Pediatric hypoparathyroidism is an orphan disease with a prevalence in the United States and Europe ranging between 23 and 37 per 100,000 individuals (1). The association of hypocalcemia with an inappropriately low (or low-normal) PTH and hyperphosphatemia leads to the diagnosis (2). In children, etiologies of hypoparathyroidism are mostly genetic disorders which can be divided into three main categories: (1) disorders of parathyroid development, (2) disorders of parathyroid function, and (3) acquired parathyroid dysfunction (Table 1).

The conventional management combines native vitamin D supplementation, active vitamin D analogs, and sometimes calcium supplementation. The aim of the management is to reach calcium levels within the lower normal range so as to avoid clinical signs and/or complications of hypocalcemia. It is crucial to avoid “over-treating” these patients by fully correcting calcium levels, the risk being to induce nephrolithiasis and/or nephrocalcinosis on the long-term because of hypercalciuria (2). Therefore, this management is a daily challenge for physicians mainly because of the control of hypocalcemia that can be difficult, and because of bad compliance. Furthermore, hyperphosphatemia increases morbi-mortality and should also be considered to avoid long-term consequences of hyperphosphatemia, and notably vascular calcifications and cardio-vascular comorbidities (3). The potential long-term cardiovascular consequences explain why phosphate binders are sometimes proposed to patients with hypoparathyroidism (2).

Ideally, the treatment of hypoparathyroidism replaces the absence or insufficiency of PTH. Such a treatment, namely recombinant human PTH, rhPTH (1–34) or teriparatide, has been first developed and approved in adults with osteoporotic fractures (4). It has also been used off-label as investigational physiologic replacement therapy in Europe and USA to treat adults with hypoparathyroidism who cannot be controlled by standard therapy (5). Synthetic and recombinant PTH 1–34 have been reported rather with daily or bi-daily subcutaneous administrations; moreover it was also reported using continuous subcutaneous infusion in adults first and then in children with hypoparathyroidism (6–16). In 2008, a randomized controlled study including 14 children with hypoparathyroidism has demonstrated that teriparatide is a safe and effective alternative to calcitriol therapy, being able to maintain normal serum calcium levels without hypercalciuria.

We aimed to retrospectively report our experience of bi-daily sub-cutaneous teriparatide in 10 children having received teriparatide as a second-line therapy for hypoparathyroidism. We hypothesized that twice-daily teriparatide therapy improves calcium and phosphate control.

This retrospective observational study showed intermittent bi-daily sub-cutaneous teriparatide therapy (1) allows a better control of calcium levels, without any changes in urinary calcium, (2) significant decreases phosphate levels that may have crucial long-term consequences for improving the cardiovascular risk of these children with a life-long chronic disease, and (3) is safe and effective with a better compliance (as compared to conventional therapy).

Pharmacokinetic analyses performed in osteoporotic women showed that daily subcutaneous injection of teriparatide 20 μg increased serum calcium levels with a maximal effect observed 4 h after the administration (23). In our study, we did not observe “hypercalcemia” at H4 but the increase between H0 and H4 was significant at all time points. Indeed, our management with teriparatide aims to obtain calcium levels in the “safety” area just below or within the lower normal range (“the lower the better”), and to decrease as much as possible fasting calcium levels without clinical symptoms of hypocalcemia, so as to avoid hypercalciuria and subsequent long-term side effects such as nephrocalcinosis.

We show that teriparatide maintained adequate calcium levels in the low-normal range or just below the normal range, with a significant increase 4 h after injection. However, five children required the reintroduction of low doses of vitamin D analogs during the evening to stabilize fasting calcium levels to maintain 25-D levels between 75 and 120 nmol/L, and supplementation was modified accordingly.

In pediatrics, data are scarce on the use of teriparatide, as summarized in Table 5 (6–15). Renal function remained stable, similarly to previous papers reporting no direct effects of teriparatide on neither renal function nor urinary calcium (6–8, 10, 11, 13–15). The effects of teriparatide on calciuria and subsequent nephrocalcinosis/lithiasis remain nevertheless likely on the long-term, at least theoretically, consistent with what is observed with conventional therapy. A long-term study treating 14 children with twice or thrice-daily subcutaneous teriparatide injections showed less hypercalciuria after teriparatide introduction. However, nephrocalcinosis worsened in 5 patients out of 14 subjects whilst renal function remained normal (14). Computed tomography and ultrasound were used to visualize renal calcifications which also added to the lack of precision in follow-up results. One of the patients in this cohort had a regression of nephrocalcinosis according to follow-up ultrasound results (14). This progression observed in these patients was probably caused both by the cumulative effects of intravenous calcium administration required in case of acute symptomatic hypocalcemia, the unphysiological nature of intermittent PTH replacement by multiple daily injections, the genetic background, notably in case of CaSR mutations with hypocalcemia associated with hypercalciuria and the progression of the disease. In 2015, Levy et al. (24) reported that children with hypoparathyroidism treated with calcitriol and calcium supplements were at risk for nephrocalcinosis (38%; mean follow-up 7.4 years). It is nevertheless difficult to know whether nephrocalcinosis would have also worsened with conventional therapy, even though this is very likely. Moreover, one should not forget that the evaluation of nephrocalcinosis on renal ultrasounds, although inexpensive and harmless for the patient, can be operator-dependent and can only be “semi-quantitative” at best. In our series, moderate nephrocalcinosis appeared in two patients (without pre-therapeutic renal ultrasound). Among children with pre-existing nephrocalcinosis, one worsened from stage 1 to 2, while the other one remained stable.

Phosphate is a vascular toxin and is often seen as a “silent killer” because of its dramatic effect on vascular calcifications and mortality, in general but also in CKD populations (23) and hypoparathyroidism patients (25). When vessels are exposed in vitro to high phosphate levels conditions, extensive calcification with hydroxyapatite deposition develop (26). In the present study, we demonstrated that phosphate levels significantly decreased with teriparatide therapy; as such, we hypothesize beneficial long-term effects on the development of ectopic calcifications in these patients (27). Hyperphosphatemia could be explained notably because of the phosphate overload in western diets that is mainly due to the phosphate “hidden” in food additives. When hyperphosphatemia is secondary to hypoparathyroidism, FGF23 levels usually increase to try to inhibit tubular phosphate reabsorption (28), as also illustrated there with increased FGF23 levels (that may also have been increased by active vitamin D analogs). High FGF23 levels are associated per se with left ventricular hypertrophy and increased morbi-mortality, because of a direct toxic effect of FGF23 on cardiomyocytes (28). Here, FGF23 levels did not change overtime, however FGF23 SDS was increased at baseline and we observed a (expected) trend toward a reduction in FGF23 levels under teriparatide.

In 2015, Gafni et al. (12) evaluated the effects of recombinant PTH on bone markers in nine teenagers and adults with hypoparathyroidism. Here, we report similar results, namely increased osteocalcin levels, with no modification of BMD. In growing rat models, rhPTH can induce bone tumors, such as osteoma, osteoblastoma, and osteosarcoma in a dose-dependent manner when high doses were used (29). Important to note, these doses were 3–71-time higher than the doses used in humans, and the exposition to the product was far longer. As such, it is difficult to transfer these data from rats to humans not only because of the differences in doses but also because of the differences in skeletal physiology between the species (29). We nevertheless believe that parents and caregivers must be aware of the “off-label” use of this drug in pediatrics, with a close follow-up and a special warning in case of bone pain.

Two recombinant human PTH are available, i.e., the 1–84 approved in the USA in 2015, and the 1–34 teriparatide evaluated here (30). These two compounds have a reported acceptable tolerability. Ageusia and oral hypoesthesia have been reported after rPTH 1-84 (31), but never to date with teriparatide. However, one teenager displayed ageusia that disappeared when teriparatide doses were decreased.

Despite the fact that we were unable to scientifically assess compliance and quality of life (QOL) of these children in this retrospective series of cases, seven were non-compliant at teriparatide initiation, and after teriparatide initiation, only one teenager still displayed a poor compliance, because of a very poor socio-familial support. Moreover, the majority of patients reported an improved quality of life with teriparatide therapy, explaining that fatigue significantly decreased with the disappearance of muscular symptoms. Of note, when we told the teenager with ageusia that it could be treatment-related, he did not accept to withdraw teriparatide, only to decrease the doses. Unfortunately, we unfortunately did not assess compliance and QOL using dedicated scales, and these points obviously deserve other studies.

Only two studies reported the use of teriparatide with a continuous sub-cutaneous pump (10, 13), as opposed to what is presented here. Although bi-daily sub-cutaneous administration of teriparatide represents a safe and effective long-term therapy for children, it has been discussed and hypothesized that the use of a continuous pump could be better, and more physiological, as illustrated in Table 5 (8, 10, 13). In 2014, Winer et al. have compared bi-daily administration to continuous pump delivery in a prospective cross-over trial. They concluded that the continuous administration was more physiological both from a calcium homeostasis and bone turnover point of view, with lower daily doses of teriparatide (10). Seven basal rates and seven bolus options were programmed to mimic homeostatic circulating PTH. However, for reasons of technical feasibility, mimicking circadian PTH secretion failed and hyperphosphatemia was observed during the continuous pump administration, as opposed to the bi-daily sub-cutaneous administration. In animal models, intermittent and continuous PTH increase bone formation independently of effects on bone resorption, but only intermittent PTH increases bone mass consistently (32). In children, osteocalcin, alkaline phosphatase and NTX-telopeptide decreased significantly after teriparatide pump treatment (10).

This study has some limitations, and notably the small number of patients. However, we are in the field of orphan diseases in pediatrics, with an off-label use of novel therapies.

In conclusion, our observational data suggest that teriparatide in pediatric hypoparathyroidism can be a useful tool to correct calcium but also phosphate levels, without major side effects. Even though national guidelines already propose this management as a second-line off-label therapy in these children, notably in France, larger international studies may evaluate its long-term consequences especially for the potential risk of hypercalciuria and nephrocalcinosis later in life, and its interest to improve the quality of life of these children with life-long chronic diseases.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Local Ethical Committee (Comité d'Ethique des Hospices Civils de Lyon, session 27/06/2019, approval 19-84), and declared to the Information Technology and Liberty Commission (n°19-168). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

JBe and SF have written the manuscript. SC, SL, RC, AM, and AB-T have read and corrected the manuscript. All authors contributed to the article and approved the submitted version.

JBe received an educational grant from the ORKiD (Orphan Kidney Diseases Filière Maladies Rares) Network.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.