Pharmacology of Bisphosphonates

Bisphosphonates are drugs used in the treatment of osteoporosis, Paget’s disease and multiple myeloma. Examples of bisphosphonates include alendronic acid, etidronate, pamidronate and risedronate. They work by binding to hydroxyapatite crystals in the bone matrix – and tend to be deposited under osteoclasts. This inhibits the resorption of bone. Bisphosphonates are poorly absorbed from the gut and must be taken on an empty stomach – with the patient erect at all times – and with a full glass of water. Adverse effects include gastrointestinal disturbances, headache, dizziness, oesophagitis, pyrexia and osteonecrosis of the jaw. First, though, let's take a closer look at the pharmacology of bisphosphonates - how and why they work.

Examples
Alendronic Acid Etidronate Pamidronate
Ibandronic Acid Risedronate Zoledronic Acid

Pharmacology of Bisphosphonates

Bisphosphonates are a class of drugs which inhibit the resorption of bone. This permits the drugs to be used in conditions such as osteoporosis, Paget’s disease and multiple myeloma. Bisphosphonates may also be effective in the treatment of complex regional pain syndrome, though evidence is patchy as of yet.

Bisphosphonates are first-line treatment in patients with post-menopausal osteoporosis, and may also be used to reduce fractures and bone pain in patients with certain types of cancers. Their name derives from the P-C-P (P = PO3) backbone – though their chemical effect is primarily determined by its long side-chain (R2). R1 is typically a hydroxyl group.

Bisphosphonates

Mechanism of Action

Bisphosphonates are, in terms of structure, analogues of pyrophosphate. This allows these drugs to bind to hydroxyapatite crystals under osteoclasts, resulting in an inhibition of bone resorption. Depending on the structure of the bisphosphonate in question, its cellular effects on osteoclasts may be one of the following:

  • Forming a toxic version of ATP which induces osteoclast apoptosis. This tends to occur with non-nitrogen containing bisphosphonates, such as clodronate and etidronate.
  • Lipids are essential for osteoclast function. Nitrogen-containing bisphosphonates (such as alendronate, pamidronate, risedronate and zoledronic acid) inhibit the ATP-dependent enzyme farnesyl pyrophosphate synthase – an enzyme which is responsible for the production of lipids essential for osteoclast function. This disruption in lipid formation affects, among other things, membrane permeability – ultimately leading to osteoclast apoptosis.

Pharmacokinetics

Bioavailability with bisphosphonates is low, oscillating around the 0.6 percent mark. This bioavailability is yet further reduced if the drug is taken with food or drink (other than water), or supplements which contain aluminium, magnesium or calcium ions. Ranitidine – when administered in IV form – actually increases the bioavailability of bisphosphonates.

Oral formulations are best administered on an empty stomach, where the patient remains upright, and the drug is taken with a full glass of water. The effect of bisphosphonates is prolonged given their propensity for bone, though 50 percent is rapidly removed via the kidney.

Adverse Effects

Patients taking bisphosphonates may experience gastrointestinal discomfort – such as nausea, abdominal pain, diarrhoea or constipation. Headache and dizziness is also commonly reported. Alendronate and risedronate can cause oesophagitis, particularly if the medicine is not administered as per the recommended guidelines. With intravenous use, patients often experience mild pyrexia – which tends to fizzle out with subsequent doses. Osteonecrosis of the jaw, though, is a considerable risk with intravenous use.

If you'd like to test your knowledge of the pharmacology of bisphosphonates, see here for more.

By | 2016-12-03T17:53:48+00:00 October 16th, 2015|Pharmacology Guides|0 Comments

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