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Background: Due to the potentially crucial role of vitamin K 2 in calcium metabolism, a deficit can disrupt many mechanisms, resulting in an array of different issues, such as broken bones, stiff arteries and poor fertility. Although there has been existing research, the potential of vitamin K 2 as a treatment for conditions including cerebral palsy, parathyroid disease, heart disease and gastrointestinal disease is unknown. This review discusses the biochemistry of vitamin K and the metabolism of calcium, followed by an analysis of the current literature available on vitamin K 2 and its prospects., Methods: Using public libraries including PubMed and Wiley, we searched for existing research on the metabolism and use of vitamin K 2 that has been conducted in the preceding two decades., Results: Data indicated that vitamin K 2 had a positive impact on osteoporosis, cardiovascular disease, parathyroid disorders, cerebral palsy and sperm motility., Conclusion: Due to the existence of confounding variables and limitations in the quality and volume of research conducted, further investigation must be done to see whether the beneficial effects seen are reproducible and must assess the viability of vitamin K 2 as treatment in isolation for these conditions.

Background/aims: Parathyroid hormone (PTH) derivatives exert pronounced renal and osteoanabolic properties when given intermittently. The current study was performed to assess the pharmacokinetic and pharmacodynamic properties as well as safety of subcutaneously applied PTH-1-37 after repeated dosing in healthy subjects., Methods: This randomized, double-blind, dose-escalating, placebo and active comparator controlled study was conducted in 33 healthy postmenopausal women. Subjects were allocated to one of five treatment options: 10, 20, or 40 µg PTH-1-37, 20 µg PTH-1-34 or placebo, administered as once daily subcutaneous doses for three days. Plasma drug concentrations and serum levels of endogenous PTH-1-84, and calcium as markers of biological activity were monitored during the treatment., Results: PTH was absorbed rapidly from the subcutaneous tissue with a median tmax of 30 minutes for 20 and 40 µg of PTH-1-37. tmax was 45 minutes for 20 µg PTH-1-34. Elimination half-lives were estimated as 76 ± 34 min and 70 ± 13 min for 20 µg and 40 µg PTH-1-37 (mean ± SD), and 78 ± 34 for 20 µg PTH-1-34. Both PTH fragments (PTH-1-37 and PTH-1-34) increased serum calcium. For PTH-1-37 the effect on serum calcium was dose-dependent. Suppression of endogenous PTH-1-84 was seen after the application of both PTH-1-37 and PTH-1-34. During the study period, the subjects experienced no unexpected or serious adverse events., Conclusions: PTH-1-37 is rapidly absorbed after s.c. injection, has a short plasma elimination half-life, and does not accumulate during multiple dosing. Biological activity was demonstrated by rising serum calcium and decreasing endogenous PTH-1-84 in blood plasma. The study drugs were well tolerated and safe. Our investigation presents data that PTH-1-37 is an excellent drug candidate for intervening with syndromes of dysregulation of calcium metabolism., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

The majority of clinical complaints derive from disorders of calcium metabolism and are associated with a wide variety of clinical symptoms caused by numerous diseases with entirely different types of pathophysiology. The prognosis varies from favorable to fatal depending on the pathophysiology of the underlying disorder of calcium metabolism; therefore, the diagnostic work-up aims to quickly identify the underlying disease causing the disturbance in calcium homeostasis. Every clinical situation with a diminished state of calcium absorption is treated with calcium and vitamin D in varying doses whereas every disorder with an increased calcium absorptive or resorptive state is treated with improved diuresis in addition to antiresorptive drugs, such as bisphosphonates. In many situations the management of a disturbed calcium balance requires an interdisciplinary approach in order to treat the underlying disease in parallel with correction of the calcium homeostasis.

Aim: To evaluate the efficacy and safety of alfacalcidol and paracalcitol used to correct impaired phosphorus-calcium metabolism (PCM) in patients with predialysis chronic kidney disease (CKD)., Subjects and Methods: Examinations were made in 128 patients with Stages III-V CKD, including 89 (69.5%) patients with chronic glomerulonephritis, 30 (23.4%) with chronic tubulointerstitial nephritis, and 9 (7.1%) with hypertensive nephrosclerosis. Impaired PCM was detected in 90 (70.3%) of the examined patients. According to the pattern of the previous therapy, all the 90 CKD patients with PCM disorders were divided into 3 groups: 1) 32 patients with Stages IIIB-V CKD who had taken oral alfacalcidol 0.25 microg/day; 2) 28 patients with Stages IIIB-V CKD who had used oral paricalcitol 1 microg/day; 3) 30 patients with Stages IIIB-V CKD who had not received, as self- motivated, active vitamin D metabolites at the predialysis stage., Results: Alfacalcidol and paricalcitol were quite satisfactorily tolerated by the patients. After 3 months of initiation of the use of these agents, Groups 1 and 2 patients with predialysis CKD and baseline elevated blood intact parathyroid hormone (iPTH) levels could not only achieve, but also maintain target blood iPTH levels. In the patients taking paricalcitol, the urinary protein level decreased more promptly; moreover, by the end of month 6 the reduction in blood pressure (BP) was more significant than in those using alfacalcidol (p < 0.05). Comparison of the effects of angiotensin-converting enzyme inhibitors in combination with alfacalcidol or paricalcitol on BP changes and left ventricular mass index indicated that the most pronounced positive changes occurred when angiotensin-converting enzyme inhibitors were used in combination with paricalcitol., Conclusion: The use of paricalcitol in predialysis CKD with PTH hyperproduction results in not only normalization of the levels of both PTH and osseous isoenzyme of alkaline phosphatase, but also in significantly reduced daily proteinuria and regression of left ventricular hypertrophy and chronic heart failure.

Recombinant human parathyroid hormone (PTH) analogues reduce fractures in patients with osteoporosis by enhancing bone formation and improving bone quality. Furthermore, many studies have demonstrated the efficacy of these analogues in diseases such as PTH-deficient hypoparathyroidism, bisphosphonate-related osteonecrosis of the jaw and hypophosphatasia. Further studies are needed to examine the long-term effects and the safety of these analogues in children and cancer patients.

Purpose of Review: Calcium metabolism impairments have long been recognized as a complication of sarcoidosis. For more than six decades physicians and investigators have been trying to elucidate this severe problem; nevertheless it seems puzzlingly new for both readers and researchers., Recent Findings: This review highlights the problems of calcium metabolism in sarcoidosis in relation to vitamin D synthesis, which is definitely altered by granulomatous inflammation. Increasing evidence suggests that vitamin D is an immunomodulating hormone that inhibits both antigen presentation by cells of the innate immune system, and the cytokine release and proliferation of Th1 cells. As calcium homeostasis is primary controlled by levels of vitamin D, parathyroid hormone (PTH) and calcitonin, this literature review emphasizes the role of general immunomodulating properties of vitamin D and the correlation with calcium metabolism impairments, with the special accent on already known interactions with sarcoidosis., Summary: Granuloma formation has been related to a failure of the innate immune system. One of the possible explanations is a vitamin D deficiency. The evidence-based findings on calcium metabolism impairments and the interactions with vitamin D might help both clinicians and researchers in developing new strategies.

The authors present literature data on the role of Ca-P metabolism and its regulators in the development of bone and cardiovascular pathology, intrauterine development, organogenesis, cell growth and differentiation. A large number of agents are currently available to modify Ca-P metabolism. (calcium and vitamin Dpreparations, PTH, calcitonin, stimulators of Ca-sensitive receptors, calcitriol receptor ligands, etc.) although their application is hampered by the dificulty of laboratory control and the lack of basic knowledge. It is maintained that raising awareness among practitioners about these issues may improve diagnostics of Ca-P metabolic disorders (in the first place, calcium and vitamin D deficiency, secondary hyperthyroidism) and promote their medicamental and non-medicamental therapy.

Importance of the Field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders., Areas Covered in This Review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation., What the Reader Will Gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction., Take Home Message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.

Widespread vascular calcification is a ubiquitous feature of aging and is prevalent in association with a number of common pathologies including atherosclerosis, renal failure, and diabetes. Once thought of as innocuous, emerging evidence suggests that calcification is causal in precipitating vascular events and mediating chronic cardiovascular damage, independent of disease context. Importantly, a large body of data has shed light on the factors that favor the formation of calcification in vivo, as well as on the complex mechanisms that initiate and promote it. This has identified some novel targets and allowed for the possibility that calcification can potentially be blocked and ultimately regressed. Targets include local and circulating inhibitors of calcification as well as factors that may ameliorate vascular smooth muscle cell (VSMC) apoptosis. Despite this, the vasculature remains a difficult tissue to target and currently there are no effective treatments in general use. More crucially, any potential treatments will need to be carefully evaluated as they may impinge on bone metabolism. Our best hope for the near future is to normalize factors associated with accelerated calcification in pathologies such as renal failure where, aberrant mineral metabolism, as well as treatment regimes, may contribute to the initiation and progression of calcification.

Calcium and bone disorders in paediatrics are treated with a variety of drugs, many of which, although licensed for use in adults, are not so in children but are nevertheless used on the basis of accepted practice. The mainstay of drug treatment for osteoporosis is the bisphosphonates which alter the balance between bone accretion and reabsorption mainly by temporarily reducing the activity of osteoclasts. Vitamin D and its metabolites are used for the treatment of various forms of rickets and vitamin D deficiency and the active metabolites are also employed when hypoparathyroidism causes hypocalcaemia. Phosphate supplements may also be required in some forms of rickets. Hypercalcaemia is treated initially with hyperhydration and diuretics but may require more specific treatment with either calcitonin or bisphosphonates. Several newer drugs have either recently been introduced or are under consideration. These include the calcimimetics (cinacalcet), rank ligand inhibitors (osteoprotegerin and denusomab), cathepsin K inhibitor, sclerostin, bone morphogenic protein 2, and calciolytic drugs. More recently, recombinant alkaline phosphatase and PTH have been used to treat hypophosphatasia and hypoparathyroidism respectively. These developments promise to direct treatment more specifically to targeting individual conditions as our understanding of these conditions increases., (Copyright (c) 2009 S. Karger AG, Basel.)

Mineral metabolism disorders are well-recognized complications in patients with chronic kidney disease (CKD). Furthermore, hyperphosphatemia and secondary hyperparathyroidism are associated with both renal osteodystrophy and cardiovascular disease. During the last 5 years, new therapeutic options have become available to treat these conditions in CKD. We describe the case of a 70-year-old lady with a dialysis history of 5 years and a number of cardiovascular risk factors (hypertension, hypercholesterolemia and obesity). Unfortunately, the patient was poorly compliant with any pharmaceutical treatment. After 2 years, a pharmacological approach with a low dosage of calcium salts and sevelamer HCl, subsequently changed to lanthanum carbonate, intravenous paricalcitol, and cinacalcet HCl reached the goals suggested by the current guidelines. Every nephrologist should look at the pathogenesis and treatment of hyperphosphatemia and secondary hyperparathyroidism. New options are now available and may help the clinician to obtain satisfactory short- and long-term outcomes in the treatment of this disease.

Chronic kidney disease (CKD) causes various bone mineral disorders, which have recently been named CKD mineral and bone disorder (CKD-MBD). CKD-MBD is associated with extremely high cardiovascular disease (CVD) morbidity and mortality in the endstage kidney disease (ESKD) population. Thus, optimal management of CKD-MBD would lead to a reduction in cardiovascular morbidity and mortality in uremic patients. In addition, it has been suggested that the treatment of CKD-MBD has some favorable effects on the progression of CKD. Recently, novel therapeutic agents, including active vitamin D analogues, noncalcium-containing phosphate binders, and cinacalcet, have become clinically available. In this article, we review novel therapeutic strategies for CKD-MBD.

Disorders of the phosphocalcic metabolism are frequent in dialysis patients. Such disorders are difficult to treat and have negative impact on bone health, but also on cardiovascular mortality. Hyperphosphoremia is a strong predictor of cardiovascular mortality. New phosphate binders are now available in Belgium. A new molecule acting on the calcium receptor of the parathyroid glands is able to control secondary and tertiary hyperparathyroidism in dialysis patients. These new therapies, specific for dialysis patients, will be reviewed in this article.

Objective: Total gastrectomy produces osteopenia with calcium malabsorption. We previously demonstrated that difructose anhydride III (DFAIII), a non-digestible disaccharide, stimulates intestinal calcium absorption in normal and ovariectomized rats. In the present study, we examined the effects of feeding DFAIII on gastrectomy-induced calcium malabsorption and osteopenia in rats. The potential of DFAIII to promote large intestinal calcium absorption was also evaluated through comparison with that of fructooligosaccharides (FOS)., Material and Methods: Male Sprague-Dawley rats were divided into two groups: totally gastrectomized and sham-operated rats. After a postoperative recovery period, rats from each group were divided into three subgroups and fed the control, DFAIII (30 g/kg), or FOS (30 g/kg) diet for 28 days., Results: Total gastrectomy severely reduced net calcium absorption, femoral calcium content and bone mineral density, resulting in fragility of the femur. DFAIII or FOS feeding partly and similarly restored the lowered calcium absorption and femoral variables, with an increase in the total short-chain fatty acid pool in the cecum. In gastrectomized rats, net calcium absorption was correlated with several cecal parameters, suggesting that cecal fermentation of DFAIII is associated with the improvement in gastrectomy-induced calcium malabsorption. Urinary excretion of deoxypyridinoline (D-Pyr) as a marker of bone resorption was increased by gastrectomy, and the elevated D-Pyr excretion was suppressed by feeding DFAIII., Conclusions: Supplemental feeding of DFAIII partly prevents postgastrectomy osteopenia as a result of an improvement in calcium absorption. Our results suggest that the promotive effects of DFAIII on calcium absorption in the large intestine are comparable to those of FOS.

Bone disease in patients with type 2 diabetes mellitus (DM) is characterized by low bone turnover, resulting from either impaired secretion of parathyroid hormone or osteoblasts dysfunction. We have reported that intracellular sorbitol accumulation via. sorbitol pathway might be involved in the development of osteoblast dysfunction and osteoclast formation, as evidenced by either in vitro or in vivo study. The importance of metabolic pathway is further supported by the protective effect of aldose reductase inhibitor against the development of galactose-induced bone diseases in vivo and of functional impairments of human osteoblasts-like MG-63 cells. In conclusion, sorbotol pathway might be important in the development of low bone turnover disease in DM patients, and thus aldose reductase inhibitor might be clinically useful in the protection against the development of bone diseases in DM patients.

Abnormalities of mineral metabolism, including those of calcium (Ca), phosphorus (P), and parathyroid hormone (PTH) in patients on maintenance hemodialysis induce severe bone involvement, which manifests as renal osteodystrophy. Recently, vascular calcification caused by abnormal mineral metabolism has been attracting attention because cardiovascular diseases (CVD) are a major cause of death in hemodialysis patients. Since 2000, the treatment standard for overt secondary hyperparathyroidism (SHPT) in our facilities has shifted from conventional or pulse therapy with oral vitamin D3 (VitD) to intravenous pulse therapy with maxacalcitriol or calcitriol. After selecting the criterion of overt SHPT as intact-PTH>500 pg/mL, the proportion of overt SHPT cases among all hemodialysis patients decreased from 12% at the start of intravenous pulse treatment to 6.4% after 4 years' treatment. However, the number of patients who had an interruption to pulse treatment because of hypercalcemia and/or hyperphosphatemia was high and it became a bottleneck for the continuation of the therapy. The major cause of hypercalcemia is considered to be Ca load derived from oral calcium carbonate. In Japan, sevelamer hydrochrolide (SH), which does not contain Ca, has been available commercially since 2003 and potentially should enable a reduction in the incidence of overt SHPT during long-term intravenous treatment when combined with careful adjustment of the dose of VitD and strict monitoring of Ca and P level concentrations. In this study, we found that the proportion of patients who satisfy the recommended serum concentrations of Ca and P reported by K/DOQI guideline was low irrespective of the serum concentration of intact-PTH. The aortic calcification index was high in the patient group with lower intact-PTH level concentration, probably because of reduced Ca and P buffering ability associated with reduced bone turnover. We consider that VitD treatment with SH might give better control of the intact-PTH level concentration within the range recommended by the K/DOQI guideline.

In chronic renal failure, hyperphosphatemia, hypocalcemia, hyperparathyroidism, reduced activation of vitamin D, decreased level of calcium-sensing receptor, osteitis fibrosa, and osteomalacia are features related to calcium abnormalities. Hyperparathyroidism is a risk factor for survival of hemodialysis patients as well as hypoparathyroidism, which is another feature in hemodialysis patients. Treatment of these abnormalities includes control of parathyroid hormone (PTH) secretion, counteracting hyperphosphatemia, correction of hypocalcemia, and others. Various kinds of vitamin D analogs have been introduced recently in addition to calcitriol and alfacalcidol, which have a rather long history (eg, maxacalcitol and falecalcitriol). Sevelamer is a newly developed phosphate binder to treat soft-tissue calcification.

Purpose: We tested whether UroPhos-K, a new slow release neutral form of potassium phosphate (155 mg. phosphate, 8 mEq. potassium per tablet) in a dose of 4 tablets twice daily would produce a sustained hypocalciuric response and maintain bone mass in patients with absorptive hypercalciuria, a major cause of nephrolithiasis characterized by excessive intestinal calcium absorption accompanied in some patients by excessive bone loss., Materials and Methods: A total of 25 patients with absorptive hypercalciuria were studied in a 4-year, prospective, open trial with UroPhos-K at yearly intervals during a 4-day inpatient physiological study with a constant metabolic diet containing 400 mg. calcium, 100 mEq. sodium and 800 mg. phosphate daily., Results: Treatment with UroPhos-K caused a sustained, marked reduction in urinary calcium (264 to 181 mg. daily). Fractional 47calcium absorption decreased modestly (74.0 to 64.6%) commensurate with a reduction in serum 1,25-dihydroxyvitamin D (42 to 34 pg./ml.). Intact parathyroid hormone increased within the normal range (30 to 42 pg./ml.). Bone mineral density was stable at the lumbar spine, femoral neck and distal third of the radius., Conclusions: UroPhos-K may provide a long-term alternative for hypercalciuric patients in whom thiazide therapy fails.

Correction of impaired phosphoric-calcium metabolism was performed in 15 hemodialysis patients with terminal chronic renal failure (TCRF). For this purpose a synthetic analogue of pyrophosphoric acid xidiphone produced in Russia was used (2% aqueous solution 1 tablespoon 3 times a day 0.5 h before meal for 2-3 months). Prior to and in the course of xidiphone treatment all the patients received calcium gluconate (1 g x 3 daily), polyvitamins, on-demand digoxine. Measurements of serum concentrations of urea, potassium, sodium, total calcium, alkaline phosphatase activity demonstrated xidiphone-related normalization of serum total calcium, serum activity of alkaline phosphatase, a mild rise of sodium. The results say in favor of using xidiphone in the TCRF patients.

Background: Etidronate and pamidronate are bisphosphonates, a class of chemical compounds originally used to soften hard water and prevent soap scum. Etidronate was serendipitously found to abate calcification in a child with myositis ossificans progressiva., Objective: Review the basic pharmacology of these compounds, as well as clinical uses of the approved and nonapproved forms., Discussion: Etidronate is approved for the treatment of hypercalcemia, Paget's disease of bone, and ectopic calcification, and has been used to treat hyperparathyroidism and nephrolithiasis with limited success. Recently it has been used to treat osteoporosis. Pamidronate is approved to treat hypercalcemia. These two drugs are the only bisphosphonates available in the United States., Conclusions: Clinical trials with etidronate have aroused widespread interest in the application of bisphosphonates to treat osteoporosis. Many trials are underway to evaluate these new drugs. More information will be available within the next 5 years.

Background: The effect of calcium restriction on the plasma concentration of 1,25(OH)2D in normo- and hypercalciuric children remains unknown., Methods: We studied phosphate and calcium metabolism of 8 normocalciuric and 8 hypercalciuric children aged 4 to 16 years, under 3 conditions: on a normal dietary calcium intake after a 5-day calcium-restricted diet, and after oral calcium loading. The healthy, normocalciuric children had histories that included no renal failure of abnormalities of phosphate and calcium metabolism. Four of the 8 hypercalciuric children had urolithiasis, 1 had hematuria and the 3 others had idiopathic hypercalciuria. Blood samples were analyzed for calcium, creatinine, immunoreactive parathyroid hormone, cAMP, 25(OH)D and 1,25(OH)2D concentrations. Urine samples were analyzed for calcium, phosphorus, creatinine and cAMP., Results: On the normal dietary calcium intake, the hypercalciuric children had higher urinary calcium excretion and plasma 1,25(OH)2D levels and lower TmP that did the controls. The 1,25(OH)2D levels of the normocalciuric children were significantly increased after 5 days of dietary calcium deprivation, but those of the hypercalciuric children were not. The other parameters (essentially PTH, cAMP and TmP) varied similarly in the two groups., Conclusion: The results suggest that: a) calcium restriction influences 1,25(OH)2D levels in normocalciuric subjects via a PTH- and phosphor-independent mechanism; b) dietary control of renal vitamin D metabolism is impaired in hypercalciuric patients.

Children with hyperprostaglandin E syndrome, a neonatal variant of Bartter syndrome with enhanced renal and systemic formation of prostaglandin E2, have hypercalciuria, nephrocalcinosis, and osteopenia. Because prostaglandin E2 affects tubular calcium handling, stimulates the formation of calcitriol in vitro, and has osteolytic activity, we studied calcium homeostasis and the influence of prostaglandin E2 formation on hypercalciuria in nine patients with hyperprostaglandin E syndrome during long-term indomethacin treatment and after its withdrawal. Suppression of prostaglandin E2 formation by indomethacin resulted in improvement of biochemical and clinical features of hyperprostaglandin E syndrome. However, hypercalciuria, osteopenia, and nephrocalcinosis did not completely resolve. Despite a low calcium diet, daily urinary calcium excretion was enhanced during and after withdrawal of indomethacin treatment (median 6.3, range 5.3 to 14, and median 9.4, range 4.4 to 38 mg/kg per day, respectively). Daily urinary calcium excretion was greater after withdrawal than during indomethacin treatment. Urinary calcium excretion was not correlated with urinary prostaglandin E2 excretion. Plasma levels of intact parathyroid hormone (median 11, range 6.8 to 12 pmol/L) and calcitriol (median 157, range 108 to 236 pg/ml) were elevated during indomethacin treatment and decreased after withdrawal of indomethacin. These data suggest that hypercalciuria in hyperprostaglandin E syndrome is mainly due to a renal leak of calcium, which is caused by enhanced renal formation of prostaglandin E2 and a tubular defect not related to prostaglandin E2 formation. There is no evidence for prostaglandin-stimulated calcitriol formation. Decreasing plasma levels of parathyroid hormone in the presence of renal calcium losses after withdrawal of indomethacin treatment may be due to a bone resorption process caused by systemic prostaglandin formation; the process may contribute to hypercalciuria in the patient not receiving indomethacin.

The investigation of a number of 286 patients having disorders of binocular seeing shows a very frequent association of these to spasmophilia, especially for persons of feminine sex during their third or fourth decades of life. The medicamentous treatment of spasmophilia has ameliorated the disturbing binocular seeings, which had appeared again after stopping the treatment for a long time. The authors recommend the cover-test end the examination using Maddox's experiment for tracing rapidly out the binocular seeing disturbings. In order to stimulate the movements of the ocular globe in an reverse sense to the deviation formed by the oculomotor existed lack of poise, it had been used the prescription of classes with prisms assembled conversely to the classic rules, having the indication of wearing them for 3-4 hours a day.

The aim of the present work was to reveal the relationship between vitamin A serum levels and some indicators of metabolic calcium and phosphorus disorders in patients in a long-term dialyzation programme. Thirty-six patients in a long-term dialyzation programme were divided into three groups. Group A comprised 11 patients who were treated for 3-9 months but without specific treatment, group B was formed by 10 patients treated for 2-5 years who were given calcium carbonate, 3 g/24 h, by the oral route for a period of six months and group C which comprised 15 patients treated for 3-10 years who were given 1 alpha, 25-dihydroxycholecalciferol (Rocaltrol), 0.25 micrograms/24 h for a period of six months. At the end of the investigation a significant rise of total calcium and serum Ca2+ occurred in all three groups of patients an a significant decrease of increased value of phosphorus, C-PTH and vitamin A in serum in groups B and C. In group A which was without treatment there was a significant increase of serum C-PTH and vitamin A after six months. The concentration of retinyl esters in serum was within the reference range of there were undetectable values throughout the investigation in all patients. A direct relationship was found between total calcium and vitamin A, alkaline phosphatase and C-PTH in serum in all 36 patients at the onset of the dialyzation programme. Moreover there was a direct relationship between C-PTH and vitamin A in groups, A, B and C at the onset of the investigation and in groups and vitamin C at the end of the investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanism of hypocalcemia was assessed prospectively in 10 gastroenterological hypomagnesemic patients. Baseline serum magnesium was 0.9 +/- 0.1 mg/dl and calcium, 7.2 +/- 0.4 md/dl. Plasma 25-hydroxyvitamin D (25 (OH)D) was low in 5 patients and normal in the others. Plasma parathormone (PTH) and urinary cyclic AMP (ur. cAMP), although twofold above normal values, were inappropriately low and increased sharply after a magnesium bolus injection. There was no renal resistance to PTH as ur. cAMP increased after i.v. bovine PTH bolus injection. Subsequently, patients were randomly divided into 2 groups, each including patients with low or normal levels of 25 (OH)D, receiving either MgCl2 (group I) or 1 microgram/d of 1-alpha (OH)D (group II) for one week. Although magnesium status remained low in group II patients, increase in plasma calcium was identical in both groups. Serum calcium levels in patients receiving combined 1-alpha (OH)D and MgCl2 during a second week of treatment returned to normal. In the 4 tested patients, plasma 1,25 (OH)2D levels were low before, but also after correction of hypomagnesemia, suggesting that low level of 1,25 (OH)2D might not be due to hypomagnesemia. Therefore, treatment with low dosage of 1-alpha (OH)2D associated with magnesium chloride repletion can be recommended to restore normal calcium homeostasis in patients with intestinal hypomagnesemia.

Xydofon was applied to the treatment of 68 children suffering from different renal diseases associated with metabolic disorders. The latter ones involved oxaluria (28 children), uraturia (17 children), cystinuria (14 children), and phosphaturia (9 children). To appraise the action of xydofon, use was made of the indicators of membranolysis, cellular homeostasis of calcium, lipid peroxidation, and of the level of beta 2-microglobulin in urine. The results obtained indicate that xydofon can be used as an effective remedy for the treatment of children suffering from nephropathies associated with metabolic disorders.

In inherited renal tubular disorders with isolated defects of tubular transport medical treatment is usually either not indicated or is simple and effective. In some inherited metabolic disorders with complex defects of renal tubular transport a specific therapy is known. For example, in galactosemia and hereditary fructose intolerance crude products may be restricted or in cases of Wilson's disease copper stores may be reduced. In idiopathic Fanconi syndrome, cystinosis, oculocerebrorenal syndrome and glycogenosis Fanconi-Bickel, a symptomatic replacement treatment based on supplementation of water, electrolytes and vitamin D has improved the non-uremic survival of these patients considerably within the last 20 years. For long-term management of inherited renal tubular disorders, treatment of tubular dysfunction, chronic renal failure, and involved extrarenal organs must be supported by genetic counseling and assistance for social integration.

The geminal bisphosphonates are characterized by a PCP bond and are therefore analogs of pyrophosphate. They bind strongly to hydroxyapatite crystals and in vitro inhibit both crystal formation and dissolution. In vivo they inhibit soft tissue calcification and when given in large amounts also normal calcification. This effect is due to the inhibition of calcium phosphate crystal growth. Furthermore, the bisphosphonates are very potent inhibitors of bone resorption. The mechanism(s) of action is not yet known but is likely to be at a cellular level. The extent of the biological activity of each compound depends on the specific chemical structure, so that each individual bisphosphonate must be considered as a separate compound. The only common characteristic is the PCP group, which gives the compound its high affinity to bone. The individual effects, however, are determined by the side groups on the carbon atom. This opens interesting possibilities for the development of new compounds. No bisphosphonate analyzed so far can be degraded in vivo; all are either deposited in the skeleton, where they remain for years until the bone is destroyed, or are excreted in the urine. The high affinity for bone explains the specificity of the compounds for bone and the fact that they have relatively few nonosseous effects. Bisphosphonates are used in man to inhibit ectopic calcification, including dental tartar and ectopic ossification. Furthermore, they are used to inhibit bone resorption, especially in diseases such as Paget's disease and tumoral osteolysis. Finally, when linked to 99nTc, bisphosphonates are employed as bone scanning agents.

Hypercalciuria may be due to increased bone resorption, increased intestinal absorption, increased renal excretion or due to hypophosphatemia. Examination of the serum for calcium, phosphorus, parathyroid hormone and 1,25(OH)2D3, and of the urine for calcium, phosphorus and cyclic AMP will help arrive at the correct diagnosis. Therapies specific for each type of hypercalciuria are available and can be used. However, a more simplified diagnostic approach, and the use of thiazide diuretics for therapy, will usually suffice in the majority of patients.

Orthophosphate treatment of patients with idiopathic hypercalciuria reduces the urinary excretion of calcium. To examine the role of altered vitamin D metabolism in reducing the renal excretion of calcium, we studied 11 patients with idiopathic hypercalciuria before and after 2 weeks of treatment with oral neutral orthophosphate (2 g phosphorus/day). Variables measured were urine calcium and phosphorus and seseserum calcium, phosphorus, immunoreactive parathyroid hormone, and 1,25-dihydroxyvitamin D [1,25-(OH)2D]. Oral phosphate treatment significantly decreased urine calcium excretion [mean change (delta), -123 mg/24 h], increased urine phosphorus (mean delta, serum levels of 1,25-(OH)2D (mean delta, -22 pg/ml). Pretreatment levels of 1,25-(OH)2D were high when compared with levels in age-matched controls, whether assessed as the arithmetic mean (57 vs. 33 pg/ml; P < 0.025), the logarithmically normalized (42 vs. 27 pg/ml). Phosphate treatment decreased serum levels of 1,25-(OH)2D to a mean of 35 pg/ml (logarithmically normalized mean, 22 pg/ml; median, 21 pg/ml), values not significantly different from those of normal controls. Serum calcium and phosphorus concentrations were not changed by treatment. Serum immunoreactive parathyroid hormone values increased minimally within the normal range (mean delta, +2 microleq/ml; P <0.025). We conclude that the effect of oral phosphate therapy in decreasing urinary calcium excretion may involve the reduced synthesis of 1,25-(OH)2D, independent of altered parathyroid function.

The effect of long-term hydrochlorothiazide therapy on renal calcium excretion was measured in 12 well defined cases of absorptive hypercalciuria and 10 of renal hypercalciuria. Patients were studied during a control phase, at 3 to 6 months of therapy and after long-term treatment with hydrochlorothiazide (mean 61 months for absorptive hypercalciuria and 71 months for renal hypercalciuria). Evaluation comprised measurement of urinary calcium and fractional (intestinal) calcium absorption while patients were maintained on a constant metabolic diet (400 mg. calcium per day) for 3 days. In patients with absorptive hypercalciuria urinary calcium decreased significantly at 3 months of treatment (from 266 to 137 mg. per day, p less than 0.001). However, with continued treatment urinary calcium rebounded to 197 mg. per day. Of the patients with absorptive hypercalciuria 50 per cent were hypercalciuric (greater than 200 mg. per day) on long-term treatment, whereas none was hypercalciuric at 3 months. In contrast, urinary calcium in the patients with renal hypercalciuria decreased from 299 to 104 mg. per day (p less than 0.001) at 3 months of treatment and remained reduced (116 mg. per day) during long-term treatment. Intestinal calcium absorption was increased initially and remained unchanged throughout treatment in the patients with absorptive hypercalciuria. In patients with renal hypercalciuria intestinal calcium absorption decreased significantly after short-term treatment with hydrochlorothiazide and remained so after long-term therapy. The results suggest that, unlike patients with renal hypercalciuria, some with absorptive hypercalciuria lose the hypocalciuric effect of hydrochlorothiazide during long-term treatment.

Forty-two patients with sarcoidosis were studied with special attention to renal disease and disturbance of calcium metabolism. Abnormal calcium metabolism was found in 19 patients and prednisone corrected hypercalcaemia in those affected within two weeks, except in one patient who had concomitant primary hyperparathyroidism. Renal failure was found in 19 patients, 15 of whom had hypercalcaemia. Prednisone had a beneficial effect on kidney function within four weeks in all patients except in one with co-existing glomerulonephritis. Arterial hypertension was found in six patients, proteinuria in six, and calcinosis in six. Among 14 patients who underwent renal biopsy, granulomas were found in five. In only one of these was granulomatosis extensive bringing out renal failure and death within two years after temporary remission with prednisone. Co-existent non-sarcoid diseases affecting the kidneys or calcium metabolism occurred in ten out of 23 patients with sarcoidosis and kidney disease/calcium abnormality. In most cases these conditions contributed more to the prognosis than did sarcoidosis. From the present series and review of the literature it appears that young males within the first two years of diagnosis are at the greatest risk of hypercalcaemia or kidney disease.

Extensive metabolic studies were performed in a 14-year-old boy suffering from the rare clinical entity known as childhood idiopathic hypercalciuria associated with dwarfism, renal tubular abnormalities and bone lesions. The salient features were: hyperphosphaturia with hypophosphatemia, hypercalciuria with normocalcemia, elevated serum 1,25-dihydroxycholecalciferol[1,25(OH)2D3] levels, marked intestinal hyperabsorption of calcium and phosphorus, with low serum parathyroid hormone (PTH) and urinary adenosine 3':5'-cyclic monophosphate (c-AMP). Bone biopsy confirmed the clinical and radiological diagnosis of rickets. It appears that the following pathophysiological sequence is operating: primary renal phosphate leak with hypophosphatemia, increased 1,25(OH)2D3 synthesis, enhanced intestinal calcium absorption which in turn inhibits release of PTH and c-AMP. Hypercalciuria is seen to be secondary to both avid intestinal calcium absorption and depressed PTH activity, and rickets the result of phosphate depletion. Treatment with oral phosphorus only resulted in an acceleration of growth rate, cure of rickets, and return of urinary calcium excretion to normal values.

The association of hypercalciuria, salt losing renal disease, and a defect in urine concentrating ability with high renin and aldosterone levels is described in two brothers. One child had marked nephrocalcinosis by the age of 3 and the other severe growth retardation. In one child all the abnormalities were abolished with indomethacin which was responsible for a marked decrease in urinary. The data and the family study suggest that this condition is a proximal tubular disorder with atuosomal recessive inheritance.

The effect of short term hydrochlorothiazide therapy on urinary calcium excretion was compared to that of low calcium and a combined low calcium and low sodium diet in 30 children with postglomerular hematuria. On basal conditions 9 children were normocalciuric, 11 had absorptive, 10 renal hypercalciuria. The effect of thiazide treatment on the haematuria was also evaluated. Thiazide revealed to be more effective in reducing calcium excretion than low calcium diet alone in all groups (p less than 0.001 in normocalciuria; p less than 0.01 in both hypercalciuric groups). Combined low calcium--low sodium diet and thiazide treatment were equally effective in reducing calcium excretion in the hypercalciuric groups. On the first 3 days of thiazide treatment a slight increase of hematuria was observed; in the following period a significant decrease in the occurrence (p less than 0.01 in both hypercalciuric groups) and degree (p less than 0.01 in absorptive; p less than 0.02 in renal hypercalciuria) of hematuria was noted. These data furnish further evidence on the relation of hypercalciuria and post-glomerular hematuria.

The authors analyse the results obtained during 54 radioisotope investigations using 45Ca in 13 cases of idiopathic hypercalciuria, 12 cases of osteoporosis, 3 cases of Paget's disease, and 2 cases of osteomalacia including one of Fanconi's disease in an adult. In 12 patients, repetition of the radio-isotope test two, three or four times; permitted the authors to study the effects of the treatments administered: calcitonin, phosphate, vitamin D, parathormon, oestrogen. Calcitonin increases intestinal absorption and reduces bone reabsorption and also accretion. Phosphate greatly increases accretion and bone reabsorption in vitamin-resistant osteomalacia of adults. The synthetic fragment 1--34 of human parathormone increases accretion and reabsorption but does not modify the calcium balance. The addition of estrogen reduces reabsorption and slightly increases accretion in two osteoporotic patients producing a positive calcium balance. This method of investigation is of great interest to assess the effects of a drug on calcium metabolism and on the two processes of bone remodelling.