Aetna considers zoledronic acid (Zometa, Reclast**) medically necessary for the following indications:
* 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).
Zometa (zoledronic therapy) is considered experimental and investigational for persons concurrently receiving Reclast (also zoledronic acid) or another bisphosphonate. Zoledronic acid is contraindicated and considered experimental and investigational in persons with hypocalcemia.
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):
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.
**Note: Reclast is contraindicated in persons with creatinine clearance less than 35 ml/min or in persons with evidence of acute renal impairment.
Zoledronic acid) (Zometa, Reclast), 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.
Zometa (zoledronic acid) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypercalcemia of malignancy, for the treatment of bone metastasis associated with solid tumors, and for the treatment of multiple myeloma patients with documented osteolytic lesions. Reclast (zoledronic acid) is approved for the treatment and prevention of osteoporosis in postmenopausal women, osteoporosis in men, treatment and prevention of glucocorticoid‐induced osteoporosis, and Paget’ disease of bone in men and women.
Warnings and Precautions:
Zoledronic acid should not be used in the following:
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 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.
Table: Reduced doses for patients with baseline CrCl of 60 ml/min or less
|Baseline Creatine Clearance (ml/min)||Zometa Dose*|
|Greater than 60||4 mg|
|50 - 60||3.5 mg|
|40 - 49||3.3 mg|
|30 - 39||3 mg|
*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:
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.
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.
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).
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.
According to National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2016), zoledronic acid is indicated for use in multiple myeloma in combination with primary myeloma therapy.
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.
The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2016) recommends zoledronic acid for prevention of skeletal-related events in men with castration-recurrent prostate cancer who have documented bone metastases and creatinine clearance greater than 30 mL/min.
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).
The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2016) recommends zoledronic acid for prevention or treatment of osteoporosis during androgen deprivation therapy for patients with prostate cancer at high fracture risk.
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:
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.
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.
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.
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.
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.
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.
The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2016) recommends use of zoledronic acid with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in patients with breast cancer who have an expected survival of ≥3 months and adequate renal function.
Breast cancer adjuvant/neoadjuvant treatment:
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.
Hue and colleagues (2014) noted that studies have shown that bisphosphonates may have anti-tumor and anti-metastatic properties. Recently, 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.
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.
The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2016) recommends zoledronic acid for: 1) bone metastases from thyroid cancer (follicular carcinoma, Hürthle cell carcinoma, medullary carcinoma, and papillary carcinoma); 2) supportive therapy for bone metastases from non-small cell lung cancer (NSCLC); 3) as a component of best supportive care for bone metastases from kidney cancer; 4) prevention of skeletal-related events in men with castration-recurrent prostate cancer who have documented bone metastases and creatinine clearance greater than 30 mL/min; and 5) Used with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in patients with breast cancer who have an expected survival of ≥3 months and adequate renal function.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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."
An UpToDate review on “Assessment and treatment of ankylosing spondylitis in adults” (Yu, 2016) does not mention zoledronic acid as a therapeutic option.
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.
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”.
Zoledronic acid is available as Zometa Injection containing 4 mg per 5 mL vial and 4 mg per 100 mL ready‐to‐use bottle, and as Reclast 5mg/100mL.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|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:|
|84076||heat stable (total not included)|
|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|
|ICD-10 codes covered if selection criteria are met:|
|C00.0 - C86.6
C88.2 - C94.32
C94.80 - C96.4
C96.6 - C96.9
|Malignant neoplasm [with hypercalcemia] [not covered as adjuvant/neoadjuvant for breast cancer and 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]|
|M85.88||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]|
|Q78.0||Osteogenesis imperfecta [covered for persons who have failed or are intolerant of pamidronate]|
|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)|
|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|
|E83.52||Hypercalcemia [covered when due to malignancy only]|
|H80.00 - H80.93||Otosclerosis|
|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|
|N39.0||Urinary tract infection, site not specified [following spinal cord injury]|
|Q78.1||Polyostotic fibrous dysplasia [Albright(-McCune)(-Sternberg) 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]|