Bone pathology in hypervitaminosis D an experimental study in young pigs.

Five groups of 4 weanling pigs were fed a diet with 1.2% calcium and 1.0% phosphorus for 8 weeks with vitamin D3 at 1, 5, 25, 125 and 625 times the recommended levels, respectively. Hypercalcemia and hypophosphatasemia developed rapidly and persisted in Group 5 and developed more slowly but steadily in Group 4. Increasing levels of vitamin D3 influenced progressively and negatively the activity of resorbing osteocytes with osteopetrosis in Groups 2 and 3 and with osteonecrosis in Group 5. Atrophy of osteoblasts further contributed to the osteopenia in Group 5. Cartilage growth activity was arrested in Group 5. The negative effect on the resorbing osteocytes, which finally lead to death of the cells, was ascribed directly to vitamin D3 toxicosis since hypoparathyroidism and hypercalcitonism, both resulting from hypercalcemia, are not known to induce osteonecrosis. Since hypercalemia was finally as severe in Group 4 as in Group 5 and since there was soft tissue calcinosis only in Group 5, the calcinosis was always considered dystrophic, an interpretation supported by the observation that degenerative histologic changes preceded soft tissue calcinosis.     

Solanum malacoxylon toxicity: inhibition of bone resorption.

Young rabbits on high (0.57%) or low (0.24%) calcium were given an aqueous extract of Solanum malacoxylon (S.m.) leaves (20 g dried leaves/200 ml distilled water) intragastrically at 0, 12 and 36 hours. On bothe diets S.m. induced progressive hypophosphatasemia but serum calcium and phosphorus underwent only minor changes. In rabbits necropsied at 0, 12, 36, 60, 84 and 108 hours, S.m. was shown to have a negative effect on the resorbing osteocytes. With retarded osteocytic osteolysis, osteopetrosis resulted. Further regressive changes in the osteocytes resulted in osteonecrosis which was observed within 12 hours after administration of S.m. extract. The osteonecrosis, combined with retarded apposition, later resulted in osteopenia. It was concluded that the recommended dietary calcium for growing rabbits--about 0.6%--is too high. Whereas the histologic appearance of bone in rabbits fed low calcium was normal, bones from rabbits on high calcium showed retarded resorption and the rabbits had a relative hypophosphatasemia.     

Hypercalcemia and high serum parathyroid hormone-related protein concentration in a horse with multiple myeloma

A 13-year-old gelding was examined because of weight loss, hyperglobulinemia, and hypercalcemia. Possible causes of hypercalcemia that were considered included renal failure, primary hyperparathyroidism, vitamin D toxicosis, and malignancy. There was no history of vitamin D ingestion, and serum creatinine and parathyroid hormone concentrations were normal, making renal failure and primary hyperparathyroidism unlikely. The hypercalcemia was suspected to be a result of malignancy, but thorough testing did not reveal any neoplastic disease. Eight months later, serum parathyroid hormone-related protein (PTHrP) concentration was high, supporting the suggestion that hypercalcemia was a result of malignancy. In addition, radial immunodiffusion confirmed a selective 300-fold increase in serum IgA concentration. The horse was euthanatized, and postmortem examination revealed neoplastic infiltrates in the kidneys, lymph nodes, liver, and bone marrow. Neoplastic cells had morphologic characteristics of plasma cells, and immunohistochemical staining confirmed that neoplastic cells were expressing PTHrP and IgA. The final diagnosis was multiple myeloma with expression of IgA paraprotein.     

Cestrum diurnum poisoning in Florida cattle.

Cestrum diurnum poisoning was described in a Florida bull. Clinical signs included chronic wasting and progressive lameness. Plasma clacium was elevated for long periods of time but decreased toward low normal values. There was pronouced C-cell hyperplasia. Osteopetrosis was very severe and reflected retarded osteocytic osteolysis and chondrolysis. Further negative effects on the osteocytes eventually lead to osteonecrosis. Soft tissue calcinosis involved tendons and ligaments, major arteries and veins but kidneys and lungs were spared. Whereas the osteopetrosis could be explained by hypercalcitoninism, the osteonecrosis was believed to result from direct action by the Cestrum diurnum factor, previously shown to have an action similar to that of 1,25-dihydroxy-cholecalciferol, which is the biologically active metabolite of vitamin D3.     

Vitamin D intoxication and the pathogenesis of vitamin D nephropathy in the dog.

Dogs given excess vitamin D (500 or 1,000 micrograms/kg of body weight each day for 1 to 3 weeks were observed for clinical and pathologic changes of increased blood pressure and of characteristic nephropathy associated with vitamin D toxicosis or hypercalcemia. Serum calcium and serum urea nitrogen (UN) increased throughout the treatment period, but serum phosphorus remained within the normal range. Plasma renin activity increased markedly. Blood pressure showed only insignificnat changes (P = greater than 0.05). Gross and microscopic examination of the kidneys suggested vascular-oriented changes with an ischemic basis. Glomerular vascular poles showed hypertrophy and hyperplasia of juxtaglomerular cells. Ultrastructually, an increase in the number of secretory granules was noticed in these cells. A hypothesis regarding the mechanism of renal injury during vitamin D toxicosis is presented.     

Acute toxicosis in swine associated with excessive dietary intake of vitamin D

Acute toxicosis developed in a group (n = 35) of fattening hogs and replacement gilts that had excessive vitamin D3 inadvertently added to their feed. All of the pigs were lethargic, and emesis was evident in about half of the pigs 1 to 2 days after they consumed the feed. On the 2nd day, 3 of the pigs died. The remaining pigs were given a different ration. Five additional pigs died during the next 2 weeks. Clinical toxicosis also was observed in 1 of 2 feeder pigs fed the suspect feed in the laboratory and in 2 of 2 pigs fed the suspect feed by the company that had mixed the feed. Gross necropsy findings consistently observed were hemorrhagic gastritis and diffuse interstitial pneumonia. Myocardial degeneration and nephrosis were seen in, respectively, 1 of 6 and 4 of 6 pigs necropsied. Histologically, necrosis and mineralization of variable severity were observed in the fundic gastric mucosa, lungs, kidneys, bone, heart, and small blood vessels of the lungs and heart. Less necrosis and more mineralization were observed in pigs that survived longer than 6 days. The 2 pigs fed the suspect feed in the laboratory had increased concentrations of serum calcium from the 3rd to the 9th days or the 1st to the 3rd days, after feeding the suspect feed. Serum phosphorus concentrations were increased from the 1st until the 2nd or 3rd day, and serum magnesium concentrations were increased from the 1st or 2nd to the 3rd day after feeding the suspect feed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute Management of Calcium Disorders

Acute management of hypercalcemia and hypocalcemia is an important part of small-animal emergency practice. In addition to hypercalcemia of malignancy and hyperparathyroidism, vitamin D toxicosis is becoming more common in companion animals as new and improved rodenticides and human pharmaceutical preparations (vitamin D analog skin creams) become more available. This article provides complete details regarding the emergency management of life-threatening hypercalcemia with focus on vitamin D intoxication. At the other end of the spectrum, hypocalcemic emergencies, such as periparturient hypocalcemia (eclampsia), may be less common but are often life threatening. This article contains guidelines for the emergency management of hypocalcemia. In summary, the urgent care of calcium disorders in small animals is reviewed.     

Effects of vitamin or mineral deficiency on the morphology of medullary bone in laying hens.

Adult laying hens were fed diets deficient in phosphorus, calcium, calcium and phosphorus, and vitamin D3 to determine their effects on bone histology and parathyroid gland size. The phosphorus deficient diet caused an insignificant decrease in parathyroid size while the other diets caused significant increases. A considerable amount of individual variation in medullary bone volume and osteoid seam width was observed in all groups but, despite this, the calcium, calcium and phosphorus and vitamin D3 deficient diets clearly resulted in increased osteoid. Birds receiving diets deficient in calcium and phosphorus, and in vitamin D3 for longer periods were observed to have partially or completely resorbed medullary bone. Osteodystrophia fibrosa was noted in vitamin D3 deficient birds which had no follicular activity.     

Osteopenic disease in growing pigs: diagnostic methods using serum and urine calcium and phosphorus values, parathoromone assay, and bone analysis.

This research was performed to evaluate the utility of several serum and urine parameters as well as bone ash and plasma parathormone assay to diagnose and monitor diet-related osteopenia in growing pigs. Five diets were tested as follows: calcium-deficient, phosphorus-replete; moderate-deficiency of calcium and phosphorus; marked deficiency of calcium and phosphorus; calcium replete, phosphorus deficient; and vitamin D deficient. Parameters monitored included serum calcium and phosphorus as well as ratios of urine calcium to creatinine, phosphorus to creatinine, calcium to phosphorus, and percent fractional excretions of calcium and phosphorus. Plasma parathormone (PTH) levels were monitored in 2 of 3 experiments. Osteopenic bone differences at necropsy were evaluated by bone density, percent ash, ash per milliliter bone, calcium per milliliter bone, and phosphorus per milliliter bone. Marked change in urine mineral parameters, especially the calcium-to-phosphorus ratio, typically occurred within 1 to 2 days of treatment and preceded significant change in serum mineral or plasma PTH by 2 to 3 weeks. When monitored, plasma PTH levels were elevated following treatment, which confirms the hyperparathyroid state induced by the test diets. Significant differences in bone mineralization between control and treatment diets at necropsy were generally observed. The results of this study indicate that the analysis of urine minerals offers an early, noninvasive technique to investigate diet-associated osteopenic disease in growing pigs, which can be supported further by bone mineral analysis at postmortem using techniques herein described. Several urine mineral reference intervals for application to field investigations are included. Research into application of similar techniques to evaluate calcium and phosphorus homeostasis in pigs of all ages, including gestating and lactating gilts and sows, appears warranted.     

The postmortem diagnosis of cholecalciferol toxicosis: a novel approach and differentiation from ethylene glycol toxicosis.

The objectives of this study were to develop a novel approach to postmortem diagnosis of cholecalciferol (CCF) toxicosis in dogs using kidney, bile, and urine samples, and to differentiate CCF from ethylene glycol (EG) toxicosis. To achieve these objectives, specimens collected from 2 previous laboratory studies in which dogs were given a single oral toxic dose of CCF (8.0 mg/kg) were used. For EG toxicosis, historical data from the previous 13 years (1985-1998) were reviewed and confirmed cases of EG toxicosis were selected. The historical data were used to compare trace mineral concentrations, specifically of calcium and phosphorus to differentiate between intoxications caused by CCF from that caused by EG in dogs. Kidneys, bile, and urine from dogs that died of CCF toxicosis were analyzed for 25 monohydroxy vitamin D3 (25(OH)D3) and 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) and compared to known control unexposed dogs. Results of this study show that biliary and renal 25(OH)D3 concentrations and renal calcium to phosphorus ratio are of diagnostic value in dogs exposed to toxic concentrations of CCF. The renal calcium to phosphorus ratio was <0.1 in normal dogs, 0.4-0.9 in dogs that died of CCF toxicosis, and >2.5 in dogs that died of EG toxicosis.     

Primary Hyperparathyroidism Associated With Atypical Headshaking Behavior in a Warmblood Gelding

A 14-year-old Zweibrücker Warmblood gelding was presented for evaluation of lethargy and headshaking. The horse had a history of bouts of lameness in different limbs and back problems. It also had many mild colic episodes in the past. Results of repeat laboratory tests had shown persistent hypercalcemia (4.8 mmol/L; reference interval [RI]: 2.0–3.2 mmol/L) for 1.5 years and later on hypophosphatemia (0.4 mmol/L; RI: 0.5–1.3 mmol/L) and mild hypermagnesemia (1.0 mmol/L; RI: 0.5–0.9 mmol/L). Parathyroid hormone (PTH) concentration was within the RI. Other causes of hypercalcemia, such as renal failure, vitamin D toxicosis, and granulomatous disease, and nutritional secondary hyperparathyroidism were ruled out. Furthermore, there was no evidence of neoplastic disease. Parathyroid hormone–related protein was measured but inconclusive. A diagnosis of primary hyperparathyroidism was established on the basis of hypercalcemia, hypophosphatemia, low fractional excretion of calcium, and high fractional excretion of phosphorus in combination with a PTH secretion refractory to high calcium levels. Because of the bad prognosis, the owner decided to euthanize the horse. Results of postmortem examination were unremarkable. Hypercalcemia should always be considered abnormal, and further examinations need to be performed to proof hypercalcemia and subsequently find the cause. The main differential diagnoses are renal insufficiency and humoral hypercalcemia of malignancy, but also rare diseases, such as hyperparathyroidism, have to be taken into account.     

Pathology of vitamin D deficiency in growing turkeys

Turkey poults were fed a vitamin D-deficient diet and examined for clinical signs and structural changes of bone and parathyroid glands. Vitamin D-deficient poults developed ricketic changes during days 10 to 14. Control poults (deficient diet plus vitamin D) did not develop rickets. In deficient poults, lengths of proliferating-prehypertrophied zones of growth plates increased significantly in the proximal tibiotarsus but were only slightly elongated in the distal tibiotarsus. Unmineralized hypertrophic chondrocyte zones increased in length rapidly in conjunction with a decrease in the length of mineralized hypertrophic degenerative zones; this occurred more rapidly in proximal than in distal tibiotarsus. Other ricketic changes included decreases in bone ash, total femoral bone ash (calcium, phosphorus, magnesium), bone length, and body weight. Plasma alkaline phosphatase was increased, calcium was normal, and phosphorus was normal or elevated. Parathyroids were hyperplastic and had foci of degeneration. Vitamin D3 metabolites 25OHD3, 1,25(OH)2D3, and 24,25(OH)2D3 were rapidly depleted. Increase in bone ash Ca/P ratios in deficient poults suggests that phosphorus may be selectively released from ricketic bone. Low 25OHD3 and 1,25(OH)2D3 of control poults early in the experiment suggests that 1,400 IU of vitamin D3/kg of feed may not be an adequate level of vitamin D3 for growing turkey poults.     

Canine calcium oxalate urolithiasis. Case-based applications of therapeutic principles.

The case study presented here illustrates the diagnosis and management of calcium oxalate urolithiasis in a Bichon Frise, a breed at increased risk for this type of stone. If the Bichon Frise had persistent hypercalcemia, we would have evaluated serum concentrations of ionized calcium, parathyroid hormone, and vitamin D to identify an underlying cause. Because his urine was alkaline, additional potassium citrate was not provided. Likewise, as a fortified diet was fed to him, vitamin B6 therapy was not considered. This case study illustrates the benefits of radiographic evaluation immediately following surgery and during follow-up examinations. If we had postponed radiographs until the patient developed clinical signs, additional surgical procedures may have been required.     

Pathology of experimental vitamin D deficiency in chickens and effects of treatment with vitamin D metabolites

Structural changes in bone, parathyroid, and ultimobranchial body were examined in three groups of chicks fed a vitamin D-deficient diet; one group was treated with vitamin D3 and another with 1,25(OH)2D3. Diets were fed from day of hatching until 5 weeks old, when deficient chicks were near death due to hypocalcemic tetany, loss of fat and muscle, and marked bone deformities. In deficient chicks, parathyroid mass increased linearly to 7.5 times normal at 5 weeks. Parathyroid cells were irregular and vacuolated, with few granules. 1,25(OH)2D3 had normal parathyroids until the fifth week, when parathyroid mass increased greatly. There were few differences in length of growth cartilage, but marked changes in length of metaphyses. Deficient chicks had metaphyses nearly five times longer than vitamin D3-treated chicks. Metaphyses in chicks given 1,25(OH)2D3 were twice as long as those of vitamin D-treated chicks at 5 weeks. Both osteoblasts and osteoclasts were more numerous in deficient chicks. These studies suggest that vitamin D3 is more effective than 1,25(OH)2D3 in preventing parathyroid and bone lesions of vitamin D deficiency.     

High vitamin D3 requirements in broilers for bone quality and prevention of tibial dyschondroplasia and interactions with dietary calcium, available phosphorus and vitamin A

1. Two experiments were carried out to investigate responses in performance and bone compositional and structural characteristics in broilers fed diets containing 4 concentrations of vitamin D3 (5, 20, 125 and 250 microg cholecalciferol/kg) at different concentrations of calcium, available phosphorus and vitamin A. 2. In experiment 1, body weight and tibia breaking strength were maximised at 14d with 250 microg vitamin D3/kg, tibia ash was maximised with 125 microg vitamin D3/kg. A high incidence of tibial dyschondroplasia (TD) was decreased to very low levels with 125 microg vitamin D/kg. 3. At 42d, performance and bone characteristics showed no response to vitamin D3 concentrations above 20 microg/kg. 4. Dietary vitamin A within the range 2-4 to 4.5 mg retinol/kg did not show any interaction with vitamin D3 status at either age. 5. In experiment 2, responses to vitamin D3 were strongly influenced by dietary calcium/available phosphorus. With 13 g calcium and 5 g available phosphorus/kg, performance and bone characteristics responded to vitamin D3 concentrations up to 125 microg/kg but more was needed at less optimal concentrations of calcium and available phosphorus. TD incidence was minimised with 250 microg/kg. 6. This study shows that high dietary concentrations of vitamin D3 can prevent TD. It is concluded that the vitamin D3 requirement of broilers up to 14 d of age at optimal dietary calcium and available phosphorus concentrations may be in the range 35 to 50 microg/kg for cortical bone quality and up to 250 microg/kg for prevention of TD. The vitamin D3 requirement for cortical bone quality after 14 d is not higher than 20 microg/kg. These requirements are much higher than earlier estimates and may be related to higher calcium requirements of modern broiler genotypes. Current regulations limiting maximum vitamin D3 concentrations in broiler starter diets may need to be reviewed.     

Salmon calcitonin as adjunct treatment for vitamin D toxicosis in a dog

Calcitonin was used in conjunction with saline diuresis, furosemide, and prednisone in treatment of a dog that consumed a rodenticide that contained cholecalciferol and has been touted as safe for nontarget species. This report shows that the rodenticide is toxic to dogs and that salmon calcitonin is a useful treatment for the often refractory hypercalcemia induced by vitamin D toxicosis.     

成纤维细胞生长因子23在骨矿物质代谢中的作用及其调控机理

骨源性激素成纤维细胞生长因子23(FGF23)介导由甲状旁腺、肾脏、骨骼和维生素D组成的负反馈回路,建立"骨骼-肾脏-甲状旁腺"内分泌轴,参与骨矿物质代谢并发挥重要作用。钙、磷、铁、维生素D、甲状旁腺素(PTH)、成纤维细胞生长因子受体(FGFR)/FGF以及蛋白质翻译后修饰调控FGF23的分泌、活性和胞内过程。随着深入的研究,探索出了一些以FGF23为靶点治疗骨矿物质代谢障碍疾病的新疗法。本文综述了FGF23在骨矿物质代谢中的作用及其调控机理的研究进展,以期为相关研究提供参考依据。     

Hypocalcemia in a dog

A case of hypocalcemia was presented with a concurrent hyperphosphatemia. Normal renal function tests excluded primary renal insufficiency. The diet was thought to contain a normal ratio of calcium and phosphorus and, therefore, nutritional secondary hyperparathyroidism was not considered. The radiographs showed normal bone density and the dog was not lame. Concentrations of immunoreactive parathyroid hormone were measured in an attempt to classify the etiology. The dog was successfully managed with calcium supplementation and vitamin D(3) or oral calcium alone.     

Osteodystrophia fibrosa in two guinea pigs.

Two adult guinea pigs were examined because they were lethargic and reluctant to walk. Additionally, I guinea pig had otitis media, and the other had dental malocclusion. Both guinea pigs had been fed a commercially available diet of cereals and pellets enriched with vitamin C and formulated for this species. Radiographically, the guinea pigs had coarse trabecular bone patterns, skeletal deformations, pathologic fractures, and polyarthritic degenerative joint disease. A double cortical line was also evident on several long bones, the pelvis, and the vertebrae. A diagnosis of osteopenia was confirmed by use of dual-energy x-ray absorptiometry. Analysis of a food sample fed to 1 guinea pig revealed calcium and phosphorus contents of 0.524 and 0.425%, respectively (Ca:P ratio, 1.23:1). Microscopic examination of bone tissue from both guinea pigs revealed severe fibrous osteodystrophy. Nutritional secondary hyperparathyroidism caused by calcium-phosphorus imbalance was considered to be the underlying cause of osteodystrophia fibrosa in both guinea pigs.     

Successful therapy of vitamin D-dependant rickets in a kitten

A 7 mo old, 2.4 kg, intact female kitten was evaluated for an inability to walk after falling out of the owner's arms. Diagnostic testing abnormalities included hypocalcemia, low ionized calcium, and elevated intact parathyroid hormone concentration. The 25-hydroxyvitamin D level was normal. Radiographic abnormalities included generalized osteopenia, a nondisplaced, folding fracture of the proximal right fibula, and sclerosis with a compression fracture of the proximal right tibia. Based on these findings and response to calcium carbonate and calcitriol therapy, a diagnosis of vitamin D-dependent rickets was made. Reports of similar cases in veterinary medicine are sparse and no other reports to date document radiographic abnormalities with a successful therapeutic outcome.