Denosumab for the Treatment of Osteoporosis and

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REVIEW. Osteoporosis is a skeletal disease characterized by low bone ..... weekly and placebo.31 The primary end point of the study was the percentage ...
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Denosumab for the Treatment of Osteoporosis and Cancer-Related Conditions EM Lewiecki1 and JP Bilezikian2 Osteoporotic fractures and adverse skeletal effects of malignancies are associated with high bone turnover. Denosumab is a potent inhibitor of bone resorption with a novel mechanism of action. It is administered as an infrequent subcutaneous injection with no restrictions relating to renal function. This review summarizes data on the efficacy and safety of denosumab that led to its approval for the treatment of postmenopausal osteoporosis, cancer treatment–induced bone loss, and skeletal complications of malignancies.

Osteoporosis is a skeletal disease characterized by low bone strength resulting in increased risk of fractures.1 Approximately 30% of postmenopausal women in the United States and Europe are estimated to have osteoporosis, with ~40–50% of them likely to have at least one fragility fracture in their remaining lifetime.2 Fractures can be associated with acute or chronic pain and disability and with a marked increase in mortality rates.3,4 Over the past 15 years, highly efficacious therapies have been developed for the prevention and treatment of osteoporosis.5 However, the diagnosis of osteoporosis is often not made, either because dual-energy X-ray absorptiometry, an entitlement for all women of age >65 years in the United States, is not carried out, or because a fragility fracture is not recognized as being due to osteoporosis. Consequently, osteoporosis is underdiagnosed5 and undertreated.6 Another challenge facing clinicians is that, even when the disease is diagnosed and treatment to reduce fracture risk is prescribed, compliance and persistence with therapy are generally poor.7 When patients do not take their medicines as prescribed, the antifracture efficacy of pharmacological therapy is reduced8 and greater health-care costs ensue.7 Poor compliance and persistence with medication regimens are related, in part, to real or perceived adverse effects of drugs and/ or inconvenient dosing regimens. The challenge is to develop drugs that are more likely to be associated with better compliance and that also have an acceptable safety profile and broadspectrum efficacy in reducing the rate of fragility fractures. This review also addresses the adverse skeletal effects of malignancies. Skeletal disease in cancer patients is a major cause of morbidity and mortality. Some cancers, such as multiple myeloma, are innately resident in bone; other malignancies, such as

breast and prostate cancer, have the potential to metastasize to bone. Multiple myeloma is a B-cell neoplasm characterized by clonal expansion of plasma cells in the bone marrow. Osteolytic bone lesions are common. Multiple myeloma accounts for ~13% of hematologic cancers and is associated with a 10-year survival rate of ~30% in patients who are first diagnosed under the age of 60 years.9 Up to 70% of patients (and even more in some studies) with advanced breast or prostate cancer have bone metastases, as do ~15–30% of those with cancer of the lung, stomach, bladder, uterus, rectum, thyroid, or kidney.10 It has been estimated that ~350,000 people in the United States die each year with metastatic bone disease.11 The skeletal complications of malignancies include pathologic fractures, bone pain, hypercalcemia, spinal cord compression, and other nerve compression syndromes. In addition to the effects of malignancies on bone, some of the drugs (e.g., glucocorticoids, chemotherapeutic drugs, aromatase inhibitors, and drugs for androgen deprivation therapy (ADT)) or surgery (e.g., oophorectomy and orchiectomy) used to treat certain aspects of these diseases may themselves cause bone loss and increase skeletal fragility, contributing further to fracture risk. Common to bone loss in osteoporosis and in malignancy is excessive osteoclast-mediated bone resorption. For example, estrogen deficiency in postmenopausal osteoporosis leads to high bone remodeling with bone resorption exceeding bone formation. In malignancy, growth factors released during osteoclastic bone resorption may promote tumor cell proliferation, metastases, and cell survival, which in turn could increase levels of parathyroid hormone–related peptide, a stimulator of osteoclastogenesis. It has been suggested that this process, if it occurs, is a “vicious cycle” (Figure 1) of tumor expansion and bone

1New Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico, USA; 2College of Physicians and Surgeons, Columbia University, New York, New York, USA. Correspondence: JP Bilezikian ([email protected])

Received 15 August 2011; accepted 27 September 2011; advance online publication 7 December 2011. doi:10.1038/clpt.2011.268 Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 1 | January 2012

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Osteolytic bone disease cycle

Cancer cells TGF-β IGFs FGFs BMPs PDGF

PTHrP IL-6 PGE2 TNF M-CSF

Osteoclasts

Bone

Figure 1  Vicious cycle of osteolytic bone disease. Tumor cells may produce parathyroid hormone–related peptide and other factors that stimulate osteoclastic bone resorption; this may result in the expression and release of factors that, in turn, stimulate tumor growth. A “vicious” positive reinforcing cycle is established between tumor cells and osteoclasts. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL-6, interleukin-6; M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTHrP, parathyroid hormone–related peptide; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor. From ref. 10.

resorption10,12 that might explain the development of adverse skeletal events in some cancer patients. In both osteoporosis and malignancy-associated bone disease, bisphosphonates are widely used as treatment. Although their efficacy in osteoporosis has been proven, the oral bisphosphonates may be associated with adverse gastrointestinal effects, contributing to suboptimal compliance and adherence to ­therapy.13 Such gastrointestinal intolerance is not seen when intravenous (i.v.) bisphosphonates are administered. Nephrotoxicity, which has been reported with the use of i.v. bisphosphonates, is related to dose, time of infusion, and baseline renal function. For these reasons, i.v. zoledronic acid should be infused only at approved dosages and over a duration of at least 15 min. It is contraindicated for the treatment of osteoporosis in patients with a creatinine clearance value