Calcium metabolic disorders

Preparation and Medicaments Containing These Compounds C. Tsaklakidis etal, US Patent 5,538,957 (July 23, 1996) Assignee Boehringer Mannheim GmbH Utility Treatment of Calcium Metabolic Disorders... 

Bisacylphosphonates (50) and bishydroxyiminophosphonates (51) were found to be the first examples of non-geminal bisphosphonates biologically active in calcium metabolism disorders such as pathological calcification and bone resorption These compounds showed less toxic side-effects and improved bioavailability than bisphosphonates approved for clinical use. ... 

In addition to the well-known iron effects on peroxidative processes, there are also other mechanisms of iron-initiated free radical damage, one of them, the effect of iron ions on calcium metabolism. It has been shown that an increase in free cytosolic calcium may affect cellular redox balance. Stoyanovsky and Cederbaum [174] showed that in the presence of NADPH or ascorbic acid iron ions induced calcium release from liver microsomes. Calcium release occurred only under aerobic conditions and was inhibited by antioxidants Trolox C, glutathione, and ascorbate. It was suggested that the activation of calcium releasing channels by the redox cycling of iron ions may be an important factor in the stimulation of various hepatic disorders in humans with iron overload. 

In light of the increased number of man-6-P/IGF-II receptors in I-cell fibroblasts, the above interactions of IGF could have far-reaching effects. For example, I-cell disease has not been typically associated with abnormalities in phos-phorous/calcium metabolism. The extensive skeletal deformities could involve impairment of mechanisms of orderly calcium deposition. Rather than resulting from a primary disorder of calcium metabolism, it is possible that the bone lesions in I-cell disease are secondary to altered lysosomal processing events in the kidney or liver. 

The average adult contains more that 1 kg of calcium, this being the most prevalent metallic element. The major proportion is contained within the bone (99%) the remainder being in teeth and soft tissues [20]. Plasma calcium represents only a minute fraction (0.03%) of total body calcium yet alteration in the concentration of this fraction can usually accurately reflect underlying disorders of calcium metabolism which are of great importance in clinical medicine. 

Not all calcium present in the diet is absorbed by the small intestine and mechanisms are present to ensure only amounts appropriate to body needs are absorbed. These processes are complex and involve the interaction of special transport protein, vitamin D and parathormone. Thus, abnormalities of calcium metabolism may result from many different disease processes. Diseases affecting the bowel may prevent normal absorption, diseases of the parathyroid gland may result in inappropriate levels of parathormone for calcium requirement and a nutritionally inadequate diet may cause vitamin D deficiency with consequent disordered calcium absorption. 

In patients with suspected disorders of vitamin D and calcium metabolism, caution has to be taken (SEDA-9, 269). 

Disorders of calcium metabolism are separated into those causing hypocalcemia and hypercalcemia. 

Bone and mineral disorders are common in patients with renal disease. Therapy and calcium metabolism of these patients are best evaluated with the determination of free calcium because of alterations in protein, pH, protein binding of calcium, and calcium complexes with organic and inorganic anions. Total and adjusted calcium concentrations are often invalid when compared with free calcium measurements... 

Saggese G, BaronceUi GI, Bertelloni S. Determination of intact parathyrin by immunoradiometric assay evaluated in normal children and in patients with various disorders of calcium metabolism. Clin Chem 1991 37 1999-2001. 

Thode J, Hohnegaard N, Transbol I, Fogh-Andersen N, Siggaard-Andersen O. Adjusted ionized calcium (at pH 7.4) and actual ionized calcium (at actual pH) in capillary blood compared for clinical evaluation of patients with disorders of calcium metabolism. Chn Chem 1990 36 541-4. 

Calcitonin is used in the treatment of Paget s disease (osteitis deformans), a chronic disorder characterized by increased bone remodeling, normocalcemia and normophosphatemia, frequent episodes of hypercalciuria leading to stone formation, and elevation of serum alkaline phosphatase and urinary hydroxyproline levels. The disease does not appear to be primarily a derangement of calcium metabolism. Calcitonin reduces the levels of serum alkaline phosphatase and urinary hydroxyproline, and may relieve other symptoms of the disease as well. Diphosphonates, especially etidronate disodium, also reduce bone resorption in this disease. Various cancers are accompanied by hypercalcemia and may respond to treatment with calcitonin. 

A multiphcity of metabolic disorders in patients with CKD contributes to worsening sHPT and the consequences associated with elevated PTH (Fig. 44-4). The continuous production of PTH by the parathyroid glands leads to parathyroid hyperplasia (nodular or diffuse). Nodular tissue demonstrates more rapid growth potential and appears to be associated with fewer vitamin D and calcium-sensing receptors, which results in resistance to the effects of calcium and vitamin D therapy and subsequent development of ROD. Bone loss can be detected in patients with early stages of kidney disease and multiple types of bone lesions have been identified from bone biopsies of patients on dialysis. The skeletal complications associated with ROD... 

Extraskeletal calcification occurs in several conditions unrelated to demonstrable abnormalities of calcium metabolism, such as scleroderma, myositis ossificans, calcinosis universalis, calcinosis cutis, and local tissue damage in the kidney. These disorders are not usually associated with changes in serum alkaline phosphatase (B30). Elevated values have, however, been reported in paraplegic patients with ectopic bone formation (F23), and a positive correlation has been demonstrated between the activity of serum alkaline phosphatase and the progression of this disorder. Nicholas (N4) claimed that hyperphosphatasemia in such a situation may help to differentiate thrombophlebitis, septic arthritis, and cellulitis from ectopic bone formation. 

Coe, F.L. Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria or no metabolic disorders. Ann. Int. Med. 87 404-410 (1977). 

Vascular calcification is a process that involves accumulation of calcium deposits in vessel walls, resulting in increased arterial wall stiffness. Extra-osseous calcification occurs in areas of chronic inflammation, as in atherosclerotic lesions, in which oxidized lipids are the inflammatory stimulus. However, nonatherosclerotic calcification can occur in metabolic disorders like end-stage renal disease, diabetes, hyperparathyroidism, and vitamin K deficiency. This involves a complex interplay of various factors such as serum calcium and phosphate levels, activity of calcification promoters and inhibitors. Vascular calcification is associated with increased morbidity and mortality, predominantly from cardiovascular causes. ... 

Calcium metabolism is disregulated in active sarcoidosis. The primary disorder in calcium metabolism stems from an increase 1-a hydroxylase activity in sarcoid alveolar macrophages that converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active form of the vitamin (177-179). This may manifest as hypercaluria, hypercalcemia, and nephrolithiasis with possible renal insufficiency (180). 

The reported incidence of hypercalcemia in sarcoidosis has varied from 2% to 63% in various series (180). These disparate findings may be attributable to differences in sunlight exposure, dietary calcium, skin color, and genetic factors of the populations studied. ACCESS found that a disorder in calcium metabolism from sarcoidosis was more common in men than women [17/268 (6.3%) versus 10/468 (2.1%), chi-square 7.38, p < 0.01], Caucasians compared to African Americans [20/393 (5.1%) versus 6/325 (1.8%), chi-square 223, p < 0.0001], and those diagnosed >age 40 years compared to <40 years [22/401 (5.5%) versus 5/335 (1.5%), chi-square 7.15, p < 0.01] (2). 

It is important to exclude alternative causes of hypercalcemia and hypercaluria before concluding that sarcoidosis is the cause. The three most common causes of hypercalcemia are primary hyperthyroidism, granulomatous disorders, and mahgnancies (183). It is important to exclude these disorders before initiating treatment for sarcoidosis-related disorders in calcium metabolism. At a minimum, a seram parathyroid hormone should be obtained and a medical history and physical examination should be performed. 

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