Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.

Abstract

Bisphosphonates inhibit bone resorption in vivo and in vitro by unknown mechanisms. The effect of bisphosphonates on the formation of osteoclasts from their mononuclear hematopoietic precursors was investigated using human long-term marrow cultures in which multinucleated cells form that express most of the known features of the osteoclast phenotype (e.g., bone resorption, tartrate-resistant acid phosphatase, calcitonin responsiveness, and reactivity with specific MAbs). The five bisphosphonates that were tested strongly inhibited 1,25-dihydroxyvitamin D3-stimulated formation of these cells with the same relative pqtencies as they inhibit ione resorption in vivo. Two representative compounds (3-amino-1-hydroxypropylidene-1,1-bisphosphonate and dichloromethylene bisphosphonate) failed to inhibit the proliferation of precursors of the osteoclast-like cells. However, these compounds decreased the proportion of mononuclear and multinucleated cells expressing an osteoclast antigen, thus suggesting a degree of specificity for cells of the osteoclast lineage. We conclude that bisphosphonates are potent inhibitors of osteoclast-like cell formation in long-term human mprrow cultures, #nd that this may be related to their ability to inhibit bone resorption in vivo.

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

“…Such inhibition results in dysregulation of intracellular transport, cytoskeletal organization, and cell proliferation, leading to inhibition of osteoclast function. In addition, aminobisphosphonates reduce recruitment of osteoclasts and induce osteoblasts to produce an osteoclast-inhibiting factor (5,6).…”

Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

“…21,22 Bisphosphonates are potent inhibitors of osteoclastic bone resorption and have effects on osteoclast recruitment, differentiation, activity, and apoptosis. [23][24][25][26] This study examined the effects of bisphosphonate treatment on stress fracture healing over an extended period. In contrast to complete fractures, stress fractures require early resorption during healing to enable new bone formation along the fracture line.…”

Bisphosphonates induce apoptosis in human breast cancer cell lines

“…Bisphosphonates are also used in the treatment of Paget's disease of bone (Altman et al, 1973;Plasmans et al, 1978) and bone lesions associated with multiple myeloma (Berenson et al, 1996). The mechanisms by which bisphosphonates inhibit osteoclast-mediated bone resorption remain to be determined, but may involve inhibition of formation of osteoclasts from immature precursor cells (Boonecamp et al, 1986;Lowik et al, 1988;Hughes et al, 1989) and/or direct inhibition of resorption via induction of apoptosis in mature osteoclasts (Lowik et al, 1988;Hughes et al, 1995;Selander et al, 1996). More recently, several reports have indicated that bisphosphonates have direct effects on other cell types which may have important implications in the treatment of patients with cancer-induced bone disease.…”