Prolia (Page 6 of 9)

14 CLINICAL STUDIES

14.1 Treatment of 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 subcutaneous 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 3. 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 3. The Effect of Prolia on the Incidence of New Vertebral Fractures in Postmenopausal Women
Proportion of Women with Fracture (%)* Absolute Risk Reduction (%)(95% CI) Relative Risk Reduction (%)(95% CI)
PlaceboN = 3691(%) ProliaN = 3702(%)
*
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.
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
Figure 1
(click image for full-size original)
N = number of subjects randomized

Effect on Nonvertebral Fractures

Treatment with Prolia resulted in a significant reduction in the incidence of nonvertebral fractures (Table 4).

Table 4. The Effect of Prolia on the Incidence of Nonvertebral Fractures at Year 3
Proportion of Women with Fracture (%)* Absolute Risk Reduction (%)(95% CI) Relative Risk Reduction (%)(95% CI)
PlaceboN = 3906(%) ProliaN = 3902(%)
*
Event rates based on Kaplan-Meier estimates at 3 years.
Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, and finger and toe phalanges.
p-value = 0.01.
Nonvertebral fracture 8.0 6.5 1.5 (0.3, 2.7) 20 (5, 33)

Effect on Bone Mineral Density (BMD)

Treatment with Prolia significantly increased BMD at all anatomic sites measured at 3 years. The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover.

After Prolia discontinuation, BMD returned to approximately baseline levels within 12 months.

Bone Histology and Histomorphometry

A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Prolia group, 62 specimens in placebo group). Of the biopsies obtained, 115 (100%) were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment.

Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Prolia.

The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Prolia, 35% had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-treated patients had double label present at both time points. When compared to placebo, treatment with Prolia resulted in virtually absent activation frequency and markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.

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