Bisphosphonate Drug Therapy

Title XVIII of the Social Security Act section 1833 (e). This section prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

Title XVIII of the Social Security Act section 1862 (a)(1)(A). This section allows coverage and payment of those services that are considered to be medically reasonable and necessary. This Act requires that drugs must be reasonable and necessary in order to be covered by Medicare. This means, in the case of drugs, the FDA must approve them for marketing.

Title XVIII of the Social Security Act section 1862 (a)(1)(B) and 1862 (a)(1)(P). In the case of items and services described in section 1861(s)(10) and 1861 (ddd)(1), which relate to preventive services.

Title XVIII of the Social Security Act section 1862 (a) (1) (D). This section states that no Medicare payment may be made under part A or part B for any expenses incurred for items or services that are investigational or experimental.

Title XVIII of the Social Security Act section 1862 (a)(7). This section excludes routine physical examinations and services.

CMS Pub 100-02 Medicare Benefit Policy Manual - Chapter 15 – Covered Medical and Other Health Services, Section
50 – Drugs and Biological, and
60 – Services and Supplies.

CMS Pub. 100-04 Medicare Claims Processing Manual, Chapter 17- Drugs and Biologicals, Section 10- Payment Rules for Drugs and Biologicals, and
Chapter 12 – Physicians/Nonphysician Practitioners, Section 30.5 –Payment for Codes for Chemotherapy Administration and Nonchemotherapy Injections and Infusions.

CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13, Section 13.5.4 - Reasonable and Necessary Provisions in an LCD.

Note: Etidronate disodium IV has been removed from this policy because it is no longer available in the United States.

Bisphosphonate drugs act to inhibit normal and abnormal bone reabsorption. This action is helpful in reducing pain, reversing hypercalcemia, 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. Coverage is limited to those drugs administered parenterally (IV). Bisphosphonates are indicated parenterally for osteoporosis and heterotrophic ossification when the patient has failed a trial of the oral drug or has insurmountable issues related to absorption, compliance or dosing posture.

 pamidronate disodium IV, and zoledronic acid IV, are covered for the following indications:

1. 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.
2. Cancer Treatment-Induced Bone Loss (CTIBL) in Breast and Prostate Cancer
   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 premenopausal women, surgery (oophorectomy) or radiation therapy to the ovary results in bone loss. Hormone therapy, 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.
3. Bone metastases secondary to solid tumors, breast cancer, and prostate cancer
4. Multiple Myeloma
5. Osteolytic lesions due to metastases
6. Paget’s Disease of bone (osteitis deformans) *See additional information for zoledronic acid below.
   Intravenous bisphosphonates are indicated for moderate to severe Paget’s disease of bone.
7. Prophylaxis and treatment of heterotopic ossification associated with spinal cord injury, traumatic brain injury, hip replacement, and burns
   It is indicated parenterally when the patient has failed a trial of the oral drug or has insurmountable issues related to absorption, compliance or dosing posture.

Besides the indication listed above, pamidronate sodium is covered for the following indications:

1. Osteogenesis Imperfecta
2. Fibrous dysplasia of bone (McCune-Albright syndrome)

Ibandronate sodium, pamidronate or zoledronic acid are covered for the following indication:

Treatment of osteoporosis when there are no drug classification contraindications. There also needs to exist either one or more of the following:

• • Demonstrated intolerance or contraindication for FDA approved oral bisphosphonates dosing regimens, or insurmountable issues related to absorption, compliance or dosing posture.
  • When adequate trials 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).

Evidence in the medical record should clearly support the need for the intravenous administration of bisphosphonates for the treatment of osteoporosis.

Ibandronate sodium is covered for:

1. Hypercalcemia associated with malignancy
2. Bone metastases secondary to solid tumors, breast cancer, prostate cancer

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

• • when there is an elevation in serum alkaline phosphatase two 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 one 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

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Documentation Requirements
Note: If bone metastasis (C79.51 or C79.52) is the condition being treated, the diagnosis of a primary malignant neoplasm must be present in the patient’s medical record and available if requested.

Information in the medical record including diagnostic information and lab results should support the medical necessity of this service. Based on the indications listed, the specific signs and symptoms must be documented to substantiate the FDA labeled or the FDA off labeled reasons for drug usage. An indication that the patient has been advised to take adequate calcium and vitamin D supplementation should be in the medical record. The medical record must be available on request. Diagnosis codes supporting medical necessity should be submitted on the claim.

Evidence in the medical record should clearly support the need for the intravenous administration of bisphosphonates for the treatment of osteoporosis including description of treatment failure of oral or self-administered drugs for osteoporosis and heterotrophic ossification. Lab work should include serum creatinine measured prior to the administration of the drug.

Utilization Guidelines
It is expected that these services would be performed as indicated by current literature and/or standards of practice and should follow the guidelines for administration and safety found in the FDA approved labels for these drugs along with the indications found in the Coverage Indications, Limitations, and/or Medical Necessity section of this policy. When services are performed in excess of established parameters, it may result in medical review to determine if the services were medical necessity.

Preventive services other than those payable by statute are excluded from Medicare coverage. Therefore, at this time, WPS GHA is not paying for the prevention of osteoporosis.

American College of Obstetricians and Gynecologists (ACOG). (2012, Sep). Osteoporosis. National Guideline Clearinghouse. ACOG practice bulletin: no.129. Accessed 10/15/2015.

Berenson, J.R., Rosen, L.S., Howell, A., & et al. (2001, Apr 1). Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. 91(7):1191-1200. Accessed 10/14/2015.

Black, D. M., Delmas, P.D., Eastell, R., & et al. (2007, May 3). Once-yearly Zoledronic acid for treatment of postmenopausal osteoporosis. The New England Journal of Medicine. 356(18):1809-1822. Accessed 10/14/ 2015.

Black, D.M., Bauer, D.C., Schwartz, A.V., & et at. (2012, May 31). Continuing bisphosphonate treatment for osteoporosis-for whom and for how long? The New England Journal of Medicine. 366(22):2051-2053. Accessed 10/14/2015.

Cameron, D., Fallon, M., & Diel, I. (2006). Ibandronate: Its role in metastatic breast cancer. The Oncologist. 11(Suppl 1):27-33. Accessed 10/14/15.

Clemons, M., Gelmon, K.A., Pritchard, K.I., & Paterson, A.H.G. (2012, Oct). Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: The state of the art. Current Oncology. 19(5):259-268. Accessed 10/15/2015.

Devitt, B., & McLachlan, S.A. (2008, Apr). Use of Ibandronate in the prevention of skeletal events in metastatic breast cancer. Therapeutics and Clinical Risk Management. 4(2):453-458. Accessed 10/14/15.

Drake, M.T., Clarke, B.L., & Khosla, S. (2008, Sep). NIH Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clinical Procedures. 83(9):1032-1045. Accessed 10/15/2015.

Favus, M.J. (2010, Nov 18). Bisphosphonates for osteoporosis. The New England Journal of Medicine. 363(21):2027-2035. Accessed 10/15/2015.

Gnant, M., Mlineritsch, B., Schippinger, W., & et al. (2009, Feb 12). Endocrine therapy plus zoledronic acid in premenopausal breast cancer. The New England Journal of Medicine. 360(7):679-691. Accessed 10/15/2015.

Grossman, J.M., Gordon, R., Ranganath, V.K., & et al. (2010, Nov). American College of Rheumatology 2010 Recommendations for the prevention and treatment of Glucocorticoid induced osteoporosis. Arthritis Care and Research. 62(11):1515-1526. Accessed 10/15/2015.

Hillner, B.E., Ingle, J.N., Chlebowski, R.T., & et al. (2003, Nov 1). American Society of Clinical Oncology 2003 Update on the role of bisphosphonates and bone health issues in women with breast cancer. Journal of Clinical Oncology. 21(21):4042-4057. Accessed 10/20/2015.

Kanis, J.A., Johansson, H., Oden, A., Dawson-Hughes, B., Melton III, L.J., & McCloskey, E.V. (2010). The effects of a FRAX® revision for the USA. Osteoporos International. 21:35-40. Accessed 10/15/2015.

Lee, R.J., Saylor, P.J., Smith, M.R. (2011, Jan 1). Treatment and prevention of bone complications from prostate cancer. Bone. 48(1):88-95. Accessed 10/15/2015.

Levis, S., & Theodore, G. (2012, May). Summary of AHRQ’s comparative effectiveness review of treatment to prevent fracture in men and women with low bone density or osteoporosis: update of the 2007 report. Journal of Managed Care Pharmacy. 18(4 Supplement B):S1-15.

MacLean, C., Alexander, A., Carter, J., & et al. (2007, Dec). Comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Comparative Effectiveness Review no. 12. Rockville, MD: Agency for Healthcare Research and Quality. AHRQ Publication No. 08-EHC008-EF. Accessed 10/20/2015.

Metta, Harinarayan, C.V., Marwah, R., Sahay, R., Kalra, S., & Babhulkar, S. (2013, Apr-Jun). Clinical practice guidelines on postmenopausal osteoporosis: an executive summary and recommendations. Journal of Mid-Life Health. 4(2):107-126. Accessed 10/15/2015.

Moreta, J., & Martinez-de los Mozos, J.L. (2014, Feb 19). Heterotopic ossification after traumatic brain injury. Traumatic Brain Injury. Chapter 15 pp.331-349. Accessed 10/14/2015.

National Osteoporosis Foundation. (2010, Jan). Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation. pp 1-40. Accessed 10/20/2015.

Nelson, H.D., Haney, E.M., Chou, R., Dana, T., Fu, R., & Bougatsos, C. (2010, Jul). Screening for Osteoporosis: System review to update the 2002 U.S. Preventive Services Task Force Recommendation. Agency for Healthcare Research and Quality. No. 77. Maryland, Rockville. Accessed 10/15/2015.

Pazianas, M., Cooper, C., Ebetino, F.H., & Russel, R.G.G. (2010, Jul 16). Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. Therapeutics and Clinical Risk Management. 6:325-343. Accessed 10/15/2015.

Pecherstorfer, M., Rivkin, S., Body J.J., Diel, I., & Bergstrom, B. (2006). Long-term safety of intravenous Ibandronic Acid for up to 4 years in metastatic breast cancer. Clinical Drug Investigation. 26(6):315-322. Accessed 10/15/15.

Perazella, M.A., & Markowitz, G.S. (2008). Bisphosphonate Nephrotoxicity. Kidney International. 74(11):1385-1393. Accessed 10/15/2015.

Polascik, T.J. (2009, Sep). Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases. Drug Design, Development and Therapy. 3:27-40. Accessed 10/15/2015.

Reid, I.R.,  Brown, J.P., Burchkhardt, P., & et al. (2002). Intravenous Zoledronic Acid in postmenopausal women with low bone mineral density. The New England Journal of Medicine. 346(9):653-661. Accessed 10/15/2015.

Smith, M.R., Eastham, J., Gleason, D.M., Shasha, D., Tchekmedyian, S., & Zinner, N. (2003, Jun). Randomized controlled trial of Zoledronic Acid to prevent bone loss in men receiving Androgen deprivation therapy for nonmetastatic cancer. The Journal of Urology. 169(6):2208-2012. Accessed 10/15/2015.

Stevenson, M., Jones, M.L., De Nigris, E., Brewer, N., Davis, S., & Oakley, J., (2005, Jun). A systemic review and economic evaluation of alendronate, etidronate, risedronate, ralozifene, and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technology Assessment. 9(22):1-160. Accessed 10/15/2015.

Sullivan, M.P., Torres, S.J., Mehta, S., & Ahn, J. (2013, Mar). Heterotopic ossification after central nervous system trauma. Bone and Joint Research. 2(3):51-57. Accessed 10/15/1015.

Teasell, R.W., Mehta, S., Aubut, J.L., Ashe, M.C., Sequeira, K., Macaluso, S., & Tu, L. (2010, Jul). A systemic review of the therapeutic interventions for heterotopic ossification following spinal cord injury. Spinal Cord. 48(7):512-521. Accessed 10/14/2015.

Valachis, A., Polyzos, N.P., Coleman, R.E., & et al. (2013). Adjuvant therapy with Zoledronic acid in patients with breast cancer: A systemic review and meta-analysis. The Oncologist. 18:353-361. Accessed 10/20/2015.

Watts, N.B., Bilezilian, J.P., Camacho, P.M., & et al. (2010, Nov-Dec). American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocrine Practice. 16(Suppl3):1-37. Accessed 10/25/2015.

Whitaker, M., Guo, J., Kehoe, T., & Benson, G. (2012, May 9). Bisphosphonates for osteoporosis-where do we go from here? The New England Journal of Medicine. 366:2048-2051. Accessed 10/15/2015.

FDA approval Letter dated 04/16/2007 for coverage of Reclast® (zoledronic acid) for Paget’s disease of the bone.

FDA approval Letter dated 08/17/2007 for coverage of Reclast® (zoledronic acid) for post-menopausal osteoporosis.

*FDA Drug Safety Communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures [10-13-2010]

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