Denosumab is a monoclonal antibody to the RANK ligand which plays an important role in bone remodeling. Denosumab is used in the therapy of osteoporosis and for bone metastases and rare bone tumors. Denosumab therapy has not been associated with serum enzyme elevations during therapy, nor has it been convincingly implicated in cases of clinically apparent drug induced liver injury with jaundice.
Denosumab (den oh’ sue mab) is a recombinant, human monoclonal IgG2 antibody to the ligand for RANK (receptor activator of NF kappa B) which plays an important role in bone remodeling and stimulates differentiation, maturation and activation of bone osteoclasts. Inhibition of the RANK ligand (RANK-L) inhibits osteoclast activity and increases bone density by the lessen osteoclast and the unopposed osteoblast activity. Treatment with denosumab has been shown to increase bone mineral density scores as assessed by DEXA scan, and long term therapy has been associated with a lower rate of bone fractures. Denosumab was approved for use in the United States in 2010, and current indications are for men and postmenopausal women with osteoporosis at increased risk for bone fractures and for men with reduced bone mineral density on antiandrogen and women on antiestrogen therapy. Denosumab has also been approved for use in patients with bone metastases from solid tumors and in giant cell tumor of bone. For treatment of osteoporosis, denosumab is available in single use vials or prefilled syringes of 60 mg under the brand name Prolia. The recommended dose is 60 mg subcutaneously every 6 months. Denosumab is also available in single use vials of 120 mg (70 mg/mL) for malignant bone disease under the brand name of Zgeva. The recommended dose for bone metastases is 120 mg subcutaneously every 4 weeks. More frequent dosing is used initially in treating giant cell tumor of bone. All patients receiving denosumab should also take oral calcium (1000 mg) and vitamin D (400 IU) daily. Side effects of denosumab are uncommon, but can include injection site reactions, back and join pains, rash, diarrhea, nausea and vomiting and headache. Rare side effects include severe infusion reactions, hypersensitivity reactions, anaphylaxis, hypocalcemia, osteonecrosis of the jaw and atypical femoral fractures.
In large clinical trials, denosumab was not associated with changes in serum aminotransferase levels during therapy and rates of most adverse reactions were similar in patients who received denosumab as placebo. Since its approval and more wide-scale use, it has been implicated in only one instance of clinically apparent acute liver injury which resulted in chronic injury that was responsive to corticosteroid therapy and likely represented an unrelated onset of autoimmune liver disease. Thus, significant liver injury from denosumab must be very rare, if it occurs at all.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
Denosumab is a human monoclonal antibody and is unlikely to be inherently hepatotoxic. While most recombinant proteins are metabolized by the liver, the metabolism leads largely to small peptides and amino acids which may be reused to synthesize proteins and are unlikely to be toxic or immunogenic. The RANK ligand pathways are important in bone turnover and formation. RANK is found on the surface of marrow stromal cells and on activated T cells, but its engagement by ligand has no recognized effect on the liver. However, its engagement of immunocytes suggests that it might lead to a self-perpetuating autoimmune condition such as autoimmune hepatitis.
REPRESENTATIVE TRADE NAMES
Denosumab – Prolia®, Xgeva®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 28 December 2017
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Lancet Diabetes Endocrinol 2017; 5: 513-23. PubMed Citation (In a long term extension study after a randomized, placebo controlled trial [Cummings 2009], 4550 postmenopausal women with osteoporosis were treated for another 7 years with denosumab; serious adverse events included osteonecrosis of the jaw (n=13) and atypical fractures, but there was no mention of ALT elevations or hepatotoxicity).
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