Clarification regarding osteonecrosis of the jaw

The purpose of this article is to update readers about innovations on osteonecrosis of the jaw, but above all, to outline more clearly some of the fundamental aspects that distinguish osteonecrosis of the jaw in the context of oncology, and in the context of osteoporosis.
Differences in the incidence, risk factors, clinical settings and management are such that they have a profound impact on recommendations in guidelines for prevention and treatment. Nevertheless, in clinical practice, all patients who are taking bone resorption inhibitors (bisphosphonates and denosumab), with different indications and dosages, are considered to be at the same level of risk for osteonecrosis of the jaw, merely from the fact they are using them.
Bisphosphonates and denosumab are prescribed in cancer, where they are highly effective at preventing complications in metastatic skeletal disease, as well as for reducing the risk of fractures in osteoporosis. However, the differences between their use for these two conditions are now so macroscopically evident (doses and schedules of administration, concomitant therapies and clinical conditions, type of oral pathology) that a superficial and indiscriminate approach is no longer acceptable (see table).

Definition, pathogenesis and clinical contexts

The definition of osteonecrosis of the jaw provides for the presence of three criteria: "A) an area of ​exposed bone in the oral cavity at the maxillary/mandibular level, that does not heal within 8 weeks of identification by healthcare workers, B) in subjects who are receiving or have taken bisphosphonates or denosumab and C) who are not and have never been treated with radiation therapy in the head and neck region".¹
This recent definition, in comparison to the previous one, even fits denosumab, and will be updated soon for detecting osteonecrosis of the jaw associated with the use of anti-angiogenic agents.^1-2 It should be noted that rare cases of jaw osteonecrosis also arise in populations who have never been treated with bisphosphonates, denosumab or anti angiogenics, and that a list of oral diseases fall under the differential diagnosis of osteonecrosis of the jaw. Briefly, the nature of this condition is, due to a chronic osteomyelitis, generally supported by bacteria of the oral microbial flora (Actinomyces, but also staphylococci, streptococci and candida), leading to bone necrosis, bone exposure, with a poor tendency for healing. Its pathogenesis is complex and multifactorial, and the sequence is variously defined.^2-3 It is not a direct necrotic/toxic effect of drugs, but due to the protracted inhibition of osteoclastic activity and angiogenesis, innate or acquired immunodeficiencies and invasive dental procedures exposing to infection.
The clinical picture was originally grouped into three stages depending on the presence of exposed bone, but without pain or signs of infection (Stage 1), with pain and signs of infection (Stage 2) and the appearance of fistulas, fractures and osteolysis (Stage 3). Recently, a Stage 0 has been proposed, characterized by certain symptoms and radiological changes in the absence of exposed bone. This "preclinical" stage has not yet been unanimously approved and accepted in the specialist guidelines.^1,2,4 Every stage corresponds to a level of treatment that runs from follow up at Stage 0, to mouthwashes and antibiotics at Stages 1-2, to curettage and surgical resection in Stage 3. The majority of cases of osteonecrosis of the jaw in patients with osteoporosis are placed at Stage 0-1, whilst cancer patients with jaw osteonecrosis are in Stage 2-3.⁵

Epidemiology

One element that differentiates osteonecrosis of the jaw during osteoporosis from that arising in cancer is its frequency. In patients with osteoporosis, the condition is uncommon, with an incidence of 0.01%-0.15% patients per year of exposure, and appears only slightly higher than that detected in the general population. Furthermore, in this type, no higher incidence in the use of oral bisphosphonates (alendronate 70 mg/week) or intravenous (zoledronic acid 5 mg /year) was found. In osteoporosis, the risk of osteonecrosis of the jaw from denosumab (60 mg /6 months) is 0.017- 0.04%, which is equal to that of the control population (0-0.02%).2 With regard to the incidence of osteonecrosis of the jaw in cancer patients, this is similar in those treated with zoledronic acid (4 mg /month, 1%) and denosumab (120 mg /month, between 0.7 and 1.9%), and in any case, is about 100 times higher than in untreated subjects.
Overall, the risk of osteonecrosis of the jaw in patients with osteoporosis is about 100 times lower than that of patients with cancer.^1-2

Risk factors

Recognized risk factors with a strong level of evidence are the use of drugs that inhibit bone resorption, invasive dental work (basically extractions), the patient's underlying disease (cancer) and concomitant medications. Amongst the bisphosphonates, almost exclusively amino-bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) have been associated with osteonecrosis of the jaw. The route of administration (intravenous or orally) does not constitute a risk factor. For bisphosphonates, the risk is related to the cumulative dose and/or duration of exposure. For osteonecrosis of the jaw in cancer patients, the median risk of onset is 15 months of treatment with zoledronic acid, in patients with osteoporosis it is >4 years of treatment with alendronate or zoledronic acid.^1-2 Because the dosing schedule for zoledronic acid in oncology is 4 mg/month, the cumulative dose of risk for osteonecrosis of the jaw is about 60 mg (15 months at 4 mg). In osteoporosis, you use zoledronic acid at 5 mg/year, for which an osteoporotic patient reaches the cumulative risk dose after 12 years of therapy (12 years at 5 mg). The relationship is similar for denosumab: in oncology, the dose is 120 mg/month, and in osteoporosis 60 mg/6 months. This significant difference in dose in the two types of patient accounts for a good part of the epidemiological differences between osteonecrosis of the jaw in osteoporosis and in oncology, and this must be taken into account in patient information, in the assessment of risk and in treatment and preventive decision-making.
Recent data derived from the Italian National Pharmacovigilance Network confirms this difference and showed for example that amongst reported cases of osteonecrosis of the jaw, the rate with zoledronic acid is 0.9% in patients with osteoporosis compared to 43% in cancer patients.⁶
The type of cancer represents another risk condition. When compared to other onco-hematologic conditions, osteonecrosis of the jaw is particularly associated with multiple myeloma and breast cancers. Prostate cancer has a higher risk of osteonecrosis of the jaw if zoledronic acid is associated with anti angiogenic drugs.^4,5,7-10 Amongst concomitant medications are anti angiogenics and steroids. For osteonecrosis of the jaw in patients with osteoporosis, from the many risk factors reported (diabetes, smoking, alcohol, immunodeficiency), there is only robust evidence for rheumatoid arthritis and steroid therapy. Poor oral hygiene is a common risk factor in osteonecrosis of the jaw in osteoporosis and in cancer.
In September 2014, AIFA (based on EMA) produced a briefing note about osteonecrosis of the jaw due to denosumab in oncology and osteoporosis, which unified the risk factors and recommendations, regardless of the type of patient, creating further confusion.
Although there are reported cases of osteonecrosis of the jaw arising spontaneously, an almost constant risk factor (trigger) is invasive dental work, mainly tooth extraction. In cancer patients a dental assessment and possibly pre-cleaning of the oral cavity (prior to initiating therapy with bisphosphonates or denosumab) has drastically reduced the risk of osteonecrosis of the jaw.¹¹ Furthermore, tooth extraction, with appropriate antibiotic prophylaxis and monitoring of extraction site healing, does not seem to cause osteonecrosis of the jaw.¹² Contrary to suggestions in the AIFA note of September 2014, it should be emphasized that failure to treat dental disease to avoid risk represents a risk in itself.^2-6,11,12 Evaluation before the start of therapy and pre-cleaning are not necessary in patients with osteoporosis. After more than four years of treatment for osteoporosis, with a compliance to therapy >80%, extractions or invasive procedures within the oral cavity can be made with appropriate antibiotic therapy. Discontinuation of a bone resorption inhibitor drug before dental work has no rationale with bisphosphonates, and there is no evidence it prevents osteonecrosis of the jaw. Because of the different pharmacodynamic profile of denosumab when compared to bisphosphonates, discontinuation of this drug leads to a rapid cessation of its action, thus eliminating the risk (but also partly the benefits) linked to the same. In the literature, cases of osteonecrosis of the jaw in cancer patients receiving denosumab have all been resolved with conservative therapy, as compared to those arising during treatment with zoledronic acid. Dental implants are not considered in the guidelines either, yet are a procedure to be avoided according to the consensus conference, particularly in people with osteoporosis.^2,4
Discontinuation of the drug in anticipation of dental work has a favourable risk/benefit ratio in oncology as well as osteoporosis, though the dentist should discuss every decision with the specialist who prescribed the drug. Deciding unilaterally, or worse still, deciding not to intervene, is an attitude that is unacceptable nowadays.