Medical Uses of Bisphosphonates
- Treat osteoporosis, osteitis deformans (Pagets disease of the bone), bone metastasis, multiple myeloma, and other conditions involving fragile bone
- Alendronate and risedronate are commonly used for osteoporosis and Pagets disease
- Intravenous pamidronate may be used if oral medications are ineffective or cause digestive tract problems
- Strontium ranelate or teriparatide are used for refractory disease
- Raloxifene may be used instead of bisphosphonates in postmenopausal women
- Bisphosphonates recommended as first-line treatment for post-menopausal osteoporosis
- Long-term treatment produces anti-fracture and bone mineral density effects
- Alendronate reduces the risk of hip, vertebral, and wrist fractures
- Zoledronate reduces the risk of hip and vertebral fractures
- Risedronate also reduces the risk of hip fractures
- Bisphosphonates reduce the risk of fracture and bone pain in breast, lung, and other metastatic cancers, and multiple myeloma
- Mixed evidence regarding whether bisphosphonates improve survival in breast cancer
- Bisphosphonate treatment may reduce the risk of cancer spreading to the bone in early breast cancer
- Bisphosphonates can reduce mortality in multiple myeloma and prostate cancer
- Bisphosphonates may be useful in the treatment of complex regional pain syndrome
- Used to reduce fracture rates in children with osteogenesis imperfecta
- Used to treat otosclerosis by minimizing bone loss
- Medronate and oxidronate mixed with radioactive technetium for bone imaging and detection of bone disease
- Evidence of bisphosphonate use as a risk factor for atrial fibrillation, but conflicting reports

Adverse Effects and Risks
- Common side effects include upset stomach, inflammation, and erosions of the esophagus
- Fever and flu-like symptoms may occur after the first infusion of intravenous bisphosphonates
- Osteonecrosis of the jaw may occur with high-dose intravenous administration in cancer patients
- Severe bone, joint, or musculoskeletal pain reported
- Bisphosphonate use may be a risk factor for atrial fibrillation, but no recommendation for alteration in prescribing based on AF concerns
- Osteonecrosis of the jaw
- Atypical fractures of the femur
- Esophageal cancer risk
- Gastrointestinal tract cancer risk
- Atrial fibrillation risk

Chemistry and Classes
- All bisphosphonate drugs have a common phosphorus-carbon-phosphorus backbone.
- The name 'bisphosphonate' and the function of the drugs are determined by the two phosphonate groups covalently linked to carbon.
- The presence of two phosphonate groups in the molecule gives rise to the term 'bis' in bisphosphonate.
- The chemical properties, mode of action, and strength of bisphosphonate drugs are determined by the long side-chain (R) in the molecule.
- The short side-chain (R), also known as the hook, mainly influences chemical properties and pharmacokinetics.
- Nitrogenous bisphosphonates block the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-CoA reductase pathway.
- Bisphosphonates containing isoprene chains at R or R position can specifically inhibit GGPS1.
- Disruption of the HMG-CoA reductase pathway prevents the formation of metabolites essential for connecting small proteins to the cell membrane.
- Bisphosphonates affect protein prenylation, which can impact osteoclastogenesis, cell survival, and cytoskeletal dynamics.
- Statins, another class of drugs that inhibit the HMG-CoA reductase pathway, do not have high affinity for bone surfaces like bisphosphonates.

Pharmacokinetics
- Approximately 50% of resorbed or infused bisphosphonates are excreted unchanged by the kidney.
- Bisphosphonates have a high affinity for bone tissue and are rapidly adsorbed onto the bone surface.
- Once in the bone, bisphosphonates have a very long elimination half-life, which can exceed ten years.
- Bisphosphonates accumulate to a high concentration only in bones due to their preference for binding to calcium ions.
- The high concentration of bisphosphonates in bones is due to their release by osteoclasts, the bone cells responsible for bone resorption.

History and Development
- Bisphosphonates were first investigated in the 1960s for use in bone metabolism disorders.
- They were initially used to soften water in irrigation systems for orange groves.
- The potential of bisphosphonates in preventing bone loss by preventing the dissolution of hydroxylapatite was the initial rationale for their use in humans.
- The actual mechanism of action of bisphosphonates was demonstrated in the 1990s with the launch of alendronate by Merck & Co.
- Bisphosphonates have a long history of development and research in the field of bone health.
- Safety reviews and updates by regulatory authorities.

Bisphosphonate (Wikipedia)

Not to be confused with Biphosphate.

"Diphosphonate" redirects here. Not to be confused with Diphosphate.

Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they have two phosphonate (PO(OH)
₂) groups. They are thus also called diphosphonates (bis- or di- + phosphonate).

Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.

Bone tissue undergoes constant remodeling and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss.

The uses of bisphosphonates include the prevention and treatment of osteoporosis, Paget's disease of bone, bone metastasis (with or without hypercalcemia), multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, fibrous dysplasia, and other conditions that exhibit bone fragility.