Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities of bone mineral parameters (calcium, phosphate, vitamin D, and parathyroid hormone) are nearly omnipresent in patients with advanced chronic kidney disease (CKD). These typically consist of hypocalcemia, hyperphosphatemia, abnormalities of vitamin D metabolism, and secondary hyperparathyroidism (SHPT). Currently, several lines of evidence suggest that these abnormalities may have consequences beyond the typical consequence of renal bone disease, with a major role in determining cardiovascular disease, including arterial calcification. The 'classical' treatment of SHPT and hyperphosphatemia in HD patients consists of phosphate binders, vitamin D receptor activators (VDRAs), and/or calcimimetics. Calcium- or aluminum-based phosphate binder prescriptions and calcitriol administration are therapeutic tools not free of complications, increasing the risk of cardiovascular calcification in the HD population. New calcium- and aluminum-free phosphate binders, such as lanthanum carbonate and sevelamer hydrochloride, new VDRA (paricalcitol), and cinacalcet hydrochloride can be used to treat SHPT, slow down the atherosclerotic process, and prevent vascular calcification in HD patients.
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PMID:Preventive measures and new pharmacological approaches of calcium and phosphate disorders. 1845 82

Hyperphosphatemia is a complication that appears in the early stages of chronic kidney disease (CKD) and that has been shown to have serious consequences in kidney disease patients. New phosphate regulators are currently being studied such as FGF- 23, a counter-regulatory phosphaturic hormone for vitamin D, and klotho, a cofactor necessary for activation of FGF-23. The main consequences of hyperphosphatemia described in CKD patients not on dialysis are ectopic calcification, increased mortality and more rapid progression of CKD. All this indicates the need for strict control of Pi. The two most currently used drugs for this purpose are lanthanum carbonate and sevelamer. Although there are no studies specifically designed for this predialysis population, these drugs appear to be effective and safe. Another complication of CKD is vitamin D deficiency which, according to recently published studies, is more prevalent and appears in earlier stages of the disease than was initially thought. There is wide debate on the need to administer vitamin D supplements systematically due to the pleiotropic effects of this hormone and which are unrelated to development of renal bone disease. Because of these doubts, there is no agreement on routine administration, although there is consensus on the need to measure 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D values and to wait for the result of numerous studies that are being carried out on the impact of vitamin D on progression of cardiovascular risk factors in CKD and the possible consequences of its indiscriminate administration.
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PMID:[Control of phosphorus and treatment with vitamin D in chronic kidney disease prior to the start of dialysis]. 1884 19

Renal osteodystrophy is characterized by abnormalities in bone turnover, mineralization, and bone volume. The effects of treatment modalities for renal osteodystrophy on bone should be analyzed with respect to these abnormalities. The major treatment modalities for renal osteodystrophy include phosphate binders, vitamin D compounds, and calcimimetics. Aluminum-containing phosphate binders have been shown to be toxic to bone secondary to their effects on bone turnover, mineralization, and bone volume. The use of calcium-based phosphate binders has been associated with the development of adynamic bone disease (low bone turnover), bone loss, and worsening of vascular calcifications. New nonaluminum, noncalcium phosphate binders have been developed (sevelamer hydrochloride and lanthanum carbonate). These agents show a potential for improvement in bone turnover and bone volume. Patients with renal osteodystrophy are deficient in calcitriol and often in calcidiol. Calcidiol deficiency has been underappreciated and deserves to be addressed in the treatment of patients with renal osteodystrophy. Calcitriol replacement therapy by daily oral administration is associated with frequent episodes of hypercalcemia and suppression of bone turnover in patients with stages 3 to 5 chronic kidney disease. Pulse oral or intravenous calcitriol administration induces frequent episodes of hypercalcemia or hyperphosphatemia, respectively, and achieves the same degree of correction of bone abnormalities. There are no data on the effects of paricalcitol or doxercalciferol on human bone. Experimental data, however, show that these two analogues and maxacalcitol may control serum parathyroid hormone levels without suppressing bone turnover. Calcimimetics lower parathyroid hormone levels and bone turnover.
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PMID:Effects of treatment of renal osteodystrophy on bone histology. 1898 1

The management of hemodialysis patients with chronic kidney disease-mineral bone disorder includes treatment to control levels of calcium, phosphorus and parathyroid hormone, so as to prevent bone and soft-tissue complications. Recently, pleiotropic effects of active vitamin D have attracted much attention, and its effect on outcome has also gained recognition. However, administration of active vitamin D may cause hypercalcemia and hyperphosphatemia. Now, the use of a novel class of drugs, cinacalcet hydrochloride, has been proposed as a strategy to reduce parathyroid hormone secretion, while decreasing levels of serum calcium, phosphorus, and calcium x phosphorus products. Among subjects with secondary hyperparathyroidism undergoing hemodialysis, combined therapy with cinacalcet and vitamin D sterols improved achievement of the biochemical targets for chronic kidney disease-mineral bone disorder recommended by the guidelines.
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PMID:Role of cinacalcet in management of mineral bone disorder in chronic kidney disease (control of calcium, phosphorus and parathyroid hormone). 1903 24

In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Vascular calcifications have been associated with low bone turnover, low bone volume and lower activation frequency. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact parathyroid hormone and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. A randomized, prospective, open label study, evaluated patients with bone biopsies at the beginning and after 1 year treatment period with sevelamer hydrochloride or calcium carbonate. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years.In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a non-calcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations.
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PMID:Treatment of hyperphosphatemia with sevelamer hydrochloride in dialysis patients: effects on vascular calcification, bone and a close look into the survival data. 1903 24

The main forms of renal osteodystrophy are secondary hyperparathyroidism, aluminum-induced bone disease and adynamic bone disease without aluminum intoxication. Aluminum intoxication has become rare because of control of the dialysate solution and avoidance of aluminum containing phosphate binders. Secondary hyperparathyroidism still develops early in the course of renal failure and remains the most frequent form of osteodystrophy in patients treated by maintenance hemodialysis. Several factors, including hyperphosphatemia and deficient synthesis of 1,25-dihydroxyvitamin D are involved in its pathogenesis. Secondary hyperparathyroidism is symptomatic only in severely affected patients. Prevention depends on control of serum phosphorus +/- prescription of 1-alpha-hydroxylated vitamin D derivatives or may require subtotal parathyroidectomy when hyperparathyroidism is refractory.Adynamic bone disease not related to aluminum intoxication has been increasingly recognized in recent years and is presently the most frequent form of osteodystrophy in continuous ambulatory peritoneal dialysis patients. This condition, characterized by low bone turnover and depression of bone formation, appears to be associated with an increased risk of bone fracture. The main pathophysiologic feature is excessive treatment of hyperparathyroidism leading to hypoparathyroidism. Serum immunoreactive 1,84-parathormone levels should therefore be kept at a level of 1.5-fold to 3-fold the upper limit of normal in patients treated by maintenance hemodialysis.
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PMID:Renal osteodystrophy. 1907 65

Dietary management of hyperphosphatemia and hyperparathyroidism have long been important elements in the clinical management of CKD stage 4 and 5 for the prevention of mineral bone disease. The rationale for phosphate lowering has been further justified, given the accumulating data to support the association of phosphate with vascular damage, in this population who are at high risk of cardiovascular (CV) death. Phosphate is a novel CV risk factor in both CKD and in the general population, and a growing body of literature suggests that high normal serum phosphate may be a risk factor for progression of CKD. Few studies have examined hard outcomes after phosphate lowering. Nonetheless, given the balance of data both in cell, animal and human studies, the use of phosphate lowering strategies at earlier stages of CKD, perhaps even prior to serum phosphate level rising, may well be justified. This review will discuss the complications associated with higher serum phosphate, the potential benefits of early phosphate intervention, practical considerations of low phosphate diets and novel strategies for evaluating these strategies in clinical practice.
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PMID:Early initiation of phosphate lowering dietary therapy in non-dialysis chronic kidney disease: a critical review. 1922 35

Chronic uremia is characterized by decreased levels of plasma 1,25(OH)2D3 due to decreased renal 1-hydroxylase activity and by decreased renal phosphate excretion. The consequence is an increased synthesis and secretion of parathyroid hormone--secondary hyperparathyroidism--due to the low levels of plasma calcium, low levels of plasma 1,25(OH)2D3 and high levels of phosphate. The association between renal bone disease and chronic renal failure is well described. Epidemiological studies have indicated that an association also exists between secondary hyperparathyroidism and increased mortality and cardiovascular calcifications in chronic uremic patients. Treatment of secondary hyperparathyroidism in chronic uremia focuses on avoiding hyperphosphatemia by the use of oral phosphate binders, which bind phosphate in the intestine and a concomitant substitution by a 1 alpha-hydroxylated vitamin D analog in order to compensate for the reduced renal hydroxylation. Additional treatment with aluminum containing phosphate binders to overcome phosphate absorption and retention was initiated already in the 1960s and used extensively until aluminum toxicity was disclosed in the mid-1980s. Instead calcium carbonate and calcium acetate were used as phosphate binders. Until recently, the most commonly used active vitamin D drug was either the natural 1,25(OH)2D3, or the 1 alpha-hydroxylated analog, 1alpha(OH)D3 which after 25-hydroxylation in the liver is converted to 1,25(OH)2D3. 1alpha(OH)D3 was produced by LEO Pharma in 1973. The two vitamin D analogs were used in different geographical areas: In Europe 1alpha(OH)D3 was mainly used, while 1,25(OH)2D3 was mainly used in the USA. 1,25(OH)2D3 increases the intestinal absorption of calcium and improves skeletal abnormalities. The combined treatment with calcium containing phosphate binders and active vitamin D induces an increase in plasma Ca 2+ and hypercalcemia became a clinical problem. Subsequently therefore, dialysis fluid with a reduced calcium concentration ("low-calcium") was introduced. In 1981 Madsen et al. [148] demonstrated for the first time a direct suppressive effect of intravenous 1,25(OH)2D3 on plasma PTH in acutely uremic patients. In 1984, Slatopolsky et al. [74] demonstrated that intravenous 1,25(OH)2D3 induces a marked suppression of plasma PTH with no increase in plasma Ca 2+ in chronic uremic patients. In the middle of the 1980s, 1alpha(OH)D3 became available not only as an oral, but also as an intravenous formulation. The main purpose of the present studies was to increase the knowledge of the action and effects of different treatment regimes with 1alpha(OH)D3, and thereby to improve the prophylaxis and treatment of secondary hyperparathyroidism in uremic patients on chronic dialysis. 168 patients on chronic dialysis treatment and six healthy volunteers were included in the seven studies included in this thesis. The first part of the studies, focused on short- (12 weeks) and long-term (103 weeks) effects of intravenous 1alpha(OH)D3 on plasma PTH and plasma Ca 2+ in relation to the doses of 1alpha(OH)D3 given. Further, it was examined whether the marked suppression of plasma PTH induced by 300 days of intermittent intravenous treatment with 1alpha(OH)D3, could be maintained when the administration was changed from intravenous to the oral route for 16 further weeks and then shifted back to intravenous administration for another 16 weeks. The second part focused on long-term effects (88 weeks in hemodialysis patients and 52 weeks in CAPD patients) of a treatment modality combining 1alpha(OH)D3, and CaCO3 as phosphate binders instead of aluminum containing compounds and a decreased calcium concentration in the dialysis fluid to 1.25 mmol/l in an attempt to avoid development of hypercalcemia. The third part focused upon the pharmacokinetic differences between intravenous and oral administration of 1,25(OH)2D3 and 1alpha(OH)D3 and upon the acute effects of different doses of the two compounds on the plasma levels of PTH, Ca 2+ and phosphate. Plasma PTH is a biochemical parameter most often used for the diagnosis and monitoring of bone disease in patients with chronic uremia. The level of plasma PTH measures depends on the assay used. More specific assays measuring only whole PTH 1-84 without co-measuring large C-terminal fragments have been developed. In this thesis, five different assays were used - one "N-terminal", one "C-terminal", two "Intact" and one "Whole" PTH assay. Each sample was analyzed by 1-3 different assays. Based on the results of my studies [1-7], it is concluded that: 1a. Intravenous administration of 1alpha(OH)D3 induces a marked suppression of plasma PTH without causing serious side-effects in patients on chronic hemodialysis. It is possible to prevent hypercalcemia by closely monitoring plasma Ca 2+ levels and by adjusting the dose of 1alpha(OH)D3 accordingly. 1b. Long-term intermittent intravenous treatment with 1alpha(OH)D3 was effective in suppressing plasma levels of Intact PTH. 1c. When plasma intact PTH was suppressed to a stable level by intravenous 1alpha(OH)D3 the suppression could be maintained by intermittent oral 1alpha(OH)D3 therapy. It was not examined whether a similar degree of suppression of severe secondary hyperparathyroidism could be induced by intermittent oral 1alpha(OH)D3 treatment alone. The responses following chronic intravenous or oral administration of 1alpha(OH)D3 on circulating levels of intact PTH and N- and C-terminal PTH fragments did not reveal any significant differences between the two routes of administration on the actions on the parathyroid glands. 2a. The combination of "low-calcium" hemodialysis fluid (1.25 mmol/l), CaCO3 as a phosphate binder, and intermittent intravenous 1alpha(OH)D3 prevented development of secondary hyperparathyroidism in uremic patients with normal PTH at the initiation of the study and induced a long-term suppression of PTH in patients with secondary hyperparathyroidism. No clinical or biochemical indications of development of adynamic bone disease were observed. Intravenous administration of 1alpha(OH)D3 prevented a decrease of BMC in the lumbar spine and femoral neck of hemodialysis patients both with normal and with elevated PTH levels. It was possible to use larger doses of CaCO3 and to reduce, but not exclude, the use of aluminum-containing phosphate binders in combination with intravenous administration of 1alpha(OH)D3. A decrease of plasma Ca 2+ was induced during dialysis, and special care had to be taken on the compliance of the patients as to the use of CaCO3 binders in order not to aggravate secondary hyperparathyroidism. 2b. In patients on CAPD, the use of low-calcium dialysis (1.25 mmol/l) made it possible to use larger doses of CaCO3 phosphate binders and to reduce, but not exclude, the use of aluminium containing phosphate binder in combination with oral pulses of 1alpha(OH)D3. A negative calcium balance was induced, and it is therefore recommended that a reduction of the calcium concentration in the dialysis fluid is only used in patients under strict control. 3a. The metabolic clearance rate of 1,25(OH)2D3 was 57% lower in uremic patients than in normal subjects (p < 0.03). The bioavailability of 1,25(OH)2D3 in both normal subjects and uremic patients was markedly lower following administration of 1alpha(OH)D3 both intravenously and orally than after administration of oral 1,25(OH)2D3. Despite lower plasma 1,25(OH)2D3 levels after administration of 1alpha(OH)D3 than after 1,25(OH)2D3, no significant difference was observed in the PTH suppressive effect in uremic patients of 4 mug intravenously of either of the two vitamin D analogs. 3b. A single intravenous high dose of 10 mug of 1alpha(OH)D3 or 1,25(OH)2D3 significantly suppressed plasma PTH. The acute suppressive effect of 1,25(OH)2D3 was three times greater than that of 1alpha(OH)D3.The increase in plasma Ca 2+ after intravenous administration of 10 mug 1,25(OH)2D3 was significantly higher than that of 1alpha(OH)D3. Due to the simultaneous effect on plasma Ca 2+ observed it was not possible to decide whether 1alpha(OH)D3 has a direct effect per se on the parathyroid glands or not. The study further did not give any further knowledge about the possible therapeutic equivalence of long-term treatment with 1alpha(OH)D3 or 1,25(OH)2D3. The PTH responses to acute administration of the 1alpha(OH)D3 and 1,25(OH)2D3 analogs were in principle the same when measured by one "whole" PTH and two "intact" PTH assays, namely mainly in a parallel shift of the PTH response curve. In this study on chronic uremic patients circulating levels of large C-terminal PTH fragments were not affected by differences in plasma Ca 2+ concentration or by the intravenous administration of 1alpha(OH)D3 or 1,25(OH)2D3. There is now a general agreement on the importance of carefully controlling plasma phosphate, normalize and avoid increases of plasma Ca 2+, and not to oversuppress PTH during treatment. Focus today is on the potential deleterious role of calcium overloading in the development of vascular calcifications in uremic patients. There is an urgent need for a development of an algorithm for the use of phosphate binders and vitamin D supplementation in combination with calcimimetics focusing upon long term morbidity and mortality in uremic patients.
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PMID:1alpha(OH)D3 One-alpha-hydroxy-cholecalciferol--an active vitamin D analog. Clinical studies on prophylaxis and treatment of secondary hyperparathyroidism in uremic patients on chronic dialysis. 1923 59

Chronic kidney disease (CKD) is frequently complicated by arterial calcification. The latter is part of the associated mineral and bone disorder (CKD-MBD). Hypercalcemia and hyperphosphatemia have long been known to play a major role in the occurrence of vascular and other soft tissue calcification in patients with CKD, together with endocrine disturbances including vitamin D, parathyroid hormone, fibroblast growth factor-23, and klotho. In addition, many other systemic and local promoters, including inflammation and uremic toxins, contribute to the occurrence of vascular calcification, despite a powerful defense system made up of systemic and local inhibitors, as demonstrated in elegant experimental studies done in vitro and in vivo. Most importantly, several reports have shown that both hyperphosphatemia and hypophosphatemia, and to a lesser degree hypercalcemia and hypocalcemia, are associated with an increased relative risk of mortality in patients with CKD. However, all these reports were observational in nature and must therefore be considered as hypothesis generating. It remains to be demonstrated in prospective randomized trials whether normalization of serum phosphorus and/or calcium leads to better patient outcome. In order to improve outcome in patients with CKD-MBD, early medical intervention is of utmost importance.
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PMID:Impact of disturbances of calcium and phosphate metabolism on vascular calcification and clinical outcomes in patients with chronic kidney disease. 1929 98

Chronic kidney disease-mineral and bone disorder (CKD-MBD) develops as renal function deteriorates. The presence of diabetes mellitus as comorbidity modulates the severity of CKD-MBD. The prevalence of vascular calcification, which becomes higher in diabetic CKD patients than in non-CKD counterparts, increases cardiovascular mortality in diabetic patients. The main factor which causes vascular calcification in diabetic CKD patients is poor glycemic control, in contrast to hyperphosphatemia in non-diabetic CKD patients. Diabetes directly impairs osetoblasts to decrease bone mass, suppresses bone turnover to impair bone quality by impairing secretion of parathyroid hormone and increase AGE-modification of bone collagen. Therefore, therapeutic regimens for CKD-MBD should be considered specifically for diabetic CKD patients since the mode of its development differs between diabetic and non-diabetic CKD patients.
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PMID:[Chronic kidney disease (CKD) and bone. Impact of diabetes mellitus on the development of CKD-MBD]. 1932 28


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