The effect of zoledronic acid on the life expectancy of patients with metastatic bone lesions from lung cancer against the background of increased titers of markers of osteoclast activity. Zoledronic acid: instructions for use Zoledronic acid release form

Zoledronic acid belongs to a group of substances called bisphosphonates. Zoledronic acid slows the progression of bone changes and is used for:
- to prevent the development of bone complications, such as fractures, in adult patients with bone metastases (spread of cancer from the primary site to the bone);
- to reduce the amount of calcium in the blood in adult patients in whom it is too high due to the presence of a tumor. Tumors can accelerate normal changes in bone in such a way that the release of calcium from the bone increases. This condition is known as tumor-induced hypercalcemia (TIH).

Do not take this medicine if

You are allergic to ZOLEDRONIC ACID or any of the other ingredients of the drug listed in the Composition section.
You are pregnant.
You are planning a pregnancy or are not using adequate contraceptive methods.
You are breastfeeding.
If any of the above applies to you, tell your doctor before starting treatment with Zoledronic Acid.
Zoledronic acid is not recommended for use in children (under 18 years of age).

Special instructions and precautions

Before starting treatment with Zoledronic Acid, tell your doctor:
- If you have or have had kidney problems.
- If you have or have had pain, swelling or numbness in your jaw, a feeling of heaviness in your jaw or loose teeth. Your doctor may recommend a dental examination before starting ZOLEDRONIC ACID treatment.
- If you have had dental treatment or need dental surgery, tell your dentist that you need ZOLEDRONIC ACID treatment and tell your doctor about the need for dental treatment.
During treatment with ZOLEDRONAIC ACID, you should maintain good oral hygiene (including regular tooth brushing) and undergo routine dental checkups.
Contact your doctor or dentist right away if you have problems with your mouth or teeth, such as loose teeth, pain or swelling, or sores or discharge in your mouth that won't heal, as these may be signs of a condition called osteonecrosis of the jaw. .
Patients who require chemotherapy and/or radiation therapy, dental surgery, have gum disease, take steroids, smoke, do not receive routine dental care, or have previously taken bisphosphonates (used for treatment or prevention of bone diseases).
In patients taking ZOLEDRONIC ACID, a decrease in calcium levels in the blood (hypocalcemia) can sometimes lead to muscle cramps, dry skin, and a burning sensation. Irregular heartbeat (cardiac arrhythmia), seizures, spasms, and twitching (tetany) have been reported as secondary manifestations of severe hypocalcemia. In some cases, hypocalcemia can be life-threatening.
If any of the above applies to you, tell your doctor immediately.
If you already have hypocalcemia, it should be treated before starting ZOLEDRONIC ACID treatment. You should receive additional calcium supplements and vitamin D.
Patients aged 65 years and older
Treatment with ZOLEDRONIC ACID can be used in patients aged 65 years and older. There is no evidence that additional precautions are necessary.
Children and teenagers
ZOLEDRONIC ACID is not recommended for use in children and adolescents under 18 years of age.

Other drugs and ZOLEDRONIC ACID

Tell your doctor if you are taking, have recently taken, or are about to take any other medications. This applies to any herbal medicines or medicines that you have purchased without a prescription.
There are some medications that may change the effect of ZOLEDRONIC ACID, or their effect may be altered by ZOLEDRONIC ACID. Tell your doctor if you are taking any other medicines.
It is especially important to tell your doctor if you are already taking any of the following medications:
- Aminoglycosides (medicines used to treat severe infection), calcitonin (medicine to treat postmenopausal osteoporosis and hypercalcemia), loop diuretics (medicines to treat high blood pressure or edema) or other drugs that lower calcium levels, as they are combined with bisphosphonates can cause a very strong decrease in calcium levels in the blood.
- Thalidomide (a medicine used to treat a certain type of blood cancer that affects the bone) or any other medicines that may harm your kidneys.
- Aclasta (a medicine that also contains zoledronic acid and is used to treat osteoporosis and other non-cancerous bone diseases) or any other bisphosphonates, since the combined effects of these medicines when taken together with ZOLEDRONIC ACID are unknown.
- Antiangiogenic drugs (used to treat cancer), as their combination with ZOLEDRONIC ACID is associated with an increased risk of osteonecrosis of the jaw.
If this applies to you, seek advice from your doctor.

Pregnancy, breastfeeding and fertility

Do not take Zoledronic Acid if you are pregnant or breastfeeding.
If you think you are pregnant or planning to have a baby, consult your doctor or pharmacist before taking this medicine.

Driving vehicles and working with machinery

Due to the risk of developing adverse reactions, such as dizziness and drowsiness, when using the drug, during treatment it is necessary to avoid driving vehicles and engaging in activities that require increased concentration.

Application

Zoledronic acid therapy will be prescribed and monitored by a physician experienced in the use of intravenous bisphosphonates.
- Your doctor will recommend that you drink enough fluids before each treatment to prevent dehydration.
- Follow all other instructions given to you by your doctor or nurse carefully.
- If in doubt, consult your doctor.
How much ZOLEDRONIC ACID should you take?
- The usual single dose is 4 mg.
- If you have kidney problems, your doctor will prescribe a lower dose depending on the severity of your kidney disease.
Duration of use of ZOLEDRONIC ACID
- If you are receiving treatment to prevent skeletal complications due to bone metastases, a single infusion of Zoledronic Acid will be given every three to four weeks.
- If you are receiving treatment to reduce calcium levels in the blood, a single infusion of ZOLEDRONIC ACID is prescribed.
Introduction of Zoledronic Acid
- ZOLEDRONIC ACID is administered drip (infusion) into a vein over at least 15 minutes, as a single infusion using a separate infusion system.
Patients who have low blood calcium levels will also be prescribed daily calcium and vitamin D supplements.
If you receive more medicine than prescribed
Given that the drug will be administered by qualified medical personnel, overdose is unlikely. However, if you have received doses higher than recommended, your doctor will monitor you very closely. This is because you may develop serum electrolyte imbalances (such as abnormal levels of calcium, phosphorus, and magnesium) and/or changes in kidney function, including severe kidney failure. If your calcium levels drop too much, you may need to take extra calcium supplements.
If you have any additional questions about using this drug, ask your doctor.

Possible adverse reactions

Like all medicines, ZOLEDRONIC ACID can cause side effects, although not everyone gets them.
If you experience any of the following serious side effects after receiving ZOLEDRONIC ACID, seek immediate medical attention.
Often
- Severe kidney failure (usually determined by a doctor using certain blood tests).
- Decrease in calcium levels in the blood.
Infrequently
- Pain in the mouth, teeth and/or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness or heaviness in the jaw or loosening of teeth. This may be a sign of damage to the bones in the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience any of these symptoms during treatment with ZOLEDRONIC ACID or after stopping treatment.
- Irregular heart rhythm (atrial fibrillation) has been observed in patients receiving zoledronic acid for the treatment of postmenopausal osteoporosis. It is currently unclear whether ZOLEDRONIC ACID causes irregular heart rhythm, but you should tell your doctor if you experience such symptoms after you have received ZOLEDRONIC ACID.
- Severe allergic reaction: shortness of breath, swelling, mainly of the face and throat.
Rarely
- As a consequence of low calcium levels: irregular heart rhythm (cardiac arrhythmia secondary to hypocalcemia).
- A kidney disorder called Fanconi syndrome (usually determined by a doctor using certain urine tests).
Very rarely
- As a consequence of low calcium values: cramps, numbness and tetany (secondary to hypocalcemia).
- Tell your doctor if you have ear pain, ear discharge and/or ear infection. This may be a sign of damage to the inner ear bones.
- Osteonecrosis of other bones, especially the hip joint or femur. Tell your doctor immediately if you experience these symptoms for the first time or if you experience increased pain, pain, or stiffness while using ZOLEDRONIC ACID or after stopping treatment.
Also, tell your doctor immediately if you experience any of the following side effects:
Often(may affect more than 1 in 10 people):
- Low levels of phosphate in the blood.
Often(may affect less than 1 in 10 people):
- Headache and flu-like syndrome, including fever, fatigue, weakness, drowsiness, bone aches, joint and/or muscle pain. In most cases, no specific treatment is required and symptoms disappear after a short time (a couple of hours or days).
- Gastrointestinal reactions such as nausea and vomiting, as well as loss of appetite.
- Conjunctivitis.
- Low level of red blood cells (anemia).
Infrequently(may affect less than 1 in 100 people):
- Hypersensitivity reactions.
- Low blood pressure.
- Chest pain.
- Skin reactions (redness and swelling) at the infusion site, rash, itching.
- High blood pressure, shortness of breath, dizziness, anxiety, sleep disturbances, taste disturbances, trembling, tingling or numbness in the hands or feet, diarrhea, constipation, abdominal pain, dry mouth.
- Low levels of white blood cells and platelets.
- Low levels of magnesium and potassium in the blood. Your doctor will monitor these values ​​and take necessary measures.
- Weight gain.
- Increased sweating.
- Drowsiness.
- Blurred vision, lacrimation, eye sensitivity to light.
- Sudden feeling of cold with fainting, lameness or collapse.
- Difficulty breathing with wheezing or coughing.
- Hives.
Rarely(may affect less than 1 in 1,000 people):
- Slow heartbeat.
- Confusion.
- Unusual fracture of the femur, especially in patients with long-term treatment for osteoporosis. Tell your doctor if you experience pain, weakness, or discomfort in your hip, hip, or groin area, as this may be an early sign of a possible femur fracture.
- Interstitial lung disease (inflammation of the tissue around the alveoli of the lungs).
- Flu-like symptoms, including arthritis and joint swelling.
- Painful redness and/or swelling of the eyes.
Very rarely(may affect less than 1 in 10,000 people):
- Fainting due to low blood pressure.
- Severe pain in bones, joints and/or muscles.
If any of these side effects worsen, or if you experience an side effect not listed in this leaflet, please tell your doctor.
Reporting Adverse Reactions
You can also report adverse reactions to the information database on adverse reactions (actions) to drugs, including reports of ineffectiveness of drugs identified in the state (UE “Center for Expertise and Testing in Healthcare M3 RB”, website rceth.by) . By reporting adverse reactions, you can help provide more information about the safety of the drug.

Zoledronic acid: instructions for use and reviews

Latin name: Zoledronic acid

ATX code: M05BA08

Active substance: zoledronic acid

Manufacturer: Farmidea LLC (Latvia), Biocad CJSC, Pharm-Sintez CJSC (Russia), Bion LLC (Russia)

Updating the description and photo: 18.10.2018

Instructions:

Clinical and pharmacological groups

pharmachologic effect

Bone resorption inhibitor, bisphosphonate. Has a selective effect on bone. It has an inhibitory effect on bone resorption mediated by osteoclasts.

The selective effect of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue, but the exact molecular mechanism that provides inhibition of osteoclast activity remains unclear.

In addition to its inhibitory effect on bone resorption, zoledronic acid has other antitumor properties that provide therapeutic efficacy in bone metastases.

In vivo: inhibition of osteoclastic bone resorption, changing the microenvironment of the bone marrow, leading to a decrease in the growth of tumor cells; antiangiogenic activity. Suppression of bone resorption is clinically accompanied by a pronounced decrease in pain.

In vitro: inhibition of osteoblast proliferation, direct cytotoxic and proapoptotic activity, synergistic cytostatic effect with antitumor drugs; anti-adhesive/invasive activity.

Zoledronic acid, by inhibiting proliferation and inducing apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer, and also reduces the penetration of breast cancer cells through the extracellular matrix, which indicates the presence of antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human endothelial cells and causes an antiangiogenic effect in animals.

In patients with tumor-induced hypercalcemia, zoledronic acid has been shown to act by decreasing serum calcium concentrations and decreasing urinary calcium excretion.

Pharmacokinetics

Once the infusion is started, serum concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in concentrations of 10% after 4 hours and less than 1% after 24 hours, with a successively prolonged period of low concentrations not exceeding 0.1% from the maximum to repeated infusion on the 28th day.

Zoledronic acid administered intravenously is excreted by the kidneys in 3 stages: rapid two-phase elimination of the drug from the systemic circulation with T1/2 of 0.24 hours and 1.87 hours and a long phase with a final T1/2 of 146 hours. No accumulation was noted with repeated administrations every 28 days.

Zoledronic acid does not undergo systemic metabolism and is excreted unchanged by the kidneys. During the first 24 hours, 39±16% of the administered dose is found in the urine. The remaining amount is mainly associated with bone tissue. Zoledronic acid is then slowly released back from bone tissue into the systemic circulation and excreted by the kidneys. The total plasma clearance is 5.04±2.5 l/h. Increasing the infusion time from 5 to 15 minutes resulted in a 30% decrease in zoledronic acid concentration at the end of the infusion but had no effect on AUC.

Less than 3% is excreted in feces.

Renal clearance of zoledronic acid is positively correlated with creatinine clearance.

Zoledronic acid has been shown to have a low affinity for blood components. Plasma protein binding is low (about 50%) and does not depend on the concentration of zoledronic acid.

Dosage

Drug interactions

When bisphosphonates and aminoglycosides are used concomitantly, serum calcium levels may remain depressed for longer than required because additive effects on serum calcium concentrations are possible.

When used simultaneously with drugs that potentially have nephrotoxic effects, the risk of deterioration of renal function increases.

Side effects

From the hematopoietic organs: sometimes - thrombocytopenia, anemia, leukopenia; rarely - pancytopenia.

From the central and peripheral nervous system: often - headache; sometimes - weakness, paresthesia, impaired taste, hypoesthesia, hyperesthesia, tremor.

From the mental side: sometimes - anxiety, sleep disorders; rarely - confusion.

From the organ of vision: often - conjunctivitis; sometimes - blurred vision.

From the digestive system: often - nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system: sometimes - dyspnea, cough.

Dermatological reactions: sometimes - itching, rash (including erythematous and macular), increased sweating.

From the musculoskeletal system: often - bone pain, myalgia, arthralgia; sometimes - muscle cramps.

From the cardiovascular system: rarely - bradycardia.

From the kidneys: often - impaired renal function; sometimes - acute renal failure, hematuria, proteinuria.

Allergic reactions: sometimes - hypersensitivity reactions; rarely - angioedema.

From the body as a whole: often - fever, flu-like syndrome, manifested by fever, chills, pain in the bones and/or muscles; sometimes - asthenia, peripheral edema, chest pain, weight gain.

Local reactions: sometimes - pain, irritation, swelling and formation of infiltrate at the injection site.

From laboratory parameters: very often - hypophosphatemia; often - increased levels of creatinine and urea in the blood serum, hypocalcemia; sometimes - hypomagnesemia; rarely - hyperkalemia, hypokalemia, hypernatremia.

Indications

Osteolytic, osteoblastic and mixed bone metastases of solid tumors and osteolytic foci in multiple myeloma, as part of combination therapy; hypercalcemia caused by a malignant tumor.

Contraindications

Pregnancy; lactation (breastfeeding); hypersensitivity to zoledronic acid and other bisphosphonates.

special instructions

When repeated use, the concentration of creatinine in the blood serum should be determined before each administration. If the data obtained indicate a deterioration in renal function, it is necessary to evaluate the risks and benefits of the therapy.

It is not recommended for use in patients with severely impaired renal function (serum creatinine concentration ≥400 µmol/L or ≥4.5 mg/dL) unless the expected benefit of therapy outweighs the potential risk.

Before infusion, the patient should be excluded from dehydration. To ensure adequate hydration, administration of saline before, during, or after the zoledronic acid infusion is recommended. Overhydration of the patient should be avoided due to the risk of cardiovascular complications.

After administration of zoledronova, constant monitoring of the concentrations of calcium, phosphorus, magnesium and creatinine in the blood serum is necessary.

If hypocalcemia, hypophosphatemia, or hypomagnesemia develops, short-term maintenance therapy is necessary.

There are isolated reports of renal dysfunction associated with the use of bisphosphonates. Risk factors for the development of such complications include previous renal failure and long-term use of zoledronic acid in high doses (8 mg), reducing infusion time.

The effectiveness and safety of zoledronic acid in pediatric practice have not been established.

Preparations containing ZOLEDRONIC ACID

Zoledronic acid, first patented by Swiss scientists from Novartis, is currently marketed under a variety of names. The drug has become widespread as an element of complex therapy for osteochondrosis. It is used quite successfully in the treatment of certain types of malignant neoplasms. The product stops the processes of bone resorption. It is sold in bottles containing white powder or a porous mass that absorbs liquid well.

Pharmacology

As indicated in the instructions for zoledronic acid, the use of the drug is possible in situations where aminobisphosphonates are indicated. These compounds, and especially the drug in question, have a pronounced selective effect on bone tissue. Scientists have not yet fully figured out exactly how the drug works, by what mechanism it affects the human body, but they have been able to prove that the active substance has an affinity for mineralized bones, and therefore can inhibit degenerative processes. At the same time, clinical trials have shown that zoledronic acid does not have a negative effect on the formation of bone tissue, does not correct its chemical composition, elasticity, or physical strength.

Once in the human body, the substance quickly affects the bone marrow at the microscopic level. This stops the development of atypical cell formations. According to the instructions for use, zoledronic acid simultaneously eliminates pain and fights tumors. In parallel, inhibition of the formation of endothelial cells is observed. If a cancerous tumor is associated with excess calcium, the concentration of this component under the influence of the drug in question gradually returns to normal, which improves the quality of functioning of the vascular system.

Osteoporosis: effective and efficient

Zoledronic acid preparations are widely used in the treatment of osteoporosis in patients of different age groups. Taking the medication correctly helps normalize metabolic processes. In a short period of time, the indicators stabilize to the biological human norm, then they are maintained in this state for a long period. On average, under the influence of the drug, metabolic parameters characteristic of premenopause are established. Carrying out annual infusions does not result in progress in reducing the number of metabolic markers in the tissues of the skeletal system.

Pharmacokinetics

Treatment with zoledronic acid involves intravenous infusion of powder dissolved in a special liquid (the acid is practically insoluble in water). Immediately after the start of the procedure, a sharp increase in the concentration of the substance in the blood plasma is observed. The highest indicator is recorded by the time the infusion is completed. The decrease in concentration is also rapid; after only a day, zoledronic acid decreases in concentration and reaches no more than one percent relative to the maximum value obtained at the time of infusion. For a long period of time in the circulatory system, the substance is present in an amount of 0.1% of the largest.

No cumulative effect is observed. The use of zoledronic acid must strictly comply with the rules for using the drug. This takes into account that the substance is excreted from the body in the urine. The process is three-step. The first step is 0.25-1.87 hours, then the second step is longer. The overall estimated half-life is 146 hours.

When will it help?

The use of zoledronic acid is indicated for:

1. Osteoporosis diagnosed during the period after menopause.
2. Osteoporosis caused by long-term use of glucocorticosteroids.
3. Osteodystrophy, causing deformation.

In the postmenopausal period, zoledronic acid helps prevent fractures caused by decreased skeletal strength.

Preparations based on this compound have shown good results as part of a therapeutic course for excess calcium in the body. This is often observed against the background of malignant tumor processes, cancer that has metastasized into bone tissue.

Absolutely not

As indicated in the instructions, zoledronic acid is not used if the patient has an allergic reaction to this substance or hypersensitivity to it. It is unacceptable to undergo treatment while pregnant or breastfeeding. Zoledronic acid is not approved for the treatment of minor patients and persons in whose body a calcium deficiency has been established. The composition cannot be used if the kidneys are not functioning actively enough; creatine clearance is estimated at 35 ml/min or less.

It's possible, but very carefully

The instructions for zoledronic acid contain instructions on the possibility of using the medication for severe liver diseases, but only in conditions where it is possible to constantly monitor the patient’s condition and measure functioning indicators that are important for life. Similar conditions apply to the use of medication for aspirin-induced bronchial asthma. In these cases, the doctor first analyzes how great the risks are for the patient and what positive aspects are associated with the use of this particular medication, then introduces the patient to the possible dangers and consequences of the course of treatment. Only on the basis of a detailed analysis can a final decision be made about the wisdom of using zoledronic acid in this case.

Special case

Zoledronic acid cannot be used to treat minor patients, since there is no official information to indicate its safety. There is no information confirming the effectiveness of drugs based on this substance. For similar reasons, the drug is not used in the treatment of pregnant and nursing mothers. There is no information about what consequences the use of the medication may cause in patients suffering from impaired renal or liver function. In general, acid treatment is not recommended, although occasionally doctors may offer this option, but only by justifying it with really important arguments.

According to reviews, zoledronic acid is used in the treatment of people who have kidney abnormalities. If the creatine clearance exceeds 35 ml/min, you can safely use the medication without adjusting the standard regimen.

Negative phenomena

It is known that the use of the described medication can cause a negative response from the body. Medical practice has clearly established the following possible side effects when consuming zoledronic acid:

• It hurts and I feel dizzy.
• The patient is worried and anxious.
• Temporary clouding of consciousness.
• Sleep disturbance.
• Shortness of breath and cough.
• Abnormal stool, abdominal pain.
• Inflammatory processes of the mucous membrane.
• Deterioration in the quality of vision.

From the reviews formulated by experts: zoledronic acid can cause taste disturbances, lethargy, anorexia, and glaucoma. There are cases where the drug provoked skin rashes, kidney failure, and allergic reactions. Under the influence of the active component, a disturbance in pressure (up or down relative to the norm) and a weakening of the heart rhythm may be observed.

More often, a negative response from the body is felt at the beginning of the therapeutic course. As can be seen from patient reviews, zoledronic acid first causes a feverish state and pain that disappears within 72 hours after the first administration of the substance.

How to use?

The drug is most often used, as mentioned above, in the treatment of osteoporosis and oncology. Zoledronic acid should be used strictly under the supervision of a doctor. This connection should not be used at home. It is not allowed to use acid-based medications on your own.

According to the rules, the substance is injected into a vein, the infusion lasts more than a quarter of an hour. The solution must be prepared in absolute sterility. The standard dose involves diluting 4 g of the substance in 5 ml of liquid. The finished product is mixed with 100 ml of saline or dextrose (concentration - 5%). The finished product must be used immediately; storage is not allowed. The composition is recommended to be used once a year.

Important aspects

As can be seen from patient reviews, zoledronic acid in oncology and the treatment of osteoporosis is used strictly under the supervision of a doctor, otherwise there is a high probability of side effects and deterioration of the patient’s condition. Before starting the procedure, the doctor makes sure that the patient drinks enough fluids. This is also required during the treatment process. It is important to ensure the flow of fluid in an adequate volume, avoiding its excess, so the drinking process is under the supervision of a doctor, and specific amounts are calculated taking into account the individual characteristics of the patient.

It is necessary to analyze the patient's diet. If a person does not receive enough vitamin D or calcium from food, it is important to provide an additional supply of these compounds to prevent their deficiency.

Too much!

If too much is administered, signs of overdose are observed. Zoledronic acid negatively affects the functioning of the kidneys; laboratory tests show a lack of magnesium, phosphorus, and calcium deficiency. The main task of the doctor is the symptomatic treatment of mineral deficiency in the tissues of the body. The patient is immediately given injections of magnesium sulfate, calcium gluconate, potassium, and sodium phosphate. Calcium can be taken orally.

Combine: how to do it right?

It is unacceptable to mix zoledronic acid and other substances and compounds in a syringe. When using the drug and some types of diuretics, there is a possibility of mineral deficiency, so it is important to monitor the patient’s condition. A similar effect is observed when combined with aminocyclitols.

If plasmacytoma is diagnosed in a generalized form, and the therapeutic course involves the use of Thalidomide, the use of zoledronic acid is highly likely to cause a failure of renal function.

It is unacceptable to drink alcohol during treatment.

Note!

It is not permitted to use substances containing calcium cations as a solvent for zoledronic acid. During therapy, the doctor must monitor the patient’s condition, check the concentration of phosphorus, calcium, and magnesium in the body. It is necessary to regularly take a test for creatine clearance. It is important to inform the patient how mineral deficiency in the body is expressed and how to behave at the first suspicion of such changes. If the patient is at risk for mineral deficiency, it is important to closely monitor the client's condition at all times.

At the beginning of the therapeutic course, you can take specialized drugs to alleviate side effects after the first administration. The most common and effective are substances based on ibuprofen and paracetamol. The first ones are presented on pharmacy shelves under the trade names “Nurofen”, “Mig”, the second category is “Panadol” and its analogues.

Since zoledronic acid can have a negative effect on the central nervous system, when undergoing treatment with this drug it is wise to refrain from driving and also avoid tasks that require increased alertness and concentration.

Analogs

Zoledronic acid is an active component of pharmaceutical products:

• "Rezorba";
• "Aklasta".

In some cases, experts advise choosing the drug Belklasta.

When choosing a specific name, you should consult your doctor.

In some cases, zoledronic acid can be replaced with other drugs from the bisphosphonate group. On pharmacy shelves they are presented under the trade names “Bonefos” and “Bonviva”. The drug Ibandronate-Teva has a good reputation. Under no circumstances should you independently replace prescribed zoledronic acid with these medications; be sure to coordinate this step with your doctor.

The fight against cancer: taking it to the next level

According to reviews, zoledronic acid in oncology has become almost a breakthrough. The product presented on pharmacy shelves as “Rezoscan” deserves special attention. This drug is the first on our planet from the category of commercial radiopharmaceuticals, created specifically for identifying pathologies of the skeletal system using modern nuclear technologies. The main substance of Rezoscan is the zoledronic acid in question. Rezoscan differs from all other radiopharmaceutical medicines in its main component. As a targeted carrier, the manufacturer used an acid that has the highest level (when compared with other bisphosphonates) of affinity for areas of high resorption. This helps to quickly and accurately determine the presence of metastases and localize them. "Rezoscan" shows reliable results in the study of patients with different types of tumors, provoked by different factors and developed in different areas of the body.

Osteoscintigraphy

Using Rezoscan, you can quickly detect lytic metastasis by performing primary diagnostics. This is especially true if a tumor is detected in the prostate gland. Based on the information obtained from the study, zoledronic acid injection can be prescribed. This allows you to start therapy in a timely manner, which means achieving maximum effect and preventing the occurrence of metastases in the future.

Using Rezoscan, you can differentially diagnose degenerative changes caused by oncology and other factors. The accuracy of such information is the key to a successfully chosen therapeutic course. Diagnostic methods involving the use of Rezoscan help to accurately identify all the features of the patient’s condition if destructive processes in bone tissue are associated with factors that have nothing to do with oncology. This makes the product an important doctor’s assistant in identifying the characteristics of joint pathologies and spinal diseases.

Oncology: how does it work?

The use of zoledronic acid in the treatment of cancer patients shows good results when the course is started in a timely manner. In some cases, drugs based on this substance are the main component of therapy, but can act as an auxiliary item in the rehabilitation period after chemotherapy.

Like other bisphosphonates, zoledronic acid simultaneously stops the proliferation of atypical cells and prevents bone destruction. However, it was not possible to detect negative changes in body tissues caused by the substance. Zoledronic acid is considered safe if used according to the instructions, taking into account contraindications. Indeed, taking it is often associated with side effects, but they are all short-term and pass quickly, and there is no cumulative effect.

When treating cancer, zoledronic acid is prescribed in a course, the duration of the program is up to a month. The doctor should choose the features, focusing on the type of malignant neoplasm, the patient’s condition and the body’s response to therapy. In some cases, the duration is up to nine months, one and a half years. If excess calcium is detected in the body, the frequency of procedures is reduced.

For quotation: Hirsch W., Major P.P., Lipton A., Cook R.D., Langer K.D., Smith M.R., Brown J.E., Coleman R.E. The effect of zoledronic acid on the life expectancy of patients with metastatic bone lesions from lung cancer against the background of increased titers of osteoclast activity markers // RMZh. 2008. No. 13. P. 949

Of all cancers, lung cancer is the most common; the most common type is non-small cell lung cancer (NSCLC). Late stages of NSCLC are often characterized by vivid clinical symptoms, and in 30-40% of patients the tumor metastasizes to the bones. In such cases, damage to bone tissue can lead to a decrease in the patient's functional activity and loss of the ability to move. Progression of bone metastases can trigger disabling skeletal-related events (SREs, also called complications of bone metastases) such as pathological fractures and bone pain, requiring palliative radiotherapy. SREs not only participate in the formation of the clinical picture of the underlying disease; when they occur, the cost of treatment increases and the quality of life decreases. Moreover, the occurrence of pathological fractures is associated with a significant increase in the risk of death in patients with malignant processes in bone tissue in multiple myeloma and with metastases of breast or prostate cancer in the bones. Although, due to the short average life expectancy of patients with lung cancer and other aggressive solid tumors, there was no significant correlation between the occurrence of fractures and the incidence of death, the risk of death in the event of a pathological fracture increases even with a positive effect from treatment of the primary tumor. Therefore, preventing SRE not only helps improve quality of life, but also potentially increases life expectancy.

Against the background of the occurrence of metastases in bone tissue, metabolism usually increases, as evidenced by an increase in biochemical markers. For example, an increase in the level of bone fraction of alkaline phosphatase (ALP) in blood serum is noted in the process of bone tissue formation, and type I collagen N-telopeptide (NTX) is a sensitive marker of osteolysis. These markers serve as indicators of the degree of aggressiveness of bone metastases. According to the results of an analysis of placebo-controlled phase III clinical trials of zoledronic acid, the occurrence of bone metastases and an increase in NTX titer (≤50 nmol/mmol creatinine) approximately doubles the risk of developing SRE and progression of bone tissue damage, while the likelihood of death increases 3-5 times compared to patients whose NTX levels remain low (in all cases p<0,01) . От-но-сительный риск появления SRE и смерти повышается и с нарастанием содержания костной фракции ЩФ сыворотки крови. Прогностически значимы также и маркеры костной ткани, оцениваемые на фоне лечения бисфосфонатами .
Bisphosphonates are bone resorption inhibitors used in oncology to prevent SRE in patients with bone metastases and treat hypercalcemia associated with malignant neoplasms. The only drug for the prevention of SRE in solid tumors - breast cancer, prostate cancer, lung cancer - with proven effectiveness is zoledronic acid (ZOMETA, Novartis Pharmaceutical Corporation, East Hanover, USA; Novartis Pharma AG, Basel, Switzerland). In patients with bone metastases from lung cancer and other aggressive solid tumors, zoledronic acid (4 mg IV over 15 minutes every 3 weeks for up to 21 months) has been shown to significantly delay the onset of SRE and reduce the risk of developing it in a multicenter, randomized, placebo-controlled, phase III trial. compared to placebo. Zoledronic acid also significantly reduced NTX titer relative to baseline. Approximately half of the patients enrolled in the study had a diagnosis of NSCLC, and the 1-year survival rate was approximately 30%. However, in patients with NSCLC, the correlation between baseline NTX levels (currently considered the upper limit of normal in cancer patients to be 64 nmol/mmol creatinine) and disease outcomes has not been specifically assessed. It is necessary to develop a prognostic model for the life expectancy of patients with bone metastases of NSCLC. Moreover, although survival was not the primary objective of this study, patients in the study group lived an average of 1 month longer compared with placebo (not statistically significant).
The present study (a phase III randomized, placebo-controlled clinical trial) was initiated to determine whether bone turnover markers have prognostic significance in patients with NSCLC treated with zoledronic acid and whether the statistically insignificant increase in life expectancy in patients of the study group is due to Compared with placebo, zoledronic acid is more effective in this cohort of patients than in the general NSCLC population.
Patients and methods
This phase III, multicenter, randomized, placebo-controlled trial was a retrospective analysis of patients with bone metastases from NSCLC and other solid tumors (excluding breast and prostate cancer) treated with zoledronic acid. The study design has been described in detail previously and is briefly described below.
Patients and treatment
Patients with diagnosed metastases of NSCLC and other solid tumors (except breast and prostate cancer) to bone tissue were selected to participate in the study. Before starting treatment, initial clinical characteristics were assessed, X-ray examinations were performed, the general condition of the patients was assessed according to the Eastern Cooperative Oncology Group (ECOG) scale, and the profile of biochemical parameters of blood and urine was examined. After randomization, patients were treated with zoledronic acid (4 mg or 8 mg) or placebo as 15-minute infusions every 3 weeks for 9 months. After completion of the main phase of the study, patients were offered to continue treatment in accordance with randomization for another year. The final analysis was carried out after 21 months. After the start of the study, the initial dose of zoledronic acid (8 mg) was reduced to 4 mg in order to avoid renal complications (zoledronic acid 8/4 mg group). In most cases, patients in this cohort received 4 mg infusions, and outcomes were similar between 4 mg and 8/4 mg doses. Thus, the analysis of the results of this study (as well as previous experiments) included data from both groups.
Patients with NSCLC treated with zoledronic acid or placebo were included in a retrospective analysis based on baseline NTX levels.
Research objectives
The primary objective of the prospective study was to determine the proportion of patients who developed SRE. SRE as an event served as a measure of objective assessment of the course of pathology of the skeletal system and the clinical significance of complications of bone metastases. The study determined survival rates, since this parameter is universal in clinical studies in oncology and is not affected by errors during observations. The rate of progression of bone metastases was also analyzed, since this indicator was variably correlated with an increase in the level of bone markers, although this indicator is influenced by the frequency of radiological examinations (approximately every 3 months).
Bone turnover markers
Baseline urinary NTX levels were measured only in study participants who received treatment in the United States or Canada. Determination of the initial level of NTX was carried out using the immunosorbent method with immobilized enzymes, normalized by urine creatinine and distributed into the following categories depending on the value of the indicator: low NTX -<64 нмоль/ммоль креатинина, высокий NTX - ?64 нмоль/ммоль креатинина (в соответствии с верхней границей нормы NTX у клинически здоровых женщин пременопаузального возраста). Титр костной фракции ЩФ сыворотки крови определяли тем же методом.
Statistical analysis
Cox regression models were used to identify relationships between bone markers and outcomes (SRE, progression of bone metastases, death) and bisphosphonate treatment and survival in patients with normal or elevated NTX levels. Survival rates were calculated for the proportion of participants in each group still alive over time. Given the competing risks of mortality, the cumulative probability of SRE occurring over the course of the study was calculated using cumulative incidence functions adjusted for survival. After zoledronic acid was shown to be highly effective in patients with high NTX levels, an additional multivariate analysis was planned and performed to further evaluate the drug's effectiveness.
Multivariate regression analyzes were performed to examine the potential influence of baseline characteristics and treatment effects on survival. For parameters without established extreme values ​​(i.e., upper limit of normal) for study participants in each cohort, the median was calculated within the model, or the parameter was treated as a continuous variable. The baseline characteristics of each model were treatment protocol (zoledronic acid 4 mg or 8/4 mg versus placebo); floor; race; duration of history of malignant neoplasm; age at the start of the study; body weight at the start of the study; functional status as assessed by the Functional Assessment of Cancer Treatment - General Symptoms (FACT-G) scale; severity of pain syndrome in points, sum of points on the pain scale (BPI); SRE history (yes/no); the need to use painkillers (no need/minimal need/use of a combination of analgesics compared to narcotic analgesics); general condition according to the ECOG scale; predominant type of lesion; NTX level (normal/increased); titer of the bone fraction of alkaline phosphatase (norm/?146 U/l); and the following variables using the median (in parentheses are values ​​for the NTX-elevated cohort) as cutoffs: urinary NTX level (102 nmol/mmol creatinine), serum creatinine (1 mg/dL), serum lactate dehydrogenase/LDH ( 246.5 U/L), lymphocytes (14.025%; and as a continuous variable), albumin (38 g/L; and as a continuous variable), and hemoglobin (11.7 g/dL; and as a continuous variable). All available baseline demographic and clinical characteristics were entered into univariate and full multivariate models to ensure that variables with potential statistical significance were included in the optimized model. To reduce the initial model to a simpler form, only those patients for whom it was possible to collect a complete set of data on all variables were included in the analysis, in order to minimize the effect of confounding by correlated random variables. Most patients not included in this model had missing NTX test results and BPI scores.
To identify any statistically significant relationships between treatment and each outcome variable, multivariate models were developed taking into account treatment group, the corresponding outcome predictor variable, and their interaction effect. The multivariate model included all original variables, and the optimized model was generated by backward elimination of the data until only statistically significant variables remained (variables were considered statistically significant if p<0,05).
results
Baseline characteristics of patients with NSCLC
The phase III clinical trial of zoledronic acid included 382 patients with NSCLC, of ​​which 259 patients were randomized to receive the study drug, 123 to placebo (Table 1). There were no differences between groups in demographic and clinical characteristics. Baseline NTX levels were assessed in 263 patients and were found to be elevated in 144 cases (55%). In this cohort of patients, on average, less time passed from the moment of detection of bone metastases to inclusion in the study compared to other patients.
Original NTX Content
and the risk of complications
Baseline NTX analysis was performed on 80 patients in the placebo group, and 42 patients (53%) had high levels. Elevated NTX titer was associated with a statistically nonsignificant increase in the risk of SRE (RR=1.64; p=0.068) and first SRE during the study (RR=1.49; p=0.225) compared with normal baseline NTX (Figure 1A ). Compared with the placebo group with normal baseline NTX levels, the cohort of patients with initially high NTX levels significantly increased the risk of progression to bone metastases (RR=2.15; p=0.039) and the likelihood of death (RR=2.39; p=0.001).
Baseline NTX was analyzed in 183 patients receiving zoledronic acid, and 102 (56%) had high levels. Elevated NTX titer in this group was associated with a statistically significant 81% risk of any SRE (RR=1.81; p=0.012) and a trend towards an increased risk of a first SRE during the study (RR=1.30; p=0.287) compared with normal initial NTX content. In contrast to the placebo group, in those receiving zoledronic acid, baseline high levels of NTX were not associated with a statistically significant increase in the risk of progression of bone metastases or the likelihood of death (p=0.186 and p=0.142, respectively; Fig. 1B), even when adjusted for higher volume sample compared to both treatment groups as a whole.
Bone events and overall survival
Among all patients with NSCLC, zoledronic acid significantly reduced the risk of a first SRE during the study compared with placebo (p=0.028; Figure 2). The results of the Andersen-Gill complex event analysis, taking into account all SRE episodes and the time of their occurrence, indicate a significant reduction in the risk of developing SRE (38%) in the group receiving zoledronic acid compared to the placebo group (RR=0.62; p?0.001 ). There were no statistically significant differences between the groups in terms of progression of bone metastases. However, until the bone event manifested itself clinically, radiological examinations were performed no more than once every 3 months.
The median survival of patients with NSCLC from the start of the study was 177 days. Patients receiving zoledronic acid lived an average of 1 month longer compared with those receiving placebo, but this difference was not statistically significant (median life expectancy for the group receiving zoledronic acid - 187 days, for the group receiving placebo - 157 days; p = 0.539 ). Given the survival data and the lower prognostic significance of baseline high NTX levels in the zoledronic acid group compared with the placebo group, the next step was to evaluate the effect of baseline NTX levels on the effectiveness of treatment with zoledronic acid.
Analysis depending on NTX titer
in patients with NSCLC
The analysis was performed in a cohort of 262 patients who had baseline NTX measurements available. The analysis revealed statistical heterogeneity in the effectiveness of treatment with zoledronic acid in patients with baseline high and low NTX levels (p = 0.018), indicating differences between groups, and adjustments that may affect treatment outcome should be made separately. With normal NTX at baseline (n=118), the survival curves (Figure 3A) and the risk of death were similar between the zoledronic acid and placebo groups (RR=1.326; p=0.223). In contrast, when NTX titre was initially high (n=144), the survival curves (Figure 3B) were markedly different between the zoledronic acid and placebo cohorts, and the risk of death was 35% lower with zoledronic acid compared with placebo (RR=0.652). ; p=0.025). To identify factors that may account for differences in survival between the zoledronic acid and placebo groups, further analysis was performed in the NTX-enhanced cohort.
In the high titer NTX subgroup, the majority (85%) of patients in both cohorts (i.e., those receiving active drug or placebo) had ECOG performance status 0-1, about half were over 65 years of age, and patient characteristics were largely similar (Table 1) . Moreover, among patients in the study population as a whole and the subgroup with high NTX levels, the same number of patients in each treatment group received specific chemotherapy treatment. 80% of all patients received zoledronic acid, and patients with high NTX levels treated with this drug also received chemotherapy at the same time. Chemotherapy was administered to 76% of patients in both cohorts, both in the study population as a whole and in the subgroup with a high titer of NTX.

life (in the entire population)
In a population of patients with NSCLC in whom titers of bone tissue markers were assessed, it was found that in a univariate model, an increase in life expectancy was statistically significantly correlated with 12 initial factors, namely: a high score on the FACT-G scale, a lower score on the comprehensive pain questionnaire BPI, female gender, no initial need for pain relief with narcotic analgesics, ECOG status 0-1, normal bone alkaline phosphatase level, serum creatinine level<0,1 мг/дл, абсолютным количеством лимфоцитов и титрами сывороточной глутамат-оксалоацетат-трансаминазы, альбумина и ЛДГ ниже средних значений. Согласно поправкам, сделанным для многомерной модели, уровни NTX и костной фракции ЩФ, содержание креатинина, титр сывороточной глутамат-оксалоацетат-трансаминазы и количество лимфоцитов имеют меньшую прогностическую значимость, а лечение золедроновой кислотой увеличивает продолжительность жизни в большей степени по сравнению с плацебо (RR=0,765; р=0,103).
The effect of baseline covariates on survival in different patient cohorts was assessed in two multivariate models (Table 2). The first model included all patients with data on each of the relevant outcome variables (the number of patients varied depending on the variable), and the second included only those with complete data on each variable (n=244). In both models, the extent of survival benefit with zoledronic acid varied significantly by race, ECOG status, and baseline NTX. According to the analysis of the second model, the initial level of LDH also has a significant effect on life expectancy. After adjustments were made to the reduced model for FACT-G score, narcotic analgesic use, ECOG status, history of SRE, baseline lymphocyte count, and baseline albumin titer in patients with complete data (n=244), survival was shown to be while receiving zoledronic acid, it changes significantly depending on the initial LDH level (p = 0.005 for elevated LDH compared with the mean values, i.e. testing the effect of treatment based on the interaction of covariates). With an increased LDH titer, treatment with zoledronic acid reduces the risk of death by 2.4 times compared with placebo (p = 0.0015), and with a low titer, it statistically insignificantly increases by 4.3% (p = 0.823). Analysis of a reduced multivariate model examining the effect of LDH levels on treatment outcomes indicates that factors such as the total score on the FACT-G scale, the use of narcotic analgesics, ECOG status, SRE history, initial number of patients are statistically significant in terms of the effectiveness of zoledronic acid therapy. lymphocytes and albumin content, and the NTX titer had no noticeable effect.
Analysis of baseline covariates and influences
of treatment for the duration
life (in a population with increased NTX)
In a univariate model, the following covariates were associated with increased survival: treatment with zoledronic acid (versus placebo), higher FACT-G score, no baseline need for narcotic pain medications, ECOG status 0-1, lymphocyte count above average (Table 3). In the multivariate model adjustments, zoledronic acid treatment (versus placebo), higher FACT-G score, and no baseline need for narcotic analgesics were found to be statistically significant. Reduced multivariate model analysis showed that zoledronic acid reduced the risk of death by 43% compared with placebo (RR=0.565; p=0.0047). In summary, the multivariate model results support the beneficial effect of zoledronic acid on survival compared with placebo, as found in the primary analysis of the NTX-elevated cohort.
As in the general NSCLC population, the effect of baseline covariates on survival during treatment with zoledronic acid in the cohort of individuals with elevated NTX was analyzed using two multivariate models (Table 4). It was found that in patients with elevated NTX, treatment outcomes varied markedly depending on age, race, serum LDH and NTX levels compared with the average value (102 nmol/mmol creatinine). The life expectancy of younger subjects with a less pronounced rise in NTX, in whom less time had passed since diagnosis, turned out to be longer.
The design of this study was designed to evaluate the effectiveness of treatment depending on the level of bone tissue markers. However, during the analysis, other statistically significant factors were identified - race, general condition on the ECOG scale and LDH levels. In the future, it is planned to study the nature of the interaction of covariates associated with a statistically significant increase in life expectancy during therapy with zoledronic acid compared to placebo (especially with regard to LDH levels).
Discussion
Zoledronic acid is the only drug from a series of bisphosphonates whose effectiveness in the treatment of osteolytic and osteoblastic bone metastases of various tumors, including NSCLC, has been assessed quite fully. Zoledronic acid has been shown to statistically significantly reduce the incidence and total complications of bone metastases (SRE). The drug allows for the prevention of the development of SRE, while simultaneously having a positive effect on bone pain, and in addition, with an initially elevated NTX, this drug has a positive effect on treatment outcomes, as evidenced by the results of the study.
With initially elevated NTX, zoledronic acid statistically significantly increases life expectancy compared with placebo, while in the cohort of patients with lower NTX, life expectancy is comparable. Although the reasons for this are not entirely clear, it has been suggested that when NTX is elevated, pathophysiological changes in bone are more sensitive to treatment, or (more likely) early therapy is more effective in such cases due to an inherently higher risk of developing disabling SREs. This correlates with the data of other authors obtained during the study of correlations of titers of bone tissue markers and treatment outcomes of patients with solid tumors (including NSCLC), according to which an increase in the values ​​of these indicators is associated with a greater risk of SRE and a greater likelihood of death compared with initial parameters. Moreover, in breast cancer, in the case of an initial elevated NTX, the level of which is normalized by taking zoledronic acid, life expectancy will be longer than in situations where the NTX level remains stably high. On the contrary, with an initially normal NTX titer, the risk of SRE is lower, and the clinical course and prognosis of the disease are determined by other manifestations not related to bone damage.
Although this analysis was essentially exploratory, the reduction in mortality in the zoledronic acid group compared with the placebo group may be due to a variety of effects that have been previously established in preclinical and other clinical studies. For example, zoledronic acid reduces the risk of potentially life-limiting SREs. According to the results of phase III clinical trials, which indicate a decrease in the likelihood of SRE when taking bisphosphonates, life expectancy during active therapy appears to be longer compared with placebo, although these differences rarely reach statistical significance. Data have also been obtained at the preclinical stage, according to which zoledronic acid inhibits tumor growth - both in general and in the microenvironment of bone tissue. Determining the contribution of each of these factors to increasing life expectancy is quite difficult; it can vary depending on the type of tumor and other characteristics of the disease.
Although the retrospective analysis did not randomize patients with NSCLC who had bone marker titers assessed, all baseline covariates were included in the comprehensive multivariate model. To construct a reduced multivariate model, the least significant variables were eliminated sequentially. In general, in patients with NSCLC, life expectancy was correlated with many factors. However, in the case of increased NTX content, life expectancy increased only against the background of treatment with zoledronic acid, no need to take narcotic analgesics, satisfactory general condition, absence of severe lymphopenia and normal LDH levels. Of all the parameters reported, treatment with zoledronic acid prolonged survival compared with placebo, and this was the only factor that could be easily influenced by physician treatment.
The increase in survival was most pronounced in patients with less advanced disease or bone involvement (shorter duration of malignancy and increased NTX titer, but not to extreme levels). It was found that an increase in LDH levels (and it is regarded as an unfavorable prognostic factor for NSCLC) is associated not only with a decrease in life expectancy, but also with a less noticeable positive effect on life expectancy of zoledronic acid compared with placebo. The data obtained indicate that early administration of zoledronic acid in the presence of bone metastases against the background of disease progression is the optimal treatment strategy. It should be noted, however, that currently the main indication for the use of zoledronic acid is the prevention of SRE in bone metastases, and all patients with such metastases are at risk for SRE, regardless of clinical presentation or general condition.
A prospective phase III clinical trial is currently ongoing, which will analyze the effectiveness of zoledronic acid in preventing the development of bone metastases in patients with stage III NSCLC. The results of this study, conducted in patients with earlier stages of NSCLC, may demonstrate the need for specific bone disease-targeting therapies, even in those without obvious bone disease, and support the clinical utility of treating bone metastases in a high-risk cohort.