Giant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy

Abstract

BACKGROUND Bisphosphonates decrease bone resorption and are commonly used to treat or prevent osteoporosis. However, the effect of bisphosphonates on their target cells remains enigmatic, since in patients benefiting from therapy, little change, if any, has been observed in the number of osteoclasts, which are the cells responsible for bone resorption. METHODS We examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods. RESULTS The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01). Moreover, the number of osteoclasts increased as the cumulative dose of the drug increased (r = 0.50, P<0.001). Twenty-seven percent of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling. CONCLUSIONS Long-term alendronate treatment is associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that are undergoing protracted apoptosis.

Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening

“…We have noted this previously in this model [2], and it has later also been described in several species, including humans [19]. In this experiment, the phenomenon probably reflects the strong recruitment of osteoclasts due to the mechanical stimulus.…”

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

“…DMAb and Aln exert their antiresorptive action through different mechanisms. DMAb selectively binds to RANKL and inhibits osteoclast-mediated bone resorption, osteoclast maturation, and survival, while Aln binds to the mineralized bone matrix and decreases osteoclast activity, without necessarily reducing the number of osteoclasts (37)(38)(39). Treatment of OVX huRANKL mice with DMAb alone was associated with a marked reduction of osteoclast surfaces and with histological parameters of bone formation that were barely detectable.…”

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

“…40 Interestingly, increased osteoclast numbers (though mostly dysfunctional) also have been observed as a response to anti-resorptive bisphosphonates in osteoporotic patients. 41 However, how can we explain that Idua-deficiency leads to an insufficient degradation of epiphyseal cartilage, despite an overall increase in cathepsin K expressing osteoclasts? This could be due in part to a general lysosomal dysfunction caused by GAG accumulation in MPS I osteoclasts.…”