osteomalacia
Introduction
Introduction Osteomalacia and rickets (osteopenic softening in adults) are a bone disease characterized by newly formed bone mineralization disorders. As a result, non-mineralized bone-like tissue (osteoid) accumulates, bones soften, and a series of clinical symptoms and signs such as bone pain, bone deformity, and fracture occur. The cause of the disease is diverse and is mainly divided into four categories: 1 vitamin D nutritional deficiency. 2 Vitamin D is deficient in metabolic activity. 3 The mineral content of the bone mineralization site is lacking. 4 bone cells, bone matrix disorders. Before puberty, that is, the damage of the long bone growth plate before the closure to the closure period is rickets. In adults, bone mineralization damage after closure of the epiphyseal growth plate is called osteomalacia.
Cause
Cause
(1) Causes of the disease
Mineralization of bone is a very complicated process. From the formation of basic chondrocytes and bone matrix, the supply of calcium, phosphorus and magnesium to the local environment is stable, such as parathyroid hormone (PTH), l,25-(OH)2D3, calcitonin (CT). The regulation, failure of any link can affect the mineralization of bone and lead to rickets and osteomalacia.
There are many causes of osteomalacia and rickets, and vitamin D deficiency is still the main cause in a large number of countries before the 1970s, especially in developing countries. In recent years, with the improvement of people's nutritional status and living conditions, awareness and prevention of the disease, nutritional vitamin D deficiency rickets and osteomalacia are significantly reduced, while hereditary and metabolic defects caused by rickets and osteomalacia will Be the more important reason. With the improvement of inspection technology and the application of molecular biology, the latter may become the main direction of future research. Due to the complexity of rickets and osteomalacia, rickets and osteomalacia may have multiple factors at the same time. Therefore, the etiology and classification of rickets and osteomalacia are more confusing. in FIG. 1.
The disease is characterized by the fact that the newly formed bone matrix cannot be mineralized in the normal way. Mineralization of bone is a complex process involving many factors such as calcium and phosphorus metabolism, osteoblast function and acid-base environment in mineralized parts. The causes of osteomalacia and rickets mainly include the following aspects:
1. Vitamin D deficiency vitamin D plays an important role in the body's calcium and phosphorus metabolism, can promote the absorption of calcium and phosphorus in the small intestine, increase the absorption of calcium and phosphorus in the renal tubules; stimulate the absorption of bone calcium; synergy in PTH Next, mobilize the dissolution of bone salt; maintain the normal concentration of calcium and phosphorus in the blood, which is conducive to the deposition of bone salt in the bone and promote the formation of new bone. Therefore, vitamin D deficiency and metabolic disorders are important causes of rickets and osteomalacia. There are many reasons for vitamin D deficiency, including:
(1) Insufficient sunshine: It is estimated that when exposed to sunlight, people can produce 6 U of vitamin D3 per square centimeter of skin per hour. Normal daylight can produce vitamin D of 310-100 g per day. If there is sufficient calcium and phosphorus diet, Prevent the occurrence of rickets and osteomalacia, but many factors can affect the amount of sunshine and UV absorption, such as seasons, temperature, air pollution. Season can significantly affect the amount of sunshine and vitamin D. In winter and spring, due to the decrease of solar radiation, the relationship between 25-(OH)D3 level and ambient temperature is greater than the average daily sunlight. With the development of industry, industrial smoke, Coal dust pollution further reduces useful UV light. In fact, rickets may be the first example of air pollution. Furthermore, skin pigmentation, traditional clothing habits, and reduced outdoor activities are also important reasons for the reduction in daylight exposure. Skin pigmentation can lead to a decrease in UV absorption. In cold areas or near the equator, to avoid cold or hot sun, the baby is used to staying in the house, wearing traditional clothes and the habit of closing the curtains in the boudoir. Allows mothers and children to have insufficient sun exposure. In recent years, the cities are increasingly crowded, the buildings are dense, the floors are rapidly increasing, the street sunshine is gradually decreasing, people are working hard, and outdoor activities are reduced. In particular, many elderly people have prolonged lifespan and metabolic decay in the body, and inconvenient movements make fewer outing activities. Lead to nutritional vitamin D deficiency, rickets and osteomalacia or subclinical osteomalacia.
(2) Insufficient intake: Some children in the United States have reported rickets caused by vegetarian diet. In some areas, the flour contains higher amounts of phytate and lignin. Phytate can bind calcium and zinc to increase its excretion. Lignin can form a complex with bile acid and affect the absorption of vitamin D. Causes rickets.
(3) gastrointestinal lesions and postoperative often accompanied by malabsorption of vitamin D; biliary tract diseases such as biliary cirrhosis, biliary obstruction affects the absorption of fat, also affects the absorption of fat-soluble vitamin D; pancreatic dysfunction can also cause vitamins D absorption is reduced.
(4) Absorption: Many of the causes of vitamin D deficiency are small bowel, hepatobiliary disorders, and pancreatic disorders with intestinal malabsorption. In the case of malabsorption syndrome, vitamin D loss includes not only oral vitamin D, but also endogenous products. These disorders include: post-gastrectomy, small bowel resection or bypass anastomosis, Crohn's disease, gluten dystrophy, regional enteritis, diverticulum multiple dystrophy, stagnation (blind) ring syndrome, scleroderma, pancreatic exocrine Insufficient, obstruction of pancreatic duct adhesion, chronic steatorrhea, biliary obstruction, obstruction of extrahepatic bile duct, congenital biliary atresia. In the UK, 25% of patients with small bowel bypass surgery had histological evidence of osteomalacia and had a decrease in 25-(0H)D3 levels, but X-ray findings of osteomalacia were less common. Osteomalacia is also one of the surgical complications of partial gastrectomy (usually Bi-type II), but the reported incidence of bone disease varies widely. Edd compared the radiological examination of patients who underwent gastrectomy and peptic ulcer without surgery. It showed that the former group had obvious lesions in the mineralization of the thoracic and lumbar vertebrae, and 5.8% had pathological fractures. Most of the previous studies considered that an important common feature of vitamin D deficiency in gastrointestinal dystrophy and hepatobiliary disorders was the disruption of the enterohepatic circulation of 25-(0H)D3, but recent studies by Clement et al showed that the intestine of 25-(OH)D3 The liver circulation is negligible, so the intestinal hepatic circulation of 25-(OH)D3 is responsible for vitamin D deficiency. There is no unified statement. For the absorption of vitamin D, bile salts are necessary, and biliary obstruction such as congenital bile duct atresia and extrahepatic bile duct obstruction have decreased vitamin D levels. The incidence of bone softening in pancreatic disorders with malabsorption is not high, and there are also differences in 25-(OH)D3 levels, but they may have significant hypocalcemia with secondary hyperparathyroidism. In short, rickets and osteomalacia caused by gastrointestinal and hepatobiliary diseases are often the result of multiple factors. In addition to vitamin D absorption disorders, they are often accompanied by malabsorption of calcium, phosphorus and magnesium, combined with reduced sun exposure and chronic Diarrhea causes systemic malnutrition, which can affect vitamin D levels and bone mineralization. Also, the drug cholestyramine can bind bile acid in the intestine, increasing the risk of bone softening, even exceeding the primary disease of its treatment.
(5) The increase in vitamin D requirements causes a relative lack
It is not uncommon for women who are early married and prolific to develop osteomalacia during the end of pregnancy and lactation, especially in Asia. This may be related to the tradition of many children in the region, the end of pregnancy and lactation, not leaving the house, the customs of doors and windows closed. Pregnancy and breastfeeding greatly increase the amount of calcium required by the mother. The bones of newborn babies contain about 23 g of calcium and 14 g of phosphorus. Most of these minerals are obtained from the mother at the end of pregnancy, and lactating women pay 300-500 mg of calcium per day. At this time, the mother does not have a large amount of vitamin D synthesis and a sufficient amount of calcium supplement, which easily leads to osteomalacia. Infants, especially premature babies, also have a period of increased vitamin D. In addition to artificially fed babies, the proportion of calcium and phosphorus in milk is dysfunctional. Recent studies have shown that vitamin D in breast milk is only 40-50 U/L, water-soluble vitamins. D sulfate activity is also only 1% to 5%, which cannot prevent the occurrence of rickets. In addition, puberty (11 to 17 years old) has strong bone development, plasma 25-(0H)D3 is flat and low, and this period often ignores the supplement of vitamin D, which is an important cause of delayed type rickets.
2. Vitamin D metabolism defects
The main pathogenesis of this type of disease is not due to maternal vitamin D deficiency, but due to metabolic disorders in the conversion of maternal vitamin D into active vitamin D. There are many reasons for this, including congenital genetic defects, acquired disorders and drugs, which lead to a decrease in the synthesis of 1,25-(OH)2D3 and a series of damage caused by target organ receptor defects. Many pathological mechanisms are still not fully understood. With the development of molecular biology, this type of disease will become the main object of research.
Reduction of liver 25-(OH)D3 production: a decrease in 25-(OH)D3 can directly lead to a decrease in 1,25-(OH)2D3 synthesis leading to rickets and osteomalacia. The reason for the decrease of 25-(OH)D3, one is due to the lack of maternal vitamin D, is a nutritional vitamin D deficiency, has been discussed previously; the second is due to the conversion of maternal vitamin D2 and D3 into 25-(0H)D3 The level is lowered. The liver is the main site for vitamin D in the 25th place. In various liver diseases, including severe chronic alcoholic hepatitis, cirrhosis, chronic active hepatitis and primary biliary cirrhosis, it can lead to 25-( OH) D3 production is reduced and 1,25-(OH)2D3 levels are reduced, affecting bone mineralization. The bone disease caused by this condition is also called "hepatic bone dystrophy." Although many patients are asymptomatic, histology has found osteoporosis and osteomalacia. As mentioned above, liver and biliary diseases often lead to cholestasis, reduced bile salts, vitamin A malabsorption, and protein synthesis disorders in liver disease. The reduction of vitamin D and active vitamin D binding protein also affects its transport function. The drug cholestyramine binds to endogenous 25-(OH)D3, aggravating a decrease in 25-(0H)D3 in the blood. Therefore, the cause of osteomalacia in liver disease may be multifaceted. Iong et al found that although the level of 25-(0H)D3 in most untreated liver patients can be significantly reduced, the level will be normal if there is sufficient ultraviolet radiation. A similar situation can also occur in premature infants, especially low-weight, immature children, whose birth weight is often less than 1000g, and the number of months of pregnancy is less than 28 weeks. Because the liver 25 hydroxylation function is still immature, resulting in a decrease in the concentration of 25-(OH)D3 in the blood, bone disease often occurs 12 weeks after birth, and can be prevented and treated by administering vitamin D.
3. Phosphorus metabolism disorders
Phosphorus is an important bone salt component, and 80% to 85% of the body's phosphorus is deposited in the bone and combines with calcium to form hydroxyapatite crystals. Phosphorus deficiency (insufficient intake or malabsorption) and metabolic disorders are also important causes of rickets and osteomalacia. Genetic factors such as X-linked anti-vitamin D hypophosphatemic rickets (as X-linked dominant hereditary disease) or secondary to other lesions such as tumors can also cause hypophosphatemia.
(1) Rickets and osteomalacia caused by antiepileptic drugs
Since Wright first raised the blood alkaline phosphatase in patients treated with antiepileptic drugs in 1965, anti-epileptic drugs have been known to cause rickets and osteomalacia, but the incidence reports vary, mostly in 15% to 20%. %. These drugs are mainly phenytoin and phenobarbital. It has been confirmed that patients treated with acetophenone and phenylbutylacid have a lower level of 25-(0H)D3, acetazolamide and glumectamide (clinical energy). It can induce aggravation of bone softening. The mechanism of rickets and osteomalacia is not completely clear, but most people believe that: 1 This class of drugs can induce liver microsomal mixed oxidase system, accelerate the vitamin D3, 25-(0H)D3 and l,25-(OH)2D3 metabolism. In recent years, it has been suggested that the decrease of 1,25-(OH)2D3 is due to the drug-induced smoothing of endoplasmic reticulum and vitamin D metabolism in hepatocytes, and the production of active metabolites is reduced. 2 This class of drugs can reduce liver 25-hydroxylase activity. 3 phenytoin can reduce intestinal calcium absorption and decrease the activity of vitamin D-dependent calcium-binding protein. Phenytoin is the most important drug leading to rickets and osteomalacia. 4 Because the level of vitamin D deficiency is not consistent with the degree of osteomalacia, it is believed that this type of drug can partially inhibit the reaction of bone and intestine to active vitamin D products, and it is agreed that The dose and duration of treatment are directly related to the degree of lesions in rickets and osteomalacia. This class of drugs causes bone lesions and X-ray signs to be non-specific.
The bone disease can be prevented and treated by administering vitamin D 5000-10000 U/week or 25-(OH)D3 20 g/d, which can improve biochemical and X-ray signs abnormalities and reduce the incidence of fracture. The introduction of new anti-epileptic drugs carbame-cepime and valproic acid derivatives such as dpakote may replace phenytoin and phenobarbital, but whether these new drugs cause osteomalacia and rickets need to be observed. The patient's blood urinary calcium should be checked regularly, because low blood calcium can aggravate seizures, which in turn increases the dose of anti-epileptic drugs, thereby further aggravating bone damage.
(2) hereditary vitamin D-dependent rickets: it is a rare hereditary disease, due to defects in congenital renal 1-hydroxylase, resulting in the inability of 25(OH)D3 to be converted to 1,25-(OH)2D3 To make bone mineralization disorder, it is also called pseudo-vitamin D deficiency rickets type I. The disease is mostly autosomal recessive, with onset from 3 to 12 months after birth, and there are reports of autosomal dominant inheritance and morbidity in children, suggesting the genetic heterogeneity of the disease. It is characterized by hypocalcemia, hypophosphatemia, and alkaline phosphatase, often secondary to parathyroidism. The bone lesions of rickets may be severe or rapidly progressing, often with permanent permanent enamel dysplasia and amino aciduria. The level of 25-(OH)D3 in the blood is increased or normal, and the concentration of 1,25-(OH)2D3 is very low.
(3) rickets and osteomalacia (renal osteopathy) caused by chronic kidney disease: also known as renal osteodystrophy, which is an important cause of rickets and osteomalacia, and has its characteristic manifestations and histology A group of disorders that have changed. Clinically, calcium and phosphorus metabolism disorders, metabolic acidosis, 1,25-(OH)2D3 reduction, secondary lesions caused by parathyroidism are characteristic. The disease is mainly caused by various chronic kidney diseases, including chronic glomerulonephritis, chronic pyelonephritis, kidney stones, renal tuberculosis, and urinary tract obstruction. The pathogenesis is currently considered to be mainly the following: 1 mainly due to the reduction of renal units (or renal cell mass) caused by chronic kidney disease, impairing the activity of 1-hydroxylase in the kidney, and converting 25-(OH)2D3 into 1,25-(0H)2D3 is reduced, causing bone mineralization disorder. 2 Recent studies have shown that phosphorus retention in renal parenchymal cells is also one of the main factors affecting the activation of 25-(OH)D3 in renal tissue. Hyperphosphatemia caused by chronic renal failure can further inhibit 1-hydroxylase and interfere with PTH,1. The synergistic effect of 25-(OH)2D3 in bone inhibits PTH-mediated calcium ascending, reduces intestinal calcium absorption, and lowers blood calcium levels. 3 hypocalcemia, hyperphosphatemia, 1,25-(OH)2D3 reduction can lead to increased PTH secretion and secondary hyperparathyroidism. The decrease of 1,25-(OH)2D3 level is reduced with the binding of parathyroid receptors, and the inhibition of PTH is weakened. The decomposition and excretion of PTH during renal failure are reduced, and the level of PIH is also increased, so the bone absorption is increased, and the fiber is increased. Secondary parathyroid bone lesions such as cystic osteitis are more common and more severe than other types of rickets and osteomalacia. 4 Metabolic acidosis in chronic renal failure, accumulation of H in body fluids, bone calcium bicarbonate is also buffered, so that the bone loses a lot of calcium in the regulation of acid-base balance, and the mineralization site pH.
In summary, the complex effects of various factors lead to a series of bone lesions. Its histological features not only the changes of rickets and osteomalacia caused by hormone vitamin D deficiency; osteoporosis caused by secondary hyperparathyroidism, increased bone resorption, and even the performance of fibrocystic osteitis; Osteoclastosis and soft tissue calcification caused by increased product of phosphorus, calcium and phosphorus. Therefore, X-ray performance is a mixture of these three, but it may be more obvious in different aspects of different patients. Children with uremic bone disease may have a higher demand for vitamin D and calcium due to the bone growth period, and the rickets performance is more obvious and the height growth is hindered. X-ray surface has bone softening changes, and bone sclerosis signs, which are characteristic of renal osteopathy, which can be characterized by regional bone density increase, mostly located in the cortical bone of the spina cartilage, pelvis and long bone; and cancellous bone The trabecular bone can be characterized by bone softening, the brightness is reduced, the blur is unclear, and the bone structure is like a glassy shape. The vertebral body of the vertebrae has a characteristic sandwich-like changethe density of the upper and lower layers is increased, and the density of the middle 1/3 is reduced. It is more common in the lumbar vertebrae, and there are different degrees of subperiosteal absorption. Changes in biochemical indicators showed decreased blood calcium, increased blood phosphorus, increased alkaline phosphatase, increased urinary hydroxyproline, normal 25-(0H)D3 levels, and significantly decreased 1,25-(OH)2D3 levels. The clinical manifestations may vary greatly depending on the cause, the age of the patient, the severity of the primary disease, and the Ca, P, protein content of the diet, and the presence or absence of treatment or treatment. The X-ray signs and laboratory tests are not very good. Correlation. Diabetes and kidney transplantation without timely supplementation of calcium or vitamin D can be iatrogenic to increase the degree of osteomalacia and rickets, large doses of glucocorticoids in kidney transplantation, nephrotic syndrome or immune diseases also lead to further decline in bone mineral content Steroid-related avascular necrosis of the femoral head may occur.
(4) hypoparathyroidism and pseudohypoparathyroidism: Many studies have discussed the important role of PTH on vitamin D. PTH can directly act on kidney cells, enhancing l-hydroxylase activity and promoting Synthesis of l,25-(OH)2D3. It can be expected that vitamin D metabolism is associated with hypoparathyroidism and pseudohypoparathyroidism, and it has been confirmed in clinical cases. Checking such patients, there is a decrease in the level of 1,25-(OH)2D3, while the 25-(0H)D3 level is normal, revealing the process of converting 25-(0H)D3 to 1,25-(0H)2D3. Damaged. It has also been shown in therapy that if vitamin D and 25-(0H)D3 are used, a larger pharmacological dose is required to correct hypocalcemia, whereas a physiological dose of 1,25-(0H)2D3 can achieve a similar response. Similarly, hyperphosphatemia in the presence of hypoparathyroidism and pseudohypoparathyroidism is also toxic to the production of active vitamin D. However, in this type of disease, bone mineralization defects are uncommon because of decreased plasma levels or normal PTH levels, but bones do not respond to them, resulting in decreased bone cell activity and minimal bone matrix construction. Among the patients with pseudohypoparathyroidism, one of them is a kidney-responsive bone-insensitive type, which is easily misdiagnosed as osteomalacia. Because this type of bone cells does not respond to PTH, PTH can not mobilize bone salt to maintain normal blood calcium levels, low blood calcium leads to secondary hyperparathyroidism, and renal tubules respond to PTH, which reduces renal reabsorption of phosphorus and loses a large amount. Phosphate. Results The patient had hand and foot spasm, low blood calcium, low blood phosphorus, low urinary calcium, increased urinary phosphorus, but normal blood alkaline phosphatase, high PTH, X-ray showed normal or increased bone density.
Patients with idiopathic hypoparathyroidism are susceptible to chronic fungal infections. At this time, ketoconazole is commonly used to inhibit the synthesis of 1,25-(OH)2D3, and long-term use requires an increase in the dose of vitamin D.
(5) Hereditary vitamin D resistance rickets: also known as vitamin D-dependent rickets type II or pseudo-vitamin D deficiency rickets type II. Because clinical features and genetic characteristics are similar to type I, it has been considered a different type of disease in the past. Later, it was found that the blood of 1,25 in -(0H)2D3 was not low, but it was significantly increased; the activity was normal, but it could not exert anti-rickety effect. The treatment of large doses of vitamin D, the efficacy is not good, showing that the disease is not a hormone deficiency and the hormone itself, but the target organ resistance or insensitivity to 1,25-(0H)2D3. The cause may be due to genetic factors caused by a variety of abnormalities at the level of alfacalcitol receptor or receptor, the genetic characteristics of autosomal recessive inheritance, family tendencies. Recent cell culture studies from these patients have revealed a series of functional defects in the 1,25-(0H)2D3 receptor, and studies have confirmed that some patients lack 1,25-(0H)2D3 receptors or receptor linkages. Defects of 1,25-(0H)2D3, Hughes et al. reported that one of the two families of hereditary vitamin D resistant rickets showed abnormal binding of DNA to the vitamin D receptor, which was confirmed to be a point mutation of the vitamin D receptor gene. The patient is more likely to develop the disease within one year after birth, and there are delays. It is characterized by progressive rickets, bone growth, growth retardation, mental retardation, and more than half of patients with congenital alopecia, due to vitamin D hormone should not, immune function is affected, prone to various infections and skin fungal infections. Biochemical indicators were associated with rickets type I, and PTH increased, blood 25-(0H)D3 was normal or slightly increased, 1,25-(0H)2D3 was significantly increased, and 24,25-(OH)2D3 was decreased.
4. Acidosis
There are many causes of acidosis. The common causes of chronic acidosis are uremia and renal tubular acidosis caused by various causes. Renal tubular acidosis can be divided into primary and secondary. Primary renal tubular acidosis such as Debre-DeToni-Fanconi syndrome, Lignac-Fanconi syndrome, Love's syndrome, and the like. Secondary renal tubular acidosis is mainly secondary to various chronic diseases such as chronic pyelonephritis, Sjogren's syndrome, systemic lupus erythematosus, hyperthyroidism, hyperparathyroidism and the like. In renal tubular acidosis, the renal tubules cannot exchange hydrogen ions normally, and the carbonate is lost, causing low sodium and low potassium acidosis accompanied by urinary alkalization, which can lead to rickets and osteomalacia.
5. Mineral deficiency in bone mineralization
In bone mineralization and reconstruction, hormones vitamin D and PTH always play an important role. Their role is to maintain the body's mineralized environment of normal calcium, phosphorus and magnesium concentrations, maintaining a sufficient supply of bone minerals to meet all aspects of the needs and healthy growth, mineralization and reconstruction of bone. If the body ingests calcium, phosphorus, magnesium and other mineralized substances for a variety of reasons or is lost from the intestines and kidneys, even if vitamin D and PTH are normal, abnormal bone metabolism or mineralization may occur, resulting in bone softening. Symptoms and rickets.
(1) Calcium deficiency syndrome: Calcium is the most important mineral element in bone formation. The amount of bone calcium accounts for 99% of the total calcium in the human body. From fetal bone formation to adult bone rebuilding, a certain amount of calcium is consumed every day, but the amount is different in different physiological states. Children need an average daily calcium intake of 240-900 mg, an adult of about 360-500 mg, and at least a doubling of calcium during pregnancy and lactation. Therefore, it is generally said that any lack of calcium intake or excessive loss of intestinal calcium and urinary calcium may affect bone development and reconstruction, resulting in poor mineralization. However, due to the body's own regulation, including the adjustment of the three major calcium-promoting hormones, blood calcium, especially ionized calcium, can often be adjusted. Under normal conditions of metabolism, there is generally no obvious hypocalcemia and severe rickets and osteomalacia. However, calcium deficiency rickets with high plasma levels of 1,25-(OH)2D3 can occur in the following three cases.
1 Premature infants with few surviving bones grow rapidly, requiring more calcium than the calcium supplied by the intestine. A few people believe that intestinal calcium absorption does not respond to 1,25-(OH)2D3.
2 rickets occur in fast-growing adolescence, while calcium in the diet is low (such as Bantu children in Africa). Compensatory increases in blood PTH and 1,25-(OH)2D3 in this group of patients, keeping blood calcium normal.
3 In the low-calcium diet, accompanied by high fluoride intake (high fluoride area), blood calcium can be reduced, partial osteomalacia, and secondary hyperparathyroidism.
(2) Chronic hypophosphatemia: Some scholars have suggested that rickets and osteomalacia can be divided into two categories from biochemical characteristics. One type is low-calcium rickets, characterized by hypocalcemia, and some may also be accompanied by hypophosphatemia; the other is hypophosphatemic rickets, normal or mildly reduced blood calcium, and the latter uses calcium and vitamin D. Treatment, poor efficacy, sometimes need a large dose of vitamin D, it is also called hypophosphatemia anti-vitamin D rickets and osteomalacia. Thus, phosphorus plays an important role in metabolic bone disease. Phosphorus promotes bone matrix synthesis and bone mineral deposition and promotes bone formation. Phosphorus also has an effect on bone regulation. Tissue culture shows that reducing the concentration of phosphate in the culture medium promotes bone resorption, increases the concentration of phosphate, and inhibits bone resorption. Phosphate reduction also leads to abnormal bone structure and function. Phosphate deficiency can cause rickets and osteomalacia, but there are also blood phosphorus low bone lesions are not obvious, therefore, the pathogenesis of hypophosphatemia anti-vitamin D rickets and osteomalacia may be multi-faceted, and may also have Defects in vitamin D activity. There are many causes of chronic hypophosphatemia: such as X-linked familial hypophosphatemia and other forms of congenital hypophosphatemia, renal tubular acidosis, Fanconi syndrome, Wilson disease, Lowe syndrome, etc. Metabolic diseases, neoplastic osteomalacia, and the use of a large amount of aluminum hydroxide gel, low-phosphorus solution for hemodialysis, or long-term intravenous nutrition can cause large amounts of phosphorus to be lost or insufficiently ingested. The most important features of hypophosphatemic rickets and osteomalacia are: hypophosphatemia, normal or reduced blood calcium, and significant muscle weakness. Some patients have insignificant bone disease, but also have severe muscle weakness, which limits their activity. The upper limbs of the patient are unable to lift and can not comb the hair; the lower limbs are weak, and they cannot stand up independently after squatting. The gait is squatting or duckling, and can not walk longer distances. Phosphorus deficiency can also affect cell energy metabolism, leading to decreased function of muscle cells, white blood cells, and red blood cells, resulting in anorexia, respiratory dysfunction, tachycardia, and migratory body pain. However, it should be noted that the decrease of blood phosphorus is sometimes not completely consistent with the degree of bone lesions. In patients with hypophosphatemic rickets and osteomalacia, simply supplementing phosphorus with vitamin D does not effectively improve bone lesions.
(3) X-linked familial hypophosphatemia: also known as hereditary or familial hypophosphatemic vitamin D-resistant rickets (VDRR), X-linked familial hereditary rickets or osteomalacia, a congenital disease Most of them are X-linked and dominant, with a family history, but there are also reports of sporadic forms and X-linked recessive inheritance, autosomal dominant or recessive inheritance. The lesion is mainly caused by the reabsorption of phosphorus by the proximal tubules of the kidney and the decrease of the absorption of phosphorus by the intestine, resulting in a decrease in blood phosphorus and a bone change caused by rickets. However, the mechanism of phosphorus loss in the kidney and intestine is unclear and may be related to abnormal phosphorus transport in the membrane. Some people think that the phosphorus and protein in the kidney and intestine may be controlled by the same gene locus. The defects of this gene make the phosphorus-operating protein abnormal, the urinary phosphorus is lost too much, and the intestinal phosphorus absorption is reduced, resulting in the uncorrectable hypophosphatemia. Recently, Harriet et al found that the mice with the disease had a Hyp mutation on the chromosome, a high affinity on the brush border of the renal proximal tubule, and a low-capacity Na-P cotransport and its mRNA were significantly reduced. The gene expression product of the Hyp site may regulate the expression of Na-P gene, reduce its transcription or increase the destruction of transcripts, eventually reduce Na-P, resulting in reduced renal tubular reabsorption of phosphorus, and found that the patient's plasma Both 25-(0H)D3 and iPTH were normal, and the concentration of 1,25-(OH)2D3 was decreased. Therefore, it is believed that the cause of the disease may be a defect in the reaction of renal 1-hydroxylase, and the calcitriol synthesis is impaired. The age of onset varies from 6 months after birth to old age, and the degree of performance can vary greatly. Most of them have obvious performance during childhood, and their symptoms may be alleviated as the growth plate is closed, but common symptoms relapse in old age. Adults are milder or asymptomatic, but have histological evidence of persistent osteomalacia. Male bone lesions are more severe, and some female patients may have only hypophosphatemia. Typical performance is short stature, deformed lower limbs, delayed bone age, muscle weakness and decreased muscle tone, and rickets bone lesions. The genetic heterogeneity of this disease is obvious, children can have skull fusion, and a few people have neurogenic deafness. X-ray signs are basically the same as nutrient vitamin D deficiency rickets and osteomalacia, but some X-ray signs have contradictory points, there may be an increase in bone mineral content, although mineralization is lacking, but a large number of bones Agglomeration can lead to sclerosing disorders. In particular, multiple calcifications of the central axis and pelvis may involve the lumbar, sacral, and caudal ligaments, and new bone formation may occur at the attachment of the muscle ligament. Biochemical examination showed normal blood calcium, increased urinary phosphorus, normal or elevated alkaline phosphatase, and no amino aciduria.
(4) damage to the renal tubules of severe tubular damage can lead to rickets and osteomalacia: although it is also a category of renal osteopathy, but also with glomerular bone disease (or uremic osteopathy) Significantly different features. It is not parallel to the extent of renal failure, and in the case of good kidney function, obvious bone disease can occur. The biochemical characteristics are also accompanied by obvious hypophosphatemia and renal phosphorus loss, while blood calcium is normal or only slightly decreased, and AKP is increased. Bone lesions have different manifestations. Severe patients can have obvious rickets bone disease from childhood. Mild lesions can only show osteomalacia in adulthood. They can also be secondary to parathyroidism, and there is obvious bone decalcification and bone mass. Loose or fibrous cystic osteitis, bone deformity and pathological fractures. Other manifestations of renal tubular acidosis, may have high chloride acidosis, hypokalemia, muscle weakness and limbs soft palate, proximal convoluted tubule dysfunction may be associated with amino acid urine, diabetes, phosphate urine and polyuria, and some may also There are high urinary calcium, kidney stones and proteinuria, which eventually leads to kidney failure.
There are many causes of renal tubular damage, such as primary renal tubular damage, such as primary renal tubular acidosis is an autosomal dominant genetic disease, the pathogenesis of the distal convoluted tubule, collecting tube active secretion of H ability decreased or near The curved tubules absorb the HC03-obstruction. There is also Fanconi syndrome, which is also a congenital tubular dysfunction. It is an autosomal recessive hereditary disease, mainly involving proximal convoluted tubules, leading to a decrease in renal tubular reabsorption and amino aciduria (with or without Cystineuria, diabetes, uric acid, uric acid, and bicarbonate urine may be associated with cystine deposition in systemic tissues in infants and childhood, and cystine-free deposition in adult cases. Furthermore, it is secondary to various causes such as infection, heavy metal poisoning, expired tetracycline, streptozotocin, cresol and other drug poisoning; congenital systemic metabolic defects (cystins, galactosemia, glycogen accumulation Disease, liver and kidney genetic tyrosineuria, hereditary fructose intolerance, hepatolenticular degeneration and eye and brain syndrome; immune disease (amyloidosis, Sjogren's syndrome); multiple Myeloma; radiation factors, etc., can cause secondary renal tubular dysfunction, can also cause secondary Fanconi syndrome. The mechanism of renal tubular damage caused by bone damage, in addition to the previous thought of hypophosphatemia, acidosis, it is also believed that the reduction and activity of 1,25-(OH)2D3 products are reduced, and bone lesions can be given by Alpha Calcified alcohol (calcium triol) is used for prevention. Some simple renal tubular acidosis, bone lesions can also be prevented by giving enough sodium bicarbonate [5 ~ 15mmoL / (kg? d)] to correct the blood pH to normal. This treatment also prevents osteomalacia caused by acidosis after ureteral sigmoid anastomosis.
(5) neoplastic osteomalacia: also known as tumor-related osteomalacia, tumor-derived hypophosphatemia, osteonecrosis, and clinical features similar to low-phosphorus vitamin D-resistant rickets. It was first reported by Prader in 1959. An 11-year-old girl developed severe rickets and hypophosphatemia, high urinary phosphorus with giant cell tumor of ribs within one year, and recovered from rickets after resection of the tumor. So far, nearly 100 cases have been reported. example. Related tumors can occur in adults and children, and can be located in soft tissues or bones, most commonly benign tumors of mesodermal tissue. According to Nuovo et al., 372 cases of bone tumors accounted for 56.3%, half of which were located in long bones, followed by skull and including mandible, paranasal sinus, and ethmoid sinus tumors; 43.05% were soft tissue tumors, which were more common in lower limbs and could be located in the skin. Most of the tumors are benign, including hemangioma, angiosarcoma, fibroangioma, bone mesenchymal tumor, multiple neurofibromatosis, chondroma, giant cell tumor, osteoblastoma and non-neoplastic disease (fibrous dysplasia and malignancy) Multiple myeloma, breast cancer, prostate cancer, oat cell cancer, etc.). Most tumors are small, with an average of 1 to 4 cm, a minimum of 0.5 cm, and a maximum of 15 cm. The clinical features are hypophosphorus rickets and osteomalacia that occur in previously healthy children or adults, and the radiological features of rickets and osteomalacia may also be advanced. The patient presented with severe muscle weakness, proximal myopathy, pain in the lower back, chest ribs and feet, and pelvic, spinal, limb deformities and pathological fractures. Laboratory examination: normal blood calcium, low blood phosphorus, increased urinary phosphorus, normal PTH and calcitonin, 25-(0H)D3 normal, 1,25-(0H)2D3 often decreased, blood alkaline phosphatase increased, urine HOP has increased, and there are reports of amino acid urine and diabetes. Osteopathic bone softening and tumor manifestations can occur simultaneously, or several years apart. The skeletal softening performance of rickets can be found 1 to 13 years earlier than the tumor, with an average of 5 years. Therefore, in the past, idiopathic and sporadic osteomalacia rickets have been diagnosed, and some cases may be neoplastic osteomalacia. The pathogenesis of the disease is still not very clear, most scholars believe that the tumor may release a factor or substance, directly acting on the renal proximal convoluted tubules, inhibiting the absorption of phosphorus, reducing blood phosphorus and increasing urinary phosphorus. It was found that the extract of tumor cells can directly inhibit the activity of l-hydroxylase in the kidney, while the intracellular cAMP does not increase, indicating that this substance is different from PTH, and many cases have reported abnormalities of vitamin D. And a decrease in 25-(OH)D3. Recent studies have also shown that the extract of this type of tumor is a peptide substance, non-lipid-soluble, heat-resistant, anti-trypsin, molecular weight of 8 ~ 25kD, it can inhibit the proximal tubular epithelial cell brush border Na-P co-transports body weight to absorb phosphorus, which can also alter the function of the proximal tubules, causing a series of pathological changes. In conclusion, it is very important for many clinical tumors to be associated with rickets osteomalacia. This damage should be carefully investigated in the diagnosis of hypophosphatemic anti-vitamin D rickets.
Excision of these tumors, osteomalacia and rickets can be cured without treatment. When no tumor is found or the malignant tumor cannot be removed, it is necessary to supplement both phosphorus and alfacalcidol in the same dose and method as X-linked familial hypophosphatemia.
(6) Magnesium deficiency syndrome: Magnesium is closely related to bone metabolism. Magnesium in bone tissue accounts for 60% to 70% of total magnesium in human body. In animal experiments, growth plate obstruction is observed when magnesium is deficient, and the tarsal plate is narrowed, almost no Chondrocytes, trabecular bones also disappeared, matrix proteins, mucopolysaccharides were lost, and collagen synthesis was impaired. Smith et al. (1972) found that magnesium-deficient immature rats had a significant reduction in bone mineral content and complete cessation of proximal tibia. According to the 1973 Nielsen study, the concentration of extracellular magnesium can regulate the formation of calcification of immature bone and conversion of non-crystalline salts to hydroxyapatite. The effects of magnesium on vitamin D levels have been reported. In a recent study with a large number of cases, nearly half of the patients had decreased blood l,25-(OH)2D3, and most had 25-(0H)D3 deficiency. Therefore, the role of magnesium in the metabolism of bone disease has received more and more attention. Magnesium is widely present in food and vegetables, combined with the regulation of kidney magnesium. When magnesium intake is reduced, urinary magnesium can be reduced to below 0.5 mmol/d, and fecal magnesium is also reduced, so it generally does not cause hypomagnesemia. The cause of hypomagnesemia is often congenital hereditary magnesium malabsorption or secondary renal failure, gastrointestinal diseases and malabsorption syndrome after surgical bowel resection. Among the rickets osteomalacia, there have been many reports of a marked decrease in blood magnesium, and the lowest serum magnesium may be 0.7 mmol/L. In recent years, magnesium-dependent anti-vitamin D rickets have also been reported. In 1974, Reddy et al reported 2 cases with typical manifestations of rickets and biochemical and X-ray characteristics. Blood magnesium levels were significantly reduced, 0.5 mg% and 0.74 mg%, respectively, given vitamin D. Treatment for 2 to 3 weeks did not improve, given oral MgCl 210mmoL / d, the condition improved significantly after 1-2 months. In 1975, Rwpado et al reported that a 12-year-old child had polyuria, high urinary calcium, and kidney stones. After treatment with sodium phosphate phosphate and hydrochlorothiazide for a period of time, hypocalcemia (6.9 mg/d1) appeared. Blood magnesium (0.25mmol / L), the wrist and ankle have obvious signs of rickets.D
6.
(1)1948Rathbun1/10D
Seriver
(2)1961Frame60DNelson42
Paget(polarized light)50
(3)SchmidX
(4)()()PTHD(desferrioxamine)
(5)
1-D0H-F-;;
1-125-(0H)2D3
99%
7. Other factors
(two) pathogenesis
Pathogenesis
DDD
2. Pathology
()Looser'sX
()
Examine
an examination
Related inspection
Ca2+,Ca BGP CT
Rickets
624D23251O()X()
D125-(0H)2D3;D
2.
5%
3.
(Harrison)
OX
X
Rickets
(1)
(2)
(3)()
(4)
(5)Harrison
(6)
X
2.
3.X
4.
[2.22.7mmol/L(911mg/dl)];[0.91.3mmol/L(2.84mg/dl)][1.31.9mmol/L(46mg/dl)]
5.X
XX(Looser);XX
Diagnosis
Differential diagnosis
1.D
1
2.D
123
3.
4.
125-(0H)2D3
Rickets
624D23251O()X()
D125-(0H)2D3;D
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3.
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OX
X
Rickets
(1)
(2)
(3)()
(4)
(5)Harrison
(6)
X
2.
3.X
4.
[2.22.7mmol/L(911mg/dl)];[0.91.3mmol/L(2.84mg/dl)][1.31.9mmol/L(46mg/dl)]
5.X
XX(Looser);XX
