Osteoporosis: Current and Emerging Therapies Targeted to Immunological Checkpoints

Abstract

Osteoporosis is a skeletal pathology characterized by compromised bone strength leading to increased risk of fracture, mainly the spine and hip fractures. Osteoporosis affects more than 200 million people worldwide and because of the skeletal fractures it causes, represents a major cause of morbidity, disability and mortality in older people. Recently, the new discoveries of osteoimmunology have clarified many of the pathogenetic mechanisms of osteoporosis, helping to identify new immunological targets for its treatment opening the way for new and effective therapies with biological drugs. Currently, there are basically two monoclonal antibodies for osteoporosis therapy: denosumab and romosozumab. Here, we focus on the modern approach to the osteoporosis management and in particular, on current and developing biologic drugs targeted to new immunological checkpoints, in the landscape of osteoimmunology.

Keywords: Osteoporosis; biological therapies; bone remodeling; cytokines; immunological checkpoints; osteoimmunology.

Fig. (1)

Mechanism of action of denosumab. Denosumab is a humanized monoclonal antibody capable of neutralizing RANKL, a cytokine produced by osteoclasts and immune cells, that interacts with the RANK receptor on the membrane of osteoclast precursors and mature osteoclasts, where it blocks the activation cascade of intracellular transcription factors thus affecting osteoclast recruitment, maturation, and survival. Denosumab, therefore, suppresses bone resorption by inhibiting both osteoclast formation and function. Abbreviations: Wingless/Integrated (Wnt), Receptor activator of nuclear-factor k-B ligand (RANKL), Frizzled proteins (FRZ), Low-density lipoprotein receptor proteins 5 and 6 (LPR 5/6). (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Mechanism of action of romosozumab. The Wnt pathway is activated by the interaction between LRP5/6, Wnt and Frizzled. As a consequence, b-catenin is released, enters the nucleus and activates transcription from Wnt target genes. Sclerostin binding to LRP5/6 and Frizzled coreceptors on osteoblasts inhibits Wnt canonical pathway and b-catenin is consequently phosphorylated and degraded. Sclerostin inhibits bone formation by inhibiting osteoblasts and increases bone resorption by increasing RANKL production by osteoblasts. Romosozumab inhibits sclerostin allowing for increased Wnt signaling. Sclerostin inactivates the Wnt pathway by binding to LRP5/6 and b-catenin is consequently phosphorylated and degraded. Abbreviations: Low-density lipoprotein receptor proteins (LRP), Runt-related transcription factor 2 (Runx2), Protein kinase A (PKA), cAMP response element-binding protein (CREB). (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Other potential targets: cytokines and transcription factors. Other potential targets for osteoporosis therapy have been identified and against some of them have been produced monoclonal antibodies or recombinant analogues. In addition to anti-sclerostin monoclonal antibody (Anti-sclerostin MoAb) and Anti-tumor necrosis factor-α monoclonal antibody (Anti-TNF-α MoAb), other relevant checkpoints of the Wingless/Integrated (Wnt) pathway in osteoblasts seem to be promising targets: Dickkopf-related protein (DKK) antagonists, Proteasome inhibitors, Tyrosynkinase inhibitors (TKIs), Recombinant Bone morphogenetic protein (rBMP), Tryptophan hydroxylase 1 (Tph1), Recombinant transforming growth factor-β (rTGF-β), Recombinant insulin-like growth factor-1 (rIGF-1), Secreted frizzled-related protein 1 (SFRP1) antagonists. Abbreviations: Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Receptor Activator of Nuclear-factor k-B (RANK), Receptor Activator of Nuclear-factor k-B Ligand (RANKL), Osteoprotegerin (OPG), Tumor Necrosis Factor receptor-associated Factor 6 (TRAF6), Inhibitor of nuclear factor Kappa-B Kinases (IKKs), Nuclear factor-kB (NF-kB), Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). (A higher resolution / colour version of this figure is available in the electronic copy of the article).