Bisphosphonates and avascular necrosis of the mandible: Case report and review of the literature

Case report 

A 60-year-old male presented initially with a lytic scalp lesion and hypocalcaemia. In February 2000, the patient was diagnosed with IgA multiple myeloma. His past social/medical history included alcoholism, hypertension and chronic obstructive airway disease as well as a silent myocardial infarct some years previously.

His medical comorbidity precluded stem cell transplantation and he was commenced on standard melphan and prednisone and pamidronate to treat the lytic scalp lesion and the hypocalcaemia. Within a year, he was found to be resistant to the melphan/prednisone combination and was treated with weekly cylophosphamide and alternate day prednisone. This was complicated by severe hyperglycaemia. In April 2002, because of disease progression he began decadron 40mg daily every 2 weeks combined with thalidomide 200mg/day. Eventually, corticosteroids were discontinued and he remained on thalidomide (100–200mg/day). He was noted to have a good response to this combination in August 2002.

In January 2004, he presented to his physicians with a chronic painful ulcer in the lower right buccal sulcus. It was noted that the patient had poor oral hygiene and a recent tooth extraction in the area. After a number of unsuccessful conservative debridements, he was referred to our head and neck service. A biopsy confirmed that the boney lesion was osteonecrosis and not a metastatic deposit of myeloma.

It was decided that a more extensive debridement would be necessary. He underwent a partial mandibulectomy with an osseocutaneous scapula free flap reconstruction. The skin paddle was used to replace the soft tissue defect caused by the chronic ulcer (Figure 1, Figure 2, Figure 3, Figure 4).

View Large Image Download to PowerPoint

Figure 1 Area of avascular necrosis seen on computerized tomography (CT).

View Large Image Download to PowerPoint

Figure 2 Area of extensive ulceration adjacent to the necrotic mandible.

View Large Image Download to PowerPoint

Figure 3 Harvesting of osseocutaneous scapula free flap.

View Large Image Download to PowerPoint

Figure 4 The patient presents at six months postoperatively.

Discussion 

Bisphosphonates in the form of pamidronate and zoledronate are used regularly in the management of osteoporosis. Although they have been associated with a number of adverse side effects, avascular necrosis of the mandible or maxilla was not reported in phase III trials and until recently, not acknowledged in the product information for these medications.

The typical presentation of patients with avascular necrosis is a non-healing extraction socket or a pressure area caused by an ill-fitting denture. Pain, swelling and discharge are followed by the sequestration of bone and the progression may vary from a rapidly progressive disease process to a slow undulating course.

Avascular necrosis in patients who have been treated with bisphosphonates is likely due to the inhibition of osteoclastic function, which may be mediated in different ways (Table 1).

Table 1. Mechanism of action of bisphosphonates

	Inhibition of monocyte differentiation to osteoclasts3
	Increase in osteoclast apoptosis3
	Stimulation of osteoclast inhibitory factor1, 2, 9, 10
	Prevention of osteoclastic development from bone marrow precursors11
	Reduction of osteoclast activity12
	Down regulation of matrix metalloproteinases13, 14

This will result in reduced bone resorption and therefore the indication for the treatment of patients with osteoporosis, bone metastases or multiple myeloma.15 However, bone undergoes osteoclastic bone resorption as part of its normal turnover and inhibiting the resorption of bone in this setting can result in the development of large areas of non-vital bone. As a secondary effect, the lack of cytokines and other bone morphogenic proteins that stimulate the differentiation of osteoblasts will cause a corresponding reduction in the laying down of new mineral. The result is a bone with large areas of non-vital osteoclasts and micro-fractures of the old bone matrix.12

Another possible mechanism of the action of bisphosphonates has recently been described.13, 16 In vitro, zoledronic acid inhibits proliferation of human endothelial cells, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor.13 Santini et al. showed a significant and lasting decrease of VEGF serum levels produced by pamidronate.16 These antiangiogenic properties may also contribute to the relative ischaemia of the affected bone.

Although there are a number of bisphosphonates available, there are some differences in their mechanism of action. Those, such as pamidronate and zoledronate, are nitrogen-containing bisphosphonates, and unlike their nitrogen-free counterparts (etidronate and residronate), they accumulate in the bone. It may be this prolonged mechanism that is responsible for the development of avascular bone necrosis that is not seen with the other bisphosphonates.

There are many reports of osteonecrosis in patients undergoing chemotherapy 17, 18 although the wide range of drugs used in these patients makes it difficult to establish a causal relationship.19 Bisphosphonates have even been advocated for the treatment of avascular necrosis of the femoral head.20 Despite this it is difficult to dismiss the recent rise in the number of cases reported together with the greater understanding of the mechanism of action of the new generation of bisphosphonates. It is possible that the earlier reports of bone necrosis overlooked the influence of these drugs and assumed that the antineoplastic medication or the steroids were solely responsible. It is therefore very probable that bisphosphonates play a significant role in the development of AVN.21

To our knowledge, there have been no reports of avascular necrosis of the long bones associated with the use of bisphosphonates. The mandible and maxilla are unique because of the presence of teeth and periodontal ligaments. Radiotherapy or periodontal infections in the form of periodontitis or periapical disease can be the catalyst for the initiation of the rapid bony destruction that is often reported in these patients.22, 7

Tooth extractions can expose the bone to a sudden bacterial colonization. Poorly vascularised bone, with little capacity to repair as a result of dampened osteoblastic and osteoclastic activities, would therefore succumb to necrosis and a non-healing socket. Indeed, Marx2, 22 and Bagan et al.10 have independently reported 77% and 70%, respectively, of patients with avascular necrosis, who had undergone recent tooth extractions.2, 10, 22 The manufacturer of zoledronic acid recently included in the drug information leaflet, a recommendation regarding the avoidance of ‘invasive dental procedures’ while on the medication (http://www.pharma.us.novartis.com). Other authors have, however, reported osteonecrosis in patients who had not undergone dental extractions.4

Avascular necrosis is very difficult to treat and debridement is often unsatisfactory8 because areas of previously uninvolved bone become exposed and develop necrosis. Adjunctive treatment such as hyperbaric oxygen has not been shown to be universally effective and discontinuation of the bisphosphonates does not impact significantly on the progression of the disease.1, 8, 23 Treatments to date have ranged from aggressive debridement of the necrotic and sequestrated bone to more conservative approach, with debridement only in the affected bone.

These patients should be treated aggressively with antibiotics to prevent the development of a frank osteomyelitis. Bacteria are a common feature of the sequestra 23, 24 and local measures such as irrigation and antimicrobial mouthwash should reduce the number of infective episodes. Sequestration should be allowed to take its natural course and surgical intervention should be considered only when the patient becomes symptomatic.

To minimize the risk of developing avascular necrosis of the mandible, prophylaxis and preventive strategies are essential for the patients being treated with bisphosphonates. A screening dental examination prior to the commencement of the medication is imperative. Teeth that require treatment can be identified and those teeth that are not salvageable should be extracted prior to the commencement of bisphosphonates. Patient education regarding gingival health must be stressed. Mouthwashes, particularly those containing chlorhexidine which reduces the overall oral bacterial count,25 should be used regularly by these patients and regular dental examination will reduce the risk of exposing the patient to infections or extractions.

Edentulous patients should have a denture assessment to ensure an adequate fit with no areas of mucosal impingement, particularly in the buccal sulci. Extensive manipulation of the dentoalveolar structures (e.g. deep scaling) or occlusal rehabilitative procedures, such as dental implants, should be avoided while these patients are being treated with bisphosphonates.

Appropriate indications for the use of these drugs in susceptible patients need to be established. Those who are eucalcaemic (normocalcaemic), or in those with no obvious lytic bony changes should not be prescribed bisphosphonates without other reasons.

Bisphosphonates interfere with the osteoblastic/osteoclastic axis and there is an evidence to indicate that this class of drug may be responsible for the increased prevalence of avascular jaw necrosis. This condition causes significant morbidity in a patient population that can ill afford it. Given the obvious beneficial effects of bisphosphonates, and the probable widening of its indications for use as an antitumour medication, it is incumbent on those who prescribe these drugs to be aware of this very serious complication. Prophylactic measures and early diagnosis are essential for the optimal management.