Maxfacts

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Denusomab

Denusomab belongs to a class of drugs called antiresorptive agents. These agents interfere with regular bone remodelling by hindering the bone resorption step in this process. Denusomab inhibits the activation of the osteoclasts (the cells driving the resorption part of the bone renewal process). Denusomab is used in the treatment of metastatic bone disease, other bone malignancies, such as multiple myeloma, hypercalcaemia (too high a concentration of calcium ions, Ca2+, in plasma) secondary to a malignancy, and severe osteoporosis.

Denusomab is relevant in a maxillofacial context because of its adverse effects. Antiresorptive agents, bisphosphonates as well denusomab are nowadays the most common cause of medication-related osteonecrosis of the jaws, a debilitating condition often in need of surgical intervention, including major reconstructive surgery.

Denusomab is a monoclonal antibody (a protein with a strong affinity to a specific receptor), designed such that it outcompetes the signalling protein (RANKL) that initiates the bone resorption stage of bone renewal. Denusomab has a high affinity for the target receptor, RANK, of RANKL. By preventing the RANKL/RANK interaction, denusomab inhibits the formation of osteoclasts (the cells responsible for bone resorption) from their precursor cells as well as inhibiting the survival of mature osteoclasts. This leads to overall reduced bone resorption. The mechanism of action of denusomab as an antiresorptive agent differs from that of bisphosphonates.

Clinical studies have shown similarities and differences between denusomab and (third generation) bisphosphonates . Denusomab appears to lead to a more profound inhibition of bone remodelling, probably because of a more even distribution across all skeletal sites. This may explain the higher gain of bone mass density after one year of treatment with denusomab. When treatment is discontinued, the effects of denusomab are more rapidly reversed (within a few months) than for bisphosphonates (where persistence of more than 10 years has been observed). The concept of ‘drug holidays’ for denusomab to reduce the risk of developing osteonecrosis after invasive dental treatment (dentoalveolar procedures), is potentially useful but is not a realistic option for bisphosphonate treatment schemes. ‘Drug holidays’ for denusomab have to be carefully managed as overcompensating / rebound effects (including pathological fractures) have been observed after termination of denusomab treatment.

Despite these clinical differences and different biochemical mechanisms of action, the association of denusomab and bisphosphonates with necrosis of the jaw bones is very similar, if not identical. This finding strongly indicates that overall the inhibition of osteoclasts is a crucial component in the pathology of osteonecrosis: other medicinal agents (calcitonin and oestrogen) that also reduce bone resorption rates, albeit by different mechanisms, have no such association with osteonecrosis of the jaws.

Table 1 summarises some of the key properties of denusomab and bisphosphonates.

Table 1 Comparison of denusomab and bisphosphonates

Bisphosphonates* Denusomab
Category chemical agent biological agent (monoclonal antibody)
Target; general high affinity for hydroxyl apatite (bone mineral); inhibition of enzyme (FPP synthase) high affinity and selectivity for RANKL receptor
Target; cellular mature osteoclasts; possibly some effects on osteocytes precursors of osteoclasts and mature osteoclasts
Mechanism of action inhibition of osteoclast resorptive function(s) prevents formation, function and survival of osteoclasts; depletion of osteoclasts
Distribution bone mineral surface circulating (blood and extracellular fluid)
Onset of action fast (if given intravenously); slow (if given orally) fast
Offset and reversibility of action slow; reversibility unclear (depending on type of drug and duration of treatment) (relatively) rapid; fully reversible

* the range of bisphosphonates in clinical use cover a range of properties and potencies