Prolia (Page 7 of 9)

14.2 Treatment to Increase Bone Mass in Men with Osteoporosis

The efficacy and safety of Prolia in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age of 65 years. Men were randomized to receive SC injections of either placebo (n = 121) or Prolia 60 mg (n = 121) once every 6 months. All men received at least 1000 mg calcium and at least 800 IU vitamin D supplementation daily.

Effect on Bone Mineral Density (BMD)

The primary efficacy variable was percent change in lumbar spine BMD from baseline to 1-year. Secondary efficacy variables included percent change in total hip, and femoral neck BMD from baseline to 1-year.

Treatment with Prolia significantly increased BMD at 1-year. The treatment differences in BMD at 1-year were 4.8% (+0.9% placebo, +5.7% Prolia; (95% CI: 4.0, 5.6); p < 0.0001) at the lumbar spine, 2.0% (+0.3% placebo, +2.4% Prolia) at the total hip, and 2.2% (0.0% placebo, +2.1% Prolia) at femoral neck. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, BMD, testosterone concentrations, and level of bone turnover.

Bone Histology and Histomorphometry

A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in Prolia group, 12 specimens in placebo group). Of the biopsies obtained, 29 (100%) were adequate for qualitative histology and, in Prolia patients, 6 (35%) 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, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo-treated patients had double label present. When compared to placebo, treatment with Prolia resulted in markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.

14.3 Treatment of Glucocorticoid-Induced Osteoporosis

The efficacy and safety of Prolia in the treatment of patients with glucocorticoid-induced osteoporosis was assessed in the 12-month primary analysis of a 2-year, randomized, multicenter, double-blind, parallel-group, active-controlled study (NCT 01575873) of 795 patients (70% women and 30% men) aged 20 to 94 years (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent) for < 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-initiating subpopulation; n = 290) or ≥ 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-continuing subpopulation, n = 505). Enrolled patients < 50 years of age were required to have a history of osteoporotic fracture. Enrolled patients ≥ 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture.

Patients were randomized (1:1) to receive either an oral daily bisphosphonate (active-control, risedronate 5 mg once daily) (n = 397) or Prolia 60 mg subcutaneously once every 6 months (n = 398) for one year. Randomization was stratified by gender within each subpopulation. Patients received at least 1000 mg calcium and 800 IU vitamin D supplementation daily.

Effect on Bone Mineral Density (BMD)

In the glucocorticoid-initiating subpopulation, Prolia significantly increased lumbar spine BMD compared to the active-control at one year (Active-control 0.8%, Prolia 3.8%) with a treatment difference of 2.9% (p < 0.001). In the glucocorticoid-continuing subpopulation, Prolia significantly increased lumbar spine BMD compared to active-control at one year (Active-control 2.3%, Prolia 4.4%) with a treatment difference of 2.2% (p < 0.001). Consistent effects on lumbar spine BMD were observed regardless of gender; race; geographic region; menopausal status; and baseline age, lumbar spine BMD T-score, and glucocorticoid dose within each subpopulation.

Bone Histology

Bone biopsy specimens were obtained from 17 patients (11 in the active-control treatment group and 6 in the Prolia treatment group) at Month 12. Of the biopsies obtained, 17 (100%) were adequate for qualitative histology. Qualitative assessments showed bone of normal architecture and quality without mineralization defects or bone marrow abnormality. 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 active-control, 100% of biopsies had tetracycline label. In patients treated with Prolia, 1 (33%) had tetracycline label and 2 (67%) had no tetracycline label present at the 12 month biopsy. Evaluation of full quantitative histomorphometry including bone remodeling rates was not possible in the glucocorticoid-induced osteoporosis population treated with Prolia. The long-term consequences of this degree of suppression of bone remodeling in glucocorticoid-treated patients is unknown.

14.4 Treatment of Bone Loss in Men with Prostate Cancer

The efficacy and safety of Prolia in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had either a BMD T-score at the lumbar spine, total hip, or femoral neck between -1.0 and -4.0, or a history of an osteoporotic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Prolia 60 mg (n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age (< 70 years vs. ≥ 70 years) and duration of ADT at trial entry (≤ 6 months vs. > 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

Effect on Bone Mineral Density (BMD)

The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key secondary efficacy variable was the incidence of new vertebral fracture through month 36 diagnosed based on x-ray evaluation by two independent radiologists. Lumbar spine BMD was higher at 2 years in Prolia-treated patients as compared to placebo-treated patients [-1.0% placebo, +5.6% Prolia; treatment difference 6.7% (95% CI: 6.2, 7.1); p < 0.0001].

With approximately 62% of patients followed for 3 years, treatment differences in BMD at 3 years were 7.9% (-1.2% placebo, +6.8% Prolia) at the lumbar spine, 5.7% (-2.6% placebo, +3.2% Prolia) at the total hip, and 4.9% (-1.8% placebo, +3.0% Prolia) at the femoral neck. Consistent effects on BMD were observed at the lumbar spine in relevant subgroups defined by baseline age, BMD, and baseline history of vertebral fracture.

Effect on Vertebral Fractures

Prolia significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 5.

Table 5. The Effect of Prolia on the Incidence of New Vertebral Fractures in Men with Nonmetastatic Prostate Cancer
Proportion of Men with Fracture (%)* Absolute Risk Reduction (%)(95% CI) Relative Risk Reduction (%)(95% CI)
PlaceboN = 673(%) ProliaN = 679(%)
*
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 and ADT duration variables.
0-1 Year 1.9 0.3 1.6 (0.5, 2.8) 85 (33, 97)
0-2 Years 3.3 1.0 2.2 (0.7, 3.8) 69 (27, 86)
0-3 Years 3.9 1.5 2.4 (0.7, 4.1) 62 (22, 81)

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