Osteonecrosis of the jaw secondary to haematopoietic stem cell transplantation

Abstract

Osteonecrosis of the jaw (ONJ) is necrosis of mandibular or maxillary bone, which sometimes leads to bone exposure and sequestration. There is evidence that the microenvironment of the marrow stromal system is severely and irreversibly damaged after haematopoietic stem cell transplantation (HSCT) leading to a deficit in the quantity and quality of osteoblastic progenitors, compromising the ability to regenerate a normal osteogenic cell population and abnormality in bone remodelling/turnover. While osteonecrosis of the appendicular skeleton is a common complication after HSCT, there have been no reports of an association with ONJ. This is a report of the first case of ONJ secondary to HSCT in a 69-year-old woman who developed a unique pattern of osteonecrosis involving all four quadrants of the jaw 2 months after allogeneic stem cell transplantation.

Background

Osteonecrosis of the jaw (ONJ) is defined as necrosis of mandibular or maxillary bone which may lead to bone exposure. It is thought to be attributed to insufficient blood supply, and altered bone turnover, resulting in a disrupted repair process eventually leading to the collapse of the bone in the setting of microfractures.¹ Since 1867,² several aetiological factors contributing to ONJ have been identified, the most common being secondary to antiresorptive medication.

The risk of development of osteoradionecrosis (ORN) is 2–6.8% among irradiated head and neck cancer patients, and the risk of medication related ONJ (MRONJ) in patients on intravenous bisphosphonates is 1–7%.³ ONJ is commonly classified according to the American Association of Oral and Maxillofacial Surgeons classification as: stage 0, non-specific clinical findings, with symptoms such as pain and radiographic changes (no evidence of exposed bone); stage 1, bone exposure without signs or symptoms of infection; stage 2, exposed necrotic bone with pain and clinical evidence of infection; stage 3, the above manifestations with alterations such as pathological fractures, extraoral fistulas, or osteolysis extending to the inferior mandibular margin.⁴ The mandible is at a higher risk for the development of ONJ compared with the maxilla, which could be attributed to increased vascularity of the latter.^{3 4} Any haematopoietic stem cell transplantation (HSCT) related damage to the marrow stromal microenvironment can cause a deficit in the quantity and quality of osteoblastic progenitors contributing to an abnormal bone turnover.^{5 6} While there have been reports of osteonecrosis of the appendicular skeletal bone after HSCT, we report what is, to our best knowledge, the first case of ONJ secondary to HSCT.

Case presentation

A 69-year-old woman was referred to our oral medicine service with complaints of exposed bone causing irritation to the inner aspects of her upper and lower lips. Her medical history was significant for myelodysplastic syndrome, hypertension, and osteopenia. She was diagnosed with myelodysplastic syndrome in June 2017 and treated with two cycles of induction chemotherapy (decitabine) followed by conditioning chemotherapy (cyclophosphamide and fludarabine) and total body irradiation of 2 Gy in February 2018. Haploidentical stem cell transplantation (SCT) was performed on 7 March 2018, with her son being the donor. Graft versus host disease (GVHD) prophylaxis consisted of cyclophosphamide, tacrolimus, and mycophenolate mofetil. Her past medical history was not significant for radiotherapy to the head and neck nor exposure to bisphosphonates, RANKL inhibitors, or antiangiogenic medication. The patient had a remote history of one intra-articular corticosteroid administration to her wrist joint due to a sports injury she suffered approximately 35 years ago. Her medications included amlodipine, metoprolol, omeprazole, tacrolimus, sulfamethoxazole–trimethoprim (antibacterial prophylaxis), acyclovir (antiviral prophylaxis), cholecalciferol, and folic acid. She was a former smoker, with a history of smoking one pack a day for 5 years, having quit 45 years ago, and no alcohol consumption.

Prior to her SCT, she attended routine twice yearly dental visits with her long time dentist. She had no history of gingivitis or active periodontal disease but did have gingival grafting of the mandibular anterior teeth due to gingival recession about 30 years ago. The patient developed exposed bone fragments on the facial aspect of her maxillary and mandibular gingiva 2 months after her transplantation. Our institution recommends temporary suspension of dental visits until 6 months post-transplant when patients are less likely to be immune suppressed, so she saw her dentist in September who was unable to find a cause for her exposed bone. The patient was then referred to our oral Medicine service for evaluation and management.

The patient was afebrile with no constitutional signs or symptoms. She was asymptomatic except for irritation of the inner aspect of the lip due to the sharp pieces of bone protruding from her gingiva. Her extraoral examination was unremarkable with no lymphadenopathy. Intraoral examination revealed thin sheets of necrotic sequestra of the facial/buccal aspect of several maxillary and mandibular teeth and the interdental spaces (Nos 3, 4, 6, 7, 10, 19, 23, 24, 25, 27, 28, 30, and 31) (figure 1). Although the patient had maxillary and mandibular buccal exostoses, which are common locations for ONJ, these structures were not involved. There was generalised gingival recession associated with past periodontal disease, but periodontal probing depths were in the range of 1–3 mm with no bleeding on probing indicating arrested periodontal disease and healthy gingiva (figure 1). It is common to see bone loss in between teeth in patients with periodontal disease but bone sequestra are not generated. Preferential bone loss surrounding the front/facial aspect of the teeth is uncommon; therefore, cone beam CT (CBCT) was obtained to determine if bone levels were affected on the lingual surfaces or circumferentially.

Figure 1.

Clinical presentation of osteonecrosis of the jaw. (A) Necrotic sequestra on the buccal aspect of the right maxillary molars Nos 2 and 3. (B) Sequestra on the facial of teeth Nos 6 and 7. (C) Multiple necrotic sequestra on the facial aspect of mandibular teeth Nos 23, 24, 25, 27, and 28. (D) Sequestration on the buccal of tooth No 19.

Investigations

CBCT revealed the preservation of lingual bone and loss of interproximal, and up to 75% loss of facial bone height (image not shown). Interestingly, the bone underlying the sequestra was intact and corticated (figure 2).

Figure 2.

Cone beam CT (CBCT) images demonstrating (A) sequestrations in the buccal aspect of the right maxillary teeth Nos 6, 7, and 8. (B) Intact cortical bone below the sequestra of tooth No 6 (arrow). (C) Three-dimensional reconstruction of the anterior maxilla revealing multiple sequestra on the facial of teeth Nos 6, between 7 and 8, and 10–11. (D) Panoramic radiograph showing generalised horizontal bone loss and a periapical radiolucency with respect to the mandibular left posterior second molar (No 18).

On clinical and radiographic examination, the patient’s lower left molar (tooth No 18) was deemed non-salvageable due to severe recession, bone loss, and periapical radiolucency (figure 2D) so it was extracted under local anaesthesia. The periapical tissue and adjoining necrotic sequestra were submitted in 10% neutral buffered formalin for histopathological examination. Amoxicillin 500 mg three times daily for 14 days, and chlorhexidine 0.12% mouth rinse, were prescribed postoperatively. The pathology report indicated fragments of necrotic bone with acute inflammation and bacterial overgrowth consistent with osteonecrosis (figure 3A, B).

Figure 3.

Histopathological (haematoxylin and eosin) features consistent with osteonecrosis of the jaw. Low powered view, 40× (A), and high powered view, 100× (B), showing empty lacunae without osteocytes and increased inflammatory infiltrate. (C) Clinical image of the anterior maxillary and mandibular area after sequestrectomy showing healthy appearing gingiva underneath the necrotic sequestra.

Differential diagnosis

After clinical, pathological, and radiographic examination, the diagnosis of ONJ secondary to allogeneic SCT was made, as ONJ related to antiresorptive medications such as bisphosphonates, corticosteroids, radiation treatment, infection, autoimmune or haematological disorder (sickle cell anaemia), and trauma was ruled out.

Outcome and follow-up

At the 3 month follow-up visit, the extraction site of No 18 had healed completely with no signs of ONJ but additional mobile bony sequestrations in the maxillary and mandibular anterior quadrant were removed conservatively revealing healthy appearing underlying gingival tissue (figure 3C). She is currently being followed in our clinic quarterly for conservative management. To our knowledge, there have been no other reports of sequestered bone following this unusual pattern.

Discussion

The most widely known aetiological factors of ONJ include radiation therapy, use of antiresorptive (bisphosphonates and denosumab), and antiangiogenic (bevacizumab, sunitinib, sorafenib) medications, and trauma (eg, dental extraction).^{3 4} Other less common causes linked to ONJ are bacterial, viral, and deep fungal infections, haematological disorders such as thrombophilia and sickle cell disease, autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus, methotrexate use, systemic corticosteroid usage, mTOR inhibitor usage, altered fat metabolism, benign lingual sequestration, and idiopathy.^7–13 There are several proposed mechanisms explaining the pathophysiology of ONJ, yet the exact mechanism is not clearly elucidated. Based on the contributing aetiology, disturbed bone remodelling, inflammation or infection, altered immunity, toxic damage of soft tissue, radiation induced fibrosis, inhibition of angiogenesis with disruption of the blood supply due to intravascular thrombosis, hypofibrinolysis or sickling in the microvascular circulation causing infarction of bone marrow, and progressive destruction of osteocytes, have been regarded as possible mechanisms.^7–13 We thoroughly investigated reasons for ONJ in this patient, but we could not find any known aetiological factors in her medical history contributing to the ONJ.

Our patient was 2 months post-allogeneic SCT when she developed the pattern of jaw bone exposure described. She was under continuous surveillance by her oncology team with regular laboratory work and monitoring. Her appendicular skeleton, including hip/knee, was not affected by osteonecrosis. There was no history of antiresorptive (bisphosphonates or RANKL inhibitors), antiangiogenic medications (anti-VEGF inhibitors), methotrexate, or corticosteroid use. She did not have any thrombotic disorders, autoimmune disorders, or systemic infections. Local odontogenic infection of tooth No 18 may have been related to localised osteonecrosis, but her ONJ bone sequestra were widespread.

Benign lingual sequestration associated with the prominence of the mylohyoid ridge and the area of lingual tori/exostosis is common. The underlying hypothesis is that the relatively reduced thickness of non-keratinised oral mucosa over areas of prominent bone is prone to trauma. Trauma, when it involves the subjacent periosteum, causes the development of a focus of ischaemic bone necrosis.¹⁴ Reduction in blood supply to the sclerotic bone of tori and the lack of the normal protective anatomical contour may also be contributing risk factors.¹⁴ What is peculiar about this case is that the sequestra were occurring only on the facial and interdental locations of existing teeth and not in regions of bony protuberances or locations prone to trauma. The devitalised bone was in the buccal/facial locations rather than the lingual location, also regions less prone to trauma.

Osteonecrosis of the appendicular skeleton was first reported in 1987 in 50 SCT recipients who survived longer than 2 years, and is recognised as a common complication after SCT.¹⁵ This has not yet been associated with ONJ. Allogeneic SCT, older age at transplant, female gender, acute or chronic GVHD, treatment with corticosteroids, primary diagnosis, and total body irradiation are the factors that have been identified as risk factors for the development of appendicular skeleton osteonecrosis in SCT recipients.^{5 6 16} Our patient was 68 years old when she received the allogeneic SCT but did not develop any acute/chronic GVHD and consequently did not receive any treatment with corticosteroids. Osteoblasts are derived from the marrow stromal system containing mesenchymal stem cells.¹⁷ Multinucleated osteoclasts are haematopoietic cells derived from the monocyte/macrophage lineage.¹⁷ The colony forming units fibroblasts (CFU-f), which is the precursor compartment for osteogenic lineage, supports haemopoiesis, differentiate to the osteogenic lineage, and form bone tissue in in vivo assays.¹⁸ There is evidence in the literature demonstrating that the microenvironment of the marrow stromal system is severely and irreversibly damaged after SCT due to cytotoxic chemotherapy.¹⁹ Galotto and colleagues showed a 60–90% reduction in CFU-f frequencies in SCT recipients, and the numbers did not recover up to 12 years post transplant.¹⁹ Thus the increased risk of osteonecrosis after SCT may, in part, be explained by a deficit in the quantity and quality of osteoblastic progenitors in the stromal stem cell compartment, compromising the ability to regenerate a normal osteogenic cell population.^{16 18} A cross sectional study also demonstrated a considerable reduction in the bone mineral density using dual energy x-ray absorptiometry and phalangeal osteosonogrammetry, and decreased functional capacity of osteoblastic precursors using a CFU-f assay in post transplant long-term survivors.²⁰

Additionally, there is an abnormality in bone turnover, as evidenced by a decrease in markers of bone formation, such as insulin-like growth factor 1, and an increase in resorption markers, such as macrophage colony stimulating factor, immediately after allogeneic SCT.²¹ A prospective cohort study including 255 patients who underwent allogeneic SCT indicated that the relative risk of avascular necrosis leading to osteonecrosis of the hip was 4.3 times higher for female stem cell recipients than males.⁶ The study concluded that the risk of osteonecrosis is diagnosis dependent (acute lymphoid leukaemia >myelodysplastic syndrome >acute myeloid leukaemia >chronic myeloid leukaemia) independent of treatment.⁶ A retrospective study including 1346 SCT patients showed that the cumulative incidence of osteonecrosis at 10 years was 2.9% after autologous SCT, 5.4% after allogeneic matched related donor SCT, and 15% after unrelated donor SCT.²² ONJ was not found in any of these studies; however, it is not known if the oral cavity was examined.

In vitro animal studies have demonstrated differences between the iliac crest haematopoietic stem cells and the orofacial mesenchymal stem cells.²³ When osteo induced, orofacial mesenchymal stem cells proliferate more rapidly, expressed higher levels of alkaline phosphatase, and showed increased calcium accumulation forming bone consisting of isolated nodules without haematopoietic tissue, in comparison with the iliac crest stem cells.²³ Increased bony nodules could potentially lead to localised areas of sclerosis with the subsequent reduction in blood supply, increasing the risk of ischaemic bone necrosis.

In conclusion, to the best of our knowledge, this is the first case of ONJ secondary to allogeneic HSCT. Furthermore, this pattern of osteonecrosis involving the four quadrants of the jaw has not been described in the literature. Studies are required to investigate effects on the craniofacial skeleton bone marrow stem cells after HSCT.

Learning points.

• A thorough review of the medical history is required to determine the underlying aetiology of osteonecrosis of the jaw (ONJ).

• Clinicians should be cognisant of the possible association between ONJ and haematopoietic stem cell transplant.

• The treatment of ONJ is guided by the subjective and objective findings and can range from no treatment for asymptomatic ONJ to systemic antibiotics for those with signs of infection.