ATC Class:M05BA08

VA Class:HS900

AHFS Class:

• Bone Resorption Inhibitors 92:24

Generic Name(s):

• Zoledronic Acid

Chemical Name:

• [1-Hydroxy-2-(1 H -imidazol-1-yl)ethylidene]bis-phosphonic acid monohydrate

Molecular Formula:

• C₅H₁₀N₂O₇P₂ • H₂O

Zoledronic acid, a synthetic imidazole bisphosphonate analog of pyrophosphate, is a bone resorption inhibitor.1,4,5

Hypercalcemia Associated with Malignancy

Zoledronic acid is used in conjunction with achievement and maintenance of adequate hydration for the treatment of hypercalcemia (albumin-corrected serum calcium concentration of 12 mg/dL or greater) associated with malignant neoplasms.1,2,3,5,6 For the treatment of mild or asymptomatic hypercalcemia, measures more conservative (e.g., hydration alone or combined with loop diuretics) than therapy with agents such as zoledronic acid generally are used.1

Controlled clinical studies have shown that single-dose IV zoledronic acid (4 mg infused over 5 minutes) is more effective in the treatment of moderate to severe malignancy-associated hypercalcemia (albumin-corrected serum calcium concentration of 12 mg/dL or greater) than single-dose IV pamidronate disodium (90 mg infused over 2 hours).1,2,3,5 In these studies, patients received zoledronic acid or pamidronate disodium in conjunction with IV hydration (750 mL of fluid, of which 250 mL was administered prior to study drug administration).2,3 Normocalcemia (corrected serum calcium concentrations not exceeding 10.8 mg/dL) was attained more quickly and maintained for a longer period of time in patients receiving zoledronic acid than in those receiving pamidronate.1,2,3 Analysis of pooled data from these studies indicates that 70 or 88% of patients receiving pamidronate disodium or zoledronic acid, respectively, achieved a normal serum calcium concentration within 10 days of treatment.1,2,3 For responders, the median duration of complete response (defined as the time from onset of normocalcemia until the last corrected serum calcium concentration of 10.8 mg/dL or less) following a single dose was approximately 32 or 18 days for zoledronic acid or pamidronate, respectively.1,2,3 The median time to recurrence (defined as the time from drug administration until the last corrected serum calcium concentration of less than 11.6 mg/dL) was longer with zoledronic acid (30 days) than with pamidronate (17 days).1,2,3 Subgroup analysis indicates that complete response rates were not affected by cancer type, the presence or absence of bone metastases, baseline blood parathyroid hormone-related protein concentrations, baseline BUN-to-creatinine ratio, age, sex, or race.2

Retreatment with zoledronic acid may be considered in patients with recurrent or refractory hypercalcemia of malignancy.1,2,3 Data from a limited number of patients indicate that a second course of IV zoledronic acid therapy can normalize serum calcium concentrations when malignancy-associated hypercalcemia is refractory to or recurs following an adequate response to an initial course of therapy.2,3 A second course of therapy with zoledronic acid at a higher than recommended dose (8 mg) returned corrected serum calcium concentrations to normal within 10 days after retreatment in 52% of patients whose hypercalcemia was refractory to or recurred following an adequate response to an initial dose of zoledronic acid 4 mg.1,2,3,5 For responders, the median duration of complete response following retreatment was 11 days.2,3 The median time to recurrence following retreatment was 8 days.2,3

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

Zoledronic acid is used as an adjunct to antineoplastic therapy for the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma.1,7 In patients with bone metastases associated with prostate cancer, zoledronic acid should be used as second-line therapy and is reserved for those with disease progression following one or more hormonal therapies.1,3

The efficacy of zoledronic acid in combination with antineoplastic therapy (e.g., chemotherapy or hormonal therapy) for the treatment of bone metastases in patients with advanced solid tumors or osteolytic bone lesions associated with multiple myeloma has been demonstrated in several large clinical trials.1,3,7 In a long-term (12 months' duration) comparative study in patients with breast cancer and bone metastases or with stage III multiple myeloma and at least one osteolytic bone lesion, combined zoledronic acid (4 mg, administered as a 5- or 15-minute IV infusion once every 3-4 weeks) and antineoplastic therapy (chemotherapy or hormonal therapy) was as effective as combined pamidronate disodium (90 mg, administered as a 2-hour IV infusion once every 3-4 weeks) and antineoplastic therapy in reducing the incidence of bone-related complications (e.g., fractures or spinal cord compression, bone deterioration requiring radiotherapy or orthopedic surgery) and in delaying the development of such complications.1,3,7 The median time to the first bone-related complication was 373 days in patients receiving zoledronic acid and 363 days in patients receiving pamidronate.1 Patients with pain experienced a decrease in pain during adjunctive zoledronic acid or pamidronate therapy, while the need for supplemental analgesic therapy decreased or remained relatively unchanged.3,7 Secondary end points such as change in performance status or median time to overall disease progression or death did not differ between the treatment groups.1,7

In a long-term (10.5 months' duration) placebo-controlled trial, patients with hormone-refractory prostate cancer and bone metastases who were receiving combined zoledronic acid (4 mg, administered as a 5- or 15-minute IV infusion once every 3 weeks) and hormonal therapy showed a decrease in the incidence and a delay in the development of bone-related complications (e.g., fractures or spinal cord compression, bone deterioration requiring radiotherapy or orthopedic surgery, bone pain necessitating a change in hormonal therapy) compared with those receiving hormonal therapy alone.1,3 The incidence of bone-related complications was lower in patients receiving adjunctive zoledronic acid (33%) than in those receiving hormonal therapy alone (44%).1,3 The first bone-related complication was observed at 321 days in those receiving hormonal therapy alone and such complications were not observed at that time in those receiving adjunctive zoledronic acid.1,3

Data from a long-term placebo-controlled trial in patients with bone metastases and solid tumors other than breast or prostate cancer showed no appreciable difference in the incidence of bone-related complications (e.g., fractures or spinal cord compression, bone deterioration requiring radiotherapy or orthopedic surgery, bone pain necessitating a change in antineoplastic therapy) in patients receiving combined zoledronic acid (4 mg, administered as a 15-minute IV infusion once every 3 weeks) and antineoplastic therapy compared with those receiving antineoplastic therapy alone; however, there was a median delay of 67 days in the development of such complications in the group receiving zoledronic acid.1,3 Bone-related complications were observed in 38% of patients receiving adjunctive zoledronic acid compared with 44% of those receiving antineoplastic therapy alone.1,3 The median time to the first bone-related complication was 230 or 163 days, respectively, in patients receiving adjunctive zoledronic acid or antineoplastic therapy alone.1,3 More than two-thirds of the patients had preexisting bone-related complications; the median survival of patients enrolled in the trial (6 months) was less than the planned trial duration (9 months).3

Osteoporosis

Zoledronic acid is used for the prevention and treatment of postmenopausal osteoporosis; the drug also is used to increase bone mass in men with osteoporosis.17

In addition to adequate intake of calcium/vitamin D and other lifestyle modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use), experts recommend that pharmacologic therapy for osteoporosis be considered in postmenopausal women and in men 50 years of age or older who are at high risk of fractures (generally those who have experienced a previous hip or vertebral fracture or who have low bone mineral density [BMD]);44,45 pharmacologic therapy also may be considered in postmenopausal women and in men 50 years of age or older who have low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients.44 When selecting an appropriate pharmacologic agent, use of a drug with proven antifracture efficacy is recommended.45 Available options include bisphosphonates (e.g., alendronate, risedronate, zoledronic acid, ibandronate), denosumab, raloxifene, calcitonin, or teriparatide with varying levels of recommendation given in expert guidelines based on the available evidence supporting fracture risk reduction for each drug.44,45 Choice of therapy should be individualized based on the potential benefits and adverse effects of therapy as well as patient preferences, comorbidities, and risk factors.44,45 For additional information on the prevention and treatment of osteoporosis, see Uses: Osteoporosis, in Alendronate 92:24.

Prevention in Postmenopausal Women

Zoledronic acid is used for the prevention of osteoporosis in postmenopausal women.17,41 Risk factors for postmenopausal osteoporosis and related fractures include early menopause, decreased BMD, low body mass index (BMI), previous fracture or family history of fracture/osteoporosis, excessive alcohol intake, smoking, inadequate physical activity, low calcium and vitamin D intake, certain drugs (e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).44,45

In a 2-year, double-blind, placebo-controlled study in postmenopausal women 45 years of age or older with osteopenia, treatment with zoledronic acid resulted in a substantial increase in total hip and lumbar spine BMD compared with placebo at 2 years.17,41 In this study, zoledronic acid 5 mg was administered as a once-yearly IV infusion (total of 2 doses) or as a single IV infusion at study randomization (total of 1 dose); both dosage regimens were effective in preventing bone loss over the 2-year study period.17,41 Levels of bone turnover markers were reduced at all time points in both zoledronic acid treatment groups, but the effect was more sustained with the once-yearly regimen.41

Treatment in Postmenopausal Women

Zoledronic acid is used for the treatment of osteoporosis in postmenopausal women.17,21 Efficacy of zoledronic acid given as a once-yearly IV infusion has been established in 2 long-term (3 years' duration) randomized, double-blind, placebo-controlled, multinational studies in postmenopausal women with osteoporosis (diagnosed by BMD with or without vertebral fracture[s]).17,21 In each study, zoledronic acid was given as a single 5-mg dose by IV infusion over at least 15 minutes.17,21 In these studies, the incidence of new fractures (hip, vertebral, non-vertebral fractures) was reduced among patients receiving zoledronic acid compared with that observed with placebo with or without background therapies for osteoporosis (excluding bisphosphonates).17,21 Bone histology studies of patients from one of the studies indicated that the bone formed during therapy with zoledronic acid had normal architecture and mineralization.17 In patients at high risk of fractures (defined as those with a history of a recent, low-trauma hip fracture), zoledronic acid reduced the incidence of subsequent fractures.17

Treatment in Men

Zoledronic acid is used to increase bone mass in men with osteoporosis.17 Efficacy of zoledronic acid given as a once-yearly IV infusion was established in a long-term (2 years' duration) randomized, double-blind, active-controlled, multicenter study in men with osteoporosis or osteoporosis secondary to hypogonadism.17 Zoledronic acid was given as a single 5-mg dose by IV infusion over at least 15 minutes; this dose could be repeated once.17 The active control was an oral bisphosphonate administered once weekly for up to 2 years.17 All patients received elemental calcium 1 g and vitamin D 800-1000 international units (IU, units) daily.17 In this study, once-yearly zoledronic acid by IV infusion was noninferior to the once-weekly oral bisphosphonate based on the percent change in lumbar spine BMD at month 24 compared with baseline (6.1 versus 6.2% increase in BMD with zoledronic acid versus oral bisphosphonate, respectively).17

Glucocorticoid-induced Osteoporosis

Zoledronic acid is used in the treatment and prevention of glucocorticoid-induced osteoporosis.17,40 The manufacturer recommends use of zoledronic acid in men and women who are either initiating or receiving long-term (at least 12 months) systemic glucocorticoid therapy in a daily dosage equivalent to at least 7.5 mg of prednisone.17

The American College of Rheumatology (ACR) recommends optimizing calcium and vitamin D intake and lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) in all patients receiving long-term glucocorticoid therapy; in addition, pharmacologic therapy with an oral bisphosphonate is recommended in patients who are considered to be at moderate-to-high risk of fracture.622 Oral bisphosphonates generally are preferred because of their antifracture benefits as well as their safety and low cost; other options include IV bisphosphonates, teriparatide, denosumab, and raloxifene (for postmenopausal women if no other therapy is appropriate).622 For additional information on the use of bisphosphonates for prevention and treatment of glucocorticoid-induced osteoporosis, see Uses: Glucocorticoid-induced Osteoporosis, in Alendronate 92:24.

Safety and efficacy of zoledronic acid for the treatment and prevention of glucocorticoid-induced osteoporosis were evaluated in a randomized, double-blind, active-controlled study in men and women receiving glucocorticoid therapy (daily dosage of at least 7.5 mg of prednisone or equivalent).17,40 Patients were stratified according to their duration of glucocorticoid use: up to 3 months (prevention group) or more than 3 months (treatment group).17,40 In this study, zoledronic acid was administered in a single 5-mg dose by IV infusion over 15-20 minutes, and the active control (risedronate) was administered orally in a dosage of 5 mg once daily.17,40 At 12 months, zoledronic acid increased lumbar spine BMD to a greater extent than risedronate; lumbar BMD increased by an average of 4.1 versus 2.7%, respectively, in the treatment group and by an average of 2.6 versus 0.6%, respectively, in the prevention group.17,40 Qualitative histology assessments in a subset of patients who received zoledronic acid revealed normal architecture with no evidence of mineralization defects.17 However, there was an apparent reduction in activation frequency and bone remodeling rates when compared with histomorphometry results seen with zoledronic acid in the postmenopausal osteoporosis population; the long-term consequences of such effects are unknown.17

Paget Disease of Bone

Zoledronic acid is used for the management of moderate-to-severe Paget disease of bone (osteitis deformans).17 Efficacy of the drug in the treatment of Paget disease of bone has been established in 2 randomized, double-blind studies of 6 months' duration, in which zoledronic acid 5 mg as a single dose by IV infusion produced a more rapid and effective therapeutic response (as defined by either normalization of serum alkaline phosphatase concentrations or a reduction of at least 75% from baseline in total serum alkaline phosphatase excess [i.e., “excess” being defined as the difference between the measured concentration and the midpoint of the normal range] at the end of 6 months) than risedronate 30 mg orally once daily for 2 months.17 Most patients achieved a response to zoledronic acid by day 63 of the study.17

Treatment with zoledronic acid should be considered in patients with serum alkaline phosphatase concentrations of at least twice the age-specific upper limit of normal, in those who are symptomatic, or in those at risk for future complications from their disease.17 After a single treatment of zoledronic acid in patients with Paget disease of bone, an extended remission period is observed.17 Specific data on retreatment of the disease are not available.17 However, retreatment may be considered in patients who have relapsed based on increases in serum alkaline phosphatase concentrations, in those who failed to achieve normalization of serum alkaline phosphatase concentrations, or in patients who are symptomatic, according to current standards of medical care.17

Prevention of Aromatase Inhibitor-associated Bone Loss

Zoledronic acid has been studied for the prevention of aromatase inhibitor-associated bone loss in women receiving adjuvant hormonal therapy for early-stage breast cancer†.10001,10003,10004,10017,10018,10019,10020,10021,10022,10023

Prevention in Postmenopausal Women

Efficacy and safety of zoledronic acid for the prevention of aromatase inhibitor-associated bone loss in women receiving adjuvant hormonal therapy for early-stage breast cancer† have been studied in several phase 3, open-label, randomized studies (Zometa-Femara Adjuvant Synergy Trial [Z-FAST], ZO-FAST, E-ZO-FAST, and North Central Cancer Treatment Group [NCCTG]-N03CC study).10017,10019,10021,10022 The Z-FAST, ZO-FAST, and E-ZO-FAST studies included postmenopausal women with stage I-IIIa estrogen receptor-positive and/or progesterone receptor-positive breast cancer; patients had a baseline T-score of -2 standard deviations (SD) from normal or better and did not have a history of a low-intensity fracture or evidence of an existing fracture.10001,10019,10022 Patients enrolled in these studies were randomized to receive upfront or delayed zoledronic acid.10017,10019,10022 Women in the upfront group received zoledronic acid following randomization; women in the delayed group did not begin treatment with zoledronic acid until their T-score declined to less than -2 standard deviations or after occurrence of a nontraumatic fracture or evidence of an asymptomatic fracture.10001,10002,10019,10022 Patients received zoledronic acid 4 mg by IV infusion over 15 minutes every 6 months for 5 years in addition to oral calcium and vitamin D.10001,10019,10022 All patients received letrozole 2.5 mg orally daily for 5 years.10001,10018,10022 Patients enrolled in these studies were not permitted to receive other drugs known to affect the skeleton (e.g., IV bisphosphonates, chronic corticosteroids) during the study or for a specified period of time prior to study entry.10001,10019,10022

In the Z-FAST study, BMD in both the lumbar spine and total hip sites was improved at 61 months for the upfront group but declined in the delayed group in women still remaining in the study at that time (approximately 60% of those initially enrolled), regardless of baseline T-score, clinically important risk factors, or chemotherapy status.10017 A decline in BMD of at least 8% in the lumbar spine in women with a normal BMD at baseline (defined as T-score better than -1 SD from normal) occurred more frequently in those receiving delayed treatment than in those receiving upfront treatment (20 versus 1.7%, respectively, based on intent-to-treat analysis).10017 In women with preexisting mild to moderate osteopenia (i.e., a decline to a T-score between -1 and -2 SD), a BMD decrease of at least 8% in the lumbar spine occurred in 5.7 and 0.3% of patients in the delayed and upfront treatment groups, respectively, based on intent-to-treat analysis.10017 At 61 months, upfront administration of zoledronic acid reduced progression to mild to moderate osteopenia in women with a normal BMD at baseline compared with delayed administration of the drug (2 versus 11%, respectively), and reduced progression to severe osteopenia (i.e., a decline to a T-score below -2 SD) in women with preexisting mild to moderate osteopenia (0 versus 4.9%, respectively).10001,10017 The 2-year fracture rate was similar (4.3 and 4%) for both treatment groups, with an increase at 5 years to 9.3 and 11% in the upfront and delayed groups, respectively.26,10002,10017 The mean difference in percentage change from baseline BMD for the lumbar spine and total hip sites at 61 months was 8.9 and 6.7%, respectively, between the upfront treatment and delayed treatment groups.10017 At the time of the final analysis at a follow-up of 61 months, 24.6% of the women in the delayed group had begun treatment with zoledronic acid; 66.2% of these women had met protocol-defined criteria to receive zoledronic acid.10017 Bone turnover marker analysis at 61 months revealed lower serum N-telopeptide (NTx) and bone-specific alkaline phosphatase (BSAP) concentrations in the upfront group than those in the delayed group.10017 Renal impairment occurred at a similar rate in both treatment groups; however, potential osteonecrosis of the jaw occurred more frequently in women receiving upfront therapy than in those receiving delayed therapy (2 versus 0 cases).10017

Data from the ZO-FAST study also demonstrated improvement of BMD in both the lumbar spine and total hip sites at 60 months for the upfront group but BMD declined in the delayed group.10019 Upfront administration of zoledronic acid increased BMD in the lumbar spine by 3.9% in women with a normal BMD at baseline, but a 7.1% decrease occurred in those receiving delayed administration of the drug.10019 Upfront zoledronic acid substantially improved BMD in the lumbar spine by 5.3% compared with delayed administration, which resulted in a 4.2% decrease in women with established (natural) postmenopausal status.10019 In women who were newly (induced) postmenopausal, a decrease of 0.3 or 9.3% in BMD in the lumbar spine was reported in the upfront or delayed treatment groups, respectively.10019 At the time of the final analysis, the mean difference in percentage change from baseline BMD in the lumbar spine and total hip sites was 9.7 and 5.8%, respectively, between the upfront treatment and delayed treatment groups.10019 At the time of the final analysis at a follow-up of 60 months, 27% of the women in the delayed group had met criteria to receive zoledronic acid.10019 Renal impairment occurred at a similar rate in both treatment groups, and 9 potential osteonecrosis of the jaw events were reported in the overall study population.10019

Data from the E-ZO-FAST study were consistent with the Z-FAST and ZO-FAST studies.10022 Improvement of BMD at both the lumbar spine and total hip sites was observed at 12 months for the upfront group, but BMD declined in the delayed group regardless of baseline T-score, postmenopausal status, or chemotherapy status.10022 At 12 months, 13% of the women in the delayed group had met criteria to receive zoledronic acid.10022 In this study, upfront administration of zoledronic acid reduced progression to osteopenia in women with a normal BMD at baseline compared with delayed administration of the drug (2.1 versus 12.5%, respectively).10022 In women with preexisting osteopenia, improvement to a normal BMD occurred more frequently in women receiving upfront administration of zoledronic acid compared with those receiving delayed administration of the drug (18.3 versus 8%, respectively), and maintenance of a normal BMD in women with a normal BMD at baseline occurred more frequently in those receiving upfront therapy than in those receiving delayed therapy (71.1 versus 57.2%, respectively).10022 The 1-year fracture rate was 0.8 and 1.9% in the upfront and delayed groups, respectively.10022 At 12 months, the mean difference in percentage change from baseline BMD in the lumbar spine and total hip sites was 5.4 and 3.3%, respectively, between the upfront and delayed treatment groups.10022 Among women with established postmenopausal status and those who were recently (induced) menopausal, the percentage change from baseline BMD between the upfront and delayed treatment groups was 5.2 and 6.8%, respectively.10022 Adverse effects generally were similar in both treatment groups, although bone pain (8.3 versus 4.1%), pyrexia (6.7 versus 0%), and influenza-like illness (6 versus 1.1%) occurred more frequently in women in the upfront group compared with those in the delayed group.10022 Osteonecrosis of the jaw occurred in 0.4% of women receiving upfront therapy compared with none of those receiving delayed therapy.10022

Data from a similarly designed study (NCCTG-N03CC) also demonstrated an improvement in lumbar spine BMD in postmenopausal women treated with letrozole who had received prior tamoxifen therapy and were randomized to receive upfront zoledronic acid therapy.10020,10021 At the time of the final analysis at a follow-up of 60 months, 42% of women initially enrolled in the study were evaluable for the primary BMD end point and 14.7% of women in the delayed group crossed over to receive zoledronic acid.10021 Clinically important lumbar spine bone loss (i.e., BMD decrease of 5% or greater from baseline) occurred more frequently in women receiving delayed therapy compared with those receiving upfront therapy (41.2 versus 10.2%), and clinically important total hip and femoral neck bone loss was reported in 45.8 or 7.6% of those receiving delayed or upfront therapy, respectively; a BMD decrease of 10% from baseline in the lumbar spine occurred in 16.8 and 5.1% of women in the delayed and upfront treatment groups, respectively.10021 The mean difference in BMD for the lumbar spine was 9.4% between the upfront treatment and delayed treatment groups.10021 However, there was no difference between the groups in the 5-year fracture rate.10021 Adverse effects generally were similar between both treatment groups, although pyrexia (9 versus 3%) and elevated serum creatinine concentrations (9 versus 5%) occurred more frequently in women receiving upfront therapy compared with those receiving delayed therapy.10021 Osteonecrosis of the jaw occurred in 2 or 1% of women receiving upfront or delayed therapy, respectively.10021

Although longer-term follow-up of the 3 companion Zometa-Femara Adjuvant Synergy Trials (Z-FAST, ZO-FAST, E-ZO-FAST) and NCCTG-N03CC study is needed to further clarify between-treatment differences in fracture incidence,10017,10019,10021,10022 upfront administration of zoledronic acid in postmenopausal women receiving aromatase inhibitor therapy significantly prevented lumbar spine and total hip BMD losses compared with those whose therapy was delayed until a decline in T-score to less than -2 SD or nontraumatic fracture, or evidence of an asymptomatic fracture occurred.10017,10019,10021,10022 Based on current evidence, use of zoledronic acid in postmenopausal women receiving aromatase inhibitor therapy may be considered a reasonable choice (accepted, with possible conditions); factors that should be considered when determining the optimal time to initiate therapy are baseline BMD and history of prior fractures.10034

Prevention in Premenopausal Women

Efficacy and safety of zoledronic acid for the prevention of aromatase inhibitor-associated bone loss in premenopausal women receiving adjuvant hormonal therapy plus a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone) agonist (e.g., goserelin) for stage I or II estrogen receptor-positive or progesterone receptor-positive breast cancer† were studied in a BMD substudy of a phase 3, open-label, randomized study (Austrian Breast and Colorectal Cancer Study Group-12 [ABCSG-12]).10004 The ABCSG-12 study included premenopausal women with early-stage estrogen receptor-positive and/or progesterone receptor-positive breast cancer.10004 In this substudy, 401 patients were randomized in a 1:1:1:1 ratio to receive hormonal therapy with tamoxifen (20 mg orally daily) or anastrozole (1 mg orally daily) plus a GnRH agonist (goserelin acetate 3.6 mg by subcutaneous injection every 28 days) to induce ovarian suppression with or without zoledronic acid.10004 An initial zoledronic acid dosage of 8 mg IV every 6 months was used; the protocol was subsequently amended to reduce the dosage to 4 mg by IV infusion over 15 minutes every 6 months following reports of increased toxicity (e.g., nephrotoxicity) with the higher dose.10004 Therapy was continued for a duration of 3 years in all treatment groups.10004

A lower rate of decline in bone loss after 3 years of treatment was reported in those premenopausal women still remaining in the study at that time (about one-third of those initially enrolled) who were receiving zoledronic acid with anastrozole-goserelin or tamoxifen-goserelin compared with those receiving anastrozole-goserelin or tamoxifen-goserelin alone.10004 The incidence of osteopenia at 3 years in the lumbar spine was 44 or 54% in patients receiving zoledronic acid-anastrozole-goserelin or anastrozole-goserelin alone, respectively.10004 Osteoporosis was not reported in patients receiving zoledronic acid-anastrozole-goserelin, but 25% of women receiving anastrozole-goserelin alone became osteoporotic.10004 Two years after the completion of the study treatment, partial improvement in BMD at both the lumbar spine and trochanter sites was observed in those receiving anastrozole-goserelin or tamoxifen-goserelin alone, although BMD had not fully recovered to the baseline measurement; in contrast, an improvement in BMD was reported in those receiving zoledronic acid with anastrozole-goserelin or tamoxifen-goserelin.10025 Although not specific for the anastrozole-goserelin regimen, no fractures were reported in patients receiving zoledronic acid at 5 years; 2 fractures occurred in women receiving anastrozole-goserelin or tamoxifen-goserelin alone.10025

Improvements in BMD were observed in premenopausal women with early-stage breast cancer when zoledronic acid was administered concurrently with an aromatase inhibitor and GnRH agonist.10004 However, longer-term follow-up of this study is needed, especially as these women enter menopause, to further clarify lasting clinical efficacy (i.e., clinically important fracture reduction) and late adverse effects of zoledronic acid therapy.10004 Based on current evidence, use of zoledronic acid for the prevention of aromatase inhibitor-associated bone loss in premenopausal women is not fully established because of unclear risk/benefit.10034

Breast Cancer

Efficacy and safety of zoledronic acid in combination with adjuvant systemic therapy in postmenopausal women with early or locally advanced breast cancer† have been studied in 2 open-label, randomized phase 3 studies (Austrian Breast and Colorectal Cancer Study Group-12 [ABCSG-12] and Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]-BIG 01/04 study),10024,10030 with supportive data from a meta-analysis and 3 open-label, randomized phase 3 studies evaluating the use of zoledronic acid for the prevention of aromatase inhibitor-associated bone loss†.10001,10017,10018,10019,10022,10032

In the ABCSG-12 study, 1803 premenopausal women with estrogen receptor-positive and/or progesterone receptor-positive stage I or II breast cancer were randomized in a 1:1:1:1 ratio to receive hormonal therapy with tamoxifen (20 mg orally daily) or anastrozole (1 mg orally daily) plus a GnRH agonist (goserelin acetate 3.6 mg by subcutaneous injection every 28 days) to induce ovarian suppression with or without zoledronic acid.10023 An initial zoledronic acid dosage of 8 mg IV every 6 months was used; the protocol was subsequently amended to reduce the dosage to 4 mg by IV infusion over 15 minutes every 6 months following reports of increased toxicity (e.g., nephrotoxicity) with the higher dose.10004 Therapy was continued for a duration of 3 years in all treatment groups.10023 In this study, the primary measure of efficacy was disease-free survival.10023 The median age of patients enrolled in the study was 45 years (range: 25-58); 31% had positive lymph node involvement and 85% did not receive neoadjuvant chemotherapy.10023 All patients enrolled in the study had hormone receptor-positive tumors.10023 At a median follow-up of 62 months, addition of zoledronic acid to hormonal therapy improved the rate of disease-free survival compared with hormonal therapy alone (92 versus 88%; hazard ratio of 0.68).10023 Similar results were observed but predefined statistical significance was not achieved at a median follow-up of 94.4 months.10024 Zoledronic acid administered concurrently with hormonal therapy was associated with numerically, but not significantly, improved overall survival compared with hormonal therapy alone (96.7 versus 94.5%).10024 A subset analysis of disease-free survival and overall survival based on clinically relevant baseline patient and disease characteristics demonstrated consistent treatment benefit with zoledronic acid regardless of lymph node status and disease stage (T1 or T2/3), but no difference in disease-free survival or overall survival was apparent in patients 40 years of age or younger receiving zoledronic acid compared with those receiving hormonal therapy alone.10024 Adverse effects generally were consistent with known safety profiles of each agent, although arthralgia (24 versus 18%), bone pain (35 versus 25%), nausea/vomiting (8.6 versus 6.1%), pyrexia (8.9 versus 2.2%), dermatologic effects (6.5 versus 4.3%), peripheral nerve disease (5.7 versus 3.4%), tachycardia (2.1 versus 0.8%), cognitive disorder (1.4 versus 0.3%), and hypocalcemia (0.4 versus 0%) occurred more frequently in women receiving zoledronic acid concurrently with hormonal therapy compared with those receiving hormonal therapy alone.10033 No confirmed cases of osteonecrosis of the jaw were reported.10024

In the AZURE-BIG 01/04 study, 3360 patients with stage II or III invasive breast cancer were randomized to receive zoledronic acid in addition to adjuvant antineoplastic therapy (i.e., hormonal therapy, chemotherapy, or both) or adjuvant antineoplastic therapy alone.10030 Patients randomized to receive zoledronic acid received 4 mg by IV infusion every 3-4 weeks for 6 doses, then every 3 months for 8 doses, followed by every 6 months for 5 doses (for a total duration of 5 years).10030 The majority of patients had positive lymph node involvement (98%), 78% had estrogen receptor-positive tumors, 45% were premenopausal, 31% had been postmenopausal for greater than 5 years, and 15% had been postmenopausal for 5 years or less.10029 Most patients (74%) enrolled in the study planned to receive hormonal therapy in combination with chemotherapy.10030 The majority of patients enrolled in the study planned to receive an anthracycline-containing regimen (93%) and 23% planned to receive a taxane-containing regimen.10030 In this study, the primary measure of efficacy was disease-free survival.10030 At median follow-up times of 59 and 84 months, no significant difference in disease-free survival (hazard ratios of 0.98 and 0.94, respectively) or overall survival (hazard ratios of 0.85 and 0.93, respectively) was observed between patients receiving zoledronic acid and antineoplastic therapy and those receiving antineoplastic therapy alone;10029,10030 however, zoledronic acid substantially reduced the incidence of bone fractures and bone metastasis by 31 and 19-22%, respectively, compared with antineoplastic therapy alone.10030 A preplanned subset analysis of invasive disease-free survival based on menopausal status suggested a treatment benefit, primarily a reduction in extraskeletal invasive disease-free events, with the addition of zoledronic acid to antineoplastic therapy in women who had experienced menopause at least 5 years before study entry (hazard ratio of 0.77), but not in women in other menopausal groups (e.g., premenopausal, perimenopausal, unknown menopausal status) (hazard ratio of 1.03).10030 Adverse effects were similar between both treatment groups, although 33 cases (confirmed in 26 cases) of potential osteonecrosis of the jaw occurred in women receiving zoledronic acid plus antineoplastic therapy compared with no cases in those receiving antineoplastic therapy alone.10030

Use of zoledronic acid in combination with adjuvant endocrine therapy in postmenopausal women also has been evaluated in several phase 3, open-label, randomized bone mineral density (BMD) studies (Z-FAST, ZO-FAST, and E-ZO-FAST).10001,10017,10018,10019,10022 (See Prevention in Postmenopausal Women under Uses: Prevention of Aromatase Inhibitor-associated Bone Loss.) Women enrolled in these studies were postmenopausal with stage I to IIIa estrogen receptor-positive and/or progesterone receptor-positive breast cancer.10001,10018,10022 Patients enrolled in these studies were randomized to receive zoledronic acid as either upfront therapy or delayed therapy (based on decline in BMD).10001,10018,10022 Patients received zoledronic acid 4 mg by IV infusion over 15 minutes every 6 months for 5 years.10001,10018,10022 All patients received letrozole 2.5 mg orally daily for 5 years. 10001,10018,10022 In the E-ZO-FAST study at a median follow-up of 12 months, no difference in disease-free survival rate was observed between women receiving upfront or delayed zoledronic acid (97.2 versus 98.1%, respectively).10022 Although no difference in disease-free survival was observed between the 2 treatment groups in the Z-FAST study at a median follow-up of 61 months (absolute difference of 0.7%),10017 upfront administration of zoledronic acid therapy prolonged disease-free survival compared with delayed administration of the drug (hazard ratio of 0.66) in the ZO-FAST study.10019 In the ZO-FAST study, breast cancer-related events in patients receiving upfront administration versus delayed administration of zoledronic acid included locoregional recurrence (0.9 versus 2.3%), distant recurrence (5.5 versus 7.7%), and bone metastases (2.6 versus 4.5%).10019 No difference in overall survival was observed between the 2 treatment groups in the Z-FAST and ZO-FAST studies.10017,10019 At the time of analysis in the Z-FAST, ZO-FAST, and E-ZO-FAST studies, 25, 27, and 13%, respectively, of women in the delayed treatment group had begun treatment with zoledronic acid.10017,10019,10022

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) conducted a meta-analysis of individual patient data from 26 randomized clinical trials evaluating addition of bisphosphonate (any drug, dose, and schedule) therapy to standard adjuvant systemic therapy in women with early-stage breast cancer.10031,10032 This meta-analysis indicated that addition of bisphosphonate therapy to standard systemic therapy (median duration of therapy of 3.4 years) modestly reduced the risk of bone recurrence (rate ratio of 0.83) and bone fractures (rate ratio of 0.85) at 10 years compared with standard systemic therapy alone.10031,10032 Addition of bisphosphonate therapy to adjuvant systemic therapy also resulted in small reductions in the risk of recurrence (rate ratio of 0.94, which corresponded to an absolute difference in recurrence rate of 1.1% at 10 years), distant recurrence (rate ratio of 0.92, which corresponded to an absolute difference in rate of distance recurrence of 1.4% at 10 years), and breast cancer mortality (rate ratio 0.91, which corresponded to an absolute difference in breast cancer mortality rate of 1.7% at 10 years).10032 However, consistent with data from the ABCSG-12 and AZURE-BIG 01/04 studies, subset analysis based on menopausal status suggested clinical benefit with adjuvant bisphosphonate therapy in postmenopausal women but not in premenopausal women.10031,10032,10033 In postmenopausal women, the addition of bisphosphonate therapy to adjuvant systemic therapy reduced the risk of bone recurrence (rate ratio of 0.72, which corresponded to an absolute difference in bone recurrence rate of 2.2% at 10 years) and breast cancer mortality (rate ratio of 0.82, which corresponded to an absolute difference in breast cancer mortality rate of 3.3% at 10 years).10032

Based on current evidence,10001,10017,10018,10019,10022,10024,10030,10032 use of zoledronic acid in combination with adjuvant systemic therapy may be considered a reasonable choice (accepted) in postmenopausal women with early or locally advanced breast cancer.10035 The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) state that postmenopausal women who are candidates for adjuvant systemic therapy for the treatment of breast cancer should consider receiving a bisphosphonate (i.e., zoledronic acid) during the course of adjuvant therapy for up to 5 years.10031 Although some clinicians state that any bone-modifying agent that has demonstrated a reduction in the risk of fragility fractures in at-risk populations (e.g., postmenopausal women, drug-induced osteoporosis) may be effective as adjuvant therapy for breast cancer, sufficient data are only available from clinical trials evaluating zoledronic acid or clodronate (not commercially available in the US); additional data are needed to further elucidate clinical benefit of other bone-modifying agents.10031 The optimal time for initiating bisphosphonates is not known; however, bisphosphonate therapy was generally initiated soon after surgery or chemotherapy in most clinical trials.10031 The optimal duration of adjuvant bisphosphonate therapy is not known; however, the duration should not exceed 5 years since toxicity of long-term (e.g., beyond 5 years) use of bisphosphonates, including zoledronic acid, has not been determined.10031 ASCO states that clinicians should consider patient and disease characteristics (e.g., risk of recurrence) and adverse effects when deciding whether bisphosphonate therapy should be added to adjuvant systemic therapy.10031

General

Hypocalcemia and other disturbances of bone and mineral metabolism must be corrected before zoledronic acid therapy is initiated for the management of osteoporosis or Paget disease.17

Renal function should be evaluated (with creatinine clearance or serum creatinine concentrations) prior to each dose of zoledronic acid; more frequent monitoring is recommended in patients at high risk of acute renal failure (e.g., geriatric patients, those receiving diuretic therapy).1,17 (See Renal Effects under Cautions: Warnings/Precautions.) Zoledronic acid should not be administered for prevention or treatment of osteoporosis or for treatment of Paget disease of bone in patients who have severe renal impairment (creatinine clearance less than 35 mL/minute) or evidence of acute renal impairment.17

Administration

Zoledronic acid is administered by IV infusion over no less than 15 minutes.1,3,7,17 (See Renal Effects under Cautions: Warnings/Precautions.)

Zoledronic acid is commercially available as a solution concentrate containing 4 mg of the drug per 5 mL (Zometa^® concentrate or generic equivalents) and as a ready-to-use injection containing 4 mg of the drug per 100 mL (Zometa^® ready-to-use or generic equivalents) for use in patients with cancer-related indications.1 Zoledronic acid also is available as a ready-to-use injection containing 5 mg of the drug per 100 mL (Reclast^® or generic equivalents) for use in the prevention or treatment of osteoporosis or for treatment of Paget disease of bone.17

Zoledronic acid should be administered through separate vented infusion lines apart from other drugs and should not be allowed to come in contact with any solutions containing calcium or other divalent cations.1,17

Zoledronic Acid for Cancer-related Indications

The concentrated zoledronic acid solution (Zometa® concentrate or generic equivalents) must be diluted in 100 mL of 0.9% sodium chloride or 5% dextrose injection prior to IV administration. 1 The commercially available 5-mL vial of injection concentrate is formulated to provide the full labeled dose of zoledronic acid (4 mg) when diluted as directed for patients with normal renal function (baseline creatinine clearance exceeding 60 mL/minute).1 For preparation of reduced doses in patients with mild to moderate renal impairment (baseline creatinine clearance of 30-60 mL/minute), the appropriate volume of drug concentrate should be withdrawn from the vial and further diluted as directed.1 For patients with a baseline creatinine clearance of 50-60 mL/minute, 4.4 mL of the concentrated drug solution should be withdrawn from the 5-mL vial to obtain a dose of 3.5 mg (for subsequent dilution).1 For patients with a baseline creatinine clearance of 40-49 mL/minute, 4.1 mL of the concentrated drug solution should be withdrawn to obtain a dose of 3.3 mg (for subsequent dilution).1 For patients with a baseline creatinine clearance of 30-39 mL/minute, 3.8 mL of the concentrated drug solution should be withdrawn to obtain a dose of 3 mg (for subsequent dilution).1 The withdrawn amount of drug concentrate should then be diluted in 100 mL of 0.9% sodium chloride or 5% dextrose injection.1 (See Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma under Dosage and Administration: Dosage.) To avoid inadvertent injection of the concentrated solution, the undiluted drug concentrate should not be stored in a syringe .1

The ready-to-use 4-mg/100-mL formulation of zoledronic acid (Zometa^® ready-to-use or generic equivalents) may be administered directly without further dilution in patients with normal renal function (baseline creatinine clearance greater than 60 mL/minute).1 For preparation of reduced doses of the drug for patients with mild to moderate renal impairment (baseline creatinine clearance of 30-60 mL/minute), the appropriate volume of the drug solution should be withdrawn from the 100-mL bottle and replaced with an equal volume of 0.9% sodium chloride or 5% dextrose injection.1 For patients with a baseline creatinine clearance of 50-60 mL/minute, 12 mL of the drug solution should be withdrawn from the 100-mL bottle (and replaced with 12 mL of 0.9% sodium chloride or 5% dextrose injection) to obtain the recommended dose of 3.5 mg.1 For patients with a baseline creatinine clearance of 40-49 mL/minute, 18 mL of the drug solution should be withdrawn (and replaced with 18 mL of 0.9% sodium chloride or 5% dextrose injection) to obtain the recommended dose of 3.3 mg.1 For patients with a baseline creatinine clearance of 30-39 mL/minute, 25 mL of the drug solution should be withdrawn (and replaced with 25 mL of 0.9% sodium chloride or 5% dextrose injection) to obtain the recommended dose of 3 mg.1

Zoledronic acid should not be mixed or diluted with calcium-containing solutions (e.g., lactated Ringer's solution).1

Strict adherence to administration recommendations for diluted zoledronic acid concentrate (Zometa® concentrate or generic equivalents) is important, since smaller infusion volumes (e.g., 50 mL) and rapid (over 5 minutes) IV infusion rates have been associated with an increased risk of renal impairment, which may progress to renal failure. 1,3,4,7,11

Prior to initiating zoledronic acid therapy in the treatment of malignancy-associated hypercalcemia, it is important to establish adequate hydration and urinary output in order to increase renal excretion of calcium; adequate hydration should be maintained throughout therapy with the drug.1,3 Overhydration should be avoided, especially in those with heart failure.1,3 An attempt should be made to achieve and maintain a urinary output of 2 L per day throughout therapy with zoledronic acid.1

Zoledronic Acid for Osteoporosis and Paget Disease of Bone

To minimize risk of renal toxicity, patients receiving zoledronic acid for prevention or treatment of osteoporosis or for treatment of Paget disease of bone must be appropriately hydrated prior to administration of the drug.17 Zoledronic acid therapy should be withheld in such patients with evidence of dehydration and may be resumed once normovolemic status has been achieved.17 Each dose of zoledronic acid should be followed by a flush with 10 mL of 0.9% sodium chloride.17

Administration of acetaminophen following zoledronic acid administration may reduce the incidence of acute-phase inflammatory reactions (e.g., fever, myalgia, flu-like symptoms, headache, arthralgia).17

Dosage

Dosage of zoledronic acid, which is commercially available for parenteral use as the monohydrate, is calculated on the anhydrous basis.1,17

Hypercalcemia Associated with Malignancy

For the treatment of hypercalcemia (albumin-corrected serum calcium concentration of at least 12 mg/dL) associated with malignancy in adults, the manufacturer recommends that zoledronic acid (Zometa^®) be infused IV as a single dose of 4 mg over no less than 15 minutes.1,3

Single doses of the drug should not exceed 4 mg since renal impairment, which may progress to renal failure has occurred following administration of zoledronic acid in recommended or higher than recommended dosages.1,3,5,7,11

After a post-treatment observation period of at least 7 days, a second course of zoledronic acid at the same dosage may be considered if there is evidence of recurrence of the disease process or if the initial treatment fails to normalize serum calcium concentrations.1 If patients with hypercalcemia of malignancy experience a deterioration of renal function during therapy with zoledronic acid, the possible risk of renal failure with subsequent doses of the drug must be carefully weighed against the potential benefits of treatment.3 No data are available to date on the safety and efficacy of more than one course of retreatment with zoledronic acid or of the recommended retreatment dosage of 4 mg of zoledronic acid in patients with hypercalcemia of malignancy.2,3

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

For the treatment of bone metastases associated with solid tumors or the treatment of osteolytic lesions associated with multiple myeloma in adults, the manufacturer-recommended dosage of zoledronic acid is 4 mg given IV over no less than 15 minutes once every 3-4 weeks.1,3 Single doses of the drug should not exceed 4 mg since renal impairment, which may progress to renal failure has occurred following administration of zoledronic acid in recommended or higher than recommended dosages.1,3,5,7,11 The optimum duration of such therapy is not known.1,3,7

In patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma and mild to moderate renal impairment (baseline creatinine clearance of 30-60 mL/minute), lower initial dosages of zoledronic acid are recommended.1 The following dosages are recommended:

If patients with bone metastases associated with solid tumors or with osteolytic lesions associated with multiple myeloma experience a deterioration of renal function during therapy with zoledronic acid (defined as an increase in serum creatinine concentration of at least 0.5 or 1 mg/dL, respectively, in patients with normal [less than 1.4 mg/dL] or elevated [1.4 mg/dL or greater] baseline serum creatinine concentrations), the drug should be withheld until serum creatinine concentrations return to within 10% of baseline concentrations.1,3,7 Zoledronic acid should be reinitiated at the same dosage that was used prior to the treatment interruption.1 Studies in this patient population included individuals with serum creatinine concentrations up to 3 mg/dL.1,3,7

Patients with multiple myeloma or bone metastases associated with solid tumors who are receiving zoledronic acid therapy should receive supplemental therapy with oral calcium (500 mg of elemental calcium daily) and a multivitamin containing vitamin D (400 international units [IU, units] daily).1,7

Osteoporosis in Postmenopausal Women

For prevention of osteoporosis in postmenopausal women, the recommended dosage of zoledronic acid is 5 mg by IV infusion over no less than 15 minutes every 2 years in patients with a creatinine clearance of at least 35 mL/minute.17 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) Patients must receive supplemental calcium and vitamin D if dietary intake is inadequate; postmenopausal women generally require at least 800-1000 units of vitamin D and 1.2 g of calcium daily.17

For treatment of osteoporosis in postmenopausal women, the manufacturer recommends that zoledronic acid be infused IV as a single 5-mg dose over no less than 15 minutes once yearly in patients with a creatinine clearance of at least 35 mL/minute.17 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) For treatment of osteoporosis and to reduce the risk of hypocalcemia, patients must receive supplemental calcium and vitamin D if dietary intake is inadequate; generally, women older than 50 years of age require 800-1000 units of vitamin D daily and at least 1.2 g of elemental calcium daily.17

The optimal duration of bisphosphonate treatment for osteoporosis has not been established.17,29,30,32 Safety and efficacy of zoledronic acid for the treatment of osteoporosis is based on clinical data supporting fracture reduction over 3 years of treatment.17 Some evidence suggests that increased durations of bisphosphonate use may be associated with an increased risk of some adverse effects (e.g., atypical fractures, jaw osteonecrosis).17,32 All patients receiving a bisphosphonate should have periodic evaluations to determine the need for continued therapy with the drug.17,29,32 Discontinuance of bisphosphonate therapy may be considered after 3-5 years of use for patients who are assessed to be at low risk of fracture.17 Patients who discontinue therapy should have their risk for fracture evaluated periodically.17

Osteoporosis in Men

For the treatment of osteoporosis or osteoporosis secondary to hypogonadism in men, the manufacturer recommends that zoledronic acid be infused IV as a single 5-mg dose over no less than 15 minutes once yearly in patients with a creatinine clearance of at least 35 mL/minute.17 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) For treatment of osteoporosis and to reduce the risk of hypocalcemia, patients must receive supplemental calcium and vitamin D if dietary intake is inadequate; generally, 800-1000 units of vitamin D daily and at least 1.2 g of elemental calcium daily is recommended.17

The optimal duration of bisphosphonate treatment for osteoporosis has not been established.17,29,30,32 Some evidence suggests that bisphosphonate therapy for more than 3 years (median 7 years in one analysis of available data) in patients with osteoporosis may be associated with an increased risk of atypical fracture of the femur.32 (See Atypical Fracture of the Femur under Cautions: Warnings/Precautions.) All patients receiving a bisphosphonate should have periodic evaluations to determine the need for continued therapy with the drug.29,32

Glucocorticoid-induced Osteoporosis

For the treatment or prevention of glucocorticoid-induced osteoporosis, the manufacturer recommends that zoledronic acid be infused IV as a single 5-mg dose over no less than 15 minutes once yearly in patients with a creatinine clearance of at least 35 mL/minute.17 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) Patients must receive supplemental calcium and vitamin D if dietary intake is inadequate; an average of at least 800-1000 units of vitamin D and 1.2 g of calcium daily is recommended.17

Paget Disease of Bone

For the treatment of Paget disease of bone, the initial adult dosage of zoledronic acid is 5 mg, infused IV over at least 15 minutes, in patients with a creatinine clearance of at least 35 mL/minute.17 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) Retreatment with zoledronic acid may be considered if relapse occurs based on increases in serum alkaline phosphatase, if initial treatment failed to normalize serum alkaline phosphatase concentrations, or if the patient is symptomatic, according to current standards of medical care.17 However, no data are available to date on the safety and efficacy of more than one course of treatment with zoledronic acid in patients with Paget disease of bone.17 To reduce the risk for hypocalcemia, all patients with Paget disease of bone should receive 1.5 g of elemental calcium daily in divided doses (750 mg twice daily or 500 mg 3 times daily) and 800 units of vitamin D daily, particularly in the first 2 weeks following zoledronic acid administration.17

Prevention of Aromatase Inhibitor-associated Bone Loss in Postmenopausal Women

When zoledronic acid has been used for prevention of bone loss associated with use of aromatase inhibitor therapy in postmenopausal women†, zoledronic acid 4 mg has been administered by IV infusion over 15 minutes every 6 months for 5 years.10001,10019,10022 In clinical trials, patients were encouraged to take supplemental oral calcium (500 mg to 1.2 g daily) and vitamin D (400-800 units daily).10001,10019,10022 (See Prevention in Postmenopausal Women under Uses: Prevention of Aromatase Inhibitor-associated Bone Loss.)

Adjuvant Therapy for Early or Locally Advanced Breast Cancer

When zoledronic acid has been used in combination with adjuvant systemic therapy in postmenopausal women with early or locally advanced breast cancer†, zoledronic acid 4 mg has been administered by IV infusion over 15 minutes every 6 months for 3-5 years.10001,10004,10019,10022,10023 In clinical trials, patients were encouraged to take supplemental oral calcium (400 mg to 1.2 g daily) and vitamin D (200-800 units daily).10001,10019,10022,10029 (See Uses: Breast Cancer.)

Special Populations

The manufacturer states that dosage adjustments of zoledronic acid are not necessary in patients with hypercalcemia of malignancy who have mild to moderate renal impairment (serum creatinine concentrations less than 4.5 mg/dL) prior to initiation of therapy.1

In patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma and mild to moderate renal impairment (baseline creatinine clearance of 30-60 mL/minute), lower initial dosages of zoledronic acid are recommended.1 (See Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma under Dosage and Administration: Dosage.)

The manufacturer states that dosage adjustments of zoledronic acid are not necessary in patients receiving the drug for prevention or treatment of osteoporosis or for treatment of Paget's disease of bone who have a creatinine clearance of 35 mL/minute or greater.17

Contraindications

Known hypersensitivity to zoledronic acid, other bisphosphonates, or any ingredient in the formulations.1,2,17

Hypocalcemia.1,17

Use of zoledronic acid for prevention or treatment of osteoporosis or for treatment of Paget disease of bone is contraindicated in patients with creatinine clearance of less than 35 mL/minute or those with evidence of acute renal impairment.17

Warnings/Precautions

Osteonecrosis of the Jaw

Osteonecrosis and osteomyelitis of the jaw have been reported in patients receiving bisphosphonates.1,12,13,14,15,16,17 Most of these patients had neoplasms and were receiving IV bisphosphonates and concurrent chemotherapy, head and neck radiation therapy, or corticosteroids,1,13,14,15,16,17 and most cases have been associated with dental procedures such as tooth extraction.1,12,13,14,15,16,17 Some cases also have occurred in patients with postmenopausal osteoporosis treated with oral or IV bisphosphonate therapy.12,17 Other risk factors for the development of osteonecrosis of the jaw may include coexisting infection(s), anemia, coagulation disorders, preexisting oral disease, and/or trauma.1,15,16 Risk also may be increased with increased duration of bisphosphonate use.1,17

A dental examination (panoramic jaw radiograph) to detect dental and periodontal infections with appropriate preventive dentistry (e.g., removal of abscessed and nonrestorable teeth and involved periodontal tissues, rehabilitation of salvageable dentition, dental prophylaxis, caries control, restorative dental care) should be considered prior to treatment with bisphosphonates in patients with risk factors (e.g. cancer; concomitant chemotherapy, corticosteroids, angiogenesis inhibitors, or radiation therapy; poor oral hygiene).1,12,13 Follow-up hard and soft tissue oral assessment should be performed every 3-4 months, depending on risk, and oncologists should briefly inspect the oral cavity of prospective candidates for bisphosphonate therapy at baseline and at every follow-up visit.16 If bisphosphonate therapy can be briefly delayed without risk of a skeletal-related complication, teeth with a poor prognosis should be extracted and other dental surgeries should be completed prior to initiation of bisphosphonate therapy.16 The benefit or risk of withholding bisphosphonate therapy in cancer patients requiring dental surgery has not been evaluated to date.16 The decision to withhold bisphosphonate therapy in such patients must be made by an oncologist in consultation with an oral maxillofacial surgeon or another dental specialist.16 During treatment with bisphosphonates in cancer patients with risk factors for osteonecrosis, dentists should check and adjust removable dentures for potential soft-tissue injury, especially tissue overlying bone.16 Such patients should avoid invasive dental procedures if possible during treatment with bisphosphonates, as dental surgery may exacerbate the condition.1,13,15,16,17 In patients requiring dental procedures during bisphosphonate treatment or patients with established osteonecrosis, no data are available to suggest whether discontinuance of therapy reduces the risk of osteonecrosis of the jaw or disease progression, respectively.1,13,16,17 Management of patients requiring dental treatment should be based on an individual assessment of risks and benefits.1,13 Dental infections should be managed aggressively nonsurgically with root canal treatment if possible or with minimal surgical intervention.16

In patients with established osteonecrosis requiring dental surgery, cessation or interruption of therapy may be considered taking into account the potential risk of further osteonecrosis versus the risk of skeletal complication or hypercalcemia of malignancy.16 The decision to withdraw bisphosphonate therapy may be coordinated between the oncologist and an oral surgeon.16

Atypical Fracture of the Femur

Findings from several case reports and case series suggest that therapy with bisphosphonates, particularly when used for more than 3 years (median 7 years in this analysis), may be associated with an increased risk of atypical fractures of the femur.17,32 The magnitude of this risk with bisphosphonate therapy is unclear, although such fractures appear to be rare;30,32,33 in addition, causality has not been established since atypical fractures also have occurred in patients not receiving bisphosphonates.17,30,31,32,33 Most cases of atypical femoral fractures with bisphosphonate therapy have been reported in individuals receiving treatment for osteoporosis.30

Atypical femoral fractures represent a subset of femoral fractures occurring in the subtrochanteric region (i.e. below the lesser trochanter) or femoral diaphysis (or shaft) of the femur, which are not common sites associated with osteoporosis-related hip fractures.17,29,30,31,32,36 Such fractures often occur with minimal or no trauma, are referred to as low-energy or low-trauma fractures (i.e., equivalent to a fall from a standing height or less), and may be associated with activities of normal daily living.17,29,30,32,36 Radiographically, these fractures have unique characteristics described as a transverse or short oblique configuration and often lack evidence of comminution; both complete (extension through both cortices) and incomplete (involving only the lateral cortex) fractures have been reported with bisphosphonate therapy.17,29,30,32

The pathophysiology of bisphosphonate-associated atypical femoral fractures is not fully known; however, severely suppressive (or oversuppressive) effects on both bone turnover and bone remodeling, leading to accumulation of localized microdamage and a subsequent impairment in bone repair have been proposed as possible mechanisms.32,36,37 Reports of atypical fractures in the general population and in individuals receiving bisphosphonate therapy are rare, accounting for less than 1% of all reported hip and femur fractures.30,31

In a report published by the Task Force of the American Society for Bone and Mineral Research (ASBMR), 310 cases of bisphosphonate-associated atypical femoral fractures were identified through case reports/series; the majority (286 of 310) of reported cases involved the use of bisphosphonate therapy for an osteoporosis-related condition.32 The age range of individuals was 36-92 years; the median duration of bisphosphonate therapy at the time of fracture was 7 years (range: 1.3-17 years).32 Most individuals, including 70% of cases reported in the ASBMR analysis, reported prodromal symptoms presenting as a dull, aching thigh pain, weeks to months prior to occurrence of an atypical fracture.29,30,32 Bilateral involvement, either as a confirmed fracture (i.e., a simultaneous or sequential fracture) or the presence of a radiographic change in the contralateral limb, also may be present at the time of diagnosis of an atypical femoral fracture and was reported in 28% (60 of 215) of cases in the ASBMR analysis.17,30,32 Delayed healing of the fracture site, possibly related to suppressive effects on bone turnover associated with bisphosphonate therapy, has been described with atypical femoral fractures and was reported in 26% (29 of 112) of cases in the ASBMR analysis.32,37 Concomitant use of glucocorticoid, estrogen, and proton-pump inhibitor therapy may increase the risk of an atypical fracture.32,34,35,37 In the ASBMR analysis, 34% of cases occurred in individuals receiving concomitant glucocorticoids (i.e., prednisone) at the time of fracture;17,29,32 in one series, the risk of subtrochanteric fracture was increased in individuals receiving concomitant bisphosphonate and glucocorticoid therapy.32 Use of concomitant proton-pump inhibitor therapy was reported in 39% of evaluable cases.32,34 Vitamin D deficiency, defined as a serum 25-hydroxyvitamin D (25-OHD) concentration of 20 ng/mL or less, also has been identified as a risk factor in some patients experiencing a bisphosphonate-related fracture.32,35

The safety and efficacy of zoledronic acid for the treatment of osteoporosis are based on clinical data supporting fracture reduction over 3 years of treatment.29 The optimal duration of bisphosphonate treatment for osteoporosis has not been established.29,30,32 The US Food and Drug Administration (FDA) is continuing to collect data on the safety and efficacy of long-term bisphosphonate use (i.e., greater than 3 to 5 years) when used for the prevention and treatment of osteoporosis.30 FDA and some experts recommend reevaluation of the need for continued bisphosphonate therapy in individuals receiving treatment for 5 years or longer, taking into consideration bone mineral density (particularly in the hip region), fracture history, and possible risk factors (i.e., a co-morbid condition and/or use of concomitant drugs known to adversely affect bone integrity);32,33 some experts recommend an annual evaluation in such patients.32 Because atypical fractures also have been reported in some individuals receiving bisphosphonate therapy in combination with other drugs known to affect bone integrity and/or bone remodeling (i.e., glucocorticoids, proton pump inhibitors, estrogen, tamoxifen), some experts recommend performing a risk-benefit assessment in individuals determined to have a low or slightly elevated fracture risk, to determine the need for continued bisphosphonate therapy in light of the potential increased risk associated with the use of required concomitant therapy.32,34

Individuals with a history of bisphosphonate exposure presenting with new thigh or groin pain should be evaluated for possible atypical femur fracture; 17,29,30,32 an assessment of the contralateral limb also should be performed to rule out possible bilateral involvement (i.e., presence of a radiographic change or fracture).17,29,32 Interruption of bisphosphonate therapy should be considered in individuals presenting with symptoms suggestive of a possible femoral fracture following completion of a comprehensive risk-benefit assessment performed on an individualized basis.17,29 Bisphosphonate therapy should be discontinued if a femoral shaft fracture is confirmed.30,31,32

Musculoskeletal Pain

Severe, occasionally incapacitating bone, joint, and/or muscle pain have been reported infrequently through postmarketing experience in patients receiving bisphosphonates, including zoledronic acid.1,17,19,20 The time to the onset of symptoms varied from 1 day to years after treatment initiation.1,17,19,20 Musculoskeletal pain has improved following discontinuance of the drug in some patients, whereas other patients have reported slow or incomplete resolution of such pain.1,19 In some patients, musculoskeletal pain recurred upon subsequent rechallenge with the same drug or another bisphosphonate.1,17,19 The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.19 The association between bisphosphonates and severe musculoskeletal pain may be overlooked by clinicians, which may delay diagnosis, prolong pain and/or impairment, and necessitate the use of analgesics.19 Clinicians should evaluate whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms; temporary or permanent discontinuance of therapy should be considered in such cases.19

Fetal/Neonatal Morbidity and Mortality

Although no data are available on the fetal risk of bisphosphonates in humans, these drugs do cause fetal harm in animals.1 Data from animals suggest that uptake of bisphosphonates into fetal bone is greater than that into maternal bone.1 A theoretical risk to the fetus (e.g., skeletal and other abnormalities) exists if a woman becomes pregnant after completing a course of bisphosphonate therapy.1 The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (IV versus oral) on this risk has not been established.1

Renal Effects

Bisphosphonates, including zoledronic acid, have been associated with renal toxicity, manifested as deterioration of renal function and potential renal failure.1,2,3,4,7,17 Acute renal failure requiring dialysis and sometimes resulting in hospitalization and/or death, has occurred rarely in patients receiving zoledronic acid (Reclast^®), mostly for osteoporosis indications.17,38,42 At least 24 cases of renal impairment and acute renal failure were identified in an FDA postmarketing safety review of Reclast^® in 2009; 7 deaths were reported.42 Since the initial safety review, additional reports of renal toxicity associated with the use of Reclast^® have been received by the FDA.38 The time to onset of renal toxicity was approximately 11 days following infusion of the drug.42 More than half of the patients in these reports also experienced a transient increase in serum creatinine concentrations following infusion of zoledronic acid; the median increase in serum creatinine concentration was 4 mg/dL.42 Many of the patients had underlying renal disease or other risk factors (e.g., dehydration, advanced age, concomitant use of nephrotoxic agents) that may have contributed to their risk of renal impairment.17,38,42 Renal function deterioration progressing to renal failure and dialysis also has been observed in clinical trials and during postmarketing experience in patients receiving Zometa^®.1 Such renal function deterioration has occurred following administration of higher than recommended doses, but also after administration of the usual dose of 4 mg infused over the recommended infusion period (15 minutes).1 In some cases, renal impairment occurred after administration of the initial zoledronic acid dose.1

Renal function should be evaluated (with creatinine clearance or serum creatinine concentrations) prior to administering each dose of zoledronic acid and more frequently in patients at high risk of acute renal failure, including geriatric patients and those receiving diuretic therapy.1,17 Interim monitoring of renal function also should be considered in patients receiving concomitant drugs (e.g., digoxin) that are primarily eliminated by the kidneys.17 (See Drug Interactions: Drugs Eliminated by Renal Excretion.) Use of zoledronic acid for prevention or treatment of osteoporosis or for treatment of Paget disease of bone is contraindicated in patients with creatinine clearance less than 35 mL/minute and in those with evidence of acute renal impairment; the drug should be used with caution in patients with chronic renal impairment.17 Risk factors predisposing patients to renal deterioration, such as dehydration (e.g., secondary to fever, sepsis, GI loss, or diuretic therapy) or use of other nephrotoxic agents, should be identified and managed.1,17 To help prevent renal impairment, patients should be appropriately hydrated prior to administration of zoledronic acid, especially geriatric patients and those receiving concomitant diuretic therapy.17 Transient increases in serum creatinine concentrations during therapy may be corrected with administration of IV fluids.17

Administration of zoledronic acid 4 mg by IV infusion over a period of 5 minutes has been shown to increase the risk of renal toxicity (i.e., increases in serum creatinine), which can progress to renal failure.1 The incidence of renal toxicity and renal failure is reduced when the same dose is administered IV over a period of 15 minutes.1 Zoledronic acid should be administered by IV infusion over no less than 15 minutes .1,17 (See Dosage and Administration: Administration.)

Metabolic Effects

Hypocalcemia and other factors affecting bone and mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine) must be corrected before zoledronic acid therapy is initiated in patients with Paget's disease of bone or postmenopausal osteoporosis.17 Serum calcium, phosphorus, and magnesium concentrations should be monitored in such patients.17 Standard hypercalcemia-related metabolic parameters, including serum concentrations of calcium, phosphate, magnesium, potassium, and other electrolytes, should be monitored carefully following initiation of zoledronic acid therapy in patients with hypercalcemia of malignancy.1,3,17 If hypocalcemia, hypophosphatemia, or hypomagnesemia occurs, short-term supplemental therapy may be necessary.1,3

Respiratory Effects

Bisphosphonates have been associated with bronchoconstriction in aspirin-sensitive asthmatic patients.1,17 Zoledronic acid should be used with caution in such patients.1,17

Atrial Fibrillation

While data are conflicting, a possible increased risk of atrial fibrillation has been identified with use of bisphosphonates.21,22,23 In 1 of the 2 pivotal preapproval studies in women with postmenopausal osteoporosis, an increased incidence of serious (i.e., events resulting in hospitalization or disability or considered life-threatening) atrial fibrillation was observed in patients receiving zoledronic acid compared with that in placebo recipients.17,21,22 Most of these cases occurred more than 1 month after infusion of zoledronic acid.17,21 However, an increased incidence of serious atrial fibrillation with zoledronic acid was not confirmed in a second preapproval study in women with osteoporosis or in a study in men with osteoporosis.17 Among patients with postmenopausal osteoporosis with or without vertebral fractures who received alendronate, another bisphosphonate drug, in 2 randomized, placebo-controlled trials, the incidence of atrial fibrillation was numerically higher in the alendronate-treated groups compared with that observed in the placebo-treated groups.22

To further evaluate the potential for increased risk of atrial fibrillation with certain bisphosphonates, the FDA reviewed data from long-term (6 months' to 3 years' duration) placebo-controlled clinical trials from the sponsors of alendronate, ibandronate, risedronate, and zoledronic acid.23 Analysis of data from approximately 19,700 patients receiving bisphosphonates and approximately 18,300 patients receiving placebo indicated a difference in event rates of 0-3 events per 1000 patients between bisphosphonates and placebo.23 The occurrence of atrial fibrillation was rare in each study; 2 or fewer instances of atrial fibrillation occurred in most studies.23 Across all studies reviewed, no clear association was observed between overall bisphosphonate exposure, dosage, or duration of bisphosphonate therapy and the rate of atrial fibrillation.23 FDA is continuing to monitor postmarketing adverse event reports of atrial fibrillation and is exploring the feasibility of conducting additional epidemiologic studies to examine the incidence and clinical course of atrial fibrillation in patients exposed to bisphosphonates.23

Formulation Considerations

Patients receiving Zometa^® should not receive Reclast^® or other bisphosphonates, nor should patients receiving Reclast^® be treated concomitantly with Zometa^® or other bisphosphonates.1,17

Specific Populations

Pregnancy

Category D.1 (See Users Guide and see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether zoledronic acid is distributed into milk; because of the potential for serious adverse effects in nursing infants from zoledronic acid, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,17 It is also important to consider that zoledronic acid is retained by bone for prolonged periods and may be released over weeks to years, possibly affecting nursing infants.1

Pediatric Use

Zoledronic acid is not indicated for use in children.1,17

Geriatric Use

No overall differences in safety and efficacy of zoledronic acid relative to younger adults;1,17 however, the incidence of acute-phase inflammatory reactions was less in geriatric patients with osteoporosis or Paget disease of bone than in younger adults.17 Because of the greater frequency of impaired renal function in geriatric patients, the manufacturer states that renal function should be monitored with particular care in this age group.1

Renal Impairment

In clinical studies of zoledronic acid in patients with multiple myeloma or bone metastases associated with solid tumors or in those with hypercalcemia associated with malignancy, individuals with severe renal impairment (serum creatinine concentrations exceeding 3 or 4.5 mg/dL, respectively) were excluded.1,2,3,7 Limited data are available in patients with a baseline serum creatinine concentration exceeding 2 mg/dL or with a creatinine clearance of less than 30 mL/minute.1 The drug should be used in patients with hypercalcemia of malignancy and severe renal impairment only after consideration of other treatment options and only when the potential benefit from the drug outweighs the possible risk of worsening renal function.1,3 Zoledronic acid is not recommended in patients with bone metastases associated with solid tumors or multiple myeloma and severe renal impairment.1,3 Use of zoledronic acid for prevention or treatment of osteoporosis or for treatment of Paget disease of bone is contraindicated in patients who have severe renal impairment (creatinine clearance of less than 35 mL/minute); the drug should be used with caution in such patients with chronic renal impairment.17

Common Adverse Effects

Hypercalcemia of Malignancy

Fever,1,2,3,5 nausea,1,2,3,5 constipation,1,2,3,5 anemia,1,2,3,5 dyspnea,1,2,3,5 diarrhea,1,2,3 progression of cancer,1,3 abdominal pain,1,2,3 insomnia,1,2,3 vomiting,1,2,3 urinary tract infection,1,3 anxiety,1 hypophosphatemia,1 confusion,1,2,3,5 agitation,1 moniliasis,1 hypokalemia,1,2,3,5 skeletal pain,1,3 cough,1 hypotension,1 hypomagnesemia.1

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

Nausea,1,3,5,7 fatigue,1,3,7 anemia,1,3,5,7 vomiting,1,3,7 fever,1,3,5,7 constipation,1,3,5,7 dyspnea,1,3,5,7 diarrhea,1,3,7 myalgia,1 cough,1,7 edema of the lower extremities,1,7 arthralgia,1,3,7 headache,1,3,7 dizziness,1,3 weight loss,1,3,7 paresthesia,1,3 back pain,1 depression,1,3 abdominal pain,1,3 dehydration,1,3 limb pain,1 decreased appetite,1 neutropenia,1,3 urinary tract infection,1,3 hypoesthesia,1,3 anxiety,1 alopecia,1,7 dermatitis,1,3 rigors,1,3 thrombocytopenia,3 dyspepsia,1 upper respiratory tract infection.1

Osteoporosis Treatment in Postmenopausal Women

Arthralgia,17,21 fever,17,21 headache,17,21 hypertension,17 myalgia,17,21 extremity pain,17 flu-like illness,17,21 dizziness,17 shoulder pain,17 diarrhea,17 bone pain,17 fatigue,17 chills,17 asthenia.17

Osteoporosis Prevention in Postmenopausal Women

Headache, dizziness, hypoesthesia, hypertension, nausea, diarrhea, vomiting, dyspepsia, abdominal pain, constipation, arthralgia, myalgia, back pain, extremity pain, muscle spasms, musculoskeletal pain, bone pain, neck pain, generalized pain, pyrexia, chills fatigue, asthenia, peripheral edema, non-cardiac chest pain.17

Osteoporosis Treatment in Men

Myalgia,17 fatigue,17 headache,17 musculoskeletal pain,17 pain (unspecified),17 chills,17 flu-like illness,17 abdominal pain,17 malaise,17 dyspnea.17

Glucocorticoid-induced Osteoporosis

Adverse effects are generally similar to those reported in the postmenopausal osteoporosis population.17 Common adverse effects that were either not observed in the postmenopausal osteoporosis treatment trial or reported more frequently in the corticosteroid-induced osteoporosis trial included abdominal pain, musculoskeletal pain, back pain, bone pain, extremity pain, nausea, and dyspepsia.17

Paget Disease of Bone

Headache,17 nausea,17 dizziness,17 arthralgia,17 bone pain,17 influenza/flu-like illness,17 fever,17 fatigue,17 rigors,17 myalgia,17 diarrhea,17 constipation, lethargy,17 dypsnea,17 dyspepsia,17 pain.17

Drugs Eliminated by Renal Excretion

When zoledronic acid is used concomitantly with drugs eliminated renally (e.g., digoxin), increased exposure of the concomitantly administered drug is possible.17

Loop Diuretics

Pharmacologic interaction (increased risk of hypocalcemia) is possible when zoledronic acid is used with loop diuretics.1 Caution is advised.1,17

Aminoglycosides

Pharmacologic interaction (additive effect in lowering serum calcium concentrations for prolonged periods) is possible when zoledronic acid is used with aminoglycosides.1 Caution is advised.1,17

Nephrotoxic Agents

Pharmacologic interaction (increased risk of renal dysfunction) is possible when zoledronic acid is used with nephrotoxic agents.1 The drugs should be used concomitantly with caution.1,17

Thalidomide

No substantial changes in pharmacokinetics of zoledronic acid or in creatinine clearance were observed with concomitant administration of thalidomide.1 Dosage adjustments are not necessary.1

Description

Zoledronic acid, a synthetic imidazole bisphosphonate analog of pyrophosphate, is an inhibitor of osteoclast-mediated bone resorption.1,4,5 Zoledronic acid is structurally and pharmacologically related to alendronate, risedronate, and pamidronate.4,5

Zoledronic acid inhibits increased osteoclastic activity and skeletal calcium release induced by tumors.1 In patients with hypercalcemia of malignancy, zoledronic acid decreases serum calcium and phosphorus and increases urinary calcium and phosphorus excretion.1

Zoledronic acid is eliminated in urine as unchanged drug.1 In patients with cancer and bone metastases, an average of 39% of an IV dose of zoledronic acid was excreted in urine within 24 hours.1 Nonrenal clearance is believed to result from uptake of the drug by bone; subsequently, the drug is released systemically via bone turnover.1,6,8,9,10 Results of in vitro studies indicate that zoledronic acid does not inhibit the cytochrome P-450 (CYP) enzyme system.1,5

Advice to Patients

Importance of calcium and vitamin D supplementation for maintenance of serum calcium concentrations in patients with Paget's disease of bone, multiple myeloma and bone metastasis of solid tumors, or osteoporosis.1,17 Importance of contacting a clinician promptly if symptoms of hypocalcemia (e.g., numbness or tingling feeling [especially in or around the mouth], muscle spasms) occur.17

Importance of informing a clinician if severe bone pain, joint pain, muscular pain, or jaw disease develops.20

Importance of informing a clinician if new thigh or groin pain develops.30

Importance of informing patients that zoledronic acid should not be used for prevention or treatment of osteoporosis or for treatment of Paget's disease of bone in patients with severe renal impairment.17 Patients should be advised of the importance of monitoring kidney function during therapy.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., diuretics, nonsteroidal anti-inflammatory agents, antibiotics), as well as any concomitant conditions (e.g., kidney disease, aspirin sensitivity).1,17 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women of childbearing potential to avoid pregnancy.1 Apprise pregnant patients of potential fetal hazard.1 Importance of advising patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide.). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Novartis. Zometa^®(zoledronic acid) injection concentrate for IV infusion prescribing information. East Hanover, NJ; 2016 Dec.

2. Major P, Lortholary A, Han 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; 19:558-67. [PubMed 11208851]

3. Novartis Pharmaceuticals, East Hanover, NJ; Personal communication.

4. Brown DL, Robbins R. Developments in the therapeutic applications of bisphosphonates. J Clin Pharmacol . 1999; 39:651-60. [PubMed 10392318]

5. Cheer SM, Noble S. Zoledronic acid. Drugs . 2001; 61:799-805. [PubMed 11398911]

6. Anon. Zoledronate (Zometa). Med Lett Drugs Ther . 2001; 43:110-11. [PubMed 11740412]

7. Rosen LS, Gordon D, Kaminski M 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; 7:377-87. [PubMed 11693896]

8. Green JR. Chemical and biological prerequisites for novel bisphosphonate molecules: Results of comparative preclinical studies. Semin Oncol . 2001; 28(Suppl. 6):4-10 [PubMed 11346859]

9. Plosker GL, Goa KL. Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs . 1994; 47:945-82. [PubMed 7521833]

10. Coukell AJ, Markham A. Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone. Drugs Aging . 1998; 12:149-68. [PubMed 9509293]

11. Bone HG, Santora AC. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med . 2004; 351:191-2.

12. Ruggiero SL, Mehrotra B, Rosenberg TJ et al. Osteonecrosis of the jaw associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg . 2004; 62:527-34. [PubMed 15122554]

13. Hohneker JA. Dear doctor letter regarding osteonecrosis of the jaw in patients with cancer receiving bisphophonates. East Hanover, NJ: Novartis; 2004 September 24.

14. Ruggiero SL, Mehrotra B. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med . 2004; 351:191.

15. Hohneker JA. Dear dental professional letter: important drug precautions for dental health professional with patients being treated for cancer. East Hanover, NJ: Novartis; 2005 May 5. From FDA website. [Web]

16. Food and Drug Administration. Oncologic Drugs Advisory Committee meeting. Expert panel recommendation for the prevention, diagnosis, and treatment of osteonecrosis of the jaw. Bethesda, MD; Mar. 4, 2005. From FDA website. [Web]

17. Novartis. Reclast^® (zoledronic acid) injection solution for IV infusion prescribing information. East Hanover, NJ. 2017 Jul.

19. Center for Drug Evaluation and Research, Food and Drug Administration. FDA Alert: Information for healthcare professionals on bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). 2008 Jan 7. Available from FDA website. Accessed 2008 Oct 28. [Web]

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21. Black DM, Delmas PD, Eastell R et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med . 2007; 356:1809-22. [PubMed 17476007]

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23. Center for Drug Evaluation and Research, Food and Drug Administration. Update of safety review follow-up to the October 1, 2007 early communication about the ongoing safety review of bisphosphonates. Bisphosphonates: alendronate (Fosamax, Fosamax plus D) etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel, Actonel w/calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa). 2008 Nov 12. Available at FDA website. Accessed 2008 Nov 21. [Web]

26. Eidtmann H, Bundred NJ, DeBoer R et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow up of ZO-FAST. Oral presentation at Annual San Antonio Breast Cancer Symposium. San Antonio, TX: 2008 Dec 12. Accessed from website on 12/15/2008. [Web]

29. Food and Drug Administration. Reclast (zoledronic acid) injection [2010 Oct 13: Novartis]. Safety labeling change and REMS notification. Silver Spring, MD; 2010 Oct 13. From FDA web site. [Web]

30. Food and Drug Administration. FDA drug safety communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. Silver Spring, MD; 2010 Oct 13. From FDA web site. Accessed 2010 Nov 4. [Web]

31. Food and Drug Administration. FDA MedWatch label change: Atypical fractures update for bisphosphonates (osteoporosis drugs), including alendronate (marketed as Fosamax), alendronate with cholecalciferol (marketed as Fosamax plus D), risedronate (marketed as Actonel and Atelvia), risedronate with calcium carbonate (marketed as Actonel with Calcium), ibandronate (marketed as Boniva), and zoledronic acid (marketed as Reclast). Silver Spring, MD; 2010 Oct 13. From FDA web site. Accessed 2010 Nov 4. [Web]

32. Shane E, Burr D, Ebeling PR et al. Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res . 2010; 25:2267-94. [PubMed 20842676]

33. Food and Drug Administration. FDA news release: Possible increased risk of thigh bone fracture with bisphosphonates. Silver Spring, MD; 2010 Oct 13. From FDA web site. Accessed 2010 Nov 4. [Web]

34. Giusti A, Hamdy NA, Papapoulos SE. Atypical fractures of the femur and bisphosphonate therapy: A systematic review of case/case series studies. Bone . 2010; 47:169-80. [PubMed 20493982]

35. Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. N Engl J Med . 2010; 362:1848-9. [PubMed 20463351]

36. Sellmeyer DE. Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA . 2010; 304:1480-4. [PubMed 20924014]

37. Schmidt GA, Horner KE, McDanel DL et al. Risks and benefits of long-term bisphosphonate therapy. Am J Health Syst Pharm . 2010; 67:994-1001. [PubMed 20516469]

38. Food and Drug Administration. FDA drug safety communication: New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid). Rockville, MD; 2011 Sept 1. Available from FDA website. Accessed 2011 Sept 12. [Web]

40. Reid DM, Devogelaer JP, Saag K et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomized controlled trial. Lancet . 2009; 373:1253-63. [PubMed 19362675]

41. McClung M, Miller P, Recknor C et al. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol . 2009; 114:999-1007. [PubMed 20168099]

42. Food and Drug Administration. Postmarket reviews-volume 2, number 2, 2009: Zoledronic acid (marketed as Reclast^®) renal impairment and acute renal failure. Available from FDA website. Accessed 2011 Sept 22. [Web]

43. Kanis JA, Oden A, Johansson H et al. FRAX and its applications to clinical practice. Bone . 2009; 44:734-43. [PubMed 19195497]

44. Cosman F, de Beur SJ, LeBoff MS et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int . 2014; 25:2359-81. [PubMed 25182228]

45. Watts NB, Bilezikian JP, Camacho PM et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract . 2010 Nov-Dec; 16 Suppl 3:1-37. [PubMed 21224201]

622. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol . 2017; 69:1521-1537. [PubMed 28585373]

10001. Brufsky A, Harker WG, Beck JT et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol . 2007; 25: 829-36. [PubMed 17159193]

10002. Brufsky A, Lund K, Cobb P et al. Twenty-four month follow-up of the effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Poster presented at Annual San Antonio Breast Cancer Symposium. San Antonio, TX: 2006 Dec 16. Abstract 5060. Accessed from website on 4/29/2008. [Web]

10003. Mincey BA, Dentchev TG, Sloan JA et al. NO3CC- A randomized, controlled, open-label trial of upfront versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with primary breast cancer starting letrozole after tamoxifen. J Clin Oncol . 2008; 26: Abstract No. 564.

10004. Gnant MF, Mlineritsch B, Luschin-Ebengreith G et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol . 2007; 25: 820-8. [PubMed 17159195]

10005. Hillner BE, Ingle JN, Chelebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol . 2003; 21:4042-57. [PubMed 12963702]

10006. Eastell R. Breast cancer and the risk of osteoporotic fracture: a paradox. J Clin Endocrinol Metab . 2007; 92: 42-3. [PubMed 17,209223]

10007. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA . 2002; 288: 1889-97. [PubMed 12377088]

10008. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab . 2000; 85; 231-6. [PubMed 10634392]

10009. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab . 2002; 87: 1586-92. [PubMed 11932287]

10010. Phase III randomized study of immediate versus delayed zoledronate for prevention of bone loss in postmenopausal women with stage I-IIIA breast cancer initiating letrozole after prior treatment with tamoxifen. Accessed from website on June 4, 2008. [Web]

10011. US Food and Drug Administration (FDA). Guidance for preclinical and clinical evaluation of agents used in the prevention of postmenopausal osteoporosis. Rockville, MD: FDA; 1994 Apr.

10012. Gnant MF, Jakesz R, Mlineritsch B et al. Zoledronic acid effectively counteracts cancer treatment induced bone loss in premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen—bone density subprotocol results of a randomized multicenter trial (ABCSG-12). Poster presented at Annual San Antonio Breast Cancer Symposium. San Antonio, TX; 2004 Dec 8.

10013. LaFleur J, McAdam-Marx C, Kirkness C et al. Clinical risk factors for fracture in postmenopausal osteoporotic women: a review of the recent literature. Ann Pharmacother . 2008; 42:375-86. [PubMed 18230704]

10014. Silverman SL. Selecting patients for osteoporosis therapy. Curr Osteoporos Rep . 2006; 4: 91-5. [PubMed 16907997]

10015. Anastrozole bisphosphonate study in postmenopausal women with hormone-receptor-positive early breast cancer (SABRE). Accessed from website on 2008 Apr 25. [Web]

10016. Novartis. Zoledronic acid (Reclast^®) injection prescribing information. East Hanover, NJ. 2007 Aug.

10017. Brufsky AM, Harker WG, Beck JT et al. Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer . 2012; 118:1192-201. [PubMed 21987386]

10018. Bundred NJ, Campbell ID, Davidson N et al. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer . 2008; 112:1001-10. [PubMed 18205185]

10019. Coleman R, de Boer R, Eidtmann H et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol . 2013; 24:398-405. [PubMed 23047045]

10020. Hines SL, Mincey B, Dentchev T et al. Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC. Breast Cancer Res Treat . 2009; 117:603-9. [PubMed 19214743]

10021. Wagner-Johnston ND, Sloan JA, Liu H et al. 5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial. Cancer . 2015; 121:2537-43. [PubMed 25930719]

10022. Llombart A, Frassoldati A, Paija O et al. Immediate administration of zoledronic acid reduces aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer: 12-month analysis of the E-ZO-FAST trial. Clin Breast Cancer . 2012; 12:40-8. [PubMed 22014381]

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10034. AHFS final determination of medical acceptance: Off-label use of zoledronic acid for the prevention of aromatase inhibitor-associated bone loss. Published November 25, 2019.

10035. AHFS final determination of medical acceptance: Off-label use of zoledronic acid in combination with systemic therapy for the adjuvant treatment of early or locally advanced breast cancer. Published November 25, 2019.