Denosumab (Prolia® & Xgeva®) – Commercial Medical Benefit

Denosumab (Prolia

& Xgeva

)

Page 1 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

UnitedHealthcare

Commercial

Medical

Benefit

Drug

Policy

Denosumab (Prolia

& Xgeva

)

Policy Number: 2024D0068N

Effective Date: April 1, 2024



Instructions for Use

Table of Contents Page

Coverage Rationale ....................................................................... 1

Applicable Codes .......................................................................... 5

Background.................................................................................. 17

Benefit Considerations ................................................................ 17

Clinical Evidence ......................................................................... 17

Centers for Medicare and Medicaid Services ........................... 21

U.S. Food and Drug Administration ........................................... 20

References ................................................................................... 21

Policy History/Revision Information ........................................... 22

Instructions for Use ..................................................................... 22

Coverage Rationale

 See Benefit Considerations

This policy refers to the following denosumab products:

Prolia

Xgeva

Prolia (Denosumab)

Prolia is proven for the treatment of postmenopausal patients with osteoporosis or to increase bone mass in patients

with osteoporosis at high risk for fracture when all of the following criteria are met:

Initial Therapy

o Diagnosis of osteoporosis; and

o Patient is at high risk for fracture (e.g., history of osteoporotic fracture, multiple risk factors for fracture, patients who

have failed or are intolerant to other available osteoporosis therapy); and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Prolia is proven to treat glucocorticoid-induced osteoporosis in patients at high risk for fracture when all of the following

criteria are met:

Initial Therapy

o Diagnosis of glucocorticoid-induced osteoporosis; and

o Patient is at high risk for fracture (e.g., history of osteoporotic fracture, multiple risk factors for fracture, patients who

have failed or are intolerant to other available osteoporosis therapy); and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

Community Plan Policy

•

Denosumab (Prolia

& Xgeva

)

Denosumab (Prolia

& Xgeva

)

Page 2 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Prolia is proven to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for

non-metastatic prostate cancer. Prolia is medically necessary when all of the following criteria are met:

Initial Therapy

o Diagnosis of non-metastatic prostate cancer; and

o Patient is receiving androgen deprivation therapy; and

o One of the following (for Medicare reviews, refer to the CMS section):

 Both of the following:

History of intolerance to oral bisphosphonate therapy; and

History of failure, contraindication, or intolerance to intravenous (IV) bisphosphonate therapy (e.g.,

pamidronate, zoledronic acid)

 History of failure or contraindication to oral bisphosphonate therapy; or

 History of failure, contraindication, or intolerance to IV bisphosphonate therapy

and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Patient is receiving androgen deprivation therapy; and

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Prolia is proven to treat patients at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

Prolia is medically necessary when all of the following criteria are met:

Initial Therapy

o Diagnosis of breast cancer; and

o Patient is receiving aromatase inhibitor therapy; and

o One of the following (for Medicare reviews, refer to the CMS section):

 Both of the following:

History of intolerance to oral bisphosphonate therapy; and

History of failure, contraindication, or intolerance to intravenous (IV) bisphosphonate therapy (e.g.,

pamidronate, zoledronic acid)

 History of failure or contraindication to oral bisphosphonate therapy; or

 History of failure, contraindication, or intolerance to IV bisphosphonate therapy

and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Patient is receiving aromatase inhibitor therapy; and

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Xgeva (Denosumab)

Xgeva is proven for the prevention of skeletal-related events in patients with multiple myeloma and with bone metastases

from solid tumors. Xgeva is medically necessary when all of the following criteria are met:

Initial Therapy

Denosumab (Prolia

& Xgeva

)

Page 3 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

o Patient is one of the following:

 Patient is ≥ 18 years of age

 Patient is a skeletally mature adolescent as defined by having at least 1 mature long bone (e.g., closed epiphyseal

growth plate of the humerus)

and

o One of the following:

 Diagnosis of multiple myeloma

 Presence of metastatic disease secondary to a solid tumor (e.g., bladder, breast, kidney, lung, ovarian, thyroid,

etc.)

and

o Individual has an expected survival of 3 months or greater; and

o Refractory (within the past 30 days), contraindication (including renal insufficiency), or intolerance to treatment with

intravenous bisphosphonate therapy (e.g., pamidronate, zoledronic acid) (for Medicare reviews, refer to the CMS

section); and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Individual has an expected survival of 3 months or greater; and

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Xgeva is proven for the treatment of giant cell tumor of the bone. Xgeva is medically necessary when all of the following

criteria are met:

Initial Therapy

o Patient is one of the following:

 Patient is ≥ 18 years of age

 Patient is a skeletally mature adolescent as defined by having at least 1 mature long bone (e.g., closed epiphyseal

growth plate of the humerus)

and

o Diagnosis of localized, recurrent, or metastatic giant cell tumor of the bone; and

o Disease is one of the following:

 Unresectable

 Surgical resection is likely to result in severe morbidity

and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Xgeva is proven for the treatment of hypercalcemia of malignancy. Xgeva is medically necessary when all of the following

criteria are met:

Initial Therapy

o Patient is one of the following:

 Patient is ≥ 18 years of age; or

 Patient is a skeletally mature adolescent as defined by having at least 1 mature long bone (e.g., closed epiphyseal

growth plate of the humerus)

and

o Diagnosis of hypercalcemia of malignancy (i.e., albumin-corrected serum calcium level greater than 12.5 mg/dL); and

o No pre-existing hypocalcemia (i.e., serum calcium or corrected calcium within normal limits per laboratory reference);

and

Denosumab (Prolia

& Xgeva

)

Page 4 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

o Refractory (within the past 30 days), contraindication (including renal insufficiency), or intolerance to treatment with

intravenous bisphosphonate therapy (e.g., pamidronate, zoledronic acid); and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Xgeva is proven for the prevention of skeletal-related events in men with castration-resistant prostate cancer who have

bone metastases. Xgeva is medically necessary for the prevention of skeletal-related events in men with castration-

resistant prostate cancer who have bone metastases when all of the following criteria are met:

Initial Therapy

o Diagnosis of castration-resistant prostate cancer; and

o Presence of metastatic bone disease; and

o Refractory (within the past 30 days), contraindication (including renal insufficiency), or intolerance to treatment with

intravenous bisphosphonate therapy (e.g., pamidronate, zoledronic acid) (for Medicare reviews, refer to the CMS

section); and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Reauthorization/Continuation of Care Criteria

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Xgeva is proven for treatment of osteopenia/osteoporosis in patients with systemic mastocytosis with bone pain not

responding to bisphosphonates. Xgeva is medically necessary for the treatment of osteopenia/osteoporosis in patients

with systemic mastocytosis with bone pain not responding to bisphosphonates when all of the following criteria are met:

Initial Therapy

o Diagnosis of systemic mastocytosis; and

o Patient has bone pain; and

o Diagnosis of osteoporosis or osteopenia; and Refractory (within the past 30 days), contraindication (including renal

insufficiency), or intolerance to treatment with intravenous bisphosphonate therapy (e.g., pamidronate, zoledronic acid)

(for Medicare reviews, refer to the CMS section); and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization for no more than 12 months

Reauthorization/Continuation of Care Criteria

For patients currently on Xgeva for the treatment of osteopenia/osteoporosis in patients with systemic mastocytosis with

bone pain not responding to bisphosphonates, continued use will be approved based on the following criteria:

o Documentation of positive clinical response to therapy; and

o Dosing is in accordance with the United States Food and Drug Administration approved labeling; and

o Authorization is for no more than 12 months

Unproven/Not Medically Necessary

Denosumab is unproven and not medically necessary for the following indications:

Combination therapy of denosumab and intravenous bisphosphonates

Bone loss associated with hormone-ablation therapy (other than aromatase inhibitors) in breast/prostate cancer

Cancer pain

Central giant cell granuloma

Hyper-parathyroidism

Immobilization hypercalcemia

Osteogenesis imperfecta

Osteopenia

Denosumab (Prolia

& Xgeva

)

Page 5 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Applicable Codes

The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive.

Listing of a code in this policy does not imply that the service described by the code is a covered or non-covered health service.

Benefit coverage for health services is determined by the member specific benefit plan document and applicable laws that may

require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim

payment. Other Policies and Guidelines may apply.

HCPCS Code

Description

J0897

Injection, denosumab, 1 mg

Diagnosis Code

Description

Prolia

C61

Malignant neoplasm of prostate

C79.81

Secondary malignant neoplasm of breast

M80.00XA

Age-related osteoporosis with current pathological fracture, unspecified site, initial encounter for fracture

M80.00XD

Age-related osteoporosis with current pathological fracture, unspecified site, subsequent encounter for

fracture with routine healing

M80.00XG Age-related osteoporosis with current pathological fracture, unspecified site, subsequent encounter for

fracture with delayed healing

M80.00XK

Age-related osteoporosis with current pathological fracture, unspecified site, subsequent encounter for

fracture with nonunion

M80.00XP Age-related osteoporosis with current pathological fracture, unspecified site, subsequent encounter for

fracture with malunion

M80.00XS

Age-related osteoporosis with current pathological fracture, unspecified site, sequela

M80.0AXA

Age-related osteoporosis with current pathological fracture, other site, initial encounter for fracture

M80.0AXD Age-related osteoporosis with current pathological fracture, other site, subsequent encounter for

fracture with routine healing

M80.0AXG

Age-related osteoporosis with current pathological fracture, other site, subsequent encounter for

fracture with delayed healing

M80.0AXK Age-related osteoporosis with current pathological fracture, other site, subsequent encounter for

fracture with nonunion

M80.0AXP

Age-related osteoporosis with current pathological fracture, other site, subsequent encounter for

fracture with malunion

M80.0AXS

Age-related osteoporosis with current pathological fracture, other site, sequela

M80.011A

Age-related osteoporosis with current pathological fracture, right shoulder, initial encounter for fracture

M80.011D Age-related osteoporosis with current pathological fracture, right shoulder, subsequent encounter for

fracture with routine healing

M80.011G Age-related osteoporosis with current pathological fracture, right shoulder, subsequent encounter for

fracture with delayed healing

M80.011K Age-related osteoporosis with current pathological fracture, right shoulder, subsequent encounter for

fracture with nonunion

M80.011P Age-related osteoporosis with current pathological fracture, right shoulder, subsequent encounter for

fracture with malunion

M80.011S

Age-related osteoporosis with current pathological fracture, right shoulder, sequela

M80.012A

Age-related osteoporosis with current pathological fracture, left shoulder, initial encounter for fracture

M80.012D

Age-related osteoporosis with current pathological fracture, left shoulder, subsequent encounter for

fracture with routine healing

Denosumab (Prolia

& Xgeva

)

Page 6 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.012G Age-related osteoporosis with current pathological fracture, left shoulder, subsequent encounter for

fracture with delayed healing

M80.012K Age-related osteoporosis with current pathological fracture, left shoulder, subsequent encounter for

fracture with nonunion

M80.012P Age-related osteoporosis with current pathological fracture, left shoulder, subsequent encounter for

fracture with malunion

M80.012S

Age-related osteoporosis with current pathological fracture, left shoulder, sequela

M80.019A Age-related osteoporosis with current pathological fracture, unspecified shoulder, initial encounter for

fracture

M80.019D

Age-related osteoporosis with current pathological fracture, unspecified shoulder, subsequent

encounter for fracture with routine healing

M80.019G Age-related osteoporosis with current pathological fracture, unspecified shoulder, subsequent

encounter for fracture with delayed healing

M80.019K

Age-related osteoporosis with current pathological fracture, unspecified shoulder, subsequent

encounter for fracture with nonunion

M80.019P Age-related osteoporosis with current pathological fracture, unspecified shoulder, subsequent

encounter for fracture with malunion

M80.019S

Age-related osteoporosis with current pathological fracture, unspecified shoulder, sequela

M80.021A

Age-related osteoporosis with current pathological fracture, right humerus, initial encounter for fracture

M80.021D Age-related osteoporosis with current pathological fracture, right humerus, subsequent encounter for

fracture with routine healing

M80.021G Age-related osteoporosis with current pathological fracture, right humerus, subsequent encounter for

fracture with delayed healing

M80.021K Age-related osteoporosis with current pathological fracture, right humerus, subsequent encounter for

fracture with nonunion

M80.021P Age-related osteoporosis with current pathological fracture, right humerus, subsequent encounter for

fracture with malunion

M80.021S

Age-related osteoporosis with current pathological fracture, right humerus, sequela

M80.022A

Age-related osteoporosis with current pathological fracture, left humerus, initial encounter for fracture

M80.022D Age-related osteoporosis with current pathological fracture, left humerus, subsequent encounter for

fracture with routine healing

M80.022G

Age-related osteoporosis with current pathological fracture, left humerus, subsequent encounter for

fracture with delayed healing

M80.022K Age-related osteoporosis with current pathological fracture, left humerus, subsequent encounter for

fracture with nonunion

M80.022P

Age-related osteoporosis with current pathological fracture, left humerus, subsequent encounter for

fracture with malunion

M80.022S

Age-related osteoporosis with current pathological fracture, left humerus, sequela

M80.029A Age-related osteoporosis with current pathological fracture, unspecified humerus, initial encounter for

fracture

M80.029D Age-related osteoporosis with current pathological fracture, unspecified humerus, subsequent

encounter for fracture with routine healing

M80.029G Age-related osteoporosis with current pathological fracture, unspecified humerus, subsequent

encounter for fracture with delayed healing

Denosumab (Prolia

& Xgeva

)

Page 7 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.029K Age-related osteoporosis with current pathological fracture, unspecified humerus, subsequent

encounter for fracture with nonunion

M80.029P Age-related osteoporosis with current pathological fracture, unspecified humerus, subsequent

encounter for fracture with malunion

M80.029S

Age-related osteoporosis with current pathological fracture, unspecified humerus, sequela

M80.031A

Age-related osteoporosis with current pathological fracture, right forearm, initial encounter for fracture

M80.031D Age-related osteoporosis with current pathological fracture, right forearm, subsequent encounter for

fracture with routine healing

M80.031G

Age-related osteoporosis with current pathological fracture, right forearm, subsequent encounter for

fracture with delayed healing

M80.031K Age-related osteoporosis with current pathological fracture, right forearm, subsequent encounter for

fracture with nonunion

M80.031P

Age-related osteoporosis with current pathological fracture, right forearm, subsequent encounter for

fracture with malunion

M80.031S

Age-related osteoporosis with current pathological fracture, right forearm, sequela

M80.032A

Age-related osteoporosis with current pathological fracture, left forearm, initial encounter for fracture

M80.032D

Age-related osteoporosis with current pathological fracture, left forearm, subsequent encounter for

fracture with routine healing

M80.032G Age-related osteoporosis with current pathological fracture, left forearm, subsequent encounter for

fracture with delayed healing

M80.032K

Age-related osteoporosis with current pathological fracture, left forearm, subsequent encounter for

fracture with nonunion

M80.032P Age-related osteoporosis with current pathological fracture, left forearm, subsequent encounter for

fracture with malunion

M80.032S

Age-related osteoporosis with current pathological fracture, left forearm, sequela

M80.039A Age-related osteoporosis with current pathological fracture, unspecified forearm, initial encounter for

fracture

M80.039D

Age-related osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter

for fracture with routine healing

M80.039G Age-related osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter

for fracture with delayed healing

M80.039K

Age-related osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter

for fracture with nonunion

M80.039P Age-related osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter

for fracture with malunion

M80.039S

Age-related osteoporosis with current pathological fracture, unspecified forearm, sequela

M80.041A

Age-related osteoporosis with current pathological fracture, right hand, initial encounter for fracture

M80.041D Age-related osteoporosis with current pathological fracture, right hand, subsequent encounter for

fracture with routine healing

M80.041G

Age-related osteoporosis with current pathological fracture, right hand, subsequent encounter for

fracture with delayed healing

M80.041K Age-related osteoporosis with current pathological fracture, right hand, subsequent encounter for

fracture with nonunion

M80.041P

Age-related osteoporosis with current pathological fracture, right hand, subsequent encounter for

fracture with malunion

Denosumab (Prolia

& Xgeva

)

Page 8 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.041S

Age-related osteoporosis with current pathological fracture, right hand, sequela

M80.042A

Age-related osteoporosis with current pathological fracture, left hand, initial encounter for fracture

M80.042D Age-related osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture

with routine healing

M80.042G

Age-related osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture

with delayed healing

M80.042K Age-related osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture

with nonunion

M80.042P

Age-related osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture

with malunion

M80.042S

Age-related osteoporosis with current pathological fracture, left hand, sequela

M80.049A Age-related osteoporosis with current pathological fracture, unspecified hand, initial encounter for

fracture

M80.049D Age-related osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with routine healing

M80.049G Age-related osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with delayed healing

M80.049K Age-related osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with nonunion

M80.049P Age-related osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with malunion

M80.049S

Age-related osteoporosis with current pathological fracture, unspecified hand, sequela

M80.051A

Age-related osteoporosis with current pathological fracture, right femur, initial encounter for fracture

M80.051D

Age-related osteoporosis with current pathological fracture, right femur, subsequent encounter for

fracture with routine healing

M80.051G Age-related osteoporosis with current pathological fracture, right femur, subsequent encounter for

fracture with delayed healing

M80.051K

Age-related osteoporosis with current pathological fracture, right femur, subsequent encounter for

fracture with nonunion

M80.051P Age-related osteoporosis with current pathological fracture, right femur, subsequent encounter for

fracture with malunion

M80.051S

Age-related osteoporosis with current pathological fracture, right femur, sequela

M80.052A

Age-related osteoporosis with current pathological fracture, left femur, initial encounter for fracture

M80.052D Age-related osteoporosis with current pathological fracture, left femur, subsequent encounter for

fracture with routine healing

M80.052G

Age-related osteoporosis with current pathological fracture, left femur, subsequent encounter for

fracture with delayed healing

M80.052K Age-related osteoporosis with current pathological fracture, left femur, subsequent encounter for

fracture with nonunion

M80.052P

Age-related osteoporosis with current pathological fracture, left femur, subsequent encounter for

fracture with malunion

M80.052S

Age-related osteoporosis with current pathological fracture, left femur, sequela

M80.059A

Age-related osteoporosis with current pathological fracture, unspecified femur, initial encounter for

fracture

Denosumab (Prolia

& Xgeva

)

Page 9 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.059D Age-related osteoporosis with current pathological fracture, unspecified femur, subsequent encounter

for fracture with routine healing

M80.059G Age-related osteoporosis with current pathological fracture, unspecified femur, subsequent encounter

for fracture with delayed healing

M80.059K Age-related osteoporosis with current pathological fracture, unspecified femur, subsequent encounter

for fracture with nonunion

M80.059P Age-related osteoporosis with current pathological fracture, unspecified femur, subsequent encounter

for fracture with malunion

M80.059S

Age-related osteoporosis with current pathological fracture, unspecified femur, sequela

M80.061A

Age-related osteoporosis with current pathological fracture, right lower leg, initial encounter for fracture

M80.061D Age-related osteoporosis with current pathological fracture, right lower leg, subsequent encounter for

fracture with routine healing

M80.061G

Age-related osteoporosis with current pathological fracture, right lower leg, subsequent encounter for

fracture with delayed healing

M80.061K Age-related osteoporosis with current pathological fracture, right lower leg, subsequent encounter for

fracture with nonunion

M80.061P

Age-related osteoporosis with current pathological fracture, right lower leg, subsequent encounter for

fracture with malunion

M80.061S

Age-related osteoporosis with current pathological fracture, right lower leg, sequela

M80.062A

Age-related osteoporosis with current pathological fracture, left lower leg, initial encounter for fracture

M80.062D

Age-related osteoporosis with current pathological fracture, left lower leg, subsequent encounter for

fracture with routine healing

M80.062G Age-related osteoporosis with current pathological fracture, left lower leg, subsequent encounter for

fracture with delayed healing

M80.062K

Age-related osteoporosis with current pathological fracture, left lower leg, subsequent encounter for

fracture with nonunion

M80.062P Age-related osteoporosis with current pathological fracture, left lower leg, subsequent encounter for

fracture with malunion

M80.062S

Age-related osteoporosis with current pathological fracture, left lower leg, sequela

M80.069A Age-related osteoporosis with current pathological fracture, unspecified lower leg, initial encounter for

fracture

M80.069D

Age-related osteoporosis with current pathological fracture, unspecified lower leg, subsequent

encounter for fracture with routine healing

M80.069G Age-related osteoporosis with current pathological fracture, unspecified lower leg, subsequent

encounter for fracture with delayed healing

M80.069K

Age-related osteoporosis with current pathological fracture, unspecified lower leg, subsequent

encounter for fracture with nonunion

M80.069P Age-related osteoporosis with current pathological fracture, unspecified lower leg, subsequent

encounter for fracture with malunion

M80.069S

Age-related osteoporosis with current pathological fracture, unspecified lower leg, sequela

M80.071A Age-related osteoporosis with current pathological fracture, right ankle and foot, initial encounter for

fracture

M80.071D Age-related osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter

for fracture with routine healing

Denosumab (Prolia

& Xgeva

)

Page 10 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.071G Age-related osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter

for fracture with delayed healing

M80.071K Age-related osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter

for fracture with nonunion

M80.071P Age-related osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter

for fracture with malunion

M80.071S

Age-related osteoporosis with current pathological fracture, right ankle and foot, sequela

M80.072A Age-related osteoporosis with current pathological fracture, left ankle and foot, initial encounter for

fracture

M80.072D

Age-related osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter

for fracture with routine healing

M80.072G Age-related osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter

for fracture with delayed healing

M80.072K

Age-related osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter

for fracture with nonunion

M80.072P Age-related osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter

for fracture with malunion

M80.072S

Age-related osteoporosis with current pathological fracture, left ankle and foot, sequela

M80.079A Age-related osteoporosis with current pathological fracture, unspecified ankle and foot, initial encounter

for fracture

M80.079D

Age-related osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent

encounter for fracture with routine healing

M80.079G Age-related osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent

encounter for fracture with delayed healing

M80.079K

Age-related osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent

encounter for fracture with nonunion

M80.079P Age-related osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent

encounter for fracture with malunion

M80.079S

Age-related osteoporosis with current pathological fracture, unspecified ankle and foot, sequela

M80.08XA

Age-related osteoporosis with current pathological fracture, vertebra(e), initial encounter for fracture

M80.08XD Age-related osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for

fracture with routine healing

M80.08XG

Age-related osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for

fracture with delayed healing

M80.08XK Age-related osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for

fracture with nonunion

M80.08XP

Age-related osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for

fracture with malunion

M80.08XS

Age-related osteoporosis with current pathological fracture, vertebra(e), sequela

M80.811A

Other osteoporosis with current pathological fracture, right shoulder, initial encounter for fracture

M80.811D Other osteoporosis with current pathological fracture, right shoulder, subsequent encounter for fracture

with routine healing

M80.811G Other osteoporosis with current pathological fracture, right shoulder, subsequent encounter for fracture

with delayed healing

Denosumab (Prolia

& Xgeva

)

Page 11 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.811K Other osteoporosis with current pathological fracture, right shoulder, subsequent encounter for fracture

with nonunion

M80.811P Other osteoporosis with current pathological fracture, right shoulder, subsequent encounter for fracture

with malunion

M80.811S

Other osteoporosis with current pathological fracture, right shoulder, sequela

M80.8AXA

Other osteoporosis with current pathological fracture, other site, initial encounter for fracture

M80.8AXD Other osteoporosis with current pathological fracture, other site, subsequent encounter for fracture with

routine healing

M80.8AXG

Other osteoporosis with current pathological fracture, other site, subsequent encounter for fracture with

delayed healing

M80.8AXK Other osteoporosis with current pathological fracture, other site, subsequent encounter for fracture with

nonunion

M80.8AXP

Other osteoporosis with current pathological fracture, other site, subsequent encounter for fracture with

malunion

M80.8AXS

Other osteoporosis with current pathological fracture, other site, sequela

M80.812A

Other osteoporosis with current pathological fracture, left shoulder, initial encounter for fracture

M80.812D

Other osteoporosis with current pathological fracture, left shoulder, subsequent encounter for fracture

with routine healing

M80.812G Other osteoporosis with current pathological fracture, left shoulder, subsequent encounter for fracture

with delayed healing

M80.812K

Other osteoporosis with current pathological fracture, left shoulder, subsequent encounter for fracture

with nonunion

M80.812P Other osteoporosis with current pathological fracture, left shoulder, subsequent encounter for fracture

with malunion

M80.812S

Other osteoporosis with current pathological fracture, left shoulder, sequela

M80.819A

Other osteoporosis with current pathological fracture, unspecified shoulder, initial encounter for fracture

M80.819D Other osteoporosis with current pathological fracture, unspecified shoulder, subsequent encounter for

fracture with routine healing

M80.819G Other osteoporosis with current pathological fracture, unspecified shoulder, subsequent encounter for

fracture with delayed healing

M80.819K Other osteoporosis with current pathological fracture, unspecified shoulder, subsequent encounter for

fracture with nonunion

M80.819P Other osteoporosis with current pathological fracture, unspecified shoulder, subsequent encounter for

fracture with malunion

M80.819S

Other osteoporosis with current pathological fracture, unspecified shoulder, sequela

M80.821A

Other osteoporosis with current pathological fracture, right humerus, initial encounter for fracture

M80.821D Other osteoporosis with current pathological fracture, right humerus, subsequent encounter for fracture

with routine healing

M80.821G

Other osteoporosis with current pathological fracture, right humerus, subsequent encounter for fracture

with delayed healing

M80.821K Other osteoporosis with current pathological fracture, right humerus, subsequent encounter for fracture

with nonunion

M80.821P

Other osteoporosis with current pathological fracture, right humerus, subsequent encounter for fracture

with malunion

M80.821S

Other osteoporosis with current pathological fracture, right humerus, sequela

Denosumab (Prolia

& Xgeva

)

Page 12 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.822A

Other osteoporosis with current pathological fracture, left humerus, initial encounter for fracture

M80.822D

Other osteoporosis with current pathological fracture, left humerus, subsequent encounter for fracture

with routine healing

M80.822G Other osteoporosis with current pathological fracture, left humerus, subsequent encounter for fracture

with delayed healing

M80.822K

Other osteoporosis with current pathological fracture, left humerus, subsequent encounter for fracture

with nonunion

M80.822P Other osteoporosis with current pathological fracture, left humerus, subsequent encounter for fracture

with malunion

M80.822S

Other osteoporosis with current pathological fracture, left humerus, sequela

M80.829A

Other osteoporosis with current pathological fracture, unspecified humerus, initial encounter for fracture

M80.829D Other osteoporosis with current pathological fracture, unspecified humerus, subsequent encounter for

fracture with routine healing

M80.829G Other osteoporosis with current pathological fracture, unspecified humerus, subsequent encounter for

fracture with delayed healing

M80.829K Other osteoporosis with current pathological fracture, unspecified humerus, subsequent encounter for

fracture with nonunion

M80.829P Other osteoporosis with current pathological fracture, unspecified humerus, subsequent encounter for

fracture with malunion

M80.829S

Other osteoporosis with current pathological fracture, unspecified humerus, sequela

M80.831A

Other osteoporosis with current pathological fracture, right forearm, initial encounter for fracture

M80.831D Other osteoporosis with current pathological fracture, right forearm, subsequent encounter for fracture

with routine healing

M80.831G

Other osteoporosis with current pathological fracture, right forearm, subsequent encounter for fracture

with delayed healing

M80.831K Other osteoporosis with current pathological fracture, right forearm, subsequent encounter for fracture

with nonunion

M80.831P

Other osteoporosis with current pathological fracture, right forearm, subsequent encounter for fracture

with malunion

M80.831S

Other osteoporosis with current pathological fracture, right forearm, sequela

M80.832A

Other osteoporosis with current pathological fracture, left forearm, initial encounter for fracture

M80.832D

Other osteoporosis with current pathological fracture, left forearm, subsequent encounter for fracture

with routine healing

M80.832G Other osteoporosis with current pathological fracture, left forearm, subsequent encounter for fracture

with routine healing

M80.832K

Other osteoporosis with current pathological fracture, left forearm, subsequent encounter for fracture

with nonunion

M80.832P Other osteoporosis with current pathological fracture, left forearm, subsequent encounter for fracture

with malunion

M80.832S

Other osteoporosis with current pathological fracture, left forearm, sequela

M80.839A

Other osteoporosis with current pathological fracture, unspecified forearm, initial encounter for fracture

M80.839D Other osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter for

fracture with routine healing

M80.839G Other osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter for

fracture with delayed healing

Denosumab (Prolia

& Xgeva

)

Page 13 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.839K Other osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter for

fracture with nonunion

M80.839P Other osteoporosis with current pathological fracture, unspecified forearm, subsequent encounter for

fracture with malunion

M80.839S

Other osteoporosis with current pathological fracture, unspecified forearm, sequela

M80.841A

Other osteoporosis with current pathological fracture, right hand, initial encounter for fracture

M80.841D Other osteoporosis with current pathological fracture, right hand, subsequent encounter for fracture with

routine healing

M80.841G

Other osteoporosis with current pathological fracture, right hand, subsequent encounter for fracture with

delayed healing

M80.841K Other osteoporosis with current pathological fracture, right hand, subsequent encounter for fracture with

nonunion

M80.841P

Other osteoporosis with current pathological fracture, right hand, subsequent encounter for fracture with

malunion

M80.841S

Other osteoporosis with current pathological fracture, right hand, sequela

M80.842A

Other osteoporosis with current pathological fracture, left hand, initial encounter for fracture

M80.842D

Other osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture with

routine healing

M80.842G Other osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture with

delayed healing

M80.842K

Other osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture with

nonunion

M80.842P Other osteoporosis with current pathological fracture, left hand, subsequent encounter for fracture with

malunion

M80.842S

Other osteoporosis with current pathological fracture, left hand, sequela

M80.849A

Other osteoporosis with current pathological fracture, unspecified hand, initial encounter for fracture

M80.849D Other osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with routine healing

M80.849G Other osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with delayed healing

M80.849K Other osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with nonunion

M80.849P Other osteoporosis with current pathological fracture, unspecified hand, subsequent encounter for

fracture with malunion

M80.849S

Other osteoporosis with current pathological fracture, unspecified hand, sequela

M80.851A

Other osteoporosis with current pathological fracture, right femur, initial encounter for fracture

M80.851D Other osteoporosis with current pathological fracture, right femur, subsequent encounter for fracture

with routine healing

M80.851G

Other osteoporosis with current pathological fracture, right femur, subsequent encounter for fracture

with delayed healing

M80.851K Other osteoporosis with current pathological fracture, right femur, subsequent encounter for fracture

with nonunion

M80.851P

Other osteoporosis with current pathological fracture, right femur, subsequent encounter for fracture

with malunion

M80.851S

Other osteoporosis with current pathological fracture, right femur, sequela

Denosumab (Prolia

& Xgeva

)

Page 14 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.852A

Other osteoporosis with current pathological fracture, left femur, initial encounter for fracture

M80.852D

Other osteoporosis with current pathological fracture, left femur, subsequent encounter for fracture with

routine healing

M80.852G Other osteoporosis with current pathological fracture, left femur, subsequent encounter for fracture with

delayed healing

M80.852K

Other osteoporosis with current pathological fracture, left femur, subsequent encounter for fracture with

nonunion

M80.852P Other osteoporosis with current pathological fracture, left femur, subsequent encounter for fracture with

malunion

M80.852S

Other osteoporosis with current pathological fracture, left femur, sequela

M80.859A

Other osteoporosis with current pathological fracture, unspecified femur, initial encounter for fracture

M80.859D Other osteoporosis with current pathological fracture, unspecified femur, subsequent encounter for

fracture with routine healing

M80.859G Other osteoporosis with current pathological fracture, unspecified femur, subsequent encounter for

fracture with delayed healing

M80.859K Other osteoporosis with current pathological fracture, unspecified femur, subsequent encounter for

fracture with nonunion

M80.859P Other osteoporosis with current pathological fracture, unspecified femur, subsequent encounter for

fracture with malunion

M80.859S

Other osteoporosis with current pathological fracture, unspecified femur, sequela

M80.861A

Other osteoporosis with current pathological fracture, right lower leg, initial encounter for fracture

M80.861D Other osteoporosis with current pathological fracture, right lower leg, subsequent encounter for fracture

with routine healing

M80.861G

Other osteoporosis with current pathological fracture, right lower leg, subsequent encounter for fracture

with delayed healing

M80.861K Other osteoporosis with current pathological fracture, right lower leg, subsequent encounter for fracture

with nonunion

M80.861P

Other osteoporosis with current pathological fracture, right lower leg, subsequent encounter for fracture

with malunion

M80.861S

Other osteoporosis with current pathological fracture, right lower leg, sequela

M80.862A

Other osteoporosis with current pathological fracture, left lower leg, initial encounter for fracture

M80.862D

Other osteoporosis with current pathological fracture, left lower leg, subsequent encounter for fracture

with routine healing

M80.862G Other osteoporosis with current pathological fracture, left lower leg, subsequent encounter for fracture

with delayed healing

M80.862K

Other osteoporosis with current pathological fracture, left lower leg, subsequent encounter for fracture

with nonunion

M80.862P Other osteoporosis with current pathological fracture, left lower leg, subsequent encounter for fracture

with malunion

M80.862S

Other osteoporosis with current pathological fracture, left lower leg, sequela

M80.869A

Other osteoporosis with current pathological fracture, unspecified lower leg, initial encounter for fracture

M80.869D Other osteoporosis with current pathological fracture, unspecified lower leg, subsequent encounter for

fracture with routine healing

M80.869G Other osteoporosis with current pathological fracture, unspecified lower leg, subsequent encounter for

fracture with delayed healing

Denosumab (Prolia

& Xgeva

)

Page 15 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.869K Other osteoporosis with current pathological fracture, unspecified lower leg, subsequent encounter for

fracture with nonunion

M80.869P Other osteoporosis with current pathological fracture, unspecified lower leg, subsequent encounter for

fracture with malunion

M80.869S

Other osteoporosis with current pathological fracture, unspecified lower leg, sequela

M80.871A

Other osteoporosis with current pathological fracture, right ankle and foot, initial encounter for fracture

M80.871D Other osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter for

fracture with routine healing

M80.871G

Other osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter for

fracture with delayed healing

M80.871K Other osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter for

fracture with nonunion

M80.871P

Other osteoporosis with current pathological fracture, right ankle and foot, subsequent encounter for

fracture with malunion

M80.871S

Other osteoporosis with current pathological fracture, right ankle and foot, sequela

M80.872A

Other osteoporosis with current pathological fracture, left ankle and foot, initial encounter for fracture

M80.872D

Other osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter for

fracture with routine healing

M80.872G Other osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter for

fracture with delayed healing

M80.872K

Other osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter for

fracture with nonunion

M80.872P Other osteoporosis with current pathological fracture, left ankle and foot, subsequent encounter for

fracture with malunion

M80.872S

Other osteoporosis with current pathological fracture, left ankle and foot, sequela

M80.879A Other osteoporosis with current pathological fracture, unspecified ankle and foot, initial encounter for

fracture

M80.879D

Other osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent encounter

for fracture with routine healing

M80.879G Other osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent encounter

for fracture with delayed healing

M80.879K

Other osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent encounter

for fracture with nonunion

M80.879P Other osteoporosis with current pathological fracture, unspecified ankle and foot, subsequent encounter

for fracture with malunion

M80.879S

Other osteoporosis with current pathological fracture, unspecified ankle and foot, sequela

M80.88XA

Other osteoporosis with current pathological fracture, vertebra(e), initial encounter for fracture

M80.88XD Other osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for fracture

with routine healing

M80.88XG

Other osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for fracture

with delayed healing

M80.88XK Other osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for fracture

with nonunion

M80.88XP

Other osteoporosis with current pathological fracture, vertebra(e), subsequent encounter for fracture

with malunion

Denosumab (Prolia

& Xgeva

)

Page 16 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code

Description

Prolia

M80.88XS

Other osteoporosis with current pathological fracture, vertebra(e), sequela

M81.0

Age-related osteoporosis without current pathological fracture

M81.8

Other osteoporosis without current pathological fracture

Z78.310

Personal history of (healed) osteoporosis fracture

Z79.52

Long-term (current) use of systemic steroids

Z79.811

Long-term (current) use of aromatase inhibitors

Z79.818

Long-term (current use of other agents affecting estrogen receptors and estrogen levels

Xgeva

C61

Malignant neoplasm of prostate

C79.00

Secondary malignant neoplasm of unspecified kidney and renal pelvis

C79.01

Secondary malignant neoplasm of right kidney and renal pelvis

C79.02

Secondary malignant neoplasm of left kidney and renal pelvis

C79.10

Secondary malignant neoplasm of unspecified urinary organs

C79.11

Secondary malignant neoplasm of bladder

C79.19

Secondary malignant neoplasm of other urinary organs

C79.2

Secondary malignant neoplasm of skin

C79.31

Secondary malignant neoplasm of brain

C79.32

Secondary malignant neoplasm of cerebral meninges

C79.40

Secondary malignant neoplasm of unspecified part of nervous system

C79.49

Secondary malignant neoplasm of other parts of nervous system

C79.51

Secondary malignant neoplasm of bone

C79.52

Secondary malignant neoplasm of bone marrow

C79.60

Secondary malignant neoplasm of unspecified ovary

C79.61

Secondary malignant neoplasm of right ovary

C79.62

Secondary malignant neoplasm of left ovary

C79.63

Secondary malignant neoplasm of bilateral ovaries

C79.70

Secondary malignant neoplasm of unspecified adrenal gland

C79.71

Secondary malignant neoplasm of right adrenal gland

C79.72

Secondary malignant neoplasm of left adrenal gland

C79.81

Secondary malignant neoplasm of breast

C79.82

Secondary malignant neoplasm of genital organs

C79.89

Secondary malignant neoplasm of other specified sites

C79.9

Secondary malignant neoplasm of unspecified site

C90.00

Multiple myeloma not having achieved remission

C90.02

Multiple myeloma in relapse

D47.02

Systemic mastocytosis

D48.0

Neoplasm of uncertain behavior of bone and articular cartilage

E83.52

Hypercalcemia

Denosumab (Prolia

& Xgeva

)

Page 17 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Background

Osteoporosis is characterized by low bone mass, microarchitectural disruption, and increased skeletal fragility. The Word

Health Organization (WHO) established diagnostic thresholds for bone mineral density (BMD) by dual-energy x-ray

absorptiometry (DXA) according to the standard deviation (SD) difference between a patient’s BMD and that of a young adult

reference population (T-score). A T-score of -2.5 SD or below is defined as osteoporosis, provided that other causes of low BMD

have been ruled out, and a T-score between -1 and -2.5 SD is defined as osteopenia. Additionally, guidelines state that

osteoporosis can be diagnosed by one of the following

: (1) Presence of fragility fractures in the absence of other metabolic

bone disorders; (2) T-score ≤ −2.5 SD in the lumbar spine (antero-posterior), femoral neck, total hip, or one-third radius; or (3) T-

score between −1.0 and −2.5 and increased fracture risk using the FRAX

(fracture risk assessment tool) country-specific

thresholds. The FRAX tool is designed to assist clinicians in predicting the ten-year probability of hip fracture and 10-year

probability of a major osteoporotic fracture (spine, forearm, hip or shoulder fracture) with or without the addition of femoral

neck BMD.

In the United States, a clinical diagnosis of osteoporosis may be made when the FRAX 10-year probability of major

osteoporotic fracture (hip, clinical spine, proximal humerus, or forearm) is greater than or equal to 20 percent or the FRAX 10-

year probability of hip fracture is greater than or equal to 3 percent.

Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of

osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. Denosumab prevents

RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells.

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. Increased osteoclast activity,

stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases. Similarly, giant cell tumors of

bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptor, and signaling

through the RANK receptor contributes to osteolysis and tumor growth.

13,14

Benefit Considerations

Some Certificates of Coverage allow for coverage of experimental/investigational/unproven treatments for life-threatening

illnesses when certain conditions are met. The member specific benefit plan document must be consulted to make coverage

decisions for this service. Some states mandate benefit coverage for off-label use of medications for some diagnoses or under

some circumstances when certain conditions are met. Where such mandates apply, they supersede language in the benefit

document or in the medical or drug policy. Benefit coverage for an otherwise unproven service for the treatment of serious rare

diseases may occur when certain conditions are met. Refer to the Policy and Procedure addressing the treatment of serious

rare diseases.

Clinical Evidence

Prolia

Postmenopausal Patients with Osteoporosis

In a post-hoc analysis of the 7-year FREEDOM Extension trial, Kendler et al, analyzed whether women who experienced fracture

while on denosumab was due to inadequate treatment response, or whether the risk of fracture remains low while continuing

denosumab treatment. During the extension trial, all study participants were to receive denosumab. The authors of this analysis

compared subsequent osteoporotic fracture rates between denosumab treated subjects during the initial FREEDOM or the

extension and placebo-treated subjects in FREEDOM. During FREEDOM, 438 placebo- and 272 denosumab-treated subjects

had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs

placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined

denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. One or more subsequent fractures occurred in

144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7

per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject years). Adjusting for prior fracture, the risk of

having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio

[95% CI]: 0.59 [0.43–0.81]; p = 0.0012). The authors concluded that the post-hoc analysis demonstrates that denosumab

decreases the risk of subsequent fracture and a fracture sustained while on denosumab, and not necessarily due to inadequate

treatment response.

Denosumab (Prolia

& Xgeva

)

Page 18 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Brown JP et al compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone

mass in a phase 3, multicenter, double-blind study.

Participants included postmenopausal women with a T-score < or = -2.0 at

the lumbar spine or total hip and received subcutaneous denosumab injections (60 mg every 6 months [Q6M]) plus oral

placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Efficacy was

measured by assessing changes in BMD at the total hip, femoral neck, trochanter, lumbar spine, and one-third radius at 6 and

12 months. Additionally, bone turnover markers at months 1, 3, 6, 9, and 12 were assessed. Adverse events were monitored to

evaluate safety. Denosumab significantly increased BMD at month 12 (3.5% versus 2.6%; p < 0.0001 for the total hip).

Significantly greater increases in BMD were observed with denosumab at all measured skeletal sites over the twelve month

treatment period. Denosumab showed significantly greater reduction of bone turnover markers compared to alendronate.

Adverse events and laboratory values were similar for the two treatment groups. The authors conclude that denosumab showed

a significantly larger gain in BMD and greater reduction in bone turnover markers compared with alendronate. Overall, the

safety profile was similar for both treatment groups.

Men with Low Bone Mineral Density

Langdahl BL et al evaluated denosumab therapy in men with low bone mineral density (BMD) in a multicenter, phase 3 study.

The study consisted of 2 treatment periods including a 12-month double-blind, placebo-controlled phase and a 12-month open-

label phase. Participants from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of

denosumab subcutaneous every 6 months. During the open-label phase, the following BMD increases occurred with long-term

denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting

in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all p < .01). The crossover group

showed BMD gains similar to the long-term treatment group during the first 12 months of treatment. Similar adverse event rates

were seen in both groups. The authors conclude that in the study population, denosumab treatment for a second year

continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. These results were similar to

previous results in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation

therapy.

Orwoll E. et al evaluated the safety and efficacy of denosumab compared with placebo in men with low BMD after 1 year of

treatment in a placebo-controlled, phase 3 study.

The primary endpoint was the percent change of BMS from baseline in

lumbar spine (LS) at one year. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip,

2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted p ≤ 0.0144 for BMD percent

differences at all sites compared with placebo). The incidence of adverse events was similar between groups. The authors

conclude that 12 months of treatment with denosumab in men with low BMD was well tolerated and resulted in a reduction in

bone resorption and significant increases in BMD at all skeletal sites assessed.

Patients at High Risk for Fracture Receiving Androgen Deprivation Therapy for Non-Metastatic Prostate

Cancer

Smith ME et al investigated the effects of denosumab in a double-blind, multicenter study, on bone mineral density and

fractures in patients with non-metastatic prostate cancer who are receiving androgen-deprivation therapy.

Patients were

randomly assigned to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (n = 734 per group).

The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Secondary end points

included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36

months, as well as frequency of new vertebral fractures. At 24 months, patients receiving denosumab experienced an increase

in bone mineral density of the lumbar spine by 5.6% as compared with a loss of 1.0% in the placebo group (p < 0.001).

Significant differences between the placebo and denosumab groups were seen at 1 month and continued through 36 months.

Treatment was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third

of the radius. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs.

3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; p = 0.006). Similar rates of adverse events were

reported in the two groups. The authors conclude that denosumab is associated with increased bone mineral density at all sites

and a reduction in the incidence of new vertebral fractures among patients receiving androgen-deprivation therapy for non-

metastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674)

Glucocorticoid-Induced Osteoporosis in Patients at High Risk for Fracture

Saag et al assessed the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis in

a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study.

The study enrolled patients aged 18 years or

Denosumab (Prolia

& Xgeva

)

Page 19 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

older who were receiving ≥ 7.5 mg prednisone daily or equivalent, for at least 3 months (glucocorticoid continuing) or less than

3 months (glucocorticoid initiating). Patients under 50 years of age were required to have a history of osteoporosis-related

fracture. Patients 50 years and older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2.0 or

less, or -1.0 or less if they had a history of osteoporosis-related fracture. Study patients received either 60 mg subcutaneous

denosumab every 6 months and oral placebo daily for, or 5 mg oral risedronate daily and subcutaneous placebo every 6

months for 24 months. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change

from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins. In addition, superiority was

also assessed. The safety analysis included all study patients who received one dose or more of their assigned investigational

product. This study is registered with ClinicalTrials.gov (NCT01575873). Denosumab was both non-inferior and superior to

risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4.4% [95% CI

3.8-5.0] vs. 2.3% [1.7-2.9]; p < 0.0001) and glucocorticoid-initiating (3.8% [3.1-4.5]vs 0.8% [0.2-1.5]; p < 0.0001) subpopulations.

Incidence of adverse events and fractures was similar between treatment groups. The most common adverse events in both

groups included back pain and arthralgia. Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%)

patients in the denosumab group. The authors conclude that denosumab could be a useful treatment option for patients taking

glucocorticoids who are at risk for fractures.

Xgeva

In an ad hoc analysis of the phase 3 clinical trial of 1,776 patients with metastases from solid tumors or multiple myeloma,

where it was shown that denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs, Henry et al reports

outcomes in the subgroup of 1,597 patients with solid tumors, excluding multiple myeloma.

In the ad hoc analysis,

denosumab significantly delayed time to first on-study SRE compared to ZA (HR, 0.81; 95% CI, 0.68–0.96) and time to first-and-

subsequent SREs (RR, 0.85; 95% CI, 0.72–1.00). Denosumab also significantly delayed time to development of moderate or

severe pain (HR, 0.81; 95% CI, 0.66–1.00), pain worsening (HR, 0.83; 95% CI, 0.71–0.97), and worsening pain interference in

patients with no/mild baseline pain (HR, 0.77; 95% CI, 0.61–0.96). Overall survival was similar in both groups. The median KM

estimate was 10.7 months for denosumab-treated patients and 10.0 months for ZA-treated patients (HR, 0.92; 95% CI, 0.81–

1.05: p = 0.215). Similarly, there was no difference between groups in time to disease progression. The median KM estimate

was 5.3 (4.9, 5.7) months for denosumab-treated and 5.4 (4.8, 5.7) months for ZA-treated patients (HR, 0.96; 95% CI, 0.85–1.08:

p = 0.497). The authors concluded that denosumab was more effective in delaying the incidence of SREs, however did not

significantly affect the overall incidence or disease progression or overall survival.

In a double-blind, double-dummy, phase III clinical trial, Henry et al compared denosumab with zoledronic acid (ZA) for delaying

or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and

prostate) or myeloma.

Patients were randomly assigned to receive either monthly subcutaneous denosumab 120mg (n = 886)

or intravenous ZA 4mg (dose adjustment for renal impairment; n = 890). The primary end point was time to first on-study SRE

(pathologic fracture, radiation or surgery to bone, or spinal cord compression). The trial demonstrated that denosumab was

noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; p = 0.0007). Denosumab was

not statistically superior to ZA in delaying time to first on-study SRE (p = 0.03 unadjusted; p = 0.06 adjusted for multiplicity) or

time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; p = 0.14). Overall survival and disease

progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw

occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as

did renal adverse events and elevations in serum creatinine. The authors concluded that denosumab was noninferior to ZA in

preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma.

Fizazi et al evaluated the comparison of denosumab with zoledronic acid (ZA) for the prevention of skeletal-related events in

men with bone metastases from castration-resistant prostate cancer.

In a phase 3 clinical study, 1904 men with castration-

resistant prostate cancer had no previous exposure to IV bisphosphonate were randomized 1:1 to either receive 120mg

subcutaneous denosumab plus IV placebo (n = 950), or 4mg IV ZA plus subcutaneous placebo (n = 951) every 4 weeks. The

primary endpoint was time to first on-study skeletal related event (pathological fracture, radiation therapy, surgery to bone, or

spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a

secondary endpoint. Efficacy analysis was by intention to treat. Median time to first on-study skeletal-related event was 20.7

months (95% CI 18.8–24.9) with denosumab compared with 17.1 months (15.0–19.4) with zoledronic acid (hazard ratio 0.82,

95% CI 0.71–0.95; p = 0.0002 for non-inferiority; p = 0.008 for superiority). While there was a three-month increase in the time to

first skeletal-related events observed with denosumab in men with prostate cancer, there was no clinically meaningful difference

in skeletal-related events for denosumab as compared with zoledronic acid: Overall confirmed events (ZA vs. denosumab) 41%

vs. 36%; radiation to bone (21% vs. 19%); pathological fracture (15% vs. 14%); spinal cord compression (4% vs. 3%); surgery to

Denosumab (Prolia

& Xgeva

)

Page 20 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

bone (< 1% vs. < 1%). The authors concluded that denosumab was better than ZA for delaying the time to first SRE, however,

was not significantly better at preventing the overall incidence of SREs versus zoledronic acid.

Professional Societies

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Several National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines

) include

denosumab as a treatment for several conditions related to malignant disease. The following NCCN Guidelines

state:

For non-small cell lung cancer, the NCCN recommends (Category 2A) denosumab to be considered in patients with bone

metastases.

For ductal carcinoma, invasive breast cancer or inflammatory breast cancer, the NCCN recommends (Category 2A)

denosumab to be considered in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibition

therapy along with calcium and vitamin D supplementation to maintain or improve bone mineral density and reduce risk of

fractures.

For invasive or inflammatory breast cancer, the NCCN recommends (Category 1) denosumab to be used with calcium and

vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in patients with expected

survival ≥ 3 months with adequate renal function.

For kidney cancer, the NCCN recommends (Category 2A) denosumab to be used as a component of best supportive care

for bony metastases.

For systemic mastocytosis, the NCCN recommends (Category 2A) denosumab as second-line therapy for

osteopenia/osteoporosis in patients with bone pain not responding to bisphosphonates or for patients who are not

candidates for bisphosphonates because of renal insufficiency.

For thyroid carcinoma (anaplastic, follicular, medullary, oncocytic, papillary), the NCCN recommends (Category 2A)

denosumab to be considered for bone metastases or palliative care for bone metastases (anaplastic).

For giant cell tumor of the bone, the NCCN recommends (Category 2A) denosumab as a single agent or combined with

serial embolization (preferred), and/or radiation therapy for resectable disease with unacceptable morbidity and/or

unresectable axial lesions for patients with localized disease, metastases at presentation, or recurrence, denosumab is also

recommended as a single agent for unresectable metastatic disease, unresectable metastatic recurrence or considered

prior to surgery for resectable local recurrence.

For prostate cancer, the NCCN recommends (Category 2A) denosumab for prevention or treatment of osteoporosis during

androgen deprivation therapy (ADT) for patients with high fracture risk, denosumab is also recommended (Category 1) as

the preferred agent for the prevention of skeletal-related events in patients with castration-resistant prostate cancer who

have documented bone metastases and creatinine clearance greater than 30 ml/min.

For multiple myeloma, the NCCN recommends (Category 2A) denosumab to be used in combination with primary myeloma

therapy and is the preferred agent in patients with renal insufficiency.

U.S. Food and Drug Administration (FDA)

This section is to be used for informational purposes only. FDA approval alone is not a basis for coverage.

Prolia (denosumab) is a RANK ligand inhibitor indicated for the following uses

• Treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic

fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis

therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, nonvertebral, and hip

fractures.

• Treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic

fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis

therapy.

• Treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or

continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to

remain on glucocorticoids for at least 6 months, high risk of fracture is defined as a history of osteoporotic fracture, multiple

risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

• Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic

prostate cancer, in these patients Prolia also reduced the incidence of vertebral fractures.

Denosumab (Prolia

& Xgeva

)

Page 21 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

• Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for

breast cancer.

Xgeva (denosumab) is a RANK ligand inhibitor indicated for the following uses

• Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid

tumors.

• Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical

resection is likely to result in severe morbidity.

• Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Centers for Medicare and Medicaid Services (CMS)

Medicare does not have a National Coverage Determination (NCD) for denosumab (Prolia

& Xgeva

). Local Coverage

Determinations/Articles (LCDs)/LCAs) exist. Refer to the LCDs/LCAs for Bisphosphonates (Intravenous [IV]) and Monoclonal

Antibodies in the Treatment of Osteoporosis and Their Other Indications and Drugs and Biologicals, Coverage of, for Label and

Off-Label Uses.

In general, Medicare covers outpatient (Part B) drugs that are furnished "incident to" a physician's service provided that the

drugs are not usually self-administered by the patients who take them. Refer to the Medicare Benefit Policy Manual, Chapter 15,

§50 - Drugs and Biologicals.

(Accessed October 9, 2023)

References

1. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the

Diagnosis and Treatment of Postmenopausal Osteoporosis – 2020 Update. Endocr Pract. 2020;26(1):1-46.

2. North American Menopause Society (NAMS). Management of osteoporosis in postmenopausal women: 2021 position

statement of The North American Menopause Society. Menopause 2021;28(9):973-997.

3. Cosman F, de Beur SJ, LeBoff MS, et al. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment

of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2014. Osteoporos Int. 2014 Oct;25(10):2359-81.

Epub 2014 Aug. 15.

4. Hodsman AB, Bauer DC, Dempster DW, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a

review of the evidence and suggested guidelines for its use. Endocr Rev. 2005(5):688-703.

5. Hodsman A, Papaioannou A, Cranney A. Clinical practice guidelines for the use of parathyroid hormone in the treatment of

osteoporosis. CMAJ. 2006;175(1):48.

6. Florence R, Allen S, Benedict L, Compo R, Jensen A, Kalogeropoulou D, Kearns A, Larson S, Mallen E, O'Day K, Peltier A,

Webb B. Diagnosis and treatment of osteoporosis. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI);

2013 Jul. 87 p.

7. WHO FRAX tool: https://frax.shef.ac.uk/FRAX/. Accessed December 30, 2022.

8. Smith MR, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009 Aug

20;361(8):745-55. doi: 10.1056/NEJMoa0809003. Epub 2009 Aug 11.

9. Langdahl BL, et al. A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low

bone mineral density: results from the ADAMO trial. J Clin Endocrinol Metab. 2015 Apr;100(4):1335-42.Epub 2015 Jan 21.

10. Orwoll E. et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone

mineral density. J Clin Endocrinol Metab. 2012 Sep;97(9):3161-9. doi: 10.1210/jc.2012-1569. Epub 2012 Jun 21.

11. Brown JP et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone

turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009

Jan;24(1):153-61.

12. Reid IR et al. Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res.

2010 Oct;25(10):2256-65.

Denosumab (Prolia

& Xgeva

)

Page 22 of 22

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

13. Prolia [prescribing information]. Thousand Oaks, CA: Amgen Inc.; May 2022.

14. Xgeva [prescribing information]. Thousand Oaks, CA: Amgen Inc.; June 2020.

15. The NCCN Drugs and Biologics Compendium

(NCCN Compendium

). Available at www.nccn.org. Accessed October 3,

2023.

16. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the

treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple

myeloma. J Clin Oncol. 2011 Mar 20;29(9):1125-32.

17. Henry D, Vadhan-Raj S, Hirsh V, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus

zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer.

2014 Mar;22(3):679-87.

18. Saag KG, Wagman RB, Geusens P, Adachi JD, Messina OD, Emkey R, Chapurlat R, Wang A, Pannacciulli N, Lems WF.

Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-

controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol. 2018;6(6):445.

19. Buckley L et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-

Induced Osteoporosis. Arthritis & Rheumatology. Vol. 69, No. 8, August 2017; 69(8):1521–1537.

20. Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with

castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377:813.

21. Kendler DL, Chines A, Brandi ML, et al. The risk of subsequent osteoporotic fractures is decreased in subjects

experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int.

2019 Jan;30(1):71-78.

Policy History/Revision Information

Date

Summary of Changes

04/01/2024

Applicable Codes

Prolia

Added ICD-10 diagnosis codes C61, C79.81, Z79.52, Z79.811, and Z79.818

Supporting Information

Archived previous policy version 2024D0068M

Instructions for Use

This Medical Benefit Drug Policy provides assistance in interpreting UnitedHealthcare standard benefit plans. When deciding

coverage, the member specific benefit plan document must be referenced as the terms of the member specific benefit plan

may differ from the standard plan. In the event of a conflict, the member specific benefit plan document governs. Before using

this policy, please check the member specific benefit plan document and any applicable federal or state mandates.

UnitedHealthcare reserves the right to modify its Policies and Guidelines as necessary. This Medical Benefit Drug Policy is

provided for informational purposes. It does not constitute medical advice.

This Medical Benefit Drug Policy may also be applied to Medicare Advantage plans in certain instances. In the absence of a

Medicare National Coverage Determination (NCD), Local Coverage Determination (LCD), or other Medicare coverage guidance,

CMS allows a Medicare Advantage Organization (MAO) to create its own coverage determinations, using objective evidence-

based rationale relying on authoritative evidence (Medicare IOM Pub. No. 100-16, Ch. 4, §90.5).

UnitedHealthcare may also use tools developed by third parties, such as the InterQual

criteria, to assist us in administering

health benefits. UnitedHealthcare Medical Benefit Drug Policies are intended to be used in connection with the independent

professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical

advice.