Version May 2024
Note: Consider a dental examination and appropriate preventative dentistry in patients with risk factors for osteonecrosis of the jaw (eg, cancer, chemotherapy, head and neck radiotherapy, corticosteroids, poor oral hygiene). Prior to clodronate treatment, promote renal excretion of excess calcium via restoration and maintenance of adequate fluid balance and urine output.
Breast cancer, early, adjuvant therapy (off-label use): Postmenopausal patients: Oral: 1,600 mg once daily for 2 to 3 years (ASCO/CCO [Eisen 2022]; Paterson 2012).
Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL [≥3 mmol/L]) (alternative agent):
Note: May also be used at the same doses for treatment of hypercalcemia due to excessive bone resorption from other causes (eg, granulomatous diseases, hyperparathyroidism, vitamin D intoxication) (Minisola 2015; Shane 2022). Asymptomatic or mildly symptomatic patients with chronic hypercalcemia may not require immediate treatment unless albumin-corrected serum calcium level is >14 mg/dL (>3.5 mmol/L) (Shane 2022).
Initial: IV: 300 mg over at least 2 hours once daily; continue until plasma calcium levels return to normal (usually 2 to 5 days); treatment duration should not exceed 7 days.
Maintenance dosage: Note: For use following calcium normalization with IV bisphosphonate therapy.
Oral: Usual dosage range: 1.6 to 2.4 g/day given in 1 or 2 divided doses; maximum daily dose: 3.2 g/day.
Re-treatment: Limited data suggest that patients who develop hypercalcemia following discontinuation of therapy or during oral therapy may be re-treated with oral therapy at a higher daily dosage (up to 3.2 g/day) or by IV infusion.
Osteolytic bone metastases: Note: Other bisphosphonates may be superior to clodronate in reducing skeletal complications related to multiple myeloma (ASCO [Anderson 2018]).
Bonefos: Initial: Oral: 1,600 mg/day; may be increased to a maximum of 3,200 mg/day.
Clasteon: Oral: 1,600 mg to 2,400 mg/day, administered as a single dose or in 2 divided doses; maximum recommended daily dose: 3,200 mg.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Clasteon:
Serum creatinine (Scr) >5 mg/dL: Use is contraindicated.
Scr ≥2.5 to 5 mg/dL: There are no specific dosage adjustments provided in manufacturer's labeling; however, the manufacturer recommends considering a dose reduction or withholding therapy.
Bonefos:
Scr >5 mg/dL: Use is contraindicated.
Oral: Note: Daily doses >1,600 mg should not be used continuously.
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 30 to 50 mL/minute: Administer 75% of normal dose.
CrCl <30 mL/minute: Administer 50% of normal dose.
IV:
CrCl >50 to 80 mL/minute: Administer 75% to 100% of normal dose.
CrCl 12 to 50 mL/minute: Administer 50% to 75% of normal dose.
CrCl <12 mL/minute: Administer 50% of normal dose.
Deterioration of kidney function during IV therapy: Stop clodronate treatment.
There are no dosage adjustments provided in the manufacturer’s labeling; however, elimination is predominantly renal.
Femoral shaft fracture: Consider interrupting clodronate treatment pending a risk/benefit assessment.
GI mucosa irritation, new or worsening dyspepsia, dysphagia, retrosternal pain: Patients should seek prompt evaluation.
Hypocalcemia (in patients with osteolytic bone metastases): Interrupt the infusion or reduce the oral dose; correction of severe or symptomatic hypocalcemia may require calcium supplementation.
Ocular effects, complicated or severe: Complicated or severe ocular adverse events may require clodronate discontinuation and referral for ophthalmic evaluation.
Osteonecrosis of the jaw: Patients developing osteonecrosis of the jaw during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). Avoid invasive dental procedures and dental surgery during clodronate treatment if possible. For patients requiring dental procedures, the start of a new course of IV treatment should be delayed if there are unhealed open soft-tissue lesions in the mouth. For both IV and oral therapy, consider interrupting treatment until condition resolves and contributing risk factors are mitigated.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reaction reported for oral administration unless otherwise indicated.
>10%: Hepatic: Increased serum transaminases (oral and IV: postmenopausal osteopenic women: ≤18%; >2 × ULN: 2%)
1% to 10%:
Endocrine & metabolic: Hypocalcemia (oral and IV: 2% to 3%)
Gastrointestinal: Anorexia (1%), gastrointestinal signs and symptoms (oral and IV: ~10%; including diarrhea, nausea, stomach pain, vomiting)
Renal: Increased serum creatinine (oral and IV: 1%)
Frequency not defined:
Gastrointestinal: Oral irritation
Hematologic & oncologic: Myelodysplastic syndrome, myeloid leukemia
Hepatic: Alkaline phosphatase abnormal
Hypersensitivity: Type I hypersensitivity reaction
Respiratory: Oropharyngeal ulcer
Postmarketing (any formulation):
Dermatologic: Erythematous rash, maculopapular rash
Endocrine & metabolic: Increased parathyroid hormone
Genitourinary: Proteinuria
Hypersensitivity: Hypersensitivity reaction (including angioedema)
Neuromuscular & skeletal: Arthralgia (severe), myalgia (severe), ostealgia (severe), osteonecrosis of the jaw
Ophthalmic: Conjunctivitis, uveitis (Fietta 2003)
Renal: Renal failure syndrome, severe renal disease
Hypersensitivity to clodronate, other bisphosphonates, or any component of the formulation; severe GI tract inflammation; renal impairment (when serum creatinine >5 mg/dL, SI 440 micromole/L); concomitant use with other bisphosphonates; pregnancy or breast-feeding
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Bone fractures: Atypical femur fractures have been reported in patients receiving bisphosphonates for treatment/prevention of osteoporosis. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures, although the majority of cases have been reported in patients taking bisphosphonates. Patients receiving long-term (>3 to 5 years) therapy may be at an increased risk.
• Bone/joint/muscle pain: Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months.
• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Strict adherence to dosing instructions is advised. Use with caution in patients unable to remain upright for ≥30 minutes after ingestion and/or with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition).
• Hypocalcemia: Risk of hypocalcemia (often asymptomatic) may be associated with both oral and intravenous use, however chelation of serum calcium observed with intravenous administration can further increase this risk.
• Hypersensitivity: Hypersensitivity reactions including dyspnea or other respiratory disorders have been observed; use caution in patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis).
• Ocular effects: Conjunctivitis, uveitis, scleritis, and episcleritis have been observed with bisphosphonates.
• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include dental surgery, cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids), poor oral hygiene, and comorbid disorders (anemia, coagulopathy, infection, preexisting oral disease). According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. Other risk factors for MRONJ include dentoalveolar surgery (eg, tooth extraction, dental implants), and preexisting inflammatory dental disease. Risk of MRONJ is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with intravenous antiresorptive use compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years (AAOMS [Ruggiero 2014]). The manufacturer’s labeling states that during therapy, invasive dental procedures and dental surgery should be avoided if possible; for patients requiring dental procedures, there are no data suggesting whether bisphosphonate discontinuation decreases ONJ risk; the start of a new course of IV treatment should be delayed if there are unhealed open soft-tissue lesions in the mouth; for both IV and oral therapy, consider interrupting treatment until condition resolves and contributing risk factors are mitigated. The AAOMS authors suggest that, if conditions permit, therapy initiation of intravenous antiresorptive agents for cancer therapy should be delayed until optimal dental health is attained. In oncology patients already receiving intravenous bisphosphonates, dental procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]).
Disease-related concerns:
• Bariatric surgery: Altered absorption and ulceration risk: Avoid oral bisphosphates after bariatric surgery; inadequate oral absorption and potential anastomotic ulceration may occur. If therapy is indicated, IV administered bisphosphonates are recommended.
Not available in the US
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Clasteon: 400 mg [contains corn starch, fd&c blue #2 (indigotine,indigo carmine)]
Oral: Swallow whole. Patient should be instructed to stay upright (not lie down) for at least 30 minutes after ingestion and until after the first food of the day (to reduce esophageal irritation).
Clasteon: Administer with a glass of plain water at least 1 hour before or after food.
Bonefos: Administer with a glass of plain water at least 2 hours before or after food or other medication; if the daily dose is divided into 2 doses, the second dose should be administered at least 1 hour before or at least 2 hours after food/medication.
IV: Infuse daily doses over at least 2 hours. Do not administer as bolus injection (may precipitate acute kidney failure). Patients should be adequately hydrated with oral or IV fluids prior to infusion. Avoid infiltration/extravasation.
Note: Not approved in the United States.
Hypercalcemia of malignancy: Management of hypercalcemia of malignancy.
Osteolytic bone metastases: Adjunct in the management of osteolysis due to bone metastases of malignant tumors.
Breast cancer, early, adjuvant therapy
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Aminoglycosides may enhance the nephrotoxic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Angiogenesis Inhibitors (Systemic): May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy
Capecitabine: Bisphosphonate Derivatives may enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy
Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Estramustine: Clodronate may increase the serum concentration of Estramustine. Risk C: Monitor therapy
Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy
Polyvalent Cation Containing Products: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral medications containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Risk D: Consider therapy modification
All food and beverages may interfere with absorption. Coadministration with dairy products may decrease absorption. Beverages (especially orange juice and coffee), food, and medications (eg, antacids, calcium, iron, and multivalent cations) may reduce the absorption of bisphosphonates as much as 60%. Management: Administer with a glass of plain water at least 2 hours (Bonefos) or 1 hour (Clasteon) before or after food.
Bisphosphonates are incorporated into the bone matrix and gradually released over time. Because exposure prior to pregnancy may theoretically increase the risk of fetal harm, most sources recommend discontinuing bisphosphonate therapy in patients who could become pregnant as early as possible prior to a planned pregnancy. Use in premenopausal patients should be reserved for special circumstances when rapid bone loss is occurring; a bisphosphonate with the shortest half-life should then be used (Bhalla 2010; Pereira 2012; Stathopoulos 2011).
Use is contraindicated during pregnancy.
It is not known if bisphosphonates cross the placenta, but based on their lower molecular weight, fetal exposure is expected (Djokanovic 2008; Stathopoulos 2011).
Bisphosphonates are incorporated into the bone matrix and gradually released over time. The amount available in the systemic circulation varies by drug, dose, and duration of therapy. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of bisphosphonate therapy (hypocalcemia, low birth weight, and decreased gestation have been observed in some case reports); however, available data have not shown that exposure to bisphosphonates during pregnancy significantly increases the risk of adverse fetal events (Djokanovic 2008; Green 2014; Levy 2009; Machairiotis 2019; Sokal 2019; Stathopoulos 2011). Exposed infants should be monitored for hypocalcemia after birth (Djokanovic 2008; Stathopoulos 2011).
It is not known if clodronate is present in breast milk.
Breastfeeding is contraindicated by the manufacturer.
Serum electrolytes including calcium (daily during IV therapy), phosphorous, magnesium, and potassium; monitor for hypocalcemia for at least 2 weeks after therapy; serum creatinine, BUN, CBC with differential, hepatic function. Monitor for signs/symptoms of GI mucosal irritation; hypersensitivity, hypocalcemia, ocular adverse effects; monitor for bone, joint, or muscle pain. Assess for atypical fracture in patients with thigh or groin pain.
Clodronate is a bisphosphonate that lowers serum calcium by inhibition of bone resorption via actions on osteoclasts or on osteoclast precursors; may also have indirect inhibitory effects through osteoblastic cells, which control recruitment and activity of osteoclasts. In responding patients, clodronate inhibits osteoclastic activity and bone resorption by decreasing the flux of calcium from bone, thus reducing calcium levels in the blood. Treatment with oral clodronate following IV infusion has been found to prolong the duration of action.
Onset of calcium-lowering effects: IV: Within 48 hours
Duration of calcium-lowering effects: 5 days to 3 weeks following discontinuation
Absorption: Oral: Rapid
Distribution: Vd: ~20 L; 20% of absorbed clodronate is bound to bone
Protein binding: Variable (2% to 36%)
Bioavailability: Oral: 1% to 3%
Half-life elimination: Terminal: Oral: ~6 hours; IV: 13 hours (serum); prolonged in bone tissue
Time to peak, plasma: Oral: 30 minutes
Excretion: Urine (60% to 80% of absorbed dose as unchanged drug); feces (as unabsorbed drug)
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