|Trade names||Prolia, Xgeva|
|Licence data||US FDA:|
|Pregnancy cat.||C (US)|
|Legal status||℞-only (US)|
|Routes||subcutaneous injection, every six months|
|Mol. mass||144.7 kDa|
|(what is this?)|
Denosumab is a fully human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma, and giant cell tumor of bone. It was developed by the biotechnology company Amgen.
Denosumab is designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defenses against bone destruction.
In June 2010, denosumab was approved by the U.S. Food and Drug Administration (FDA) for use in postmenopausal women with risk of osteoporosis under the trade name Prolia, and in November 2010, as Xgeva, for the prevention of skeleton-related events in patients with bone metastases from solid tumors. Denosumab is the first RANKL inhibitor to be approved by the FDA. In the summer of 2011 clinical trials were investigating denosumab in giant cell tumors, multiple myeloma with bone metastases, and hypercalcemia of malignancy, and further investigating its dosing and safety.
Mechanism of action
Bone remodeling is the process by which the body continuously removes old bone tissue and replaces it with new bone. It is driven by various types of cells, most notably osteoblasts (which secrete new bone) and osteoclasts (which break down bone). The role of osteocytes is still not well understood.
Precursors to osteoclasts, called "pre-osteoclasts", express surface receptors called RANK – short for receptor activator of nuclear factor-kappa B. RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily. RANK is activated by RANKL (the RANK-Ligand), which exists as cell surface molecules on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. This mimics the natural action of osteoprotegerin, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased avidity) in patients who are suffering from osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.
Amgen has reported on two clinical trials that were designed and funded by the company.
In a Phase III clinical trial ('FREEDOM') involving 7,808 women aged 60 to 90, there were significant improvements in the subset of women with more severe disease (two or more prevalent vertebral fractures and/or one or more prevalent vertebral fractures with moderate or severe deformity) at the beginning of the study. Researchers reported a 35% risk reduction with denosumab compared to placebo (17% vs. 49%). Within this subset, only 31% of those taking denosumab developed new vertebral fractures, versus 71% of those receiving placebo.
The second phase III clinical trial involved 1,468 prostate cancer patients receiving hormone-deprivation therapy who were randomized to receive either denosumab or a placebo every 6 months over a 36 month period (all patients also received supplemental calcium and vitamin D). Of those taking the placebo, 3.9% experienced bone fractures during the 36 months, compared with 1.5% of those who received denosumab.
Other studies have been discussed by Baqir and Copeland (Clinical Pharmacist 2010; 2:400),[full citation needed] including the DEFEND, DECIDE and STAND trials. One et al. investigated the effects of denosumab on bone mineral density (BMD) in women with BMD T-scores between −1.0 and −2.5 in a randomized trial comparing it with placebo. The primary endpoint was BMD change in the lumbar spine over two years as compared to baseline. The T-score for patients receiving danosumab increased by +6.5%, while the change in patients receiving placebo was −0.6% (ARR =7%; p<0.0001).
Brown et al. compared denosumab with alendronate "head-to-head" using total hip BMD as the primary outcome measure. There were increases in total hip BMD of 3.5% and 2.6% in the denosumab and alendronate groups respectively (ARR =1%; p<0.0001; NNT = 100). Although this study was not adequately powered to compare fracture rates, fractures were reported in 4% of the denosumab group and 3.2% of the alendronate group. Kendler et al. investigated denosumab therapy following on after alendronate. Women on alendronate 70 mg weekly for a "run-in" period of 1 month were then switched to denosumab or maintained on alendroanate (with matching placebo). The primary hypothesis was that denosumab was non-inferior to alendronate, and the primary endpoint was percentage change in total hip BMD at 12 months. BMD increase was +1.9% vs. +1.05% in patients given denosumab vs. those continuing on alendronate (ARR = 0.85%; p<0.0001; NNT = 118). Again, the study was not powered to compare fracture rates, but fractures were reported as adverse events in 8 patients (3.2%) in the denosumab group and 4 patients (1.6%) in the alendronate group.
The most common side effects include infections of the urinary and respiratory tracts, cataracts, constipation, rashes, and joint pain. A small study found a slightly increased risk of cancer and severe infections, but these results did not reach statistical significance. Another trial showed significantly increased rates of eczema and hospitalization due to infections of the skin. It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system. RANKL is expressed by T helper cells, and is thought to be involved in dendritic cell maturation.
Contraindications and interactions
Denosumab is contraindicated in patients with hypocalcemia, and sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy. Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.
Similarly to bisphosphonates, denosumab appears to be implicated in increasing the risk of osteonecrosis of the jaw (ONJ) following extraction of teeth or oral surgical procedures.
On 13 August 2009, a meeting was held between Amgen and the Advisory Committee for Reproductive Health Drugs (ACRHD) of the (FDA) to review the potential uses of Prolia. A press release summarizing this meeting said:
"After reviewing safety and efficacy data from 30 clinical studies involving more than 12,000 patients, the Committee recommended approval of Prolia for the treatment of postmenopausal osteoporosis, and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer.
On 2 June 2010, denosumab was approved for post-menopausal osteoporosis by the US FDA.
In November 2010, the US FDA approved denosumab (to be marketed as Xgeva) for the prevention of skeletal-related events in patients with bone metastasis from solid tumors. Dosing is one 60 mg subcutaneous injection every six months (for postmenopausal osteoporosis) and 120 mg every 4 weeks (for patients with solid tumors).
On 13 June 2013, the US FDA approved denosumab for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where resection would result in significant morbidity. Dosing is 120 mg subcutaneous injection every four weeks with additional 120 mg doses on days 8 and 14 of the first month.
On 17 December 2009, the Committee for Medicinal Products for Human Use (CHMP) issued a Positive Opinion for denosumab for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with hormone ablation therapy for prostate cancer. Denosumab was approved for marketing by the European Commission on 28 May 2010.
Sales and pricing
In September 2009, the firm Sanford Bernstein projected that annual worldwide sales of the drug would reach $5 billion in the year 2015. It projected 2010 sales of over $650 million, mostly from use as a twice-yearly injectable for osteoporosis treatment in post-menopausal women over 50.
Actress Blythe Danner is now appearing in commercials for Prolia.
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