• Percent change from baseline at month 12 with respect to Urine N-Tx/creatinine and serum CTx-1 for all treatment arms (including Fosamax), BMD of the lumbar spine for the Fosamax treatment arm [ Time Frame: 48 months ] [ Designated as safety issue: No ]
• Percent change from baseline to month 24, 36, 42, and 48 with respect to BMD of the lumbar spine for all treatment arms, Urine N-Tx/creatinine and serum CTx-1 for all treatment arms [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Percent change from baseline to months 12, 24, 36, 42, and 48 with respect to BMD of the total hip, distal radius, and total body for all treatment arms,BAP for all treatment arms [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Secondary Safety Endpoints include Subject incidence of treatment-emergent adverse events [ Time Frame: 48 Months ] [ Designated as safety issue: Yes ]
• Changes from baseline in laboratory assessments (serum chemistry, hematology, and intact parathyroid hormone) at each visit [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Changes from baseline in vital signs at each visit [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Clinical fracture incidence [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Bone histologic and histomorphometric parameters [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Subject incidence of the formation of anti-AMG 162 antibodies within each of the AMG 162 treatment arms [ Time Frame: 48 Months ] [ Designated as safety issue: No ]
• Changes in ECG - QTc interval [ Time Frame: 48 Months ] [ Designated as safety issue: No ]

To determine the effect of AMG 162 treatment compared with placebo over 12 months on bone mineral density (BMD) of the lumbar spine in postmenopausal women with low BMD. The clinical hypothesis is that AMG 162 SC injections administered every 3 or 6 months for 12 months will significantly increase lumbar spine bone mineral density and will be well tolerated.

• Drug: Placebo
• Drug: Denosumab
• Drug: Active comparator

• Experimental: AMG 162: 30 mg SC every 3 months until month 21; placebo SC every 6 months at month 24 and month 30; 60 mg SC every 6 months at month 36 and month 42
• Experimental: AMG 162: 210 mg SC every 6 months until month 21; (alternating with placebo every 3 months); placebo every 6 months beginning month 24 through 42
• Experimental: AMG 162: 6 and 14 mg SC every 3 months until month 21; 60 mg SC every 6 months beginning month 24 through 42
• Active Comparator: Fosamax 70 mg oral weekly for 24 months. No treatment through month 48
• Placebo Comparator: placebo sc every 3 months until month 21 then beginning at month 24 every 6 months until month 42
• Experimental: AMG 162: 14 60, and 100 mg SC every 6 months until month 21 (alternating with placebo every 3 months); 60 mg SC every 6 months beginning month 24 through 42

• McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ; AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006 Feb 23;354(8):821-31.
• Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J, For The Amg 162 Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. Epub 2008 Apr 26.
• Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, Wang A, Siddhanti S, Fitzpatrick LA; AMG 162 Bone Loss Study Group. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007 Dec;22(12):1832-41.

4.1 Inclusion Criteria 4.1.1 Women not more than 80 years old on date of randomization 4.1.2 At least 1 year postmenopausal on date of randomization 4.1.3 Ambulatory 4.1.4 If ≤ 60 years old or post bilateral oophorectomy based on medical history, will require serum FSH > 50mU/mL or serum estradiol < 20 pg/mL to be eligible; 4.1.5 Low bone mineral density (BMD t-score ≤ -1.8 at any one of the following sites: lumbar spine, femoral neck, or total hip; BMD t-scores must not be lower than -4.0 at the lumbar spine, or -3.5 at the femoral neck or total hip). Refer to Table 3 in Section 7.11.1 for Hologic and Lunar densitometer-specific BMD values, and more specific information.

4.1.6 Ethical - Before any study specific procedure, including the screening DXA, the subject must give informed consent for participation in the study (see Section 12.2).

4.2 Exclusion Criteria 4.2.1 Fluoride treatment for osteoporosis within the last 2 years before the enrollment date; 4.2.2 Bisphosphonate use within the last 12 months before the enrollment date; 4.2.3 Administration of the following medications within the last 6 months before enrollment date:

1. Tibolone
2. Parathyroid hormone (or any derivative)
3. Systemic glucocorticosteroids (> 5 mg oral prednisone equivalent per day for more than 10 days)
4. Inhaled corticosteroids (> 2,000 µg per day for more than 10 days)
5. Anabolic steroids or testosterone 4.2.4 Administration of the following medications within the last 3 months before the enrollment date:

a) Systemic hormone replacement therapy b) Selective estrogen receptor modulators (SERMs) c) Calcitonin d) Calcitriol 4.2.5 Evidence of any of the following conditions per subject self report or medical chart review:

1. Current hyper- or hypothyroidism (stable on thyroid replacement therapy is allowed, if the TSH is within the normal range)
2. Current hyper- or hypoparathyroidism
3. Albumin-adjusted serum calcium < 8.5 mg/dL
4. Osteomalacia
5. Rheumatoid arthritis
6. Paget's disease
7. Malignancy within the last 5 years prior to enrollment (except cervical carcinoma in situ or basal cell carcinoma)

8. Renal disease (creatinine clearance <= 35 mL/min using the following equation):

   Creatinine Clearance = 0.85 [(140 - age in years) x (weight in kg)] [72 x serum creatinine (mg/dL)]

9. Any bone disease, other than osteoporosis, which may interfere with the interpretation of the findings (e.g., osteogenesis imperfecta or osteopetrosis)
10. Malabsorption syndrome
11. Weight, height or girth which may preclude accurate DXA measurements
12. Less than 2 lumbar vertebrae (L1-L4) evaluable by DXA
13. Recent long bone fracture (within 6 months)
14. Osteoporosis-related fracture (i.e., crush or wedge vertebral fracture or hip fracture) known or suspected to have occurred within 2 years of randomization.
15. More than one single, grade 1 vertebral fracture. 4.2.6 Currently enrolled or has participated within the previous 30 days in other investigational device or drug trial(s). For some trials, this may be allowed after discussion and written approval from Amgen.

4.2.7 Known sensitivity to mammalian-derived drug preparations (e.g., Herceptin).

4.2.8 Any organic or psychiatric disorder, serum chemistry, or hematology, which, in the opinion of the investigator, may prevent the subject from completing the study or interfere with the interpretation of the study results.

4.2.9 Self-reported alcohol or drug abuse within the previous 12 months. 4.2.10 Any disorder that compromises ability to give truly informed consent for participation in this study.

4.2.11 Prior administration of AMG 162. 4.2.12 Known sensitivity or contraindication to Fosamax. 4.2.13 Known sensitivity or contraindication to tetracycline derivatives (biopsy subset subjects only).