Denosumab China Phase III Study

This study is to evaluate the efficacy and safety of denosumab 60 milligrams (mg) for 12 month treatment in Chinese postmenopausal women with osteoporosis at increased risk of fracture.

The aim of this Phase III, randomized, double-blind, placebo-controlled, parallel-group study is to evaluate the efficacy and safety of denosumab (DMAb) in Chinese postmenopausal women with osteoporosis at increased risk of fracture. The study design consists of two phases: Screening and 12-month Double-Blind treatment phase. Following the Screening phase, all eligible subjects will be randomized to receive Double-Blind DMAb (60 mg) or Placebo study medication in a 3:1 ratio. DMAb 60 mg and placebo will be administered as a single subcutaneous (SC) injection at the beginning of the Double-Blind phase and at 6 months following the initial dose. All subjects will receive daily supplementation of oral elemental calcium (at least 600 mg) and vitamin D (at least 400 International Units \[IU\]). The primary objective is to determine the effects of DMAb compared to placebo with respect to mean percent change in BMD at the lumbar spine, as measured by dual-energy x-ray absorptiometry (DXA), from Baseline to Month 12. Secondary objectives include the evaluation between the DMAb and placebo treatment groups: change in BMD: at the lumbar spine (Month 6), total hip (Months 6 and 12), femoral neck (Months 6 and 12) and trochanter (Months 6 and 12); and serum biomarkers of bone formation and resorption (Months 6 and 12). Clinical safety of denosumab will also be assessed in this population.

Eligibility Criteria:
Inclusion Criteria:

* Subject is willing and able to provide written informed consent.
* Of Chinese origin - defined as being born in China, having four ethnic Chinese grandparents.
* Ambulatory woman between the age of 60 and 90 years, inclusive.
* The subject has a BMD absolute value consistent with a T-score\<-2.5 and \>-4.0 at either the lumbar spine or total hip.
* All subjects must have at least one of following additional the risk factors:

history of fracture parental history of hip fracture increased bone turnover rate at screening (s-CTX \>1.0 SD above the mean in healthy premenopausal women) low body weight (BMI≤19kg/m2) elderly (age≥70y) current smoker

* Postmenopausal defined as \>5 years postmenopausal, which can be \>5 years of spontaneous amenorrhea or \>5 years post surgical bilateral oophorectomy. Use follicle stimulating hormone (FSH) levels \>40 mIU/mL to confirm surgical postmenopausal status, where bilateral oophorectomy status is uncertain.

Exclusion Criteria:

* Bone/metabolic disease:

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

Paget's disease Cushing's disease Hyperprolactinemia

* Current hyperparathyroidism or hypoparathyroidism by medical record
* Thyroid condition: Hyperthyroidism or hypothyroidism. Only subjects with hypothyroidism who are on stable thyroid hormone replacement therapy may be allowed per the following criteria:

If TSH level is below normal range, subject is not eligible for the study. If TSH level is elevated (\>5.5 μIU/mL and ≤10.0 μIU/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 \> 10.0 μIU/mL, subject is not eligible.

* Rheumatoid arthritis
* Malignancy:

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

* Malabsorption syndrome: malabsorption syndrome or any gastrointestinal disorders associated with malabsorption, for example Crohn's Disease and chronic pancreatitis.
* Renal disease - severe renal impairment
* Liver disease:

Cirrhosis of the liver Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Chronic stable hepatitis B and C are acceptable if the subject otherwise meets study entry criteria (e.g., presence of hepatitis B surface antigen or positive Hepatitis C test result within 3 months of Screening).

* Drug or alcohol abuse: Evidence of alcohol or substance-abuse within the last 12 months which the investigator believes would interfere with understanding or completing the study.
* Biological abnormalities:

Any disorder that compromises the ability of the subject to give written informed consent or to comply with study procedures.

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.

Known to have tested positive for human immunodeficiency virus (HIV).

* Vitamin D deficiency: Vitamin D deficiency (25-(OH) vitamin D level \<20 ng/mL). Vitamin D repletion will be permitted and after repletion subjects may be re-tested once for 25-(OH) vitamin D levels.
* Oral/Dental Conditions Prior history or current evidence of osteomyelitis or osteonecrosis of the jaw. Active dental or jaw condition which requires oral surgery. Planned invasive dental procedure. Non-healed dental or oral surgery.

Concomitant Medications:

* Previous strontium or IV bisphosphonate: Administration of intravenous (IV) bisphosphonate, fluoride, or strontium for osteoporosis within the last 5 years.
* Oral bisphosphonate: Oral bisphosphonate treatment for osteoporosis:

If used for ≥3 years cumulatively, subject is ineligible.

If used for \>3-months but \<3 years cumulatively:

If the last dose was \<1 year before enrolment, subject is ineligible. If the last dose was ≥1 year before enrolment, subject is eligible. If used ≤3 months, cumulatively, subject is eligible.

* Bone metabolism drugs: Administration of any of the following treatments within the last 6 weeks:

Parathyroid hormone (PTH) or PTH derivatives, e.g., teriparatide. Anabolic steroids or testosterone. Glucocorticosteroids (\>5 mg prednisone equivalent per day for more than 10 days).

Systemic hormone replacement therapy. Selective estrogen receptor modulators (SERMs), e.g., raloxifene Tibolone. Calcitonin. Calcitriol or vitamin D derivatives. Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin.

Chronic systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists.

* Investigational drug exposure: Currently enrolled in an investigational device or drug trial(s) or it has not been at least 30 days since the last study visit in an investigational device or drug trial(s), or subject is receiving other investigational agent(s).
* Sensitivity: Known sensitivity to mammalian cell-derived drug products.
* Clinically significant hypersensitivity to denosumab Abnormal laboratory values
* General: 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.
* Abnormal serum calcium: current hypocalcemia or hypercalcemia. Albumin adjusted serum calcium levels must be within normal limits of the central laboratory.
* Liver transaminases:

Serum aspartate aminotransferase (AST) ≥2.0 x upper limits of normal (ULN). Serum alanine aminotransferase (ALT) ≥2.0 x ULN. Alkaline phosphatase and bilirubin ≥1.5 x ULN (isolated bilirubin ≥1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%.

* DXA measurements:

Less than two lumbar vertebrae evaluable for DXA measurements. Height, weight, or girth which may preclude accurate DXA measurements.

* Subjects with a history of greater than 2 vertebral fractures.
* Subjects at very high risk of fracture who must be treated with active drugs in the opinion of investigator.