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Clodronic Acid is the first-generation bisphosphonate with anti-resorptive and anti-hypercalcemic activities. Clodronic acid adsorbs onto the surface of the hydroxyapatite crystals in bone matrix. Although the exact mechanism through which clodronic acid exerts its cytotoxic effect on osteoclasts has yet to be fully elucidated, this agent is metabolized intracellularly to a toxic beta-gamma-methylene analog of adenosine triphosphate (ATP), AppCCl2p. The ATP analog AppCCl2p competitively inhibits ADP/ATP translocase, thereby interfering with mitochondrial membrane potential and cellular energy metabolism. This may cause osteoclast apoptosis and, eventually, inhibiting osteoclast-mediated bone resorption.
Clodronate is only found in individuals that have used or taken this drug. It is a diphosphonate which affects calcium metabolism. It inhibits bone resorption and soft tissue calcification. [PubChem]The bisphosphonate group binds strongly to the bone mineral, hydroxyapatite. This explains the specific pharmacological action of these compounds on mineralized tissues, especially bone. The exact mechanism of action of clodronate is not known, however, it is known that it does not inhibit protein isoprenylation but can be metabolized intracellularly to a & beta; -& gamma; -methylene (AppUp-type) analog of ATP(AppCCl2p), which is cytotoxic to macrophages in vitro. Inhibition of the ADP/ATP translocase by the metabolite AppCCl2p is a likely route by which clodronate causes osteoclast apoptosis and inhibits bone resorption. Recently, the slime mold < i> Dictyostelium discoideum< /i> was shown to take up bisphosphonates by pinocytosis. In these cells, clodronate, but not other pharmacologically active bisphosphonates, was incorporated into adenine nucleotides, which could potentially explain why this bisphosphonate sometimes seems to act differently than the other bisphosphonates. Clodronate, like all bisphosphonates, also binds protein-tyrosine-phosphatase.
Mechanism of Action of Clodronic Acid
Indications of Clodronic Acid
- Hypercalcemia of Malignancy
- Osteolytic Bone metastases
- For the management of hypercalcemia of malignancy and as an adjunct in the management of osteolysis resulting from bone metastases of malignant tumors.
Contra-Indications of Clodronic Acid
- Hypersensitivity to ibandronic acid or to any of the excipients.
- Hypocalcemia
- Abnormalities of the esophagus which delay oesophageal emptyings such as stricture or achalasia
- Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)
- Clinically manifest osteomalacia
- Certain malformations and malfunctions of the esophagus (strictures, achalasia)
- Inability to stand, walk, or sit for 30 minutes after oral administration
- Renal impairment with a creatinine clearance below 30ml/min
- Patients below 18 yrs. of age, as no clinical data exists
- Signs of colic, which is usually self-limiting, occurs in 30-45% of horses.
- Electrolyte disturbances – primarily calcium, magnesium, and potassium, which can last for several hours. Caution should be used in horses with disease processes that could be affected by electrolyte disturbances, such as hyperkalemic periodic paralysis or cardiac disease.
- Kidney damage – it is eliminated by the kidney and is not recommended for use in animals with impaired renal function.
- Less serious reactions include stiffness of the neck, decreased appetite, fever, and increased urination.
- Inability to stand, walk, or sit for 30 minutes after oral administration
- Renal impairment with a creatinine clearance below 30ml/min
- Hypocalcemia
- Pregnancy and breastfeeding
The dosage of Clodronic Acid
Strengths: 300 mg, 600 mg ,1600 mg, 3200 mg
Osteolytic bone metastases
- Initial: 1,600 mg/day, increase as needed. Max: 3,200 mg/day.
- Hypercalcemia of malignancy Maintenance following IV therapy: 1,600-2,400 mg/day. Max: 3,200 mg/day.
- IV Hypercalcaemia of malignancy 300 mg/day for up to 7 days, or 1,500 mg as a single infusion
Hypercalcaemia of malignancy
- 300 mg daily via infusion over at least 2 hr until normocalcaemia is achieved. Max duration of treatment: 7 days. Alternatively, 1,500 mg as a single infusion over at least 4 hr.
Osteolytic bone metastases
- Initially, 1,600 mg daily as a single or in 2 divided doses, increased as necessary. Max: 3,200 mg daily.
Hypercalcaemia of malignancy
- Maintenance following Ca normalization w/ IV therapy: 1,600-2,400 mg as a single or in 2 divided doses. Max: 3,200 mg daily.
Side Effects of Clodronic Acid
- Heartburn
- The most commonrn (a burning feeling in the chest, behind the breastbone or gullet)
- Abdominal or stomach pain
- pain, warmth and/or swelling in a leg or in the pelvis
- sudden tingling or coldness in an arm or leg
- Burning, itching, stinging, redness, or other sign of irritation at the application site , rash
- Indigestion
- Constipation
- High blood pressure
- Nausea, vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- dull, aching pain in the hip, groin, or thigh
- liver problems,
- stomach pain,
- Dizziness
- a headache,
- reversible hair loss or thinning, and
- fever.
Common
- chills or fever
- headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in chest
- excessive sweating
- sudden drowsiness or need to sleep
- sharp pain when taking a deep breath
- coughing up blood
- rust colored urine
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
- decreased amount of urine
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- hallucinations
- headache
- irritability
- lightheadedness
- muscle pain or cramps
- muscle spasm or jerking of all extremities
- severe pain in your upper stomach spreading to your back, nausea, and vomiting;
Drug Interactions of Clodronic Acid
The clodronic acid may interact with the following drugs, supplements & may change the efficacy of drugs
- NSAIDS (nonsteroidal anti-inflammatory drugs) such as ibuprofen , naproxen
- aspirin
- antacids
- proton pump inhibitors such as esomeprazole , lansoprazole , omeprazole , pantoprazole,
- H2 blockers such as cimetidine, famotidine , nizatidine , ranitidine
- hormone therapy such as estrogens and estrogen agonist/blockers
- cancer chemotherapy treatments
- steroids such as dexamethasone , methylprednisolone and prednisone
- calcium supplements
- aluminum supplements
- magnesium supplements
- The additional beneficial effect of HRT (hormone replacement therapy) with estrogens/progestins or raloxifene in postmenopausal women remains to be elucidated, but no interactions have been seen.
- iron supplements
- Milk, diet, and drugs containing high amounts of calcium, magnesium or aluminum (antacids): the absorption of clodronic acid is decreased. At least half an hour should pass after intake of clodronic acid before taking the supplement or drug.
- The combination of NSAIDs and clodronic acid may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.
Pregnancy & Lactation of Clodronic Acid
FDA Pregnancy Catagory D
There are no limited amount of data from the use of clodronic acid in pregnant women. Studies in animals have shown reproductive toxicity. Clodronic acid given during pregnancy in rats caused dystocia related to hypocalcemia.Clodronic acid should not be used during pregnancy.
Lactation
It is not known whether the clodronic acid is excreted into human breast milk. Given the indication, the alendronic acid tablet should not be used by breastfeeding women.
References
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PubChem
