Bisphosphonates (Intravenous [IV]) and Monoclonal Antibodies in the Treatment of Osteoporosis and Their Other Indications

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for Bisphosphonates (Intravenous [IV]) and Monoclonal Antibodies in the Treatment of Osteoporosis and Their Other Indications. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for Bisphosphonates (Intravenous [IV]) and Monoclonal Antibodies in the Treatment of Osteoporosis and Their Other Indications and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site. 

Internet Only Manual (IOM) Citations:  

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
  • Chapter 15, Section 50 Drugs and Biologicals, Sections 50.1 Definition of Drug or Biological, 50.2 Determining Self-Administration of Drug or Biological, 50.3 Incident To Requirements, 50.4 Reasonableness and Necessity, 50.4.1 Approved Use of Drug, 50.4.2 Unlabeled Use of Drug, and 50.4.3 Examples of Not Reasonable and Necessary
• CMS IOM Publication 100-04, Medicare Claims Processing Manual,
  • Chapter 17, Section 10 Payment Rules for Drugs and Biologicals
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
  • Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:  

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury. 
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations. 

This LCD addresses “incident to” drugs that are not self-administered for certain patients with osteoporosis. The other indications for these drugs are also addressed.

History/Background and/or General Information

Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist. The diagnosis can be confirmed by a finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. While osteoporosis occurs in both men and women, it is most common among women following menopause. In healthy people, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of fracture. The World Health Organization (WHO) defines osteoporosis in a postmenopausal woman or a man over the age of 50 as a bone mineral density (BMD) T-score less than or equal to -2.5 at the total hip, femoral neck, or lumbar spine (at least two vertebral levels measured in the posterior-anterior projection, not the lateral projection) as noted below.

• Normal: T-score above (i.e., better than) or equal to -1.0
• Osteopenia: T-score between -1.0 and -2.5
• Osteoporosis: T-score below (i.e., worse than) or equal to -2.5

In addition to diagnosis through densitometry, osteoporosis can be diagnosed clinically, regardless of the T-score. The presence of a fragility fracture constitutes a clinical diagnosis of osteoporosis. It is important to distinguish between risk factors for osteoporosis as defined by BMD and risk factors for osteoporotic fracture. The use of BMD T-scores to assess fracture risk can be markedly improved by combining BMD with information about other risk factors, particularly the woman’s age and fracture history. The major risk factors in postmenopausal women are advanced age, genetics, lifestyle factors (e.g., low calcium and vitamin D intake, smoking, and heavy alcohol consumption), thinness, and menopausal status. Because nearly 50% of postmenopausal women in the community over the age of 50 years who suffer an osteoporotic fracture do not have osteoporosis as defined by a BMD test, the WHO developed the fracture risk assessment tool (FRAX) to identify clinical risk factors of patients at high risk for osteoporotic fractures:

• Age
• Sex
• Prior fragility fracture after age 50
• History of corticosteroid use (5 mg per day or more for three months or longer)
• Parental history of hip fracture
• Rheumatoid arthritis
• Secondary osteoporosis (e.g., type 1 diabetes, osteogenesis imperfecta in adults, longstanding hyperthyroidism, hypogonadism, premature menopause [before age 40], chronic malabsorption and chronic liver disease)
• Current smoker
• Alcohol use of greater than 2 medium glasses of wine or beer per day
• Body Mass Index (BMI) (less than 21 kg/m2)

Other secondary causes of osteoporosis include the following:

• Oral glucocorticosteroid therapy for longer than 3 months
• Hypogonadism
• Transplant history
• Obesity surgery
• Malabsorption disease
• Aromatase therapy for breast cancer
• Excess urinary calcium excretion
• Vitamin D deficiency
• Hypocalcemia
• Multiple myeloma
• Endocrine disorders such as hyperthyroidism, Cushing’s syndrome, and disorders of collagen structures
• Renal failure (increase bone resorption, or decreased bone formation leading to renal osteodystrophy)
• Paget’s disease
• Liver/biliary disease
• Metastatic cancer involving bone

Medical management focused on lifestyle may be all that is needed for postmenopausal women who are at low risk for osteoporotic fracture. The North American Menopause Society (NAMS) recommends adding osteoporosis drug therapy in the following populations:

• All postmenopausal women who have had an osteoporotic vertebral or hip fracture
• All postmenopausal women who have had BMD values consistent with osteoporosis (i.e., T-scores equal to or worse than -2.5) at the lumbar spine, femoral neck, or total hip region

Covered Indications

In order to be covered by Medicare, a drug or biological must be safe and effective and otherwise reasonable and medically necessary. Drugs and biologicals approved for marketing by the Food and Drug Administration (FDA) are considered safe and effective when used for indications specified in the FDA labeling. The FDA labeling lists the safe and effective indications, dosage, and frequency of the agents. Please refer to CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50 Drugs and Biologicals.

In addition to FDA approved indications, Medicare may consider coverage of off-label uses based on guidance provided in the CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.4.2 for Unlabeled Use of Drug.

Bisphosphonates

The following bisphosphonate injections (administered intravenously [IV]) will be considered medically reasonable and necessary when administered as outlined in this LCD. The coverage of IV bisphosphonates must be supported in the medical record.

• Criteria for the diagnosis of osteoporosis, and
• History of treatment as related to progression of disease and ongoing risk factors, and
• Description of treatment failure, or contraindication, or adverse side effects, of oral or self administered drugs for osteoporosis as applicable to the patient that supports IV therapy in lieu of standard oral treatment protocol.

The following IV bisphosphonate injections are considered medically reasonable and necessary when administered as outlined in this LCD:

• Ibandronate sodium injection (Boniva®)
• Pamidronate (Aredia®)
• Zoledronic acid injection (Reclast®)
• Zoledronic acid injection (Zometa®)

Boniva® is a bisphosphonate that inhibits osteoclast activity and reduces bone resorption and turnover, leading to, on average, a net gain in bone mass.

Boniva® is available in oral and IV forms. The IV form will be considered reasonable and necessary only for patients for whom oral therapy cannot be tolerated.

Given the oral equivalent and the availability of Boniva® tablets, and the Medicare manual language on the reasonable and necessary criteria for route of admission, the IV administration is allowed under the following circumstances:

• Patient has a diagnosis of esophageal stricture, achalasia, or other severe esophageal dysmotility disorder; OR
• Patient has a history of severe malabsorption making use of oral bisphosphonates ineffective; OR
• Patient has an inability to stand or sit upright for 60 minutes; OR
• Patient has documented adverse effects following the initiation of treatment of the oral form of the medication that required the withdrawal of the oral form of the medication.

See the FDA drug label for the FDA approved indications and dosages for Boniva®. https://labels.fda.gov

The following Off-label Indications for Boniva® Injection will be considered medically reasonable and necessary:

• Corticosteroid-induced osteoporosis
• Paget’s disease
• Bone metastases in patients with prostate cancer

Aredia® is a bisphosphonate which is administered intravenously, is used to inhibit bone resorption and to decrease serum calcium.

See the FDA drug label for the FDA approved indications and dosages for Aredia®. https://labels.fda.gov

The following Off-label Indications for Aredia® will be considered medically reasonable and necessary:

• Treatment of postmenopausal osteoporosis 
• Treatment of the prevention of glucocorticoid-induced osteoporosis

Zoledronic acid (Reclast® and Zometa®) is a bisphosphonic acid, which is an inhibitor of osteoclastic bone resorption. Zoledronic acid binds to the bone matrix, which decreases osteoclastic activity, prevents bone resorption and skeletal calcium release induced by various stimulatory factors released by tumors.

See the FDA drug label for the FDA approved indications and dosages for Reclast® and Zometa®. https://labels.fda.gov

Reclast® for Glucocorticoid-Induced Osteoporosis in Men and Women is allowed under the following circumstances:

• the patient is either initiating or continuing to take system glucocorticoids in a daily dosage of 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months
• the patient is taking at least 1,200 mg calcium and 800-1,000 IU vitamin D per day

Reclast® for Women or Men with Osteoporosis is allowed under the following circumstances:

• the patient is taking at least 1,200 mg calcium and 800-1,000 IU vitamin D per day

Reclast® for Paget’s Disease is allowed under the following circumstances:

• the patient has been instructed to take 1,500 mg elemental calcium daily in divided doses (750 mg two times per day, or 500 mg three times per day) and 800 IU vitamin D per day, particularly in the 2 weeks following the administration of Reclast®
• the patient has one of the following:
  • An elevated serum alkaline phosphatase of two times or higher than the upper limit of the age-specific normal reference range, or
  • The patient is symptomatic, or
  • The patient is at risk for complications from the disease, to induce remission (normalization of serum alkaline phosphatase) prior to treatment with Reclast®

Reclast® for Re-Treatment of Paget’s Disease is allowed under the following circumstances:

• the patient is experiencing a relapse based on serum alkaline phosphatase, or
• the patient has failed to achieve normalization of their serum alkaline phosphatase, or
• the patient has symptoms as dictated by current standard medical practice.

Zometa® is allowed under the following circumstances:

• the patient is not on any other bisphosphonate medication(s)
• the renal status of the patient has been monitored
• Retreatment with Zometa® 4 mg may be considered if serum calcium does not return to normal or remain normal after treatment.

Zometa® for Hypercalcemia of Malignancy is allowed under the following circumstance:

• the patient has an albumin-corrected serum calcium of ≥ 12 mg/dL (3.0 mmol/L)

Zometa® for Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors is allowed under the following circumstances:

• the patient was coadministered oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of vitamin D per day

The following Off-label Indication for Zometa® Injection will be considered medically reasonable and necessary:

• Drug-induced osteopenia, secondary to androgen-deprivation therapy in prostate cancer patients (prophylaxis).

Monoclonal Antibodies - RANK ligand (RANKL) Inhibitors:

The following monoclonal antibodies injections (administered subcutaneously [SQ]) will be considered medically reasonable and necessary when administered as outlined in this LCD. The coverage of SQ monoclonal antibodies must be supported in the medical record.

• Criteria for the diagnosis of osteoporosis, and
• History of treatment as related to progression of disease and ongoing risk factors, and
• Description of treatment failure, or contraindication, or adverse side effects of oral or self-administered drugs for osteoporosis as applicable to the patient that supports monoclonal antibodies via SQ injection therapy in lieu of standard oral treatment protocol.

Denosumab (Prolia® and Xgeva®) binds to RANKL, a transmembrane of soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab 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® (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa – B ligand). It is produced in genetically engineered mammalian (Chinese hamster ovary) cells. See the FDA drug label for the FDA approved indications and dosages for Prolia®. https://labels.fda.gov

Xgeva® (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL that is produced in genetically engineered mammalian (Chinese hamster ovary) cells. See the FDA drug label for the FDA approved indications and dosages for Xgeva®. https://labels.fda.gov

Prolia® for all patients is allowed under the following circumstances:

• the oral health of the patient was discussed
• the patient was instructed to take 1,000 mg of calcium and at least 400 IU of vitamin D per day 

Prolia® for Men and Postmenopausal Women with Osteoporosis is allowed under the following circumstances:

• criteria for the diagnosis of osteoporosis is met, and
• there is a history of treatment as related to progression of disease and ongoing risk factors, and
• The patient meets the definition of osteoporosis with high risk for fracture, or
• The patient has failed or is intolerant of other available osteoporotic therapy

Prolia® for Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer is allowed under the following circumstance: 

• the patient is a woman receiving adjuvant aromatase inhibitor therapy for breast cancer

Prolia® for Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for non-metastatic prostate cancer is allowed under the following circumstance: 

• the patient is a man receiving androgen deprivation therapy for prostate cancer 

Xgeva® for all patients is allowed under the following circumstances:

• the patient is taking calcium and vitamin D supplements as necessary to treat or prevent hypocalcemia

Limitations:

If the drug use is not indicated on the FDA label, and is not included in one of the compendium approved by CMS (American Hospital formulary Services [AHFS], Clinical Pharmacology, NCCN Drugs and Biologicals Compendium and/or Thomson Micromedex DrugDex®) and the off-label use is not listed above, the drug use would not be considered medically reasonable and necessary, and, therefore is not allowed. Not only does the indication for the use of the drug need to meet medical necessity requirements, but the route of administration is also subject to medical necessity criteria.

Medical necessity is not demonstrated in the cases where a patient has not taken the oral form of a medication before the IV form of the drug, either for patient or provider convenience purposes, or for financial or emotional reasons.

Combination use of a bisphosphonate and a monoclonal antibody for the treatment of osteoporosis during an episode of care is not considered medically reasonable and necessary.  Combination use of IV and/or oral forms of bisphosphonate therapy as treatment for osteoporosis during an episode of care is not covered. An episode of care includes the duration and frequency of the IV drugs in accordance with FDA labels. 

Hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism must be effectively treated before starting therapy. Patients must receive supplemental calcium and vitamin D. 

The optimal duration of the use of the drugs listed in this LCD has not been determined. It is expected that treatment with these drugs in a Medicare beneficiary meets the evidence-based peer reviewed literature and standards of care in the medical community. 

Boniva® Injection is contraindicated for the following conditions:

• Severe renal impairment defined as patients with serum creatinine >200µmol/L [2.3 mg/dL] or creatinine clearance measured or estimated <30 mL/min
• Known hypersensitivity to Boniva® injections or to any of its excipients
• Uncorrected hypocalcemia

Aredia® is contraindicated for the following:

• Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphosphonates.
• Pregnancy and lactation
• Patients who receive Aredia should have serum creatinine assessed prior to each treatment.
• Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with Aredia.
• Patients who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment

Reclast® used for prevention without a confirmed diagnosis of osteoporosis in postmenopausal women will not be covered because it is not considered medically reasonable and necessary in the diagnosis and treatment of a specific illness or injury as defined in the Social Security Act, Section 1862(a)(1)(A) and as stated in CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.4.

Reclast® is contraindicated in the following conditions:

• Hypocalcemia
• Hypersensitivity to the active substance (zoledronic acid) or to any of the excipients
• Pregnancy and lactation
• Patients receiving Zometa®
• Severe renal impairment defined as patients with serum creatinine clearance measured or estimated <35 mL/min

Zometa® is contraindicated for the following conditions:

• Hypersensitivity to zoledronic acid or any component of Zometa®
• Pregnancy and lactation
• Patients receiving Reclast®

Prolia® is contraindicated for the following conditions:

• Hypocalcemia
• Patients receiving Xgeva

Xgeva® is not indicated for the following indication:

• Prevention of skeletal related events in patients with multiple myeloma and other cancers of the blood. Effective for dates of service on or after 01/04/2018, the FDA has approved denosumab (Xgeva®) for the treatment of skeletal-related events in patients with multiple myeloma.

Xgeva® is contraindicated for the following conditions:

• Hypocalcemia
• Hypersensitivity to Xgeva
• Patients receiving Prolia

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Documentation Requirements

Please refer to the related Local Coverage Article: Billing and Coding: Bisphosphonates (Intravenous [IV]) and Monoclonal Antibodies in the Treatment of Osteoporosis and Their Other Indications (A57603) for documentation requirements, utilization parameters and all coding information as applicable.

First Coast Service Options, Inc., reference LCD number(s) – L32100

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Boniva® (ibandronate sodium) prescribing information. (2010). Genentech, U.S.A., Inc.

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Prolia® (denosumab) prescribing information. (2011). Amgen, Inc.

Prolia® (denosumab) prescribing information. (2012). Amgen, Inc.

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Reclast® (zoledronic acid) Injection prescribing information. (2011). Novartis Pharmaceuticals, Corp.

U.S. Food and Drug Administration. Aredia® (pamidronate disodium).

U.S. Food and Drug Administration. Boniva® (ibandronate) Injection. Accessed September 9, 2019.

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U.S. Food and Drug Administration. Reclast® (zoledronic acid) Injection. Accessed September 9, 2019.

U.S. Food and Drug Administration. Xgeva® (denosumab). Accessed September 9, 2019.

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