Korean J Pain.  2017 Apr;30(2):86-92. 10.3344/kjp.2017.30.2.86.

Can denosumab be a substitute, competitor, or complement to bisphosphonates?

• Kim SY
• Ok HG
• Birkenmaier C
• Kim KH

• KMID: 2376043
• DOI: http://doi.org/10.3344/kjp.2017.30.2.86

Abstract

Osteoblasts, originating from mesenchymal cells, make the receptor activator of the nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in order to control differentiation of activated osteoclasts, originating from hematopoietic stem cells. When the RANKL binds to the RANK of the pre-osteoclasts or mature osteoclasts, bone resorption increases. On the contrary, when OPG binds to the RANK, bone resorption decreases. Denosumab (AMG 162), like OPG (a decoy receptor), binds to the RANKL, and reduces binding between the RANK and the RANKL resulting in inhibition of osteoclastogenesis and reduction of bone resorption. Bisphosphonates (BPs), which bind to the bone mineral and occupy the site of resorption performed by activated osteoclasts, are still the drugs of choice to prevent and treat osteoporosis. The merits of denosumab are reversibility targeting the RANKL, lack of adverse gastrointestinal events, improved adherence due to convenient biannual subcutaneous administration, and potential use with impaired renal function. The known adverse reactions are musculoskeletal pain, increased infections with adverse dermatologic reactions, osteonecrosis of the jaw, hypersensitivity reaction, and hypocalcemia. Treatment with 60 mg of denosumab reduces the bone resorption marker, serum type 1 C-telopeptide, by 3 days, with maximum reduction occurring by 1 month. The mean time to maximum denosumab concentration is 10 days with a mean half-life of 25.4 days. In conclusion, the convenient biannual subcutaneous administration of 60 mg of denosumab can be considered as a first-line treatment for osteoporosis in cases of low compliance with BPs due to gastrointestinal trouble and impaired renal function.

Keyword

Bisphosphonates; Bone mineral density; Bone resorption; Denosumab; Hypocalcemia; Monoclonal antibodies; Osteoclast; Osteoporosis; Osteoprotegerin; RANK ligand

MeSH Terms

Antibodies, Monoclonal
Biomarkers
Bone Density
Bone Resorption
Compliance
Denosumab*
Diphosphonates*
Half-Life
Hematopoietic Stem Cells
Hypersensitivity
Hypocalcemia
Jaw
Miners
Musculoskeletal Pain
NF-kappa B
Osteoblasts
Osteoclasts
Osteonecrosis
Osteoporosis
Osteoprotegerin
RANK Ligand
Antibodies, Monoclonal
Biomarkers
Denosumab
Diphosphonates
NF-kappa B
Osteoprotegerin
RANK Ligand

Figure

• 

  Fig. 1 Bone remodeling cycle and medications for the treatment of osteoporosis. Bone remodeling cycle consists of at least 6 different phases: 1. resting, 2. activation, 3. resorption, 4. reversal, 5. formation, and 6. mineralization. Drugs for the treatment or prevention of osteoporosis act on different phases. In the activation phase, denosumab, like OPG (a decoy receptor produced by osteoblasts), binds the RANKL and blocks the RANKL from binding to the RANK, inhibits the differentiation steps from pre-osteoblasts via mature osteoclasts to activated osteoclasts, and finally reduces bone resorption. In the resorption phase, bisphosphonates bind to the bone mineral and take the space where activated osteoclasts attach at sites of bone resorption. Odanacatib, a cathepsin K inhibitor, inhibits the osteoclastic enzyme that degrades collagens. Saracatinib, a c-src inhibitor, inhibits osteoclastic activation. Selective estrogen receptor modulators (SERMs) and hormone (estrogen) replacement therapy interfere with various osteoblast-derived factors that stimulate osteoclasts. In the formation phase, strontium ranelate stimulates pre-osteoblasts to differentiate into osteoblasts, and stimulates osteoblasts to secrete OPG in order to prevent pre-osteoclasts from becoming activated osteoclasts via mature osteoclasts, as well. Parathyroid hormone (PTH) analogues and PTH-related protein (PTHrP) analogues increase the number and activity of osteoblasts. Romosozumab (AMG 785) and blosozumab, anti-sclerostin monoclonal antibodies, bind to the sclerostin (a glycoprotein inhibitor of osteoblast Wnt signaling produced by osteocytes) and inhibit its action. Cbl: Casitas B-lineage lymphoma, FAK: focal adhesion kinase, OPG: osteoprotegerin, PI3k: phosphoinositide 3-kinase, PTH: parathyroid hormone, PTHrP: PTH-related protein, RANK: the nuclear factor kappa B, RANKL: RANK ligand, SERMs: selective estrogen receptor modulators, Src: Src family kinase (a group of non-receptor tyrosine kinases). Modified from Connelly D. Osteoporosis: moving beyond bisphosphonates. Pharmaceutical Journal 2016 Nov [2016 Nov 23]. Available at http://www.pharmaceutical-journal.com/news-and-analysis/infographics/osteoporosis-moving-beyond-bisphosphonates/20201978.article

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