calcimimetics provide an alternative approach to the traditional therapy with active vitamin d and phosphate binders for the management of secondary hyperparathyroidism ( shpt ) . type ii calcimimetics are positive allosteric modulators of the parathyroid gland calcium - sensing receptor ( car ) that increase its sensitivity to serum calcium , so that lower concentrations of calcium are sufficient to mediate signalling through the car .
this suggests that , despite the reduced car expression observed in hyperplastic parathyroid tissues , calcimimetics have the potential to control even advanced disease by enhancing the function of the remaining car [ 47 ] .
in addition , calcimimetics have the potential to influence both car expression and car functions that have been implicated in the progression of disease , particularly effects on parathyroid hormone ( pth ) , cell proliferation and hyperplasia .
these characteristics suggest that targeting the car presents a therapeutic option for the stabilization of early disease , as well as remaining a viable therapeutic target in the face of advancing disease .
in addition to being effective in patients with mild to moderate disease , calcimimetics may be the most viable option for chronic kidney disease ( ckd ) patients with advanced hyperparathyroidism , who are often refractory to standard calcitriol therapy [ 810 ] .
the data below summarize preclinical findings providing a rationale for the clinical use of calcimimetics .
administration of cinacalcet or the calcimimetic r-568 to 5/6 nephrectomized rats prevented hyperplasia or increased car expression .
interestingly , in an in vitro study , the calcimimetic cinacalcet suppressed pth secretion in human parathyroid cells with advanced hyperparathyroidism , even though car expression was significantly diminished .
expression of vitamin d receptor ( vdr ) mrna is reduced in the parathyroid gland of hypocalcaemic rats compared with normocalcaemic rats . because the vdr is a transcriptional repressor of pth
recent studies indicate that type ii calcimimetics , in the presence of low concentrations of calcium , can up - regulate vdr mrna .
rats injected with a calcimimetic ( r-568 , 1 mg / kg intravenously 3 and 6 h before euthanasia ) exhibited an increase in vdr mrna expression compared with controls ( p < 0.001 ) , with a marked increase observed when r-568 and calcitriol were coadministered ( figure 1 ) .
rats were treated with r-568 ( 1 mg / kg intravenously 3 and 6 h before euthanasia ; n = 22 ) , calcitriol ( 10 pmol / kg intraperitoneally every 30 min for 5.5 h before euthanasia ; n = 22 ) , or a combination of r-568 and calcitriol ( n = 22 ) before euthanasia and measurement of vdr mrna by quantitative real - time polymerase chain reaction . a control group ( n = 20 ) received no treatment . mean serum concentrations of ionized calcium and pth are also included .
data are mean  standard error . adapted with permission from rodriguez et al . .
these data indicate that , in addition to regulating pth levels and restoring car density , calcimimetics can up - regulate vdr expression in parathyroid cells .
this effect of calcimimetics on vdr expression is of clinical importance because it may result in an additive interaction between calcimimetic and vitamin d sterol therapy . although parathyroid cells are relatively quiescent under normal conditions , the mineral and hormonal imbalances characteristic of shpt , particularly low serum calcium and high serum phosphorus , drive cell proliferation leading to polyclonal and oligoclonal cell expansion .
the importance of maintaining calcium homeostasis is evidenced in weanling rats fed a low - calcium diet for 10 days , in which the number of proliferating cell nuclear antigen ( pcna)-positive parathyroid cells was increased sixfold compared with controls .
calcimimetics , in the presence of low serum calcium , can hold proliferation in check , as evidenced by decreased parathyroid cell proliferation in uraemic rats following treatment   and their ability to cause regression of advanced hyperplasia in some experimental animal models .
long - term administration of the calcimimetic cinacalcet significantly reduced the number of proliferating ( pcna - positive ) cells and glandular hyperplasia , as measured by weight , in 5/6 nephrectomized rats .
this effect was parathyroid tissue - specific and was due to a direct effect on cell growth , rather than to induction of apoptosis .
taken together , the mechanistic data presented here , and reviewed in greater detail in another article in this supplement ( riccardi and martin ) , suggest that calcimimetics have the potential to retard shpt disease progression . preclinical studies in uraemic rats indicate that calcimimetics can modify the defining parameters in shpt by significantly lowering pth and blood - ionized calcium in a dose - dependent manner without inducing significant changes in serum phosphate .
administration of cinacalcet or the calcimimetic r-568 to 5/6 nephrectomized rats prevented hyperplasia or increased car expression .
interestingly , in an in vitro study , the calcimimetic cinacalcet suppressed pth secretion in human parathyroid cells with advanced hyperparathyroidism , even though car expression was significantly diminished .
expression of vitamin d receptor ( vdr ) mrna is reduced in the parathyroid gland of hypocalcaemic rats compared with normocalcaemic rats . because the vdr is a transcriptional repressor of pth
recent studies indicate that type ii calcimimetics , in the presence of low concentrations of calcium , can up - regulate vdr mrna .
rats injected with a calcimimetic ( r-568 , 1 mg / kg intravenously 3 and 6 h before euthanasia ) exhibited an increase in vdr mrna expression compared with controls ( p < 0.001 ) , with a marked increase observed when r-568 and calcitriol were coadministered ( figure 1 ) .
rats were treated with r-568 ( 1 mg / kg intravenously 3 and 6 h before euthanasia ; n = 22 ) , calcitriol ( 10 pmol / kg intraperitoneally every 30 min for 5.5 h before euthanasia ; n = 22 ) , or a combination of r-568 and calcitriol ( n = 22 ) before euthanasia and measurement of vdr mrna by quantitative real - time polymerase chain reaction . a control group ( n = 20 ) received no treatment . mean serum concentrations of ionized calcium and pth are also included .
p < 0.01 versus control ; p < 0.05 versus calcimimetic ; p < 0.05 versus control .
data are mean  standard error . adapted with permission from rodriguez et al . .
these data indicate that , in addition to regulating pth levels and restoring car density , calcimimetics can up - regulate vdr expression in parathyroid cells .
this effect of calcimimetics on vdr expression is of clinical importance because it may result in an additive interaction between calcimimetic and vitamin d sterol therapy .
although parathyroid cells are relatively quiescent under normal conditions , the mineral and hormonal imbalances characteristic of shpt , particularly low serum calcium and high serum phosphorus , drive cell proliferation leading to polyclonal and oligoclonal cell expansion .
the importance of maintaining calcium homeostasis is evidenced in weanling rats fed a low - calcium diet for 10 days , in which the number of proliferating cell nuclear antigen ( pcna)-positive parathyroid cells was increased sixfold compared with controls .
calcimimetics , in the presence of low serum calcium , can hold proliferation in check , as evidenced by decreased parathyroid cell proliferation in uraemic rats following treatment   and their ability to cause regression of advanced hyperplasia in some experimental animal models .
long - term administration of the calcimimetic cinacalcet significantly reduced the number of proliferating ( pcna - positive ) cells and glandular hyperplasia , as measured by weight , in 5/6 nephrectomized rats .
this effect was parathyroid tissue - specific and was due to a direct effect on cell growth , rather than to induction of apoptosis .
taken together , the mechanistic data presented here , and reviewed in greater detail in another article in this supplement ( riccardi and martin ) , suggest that calcimimetics have the potential to retard shpt disease progression .
preclinical studies in uraemic rats indicate that calcimimetics can modify the defining parameters in shpt by significantly lowering pth and blood - ionized calcium in a dose - dependent manner without inducing significant changes in serum phosphate .
one of the primary treatment goals of shpt is to restore mineral and hormone balance .
the national kidney foundation kidney disease outcomes quality initiative ( kdoqi ) has established recommendations regarding levels of serum calcium , phosphorus , calcium  phosphorus product ( ca  p ) , and intact pth ( ipth ) for patients based on their degree of kidney function . as kidney function decreases ,
mineral homeostasis is increasingly perturbed , resulting in increased pth , serum phosphorus , and ca  p. as this dysregulation progresses , the response to standard therapy worsens .
consequently , pth can become high enough to increase mortality and impede adequate control of phosphate [ 1921 ] .
these findings underscore the need for new or adjunct treatments with improved efficacy over current modalities that can stabilize disease progression during a long - term course when initiated early , but can also maintain effectiveness in patients with more severe disease . because of the ability of calcimimetics , demonstrated in animal studies , to modulate disease - related processes through multiple mechanisms of action implicated in the development of disease , this therapeutic modality appears to be well suited for use in combination with moderate doses of vitamin d as the primary mode of treatment in shpt management .
as described earlier , calcimimetics up - regulate car and vdr expression and inhibit parathyroid cell proliferation and hyperplasia .
these multiple mechanisms of action may allow calcimimetics to ( 1 ) maintain effectiveness during long - term therapy ; ( 2 ) maintain enhanced efficacy in patients with severe disease despite decreased car and vdr expression and ( 3 ) halt development of severe disease if initiated early in patients with mild or moderate shpt .
phase 3 clinical trials in shpt patients with advanced disease have shown that cinacalcet decreased pth , as well as serum calcium , phosphorus and ca  p .
analysis of the data from these trials has been performed to investigate the efficacy of cinacalcet in the treatment of both early- and later - stage shpt and to investigate the potential of long - term cinacalcet therapy to stabilize disease progression .
results of these analyses , presented below , suggest that calcimimetics have the ability to address these unmet therapeutic needs .
a post - hoc analysis of the combined results of three 26-week , placebo - controlled , phase 3 studies evaluating the efficacy and safety of a once - daily dose of cinacalcet for the treatment of shpt demonstrated the impact of therapy initiated in early or advanced disease .
these studies included adult patients on maintenance dialysis who had ipth levels 300 pg / ml despite standard treatment with active vitamin d and phosphate binders . patients received standard therapy in combination with cinacalcet ( n = 546 ) or placebo ( n = 408 ) .
patients included in the analysis were divided into eight subgroups according to their baseline ipth level , which was used as a marker of disease severity ( 300 to > 1000 pg / ml ) .
findings from this analysis indicated that the use of cinacalcet ( 30 mg titrated up to 180 mg ) significantly decreased both ipth and ca  p levels regardless of disease severity at baseline , compared with standard therapy ( figure 2 ) .
the progressive nature of shpt , even when patients receive standard therapy , is evidenced by positive changes from baseline in ipth seen in these patients ( figure 2a ) .
furthermore , the effect of cinacalcet on ca  p ( figure 2b ) and serum phosphorus levels was more pronounced in patients with more severe disease , suggesting a more significant impact of cinacalcet on bone turnover in these patients
. percentage change in ( a ) ipth and ( b ) ca  p by disease severity .
patients were treated with cinacalcet ( beginning at 30 mg with possible titration up to 180 mg ; n = 546 ) or placebo ( n = 408 ) for 26 weeks .
patients were divided into groups according to baseline ipth levels ( pg / ml ) .
however , although these data demonstrate that cinacalcet is effective in reducing serum ipth and ca  p , even in patients with severe disease , these patients remain less likely to achieve their kdoqi targets than patients with less severe disease .
after 6 months of treatment with cinacalcet , 76% of patients with a baseline ipth of 300500 pg / ml achieved a serum ipth level of < 300 pg / ml compared with 55% of patients with a baseline ipth of 500800 pg / ml and 16% of patients with a baseline ipth of > 800 pg / ml . similarly , 54% of patients with a baseline ipth of 300500 pg / ml achieved an ipth of < 300 pg / ml and their ca  p target ( < 55 mg / dl ) , compared with 36% and 9% of patients in the 500800 and > 800 mg / ml groups , respectively .
these data suggest that early treatment of shpt provides the best opportunity to maintain control of serum pth , calcium , phosphorus and ca  p. treatment with cinacalcet for up to 1 year resulted in increased attainment of kdoqi targets compared with standard therapy .
after 12 months , 66% of patients on dialysis receiving cinacalcet achieved an ipth of 300 pg / ml compared with 15% in the placebo group . similarly
, 55% of patients receiving cinacalcet achieved their ca  p target ( < 55 mg / dl ) compared with 43% in the placebo group .
furthermore , the proportion of patients able to achieve both an ipth of 300 pg / ml and their ca  p target was considerably higher in the cinacalcet group than in the placebo group ; 42% of patients in the cinacalcet group achieved both targets simultaneously , whereas only 8% of patients in the placebo group reached both targets ( figure 3a ) .
proportion of patients achieving serum ipth 300 pg / ml and ca  p < 55 mg / dl during treatment with either cinacalcet ( n = 122 ) or placebo ( n = 126 ) . ( a ) achievement of serum ipth 300 pg / ml and ca  p < 55 mg / dl after 1 year .
( b ) maintenance of serum ipth 300 pg / ml after 6 and 12 months of treatment .
( c ) maintenance of combined serum ipth and ca  p target after 6 and 12 months of treatment . adapted with permission from frazo et al . .
in this study , treatment with cinacalcet not only improved the ability of patients to achieve their kdoqi targets , but also their ability to maintain these targets .
seventy - one percent of cinacalcet - treated patients were able to achieve an ipth of 300 pg / ml after 6 months of cinacalcet treatment .
of the group who achieved an ipth of 300 pg / ml at 6 months , 82% also maintained an ipth of 300 pg / ml after 1 year .
in contrast , in the standard care group , 13% of patients achieved an ipth concentration of 300 pg / ml , with 53% of this group continuing to maintain an ipth 300 pg / ml after 1 year ( figure 3b ) .
cinacalcet also improved maintenance of the combined ipth and ca  p targets . in the cinacalcet group
, 52% of patients reached the combined target after 6 months compared with 7% in the standard care group .
of these patients , 59% in the cinacalcet group maintained the combined target after 1 year compared with just 22% in the standard care group ( figure 3c ) .
these data demonstrate that cinacalcet effectively reduces and maintains the four critical disease biomarkers associated with shpt in ckd patients .
cinacalcet , therefore , reduces the shifting in and out of targets often observed in patients using standard therapy .
open - label extension studies have evaluated the ability of cinacalcet to stabilize disease in shpt patients for up to 4 years [ 2628 ] .
these analyses were based on a series of double - blind randomized clinical trials in which patients received standard care treatment in combination with either placebo or cinacalcet for 26 or 52 weeks , after which patients could receive open - label cinacalcet treatment .
in one such open - label extension study , serum ipth was found to progressively increase in patients treated with standard care for 52 weeks .
after open - label cinacalcet treatment was started , serum ipth was rapidly reduced to a level matching that of cinacalcet - treated patients .
( n = 59 ) had achieved an ipth of 300 pg / ml at each study visit .
serum ca  p did not increase during this period . in a separate study , a limited number of patients ( n = 21 ) taking cinacalcet were followed up for as long as 4 years . a substantial upward trend in ipth
was noted in control patients who received standard therapy during the first year of treatment in this study , before switching to cinacalcet therapy , with levels increasing from approximately 600850 pg / ml . in these patients ,
cinacalcet reduced and maintained ipth levels throughout the follow - up period ( figure 4 ) .
after 4 years , the mean serum ipth was 396 pg / ml , 65% of patients achieved a serum ipth of 300 pg / ml , and the mean serum ca  p was 50.5 mg / dl .
these findings again highlight the progressive nature of shpt in patients receiving standard therapy as first - line treatment , as well as the inability of traditional therapies to effectively control or stabilize disease in both the short and long term . these and other clinical observations discussed in this section are also consistent with preclinical evidence supporting the car as a therapeutic target to optimize the achievement of treatment goals and slow or prevent disease progression .
patients received double - blind treatment with either cinacalcet ( n = 9 ) or placebo ( n = 12 ) for 1 year followed by a 3-year open - label extension treatment with cinacalcet .
calcimimetics are highly specific therapeutic agents that effectively lower concentrations of plasma pth and partially correct disturbances in mineral metabolism that are characteristic of shpt .
the mechanism of action involves allosteric modification of the car , rendering it more sensitive to calcium signalling , thereby helping counteract the decreased car expression and prevent and halt the progression of parathyroid hyperplasia .
in addition to effects on car signalling , new experimental studies indicate that calcimimetics may act to increase vdr expression .
these studies raise the possibility that treatment with calcimimetics might improve the sensitivity of the parathyroid glands to calcitriol and vitamin d analogues , allowing reduced doses to be used and thus minimizing the risk of hypercalcaemia and hyperphosphataemia .
preclinical mechanistic studies with calcimimetics have suggested that this modality may arrest disease progression , even in patients with advanced disease at treatment onset , and stabilize shpt , thereby allowing improved maintenance of kdoqi targets .
, cinacalcet was found to be effective for the reduction and long - term maintenance of ipth , calcium and phosphorus levels in patients with shpt .
cinacalcet has been shown to allow more patients to achieve and maintain kdoqi targets compared with standard therapy , and extended use ( up to 4 years ) has been shown to be effective and well tolerated .
 standard therapy for secondary hyperparathyroidism ( shpt ) includes dietary calcium supplementation , active vitamin d , and phosphate binders ; however , these are often insufficient to allow patients to achieve their serum parathyroid hormone ( pth ) , calcium and calcium  phosphorus product ( ca  p ) targets . 
 recent preclinical studies have demonstrated that treatment with type ii calcimimetics that increase the sensitivity of the calcium - sensing receptor ( car ) to calcium can reverse the alterations in car and vitamin d receptor expression and parathyroid cell proliferation that are associated with shpt . 
 these data suggest that calcimimetic treatment could stabilize disease progression and improve maintenance of treatment goals . in clinical trials involving shpt patients , 
 the calcimimetic cinacalcet has been shown to decrease pth , calcium , phosphorus and ca  p. significant improvements were seen regardless of initial disease severity , and benefits were maintained over the course of long - term therapy ( up to 4 years ) , indicating effective disease stabilization . in conclusion , 
 preclinical and clinical data provide both theoretical and empirical support for the use of calcimimetics in moderate and advanced shpt to effectively stabilize disease . 
Stabilization of secondary hyperparathyroidism with calcimimetics: preclinical evidence
CaR expression
Vitamin D receptor expression
Parathyroid cell proliferation and parathyroid hyperplasia
Unmet medical need in SHPT management
Effect of cinacalcet on disease stabilization in clinical trials
Conclusions