Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience

Abstract

BackgroundCinacalcet is a calcimimetic approved in adults with primary hyperparathyroidism (PHPT). Few cases reports described its use in pediatric HPT, with challenges related to the risk of hypocalcemia, increased QT interval and drug interactions. In this study, we report the French experience in this setting.MethodsWe retrospectively analyzed data from 18 pediatric patients from 7 tertiary centers who received cinacalcet for PHPT. The results are presented as median (interquartile range).ResultsAt a median age of 10.8 (2.0–14.4) years, 18 patients received cinacalcet for primary HPT (N = 13 inactive CASR mutation, N = 1 CDC73 mutation, N = 1 multiple endocrine neoplasia type 1, N=3 unknown etiology). Cinacalcet was introduced at an estimated glomerular filtration rate (eGFR) of 120 (111–130) mL/min/1.73 m2, plasma calcium of 3.04 (2.96–3.14) mmol/L, plasma phosphate of 1.1 (1.0–1.3) mmol/L, age-standardized (z score) phosphate of −3.0 (−3.5;−1.9), total ALP of 212 (164–245) UI/L, 25-OHD of 37 (20–46) ng/L, age-standardized (z score) ALP of −2.4 (−3.7;−1.4), PTH of 75 (59–123) ng/L corresponding to 1.2 (1.0–2.3)-time the upper limit for normal (ULN). The starting daily dose of cinacalcet was 0.7 (0.6–1.0) mg/kg, with a maximum dose of 1.0 (0.9–1.4) mg/kg per day. With a follow-up of 2.2 (1.3–4.3) years on cinacalcet therapy, PTH and calcium significantly decreased to 37 (34–54) ng/L, corresponding to 0.8 (0.5–0.8) ULN (p = 0.01), and 2.66 (2.55–2.90) mmol/L (p = 0.002), respectively. In contrast, eGFR, 25-OHD, ALP and phosphate and urinary calcium levels remained stable. Nephrocalcinosis was not reported but one patient displayed nephrolithiasis. Cinacalcet was progressively withdrawn in three patients; no side effects were reported.ConclusionsCinacalcet in pediatric HPT can control hypercalcemia and PTH without significant side effects.

Diagnosis and management of mineral and bone disorders in infants with CKD: clinical practice points from the ESPN CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce

“…Cinacalcet was described as giving an efficient control of PTH levels. Despite the fact that overall median calcium levels remained stable, three infants nevertheless developed hypocalcemic episodes < 2.0 mmol/L, of which one child suffered from a hypocalcemia-related convulsion, due to non-adherence to calcium substitution [108]. Interestingly, precocious puberty was reported in two children, as already described in older children [109].…”

Primary Hyperparathyroidism in Young and Adolescents: Alike or Unlike Adult Hyperparathyroidism? - A Series from South India

“…[ 18 ] A French multicenter experience suggested the use of long-term cinacalcet in hypercalcemia identified in these 18 young patients with an average age of 10 years. [ 19 ]…”

Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism

“…A multicenter French study on 18 patients (with a median age of 10.2; range between 2 and 14.4 years) included 13 individuals with primary PHP (10 of them with known genetic PHP-carrying pathogenic variants with respect to the CASR, CDC73, and MEN1 genes). Overall, under a progressively increased dose over a median of 2.2 years, cinacalcet decreased PTH and serum calcium levels, with stable alkaline phosphatase and no significant side effects [18].…”

“…Case reports and series (<10 patients/article) with data concerning genetic profiling in pediatric PHP, according to our methods (the list starts with the most recent publication date) [17,53,61,62,64,65,67]; additional studies (≥10 patients/study) that also include genetic analysis are introduced in Table 2. Data were provided by Sharma [26,46], Szabo Yamashita [27], Bernardor [18], Ramonell [47], Shariq [49], El Allali [50], Sharanappa [28].…”

“…A genetic background is found in 10-30% of juvenile cases, typically involving deletions/duplications or pathogenic variants of the MEN1, which underlines multiple endocrine neoplasia type 1 syndrome (MEN1), CDC73 (also known as HRPT2; its germline pathogenic variant causes hyperparathyroidism (jaw tumor syndrome)), CDKN1B, RET (MEN2), AIP, CDKN1B, and CASR (calcium-sensing receptor) genes, requiring differential diagnosis of familial hypocalciuric hypercalcemia, which might be complicated by severe neonatal PHP with homozygote status [16][17][18][19]. In adults, one out of ten subjects confirmed with PHP has a genetic condition, most commonly MEN1, MEN4, MEN2, hereditary hyperparathyroidism (jaw tumor syndrome), or isolated familial PHP [20][21][22].…”