maxacalcitol and Chronic-Kidney-Disease-Mineral-and-Bone-Disorder

The kidney deeply takes part in phosphorus and vitamin D metabolism. The chronic kidney disease patients usually suffer from serious bone disease. They are prescribed the glucocorticoid medication for primary kidney disease, as nephrotic syndrome and collagen renal disease, with aging. The end of therapeutic target is normal bone structure with normal bone turnover in CKD patients. The control of serum Ca and phosphorus level is important step and also another target. This issue describes the problem and the advancement of treatment and the measurement of the bone mass from this viewpoint.

Topics: Absorptiometry, Photon; Bone Density; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Deferoxamine; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Parathyroidectomy; Phosphorus; Vitamin K 2

Maxacalcitol (Oxarol) is a derivative of vitamin D compounds applied for the secondary hyperparathyroidism (2 degrees HPT) of hemodialysis (HD) patients as an injection and psoriasis as an ointment. 2 degrees HPT is one of the complications in HD patients with hyperplasia of parathyroid glands and elevated serum parathyroid hormone (PTH) levels. On the other hand, vitamin D compounds are known to have multiple actions in many organs (promotion of calcium absorption from the small intestine, induction of differentiation of leukemia cells, differentiation and proliferation of the chondrocyte, muscle cells and epidermal cells, immunosuppressive activities) and their activities on parathyroid glands seem to be mediated by the vitamin D receptor (genomic action). It was reported that both serum PTH and PTH mRNA levels were suppressed by Maxacalcitol with less calcemic action and also Maxacalcitol could ameliorate high-turnover bone and marked osteitis fibrosa in uremic rats. Here I review many reports focused on the effects of Maxacalcitol on the 2 degrees HPT.

Topics: Animals; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Clinical Trials, Phase III as Topic; Dosage Forms; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Psoriasis; Rats; Receptors, Calcitriol

Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate retention and low serum 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol). Replacement therapy with calcitriol or its precursor 1alpha-hydroxyvitamin D(3) (1alphaOHD(3), alfacalcidol) often produces hypercalcaemia, especially when combined with calcium-based phosphate binders. In addition, these vitamin D compounds can aggravate the hyperphosphataemia in these patients. Several vitamin D analogues have been developed that retain the direct suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands but have less calcaemic activity, thereby offering a safer and more effective means of controlling 2HPT. 1,25-Dihydroxy-19-norvitamin D(2) (19-norD(2)) and 1alpha-hydroxyvitamin D(2) (1alphaOHD(2)) are available in the US and 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D(3) (1,25(OH)(2)26,27F6 D(3), falecalcitriol) have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-norD(2) have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcaemic and phosphataemic activities. The low calcaemic activity of OCT has been attributed to its rapid clearance, which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and parathyroid cell growth. The calcaemic activity of 19-norD(2) diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1alphaOHD(2), compared with 1alphaOHD(3), has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of falecalcitriol may also result from an altered metabolism. A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.

Topics: Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone; Vitamin D

The semi-quantitative method of bone scintigraphy [bone to soft tissue (B/ST) ratio] has been used in diagnosing and evaluating systemic metabolic bone diseases. The aim of this study is to evaluate of the therapeutic effect of secondary hyperparathyroidism (SHP).. The subjects were ten hemodialysis patients with SHP. Seven patients underwent parathyroidectomy (PTX), and 22-Oxacalcitoriol (derivative of 1,25-dihydroxyvitamin D3) (OCT) was given to three patients. Bone scintigraphy and blood tests [intact parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium (Ca), phosphorus (P), bone alkaline phosphatase (BALP), and deoxypridinoline (DPYD)] were performed before and after treatment. Regions of interest were drown around cranium, lumbar vertebrae, femoral neck and soft tissue of left medial thigh to calculate the B/ST ratio.. The B/ST ratios of cranium, lumbar vertebrae, and femoral neck were reduced significantly after PTX (cranium, p = 0.0079, lumbar vertebrae, p = 0.0282, femoral neck, p = 0.0252). Intact PTH, ALP, Ca, P, BALP and DPYD levels were reduced significantly after PTX (intact PTH, p = 0.003, Ca, p = 0.0005, P, p = 0.0393, ALP, p = 0.0051, DPYD, p = 0.0232, BALP, p = 0.0324). After OCT administration, the B/ST ratio of each bony region showed tendency to diminish, although not significantly. Intact PTH levels were reduced significantly, although ALP, BALP, and DPYD levels were not. Ca and P levels were increased significantly because of the medicinal action of OCT.. The B/ST ratio of cranium may be non-invasive method and have potential in evaluating the therapeutic effect of SHP.

Topics: Adult; Aged; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Prognosis; Radionuclide Imaging; Thyroidectomy; Treatment Outcome

Evaluation of bone is of great importance in chronic kidney disease patients, as these patients are at an increased risk for fractures. We treated a hemodialysis patient suffering from hyperparathyroid bone disease with cinacalcet hydrochloride and concurrent administration of maxacalcitol and alfacalcidol for a year. Hyperparathyroid bone disease is characterized by cortical thinning, increased cortical porosity, reduced trabecular bone volume, and increased hypomineralized matrix volume, and there is little information to date about the effects of treatment with cinacalcet hydrochloride on the bone fragility in patients with hyperparathyroid bone disease. In the present study, histological and backscattered electron microscopic evaluation of this combination treatment revealed an excellent improvement of both bone volume and bone morphology. This treatment improved cortical thinning, cortical porosity, and trabecular thinning. Furthermore, the treatment also reduced hypomineralized matrix volume, indicative of improved mineralization by osteocytes. We speculate that the intermittent maxacalcitol administration may have effectively stimulated the vitamin D receptors expressed on osteocytes and osteoblasts, resulting in increased mineralization. Our approach for evaluating the bone in patients with chronic kidney disease by backscattered electron microscopy is novel.

Topics: Biopsy; Bone Density Conservation Agents; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Ilium; Microscopy, Electron; Middle Aged

Direct maxacalcitol (OCT) injection into a parathyroid gland (PTG) ameliorates several important etiologic factors of resistance to medical treatments for secondary hyperparathyroidism (s-HPT): the upregulations of vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in PTGs and the regression of PTG hyperplasia by the induction of apoptosis. In this study, we evaluated the bone histomorphology on the basis of maintaining these effects in advanced s-HPT. Five/six nephrectomized Sprague-Dawley rats were fed a high-phosphorus and low-calcium diet for 8 weeks. These rats were divided into four treatment groups: (1) basic uremic (at the baseline), (2) direct OCT single injection into PTGs (DI-OCT) followed by OCT intravenous administration for 4 weeks (IV-OCT), (3) direct vehicle injection and IV-OCT, and (4) no treatment for an additional 4 weeks. The effects of these treatments on serum intact-parathyroid hormone (PTH) level, PTG weight, VDR and CaSR expression levels in PTGs, and bone histomorphometric parameters were investigated. In the DI-OCT+IV-OCT group, the significant decrease in serum intact-PTH level was maintained by the following IV-OCT. A significant decrease in PTG weight and the upregulations of VDR and CaSR expression levels in PTGs were also observed. Bone histomorphometric analysis showed significant improvements in osteitis fibrosa in both cancellous and cortical bones. However, these findings were not observed in the other groups. These results suggest that osteitis fibrosa caused by advanced s-HPT can be successfully reversed by a control of PTH at an appropriate level through the improvement of PTG hyperplasia as induced by DI-OCT+IV-OCT.

Topics: Animals; Antineoplastic Agents; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Hyperparathyroidism, Secondary; Hyperplasia; Immunohistochemistry; Injections, Intralesional; Kidney Failure, Chronic; Male; Organ Size; Parathyroid Glands; Parathyroid Hormone; Periosteum; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Receptors, Calcium-Sensing; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Renal osteodystrophy is one of the major complications in patients with chronic renal failure. Large C-PTH fragments are secreted from the parathyroid glands and exert antagonistic actions against PTH-(1-84). The PTH-(1-84)/large C-PTH fragments ratio reflects both biosynthesis and processing of PTH; however the alteration of the ratio under vitamin D therapy has not been investigated.. Seventeen hemodialysis patients with intact PTH levels of >300 pg/ml were enrolled. Calcitriol or maxacalcitol were administered intravenously for 78 weeks. Intact PTH, PTH-(1-84), and the PTH-(1-84)/large C-PTH fragments ratio were measured at 0, 13, 26, 52 and 78 weeks.. Intact PTH and PTH-(1-84) levels, which were 492.0 +/- 115.7 and 303.4 +/- 105.4 pg/ml, respectively, at baseline, significantly decreased at the end of the study to 268.9 +/- 121.9 (p < 0.0001) and 190.7 +/- 106.9 pg/ml (p = 0.0008), respectively. In contrast, large C-PTH fragments, which were 152.7 +/- 53.5 pg/ml at baseline, did not significantly change at 78 weeks (144.5 +/- 72.2 pg/ml, p = 0.7612). Consequently, the PTH-(1-84)/large C-PTH fragments ratio was significantly reduced from 2.25 +/- 1.31 to 1.47 +/- 0.89 (p = 0.0004).. The PTH-(1-84)/large C-PTH fragments ratio reflects the change of PTH biosynthesis, processing and secretion from the parathyroid glands, and it may be a beneficial marker to evaluate the overall biological PTH action and predict bone turnover status in hemodialysis patients under intravenous vitamin D therapy.

Topics: Acid Phosphatase; Alkaline Phosphatase; Bone Density Conservation Agents; Bone Remodeling; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Humans; Injections, Intravenous; Isoenzymes; Male; Middle Aged; Osteocalcin; Parathyroid Hormone; Peptide Fragments; Phosphorus; Renal Dialysis; Tartrate-Resistant Acid Phosphatase; Vitamins

22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis.. 22-Oxacalcitriol (OCT) is a unique vitamin D analogue with less calcemic activity than calcitriol, and it effectively suppresses parathyroid hormone (PTH) secretion in uremic rats. This study was performed to examine the long-term effect of intravenously administered OCT on high-turnover bone disease in model rats of slowly progressive renal failure.. Slowly progressive renal failure rats were made by a single injection of glycopeptide isolated from rat renal cortical tissues. At 250 days, glycopeptide-induced nephritis (GN) rats were divided into three groups with the same levels of serum creatinine and PTH, and they received either OCT (0.03 or 0.15 microg/kg body wt) or vehicle given intravenously three times per week for 15 weeks.. Renal function of GN rats deteriorated very slowly but progressively, as assessed by the increase of serum creatinine concentration. At sacrifice, serum PTH levels, bone formation markers, bone resorption markers, and fibrosis volume were significantly elevated in vehicle-treated GN rats compared with those of sham-operated rats, suggesting the development of high-turnover bone disease with osteitis fibrosa. In contrast, in the GN-OCT 0.15 microg/kg group, these high PTH levels and high-turnover bone and fibrosis were significantly decreased. Such amelioration of bone abnormalities by OCT was not accompanied by either hypercalcemia or further deterioration of renal function.. These data indicate that OCT may be a useful and safe agent not only for the suppression of PTH, but also for the amelioration of osteitis fibrosa and high-turnover bone without causing hypercalcemia in chronic dialysis patients.

Topics: Animals; Antineoplastic Agents; Bone Remodeling; Calcitriol; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Progression; Feedback; Fibrosis; Glycopeptides; Hyperparathyroidism, Secondary; Male; Nephritis; Osteitis; Rats; Rats, Wistar; Renal Insufficiency; Uremia