A Randomized, Double-Blind Study to Compare the Efficacy of Treatment With Denosumab Versus Alendronate Sodium in Postmenopausal Women With Low Bone Mineral Density.

A Randomized, Double-Blind Study to Compare the Efficacy of Treatment With Denosumab Versus Alendronate Sodium in Postmenopausal Women With Low Bone Mineral Denisty

The purpose of this study is to determine whether in postmenopausal women with low bone mineral density, the mean percent change in total hip BMD in subjects receiving denosumab is not less than that observed in subjects receiving alendronate sodium by more than a pre-specified non-inferiority margin.

Inclusion Criteria: - Patient is an ambulatory postmenopausal woman - Patient has BMD value that corresponds to a T-score of less than or equal to -2.0 (g/cm2) at the lumbar spine OR total hip within range specific to the study protocol. Exclusion Criteria: o Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

• Evidence of any of the following per subject report, chart review or central laboratory result:

  1. Hyper- or hypothyroidism; however, subjects on stable thyroid hormone replacement therapy may be allowed per the following criteria:

     • If TSH level is normal, subject is eligible for the study.
     • If TSH level is below normal range, subject is not eligible for the study.
     • If TSH level is elevated (> 5.5 mIU/mL to 10.0 mIU/mL), serum T4 should be measured. If serum T4 is within normal range, subject is eligible. If serum T4 is outside of normal range, subject is not eligible for the study.
     • If TSH level is above 10.0 mIU/mL, subject is not eligible.

  2. Current hyper- or hypoparathyroidism

  3. Elevated transaminases

     • Serum aspartate aminotransferase (AST; serum glutamate-oxaloacetic transaminase [SGOT]) ³ 2.0 x upper limits of normal (ULN)
     • Serum alanine aminotransferase (ALT; serum glutamate-pyruvate transaminase [SGPT]) ³ 2.0 x ULN

  4. Significantly impaired renal function as determined by serum creatinine ³ 2.0 mg/dL

  5. Current hypo- or hypercalcemia based on the central laboratory reference ranges

  6. Active gastric or duodenal ulcer; history of significant gastrointestinal bleed requiring hospitalization or transfusion, or dyspepsia or gastroesophageal reflux disease that is uncontrolled by medication

  7. Rheumatoid Arthritis, Paget's disease, Cushing's disease, hyperprolactinemia, or cirrhosis of the liver

  8. Known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen

  9. Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years

  10. Any metabolic bone disease, eg, osteomalacia or osteogenesis imperfecta, which may interfere with the interpretation of the findings

  11. Malabsorption syndrome or any gastrointestinal disorders that are associated with malabsorption

• Received any solid organ or bone marrow transplant

• Vitamin D deficiency (25(OH) vitamin D level < 12 ng/mL). Vitamin D repletion will be permitted and subjects may be re-screened; see Section 7.

• Any laboratory abnormality which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results

• Contraindicated or poorly tolerant of ALN therapy; contraindications for ALN therapy include:

  1. Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia.
  2. Inability to stand or sit upright for at least 30 minutes.
  3. Hypersensitivity to ALN or other constituents of ALN tablets o Known sensitivity to mammalian cell derived drug products

• Known intolerance to calcium supplements

• Administration of intravenous bisphosphonate, or fluoride (except for dental treatment) or strontium ranelate

• Oral bisphosphonate treatment:

  • ³ 3 months cumulatively in the past 2 years, OR
  • ³ 1 month in the past year, OR
  • Any use during the 3-month period prior to randomization

• PTH or PTH derivatives (eg, teriparatide) within the last year

• Administration of any of the following treatments within 3 months of randomization:

  1. Any SERM (eg, raloxifene)
  2. Tibolone
  3. Anabolic steroids or testosterone
  4. Glucocorticosteroids (³ 5 mg prednisone equivalent per day for more than 10 days)
  5. Systemic (oral, transdermal, topical) hormone replacement therapy (local vaginal estrogen preparation will be allowed)
  6. Calcitonin
  7. Calcitriol or vitamin D derivatives
  8. Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin
  9. Chronic systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists
  10. Height, weight or girth which may preclude accurate DXA measurements

• Less than 2 lumbar vertebrae (L1-L4) evaluable for DXA measurements

• Both hips not evaluable by DXA (eg, history of bilateral hip replacement or pins in both hips)

• Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s)

• Any physical or psychiatric disorder which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results

• Evidence of alcohol or substance-abuse within the last 12 months which the investigator believes would interfere with understanding or completing the study