From the Guidelines
Bisphosphonates work primarily by inhibiting osteoclast-mediated bone resorption, binding to the bone matrix and inhibiting osteoclast activity. Their mechanism of action involves binding tightly to hydroxyapatite crystals in bone, where they are taken up by osteoclasts during bone resorption 1. Inside osteoclasts, bisphosphonates interfere with critical cellular processes through two main mechanisms.
- Nitrogen-containing bisphosphonates (like alendronate, risedronate, zoledronic acid, and ibandronate) inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway, preventing the prenylation of small GTPases necessary for osteoclast function and survival.
- Non-nitrogen containing bisphosphonates (like etidronate and clodronate) are metabolized into cytotoxic ATP analogs that accumulate in osteoclasts and directly induce cell death. By reducing osteoclast activity and number, bisphosphonates decrease bone turnover, allowing osteoblasts more time to form new bone, which leads to increased bone mineral density and reduced fracture risk, as shown in numerous randomized, placebo-controlled trials 1. This selective action on bone tissue occurs because bisphosphonates concentrate almost exclusively in bone due to their high affinity for calcium phosphate. The effects of bisphosphonates on bone mineral density and tolerability have been evaluated in HIV-infected patients, showing similar results to those found in the general population 1. Overall, the mechanism of action of bisphosphonates is well-established, and their use has been shown to be effective in reducing the risk of fracture in patients with bone disease.
From the FDA Drug Label
Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. The mechanism of action of bisphosphonates, such as alendronate, is to:
- Act as a specific inhibitor of osteoclast-mediated bone resorption
- Bind to the hydroxyapatite found in bone This action results in the inhibition of bone resorption, which is a key aspect of their therapeutic effect 2.
From the Research
Mechanism of Action of Bisphosphonates
- Bisphosphonates are antiresorptives that target osteoclasts and inhibit bone resorption 3, 4, 5, 6, 7
- They exert their anti-resorptive effects by inhibiting farnesyl pyrophosphate synthase activity within osteoclasts 4, 5
- Simple bisphosphonates are intracellularly metabolised to cytotoxic ATP analogues, while nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase 5
- Bisphosphonates primarily affect the function of resorbing osteoclasts, but may also target the osteocyte network and prevent osteocyte apoptosis 5
- They may also target monocytes and macrophages, which could explain the acute phase response and the anti-tumour activity in certain animal models 5
Effects on Bone Cells
- Bisphosphonates reduce bone turnover and re-establish the balance between bone resorption and formation 6
- They prevent bone loss, preserve bone structure, improve bone strength, and substantially reduce fracture risk in patients with osteoporosis 6, 7
- Bisphosphonates are effective in multiple clinical settings, including postmenopausal osteoporosis, low bone mass in men, and drug-induced bone loss 6
Clinical Efficacy
- Bisphosphonates have been shown to reduce the relative risk of new vertebral fractures in women with postmenopausal osteoporosis 7
- Alendronate, risedronate, and zoledronic acid reduce the relative risk of new nonvertebral and hip fractures 7
- Clinical trial extensions have shown that efficacy is maintained during long-term treatment with bisphosphonates 7