How do bisphosphonates prevent fractures in patients with osteoporosis?

From the Guidelines

Bisphosphonates are the most effective pharmacologic treatment for preventing fractures in adults with primary osteoporosis, as they have been shown to reduce the risk of fractures by inhibiting osteoclasts and increasing bone density. Bisphosphonates work by binding to bone mineral and being taken up by osteoclasts during bone resorption, causing these cells to undergo programmed cell death (apoptosis) 1. This reduces the rate of bone turnover and allows osteoblasts (bone-building cells) to work more effectively, resulting in increased bone mass and strength. According to the American College of Physicians, bisphosphonates have the most favorable balance among benefits, harms, patient values and preferences, and cost among the examined drugs 1.

Some of the key benefits of bisphosphonates include:

• Reducing vertebral fracture risk by 40-70%
• Reducing hip fracture risk by 40-50% in patients with osteoporosis
• Being much cheaper than other pharmacologic treatments and available generic formulations
• Having a strong recommendation with high-certainty evidence for initial pharmacologic treatment of primary osteoporosis 1

Common bisphosphonates include alendronate, risedronate, ibandronate, and zoledronic acid. Treatment duration typically ranges from 3-5 years, after which a "drug holiday" may be considered based on fracture risk. Patients should take oral bisphosphonates with a full glass of water on an empty stomach and remain upright for 30-60 minutes afterward to prevent esophageal irritation. Adequate calcium and vitamin D intake is essential for optimal effectiveness. The use of bisphosphonates is recommended as the initial pharmacologic treatment for adults with primary osteoporosis to reduce the risk of fractures, due to their favorable balance of benefits and harms 1.

From the Research

Mechanism of Action

• Bisphosphonates inhibit osteoclast-mediated bone resorption, which is the primary mechanism by which they prevent fractures 2, 3, 4, 5, 6.
• They act by inhibiting farnesyl pyrophosphate synthase activity within osteoclasts, preventing the prenylation of small GTPases necessary for osteoclast function and survival 3, 6.
• Bisphosphonates also target the osteocyte network, preventing osteocyte apoptosis, which may contribute to their anti-fracture effects 6.

Effects on Bone Health

• Bisphosphonates increase bone mineral density (BMD) and reduce bone turnover, re-establishing the balance between bone resorption and formation 2, 4, 5.
• They prevent bone loss, preserve bone structure, and improve bone strength, substantially reducing fracture risk in patients with osteoporosis 4, 5.
• Different bisphosphonates have varying effects on bone health, with denosumab and zoledronate associated with the greatest treatment effect size 2.

Clinical Applications

• Bisphosphonates are used to treat conditions marked by excessive osteoclast-mediated bone resorption, such as osteoporosis, Paget's disease of bone, and cancer-associated bone disease 3, 5, 6.
• They are effective in multiple clinical settings, including postmenopausal osteoporosis, low bone mass in men, and drug-induced bone loss 4.
• Bisphosphonates are generally well tolerated, with few serious side effects, and have an excellent safety profile 4, 5.