Early appearance of osteonecrosis of the jaw after zoledronic acid in a patient with a long history of taking oral bisphosphonates

Abstract

Osteonecrosis of the jaw (ONJ) is a serious side effect in patients receiving intravenous nitrogen-containing bisphosphonates (B). It has also been reported to occur due to oral administration of B. Most cases will appear after receiving B for more than 1 year. The authors report a case of a 67-year-old woman with osteoporosis who had received oral alendronate sodium for 2 years and stopped the treatment due to dyspepsia. 18 months later she was diagnosed with breast cancer and bone metastases. She started a treatment based on aromatase inhibitors and zoledronic acid (Z). She developed ONJ soon after the third administration. She was treated with antibiotics, anti-inflammatories and a chlorexidine colutory. She recovered 3 months later. ONJ secondary to Z may occur also earlier than it was thought in patients with a history of taking oral B.

Background

Osteonecrosis of the jaw (ONJ) is a serious adverse effect associated with the use of nitrogen-containing bisphosphonates (B). These drugs generally reduce bone resorption and turnover and have been used for several bone diseases such as Paget’s disease, hyperparathyroidism, osteoporosis, hypercalcaemia associated with malignancies and for metastatic bone lesions.¹ The particular B used depends on the required potency and medical condition.² In this way, oral Bs are preferred for patients with osteoporosis, whereas intravenous B are used for patients with cancer.^{2 3}

The American Society for Bone and Mineral Research defines B-associated ONJ as ‘an area of exposed bone in the maxillofacial region that has not healed within 8 weeks after identification by a healthcare provider in a patient who is receiving or has been exposed to a B and had not received radiation therapy to the craniofacial region’.⁴

The first case of B associated ONJ was reported in 2003.⁵ Since then several reports have associated ONJ with intravenous and oral B therapy.⁶ Generally ONJ associated with oral B for the treatment of osteoporosis is much less frequently reported.^{7 8} But nowadays osteoporosis represents a major public health problem due to its high cumulative fracture risk. Bs are considered for the treatment of these patients because these drugs can effectively prevent skeletal complications.⁹

One of the most important risk factors for ONJ is the length of exposure to as specific B. Moreover, Bonacina et al described that all new cases of ONJ were developed in patients who previously underwent therapy with a B.¹⁰

Zoledronic acid (Z) is considered one of the most powerful Bs and this fact has also been related to the high incidence of ONJ after repeated Z infusions.¹¹

On the contrary, yearly intravenous administration of Z has been considered safe and it is used for patients with postmenopausal osteoporosis. However, recently Lee et al have described ONJ after this regimen.¹²

A lot still remains to find out about the relationship between ONJ and Z.

We will describe here a case of a woman with a history of taking oral B and who developed ONJ early after Z treatment for bone metastases from a breast cancer.

Case presentation

A 67-year-old woman was diagnosed with postmenopausal osteoporosis and a history of teeth removal due to periodontal infections.

She had been receiving oral alendronate for 2 years and stopped taking it because of gastric dyspepsia. Eighteen months after stopping that treatment she was diagnosed with stage IV breast cancer (multiple bone metastases and axillary malignant lymph nodes). A biopsy of one of these nodes was taken and the inmunohistochemistry showed strong positivity for oestrogen receptors. The patient was recommended to start with a treatment with letrozole as well as monthly intravenous injections of Z. After the third administration of Z she developed jaw osteonecrosis (figure 1).

Figure 1.

Intraoral examination of her right lower jaw with bone exposure due to ONJ.

Intraoral examination revealed the presence of a fistula in her lower right jaw angle.

Treatment

The lesion showed slight signs of perilesional inflammation. She did not complain about pain on palpation. She visited the maxillofacial surgeon who removed necrotic bone parts in her right mandibular angle and prescribed a treatment with antibiotics (clindamycin), chlorexidine colutory and anti-inflammatories for 21 days.

Outcome and follow-up

She was advised to visit the surgeon once every 2 weeks. The doctor explored repeatedly her mouth and he did not observe any sign of infection throughout the follow-up. Eventually a complete mucosal closure was achieved in 3 months.

Discussion

ONJ is a serious adverse effect associated with the use of B. These drugs are generally used for the treatment of several bone diseases such as osteoporosis or metastatic bone lesions.¹

Although there are different Bs, in general oral Bs are preferred for osteoporosis, whereas intravenous B are used for patients with cancer.^{2 3}

The reported cumulative incidence of ONJ in patients receiving intravenous Bs for malignant diseases ranges from 0.8% to 12%,⁶ however, ONJ associated with oral B for the treatment of osteoporosis is much less frequently reported.^{7 8}

Nowadays osteoporosis is considered a major public health concern that can be effectively managed with the oral administration of B because these drugs may significantly prevent skeletal complications such as fractures.⁹ Therefore, it is expected that an increasing number of cases will appear in the near future.

The mechanism of ONJ is still not clear but many reports have ascribed a causative role to therapy with Bs.¹³ Several risk factors have been suggested such as the length of exposure to a specific B or even the previous exposure to another B.¹⁰ In fact incidence of ONJ has been described after repeated Z infusions.¹¹

However, the case reported by Lee et al has demonstrated that ONJ with a less intensive therapy with Z cannot be ignored in anyway.

We have described here an interesting case of a woman diagnosed with metastatic bone lesions from a breast cancer who underwent a treatment with Z. This patient had previously undergone a long treatment with oral B due to postmenopausal osteoporosis. We think that this fact might have influenced the early appearance of ONJ complication after the third infusion of Z.

The study by Bonacina et al¹⁰ has shown that a 10.8% of the patients in the observation group treated with B developed ONJ but none of those who participated in the ‘preventive strategies’ arm. The preventive approaches adopted for this study may have been effective and reduced the risk of ONJ. Moreover, the results shown by Dimopoulos et al¹⁴ indicated that preventive dental treatment decreased the risk of ONJ among patients with malignancy treated with intravenous Bs.

Although much remains to research, we can recommend that people under Bs treatment should undergo to repeated and detailed intraoral examinations in order to treat dentoalveolar inflammations and to detect early stages of ONJ lesions.

If diagnosed timely, the outcomes will be good; Generally surgical approaches and conservative treatment strategies will result in favourable outcomes in over 80% and 60%, respectively.^{15 16}

As a conclusion we consider that all the patients who will start a treatment with Bs should be adequately informed concerning the general risk of ONJ and should undergo oral examinations and preventive measures to reduce the risk. Finally, the potentially higher risk in cases with previous prolonged exposure to oral Bs for osteoporosis must be emphasised.

Learning points.

• ▶Oral examinations and preventive measures are very relevant to reduce the risk of developing ONJ in patients receiving B.
• ▶History of taking oral alendronate before receiving intravenous Z might influence the risk of early appearance of this complication.
• ▶Patients must be aware about this higher risk and they must be informed about the measures to meet with a preventive meaning.