Treatment with bisphosphonates for hypercalcemia in breast cancer

1.General information

In the aspect of life, health, activity and normal functioning of the human body, the most important role of the so-called micro- and macroelements - chemical substances that are not nutritional in themselves, but in small concentrations are absolutely necessary in biochemical reactions and physiological processes.

Calcium is one of the key macroelements of this kind; Moreover, the specific content of calcium compounds (salts) in the human body exceeds the concentration of any other macronutrient. The absolute majority of calcium is found in bones and teeth, and only about 1% is found in blood plasma and intracellular spaces; in addition, the biochemical interaction of calcium and magnesium is one of the most important regulators of cardiovascular activity.

Thus, calcium deficiency has a detrimental effect on the condition and functioning of a number of systems. However, its excess content, or hypercalcemia, is pathological and leads to the development of a number of serious disorders.

According to modern epidemiological statistics, the incidence of hypercalcemia in the general population varies between 0.1-1.5%; in samples of inpatients, this proportion is much higher and reaches 0.5-3.5%, which is due to a complex of reasons and interrelated factors.

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Hypercalcemia

The first step in any unclear case of hypercalcemia is to measure PTH to confirm or rule out the diagnosis of pHPT. Along with the determination of iPTH, new measurement methods using specific amino-terminal antibodies have recently emerged. (Biointact-PTH, whole PTH). Application of PTH-Fragment-Assays obsolete. Other conditions that support the diagnosis of pHPT are hypophosphatemia, high-normal or elevated 1,25(OH)2D3 (with normal 25(OH)D3), elevated bone alkaline phosphatase, decreased to low-normal renal calcium excretion (as a result of increased renal PTH action and increased renal "calcium-Loads") and high renal excretion of phosphate (however, largely dependent on diet). Diagnosis of the localization of enlarged epithelial bodies before the first parathyroidectomy may be limited to ultrasonography of the neck, which in two thirds of cases determines the indicating condition. FHH (heterozygous inactivating mutation Calcium-sensing-Rezeptors) occurs with a frequency of 1: 15,000-20,000. Based on laboratory chemical results, it cannot be reliably distinguished from pHPT. The typical conditions for FHH are mild hypercalcemia and severe hypocalcemia; specificity is however limited. Family member screening for hypercalcemia and hypocalciuria can help make the diagnosis. The diagnosis can be made with confidence only at the present moment when the question is posed scientifically using Calcium-Sensing-Rezeptor-Gens sequencing. The distinction from pHPT is therefore important because FHH can generally be considered a non-therapeutic abnormality and unnecessary parathyroid surgery is not performed on affected patients.

It is assumed that about 70-80% of tumor-associated hypercalcemia are humorally mediated. The basis of most of these forms of hypercalcemia is the secretion of PTHrP from tumor tissue (often squamous cell carcinomas, such as renal carcinoma, bronchial carcinoma, and others). In the diagnosis of unclear hypercalcemia, one of the subsequent steps is also the measurement of PTHrP. Hematological malinomas (plasmacytoma, lymphoma), as a rule, do not produce PTHrP. In case of unclear hypercalcemia, using appropriate diagnostic measures (immunoelectrophoresis, as a mandatory study for any hypercalcemia, bone marrow puncture, radiological examination of the skeleton), plasmacytoma should be excluded. Plasmacytomas and lymphomas secrete cytokines (interleukin-1, tumor necrotizing factor a), which through the activation of osteoclasts lead to hypercalcemia. Systematic detection of these cytokines has no clinical significance.

If a tumor is suspected, a search program should be carried out with a thorough clinical examination (eg lymphoma, suspected skin changes, breast tumor, prostate enlargement), serological tumor markers, Haemoccult, chest X-ray (mass process), abdominal sonography (metastases) liver, kidney tumors) and radiological studies of the skeleton (scintiography, X-ray targeted images, detection of bone metastases, osteolysis, DD to pHPT, Morbus Paget). To diagnose unexplained hypercalcemia, a 1.25 (OH)2D3 measurement is performed. In rare cases, hypercalcemia may be caused by elevated levels of 1,25(OH)2D3. This most often indicates granulomatous diseases (most often sarcoidosis, less often tuberculosis and other diseases, see Table 2). Very rarely, ectopic lymphomas secernate 1,25 (OH)2D3.

2. Reasons

According to the published results of biochemical studies, up to 90% of cases of hypercalcemia are caused by oncological processes or pathology of the parathyroid glands: tumors of the lungs, intestines, kidneys, prostate in men and mammary glands in women; malignant diseases of the hematopoietic system.

Endocrine pathology in this predominant etiological structure is represented by hyperparathyroidism (abnormally high activity of the parathyroid glands), as well as thyrotoxicosis. Other, more rare causes include Paget's deforming osteopathy, some hereditary diseases (for example, familial hypocalciuric hypercalcemia, Jansen's chondrodysplasia, etc.), impaired absorption of calcium in the intestine, excess vitamin D, prolonged stay on bed rest (hence the large percentage of hypercalcemia in patients receiving long-term courses of inpatient treatment). Excess calcium is also caused by prolonged use of certain groups of drugs (lithium compounds, thiazide diuretics, theophylline, etc.), kidney and adrenal dysfunction.

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Complications

Hypercalcemia has a wide range of adverse effects. The most common complications are osteoporosis (due to increased release of calcium ions from bones), pathological fractures, and urolithiasis. Acute pancreatitis and intestinal obstruction occur less frequently. The most life-threatening condition is considered to be hypercalcemic crisis, in which mortality reaches 60%. The cause of death is heart or kidney failure.

Another severe but rare complication is calciphylaxis (calcifying uremic arteriolopathy), characterized by ischemic necrosis of the skin and subcutaneous fat. It develops in patients with end-stage renal failure. A prolonged increase in calcium in the blood can also lead to band keratopathy, calcification of the aorta and heart valves with the formation of heart defects.

3. Symptoms and diagnosis

There are acute and chronic hypercalcemia. Acute is characterized by:

• general weakness, fatigue;
• unquenchable thirst (polydipsia) and increased volume of urination (polyuria);
• nausea, vomiting, digestive and stool disorders;
• high blood pressure;
• cardiac disorders, including life-threatening ones (arrhythmia, sudden cardiac arrest);
• epigastric pain associated with eating.

A hypercalcemic crisis is characterized by severe dyspeptic disorders, muscle weakness, sometimes epileptiform syndrome, a sharp increase in temperature, and an altered state of consciousness (up to coma). Considering the non-specificity of the symptoms, only reliable emergency diagnosis and urgent adequate intervention can save the patient’s life during such a crisis attack.

Chronic hypercalcemia leads to fibrous degeneration in the renal parenchyma, a number of progressive complications from the osteoarticular structures, central nervous system, heart, lungs, gastrointestinal tract - with the development of corresponding symptom complexes and syndromes.

If hypercalcemia is suspected, a number of specific blood and urine tests are prescribed, which must be repeated and taken under different conditions (for example, against the background of a special diet). Depending on the most likely causes of increased calcium concentration, instrumental diagnostic methods are additionally prescribed (densitometry, ultrasound of the kidneys, tests for tumor markers, ECG, etc.).

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Prognosis and prevention

Hypercalcemia is a severe and in some cases (especially in acute cases) a life-threatening pathological condition. In hypercalcemic crisis, the mortality rate is very high (60%). The frequency of deaths in chronic cases averages 20-25%. However, the prognosis is largely determined by the cause of the increase in Ca levels.

Prevention of this pathology consists in timely diagnosis and proper treatment of the diseases against which it develops. Before starting to take vitamin D or other medications that may increase Ca levels in the blood, a blood test should be performed to assess Ca levels.

4.Treatment

It is obvious that treating hypercalcemia itself is pointless: it is necessary to identify and eliminate the causes of excess calcium. Based on the results of the diagnostic examination, a decision is made on further actions - removal of the tumor and subsequent oncology therapy, specialized treatment by an endocrinologist, stopping taking medications and vitamin complexes containing vitamin D, etc. In severe cases, hospitalization with intensive therapy is required - intravenous administration of saline and calcium antagonists, hemodialysis, forced diuresis drugs, etc. For less threatening conditions, calcitonin, pamidronic acid are used, according to indications, glucocorticosteroids, gallium nitrate and other drugs prescribed based on the specific clinical situation .

CONTENT

• 1 Signs and symptoms 1.1 Hypercalcemic crisis

Diagnosis[edit]

The diagnosis should usually include either a corrected calcium level or an ionized calcium level and be confirmed after a week. [1] However, there is controversy about the usefulness of adjusted calcium, as it may be no better than total calcium. [18]

The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia . [1][2][4] Moderate hypercalcemia is 2.88–3.5 mmol/L (11.5–14 mg/dL), while severe hypercalcemia is >3.5 mmol/L (>14 mg/dl). [19]

ECG [edit]

Osborne wave, an abnormal ECG that may be associated with hypercalcemia.

Heart rhythm disturbances may also occur, and short QT interval ECG findings [20] indicate hypercalcemia. Significant hypercalcemia can cause ECG changes mimicking acute myocardial infarction. [21] Hypercalcemia is also known to cause an ECG mimicking hypothermia known as the Osborne wave. [22]

Other animals[edit]

Research has led to a better understanding of hypercalcemia in non-human animals. Often the causes of hypercalcemia are related to the environment in which the organisms live. Hypercalcemia in pets is usually due to illness, but other cases may be caused by accidental ingestion of plants or chemicals in the home. [23] Outdoor animals commonly develop hypercalcemia due to vitamin D toxicity from wild plants in the environment. [24]

Pets[edit]

Domestic pets such as dogs and cats develop hypercalcemia. It is less common in cats, and many feline cases are idiopathic. [23] In dogs, the main causes of hypercalcemia are lymphosarcoma, Addison's disease, primary hyperparathyroidism, and chronic renal failure, but there are also environmental causes usually unique to companion animals. [23] Ingestion of small amounts of calcipotriene found in psoriasis cream can be fatal to a pet. [25] Calcipotriene causes a rapid increase in calcium ion levels. [25]If left untreated, calcium ion levels may remain high for several weeks, which can lead to a variety of medical problems. [25] Cases of hypercalcemia have also been reported due to rodenticides containing a chemical similar to calcipotriene found in psoriasis cream in dogs. [25] In addition, consumption of houseplants is a cause of hypercalcemia. Plants such as Cestrum diurnum

and
Solanum malacoxylon,
contain ergocalciferol or cholecalciferol, which cause hypercalcemia. [23] Consumption of small amounts of these plants can be fatal to pets. Observable symptoms may develop, such as polydipsia, polyuria, severe fatigue, or constipation. [23]

Outdoor animals[edit]

Trisetum flavescens

(yellow oat grass)

Under certain outdoor conditions, animals such as horses, pigs, cattle and sheep commonly suffer from hypercalcemia. In southern Brazil and Mattevara, India, about 17 percent of sheep are affected, with 60 percent of these cases being fatal. [24] Many cases have also been documented in Argentina, Papua New Guinea, Jamaica, Hawaii and Bavaria. [24] These cases of hypercalcemia usually occur with the ingestion of Trisetum flavescens

before it dries.
[24] Once Trisetum flavescens
, its toxicity is reduced.[24]
Other plants known to cause hypercalcemia include Cestrum diurnum
,
Nierembergia veitchii
,
Solanum esuriale
,
Solanum torvum
, and
Solanum malacoxylon
.
[24] These plants contain calcitriol or similar substances that cause an increase in calcium ion levels. [24] Hypercalcemia is most common in grasslands at altitudes above 1500 meters, where the growth of plants such as Trisetum flavescens
. [24] Even when ingested in small amounts over a long period of time, prolonged high levels of calcium ions have large negative effects on animals. [24] Problems these animals face are muscle weakness and calcification of blood vessels, heart valves, liver, kidneys and other soft tissues, which can eventually lead to death. [24]

Links[edit]

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