Bisphosphonates are an important component in the treatment of malignant neoplasms. In clinical practice, they are used to relieve hypercalcemia in multiple melanoma, metastases and tumors of the breast, and prostate cancer.
Drugs in this group significantly reduce the risk of complications in the skeletal system and prevent bone metastasis in breast cancer.
Bisphosphonates are chemical analogs of pyrophosphates (Zometa, Veroclas) that inhibit bone resorption by osteoclasts. The main enzyme in mevalonate metabolism is inhibited by potent nitrogen-containing bisphosphonates (risedronate, zoledronic acid).
Bisphosphonates for bone damage
When bone metastases are diagnosed, the patient often has pain, fractures, compression of nerve endings, and hypercalcemia. The most common cause of death in this group of patients is lesions of the skeletal system, and inclusion of bisphosphonates in the treatment regimen is indicated.
Based on X-ray characteristics, metastases are divided into two groups: osteoblastic and osteolytic. Considering that these two types are the complete opposite of each other, the number and activity of osteoblasts increases significantly in almost any metastasis, with the exception of osteoblastic metastases of prostate cancer.
Pathological activation of osteoclasts is the cause of complications. Bisphosphonates slightly reduce the risk of developing bone complications. For example, zoledronic acid reduces the incidence of bone complications in multiple melanoma and breast tumors with bone metastases. Zoledronic acid also reduces the risk of complications in patients with bone metastases of prostate cancer, lung cancer and other tumors.
Bisphosphonates have become quite firmly established in therapeutic practice as maintenance drugs, but specialists have not formed a consensus on the method of their use, timing of treatment, and dosage regimens.
Use of bisphosphonates for bone metastases
Bone metastases result from reciprocal interactions between tumor cells and metabolically active bone tissue. The processes of tumor cell adhesion to bone structures, invasion, neoangiogenesis and proliferation occur during the development of metastases.
After research has been done on bisphosphonates, it is assumed that they block all of the above processes. Three controlled studies of the effect of clodronate on the development of bone metastases in women with high-risk primary breast cancer have been conducted. In two of these studies, clodronate significantly reduced the risk of developing new bone metastases.
Additional studies continue to be conducted to evaluate the role of bisphosphonates as preventive therapy for breast cancer and other cancers.
Classification of bisphosphonates
Different types of these drugs are used to treat bone metastases, and each has its own characteristics in operation. Doctors are studying the mechanism of action of bisphosphonates. It is known for sure that:
- Bisphosphonates interfere with the process of creating osteoclasts.
- Program osteoclasts to self-destruct or early death.
- Changes signals between osteoclasts and osteoblasts.
- Form a barrier between bone and osteoclasts.
Researchers have found that bisphosphonates can prevent or slow the development of myeloma and secondary bone cancers in some people. Cancer cells appear to be attracted to areas where bones are broken. Scientists hope that stopping this process could slow the progression of the disease and help people live longer, as well as reduce bone damage.
The choice of drugs depends on the type of tumor. Are used:
- Clodronate (Bonefos)
- Pamidronate (Aredia)
- Zoledronic acid (Zometa)
- Ibandronate (Boniva).
List of bisphosphonate drugs for oncology
Pamidronate (Aredia)
Doctors in Israel prescribe Aredia to treat cancer that destroys bone cells or to treat bone metastases:
- with myeloma;
- for secondary breast cancer;
- with secondary prostate cancer.
The drug is also used for hypercalcemia caused by a tumor.
Pamidronate is administered intravenously using a cannula, central venous catheter, portacath, or PICC line. The procedure lasts from one to several hours, the duration is determined by the dose.
To lower blood calcium levels, treatment is given every 3 to 4 weeks to prevent or reduce bone damage.
During therapy, blood tests are regularly performed to check the amount of calcium in the blood, as well as urine tests to study the functioning of the heart and kidneys.
Common possible side effects:
- Signs of the flu.
- Hypocalcemia.
- Drowsiness and dizziness.
Less common potential side effects:
- Nausea.
- Stomach ache.
- Pain in muscles and joints.
- Insomnia.
- Skin rash.
- Problems with kidney function.
- Headache.
- Decreased platelets, anemia.
- Inflammation and redness of the eyes.
- Loss of appetite.
- Bone pain.
- Constipation or diarrhea.
- Blood pressure surges.
- Osteonecrosis.
- Arrhythmia.
Bisphosphonate drugs: Ibandronate (Boniva)
Used to prevent bone problems when they are weakened by cancer. The most common indication is secondary breast cancer; it is also prescribed for hypercalcemia.
The medicine enters the body in the form of tablets and intravenously. Ibandronate is taken with a full glass of water on an empty stomach 6 hours after meals. It is very important to follow the instructions carefully.
Ibandronic acid may also be administered intravenously through a cannula, catheter, port system, or PICC line. If the indication is a decrease in calcium levels, the procedure lasts from 1 to 2 hours. When the goal is to prevent or reduce bone damage, 15 minutes every three to four weeks.
When treated with these drugs, the body should have normal levels of vitamin D and calcium. If there is a deficiency, dietary supplements are prescribed.
Before starting therapy and during its course, blood tests are regularly performed to determine the amount of calcium in the blood and study the functioning of the liver and kidneys.
Common possible side effects include:
- fever;
- hypocalcemia;
- esophageal irritation;
- decreased skin sensitivity; headaches or dizziness;
- bone pain at the beginning of therapy.
Rare potential side effects include:
- leukopenia;
- thrush in the mouth;
- nausea;
- abdominal pain;
- stomach upset;
- taste changes;
- cataract;
- changes in the level of parathyroid hormones;
- disturbances in the functioning of the heart;
- bruising;
- diarrhea;
- inflammation of the bladder or vagina;
- signs of flu, etc.
Bisphosphonate drugs: Clodronate (Bonefos)
Israeli doctors use it to treat cancer symptoms affecting the bones, most commonly myeloma and secondary breast cancer. The drug is aimed at eliminating:
- hypercalcemia;
- osteolytic lesions;
- bone pain.
It is taken in tablets or capsules.
Common possible undesirable effects of therapy include:
- diarrhea;
- nausea;
- stomach upset;
- hypocalcemia;
- disturbances in liver function.
Rare potential side effects include:
- disorders of the kidneys;
- shortness of breath and cough;
- osteonecrosis;
- redness and peeling of the skin;
- femur fractures, etc.
Bisphosphonates: Zometa (zoledronic acid)
Zoledronic acid reduces the risk of fractures in myeloma, secondary breast and prostate cancer, and eliminates hypercalcemia.
The drug attaches to bone cells and slows the rate at which bone tissue changes.
Zoledronic acid is administered intravenously. If the main goal is to prevent bone damage, the drug is administered every 3-4 days. Calcium and vitamin D may be required. When treatment is aimed at eliminating hypercalcemia, medication is prescribed as the only treatment.
During therapy, blood tests are regularly performed to check the number of blood cells and other substances in the blood to study the functioning of the liver and kidneys.
Possible undesirable consequences include:
- flu symptoms;
- hypocalcemia;
- nausea;
- loss of appetite;
- anemia;
- conjunctivitis.
Less common potential side effects include:
- bone pain;
- pain in the stomach;
- difficulty sleeping;
- changes in mood;
- disorders of the kidneys;
- changes in blood pressure;
- constipation or diarrhea;
- allergic reactions;
- dizziness, drowsiness, fatigue, etc.
Bisphosphonates for osteoporosis
Medicines used to prevent and treat osteoporosis:
- alendronate (Fosamax);
- risedronate (Actonel);
- etidronate (Didrocal, Didronel).
How is treatment carried out in Israel?
Bisphosphonates enter the body in two ways. They can be taken orally or administered intravenously.
Take once or twice a day on an empty stomach. You should wait at least 30 minutes before consuming food, drinks, or taking any medications, including vitamins and mineral supplements. Bisphosphonate tablets and capsules are poorly absorbed if taken with food or milk, for example.
How long should you be treated with bisphosphonates?
Intravenous treatment is usually given every 3-4 weeks. The procedure lasts from 15 minutes to 4 hours, depending on the type of bisphosphonate. It can be done in a hospital setting or at home with the help of a nurse.
Follow-up
When drugs are prescribed to relieve bone pain caused by metastases, the doctor evaluates how much it has decreased and whether it is under control. Bisphosphonates can affect your kidneys, so your kidney function should be checked regularly.
If drugs are used to treat hypercalcemia, the doctor will check blood calcium levels to see if they have decreased and also determine how the patient responds to treatment. A study of kidney function is being carried out.
When bisphosphonates are used to prevent or treat osteoporosis, a bone mineral density test is performed to check the body's response to the drugs. The doctor evaluates the level of pain and weakness of the bone. The functioning of the kidneys is studied.
Hypercalcemia and bisphosphonates
The main cause of hypercalcemia is high calcium rejection from bone tissue. When bones are damaged by metastases, they are destroyed by osteoclasts and, as a result, active release of calcium occurs. Also, peptides produced by tumor tissue can activate osteoclasts and reduce calcium secretion by the kidneys.
The production of the peptide can occur in oncological pathologies: breast tumors, squamous cell carcinoma, multiple melanoma, some lymphomas. When you start taking the drugs, after a few days the patient’s calcium concentration in the blood stabilizes.
In randomized trials, it was found that normal calcium levels were observed more often and lasted longer with the use of the drug zoledronic acid and bandronate, in contrast to pamidronate, although the difference was small.
Side effects of bisphosphonates
Most often, transient flu-like phenomena such as fever, arthralgia, and myalgia occur within 24 hours after intravenous administration of bisphosphonates. Asymptomatic hypocalcemia may also occur. To prevent it, it is recommended to use calcium in a dosage of 500-1000 mg/day and vitamin D 400 IU/day orally.
Parenteral administration can be prescribed only in cases of vitamin D deficiency and persistent hypocalcemia. Bisphosphonates are nephrotoxic, the degree of damage they cause to the kidneys depends on the dose and number of intravenous injections. These drugs cannot be prescribed if creatinine clearance is less than 30 ml/min. Also, doses should be reduced if clearance ranges from 30-60 ml/min.
Before each prescribed course of treatment, it is necessary to monitor the concentration of creatinine in the blood plasma. When prescribing zoledronic acid, less commonly other bisphosphonates, osteonecrosis of the mandible may occur. Patients who have a history of oral diseases are more prone to this complication.
To reduce the risk of complications, regular sanitation of the oral cavity, preventive dental examinations, as well as avoidance of surgical interventions for the entire course of treatment are necessary.
Drugs
Oncologists have three generations of bisphosphonates in their arsenal to treat complications of metastases:
- Clodronate,
- Pamidronate,
- Ibandronate and zoledronate.
All bisphosphonate drugs, regardless of generation, prevent pathological destruction of bone tissue. But bisphosphonates do not affect metastases in other organs and tissues because they do not kill malignant cells. When used, the percentage of bone complications is reduced by a third.
Bisphosphonates have been used for two decades, but it has not been possible to determine which drug is better and which should be preferred to treat complications of metastases.
- Clodronate (Bonefos™) is available in the form of capsules, 4 capsules are taken on an empty stomach at once - the daily norm, they are washed down only with clean water, for an hour after this you should not eat or take other medications so as not to inactivate the medicine.
- Ibandronate (Bandronat™) tablet is taken once in the morning an hour before meals and washed down with a glass of water, the inconvenience is that you cannot lie down for an hour after taking it. It can also be administered intravenously 15 minutes every three to four weeks.
- Pamidronate (Aredia™) should be injected into a vein over at least 2–4 hours in half a liter of saline.
- Zoledronic acid (Zometa™) is also administered intravenously over 15 minutes in 100 ml of solution, and preliminary dehydration is not allowed, for example, after taking diuretics. After a year of treatment, the drug can be used only once every 3 months.
In case of multiple metastases with severe pain, intravenous administration of bisphosphonates is advisable, since in this form they are less susceptible to inactivation by food.
