LCD L34648: Bisphosphonate Drug Therapy

Bisphosphonate drugs act to inhibit normal and abnormal bone reabsorption. This action is helpful in reducing pain, reversing hypercalcemia, and preventing and reducing fractures in a range of diseases that directly or indirectly impact bone modeling and remodeling.

Bisphosphonates are available in both oral and parenteral forms. This LCD addresses the coverage indications, limitations and/or medical necessity for the intravenous (IV) bisphosphonates: ibandronate sodium, pamidronate disodium, and zoledronic acid. Etidronate disodium IV has been previously removed from this policy because it is no longer available in the United States.

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 (natural or therapy-induced). 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 2 vertebral levels measured in the posterior-anterior projection, not the lateral projection) as noted below. 1

• 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

• Severe or established osteoporosis: T-score below -2.5 with fragility fracture

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: 1

• Age

• Sex

• Prior fragility fracture after age 50

• History of corticosteroid use (5 mg per day or more for 3 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

Osteopenia is classified by the WHO as low bone mass with a T-score between -1.0 and -2.5. An osteopenic T-score by itself does not constitute needed treatment. Osteopenia has to be associated with either lower energy fracture(s) or a high risk for future fractures which is assessed using FRAX tool. Using the FRAX score is emphasized in the osteopenic patient as the majority of fragility fractures occur in osteopenic patients.

In contrast to the large fracture-end point trials of osteoporosis therapies in women, studies in men have generally been small, with change in BMD as the primary end point. Treatment trials in men have yielded effects on BMD, biochemical markers of bone remodeling, and trends in fracture reduction that closely mirror those seen in larger trials in postmenopausal women with osteoporosis. If osteoporosis is due to another condition (e.g., hypogonadism, gastrointestinal disease, hypercalciuria), the underlying cause should be treated and potential offending agents (e.g., glucocorticoids, alcohol, tobacco) should be eliminated whenever possible. The Endocrine Society’s Clinical Guidelines and a systematic review and meta-analysis suggest that available therapies are likely to be effective in men and that it is appropriate to recommend pharmacological therapy in men with increased fracture risk. 2,3

Medical management focused on lifestyle may be all that is needed for postmenopausal women and men >/ 50 years of age who are at low risk for osteoporotic fracture. Lifestyle measures should be adopted universally to reduce bone loss. Some lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use. The North American Menopause Society (NAMS), 4 American Association of Clinical Endocrinologists (AACE), 5 and the National Osteoporosis Foundation (NOF) 1 recommend that bisphosphonates are appropriate to reduce fracture risk in women with postmenopausal osteoporosis. Additionally, the NAMS, AACE, and NOF recommend osteoporosis pharmacotherapy in the following populations:

• Postmenopausal women and men >/ 50 years of age who have had a hip or vertebral fracture, including fragility fracture.

• Postmenopausal women and men >/ 50 years of age 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.

• Postmenopausal women and men >/ 50 years of age who have T-scores from -1.0 to -2.5 and any one of the following:

• History of fracture of proximal humerus, pelvis, or distal forearm.

• History of multiple fractures at other sites (excluding face, feet, and hands).

• Pharmacologic therapy is recommended for patients with osteopenia if the FRAX 10-year probability for major osteoporotic fracture is (>/ 20%) or the 10-year probability of hip fracture is (>/ 3%).

Covered Indications

In order to be covered by Medicare, a drug or biological must be safe and effective and otherwise reasonable and medically necessary. Please refer to CMS IOM Publication 100-02, Medicare Benefit Policy Manual , Chapter 15, Section 50 Drugs and Biologicals.

IV bisphosphonate therapy will be considered medically reasonable and necessary when administered as outlined in this LCD. The coverage of IV bisphosphonates in lieu of a standard oral treatment protocol must be supported in the medical record. Medical record documentation must include:

• Covered Clinical Medical Diagnosis listed below, and

• IV bisphosphonate indication (either of the following)

• Demonstrated intolerance, adverse side effects, or contraindications for FDA approved oral bisphosphonates dosing regimens; or insurmountable issues related to absorption, compliance, or dosing posture.

• Treatment failure of oral bisphosphonate therapy. Documentation of adequate trials or attempts of FDA-approved oral bisphosphonates result in fallen Bone Mass Density and/or failure to suppress bone turnover (e.g., persisting high bone -turnover marker measurements).

Covered indications in this LCD are for all the IV bisphosphonates: ibandronate sodium, pamidronate disodium, and zoledronic acid, unless otherwise documented for a specific clinical medical condition/diagnosis noted below.

Osteoporosis and Osteopenia

Coverage for IV bisphosphonate therapy include any of the following:

• Postmenopausal women and men >/ 50 years of age who have had a hip or vertebral fracture, including fragility fracture.

• Postmenopausal women and men >/ 50 years of age 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.

• Postmenopausal women and men >/ 50 years of age who have T-scores from -1.0 to -2.5 and any one of the following:

• History of fracture of proximal humerus, pelvis, or distal forearm.

• History of multiple fractures at other sites (excluding face, feet, and hands).

• Pharmacologic therapy is recommended for patients with osteopenia if the FRAX 10-year probability for major osteoporotic fracture is (>/ 20%) or the 10-year probability of hip fracture is (>/ 3%).

• Hypercalcemia associated with malignancy

Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying complication with metastatic bone disease and hypercalcemia associated with malignancy. Most cases of hypercalcemia, associated with malignancy, occurs in patients who have breast cancer, squamous-cell tumors of the lung or head and neck, renal-cell carcinoma, and certain hematologic malignancies (multiple myeloma and some types of lymphomas). Bisphosphonates, in conjunction with hydration, are indicated for moderate or severe hypercalcemia associated with malignancy with or without bone metastases.

• Cancer Treatment-Induced Bone Loss (CTIBL) in Breast and Prostate Cancer

• Coverage: pamidronate disodium and zoledronic acid

Breast Cancer

Cytotoxic chemotherapy: There are 2 mechanisms of cytotoxic chemotherapy inducing bone loss. First, there is a direct negative effect of the cytotoxic therapy on bone cells, predominantly osteoblasts and, second, many women who are premenopausal have cytotoxic therapy effects on ovarian function, which results in gonadal loss. In addition, in (e.g.: tamoxifen) premenopausal women, surgery (oophorectomy) or radiation therapy to the ovary results in bone loss. Hormone therapy, (e.g.: tamoxifen) in premenopausal women, and the aromatase inhibitors result in bone loss, as well as gonadotropin-releasing hormone (GnRH) antagonists/agonists, which shut off ovarian function. All of these result in estrogen depletion.

Prostate Cancer

In prostate cancer, cytotoxic therapy again has a negative effect not only on testicular function but also on bone. Surgical therapy, hormone therapy, including antiandrogens and GnRH agonists/antagonists, results in androgen depletion. The final common pathway, estrogen and androgen depletion, results in a decrease in bone mineral density.

National Comprehensive Cancer Network (NCCN) guidelines 6,7 and supportive literature support use of bisphosphonates in cancer treated patients while on concurrent adjuvant hormone therapy, aromatase inhibitor, or GnRH antagonists/agonists.

• Bone metastases secondary to solid tumors, breast cancer, and prostate cancer

• Multiple Myeloma

• Coverage: pamidronate disodium and zoledronic acid

• Osteolytic lesions due to metastases

• Paget’s Disease of bone (osteitis deformans)

• Coverage: pamidronate disodium and zoledronic acid

Intravenous bisphosphonates are indicated for moderate to severe Paget’s disease of bone.

Zoledronic acid - Injection is covered for the treatment of moderate to severe Paget’s disease of bone in men and women for any of the following:

• when there is an elevation in serum alkaline phosphatase 2 times or higher than the upper limit of the age specific normal reference range

• there is risk for complications from their disease

• to induce remission (normalization of serum alkaline phosphatase)

This contractor will cover zoledronic acid once per year for these patients because, after a single treatment, an extended period of remission is observed.

If a patent relapses after 1 year of remission, re-treatment is considered reasonable and necessary if any of the following conditions occur:

• an increase in serum alkaline phosphatase

• a failure to achieve normalization of serum alkaline phosphatase

• as dictated by medical practice for symptom recurrence

• Osteogenesis Imperfecta and Fibrous dysplasia of bone (McCune-Albright syndrome)

• Coverage: pamidronate disodium

• Discontinuation of Denosumab (Prolia/Xgeva) Therapy

• Coverage: zoledronic acid

• Treatment/Prevention of Glucocorticoid-Induced Osteoporosis (GIOP) and Glucocorticoid-Induced Bone Loss in Transplant Recipients

Background

WPS GHA received 2 reconsideration requests for coverage for additional indications for parenteral bisphosphonates. The summary and analysis of the literature review that was conducted for both requests will be described below. Each section will be labeled according to each indication and the literature review that corresponds to it. Additionally, WPS performed an LCD update review which incorporated current medical literature and society guidelines supportive evidence for coverage indications, limitations and/or medical necessity.

Zoledronic Acid for Cancer Treatment-Induced Bone Loss (CTIBL) in Breast Cancer

According to the FDA label, Zometa (zoledronic acid) injection is indicated for the treatment of hypercalcemia of malignancy, for patients with multiple myeloma, and for patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy. 8