Denosumab, an alternative to bisphosphonates but also associated with osteonecrosis of the jaw – what is the risk?

Basic physiology of bone remodelling

Remodelling of bone is essential for reshaping of the growing skeleton and healing of bone during injury, for example tooth extraction. Bone remodelling is controlled by systemic and local factors:

Remodelling of bone is a balance between bone deposition and resorption. The three central cells to bone remodelling are:

Osteoblasts differentiate from osteocytes and are the key bone-forming cells. Osteocytes maintain ion control and stress communication within bone. Osteoclasts are responsible for bone resorption and originate from the monocyte-macrophage lineage under the influence of cytokine growth factors, especially macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor κ-B ligand (RANKL) and vascular endothelial growth factor (VEGF).4

Osteoblasts are responsible for the recruitment and activation of osteoclasts, through RANKL release. Osteoclast activity, differentiation and survival are primarily dependent on exposure to RANKL. Osteoclasts differentiate during bone remodelling to form Howship's lacunae, the sites of bone resorption where osteoclasts reside. Osteoclasts are inhibited by either the absence of RANKL or the presence of osteoprotegerin, which is an alternative receptor for RANKL.4 Therefore, osteoclast resorption is controlled by a balanced release of the osteoclast activator RANKL from osteoblasts and the RANKL inhibitor osteoprotegerin.

During bone resorption and formation of Howship's lacunae, osteoclasts generate mediators that in turn increase osteoblast activity to produce bone.4

Pharmacology of bisphosphonates and denosumab

The bone-targeting property of bisphosphonates is based on their high affinity for calcium within bone. The bidentate 3D structure of bisphosphonates is essential for their firm binding with divalent metals such as calcium within the bone matrix. Bisphosphonates chelate calcium ions within hydroxyapatite bone mineral surfaces.5 This explains the initial rapid removal of bisphosphonates from plasma and their localization to the bone mineral surface, hence their long half-life within bone.^4,5 Bisphosphonates selectively localize to the sites of osteoclast activity and active bone remodelling.5 During bone remodelling, ie osteoclastic activity, bisphosphonates are released from the bone matrix, resulting in locally high concentrations.4

Bisphosphonates are classified as nitrogen-containing (eg alendronate) and non-nitrogen-containing (eg clodronate), resulting in differing pharmacological activity due to differing structure and pharmacodynamics.4 For example, the introduction of a nitrogen-NH₂ into the chemical structure of a bisphosphonate enhances its potency and effect, as it is essential for binding to target proteins.5

These functional differences dictate the application of these two groups of bisphosphonates.4 Non-nitrogen-containing bisphosphonates are used to treat metabolic disorders such as osteoporosis.

Nitrogen-containing bisphosphonates are incorporated into supportive cancer therapy to manage cancer-related morbidities, such as hypercalcaemia, pathological fractures and bone pain.4

Nitrogen-containing bisphosphonates are the most potent and function by interfering with the synthesis of cholesterol and isprenaloid lipids, through inhibiting focal enzymes within the intracellular mevalonate pathway.5 The structure of nitrogen-containing bisphosphonates is fundamental to its incorporation into the mevalonate pathway.5 Cholesterol precursors are essential for cell signalling pathways.4 Isoprenaloid lipid loss causes cell apoptosis within osteoclasts and they are required for the production of prenylated proteins that are required for signalling of osteoclast morphology that is central to its function.5 Several studies have demonstrated that bisphosphonates interfere with the attachment of osteoclasts to bone matrix proteins via cell surface integrins, and hence can prevent the attachment of tumour cells to the bone surface.^6,7,8 The structural changes to osteoclasts caused by bisphosphonates that affect their ability to resorb bone include:5

These structural changes to the osteoclast by bisphosphonates are sufficient to prevent bone resorption.9

Non-nitrogen-containing bisphosphonates do not affect the mevalonate pathway or inhibit protein prenylation, instead their pharmacologic effect is induction of cell death.^4,5 Non-nitrogen-containing bisphosphonates resemble pyrophosphate and are metabolized within the osteoclast into non-hydrolyzable analogues of ATP that accumulate within the cell, causing inhibition of osteoclast function, and results in apoptosis.5

Denosumab is a non-bisphosphonate, antiresorptive drug that is used to treat advanced osteoporosis and bone metastases.4 It is a recombinant IgG antibody with affinity and specificity for RANKL.10 Denosumab is a RANKL inhibitor and therefore binds to and inhibits RANKL,10 which impedes the interaction of RANKL/RANK on the osteoblast, resulting in the inhibition of osteoclast formation, function and survival, thereby decreasing bone resorption.4^,10

Unlike bisphosphonates, denosumab does not bind to bone and hence its influence on bone remodelling is reversible after six months of ending denosumab therapy.11

What is the risk of ARONJ?

BRONJ or bisphosphonate-related osteonecrosis of the jaw was first defined in 2006 by the American Association of Oral and Maxillofacial Surgeons. The presence of osteonecrosis (ONJ) of the jaw in patients receiving non-bisphosphonate antiresorptives such as denosumab has led to the introduction of the term antiresorptive-related osteonecrosis of the jaw or ARONJ.11

The pathogeneses of BRONJ and ARONJ are believed to differ. The exact mechanism for the development of BRONJ has not yet been determined but the most accepted theory is that the bisphosphonate intensely inhibits the osteoclast function, hence inhibiting normal bone turnover to an extent that local microdamage from normal mechanical loading or injury (tooth extraction) cannot be repaired. Bone healing of the extraction/trauma site is impaired, as poor quality woven bone is laid down at the site of trauma. This results in bone necrosis. Bisphosphonates affect angiogenesis, poor blood supply and ischaemic conditions may contribute to the development of necrosis. Certain bisphosphonates, such as zolendronate, have demonstrated antiangiogenic properties that affect the local bone blood supply contributing to the ischaemic changes noted in the affected patient's jawbones, or operate in concert with the metabolic changes mediated by osteoclast suppression to produce local jawbone necrosis. Bisphosphonates can be directly toxic to the oral mucosa and cause defective re-epithelialization inside the mouth through the ageing of keratocytes. This may result in mucosal fenestration and bone exposure. These theories need to be validated by evidence-based clinical and basic science research. With denosumab, osteoclast inhibition might be the primary event in the pathogenesis of ARONJ.^12-13

Estimates of the incidence of BRONJ range from 1 in 10,000 to <1 in 100,000 people per year's exposure.13 However, the true incidence of BRONJ cannot be properly quantified because too few cases have been reported. Additionally, all patients taking any bisphosphonate drug are at risk of spontaneously developing BRONJ. Many factors have been associated with BRONJ; there is currently no high-quality evidence supporting how much any of them, alone or in combination, may actually contribute to BRONJ risk, including drug type or potency.12^,14

Patients with bone metastases from advanced cancer often experience a SRE, which cause substantial pain and morbidity. Comparisons of monthly denosumab and IV bisphosphonates have demonstrated that denosumab is equally responsible for the occurrence of ONJ lesions.11 Studies have evaluated the efficacy and safety of denosumab and concluded that denosumab is superior to zoledronic acid in reducing the incidence and delaying the onset of SRE. These studies identified that there were no significant differences in ONJ between the denosumab and zoledronic acid groups.^15,16,17 A subsequent meta-analysis of the overall incidence and risk of ONJ in cancer patients receiving denosumab concluded that the use of denosumab is associated with an increased risk of developing ONJ when compared with bisphosphonate treatment or a placebo, although the increased risk is not statistically significant between denosumab and bisphosphonate treatments.18

Conclusion

Currently, there is no specific guidance for the general dental or oral surgical management of these patients. However, for the time being, common sense would suggest that patients on denosumab therapy follow the same preventive dental guideline as for patients on bisphosphonate therapy. Therefore, patients should receive a detailed dental assessment prior to commencement of denosumab therapy and receive regular preventive dental care. This will optimize their oral health, averting the need for dental extraction after commencement of denosumab therapy. The avoidance of dental extractions after commencement of denosumab therapy is essential, as recent dento-alveolar trauma was the most prevalent and consistent risk factor for development of ARONJ.11^,14

A joint ARONJ masterclass19 between the Faculty of Dental Surgery and the British Association of Oral Surgeons agreed on the following proposals for the management of patients at risk of ARONJ. It was recommended that dentists must:

The masterclass endorsed the development of a network of dentists for shared experiences, agreed protocols, to encourage reporting, data collection and participation in research, and stated that a multidisciplinary white paper will ensue.

For the moment, always advise patient on antiresorptive therapy of the risks and benefits of dental care. The patient should be made aware of the treatment needed and any alternative treatments, preventive advice and treatment should be provided according to the above recommendations in conjunction with advice from your local OMFS team.

Novel antiresorptive medications are emerging; therefore we must detect the presence of these in the medications taken by our patients. In contrast to bisphosphonates, most of the novel drugs are not deposited within bone and therefore their antiresorptive effects are rapidly reversible, which may be advantageous if reversal of a suppressed bone turnover is required for dental treatment.21