Bisphosphonates Effects and Side Effects

Products

Bisphosphonates are commercially available in the form of film-coated tablets and as injection and infusion preparations. They are also combined fixed with vitamin D3. Their effects on bone were described in the 1960s. Etidronate was the first active ingredient to be approved (out of trade).

Structure and properties

Bisphosphonates contain a central carbon atom bonded to two phosphorus atoms (P-C-P). They are structural analogs of the naturally occurring inorganic pyrophosphates (P-O-P) found in bone. Bisphosphonates are not degraded enzymatically. They differ on the one hand in the two side chains R1 and R2 and on the other hand in the presence of a nitrogen atom (amino group).

Effects

Bisphosphonates have antiresorptive properties. Their effects are based on attachment to the hydroxyapatite of bone and inhibition of the activity of osteoclasts, by which they are taken up. Thus, they reduce bone resorption. On the other hand, they have no direct effect on bone formation. Bisphosphonates are incorporated into bone and have a very long terminal half-life. For alendronate, it is over 10 years.

Indications

Bisphosphonates are mainly used for the treatment of osteoporosis to prevent fractures. Other indications include:

  • Paget’s disease
  • Patients with bone metastases
  • Malignant hypercalcemia

Dosage and application

According to the professional information. The dosage interval can be one day, one week, one month, three months or even one year, depending on the drug. The instructions for taking should be followed carefully, because otherwise the absorption into the body, which is already so very low, will be further reduced and side effects may occur:

  • Take in the morning, depending on the active ingredient 30 to 60 minutes fasting, before the first intake of food or liquid.
  • Do not take with calcium, other medications, beverages or dietary supplements.
  • Take the tablets unchewed with a glass of tap water (> 2 dl) sitting upright or standing.
  • Do not lie down for 30 to 60 minutes after administration depending on the active ingredient.
  • For ingestion, use only tap water and not mineral water.
  • Do not suck or chew tablets.
  • Do not take before bedtime or before getting up.

The exact instructions should be taken from the package insert, because they differ slightly depending on the drug. The reasons for these specifications are on the one hand the deep oral bioavailability, the risk for interactions and on the other hand the risk for mucosal irritation. An adequate supply of calcium and vitamin D should be ensured. A calendar entry may be recommended to help patients remember to take the medication weekly or monthly. Some drugs are also administered parenterally as injections or infusions.

Active ingredients

The following drugs are currently on the market in many countries:

The following bisphosphonates are no longer marketed in many countries:

  • Clodronate (Bonefos, out of trade).
  • Etidronate (Didronel, out of trade)
  • Pamidronate (Aredia, out of trade)
  • Tiludronate (Skelid, out of trade)

Contraindications

Contraindications include (selection):

  • Hypersensitivity
  • Acute inflammation of the digestive tract
  • Clinically manifest osteomalacia
  • Diseases of the esophagus that may delay transport to the stomach
  • Inability to maintain an upright posture for 30 minutes.
  • Severe renal insufficiency
  • Untreated hypocalcemia
  • Pregnancy, lactation

Full precautions can be found in the drug label.

Interactions

Bisphosphonates have very low oral bioavailability. Foods taken at the same time, beverages such as mineral water and milk, calcium, aluminum, magnesium, and iron may further decrease the poor bioavailability. Other drugs that irritate the mucous membranes of the digestive tract may increase the adverse effects.Bisphosphonates do not usually interact with CYP450 isozymes.

Adverse effects

The most common potential adverse effects include:

Bisphosphonates can very rarely cause serious side effects. These include localized osteonecrosis of the jaw and atypical femoral fractures.