Giant osteoclast formation and long-term oral bisphosphonate therapy

N Engl J Med. 2009 Jan 1;360(1):53-62. doi: 10.1056/NEJMoa0802633.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acid Phosphatase / analysis
  • Adult
  • Alendronate / pharmacology*
  • Alendronate / therapeutic use
  • Apoptosis / drug effects*
  • Biopsy
  • Bone Density Conservation Agents / pharmacology*
  • Bone Density Conservation Agents / therapeutic use
  • Bone Remodeling / drug effects*
  • Bone and Bones / cytology
  • Bone and Bones / pathology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Isoenzymes / analysis
  • Linear Models
  • Middle Aged
  • Osteoclasts / chemistry
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / pathology
  • Postmenopause
  • Tartrate-Resistant Acid Phosphatase

Substances

  • Bone Density Conservation Agents
  • Isoenzymes
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase
  • Alendronate