Advances in pharmacotherapy for secondary hyperparathyroidism.

Review

Advances in pharmacotherapy for secondary hyperparathyroidism

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 07/11/15 For personal use only.

Mariano Rodrı´guez† & Marıá E Rodrı´guez-Ortiz †

1.

Introduction

2.

Management of phosphorus levels

3.

Vitamin D therapy

4.

Calcium intake, oral calcium supplements/phosphate binders, and dialysate calcium concentration

5.

Calcimimetics

6.

Percutaneous direct injection therapy

7.

Parathyroidectomy

8.

Conclusion

9.

Expert opinion

Nephrology Service, Reina Sofıá University Hospital/University of Co´rdoba. Instituto Maimońides de Investigacioń Biom e dica de Co´rdoba (IMIBIC), Co´rdoba, Spain. REDinREN, Madrid, Spain

Introduction: Secondary hyperparathyroidism is a frequent complication of chronic kidney disease. This review will discuss the various therapeutic options available for the management of hyperparathyroidism. Areas covered: The main therapeutic strategies available to prevent or slow down the progression of hyperparathyroidism will be detailed here. Reductions in phosphatemia may be achieved by controlling dietary phosphorus, administering phosphorus binders, or increasing the frequency of dialysis sessions. Vitamin D sterols reduce parathyroid hormone (PTH) secretion while normalizing calcium (Ca) and vitamin D levels. Calcimimetics decrease PTH levels, probably with an additional effect on hyperplasia. Percutaneous injections in parathyroids represent an option useful in cases of hyperparathyroidism resistant to pharmacological therapy. Pubmed was searched by combining the terms ‘secondary hyperparathyroidism’ and the name of each one of the drugs reported in this review. Expert opinion: PTH increases from early stages of renal disease. One of the goals in pre-dialysis is the prevention of hyperphosphatemia and the maintenance of Ca levels in the normal range. The management of hyperparathyroidism in dialysis requires control of phosphorus level. In this stage, the decision to use calcimimetics and vitamin D derivatives should be made according to serum levels of Ca and phosphorus. Keywords: calcimimetic, chronic kidney disease, dialysis, dietary phosphorus restriction, parathyroid injection, phosphorus binder, secondary hyperparathyroidism, vitamin D Expert Opin. Pharmacother. (2015) 16(11):1703-1716

1.

Introduction

Secondary hyperparathyroidism (SHPT) constitutes a complication frequently diagnosed in advanced stages of chronic kidney disease (CKD). Kidneys have a key role in the regulation of mineral metabolism; thus, renal failure is associated with progressive derangements in calcium (Ca), phosphorus (P), vitamin D, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) (Figure 1). Low levels of extracellular Ca constitute the main stimulus for PTH secretion. Parathyroid hyperplasia will develop to produce large amounts of PTH in an attempt to prevent hypocalcemia. In renal disease, plasma Ca levels tend to decreased due to: i) reduction in renal production of calcitriol (CTR), the active metabolite of vitamin D, induced by the elevation of FGF23; and ii) the skeletal resistance to the calcemic action of PTH. In CKD, the renal excretion of P is limited and the increased body burden of P stimulates the production of FGF23 by osteocytes and osteoblasts. Both, high extracellular P [1] and low CTR [2] levels may also directly stimulate the production of PTH and the generation of parathyroid hyperplasia. Bone cells produce FGF23 in response to high P, but CTR and PTH also stimulate FGF23 production. In patients with advanced renal disease, FGF23 concentration may increase up to 1000-fold. It has been observed that serum 10.1517/14656566.2015.1061994 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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M. Rodrı´guez & M. E. Rodrı´guez-Ortiz

Article highlights. . .

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SHPT is a common complication in advances stages of CKD. Therapeutic management in CKD 3 -- 4 is focused on the prevention of hyperphosphatemia. In advanced CKD, the aim is to reduce serum phosphorus (P) toward normophosphatemia. Management of P is achieved by administering P binders together with other strategies such as dietary restriction and intensification of the dialysis frequency. VDR activators are indicated to restore vitamin D levels as well as to reduce PTH secretion. Patients should be monitored in order to avoid negative side effects associated with the use of these compounds. The use of calcimimetics has substantially advanced the management of secondary hyperparathyroidism, controlling PTH production by acting directly on the CaSR. Over the next few years, research should be focused on aspects as the initiating events of SHPT, the regulatory mechanisms of the FGF23-Klotho axis, and the manipulation of P absorption.

2.

This box summarizes key points contained in the article.

Chronic kidney disease

Phosphorus retention

FGF23

Bone resistance to PTH

Calcitriol deficiency

Hypocalcemia

Secondary hyperparathyroidism

PTH secretion Down-regulation of parathyroid receptors

Figure 1. Schematic view of the pathophysiology of hyperparathyroidism secondary to chronic kidney disease. FGF23: Fibroblast growth factor 23; PTH: Parathyroid hormone.

FGF23 concentration increases since the earliest stages of chronic kidney failure [3]. FGF23 reduces serum CTR levels by inhibiting renal 1a-hydroxilase activity, which converts calcidiol [25(OH)] into CTR. In addition, FGF23 increases 24-hydroxylase activity, which also contributes to the reduction in CTR levels. Parathyroid hyperplasia is initially diffused but it may become nodular with monoclonal growth in cases of severe hyperparathyroidism. One feature of uremic hyperplastic parathyroid glands is the reduced expression of receptors for Ca (CaSR) and CTR (VDR), which makes parathyroid cell less sensitive to the inhibitory action of Ca and CTR [4]. 1704

More recently, it has been shown that parathyroid cells also possess the specific FGF23 receptor complex, FGFR-Klotho [5]. By acting on this receptor, FGF23 reduces PTH production in normal parathyroid cells [4,5]. However, in parathyroid hyperplasia there is a down-regulation of parathyroid FGFRKlotho expression, causing resistance to the inhibitory effect of FGF23 [4,6]. The therapeutic management of SHPT in CKD 3 -- 4 is focused on the prevention of hyperphosphatemia and the restoration of serum CTR levels. In advanced renal failure, including patients on dialysis, the strategy is to reduce serum P levels using P binders, as well as to decrease PTH secretion directly by administration of calcimimetics or vitamin D analogs. Parathyroidectomy (PTx) is an option in those cases of severe SHPT resistant to medical therapy. Newer active vitamin D analogs, P binders and calcimimetics have been added to the traditional therapy based on the administration of Ca salts and CTR. These therapeutic strategies will be described throughout this review.

Management of phosphorus levels

During the early stages of CKD, the progressive elevation in FGF23 and PTH levels induce phosphaturia and prevent the development of hyperphosphatemia. Hyperphosphatemia usually occurs when the GFR falls below 20 ml/min. Experimental studies have shown that P constitutes a direct stimulus for PTH secretion [1]. Control of P is critical to prevent hyperparathyroidism, to reduce the cardiovascular risk [7], and to decrease FGF23 levels that are directly responsible for the development of left ventricular hypertrophy [8]. KDIGO Guidelines consider that the treatment goal in predialysis patients is maintaining serum P in the normal range, while in CKD 5D they suggest lowering the P levels toward normophosphatemia [9]. Dietary P restriction, intensified dialysis regimens, and P binder therapy may be used to control P (summarized in Figure 2). Regarding dietary P restriction, there is recent awareness about the high content of absorbable P in food additives. Restriction of dietary phosphorus High protein intake is associated with hyperphosphatemia in dialysis patients [10], while protein restriction shows the opposite trend [11]. According to K/DOQI guidelines [12], moderate restriction of dietary P should be considered since early stages of renal disease. The beneficial effect of a low-protein diet on advanced SHPT has been largely recognized. Recently, Caria et al. have shown that low protein consumption is not only related to a better control of mineral abnormalities and anemia, but it also maintains the residual renal function, the urine volume output, and reduces the hospitalization rate [13]. In early CKD, low dietary protein is associated with a decrease in circulating FGF23 [14]. FGF23 represents an independent risk factor for cardiovascular and all-cause mortality in uremic population. 2.1

Expert Opin. Pharmacother. (2015) 16(11)

Advances in pharmacotherapy for SHPT

1. Restriction of dietary phosphorus. 2. Administration of phosphorus binders: Calcium carbonate Calcium acetate Calcium acetate/magnesium carbonate

- Calcium-containing binders


- Calcium-free binders

Sevelamer hydrochloride/carbonate Lanthanum carbonate Iron-based compounds (ferric citrate, sucroferric oxyhydroxyde) Colestilan Niacine/niacinamide

3. Increase in the frequency of dialysis sessions.

Figure 2. Therapeutic options for the management of hyperphosphatemia in patients with secondary hyperparathyroidism.

The administration of a protein-restricted diet supplemented with keto/amino acids constitutes a different nutritional strategy for uremic patients. In humans, a ketodiet has been reported to contribute to an improvement in parameters related to phosphocalcium metabolism [15]. The absorption of P varies according to the food source. While P from plants is poorly absorbed, more than 90% of the P contained in food additives is bioavailable. In this regard, educational intervention about the consumption of P-containing additives in patients with severe renal disease was associated with a reduction in phosphatemia after 3 months of study [16]. In CKD 3 -- 5D, KDIGO guidelines recommend restricting dietary P intake in the treatment of hyperphophatemia, together or not with other treatments [9]. However, in everyday practice, it is difficult to implement a reduction in protein intake. In addition, protein restriction may cause malnutrition in elderly patients. Because dietary protein restriction is not usually enough to achieve a reduction in P overload, the use of P binders is required as renal function deteriorates. Phosphorus binders Compounds that bind P reduce its intestinal absorption. The administration of P binders is normally started when serum P concentration increases above target. The ideal P binder should be efficient in reducing phosphatemia, have low or absent absorbability, minimal side-effects, low pill burden, and balanced cost-effectiveness. Aluminum salts were largely used as binders due to their effectiveness reducing hyperphosphatemia. Currently, aluminum is rarely used due to serious toxic effects in bone and nervous system [17,18].

involves a higher risk for hypercalcemia, low-turnover bone disease, and vascular and extraosseous calcifications. This is aggravated when patients are on excessive amounts of active vitamin D analogs for SHPT treatment. Despite the different content of elemental Ca between both compounds (250 mg/g in Ca acetate vs 400 mg/g in Ca carbonate), there are no available data reporting the superiority of any of them; certainly, the amount of Ca ingested is different. Calcium acetate/magnesium carbonate has been shown to be an effective P binder. It decreases P levels to the same extent that sevelamer hydrochloride with a minimal, but significant increase in total serum Ca and no change in ionized Ca [21]. In a more recent post hoc evaluation, a decrease in FGF23 levels associated with the use of Ca acetate/ magnesium carbonate [22] has also been reported. This compound may have an additional suppressive effect on PTH secretion due to a direct modulatory effect of Mg on parathyroid glands [23]. On the other hand, experimental work and observational studies suggest that Mg decreases vascular calcification [24] and it is inversely associated with mortality in hemodialysis patients [25].

2.2

Calcium-containing binders During the 80s, Ca-based binders substitute aluminumcontaining drugs, Ca carbonate and Ca acetate being the most widely used [19,20]. The use of Ca-containing P binders 2.2.1

Calcium-free binders Sevelamer hydrochloride was the first Ca- and metal-free binder administered to control P levels in CKD patients, being as effective as Ca salts without inducing hypercalcemia [26]. More recently, this compound was formulated as sevelamer carbonate to avoid the metabolic acidosis associated with sevelamer hydrochloride. There are reports showing that sevelamer reduces FGF23 levels [27,28]. The use of sevelamer is also associated with a decrease in LDL and total cholesterol levels [29]. Lanthanum carbonate (LC) is another Ca-free P binder with an extremely low intestinal absorption. A number of studies have reported the effectiveness of LC in reducing P levels in ESRD patients [30,31]. A recent meta-analysis has 2.2.2


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compared the efficacy of LC with Ca salts, finding a trend to lower levels of Ca, Ca P, and PTH associated with the use of LC. However, it failed to find differences in all-cause mortality and cardiovascular events [32]. Because lanthanum is a rare earth element and it is not present in the human organism in a natural way, its safety and toxicity are concerning issues. No potential harmful effects have been described in hemodialysis patients either after 3 [33] or 6 years of administration of LC [34]. Iron-based compounds are being developed as a new generation of P binders. Several studies have shown the efficacy of ferric citrate as P binder both in non-dialysis [35] and dialysis patients [36]. Besides, this effect is accompanied by a significant improvement in the iron status. Therefore, it is expected that the administration of this compound will be associated with a cost reduction in the management of anemia [37]. Of note, the use of ferric citrate in a rat model of uremia has been shown to improve SHPT as well as vascular calcification [38]. Sucroferric oxyhydroxide is another novel iron-based compound. When it was compared with sevelamer, Wu¨thrich et al. found a similar reduction in serum P levels, with an equal rate of adverse events [39]. These findings were supported in the study carried out by the PA21 Study Group, which also reported a lower pill burden and a better adherence to the use of sucroferric oxyhydroxide [40]. Colestilan is a metal- and Ca-free, anion-exchange resin which has been used in Japan for more than a decade for the treatment of dyslipidemia. Its effectiveness and safety has been compared with sevelamer in a recently published study. After 1 year of administration, both compounds significantly reduced P levels in dialysis patients, also showing an additional effect reducing plasma LDL concentration [41]. Niacin and its metabolite niacinamide have been proved to be effective as P binders. In experimental adenine-induced CKD, nicotinamide reduced P absorption through a downregulation of the intestinal NaPi-2b cotransporter [42]. The ability of these compounds as P binders has also been tested in hemodialysis patients. When compared with placebo, treatment with niacinamide resulted in a significant decrease in phosphatemia, whereas a slight increase in serum P was observed in the placebo-treated arm [43]. Intensification of the hemodialysis frequence In the Frequent Hemodialysis Network Daily Trial, an increase in the frequency of hemodialysis was not only associated with a benefit in the primary outcomes of the study, death, and left ventricular mass, but also with an improvement in the management of P [44]. It is clear that an increase in the dose of dialysis improves the control of hyperphosphatemia [45]. 2.3

3.

Vitamin D therapy

CTR directly regulates parathyroid function by acting through VDR, its specific receptor. CTR decreases PTH 1706

synthesis [2], inhibits parathyroid cell proliferation [46], and cause hypocalcemia by reducing intestinal absorption of Ca. In CKD, the synthesis of CTR is limited by the reduction in renal mass as well as by the inhibitory effect of elevated FGF23. Low CTR levels contribute to the development and progression of SHPT. Therefore, administration of vitamin D is part of the strategy to prevent and control uremic hyperparathyroidism. Uremic patients have a deficiency of 25(OH). Despite the lack of consensus, some studies define vitamin D deficiency as 25(OH) levels below 20 ng/ml. Low 25(OH) also contributes per se to the progression of SHPT [47]. High doses of CTR may cause hypercalcemia. Analogs of CTR have been developed aiming to achieve PTH control with less calcemic effect than CTR. Alfacalcidol [1a(OH) D3], doxercalciferol [1a(OH)D2], paricalcitol [19-nor1,25 (OH)2D3], and maxacalcitol [1a,25-(OH)222-oxavitamin D3] are therapeutic options for hyperparathyroidism. 1a vitamin D forms show a lower affinity for the VDR than CTR. Therefore, they need to be converted into the biologically active compound, with a half-life of 32 -- 37 h. CTR and paricalcitol have approximately the same half-life, which is considerably shorter than 1a compounds. We will refer to 25 (OH) as nutritional vitamin D to differentiate it from vitamin D analogs. Nutritional vitamin D (ergocalciferol and cholecalciferol) is given to restore the levels of 25(OH). Table 1 summarizes both nutritional and vitamin D analogs described here. Vitamin D analogs A number of studies have shown that CTR inhibits PTH secretion in patients with different stages of CKD. In predialysis patients, an 8-month period of CTR treatment reduced the PTH levels with preservation of bone metabolism [48]. Similar results were reported in dialysis patients receiving CTR IV [49]. In SHPT, active vitamin D therapy has been shown to increase the sensitivity of parathyroid cells to Ca (left shift of the PTH--Ca curve) [50]. This effect may not be observed if there is a concomitant elevation of extracellular Ca [51]. Hypocalcemia is a major cause of SHPT and therefore, an additional benefit derived from the use of CTR is the normalization of serum Ca. However, if hypercalcemia occurs there is a risk for extraosseous calcifications. Paricalcitol is a vitamin D analog with the ability to control SHPT with less hypercalcemic episodes [52]. In a study performed in patients with hyperparathyroidism resistant to CTR therapy, paricalcitol was administered at a dosing ration of 3:1 with respect to CTR. Patients were grouped according to the levels of intact PTH (> 800 pg/ml vs 600 -- 800 pg/ml) and a gradual decrease in PTH was observed in both groups [53]. In a more recent study, Ross et al. found a similar decrease in PTH levels in both chronic hemodialysis and peritoneal dialysis patients treated with oral paricalcitol. In addition, they reported an improvement in bone activity but minimal effect 3.1



Table 1. Summary of the reviewed Vitamin D sterols for the treatment of secondary hyperparathyroidism.


Vitamin D2

Vitamin D3

Nutritional vitamin D

Vitamin D analogs

Nutritional vitamin D

Vitamin D analogs

Ergocalciferol

Paricalcitol 19-nor1,25(OH)2D3 Doxercalciferol 1a(OH)D2

Cholecalciferol Calcifediol

Calcitriol 1,25(OH)2D3 Alfacalcidol 1a(OH)D3 Maxacalcitol 1a,25(OH)222oxaD3

on serum Ca and P levels [54]. In a meta-analysis performed by Han et al., the efficacy and safety of paricalcitol in the context of SHPT in non-dialyzed patients has been evaluated. The authors concluded that this analog is effective in reducing PTH levels in predialysis, also having a beneficial effect on proteinuria [55]. The effectiveness of paricalcitol has also been shown in cases of persistent SHPT after renal transplantation; a 6-month treatment with paricalcitol induced a significant reduction in intact PTH levels in comparison with those individuals treated with non-paricalcitol therapy. Interestingly, a decrease in proteinuria and a reduction in bone remodeling and mineral loss were also reported [56]. Multiple studies have compared the effects of CTR versus paricalcitol. In a double-blind multicenter study by Sprague et al., hemodialysis patients with PTH above 300 pg/ml were randomly allocated to receive either intravenous CTR or paricalcitol. The primary endpoint was achieving a 50% reduction in intact PTH levels and despite it was reached by a similar percentage of patients from each group, the decrease was more rapid in the paricalcitol arm [52]. A similar trend regarding the reduction in serum PTH has been observed in a smaller study in ESRD patients in peritoneal dialysis, although the authors found equal occurrence of hypercalcemic events in both treatment groups [57]. The efficacy of both compounds, as well as their safety regarding the incidence of hypercalcemic episodes, has also been tested in CKD stages 3 -- 4, with a dosing regimen based on changes in PTH and Ca. A slightly higher reduction in PTH level was found in paricalcitol-treated patients, although the difference with CTR was not significant (52 vs 46%, p = 0.17). By using this dose-titration regimen, no statistically significant changes were detected either in Ca or P levels, and the rate of hypercalcemia was very low and similar in both treatments [58]. The differences observed among these studies regarding the incidence of hypercalcemic episodes or the changes in Ca P product may be due to the baseline characteristics of the population, the use of concomitant treatments, or the study design. Alfacalcidol and doxercalciferol are compounds which require a hydroxylation in position 25 in order to be able to activate the VDR. Al-Hilali et al. showed that alfacalcidol is

effective controlling SHPT in dialyzed patients; one interesting finding of this work is the equal effectiveness of this compound when it is administered once or twice weekly, in terms of reduction in PTH and alkaline phosphatase, and no differences in Ca, P, or Ca P [59]. More recently, the efficacy of alfacalcidol compared with paricalcitol has been tested in an investigator-initiated clinical trial. Both drugs were equally effective for PTH reduction, with no difference in hypercalcemic or hyperphosphatemic events between both treatment arms [60]. Doxercalciferol, another vitamin D analog, has been reported to be as effective as CTR for PTH control when administered with Ca carbonate in pediatric patients on dialysis, with no difference in the rate of hypercalcemic events [61]. A different vitamin D analog, maxacalcitol, is also used to manage SHPT. The effect of maxacalcitol has been compared with both CTR and paricalcitol. In a multicentre prospective trial performed by Hayashi et al., hemodialysis patients were randomly assigned to receive either CTR or maxacalcitol for 12 months. PTH levels were reduced 1 month after starting the treatment and remained reduced until the end of the study. Both groups experienced similar elevations in Ca [62]. When compared with paricalcitol, maxacalcitol was found to be similarly effective in controlling PTH levels in hemodialysis patients [63]. Nutritional vitamin D therapy Uremic patients usually exhibit deficiency of nutritional vitamin D. KDIGO guidelines suggest to correct the 25 (OH) levels following the same strategies recommended for the normal population [9]. A recent work by Metzger et al. found an inverse relationship between serum concentration of PTH and 25(OH) in predialysis patients. Moreover, a concentration of 25(OH) above 20 ng/ml was associated with an appropriate control of PTH [47]. Nutritional vitamin D can be administered as ergocalciferol (or vitamin D2) and cholecalciferol (vitamin D3). A systematic review including 22 observational studies and clinical trials analyzed the impact of 25(OH) treatment on parameters of mineral metabolism in CKD patients. Besides 3.2


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a benefit in vitamin D status, in terms of 25(OH) and CTR levels, a decrease in PTH was also reported (-41.7 pg/ml, 95% CI -55.8 to -27.7, p < 0.00001 in observational studies and -31.5 pg/ml, 95% CI -57.00 to -6.1, p < 0.02 in clinical trials) [64]. In pediatric patients, the replacement of 25(OH) levels with ergocalciferol has been reported to delay the development of hyperparathyroidism without significant major adverse events [65]. In another study, Kovesdy et al. compared ergocalciferol with paricalcitol in CKD stages 3 -- 4 patients; they conclude that, when SHPT is already established, ergocalciferol is less effective than paricalcitol in reducing PTH secretion. The dose of ergocalciferol was adjusted according to the baseline levels of 25(OH); it cannot be ruled out that this apparent lack of response was due to the dose regimen used [66]. The effect of cholecalciferol was assessed in CKD patients stages 2 -- 3 in a randomized, placebo-controlled, doubleblind trial performed by Alvarez et al. [67]; patients were allocated to receive either vitamin D or placebo for 52 weeks. Treatment with cholecalciferol prevented vitamin D depletion and was associated with a significant decrease in PTH levels at 12 weeks, but not at the end of the experimental period. However, a post hoc analysis revealed that PTH reduction was greater in those patients with an established SHPT at the beginning of the study, both at 12 and 52 weeks after starting the treatment. In a comparison between cholecalciferol and doxercalciferol, the decrease in PTH with respect to the baseline was only significant in patients treated with doxercalciferol [68]. The efficacy and safety of a dual combination, cholecalciferol plus paricalcitol, has also been tested in hemodialysis patients. After 15 weeks of treatment, PTH significantly decreased from 21.7 to 18.1 pmol/l with cholecalciferol, and from 38.6 to 33.9 pmol/l with the combined treatment [69]. Taken together, these results support the notion that vitamin D sterols, and particularly those novel sterols intended to avoid negative side effects, constitute an effective therapeutic option to reduce PTH secretion in uremia. 4. Calcium intake, oral calcium supplements/ phosphate binders, and dialysate calcium concentration

PTH secretion is exquisitely regulated, being extracellular Ca its most powerful stimulus. A reduced Ca intake is observed in CKD population [70], in particular in elderly patients [71]. The negative Ca balance observed in CKD [72] is therefore caused by the reduction in Ca intake and exacerbated by a lower Ca absorption as a consequence of the decreased CTR levels [73-75]. Manipulation of the dialysate Ca concentration influences the Ca balance and therefore, may have a remarkable impact on PTH level. In CKD stage 5D, KDIGO guidelines suggest 1708

using a dialysate Ca concentration between 1.25 and 1.50 mmol/l [9]. However, KDOQI experts support the idea of individualizing Ca concentration according to serum Ca and other biochemical parameters [76]. In fact, studies in hemodialysis patients show how increases in dialysate Ca are accompanied by a marked decrease in circulating PTH levels [77,78]. On the other hand, trials comparing the effectiveness of Ca versus non Ca-P binders have shown that administration of oral Ca produces a marked reduction in PTH levels [79-81]. Taken together, these observations underline the importance of Ca as an additional therapeutic tool for a better management of SHPT. 5.

Calcimimetics

The identification and cloning of the CaSR in the 1990s prompted the development of molecules acting on the CaSR to mimic the effect of Ca. Calcimimetics increase the sensitivity of the parathyroids to extracellular Ca; consequently PTH secretion is suppressed with normal and even low serum Ca concentrations. Thus, administration of calcimimetics to uremic patients induces a left shift in the PTH--Ca curve [82], as it is depicted in Figure 3. NPS R-568 was the first calcimimetic compound evaluated in patients. The administration of a single dose of NPS R-568 acutely suppressed PTH secretion along with a concomitant stimulation of calcitonin production [83]. Similar results were obtained in a longer placebo-controlled study where the subjects received the treatment for 15 days. In this study, the decrease in PTH was associated with a reduction in serum Ca concentration [84]. Cinacalcet was the first calcimimetic drug approved for the treatment of SHPT in CKD 5D patients. In 2004, Block et al. reported the combined results from two randomized, doubleblind, placebo-controlled clinical trials conducted in North America, Europe, and Australia to determine the efficacy and safety of cinacalcet. Patients received increasing daily doses (30 -- 180 mg) of calcimimetic for 26 weeks. The percentage of subjects with a PTH concentration below 250 pg/ml was 43 versus 5% in the placebo group (p < 0.001). Levels of Ca, P, and Ca P were also moderately reduced in the calcimimetic group [85]. The effectiveness and safety of a long-term treatment with cinacalcet has also been assessed. In an open-label extension study, dialysis patients received cinacalcet at a starting dose of 30 mg, increased up to 180 mg according to serum PTH levels. After 2 years of the extension study, PTH remained decreased in the cinacalcet group [86]. A recent meta-analysis has evaluated and summarized the results of 18 studies (including 7446 CKD patients), concluding that administration of cinacalcet is associated with a reduction in plasma PTH (mean difference -281 ng/l [95% CI, -326 to -236]) and Ca (mean difference -0.22 mmol/l [95% CI, -0.25 to -0.19]). However, no effect on P was found (mean difference -0.07 mmol/l [95% CI,



1200


Intact PTH (pg/ml)

1000 Pre cinacalcet

800 600 400

Post cinacalcet

200 0 0.9

1.0

1.1

1.2

1.3

1.4

1.5

Ca (mmol/l)

Figure 3. PTH-calcium curve for intact PTH levels before (continuous line) and after (dotted line) treatment with cinacalcet. Reproduced with permission from [82]. PTH: Parathyroid hormone.

-0.19 to 0.04]). In addition, the use of cinacalcet was associated with a lower need for PTx in dialyzed subjects (RR 0.49 [95% CI, 0.40 to 0.59]) [87]. A recently published review analyzes in depth the use of calcimimetics over the last decade [88]. The effectiveness of calcimimetics has also been assessed in kidney transplant patients. A meta-analysis comprising 21 studies conducted in 411 patients showed that cinacalcet therapy is associated with a reduction in PTH and Ca, although in this population an elevation in P was also reported [89]. Several studies have assessed the effect of combining vitamin D and cinacalcet for the management of SHPT. The ACHIEVE Study was intended to test the effectiveness and safety of the administration of calcimimetic plus low doses of vitamin D sterols, in comparison with the administration of paricalcitol or doxercalciferol alone. The decrease in PTH level was more pronounced in the group with the combined treatment (-47.3%) than in the group treated with vitamin D alone (-10.9%) [90]. In a different work, the IMPACT SHPT Study, patients were randomly assigned to receive paricalcitol or cinacalcet plus low-dose vitamin D for 28 weeks and were stratified according to the administration route of vitamin D. The primary outcome was the percentage of patients achieving a PTH concentration of 150 -- 300 pg/ml in the weeks 21 -- 28 of the study. In the intravenous stratum, a significantly higher proportion of patients in the paricalcitol-treated group reached the primary endpoint (57.7 vs 32.7%, p = 0.016), whereas in the oral stratum there were no differences between groups. In addition, the administration of paricalcitol was associated with episodes of hypercalcemia, while episodes of hypocalcemia were more frequent in cinacalcet-treated patients [91]. The ADVANCE Study (A Randomized Study to Evaluate the Effects of

Cinacalcet Plus Low-Dose vitamin D on Vascular Calcification in Subjects with Chronic Kidney Disease Receiving Hemodialysis) compared the use of flexible doses of vitamin D sterols with or without cinacalcet in a population of hemodialysis patients, all of them with evidence of coronary artery calcification. This large study was intended to assess, as a primary endpoint, the progression of vascular calcification, whereas the secondary endpoints were changes in PTH, Ca, P, and Ca P. The progression of cardiovascular calcification was smaller in the group receiving calcimimetic, as well as the levels of the biochemical parameters evaluated in this study [92,93]. The EVOLVE Study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events) was designed to test whether treatment with cinacalcet might reduce the risk of death or nonfatal cardiovascular events in hemodialysis patients with moderate to severe hyperparathyroidism. Although the investigators concluded that calcimimetic did not reduce the risk of the outcomes [94], several factors as differences in baseline characteristics between arms or the higher dropout rate in the cinacalcet group might have influenced the results of the study [95]. Over the last years, an additional effect of cinacalcet in decreasing FGF23 [96] has been reported, a factor associated with mortality and left ventricular hypertrophy in dialysis patients [8]. The reduction in FGF23 levels in patients on calcimimetics may be secondary to reductions in PTH, Ca, and P, although some authors suggest that cinacalcet treatment is independently associated with changes in FGF23 [97]. Nevertheless, further studies are needed to clarify whether calcimimetic directly modulates FGF23 production in bone cells. Experimental works have shown that calcimimetics prevent and attenuate parathyroid hyperplasia. In a model of


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experimental uremia based on 5/6 nephrectomy, treatment with cinacalcet prevented the increase in the number of proliferating cells in comparison with vehicle-treated animals. Moreover, the discontinuation of the treatment resulted in a progression of hyperplasia together with an increase in PTH production [98]. A relation between calcimimetic and apoptosis has also been suggested, as the number of apoptotic cells in parathyroid human tissue from subjects treated with cinacalcet was lower than that observed in samples from untreated patients [99]. A novel and promising calcimimetic compound named AMG 416 has been recently developed for the treatment of SHPT. Whereas cinacalcet is an allosteric activator of the CaSR, AMG 416 directly stimulates the CaSR [100]. This new compound is potent, long acting, and is administered intravenously [101]. AMG 416 has also been tested in a cohort of healthy men at doses of 0.5, 2, 5, and 10 mg in order to assess its effectiveness, safety, and tolerability. The administration of AMG 416 was associated with a dose-dependent decrease in intact serum PTH and a decrease in Ca except with the lowest dose; P levels tended to be higher, although the differences did not reach statistical significance; FGF23 levels were decreased, particularly with the higher doses, and no changes either in CTR or in calcitonin were observed. In addition, this drug was well tolerated and no adverse effects have been reported [102]. Administration of AMG 416 to hemodialysis patients at doses of 5 to 60 mg produced a dose-dependent, sustained reduction in serum PTH, Ca, and P. FGF23 was also decreased, and the authors attributed this reduction to the decrease in PTH. In this study, hypocalcemia was the most frequent adverse effect reported [103]. This new calcimimetic compound therefore seems to constitute a promising tool to be added to the handful of therapeutic options for the management of hyperparathyroidism secondary to renal disease.

reasonable option in cases of persistence of SHPT after PTx. In patients with persistent hyperparathyroidism after subtotal PTx and PTH above 300 pg/ml, ethanol injection decreased PTH levels to the desirable range [107]. In another study performed by Chen et al., patients were distributed into a recurrent group and a persistent group. The target was lowering the level of intact PTH below 300 pg/ml and was equally achieved in both groups. Hypocalcemic events were reported to be significantly more frequent in the recurrent group [108]. Interestingly, these same authors have defined the role of the parathyroid vascularization index as a predictor of the efficacy of the therapy [109]. Percutaneous vitamin D injection therapy (PDIT) is another therapeutic option in the case of SHPT resistant to pharmacological treatment. vitamin D sterols are injected directly in the parathyroid gland under ultrasonographic guidance. Maxacalcitol injection diminished plasma PTH in dialysis patients, and reduced the parathyroid gland volume [110]. The advantages of injections of vitamin D sterols versus ethanol are the antiproliferative activity of vitamin D, its direct effect upregulating VDR, and apparently, a lower risk of complications. However, PDIT seems to have a moderate effect when compared with PEIT [105]. A combined therapy of intravenous maxacalcitol and ethanol injection has been proved to be successful for the management of SHPT [111]. Although both PEIT and PDIT represent an additional tool for the management of SHPT, particularly in those cases of resistance to pharmacotherapy strategies, the procedure of parathyroid injection requires personnel with expertise and proficiency, and it is not generalized to all hospitals. In addition, it is noteworthy to mention that most of these works are not true studies on effectiveness of these therapies, but observational or anecdotal reports. 7.

6.

Parathyroidectomy

Percutaneous direct injection therapy

In ESRD patients, KDIGO guidelines suggest maintaining PTH levels in the range of approximately two to nine times the upper reference limit for the assay. Despite the variety of therapeutic options available to provide an adequate management of SHPT, a proportion of patients may develop parathyroid resistance to the pharmacological therapy. One of the alternatives available for these subjects is the use of percutaneous ethanol injection therapy (PEIT). The effectiveness of this technique was shown by Solbialti et al., who reported improvements in clinical and biochemical parameters [104]. According to the Guidelines of the Japanese Society for Parathyroid Intervention, PEIT is recommended in patients with one large parathyroid gland [105]. Koiwa et al. analyzed to what extent the number of hyperplastic gland influence the PEIT effect, finding a better rate of success in terms of efficacy and remission period in those patients with one hyperplastic parathyroid gland [106]. Ethanol injection also represents a 1710

KDIGO guidelines suggest PTx for those CKD patients in Stages 3 -- 5D with severe SHPT refractory to pharmacological therapy [9]. Patients undergoing PTx experience an improvement in biochemical parameters, with significant reductions in PTH and FGF23 levels immediately after the surgery [112]. Furthermore, PTx is associated with a lower mortality rate [113]. A study by Akaberi et al. analyzed the trend for PTx in dialyzed patients. From 2005 until now, the rate of PTx has been reduced as a consequence of the introduction of new molecules for the treatment of SHPT, such as paricalcitol and cinacalcet [114]. In fact, according to the EVOLVE Study, the use of calcimimetic was associated with a lower incidence of PTx (7% in cinacalcet arm vs 14% in placebo arm) [115]. Several complications may derive from the surgical resection of parathyroid glands. Parathyromatosis is a condition of persistent hyperparathyroidism caused by functional ectopic parathyroid tissue; calcimimetics have been proposed



as a successful therapy in the case of parathyromatosis [116]. Hungry bone syndrome is another complication of PTx, characterized by severe hypocalcemia; age, alkaline phosphatase, or high PTH levels before surgery have been recently suggested as potential risk factors for the development of this pathology [117].


8.

Conclusion

SHPT is a common complication of CKD, characterized by parathyroid cell hyperplasia, excessive PTH secretion, and derangements of other parameters related to mineral metabolism, such as Ca, P, vitamin D, and FGF23. The therapeutic aims in predialysis patients are the prevention of hyperphosphatemia and the restoration of vitamin D levels. In advanced renal disease, the objective is to decrease serum P toward normophosphatemia, and reduce PTH secretion by administration of calcimimetics or vitamin D compounds. Reduction of phosphatemia may be achieved through control of P dietary consumption, administration of P binders, and intensification of dialysis treatment. Vitamin D is administered both as nutritional forms and as vitamin D analogs, both of them contributing to management of hyperparathyroidism. Calcimimetics constitute a key therapeutic tool to control PTH secretion in dialysis patients by virtue of their ability to inhibit parathyroid function. Finally, direct parathyroid injections of ethanol or vitamin D represent an alternative in those cases of SHPT resistant to pharmacological therapy. 9.

Expert opinion

PTH levels are increased in uremic patients since early stages of CKD. An optimal treatment of SHPT includes prevention of parathyroid hyperplasia. Dietary P restriction and P binders may need to be implemented as early as in CKD 3, particularly if patients have hyperphosphatemia and/or excessive phosphaturia, a sign of high P intake. A decrease in renal mass and the elevation of FGF23 due to the excess of P are the cause of the early decline in CTR production. This reduction of CTR deprives the parathyroid cells from an appropriate activation of the VDR, which allows them to maintain an elevated production of PTH and a high rate of cell proliferation. Moderate doses of VDR activators, CTR, or other analogs such as paricalcitol should be used in uremic patients before dialysis. The use of VDR activators may be associated with hypercalcemia, vascular calcification, and nephrocalcinosis; thus, patients must be monitored. The first step in the treatment of SHPT in dialysis patients is the control of serum P. This is achieved by appropriate dose of dialysis, and most dialysis patients require P binders. The use of Ca-based binders is associated with the development of vascular calcifications and adynamic bone disease; its use should be avoided in patients who are on active vitamin D compounds and in those with evidence of adynamic bone

disease, which is usually observed in old patients with diabetes. The decision to use calcimimetics versus vitamin D analogs should be based on the serum concentration of Ca and P. Patients with relatively low Ca levels (< 8.5 mg/dl) and controlled serum P may be started on vitamin D. If serum P is above 5 mg/dl, patients should not receive vitamin D analogs until P is controlled. Calcimimetics can be used in patients with normal or high serum Ca. It is likely that the administration of calcimimetics will be followed by a reduction in serum levels of Ca and P. In patients on calcimimetics, attempts to normalize serum Ca by administration of Ca and/ or vitamin D may carry the risk of soft tissue calcification. In my experience, patients with more than 8 mg/dl are asymptomatic. Over the last few years, several goals have been reached in the context of hyperparathyroidism secondary to CKD. First, the identification of CaSR has allowed clinicians to treat SHPT by acting directly on it, therefore inhibiting PTH production. Second, vitamin D analogs with lower calcemic and hyperphosphatemic effect have been developed. Lastly, the discovery of the FGF23-Klotho axis has contributed to understand the underlying molecular mechanisms connecting disturbances in mineral metabolism and cardiovascular alterations. By contrast, there is a lack of prospective clinical trials which may help determine the best strategies for an optimal control of SHPT, since the ultimate goal in this field is the improvement of CKD-MBD parameters and the reduction of cardiovascular mortality. In order to achieve this goal, we need information on the molecular basis whereby Klotho and FGF23 affect factors related to mineral metabolism. It should be determined whether FGF23 reflects accurately the body P abundance. Definitely, we are going toward the identification and control of the initiating events in the development of SHPT. Another key question that needs to be answered is how early during the progression of CKD we need to take action in order to reduce the P load in patients with reduced glomerular filtration rate. Regarding this matter, there are two interesting areas of the research in this field at the moment: the regulation of Klotho expression and the manipulation of P absorption at the gastrointestinal tract.

Declaration of interests M Rodrı´guez has received research grants from Amgen and Fresenius, and lecture fees from Abbvie, Amgen, Fresenius, and Shire. ME Rodrı´guez-Ortiz is the recipient of a ‘Sara Borrell’ research contract from the National Institute of Health Carlos III. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


1711


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Affiliation

Mariano Rodrı´guez†1 MD PhD & Marıá E Rodrı´guez-Ortiz2 PhD † Author for correspondence 1 Reina Sofıá University Hospital/University of Co´rdoba, Instituto Maimońides de Investigacioń Biomedica de Co´rdoba (IMIBIC), Spain Nephrology Service. REDinREN, Madrid, Spain Tel: +34 957 213 790; Fax: +34 957 010 452; E-mail: [email protected] 2 Laboratory of Nephrology, IIS-Fundacioń Jimenez Dıáz, REDinREN, Madrid, Spain

Advances in paediatric pharmacotherapy.

Advances in pharmacotherapy for allergic conjunctivitis.

Paricalcitol for secondary hyperparathyroidism in renal transplantation.

Propranolol therapy for secondary hyperparathyroidism in uraemia.

Advances in pharmacotherapy for wet age-related macular degeneration.

Advances in pharmacotherapy for opioid-induced constipation - a systematic review.

Advances in pharmacotherapy for treating female sexual dysfunction.

Skeletal findings in secondary hyperparathyroidism.

Racial differences in secondary hyperparathyroidism.

Clinical review 20: Recent advances in the pathogenesis and therapy of uremic secondary hyperparathyroidism.

Advances in the pharmacotherapy of cystic fibrosis.

Controversies and advances in primary hyperparathyroidism.

Brown tumor and secondary hyperparathyroidism.

Reply to "Imaging secondary hyperparathyroidism".

Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients.

Current status of parathyroidectomy for secondary hyperparathyroidism in Japan.

Thyroid carcinoma in patients with secondary hyperparathyroidism.

Hemodialysis patients' preferences for the management of secondary hyperparathyroidism.

Successful ultrasonically guided percutaneous ethanol injection for secondary hyperparathyroidism.

A new paradigm for the treatment of secondary hyperparathyroidism.

Aluminum overload hampers symptom improvement following parathyroidectomy for secondary hyperparathyroidism.

Secondary hyperparathyroidism: diagnosis of site of recurrence.

Diagnosis of primary and secondary hyperparathyroidism.

The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism.