The Medical Benefits of Vitamin K2 on Calcium-Related Disorders.

BACKGROUND: Due to the potentially crucial role of vitamin K2 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 K2 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 K2 and its prospects. METHODS: Using public libraries including PubMed and Wiley, we searched for existing research on the metabolism and use of vitamin K2 that has been conducted in the preceding two decades. RESULTS: Data indicated that vitamin K2 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 K2 as treatment in isolation for these conditions.

Pharmacokinetic and Pharmacodynamic Characteristics of Subcutaneously Applied PTH-1-37.

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.

[Disorders of calcium metabolism]. / Störungen des Kalziumstoffwechsels.

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.

[Experience with active vitamin D metabolites in phosphorus-calcium metabolic disorders in patients with predialysis chronic kidney disease].

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.

Estatinas y osteoporosis: una promesa latente / Statins and osteoporosis: A latent promise

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[Parathyroid hormone for disorders of calcium metabolism and metabolic bone diseases other than osteoporosis].

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.

[Clinical significance of disturbed calcium metabolism].

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.

How to diagnose and manage difficult problems of calcium metabolism in sarcoidosis: an evidence-based review.

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.

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I.

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.

Drugs used in paediatric bone and calcium disorders.

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.

Targeting vascular calcification: softening-up a hard target.

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.

[Therapeutic options for mineral metabolism disorders in dialysis patients: a case report]. / Opzioni terapeutiche per la gestione clinica delle alterazioni del metabolismo minerale in dialisi: un caso clinico.

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.

CKD-MBD: impact on management of kidney 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.

[New management of phosphocalcic abnormalities in dialysis patient]. / Nouveautés dans la prise en charge des anomalies du bilan phosphocalcique chez le patient dialysé.

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.

Ingestion of difructose anhydride III, a non-digestible disaccharide, improves postgastrectomy osteopenia in rats.

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.

[Effect of aldose reductase on the abnormality of calcium metabolism in diabetic patients].

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.

Management of calcium, phosphorus and bone metabolism in dialysis patients using sevelamer hydrochloride and vitamin D therapy.

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.