Kidney International, Vol. 68 (2005), pp.

17931800

Effects of the calcimimetic cinacalcet HCl on cardiovascular

disease, fracture, and health-related quality of life in secondary
hyperparathyroidism
JOHN CUNNINGHAM, MARK DANESE, KURT OLSON, PRESTON KLASSEN, and GLENN M. CHERTOW
University College London, The Middlesex Hospital, London, UK; Outcomes Insights, Inc., Newbury Park, California; Amgen,
Inc., Thousand Oaks, California; and Department of Medicine, University of California, San Francisco, California

Effects of the calcimimetic cinacalcet HCl on cardiovascular

disease, fracture, and health-related quality of life in secondary
hyperparathyroidism.
Background. Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important
role in bone and cardiovascular disease in patients with chronic
kidney disease. Cinacalcet, a calcimimetic that modulates the
calcium-sensing receptor, reduces parathyroid hormone (PTH)
secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and
secondary HPT.
Methods. We undertook a combined analysis of safety data
(parathyroidectomy, fracture, hospitalizations, and mortality)
from 4 similarly designed randomized, double-blind, placebocontrolled clinical trials enrolling 1184 subjects (697 cinacalcet,
487 control) with ESRD and uncontrolled secondary HPT (intact PTH 300 pg/mL). Cinacalcet or placebo was administered
to subjects receiving standard care for hyperphosphatemia and
secondary HPT (phosphate binders and vitamin D). Relative
risks (RR) and 95% CI were calculated using proportional
hazards regression with follow-up times from 6 to 12 months.
Health-related quality-of-life (HRQOL) data were obtained
from the Medical Outcomes Study Short Form-36 (SF-36), and
the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF).
Results. Randomization to cinacalcet resulted in significant
reductions in the risk of parathyroidectomy (RR 0.07, 95% CI
0.010.55), fracture (RR 0.46, 95% CI 0.220.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.430.86) compared
with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component
Summary score and the specific domains of Bodily Pain and
General Health Perception.
Conclusion. Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk
of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical func-

Key words: calcimimetics, cinacalcet, outcomes, PTH, secondary hyperparathyroidism.

Received for publication April 1, 2005
and in revised form April 30, 2005
Accepted for publication May 12, 2005


C

2005 by the International Society of Nephrology

tion and diminished pain. These data suggest that, in addition

to its effects on PTH and mineral metabolism, cinacalcet had
favorable effects on important clinical outcomes.

Secondary hyperparathyroidism (HPT) is a frequent

component of the natural progression of chronic kidney
disease (CKD), typically developing when the glomerular filtration rate (GFR) drops below approximately
80 mL/min/1.73m2 for 3 months [1]. Secondary HPT
is an adaptive response to CKD and arises from disruptions in the homeostatic control of serum calcium,
serum phosphorus, and vitamin D, which are associated
with CKD. Characteristic skeletal features of secondary
HPT include increased bone turnover with abnormally
high rates of bone resorption, often accompanied by
bone pain and fractures [26]. Extraskeletal manifestations of secondary HPT include vascular calcification,
hypertension, anemia with erythropoietin resistance, pruritus, and sexual dysfunction [714]. Conventional therapy for secondary HPT can contribute to hypercalcemia
and hyperphosphatemia [1517], laboratory abnormalities associated with mortality in end-stage renal disease
(ESRD) [1821]. We have recently demonstrated higher
risks of cardiovascular disease and fracture associated
with hyperphosphatemia and secondary HPT [19].
Vitamin D sterols are frequently used to control secondary HPT and have been shown to be effective in
suppressing parathyroid hormone (PTH) [2224] and
improving bone histology [22, 25]. Despite the use of
vitamin D, a large fraction of ESRD patients have refractory HPT [21]. Moreover, vitamin D enhances intestinal
absorption of calcium and phosphorus, complicating the
management of mineral metabolism [26]. Cinacalcet HCl
is a calcimimetic agent that binds the calcium-sensing receptor (CaR) of the parathyroid gland, resulting in diminished PTH secretion [27]. Cinacalcet acts by allosterically
modulating the CaR, enhancing the sensitivity of the CaR
to extracellular calcium and, thus, exerting a suppressive
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Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients

effect on PTH secretion [27]. Several published studies

have demonstrated the efficacy of cinacalcet compared
with placebo in lowering PTH concentrations in ESRD
patients with secondary HPT [2831]. In contrast with
vitamin D, when using cinacalcet the reduction in PTH
secretion has been accompanied by simultaneous reduction of the calcium phosphorus product (Ca P), serum
calcium, and phosphorus [2830].
The phase 2 and phase 3 studies comparing cinacalcet with placebo administered to subjects receiving standard care for hyperphosphatemia and secondary HPT
were designed with sufficient power to answer questions
related to biochemical end points (e.g., proportion of
subjects with end-of-study PTH concentrations below
250 pg/mL or with a reduction of 30% or more from
baseline). However, these individual studies were not
designed to evaluate the effects of cinacalcet on morbidity (including hospitalization and fracture), mortality,
or other outcomes believed to be related to the severity
of secondary HPT, such as physical function and healthrelated quality of life (HRQOL). Data for these clinical
end points were obtained for safety evaluation in selected
phase 2 and all phase 3 clinical trials, all of which shared
similar subject inclusion and exclusion criteria and virtually all basic design elements. Herein we present combined results from these clinical trials.

Study subjects
The randomized clinical trials included in this analysis had similar inclusion and exclusion criteria. Each
required that eligible subjects were 18 years old, exhibited an intact PTH level 300 pg/mL and an albumincorrected serum calcium 8.4 mg/dL, and had received
hemodialysis 3 times per week for a minimum of 1 to
3 months or peritoneal dialysis for 1 month. In 2 of the
phase 3 trials, intact PTH >800 pg/mL and Ca P >70
mg2 /dL2 were stratification variables. In these 2 studies,
the number of subjects with intact PTH >800 pg/mL was
limited to no more than 20% (similar to the percentage
observed in the general dialysis population), although this
limitation was not a requirement in the other trials.
Exclusion criteria included parathyroidectomy or myocardial infarction within 3 to 6 months of the start
of treatment and change of vitamin D therapy within
30 days of the start of treatment. Additional exclusion
criteria included the use of flecainide, lithium, thoridazine, haloperidol, or tricyclic antidepressant (except for
amitriptyline) therapy within 21 days of the start of the
trial, gastrointestinal disturbances that could impair the
absorption of the study drug, the existence of an unstable
medical condition, and pregnancy or nursing.
The studies were approved by the Independent Ethics
Committee or the Institutional Review Board, as appropriate, at each study center, and were conducted in accordance with the principles of the Declaration of Helsinki.
All subjects provided written informed consent.

METHODS
Study selection
We analyzed data pooled from all clinical trials investigating the approved dose range of cinacalcet (30 to
180 mg) with at least 6 months of follow-up. One
12-month phase 2 trial and 3 6-month phase 3 trials were
included. A 6-month extension trial of participants in 2
of the phase 3 studies was also included. The study design, including study drug dosing, was similar across all
studies included in this analysis and is described below.
The phase 2 trial was performed in the United States and
Europe and treated 48 subjects at 17 sites. The 3 phase 3
trials were performed in North America (63 sites with 410
subjects), Europe, and Australia (62 sites with 331 subjects), and North America and Australia (60 sites with 395
subjects). The extension trial included subjects from the
first 2 phase 3 trials who completed study between June
20, 2002 and December 27, 2002. All subjects completing the initial phase 3 study during this 12-month period
were asked to continue their randomized treatment for
an additional 6-month period. Of the 504 subjects who
completed the 2 initial phase 3 trials, 266 subjects agreed
to continue in the extension study (128 in the cinacalcet
group and 138 in the control group).

Study design
All trials were randomized, double-blind, and placebocontrolled. Subjects were randomized by a computergenerated randomization system. For the 2 phase
3 studies in hemodialysis subjects, 1:1 randomization was
stratified by baseline PTH and Ca P. For the phase 3
study enrolling hemodialysis and peritoneal dialysis subjects, a 3:1 ratio (cinacalcet:placebo) was used for randomization, which was stratified by dialysis modality, and
within the hemodialysis subjects by baseline PTH. The
phase 2 study utilized no stratification for the randomization. Matching placebos were used, and the blinds were
maintained through the use of numbered study drug bottles. The phase 2 study had a 24-week titration phase and
a 28-week assessment phase. The first 2 phase 3 studies used 12-week titration phases, while the third used a
16-week titration. All 3 phase 3 studies were 26 weeks
in duration, with assessment phases ranging from 10 to
14 weeks. Subjects who entered the extension portion of
the phase 3 trials received blinded treatment for an additional 26 weeks.
Subjects received cinacalcet at doses from 30 to 180 mg/
day (30, 50, 70, 90, 120, 180 mg in the phase 2 trial and
30, 60, 90, 120, 180 mg in the phase 3 and extension

Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients

trials). These doses were titrated every 3 to 4 weeks. Subjects receiving vitamin D sterols at baseline continued at
the same dose throughout the trial. Reductions in vitamin D doses were permitted for albumin-adjusted serum
calcium 11 mg/dL, serum phosphorus 6.5 mg/dL or
Ca P 70 mg2 /dL2 . Vitamin D doses could be increased
for serum calcium <8.4 mg/dL. Phosphate binders were
permitted, with dose changes allowed at the discretion
of the investigator. Detailed reports on the biochemical
effects and general safety of cinacalcet have been previously published [2831].
Clinical end points
Outcomes were identified prospectively based on reasons for discontinuation and adverse-event data [defined
using World Health Organization Adverse Reaction
Terminology [WHO-ART)] collected in all studies. Hospitalizations were captured from the adverse event form,
with a primary preferred term (i.e., reason for hospitalization) provided for each event. Vital status and hospitalization were assessed for an additional 30 days and
7 days, respectively, beyond the official study completion.
Follow-up time was adjusted accordingly for the analyses
shown here.
Outcomes examined include parathyroidectomy (considered a failure of therapy for secondary HPT and a
reason for study discontinuation), fracture, cardiovascular hospitalization (e.g., myocardial infarction, unstable
angina, exacerbation of heart failure), as well as all-cause
and noncardiovascular hospitalization. Reported events
were confirmed using source document verification, and
the medical records of all subjects were monitored during
the study to facilitate complete event capture.
Subject-reported outcomes
Subject-reported outcomes used in these analyses were
obtained in the phase 3 studies using touch-screen computer technology (Assist Technologies, Scottsdale, AZ,
USA). Instruments used in all studies included the
Medical Outcomes Study Short Form-36 (SF-36) and the
Cognitive Functioning scale from the Kidney Disease
Quality of Life (KDQOL) instrument (KDQOL-CF).
Translated and culturally adapted versions of these instruments were used where appropriate. Data were collected before the first dose of study drug (baseline), at
the end of the titration period, once during the middle of
the efficacy assessment phase, and at the end of the efficacy assessment phase (i.e., the end of the study) for the
phase 3 studies. Change from baseline was calculated as
the difference between the baseline value and the mean
of the 2 efficacy assessment phase values. Subjects with
missing baseline data were excluded from the analyses
(N = 22), as were subjects with no values during the efficacy assessment phase (N = 238). Data from the phase

1795

2 study were not included because subject-reported outcomes were not assessed during the efficacy assessment
phase of the study.
Norm-based scoring was used for the SF-36, meaning
that for all scales a score of 50 represents the U.S. general
population mean, with a standard deviation of 10 points.
The KDQOL-CF was scored from 0 to 100, with a higher
score indicating better function.
Statistical analysis
Analyses were based on all randomized subjects using
an intent-to-treat approach. Cox proportional hazards
models, stratified by study, were used to make statistical comparisons for the outcomes of parathyroidectomy,
fracture, and death. The primary analyses for hospitalizations used the Andersen-Gill model to permit multiple events [32]. As the Andersen-Gill model essentially
treats the second event as independent of the first, a conditional model (where the risk for a second event depends
on having experienced a first event) was also used to confirm the results. Relative risk (RR) estimates and 95% CIs
were calculated from model parameter coefficients and
their standard errors. Survival curves were plotted using
the time-to-event Kaplan-Meier product limit estimate.
The estimated least squares means of each of the SF-36
scale scores, as well as the KDQOL-CF score, adjusted for
study, were compared between treatment groups using t
tests. Subjects with no values either at baseline or during
the efficacy assessment phase (N = 71, 6.0%) were not
included in the analysis of the subject-reported outcomes
data. Two-tailed P values < 0.05 were considered statistically significant. All analyses were conducted using SAS
8.2 (Cary, NC, USA).
RESULTS
A total of 1184 subjects (697 cinacalcet, 487 control)
enrolled in the studies. Table 1 shows baseline characteristics of subjects enrolled in the clinical trials. Overall, the
mean SD age was 53.7 14.4 years; 38% were women
and 49% non-white. As expected, the median PTH was
higher in the studies with no limit on inclusion of subjects
with PTH 800 pg/mL. Generally, clinical characteristics
were similar across studies, and no differences in baseline
characteristics were noted among subjects enrolled in the
phase 3, 6-month extension trial and the larger population of the 2 parent studies.
Clinical end points
Parathyroidectomy
In the cinacalcet group, there was 1 parathyroidectomy in 374.2 subject-years of follow-up (0.3 parathryoidectomies per 100 subject-years). In the control group,

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Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients

Table 1. Baseline demographics and biochemical parameters

Age
<65 years
65 years
Age at randomization years, mean SD
Sex
Female
Male
Ethnicity
White
Black
Other
Dialysis modality
Hemodialysis
Peritoneal dialysis
Vintage months, mean SD
Diabetes
No
Yes
Phosphate binder use
No
Yes
Calcium-containing only
Sevelamer only
Calcium-containing plus sevelamer
Other
Vitamin D sterol use
No
Nave
Withheld for elevated Ca, P, or Ca P
Other
Not prescribed
Not indicated
Yes
Oral
Intravenous
Oral plus intravenous
Not indicated
Plasma PTH pg/mL, mean SD
Serum Ca P mg2 /dL2 , mean SD
Serum calcium mg/dL, mean SD
Serum phosphorus mg/dL, mean SD

Cinacalcet
(N = 697)
N (%)

Control
(N = 487)
N (%)

Total
(N = 1184)
N (%)

538 (77)
159 (23)
53.0 14.2

348 (71)
139 (29)
54.7 14.6

886 (75)
298 (25)
53.7 14.4

0.025

272 (39)
425 (61)

181 (37)
306 (63)

453 (38)
731 (62)

0.52

332 (48)
265 (38)
100 (14)

270 (55)
166 (34)
51 (10)

602 (51)
431 (36)
151 (13)

0.018

663 (95)
34 (5)
65.8 59.9

475 (98)
12 (2)
70.1 67.1

1138 (96)
46 (4)
67.6 63.0

0.034

480 (69)
217 (31)

333 (68)
154 (32)

813 (69)
371 (31)

0.86

49 (7)
648 (93)
258 (37)
211 (30)
86 (12)
93 (13)

36 (7)
451 (93)
200 (41)
128 (26)
49 (10)
74 (15)

85 (7)
1099 (93)
458 (39)
339 (29)
135 (11)
167 (14)

0.81

244 (35)
70 (10)
132 (19)
8 (1)
30 (4)
4 (1)
453 (65)
180 (26)
234 (34)
4 (1)
35 (5)
731 531
60.9 16.0
9.9 0.8
6.2 1.7

160 (33)
41 (8)
86 (18)
3 (1)
29 (6)
1 (0)
327 (67)
126 (26)
179 (37)
2 (0)
20 (4)
682 399
61.1 15.1
9.9 0.8
6.2 1.5

404 (34)
111 (9)
218 (18)
11 (1)
59 (5)
5 (0)
780 (66)
306 (26)
413 (35)
6 (1)
55 (5)
711 481
61.0 15.6
9.9 0.8
6.2 1.6

0.44

there were 12 parathyroidectomies in 294.5 subject-years

of follow-up (4.1 parathyroidectomies per 100 subjectyears) (Table 2). The RR of parathyroidectomy was much
lower (93% reduction) for the cinacalcet group (RR 0.07,
95% CI 0.010.55) (Fig. 1A). The median PTH at the time
of parathyroidectomy was 1056 (interquartile range 523
1502).
Fractures
Fracture rates were lower in the cinacalcet group compared with the control group (3.2 vs. 6.9 per 100 subjectyears) (Table 2). The RR of fractures was significantly
reduced in the cinacalcet group (RR 0.46, 95% CI 0.22
0.95) (Table 2, Fig. 1B). In the control group, there were 7
fractures of the lower extremities (hip, femur, tibia, etc.),
and 13 other fractures (ribs and upper extremities). Cor-

P value

0.037

0.25

0.074
0.84
0.26
0.85

responding data for the cinacalcet group were 11 fractures

of the lower extremities, and 1 other fracture, this being
equivalent to approximately half the rate observed with
placebo due to the larger number of subjects randomized
to receive cinacalcet.
Cardiovascular hospitalization
The rate of cardiovascular hospitalizations was lower
in the cinacalcet group compared with the control group
(15.0 vs. 19.7 hospitalizations per 100 subject-years)
(Table 2). Using the Andersen-Gill method, the RR
of cardiovascular hospitalization was significantly reduced among subjects receiving cinacalcet (RR 0.61,
95% CI 0.430.86) (Table 2, Fig. 1C). Results were virtually identical using the conditional model (RR 0.63,
95% CI 0.440.90). In the control group, cardiovascular

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Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients

Table 2. Event rates by treatment group

Events per 100 subject-years
Clinical outcome

Cinacalcet

Control

Hazard ratioa
(95% CI)

P value for
hazard ratio

0.3
3.2
15.0
67.0
5.2

4.1
6.9
19.7
71.0
7.4

0.07 (0.010.55)
0.46 (0.220.95)
0.61 (0.430.86)
1.03 (0.871.22)
0.81 (0.451.45)

0.009
0.04
0.005
0.74
0.47

Parathyroidectomy
Fracture
Cardiovascular hospitalization
All-cause hospitalization
Mortality
a

Placebo was used as the reference group.

C
1.00

0.95
0.90
0.85
0.80
Control

0.75
0

Cinacalcet

Event-free probability

Event-free probability

1.00

0.95
0.90
0.85
0.80

12 16 20 24 28 32 36 40 44 48 52
Week

Subjects at risk:
Placebo (N )
487 475 461 444 426 411 396 240 153 146 136 134 132 128
697 670 639 601 584 552 526 275 152 143 137 128 127 121
Cinacalcet (N )

Cinacalcet

12 16 20 24 28 32 36 40 44 48 52

Week
Subjects at risk:
Placebo (N )
487 470 445 419 404 383 367 314 136 132 120 117 112 109
Cinacalcet (N )
697 656 614 574 554 513 485 392 132 131 125 115 110 106

D
1.00

0.95
0.90
0.85
0.80
Control

0.75
0

Cinacalcet

12 16 20 24 28 32 36 40 44 48 52

Week
Subjects at risk:
Placebo (N )
487 476 454 430 411 397 384 339 148 145 132 127 125 122
Cinacalcet (N )
697 660 629 592 573 538 515 418 142 140 132 124 122 119

Event-free probability

1.00
Event-free probability

Control

0.75

0.95
0.90
0.85
0.80
Control

0.75
0

Cinacalcet

12 16 20 24 28 32 36 40 44 48 52

Week
Subjects at risk:
Placebo (N )
487 485 469 456 434 422 403 391 222 148 142 137 134 130
Cinacalcet (N )
697 688 656 625 595 574 541 513 271 145 141 134 127 124

Fig. 1. Kaplan-Meier time-to-event plots for (A) parathyroidectomy, (C) bone fractures, (B) cardiovascular hospitalization, and (D) mortality in
subjects on cinacalcet versus control.

hospitalizations included 29 hospitalizations for ischemic

heart disease (including myocardial infarction and angina
pectoris), 19 for heart failure, 18 for arrhythmia, 7 for peripheral vascular disease, and 4 for stroke. Corresponding data for the cinacalcet group were 22 hospitalizations
for ischemic heart disease, 26 for heart failure, 17 for
arrhythmia, 2 for peripheral vascular disease, and 5 for
stroke.
All-cause hospitalization
There was no significant difference in all-cause hospitalizations between treatment groups (RR 1.03, 95%
CI 0.871.22) using the Andersen-Gill method (Table 2).
These results were confirmed with the conditional model

(RR 1.02, 95% CI 0.861.21). No significant differences

were observed between the treatment groups for noncardiovascular hospitalizations (Andersen-Gill RR 1.16,
95% CI 0.961.39) or for hospitalizations unrelated to
cardiovascular disease, fracture, or parathyroidectomy
(Andersen-Gill RR 1.18, 95% CI 0.981.42).

Mortality
The rate of mortality in the study population was 5.2
and 7.4 per 100 subject-years in the cinacalcet and control groups, respectively. This difference was not statistically significant (RR 0.81, 95% CI 0.451.45) (Table 2,
Fig. 1D).

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Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients

Table 3. Mean baseline scores on the eight domains of the SF-36 and on the KDQOL-CF at baseline (combined phase 3 studies)
Cinacalcet
(N = 665)
HRQOL scales
SF-36
Physical Component Summary
Mental Component Summary
Physical functioning
Role LimitationsPhysical
Bodily Pain
General Health Perception
Social Functioning
Vitality
Role LimitationsEmotional
Emotional Well Being
KDQOL
Cognitive functioning

Control
(N = 471)

Mean (SE)

Mean (SE)

640
640
649
645
649
647
649
648
647
648

39.8 (0.39)
49.4 (0.43)
38.9 (0.46)
41.7 (0.46)
46.3 (0.45)
39.0 (0.37)
45.1 (0.43)
47.9 (0.38)
44.6 (0.50)
48.8 (0.43)

459
459
464
463
463
462
463
464
462
464

40.6 (0.47)
49.3 (0.51)
39.2 (0.55)
42.5 (0.54)
47.2 (0.55)
39.9 (0.46)
45.6 (0.51)
47.9 (0.47)
44.1 (0.60)
49.5 (0.51)

647

79.7 (0.71)

464

79.4 (0.86)

8
6
4
2
0

H
M

E
R

VT

SF

H
G

BP

P
R

PF

F
PC

Difference between treatments

Note: Higher values indicate better health status for all scales.

Fig. 2. Differences in score changes (cinacalcet-treated minus control

subject scores) of combined phase 3 data on KDQOL-CF (CF) and
SF-36 (PCS, Physical Component Summary; MCS, Mental Component Summary; SF-36 domains: PF, Physical Functioning; RP, Role
Limitations-Physical; BP, Bodily Pain; GH, General Health Perception;
SF, Social Functioning; VT, Vitality; RE, Role Limitations-Emotional;
MH, Mental Health). A positive score represents a greater improvement with cinacalcet treatment compared to control treatment. Bars
represent 95% CI.

HRQOL and self-reported cognitive function

Mean baseline scores on the 8 domains of the SF-36
were approximately one half to one standard deviation
below the population mean and were similar between the
randomized groups (Table 3). Changes in HRQOL (baseline to end-of-study) were consistently in favor of cinacalcet (Fig. 2). There were statistically significant differences
between treatment groups for the SF-36 Physical Component Summary (PCS) score (0.5-unit improvement in
the cinacalcet group compared with 0.8-unit decrease in
the control group, P = 0.01), as well as the Bodily Pain
scale (0.6-unit improvement in the cinacalcet group compared with 1.0-unit decrease in the control group, P =
0.03) and the General Health Perception scale (0.2-unit
improvement in the cinacalcet group compared with 1.0unit decrease in the control group, P = 0.02). A simi-

lar proportion of subjects in both groups experienced a

large decline in self-reported physical function (decrease
in PCS >5) points (21% vs. 23%, for cinacalcet and control groups, respectively, P = 0.52). However, significantly
more subjects in the cinacalcet group experienced a large
improvement in self-reported physical function (increase
in PCS >5) points (26% vs. 20%, P = 0.03).
Baseline values on the KDQOL-CF were 79.7 and 79.4
in the cinacalcet and control groups, respectively. There
were no significant differences in the mean change in
KDQOL-CF score by treatment group (+0.2 vs. 0.8 in
cinacalcet and control groups, respectively, P = 0.12).
DISCUSSION
Analyses of combined data from randomized, blinded,
placebo-controlled, 6- to 12-month studies of cinacalcet
versus standard care for secondary HPT showed statistically significant and clinically meaningful reductions
in the risks of parathyroidectomy, fracture, and cardiovascular hospitalization. Although the individual clinical
studies were designed to assess changes in biochemical parameters and not a priori clinical end points, the
prospective and interventional nature of the combined
data lends credibility to the clinical relevance of biochemical control in secondary HPT and suggests that therapy
with cinacalcet may lead to beneficial effects on clinical
outcomes.
Several mechanisms of action have been proposed that
support the findings observed in these trials. Reduction in
parathyroidectomy may be mediated through improved
control of PTH and reductions in parathyroid cell proliferation and gland hyperplasia, which have been demonstrated using cinacalcet in an animal model of secondary
HPT [33]. The reduction in fractures observed in this
study is consistent with preclinical evidence demonstrating that calcimimetics ameliorated high bone turnover

Cunningham et al: Cinacalcet and clinical outcomes in dialysis patients

and increased femoral cortical bone mineral density and

cortical bone strength [34, 35]. In multiple phase 2 and
phase 3 clinical trials, treatment with cinacalcet was associated with favorable changes in the biochemical markers
of bone formation (bone-specific alkaline phosphatase)
and resorption (serum N-telopeptide), as well as improvement in bone turnover parameters [28, 36]. In addition, although the increased cardiovascular risk evident
in subjects with end-stage renal disease is multifactoral,
this risk has been related to abnormalities of vascular
biology, including calcification and arterial stiffness [37
40]. Elevations in serum calcium, phosphorus, and Ca
P are known to be independent risk factors for vascular
calcification and mortality in hemodialysis subjects [11,
19, 41]. In vitro data suggest that elevated calcium and
phosphorus concentrations play a role in the calcification
of human vascular smooth muscle cells [42]. Preliminary
evidence also demonstrates that calcimimetics do not increase the arterial content of calcium and phosphorus in
vitro and may mitigate vascular calcification in uremic
rats treated with calcitriol [43, 44].
In addition to the effects on fracture and cardiovascular hospitalization, the current analysis also
demonstrated improvements in HRQOL with statistically significant improvements in the PCS scale and Pain
and General Health Perception scales, and positive trends
in other physical health domains. Several large cohort
studies and clinical trials have linked higher scores on
the PCS with reduced mortality and morbidity [4548].
The results of these analyses highlight the importance
of examining clinical outcomes in a disease dominated
by reliance on biochemical parameters for diagnosis and
therapeutic management. These data represent the first
examination of clinical outcomes collected from prospective, randomized, and placebo-controlled studies of any
therapy used for secondary HPT. Despite the introduction of newer vitamin D analogs and increased overall
utilization of vitamin D sterols during the past decade,
no outcomes data are available from prospective clinical
trials. Over the same time period, the increasing trend
in parathyroidectomy and fracture rates and unchanged
rates of mortality and cardiovascular morbidity emphasize the need to examine clinical outcomes in an unbiased
manner when evaluating therapeutic interventions [49,
50].
The analyses presented here have several strengths.
The clinical trials were randomized and blinded, and
clinical characteristics were well balanced by randomization. Although the clinical end points for this analysis were obtained from the safety records of each
clinical trial and were not independently adjudicated,
each event was verified by review of medical records.
However, this analysis has several important limitations.
The studies were not designed to evaluate differences in
event rates. Follow-up times were relatively short; longer-

1799

term follow-up would have increased the likelihood of

demonstrating significant treatment effects. Ascertainment of less severe events (e.g., fracture not requiring
hospitalization) was likely limited, and also reduced the
power to detect treatment effects.
CONCLUSION
Despite the limitations in study design, combined data
demonstrate that cinacalcet treatment of subjects on dialysis with secondary HPT resulted in improvement in
clinical outcomes, especially parathyroidectomy, fracture,
cardiovascular hospitalization, and specific components
of health-related quality of life. Future trials are required
to confirm and expand on these results.
ACKNOWLEDGMENTS
The authors are very much indebted to William W. Stark, Jr., Ph.D.,
for his assistance in the preparation of this manuscript, and to Jamie
MacMillan at Amgen for his help on this paper. Mr. Olson and Dr.
Klassen are employees of Amgen, Inc., the manufacturer of cinacalcet
HCl. Dr. Danese is a former Amgen, Inc., employee and a consultant
to Amgen, Inc. Drs. Cunningham and Chertow have served as scientific
advisors to Amgen, Inc., and have previously received research support from Amgen, Inc. All authors approved the final version of the
manuscript, which was submitted with no influence from other individuals affiliated with Amgen, Inc., or any other entity.
Reprint requests to Glenn M. Chertow, M.D., MPH, Department of
Medicine Research UCSF, University of California San Francisco, Laurel
Heights, Suite 430, 3333 California Street, San Francisco, CA 94118-1211.
E-mail: [email protected]

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