Increased osteoclastic activity is observed in many osteopathic disorders - including
postmenopausal osteoporosis, Paget's disease, primary bone tumours, lytic bone
metastases,
multiple myeloma and
rheumatoid arthritis - that involve increased
bone resorption and a loss of bone mass.
Bisphosphonates are highly effective inhibitors of
bone resorption that selectively affect the osteoclasts. The aim of this study was to obtain more information about the mechanism of action of
bisphosphonates such as
neridronic acid using a dual-cell culture model. As a model of osteoclastogenesis we used a murine monocyte/macrophage cell line RAW 264.7 type CRL 2278 co-cultured with murine osteoblasts. The monocyte-osteoblast system allows physiological experimentation of bone anti-resorption drugs, simulating bone turnover in pathologies such as
osteoporosis. The direct actions of
neridronic acid on cell proliferation and functionality in the co-culture model were examined using
tartrate-resistant acid phosphatase (TRAP) assay, immunohistochemical localization of actin, and transmission and scanning electron microscopy (SEM). Results showed that the percentage of TRAP-positive cells, an early marker of osteoclastic differentiation, was significantly higher in control cultures than in co-cultures treated with variable concentrations of
neridronic acid.
Neridronic acid induced dramatic morphological changes, characterized by the loss of the ruffled border. The actin ring associated with the plasma membrane of the cells treated with
neridronic acid was shown to break down. The tissue-specific targeting of
neridronic acid to bone
mineral suggests that it may inhibit
bone resorption by direct effects on osteoclasts or other bone cells in the immediate microenvironment of the osteoclasts. From our study, we conclude that structural alterations induced by
neridronic acid in our co-culture system lead to decreased osteoclast function. This may encourage the use of
neridronic acid to reduce
bone resorption in the
therapy of demineralizing metabolic bone disorders.