Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid
Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid
This study evaluates how patients treated with denosumab or zoledronic acid for osteoporosis
 may change the number of peripheral osteoclast precursors and osteoclast activity, and how
 that may be associated with changes in bone mass.
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.
Inclusion Criteria:

 1. Women at least 50 years of age who are postmenopausal. Postmenopausal is defined as
 being amenorrheic for at a period of at least 12 months.

 2. Diagnosis of osteoporosis by T score of < -2.5 at either lumbar spine or the
 hip/femoral neck, or osteopenia that qualifies for treatment by FRAX calculation
 (10-year risk of hip fracture > 3% and/or major osteoporotic fracture of > 20%).

 3a. Subjects who have had chronic treatment of denosumab (as defined as > 1 year [at least
 3 6-monthly injections]) or zoledronic acid (defined as ≥ 2 years [at least 2 annual
 injections]) . Note: At the time of treatment initiation, subjects must have met criteria
 for on-label use (e.g. criterion 2 above).

 OR 3b. Subjects who are naïve to treatment with denosumab and/or zoledronic acid.

 Exclusion Criteria:

 1. Renal insufficiency, with glomerular filtration rate (GFR) < 35 ml/min.

 2. Hypocalcemia within 6 months of study initiation.

 3. Known hypersensitivity to denosumab or zoledronic acid.

 4. Medications that could alter bone turnover including prednisone, anti-rheumatic
 medications, anti-metabolites (Cytoxan). Subjects who have been on stable doses of
 thyroid replacement or diabetes medications for more than 3 months are eligible.

 5. Evidence of untreated oral cavities or oral infections. Preventative dental exams
 should be performed before starting denosumab or zoledronic acid. Subjects must avoid
 invasive dental procedures during treatment with denosumab or zoledronic acid.