Osteocalcin levels in uremic patients: influence of calcitriol treatment through two different routes and type of dialysis.

Osteocalcin, the most abundant non-collagen protein of bone, is synthesized by the osteoblast. Serum osteocalcin concentration depends primarily on new cellular synthesis, and is a sensitive marker of bone turnover reflecting osteoblastic function. In uremic and hemodialysis (HD) patients, a direct relationship between serum osteocalcin and histological parameters of bone formation has been observed. The modality of dialysis may influence serum osteocalcin levels though the available data are controversial. The aim of this study is to assess the acute and chronic effects of calcitriol and the influence of modality of dialysis on serum osteocalcin levels. Twelve patients on continuous ambulatory peritoneal dialysis (CAPD) were treated with calcitriol. For control purposes, 24 patients, 12 on CAPD and 12 on HD, not treated with calcitriol serum osteocalcin levels were included. In CAPD patients previously treated with calcitriol, serum osteocalcin levels were higher than in nontreated patients. The higher levels occur independent of serum levels of parathyroid hormone (PTH), Ca and P. Hemodialysis patients had osteocalcin levels similar to those of CAPD patients under calcitriol treatment. However, the levels of HD patients were higher than CAPD nontreated patients. Serum ionized Ca was similar in CAPD and HD nontreated patients; however, total Ca was significantly higher in HD than in CAPD patients, both with and without calcitriol. After the intravenous administration of calcitriol, serum osteocalcin levels increased from 9.2 + 2.5 to 13.5 + 5.4 ng/ml (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Aluminum administration in the rat separately affects the osteoblast and bone mineralization

Aluminum administration in the experimental animal results in osteomalacia as characterized by osteoid accumulation and decreased mineralization. Previous in vivo and in vitro studies have indicated that either aluminum directly inhibits mineralization or is toxic to the osteoblast. In the present study, PTH was continuously infused in rats with aluminum-induced osteomalacia to evaluate whether aluminum administration decreased mineralization without a concomitant decrease in osteoblasts. Four groups of rats were studied: chronic renal failure (CRF); CRF + aluminum (AL); CRF + PTH; and CRF + PTH + AL. Rats were sacrificed 5 and 12 days after aluminum or diluent administration; in the PTH groups, bovine PTH (1-34) was administered at 2 units/h via a subcutaneously implanted Alzet pump. Aluminum administration decreased osteoblast surface, increased osteoid accumulation, and produced a cessation of bone formation. The infusion of PTH alone increased osteoblast surface and bone formation. The simultaneous administration of aluminum and PTH resulted in an osteoblast surface intermediate between aluminum and PTH alone; however, despite a PTH-induced restoration of osteoblast surface, bone formation did not increase. These findings indicate (1) aluminum is toxic to osteoblasts and also directly inhibits mineralization even when osteoblasts are not decreased; (2) PTH is capable of increasing osteoblasts even in the presence of aluminum; and (3) despite a PTH-induced increase in osteoblast surface, mineralization of osteoid was not improved.     

Osteocalcin levels in chronic osteomyelitis

Osteocalcin is a vitamin K-dependent bone protein synthesized by osteoblasts. In generalized bone disorders serum osteocalcin correlates with osteoblast activity. Bone resorption and new bone formation occur in chronic osteomyelitis, dependent on the level of inflammatory activity. In 17 patients with active chronic osteomyelitis undergoing surgery, the serum levels of osteocalcin, alkaline phosphatase and C-reactive protein were measured before and after treatment. The osteocalcin levels were within the normal range preoperatively (10.8 ±11.0 g/l), in the early postoperative period, and at discharge. It is therefore not a helpful marker in the clinical management of this condition.     

Effect of parathyroidectomy on aluminum toxicity and azotemic bone disease in the rat

In maintenance dialysis patients, low-turnover osteomalacia and aplastic bone disease are generally attributed to aluminum toxicity. Both groups of patients have a relative deficiency of PTH. The reason for the development of osteomalacia versus aplastic bone disease is unclear. The present study was performed to evaluate whether parathyroidectomy (PTX) modifies the effect of aluminum administration on bone histology in renal failure. Seven groups of pair-fed rats were studied: normals (N); renal failure (RF); RF + PTX; PTX; RF + aluminum (AL); RF + PTX + AL; and PTX + AL. Aluminum was administered intraperitoneally 5 days/week for 6 weeks. All groups were sacrificed at 6 weeks. Renal failure increased the serum calcium in both the parathyroid intact (RF versus N, 11 +/- 0.1 versus 10 +/- 0.3 mg/dl, X +/- SEM, P less than 0.05) and calcium-supplemented PTX groups (PTX + RF versus PTX, 9.7 +/- 0.2 versus 9.2 +/- 0.2 mg/dl, P less than 0.05). After PTX, aluminum administration increased the serum calcium (PTX + AL versus PTX, 9.8 +/- 0.3 versus 9.2 +/- 0.2, P less than 0.05, and PTX + RF + AL versus PTX + RF, 10.8 +/- 0.1 versus 9.7 +/- 0.2 mg/dl, P less than 0.05). In rats with renal failure receiving aluminum, PTX decreased osteoid volume and surface but not osteoid thickness. Rats receiving aluminum did not mineralize bone. Additionally, in PTX rats receiving aluminum, renal failure per se increased osteoblast surface, osteoid surface, osteoid volume, and osteoclast number.(ABSTRACT TRUNCATED AT 250 WORDS)     

The interaction of PTH and dietary phosphorus and calcium on serum calcitriol levels in the rat with experimental renal failure

BACKGROUND.: Renal failure results in decreased calcitriol production, akey factor in the development of secondary hyperparathyroidism.Phosphorus accumulation and high parathyroid hormone (PTH) levels,both inherent to renal failure, have different effects on calcitriolproduction; moreover, dietary calcium loading may have a separateinhibitory effect on calcitriol production. This study was designedto evaluate the relative effects of PTH and dietary phosphorusand calcium on serum calcitriol levels. METHODS.: Renal failure was surgically induced and rats were divided intonormal, moderate renal failure, and advanced renal failure basedon the serum creatinine. Each group was subdivided and receivedeither a highphosphorusdiet (HPD, 0.6% Ca, 1.2% P) or highcalcium diet (HCaD, 1.2% Ca, 0.6% P) for 14–16 days to determinethe relative effects of dietary calcium andphosphorus loadingon serum calcitriol. In addition the effect of PTH and phosphoruson calcitriol stimulation was determined with a 48-h PTH infusioncombined with either a low (0.16%) or high (1%) phosphorus dietsboth diets had negligible calcium (<0.05%) RESULTS.: With decreasing renal function, PTH increased and was greaterin rats fed the HPD than the HCaD; serum calcitriol decreasedas renal function decreased and was lower in normal rats andrats with moderate renal failure fed a HCaD (P < 0.01). Thecalcitriol response to a PTH infusion decreased as renal functiondecreased (P <0.05) but was greater on a low- (0.16%) thana high- (1%) phosphorus diet (P<0.05) CONCLUSION.: Dietary calcium loading either directly decreases serum calcitriolor acts by modifying the stimulatory effect of PTH; the stimulatoryeffect of PTH on serum calcitriol is modified by dietary phosphorus;in moderate renal failure, serum calcitriol levels depend ona complex interaction between PTH and dietary calcium and phosphorus;and in advanced renal failure, serum calcitriol levels are lowand are difficult to stimulate, presumably because of the lossof renal mass.     

Calcemic response to parathyroid hormone in renal failure: role of phosphorus and its effect on calcitriol.

The calcemic response to parathyroid hormone (PTH) is decreased in renal failure. The reduction of hyperphosphatemia improves the calcemic response to PTH in animals with advanced renal failure. However, since low calcitriol levels in renal failure may also contribute to the decreased calcemic response to PTH, the improved calcemic response observed during the reduction of serum phosphorus may be partially mediated by an increase in serum calcitriol levels. The present study evaluated the calcemic response to PTH in rats with moderate and advanced renal failure and how this response was modified by a high and a low phosphorus diet. In addition, the effect of a change in dietary phosphorus on calcitriol levels was also evaluated. A 48-hour continuous infusion of 1-34 rat PTH increased the serum calcium level to 18.2 +/- 0.4 mg/dl in normal rats, versus 13.7 +/- 0.9 and 12.1 +/- 0.2 mg/dl in rats with moderate and advanced renal failure, respectively. During the PTH infusion, a high phosphorus diet increased the serum phosphorus and resulted in a reduced calcemic response to PTH at each level of renal function; respective serum calcium levels were 13.8 +/- 0.6 mg/dl in normals, 11.2 +/- 0.2 mg/dl in moderate renal failure and 9.6 +/- 0.5 mg/dl in advanced renal failure. In normal rats and in rats with moderate renal failure, dietary phosphorus restriction during the PTH infusion increased serum calcitriol levels. In rats with advanced renal failure, serum calcitriol levels were lower than in the other two groups and were not affected by changes in dietary phosphorus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcemic response to parathyroid hormone in renal failure: role of calcitriol and the effect of parathyroidectomy.

Hyperparathyroidism due to renal failure begins in the early stages of renal insufficiency and is in part secondary to skeletal resistance to the calcemic action of parathyroid hormone (PTH). Factors which have been reported to reduce the calcemic response to PTH include: decreased calcitriol levels, hyperphosphatemia and down regulation of PTH receptors in bone. While hyperphosphatemia may directly decrease the calcemic response to PTH, it may also act indirectly by a suppression of calcitriol synthesis. In this study, the effect of calcitriol on the calcemic response to PTH was evaluated in normal rats and in rats with moderate and advanced renal failure. To determine the combined effect of calcitriol and phosphorus on the calcemic response to PTH, rats receiving calcitriol were fed either a high (1.0%) or low (0.2%) phosphorus diet during a 48-hour PTH infusion. In advanced renal failure, calcitriol administration increased the calcemic response to PTH independent of the dietary phosphorus intake. During ingestion of a low phosphorus diet, a 48 hour PTH infusion resulted in a serum calcium level of 13.7 +/- 0.5 and 12.1 +/- 0.2 mg/dl (P less than 0.02) with and without calcitriol administration, respectively. In normal rats and in rats with moderate renal failure, calcitriol administration improved the calcemic response only during a high phosphorus intake. After a 48-hour PTH infusion in normal rats, the serum calcium levels with and without calcitriol were 16.1 +/- 0.9 and 14.8 +/- 0.6 mg/dl, P less than 0.01 respectively; in rats with moderate renal failure, calcitriol administration increased serum calcium, 13.2 +/- 0.5 versus 11.2 +/- 0.4 mg/dl, P less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells

Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 3',5' monophosphate (cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter-3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.     

Effects of aluminum on rat bone cell populations

Summary Aluminum (Al) loading is associated with reduced bone formation and osteomalacia in human and certain animal models. However, uncertainty exists as to the cellular effect(s) of Al as both inhibition and stimulation of osteoblast proliferation have been reported. Furthermore, the extent to which Al affects osteoprogenitor cell populations is unknown. To determine the cellular effects of Al in the rat, an animal model in which Al bone disease has been produced, we compared thein vitro effect of 10–50 Al on the proliferation and hydroxyproline collagen formation of marrow osteoprogenitor stromal cell populations and perinatal rat calvarial osteoblasts. In subconfluent cultures, Al suppressed proliferation of both marrow fibroblast-like stromal cells and calvarial osteoblasts. In confluent cultures, however, Al selectively stimulated periosteal fibroblast and osteoblast DNA synthesis and collagen (hydroxyproline) production, both in the presence or absence of 1,25-dihydroxyvitamin D. Osteocalcin was not detected in osteoblast-conditioned media or extracellular matrix. These observations suggest that the bone formation defect associated with Al toxicity in growing rats may be a function of impaired patterns of osteoprogenitor/osteoblast proliferation. Furthermore, the Al-stimulated increase in collagen formation is consistent with the development of osteomalacia in Al-toxic humans and animals. The mechanism by which Al stimulated DNA synthesis and collagen production in more mature cultures awaits further study.     

Comparison of peripheral bone and body axis skeleton in a rat model of mild-to-moderate renal failure in the presence of physiological serum levels of calcitropic hormones

The skeleton is characterized by anatomic heterogeneity of metabolic turnover. Site-dependent differences in hormonal effects seem likely. Hyporesponsiveness of osteoclasts to parathyroid hormone (PTH) and probably calcitriol was recently demonstrated in the fifth lumbar vertebra of a rat model with moderate renal failure. We compared histomorphometric findings of the tibial head to these data. Histomorphometric measurements were carried out in sections of the right tibial head of pair-fed male Sprague-Dawley rats. Subtotally nephrectomized (SNx), parathyroidectomized (PTx), rats, which received either solvent or rat PTH(1-34) (100 ng/kg per hour) + calcitriol (5 pmol/kg per hour) via osmotic minipumps were compared with sham-operated controls. Results were compared with data from the fifth lumbar vertebra reported recently. Osteoclast numerical density and osteoclast surface density were lower in the tibial head and the lumbar vertebra of solvent-treated SNxPTx rats than in sham-operated controls (p < 0.05), and could not be returned to normal by the substitution of PTH + calcitriol (p < 0.05). On the other hand, there were differences between interventional effects on the tibial head and on the lumbar vertebra concerning parameters describing osteoblasts and trabecular bone volume. In the tibial head, osteoblast surface density was nearly unchanged in both interventions. Nevertheless, bone volume increased after SNxPTx without substitution of PTH + calcitriol (p < 0.05), and no further changes occurred after hormonal replacement. In contrast, osteoblast surface density in the lumbar vertebra was decreased slightly compared with values in sham-operated rats; a clear but nonsignificant increase occurred after the administration of calcitropic hormones. This was accompanied by unchanged trabecular bone volume after SNxPTx. Hormonal replacement, however, caused an increase in trabecular bone volume (p < 0.05), which represents an anabolic effect, which contrasts with findings from the tibial head. The different interventional effects on the lumbar spine and on peripheral bone, regarding the parameters reflecting the condition of osteoblasts, may be intrinsic to the uremic syndrome itself as well as to dissimilar growth manner, function, and mechanical requirements. The findings substantiate the site dependence of bone surface cell metabolism in renal failure and should be the subject of further study. Corresponding results with regard to bone resorption argue for a bone-site-independent, diminished response of osteoclasts to calcitropic hormones.     

Immunoreactive serum calcitonin and skeletal histology in chronic renal failure

Serum calcitonin and serum parathyroid hormone (PTH) were measured in 50 patients undergoing regular haemodialysis for end-stage chronic renal failure, and an analysis of osteoclast and osteoblast activities was made in bone biopsies obtained by iliac crest trephine. Osteoclast and osteoblast activities were studied in a multivariate analysis in relation to factors which might reasonably be thought to influence activity, namely serum calcitonin, serum PTH, serum calcium, serum inorganic phosphate, and bone aluminium. Only serum PTH correlated strongly with osteoclast activity (p = 0.0047). Serum PTH correlated also with osteoblast activity (p = 0.0024). Serum inorganic phosphate correlated negatively with osteoblast activity (p = 0.0082). Serum calcitonin did not correlate with osteoclast or osteoblast activities but did correlate strongly with bone aluminium in a multivariate analysis (p = 0.0078). Bone aluminium did not correlate independently with osteoclast or osteoblast activities. This study affirms the implied powerful role of PTH in influencing osteoclast and osteoblast activities in end-stage chronic renal failure.     

Alendronate administration and skeletal response during chronic alcohol intake in the adolescent male rat.

Alendronate is an aminobisphosphonate that inhibits bone resorption in osteoporotic humans and rats but does not induce osteomalacia. Several bisphosphonates, including alendronate, also have direct positive actions on osteoblasts, bone formation, and mineralization. We studied the effects of alendronate on skeletal development in adolescent male rats during chronic alcohol intake. Four groups of age- and weight-matched male Sprague-Dawley rats (35 days of age) were fed the Lieber-DeCarli diet containing 36% of calories as EtOH (E), the EtOH diet plus 60 mg/kg alendronate (EA) every other day intraperitoneally (ip), an isocaloric diet (I), or the isocaloric diet plus 60 mg/kg alendronate (IA) every other day ip. Body weight, femur length, serum levels of osteocalcin (OC), insulin-like growth factor 1 (IGF-1), testosterone, and luteinizing hormone (LH); femur distal metaphyseal and middiaphyseal bone mineral density (BMD) and tibial metaphyseal gene expression for alpha-1-type I collagen (Col I), OC, and bone alkaline phosphatase (AP); and femur strength by four-point bending to failure were measured after 28 days of feeding and alendronate injections. Serum alcohol levels at death were 156 +/- 13 mg/dl (E) and 203 +/- 40 mg/dl (EA). Alendronate given to alcohol-fed rats increased metaphyseal BMD by more than 3-fold over rats fed alcohol alone. Alendronate given to isocaloric pair-fed rats increased metaphyseal BMD by more than 2.5-fold over rats fed the isocaloric diet alone. Cortical BMD was reduced by alcohol but was increased by alendronate. Alcohol consumption reduced serum IGF-1 levels, and alendronate increased IGF-1 levels in alcohol-fed rats. Serum OC, testosterone, and LH were unaffected by alcohol and alendronate. Quantitative dot blot hybridization using rat complementary DNA (cDNA) probes and normalization against 18S subunit ribosomal RNA (rRNA) levels revealed no changes in tibial metaphyseal gene expression for type I collagen, osteocalcin, or alkaline phosphatase. Alcohol significantly reduced the biomechanical properties of the femurs that were partially compensated by alendronate. Chronic alcohol consumption uncouples formation from ongoing resorption, and resorption is inhibited by alendronate. However, alendronate's positive effects on osteoblast-mediated mineralization during chronic alcohol consumption point to the potential use of bisphosphonates in the treatment of decreased bone formation secondary to alcohol-induced diminished osteoblast function.     

Effect of vitamin D metabolites on calcitriol metabolism in experimental renal failure

Previous studies from our laboratory have demonstrated that metabolic clearance rate (MCR) of calcitriol is decreased in experimental renal failure. In this experiment, we examined the effects of calcitriol, 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) on the MCR of calcitriol in renal failure produced in rats by partial nephrectomy. The MCR of calcitriol in these rats with renal failure was significantly lower than in control rats with sham operations. Plasma concentrations of calcitriol did not differ between the rats with moderate renal failure and control rats (sham, 74.7 +/- 3.6 pg/ml, N = 7; renal failure, 67.7 +/- 6.0, N = 6; serum creatinine 0.56 +/- 0.02 mg/dl vs. 0.96 +/- 0.02); however, the levels were significantly lower in rats with severe renal failure (sham, 66.5 +/- 5.1 pg/ml, N = 7, severe renal failure, 49.6 +/- 2.1 pg/ml, N = 8; serum creatinine 0.53 +/- 0.01 mg/dl vs. 1.40 +/- 0.03). Subcutaneous infusion of calcitriol (10 ng/kg/day) in rats with severe renal failure for one week significantly increased the MCR of calcitriol (0.22 +/- .01 vs. 0.17 +/- .01 ml/min/kg, P less than 0.001). Infusion of 25(OH)D3 (600 ng/day) or 24,25(OH)2D3 (1 microgram/day) in rats with renal failure for one week also increased the MCR of calcitriol (25(OH)D3, 0.25 +/- 0.01 ml/min/kg; 24,25(OH)2D3, 0.25 +/- 0.01, both P less than 0.001) when compared to rats with renal failure infused with vehicle (0.21 +/- 0.01). Administration of 24,25(OH)2D3 significantly lowered the plasma levels of calcitriol in rats with renal failure (52.3 +/- 3.1 pg/ml, P less than 0.05) in comparison to the rats with renal failure infused with vehicle (67.7 +/- 6.0).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of coumestrol on expression of bone markers during primary osteoblastic cells differentiation

目的 观察植物雌激素香豆雌酚对成骨细胞增殖分化的作用并探讨其作用机制.方法 从小鼠颅盖骨获得成骨细胞并用0,10-9～10-5 M香豆雌酚孵育48 h,以17β雌二醇为阳性对照,用酶消化法测定碱性磷酸酶及Ⅰ型胶原含量,放免法测定骨钙素含量,RT-PCR法测定OPG及RANKL mRNA表达情况,Western Blot测定OPG蛋白含量.结果 干预48 h,不同浓度香豆雌酚呈剂量依赖性增加碱性磷酸酶及Ⅰ型胶原含量,10-6 M时达到最大效应(P<0.05),但10-5 M效应有所降低,香豆雌酚轻度增加成骨细胞骨钙素含量,各组间无统计学差异.香豆雌酚呈剂量依赖性增加OPG基因及蛋白的表达(P<0.05),轻度降低RANKL基因的表达.结论 香豆雌酚能增加成骨细胞增殖及分化,可能其部分通过OPG/RANKL发挥作用.     

Calcitriol and calcium carbonate therapy in early chronic renal failure

The aim of this study was to evaluate the effects of a combinedlow-dose therapy of calcitriol and calcium carbonate on bonemetabolism in the early phases of chronic renal failure. A 30-monthstudy involving 17 patients with ECRF was made: 6 months ofobservation were followed by 24 months of therapy (calcitriol0.25 µg/day plus calcium carbonate 1 g/day). The mostimportant results were that renal function was stable throughoutthe study and there was an increase in calcaemia and a decreasein plasma alkaline phosphatase, plasma osteocalcin, plasma PTHand urinary hydroxyproline. We observed a progressive slowingof the rate of loss of appendicular bone density as well asa decrease of osteoblastic and osteoclastic activity and animprovement of bone mineralization. In conclusion, low dosesof calcitriol plus calcium carbonate seem to improve the biochemicaland bone derangements in early renal failure.     

Factors influencing calcitriol metabolism in renal failure

Metabolic clearance rate (MCR) and production rate (PR) of calcitriol is decreased in experimental renal failure. In this experiment, we studied uremia and secondary hyperparathyroidism as possible causes of the abnormal calcitriol metabolism. Normal rats were made uremic by infusing phosphorus-free urine for 24 hours. Both the MCR (0.22 +/- 0.01 ml/min/kg, N = 6 P less than 0.001) and the PR (16.6 +/- 1.97 ng/kg/day, P less than 0.01) of calcitriol were significantly suppressed in normal rats following urine infusion when compared to saline infused rats (MCR, 0.30 +/- 0.01; PR, 32.9 +/- 4.1, N = 6). Different levels of protein intake by rats with renal failure produced by subtotal nephrectomy also alter the PR but not the MCR of calcitriol. Thus, the synthesis of calcitriol was significantly lower in rats with renal failure fed a high protein (50% protein) diet (17.6 +/- 0.7 ng/kg/day, N = 8, P less than 0.001) than in rats with renal failure fed a normal protein (20% protein) diet (22.2 +/- 1.4, N = 7). Thyroparathyroidectomy (TPTX) did not alter the MCR of calcitriol in renal failure, even though parathyroid hormone, which may suppress the degradation enzyme, could be elevated in this model of renal failure. The MCR of TPTXed rats with renal failure (0.15 +/- 0.01 ml/min/kg, N = 7) remained lower than that of the TPTXed control rats (0.19 +/- 0.01, N = 7, P less than 0.001), and chronic infusion of PTH to TPTXed rats with renal failure did not change the MCR of calcitriol (0.15 +/- 0.01, vs. control, 0.24 +/- 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone growth during daily or intermittent calcitriol treatment during renal failure with advanced secondary hyperparathyroidism

Calcitriol is a standard therapy for secondary hyperparathyroidism in chronic renal failure. We evaluated whether the effect of daily or intermittent calcitriol administration is more efficient in enhancing bone growth in renal failure with advanced secondary hyperparathyroidism in weanling 5/6 nephrectomized rats loaded with phosphorus to induce severe secondary hyperparathyroidism. The animals were treated daily or three times weekly with calcitriol for 4 weeks but the total weekly dose of calcitriol was the same. Although calcitriol increased the serum calcium, it did not lower parathyroid hormone (PTH) or improve tibia and body length. Animals with renal failure and advanced secondary hyperparathyroidism had decreased PTH/PTHrP, which was accompanied by an increase in the cyclin kinase inhibitor p57(Kip2). Calcitriol treatment upregulated the PTH/PTHrP receptor but also increased inhibitors of cell proliferation such as p21(Waf1/Cip1), IGFBP3, and FGFR3. Calcitriol also enhanced markers of chondrocyte differentiation, such as IGF1, Vitamin D receptor, FGF23, and bone morphogenetic protein-7. Receptor activator of nuclear factor-kappabeta ligand levels improved with calcitriol treatment but without changes in osteoprotegerin suggesting an enhancement of osteo/chondroclastogenesis and mineralization. Overall, both daily and intermittent calcitriol had similar effects on endochondral bone growth in phosphorus-loaded rats with renal failure.