2025 Volume 72 Issue 11 Pages 1197-1204
Patients with primary hyperparathyroidism (PHPT) ineligible for surgery require medical management for hypercalcemia and osteoporosis. The aim of this retrospective study was to determine the long-term effects of evocalcet on serum corrected calcium (cCa) levels and bone mineral density (BMD) in PHPT. The study included 26 patients with PHPT and hypercalcemia treated with evocalcet (7 switched from cinacalcet) for at least 24 months. Their mean age was 75.5 years. At baseline, cCa, phosphorus, and median intact parathyroid hormone levels were 10.76 mg/dL, 2.91 mg/dL, and 99.0 pg/mL, respectively. Osteoporosis was observed in 18 (69%), and 16 (62%) patients were on treatment for osteoporosis. Twenty-four months of evocalcet treatment significantly decreased cCa level to 9.77 mg/dL (mean change: –0.98 ± 0.91 mg/dL). Patients who switched from cinacalcet had a smaller reduction in cCa levels (–0.31 ± 0.72 mg/dL) than did those who were evocalcet-naïve (–1.23 ± 0.87 mg/dL, p = 0.019). By 24 months, 84.6% of patients had achieved a cCa level ≤10.3 mg/dL. Multivariate analysis identified baseline calcium levels as determinants of calcium level changes at 24 months. For patients not receiving osteoporosis treatment, lumbar spine BMD remained largely unchanged, whereas femoral neck BMD showed a decreasing trend. No other serious side effects requiring dose-lowering or withdrawal were noted. Evocalcet maintained its calcium-lowering effect for over 24 months in patients with PHPT, suggesting its potential as a medical treatment for surgery-ineligible patients. Careful monitoring of BMD is necessary during long-term evocalcet treatment to prevent worsening of osteoporosis.
Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH), which leads to hypercalcemia and hypophosphatemia. PHPT is commonly observed in older adults and postmenopausal women and is primarily caused by parathyroid adenomas. However, in rare cases, PHPT may be associated with parathyroid hyperplasia, parathyroid carcinoma, or genetic abnormalities, such as multiple endocrine neoplasia (MEN) syndrome. The hallmark of PHPT is its significant impact on the skeletal system and kidneys, often resulting in fragility fractures and recurrent nephrolithiasis [1, 2].
Surgical removal of parathyroid tumor is the first-line treatment for PHPT, as it is expected to normalize serum calcium (Ca) and PTH levels [3]. However, in clinical practice, some patients are ineligible for surgery for various reasons, necessitating medical management of hypercalcemia. In Japan, the calcimimetic agent cinacalcet was approved in 2014 for the treatment of hypercalcemia in patients with parathyroid carcinoma and inoperable PHPT [4]. Cinacalcet enhances Ca-sensing receptor (CaSR) activation and suppresses PTH secretion, effectively lowering serum Ca levels [5]. In cases of benign PHPT, relatively low doses of cinacalcet are sufficient to normalize serum Ca levels [6]. Despite its effectiveness, cinacalcet is associated with a high incidence of gastrointestinal adverse effects, such as nausea and vomiting [7], which can limit its clinical utility. Evocalcet is a newly developed calcimimetic agent introduced recently in Japan and it is reported to significantly reduce serum Ca levels in patients with PHPT [8, 9]. The effectiveness of evocalcet in suppressing PTH levels in secondary hyperparathyroidism has also been demonstrated to be equivalent to that of cinacalcet, with the additional advantage of causing fewer gastrointestinal side effects [10]. However, there is little clinical information, especially long-term data, on the effectiveness and safety of evocalcet in patients with PHPT.
This study was designed to clarify the long-term effectiveness of evocalcet on serum Ca levels in patients with PHPT as the primary endpoint, and the secondary endpoints were safety and the effects of background factors.
This retrospective study included all patients diagnosed with PHPT who were treated with evocalcet at either the Hospital of the University of Occupational and Environmental Health, Japan, or its affiliated Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan, between May 2020 and May 2022. Patients were eligible for the study if they had received evocalcet for at least 24 months. We excluded patients with secondary hyperparathyroidism or severe liver dysfunction (defined as transaminase levels more than three times the upper limit of normal).
The study was approved by the Institutional Ethics Review Committee (approval #UOEHCRB21-105). Informed consent was obtained from all the patients, and the study was conducted in accordance with the principles of the Declaration of Helsinki.
Biochemical and clinical measurementsThe medical records of the study patients were reviewed for the following data recorded on admission: age, sex, height, body weight, body mass index, arterial blood pressure, and presence or absence of vertebral fractures. In all patients, blood samples were collected during hospital stay and at follow-up to measure serum albumin, Ca, phosphorus, creatinine, and estimated glomerular filtration rate (eGFR). Furthermore, serum intact PTH levels were measured using an electrochemiluminescence immunoassay method (BML Inc., Tokyo, Japan). Bone mineral density (BMD) was measured at baseline and end of 24-month treatment period in the lumbar spine and femoral neck using a Dual-energy X-ray absorptiometry device (Delphi Discovery W; Hologic, Bedford, MA). Furthermore, vertebral fractures, if any, were identified using thoracolumbar spinal radiography. In this study, osteoporosis was diagnosed in patients who were receiving osteoporosis treatment, or based on the Japanese diagnostic criteria [11] as follows: For patients with a fragility fracture, osteoporosis was diagnosed if the lumbar spine or proximal femur, or other typical sites (such as the rib, pelvis—including the pubis, ischium, and sacrum—proximal humerus, distal radius, or tibia) were fractured and the BMD was below 80% than that of the young adult mean (YAM). In the absence of a fragility fracture, osteoporosis was diagnosed if the BMD was ≤70% of the YAM or within –2.5 standard deviations (SD).
Statistical analysisContinuous variables are presented as mean ± SD or median (interquartile range, IQR), and categorical variables as numbers or (%). Categorical variables were analyzed using the χ2 test. Depending on the data distribution pattern, continuous variables were compared between groups using either the Student’s t-test or the Wilcoxon rank-sum test. Within-group changes over time were evaluated using the paired t-test or Wilcoxon signed-rank test. Differences in biochemical parameters, including Ca levels, after evocalcet administration were analyzed using repeated-measures analysis of variance with the Bonferroni correction. The proportion of patients achieving serum Ca ≤10.3 mg/dL at baseline, 12 months, and 24 months was compared using McNemar’s test. Univariate and multivariate linear regression analyses were conducted to assess those factors associated with changes in Ca levels after 24 months of evocalcet treatment. Variables with p < 0.05 in the univariate regression analysis and prior cinacalcet use were included in the multivariate analysis. Missing data were imputed using the last observation carried forward method. All statistical analyses were performed using SPSS version 29.0 (SPSS Corp., Armonk, NY). Statistical significance was set at p < 0.05.
Twenty-six patients with PHPT were enrolled in this study, and their baseline characteristics are summarized in Table 1. The mean age was 75.5 years, and 76.9% of patients were females. The baseline serum cCa and phosphorus levels were 10.76 ± 0.90 and 2.91 ± 0.51 mg/dL, respectively. The median intact PTH level was 99.0 pg/mL (IQR: 52.3–189.3 pg/mL). Osteoporosis was present in 69.2% (n = 18) of the patients, and 50% (n = 13) had a history of vertebral fractures. Osteoporosis was being treated in 61.5% (n = 16) of the patients, with either bisphosphonates (n = 8), selective estrogen receptor modulators (n = 1), or denosumab (n = 7). Prior cinacalcet use was noted in 26.9% of the patients (n = 7). Notably, 96.2% of the patients had non-localized parathyroid tumors on ultrasonography and technetium-99m methoxy isobutyl isonitrile scintigraphy, making surgery unfeasible. Parathyroidectomy recurrence was observed in 3.8% of the cases.
| Females [n (%)] | 20 (76.9) |
| Age (years) | 75.5 ± 8.2 |
| Body weight (kg) | 53.5 ± 10.5 |
| Body mass index (kg/m2) | 23.0 ± 3.9 |
| Aspartate transaminase (IU/L) | 23.9 ± 7.3 |
| Alanine transaminase (IU/L) | 19.1 ± 7.6 |
| Creatinine (mg/dL) | 0.78 (0.67–0.88) |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 56.1 ± 17.7 |
| Corrected calcium (mg/dL) | 10.76 ± 0.90 |
| inorganic phosphorus (mg/dL) | 2.91 ± 0.51 |
| Intact parathyroid hormone (pg/mL) | 99.0 (52.3–189.3) |
| L1-4 bone mineral density (g/cm2) | 0.817 ± 0.207 |
| L1-4 bone mineral density (T-score) | –1.76 ± 1.96 |
| L1-4 bone mineral density (Z-score) | 0.63 ± 1.59 |
| Femoral neck bone mineral density (g/cm2) | 0.540 ± 0.141 |
| Femoral neck bone mineral density (T-score) | –2.33 ± 1.37 |
| Femoral neck bone mineral density (Z-score) | –0.50 ± 1.29 |
| Osteoporosis [n (%)] | 18 (69.2) |
| Vertebral fractures [n (%)] | 13 (50) |
| Treatment for Osteoporosis [n (%)] | 16 (61.5) |
| Primary disease [n (%)] | |
| Parathyroid carcinoma | 0 (0.0) |
| Unable to undergo parathyroidectomy | 25 (96.2) |
| Relapse after parathyroidectomy | 1 (3.8) |
| Prior cinacalcet use [n (%)] | 7 (26.9) |
Data are mean ± standard deviation, or n (%).
Fig. 1 illustrates the changes in serum cCa throughout the 24-month evocalcet treatment. Significant and gradual falls in serum cCa levels were observed, from 10.76 ± 0.90 at baseline to 10.05 ± 0.56, 9.98 ± 0.65, 9.91 ± 0.74, and 9.77 ± 0.71 mg/dL at 6, 12, 18, and 24 months, respectively (all p < 0.01, compared to baseline). The mean cCa reduction at 24 months was –0.98 ± 0.91 mg/dL. Patients who switched from cinacalcet (n = 7) showed a smaller calcium reduction (–0.31 ± 0.72 mg/dL) compared to those without prior cinacalcet use (–1.23 ± 0.87 mg/dL, p = 0.019, n = 19). The proportion of patients achieving serum calcium ≤10.3 mg/dL (Fig. 2) increased from 34.6% at baseline to 73.1% and 84.6% at 12 and 24 months, respectively (both p < 0.01 vs. baseline).
Data are mean ± SD. *p < 0.05, **p < 0.01 by repeated measures analysis of variance with Bonferroni correction.
**p < 0.01, by McNemar’s test.
Table 2 summarizes the effects of evocalcet treatment on various biochemical parameters. Phosphorus levels increased significantly. However, the treatment had no effect on aspartate aminotransferase, but decreased significantly alanine aminotransferase (ALT) levels (p = 0.008), and multiple comparisons using Bonferroni correction showed a significant difference between ALT values at 0 and 12 months (p = 0.009) but not at 24 months (p = 0.926). The treatment resulted in a slight increase in serum creatinine level; although the increase was insignificant. Evocalcet treatment significantly decreased eGFR to 52.46 ± 17.16 mL/min/1.73 m2 at 12 months and showed a declining trend, with values of 50.79 ± 20.02 mL/min/1.73 m2 at 24 months (p = 0.052). The intact PTH levels remained unchanged. BMD of the lumbar spine increased significantly in patients receiving osteoporosis treatment but showed no significant change in osteoporosis-untreated patients. In contrast, BMD of the femoral neck slightly decreased in patients without osteoporosis treatment and slightly increased in those receiving treatment; however, the overall change was not statistically significant.
| 0 month | 12 months | 24 months | p* | |
|---|---|---|---|---|
| Aspartate transaminase (IU/L) | 23.9 ± 7.3 | 21.6 ± 7.0 | 23.2 ± 7.9 | 0.219 |
| Alanine transaminase (IU/L) | 19.1 ± 7.6 | 14.9 ± 5.4 | 17.6 ± 7.8 | 0.008 |
| Creatinine (mg/dL) | 0.78 (0.67–0.88) | 0.87 (0.69–0.97) | 0.86 (0.69–1.06) | 0.077 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 56.09 ± 17.70 | 52.46 ± 17.16 | 50.79 ± 20.02 | 0.008 |
| Corrected calcium (mg/dL) | 10.76 ± 0.90 | 9.98 ± 0.65 | 9.77 ± 0.71 | <0.001 |
| Inorganic phosphorus (mg/dL, n = 24) | 2.90 ± 0.52 | 3.19 ± 0.52 | 3.21 ± 0.60 | 0.005 |
| Intact parathyroid hormone (pg/mL, n = 12) | 148.5 (81.3–210.3) | 130.0 (55.0–209.5) | 122.5 (62.5–187.8) | 0.662 |
| L1-4 bone mineral density (g/cm2) | ||||
| All (n = 21) | 0.806 ± 0.209 | 0.822 ± 0.202 | 0.837 ± 0.208 | 0.042 |
| Treatment for osteoporosis (no, n = 7) | 0.956 ± 0.145 | 0.951 ± 0.112 | 0.952 ± 0.130 | 0.967 |
| Treatment for osteoporosis (yes, n = 14) | 0.731 ± 0.198 | 0.757 ± 0.209 | 0.780 ± 0.220 | 0.004 |
| Femoral neck bone mineral density (g/cm2) | ||||
| All (n = 19) | 0.520 ± 0.138 | 0.512 ± 0.126 | 0.528 ± 0.130 | 0.444 |
| Treatment for osteoporosis (no, n = 7) | 0.632 ± 0.667 | 0.597 ± 0.387 | 0.607 ± 0.387 | 0.236 |
| Treatment for osteoporosis (yes, n = 12) | 0.455 ± 0.128 | 0.462 ± 0.133 | 0.482 ± 0.144 | 0.225 |
| Evocalcet dose (mg) | — | 3.5 ± 2.2 | 4.0 ± 3.9 | — |
Data are mean ± standard deviation, or n (%).
* p-value for comparisons between 0, 12 and 24 months, by repeated measures analysis of variance.
Table 3 presents the results of univariate and multivariate linear regression analyses examining the factors influencing changes in serum Ca levels after 24 months of evocalcet treatment. In the univariate analysis, changes in serum Ca levels after 24-month treatment was significantly and positively associated with baseline eGFR and negatively with baseline values of serum cCa and intact PTH. Multivariate analysis, including these three factors and prior cinacalcet use, identified baseline serum cCa levels as a significant determinant of evocalcet-induced reduction in serum cCa levels.
| Variables | Univariate | Multivariate | ||
|---|---|---|---|---|
| β (95% CI) | p | β (95% CI) | p | |
| eGFR | 0.561 (0.010, 0.042) | 0.003 | 0.309 (0.000, 0.032) | 0.056 |
| cCa | –0.693 (–1.004, –0.391) | <0.001 | –0.547 (–0.915, –0.187) | 0.005 |
| Intact PTH | –0.494 (–0.005, –0.001) | 0.010 | –0.148 (–0.003, 0.001) | 0.362 |
| Prior cinacalcet use | –0.457 (–1.670, –0.164) | 0.019 | –0.064 (–0.836, 0.577) | 0.707 |
Variables with p < 0.05 in the univariate regression analysis and prior cinacalcet use were included in the multivariate analysis.
eGFR, estimated glomerular filtration rate; cCa, corrected calcium; PTH, parathyroid hormone; CI, confidence interval.
Adverse effects were noted in 15.4% of the patients. Mild gastrointestinal symptoms, including nausea (3.8%) and abdominal pain (3.8%), were observed; however, none led to discontinuation. Apart from these gastrointestinal adverse effects, worsening of heart failure was noted in 1 (3.8%) patient and lung cancer in another (3.8%), which were deemed unrelated to evocalcet administration, and treatment was continued.
In this study, we retrospectively examined the long-term (24 months) effects of evocalcet on Ca metabolism in patients with PHPT. Reports on the effectiveness of CaSR agonists in the treatment of hypercalcemia in PHPT are limited. One of the strengths of this study is the long and continuous treatment for 24 months. A previous Phase III trial of evocalcet in Japanese patients [9] demonstrated a significant reduction in serum cCa from 11.73 mg/dL to 9.89 mg/dL over 52 weeks, with 77.8% of patients achieving serum calcium level of ≤10.3 mg/dL. In our study, serum calcium levels decreased significantly to 9.77 ± 0.71 mg/dL at 24 months, with a mean reduction of –0.98 ± 0.91 mg/dL, which was less than that observed in the previous Phase III trial [9]. This may be explained by the relatively low baseline calcium levels and the inclusion of patients previously treated with cinacalcet (26.9%). Patients who were naïve to calcimimetic therapy showed a significantly greater reduction in serum calcium levels (–1.23 ± 0.87 mg/dL) compared to those who switched from cinacalcet (–0.31 ± 0.72 mg/dL). Nevertheless, the proportion of patients who achieved the target serum calcium level of ≤10.3 mg/dL exceeded 80% at 24 months, demonstrating favorable effectiveness, consistent with the previous study [9].
A meta-analysis of cinacalcet [10] reported a greater calcium reduction in patients with baseline Ca levels of >12.0 mg/dL, compared to those with lower levels. To our knowledge, the determinant(s) of calcium reduction by evocalcet remains unclear.
In our study, the results of the multivariate analysis identified high baseline calcium levels as a significant determinant of serum calcium reduction at the end of a 24-week treatment. Hence, more severe baseline hypercalcemia potentially enhances the calcium-lowering effect of evocalcet, which is consistent with previous reports on cinacalcet [10].
Bone involvement is a critical concern in PHPT because it significantly increases the risk of fractures [3, 12]. A characteristic feature of bone lesions in PHPT is the relative preservation of the trabecular bone, compared with decreased volume of cortical bone on percutaneous bone biopsy [13]. This pattern was also observed in our study, in which the lumbar spine BMD Z-score was positive, and the femoral neck BMD Z-score was negative. Few studies have evaluated the effects of calcimimetics on BMD in patients undergoing PHPT. Cinacalcet treatment for up to 5.5 years was reported to have no significant effect on BMD [14]. Another study found that cinacalcet had a neutral effect on BMD and did not interfere with osteoporosis medications [15]. In our study, patients treated for osteoporosis showed significant increase in lumbar spine BMD, whereas no such increase was noted in those who did not receive the treatment. In contrast, patients treated for osteoporosis tended to show increased BMD in the femoral neck, although the increase was not statistically significant, whereas the BMD tended to decrease in patients who did not receive the treatment. These findings suggest that evocalcet alone does not seem sufficient to prevent cortical bone loss, particularly in the femoral neck, which contains a high proportion of cortical bone. Thus, patients with reduced femoral neck BMD may require concomitant treatment for osteoporosis (e.g., bisphosphonates or denosumab).
Renal impairment and nephrolithiasis are major concerns in patients with PHPT. Importantly, a Phase III trial of evocalcet [9] reported no significant change in serum creatinine levels (0.846–0.910 mg/dL) after 52 weeks of treatment. In our study, no new cases of urolithiasis or nephrolithiasis were diagnosed during the evocalcet treatment. The eGFR exhibited a decreasing trend over time; however, the reduction was not statistically significant at 24 weeks. Serum creatinine also exhibited an increasing trend; nonetheless, this was not statistically significant, findings consistent with those of previous studies. Similarly, a study on cinacalcet [15] reported that eGFR and urinary calcium-to-creatinine ratio remained unchanged, suggesting that treatment with calcimimetics does not seem to have a significant adverse effect on renal function.
Currently, both cinacalcet and evocalcet are available for the treatment of PHPT and both have demonstrated strong effectiveness in reducing serum calcium levels. However, key differences exist between the two agents. Cinacalcet is primarily metabolized by cytochrome P450 (CYP)3A4 and strongly inhibits CYP2D6, leading to potential drug interactions with CYP3A4 inducers, inhibitors, and CYP2D6-metabolized drugs [16]. In contrast, evocalcet is not metabolized by CYP enzymes, resulting in a lower risk of drug interactions [17]. Since PHPT often occurs in elderly patients, evocalcet, with its lower potential for drug interactions, may be a safer option, especially for those taking multiple medications. In terms of gastrointestinal tolerability, both drugs cause the same gastrointestinal symptoms; however, Phase III trials showed that evocalcet is associated with a lower rate of gastrointestinal side effects than cinacalcet [4, 9]. Moreover, a head-to-head comparison of secondary hyperparathyroidism reported fewer gastrointestinal symptoms and lower rates of drug discontinuation with evocalcet [18].
Surgery for primary hyperparathyroidism is reported to achieve a biochemical cure, including Ca, in more than 95% of patients and can increase spine and total hip BMD [19]. Therefore, surgery is recommended as the first option in patients with (1) asymptomatic primary hyperparathyroidism, (2) those with serum calcium higher than the upper limit of normal by more than 1 mg/dL, (3) fracture or decreased bone mineral density (T-score –2.5 or less), (4) reduced renal function, kidney stones, or hypercalciuria, or (5) in patients aged <50 years [20]. However, for patients who do not meet the above surgical criteria or are ineligible for surgery, calcimimetic therapy remains an effective alternative. Based on its favorable safety profile and low risk of adverse effects, evocalcet seems to be a promising treatment option for these patients.
This study had several limitations. The retrospective design and the small sample size may limit the generalizability of our findings. However, the previously reported Phase III study of evocalcet also included a small sample size (n = 18) and was of a single-arm design. In addition, the mean baseline serum calcium level in our cohort was below the commonly established threshold for recommending parathyroidectomy (i.e., the reference upper limit + 1 mg/dL), and some patients may not have required calcimimetic therapy based on the general surgical indication criteria for PHPT. This should be considered when interpreting the clinical significance of our findings. We also acknowledge that the interpretation of changes in BMD was limited by the lack of a control group and heterogeneity in the treatment of osteoporosis among the participants. These two factors may have influenced BMD outcomes, hindering a full assessment of the isolated effects of evocalcet on bone metabolism. Despite these limitations, our results provide valuable real-world evidence of the long-term effectiveness and safety of evocalcet in PHPT.
In conclusion, evocalcet effectively lowered serum calcium levels over 24 months, supporting its therapeutic use in patients with PHPT who are ineligible for surgery (Graphical Abstract). Patients on long-term evocalcet therapy who are not treated for osteoporosis should be monitored carefully and treated for any decrease in femoral neck BMD to prevent the worsening of osteoporosis.
The authors declare that they have no competing interests.
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All authors contributed to the study design. K Tanaka, KK, FU, MS and K Torimoto collected the data. K Tanaka and YO analyzed the data. K Tanaka wrote the original draft. K Tanaka, YO and YT revised the manuscript. All authors reviewed the manuscript.
