Clodronic Acid; Indications/Uses, Side Effects, Interactions, Pragnancy

Clodronic Acid; Indications/Uses, Side Effects, Interactions, Pragnancy

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

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 β-γ-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 Dictyostelium discoideum 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.

Indications of Clodronic Acid

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Contra-Indications of Clodronic Acid

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.
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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

Common

Rare

Drug Interactions of Clodronic Acid

The clodronic acid may interact with the following drugs, supplements & may change the efficacy of drugs

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Pregnancy & Lactation of Clodronic Acid

FDA Pregnancy Catagory  D

Pregnancy 

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

  1. PubChem

Clodronic Acid

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