Romosozumab

Clinical fractures include clinical vertebral fractures and nonvertebral fractures.

Fractures include new and worsening vertebral compression fractures, whether clinically silent or manifest, and nonvertebral fractures.

Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

All fracture assessments were performed by blinded central imaging readers. New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: * Grade 0 (Normal) = no fracture; * Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); * Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; * Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method.

All fracture assessments were performed by blinded central imaging readers. Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.

Change from baseline to the Month 12 visit in volumetric bone mineral content (vBMC) obtained via CT (three-dimensional) imaging of the knee.

Bone mineral density was measured using dual-energy X-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging reader.

Functional healing was measured by the timed-up-and-go test (TUG) over Weeks 6 through 20. During this assessment, the clinician timed the participant while they stood up from a seated position in a chair, walked three meters, turned around, walked three meters back to the chair, and returned to the seated position. A TUG value of ten seconds or less was considered normal for a healthy elderly person. Higher TUG values after hip fracture have been shown to be a predictor of future falls. Least squares mean (LSM) estimates were based on a repeated measures model fitted with the log-transformed TUG values at weeks 2, 6, 12, 16, 20, 24, 36, 52 as the dependent variable and adjusted for treatment, randomized strata, gender, country category, pre-fracture community-dwelling status, pre-fracture walking aid use, quality of surgical fixation, visit, and treatment-by-visit interaction and back-transformed using the exponential transformation.

Time to radiographic healing was defined as the time from intramedullary (IM) nailing to the first occurrence of bridging of 3 out of 4 cortices. Radiographic fracture healing was determined by a panel of independent reviewers (orthopedic/trauma surgeons and radiologists) blinded to treatment. The cumulative incidence function (CIF) method was used to estimate the median time to radiographic healing and the confidence intervals. Unplanned revision surgery to promote healing was considered a competing risk in CIF estimate.

Mean Cmax values following Days 1 and 57 are presented.

Median tmax values following Days 1 and 57 are presented.

Mean AUC(0-28) values following Days 1 and 57 are presented.

The accumulation ratio was calculated as AUC(0-28) at Day 57/AUC(0-28) at Day 1. Mean accumulation ratio values based on analysis at Days 1 and 57 are presented, as pre-specified.

Median terminal half-life values at Day 57 are presented.

A serious adverse event was defined as an adverse event (AE) that met at least 1 of the following serious criteria: * fatal * life-threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event. A treatment-related adverse event (TRAE) was an AE assessed by the investigator as possibly related to the study drug, indicated by a "yes" response to the question: "Is there a reasonable possibility that the event may have been caused by the investigational product?"

Two validated assays were used to detect the presence of anti-romosozumab antibodies. First, an electrochemiluminescent immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding romosozumab. Second, a non-cell-based competitive binding bioassay was used to test positive binding antibody samples for neutralizing activity against romosozumab. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.

Albumin-adjusted calcium was derived as: Where serum albumin \< 40 g/L then albumin-adjusted calcium = measured total calcium (mmol/L) + 0.02 \* \[40 - serum albumin (g/L)\]; Where serum albumin ≥ 40 g/L then albumin-adjusted calcium = measured total calcium.

Bone mineral density was assessed by dual energy X-ray absorptiometry (DXA) scans of the lumbar spine (L1-L4) and analyzed by a central imaging lab.

Participants who were negative for anti-romosozumab binding antibodies at baseline with a positive result at any time post-baseline.

The polar moment of inertia is a geometric measurement used to predict bone quality, specifically the ability to resist torsion (twisting), and is highly correlated with fracture load at the distal radius. The polar cross-sectional moment of inertia was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.

All samples were tested for binding anti-romsozumab antibodies using an immunoassay; all antibody-positive samples were further tested in a bioassay to determine if the antibodies were neutralizing. Development of antibodies to romosozumab is defined as participants with a negative result at baseline and a positive result at any time postbaseline.