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) guidelines6,7 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

**Drug** | **Ibandronate (Boniva)*** | **Pamidronate (Aredia)*** |
**Zoledronic Acid (Reclast)***  
---|---|---|---  
**Route** | IV |

IV

|

IV  
  
**INDICATIONS** |

|

|  
  
**Osteoporosis** | X |

X

|

X  
  
**Hypercalcemia of malignancy** |

X

|

X

|

X  
  
**Cancer Treatment -Induced Bone loss in Breast and Prostate Cancer** |   |

X

|

X  
  
**Bone metastases secondary to solid tumors, breast, and prostate cancer** |

X

|

X

|

X  
  
**Multiple Myeloma** |

| X |

X  
  
**Osteolytic lesions due to metastases** |

X

|

X

|

X  
  
**Paget 's Disease** |

|

X

|

X  
  
**Osteogenesis Imperfecta** |

|

X

|  
  
**Fibrous dysplasia of bone (McCune-Albright syndrome)** |

|

X

|  
  
**Discontinuation of Denosumab (Prolia/Xgeva) Therapy** |

|

|

X  
  
**GIOP and Transplant** |

X

|

|

X  
  


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 B 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 above9-11 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.