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The treatment of mineral metabolism disorders: a recent approach with new compounds and a proposed algorithm

João M. Frazão Nephrology Department, Hospital de S. João, Medical School of the University of Porto and Nephrology Research and Development Unit, Porto, Portugal

Correspondence: Prof. Doutor João Miguel Frazão Hospital de S. João, Serviço de Nefrologia Alameda Hernâni Monteiro 4200 Porto – Portugal E-mail: jmmdfrazao@netcabo.pt

cinacalcet.Introduction During the last few years there have been major developments in the management of bone and mineral disorders in chronic kidney disease (CKD) stage 5 haemodialysis patients. new compounds have been developed for the control of hyperphosphataemia and for the treatment of secondary hyperparathyroidism (SHPT). brings new questions and concerns to the mind of the clinical nephrologists taking care of dialysis patients. in contrast with the effect of active vitamin D. . Many practical questions have been raised by nephrologists on the use of noncalcium containing phosphate binders. that suppresses PTH secretion and. lowers calcium and phosphorus serum levels. cinacalcet and active vitamin D. Furthermore. the use of the new calcimimetic agent. In addition. a practical treatment algorithm will be proposed at the end of this lecture which combines the treatment of hyperphosphatemia and secondary hyperparathyroidism and highlights synergies between different compounds such as sevelamer. The knowledge that these bone and mineral abnormalities impact heavily on morbidity and mortality means the practicing nephrologist must pay major attention to control these alterations. Control of hyperphosphataemia In recent years it has become clear that the presence of disturbances of the mineral metabolism in CKD stage 5 hemodialysis patients are positively associated with increased mortality (1) (SLIDE 1). Based on published data and recommendations.

٥ Ca x P * * * n=٤٠.٥٤٣ * ١ ٠.٦ ١.٦ ١.٨ Adjusted serum calcium concentration (mg/dL) Relative risk of death ٢ ١.٤ ١. ٨٠–٨٥ ٨٥–٩٠ ٩٠–٩٥ ٩٥–١٠.٨ ٠.٢ ١.٠ >١١.٠ Reference group Calcium n=٤٠.٥ <٨٠ .٠ ٠. .٤ ١.٥ ١٠٥–١١.٦ ٠.٠ .3) (SLIDE 2).٠ Phosphorus n=٤٠. . .٥ ٠ <٣٠ ٣٠–٣٥ ٣٥–٤٠ ٤٠–٤٥ ٤٥–٥٠ ٥٠–٥٥ ٥٥–٦٠ ٦٠–٦٥ ٦٥–٧٠ ٧٠–٧٥ ٧٥–٨٠ >٨٠ < ١٥٠ ١٥٠–٣٠٠ ٣٠٠–٦٠٠ > ٦٠٠ Ca x P (mg٢/dL٢) *p<٠.٠–١٠.٠ ١٠. .٥٣٨ * ١. J Am Soc Nephrol.٨ ١.٥٣٨ * * * * * * * <٣ ٣–٤ ٤–٥ ٥–٦ ٦–٧ ٧–٨ ٨–٩ >٩ Serum phosphorus concentration (mg/dL) ٢.٢ ١.٢ Reference group * Relative risk of death Relative risk of death ٢. the latter an independent predictor of mortality.٠ ٠.٠ ٠.٠ PTH n=٣٤.٠ ١. . .٨ ١.١٥:٢٢٠٨–٢٢١٨ Hyperphosphataemia and elevated calcium-phosphorus product (Ca X P) are associated with cardiovascular calcification (2.٨ ٠.٦ ٠. ٢٠٠٤.SLIDE 1 Disturbances in mineral metabolism are associated with an increased risk of mortality ٢. Relative risk of death Reference group ١. .٠٥ Measured plasma iPTH Concentration (pg/mL) Block GA et al. .٥٣٨ * * * Reference group * ١.٨ ٠.٤ ١.٢ ١.٦ ١.

٥ mg/dL) p=٠.6) (SLIDE 3). Nephrol Dial Transplant ٢٠٠٤.١٦ ١٧٤ Adapted from Chertow GM et al.5.١٩(٦):١٤٨٩–١٤٩٦ Several authors have now reported a strong positive association between the presence and extent of vascular calcification and cardiovascular and all cause mortality (4.٠١ ١٦٣ Phosphorus (>٥.٥ mg/dL) Change in Agatston score ٢٠٠ ١٥٠ ١٠٠ ٥٠ ٠ Coronary Aorta ٣٩ ٨ p=٠. .SLIDE 2 Failure to achieve NKF-K/DOQI™ P targets is associated with a higher calcification risk Changes in calcification scores of coronary arteries and aorta after ١ year Phosphorus (<٥.

٣٨:٩٣٨ Patients with stage 5 CKD have a high prevalence of hyperphosphataemia. The clinical consequences of hyperphosphataemia include SHPT with the consequent renal bone disease. Hypertension.٠٠ Probability of survival ٠ ١ ٢ ٣ ٤ ٠. . Increased dialysis length or frequency may be effective. Until recently.٧٥ ٠.٦٦. dialysis and the use of phosphate binding agents. The dietary restriction with reduction of phosphate intake is often difficult for patients to achieve and is also limited by the associated protein restriction since all proteins contain phosphate.٠٠٠١) Blacher J et al. p<٠. extra-osseous calcification and increased mortality. ٢٠٠١. Therapeutic strategies to control phosphorus levels include dietary restrictions.٥٠ ٠.٠٠ ٠ ٢٠ ٤٠ ٦٠ ٨٠ Duration of follow-up (months) Comparison between curves was highly significant (x٢=٤٢. but it is often difficult to implement due to logistical problems and poor patient acceptance.٢٥ ٠.SLIDE 3 Cardiovascular calcification predicts mortality Calcification score (Number of calcified vessels) ١. These compounds were efficacious but also associated with significant side effects. the phosphate binders available were only aluminium or calcium based compounds. Phosphate is also difficult to remove by dialysis.

56 g of elemental calcium) in fact.7). (7) reported the results of a randomised parallel design clinical trial comparing sevelamer with the calcium-based phosphorus binders in 200 haemodialysis patients.5. at week 26 and 52.3. in the calcium-containing binders treated group. Sevelamer hydrochloride has been widely studied and shown to be effective in reducing phosphorus levels and Ca X P without causing hypercalcaemia and soft tissue calcification in the stage 5 CKD population on haemodialysis. There was a significant progression of the coronary artery and aortic calcification EBCT score. This compound is very well tolerated with very few side effects. nausea and vomiting. the actual K/DOKI recommended upper limit. despite the use of an average dose of calcium carbonate of only 3.The use of calcium-containing phosphate binders is associated with increased risk of hypercalcaemia and cardiovascular calcification (2. The excessive amount of calcium ingested from the diet and from calcium-containing binders has been associated with cardiovascular calcifications.3. even in the presence of normal calcium serum levels (2. dyspepsia. Moreover.9 g per day (1. The more frequently reported adverse effects are diarrhea. constipation. .5. It is now known that serum calcium levels are not accurate in predicting calcium balance and burden. sevelamer induces a reduction in total cholesterol and low density lipoprotein (LDL) cholesterol. Chertow et al.7). There was no significant progression in the sevelamer treated group (SLIDE 4).

٦٢:٢٤٥–٢٥٢ The high prevalence of vascular calcification seen in the dialysis population in the Chertow study (7) has been confirmed by other reports and is of major concern due to the positive association between the presence and severity of calcification and mortality in this population. 37 % of the patients that underwent treatment . Kidney Int.٠٢ Chertow GM et al. a report from Spiegel et al. (8) revealed that only 34% of patients with advanced chronic kidney disease starting dialysis had coronary artery calcifications scores that placed them above the 90th percentile for age and sex. ٢٠٠٢.SLIDE 4 Sevelamer vs calcium-containing binder: coronary artery calcification (week ٥٢) ٣٥ Calcification score % change (median) ٣٠ ٢٥ ٢٠ ١٥ ١٠ ٦ ٥ ٠ ٢٥* Sevelamer Calcium n=٧٠ n=٦٢ *within the same treatment group p<٠. In fact. between treatment groups p=٠.٠٠٠١. At baseline. There is also some evidence that most of the patients develop vascular calcifications while on haemodialysis treatment. In this same population of patients initiating dialysis. 109 patients underwent baseline and at least one additional measurement of coronary artery calcification (9).

Treatment of Secondary Hyperparathyroidism The use of calcitriol and other active vitamin D analogues has been very helpful .2 mg/dL). The patients treated with calcium-based binders showed a more rapid and severe progression when compared to those receiving sevelamer. While patients with even little evidence of coronary calcification progress with both binders. The authors conclude that patients new to dialysis with no evidence of coronary calcification showed little evidence of disease development over a period of 18 months independent of the phosphate binder used.with sevelamer and 31% of the patients that underwent treatment with calcium-based binders had no evidence of calcification. or with severe vascular calcification and/or other soft tissue calcification. using EBCT. should be treated with sevelamer. recommending that calcium based binders should be avoided in patients with evidence of severe calcification. The authors report that no patients with a zero coronary calcium score progressed to a coronary artery calcium score > 30. Patients with hypercalcemia (corrected serum calcium > 10. The use of calcium-containing phosphate binders is limited to a maximum of 1.5 g per day of elemental calcium to achieve control of hyperphosphataemia. the group treated with calcium-based binders has a much more severe progression when compared to the patients treated with sevelamer (9). or with plasma iPTH levels below 150 pg/mL on two consecutive measurements. Patients already having a coronary artery calcium score > 30 at baseline progressed during the time of the study in both arms. in a 18 months period of time. The current K/DOQI clinical practice guidelines for bone metabolism and disease state that the clinical use of sevelamer is recommended as an important firstline treatment option for the control of hyperphosphatemia and/or an elevated Ca X P product in stage 5 CKD patients (10). This study confirms without a doubt the importance of the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism and disease in chronic kidney disease.

presented the combined results of two identical. In 40% of the cinacalcet treated patients there was a suppression of the iPTH levels to a mean value below 250 pg/ml compared to 5% of the placebo group. Haemodialysis patients with SHPT not controlled despite conventional treatment with vitamin D analogues. cinacalcet has been shown to efficiently decrease PTH levels but also to have the beneficial effect of decreasing the calcium and phosphorus serum levels with a concomitant decrease in the CaXP. multicentre. During the maintenance phase there was a decrease in the iPTH levels of 43% from the baseline compared to an increase of 9% in the patients taking placebo. suggesting that these patients were not controlled despite conventional therapy. The most common secondary effects are hypercalcaemia. The basal levels of iPTH were 643 ± 18 pg/ml in the cinacalcet group and 642 ± 19 pg/ml in the placebo group. suppressing the secretion of parathyroid hormone (PTH). The cinacalcet treatment safety was well evident in this study. Block GA et al. The mean dose of phosphate binders and vitamin D was not different between groups. Of note is that 66% and 67% of the patients were being treated with vitamin D in the cinacalcet group and placebo group. The new compound cinacalcet is a calcimimetic agent that modulates the calcium sensing receptor increasing its sensitivity to circulating ionized calcium and therefore making it more responsive to the calcium suppressive effect on PTH secretion. The initial dose of cinacalcet was 30 mg a day titrated up to 180 mg a day in order to obtain suppression of iPTH to values ≤ 250 pg/ml. were randomised into 26 weeks of cinacalcet treatment (n = 371) or placebo (n = 370) in addition to conventional treatment. respectively. double blind. with no change in the placebo group.4% and 8. and increased CaXP . Frequent secondary side effects have been associated with active vitamin D treatment. The treatment with cinacalcet was associated with a reduction of calcium and phosphorus serum levels 6. In clinical trials involving SHPT patients. respectively.for the treatment of secondary hyperparathyroidism. hyperphosphatemia. The adverse . placebo controlled studies (11). randomised. Failure to control properly SHPT is frequent due to this narrow therapeutic window.4%.

rarely associated with symptoms and resolved with management of phosphate binders and/or vitamin D analogues. Less than 5% of the patients on cinacalcet and less than 1% on placebo were withdrawn from the study due to nauseas and vomiting. The incidence of hypocalcaemia defined as a corrected serum calcium level of less than 7. SLIDE 5 Percent Change in iPTH by Disease Severity ٣٠ ٢٠ ١٠ ٠ -١٠ -٢٠ -٣٠ -٤٠ -٥٠ -٦٠ -٧٠ ٣٠٠ to ٤٠٠ to ٤٠٠ ٥٠٠ ٥٠٠ to ٦٠٠ ٦٠٠ to ٧٠٠ to ٧٠٠ ٨٠٠ ٨٠٠ to ٩٠٠ ٩٠٠ to ١٠٠٠ > ١٠٠٠ n=٩٩ n=٩٣ ٩٢ ٧٦ ٧٧ ٦٣ ٥٨ ٥٢ ٥٥ ٣٣ ٢٣ ٣٥ ١٨ ١١ ١١١ ٥٦ Control (n = ٤٠٨) Cinacalcet (n = ٥٤٦) Mean (SE) % Change From Baseline Baseline iPTH Subgroup (pg/mL) Frazão J. phase III studies evaluating the efficacy and safety of a once-daily dose of cinacalcet for the treatment of SHPT demonstrated the efficacy of therapy was independent of disease severity evaluated by PTH levels (12) (SLIDE 5). These gastrointestinal adverse events were usually mild to moderate and of limited duration. respectively). Presented at ERA-EDTA Congress ٢٠٠٤ .events more frequently reported in the cinacalcet compared to placebo treated patients were nauseas (32% vs 19%. placebo-controlled. A post hoc analysis of the combined results of three 26-week. respectively) and vomiting (30% vs 16%. The hypocalcaemic episodes were transient.5 mg/dl at least in two consecutive measurements occurred in 5% of cinacalcet treated patients and in 1% of the placebo patients.

in which the doses of cinacalcet. Randomized Study Using Cinacalcet To Improve Achievement of K/DOQI Targets in Patients with ESRD” (OPTIMA). and phosphate binders were subsequently adjusted during a 16-week dose- . In this “Open-Label.The new paradigm for the treatment of secondary hyperparathyroidism involves the use of cinacalcet combined with lower doses of active vitamin D maintaining the same suppression of iPTH secretion but with an optimal effect in the reduction of the phosphorus serum levels and Ca X P (SLIDE 6). SLIDE 6 Strategies to control phosphorus levels: start cinacalcet and reduce vitamin D Vitamin D Ca & P iPTH SHPT Cinacalcet Start cinacalcet reduce vitamin D + iPTH Ca & P SHPT Traditional therapy trade-off The goal is control of both A study compared a cinacalcet-based regimen with the best unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent targets proposed by the K/DOQI (13). vitamin D sterols. haemodialysis patients with poorly controlled SHPT were randomised to receive conventional care (n=184) or a cinacalcet-based regimen (n=368) that includes vitamin D and phosphate binders.

CaxP (77% vs. using an algorithm proposal that allowed reductions of vitamin D doses when justified by the serum calcium and phosphorus levels (SLIDE 7). p<0. In the group of patients treated with cinacalcet with reduced dose of vitamin D. phosphorus levels and Ca X P (SLIDE 8). . J Am Soc Nephrol ٢٠٠٥. p<0. p<0.001. 58%.٥٠١A F-PO٧٥٨ The cinacalcet-based regimen was significantly more effective than conventional care in bringing patients to target for PTH (71% vs. respectively).١٦. there was an improved impact in the serum calcium. p<0.optimization phase.002). 22%.001). 16%. p<0.٤ mg/dL Measure PTH and titrate cinacalcet PTH low (<١٥٠) PTH controlled (١٥٠–٣٠٠) PTH high (>٣٠٠) Despite max dose of cinacalcet Ca/P controlled Ca/P high Ca/P controlled Ca/P high Reduce vit D Reduce cinacalcet if not on vitamin D Maintain vitamin D Reduce vitamin D Increase or start vitamin D Adjust phosphate binders Messa P et al. 50%. SLIDE 7 OPTIMA: algorithm overview iPTH>٣٠٠ pg/mL and Ca≥٨. calcium (76% vs. and the combined target PTH and CaxP (59% vs. phosphorus (63% vs.001).001). 33%.

Achievement of targets was greatest in patients with less . P and Ca x P Mean change from baseline (%) ١٠ ٠ -١٠ -٢٠ -٣٠ -٤٠ -٥٠ -٦٠ -٥٢ iPTH Calcium Phosphorus Ca x P -٤٤ Increased vitamin D Decreased vitamin D -٦ -٢ -٨ -٩ -٨ -١٦ Wilkie M et al. Nephrol Dial Transplant ٢٠٠٦.SLIDE 8 Decreasing the dose of vitamin D improved the lowering potential of cinacalcet on Ca. J Am Soc Nephrol ٢٠٠٥.١٦:abstract and poster F-P٠٧٥٨ The effect on phosphorus levels of cinacalcet is only due to a reduction of bone turnover in patients with secondary hyperparathyroidism and not in phosphorus intestinal absorption. therefore these patients still require effective phosphate binding therapy. In patients receiving active vitamin D at baseline there was a 22% reduction in the dosage administered.٢١(Suppl ٤):abstract and poster SP٣٥٨ Messa P et al.

According to the protocol at the start of the study active vitamin D dose was decreased to a mean equivalent of paricalcitol 6 µg per week.severe disease (iPTH range 300 to 500 pg/mL) who required lower cinacalcet doses (median=30 mg/day).١:٣٠٥–٣١٢ . This study definitely validated the rationale. the value and usefulness of the part of the algorithm dealing with SHPT proposed in this discussion and adapted from a previous publication by Cunningham e al (14). Clin J Am Soc Nephrol ٢٠٠٦. Another interesting study was conducted in adult hemodialysis patients who had controlled PTH and elevated Ca X P and where receiving paricalcitol > 6 µg per week (or equivalent dose of an alternative active vitamin D). and cinacalcet was started at 30 mg per day (15) (SLIDE 9) SLIDE 9 Patients on active vitamin D sterols with controlled PTH and elevated Ca x P Screening phase (up to ٣٠ days) Titration phase (٨ weeks) Assessment phase (٨ weeks) PTH ١٥٠-٣٠٠ pg/mL + Ca x P >٥٥ mg٢/dL٢ + > ٦mg/week paricalcitol E N R O L M E N T Cinacalcet titrated from ٣٠ mg up to maximum ١٨٠ mg/day Day ١ Wk ٢ Wk ٤ Wk ٦ Wk ٨ Wk ١٦ Decrease vitamin D on day ١ to ٦mg/week Chertow GM et al.

٠٠٠١ Chertow GM et al.٠٠١ ***p<٠. SLIDE 10 Achievement of targets with low doses of concurrent vitamin D Baseline Patients achieving target (%) ١٠٠ ٨٠ ٦٠ ٤٠ ٢١% ٢٠ ٠ iPTH ≤٣٠٠ pg/mL Ca x P ≤٥٥ mg٢/dL٢ iPTH ≤٣٠٠ mg/dL and Ca x P ≤٥٥ mg٢/dL٢ ١٧% ٩١% ٨٥% ٧٢%*** Efficacy assessment Equivalent paricalcitol dose (µg/week) ١٦ ١٢ ٨ ٤ ٠ ١٥ ** ٧ ٤٧%* n=٥٣ *p<٠. respectively (15) (SLIDE 10).١:٣٠٥–٣١٢ . the Ca X P and the combined iPTH and Ca X P NKF-K/DOQI targets were achieved in 72% and 47% of the patients.With this type of approach. at the end of the study.٠١ **p<٠. Clin J Am Soc Nephrol ٢٠٠٦.

in synergy with phosphate binders and eventually Vitamin D. The optimisation of synergies observed with the combined use of cinacalcet and sevelamer will certainly be very helpful in controlling the mineral and bone disorders seen in this population and improving outcomes. arguments and previously published recommendations for the treatment of bone and mineral disorders I propose the use of the following therapeutic algorithm to control two common disorders seen in stage 5 CKD dialysis patients: hyperphosphataemia and secondary hyperparathyroidism (16) (SLIDE 11) .The calcimimetic agent cinacalcet. is a very new and innovative compound that covers a previous therapeutic need for the CKD stage 5 dialysis patients with secondary hyperparathyroidism. SLIDE 11 . Summary In view of the presented data.

Port J Nephrol Hipertension ٢٠٠٧ Increase dose of Vit D References: 1 . and maximum dose of Cinecalcet Ca<٩.٥mg/dl Ca≥٨.٥mg/dl or Ca≥٨.maintain Cinecalcet and adjust Sevelamer dose Reduce Cinecalcet increase Sevelamer dose and adjust Vit D Maintain Cinecalcet If iPTH level >٣٠٠pg/ml.٤mg/dl P>٥. J Am Soc Nephrol 2004.٥mg/dl Ca<٨.٥mg/dl) iPTH < ١٥٠pg/ml iPTH ١٥٠ to ٣٠٠ pg/ml iPTH > ٣٠٠pg/ml Increase dose of Cinecalcet until ١٨٠mg/day Ca≥٨.٥mg/dl Increase dose of Sevelamer Frazão JM. mortality. ٣٠٠] pg/ml (١٣ to ٣٣ % patients) Ca≥٨.٥mg/dl Ca<٩.٥mg/dl P≥٥.٥mg/dl Reduce or withdraw Vit D If iPTH level <١٥٠pg/ml.٤mg/dl P>٥.MINERAL METABOLISM ABNORMALITIES TREATMENT ALGORITHM FOR STAGE ٥ CKD Treatment of Hyperphosphatemia iPTH Treatment of Secondary Hyperparathyroidism (iPTH>٣٠٠pg/ml) < ١٥٠pg/ml iPTH [١٥٠. and morbidity in maintenance hemodialysis. Ofsthun N.٥mg/dl P<٥.٤mg/dl Ca<٨.Block GA. Klassen PS. Lazarus JM. reduce dose or withdraw Cinecalcet Reduce Vit D.٥mg/dl Ca<٨.٥mg/dl P<٥.٤mg/dl (٤٠ to ٥٩ % patients) Ca≥٨. Chertow GM. Mineral metabolism.٥mg/dl Ca>٩. Lowrie EG.٤mg/dl Ca<٨.٤mg/dl P>٥.٥mg/dl P>٥.٤mg/dl P>٥. 15: 2208-2218 .٤mg/dl P≥٥.٤mg/dl Ca≥٩.٤mg/dl Treat with Sevelamer + Treat with Sevelamer Treat with Sevelamer Calcium Supplement or Vit D (if there is evidence of hypocalcemia symptoms) Treat with Cinacalcet (starting with ٣٠mg/day) and/or Vit D + Sevelamer (if P>٥.٥mg/dl iPTH > ٣٠٠pg/ml (١٩ to ٣١ % patients) Ca<٨.

Arterial stiffening and vascular calcifications in end-stage renal disease. and cardiovascular risk in end-stage renal disease. Arterial calcifications. Goldin J. 68: 1815-1824 10 – National Kidney Foundation K/DOQI Clinical Practice guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Spiegel DM. Kuizon BD. 42: S70S77 . Hypertension 2001. Pires A. Raggi P. 8: 265-272 9 – Block GA. Ehrlich J et al. 18: 1731-1740 6 – Adragão T. Marchais SJ. Coronary and aortic calcification in patients new to dialysis. Arterial stiffness. 62:245-252 8 – Spiegel DM. Marchais S. Am J Kidney Dis 2003. Nephol Dial Transplant 2003. Raggi P. London G. Kidney Int 2002. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. N Engl J Med 2000. Pannier B. Adda H. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. Métivier F.2 .Guerin A. 38: 938-942 5 – London GM. Guérin AP. London GM. 342: 1478-1483 4 – Blacher J.Chertow GM. Nephrol Dial Transplant 2000. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Kidney Int 2005. Burke SK. Metha R et al. Pannier B. Nephrol Dial Transplant 2004. Lucas C et al. Treat to Goal Working Group. Hemodialysis Int 2004. Guérin AP. Marchais SJ. A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. 15: 1014-1021 3 – Goodman WG. Metivier F. 19: 1480-1488 7 . Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.

Cinacalcet HCL effectively reduces intact parathyroid hormone (iPTH) and CaXP irrespective of the severity of secondary hyperparathyroidism (HPT). Clin J Am Soc Nephrol 2006. Port J Nephrol Hypert 2007. Torregrossa V et al. 2004.Messa P. Blumenthal S. 21: 61-66. Turner S.Cunningham J. On behalf of the OPTIMA study group.Frazão JM. 350: 1516-1525 12. Nephrol Dial Transplant 2004. 19 (Suppl. N Engl J Med . Roppolo M. Motellon JL. 16 – Frazão JM. Optimizing OPTIMA study. 2004 13 . Martin KJ. J Am Soc Nephrol 2005.11 – Block GA. Nicolini M. Cinacalcet Hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivates with controlled PTH and elevated calcium x phosphate. de Francisco ALM et al. ERA-EDTA XLI Congress Abstract Book: 219. . Achieving therapeutic targets in the treatment of Secondary Hyperparathyroidism. 5): v9-v14 the use of Cinacalcet (Mimpara®/Sensipar®) and Vitamin D: Interin results from the 15 – Chertow GM. 16:501A 14 . 1: 305-312. The treatment of mineral metabolism disorders: a recent approach with new compounds and a proposed algorithm. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. et al.