What Are Bisphosphonates?

Bisphosphonates (BPs) are a new class of drugs used in various bone disorders and calcium metabolic diseases. It can specifically bind to hydroxyphosphine limestone in bone and inhibit osteoclast activity, thereby inhibiting bone resorption. It is used to treat osteoporosis, deformable osteitis, hypercalcemia and bone pain caused by bone metastases of malignant tumors.

Chinese name: Bisphosphonate
Foreign name: bisphosphonates

Treatment: Osteoporosis
Belongs to: A new class of drugs against metabolic bone disease

Bisphosphonates are used to treat osteoporosis, deformable osteitis, hypercalcemia and bone pain caused by bone metastases from malignant tumors. In particular, osteoporosis is "characterized by a decrease in bone mass and destruction of bone structure, leading to an increase in bone fragility and fracture rate". Osteoporosis is a systemic bone disease. Bone destruction is also a common complication of various solid tumors (such as breast cancer) and hematopoietic system malignancies, which can cause hypercalcemia and bone pain. Therefore, the prevention and treatment of diseases with abnormal bone metabolism has caused widespread concern in the medical community. Compston ^[1] and Eastell ^[2] pointed out that estrogen replacement therapy may be the first choice for osteoporosis, but it may cause endometrial cancer, breast cancer and thrombosis. Bisphosphonates are alternatives to estrogen replacement therapy.

1. Bisphosphonates 1. Chemical structure and activity

More than 30 years ago, Fleisch et al. Found that pyrophosphate in plasma and urine can inhibit ectopic calcification. However, pyrophosphate is not effective when taken orally, and it is rapidly inactivated by enzymatic hydrolysis after injection. ^[3] Later research found that replacing the POP group in the pyrophosphate structure with PCP groups can change the physical and chemical properties of pyrophosphate. Increase its stability to hydrolase, change its biological properties and toxicological effects. Then a series of bisphosphonates were synthesized. Among them, the first generation of etidronate was first listed by American Proter & Gamble Company in 1987. Later, the second-generation sodium clodronate, pamidronate, and tiludronate, and the third-generation alendronate, neridronate, and opalonate were successively developed. (olpadronate), risedronate sodium, and ibandronate sodium.

The structure-activity relationship of bisphosphonates is not yet clear. However, it has been clear that its basic structure, PCP, is a necessary condition for its activity. The strength of each drug depends on the type of side chain substituted on the C atom. For example, sodium clodronate obtained by replacing R1 and R2 with Cl atoms has an anti-bone resorption strength 10 times that of etidronate. For example, R2 is -OH group, and R1 is a side chain substitution containing N atom, and its action intensity is greater. Pamidronate and alendronate are 100 times and 1,000 times stronger than etidronate, respectively; R1 The sodium ibandronate obtained by adding a methyl group and a pentyl group to the N atom of the side chain is 10,000 times more active than etidronate sodium. The substitution of the H atom on R1 with pyridylmethyl can also improve the anti-bone resorption effect. For example, the strength of risedronate sodium is 5 000 times that of etidronate sodium.

2. Bisphosphonates 2. Mechanism and pharmacological action

Bisphosphonates are a new class of drugs that resist bone resorption. Like pyrophosphate, it can be closely adsorbed on the surface of hydroxyapatite, but unlike pyrophosphate, it is easily degraded by pyrophosphatase ^[4] . After the combination of bisphosphonate and hydroxyapatite of bone, hydroxyapatite is dissolved into "amorphous" calcium phosphate and the two-way process of "amorphous" calcium phosphate into hydroxyapatite is inhibited. The mechanism of its anti-bone resorption may be related to the following three points ^[4] : directly change the morphology of osteoclasts, thereby inhibiting its function; physical and chemical combination with bone matrix, directly interfere with bone resorption; directly inhibit osteoblasts Leading cytokines such as IL-6, TNF production. Experiments have shown that bisphosphonates can be adsorbed on the binding sites of minerals, thereby interfering with osteoclast attachment, resulting in changes in the ultrastructure of osteoclasts. In particular, alendronate can selectively bind to osteoclasts. The osteoclasts cannot function at the active site under the cell's endometrial attachment surface. This also explains the long half-life of bisphosphonates in bone. However, once it is incorporated into the bone matrix, it can also be taken up by osteoclasts during the period of bone resorption. The bisphosphonate entering the cell causes a series of biochemical reactions such as reducing the production of lactic acid and inhibiting lysosomal enzymes and pyrophosphatase The activity, as well as the synthesis of prostaglandins and proteins, leads to "paralysis" of osteoclasts. Recently, it has been proposed that bisphosphonates work by affecting the process of osteolysis of osteoblasts. Preliminary studies have shown that bisphosphonates can prevent osteoclast repair by inhibiting cytokines produced by osteoblasts. Clinical studies have shown that pamidronate, clodronate and risedronate can also induce apoptosis of osteoclasts ^[5] .

Bisphosphonates prevent experimental arterial, kidney, and skin calcification, and topical application reduces tartar formation. Systemic application of etidronate can not only inhibit ectopic calcification, but also inhibit ectopic ossification. If the dose is sufficient, some bisphosphonates such as etidronate can also damage the mineralization of normal calcified tissues such as bone. The ability of bisphosphonates to inhibit calcium phosphate formation in vitro is closely related to its ability to inhibit ectopic calcification in vivo. They strongly inhibit bone resorption both inside and outside the body. Alendronate can also prevent bone loss under weight-bearing and non-weight-bearing situations ^[6] . The effect of bisphosphonates on the adsorption of non-mineralized extracellular bone matrix by breast cancer cells and prostate cancer cells has been studied. The results show that pretreatment of tumor cells with bisphosphonates can inhibit tumor cells from adsorbing to the extracellular matrix of non-mineralized and mineralized osteoblasts in a dose-dependent manner. The inhibitory intensity is: ibendronate > NE-10244> Pamidronate> Clodronate. And it does not show any cytotoxic effect in the concentration of inhibiting tumor cells ^[6] . Bisphosphonates have no direct anticancer effect, nor do they have the effect of traditional antitumor drugs ^[7] .

3. Bisphosphonates 3. Pharmacokinetics

Bisphosphonates are rarely absorbed orally, and foods containing calcium and iron affect their absorption. Such as coffee and orange juice can reduce the absorption of alendronate by 60%, food can reduce its bioavailability by 40%, and conversely increase gastric pH, can increase its bioavailability by 200%. Their bioavailability is about 1% to 10%. The t1 / 2 in blood is about 15-60 minutes. 20% to 50% of the oral dose is retained in the bone mineralization site, and the rest is excreted by the urine. The rate of etidronate entering the bone is about the same as that of calcium and phosphate. The distribution volume of the drug is 0.3 to 1.3 L / Kg. Most bisphosphonates can be stored in bone tissue for a long time. So their t1 / 2 in the bone is very long. The intra-bone t1 / 2 of clodronic acid and pamidronic acid were 120 d and 300 d, respectively. Alendronate was excreted very slowly, and the half-life of its residues could be as long as 10 years. The other pharmacokinetic parameters of each bisphosphonic acid are also different. For example, the intraosseous distribution of clodronic acid and pamidronic acid are 30% and 67%, respectively, and 90% of the dose of alendronate is taken up by the bone 1 hour after oral administration, and maintains a high concentration in the bone tissue Up to 72 h. The excretion of the above three drugs in urine was 80% (within 48 h), 20% to 55% (within 72 h), and 50% (within 72 h). The protein binding rates of clodronate and pamidronate were 5% to 7% and 54%, respectively. It has been found in animal studies that trace amounts of bisphosphonates are distributed in extra-bone tissues such as liver, spleen and other tissues. This may be caused by calcium complexes engulfed by reticuloendothelial cells, but this is rarely the case in humans because bisphosphonates are rapidly cleared in vitro. About 66% of the oral bisphosphonate dose is cleared directly by the kidney, more than 95% of which is excreted by the kidney, and a small amount is secreted by the kidney. ^[4-5]

4. Bisphosphonate 4. Clinical application

Bisphosphonates are mainly used for osteoporosis and hypercalcemia caused by abnormal bone metabolism caused by bone metastases from malignant tumors such as multiple myeloma, breast cancer, prostate cancer and lung cancer, reducing bone disease and bone pain And the incidence of fractures, and can reduce the nausea, vomiting, polyuria, thirst, and central nervous symptoms associated with hypercalcemia, improve the quality of life of patients, and can also be used to prevent paget's disease.

5. Bisphosphonates 5. Development and market situation

First generation bisphosphonates: etidronate

Second-generation bisphosphonates: sodium clodronate, pamidronate, and tiludronate

The latest generation of bisphosphonates: alendronate, neridronate, sodium opadronate, risedronate, and ibandronate, zoledronate.

6. Bisphosphonates 6. Adverse reactions

The State Food and Drug Administration issued a warning on April 15, 2011 that bisphosphonate drugs may cause serious adverse reactions such as jaw necrosis, esophageal cancer, and renal failure. The medical staff, the public and pharmaceutical manufacturers are reminded to pay attention to the safety of bisphosphonate drugs and be alert to related risks.

It is understood that bisphosphonate drugs treat osteoporosis, malignant tumor bone metastases and hypercalcemia. Since 2005, the drug regulatory agencies of the United States, Britain, Canada and other countries have successively released safety information of bisphosphonate drugs, saying that some patients have symptoms such as jaw necrosis, severe musculoskeletal pain, esophageal cancer and renal failure after taking the drug. And it is recommended to modify the relevant drug instructions.

Recently, the National Center for Adverse Drug Reaction Monitoring reported the serious adverse reactions of bisphosphonate drugs in the latest issue of "Adverse Drug Reaction Information Bulletin", which mainly included fever, vomiting, rash, diarrhea, dizziness, abdominal pain, musculoskeletal pain , Headache, allergic reaction, chest pain, flu-like symptoms, ulcerative stomatitis, hypocalcemia, palpitations, anorexia, indigestion, edema, eye symptoms, etc. As of the end of February, the center had received 1,072 reports of related adverse reactions. Among them, 191 cases of skeletal muscle damage, 53 cases of esophageal damage, 20 cases of renal function damage, and 3 cases of mandibular damage.

The State Food and Drug Administration recommends that clinicians should closely monitor the health status of patients when using bisphosphonate drugs, adjust treatment plans for different conditions, and avoid or reduce the occurrence of adverse consequences. At the same time, it is recommended that manufacturers improve product specifications in a timely manner; inform drug safety information in detail; actively monitor and collect information on adverse reactions of varieties, and formulate a classified risk management plan to maximize the safety of medication for patients.