What is the mechanism of action of bisphosphonates and who is contraindicated for their use?

From the Guidelines

Bisphosphonates work by inhibiting bone resorption through their action on osteoclasts, and they are contraindicated in patients with severe renal impairment, hypocalcemia, and inability to stand or sit upright for at least 30-60 minutes. Bisphosphonates bind to hydroxyapatite binding sites on bone surfaces, especially those undergoing active resorption, and when osteoclasts begin to resorb bone containing bisphosphonates, the drugs are released and impair the osteoclasts' ability to form ruffled borders, adhere to bone surfaces, and produce protons, ultimately inducing osteoclast apoptosis 1. Common bisphosphonates include alendronate, risedronate, ibandronate, and zoledronic acid. Some key points to consider when prescribing bisphosphonates include:

• Contraindications: severe renal impairment (creatinine clearance <30 mL/min), hypocalcemia, pregnancy, hypersensitivity to bisphosphonates, and inability to stand or sit upright for at least 30-60 minutes (for oral formulations) 1
• Cautious use: patients with active upper gastrointestinal problems, poor dental health, or planned invasive dental procedures due to the risk of osteonecrosis of the jaw 1
• Optimal absorption: oral bisphosphonates should be taken with plain water after an overnight fast, and patients should remain upright and avoid food, beverages, and other medications for 30-60 minutes after administration 1
• Monitoring: serum creatinine monitoring before each dose is administered, and dose reduction or discontinuation if renal function is reduced 1 It is essential to weigh the benefits and risks of bisphosphonate therapy, particularly in patients with metastatic disease, and to consider the potential for osteonecrosis of the jaw and other adverse effects 1.

From the FDA Drug Label

Bisphosphonates, such as zoledronic acid injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including zoledronic acid injection Zoledronic acid injection can cause fetal harm when administered to a pregnant woman

Bisphosphonates Mechanism of Action: Bisphosphonates work by being incorporated into the bone matrix, where they are gradually released over time.

Contraindications:

• Pregnancy: Zoledronic acid injection can cause fetal harm when administered to a pregnant woman 2.
• Patients with a history of hypersensitivity to zoledronic acid or other bisphosphonates.
• Patients with severe renal impairment.
• Patients with hypocalcemia.
• Asthma: While not observed in clinical trials with zoledronic acid injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates 2.

Note: The provided information is based on the available data from the drug labels and may not be comprehensive or up-to-date. It is essential to consult the latest drug labels and medical literature for the most current information.

From the Research

Mechanism of Action

• Bisphosphonates are chemically stable structural analogs of inorganic pyrophosphate that inhibit osteoclast activity, making them primary agents in treating conditions with excessive osteoclast-mediated bone resorption, such as osteoporosis, Paget's disease of bone, and cancer-associated bone disease 3.
• At the molecular level, bisphosphonates exert their anti-resorptive effects by inhibiting farnesyl pyrophosphate synthase activity within osteoclasts 3.
• The simple bisphosphonates are intracellularly metabolized to cytotoxic ATP analogues, while the more potent, nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase, preventing the prenylation of small GTPases necessary for osteoclast function and survival 4.

Clinical Use

• Bisphosphonates are effective in multiple clinical settings, including postmenopausal osteoporosis, low bone mass in men, and drug-induced bone loss, and are generally well tolerated with an excellent safety profile 5.
• They are widely used in the treatment of diseases involving excessive bone resorption, such as osteoporosis, cancer-associated bone disease, and Paget's disease of bone 4.
• Bisphosphonates are also used to prevent and treat other skeletal conditions, such as low bone density and osteogenesis imperfecta 6.

Contraindications and Side Effects

• While bisphosphonates are generally well tolerated, widespread use has revealed both short-term and long-term side effects in some patients, including osteonecrosis of the jaw 6.
• There is no specific information in the provided studies regarding absolute contraindications for bisphosphonate use, but the presence of side effects and potential risks should be considered when prescribing these medications 3, 5, 4, 6.