Reduced Serum Parathyroid Hormone Research Articles

Calcimimetics increase CaSR expression and reduce mineralization in vascular smooth muscle cells: mechanisms of action

Vascular calcification (VC) contributes to morbidity and mortality in patients with chronic kidney disease (CKD). Allosteric modulators of the calcium (Ca)-sensing receptor (CaSR) may slow the progression of VC in CKD patients either by reducing serum parathyroid hormone (PTH), Ca, and phosphate levels or by a direct effect on the vessel wall. The aim of this study was to examine the effects of calcimimetics on CaSR expression, cell phenotype, and mineral deposition in human vascular smooth muscle cells (h-VSMCs). Primary h-VSMCs were exposed for 14 days to increasing concentrations of Ca(2+) (from 1.8 to 5 mmol/L) in the presence or absence of calcimimetics R-568 or AMG 641 (0.1 μmol/L). Mineralization was detected by Alizarin red staining, and the cell phenotype was assessed using immunocytochemistry and qRT-PCR. CaSR expression was evaluated using flow cytometry. Short- and long-term exposure (1 day to 14 days) of h-VSMCs to calcimimetics promoted CaSR protein transport from the endoplasmic reticulum to the plasma membrane with enhanced CaSR expression on the cell surface, together with an increase in total cell CaSR expression due to enhanced biosynthesis. In pro-mineralizing conditions, exposure to calcimimetics counteracted the Ca(2+)-dependent reduction of CaSR expression, decreased matrix collagen secretion, and mineral deposition by ~90%. These effects involved CaSR activation since it could be inhibited by CaSR siRNA, but not scrambled siRNA. The calcimimetic-dependent increase in biosynthesis and activation of the CaSR in h-VSMCs probably play a key role in the protection against calcium-induced VC.

Role of TGF-β in a Mouse Model of High Turnover Renal Osteodystrophy

Altered bone turnover is a key pathologic feature of chronic kidney disease-mineral and bone disorder (CKD-MBD). Expression of TGF-β1, a known regulator of bone turnover, is increased in bone biopsies from individuals with CKD. Similarly, TGF-β1 mRNA and downstream signaling is increased in bones from jck mice, a model of high-turnover renal osteodystrophy. A neutralizing anti-TGF-β antibody (1D11) was used to explore TGF-β's role in renal osteodystrophy. 1D11 administration to jck significantly attenuated elevated serum osteocalcin and type I collagen C-telopeptides. Histomorphometric analysis indicated that 1D11 administration increased bone volume and suppressed the elevated bone turnover in a dose-dependent manner. These effects were associated with reductions in osteoblast and osteoclast surface areas. Micro-computed tomography (µCT) confirmed the observed increase in trabecular bone volume and demonstrated improvements in trabecular architecture and increased cortical thickness. 1D11 administration was associated with significant reductions in expression of osteoblast marker genes (Runx2, alkaline phosphatase, osteocalcin) and the osteoclast marker gene, Trap5. Importantly, in this model, 1D11 did not improve kidney function or reduce serum parathyroid hormone (PTH) levels, indicating that 1D11 effects on bone are independent of changes in renal or parathyroid function. 1D11 also significantly attenuated high-turnover bone disease in the adenine-induced uremic rat model. Antibody administration was associated with a reduction in pSMAD2/SMAD2 in bone but not bone marrow as assessed by quantitative immunoblot analysis. Immunostaining revealed pSMAD staining in osteoblasts and osteocytes but not osteoclasts, suggesting 1D11 effects on osteoclasts may be indirect. Immunoblot and whole genome mRNA expression analysis confirmed our previous observation that repression of Wnt/β-catenin expression in bone is correlated with increased osteoclast activity in jck mice and bone biopsies from CKD patients. Furthermore, our data suggest that elevated TGF-β may contribute to the pathogenesis of high-turnover disease partially through inhibition of β-catenin signaling.

Cinacalcet attenuates the renal endothelial-to-mesenchymal transition in rats with adenine-induced renal failure

Elevated serum parathyroid hormone (PTH) is an important complicated phenomenon in patients with chronic kidney disease (CKD). Emerging evidence indicates the involvement of PTH in organ fibrosis, and suppression of PTH by cinacalcet (CINA) ameliorates the progression of fibrotic disorders. However, the underlying mechanisms are largely unknown. The endothelial-to-mesenchymal transition (EndMT) has been shown to be an important mechanism involved in renal fibrosis. The present study aimed to investigate whether CINA treatment attenuated renal EndMT in rats with adenine-induced chronic renal failure (CRF). Compared with the control group, serum PTH was significantly higher in the CRF group and was suppressed after CINA treatment. Serum calcium, phosphorus, and calcium × phosphorus product levels were similar in the CRF group and CINA-treated CRF group. Renal collagen accumulation was significantly increased in the CRF group, which was markedly ameliorated by CINA treatment. Expression of the endothelial marker CD31 was significantly downregulated in rats with CRF, whereas expression of the mesenchymal markers fibroblast specific-protein 1 and α-smooth muscle actin was markedly upregulated. These changes were inhibited by CINA treatment. The protein levels of these EndMT-related markers were strongly correlated with serum PTH concentrations. Furthermore, the in vitro study showed that PTH could significantly increase the expression of fibroblast specific-protein 1 and α-smooth muscle actin and decrease CD31 in mRNA and protein levels in a concentration- and time-dependent manner. In conclusion, our study suggests that reducing serum PTH by CINA treatment could attenuate renal fibrosis via suppression of EndMT in the adenine-induced CRF rat model.

Consumption of Yogurts Fortified in Vitamin D and Calcium Reduces Serum Parathyroid Hormone and Markers of Bone Resorption: A Double-Blind Randomized Controlled Trial in Institutionalized Elderly Women

Nutritional prevention of bone deterioration with fortified foods seems particularly suitable in institutionalized elderly women at risk of vitamin D deficiency, secondary hyperparathyroidism, increased bone resorption, and osteoporotic fracture. The objective was to evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum PTH and bone resorption markers as compared with isocaloric and isoprotein dairy products in elderly women. A randomized double-blind controlled-trial, 56-day intervention was conducted in institutionalized women (mean age 85.5 years) consuming 2 125-g servings of either vitamin D- and calcium-fortified yogurt (FY) at supplemental levels of 10 μg/d vitamin D₃ and 800 mg/d calcium or nonfortified control yogurt (CY) providing 280 mg/d calcium. The endpoints were serum changes from baseline (day 0) to day 28 and day 56 in 25-hydroxyvitamin-D (25OHD), PTH, and bone resorption markers tartrate-resistant acid phosphatase isoform-5b (TRAP5b), the primary outcome, and carboxyl-terminal cross-linked telopeptide of type I collagen (CTX). At day 56, serum 25OHD increased (mean ± SEM) by 25.3 ± 1.8 vs 5.2 ± 2.5 nmol/L in FY (n = 29) and CY (n = 27), respectively (P < .0001). The corresponding changes in PTH were -28.6% ± 7.2% vs -8.0% ± 4.3% (P = .0003); in TRAP5b, -21.9% ± 4.3% vs 3.0% ± 3.2% (P < .0001); and in CTX, -11.0% ± 9.7% vs -3.0% ± 4.1% (P = .0146), in FY and CY, respectively. At day 28, these differences were less pronounced but already significant for 25OHD, PTH, and TRAP5b. This study in institutionalized elderly at high risk for osteoporotic fracture suggests that fortification of dairy products with vitamin D₃ and calcium provides a greater prevention of accelerated bone resorption as compared with nonfortified equivalent foods.

Prolonged treatment with vitamin D in postmenopausal women with primary hyperparathyroidism

Introduction/backgroundVitamin D deficiency further increases circulating parathyroid hormone (PTH) levels in patients with primary hyperparathyroidism (pHPT), with potential detrimental effects on bone mass.MethodsThis was an observational clinical study in consecutive conservatively treated postmenopausal women (n=40) with pHPT and coexistent 25-hydroxyvitamin D deficiency (25OHD ≤50 nmol/l (≤20 ng/ml)). Patients who showed an increase in serum 25OHD above the threshold of vitamin D deficiency (>50 nmol/l; n=28) using treatment with various commonly prescribed vitamin D preparations were, for the purposes of statistical analyses, allocated to the treatment group. Patients who were retrospectively identified as having received no treatment with vitamin D and/or remained vitamin D deficient were considered as non-responders/controls (n=12). Adjusted calcium (adjCa), PTH and 25OHD concentrations were monitored in all subjects up to 54 months (mean observation period of 18±2 months).ResultsProlonged increased vitamin D intake, regardless of the source (serum 25OHD, increase from 32.2±1.7 nmol/l at baseline to 136.4±11.6 nmol/l, P<0.0001), significantly reduced serum PTH (13.3±1.1 vs 10.5±1.0 pmol/l, P=0.0001), with no adverse effects on adjCa levels (2.60±0.03 vs 2.60±0.02 mmol/l, P=0.77) and renal function tests (P>0.73). In contrast, serum PTH remained unchanged (15.8±2.6 vs 16.3±1.9 pmol/l, P=0.64) in patients who remained vitamin D deficient, with a significant difference between groups in changes of PTH (P=0.0003). Intrapartial correlation analyses showed an independent negative correlation of changes in 25OHD with PTH levels (r ic=−0.41, P=0.014).ConclusionsProlonged treatment with vitamin D in various commonly prescribed preparations appeared to be safe and significantly reduced PTH levels by 21%.

Effect of cinacalcet on bone mineral density of the radius in hemodialysis patients with secondary hyperparathyroidism

Cinacalcet, an allosteric modulator of the calcium sensing receptor, effectively reduces serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. It is not well known whether bone mineral density (BMD) of hemodialysis patients with secondary hyperparathyroidism is altered after cinacalcet treatment. The BMD in the distal 1/3 of the radius and in the ultradistal radius, which are enriched with cortical and cancellous bone, respectively, was examined by dual X-ray absorptiometry, 1 year prior to, at the start, and 1 year after cinacalcet treatment, in 61 patients. The BMD of both the distal 1/3 and ultradistal radius decreased significantly in the year prior to cinacalcet treatment (p < 0.01). However, the BMD at either site did not change significantly in the year after cinacalcet treatment. The annual changes in the BMD of the distal 1/3 radius increased significantly from -0.023 ± 0.029 g/cm2/year to -0.002 ± 0.033 g/cm2/year, prior to and after cinacalcet treatment, respectively; however, the annual changes in the BMD of the ultradistal radius did not change significantly prior to and after cinacalcet treatment. There was a significant association between cinacalcet treatment and reduction in BMD loss in patients with secondary hyperparathyroidism. Cortical bone, rather than cancellous bone, was particularly affected by cinacalcet treatment.

Early Initiation of Cinacalcet for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients: A Three-Year Clinical Experience

Despite the availability of standard therapy (vitamin D sterols and phosphate binders) for the treatment of secondary hyperparathyroidism (SHPT) in hemodialyzed (HD) patients, a significant percentage of patients still fail to achieve targets recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation for parathyroid hormone (PTH), calcium, and phosphorus. The calcimimetic cinacalcet (CN) has been shown to be an effective treatment for SHPT, significantly reducing serum PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product levels, thus increasing the proportion of patients achieving the K/DOQI targets for bone mineral parameters. The aim of this study was to evaluate if early treatment with CN had beneficial effects in HD patients with mild-to-moderate SHPT in whom conventional treatments had failed to achieve NKF-K/DOQI targets for PTH, serum-corrected calcium, and phosphorus while minimizing the risk of paradoxical hypercalcemia and/or hyperphosphatemia. Clinical practice data were collected monthly, starting from 6 months prior to, and up to 36 months after, the start of CN therapy. CN was started at a dose of 30 mg daily or every other day, and titrated thereafter to achieve intact PTH (iPTH) <300 pg/mL. The dose of concomitant vitamin D and phosphate binders were also adjusted in order to achieve K/DOQI targets. Data from 32 patients were collected, 28 of whom had been treated with CN for at least 36 months at the time of data analysis. At baseline, patients had serum iPTH >300 pg/mL (570 ± 295 pg/mL) and/or serum-corrected calcium >9.5 mg/dL. CN induced significant decreases in iPTH, calcium, and calcium-phosphorus product with respect to baseline levels. The percentage of patients within K/DOQI target levels at baseline, 12, 24, and 36 months was 0, 81.2, 83.3, and 86.2% for iPTH; 34.4, 65.6, 86.6, and 89.6% for serum-corrected calcium; 40.6, 56.2, 69.6, and 72.4% for phosphorus; and 37.5, 62.5, 80, and 82.7% for calcium-phosphorus product. The mean dose of CN at the end of the observation period was 38 mg/day. The mean dose of concomitant medication (calcitriol, Al-containing phosphate binders, and sevelamer) decreased from baseline to 36 months. Early treatment with CN in HD patients with SHPT increases the proportion of patients achieving and maintaining K/DOQI targets with a low dose of CN (38 mg/day). These results suggest that the metabolic control obtained with low-dose CN administered early in the course of SHPT can be maintained or increased over time.

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI assays. All compounds had reduced activity when extracellular Ca(2+) was removed, indicating that they cooperate with Ca(2+) to activate CaSRs, and all activated CaSR isoforms with the N-terminal extracellular domain deleted, indicating that they interact with the transmembrane domains. In both cases, AC-265347 and therefore (S)-AC-265347 were significantly more efficacious than the phenylalkylamines. Mutations E837A(7.39) and I841A(7.43) strongly reduced phenylalkylamine-induced signaling, but not AC-265347- or (S)-AC-265347-induced signaling, suggesting different modes of binding. AC-265347 and (S)-AC-265347 stimulated significantly greater responses than cinacalcet or calindol at each of four loss-of-function human polymorphic CaSR variants. AC-265347 did not inhibit the CYP2D6 cytochrome P450 isozyme, unlike cinacalcet, which is a potent CYP2D6 inhibitor. In rats, AC-265347, (S)-AC-265347, and (R)-AC-265347 each reduced serum parathyroid hormone (PTH) with a rank order potency correlated with their in vitro potencies. AC-265347 and (S)-AC-265347 also reduced plasma ionizable calcium ([Ca(2+)](o)). AC-265347 was orally active, and its plasma concentrations correlated well with its effects on serum PTH. Thus, these highly efficacious CaSR allosteric agonists represent leads for developing therapeutic agents with potential advantages over existing therapies.

Therapeutic management of post-kidney transplant hyperparathyroidism

Left uncontrolled, persistent post-kidney transplant hyperparathyroidism (HPT) may lead to or exacerbate pre-existing bone and cardiovascular disease. Parathyroidectomy has long been the primary treatment option for long-term uncontrolled HPT in post-kidney transplant patients. However, patients with contraindications for surgery and parathyroidectomy-associated complications, including graft loss, highlight the need for other approaches. Conventional medical therapies have limited impact on serum calcium (Ca) and parathyroid hormone (PTH) levels. Bisphosphonates and calcitonin, used to spare bone loss, and phosphorus supplementation, to correct hypophosphatemia, do not directly regulate PTH or Ca. Although vitamin D supplementation can reduce PTH, it is often contraindicated because of hypercalcemia. Studies of the calcimimetic cinacalcet in patients with post-kidney transplant HPT suggest that it can rapidly reduce serum PTH and Ca concentrations while increasing serum phosphorus concentrations toward the normal range. Although the clearest application for cinacalcet is the non-surgical treatment of hypercalcemic patients with persistent HPT, current indications for other transplant patients are as yet uncertain. Further studies are needed to determine the utility of cinacalcet in patients with spontaneous resolution of HPT or low bone turnover. This review discusses the pathophysiology of post-kidney transplant HPT, associated complications, and current options for clinical management.

Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume. This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls. Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm(3) (group S) and 25 had at least one enlarged gland larger than 500 mm(3) (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone. Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

Decreases in Parathyroid Gland Volume after Cinacalcet Treatment in Hemodialysis Patients with Secondary Hyperparathyroidism

Background/Aim: Cinacalcet, an allosteric modulator of the calcium-sensing receptor, effectively reduces serum parathyroid hormone (PTH). It was examined whether a regression of parathyroid glands in hemodialysis patients with secondary hyperparathyroidism was induced by cinacalcet treatment. Methods: Ultrasonography of the parathyroid glands was performed to examine the changes in the parathyroid gland volumes after cinacalcet treatment in 58 patients. Results: After cinacalcet treatment, serum calcium, phosphate, alkaline phosphatase, and intact PTH significantly decreased (p < 0.0001). The total volumes of the parathyroid glands were significantly decreased 6 months after cinacalcet treatment (942 ± 747 vs. 708 ± 550 mm³, p < 0.0005). There was a significant positive correlation between the parathyroid gland volumes at the start of cinacalcet treatment and the volume reduction in parathyroid glands (r = 0.716, p < 0.0001). Of the 58 patients, the total parathyroid gland volume was decreased in 42 patients and increased in 16 although the doses of cinacalcet, phosphate binders or vitamin D were not significantly different. In both groups, the intact PTH serum levels were significantly decreased after cinacalcet treatment. Conclusion: Cinacalcet treatment in patients with secondary hyperparathyroidism significantly reduced the total parathyroid gland volume in a short 6-month period. This study suggests that cinacalcet treatment may postpone parathyroidectomy and/or reduce cases.

Eficacia del cinacalcet en el hiperparatiroidismo secundario en hemodiálisis: análisis de los factores que influyen en su respuesta

Background Several authors have shown the difficulty of achieving the targets established in published guidelines for the treatment of secondary hyperparathyroidism. Cinacalcet can reduce serum parathyroid hormone (PTHi) levels, thus helping to achieve established targets. The aim of the present study was to analyze how cinacalcet can facilitate control of secondary hyperparathyroidism by comparing our results with the target levels recommended in guidelines and to identify the factors that could influence response to this drug. Material and methods We retrospectively collected information on the response of 74 hemodialysis patients with secondary hyperparathyroidism (baseline PTHi levels >300 pg/ml) who were treated with cinacalcet for at least 6 months. We recorded serum calcium (Ca), phosphorus (P), and PTHi levels at 3, 6, 9 months and at the end of follow-up. The baseline and final doses of phosphorus captors were also recorded. Results At the end of the follow-up, cinacalcet reduced serum levels of PTHi by 36%, P by 13.2%, Ca by 6%, and calcium-phosphorus product (CaxP) by 12.9%. At the start of treatment, P was >5.5 mg/dl in 38.4% of the patients, Ca was <8.4 mg/dl in 2.7%, and CaxP was >55 mg 2/dl 2 in 37.8%. After cinacalcet treatment, 50% of patients had PTHi <300 pg/ml, the percentage of patients with P >5.5 mg/dl was reduced to 24.7%, the prevalence of hypocalcemia increased to 12.2%, and the percentage of patients with CaxP>55 mg 2/dl 2 was reduced to 14.9%. The presence of hypocalcemia was independent of baseline PTHi levels and the degree of control of hyperparathyroidism reached after cinacalcet treatment. Most patients were managed without vitamin D (paricalcitol), which was discontinued in 24.3% who received this drug before cinacalcet therapy and was added to treatment in only 13.5% of patients with inadequate control of PTHi. After cinacalcet treatment, calcium carbonate doses increased (baseline 1.5±3.8 g/day vs final 2.4±4.9 g/day; p=0.03) with a non-significant reduction in sevelamer doses. When we analyzed the degree of final response to cinacalcet, we observed that levels of PTHi at 3 months were significantly lower in patients who reached PTHi <300 pg/ml at the end of follow-up, with lower final doses of cinacalcet (78% of patients with doses of 30 mg/day or less). When we reviewed the effect of phosphorus captors, we found that patients with higher doses of sevelamer at baseline showed a worse response, required higher cinacalcet doses, and less frequently achieved target PTHi levels. Multiple regression analysis confirmed that the degree of response depended on baseline PTHi levels and baseline sevelamer doses. Conclusions Cinacalcet facilitates control of secondary hyperparathyroidism. The PTH levels reached after 3 months of cinacalcet treatment have a prognostic value in predicting final response. The degree of response depends on the severity of secondary hyperparathyroidism, reflected by baseline PTHi levels and the sevelamer doses prescribed.

Cinacalcet is effective in the treatment of hyperparathyroidism secondary to malignant transformation of autotransplanted parathyroid tissue. A case report.

Calcimimetics are effective in lowering serum parathyroid hormone (PTH) levels in hyperparathyroidism (HPT). However, they failed to reduce PTH levels in the long term in the setting of primary malignant HPT.A haemodialysis patient suffering from severe longstanding secondary HPT underwent total parathyroidectomy with autotransplantation of parathyroid tissue in her left arm. In the following years, she developed a severe HPT sustained by cancerous transformation of the parathyroid transplanted tissue and resistant both to pharmacological and repeated surgical treatments.The calcimimetic ‘cinacalcet’ was able to effectively reduce serum PTH levels over a 3-year follow-up and to induce disappearance of the neoplastic lesion on radionuclide imaging. Biochemical control of HPT was associated with a remarkable improvement in cardiac function.

Vitamin D compounds for people with chronic kidney disease not requiring dialysis

Vitamin D compounds are used to suppress elevated serum parathyroid hormone (PTH) in people with chronic kidney disease (CKD). To assess the efficacy of vitamin D therapy on biochemical, bone, cardiovascular, and mortality outcomes in people with CKD and not requiring dialysis. We searched The Cochrane Renal Group's specialised register, Cochrane's Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of retrieved articles. Randomised controlled trials (RCTs) comparing different forms, schedules, or routes of administration of vitamin D compounds for people with CKD not requiring dialysis were included. Vitamin D compounds were defined as established (calcitriol, alfacalcidol, 24,25(OH)(2)vitamin D(3)) or newer (doxercalciferol, maxacalcitol, paricalcitol, falecalcitriol) vitamin D compounds. Data were extracted by two authors. Statistical analyses were performed using the random effects model. Results were summarized as risk ratio (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes with 95% confidence intervals (CI). Sixteen studies (894 patients) were included. No formulation, route, or schedule of vitamin D compound was found to alter the mortality risk or need for dialysis. Vitamin D compounds significantly lowered serum PTH (4 studies, 153 patients: MD -49.34 pg/mL, 95% CI -85.70 to -12.97 (-5.6 pmol/L, 95% CI -9.77 to -1.48)) and were more likely to reduce serum PTH > 30% from baseline value (264 patients: RR 7.87, 95% CI 4.87 to 12.73). Vitamin D treatment was associated with increased end of treatment serum phosphorus (3 studies, 140 patients: MD 0.37 mg/dL, 95% CI 0.09, 0.66 (0.12 mmol/L, 95% CI 0.03, 0.21)) and serum calcium (5 studies, 184 patients: MD 0.20 mg/dL, 95% CI 0.17 to 0.23 (0.05 mmol/L, 95% CI 0.04 to 0.06)). Few data were available comparing intermittent with daily vitamin D administration, or other schedules of dosing. There are not sufficient data to determine the effect of vitamin D compounds on mortality and cardiovascular outcomes in people with CKD not requiring dialysis. While vitamin D compounds reduce serum PTH (49.3 pg/mL (5.6 pmol/L)) compared with placebo, the relative clinical benefits of PTH lowering versus treatment-related increases in serum phosphorus and calcium remain to be understood.

Management of Mineral and Bone Disorder in Chronic Kidney Disease: Quo Vadis?

Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a serious complication because of its profound impact on morbidity and mortality. Recent introduction of calcimimetic cinacalcet hydrochloride has led to a major breakthrough in the management of CKD-MBD. Numerous clinical studies have shown that in dialysis patients with secondary hyperparathyroidism, cinacalcet effectively reduces serum parathyroid hormone levels without increasing serum calcium and phosphorus levels. This is in contrast to vitamin D analogs that inhibit parathyroid hormone secretion at the price of enhanced intestinal absorption of calcium and phosphorus. More recent studies have focused on the efficacy of combination therapy with calcimimetics and low-dose vitamin D analogs. One of the most important issues in this context is whether treatment with cinacalcet results in improved clinical outcomes. This is currently under investigation by prospective clinical trials. However, many important questions remain unresolved, including issues with whether and how calcimimetics and vitamin D analogs should be combined and whether calcimimetics or vitamin D analogs should be preferred as primary therapy. With a view to improving patient-level outcomes, further work should establish more precisely the role of calcimimetics and vitamin D analogs in combination with other therapeutic approaches for CKD-MBD management.

Does Cinacalcet Improve the Prognosis of Dialysis Patients?

Appropriate control of serum calcium (Ca) and inorganic phosphate (Pi) levels is required for better prognosis of dialysis patients. Cinacalcet is known to reduce not only serum parathyroid hormone (PTH) but also Ca and Pi levels; however, it remains unclear whether cinacalcet can ultimately improve the prognosis of such patients. In this paper, the ongoing prospective observational study (Q Cohort Study) and double-blind randomized controlled study (EVOLVE Study) are introduced. In the Q Cohort Study, cinacalcet therapy is indicated when intact PTH levels exceed 180 pg/mL, accounting for 31.3% of the study population (N = 3009). In the EVOLVE Study, the primary endpoint is the time to occurrence of composite events including all-cause mortality or nonfatal cardiovascular events. There is a related pilot study that treated patients over a 6-month period with cinacalcet. The findings showed that cinacalcet reduced serum PTH, Ca, and Pi levels and that if the patient had lower PTH levels at baseline, the dosage of vitamin D could be greatly reduced. Thus, in some patients concomitant vitamin D and cinacalcet therapy may be preferred to vitamin D alone.

Use of Calcium, Folate, and Vitamin D3–Fortified Milk for 6 Months Improves Nutritional Status But Not Bone Mass or Turnover, in a Group of Australian Aged Care Residents

In residential care, inadequate calcium and folate intakes and low serum vitamin D (25(OH)D) concentrations are common. We assessed whether daily provision of calcium, folate, and vitamin D3–fortified milk for 6 months improved nutritional status (serum micronutrients), bone quality (heel ultrasound), bone turnover markers (parathyroid hormone, C-terminal collagen I telopeptide, terminal propeptide of type I procollagen), and/or muscle strength and mobility in a group of Australian aged care residents. One hundred and seven residents completed the study (mean (SD) age: 79.9 (10.1) years; body weight: 68.4 (15.4) kg). The median (inter-quartile range) volume of fortified milk consumed was 160 (149) ml/day. At the end of the study, the median daily vitamin D intake increased to 10.4 (8.7) μg (P < .001), which is 70% of the adequate intake (15 μg); and calcium density (mg/MJ) was higher over the study period compared with baseline (161 ± 5 mg/MJ vs. 142 ± 4 mg/MJ, P < .001). Serum 25(OH)D concentrations increased by 23 ± 2 nmol/L (83 (107)%, P < .001), yet remained in the insufficient range (mean 45 ± 2 nmol/L). Consumption of greater than the median intake of milk (160 ml/day) (n = 54, 50%) increased serum 25(OH)D levels into the adequate range (53 ± 2 nmol/L) and reduced serum parathyroid hormone by 24% (P = .045). There was no effect on bone quality, bone turnover markers, muscle strength, or mobility. Consumption of fortified milk increased dietary vitamin D intake and raised serum 25(OH)D concentrations, but not to the level thought to reduce fracture risk. If calcium-fortified milk also was used in cooking and milk drinks, this approach could allow residents to achieve a dietary calcium intake close to recommended levels. A vitamin D supplement would be recommended to ensure adequate vitamin D status for all residents.

The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats

Calcimimetics and vitamin D sterols reduce serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism receiving dialysis, a disease state associated with parathyroid hyperplasia, vascular calcification, bone disease, and increased mortality. The aim of this study was to determine the effects of the research calcimimetic AMG 641 (Amgen, Inc., Thousand Oaks, CA) or calcitriol (Sigma Aldrich Corporation, St. Louis, MO) on vascular calcification in a rodent model of progressive uremia with accompanying secondary hyperparathyroidism induced by dietary adenine. Treatment effects on parathyroid gland hyperplasia and bone loss were also investigated. Rats were treated daily with vehicle, calcitriol (10 ng), AMG 641 (3 mg/kg), or no treatment during the 4 week period the animals were fed adenine. The uremia-induced increases in serum PTH levels were significantly attenuated by both AMG 641 (> 90%) and calcitriol (~ 50%). AMG 641 significantly reduced calcium–phosphorus product (Ca × P) and significantly attenuated the development of both parathyroid hyperplasia and vascular calcification. In addition, AMG 641 prevented the defects in trabecular bone volume, trabecular number, and bone mineralization, as well as increases in trabecular spacing in this rodent model of secondary hyperparathyroidism. Calcitriol (10 ng/rat) decreased osteoid surface/bone surface, but had no effects on other bone parameters, or parathyroid hyperplasia (likely due to the lower PTH suppressive effect of calcitriol at the dose used in this study). However, this dose of calcitriol significantly exacerbated vascular calcification. These results suggest that calcimimetics can reduce the development of vascular calcification, parathyroid hyperplasia and bone abnormalities associated with secondary hyperparathyroidism.

Effect of Sevelamer Hydrochloride on Bone in Experimental Uremic Rats

Hyperphosphatemia in dialysis patients is known to cause secondary hyperparathyroidism and high-turnover bone disease. Sevelamer hydrochloride (sevelamer) is a nonabsorbed, calcium-free phosphate-binder. We determined the effect of sevelamer on parathyroid hormone (PTH)-induced high bone turnover. Rats were sham-operated or 5/6-nephrectomized (Nx) and fed a phosphate loading diet for 16 weeks or 5/6-nephrectomized and fed a phosphate loading diet for 8 weeks and then fed the same diet containing 3% sevelamer for the subsequent 8 weeks (Nx-S). Sevelamer significantly reduced serum PTH. The relative osteoid volume (OV/BV), osteoid surface (OS/BS), eroded surface (ES/BS), mineral appositional rate (MAR), volume-referent bone formation rate (BFR/TV), and bone-referent bone formation rate (BFR/BV) were measured for vertebral bone histomorphometric analysis. All parameters were statistically higher in the Nx rats than in the sham-operated control rats. The administration of sevelamer attenuated increases in OV/BV, ES/BS, BFR/TV, and BFR/BV. For femur histomorphometric analysis, the porosity area (%) (PoAr/CtAr), osteoid surface on the periosteal surface, osteoid surface on the endocortical surface (OS/Es), mineral appositional rate on the periosteal surface, mineral appositional rate on the endocortical surface, bone formation rate on the periosteal surface, and bone formation rate on the endocortical surface (Es BFR) were calculated. All parameters were higher in the Nx group than in the control group. Sevelamer inhibited the elevation of PoAr/CtAr, OS/Es, and Es BFR. Our findings suggest that the decrease in PTH by sevelamer may be beneficial in the treatment of high PTH-induced bone disease.

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics.