Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid

Postmenopausal osteoporosis is the leading cause of low trauma fractures. At the time of menopause there is an uncoupling of bone turnover, with osteoclast mediated bone resorption increased more than bone formation, resulting in both loss of bone mass and architecture such that bone fractures with very little force. Bisphosphonates are commonly used to treat postmenopausal osteoporosis, although the mechanisms of their action on bone are not completely understood. Gossiel and colleagues recently examined the effects of ibandronate, alendronate and risedronate on osteoclast precursor cells in a study of women (n=62) with postmenopausal osteoporosis. Fasting serum was collected at baseline and after 1 and 48 weeks of bisphosphonate treatment. Fluorescent-activated cell sorting (FACS)-Calibur was used to extract peripheral blood mononuclear cells (PBMC), and cells were stained for receptors of macrophage colony stimulating factor (M-CSFR) and tumor necrosis factor 2 (TNFR2), as well as adhesion molecules (CD11b and CD14). These cell surface antigens are important for osteoclast differentiation and activity. Osteoclast precursor cells were identified using flow cytometry to find cells that were dual positive (CD14+/M-CSFR+, CD14+/CD11b+, CD14+/TNFR2+). Results showed a significant (p\<0.01) reduction in in expression of M-CSFR (53% decrease) and CD11b (49% decrease) after 48 weeks of treatment, suggesting that the action of bisphosphonates on mature osteoclasts may be mediated by reduction of osteoclast precursor cells. Treatment with denosumab (a monoclonal antibody that blocks the ability of receptor activator of NFκB ligand \[RANKL\] to bind to its receptor RANK on the osteoclast surface and inhibits the maturation and activity of osteoclasts) has been found to increase bone mineral density (BMD) at the lumbar spine and hip in both postmenopausal women and elderly men with osteopenia. However, after denosumab is discontinued there can be a rapid loss of BMD and an increased incidence of vertebral fractures. Current data suggests that the incidence of vertebral fracrure increases to levels similar to placebo after denosumab discontinuation, and only the incidence of multiple vertebral fracture is higher after denosumab discontinuation compared with placebo discontinuation, though further research is needed. The increase in the observed bone loss may be from increased osteoclast maturation and activity, or an change in the number circulating monocytes (the precursors of osteoclasts) during the denosumab treatment.