Zoledronic Acid- Reclast and Zometa AHM

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Zoledronic acid- Reclast and Zometa AHM

Clinical Indications

• Zoledronic acid (Zometa, Reclast) are considered medically necessary for 1 or more of the following indications • Bone metastases or bone pain presumed due to bone metastases from breast cancer, lung cancer, neuroendocrine tumors, prostate cancer, thyroid cancer, and other solid tumor types . Consistent with Zometa’s FDA-approved labeling, zoledronic acid is considered medically necessary for bone metastases from prostate cancer if cancer has progressed after treatment with at least one hormonal therapy • Hypercalcemia of malignancy • Multiple myeloma, including smoldering multiple myeloma and solitary plasmacytomas • Osteogenesis imperfecta in persons who have failed or are intolerant of pamidronate • Paget disease of bone • Prevention of osteoporosis in post-menopausal women with osteopenia who meet 1 or more of the following [A] . Unable to tolerate two oral bisphosphonates (e.g., alendronate (Fosamax), risedronate (Actonel)) . Unable to tolerate one oral bisphosphonate plus one selecitve estrogen receptor modulator (SERM) (e.g., raloxifene (Evista)) . Oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time) [B] • Prevention of osteoporosis in persons receiving aromatase inhibitors (e.g., anastrozole (Arimidex), letrozole (Femara), exemestane (Aromasin)) who meet 1 or more of the following . Unable to tolerate two oral bisphosphonates (e.g., alendronate (Fosamax), risedronate (Actonel)) . Oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time)

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[C] • Prophylaxis of drug-induced osteopenia secondary to androgen deprivation therapy in prostate cancer [D] • Treatment of osteoporosis in men who meet 1 or more of the following . Unable to tolerate two oral bisphosphonates (e.g., alendronate (Fosamax), risedronate (Actonel)) . Oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time) [E] • Treatment of postmenopausal osteoporosis in women who meet 1 or more of the following . Unable to tolerate two oral bisphosphonates (e.g., alendronate (Fosamax), risedronate (Actonel)) . Unable to tolerate one oral bisphosphonate plus one selective estrogen receptor modulator (SERM) (e.g., raloxifene (Evista)) . Oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time [F] • Prevention and treatment of glucocorticoid-induced osteoporosis in persons meet ALL of the following . Who are receiving 5 mg of prednisone daily (or equivalent) . Are expected to be on oral or parental glucocorticoids for 12 months or more . Member has 1 or more of the following : • Unable to tolerate 2 oral bisphosphonates e.g., alendronate (Fosamax), risedronate (Actonel)) • Oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time) • Zoledronic acid is considered investigational for the following because it has not been shown to be safe and effective for these indications (not an all inclusive list):

• Aseptic necrosis (osteonecrosis) • Breast cancer (adjuvant/neoadjuvant therapy) • Charcot neuroarthropathy • Mazabraud syndrome • McCune-Albright syndrome • Non-small cell lung cancer (adjuvant/neoadjuvant therapy) • Osteopenia (not meeting the above coverage requirements) • Osteoporosis associated with hyperparathyroidism • Otosclerosis

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• Prevention of colorectal cancer in post-menopausal women • Psoriatic arthritis • SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome • The World Health Organization defines osteoporosis 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 • Reclast is contraindicated in persons with creatinine clearance less than 35 ml/min or in persons with evidence of acute renal impairment.

Indications considered Not Medically Necessary

• Zoledronic acid is considered investigational for the following because it has not been shown to be safe and effective for these indications (not an all inclusive list): • Aseptic necrosis (osteonecrosis) • Breast cancer (adjuvant/neoadjuvant therapy) • Mazabraud syndrome • McCune-Albright syndrome • Non-small cell lung cancer (adjuvant/neoadjuvant therapy) • Osteopenia (not meeting the above coverage requirements) • Osteoporosis associated with hyperparathyroidism • Otosclerosis • Prevention of colorectal cancer in post-menopausal women • Psoriatic arthritis • SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome • Reclast is contraindicated in persons with creatinine clearance less than 35 ml/min or in persons with evidence of acute renal impairment. Evidence Summary

Background

• Zoledronic acid (Zometa) is an intravenously administered bisphosphonate that has been approved by the Food and Drug Administration (FDA) for the treatment of hypercalcemia of malignancy. The clinical studies that were presented to the FDA for approval 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-minute infusion time for zoledronic

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acid versus a 2-hour infusion time for pamidronate) and a significantly higher response rate with zoledronic acid. • Pooled data from the two 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 five minutes, to patients receiving a single 90 mg dose of pamidronate infused over two hours. By day 10 of treatment, corrected serum calcium concentrations were normalized in 88.4 percent of patients treated with 4 mg zoledronic acid, and 86.7 percent treated with 8 mg zoledronic acid. In comparison, 69.7 percent 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 guidelines (NCCN, 2010), zoledronic acid may be indicated in multiple myeloma, including smoldering multiple myeloma and solitary plasmacytomas, in combination with induction chemotherapy for persons with bone disease, including osteopenia. • In two 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 percent fewer skeletal events in zoledronic acid-treated patients with metastatic prostate cancer and 7 percent fewer skeletal events in treated patients with other metastatic solid tumors compared to placebo-treated patients. • 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 of greater than 60 mL/min is 4 mg infused over 15 minutes every 3 - 4 weeks. The optimal duration of therapy is unknown. Upon initial treatment, the recommended zolerdronic acid (Zometa) doses for patients with reduced renal function (mild and moderate renal impairment) are listed in the Table below. These doses are

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calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula. • Reduced Doses for Patients with Baseline Creatine Clearance 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: for patients with normal baseline creatinine, increase of 0.5 mg/dL and for patients with a abnormal baseline creatinine, increase of 1.0 mg/dL. • In clinical studies, zolerdronic acid (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 zolerdronic acid (Zometa) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over 15 minutes. Patients who receive zolerdronic acid (Zometa) should have serum creatinine assessed prior to each treatment. Dose adjustments of zolerdronic acid (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 zolerdronic acid (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. • 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. Results of a multicenter, double-blind, placebo-controlled study demonstrated increased bone mineral density of the hip and spine of men with nonmetastatic prostate cancer beginning androgen deprivation therapy plus zoledronic acid (4 mg IV every three months) for 1 year (Smith, et al., 2005). The USPDI notes that a smaller, open-label controlled trial, published in abstract form, demonstrated similar preliminary results. The USPDI states that prostate cancer patients with clinically significant signs of bone loss

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due to androgen deprivation should be considered for treatment with intravenous zoledronic acid. Baseline bone mineral density 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). • Reid, et al. (2005) reported on the results of two double-blind, placebo-controlled clinical studies of zoledronic acid in the treatment of Paget disease of the bone. In these studies, one 15-minute 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 six months, defined as a normalization of alkaline phosphatase levels or a reduction of at least 75 percent in the total alkaline phosphatase excess. At six months, 96.0 percent of patients receiving zoledronic acid achieved a therapeutic response, as compared with 74.3 percent of patients receiving risedronate, a difference that was statistically significant. The investigators reported that alkaline phosphatase levels normalized in 88.6 percent of patients in the zoledronic acid group and 57.9 percent 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 three and six months in the zoledronic acid group and differed significantly from those in the risedronate group at three months. The investigators noted that pain scores improved in both groups. During post-trial follow-up (median, 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. • Zoledronic acid has been shown to increase bone density and decrease fracture risk in women with postmenopausal 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 three-year period. In this study, 3889 patients were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 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, 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). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%,

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and 77%, respectively (p < 0.001 for all comparisons). The investigators also found that zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 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 postmenopausal women with osteopenia was assessed in a 2-year randomized, multi- center, double-blind, placebo-controlled study of 581 postmenopausal 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 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 IU vitamin D supplementation per day. Reclast significantly increased lumbar spine bone mineral density (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 postmenopausal 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. • 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 minutes. 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

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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). • 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 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 1065 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 1054 patients in the zoledronic acid group (9.6 %) and 141 of 1057 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 two 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

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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, thromboembolic, or upper gastrointestinal 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 thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal 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. • 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 bone mineral density by 6.1% over 2 years.

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• The FDA approved zoledronic acid (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 bone mineral density 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 bone mineral density. 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 treatment 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

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concluded that zoledronic acid is at least as effective as pamidronate as treatment for pediatric osteoporosis, and has a similar safety profile. • 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.

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• 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 6886 patients randomized to treatment with bisphosphonates (n = 3414) or either placebo or no treatment (n = 3472). 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- tumour 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 tumour 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 tumour 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

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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 tumour 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-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies. • 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. • 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.

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• 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. • 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

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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. • 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. • 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,

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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. • In a pilot study, McQueen et al (2011) examined the effect of zoledronic acid on articular bone in patients with psoriatic arthritis (PsA) using 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.

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• 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. • 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. • 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.

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• 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. References

1. Novartis Pharmaceuticals. FDA approves Zometa (zoledronic acid) for hypercalcemia of malignancy. Press Release. East Hanover, NJ: Novartis; August 21, 2001. 2. No authors listed. Zolendronate (zometa). Med Lett Drugs Ther. 2001;43(1120):110-111. 3. Rosen LS, Gordon D, Antonio BS, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J. 2001;7(5):377- 387. 4. Cheer SM, Noble S. Zoledronic acid. Drugs. 2001;61(6):799-806. 5. Berenson JR. Zoledronic acid in cancer patients with bone metastases: Results of Phase I and II trials. Semin Oncol. 2001;28(2 Suppl 6):25-34. 6. Berenson JR, Vescio RA, Rosen LS, et al. A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res. 2001;7(3):478-485. 7. Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. 2001;91(7):1191-1200. 8. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-567. 9. Berenson JR, Vescio R, Henick K, et al. A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease. Cancer. 2001;91(1):144-154. 10. Novartis Pharmaceuticals Corporation. Zometa (zoledronic acid for injection) product labeling. East Hanover, NJ: Novartis; 2002. Available at: http://www.fda.gov/cder/foi/label/2002/21386lbl.pdf. Accessed March 4, 2002. 11. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002;346(9):653-661.

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12. Solomon CG. Bisphosphonates and osteoporosis. Perspective. N Engl J Med. 2002;346(9):642. 13. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20(17):3719-3736. 14. Biskobing DM. Novel therapies for osteoporosis. Expert Opin Investig Drugs. 2003;12(4):611-621. 15. Body JJ. Zoledronic acid: An advance in tumour bone disease therapy and a new hope for osteoporosis. Expert Opin Pharmacother. 2003;4(4):567-580. 16. Body JJ, Mancini I. Treatment of tumor-induced hypercalcemia: A solved problem? Expert Rev Anticancer Ther. 2003;3(2):241-246. 17. Ashcroft AJ, Davies FE, Morgan GJ. Aetiology of bone disease and the role of bisphosphonates in multiple myeloma. Lancet Oncol. 2003;4(5):284-292. 18. Eaton CL, Coleman RE. Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment. Cancer Treat Rev. 2003;29(3):189-198. 19. Smith MR. Bisphosphonates to prevent skeletal complications in men with metastatic prostate cancer. J Urol. 2003;170(6 Pt 2):S55-S57; discussion S57-S58. 20. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: A randomized, Phase III, double-blind, placebo- controlled trial. Cancer. 2004;100(12):2613-2621. 21. Saad F, Gleason DM, Murray R, et al. Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-882. 22. Weinfurt KP, Castel LD, Li Y, et al. Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med Care. 2004;42(2):164-175. 23. Rosen LS, Gordon DH, Dugan W Jr, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer. 2004;100(1):36-43. 24. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double- blind, multicenter, comparative trial. Cancer. 2003;98(8):1735-1744. 25. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol. 2003;21(16):3150-3157.

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26. Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169(6):2008-2012. 27. U.S. Pharmacopeial Convention. Zoledronic acid (systemic). USP-DI. Drug Information for the Healthcare Professional. Greenwood Village, CO: Micromedex; 2005. 28. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med. 2005;353(9):898-908. 29. National Horizon Scanning Centre (NHSC). Zoledronic acid (Aclasta); once yearly treatment for post-menopausal osteoporosis: Horizon scanning technology briefing. Birmingham, UK: NHSC; 2006. 30. Black DM, Delmas PD, Eastell R, et al.; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for the treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809-1822. 31. American Society of Clinical Oncology Bisphosphonates Expert Panel. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20(17):1-19. 32. Siris ES, Lyles KW, Singer FR, Meunier PJ. Medical management of Paget's disease of bone: Indications for treatment and review of current therapies. J Bone Miner Res. 2006;21 Suppl 2:P94-P98. 33. Novartis Pharmaceuticals Corporation. Reclast receives US approval as a highly effective treatment for patients with Paget's disease of the bone. Media Releases. Basel, Switzerland: Novartis; April 17, 2007. Available at: http://www.novartis.com/newsroom/index.shtml. Accessed July 6, 2007. 34. Keating GM, Scott LJ. Zoledronic acid: A review of its use in the treatment of Paget's disease of bone. Drugs. 2007;67(5):793-804. 35. Lyles KW, Colón-Emeric CS, Magaziner JS, et al; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357(18):1799-1809. 36. Calis KA, Pucino F. Zoledronic acid and secondary prevention of fractures. N Engl J Med. 2007;357(18):1861-1862. 37. MacLean C, Newberry S, Maglione M, et al. Systematic review: Comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008;148(3):197-213. 38. Novartis Pharmaceuticals. FDA approves once-yearly Reclast for osteoporosis in men. Press Release. East Hanover, NJ: Novartis; January 6, 2009. 39. Novartis Pharmaceuticals. Once-yearly Reclast approved by FDA to treat and prevent steroid-induced osteoporosis, marking its fourth approved indication. Press Release. East Hanover, NJ: Novartis; March 16, 2009.

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40. Novartis Pharmaceuticals. Reclast (zolerdronic acid) injection. Full Prescribing Information. T2009-36. East Hanover, NJ: Novartis; March 2009. Available at: http://www.pharma.us.novartis.com/product/pi/pdf/reclast.pdf. Accessed March 24, 2009. 41. World Health Organization (WHO). WHO scientific group on the assessment of osteoporosis at primary health care level. Summary meeting report. Brussels, Belgium; WHO; May 5-7, 2004. Available at: http://www.who.int/chp/topics/Osteoporosis.pdf. Accessed November 4, 2009. 42. National Comprehensive Cancer Network (NCCN). Multiple myeloma. NCCN Clinical Practice Guidelines in Oncology, v.3.2010. Fort Washington, PA: NCCN; 2010. 43. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al; Austrian Breast and Colorectal Cancer Study Group (ABCSG). Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG- 12 bone-mineral density substudy. Lancet Oncol. 2008;9(9):840-849. 44. Cheung MS, Glorieux FH. Osteogenesis Imperfecta: Update on presentation and management. Rev Endocr Metab Disord. 2008;9(2):153-160. 45. Yamashita S. Bisphosphonates and other new therapeutic agents for the treatment of osteogenesis imperfecta. Clin Calcium. 2009;19(2):253-257. 46. Brown JJ, Zacharin MR. Safety and efficacy of intravenous zoledronic acid in paediatric osteoporosis. J Pediatr Endocrinol Metab. 2009;22(1):55-63. 47. Mauri D, Valachis A, Polyzos NP, et al. Does adjuvant bisphosphonate in early breast cancer modify the natural course of the disease? A meta-analysis of randomized controlled trials. J Natl Compr Canc Netw. 2010;8(3):279-286. 48. Coleman RE, Winter MC, Cameron D, et al; AZURE (BIG01/04) Investigators. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: Exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010;102(7):1099-1105. 49. Saad F, Eastham J. Zoledronic Acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer. Urology. 2010;76(5):1175- 1181. 50. Morgan GJ, Davies FE, Gregory WM, et al; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial. Lancet. 2010;376(9757):1989-1999. 51. Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728-1737. 52. Rennert G, Pinchev M, Rennert HS, Gruber SB. Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol. 2011;29(9):1146-1150. 53. Van Poznak CH, Temin S, Yee GC, et al; American Society of Clinical Oncology. American Society of Clinical Oncology executive summary of the clinical practice

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guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-1227. 54. Mahtani R, Khan R, Jahanzeb M. The potential application of zoledronic acid as anticancer therapy in patients with non-small-cell lung cancer. Clin Lung Cancer. 2011;12(1):26-32. 55. Pakarinen TK, Laine HJ, Maenpaa H, et al. The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy: A pilot randomized controlled trial. Diabetes Care. 2011;34(7):1514-1516. 56. McQueen F, Lloyd R, Doyle A, et al. Zoledronic acid does not reduce MRI erosive progression in PsA but may suppress bone oedema: The Zoledronic Acid in Psoriatic Arthritis (ZAPA) Study. Ann Rheum Dis. 2011;70(6):1091-1094. 57. U.S. Food and Drug Administration (FDA). Reclast (zoledronic acid): Drug safety communication - New contraindication and updated warning on kidney impairment. Silver Spring, MD: FDA; September 1, 2011. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedical Products/ucm270464.htm. Accessed May 16, 2012. 58. Coleman RE, Marshall H, Cameron D, et al; AZURE Investigators. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365(15):1396-1405. 59. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;(2):CD003474. 60. Assmann G, Simon P. The SAPHO syndrome -- are microbes involved? Best Pract Res Clin Rheumatol. 2011;25(3):423-434. 61. Quesnel AM, Seton M, Merchant SN, et al. Third-generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis. Otol Neurotol. 2012;33(8):1308- 1314. 62. Niikura N, Liu J, Hayashi N, et al. Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases. Cancer. 2012;118(8):2039-2047. 63. Yan T, Yin W, Zhou Q, et al. The efficacy of zoledronic acid in breast cancer adjuvant therapy: A meta-analysis of randomised controlled trials. Eur J Cancer. 2012;48(2):187- 195. 64. Ralston SH. Clinical practice. Paget's disease of bone. N Engl J Med. 2013;368(7):644- 650. 65. Kyrgidis A, Tzellos TG, Toulis K, et al. An evidence-based review of risk-reductive strategies for osteonecrosis of the jaws among cancer patients. Curr Clin Pharmacol. 2013;8(2):124-134. 66. Padhye B, Dalla-Pozza L, Little DG, Munns CF. Use of zoledronic acid for treatment of chemotherapy related osteonecrosis in children and adolescents: A retrospective analysis. Pediatr Blood Cancer. 2013 Apr 26. [Epub ahead of print]

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67. Jones LC, Mont MA. Osteonecrosis (avascular necrosis of bone). Last reviewed April 2013. UpTodate Inc. Waltham, MA.

Reviewed by a Board Certified Internist Reviewed by David Evans, MD, Medical Director, Active Health Management- Aug 2016 Copyright 2016 ACTIVEHEALTH MANAGEMENT No part of this document may be reproduced without permission. Footnotes

[A] 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. [ A in Context Link 1 ]

[B] 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. [ B in Context Link 1 ]

[C] 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. [ C in Context Link 1 ]

[D] 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. [ D in Context Link 1 ]

[E] 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. [ E in Context Link 1 ]

ActiveHealth Management Medical Management Guidelines

[F] 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. [ F in Context Link 1 ] Codes

CPT® or HCPCS: 96365, 96366, 96367, 96368, 96372, 96379, J3488