Description

Prolia is used to treat osteoporosis in women after menopause who are at high risk for fracture (broken bone) and cannot use another osteoporosis medicine or other osteoporosis medicines did not work well. Prolia may also be used to increase bone mass in men with osteoporosis who are at high risk for fracture; treat bone loss in men who are at high risk for fracture receiving certain treatments for prostate cancer that has not spread to other parts of the body; and treat bone loss in women who are at high risk for fracture receiving certain treatments for breast cancer that has not spread to other parts of the body.¹ 

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia and patients must adequately supplement with calcium and vitamin D.¹ 
Prolia may cause fetal harm when administered to a pregnant woman. Prolia is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.¹ 

Prolia may increase risks for osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture.¹  The safety and effectiveness of Prolia in pediatric patients has not been established.¹ 

Background

Osteoporosis is a major metabolic bone disease that over a lifetime results in fractures in 40% of aging women and 15% of aging men. DXA scans of patients with osteoporosis reveal a T-score less than or equal to -2.5. In addition to those patients with a DXA score representing osteoporosis, treatment should be considered in those patients with a fragility fracture. A fragility fracture is a major osteoporotic fracture, sustained as a result of a low-level trauma (e.g., a fall from standing height or less) that is associated with low BMD, including vertebral (spine), hip, forearm (wrist/distal radius), and proximal humerus (shoulder) fractures. Recent studies have shown that estrogen deficiency is the cause of both the early and the late forms of osteoporosis in postmenopausal women and contributes to the development of osteoporosis in aging men. Estrogen deficiency is associated with an increase in bone resorption over bone formation, leading to excessive and sustained bone loss. The increase in bone resorption is due both to increased osteoclastogenesis and to decreased osteoclast apoptosis. Receptor activator of nuclear factor-kappaB (RANK ligand or RANKL) is a key mediator of bone resorption in normal and pathological states. In normal bone turnover and in bone metastasis, RANKL stimulates the formation and activity of bone-removing cells, osteoclasts.

Prolia is known as a RANK Ligand inhibitor; it works by decreasing the breakdown of bone by osteoclasts. It is a highly specific monocolonal antibody produced in genetically engineered mammalian (Chinese hamster ovary) cells. Prolia binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. Prolia is dosed 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.

Policy

Prolia is considered MEDICALLY NECESSARY for individuals with with osteoporosis or osteopenia at a high risk for fracture who meet all of the following criteria:

1. Diagnosis of postmenopausal osteoporosis or osteopenia
2. One of the following:
   1. Bone mineral density (BMD) scan indicative of osteoporosis: T-score less than or equal to -2.5 in the lumbar spine, femoral neck, total hip, or radius (one-third radius site)
   2. BMD scan indicative of osteopenia: T-score between -1.0 and -2.5 (BMD T-score greater than -2.5 and less than or equal to -1.0) in the lumbar spine, femoral neck, total hip, or radius (one-third radius site) AND One of the following FRAX (Fracture Risk Assessment Tool) 10-year probabilities: Major osteoporotic fracture at 20% or more in the U.S., or the country-specific threshold in other countries or regions OR Hip fracture at 3% or more in the U.S., or the country-specific threshold in other countries or regions
   3. History of one of the following resulting from minimal trauma:

•            Vertebral compression fracture

•            Fracture of the hip

•            Fracture of the distal radius

•            Fracture of the pelvis

•            Fracture of the proximal humerus

3. Trial and failure, intolerance, or contraindication to one bisphosphonate (e.g., alendronate)

Continued treatment with Prolia is considered MEDICALLY NECESSARY when the following criteria are met:

1. Patient is benefiting from therapy (e.g., improved or stabilized BMD, no new fractures, improved biochemical markers, etc.) without significant adverse effects.

Prolia is considered MEDICALLY NECESSARY for males with osteoporosis or osteopenia at a high risk for fracture who meet all of the following criteria:

1. Patient is a male with osteoporosis or osteopenia.
2. One of the following:
   1. Bone mineral density (BMD) scan indicative of osteoporosis: T-score less than or equal to -2.5 in the lumbar spine, femoral neck, total hip, or radius (one-third radius site)
   2. BMD scan indicative of osteopenia: T-score between -1.0 and -2.5 (BMD T-score greater than -2.5 and less than or equal to -1.0) in the lumbar spine, femoral neck, total hip, or radius (one-third radius site) AND one of the following FRAX (Fracture Risk Assessment Tool) 10-year probabilities: Major osteoporotic fracture at 20% or more in the U.S., or the country-specific threshold in other countries or regions OR Hip fracture at 3% or more in the U.S., or the country-specific threshold in other countries or regions
   3. History of one of the following resulting from minimal trauma:

•            Vertebral compression fracture

•            Fracture of the hip

•            Fracture of the distal radius

•            Fracture of the pelvis

•            Fracture of the proximal humerus

3. Trial and failure, intolerance, or contraindication to one bisphosphonate (e.g., alendronate)

Continued treatment with Prolia is considered MEDICALLY NECESSARY when the following criteria are met:

1. Patient is benefiting from therapy (e.g., improved or stabilized BMD, no new fractures, improved biochemical markers, etc.) without significant adverse effects

Prolia is considered MEDICALLY NECESSARY for individuals with glucocorticoid-induced osteoporosis at a high risk for fracture who meet all of the following criteria:

1. Diagnosis of glucocorticoid-induced osteoporosis
2. Patient is initiating or continuing on greater than or equal to 7.5 mg/day of prednisone (or its equivalent) and is expected to remain on glucocorticoid therapy for at least 6 months
3. One of the following:
   • BMD T-score less than or equal to -2.5 based on BMD measurements from lumbar spine, femoral neck, total hip, or radius (one-third radius site)
   • One of the following FRAX (Fracture Risk Assessment Tool) 10-year probabilities:
     • Major osteoporotic fracture at 20% or more in the U.S., or the country-specific threshold in other countries or regions
     • Hip fracture at 3% or more in the U.S., or the country-specific threshold in other countries or regions
   • History of one of the following fractures resulting from minimal trauma:
     • Vertebral compression fracture
     • Fracture of the hip
     • Fracture of the distal radius
     • Fracture of the pelvis
     • Fracture of the proximal humerus
4. Trial and failure, contraindication, or intolerance to one bisphosphonate (e.g., alendronate)

Continued treatment with Prolia is considered MEDICALLY NECESSARY when the following criteria are met:

1. Patient is benefiting from therapy (e.g., improved or stabilized BMD, no new fractures, improved biochemical markers, etc.) without significant adverse effects.

Prolia is considered MEDICALLY NECESSARY for individuals with non-metastatic prostate cancer at a high risk for fracture who meet all of the following criteria:

1. Diagnosis of non-metastatic prostate cancer
2. Patient is undergoing androgen deprivation therapy with one of the following:
   1. Luteinizing hormone-releasing hormone (LHRH)/gonadotropin releasing hormone (GnRH) agonist (e.g., Eligard/Lupron [leuprolide], Trelstar [triptorelin], Vantas [histrelin], and Zoladex [goserelin])
   2. Bilateral orchiectomy (i.e., surgical castration)
3. One of the following:
   1. Age greater than or equal to 70 years
   2. Age less than 70 years with One of the following:
      1. Bone mineral density (BMD) scan T-score less than -1.0 (1.0 standard deviation or greater below the mean for young adults)
      2. History of one of the following resulting from minimal trauma:
         • Vertebral compression fracture
         • Fracture of the hip
         • Fracture of the distal radius
         • Fracture of the pelvis
         • Fracture of the proximal humerus
4. One of the following:
   1.  Trial and failure, intolerance, or contraindication to one bisphosphonate (e.g., zoledronic acid)
   2. Patient is currently receiving therapy

Continued treatment with Prolia is considered MEDICALLY NECESSARY when the following criteria are met:

1. Patient is undergoing androgen deprivation therapy with one of the following:

• Luteinizing hormone-releasing hormone (LHRH)/gonadotropin releasing hormone (GnRH) agonist (e.g., Eligard/Lupron [leuprolide], Trelstar [triptorelin], Vantas [histrelin], and Zoladex [goserelin])
• Bilateral orchiectomy (i.e., surgical castration)

2. No evidence of metastases
3. Patient is benefiting from therapy (e.g., improved or stabilized BMD, no new fractures, improved biochemical markers, etc.)

Prolia is considered MEDICALLY NECESSARY for individuals with breast cancer at a high risk for fracture who meet all of the following criteria:

1. Diagnosis of breast cancer
2. Patient is receiving adjuvant aromatase inhibitor therapy (e.g., Arimidex [anastrozole], Aromasin [exemestane], Femara [letrozole])
3. One of the following:
   • Bone mineral density (BMD) scan T-score less than -1.0 (1.0 standard deviation or greater below the mean for young adults)
   • History of one of the following resulting from minimal trauma:
     • Vertebral compression fracture
     • Fracture of the hip
     • Fracture of the distal radius
     • Fracture of the pelvis
     • Fracture of the proximal humerus
4. One of the following:
   • Trial and failure, intolerance, or contraindication to one bisphosphonate (e.g., zoledronic acid)
   • Patient is currently receiving therapy

Continued treatment with Prolia is considered MEDICALLY NECESSARY when the following criteria are met:

1. Patient is receiving adjuvant aromatase inhibitor therapy (e.g., Arimidex [anastrozole], Aromasin [exemestane], Femara [letrozole]).
2. Patient is benefiting from therapy (e.g., improved or stabilized BMD, no new fractures, improved biochemical markers, etc.).

Rationale

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 = 3,906) or Prolia 60 mg (N = 3,902) once every 6 months. All women received at least 1,000 mg calcium and 400 IU vitamin D supplementation daily.

The primary efficacy variable was the incidence of new morphometric (radiologically diagnosed) vertebral fractures at three 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 three years.

Prolia significantly reduced the incidence of new morphometric vertebral fractures at I, 2 and 3 years (p < 0.0001). The incidence of new vertebral fractures at year 3 was 7.2% in the placebo­treated 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. 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). Treatment with Prolia resulted in a significant reduction in the incidence of nonvertebral fractures at year 3. Treatment with Prolia significantly increased BMD at all anatomic sites measured at three 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. 

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 I-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 1,000 mg calcium and at least 800 IU vitamin D supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD from baseline to I year. Secondary efficacy variables included percent change in total hip, and femoral neck BMD from baseline to I year. Treatment with Prolia significantly increased BMD at 1 year. The treatment differences in BMD at l year were 4.8% (+0.9% placebo, +5.7% Prolia; (95% confidence interval [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. 

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 ADT were demonstrated in a 3-year, randomized (1:1), double blind, placebo­controlled, 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. 2: 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 JU vitamin D supplementation daily. 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. Prolia significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125).

Treatment of Bone Loss in Women with Breast Cancer 
The efficacy and safety of Prolia in the treatment of bone loss in women receiving adjuvant Al therapy for breast cancer was assessed in a 2-year, randomized (1:1), double-blind, placebo controlled, multinational study. Women had baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1, and 2.0% of women had a vertebral fracture at baseline. The 252 women enrolled ranged in age from 35 to 84 years (median 59 years). Women were randomized to receive subcutaneous injections of either placebo (n = 125) or Prolia 60 mg (n = 127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry (6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least I,000 mg calcium and 400 TU vitamin D supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Prolia-treated patients as compared to placebo-treated patients (-0.7% placebo, +4.8% Prolia; treatment difference 5.5% [95% CI: 4.8, 6.3]; p < 0.0001). With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1 .4% placebo, +6.2% Prolia) at the lumbar spine, 4.7 % (-1.0% placebo, +3.8% Prolia) at the total hip, and 3.6% (-0.8% placebo, +2.8% Prolia) at the femoral neck.

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 of 795 patients. Included patients were aged 20 to 94 years of age and 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) or 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-continuing subpopulation). 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 of -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 or Prolia 60 mg subcutaneously once every 6 months for 1 year. Patients received at least 1,000 mg calcium and 800 IU vitamin D supplementation daily. 

In the glucocorticoid-initiating subpopulation, Prolia significantly increased lumbar spine BMD compared to the active control at one year (Active control 2.3%, Prolia 4.4%) with a treatment difference of 2.2% (p < 0.001). In the glucocorticoid-continuing subpopulation, Prolia significantly increased lumbar spine BMD compared to active-control at one year (Active control 0.8%, Prolia 3.8%) with a treatment difference of2.9% (p < 0.001 ). Consistent effects on lumbar spine BMD were observed regardless of gender, race, geographic region, menopausal status, baseline age, lumbar spine BMD T-score, and glucocorticoid dose within each subpopulation. 

Reference

1. Prolia (denosumab) [package insert]. Thousand Oaks, CA: Amgen, Inc. March 2020.

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