Hypocalcemic effect of zoledronic acid or other bisphosphonates may contribute to their antiangiogenic properties
ABSTRACT Bisphosphonates, effectively used for metastatic bone disease and hypercalcemia, may evidentially have antiangiogenic properties. However, mechanism(s) of antiangiogenic effects of bisphosphonates are not fully understood. Their most pronounced effect is on metabolism of calcium, which is a main point of intersection for many distinct molecular signaling pathways that promote and modulate angiogenesis. An elevation of Ca(2+) plays a role in the mitogenic and secretory effects of growth factors. Some preclinical clues imply that antiangiogenic effects of bisphosphonates are related to its well-known hypocalcemic activity. Consequently, it may not be right to routinely recommend vitamin D and calcium supplementation to correct hypocalcemia unless it is symptomatic.
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ABSTRACT: This study tested the effects of bisphosphonates (BPs) on the suppressor of cytokine signaling 3 (SOCS3) protein in macrophages. SOCS3 has been shown to regulate cell differentiation and survival; however, its potential role in mediating the effects of BPs has not been explored. The cell viability of murine RAW 267.4 macrophages was assessed after culturing with control medium or media containing increasing concentrations of 2 BPs (ibandronate or clodronate) for 24, 48, and 72 hours. The phosphorylation status of signal transducer and activator of transcription 3 (STAT3) and the expression of SOCS3 protein levels were determined by Western blot analysis. In control cultures, STAT3 phosphorylation and STAT3 and SOCS3 protein levels increased within 5 minutes after the addition of fresh medium. This increase was inhibited in cultures treated with both BPs. Macrophage cell viability also decreased after BP treatment. These data demonstrate that, in addition to their effects on macrophage viability, BPs can decrease STAT3 and SOCS3 expression, which are important modulators of immune responses and bone homeostasis.Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 02/2011; 111(2):196-204. DOI:10.1016/j.tripleo.2010.09.068 · 1.46 Impact Factor
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ABSTRACT: Bone metastasis are a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. The consequences of bone metastasis are often devastating. Osteolytic metastasis can cause different kinds of skeletal related events including severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. These skeletal-related events are the result of the resorption of mineralized bone by osteoclasts. Bisphosphonates are synthetic analogues of naturally occurring pyrophosphate compounds that inhibit bone resorption. Potent bisphosphonates, pamidronate and, more importantly zoledronic acid may cause hypocalcemia, but mostly asymptomatic, mild, transient in most cases. Sufficient calcium and vitamin D intake needs to be ensured in patients with malignancy who have borderline or low levels of calcium when commencing treatment with bisphosphonates. Vitamin D itself induce the formation of osteoclasts by increasing the expression of RANKL on marrow stromal cells. Local calcium also promotes tumor growth and the production of parathyroid hormone-related peptide which in turn stimulates bone resorption. Vitamin D and calcium supplementation during bisphosphonate administration for the purpose of elimination of the side effects related to hypocalcemia in patients with bone metastasis may increase the bone resorption and decrease the efficacy of bisphosphonates. Therefore, vitamin D and calcium supplementation must not be routinely recommended during bisphosphonate administration.Medical Hypotheses 02/2004; 63(6):1010-3. DOI:10.1016/j.mehy.2004.04.022 · 1.15 Impact Factor
Article: Additional Reading: Bisphosphonates