lveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued [see Use in Specific Populations (8.1, 8.4)].
14 CLINICAL STUDIES
14.1 Postmenopausal Women with Osteoporosis
The efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled, trial. Enrolled women had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the mean baseline lumbar spine BMD T-score was -2.8 and 23% of women had a vertebral fracture at baseline. Women were randomized to receive SC injections of either placebo (N = 3906) or Prolia 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.
Effect on Vertebral Fractures
Prolia significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Prolia-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.
Table 2. The Effect of Prolia on the Incidence of New Vertebral Fractures *
Event rates based on crude rates in each interval
†
Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group variable
Proportion of Women With Fracture (%)* Absolute Risk Reduction (%)†
(95% CI) Relative Risk Reduction (%)†
(95% CI)
Placebo
N = 3691
(%) Prolia
N = 3702
(%)
0-1 Year 2.2 0.9 1.4 (0.8, 1.9) 61 (42, 74)
0-2 Years 5.0 1.4 3.5 (2.7, 4.3) 71 (61, 79)
0-3 Years 7.2 2.3 4.8 (3.9, 5.8) 68 (59, 74)
Prolia was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis.
Effect on Hip Fractures
The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Prolia-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).
Figure 1. Cumulative Incidence of Hip Fractures Over 3 Years
Effect on Nonvertebral Fractures
Treatment with Prolia resulted in a significant reduction in the incide
