of hypercalcemia of malignancy because they are not as potent as the second- and third-generation intravenous drugs. Intravenous bisphosphonates are also used with standard antineoplastic therapy in the treatment of breast, lung, and prostate cancer metastatic to bone to prevent bone complications and in multiple myeloma by interfering with bone marrow activities (through inhibition of osteoclastic activity).


Risk Factors for Osteonecrosis of the Jaws
Documented risk factors for osteonecrosis of the jaws are listed in Table 3. As mentioned earlier, it is unknown if dental extraction/surgery is a cause of ONJ or just a precipitating or exacerbating factor that hastens bone necrosis. Invasive dental procedures that may precipitate osteonecrosis include tooth extractions, placement of dental implants, and periodontal surgery. Even pressure from dentures, which results in local mucosal infections beneath the denture, may be followed by bone involvement.

8_1741_3


Adverse Events: Reported Cases of Osteonecrosis of the Jaws

Wang et al. reported the first cases of ONJ associated with bisphosphonate therapy in cancer patients.2 These cancer patients were undergoing many treatments with chemotherapy drugs, corticosteroids, and bisphosphonates. Marx10 reported on a group of 36 patients receiving intravenously either pamidronate or zoledronate for the management of bone disease associated with metastatic cancer, multiple myeloma, and osteoporosis, who had developed avascular necrosis of the jaws. In the majority of cases, the necrosis developed after tooth extractions (nonhealing extraction sites), and in about 30% of cases it occurred spontaneously.

Instances of osteonecrosis of the jaw bones have been reported for both injectable and oral bisphosphonates and may be a class effect, according to the FDA, as exhibited by alendronate, zoledronic acid, and pamidronate cases. In a 2005 report, Marx et al.11 studied 119 cases of bisphosphonate-associated bone exposure in patients taking Aredia (26%), Zometa (40.3%) and Fosamax (3%). The mean time for bone to be exposed in the oral cavity with accompanied symptoms was 14.3 months. Precipitating events that caused the bone exposure were as follows: 37.8% tooth extractions, 28.6% advanced periodontal disease, 25.2% spontaneous, 11.2% periodontal surgery, 3.4% placement of dental implants, and 0.8% root canal surgery.11

Clinical Features of Osteonecrosis of the Jaws
The exact mechanism underlying this reaction is unknown; however, it has been postulated that bisphosphonates inhibit new vessel formation in the bone, which is associated with absent or delayed hard (alveolar) and soft tissue healing, usually after dental extractions.12,13 The oral lesions seen in ONJ appear similar to those of radiation-induced osteonecrosis.13,14 Clinically, there is oral ulceration with exposed underlying necrotic ("dead") bone (Figures 2 and 3 ). This oral condition causes chronic pain and severe, irreversible dysfunction and disfigurement of the jaw. Other symptoms include soft tissue swelling, infection, and mobility of teeth.

Patients may remain asymptomatic for many weeks or months, and ONJ may be recognized only by the presence of exposed "painful" bone in the mouth. These lesions most likely become symptomatic when the necrotic sites become secondarily infected or if there is trauma to the soft tissue.

8_1741_4


Although dental surgery or extractions have been identified as precipitants in many of these cases, as ONJ developed after tooth extraction, there is evidence suggesting that the jaw (alveolar) bone can be involved before and independent of dental procedures.15 The condition can develop spontaneously.

Treatment Management
Treatment management involves educating the dentist (periodontist, oral surgeon, prosthodontist), pharmacist, physician , and patient about ONJ and preventive measures that need to be taken to avoid these oral complications. The American Academy of Oral Medicine published a position paper addressing the prevention of bisphosphonate -associated osteonecrosis and the dental care management of patients with cancer and/or osteoporosis who are taking bisphosphonates.12 In 2005, The American Academy of Periodontology (AAP) published a statement on bisphosphonates, making periodontists aware of the need to determine if patients are currently taking intravenous bisphosphonates or if any patients will be treated with these drugs. The AAP stresses the importance of identifying ONJ and other oral complications of cancer and cancer therapy.

The FDA and drug companies have published statements for dental health professionals regarding the development of ONJ in patients being treated for cancer with intravenous bisphosphonates. In late 2004, for example, Novartis had implemented changes to Zometa and Aredia product labels to include precautions on osteonecrosis of the jaws. The precaution states that a dental exam and preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors such as cancer, chemotherapy, corticosteroids, and poor oral hygiene. In February 2005, the FDA released a statement that ONJ is a risk of all bisphosphonates, not just the IV formulations.

Prior to starting on bisphosphonate therapy, patients should be counseled regarding the possible occurrence of ONJ.16 If possible, invasive dental procedures should be avoided while patients are taking the medications. It is recommended that dentists perform a thorough soft tissue and dental examination before a patient starts using bisphosphonate drugs. If bisphosphonate therapy can be briefly delayed without the risk of skeletal-related complications, dental procedures should be performed on the patient who requires root canal therapy or tooth extraction, denture adjustment, periodontal surgery, or placement of dental implants.17 Avoiding tooth extractions while patients are taking bisphosphonates should minimize the incidence of ONJ.18 Once bisphosphonate therapy has begun, the dentist should monitor the patient's oral health on a regular basis. Early detection is the key.

The pharmacist should counsel the patient taking a bisphosphonate on self-care oral hygiene. Some recommendations include using a soft-bristled toothbrush, replacing the toothbrush frequently to maintain its shape and effectiveness, and avoiding alcoholic over-the-counter mouthrinses since the alcohol will "dry" oral tissues.

Dental consultation before initiating bisphosphonate therapy is essential. Dental health and maintenance of oral tissues are extremely important for cancer patients taking bisphosphonates. Pharmacists and dentists should report suspected cases of ONJ to the FDA's MedWatch Adverse Event Reporting Program online at www.fda.gov/medwatch/report.htm or by phone at 1-800-FDA-1088.

Mouthrinses, systemic antibiotics, hyperbaric oxygen, and surgical debridement have been tried as treatments for ONJ, but no treatment has been proven effective. Marx et al. 11 found that a combination of antibiotics and 0.12% chlorhexidine mouthrinse was about 90% effective in controlling pain in patients with painful exposed bone. Discontinuing the bisphosphonate is not recommended once necrosis of the jaws has occurred.19 Focus should be placed on prevention--the patient should have regular dental examinations and any invasive dental treatment done before bisphosphonate therapy begins.

Individuals using oral or intravenous bisphosphonates have contact with their pharmacist. Some may report to the pharmacist that they have oral pain or bleeding from inside their mouth. After consulting with such patients about their medications and dental visits, the pharmacist should refer the patient to the dentist and/or physician.

Summary
The pharmacist, dentist, and physician all play a pivotal role in the patient's chemotherapy regimen. The pharmacist and dentist are in the best positions to educate the patient about the potential adverse events that can occur once starting bisphosphonates and of the necessary preventive measures. Complete prevention of ONJ is not currently possible.11 Therefore, the patient must maintain excellent oral hygiene to reduce the risk of dental and periodontal infections. Patients should be advised to have routine dental examinations before and during cancer/bisphosphonate treatment and to report any oral symptoms to their dentists and physicians promptly.

REFERENCES
1. America's Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation: The National Osteoporosis Foundation; February 2002.
2. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with chemotherapy. J Oral Maxillofac Surg 2003;61:1104-1107.
3. Fleisch H. Bisphosphonates--history and experimental basis. Bone 1987;8:Suppl 1:S23-28.
4. Fleish H. Bisphosphonates: pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs 1991;42(6):919-944.
5. Licata AA. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 2005;39:668-677.
6. Green JR. Antitumor effects of bisphosphonates.Cancer.2003;97(3 suppl):840-847.
7. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301.
8. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23(24):8580-8587.
9. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphophonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-534.|
10. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115-1117.
11. 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 Nov;63(11):1567-1575.
12. Migliorati CA, Casiglia J, Epstein J, et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc. 2005;136(12):1658-1668. Erratum in: J Am Dent Assoc. 2006;137(1):26.
13. 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.
14. Melo MD,Obeid G. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy. Strategies for prevention and early recognition. J Am Dent Assoc 2005;136:1675-1681.
15. Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med J Aust 2005;182:417-418.
16. Zarychanski R, Elphee E, Walton P, Johnston J. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol 2006;81:73-75.
17. Katz H. Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod 2005;31(11):831-834.
18. Gibbs SDJ, O'Grady J, Seymour JF, Prince HM. Bisphosphonate-induced osteonecrosis of the jaw requires early detection and intervention. Med J Aust 2005;183(10):549-550.
19. Lenz JH, Steiner-Krammer B, Schmidt W, et al. Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates? J Craniomaxillofac Surg 2005;33(6):395-403.

To comment on this article, contact editor@uspharmacist.com.

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