Bisphosphonates Bisphosphonates are a newly synthesized class of chemicals that bind strongly to hydroxyapatite crystals and have a half-life of many years or decades because they resist digestion by enzymes. This class of drugs has the effect of reducing the metabolic activity of osteoclasts, thus diminishing their ability to resorb bone. Bisphosphonates also act on osteoblasts and can inhibit the stimulatory effect of osteoblasts on osteoclasts.
(I) Mechanism of prevention and treatment
Bisphosphonates (BPS) are chemically stable, acid-resistant and not decomposed by hydrolytic enzymes due to the substitution of carbon atoms for the oxygen atom position of pyrophosphate , forming a P-C-P structure. BPS with the P-C-P structure has a strong affinity for bone tissue.
Binding of BPS to bone mineral salts is enhanced by the attachment of hydroxyl groups (OH-) to the R1 side chain, while the R2 side chain shows differences in the inhibition of bone resorption due to differences in the linkage chemical genes.
BPS acts through accumulation in bone tissue after osteoclast (OC) uptake during osteolysis, acidification of OC brush border during bone resorption, and release of BPS from bone tissue at the resorption lumen.
OC uptake of BPS can no longer form the brush border, thus losing the function of bone resorption, while the cytoskeleton ruptures, preventing the formation of actin rings; rupture of the cytoskeleton, most BPS can reduce the number of OC, prevent the maturation of OC, prevent the fusion of osteoclast precursors, causing apoptosis of OC, as well as including macrophages and human myeloma cells.
BPS prevents osteoclast apoptosis.
BPS stimulates the secretion of osteoblasts (OB), an OC inhibitor with a molecular weight of <10 KD, at nanomolar concentrations of BPS.
BPS acts through two different molecular mechanisms: BPS without nitrogen atoms (e.g., CLO, ETI) affects cellular energy metabolism by binding to adenosine triphosphate (ATP or APPP) through amyl-tRNA synthetase in the cell membrane to form an ATP analogue that is not hydrolyzed.
The mechanism of action of nitrogen-containing atomic BPSs such as alan and epophosphonates inhibits the cellular metabolic pathway of mevalonate, which in turn inhibits the bone resorption function of OC, while blocking the isoprenyl action of proteins, leading to the loss of small GTPase function.
Bisphosphonates are synthetic drugs that are not naturally synthesized in living organisms and are not metabolized in vivo to change their structure.
After oral administration, the bioavailability is low and the absorption is less than 1% and 10% of the ingested amount. Roughly, the stronger the biological activity, the lower the absorption rate. Some bisphosphonates, such as EHDP, inhibit bone resorption at doses that are extremely close to the amount that causes mineralization impairment.
Absorption site: the stomach begins, most of the absorption in the small intestine, mainly through passive diffusion mode absorption, food, especially food containing calcium, iron hinder the absorption of drugs, not in the meal or with milk, dairy products or iron at the same time, orange juice, coffee can also reduce absorption.
Absorbed into the blood of bisphosphonates its 2/3 or more EHDP (sodium hydroxyethylphosphonate), CLO (chloromethylbisphosphonate), or its 1/2 pamidnonate (Pamidnonate), or less ALN (alendronate) amount, that is, blood content of 50-80% from the renal route of ultrafiltration, 20-50% of the absorbed amount is absorbed by bone tissue, such as 20% of the amount of CLO absorption, 50% of EHDP, Alendronate (Alendronate). Some bisphosphonates such as Pamidnonate can also be deposited in the liver, spleen and other organs, the higher the dose, the more deposition, especially in large doses or after rapid intravenous infusion, more deposition, and metal ions to form complexes or self-agglutination, and subsequently by the reticulum Therefore, bisphosphonates should not be infused rapidly in large quantities, otherwise they may lead to renal failure due to coagulation formation.
The half-life of bisphosphonates in the blood is very short, only a few minutes in mice and about 30-60 minutes in humans. ALN accumulates mainly under osteoclasts, while EHDP accumulates under osteoclasts and osteoblasts, and large doses are deposited at the site of osteoclasts and osteogenesis.
The accumulation and retention of bisphosphonates in bone is long-lasting and does not appear to saturate when administered at clinically therapeutic doses, reaching a plateau state for at least several years or decades. In contrast, the anti-bone resorption effect of continuous dosing, both in animals and humans, reaches maximum effectiveness relatively quickly. Bisphosphonates buried in bone tissue are not active.
The half-life of bisphosphonates in vivo depends largely on the rate of bone conversion itself, and bisphosphonates deposited in bone and bound to hydroxyapatite are released only when bone conversion occurs, and it is the deposition of the drug that slows bone resorption. The half-life of different types of bisphosphonates is also inconsistent, ranging from about 3 months to 1 year in rats, with CLO being faster than EHDP and Pamidnoate, and some having half-lives of up to 10 years in humans.
Bisphosphonates deposited in skeleton have no pharmacological activity, but recent murine results suggest that bone tissue formed under high-dose ALN administration can be absorbed normally, suggesting that a single dose can be active for a long time.
Renal clearance: 50-80% of the absorbed amount of bisphosphonate, i.e., the amount absorbed by bone, is rapidly excreted from the kidneys.
Other routes of administration: It has been found to be biologically active when administered by nasal spray and dermal routes.
(ii) Clinical applications.
At present, the common clinical bisphosphonates include sodium hydroxyethylphosphonate (etidronate, EHDP), chloromethylbisphosphonate (clodronate, also known as bone phosphine, CLO), pamidronate (Pamidronate) and alendronate (alendronate, ALN), risedronate (residronate) The use of bisphosphonates as an anti-tumor agent for patients with cancer has been studied and developed continuously. The application of bisphosphonates as an adjuvant treatment for antitumor osteolysis in oncology patients can relieve bone pain, reduce hypercalcemia, and reduce fractures, thus improving their quality of life. The main targets for the use of bisphosphonates are bone diseases characterized by increased osteolytic activity, such as Peget’s disease, hypercalcemia caused by various diseases and osteolysis caused by tumors. The success of treatment of osteoporosis is reflected in the stabilization or even increase of bone mass in the trabeculae. The effective effect of bisphosphonates on cortical bone is not obvious.
(iii) Methods of application
Oral bisphosphonate preparations are generally advocated to be taken in the following correct way: take the drug on an empty stomach, using 200 ml of plain water, taking care not to take it with tea, drinks, milk, coffee or mineral water. Within 30 minutes after taking the drug, no other drugs or food should be taken, and a sitting or standing position should be used, not lying down, in order to increase the bioavailability of bisphosphonates and reduce gastrointestinal adverse reactions.
Common doses and uses of such drugs are as follows.
Etidronate: intermittent, cyclic dosing of 400 mg/day orally for 14 days, with 10-13 weeks off for one cycle.
Clodronate: The recommended dose is 400 mg or 800 mg/day.
Pamidrnate: Generally 30 mg/dose intravenously every 3 months.
Alendronate: The common dose of the oral formulation is 10 mg/day orally. Recently, a dosing regimen of 70 mg/times once weekly has been reported as effective in treatment and with reduced adverse effects.
Residronate: 2.5 mg or 5 mg orally daily.
Cimadronate: 5 mg orally daily. Ibandronate: Ibandronate 0.5 mg to 5 mg orally daily or 0.5 mg-2 mg intravenously every 3 months.
(iv) Safety
Only acute, subacute and chronic toxicity tests of five bisphosphonates, Alendronate, Etidionate Clodnonate Pamidionate Tiludionate, have been reported, with few toxic reactions and negative tests for teratogenicity, mutagenicity and carcinogenicity. Local necrosis can occur during subcutaneous injection.
The acute toxic reaction is mainly hypocalcemia, which occurs mainly during intravenous infusion. Etidnouate and Pamidnonate can cross the placenta and affect the fetus. Toxic reactions also vary among bisphosphonates.
Bisphosphonates can cause gastrointestinal symptoms after oral administration, such as heartburn, nausea and vomiting after oral administration of aminobisphosphonates. Patients with ulcer disease, esophageal stricture, esophageal hiatal hernia and gastric reflux should be cautiously used or prohibited from taking oral bisphosphonates. Use the correct method of drug administration to reduce the occurrence of adverse reactions.
Intravenous use of bisphosphonates can cause vasculitis, and rapid intravenous dosing of high concentrations of bisphosphonates can cause nephrotoxicity by coupling with calcium in the blood. Others have reported that pamidronate can cause severe esophagitis, fever, hypocalcemia, hypophosphatemia, and less commonly, cold-like symptoms and gastrointestinal reactions.