Imperialendo.co.uk2

The Journal of Clinical Endocrinology & Metabolism 90(1):135–141 Copyright 2005 by The Endocrine Society Cinacalcet Hydrochloride Maintains Long-Term
Normocalcemia in Patients with Primary
Hyperparathyroidism
Munro Peacock, John P. Bilezikian, Preston S. Klassen, Matthew D. Guo, Stewart A. Turner, andDolores Shoback Department of Medicine (M.P.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department ofMedicine (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Amgen Inc.
(P.S.K., M.D.G., S.A.T.), Thousand Oaks, California 91320; and Department of Veterans Affairs Medical Center (D.S.),Department of Medicine, University of California, San Francisco, California 94121 Calcimimetics increase the sensitivity of parathyroid calci-
chemistry, biochemical measures of bone turnover, bone min-
um-sensing receptors to extracellular calcium, thereby reduc-
eral density, and safety were also assessed. Seventy-three
ing PTH secretion. This multicenter, randomized, double-
percent of cinacalcet-treated patients vs. only 5% of placebo-
blind, placebo-controlled study assessed the ability of the oral
treated patients achieved the primary endpoint (P < 0.001).
calcimimetic cinacalcet HCl to achieve long-term reductions
Fasting predose plasma PTH decreased 7.6% in cinacalcet pa-
in serum calcium and PTH concentrations in patients with
tients but increased 7.7% in placebo patients (P < 0.01). Bone
primary hyperparathyroidism (HPT). Patients (n ؍ 78) were
mineral density was unchanged by cinacalcet, but bone re-
randomized to cinacalcet or placebo. Cinacalcet was titrated
sorption and formation markers increased (P < 0.05). Adverse
from 30 –50 mg twice daily during a 12-wk dose-titration
events were mild and similar between treatment groups. Ci-
phase. Efficacy was assessed during 12-wk maintenance and
nacalcet rapidly normalizes serum calcium and reduces PTH
28-wk follow-up phases. The primary endpoint was the
in patients with primary HPT, and these effects are main-
achievement of normocalcemia [serum calcium < 10.3 mg/dl
tained with long-term treatment. Cinacalcet may be an effec-
(2.57 mmol/liter)] with at least 0.5 mg/dl (0.12-mmol/liter) re-
tive, nonsurgical approach for management of primary HPT.
duction from baseline. Plasma PTH, serum and urine bio-
(J Clin Endocrinol Metab 90: 135–141, 2005)
PRIMARY HYPERPARATHYROIDISM (HPT) is a com- calcet HCl, hereafter referred to as cinacalcet, is a calcimi- mon disorder characterized by chronically elevated se- metic that has been shown to lower plasma PTH, serum rum calcium and PTH concentrations. In the United States, calcium, and serum phosphorus in patients with secondary many patients with primary HPT have mild, asymptomatic HPT (6, 7). In an earlier study, we showed that cinacalcet also disease and do not meet the criteria for surgery (1). Patients had efficacy in the short-term reduction of serum calcium with moderate to severe disease can experience worsening and PTH concentrations in patients with primary HPT (8).
hypercalcemia, nephrolithiasis, loss of bone mineral density We conducted this 52-wk, randomized, double-blind, (BMD), neuromuscular weakness, and neurobehavioral placebo-controlled study to investigate the long-term effi- symptoms including easy fatigability and impaired cognitive cacy and safety of cinacalcet in reducing serum calcium and function (2). Parathyroidectomy is usually curative, but there PTH levels in patients with mild to moderate primary HPT.
are few nonsurgical treatment alternatives for patients who In addition, the impact of cinacalcet on bone turnover and fail surgery, have contraindications to surgery, do not wish to have surgery, or do not meet current guidelines for sur-gery. Thus, there is a need for therapeutic agents that directly Patients and Methods
reduce serum calcium and PTH concentrations in patientswith primary HPT.
The calcium-sensing receptor (CaR) located on cells of the The study was conducted at 18 centers in the United States. Seventy- parathyroid gland is the principal regulator of PTH secretion eight adult patients, 21 men and 57 women, aged 27– 83 yr, with primary (3). Type II calcimimetics are a novel class of compounds that HPT were enrolled in the study over 14 wk between 1999 and 2000.
Eligibility requirements included serum calcium concentration greater directly reduce PTH levels by binding to the CaR and in- than 10.3 mg/dl (2.57 mmol/liter) and less than 12.5 mg/dl (3.12 mmol/ creasing its sensitivity to extracellular calcium (4, 5). Cina- liter) and plasma PTH concentration greater than 45 pg/ml (4.73 pmol/liter). PTH was measured on at least two occasions at least 7 d apartduring the 12-month period before baseline. Exclusion criteria included First Published Online November 2, 2004
pregnancy, creatinine clearance less than 50 ml/min (0.83 ml/sec) (9), Abbreviations: BALP, Bone-specific alkaline phosphatase; BMD, treatment with bisphosphonates or fluoride in the 90 d before baseline, bone mineral density; CaR, calcium-sensing receptor; DPD, deoxypyr- familial hypocalciuric hypercalcemia, or fasting urine calcium/creati- idinoline; HPT, hyperparathyroidism; NTx, N-telopeptide.
nine in milligrams (molar) ratio less than 0.05 (0.14). Because cinacalcet JCEM is published monthly by The Endocrine Society (http://www.
inhibits cytochrome P450 2D6 (CYP2D6), patients were excluded if they endo-society.org), the foremost professional society serving the en-
required drugs that are metabolized by this enzyme and have a narrow docrine community.
therapeutic index, such as flecainide, thioridazine, and many tricyclic J Clin Endocrinol Metab, January 2005, 90(1):135–141 Peacock et al. • Cinacalcet for Primary Hyperparathyroidism antidepressants. Women on stable doses of selective estrogen receptor modulators or estrogen replacement therapy were eligible. The Insti-tutional Review Board at each center approved the study, and written The proportion of patients achieving a serum calcium less than or informed consent was obtained from all patients.
equal to 10.3 mg/dl (2.57 mmol/liter) and a reduction in serum calciumof at least 0.5 mg/dl (0.12 mmol/liter) from baseline was determinedusing mean values for each patient derived from up to three measure- ments obtained during the maintenance phase. The difference in theproportion of patients achieving the primary endpoint in the cinacalcet This was a multicenter, randomized, double-blind, placebo-con- and placebo groups was determined using logistic regression and in- trolled study. Patients were randomized in a 1:1 ratio to receive either cluded all randomized patients. For this analysis, patients leaving the cinacalcet or placebo after a 30-d screening period. The study included study before the maintenance phase were considered not to have a 12-wk dose-titration phase, a 12-wk maintenance phase during which achieved the primary endpoint, regardless of serum calcium values at the primary efficacy endpoint was measured, and a 28-wk follow-up the time of withdrawal. An additional analysis was performed using the phase to gather additional safety and efficacy information. Patients last on-study serum calcium value for patients who withdrew before the initially received 30 mg cinacalcet or placebo twice daily. The dose was maintenance phase. Biochemical and BMD variables were compared increased sequentially to 40 and 50 mg twice daily at study wk 4 and 8 between placebo and cinacalcet groups at wk 24 and 52 using one-way if patients were still hypercalcemic (serum calcium Ͼ 10.3 mg/dl).
ANOVA. Adverse events were tabulated by treatment group and an- Patient visits occurred weekly during the titration phase (wk 1–12) and alyzed using descriptive statistics.
monthly during the maintenance (wk 13–24) and follow-up (wk 25–52)phases. Pharmacodynamic data were collected at wk 3, 12, and 24 after the morning dose of study drug to assess effects of study drug on serumcalcium and PTH concentrations over 8 h.
A total of 78 patients with primary HPT were randomized The primary endpoint was the proportion of patients achieving a (40 cinacalcet, 38 placebo). One patient who was randomized mean serum calcium less than or equal to 10.3 mg/dl (2.57 mmol/liter)and a reduction from baseline of at least 0.5 mg/dl (0.12 mmol/liter) to placebo withdrew before receiving the study drug. The during the maintenance phase. Secondary endpoints included changes mean age was 62 yr in both groups (range, 27– 83 yr), and the from baseline in serum and urine biochemistries and BMD. Adverse majority of patients were women (70% cinacalcet, 76% pla- events were recorded throughout the study.
cebo). Nine patients in each group had a prior history ofparathyroidectomy. Twenty-eight of 40 patients (70%) in the cinacalcet group and 28 of 38 patients (74%) in the placebogroup completed the 52-wk study.
Blood samples were collected for measurement of serum calcium and PTH at each study visit after an overnight fast and before the morning Mean baseline biochemical values were similar between dose of study drug. Samples for serum calcium and PTH were also treatment groups and characteristic of patients with mild to collected at 2, 4, and 8 h after the morning dose of study drug at wk 3, moderate primary HPT (Table 1). In the cinacalcet group, the 12, and 24 for pharmacodynamic analysis. Serum calcium [coefficient of mean baseline serum calcium level was 10.7 Ϯ 0.5 mg/dl variation (CV) ϭ 1.4 –1.5%] was measured by standard methods. Intact (2.67 Ϯ 0.12 mmol/liter), and the mean PTH level was 105 Ϯ PTH (CV ϭ 4.2– 6.4%) was measured using a double-antibody immu-noradiometric assay (Allegro PTH, Nichols Institute Diagnostics, San 36 pg/ml (11.0 Ϯ 3.78 pmol/liter) compared with 10.7 Ϯ 0.4 mg/dl (2.67 Ϯ 0.10 mmol/liter) and 120 Ϯ 54 pg/ml (12.6 Ϯ Serum phosphorus (CV ϭ 2.2–2.4%), creatinine (CV ϭ 1.6 –13.5%), 5.68 pmol/liter), respectively, in placebo-treated patients.
1,25-dihydroxyvitamin D (CV ϭ 9.1–20.3%), bone-specific alkaline phos- Mean (sd) baseline Z scores for cinacalcet were 0.15 (2.20) phatase (BALP) (CV ϭ 9.9 –11.4%), and N-telopeptide (NTx) (CV ϭ6.4 –9.5%) were measured at baseline and at wk 24 and 52. Serum 1,25- at the lumbar spine, – 0.31 (0.91) at the total femur, and – 0.46 dihydroxyvitamin D was measured by radioreceptor assay (Endocrine (1.41) at the 1/3 distal radius. For placebo patients, the base- Sciences, Calabasas Hills, CA). Serum NTx levels were determined by line Z scores were – 0.10 (2.27) at the lumbar spine, – 0.33 ELISA (Osteomark NTx assay, Ostex International, Seattle, WA). Urine (0.96) at the total femur, and – 0.31 (1.38) at the 1/3 distal was collected over 24 h and after an overnight fast at baseline and at wk radius. Mean (sd) baseline T scores for the cinacalcet group 24 and 52 for the measurement of calcium (CV ϭ 3.4 – 4.9%), phosphorus(CV ϭ 1.7–1.9%), NTx (CV ϭ 5.1–11.3%), and deoxypyridinoline (DPD) were – 0.90 (1.55) at the lumbar spine, –1.20 (1.02) at the total (CV ϭ 8.6 –17.1%), which were expressed as a ratio with urine creatinine.
femur, and –1.61 (1.58) at the 1/3 distal radius. For placebo Urine calcium, phosphorus, creatinine, and urine-free DPD were mea- patients, the baseline T scores were –1.22 (1.57) at the lumbar sured by Covance Central Laboratories (Indianapolis, IN). Tubular re- spine, –1.32 (1.07) at the total femur, and –1.79 (1.62) at the absorption of calcium (TmCa ϭ [total plasma calcium ϫ 0.59 – urinecalcium ϫ plasma creatinine/urine calcium]/1 – 0.08 log calcium ϫ 0.59/{urine calcium ϫ plasma creatinine/urine calcium}]) During the maintenance phase, 73% of patients in the and tubular reabsorption of phosphorus (TmP ϭ [plasma phosphate cinacalcet group achieved the primary endpoint [predose – urine phosphate ϫ plasma creatinine/urine phosphate]/1 – 0.1 loge serum calcium Յ 10.3 mg/dl (2.57 mmol/liter) and a de- [plasma phosphate/{urine phosphate ϫ plasma creatinine/urine phos- crease from baseline of Ն0.5 mg/dl (0.12 mmol/liter)] com- phate}]) were calculated from the calcium and phosphate (in milligrams)values in the respective fasting blood and urine samples using the pared with 5% of the placebo group (P Ͻ 0.001). When serum calcium values from patients who withdrew during the dose- BMD of the lumbar spine, total femur, and 1/3 distal radius was titration phase were included in the analysis, 88% of the measured either by dual-energy x-ray absorptiometry at baseline and at cinacalcet group achieved the primary endpoint, compared wk 24 and 52 using a Hologic densitometer (Hologic, Waltham, MA)(n ϭ 27, cinacalcet; n ϭ 26, placebo) or a Lunar densitometer (Lunar Inc., with 5% of the placebo group (P Ͻ 0.001). Mean serum Madison, WI) (n ϭ 13, cinacalcet; n ϭ 12, placebo). For each patient, BMD calcium levels were reduced to the normal range within the was measured on the same densitometer throughout the study. To first 2 wk of treatment with cinacalcet (Fig. 1) and remained combine measurements in men and women over a wide age range made normal throughout the 52 wk of the study. In the placebo on either Hologic or Lunar machines, BMD was expressed as a Z score.
group, the mean serum calcium levels did not change sig- To examine for longitudinal changes, the changes in Z score for eachindividual were calculated, and the mean changes for the placebo and nificantly from baseline levels throughout the study.
cinacalcet groups were presented as mean change in Z score.
Corresponding modest but significant reductions in fast- Peacock et al. • Cinacalcet for Primary Hyperparathyroidism J Clin Endocrinol Metab, January 2005, 90(1):135–141 ing plasma PTH (measured ϳ12 h after administration of study drug) were observed in the cinacalcet group. Mean plasma predose PTH decreased by 7.6% from 105 Ϯ 36 pg/ml Ϯ 3.78 pmol/liter) to 95 Ϯ 34 pg/ml (10.0 Ϯ 3.55 pmol/ liter) during the maintenance phase compared with a 7.7%increase from 120 Ϯ 54 to 127 Ϯ 53 pg/ml (12.6 Ϯ 5.69 to13.3 Ϯ 5.52 pmol/liter) in the placebo group (P Ͻ 0.01; Fig.
2). In the cinacalcet group, predose plasma PTH reductions were maintained throughout the follow-up period.
Pharmacodynamic data collected at wk 24 demonstrated that the serum calcium concentrations remained unchanged after the morning dose of cinacalcet, whereas the correspond- ing plasma PTH concentrations underwent cyclic changeswith dosing. At wk 24, mean serum calcium was normal, whereas mean plasma PTH remained elevated at the predose measurement. After the morning dose of cinacalcet, serum calcium was unchanged at all time points measured (Fig. 3A), whereas PTH decreased by 37% into the normal range at 2 h after dose (P Ͻ 0.0001) and gradually returned toward pre- dose levels by 8 h (Fig. 3B). In the placebo group, no changes in calcium or PTH concentrations were observed over thecorresponding time period. Results were similar at wk 3 and 12 (data not shown), indicating that no changes in serum calcium occurred once steady state had been achieved, but plasma PTH continued to undergo pharmacodynamic Mean fasting predose biochemistries at baseline and at wk 24 and 52 are shown in Table 1. Serum phosphorus increasedin the cinacalcet group and at wk 52 was higher (P Ͻ 0.001) than in the placebo group. The fasting urine calcium-creat- inine ratio and the 24-h urine calcium-creatinine ratio de- creased in the cinacalcet group, although the difference be- tween treatment groups was statistically significant only for the fasting calcium-creatinine ratio (P tubular reabsorption of calcium decreased (P phosphorus reabsorption increased (P Ͻ 0.001) from baseline in the cinacalcet group, whereas there were no changes in the placebo group. Serum 1,25-dihydroxyvitamin D concentra- tions were similar in both groups at wk 52 and unchanged from baseline. Serum creatinine and 24-h urine creatinine remained relatively constant and similar in both groups Some markers of bone turnover—serum BALP, serum NTx, and the urine NTx-creatinine ratio—were increased (P Ͻ 0.05) at wk 52 in the cinacalcet group compared with placebo, but remained in the normal range. The urine DPD- creatinine ratio increased in the cinacalcet group, but at wk 52, it was not significantly higher than in the placebo group.
In the placebo group, there was no significant change in any of the biochemical markers of bone turnover during the BMD was measured at baseline and at wk 24 and 52 and expressed as a Z score. In general, few differences in mean change in Z score occurred between the cinacalcet and pla- cebo groups after 24 or 52 wk of treatment. At wk 24, the mean change in Z score at the lumbar spine was significantly lower in the cinacalcet group compared with the placebo group (P Ͻ 0.05) (Table 2); however, no difference between groups was observed at wk 52. No other significant differ- ences for the lumbar spine, total femur, or 1/3 distal radius J Clin Endocrinol Metab, January 2005, 90(1):135–141 Peacock et al. • Cinacalcet for Primary Hyperparathyroidism FIG. 1. Comparison of predose serumcalcium concentrations in patients re-ceiving cinacalcet or placebo. The nor-mal serum calcium concentration range(8.4 –10.3 mg/dl) is indicated by theshaded area. Patients receiving cinacal-cet experienced a significant reductionin serum calcium compared with pa-tients 0.001). BL, Baseline value. Data arepresented as mean Ϯ SE.
at wk 24 or 52 were observed between treatment groups lyzed separately for these patients, the data were not differ- ent from the treatment groups as a whole (data not shown).
Nine patients in each treatment group (23% of the study Cinacalcet was well tolerated in this study, and occurrence population) had previously undergone unsuccessful para- of adverse events was similar between treatment groups. The thyroidectomy. Seven of these patients in the cinacalcet two most common adverse events were nausea (28% cina- group normalized their serum calcium and achieved the calcet, 16% placebo) and headache (23% cinacalcet, 41% pla- primary outcome, compared with one patient in the placebo cebo). Similar numbers of patients in each group withdrew group. In the cinacalcet group, mean serum calcium de- from the study because of adverse events (eight cinacalcet, creased from 10.8 mg/dl (2.70 mmol/liter) at baseline to 9.5 six placebo). Three of these patients from the cinacalcet group mg/dl (2.38 mmol/liter) at wk 52. In placebo-treated patients experienced serum calcium levels less than 8.0 mg/dl (2.00 who had previous parathyroidectomy, serum calcium re- mmol/liter) while receiving the lowest dose of study drug mained at baseline levels [11.1 mg/dl (2.78 mmol/liter)] and, in accordance with the study protocol, were withdrawn throughout the study. PTH levels decreased by 10.5% in from the study. Two cinacalcet-treated patients experienced cinacalcet-treated patients with a previous parathyroidec- mild paresthesias that were considered treatment related.
tomy and increased 3.1% in placebo-treated patients with Serum calcium values were 7.9 mg/dl (1.98 mmol/liter) in previous parathyroidectomy. When BMD data were ana- the three patients who withdrew because of asymptomatic FIG. 2. Comparison of percent changeof predose plasma PTH concentrationsin patients receiving cinacalcet or pla-cebo. Patients receiving cinacalcet ex-perienced a 7.6% reduction in plasmaPTH compared with a 7.7% increase inthe placebo group (P Ͻ 0.01) duringthe maintenance phase. BL, Baselinevalue. Data are presented as mean Ϯ SE.
Peacock et al. • Cinacalcet for Primary Hyperparathyroidism J Clin Endocrinol Metab, January 2005, 90(1):135–141 ous short-term study (15 d plus a 7-d follow-up) that showedcinacalcet is effective in reducing serum calcium in patientswith primary HPT (8). During the maintenance phase, 73%of cinacalcet-treated patients achieved normocalcemia witha decrease of at least 0.5 mg/ml (0.12 mmol/liter) frombaseline, whereas only 5% of placebo-treated patientsachieved this target. The proportion increased to 88% in thecinacalcet group compared with 5% in the placebo groupwhen serum calcium values for patients who withdrew be-fore the maintenance phase were included. In 90% of pa-tients, the lowest dose of cinacalcet, 30 mg twice daily, wassufficient to induce normocalcemia, and no patients requiredtitration to the maximum permitted dose of 50 mg twicedaily.
During the maintenance phase, predose plasma PTH con- centrations were reduced by approximately 8% with cina-calcet treatment. It should be noted that this value, whichreflects hormone concentration before the morning dose ofcinacalcet, underestimates PTH reduction over 24 h. At wk24, pharmacodynamic data demonstrated that plasma PTHconcentration 2 h after dosing decreased into the normalrange (Fig. 3B), corresponding to a 60% reduction from base-line. Assuming that the decrease in PTH after the eveningdose was similar to that after the morning dose, the areaunder the curve indicates that there was an approximately20% reduction in plasma PTH over each 24-h cycle. Further-more, there was no indication from the pharmacodynamicdata that this response changed with length of time on drug.
FIG. 3. Response to cinacalcet or placebo before (0), and at 2, 4, and In contrast to the cyclic change seen in PTH, serum calcium 8 h after the morning dose for serum calcium (A) and plasma PTH (B).
remained unchanged over the 8-h sampling period after the Data were collected at wk 24. The normal ranges for serum calcium(8.4 –10.3 mg/dl) and plasma PTH (10 – 65 pg/ml) are indicated by the morning dose of cinacalcet. These serum calcium results shaded areas. BL, Baseline value. Data are presented as mean Ϯ SE.
indicate that once steady state has been achieved, no sharpdeclines in serum calcium occur after individual doses; thus hypocalcemia and 7.8 mg/dl (1.95 mmol/liter) and 8.1 the risk of acute hypocalcemia and accompanying symptoms mg/dl (2.02 mmol/liter) in the patients who experienced appears to be avoided with twice-daily dosing with cinacal- Drugs to manage the hypercalcemia of primary HPT, such Discussion
as estrogens, selective estrogen receptor modulators, and In this study, cinacalcet administered twice daily rapidly bisphosphonates, have shown a limited ability to treat the normalized predose serum calcium in the majority of pa- disorder (11–14). These agents act primarily by inhibiting tients and caused modest reductions in predose PTH con- bone resorption, although their effects on serum calcium are centrations in patients with mild to moderate primary HPT.
relatively small. Cinacalcet treatment was highly effective in The effect of cinacalcet was sustained over 52 wk with no reducing serum calcium levels in this study, and suppression evidence of fluctuations in serum calcium concentration after was maintained during 1 yr of treatment, suggesting that individual doses once steady state had been established.
cinacalcet may be an important therapeutic agent for man- These results confirm and extend the findings of our previ- aging primary HPT, particularly when parathyroidectomy isnot a viable option. Indeed, nine patients in each group (23% TABLE 2. Mean change in Z score from baseline at wk 24 and 52
of the study population) had previously undergone unsuc-cessful parathyroidectomy. Seven of these patients in the cinacalcet group normalized their serum calcium and achieved the primary outcome, compared with one patient in the placebo group. Although this study did not include patients with severe primary HPT or parathyroid carcinoma, our preliminary reports indicate that cinacalcet may also successfully reduce serum calcium in these patients (15, 16).
In addition to normalizing serum calcium, cinacalcet treat- ment increased serum phosphorus. By wk 12, serum phos-phorus levels and tubular reabsorption of phosphorus had increased, and the fasting urine calcium-creatinine ratio and ϭ 0.023 for change in cinacalcet compared with change in tubular reabsorption of calcium had decreased in the cina- J Clin Endocrinol Metab, January 2005, 90(1):135–141 Peacock et al. • Cinacalcet for Primary Hyperparathyroidism calcet group, probably reflecting the renal effect of the overall wise asymptomatic mild hypercalcemia, and what the choice decrease in plasma PTH over a 24-h cycle of dosing. The of such therapy should be, require additional study before a observation that serum calcium and tubular reabsorption of change from the current management of watchful waiting calcium were normal while predose PTH levels remained elevated suggests that cinacalcet, in addition to its effects on In conclusion, in these patients with primary HPT, cina- PTH secretion, also alters the relationship between PTH and calcet was highly effective in normalizing serum calcium its action on tubular calcium reabsorption. In kidney, this levels and reducing PTH, and this effect was maintained over could be through a shift in the dose-response curve of PTH long-term administration. The drug was well tolerated and on tubular calcium reabsorption and/or by a direct effect of may provide a valuable and effective management option for cinacalcet on the CaR in the renal tubule. The decrease in fasting urine calcium excretion was not accompanied by acorresponding significant decrease in 24-h calcium excretion.
Acknowledgments
Because 24-h urine calcium has a component from intestinalabsorption of calcium, this lack of decrease is consistent with Received May 7, 2004. Accepted October 25, 2004.
the finding that the predose serum 1,25-dihydroxyvitamin D Address all correspondence and requests for reprints to: Munro Pea- levels were not altered by cinacalcet.
cock, M.D., Director, General Clinical Research Center, University Hos- Bone turnover may be increased in primary HPT. In our pital, 550 University Boulevard, UH5595, Indianapolis, Indiana 46202.
HPT patients, the biochemical markers of bone turnover for This study was sponsored by Amgen Inc.
the group were in the normal range at baseline, reflecting the The following primary investigators also participated in the 990120 relative mildness of the disease. After treatment, some bone Study: M. Block (Phoenix, AZ), M. Bolognese (Bethesda, MD), B. Esayag- turnover markers significantly increased in the cinacalcet Tendler (Farmington, CT), A. Firek (Loma Linda, CT), W. Greth (West group, although the mean value remained in the normal Reading, PA), H. Katzeff (New Hyde Park, NY), M. Kipnes (San Antonio, range. The increase in bone turnover markers is of interest TX), R. Lang (Hamden, CT), R. Levy (Olympia, WA), R. Marcus (PaloAlto, CA), R. Rude (Los Angeles, CA), S. Scumpia (Austin, TX), S.
because it occurred in conjunction with an overall decrease Silverman (Beverly Hills, CA), F. Singer (Santa Monica, CA), R. Small- of approximately 20% in plasma PTH levels. A possible ex- ridge (Jacksonville, FL), J. Tucci (Providence, RI), and S. Wallach (New planation is the effect of daily fluctuating plasma PTH levels on bone turnover induced by the twice-daily dosing of ci-nacalcet, because it is known that daily injected PTH (1–34) References
has a stimulatory effect on bone turnover (17). A direct effect 1. Bilezikian JP, Potts Jr JT, Fuleihan G-H, Kleerekoper M, Neer R, Peacock M,
of cinacalcet on bone turnover cannot be excluded, however, Rastad J, Silverberg SJ, Udelsman R, Wells SA 2002 Summary statement from
and additional studies will be needed in this area.
a workshop on asymptomatic primary hyperparathyroidism: a perspective for In our patients, spine BMD was normal, but hip and fore- the 21st century. J Bone Miner Res 17:N2–N11 2. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH 1995 Clinical man-
arm BMDs were in the osteopenic range, as expected in ifestations of primary hyperparathyroidism before and after parathyroidec- patients with this degree of primary hyperparathyroidism.
tomy. A case-control study. Ann Surg 222:402– 412 Over the 52 wk of the study, no clinically significant differ- 3. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A,
Hediger MA, Lytton J, Hebert SC 1993 Cloning and characterization of an
ences in change in BMD were observed between the cina- extracellular Ca(2ϩ)-sensing receptor from bovine parathyroid. Nature 366: 4. Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC,
Cinacalcet was well tolerated in this study. Occurrences of DelMar EG, Balandrin MF 1998 Calcimimetics with potent and selective
adverse events and treatment-related adverse events were sim- activity on the parathyroid calcium receptor. Proc Natl Acad Sci USA 95: ilar between the placebo and cinacalcet groups. Adverse events 5. Nemeth EF, Fox J 1999 Calcimimetic compounds: a direct approach to con-
reported during the study were generally mild or moderate and trolling plasma levels of parathyroid hormone in hyperparathyroidism.
resulted in only a small number of withdrawals.
The comparative utility and cost-benefit between cinacal- 6. Lindberg JS, Moe SM, Goodman WG, Coburn JW, Sprague SM, Liu W,
Blaisdell PW, Brenner RM, Turner SA, Martin KJ 2003 The calcimimetic AMG
cet and parathyroidectomy as treatment modalities for pri- 073 reduces parathyroid hormone and calcium x phosphorus in secondary mary HPT have yet to be established. Although parathy- hyperparathyroidism. Kidney Int 63:248 –254 7. Quarles LD, Sherrard DJ, Adler S, Rosansky SJ, McCary LC, Liu W, Turner
roidectomy is usually curative and reverses abnormal SA, Bushinsky DA 2003 The calcimimetic AMG 073 as a potential treatment
biochemistry and symptoms, there is a pressing need for for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Neph- medical therapy to normalize serum calcium in patients who 8. Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M
have either a contraindication to or have failed parathyroid- 2003 The calcimimetic cinacalcet normalizes serum calcium in subjects with ectomy. Disease severity in this study ranged from symp- primary hyperparathyroidism. J Clin Endocrinol Metab 88:5644 –5649 tomatic, with 18 of the 79 patients having previously had a 9. Cockcroft DW, Gault MH 1976 Prediction of creatinine clearance from serum
failed parathyroidectomy, to asymptomatic. In patients who 10. Peacock M 2002 Primary hyperparathyroidism and the kidney: biochemical
had symptoms, had a failed parathyroidectomy, or who were and clinical spectrum. J Bone Miner Res 17:N87–N94 11. Selby PL, Peacock M 1996 Ethinyl estradiol and norethindrone in the treat-
apparently asymptomatic, cinacalcet was equally effective in ment of primary hyperparathyroidism in postmenopausal women. N Engl normalizing serum calcium. Although mild primary HPT with no apparent symptoms is currently managed by regular 12. Rubin MR, Lee KH, McMahon DJ, Silverberg SJ 2003 Raloxifene lowers
serum calcium and markers of bone turnover in postmenopausal women with medical follow-up, i.e. watchful waiting, the long-term ef- primary hyperparathyroidism. J Clin Endocrinol Metab 88:1174 –1178 fects of mild hyperparathyroidism (18, 19) and hypercalce- 13. Reasner CA, Stone MD, Hosking DJ, Ballah A, Mundy GR 1993 Acute
mia (20) on increasing premature cardiovascular death is of changes in calcium homeostasis during treatment of primary hyperparathy-roidism with risedronate. J Clin Endocrinol Metab 77:1067–1071 concern. Whether therapy should be considered for other- 14. Chow CC, Chan WB, Li JK, Chan NN, Chan MH, Ko GT, Lo KW, Cockram
Peacock et al. • Cinacalcet for Primary Hyperparathyroidism J Clin Endocrinol Metab, January 2005, 90(1):135–141 CS 2003 Oral alendronate increases bone mineral density in postmenopausal
2001 Effect of parathyroid hormone (1–34) on fractures and bone mineral women with primary hyperparathyroidism. J Clin Endocrinol Metab 88:581– density in postmenopausal women with osteoporosis. N Engl J Med 334:1434 – 15. Peacock M 2002 Normalization of hypercalcemia with calcimimetic AMG 073
18. Lundgren E, Lind L, Palmer M, Jakobsson S, Ljunghall S, Rastad J 2001
in a patient with metastatic parathyroid cancer. J Bone Miner Res 17:S381 Increased cardiovascular mortality and normalized serum calcium in patients 16. Silverberg SJ, Faiman JP, Bilezikian JP, Shoback DM, Rubin MR, McCary
with mild hypercalcemia followed up for 25 years. Surgery 130:978 –985 LC, Olson KA, Turner SA, Peacock M 2003 The effects of cinacalcet HCl (AMG
19. Nilsson IL, Yin L, Lundgren E, Rastad J, Ekbom A 2002 Clinical presen-
073) on serum calcium levels in patients with parathyroid carcinoma or re- tation of primary hyperparathyroidism in Europe–nationwide cohort anal- current primary hyperparathyroidism after parathyroidectomy. J Bone Miner ysis on mortality from nonmalignant causes. J Bone Miner Res 17(Suppl 17. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY,
20. Leifsson BG, Ahren B 1996 Serum calcium and survival in a large health
Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH
screening program. J Clin Endocrinol Metab 81:2149 –2153 JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.

Source: http://www.imperialendo.co.uk/cinacalcet2005.pdf