Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo

Abstract

Bisphosphonates inhibit bone resorption and are therapeutically effective in diseases of increased bone turnover, such as Paget's disease and hypercalcemia of malignancy. The mechanisms by which they act remain unclear. Proposed mechanisms include inhibition of osteoclast formation from precursors and inhibitory or toxic effect on mature osteoclasts. We have developed a new in vitro model to study osteoclast survival and in this paper present in vitro and in vivo evidence that may explain both the observed reduction in osteoclast numbers and in bone resorption by mature osteoclasts, namely that bisphosphonates induce programmed cell death (apoptosis). Three bisphosphonates (risedronate, pamidronate, and clodronate) caused a 4- to 24-fold increase in the proportion of osteoclasts showing the characteristic morphology of apoptosis in vitro. This observation was confirmed in vivo in normal mice, in mice with increased bone resorption, and in nude mice with osteolytic cancer metastases, with similar-fold increases to those observed in vitro. Of the three compounds, risedronate, the most potent inhibitor of bone resorption in vivo, was the strongest inducer of osteoclast apoptosis in vitro. Osteoclast apoptosis may therefore be a major mechanism whereby bisphosphonates reduce osteoclast numbers and activity, and induction of apoptosis could be a therapeutic goal for new antiosteoclast drugs.

High-frequency loading positively impacts titanium implant osseointegration in impaired bone

“…Indeed, no differences were observed in none of the quantified parameters between shOVX and OVX-ALN groups. We therefore anticipate that ALN, via its evidenced role in inhibiting osteoclast-mediated bone resorption [41], also acted on bone healing related to titanium osseointegration. However, a significant positive effect of ALN on the interfacial and remote bone, compared to the OVX status, was only found at the cortical peri-implant level, where mainly bone remodeling is occurring.…”

Increased risk of dementia in patients with osteoporosis: a population-based retrospective cohort analysis

“…However, because of estrogen supplementation for osteoporosis prevention, a person who receives estrogen supplementation is not necessarily an osteoporosis patient (Orimo et al 2012). The most common medication prescribed to osteoporosis patients in Taiwan is bisphosphonates, which can cause apoptosis in osteoclasts (Hughes et al 1995). Therefore, bisphosphonates would only be prescribed after a confirmed medical diagnosis of osteoporosis.…”

“…Patients with severe dementia are less likely to receive osteoporosis treatment (Jilka et al 1992). Second, the NHIRD does not contain detailed information on patients' smoking habits, alcohol consumption, socioeconomic status, or family history of systemic diseases, all of which could represent risk factors for osteoporosis or dementia (Orimo et al 2012;Hughes et al 1995). Third, the statistical quality of a retrospective cohort study is regarded as lower than that of a randomized trial because of potential biases related to adjustments for confounding variables.…”

Efeito do extrato de Ginkgo biloba L., Ginkgoaceae, na osteoporose induzida em ratas Wistar

“…O alendronato de sódio é amplamente utilizado no tratamento da osteoporose e atua reduzindo a atividade reabsortiva dos osteoclastos através da alteração estrutural dos osteoclastos e de sua morte celular (Hugges et al, 1995). O tratamento dos animais osteoporóticos com alendronato de sódio evidenciou aumento significativo da SOPM, mas na análise histomorfométrica não mostrou aumento significativo do POA da mandíbula e do POT do fêmur.…”