Study to Compare the Efficacy and Safety of DenosumAb Versus Placebo in Males With Osteoporosis

A Multicenter, Randomized, Double-Blind, Placebo Controlled Study to Compare the Efficacy and Safety of Denosumab Versus Placebo in Males With Low Bone Mineral Density

The purpose of this study is to assess how effective and safe denosumab is in a population of males with low bone mass at risk of fracture. The primary clinical hypothesis is that in men with low bone mineral density, the mean percent change in lumbar spine bone mineral density at 12 months in subjects receiving denosumab will be greater than in subjects receiving placebo. Denosumab is a fully human monoclonal antibody with a high affinity for Receptor Activator of Nuclear Factor (RANK) Ligand that can bind and neutralize the activity of human RANK Ligand similar to the action of endogenous osteoprotegerin.

Inclusion Criteria:

• Bone Mineral Density (BMD) values (g/cm2) assessed by the local site at either the lumbar spine OR femoral neck that occur within the ranges specified in the protocol OR For subjects with a history of a major osteoporotic fracture (clinical vertebral, hip, humerus and distal radius fractures) occurring more than 6 months prior to screening, BMD values (g/cm2) assessed by the local site, at either the lumbar spine OR femoral neck that occur within the ranges specified in the protocol.
• At least 2 lumbar vertebrae, at least 1 hip and at least one forearm must be evaluable by Dual X ray Absorptiometry (DXA).
• Ambulatory males 30 to 85 years of age inclusive at the start of screening.
• Provide the appropriate written informed consent before any study specific procedure.

Exclusion Criteria:

• BMD values (g/cm2) as specified in the protocol in subjects with or without a history of major osteoporotic fractures, based on the particular scanner that is used.
• Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.
• Any severe or more than 1 moderate vertebral fractures on screening spinal x ray
• Any vertebral fracture diagnosed within the 6 months prior to screening
• Any clinical fracture within the last 6 months prior to screening
• For males with a partner of childbearing potential: Subject refuses to use 2 highly effective methods of contraception for the duration of the study and for 10 months after the last dose of study medication.
• For males with a partner who is pregnant: Subject refuses to use a condom for the duration of the study and for 10 months after the last dose of study medication.
• Previous participation in clinical trials with denosumab or administration of commercial denosumab.
• 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).
• Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (< 49.9 nmol/L)]. Vitamin D replenishment will be permitted and subjects may be re-screened; see Section 7.
• Hyper- or hypothyroidism; however, stable subjects, in the investigator's opinion, on thyroid hormone replacement therapy are allowed.
• Hyper- or hypoparathyroidism. Intact parathyroid hormone (iPTH) values outside of the reference range as determined by the central laboratory
• Elevated transaminases. Serum aspartate aminotransferase; serum glutamate-oxaloacetic transaminase > 2.5 x upper limit of normal. Serum alanine aminotransferase; serum glutamate pyruvate transaminase > 2.5 x upper limit of normal (both as determined by the central laboratory).
• Significantly impaired renal function as determined by a derived glomerular filtration rate (using the Modification of Diet in Renal Disease formula) of less than or equal to 30 mL/min/1.73 m2 calculated by the central laboratory.
• Hypo- or hypercalcemia based on the central laboratory reference ranges for albumin-adjusted serum calcium.
• Known to have tested positive for human immunodeficiency virus, hepatitis C virus, hepatitis B surface antigen or cirrhosis of the liver.
• Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma) within the last 5 years.
• Any metabolic bone disease, eg osteomalacia, osteogenesis imperfecta, rheumatoid arthritis, Paget's disease, Cushing's disease or, hyperprolactinemia which may interfere with the interpretation of the findings OR evidence of malabsorption syndromes which might interfere with absorption of vitamin D.
• Received any solid organ or bone marrow transplant or is on chronic immunosuppression for any reason.
• Any laboratory abnormality, which in the opinion of the investigator or Amgen, will prevent the subject from completing the study or interfere with the interpretation of the study results.
• Administration of intravenous bisphosphonate, or fluoride (except for dental treatment) or strontium ranelate.
• Oral bisphosphonate treatment:
• greater than or equal to 3 months cumulatively in the past 2 years, OR
• greater than or equal to 1 month in the past year, OR
• Any use during the 3-month period prior to randomization
• Administration of any of the following treatments 3 months prior to screening:
• Anabolic steroids or testosterone
• Glucocorticosteroids (greater than or equal to 5 mg prednisone equivalent per day for more than 10 days or a total cumulative dose of greater than or equal to 50 mg)
• Calcitonin
• Calcitriol or vitamin D derivatives [vitamin D contained in supplements or multivitamins is allowed]
• Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin
• Chronic systemic ketoconazole, adrenocorticotrophic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists.
• Androgen deprivation therapy
• Known sensitivity to mammalian cell derived drug products.
• Known intolerance to calcium or vitamin D supplements.
• Height, weight or girth which may preclude accurate DXA measurements.
• Bilateral hip replacements
• Any physical or psychiatric disorder which, in the opinion of the investigator or Amgen, 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 of or completion of the study.