Zoledronic Acid

Number: 0524

Policy

1. Zoledronic acid (e.g., Reclast)

   1. Aetna considers zoledronic acid (e.g., Reclast) medically necessary for the following indications:

      1. Postmenopausal osteoporosis

         - for the treatment or prevention of osteoporosis when ANY of the following criteria are met:
         
         

         1. Member has a history of fragility fractures; or
         2. Member has a pre-treatment T-score less than or equal to -2.5; or
         3. Member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1)

      2. Osteoporosis in men

         - male members with osteoporosis when ANY of the following criteria are met:
         
         

         1. Member has a history of an osteoporotic vertebral or hip fracture; or
         2. Member has a pre-treatment T-score less than or equal to -2.5; or
         3. Member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1) with a high pre-treatment FRAX fracture probability (See Appendix B)

      3. Glucocorticoid-induced osteoporosis

         - when BOTH of the following criteria are met: 
         
         

         1. Member is currently receiving or will be initiating glucocorticoid therapy at an equivalent prednisone dose of greater than or equal to 2.5 mg/day for at least 3 months; and
         2. Member meets ANY of the following criteria:
            
            
            1. Member has a history of a fragility fracture; or
            2. Member has a pre-treatment T-score of less than or equal to -2.5; or
            3. Member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1) with a high pre-treatment FRAX fracture probability (See Appendix B).

      4. Paget’s disease of bone

   2. Aetna considers continuation of zoledronic acid (e.g., Reclast) therapy medically necessary for the following indications:

      1. Paget's disease of bone

         - for all members (including new members) meeting all initial selection criteria; or
         

      2. All other indications

         - for all members (including new members) who are currently receiving the requested medication through a previously authorized pharmacy or medical benefit, who meet one of the following: 
         
         

         1. Member has experienced clinical benefit as evidenced by a bone mass measurement showing an improvement or stabilization in T-score compared with the previous bone mass measurement and member has not experienced any adverse effects; or
         2. Member has received less than 24 months of therapy and has experienced clinical benefit as evidenced by no adverse events during therapy (i.e., no clinically significant adverse reaction to the requested drug, no new fracture seen on radiography).

2. Zoledronic acid (e.g., Zometa)

   1. Aetna considers zoledronic acid (e.g., Zometa) medically necessary for the following indications:
      
      

      1. Bone metastases from a solid tumor

         - for prevention of skeletal-related events in members with bone metastases from a solid tumor; or

      2. Breast cancer

         - for postmenopausal (natural or induced by ovarian suppression) members who are receiving adjuvant therapy for the treatment of breast cancer to maintain or improve bone mineral density and reduce the risk of fractures; or
         

      3. Hypercalcemia of malignancyFootnotes for Hypercalcemia of malignancy^*; or

      4. Multiple myeloma

         - for prevention of skeletal-related events in members with multiple myeloma; or 
         

      5. Prostate cancer

         - for treatment or prevention of osteoporosis during androgen deprivation therapy (ADT); or
         

      6. Systemic mastocytosis

         - for the treatment of osteopenia or osteoporosis in members with systemic mastocytosis. 

   2. Aetna considers continuation of zoledronic acid (e.g., Zometa) therapy medically necessary for members with an indication listed in section II.A who are experiencing benefit from therapy as evidenced by disease stability or disease improvement.

   Footnotes for Hypercalcemia of malignancy^* Note: Hypercalcemia of malignancy is defined as tumor related hypercalcemia (albumin-corrected calcium (cCa) of ≥12 mg/dL) using the corrected calcium formula= (((4 g/dL – patient albumin g/dL) x0.8) + observed calcium in mg/dL).

3. Experimental and Investigational

   Zoledronic acid (e.g., Zometa) is considered experimental and investigational for concurrent use with other zoledronic acid therapy (e.g., Reclast) or another bisphosphonate. 

   Aetna considers zoledronic acid experimental and investigational for the following indications because it has not been shown to be safe and effective for these indications (not an all-inclusive list):

   • Ankylosing spondylitis
   • Aortic valve stenosis
   • Aseptic necrosis (osteonecrosis)
   • Celiac disease (to increase bone mineral density)
   • Charcot neuroarthropathy
   • Chronic low back pain associated with Modic changes
   • Chronic multi-focal osteomyelitis
   • Colon cancer (other than bone metastases or bone pain)
   • Ehlers-Danlos syndrome
   • Hyperparathyroidism
   • Improvement of outcomes of hip or knee replacement
   • Lymphangiomatosis
   • Mazabraud syndrome
   • Non-small cell lung cancer (adjuvant/neoadjuvant therapy)
   • Non-tumor-related hypercalcemia
   • Osteogenesis imperfecta
   • Osteopenia (not meeting the above coverage requirements)
   • Osteoporosis associated with anorexia nervosa and secondary amenorrhea
   • Osteoporosis associated with hyperparathyroidism
   • Otosclerosis
   • Pleural mesothelioma
   • Polyostotic fibrous dysplasia
   • Prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy
   • Prevention of colorectal cancer in post-menopausal women
   • Psoriatic arthritis
   • SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome
   • Spinal cord injury (prevention and treatment of osteoporosis, reduction of urinary tract infection)
   • Spinal giant cell tumors
   • Tendon-to-bone healing.

Note: The World Health Organization defines osteoporosis as a bone mineral density value at the spine, hip, or forearm of 2.5 or more SD (standard deviations) below the young adult mean (T-score less than or equal to 2.5), with or without the presence of a fragility fracture.  Osteopenia is any bone density below the young adult mean.

Dosing Recommendations

Note: generic versions of zoledronic acid are available on the market.

Reclast

• Zoledronic acid is available as Reclast for injection as 5 mg in a 100 mL ready-to-infuse solution. Reclast injection must be administered as an intravenous (IV) infusion over no less than 15 minutes.

  • Treatment of Osteoporosis in Postmenopausal Women:

    The recommended regimen is a 5 mg infusion once a year given IV over no less than 15 minutes.

  • Prevention of Osteoporosis in Postmenopausal Women:

    The recommended regimen is a 5 mg infusion given once every 2 years IV over no less than 15 minutes.

  • Osteoporosis in Men: 

    The recommended regimen is a 5 mg infusion once a year given IV over no less than 15 minutes.

  • Treatment and Prevention of Glucocorticoid-Induced Osteoporosis: 

    The recommended regimen is a 5 mg infusion once a year given IV over no less than 15 minutes.

  • Treatment of Paget’s Disease of Bone: 

    The recommended dose is a single 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate. Individuals should receive 1500 mg elemental calcium and 800 international units vitamin D daily.
    
    

• Reclast is contraindicated in persons with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment, or persons with hypocalcemia.

Source: Novartis Pharmaceuticals, 2020

Zometa

• Zoledronic acid is available as Zometa Injection as 4 mg/100 mL (0.04 mg/mL) single-dose ready-to-use bottle and 4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior to intravenous infusion.

  • Hypercalcemia of Malignancy: 

    The maximum recommended dose of Zometa in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Persons who receive Zometa should have serum creatinine assessed prior to each treatment. Retreatment with Zometa 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all persons receiving Zometa and serum creatinine must be assessed prior to retreatment with Zometa. 

  • Multiple Myeloma and Bone Metastases of Solid Tumors: 

    The recommended dose of Zometa in persons with multiple myeloma and metastatic bone lesions from solid tumors for persons with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Source: Novartis Pharmaceuticals, 2018

Background

U.S. Food and Drug Administration (FDA)-Approved Indications for Reclast

• Treatment and prevention of osteoporosis in postmenopausal women
• Treatment to increase bone mass in men with osteoporosis
• Treatment and prevention of glucocorticoid-induced osteoporosis
• Treatment of Paget’s disease of bone in men and women
• Limitations of Use: Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use

U.S. Food and Drug Administration (FDA)-Approved Indications for Zometa

• Zometa/zoledronic acid is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL – patient albumin [g/dL]).
• Zometa/zoledronic acid is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.
• Limitation of Use: The safety and efficacy of Zometa/zoledronic acid in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established.

Compendial Uses for Zometa

• Treatment or prevention of osteoporosis during androgen-deprivation therapy (ADT) in prostate cancer patients with high fracture risk
• Treatment in postmenopausal patients with breast cancer who are receiving adjuvant therapy to maintain or improve bone mineral density and reduce risk of fractures
• Treatment for osteopenia or osteoporosis in patients with systemic mastocytosis.

Zoledronic acid (Reclast, Zometa), a member of the bisphosphonate class, inhibits osteoclast-mediated bone resorption. The antiresorptive mechanism is not fully understood and several factors are thought to contribute to this action. Bisphosphonates have high affinity for mineralized bone, with relatively long duration of action. In the osteoclast, the main molecular target of zoledronic acid is the enzyme farnesyl pyrophosphate synthase. However, this does not exclude other inhibitory mechanisms. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Osteoclastic resorption of mineralized bone and cartilage through its binding to bone is blocked by zoledronic acid. Increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors are inhibited by zoledronic acid.

Warnings and Precautions:

• Reclast contains the same active ingredient found in Zometa, used for oncology indications, thus, a patient being treated with Zometa should not be treated with Reclast. 
• Adequately rehydrate patients with hypercalcemia of malignancy prior to administration of Zometa and monitor electrolytes during treatment.
• Correct hypocalcemia before initiating zoledronic acid. Adequately supplement patients with calcium and vitamin D. Monitor serum calcium closely with concomitant administration of other drugs known to cause hypocalcemia to avoid severe or life-threatening hypocalcemia.
• Zoledronic acid is primarily eliminated through the kidney and may put patients with decreased renal function at increased risk for nephrotoxicity. Dosing adjustments are required when creatinine clearance (CrCl) drops below 60 mL/min and Zometa is not recommended for use once CrCl drops below 30 mL/min.
• Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min or in patients with evidence of acute renal impairment.
• Renal toxicity may be greater in patients with renal impairment. A single dose of Reclast should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Do not use Zometa doses greater than 4 mg. Treatment in patients with severe renal impairment is not recommended. Monitor creatinine clearance before each dose. 
• Severe incapacitating bone, joint, muscle pain may occur. Discontinue zoledronic acid if severe symptoms occur.
• Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy. These fractures may occur after minimal or no trauma. Evaluate patients with thigh or groin pain to rule out a femoral fracture. Consider discontinuation of zoledronic acid in patients suspected to have an atypical femur fracture. 
• Zoledronic acid has been linked to osteonecrosis of the jaw. Preventive dental examinations should be performed before starting zoledronic acid. Avoid invasive dental procedures. Per National Comprehensive Cancer Network (NCCN): Results from the study conducted by Zervas et al. in patients with multiple myeloma show a 9.5 fold greater risk for the development of osteonecrosis of the jaw with Zometa (zoledronic acid) compared to Aredia (pamidronate).
• The safety and efficacy of Zometa (zoledronic acid) has not been established for use in hyperparathyroidism or nontumor‐related hypercalcemia.
• Zoledronic acid can cause fetal harm. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Zoledronic acid should not be given if the patient is pregnant or plans to become pregnant, or if she is breastfeeding.

In September 2011, the FDA notified healthcare professionals as well as patients of an update to the drug label for Reclast regarding the risk of renal failure.  Cases of acute renal failure requiring dialysis or having a fatal outcome following Reclast use have been reported to FDA.  The revised label states that Reclast is contraindicated in patients with creatinine clearance less than 35 ml/min or in patients with evidence of acute renal impairment.  The label also recommends that healthcare professionals screen patients prior to administering Reclast in order to identify at-risk patients.

Zometa Dosing in Renal Impairment

The FDA-approved labeling for zolerdronic acid (Zometa) injections in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with a creatinine clearance (CrCl) of greater than 60 ml/min is 4 mg infused over no less than 15 mins every 3 to 4 weeks.  The optimal duration of therapy is unknown.  Upon initial treatment, the recommended Zometa doses for patients with reduced renal function (mild and moderate renal impairment) are listed in the Table below.  These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 ml/min.  Creatinine clearance is calculated using the Cockcroft-Gault formula (Novartis Pharmaceuticals, 2018).

Table: Reduced Zometa doses for persons with baseline CrCl less than or equal to 60 ml/min

Baseline Creatine Clearance (ml/min)	Zometa DoseFootnotes for Zometa Dose*
Greater than 60	4 mg
50 - 60	3.5 mg
40 - 49	3.3 mg
30 - 39	3 mg

Footnotes for Zometa Dose^*Doses calculated assuming target AUC of 0.66 (mg•hr/L) (CrCl = 75 ml/min)

During treatment, serum creatinine should be measured before each zolerdronic acid (Zometa) dose and treatment should be withheld for renal deterioration.  In clinical studies, renal deterioration was defined as follows:

• For patients with normal baseline creatinine, increase of 0.5 mg/dL
• For patients with an abnormal baseline creatinine, increase of 1.0 mg/dL

In clinical studies, Zometa treatment was resumed only when the creatinine returned to within 10 % of the baseline value and should be reinitiated at the same dose as that prior to treatment interruption.

In patients with hypercalcemia of malignancy (albumin-corrected serum calcium 12 mg/dL [3.0 mmol/L] or greater), the recommended dose of Zometa is 4 mg.  The 4 mg dose must be given as a single-dose intravenous infusion over 15 mins.  Patients who receive Zometa should have serum creatinine assessed prior to each treatment.  Dose adjustments of Zometa are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).  Re-treatment with Zometa 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment.  It is recommended that a minimum of 7 days elapse before re-treatment to allow for full response to the initial dose.

Androgen-Deprivation Therapy in Prostate Cancer

The United States Pharmacopeial Convention has concluded that zoledronic acid has an established role in prophylaxis of drug-induced osteopenia secondary to androgen-deprivation therapy in prostate cancer patients (USPDI, 2005).  The USPDI explains that long-term androgen-deprivation therapy can lead to significant decreases in bone mineral density (BMD).  Results of a multi-center, double-blind, placebo-controlled study demonstrated increasedBMD of the hip and spine of men with non-metastatic prostate cancer beginning androgen-deprivation therapy plus zoledronic acid (4 mg, intravenous, every 3 months) for 1 year (Smith et al, 2005).  The USPDI notes that a smaller, open-label controlled trial, published in abstract form, reported similar preliminary results.  The USPDI states that prostate cancer patients with clinically significant signs of bone loss due to androgen deprivation should be considered for treatment with intravenous zoledronic acid.  Baseline BMD and follow-up monitoring are warranted.  The USPDI notes, however, that further studies are needed to assess the long-term effects of bisphosphonates on fracture risk and disease-related outcomes (USPDI, 2005).

Poon and colleagues (2018) androgen-deprivation therapy (ADT) is an effective treatment for men with advanced prostate cancer (PCa), but loss of BMD is a major risk factor for fractures.  These investigators compared the efficacy of available treatments to provide prescribing guidance to healthcare professionals.  This was the 1st review to compare the effectiveness of different osteoporotic treatments (bisphosphonates, denosumab, toremifene, and raloxifene) on BMD in patients with non-metastatic PCa on ADT using network meta-analysis.  Results suggested that all evaluated treatments are effective in improving BMD compared to placebo.  Zoledronic acid (ZA) was found to have a greater improvement in BMD compared to other active treatments at all 3 studied sites, except for risedronate, which had better BMD improvement compared to ZA at the femoral neck site in 1 small study.  The authors concluded that the findings of this study did not identify evidence that one drug is unequivocally more effective than another.  All drugs appeared to be effective in reducing the rate of bone loss. 

Kozyrakis and associates (2018) carried out a non-systematic review of the international literature regarding the use of ZA and denosumab (DEN) in patients with PCa.  DEN and ZA have proved their efficacy in preventing osteoporosis and bone mass loss in patients treated with hormonal therapy with no proven superiority of one agent over the other.  However, the effectiveness in reducing fragility fractures has been proved only for DEN so far.  In metastatic-free, castrate-sensitive high-risk PCa patients, ZA has not shown any efficacy in preventing osseous metastasis, and evidence is lacking in favor or against the use of DEN.  The use of osteoclasts inhibitors had no evident positive effect in overall and disease-specific survival in this group of patients.  In advanced castrate-refractory malignancy, DEN has shown clinical superiority over ZA in preventing new skeletal-related events (SREs); but not in OS.  The authors concluded that superiority of DEN over ZA has been proved only in advanced castrate refractory disease in terms of preventing new SRE.  In the rest of the cases, the selection of either agent should be based on the clinical condition of each patient and the cost of the treatment.

Wu and co-workers (2018) noted that patients receiving ADT are associated with increasing loss of BMD and higher risk of SREs.  These investigators reviewed and analyzed the influence of diphosphonates on BMD change.  A systemic literature research was performed in PubMed and related bibliographies.  The focus of data extraction was BMD percentage change of lumbar spine, total hip, and femoral neck after 12 months.  Standardized mean difference (SMD) was pooled with the random-effects model, and meta-regression and subgroup analysis were performed to explore heterogeneity.  A total of 9 articles (n = 920) were included and finally analyzed after screening 118 articles.  These researchers found significant improvement in BMD percentage changes of the lumbar spine, total hip, and femoral neck at 1 year (respectively, SMD = 6.379, 95 % CI: 3.740 to 9.018, p < 0.001, I2 = 98.8 %, p < 0.001; SMD = 4.870, 95 % CI: 2.256 to 7.485, p < 0.001, I2 = 98.9 %, p < 0.001; SMD = 3.634, 95 % CI: 1.989 to 5.279, p < 0.001, I2 = 97.3 %, p < 0.001).  In individual variable meta-regression analysis, application of ZA or not showed a statistically significant influence on BMD percentage change of total hip (p = 0.018).  In subgroup analyses, both ZA and alendronate showed a significant improvement in BMD percentage changes.  Diphosphonates significantly increased BMD percentage changes of the lumbar spine, total hip, and femoral neck in men receiving ADT for PCa.  The authors concluded that patients with ADT should be evaluated BMD loss, and timely therapy with diphosphonates may be an appropriate strategy to prevent osteoporosis.

Kim and colleagues (2019) examined the change in BMD in patients with PCa receiving ADT compared to those with PCa or other urologic conditions not receiving ADT.  Literature searches were conducted throughout October 2018.  The eligibility of each study was assessed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the Participant, Intervention, Comparator, Outcome, and Study design method.  The outcomes analyzed were the mean difference (MD) of percent changes in BMD of lumbar spine, femur neck, and total hip.  A total of 5 prospective cohort studies with 533 participants were included in the present study.  Statistically significant decreases of BMD change relative to the control group were observed in the ADT treatment group in the lumbar spine (MD -3.60, 95 % CI: -6.72 to -0.47, p = 0.02), femoral neck (MD -3.11, 95 % CI: -4.73 to -1.48, p = 0.0002), and total hip (MD -1.59, 95 % CI: -2.99 to -0.19, p = 0.03).  There was a significant relationship between ADT and BMD reduction in patients with PCa.  The authors concluded that regular BMD testing and the optimal treatment for BMD loss should, therefore, be considered in patients with PCa undergoing ADT.  These researchers stated that NCCN’s guidelines regarding ADT-induced bone loss also recommend supplementation with either 60-mg of DEN subcutaneously every 6 months, 5-mg of ZA intravenously every year, or 70-mg of alendronate orally every week for men with a 10-year risk of hip fracture greater than 3 %, calculated using the fracture risk assessment tool.

Ankylosing Spondylitis

An UpToDate review on “Assessment and treatment of ankylosing spondylitis in adults” (Yu, 2016) does not mention zoledronic acid as a therapeutic option.

Aortic Valve Stenosis

In an experimental study, Synetos and colleagues (2018) evaluated the effectiveness of ZA on the inhibition of calcification in an experimental model of aortic valve (AV) stenosis.  A total of 16 New Zealand rabbits were placed on vitamin D-enriched diet for 3 weeks.  All animals underwent PET/CT at baseline and before euthanasia to assess calcification.  Thereafter, the AVs of 8 animals were treated with local delivery of 500 μg/L ZA.  A placebo mixture was administered in the remaining 8 animals.  Standardized uptake values were corrected for blood pool activity, providing mean tissue to background ratios (TBRmean).  In the ZA group, there was no progression of AV calcification (TBRmean 1.20 ± 0.12 versus 1.17 ± 0.78, p = 0.29), while AV calcification progressed in the placebo group (1.22 ± 0.15 versus 1.53 ± 0.23, p = 0.006).  Ascending aorta calcification progressed in both ZA and placebo groups.  Histology confirmed the results of the PET/CT.  The authors concluded that inhibition of AV calcification by local delivery of ZA was feasible and effective.  These findings need to be further investigated in human studies.

Bone Loss from Aromatase Inhibitors

In a randomized, open-label, phase III study, Gnant et al (2008) evaluated zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reported on long-term findings of BMD during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid.  The study was a 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in pre-menopausal women with endocrine-responsive breast cancer.  This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months.  The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients.  Analyses were intention-to-treat; statistical significance was assessed by t-tests.  A total of 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n = 199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n = 205).  After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3 %, mean difference -0.119 g/cm(2) [95 % CI: 0.146 to -0.091], p < 0.0001) and trochanter (-7.3 %, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p < 0.0001).  In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6 %, mean difference -0.141 g/cm(2) [-0.179 to -0.102] versus -9.0 %, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p < 0.0001 for both).  Two years after the completion of treatment (median follow-up 60 months [range of 15.5 to 96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3 %, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p = 0.001; trochanter -4.1 %, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p = 0.058).  Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4 %, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8 %, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0 %, mean difference 0.039 g/cm(2) [0.005 to 0.075], p = 0.02; trochanter +3.9 %, mean difference 0.028 g/cm(2) [0.003 to 0.058], p = 0.07) compared with baseline.  The authors concluded that goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss.  Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels.  Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.

Bone Metastases from Prostate Cancer

In 2 placebo-controlled clinical studies in patients with bone metastases from prostate cancer (n = 643) or from other solid tumors (n = 773), both the percentage of patients with skeletal events (e.g., pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression) and the time to first skeletal event were decreased relative to placebo.  In randomized controlled studies submitted to FDA for approval, there were 11 % fewer skeletal events in zoledronic acid-treated patients with metastatic prostate cancer and 7 % fewer skeletal events in treated patients with other metastatic solid tumors compared to placebo-treated patients.

Bone Metastases from Solid Tumors

The American Society of Clinical Oncology (Van Poznak et al, 2010) updated the recommendations on the role of bone-modifying agents in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases.  A literature search using MEDLINE and the Cochrane Collaboration Library identified relevant studies published between January 2003 and November 2010.  The primary outcomes of interest were SREs and time to SRE.  Secondary outcomes included adverse events and pain.  An Update Committee reviewed the literature and re-evaluated previous recommendations.  Recommendations were modified to include a new agent.  A recommendation regarding osteonecrosis of the jaw was added.  According to ASCO, bone-modifying agent therapy is only recommended for patients with breast cancer with evidence of bone metastases; denosumab 120 mg subcutaneously every 4 weeks, intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 mins every 3 to 4 weeks is recommended.  There is insufficient evidence to demonstrate greater efficacy of one bone-modifying agent over another.  In patients with a calculated serum CrCl of more than 60 mg/min, no change in dosage, infusion time, or interval of bisphosphonate administration is required.  Serum creatinine should be monitored before each dose.  All patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health.  Current standards of care for cancer bone pain management should be applied at the onset of pain, in concert with the initiation of bone-modifying agent therapy.  The use of biochemical markers to monitor bone-modifying agent use is not recommended.

Mahtani et al (2011) stated that non-small-cell lung cancer (NSCLC) is frequently characterized by metastases to bone.  Bisphosphonates have shown efficacy in reducing the risk of SREs in cancer patients with bone metastases, including those with NSCLC.  Zoledronic acid is one of the most potent bisphosphonates and is approved for the first-line treatment of patients with multiple myeloma and bone metastases from solid tumors.  Recent preclinical and clinical data suggest that ZOL may also have direct and indirect anti-cancer effects.  Several pre-clinical studies have provided insight into the potential mechanisms responsible for the anti-cancer activity of ZOL, including inhibiting farnesyl pyrophosphate or geranylgeranyl pyrophosphate and activation of immune-mediated anti-cancer response by gammadelta T cells.  In patients with NSCLC, ZOL has been shown to reduce vascular endothelial growth factor levels with a direct correlation to clinical response.  Clinical studies in this setting have shown that ZOL may also provide a survival benefit and prolong time to progression.  Ongoing studies are evaluating the efficacy of ZOL for anti-cancer activity and prevention of bone metastases.

Rennert and colleagues (2011) noted that bisphosphonates are commonly used for the treatment of osteoporosis and bone metastases caused by breast cancer and were recently reported to be associated with a reduced risk of breast cancer, possibly acting through the mevalonate pathway, but their association with risk of other cancers is unknown.  The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study of patients with colorectal cancer and age-, sex-, clinic-, and ethnic group-matched controls.  Long-term use of bisphosphonates before diagnosis was assessed in a subset of 933 pairs of post-menopausal patients and controls using computerized pharmacy records.  The use of bisphosphonates for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk (RR) of colorectal cancer (RR, 0.50; 95 % CI: 0.35 to 0.71).  This association remained statistically significant after adjustment in a model for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and post-menopausal hormones (RR, 0.41; 95 % CI: 0.25 to 0.67).  Concomitant use of bisphosphonates and statins did not further reduce the risk.  The authors concluded that the use of oral bisphosphonates for more than 1 year was associated with a 59 % relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk.  They stated that this significant negative association calls for consideration of bisphosphonates for future chemo-prevention studies.

In a Cochrane review, Wong et al (2012) evaluated the effect of bisphosphonates on skeletal-related events (SREs), bone pain, quality of life (QoL), recurrence and survival in women with breast cancer with bone metastases (BCBM), advanced breast cancer (ABC) without clinical evidence of bone metastases and early breast cancer (EBC).  The authors concluded that in women with clinically evident BCBM, bisphosphonates (oral and i.v.) and denosumab (s.c.) reduced the risk of developing SREs, as well as delaying the time to SREs.  Some bisphosphonates may also reduce bone pain and may improve QoL.  The optimal timing and duration of treatment for patients with BCBM remains uncertain.  There is currently insufficient evidence to support the routine use of bisphosphonates as adjuvant treatment for patients with EBC.  However, a number of large clinical trials investigating bisphosphonates in EBC have completed accrual and are awaiting results.

Breast Cancer Adjuvant/Neoadjuvant Treatment

Guidelines from the American Society for Clinical Oncology and Cancer Care Ontario (Dhesy-Thind, et al., 2017) recommend that zoledronic acid (4 mg intravenously every 6 months) or clodronate (1,600 mg per day orally) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. The guidelines state that data for adjuvant denosumab look promising but are currently insufficient to make any recommendation.

The guidelines recommend that administration of bisphosphonates as adjuvant therapy be considered for postmenopausal patients with breast cancer (including patients premenopausal before treatment who have menopause induced by ovarian suppression) deemed candidates for adjuvant systemic therapy. The guidelines state that, for purposes of adjuvant bisphosphonate use, the definition of menopause should include both natural menopause (at least 12 months of amenorrhea prior to initiation of chemotherapy or endocrine therapy) and menopause induced by ovarian ablation or suppression (but not the cessation of menses due to chemotherapy alone). In women age ≤ 60 years with a previous hysterectomy and ovaries left in place, luteinizing hormone, follicle-stimulating hormone, and serum estradiol should be in the postmenopausal range and measured prior to initiation of any systemic therapy to receive adjuvant bisphosphonates.

The guidelines noted that, "while the Early Breast Cancer Trialists' Collaborative Group (citing EBCTCG, 2015) meta-analysis found benefit for bisphosphonates in all subgroups of postmenopausal patients, the absolute benefit was small. For patients with cancers assessed as having low risk of recurrence, the use of bisphosphonates may not result in clinically meaningful effect." Considerations in deeming patients at high enough recurrence risk to receive adjuvant systemic therapy may also apply in deciding on bisphosphonate use.

Breast cancer guidelines from the National Comprehensive Cancer Network (NCCN, 2017) recommend “Consider adjuvant bisphosphonate therapy in postmenopausal (natural or induced) patients receiving adjuvant endocrine therapy.” 

In a meta-analysis, Mauri et al (2010) examined if the use of bisphosphonates in the adjuvant setting of breast cancer might have any effect on the natural course of the disease.  Published and unpublished randomized controlled trials found in PubMed, the Cochrane Central Register of Controlled Trials, the ISI Web of Knowledge, and abstracts of major international conferences up to January 2009 were considered in this analysis.  All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with any bisphosphonate versus non-use were considered eligible.  Analysis included data from 13 eligible trials involving 6,886 patients randomized to treatment with bisphosphonates (n = 3,414) or either placebo or no treatment (n = 3,472).  Compared with no use, adjuvant breast cancer treatment with bisphosphonates did not reduce the overall number of deaths (odds ratio [OR], 0.708; 95 % CI: 0.482 to1.041; p = 0.079), bone metastases (OR, 0.925; 95 % CI: 0.768 to 1.114; p = 0.413), overall disease recurrences (OR, 0.843; 95 % CI: 0.602 to 1.181; p = 0.321), distant relapse (OR, 0.896; 95 % CI: 0.674 to 1.192; p = 0.453), visceral recurrences (OR, 1.051; 95 % CI: 0.686 to 1.609; p = 0.820), or local relapses (OR, 1.056; 95 % CI: 0.750 to 1.487; p = 0.756).  No significant heterogeneity was observed among the trials except for estimates of deaths and disease recurrences (p = 0.034 and p = 0.016, respectively).  In subgroup analyses, use of zoledronic acid was associated with a statistically significant lower risk for disease recurrence (OR, 0.675; 95 % CI: 0.479 to 0.952; p = 0.025).  However, these results should be interpreted with caution because the statistical significance for this association was weak and might be attributed to chance from multi-test analyses.  Use of zoledronic acid was not associated with any significant difference in death (OR, 0.642; 95 % CI: 0.388 to 1.063) and bone metastasis rates (OR, 0.661; 95 % CI: 0.379 to 1.151).  Currently available evidence does not support the hypothesis that use of bisphosphonates in adjuvant treatment of early breast cancer will alter the natural course of the disease.  Nonetheless, a non-significant trend seems to exist for better outcomes in patients undergoing bisphosphonate treatment.  The authors stated that until further evidence from new clinical trials becomes available, adjuvant bisphosphonates should not be recommended routinely.

Coleman et al (2010) noted that pre-clinical studies have demonstrated synergistic anti-tumor effects of chemotherapy (CT) and zoledronic acid (ZOL).  Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT.  These investigators reported a retrospective evaluation comparing pathological response in the primary tumor between treatment groups.  A total of 205 patients received neoadjuvant CT +/- ZOL (CT + ZOL, n = 102; CT, n = 103).  The primary end point was pathologically assessed residual invasive tumor size (RITS) at surgery.  Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement.  Following review of surgical pathology reports (n = 195), outcome differences between groups were assessed adjusting for potential response modifiers.  Baseline characteristics and CT treatments were similar.  In multi-variate analysis, allowing for biological and clinical factors known to influence tumor response, the adjusted mean RITS in CT and CT + ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95 % CI: 3.5 to 20.4 mm; p = 0.006).  The pCR rate was 6.9 % in the CT group and 11.7 % in the CT + ZOL group (p = 0.146).  There was no difference in axillary nodal involvement (p = 0.6315).  The authors concluded that these findings suggest a possible direct anti-tumor effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

Coleman et al (2011) stated that data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer.  These investigators examined if treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients.  In this open-label, phase III clinical trial, a total of 3,360 patients were randomly assigned to receive standard adjuvant systemic therapy either with or without zoledronic acid.  The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment.  The primary end point of the study was disease-free survival.  A second interim analysis revealed that a pre-specified boundary for lack of benefit had been crossed.  At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77 % in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95 % CI: 0.85 to 1.13; p = 0.79).  Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group.  The numbers of deaths -- 243 in the zoledronic acid group and 276 in the control group -- were also similar, resulting in rates of overall survival of 85.4 % in the zoledronic acid group and 83.1 % in the control group (adjusted hazard ratio, 0.85; 95 % CI: 0.72 to 1.01; p = 0.07).  In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1 %; 95 % CI: 0.6 to 1.7; p < 0.001) and 9 suspected cases; there were no cases in the control group.  Rates of other adverse effects were similar in the 2 study groups.  The authors concluded that these findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer.

He and colleagues (2013) evaluated the clinical outcome of zoledronic acid as an adjuvant therapy for patients with early stage breast cancer.  Entries in the PubMed and EMBASE databases up to July 12, 2013 were systematically reviewed.  Online abstracts from the proceedings of the Annual Meetings of the American Society of Clinical Oncology (ASCO) (1992 to 2013) and the San Antonio Breast Cancer Symposium (SABCS) (2004 to 2013) were also reviewed.  Primary end-points included overall survival (OS) and disease-free survival (DFS), while secondary end-points included bone metastasis-free survival (BMFS), distant metastasis-free survival (DMFS), and fracture-free rate (FFR).  A total of 8 studies including 3,866 subjects and 3,864 controls met the search criteria and were evaluated.  The use of zoledronic acid was found to improve OS (RR, 0.88; 95 % CI: 0.77 to 1.01; p = 0.06) and DMFS (RR, 0.77; 95 % CI: 0.60 to 1.00; p = 0.05).  Furthermore, statistically significant benefits were associated with BMFS (RR, 0.81; 95 % CI: 0.66 to 0.99; p = 0.04) and FFRs (RR, 0.75; 95 % CI: 0.61 to 0.92; p = 0.007).  In contrast, there was no significant difference in DFS with the application of zoledronic acid (RR, 0.88; 95 % CI: 0.72 to 1.09; p = 0.24).  Sensitivity analysis further identified the improvement of 5-year OS for the adjuvant zoledronic acid therapy in early stage breast cancer patients (RR, 0.86; 95 % CI: 0.75 to 0.99; p = 0.03), while a borderline statistically significant benefit was observed for 5-year DFS (RR, 0.90; 95 % CI: 0.81 to 1.00; p = 0.06).  The authors concluded that zoledronic acid as an adjuvant therapy appears to improve the 5-year OS rate for early stage breast cancer patients, and was associated with a protective effect for the bone metastases and fractures evaluated in more than 7,000 patients.  Moreover, they stated that further research is needed to confirm these findings, and sub-group analyses according to menopause status or hormone status may provide further insight.

Brufsky et al (2009) stated that post-menopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures.  The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the safety and effectiveness of zoledronic acid in preventing such bone loss.  In this multi-center study, post-menopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years.  Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a non-traumatic fracture occurred.  The primary end-point was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary end-points, measured at other pre-determined time-points, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence.  These investigators reported the results of the 36-month interim analysis.  Overall, 301 patients were randomized to each group.  At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7 % and 5.2 %, respectively (p < 0.0001 for both).  Although this study was not designed to show anti-fracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7 %] versus delayed, 19 [6.3 %]) but not statistically significant (p = 0.8638).  Pyrexia (27 [9 %] versus 6 [2 %]; p = 0.0002) and bone pain (39 [13 %] versus 20 [6.7 %]; p = 0.01) were more common in up-front patients; cough (13 [4.3 %] versus 27 [9 %]; p = 0.03) was more common in delayed patients.  No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported.  Disease recurrence was reported in 9 up-front (3.0 %) and 16 delayed (5.3 %) patients (Kaplan-Meier analysis, p = 0.127), with an absolute decrease of 2.3 %.  The authors concluded that up-front ZA more effectively prevented AI-associated bone loss in post-menopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs. 

Valachis et al (2013) estimated the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I-III) breast cancer.  These researchers performed a systematic review and meta-analysis of randomized clinical trials (RCTs).  Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches.  All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus non-use, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible.  Standard meta-analytic procedures were used to analyze the study outcomes.  A total of 15 studies were considered eligible and were further analyzed.  The use of zoledronic acid resulted in a statistically significant better overall survival (OS) outcome (5 studies, 6,414 patients; hazard ratio [HR], 0.81; 95 % confidence interval [CI]: 0.70 to 0.94).  No significant differences were found for the disease-free survival (DFS) outcome (7 studies, 7,541 patients; HR, 0.86; 95 % CI: 0.70 to 1.06) or incidence of bone metastases (7 studies, 7,543 patients; odds ratio [OR], 0.94; 95 % CI: 0.64 to 1.37).  Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95 % CI: 0.63 to 0.96).  Finally, the rate of osteonecrosis of the jaw was 0.52 %.  The authors concluded that zoledronic acid as adjuvant therapy in breast cancer patients appeared to not only reduce the fracture risk but also offered a survival benefit over placebo or no treatment.

Hue and colleagues (2014) noted that studies have shown that bisphosphonates may have anti-tumor and anti-metastatic properties. Observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials.  These researchers assessed the relationship of post-menopausal breast cancer incidence and bisphosphonate use by means of data from 2 randomized (1:1), double-blind, placebo-controlled trials.  The Fracture Intervention Trial (FIT) randomly assigned 6,459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years.  The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7,765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years.  Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT).  Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses.  In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases.  The primary analysis compared events in the active versus placebo group using a log-rank test.  Hazard ratio (HR) for incident breast cancer in the bisphosphonate treatment group compared to the placebo group was compiled.  There was no significant difference in the rate of breast cancer in FIT: 1.5 % (n = 46) in the placebo group and 1.8 % (n = 57) in the alendronate group (HR, 1.24 [95 % CI: 0.84 to 1.83]).  In HORIZON-PFT, there was also no significant difference: 0.8 % (n = 29) in the placebo group and 0.9 % (n = 33) in the zoledronic acid group (HR, 1.15 [95 % CI: 0.70 to 1.89]).  There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95 % CI: 0.89 to 1.63]).  The authors concluded that the results of these 2 randomized clinical trials did not support the findings from observational research.  Contrary to the results from observational studies, these researchers found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive post-menopausal breast cancer.

The Early Breast Cancer Triallists' Collaborative Group (EBCTCG, 2015) undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. The authors sought individual patient data from all unconfounded trials in early breast cancer that randomized between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [e.g., zoledronic acid, ibandronate, pamidronate] or other [i.e., clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). The authors received data on 18,766 women (18,206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11,767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, estrogen receptor status, nodes, tumor grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02). The authors concluded that 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.

Celiac Disease

In a prospective, randomized, pilot study, Kumar et al (2013) examined the effect of ZA on BMD in patients with celiac disease (CD).  A total of 28 CD patients were randomized to receive gluten-free diet (GFD), calcium and cholecalciferol (group A), and ZA (group B).  Baseline biochemical tests and T-score by DXA were done and repeated after 12 months.  The T-score showed improvement in the control-arm (group A) from -3.31 ± 1.46 to -2.12 ± 1.44, a gain of 35.9 % (p < 0.05) and in drug-arm (group B) -2.82 ± 1.27 to -1.06 ± 1.84, registering a gain of 62.4 % (p < 0.001).  However, there was no difference in improvement of T-score in ZA group as compared to the control group.  The authors concluded that administration of ZA was not found to be better than GFD alone in increasing BMD in CD patients with low BMD in this pilot study.

Charcot Arthropathy

In a pilot study, Pakarinen et al (2011) examined the clinical effectiveness of zoledronic acid in patients with diabetes and acute Charcot neuroarthropathy.  A total of 39 consecutive patients were randomly assigned to placebo or 3 intravenous infusions of 4 mg zoledronic acid.  The primary outcome was clinical resolution of acute Charcot neuroarthropathy determined by total immobilization time (casting plus orthosis).  At baseline, there was no significant difference between the randomly assigned groups with respect to Charcot disease activity or other baseline values.  In the zoledronic acid group, the median time for total immobilization was 27 weeks (range of 10 to 62), and in the placebo group it was 20 weeks (20 to 52) (p = 0.02).  The authors concluded that zoledronic acid had no beneficial effect on the clinical resolution of acute Charcot neuroarthropathy in terms of total immobilization time.  It is possible that it may prolong the time to clinical resolution of Charcot neuroarthropathy.

Al-Nammari and associates (2013) outlined advances in the pharmacotherapy of acute Charcot neuroarthropathy.  PubMed and the Cochrane Database of systematic reviews were searched; relevant papers were cross-referenced.  A total of 11 original studies were identified.  The limited data available suggested pamidronate, alendronate and calcitonin provide some clinical and biochemical improvements.  On the other hand, zoledronic acid is deleterious and, increases off-loading times.  However, the data are not robust enough to convincingly demonstrate clinically meaningful effects.  The studies were predominantly low-quality and heterogeneous.  They differed markedly in study type, pharmacological agent used, dosing regimen, disease, etiology/stage/location, concurrent off-loading regimen, outcomes and, follow-up.  Few were rigorous in controlling for associated confounding variables and none investigated long-term outcomes.  The authors concluded that the routine use of pharmacological treatment modalities for this condition is not recommended in the United States FDA or in the United Kingdom by the National Institute for Health and Clinical Excellence.  They stated that given the evidence available this is justified and further higher quality research is needed.

Colon Cancer

Zhu and co-workers (2017) noted that ZA is the 3rd generation of bisphosphonates, which can inhibit many tumors growth, especially to inhibit the growth of colon cancer.  However, the molecular mechanism is still unclear.  In this study, these researchers observed that ZA could regulate CT26 colon cancer cells autophagy, promote CT26 cells apoptosis, and inhibit CT26 cells proliferation.  Western blotting analysis showed that pro-apoptosis protein caspase-3 was basically unchanged, whereas the expression of the activated caspase-3 was significantly increased, after CT26 cells were treated with different doses of ZA.  Western blot also showed that ZA could significantly affect the expression of p-p53 and autophagy-related proteins beclin-1 and p62.  The authors concluded that these findings demonstrated that ZA was an effective inhibitor of CT26 colon cancer cells.  Its anti-cancer activities were mediated by induction of apoptosis and regulation of autophagy.  These investigators stated that they only conducted the experiments in-vitro, but more in-vivo experiments with animals needed to be conducted; and further observation on the blood concentration of ZA within the patient's body are also needed to be carried out to examine if ZA at this blood concentration can cause the same effects on colon cancer tissue and the related toxic side effects.

Ehlers-Danlos Syndrome

An UpToDate review on “Overview of the management of Ehlers-Danlos syndromes” (Pauker and Stoler, 2019) does not mention zoledronic acid as a therapeutic option.

Hypercalcemia of Malignancy

The clinical studies that were presented to the FDA for approval for hypercalcemia of malignancy directly compared zoledronic acid to the intravenous bisphosphonate pamidronate (Aredia).  The advantages of zoledronic acid over pamidronate, from clinical studies, include a more rapid rate of infusion (a 15-min infusion time for zoledronic acid versus a 2-hr infusion time for pamidronate) and a significantly higher response rate with zoledronic acid.

Hypercalcemia of malignancy is defined as an albumin‐corrected calcium (cCa) of ≥2 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL –patient albumin (g/dL)).

Pooled data from 2 multi-center trials involving 275 patients with hypercalcemia of malignancy compared patients receiving a single dose of either 4 mg or 8 mg zoledronic acid infused over 5 mins, to patients receiving a single 90 mg dose of pamidronate infused over 2 hrs.  By day 10 of treatment, corrected serum calcium concentrations were normalized in 88.4 % of patients treated with 4 mg zoledronic acid, and 86.7 % treated with 8 mg zoledronic acid. In comparison, 69.7 % of patients treated with pamidronate achieved normalized serum calcium concentrations.  The median duration of complete response (maintaining normalized calcium levels) was higher in patients treated with zoledronic acid than pamidronate (32 and 43 days for zoledronic acid 4 and 8 mg, and 18 days for pamidronate).

Hyperparathyroidism and Non-Tumor-Related Hypercalcemia

Per the Prescribing Information, the safety and efficacy of zoledronic acid  (Zometa) has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.

Improvement of Patient-Reported Outcomes after Hip or Knee Replacement

Brandt and colleagues (2020) noted that in Sweden, roughly 3,000 patients are re-operated each year due to pain and loss of function related to a loosened hip or knee prosthesis.  These re-operations are strenuous for the patient, technically demanding and costly for the healthcare system.  Any such re-operation that can be prevented would be of great benefit.  Bisphosphonates are drugs that inhibit osteoclast function.  Several clinical trials suggested that bisphosphonates led to improved implant fixation and 1 small study even indicated better functional outcome.  Furthermore, in epidemiological studies, bisphosphonates have been shown to reduce the rate of revision for aseptic loosening by 50 %.  Therefore, there are several indirect indications that bisphosphonates could improve patient-reported outcome (PRO), but no firm evidence.  This is a pragmatic, randomized, placebo-controlled, double-blinded, clinical trial of a single post-operative dose of ZA, in patients younger than 80 years undergoing primary total hip or knee replacement (THA or TKA) for osteoarthritis (OA).  Subjects will be recruited from 2 orthopedic departments.  All surgeries will be performed, and study drugs given at Motala Hospital, Sweden.  The primary end-point is to examine between-group differences in the Hip dysfunction and Osteoarthritis Outcome Score and the Knee injury and Osteoarthritis Outcome Score at 3-year follow-up.  Secondary outcomes will be examined at 1 year, 3 years and 6 years, and stratified for hip and knee implants.  These secondary end-points are supportive, exploratory or explanatory; a total of 1,000 patients will be included in the study.  The study has been approved by the Regional Ethical Review Board in Linkoping (DNR 2015/286-31).  The study will be reported in accordance with the Consolidated Standards of Reporting Trials statement for pharmacological trials.  The results will be submitted for publication in peer-reviewed academic journals and disseminated to patient organizations and the media.

Zhu and associates (2020) validated the therapeutic efficacy of ZA in elderly patients with femoral neck fracture who received THA or hemiarthroplasty (HA).  Included in this study were 95 elderly patients with femoral neck fractures who received THA/HA between August 2015 and June 2018.  They were randomized into a ZA group and a control group.  Patients in ZA group received a yearly single-dose of 5 mg ZA intravenous injection plus 0.5 μg/day calcitriol and 1,000 mg/day calcium carbonate 2 days before THA or HA.  Patients in the control group were treated with the same dose of calcitriol and calcium carbonate only without ZA; BMD was measured by dual-energy X-ray absorptiometry (DEXA).  Bone metabolism markers including the total extension of the peptide type I collagen amino end (P1NP) and beta collagen degradation product (β-CTX) were obtained by serum examination.  The post-operative functional outcome was assessed using Harris Hip Score (HHS).  During the follow-up period, BMD in the ZA group was improved and significantly higher than that in the control group at 6 and 12 months post-operation.  Bone metabolism markers P1NP and β-CTX in ZA group remained at a relatively low level as compared with that in the control group at 6 months after treatment.  No significant difference in the mean HHS and the excellent/good rate of joint function was observed during the follow-up period between the 2 groups.  The occurrence of AEs in the ZA group was significantly higher than that in the control group.  The authors concluded that a single infusion of ZA showed promise in improving BMD of the healthy side of the femoral neck, lumbar spine, and total hip and decreasing the level of bone markers, which may improve the clinical outcome of patients with osteoporotic femoral neck fractures receiving THA/HA.

Low Back Pain

Koivisto and colleagues (2014) noted that modic changes (MC) are associated with low back pain (LBP), but effective treatments are lacking.  In a randomized, placebo-controlled, double-blinded trial, these researchers evaluated the effectiveness of ZA for chronic LBP among patients with MC in MRI.  Inclusion criteria were LBP lasting greater than or equal to 3 months, with an intensity of greater than or equal to 6 on a 10-cm visual analog scale (VAS) or an Oswestry Disability Index (ODI) of greater than or equal to 30 %, and MC in MRI.  Patients were randomized into single intravenous infusion of ZA 5 mg (n = 20), or placebo (n = 20) groups.  The primary outcome was LBP intensity; secondary outcomes included leg pain intensity, ODI, health-related quality of life (RAND-36), lumbar flexibility, sick leaves and use of pain medication.  The treatment differences at 1 month and 1 year were analyzed using ANCOVA with adjustment for the baseline score.  The mean difference (MD) between the groups in the primary outcome, intensity of LBP, was 1.4 (95 % CI: 0.01 to 2.9) in favor of ZA at 1 month.  These researchers observed no significant between-group difference in the intensity of LBP at 1 year (MD 0.7; 95 % CI: -1.0 to 2.4) or in secondary outcomes at any time-point except that 20 % of patients in the ZA group used non-steroidal anti-inflammatory drugs (NSAIDs) at 1 year compared to 60 % in the placebo group (p = 0.022).  Acute phase reactions (fever, flu-like symptoms, arthralgia) emerged in 95 % of the patients in the ZA group, compared to 35 % in the placebo group.  The authors concluded that ZA was effective in reducing the intensity of LBP in the short-term and in reducing the use of NSAIDs within the time span of 1 year among patients with chronic LBP and MC confirmed in MRI.  Moreover, they stated that although the results appeared encouraging, larger studies are needed to analyze the safety and effectiveness of ZA for patients with MC.

Lymphangiomatosis

Blei (2011) stated that lymphangiomatosis is a general term for excessive growth of aberrant lymphatic vessels. The impact of lymphangiomatosis can be devastating due to osteolysis and/or multi-organ involvement.  The disorders are heterogeneous, and treatment is dependent upon disease location and symptoms.  Most reports were single cases or small case series, predominantly in the orthopedic and radiologic literature.  Basic research focused on lymphatic disorders may translate into new therapies for these disorders.  The author noted that bisphosphonates and vitamin D have been utilized in many cases, with results ranging from stabilization to lack of response.

Venkatramani et al (2011) stated that Gorham's disease is a rare disorder of unknown etiology and variable clinical presentation that is characterized by proliferation of thin-walled vascular channels resulting in destruction and resorption of osseous matrix. The condition is frequently under recognized or misdiagnosed.  There is no standard treatment defined for this disease.  These investigators reported on 8 children diagnosed with Gorham's disease at the authors’ institution over a 10-year period.  Soft tissue lymphangioma was present in 7 and 6 children had splenic involvement.  Disease stabilization and improvement was observed on treatment with interferon alpha-2b and bisphosphonate therapy.   These investigators noted that 6 patients received monthly intravenous pamidronate therapy (1 mg/kg/dose).  Quantitative computed tomography (QCT) densitometry was performed at baseline and annually to evaluate bone health.  In 5 patients who had at least 2 QCT (range of 2 to 5) examinations, the mean cancellous bone density significantly improved with bisphosphonate therapy from baseline (177.6 +/- 74.8 to 209.4 +/- 94 mg/cm3) after a median follow-up of 24 months (paired t-test, p = 0.019).  However, there was no significant improvement in the mean cortical bone density (2066.2 +/- 202.7 versus 2113 +/- 57 mg/cm3, paired t-test, p = 0.29).  Moreover, the authors stated that there is no standard medical therapy available for Gorham’s disease and various treatments have been attempted.  Bisphosphonate therapy is used for both its putative anti-osteoclastic and anti-angiogenic activity. The effectiveness of this treatment is difficult to assess as spontaneous arrest and regression of Gorham’s lesions have been described.  The authors concluded that interferon alpha- 2b and bisphosphonates may be helpful in arresting disease progression and improvement of symptoms in children with Gorham’s disease.  They stated that further research to elucidate etiology, biological pathways, and hypothesis driven clinical trials for this fascinating disease are needed.

Gordon and Mortimer (2011) stated that lymphangiomatosis is a rare proliferative disorder of the lymphatic system. The etiology is unknown, rendering it difficult to manage.  This case report of lymphangiomatosis with features of Gorham's disease revealed the progressive and unexpected nature of the condition.  It highlighted the need for further research into the pathophysiology and management of lymphangiomatosis as current treatment options are limited.  The authors stated that it was difficult to assess the efficacy of the bisphosphonates.  Nonetheless, she continues to receive 3-monthly infusions to this date in case they are of benefit.  Bisphosphonates were introduced relatively early in the disease course.  They have not halted the lymphangiomatosis, but it is impossible to say whether they have slowed down the process.

Mastocytosis-Related Osteoporosis

Rossini et al (2014) examined the effectiveness of zoledronic acid in patients with mastocytosis-related osteoporosis.  A total of 25 patients with osteoporosis secondary to indolent systemic mastocytosis were given a single intravenous infusion of 5-mg zoledronic acid dissolved in 100 ml of 0.9 % saline over 60 minutes.  After 1 year, the mean increase in BMD was 6.0 % ± 4.4 % at the spine and 2.4 % ± 3.2 % at the total hip.  Serum levels of bone turnover markers decreased versus baseline: bone alkaline phosphatase -34 % and -35 %, and C-terminal telopeptide -68 % and -56 % at 6 and 12 months, respectively.  None of the patients reported new fractures during the year of follow-up.  In all the first 20 treated patients, a transitory acute phase response was observed, but this was prevented in 4 of 5 subsequent patients in whom acetaminophen was given systematically during the 3 days post-infusion.  The authors concluded that single 5-mg zoledronic acid intravenous infusion in patients with osteoporosis secondary to indolent systemic mastocytosis was associated with significant increases in spine and hip BMD and decreases of bone turnover markers over at least 1 year.  They stated that yearly zoledronic acid might represent a therapeutic option for indolent systemic mastocytosis-associated osteoporosis.  These preliminary findings need to be validated by well-designed studies with larger sample size and longer follow-up.

Rossini et al (2016) stated that the central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.

Furthermore, an UpToDate review on “Treatment and prognosis of systemic mastocytosis” (Castells and Akin, 2015) states that “Osteoporosis and fractures -- Patients should be monitored for osteoporosis and treated appropriately.  Appropriate daily intake of calcium and vitamin D should be maintained.  For patients with osteoporosis-related fractures, treatment with the combination of pamidronate and low dose interferon-alpha has been reported to be helpful”.  This review does not mention zoledronic acid as a therapeutic option.

Multiple Myeloma

Zoledronic acid has been compared to pamidronate in a 13-month phase III study of 1,648 patients with advanced stage III multiple myeloma or advanced breast cancer with bone metastases.  The study showed that zoledronic acid and pamidronate are approximately equal in effectiveness with respect to the primary efficacy endpoint, the proportion of patients experiencing at least one skeletal-related event.  The skeletal morbidity rate was slightly lower in patients treated with zoledronic acid than in those treated with pamidronate, and zoledronic acid significantly decreased the incidence and event rate for radiation therapy to bone.  Pain scores decreased in all treatment groups, and zoledronic acid and pamidronate were equally well-tolerated.

Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragile bone and reduced BMD.  Cheung and Glorieux (2008) stated that intravenous pamidronate is now the standard of care for moderately to severely affected children with OI, given in combination with good orthopedic, physiotherapy and rehabilitation programs.  The benefits and short-term safety of cyclic bisphosphonates have been amply reported in the literature; however their long-term effects are still under investigation.  Newer, more potent forms of bisphosphonates such as zoledronic acid have undergone and are still being subject to international multi-center drug trials and are beginning to replace pamidronate in some centers.  In a review on bisphosphonates and other new therapeutic agents for the treatmednt of OI, Yamashita (2009) stated that cyclic intravenous pamidronate is now the standard treatment for moderate-to-severe forms of OI, however clinical studies are not yet sufficient to conclude appropriate annual dosage and ideal duration of therapy at present time.  Oral alendronate is also effective in milder forms of OI.  Zoledronic acid has undergone international multi-center clinical trials to examine efficiency and long-term side effects including osteonecrosis of the jaw.  Teriparatide (rhPTH1-34) and denosumab (monoclonal antibody against RANK ligand) have the potential for management of OI.  Stem cell and gene therapy are currently being actively investigated and may become clinically applicable in the near future.

In an observational study, Brown and Zacharin (2009) studied the safety and efficacy of zoledronic acid treatment in children with osteoporotic bone disorders.  A total of 22 patients with OI and related conditions were treated.  These patients had initial treatment with pamidronate.  Lumbar spine z-scores, annual change in areal BMD, bone mineral adjusted density, fracture number and linear growth before and after zoledronic acid treatment was commenced, were compared.  Patients were treated for a mean of 3.4 years with zoledronic acid after a mean of 3.75 years of pamidronate therapy.  There was no difference in areal BMD accrual in the first year of zoledronic acid treatment compared to the preceding year of pamidronate treatment.  Lumbar spine z-scores and bone mineral adjusted density continued to increase with zoledronic acid.  Number of fractures during treatment was significantly reduced compared to baseline with either bisphosphonate, with no difference between treatments.  Linear growth was not affected.  The authors concluded that zoledronic acid is at least as effective as pamidronate as treatment for pediatric osteoporosis, and has a similar safety profile.

Osteonecrosis

Padhye et al (2013) stated that osteonecrosis (ON) is a disabling complication of chemotherapy, especially steroids in children and adolescents.  There are few reports in the literature of non-surgical management of ON.  Patients with chemotherapy related ON, treated with zoledronic acid (ZA) were analyzed for clinical and radiological outcome.  Serial joint radiographs were performed to assess response and graded according to Association Research Circulation Osseous (ARCO) system.  All patients were evaluated for bone turnover and BMD at set intervals.  A total of 20 children with ON were treated with ZA for median duration of 13 months (range of 5 to 25) with median number of doses being 6 (2, 8).  Five (25 %) patients were pain-free at the end of treatment and had minimal joint destruction on X-ray (ARCO score II); 5 (25 %) underwent arthroplasty due to severe joint destruction and pain limiting activity (ARCO score III/IV); 10 (50 %) reported ongoing pain with activity, none on regular analgesia.  Bone mineral density analysis showed increase in lumbo-sacral BMD after 1 year of treatment.  Compared to patients with ON of the knees, majority of patients with ON of the hips had radiological progression.  The authors concluded that ZA was well- tolerated and improved joint pain in the majority of patients.  Despite treatment with ZA, most patients with ON of hips had progressive joint destruction requiring arthroplasty.  Patients with ON of the knees appeared to have radiological stabilization.  They stated that novel treatment strategies should be considered to prevent this debilitating complication in survivors of childhood cancer.

However, in an evidence-based review on “Risk-reductive strategies for osteonecrosis of the jaws among cancer patients”, Kyrgidis et al (2013) concluded that “denosumab and zoledronic acid might cause osteonecrosis of the jaws more frequently compared with chlodornate or pamidronate.  Prescription pamidronate and clodronate helps avoid the complication.  Reducing the administered dose for denosumab and zoledronic acid might reduce risk for ONJ as well.  More randomized clinical trials comparing reduced doses of these regimens against those currently approved are needed”.  Furthermore, an UpToDate review on “Osteonecrosis (avascular necrosis of bone)” (Jones and Mont, 2013) does not mention the use of zoledronic acid as a therapeutic option.

Osteoporosis Associated with Anorexia Nervosa and Secondary Amenorrhea

UpToDate reviews on “Eating disorders: Overview of prevention and treatment” (Forman, 2019) and “Evaluation and management of secondary amenorrhea” (Welt and Barbieri, 2019) do not mention zoledronic acid as a therapeutic option.

Osteoporosis in Men

On December 22, 2008, the FDA approved zoledronic acid (Reclast) injection for treatment to increase bone mass in men with osteoporosis.  The FDA approval for osteoporosis in men was based on data from a 2-year, double-blind, head-to-head trial in more than 300 osteoporotic men.  The study compared the efficacy and safety of Reclast with a commercially available oral weekly bisphoponate and found that Reclast increased lumbar spine BMD by 6.1 % over 2 years.

Otosclerosis-Related Hearing Loss

In a retrospective review, Quesnel et al (2012) evaluated hearing outcomes in patients treated with third generation bisphosphonates for otosclerosis-related sensori-neural hearing loss (SNHL).  Bone conduction pure tone threshold averages (PTAs) and word recognition (WR) scores were examined for each ear before and after bisphosphonate treatment.  Criteria for significant change were defined as greater than 10 decibels in PTA or between 4 % and 18 % in WR based on binomial variance.  All 10 patients had audiometric progression of SNHL in the pre-treatment monitoring interval and 12 ears met criteria for significant progression.  All 10 patients (19 ears) showed at least no significant progression of SNHL (i.e., stabilization) at an average follow-up of 13 months.  Two patients (3 ears) showed improvement by defined audiometric criteria.  There were no major complications.  The authors concluded that treatment with zoledronate or risedronate stabilized progressive SNHL related to otosclerosis in this small group of patients.  Moreover, they stated that further evaluation of third-generation bisphosphonate treatments is needed.

Paget's Disease

Reid et al (2005) reported on the results of 2 double-blind, placebo-controlled clinical studies of zoledronic acid in the treatment of Paget disease of the bone.  In these studies, one 15-min infusion of 5 mg of zoledronic acid was compared to 60 days of oral risedronate (Actonel) (30 mg per day) in a total of 347 patients with Paget disease of the bone.  The primary efficacy end point was the rate of therapeutic response at 6 months, defined as a normalization of alkaline phosphatase levels or a reduction of at least 75 % in the total alkaline phosphatase excess.  At 6 months, 96.0 % of patients receiving zoledronic acid achieved a therapeutic response, as compared with 74.3 % of patients receiving risedronate, a difference that was statistically significant.  The investigators reported that alkaline phosphatase levels normalized in 88.6 % of patients in the zoledronic acid group and 57.9 % of patients in the risedronate group (p < 0.001).  Zoledronic acid was associated with a shorter median time to a first therapeutic response (64 days versus 89 days, p < 0.001).  The investigators reported that the physical-component summary score of the Medical Outcomes Study 36-item Short-Form General Health Survey, a measure of the quality of life, increased significantly from baseline at both 3 and 6 months in the zoledronic acid group and differed significantly from those in the risedronate group at 3 months.  The investigators noted that pain scores improved in both groups.  During post-trial follow-up (median of 190 days), 21 of 82 patients in the risedronate group had a loss of therapeutic response, as compared with 1 of 113 patients in the zoledronic acid group (p < 0.001).  The investigators concluded that a single infusion of zoledronic acid produces more rapid, more complete, and more sustained responses in Paget disease than does daily treatment with risedronate.

On April 16, 2007, the FDA approved zoledronic acid 5-mg solution for infusion (Reclast) for the treatment of patients with Paget's disease of the bone.  The single-dose bisphosphonate is administered by intravenous infusion for 15 mins.  The approval is based on data from clinical studies linking zoledronic acid to a greater therapeutic response, faster onset of action, and longer remission period when compared to risedronate therapy.  Results showed that a significantly greater proportion of patients given a single-dose of zoledronic acid showed therapeutic response at 6 months, compared with their counterparts given a 60-day oral regimen (30 mg/day) of risedronate (96 % versus 74 %).  A great majority of those responding to the zoledronic acid infusion remained in remission for 1 year or longer (Novartis, 2007).  Normalization of serum alkaline phosphatase levels (a key marker for bone turnover) at 6 months was also achieved in a significantly greater proportion of patients receiving single-dose zoledronic acid than those receiving the 60-day risedronate regimen (89 % versus 58 %).  The overall frequency of adverse events was similar in both groups.  Calcium and vitamin D repletion are mandatory with these potent anti-osteoclast therapies to avoid hypocalcemia (Siris et al, 2006).

Treatment is indicated in patients with Paget’s disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the age‐specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease to induce remission (normalization of serum alkaline phosphatase).

Information regarding administration for patient’s taking Reclast for Paget’s Disease:

• Patients must be appropriately hydrated prior to administration of zoledronic acid and this is especially important for patients receiving diuretic therapy.
• It can be dosed without regard to meals.
• To reduce the risk of hypocalcemia, all patients with Paget’s disease receiving zoledronic acid should receive 1500 mg elemental calcium daily in divided doses and 800 IU vitamin D daily, particularly in the two weeks following zoledronic acid administration.
• All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia.
• Specific re‐treatment data for Paget’ disease are not available. Re‐treatment may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase or in those patients who failed to achieve normalization of their serum alkaline phosphatase or in those patients with symptoms, as dictated by medical practice.

Keating and Scott (2007) stated that the third-generation nitrogen-containing bisphosphonate zoledronic acid is approved in the European Union for the treatment of Paget's disease of bone.  Results of well-designed clinical studies showed that an intravenous single-dose (5 mg) of zoledronic acid is effective and well-tolerated in the treatment of Paget's disease of bone.  This approach was associated with a significantly higher therapeutic response rate and a more rapid reduction in bone turnover than that achieved with 60 days of oral risedronic acid.  Moreover, biochemical remission was sustained after 24 months of follow-up in zoledronic acid recipients.  The authors noted that preliminary results suggested that zoledronic acid infusion is a cost-effective option in the treatment of Paget's disease of bone; it is an important first-line treatment for this condition.

In a review on “Paget's disease of bone”, Ralston (2013) stated that bisphosphonate therapy is indicated in patients with Paget disease when there is localized pain in an affected bone that is attributable to increased metabolic activity.  Asymptomatic disease does not require treatment.

Pleural Mesothelioma

Jamil and associates (2017) stated that malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal median survival of less than 12 months with current therapy.  Single and combination chemotherapy regimens have shown only modest clinical benefit.  In pre-clinical studies, nitrogen-containing bisphosphonates (e.g., ZA) inhibited growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells.  In a pilot, single-arm study, these investigators examined the role of ZA in MPM patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2 who had progressed on prior treatments or had not received systemic therapy due to poor PS.  Primary end-point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) positron emission tomography criteria.  Secondary end-points were progression-free survival (PFS) and OS.  Exploratory end-points included the effect of ZA therapy on vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels.  A total of 8 men (median age of 62 years) with the following clinical characteristics were treated; ECOG PS was 0 to 2, 75 % with epithelioid type, and 62 % had prior chemotherapy.  Overall composite response rate was 12.5 % and the clinical benefit rate (response + stable disease) was 37.5 %.  Median PFS was 2 months (0.5 to 21 months) and median OS was 7 months (0.8 to 28 months).  No treatment-related toxicities were observed.  Lower VEGF levels were predictive of favorable response and mesothelin levels correlated with disease course.  The authors concluded that the findings of this pilot study suggested modest activity of ZA as a single agent in the treatment of mesothelioma and warrants further investigation in combination with other agents.

Polyostotic Fibrous Dysplasia

Mrabet and colleagues (2012) reported a new case of polyostotic fibrous dysplasia (PFD).  A 26-year old woman was referred to the authors’ department complaining of pain in her left arm.  She had suffered tow fractures in left leg and arm previously.  Plain radiographs showed osteolytics lesions at the left humerus and radius.  Histological examination of the surgical specimens showed PFD.  The authors noted that the patient has benefitted from zoledronic acid (ZOL) perfusion.

Muthusamy and associates (2015) noted that FD is a benign fibro-osseous bone tumor that accounts for 5 % to 10 % of benign bone tumors.  It can present as monostotic FD (70 % to 80 %), PFD (20 % to 30 %), McCune-Albright syndrome (2 % to 3 %), or Mazabraud's syndrome in rare cases.  Bone lesions in FD arise in the medullary canal and usually are confined to the bone.  Cortical destruction and extension into soft tissue usually indicates malignant transformation or secondary aneurysmal bone cyst formation.  Locally aggressive FD with cortical destruction and extension into soft tissue in the absence of these 2 possibilities is extremely rare.  It is important for the treating physician to distinguish this entity from more aggressive or malignant tumors to avoid over-treating the patient for a benign condition or inattention to a malignant tumor.  These investigators reported 4 unusual cases of FD with an aggressive radiographic appearance.  They occurred in the rib (n = 1), ilium (n = 2), and distal femur (n = 1).  Two patients had pain and 2 had swelling.  Radiologically, all were associated with cortical destruction and an associated soft tissue mass, and initially they were interpreted as potentially malignant.  Three patients underwent biopsy and 1 patient did not have a biopsy.  Histopathologic analysis by an experienced bone pathologist confirmed FD in all patients; 2 patients were treated surgically; 1 patient with ZOL; and 1 patient was followed by observation alone.  There were only a few reports in the literature that described the locally aggressive variant of FD that presents with pain and progressive swelling clinically and with cortical destruction and soft tissue extension on imaging that suggested malignancy.  These researchers could not find any article that described the use of bisphosphonates in such lesions or the response to bisphosphonates clinically, on laboratory parameters or imaging.  To the authors’ knowledge, this was the largest case report published regarding locally aggressive FD arising outside the craniofacial skeleton.  They stated that the locally aggressive variant of FD may be confused with a malignant tumor or malignant degeneration of FD.  It is important to properly evaluate these lesions to ensure that a proper diagnosis is made, especially with respect to a malignant versus benign mass.

Wu and associates (2015) stated that PFD is a rare non-inherited genetic disorder characterized by osteolytic lesions in multiple bones causing bone pain, deformity, and pathological fracture.  As an anti-osteolytic agent, the new generation bisphosphonate ZOL restricts lesion progression by inhibiting osteoclastic activity.  Although ZOL is more effective than pamidronate, its efficacy and safety in long-term therapy in PFD is unknown.  These researchers reported a case of PFD advanced to extensive bone destruction in the skull and ribs and evaluated the long-term safety and effectiveness of early first-line ZOL in PFD with severe bone disease.  The annual infusion of 5 mg ZOL was intravenously administered, cumulatively 20 mg over 4 courses, with oral supplementation of calcium, vitamin D, and potassium.  No long-term side effect was observed, and mild transient symptoms were easily resolved.  Significant radiological improvement was seen in filling of destroyed bone and cortical thickening.  Zoledronic acid decreased both serum collagen type 1 cross-linked C-telopeptide and type 1 procollagen N-terminal (P1NP) from extremely high baseline levels.  An unexpected direct increase in P1NP after long-term therapy could indicate discontinuation of ZOL to observe its prolonged effect.  Early first-line ZOL therapy is effective in PFD with severe bone destruction and is safe for long-term therapy.  The authors stated that the use of bisphosphonates in FD remains off-label, and regular monitoring is highly advised.

Clinical guidelines for the management of craniofacial fibrous dysplasia (Lee, et al., 2012) state: “The use of bisphosphonates such as alendronate, pamidronate, or zoledronic acid for craniofacial FD has been considered for pain reduction and to reduce the rate of growth of the lesion. In general, the clinical studies have demonstrated mixed results on the efficacy of bisphosphonates and FD-related pain with small sample sizes and with most studies examining all skeletal regions, not just the craniofacial sites. . . Further studies are necessary to determine the efficacy osteoclast inhibitor therapies such as bisphosphonates or denosumab in slowing the growth of craniofacial FD and reducing intractable craniofacial FD pain. The variation in response between children and adults with FD and the safety of prolonged bisphosphonate use in children also require more investigation.”

The International Osteoporosis Foundation (Chapurlat, 2015) states "when common pain killers are not effective, bisphosphonates can be proposed to reduce bone pain. Intravenous pamidronate has been the most widely tested, only in open studies. Data for other compounds is lacking." The National Organization for Rare Disorders (2014) reports "Individuals with FD have been treated with drugs known as bisphosphonates such as pamidronate or alendronate. These drugs reduce bone turnover by inhibiting bone resorption. Calcium and vitamin D may be given along with the drug. Some affected individuals respond favorably to such therapy with the main benefit being decreased bone pain. Other affected individuals do not respond to therapy with bisphosphonates or relapse after an initial period of improvement. Relapse of bone pain is more common in individuals with polyostotic FD. Stronger bisphosphonate medications such as zoledronic acid may be used in such cases and may be most effective in improving bone pain."

Post-Menopausal Osteoporosis

The safety and effectiveness of Reclast for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re‐evaluated on a periodic basis. Patients at low‐risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re‐evaluated periodically.

Zoledronic acid has been shown to increase bone density and decrease fracture risk in women with post-menopausal osteoporosis.  Black et al (2007) reported on the results of the HORIZON Pivotal Fracture Trial, a double-blind, randomized controlled clinical trial of a once-yearly infusion of zoledronic acid on fracture risk over a 3-year period.  In this study, 3,889 patients were randomly assigned to receive a single 15-min infusion of zoledronic acid (5 mg) and 3,876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months.  The investigators reported that treatment with zoledronic acid reduced the risk of vertebral fracture by 70 % during a 3-year period, as compared with placebo (3.3 % in the zoledronic-acid group versus 10.9 % in the placebo group; relative risk [RR], 0.30; 95 % confidence interval [CI]: 0.24 to 0.38) and reduced the risk of hip fracture by 41 % (1.4 % in the zoledronic-acid group versus 2.5 % in the placebo group; hazard ratio, 0.59; 95 % CI: 0.42 to 0.83).  Non-vertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25 %, 33 %, and 77 %, respectively (p < 0.001 for all comparisons).  The investigators also found that zoledronic acid was also associated with a significant improvement in BMD and bone metabolism markers.  Adverse events, including change in renal function, were similar in the 2 study groups.  However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (50 versus 20 patients, p < 0.001).  The investigators concluded that a once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures.

The safety and efficacy of zoledronic acid (Reclast) in preventing osteoporosis in post-menopausal women with osteopenia was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 post-menopausal women 45 years of age or older.  The study included women in early menopause (i.e., within 5 years of menopause) and late menopause (i.e., more than 5 years from menopause).  Patients were divided into the following 3 groups: (i) Reclast was administered at the beginning of the study and again at 1 year, (ii) Reclast was administered at the beginning of the study and placebo was administered at 1 year, and (iii) placebo was administered at the beginning of the study and again at 1 year.  Reclast was administered as a single 5 mg dose in 100 ml solution infused over at least 15 mins.  All women received 500 to 1,200 mg elemental calcium plus 400 to 800 IU vitamin D supplementation per day.  Reclast significantly increased lumbar spine BMD and total hip BMD relative to placebo at 24 months.  Reclast administered at the beginning of the study increased lumbar spine BMD by 6.3 % in the early menopause group and by 5.4 % in the late menopause group at 24 months (Novartis Pharmaceuticals, 2009).

The World Health Organization defines osteoporosis in post-menopausal women as a BMD value at the spine, hip, or forearm of 2.5 or more SD (standard deviations) below the young adult mean (T-score less than or equal to 2.5), with or without the presence of a fragility fracture.  Osteopenia is any bone density below the young adult mean. 

In a randomized, double-blind, placebo-controlled study, Lyles et al (2007) examined if zoledronic acid would improve clinical fractures and mortality following hip fracture.  A total of 1,065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1,062 patients were assigned to receive placebo.  The infusions were first administered within 90 days after surgical repair of a hip fracture.  All patients (mean age of 74.5 years) received supplemental vitamin D and calcium.  The median follow-up was 1.9 years.  The primary end point was a new clinical fracture.  The rates of any new clinical fracture were 8.6 % in the zoledronic acid group and 13.9 % in the placebo group, a 35 % risk reduction with zoledronic acid (p = 0.001); the respective rates of a new clinical vertebral fracture were 1.7 % and 3.8 % (p = 0.02), and the respective rates of new non-vertebral fractures were 7.6 % and 10.7 % (p = 0.03).  In the safety analysis, 101 of 1,054 patients in the zoledronic acid group (9.6 %) and 141 of 1,057 patients in the placebo group (13.3 %) died, a reduction of 28 % in deaths from any cause in the zoledronic acid group (p = 0.01).  The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain.  No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted.  The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the 2 groups.  The authors concluded that an annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival.

An editorial that accompanied the afore-mentioned study (Calis and Pucino, 2007) stated that "zoledronic acid appears to offer several advantages over other potential therapies, with one important caveat: although the risk-benefit pendulum has now swung in favor of treatment, additional long-term safety data are essential.  Furthermore, data are needed to identify significant differences in the incidence of new fractures and death within subgroups defined on the basis of factors such as age, sex, and bone mineral density -- something the study by Lyles et al was not adequately powered to do.  Further characterization of the study population (e.g., smoking history, degree of mobility, and medications or conditions that may affect bone mineral density or fracture risk) also would be helpful to assess the generalizability of the study results.  In addition, long-term efficacy data and comparative studies with other therapeutic options are needed.  Future research efforts should address improvement in physical function and quality of life, cost-effectiveness and cost-utility analyses of available therapies, access to health care, and adherence to clinical-practice guidelines.  Efforts to achieve even greater reductions in morbidity and mortality in patients at greatest risk also deserve further study.  Early identification and optimal treatment of people at risk for fracture recurrence remain imperative".

MacLean and colleagues (2008) stated that although several agents are available to treat osteoporosis, the relative effectiveness and toxicity of these agents when used to prevent fractures has not been well described.  In a systematic review, these researchers compared the benefits in fracture reduction and the harms from adverse events of various therapies for osteoporosis.  For the effectiveness analysis, they selected studies that reported the rate of or risk for fractures.  For the adverse event analysis, they selected studies that reported the relationship between an agent and cardiovascular, thrombo-embolic, or upper gastro-intestinal events; malignant conditions; and osteonecrosis.  Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair.  Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair.  The effects of vitamin D varied with dose, analog, and study population for both vertebral and hip fractures.  Raloxifene, estrogen, and estrogen-progestin increased the risk for thrombo-embolic events, and etidronate increased the risk for esophageal ulcerations and gastro-intestinal perforations, ulcerations, and bleeding.  Few studies have directly compared different agents or classes of agents used to treat osteoporosis.  The authors concluded that although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative safety and effectiveness of these agents.

Prevention of Insufficiency Fractures and Avascular Necrosis Associated with Pelvic Radiotherapy

van den Blink and colleagues (2018) stated that pelvic radiotherapy is a treatment delivered to an estimated 150,000 to 300,000 people annually across high-income countries.  Fractures due to normal stresses on weakened bone due to radiotherapy are termed insufficiency fractures.  Pelvic radiotherapy-related interruption of the blood supply to the hip is termed avascular necrosis (AVN) and is another recognized complication.  The reported incidences of insufficiency fractures are 2.7 % to 89 % and risk of developing AVN is 0.5 %.  These complications lead to significant morbidity in terms of pain, immobility and consequently risk of infections, pressure sores and mortality.  In a Cochrane review, these researchers examined the effects of pharmacotherapies for preventing insufficiency fractures and AVN in adults over 18 years of age undergoing pelvic radiotherapy.  They performed electronic literature searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and DARE to April 19,  2017; they also searched trial registries.  Further relevant studies were identified through hand-searching of citation lists of included studies; RCTs or non-RCTs with concurrent comparison groups including quasi-RCTs, cluster RCTs, prospective cohort studies and case series of 30 or more subjects were screened.  These investigators included studies evaluating the effect of pharmacotherapies in adults over 18 years of age undergoing radical pelvic radiotherapy as part of anti-cancer treatment for a primary pelvic malignancy.  They excluded studies involving radiotherapy for bone metastases; and examined the use of pharmacotherapies at any stage before or during pelvic radiotherapy.  Interventions included calcium or vitamin D (or both) supplementation, bisphosphonates, selective estrogen receptor modulators (SERMs), hormone replacement therapy (estrogen or testosterone), denosumab and calcitonin.  Two review authors independently evaluated trial quality and extracted data; they contacted study authors to obtain missing data.  Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively.

These researchers included 2 RCTs (1,167 subjects).  The 1st RCT compared ZA with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic PCa.  The 2nd RCT had 4 treatment arms, 2 of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1,071 men undergoing pelvic radiotherapy for non-metastatic PCa.  Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.  The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible.  Both studies focused on interventions to improve bone health in relation to ADT rather than radiation-related insufficiency fractures and AVN.  Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy.  Both studies reported that ZA in addition to ADT and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently.  There was no available evidence regarding adverse events (AEs).  The authors concluded that the evidence relating to interventions to prevent insufficiency fractures and AVN associated with pelvic radiotherapy in adults was of very low certainty.  This review highlighted the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and AVN.  These researchers stated that future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy.  The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months.  Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of AVN.  Clinical assessments and patient reported outcomes would help to identify any associated AEs of treatment and quality of life (QOL) outcomes.

Psoriatic Arthritis

In a pilot study, McQueen et al (2011) examined the effect of zoledronic acid on articular bone in patients with psoriatic arthritis (PsA) using magnetic resonance imaging (MRI).  Patients with erosive PsA were randomized to receive 3-monthly infusions of zoledronic acid or placebo for 1 year.  An additional "tests alone" group received no infusions.  Clinical assessments and MRI scans were performed at baseline and 1 year.  Paired 1.5T MRI scans were available in 22 patients including 6 who received zoledronic acid and 16 who did not (non-zoledronic acid = 6 placebo + 10 "tests alone" patients).  The Disease Activity Score (28 swollen and tender joints, C-reactive protein fell over 12 months to a greater degree in patients on zoledronic acid than in non-zoledronic acid patients (-1.6 versus -0.3, p = 0.023).  The MRI bone edema score decreased in the zoledronic acid group (15.5 to 8.5) but increased in the non-zoledronic acid group (14.0 to 18.0) (p = 0.0056) with regression of bone edema at 13.5 % of sites in zoledronic acid patients versus 1.3 % in non-zoledronic acid patients (p = 0.0073) and progression in 1.3 % of sites in zoledronic acid patients versus 6.9 % in non-zoledronic acid patients (p = 0.072).  There was no difference between groups in change in MRI erosion score.  The authors stated that zoledronic acid does not reduce MRI erosive progression in PsA but may suppress bone edema.

SAPHO Syndrome

Assmann and Simon (2011) stated that the syndrome of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) includes a rare group of chronic, relapsing, inflammatory osteo-articular disorders that is conventionally associated with manifestations in the skin.  Diagnostic dilemmas can arise due to incomplete manifestations or confusion generated through mimicking of other conditions, such as osteomyelitis.  The etiology of SAPHO syndrome remains unclear, but probably involves genetic, immunological as well as infectious mechanisms.  The possible pathogenetic role of infectious agents in genetically predisposed individuals, resulting in a “reactive osteitis”, has been suggested because microbes such as Propionibacterium acnes have been recovered from bone biopsy samples.  However, this hypothesis has not been demonstrated as yet.  Current knowledge with regard to treatment of SAPHO syndrome is based on results reported from small case studies and, thus, is still empiric.  The use of antibiotics, instituted based on the isolation of Propionibacterium acnes, has been reported to show conflicting results.  The authors noted that promising results for potential future application have recently been reported for treatment of SAPHO with bisphosphonates and antagonists of tumor necrosis factor-alpha.

Spinal Cord Injury

Ooi et al (2012) stated that spinal cord injury (SCI) is associated with rapid and sustained bone loss and increase risk of fracture.  Disuse is the primary cause for bone loss, although neural and hormonal changes may also contribute via different mechanisms.  Bisphosphonates are used widely to treat osteoporosis in adults and are used increasingly for primary and secondary osteoporosis in children.  Current data are insufficient to recommend routine use of bisphosphonates for fracture prevention in adult patients post-SCI and there are no available data in pediatric SCI.  These researchers reported the case of a 12-year old boy with non-traumatic SCI who was treated with 6-monthly ZA (0.05 mg/kg/dose) for 18 months.  The patient was diagnosed with transverse myelitis at 8.1 years of age, resulting in ventilator-dependent incomplete C3 tetraplegia.  Following a fragility fracture to the surgical neck of the right humerus at 9.5 years of age, he was started on ZA.  Bone turnover decreased and bone densitometry data (dual energy x-ray absorptiometer [DXA] and peripheral quantitative computed tomography [pQCT]) showed improvement in metaphyseal and diaphyseal bone mineral content (BMC), volumetric BMD (vBMD), and size, after 18 months of treatment.  In the growing skeleton post-SCI, ZA potentially increases vertebral and long-bone strength by preserving trabecular bone (increased BMC and vBMD) and increasing cortical vBMD and cross-sectional area (CSA).

Also, an UpToDate review on “Chronic complications of spinal cord injury” (Abrams and Wakasa, 2014) states that “Occasionally, symptomatic hypercalcemia and hypercalciuria complicate early resorption of bone mass within the first few months of SCI.  Manifestations can include nausea, vomiting, anorexia, lethargy, and polyuria.  There is an increased risk of nephrolithiasis.  Treatment is graded to severity of symptoms.  Intravenous pamidronate has been used for acute immobilization hypercalcemia after SCI”.  Zoledronic acid is not mentioned as a therapeutic option.

Soleyman-Jahi and colleagues (2018) noted that SCI results in accelerated BMD loss and disorganization of trabecular bone architecture.  The mechanisms underlying post-SCI osteoporosis are complex and different from other types of osteoporosis.  Findings of studies examining efficacy of pharmacological or rehabilitative interventions in SCI-related osteoporosis are controversial.  These investigators reviewed the literature pertaining to prevention and evidence-based treatments of SCI-related osteoporosis.  In this systematic review, Medline, Embase, PubMed, and the Cochrane Library were used to identify papers from 1946 to December 31, 2015.  The search strategy involved the following keywords: spinal cord injury, osteoporosis, and bone loss.  A total of 56 studies were included according to the inclusion criteria.  Only 16 RCTs (involving 368 subjects) were found.  These researchers found following evidences for effectiveness of bisphosphonates in prevention of BMD loss in acute SCI: very low-quality evidence for clodronate and etidronate, low-quality evidence for alendronate, and moderate-quality evidence for ZA.  Low-quality evidence showed no effectiveness for tiludronate.  In chronic SCI cases, these investigators found low-quality evidence for effectiveness of vitamin D3 analogs combined with 1-alpha vitamin D2.  However, low-quality inconsistent evidence exists for alendronate.  For non-pharmacologic interventions, very low-quality evidence exists for effectiveness of standing with or without treadmill walking in acute SCI.  Other low-quality evidences indicated that electrical stimulation, tilt-table standing, and ultrasound (US) provided no significant effects.  Very low-quality evidence did not show any benefit for low-intensity (3 days per week) cycling with functional electrical stimulator in chronic SCI.  The authors concluded that no recommendations could be made from this review, regarding overall low quality of evidence as a result of high risk of bias, low sample size in most of the studies, and notable heterogeneity in type of intervention, outcome measurement, and duration of treatment.  These researchers stated that future high-quality RCT studies with higher sample sizes and more homogeneity are needed to provide high-quality evidence and make applicable recommendations for prevention and treatment of SCI-related bone loss.

Spinal Giant Cell Tumors

Luksanapruksa et al (2016) noted that spinal giant cell tumors (SGCT) remain challenging tumors to treat. Although advancements in surgical techniques and adjuvant therapies have provided new options for treatment, evidence-based algorithms are lacking.  These investigators reviewed the peer-reviewed literature that addresses current treatment options and management of SGCT to produce an evidence-based treatment algorithm.  Articles published between January 1, 1970 and March 31, 2015 were selected from PubMed and EMBASE searches using keywords "giant cell tumor" and "spine" and "treatment".  Relevant articles were selected by the authors and reviewed.  A total of 515 studies were identified, of which 81 studies were included.  Complete surgical resections of SCGT resulted in the lowest recurrence rates.  However, morbidity of en bloc resections is high and in some cases, surgery is not possible.  Intralesional resection can be coupled with adjuvant therapies, but evidence-based algorithms for use of adjuvants remain elusive.  Several recent advancements in adjuvant therapy may hold promise for decreasing SGCT recurrence, specifically stereotactic radiotherapy, selective arterial embolization, and medical therapy using denosumab and interferon.  The authors concluded that complete surgical resection of SGCT should be the goal when possible, particularly if neurologic impairment is present.  They stated that denosumab holds promise as an adjuvant and perhaps stand-alone therapy for SGCT.  These researchers also noted that there is emerging evidence that bisphosphonates also have anti-tumoral effects as adjuvant therapy for GCT; however, the best level of evidence for this indication is “IV”.

Steroid-Induced Osteoporosis

The FDA approved Reclast injection for the treatment and prevention of osteoporosis caused by glucocorticoids for patients expected to be on  glucocorticoids for at least 12 months.  This approval was based on data from a multi-national, double-blind, head-to-head study comparing Reclast to an established therapy.  The study involved 833 men and women who were on high-dose glucocorticoid therapy for more than 3 months (treatment group) or less than 3 months (prevention group) before the start of the study and who were expected to stay on the therapy for at least 12 months.  Results showed that Reclast increased BMD significantly more than the active control in both the treatment and prevention groups.

Tendon-to-Bone Healing

Hjorthaug and associates (2018) stated that outcome after ligament reconstruction or tendon repair depends on secure tendon-to-bone healing.  Increased osteoclastic activity resulting in local bone loss may contribute to delayed healing of the tendon-bone interface.  These researchers examined the effect of ZA on tendon-to-bone healing.  Wistar rats (n = 92) had their right Achilles tendon cut proximally, pulled through a bone tunnel in the distal tibia and sutured anteriorly.  After 1 week animals were randomized to receive a single dose of ZA (0.1 mg/kg IV) or control.  Healing was evaluated at 3 and 6 weeks by mechanical testing, dual-energy X-ray absorptiometry and histology including immunohistochemical staining of osteoclasts.  Treatment with ZA resulted in 19 % (95 % CI: 5 to 33 %) lower pullout strength and 43 % (95 % CI: 14 to 72 %) lower stiffness of the tendon-bone interface, compared with control (2-way ANOVA; p = 0.009, p = 0.007).  Administration of ZA did not affect BMD or BMC.  Histological analyses did not reveal differences in callus formation or osteoclasts between the study groups.  The authors concluded that ZA reduced pullout strength and stiffness of the tendon-bone interface; this study did not provide support for ZA as adjuvant treatment in tendon-to-bone healing.

Appendix

Appendix A: Clinical reasons to avoid oral bisphosphonate therapy

• Presence of anatomic or functional esophageal abnormalities that might delay transit of the tablet (e.g. achalasia, stricture, or dysmotility)
• Active upper gastrointestinal problem (e.g., dysphagia, gastritis, duodenitis, erosive esophagitis, ulcers)
• Presence of documented or potential gastrointestinal malabsorption (e.g. gastric bypass procedures, celiac disease, Crohn’s disease, infiltrative disorders, etc.)
• Inability to stand or sit upright for at least 30 to 60 minutes
• Inability to take at least 30 to 60 minutes before first food, drink, or medication of the day
• Renal insufficiency (creatinine clearance <35 mL/min)
• History of intolerance to an oral bisphosphonate

Appendix B: WHO Fracture Risk Assessment Tool

• High FRAX fracture probability: 10 year major osteoporotic fracture risk ≥ 20% or hip fracture risk ≥ 3%
• 10-year probability; calculation tool available at: FRAX - Fracture Risk Assessment Tool
• The estimated risk score generated with FRAX should be multiplied by 1.15 for major osteoporotic fracture (including fractures of the spine (clinical), hip, wrist, or humerus) and 1.2 for hip fracture if glucocorticoid treatment is greater than 7.5 mg (prednisone equivalent) per day.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
84075	Phosphatase, alkaline
84078	heat stable (total not included)
84080	isoenzymes
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
HCPCS codes covered if selection criteria are met:
J3489	Injection, zoledronic acid, 1 mg
Other HCPCS codes related to the CPB:
J1436	Injection, etidronate disodium, per 300 mg
J1740	Injection, ibandronate sodium, 1 mg
J2430	Injection, pamidronate disodium, per 30 mg
S0187	Tamoxifen citrate, oral, 10 mg
ICD-10 codes covered if selection criteria are met:
C00.0 - C19.9, C19 - C4A.9, C45.1 - C86.6, C88.2 - C94.32, C94.80 - C96.4, C96.6 - C96.9	Malignant neoplasm [with hypercalcemia] [not covered as adjuvant/neoadjuvant treatment for non-small lung cancer]
D00.00 - D09.9	In situ neoplasms
D3a.00 - D3a.8	Benign neuroendocrine tumors
D47.Z9	Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue [solitary plasmacytoma]
M80.00x+ - M81.8	Osteoporosis [see criteria for treatment in men vs. women; not covered for mastocytosis-related osteoporosis]
M85.80	Other specified disorders of bone density and structure, unspecified site [osteopenia] [drug induced osteopenia]
M85.88	Other specified disorders of bone density and structure, other site [see criteria for prevention of osteoporosis with osteopenia]
M85.89	Other specified disorders of bone density and structure, multiple [see criteria for prevention of osteoporosis with osteopenia]
M85.9	Disorder of bone density and structure, unspecified [see criteria for prevention of osteoporosis with osteopenia]
M88.0 - M88.9	Osteitis deformans [Paget's disease of bone]
Q78.1	Polyostotic fibrous dysplasia [with bone pain refractory to an oral bisphosphonate or pamidronate]
Z79.52	Long term (current) use of systemic steroids [medically necessary to prevent osteoporosis in persons taking prednisone daily]
Z79.811	Long term (current) use of aromatase inhibitors [see criteria for prevention of osteoporosis in persons receiving aromatase inhibitors]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive) :
A52.16	Charcot's arthropathy (tabetic)
C18.0 - C18.9	Malignant neoplasm of colon
C45.0	Mesothelioma of pleura
D16.6	Benign neoplasm of vertebral column [spinal giant cell tumors]
D16.8	Benign neoplasm of pelvic bones, sacrum and coccyx [spinal giant cell tumors]
E21.0 - E21.3	Hyperparathyroidism
E58	Dietary calcium deficiency
E83.51	Hypocalcemia
E83.52	Hypercalcemia [covered when due to malignancy only]
F50.0	Anorexia nervosa
H80.00 - H80.93	Otosclerosis
I35.0	Nonrheumatic aortic (valve) stenosis
J84.81	Lymphangiomatosis
K90.0	Celiac disease [to increase bone mineral density]
L40.50 - L40.59	Arthropathic psoriasis
M45.0 - M45.9	Ankylosing spondylitis
M54.5	Low back pain [chronic low back pain associated with Modic changes]
M83.0 - M83.9	Adult osteomalacia
M84.311A - M84.38xS	Stress fracture [insufficiency]
M86.30 - M86.39	Chronic multifocal osteomyelitis
M87.059	Idiopathic aseptic necrosis of unspecified femur
N39.0	Urinary tract infection, site not specified [following spinal cord injury]
N91.1	Secondary amenorrhea
Q78.0	Osteogenesis imperfecta
Q78.1	Polyostotic fibrous dysplasia
Q79.6	Ehlers-Danlos syndrome
S12.000+ - S12.9xx+ S22.000+ - S22.089+ S32.000+ - S32.2xx+	Fracture of vertebral column [to reduce urinary tract infection] [must be billed with code for spinal cord injury
S14.101+ - S14.159+ S24.101+ - S24.159+ S34.101+ - S34.139+	Spinal cord injury [to reduce urinary tract infection] [may be billed without mention of spinal column fracture]
Z47.1	Aftercare following joint replacement surgery [improvement of outcomes after hip or knee replacement]

The above policy is based on the following references: