The dilemma of jaw osteonecrosis in patients with multiple myeloma

In this issue of Leukemia and Lymphoma, Montefusco and coworkers report on 178 patients with multiple myeloma seen contemporaneously at two medical centres [1]. Although not a prospective randomised study, two important observations were made. First, jaw osteonecrosis was only seen following dental extraction and not with other forms of dental intervention. Second, and most important, the prospect exists that pretreatment with antibiotics, in this case amoxicillin clavulanic acid, can reduce and possibly eliminate the risk of developing osteonecrosis of the jaw (ONJ), although confirmation would require a prospective randomised trial. To be able to reduce the risk of ONJ with a non-invasive, relatively inexpensive and easily administered medication, such as oral antibiotic therapy, would be most desirable.

In oncology practice previously, ONJ was essentially limited to patients with squamous cell carcinomas of the head and neck that received high-dose radiation therapy. ONJ's existence in multiple myeloma was rare before the year 2000 and correlated with the introduction of the high-potency nitrogen-containing bisphosphonates [2]. Osteoclastic activity is increased in patients with multiple myeloma and contributes to the bone mineral loss that occurs in nearly 80% of the patients with the disease. Pyrophosphate is a simple molecule that is a known potent inhibitor of osteoclasts. However, pyrophosphates' ability to inhibit bone resorption in vitro is not seen in vivo because it is readily hydrolysed and is, therefore, ineffective [3]. By substituting a carbon atom for the central oxygen molecule and adding a hydroxyl chain, both resistance to hydrolysis and a high affinity for calcium crystals and bone mineral develops. The three oral bisphosphonates currently used in the United States are alendronate, ibandronate and risedronate [4]. However, these nitrogen-containing bisphosphonates are relatively poorly absorbed and are of low potency compared with their parenteral counterparts. Reports of ONJ have occurred in the literature with the use of oral bisphosphonates, but the frequency is very low. The risk of osteonecrosis in patients receiving oral bisphosphonates for osteoporosis is estimated to be approximately one patient per 100,000, far below the 5–10% actuarial risk at 3 years for myeloma patients [5]. Because less than 1% of a bisphosphonate dose is absorbed orally, parenteral bisphosphonates were developed. The prototype parenteral bisphosphonate is pamidronate and its successor is zoledronic acid. Initial studies demonstrated that pamidronate significantly decreases the time to the first skeletal event defined by orthopedic intervention, the need for radiation therapy or the radiographic demonstration of a new fracture or compression [6]. The median time to first skeletal event in placebo-treated patients was 10 months and was not reached in the pamidronate arm. Significant toxicities were subsequently detected with high-potency bisphosphonates, including the development of proteinuria and renal insufficiency [7]. Subsequently, patients presented with jaw osteonecrosis characterised by inflamed gingival tissues adjacent to exposed mandibular bone. Maxillary osteonecrosis and bilateral osteonecrosis have been reported as well, but are not as common as the mandibular site. The definitions of bisphosphonate-associated ONJ offered by consensus groups representing the American Society of Bone and Mineral Research (ASBMR) and the American Association of Oral and Maxillofacial Surgeons (AAOMS) both state that exposed bone for 8 weeks is necessary and sufficient for a diagnosis of ONJ to be justified. In most previously reported instances, the exposed bone has resulted from a dental extraction. In this report by Montefusco et al. the median time to diagnosis of ONJ was 8-weeks post-extraction which approximates the ASBMR and AAOMS definitions well.

Hitherto, the principal mechanism of bisphosphonate action culminating in risk of ONJ has been proposed to be reduced bone turnover. Furthermore, anti-angiogenic effects of bisphosphonates are suggested to contribute to the reduced healing potential of bone as evidenced by poor osseous healing at ONJ sites. The data presented by Montefusco et al. lend credence to the belief that bacterial insult may also play an important role in ONJ development. However, whether the beneficial antibacterial effect is on osseous healing or on soft tissue healing is presently unknown. Certainly, antibiotic coverage is routinely used by dental practitioners for patients undergoing a variety of forms of dental surgery with the premise that soft tissue healing is enhanced. Should antibiotic coverage facilitate complete coverage of exposed bone after a dental extraction, would be a significant advantage. However, this must be reconciled with the fact that some of the ONJ cases in this report were diagnosed well after the dental extraction took place.

One study suggests the incidence of ONJ at 36 months with pamidronate is ∼3%versus nearly 10% with zoledronic acid [8]. No randomised studies exist to prove that zoledronic acid carries a higher risk of osteonecrosis than pamidronate, however, most investigators believe this to be the case. A report by the Greek myeloma group also has demonstrated a higher risk of osteonecrosis in patients treated with zoledronic acid compared with those who received either pamidronate, pamidronate with zoledronic acid or ibandronate and zoledronic acid. The 50-month incidence of ONJ was ∼15% zoledronic acid compared with under 5% pamidronate (p = 0.003) [9]. The development of osteonecrosis has led to a number of guidelines, including those from the American Society of Clinical Oncology and Mayo Clinic [10,11]. Mayo Clinic guidelines currently recommend that bisphosphonates be used monthly when lytic disease is seen on the radiograph. If osteopenia only is present by radiographic studies, bisphosphonates are recommended if bone mineral density is abnormal. Bisphosphonates are not recommended for MGUS or smoldering multiple myeloma. The current Mayo recommendation is monthly bisphosphonate for 2 years and if a remission or stable plateau occurs, treatment can be discontinued, but if there has been relapse or the patient is on treatment, quarterly bisphosphonates are continued.

These guidelines are consensus because the studies do not exist to make a decision that is evidence based. Currently, at Mayo Clinic, pamidronate is the bisphosphonate of choice for newly diagnosed patients, based on the suggestion of a higher ONJ risk with zoledronic acid. All new patients with multiple myeloma require a dental evaluation at diagnosis and extractions are avoided if possible. It is currently recommended if a procedure is required, bisphosphonate be held for 1 month and not resumed until healing. The management of ONJ is difficult and there is controversy as to whether devitalised bone should be surgically removed or the patient should be managed conservatively [12]. Some patients can have ONJ with no symptoms. Others require narcotics for pain control. Once ONJ does develop, it is difficult for the patient and prevention is preferred. Although excellent dental hygiene is the best preventative, this cannot be controlled when patients present with newly diagnosed multiple myeloma and need to start bisphosphonate therapy. Therefore, the suggestion in this article that antibiotics might substantially reduce the risk of ONJ following dental extraction is an important clinical step forward in the management of patients with multiple myeloma who, appropriately, should be receiving nitrogen-containing bisphosphonate therapy.