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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Denosumab is the first RANKL inhibitor to be approved by the FDA, and the first licensed antibody with an effect on bone remodelling, the process by which the body continuously removes old bone tissue and replaces it with new bone. This process is driven by various types of cells, including osteoclasts (which break down existing bone) and osteoblasts (which secrete new bone). Other cells known as osteocytes are also involved but their function is not well understood. The osteoclast precursor cells (known as “pre-osteoclasts”) express surface receptors known as RANK, an abbreviation for Receptor Activator of Nuclear Factor-Kappa B. The RANK receptor is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily and is activated by the RANK Ligand (known as RANKL) which exists as cell-surface markers on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts, and denosumab inhibits this maturation process by binding to and inhibiting RANKL. This process mimics the action of the endogenous RANKL inhibitor osteoprotegerin, which is found in decreasing concentrations and function in patients with osteoporosis. Thus, denosumab counters the declining levels of osteoprotegerin and protects bone from degradation, thus slowing the progression of bone loss.
Biochemistry of Exercise Training: Effects on Bone
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Panagiota Klentrou, Rozalia Kouvelioti
RANKL is secreted by many tissues, including the osteoclast, and is a marker of bone resorption that is necessary to osteoclast function (60, 74) by promoting differentiation of osteoclast precursors into mature osteocytes (64), as well as through the induction of osteoclast activation (150). When RANKL binds to its associated receptor RANK on osteoclast precursors, it allows osteoclast differentiation and function to be enhanced (2, 111). RANKL stimulates the fusion of osteoclasts to bone and subsequently promotes their activation and survival (74, 111), as well as promoting osteocyte apoptosis (60).
Current and emerging pharmacological agents in the treatment of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
James X. Liu, Thomas A. Einhorn
Over the past 15 years, there have been significant strides in the advancement of new pharmacologic agents in the treatment of osteoporosis. Current treatment options include drugs that reduce both bone resorption and formation and strengthen trabecular bone to prevent stress risers (concentrated points of stress that lead to acute fractures). The most effective drugs that are currently available to treat osteoporosis include the antiresorptives agents such as the bisphosphonates, and the receptor activator of nuclear factor–κB ligand (RANKL) inhibitor, denosumab. Bone-building agents that stimulate bone formation and resorption, also known as the anabolic class of drugs, are parathyroid hormone (PTH) analogues. Collectively, these agents have established efficacy that is supported in the literature. Denosumab has been shown to reduce the risk of vertebral fracture by 70%, hip fractures by 40%–50%, and nonvertebral fractures by 20%–30% (1), while PTH analogues reduce the risk of vertebral fractures by 60%–65% (2).
State-of-the-art, approved therapeutics for the pharmacological management of osteosarcoma
Published in Expert Opinion on Pharmacotherapy, 2021
Cristina Meazza, Sebastian Dorin Asaftei
Osteoclast-regulating drugs, such as bisphosphonates (BPs; e.g. zoledronic acid) or denosumab, may be useful in patients with multiple bone metastases [23]. In particular, denosumab is a fully human monoclonal antibody against the receptor activator of the nuclear factor kB ligand (RANKL). RANKL is a key factor essential to the differentiation and activation of osteoclasts. We know that RANKL signaling promotes OS cell growth, motility, and anchorage-independent viability. OS cells expressing more RANKL are associated with a weaker response to chemotherapy prior to surgery, bone metastases, and a shorter survival for patients [96]. Denosumab might be usefully administered together with chemotherapy, especially for patients who have bone metastases and experience symptoms. When Janeway et al. ran a phase II study with denosumab alone for patients with relapsing/refractory OS, they found the treatment had little effect [97].
Targeting the RANK/RANKL pathway in autoimmune disease and malignancy: future perspectives
Published in Expert Review of Clinical Immunology, 2021
Finally, little is known about how the immune response against cancer is inhibited by central tolerance, and a pharmacologic strategy to modulate key role central tolerance is not yet available. Key thymic pathways that restrict antitumor immunity have been recently identified and described. Importantly, it is now accepted that the autoimmune regulator (aire) gene plays a crucial role in preventing antitumor immunity [18,19]. Interestingly, a synergistic antitumor effect of central Aire-mediated tolerance and peripheral checkpoint proteins have been recently highlighted and are leading to growing interest in using RANKL blockage (denosumab), to enhance peripherally acting checkpoint inhibition. However, the potential benefic effects of RANKL blockade in cancer need to be carefully validated under the various tumor conditions in humans and possible adverse effects need to be carefully excluded [20].
The safety profile of denosumab in oncology beyond the safety of denosumab as an anti-osteoporotic agent: still more to learn
Published in Expert Opinion on Drug Safety, 2021
Maria V. Deligiorgi, Dimitrios T. Trafalis
Whether the correlation of denosumab with the development of second primary cancer is causal remains uncertain; nevertheless, it could reflect, among others, the denosumab-induced inhibition of the potential anticancer effect of RANKL. The emerging anticancer effect of RANKL is insinuated by the increasingly reported correlation of RANKL expression with favorable breast cancer prognosis [131–134,148–151]. The pathogenetic background of the anticancer potential of RANKL is elusive; however, it may involve: (i) the RANKL-induced enhancement of the antitumor immune response [12]; (ii) the anticancer signaling of a novel human RANK isoform (RANKc) [152]; and (iii) the abrogation of the interaction of RANK expressed on cancer cells with RANKL expressed on potential metastatic foci, which is supposed to drive the metastatic process [150]. An interesting hypothesis is that denosumab exerts opposite effects on the antitumor immune response, occurring at different times, reflecting the abrogation of the dual role of RANKL in antitumor immunity. For example, the initiation of denosumab can inhibit the immunosuppressive function of Tregs or the immune tolerance mediated by the medullary thymic epithelial cells (mTECs), promoting the antitumor immune response. On the other hand, in cancer patients who receive the agent at high and frequent doses, denosumab can activate the dendritic cells and promote immune tolerance, suppressing antitumor immunity [12].