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 (1) (5) (D). 21st Century Cures Act of 2016 (Public Law 114-255)- The 21st Century Cures Act of 2016 added language to section 1862(l)(5)(D) of the Social Security Act (the Act) directing the Secretary of the Department of Health and Human Services (DHHS) to improve the transparency of the LCD process.

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.

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 two 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 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

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.
  • Treat 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.

1. 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%).
2. 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.
3. 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.
4. Bone metastases secondary to solid tumors, breast cancer, and prostate cancer
5. Multiple Myeloma
   • Coverage: pamidronate disodium and zoledronic acid
6. Osteolytic lesions due to metastases
7. 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 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 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
8. Osteogenesis Imperfecta and Fibrous dysplasia of bone (McCune-Albright syndrome)
   • Coverage: pamidronate disodium
9. Discontinuation of Denosumab (Prolia/Xgeva) Therapy
   • Coverage: zoledronic acid
10. Treatment/Prevention of Glucocorticoid-Induced Osteoporosis (GIOP) and Glucocorticoid-Induced Bone Loss in Transplant Recipients
    • Coverage: ibandronate sodium and zoledronic acid
    • LCD coverage will follow the 2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis
      • Adults taking glucocorticoids (any dose with an anticipated duration of ≥3 months) maintain a total calcium intake of 1000 to 1200 mg/day and vitamin D intake of 600 to 800 international units/day through either diet and/or supplements
      • Adults receiving high-dose glucocorticoids and at moderate, high, or very high risk of fracture, IV bisphosphonate therapy is a conditionally recommended treatment
      • Adults receiving high-dose glucocorticoids with solid organ transplants, GFR > 35 mL/min, and no evidence of chronic kidney disease-mineral and bone disorder (CKD-MBD) or hyperparathyroidism, IV bisphosphonate therapy is a conditionally recommended treatment

Summary Table of Covered Indications (*)
(*) = Must meet coverage criteria outlined in LCD
X=Coverage

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

Valachis et al⁹ performed a systematic review (SR) and meta-analysis (MA) of randomized clinical trials. The researchers set out to estimate the impact on survival outcomes and fracture rates of the use of zoledronic acid, versus no use, in the adjuvant treatment of patients with early-stage (stages I–III) breast cancer. A SR of the literature was performed, and pooled estimates from the cumulative available randomized evidence were analyzed. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Fifteen studies were considered eligible and were further analyzed. This MA provides evidence in favor of zoledronic acid use in the adjuvant breast cancer setting. Zoledronic acid not only has a protective effect for fractures, with a 21% lower risk, it also reduces the risk of death by 19%. Thus, taking into account this substantial benefit, along with the acceptable toxicity regarding osteonecrosis of the jaw, with an incidence rate of 0.52%, it appears that the use of zoledronic acid in adjuvant breast cancer treatment should be considered.

Eisen et al¹⁰ states that adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. This SR-based guideline product was developed by a joint ASCO-Ontario Health (OH; Cancer Care Ontario [CCO]) multidisciplinary Expert Panel, which included a patient representative and ASCO and OH (CCO) guidelines staff members with health research methodology expertise. The Program in Evidence-Based Care (PEBC) Practice Guidelines Development Cycle and the ASCO guideline development methods include a SR, interpretation of the evidence, drafting of recommendations, and internal review by content and methodology experts. The Panel supports starting bisphosphonate therapy early; many studies initiated bisphosphonate within 3 months of definitive surgery or within 2 months of completion of adjuvant chemotherapy. They also recommend that adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients with primary breast cancer, who are candidates to receive adjuvant systemic therapy. In Table 2, patient characteristics of the clinical trials studied include receiving nonsteroidal aromatase inhibitors, early-stage (I-III), adjuvant systemic therapy (exclude patients at such low risk that adjuvant therapy not prescribed), and primary invasive breast cancer.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)¹¹ undertook a collaborative MA to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Individual patient datasets were provided for 26 trials with 18,766 participants, 97% of all 19,291 women in the 32 completed trials that recorded recurrence data. The greater efficacy of bisphosphonates in preventing distant recurrence than in preventing other (local or contralateral) breast cancer recurrence was significant. The effect on distant recurrence was mainly because of a reduction in bone recurrence. Breast cancer mortality was borderline significantly lower in patients allocated bisphosphonate than control, and all-cause mortality was similarly reduced. The efficacy of bisphosphonates in reducing bone recurrence appeared to be greater in older women, or, similarly, in postmenopausal women. These trials have shown that some years of adjuvant bisphosphonate treatment can reduce breast cancer recurrence rates in bone and improve breast cancer survival but have provided clear evidence of benefit only in women who are postmenopausal (natural or induced) at the time bisphosphonates are started. The use of bisphosphonates in breast cancer is mainly to reduce bone loss and risk of fracture in postmenopausal women with ER-positive disease treated with aromatase inhibitors.

In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer Version 3.2023,⁶ the NCCN recommendations for the use of bisphosphonates as adjuvant therapy indicate that the panel recommends considering adjuvant bisphosphonate therapy for postmenopausal (natural or induced) patients receiving adjuvant endocrine therapy. In the NCCN Compendium for zoledronic acid, there is a 2A recommendation related to ductal carcinoma in situ breast cancer for treatment to be considered in postmenopausal patients who are receiving adjuvant aromatase inhibition therapy along with calcium and vitamin D supplementation. In addition, the NCCN Compendium also includes a 2A recommendation for inflammatory breast cancer in postmenopausal patients receiving adjuvant aromatase inhibition therapy, and for invasive breast cancer in postmenopausal patients receiving adjuvant therapy.

Treatment with Zoledronic Acid when Completing Therapy with Prolia/Xgeva (denosumab)

Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), is a potent antiresorptive agent that profoundly suppresses bone turnover markers (BTMs), continuously increases bone mineral density (BMD), and reduces fracture risk, along with a good safety profile for up to 10 years. Denosumab discontinuation leads to a complete and rapid reversal of its effects on BTMs and BMD.

Leder¹² performed a follow up study to compare rates of bone loss in postmenopausal women who discontinue denosumab or teriparatide and receive no additional prescription osteoporosis medications, to women who discontinue these drugs followed by prompt antiresorptive therapy. The researchers asked women concluding the Denosumab and Teriparatide Administration (DATA) study and its extension, DATA-Switch, to return for BMD measurements 1–2 years after study completion. In these studies, women received 2-years of either teriparatide, denosumab, or both medications followed by 2-years of the alternate therapy (women who received combination therapy initially received an additional 2-years of denosumab alone). Fifty of 69 women who completed DATA-Switch returned, and of the 28 women who received antiresorptive therapy (10 denosumab, 10 oral bisphosphonates, 8 intravenous zoledronic acid), the mean interval between ending DATA-Switch and beginning antiresorptive therapy was 3.8 ± 3.1 months. The large teriparatide and denosumab-induced gains in BMD achieved with 4 years of intensive therapy in the DATA and DATA-Switch studies were maintained in patients who received prompt antiresorptive therapy, but not in those left untreated. The results of this study underscore the importance of avoiding ‘drug holidays’ in postmenopausal osteoporotic women who are discontinuing denosumab; the findings also demonstrate the capacity of bisphosphonates to consolidate the large gains in BMD accrued during initial phase of sequential or combination therapy.

Anastasilakis¹³ conducted a prospective 2-year clinical trial focusing on zoledronic acid for the prevention of bone loss in women who are discontinuing denosumab treatment. The researcher explains that cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. The researchers investigated the efficacy of zoledronic acid to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. In this trial, women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or 2 additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months, lumbar spine–bone mineral density (LS-BMD) was not different from baseline in the ZOL group but decreased in the Dmab group from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant. Results of femoral neck (FN)-BMD changes were similar. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, 3 patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover.

Makras¹⁴ conducted an observational extension/statistical analysis to report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in LS-BMD; secondary endpoints were changes in FN-BMD and markers of BTM during the 3rd year from the zoledronate infusion. LS-BMD did not change significantly at year 3 compared to year 2 and compared to baseline. In 4 of the 23 studied women, BMD values returned to the osteoporotic range at 3 years. In conclusion, the researchers stated a single intravenous infusion of zoledronic acid 5 mg, given 6 months after the last injection of denosumab therapy, maintains BMD gains for 3 years in most patients previously treated with denosumab for an approximate period of 2.5 years.

• Society Guidance
  • AACE – Recommend in postmenopausal women with osteoporosis who are taking denosumab, administration of denosumab should not be delayed or stopped without subsequent antiresorptive (e.g., bisphosphonate) or other therapy to prevent a rebound in bone turnover and to decrease the risk of rapid bone mineral density loss and an increased risk of fracture.⁵
  • NAMS – State that whenever denosumab is stopped, therapy with a bisphosphonate should be used to prevent bone loss.⁴

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

Kendler et al¹⁵ wrote an executive summary about monitoring of bone fragility in hematopoietic stem cell transplant (HSCT) patients. The summary reports on the main recommendations published previously including bone assessment, dietary and lifestyle recommendations, and osteoporosis medication. They state that bisphosphonates like pamidronate or zoledronic acid, prevent bone loss or even increase bone mass, and recommend considering intervention with intravenous zoledronic acid if pre-HSCT BMD T-score < -1.5 at any one of the relevant sites (total hip, femoral neck, lumbar spine, one third radius), and if renal function permits. The summary also reports that all patients receiving prolonged courses of glucocorticoid for chronic graft-versus-host disease (GVHD) are at high risk for bone loss and fracture. Therefore, prophylaxis with bisphosphonates, ideally zoledronic acid 5 mg, may be considered regardless of the T-score.

Kovvuru et al¹⁶ wrote a review article on the topic of risk factors and management of osteoporosis post-transplant. Glucocorticoids (GC) are commonly used after transplantation to reduce the risk of graft rejection. GCs harm skeletal health by reducing bone formation and potentiating bone destruction, leading to decreases in bone density. Some authors consider prophylactic therapies with anti-resorptive medications for patients with osteopenia and a high risk of fracture. In renal transplant patients with no evidence of low-turnover bone disease and GFR > 30 mL/min, antiresorptive therapies, such as bisphosphonates, could be considered. Considering that transplant recipients are more vulnerable to fractures in the immediate post-transplant period, especially while on GCs, preventive therapy is recommended for all heart, liver, lung, and stem cell transplant recipients, up to 1-year post-transplant. Bisphosphonates attenuate GC-induced bone loss, reduce the incidence of fractures in post-transplant recipients, and are frequently administered for the prevention and treatment of osteoporosis. Additionally, the authors conclude that there is still a significant need for high-quality, evidence-based studies, to develop treatment modalities that could help mitigate fracture risks following organ transplantation.

Ebeling¹⁷ wrote a case report that explained the approach to patients with transplantation-related bone loss. He discussed prevention and treatment related to transplants of bone marrow, kidney, cardiac, liver, and lung. The article states that highest GC-associated rates of bone loss are in the first 3 to 12 months after transplant.

• Society Guidance
  • American College of Rheumatology – For adults receiving high-dose GC, conditionally recommend treatment for those at moderate, high, or very high risk of fracture with IV bisphosphonates. Bisphosphonates should generally not be used in patients with an eGFR < 35 mL/min. Additionally, for adults with solid organ transplants, GFR > 35 mL/min, and no evidence of chronic kidney disease-mineral and bone disorder (CKD-MBD) or hyperparathyroidism, conditionally recommend treatment with IV bisphosphonates.¹⁸

Heterotopic ossification associated with trauma and surgery

Heterotopic ossification is the formation of bone in atypical, extraskeletal tissues that may occur following localized trauma, following a neurological injury, or as a post-surgical complication. Meyers et al., performed a comprehensive review of heterotopic ossification which discussed the diverse pathologic process, clinical presentation, radiographic findings, and current methods of treatment.¹⁹ The authors noted that despite early enthusiasm for the potential role of bisphosphonates in the prevention of heterotopic ossification, further analysis failed to demonstrate a clear benefit for the use of these medications in prevention of heterotopic ossification and some evidence suggested that antiresorptive therapy may increase the risk of developing heterotopic ossification or may simply delay rather than prevent the bone formation.

Medical literature review for this policy utilized the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.²⁰

The LCD process for this policy followed the current regulations as outlined in CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13 with updates after the 21^st Century Cures Act. (Public Law 114-255)

There is robust evidenced-based medical literature and multiple society guidelines that address osteoporosis and pharmacotherapy. Current medical literature and society guidelines outlined in the History/Background/and/or General Information section supports the treatment of osteopenia with IV bisphosphonates.^1-5 This LCD policy has been updated to include coverage criteria for osteopenia treatment with IV bisphosphonates.

The systematic review/meta-analyses described above^9-11 in the CTIBL summary section do provide evidence in favor of using zoledronic acid in the adjuvant breast cancer setting. However, these studies were done on patients with active breast cancer; there is no discussion of using zoledronic acid as a preventive measure. Medical evidence supports the use of bisphosphonate therapy in cancer patients treated with hormone therapy; however, evidence is lacking to support the use of bisphosphonates solely for a history of breast cancer without additional coverage indications as listed in this policy. In addition, preventive services, other than those payable by statute, are excluded from Medicare coverage. Thus, this policy reflects non-coverage for bisphosphonate therapy solely for prevention of osteoporosis with a history of breast cancer.

The follow up study by Leder¹² demonstrated the importance of avoiding “drug holidays” in postmenopausal osteoporotic women who are discontinuing denosumab. Although this study included a small number of participants, it confirms the efficacy of antiresorptive agents in preventing bone loss and emphasizes the critical importance of timely medication transitions in osteoporotic patients. In the RCT conducted by Anastasilakis,¹³ a single IV infusion of zoledronic acid given 6 months after the last denosumab injection prevented bone loss for at least 2 years independently of the rate of bone turnover. In addition, the analysis by Makras¹⁴ showed BMD gains were maintained for 3 years following an IV infusion of zoledronic acid given 6 months after the last denosumab injection. Although these studies had a smaller number of participants, the conclusions noted are in line with additional society guidelines that support the use of bisphosphonates upon discontinuation of denosumab therapy. According to the AACE and NAMS guidelines,^4,5 if denosumab therapy is discontinued, patients should be transitioned to another antiresorptive. Therefore, this will be added as a covered indication in this policy.

The executive summary by Kendler¹⁵ reports that all patients receiving prolonged courses of glucocorticoid for chronic graft-versus-host disease (GVHD) are at high risk for bone loss and fracture. Kovvuru¹⁶ concluded that multiple medications have been shown to reduce bone loss post-transplant, and that preventive strategies should be implemented to help minimize fracture risk. In addition, Ebeling¹⁷ stated that preventive therapy initiated in the immediate post-transplantation period is indicated because further bone loss will occur in the first several months after transplantation. Oral or parenteral bisphosphonates are the most promising approach for the prevention and treatment of transplantation osteoporosis. Current guidelines from the American College of Rheumatology¹⁸ recommend use of bisphosphonates for GIOP patients. Therefore, this will be added as a covered indication in this policy.

The comprehensive medical review by Meyers et al addressed the current medical and surgical management modalities for heterotopic ossification.¹⁹ Current medical literatures does not support a medical benefit for bisphosphonate therapy. Additionally, the previously cited medical literature resources addressed the use of etidronate. Etidronate disodium IV had been previously removed from this policy because it is no longer available in the United States. Given the current evidenced-based literature and LCD non-inclusion of etidronate, heterotopic ossification treatment with IV bisphosphonates will be removed from this LCD.

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.

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

Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer.2001;91(7):1191-1200.

Black DM, Delmas PD, Eastell R, et al. Once-yearly Zoledronic acid for treatment of postmenopausal osteoporosis. The New England Journal of Medicine. 2007;356(18):1809-1822.

Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis-for whom and for how long? The New England Journal of Medicine. 2012;366(22):2051-2053.

Cameron D, Fallon M, Diel I. Ibandronate: Its role in metastatic breast cancer. The Oncologist. 2006;11(1):27-33.

Clemons M, Gelmon KA, Pritchard KI, Paterson AHG. Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: The state of the art. Current Oncology. 2012;19(5):259-268.

Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R; National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81.

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