New drugs: Denosumab, dienogest/estradiol valerate, and polidocanol

Abstract

Agent for osteoporosis Osteoporosis is characterized by decreased bone mass and an increased risk of fracture, most often at the spine, hip, and wrist. Because of the reduction in estrogen production that occurs following menopause, women are more likely than men to experience osteoporosis, and one of every two women older than 50 years will experience a bone fracture as a consequence. Bisphosphonates such as alendronate (e.g., Fosamax), ibandronate (Boniva), and risedronate (Actonel) have been widely prescribed for the treatment and prevention of osteoporosis. These agents are administered orally, and ibandronate is also available in a formulation that is administered intravenously every 3 months. Another bisphosphonate, zoledronic acid (Reclast), is administered intravenously once a year for the treatment (and every 2 years for prevention) of osteoporosis in postmenopausal women. Denosumab (Prolia—Amgen) is a human monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL), a protein that is essential for the formation, function, and survival of osteoclasts, the cells that are responsible for bone resorption. Denosumab prevents RANKL from activating its receptor on the surface of osteoclasts and their precursors, with a resultant decrease in bone resorption and increase in bone mass and strength. Denosumab is administered subcutaneously and is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture, or of patients who have failed or are intolerant to other available therapies for osteoporosis. The effectiveness of the new drug was demonstrated in placebocontrolled studies, in which it reduced the incidence (identified as new fractures at year 3 for the denosumab and placebo groups, respectively) of vertebral (2.3%, 7.2%), nonvertebral (6.5%, 8%), and hip (0.7%, 1.2%) fractures. Treatment with denosumab significantly increased bone mineral density (BMD) at all anatomic sites measured at 3 years. Following discontinuation of treatment, BMD returned to approximately baseline levels within 12 months. Whereas the labeled indication for denosumab is for the treatment of women who are considered to be at high risk of fracture, the indications for alendronate, ibandronate, risedronate, and zoledronic acid include the prevention, as well as treatment, of osteoporosis in postmenopausal women, and the indication is not limited to those at high risk of fracture. The indications for alendronate, risedronate, and zoledronic acid also include the treatment of osteoporosis in men, glucocorticoid-induced osteoporosis in men and women, and Paget’s disease in men and women. Denosumab is also being evaluated to determine whether it may reduce the risk of fractures in patients with certain cancers (e.g., prostate cancer) that have metastasized to bone tissue or whether it may prevent tumors from metastasizing to bone. However, these are not labeled indications at the present time. The use of denosumab may exacerbate hypocalcemia, and it is contraindicated in patients with hypocalcemia. Preexisting hypocalcemia should be corrected before initiating treatment with the new drug. In patients who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., history of hypoparathyroidism, malabsorption syndromes, severe renal impairment), concentrations of calcium and minerals (e.g., phosphorus, magnesium) should be monitored. Supplementation with calcium and vitamin D should be provided during treatment. In the clinical studies, serious infections (e.g., skin, abdominal, urinary tract, ear, endocarditis) that necessitated hospitalization were reported more frequently in patients treated with denosumab than in those receiving placebo. Patients who are also being treated with immunosuppressive agents or who have impaired immune function should be considered at greater risk for serious infection. Patients should be advised to promptly report signs or symptoms of severe infection. Denosumab has been reported to cause dermatologic adverse events (e.g., dermatitis, eczema, rash) at a significantly higher incidence than was observed in the placebo group. The discontinuation of treatment should be considered if severe symptoms occur. As with the bisphosphonates, some patients treated with denosumab have experienced osteonecrosis of the jaw (ONJ) that may be related, in part, to suppression of bone remodeling. A routine oral exam should be performed by the prescriber before initiating treatment. In patients with risk factors for ONJ (e.g., tooth extraction, oral surgery, poor oral hygiene), a dental examination with appropriate preventive dentistry should be considered. Patients should be advised to inform their dentists that they are taking denosumab before having dental work done. The most frequently experienced adverse events with denosumab include back pain (35%), pain in extremity (12%), musculoskeletal pain (8%),