New therapies for osteoporosis: Zoledronic acid, bazedoxifene, and denosumab

Abstract

Intravenous (IV) zoledronic acid, a new once-yearly bisphosphonate therapy, is approved by the US Food and Drug Administration for treatment of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and osteoporosis in men. IV zoledronic acid significantly reduced the risk of vertebral, nonvertebral, and hip fractures in postmenopausal women and decreased risk of clinical fracture and clinical vertebral fracture in men and women with hip fracture. Two promising new therapies are in late clinical development. Denosumab is a monoclonal receptor activator of nuclear factor- kappaB ligand (RANKL) antibody given by subcutaneous injection every 6 months that has been shown to significantly reduce risk of vertebral-, nonvertebral-, and hip fracture in postmenopausal women. Bazedoxifene, an estrogen agonist/antagonist, has significantly reduced the risk of vertebral fracture in postmenopausal women; a post hoc analysis showed reduction in risk of nonvertebral fracture in high-risk women.

Mouse Rankl Expression Is Regulated in T Cells by c-Fos through a Cluster of Distal Regulatory Enhancers Designated the T Cell Control Region

“…The role of RANKL in the immune system is equally important because it modulates the activation and survival of dendritic cells and the expansion of regulatory T cells. As a result of its effects on the skeleton, RANKL is a major therapeutic target for the suppression of bone resorption, reduction in arthritic disease, and the prevention and treatment of cancer metastasis to bone (11,13). Understanding the mechanism whereby the RANKL gene is regulated in a cell type-specific manner could therefore lead to more targeted approaches to the modulation of RANKL signaling, thus providing new therapeutic options that preserve the many beneficial effects of RANKL.…”

“…Although RANKL is best known for its role in bone resorption where it controls the differentiation of precursors into functional osteoclasts (7,8), this factor also plays multiple roles within the immune system to promote lymph node organogenesis (5), dendritic cell survival (1, 2, 9), tolerance to self-antigens (6), and T regulatory cell activation and proliferation (4,10). RANKL is currently a key therapeutic target for the treatment of osteoporosis (11), rheumatoid arthritis (12), and the prevention and treatment of cancer metastases to the bone (13). Although inhibition of RANKL activity can prevent the loss of bone mass, concerns have been raised as to whether general inhibition of this factor may also impact the beneficial effects of RANKL-RANK signaling as indicated above.…”

The Role of Microbial Biofilms in Osteonecrosis of the Jaw Associated with Bisphosphonate Therapy

“…Current antiresorptive therapies include oral daily, weekly, and monthly BP, which are now complemented by quarterly and yearly intravenous BP, nasal calcitonin, an approved estrogen agonist/antagonist and others in late clinical development, and a single anabolic agent, teriparatide or parathyroid hormone [50]. A novel drug called denosumab is in phase 3 clinical trials and uses a unique pathway as its mechanism of antiresorptive action in bone.…”

New Approaches to the Treatment of Osteoporosis

“…Issues of adherence and compliance appear to be much less problematic with this bisphosphonate formulation (23). It follows upon the development of intravenous ibandronate, which is administered every three months (24).…”