Teriparatide Therapy in Children with Hypoparathyroidism: A Systematic Review and Meta-Analysis

Abstract

Hypoparathyroidism in children is conventionally treated with calcium and active vitamin D, however, this approach does not restore parathyroid hormone (PTH) action and may leave hyperphosphatemia unresolved while increasing the risk of hypercalciuria. Teriparatide (PTH 1–34) offers a physiologic replacement, although evidence regarding its role in children remains limited. We systematically reviewed biochemical and skeletal effects of teriparatide in children with hypoparathyroidism. MEDLINE and Embase were searched from inception to January 2026, including studies of patients ≤ 21 years treated with teriparatide for ≥ 4 weeks. Outcomes included calcium and phosphate homeostasis, skeletal outcomes, growth, renal complications, and use of concomitant therapy. Data extraction followed Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines by 2 independent reviewers. Meta-analysis using weighted mean differences (WMDs) was performed when feasible. Other outcomes were summarized descriptively. Eighteen studies met the eligibility criteria, and a total of 94 pediatric patients were included. Serum calcium was maintained within target range with teriparatide, with no significant difference compared with conventional therapy (WMD −0.02, 95% CI −0.10 to 0.07). Serum phosphate was lower with teriparatide (WMD −0.28, 95% CI −0.45 to −0.12). Urinary calcium excretion findings were variable, although longer-term studies suggested reductions. Growth and bone mineral density remained within normal ranges. Renal outcomes were heterogeneous. Overall teriparatide maintains serum calcium and may improve phosphate balance in children with hypoparathyroidism. However, given limited and heterogeneous evidence, conventional therapy should remain first-line, with teriparatide considered in selected patients.

Introduction

Hypoparathyroidism is a rare endocrine disorder caused by deficient parathyroid hormone (PTH) secretion, characterized by hypocalcemia and hyperphosphatemia with low or inappropriately normal circulating PTH levels [1]. Clinical manifestations range from no symptoms to life-threatening hypocalcemia [2]. The overall prevalence of hypoparathyroidism is estimated at 22–30 per 100,000 person-years, although pediatric data remain limited [3].

Hypoparathyroidism is most commonly an acquired condition in adults, typically resulting from postsurgical causes. Pediatric hypoparathyroidism, in contrast, has a distinct etiologic distribution, with genetic and autoimmune disorders accounting for the majority of cases, among which DiGeorge syndrome is the most common identifiable etiology [4, 5].

Hypoparathyroidism has traditionally been managed with conventional therapy consisting of calcium supplementation and activated vitamin D [1]. This approach aims to maintain serum calcium in the low-normal range while minimizing symptoms. However, this strategy does not fully address the renal tubular consequences of PTH deficiency and has important limitations [1]. Hypercalciuria is common and is the major complication, increasing the risk of nephrocalcinosis, nephrolithiasis, and progressive renal insufficiency. In addition, hyperphosphatemia is frequently observed due to impaired renal phosphate excretion in the absence of PTH [6, 7].

PTH replacement was first described using bovine parathyroid extract, however, the experiment was discontinued [8]. Synthetic human PTH (PTH 1–34; teriparatide) was subsequently developed in the mid-1970s and later approved for the treatment of osteoporosis.

Although teriparatide has not been approved for the treatment of hypoparathyroidism, its use as a physiologic hormone replacement therapy has been explored since the mid-1990s. Given that children have ongoing skeletal growth, open epiphyses, and higher bone turnover [9], the efficacy and safety of PTH replacement may differ from those in adults. Nevertheless, several studies in pediatric cohorts have demonstrated that subcutaneous teriparatide can safely and effectively manage hypoparathyroidism and achieve improved biochemical control compared with conventional therapy [10].

More recently, the approval of palopegteriparatide, a long-acting PTH (1–34) prodrug designed to provide continuous physiologic PTH exposure, for adults with hypoparathyroidism highlights a shift toward PTH-based replacement therapy [11, 12]. Although palopegteriparatide has not been approved for use in children, existing evidence on teriparatide provides important insights into the potential role of PTH-based therapies in pediatric hypoparathyroidism.

Despite evidence from diverse literature, the available pediatric evidence regarding the indications, efficacy, safety, and clinical outcomes has not been comprehensively synthesized. Therefore, we aimed to systematically evaluate the existing literature to better characterize the biochemical and skeletal effects of teriparatide in children with hypoparathyroidism.

Materials and Methods

Data Sources and Search Strategy

Two reviewers (N.T. and S.P.) independently searched MEDLINE and Embase from database inception to January 2026. The search strategy was developed a priori and included a combination of controlled vocabulary terms and free-text keywords related to hypoparathyroidism (including hypoparathyroidism, CaSR mutations, autoimmune polyglandular syndrome), pediatric populations (children, child, pediatrics, pediatric), and PTH-based therapies (teriparatide, PTH analog, PTH 1–34, PTH (1–34), recombinant human PTH [rhPTH]). The detailed search strategy is presented in the Supplementary Material 1. The reference lists and citation records of eligible studies were also manually screened to identify additional relevant publications. Searches were performed independently by both reviewers, and discrepancies were resolved by discussion.

Inclusion and Exclusion Criteria

Eligible studies included randomized controlled trials, non-randomized interventional studies, prospective and retrospective observational studies, case series, and case reports. Studies were eligible if they enrolled pediatric patients aged 21 years or younger at the time of teriparatide initiation. Studies with mixed adult and pediatric populations were included only when pediatric data were separately extractable. Eligible participants had chronic hypoparathyroidism of any cause, including genetic or syndromic etiologies, such as DiGeorge syndrome and disorders related to CaSR, GNA11, or PTH, as well as postoperative, autoimmune, or idiopathic hypoparathyroidism. Hypoparathyroidism was defined as hypocalcemia with inappropriately low or normal PTH levels, or by a clear diagnosis documented by the treating team. Eligible interventions were teriparatide administered either as intermittent subcutaneous injections, including twice- or three-times-daily regimens, or as continuous delivery, such as pump-based infusion, with a minimum treatment duration of 4 weeks.

Studies were excluded if teriparatide was used for indications other than hypoparathyroidism, such as secondary osteoporosis, and studies evaluating PTH analogs other than teriparatide. Publications lacking original patient- or study-level data (e.g., reviews, editorials, commentaries) and conference abstracts or posters without full-text publication were excluded.

Data Extraction

Two authors (N.T. and S.P.) independently extracted data from included studies using a standardized data extraction form. Extracted variables included authors, year of publication, country, study design, sample size, patient age, duration of follow-up on teriparatide, route of administration, and study outcomes. Discrepancies were resolved by discussion and consensus.

Outcome Measures

Outcomes were extracted and analyzed when available. This included calcium homeostasis, assessed by serum calcium levels and urinary calcium excretion (24-h urinary calcium and spot urine calcium-to-creatinine ratio), and phosphate homeostasis, evaluated using serum and urine phosphate levels. Additional outcomes included bone turnover markers, growth and skeletal outcomes (e.g., height velocity, height-for-age z-scores, and bone mineral density [BMD]), renal complications, including nephrocalcinosis on imaging, and changes in calcium and calcitriol requirements.

Quality Assessment

Risk of bias was assessed using study design-specific tools. Randomized controlled trials were evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool, and non-randomized studies were assessed using the Joanna Briggs Institute (JBI) critical appraisal checklists, as appropriate.

Statistical Analysis

Studies were categorized into three analytical groups: (1) all included studies for assessment of study-level characteristics and risk of bias, (2) studies evaluating intermittent teriparatide injections, and (3) studies evaluating continuous subcutaneous PTH infusion (CSPI).

Studies were included in each analysis if they reported the outcome of interest, therefore, not all studies contributed data to every analysis. For outcomes with sufficient comparable data, pooled analyses were performed using weighted mean differences (WMDs) with 95% confidence intervals (CIs) for continuous variables. Meta-analyses were conducted using a random-effects model with restricted maximum likelihood (REML) estimation to account for between-study heterogeneity. The Hartung-Knapp adjustment was applied to provide more robust CIs, particularly given the small number of included studies. Heterogeneity was assessed using the I² statistic and Cochran’s Q test, with values > 50% considered indicative of substantial heterogeneity. All analyses were performed in R (version 4.5.2; R Foundation for Statistical Computing, Vienna, Austria) using the meta package (version 8.2.1).

Due to heterogeneity in study design, treatment duration, outcome, and incomplete reporting of variance across several included studies, quantitative synthesis was not possible for all outcomes. Pooled analyses included only data from studies evaluating intermittent teriparatide injections. Studies evaluating CSPI were summarized descriptively because of the limited number of studies and insufficient comparable data for meta-analysis.

Results

Literature Search

The initial literature search identified 229 records from MEDLINE and Embase. After removal of 55 duplicates, 174 records underwent title and abstract screening, of which 118 were excluded as they did not meet eligibility criteria. Fifty-six studies were assessed for full-text eligibility. Of these, 39 were excluded for reasons detailed in the PRISMA flow diagram (Fig. 1). Manual screening of reference lists and citation records identified one additional eligible study. A total of 18 studies were included in the systematic review [13–30].

Fig. 1.

PRISMA flow diagram of study selection. Flow diagram illustrating the number of records identified, screened, excluded, and included

Description of Included Studies

Table 1 summarizes the study-level characteristics of the included studies. Studies were conducted in the United States, Italy, France, United Kingdom (UK), India, and Portugal. The oldest study included was published in 2006 and the most recent study included was published in 2024. The included studies comprised 2 randomized crossover trials [13, 14], 1 randomized parallel trial [15], 5 observational cohort studies [16–20], 2 case series [21, 22], and 8 case reports [23–30]. Most studies evaluated intermittent teriparatide injections, whereas 5 studies reported CSPI [14, 20, 21, 22, 29].

Table 1.

Study-level characteristics of included studies

Study	Country	Study Design	n	Diagnosis	Age	Follow-up	Teriparatide route	Main conclusion
Winer 2008 [13]	US	RCT crossover	14	APS-1 (5) CaSR mutation (1) Post-surgical (1) Idiopathic (7)	4–17 years	28 weeks	Subcutaneous injection (once vs twice daily); baseline data included	Twice daily teriparatide regimen provides a more effective treatment
Winer 2015 [14]	US	RCT crossover	12	APS-1 (5) CaSR mutation (7)	7–20 years	26 weeks	Subcutaneous injection twice daily vs CSPI	CSPI achieves more physiologic calcium homeostasis and bone turnover
Winer 2010 [15]	US	RCT parallel	12	APS-1 (3) CaSR mutation (1) Idiopathic (5) Not reported (3)	5–14 years	3 years	Conventional therapy vs. subcutaneous injection twice daily	Teriparatide therapy is safe and effective in maintaining stable calcium homeostasis and supports normal skeletal development, with no differences in bone mineral accrual, linear growth, or weight gain
Matarazzo 2014 [16]	Italy	Observational cohort	6	APS-1 (3) DiGeorge syndrome (2) HDR syndrome (1)	9.8 ± 5.1 years (Range 3.5–18.5)	2.5 years	Subcutaneous injection twice daily	Teriparatide therapy maintains adequate serum calcium and normalizes urinary calcium excretion while reducing the need for calcium and vitamin D supplementation
Winer 2018 [17]	US	Observational cohort	14	APS-1 (5) CaSR mutation (9)	7–12 years	6.9 ± 3.1 years (range 1.5–10)	Subcutaneous injection 2–3 times daily	Twice-daily or thrice-daily teriparatide therapy provided safe and effective replacement therapy for up to 10 years
Tuli 2020 [18]	Italy	Observational cohort	6	APS-1 (3) DiGeorge syndrome (2) HDR syndrome (1)	9.4 ± 5.2 years (range 3.4–18.6)	9.2 years (range 1.0–10.7)	Subcutaneous injection twice daily	Replacement therapy with teriparatide maintains calcium and phosphate levels, normalizes urinary calcium excretion, and reduces tetanic episodes
Bernardor 2021 [19]	France	Observational cohort	10	APS-1 (3) CaSR mutation (4) DiGeorge syndrome (1) Post-surgical (1) Idiopathic (1)	10.7 years (range 8.1–12.6)	2.8 years (IQR 2.2–3.0)	Subcutaneous injection twice daily	Intermittent teriparatide therapy improves calcium and phosphate control without increasing calciuria
Sastre 2021 [20]	UK	Observational cohort	5	CaSR mutation (5)	0.1–6 years	0.8–5.5 years	CSPI	CSPI appears to be an effective long-term treatment for children with severe ADH1 refractory to conventional therapy
Lingart 2011 [21]	France	Case series	3	APS-1 (2) Idiopathic (1)	8–13 years	3 years	CSPI	CSPI appears effective and safe in the short term
Saraff 2018 [22]	France	Case series	4	APS-1 (3) Idiopathic (1)	13–19 years	3–8 years	CSPI	CSPI is effective treatment option in children with hypoparathyroidism
Mittleman 2006 [23]	US	Case report	1	CaSR mutation (1)	14 months	17 months	Subcutaneous injection twice daily	Short-term teriparatide use raises calcium levels more rapidly and safely
Sanda 2008 [24]	US	Case report	1	CaSR mutation (1)	1 year	1.6 years	Subcutaneous injection twice daily	Teriparatide therapy rapidly and markedly improved serum calcium levels
Theman 2009 [25]	US	Case report	1	CaSR mutation (1)	6 years 2 months	13.5 years	Subcutaneous injection twice daily	Long-term teriparatide therapy increases bone mass with little long-term impact on mineralization
Dayal 2021 [26]	India	Case report	1	Jacobsen syndrome (1)	6.5 years	10 years	Subcutaneous injection	Long-term teriparatide therapy is safe and reduces the need for additional treatments
Festas Silva 2021 [27]	Portugal	Case report	1	CaSR mutation (1)	14 years	12 months	Subcutaneous injection 2–3 times daily	Teriparatide therapy may be considered for patients with inadequate control on conventional therapy
Bhatt 2022 [28]	US	Case report	1	DiGeorge syndrome (1)	4 months	6 months	Subcutaneous injection twice daily	Teriparatide therapy effectively increased serum ionized calcium and decreased serum phosphorus
Lindsay Mart 2023 [29]	US	Case report	1	CaSR mutation (1)	14 years	2 years	CSPI	CSPI reduces hospital admissions for calcium abnormalities and allowed discontinuation of conventional therapy
Thambundit 2024 [30]	US	Case report	1	Homozygous GCM2 mutation (1)	15 months	6 years	Subcutaneous injection twice daily	Teriparaitde therapy is a safe and effective treatment

APS-1, autoimmune polyglandular syndrome type 1; CaSR, calcium-sensing receptor gene; CSPI, continuous subcutaneous parathyroid hormone infusion; HDR, hypoparathyroidism-deafness-renal dysplasia syndrome; IQR, interquartile range; n, number of participants; RCT, randomized controlled trial

Quality Assessment Tool

The Cochrane Risk of Bias 2 (RoB 2) tool was used to assess randomized controlled trials. Non-randomized studies, including observational studies, case series, and case reports, were assessed using the Joanna Briggs Institute (JBI) critical appraisal checklists (Supplementary Material 2).

The quality of the included studies was generally acceptable across all designs. The three randomized controlled trials assessed via RoB 2 showed a low risk of bias for missing data and measurement, while some concerns were noted regarding the randomization process and selection of reported results. Among the 5 cohort studies, there was consistent compliance with criteria for group similarity and valid outcome measurement. The 2 case series met nearly all requirements, with only minor uncertainty regarding consecutive participant inclusion. Most of the 8 case reports fulfilled the majority of the JBI criteria, although some lacked clarity regarding adverse events.

Characteristics of Individuals with Hypoparathyroidism Treated with Teriparatide

Table 2 summarizes the characteristics of individuals with hypoparathyroidism treated with teriparatide. The cohort included 94 patients, with a slight male predominance (52%). Age at diagnosis ranged from birth to 14.3 years, while age at teriparatide initiation ranged from 0.3 to 20 years. The most common etiologies were APS-1 (34%) and CaSR mutations (34%), with smaller contributions from syndromic causes such as DiGeorge syndrome and rare genetic conditions. A minority of cases were post-surgical or idiopathic, and diagnosis was not reported in a small proportion of patients.

Table 2.

Characteristics of individuals with hypoparathyroidism treated with teriparatide

Characteristics	Value
Total, n	94
Sex, n (%)
Male	49 (52%)
Female	45 (48%)
Age at diagnosis, years	Range:
	0–14.3
Age at teriparatide initiation, years	Range:
	0.3–20
Diagnosis, n (%)
APS-1	32 (34%)
CaSR mutation	32 (34%)
DiGeorge syndrome	6 (6%)
HDR syndrome	2 (2%)
Jacobsen syndrome	1 (1%)
Homozygous GCM2 mutation	1 (1%)
Post-surgical	2 (2%)
Idiopathic	15 (16%)
Not reported	3 (3%)
Rationale for teriparatide initiation, n (%)
Symptomatic hypocalcemia despite optimized standard of care	29 (31%)
Non-adherence to conventional therapy	7 (7%)
Family preference based on prior use of teriparatide in a sibling	2 (2%)
Study protocol-driven or not clearly reported	56 (60%)

Rounding adjustments may result in totals that do not precisely equal 100%

APS-1, autoimmune polyglandular syndrome type 1; CaSR, calcium-sensing receptor gene; HDR, hypoparathyroidism-deafness-renal dysplasia syndrome

Rationale for teriparatide initiation varied across studies. Symptomatic hypocalcemia despite optimized standard of care was reported in 29 patients (31%). Non-adherence to conventional therapy accounted for 7 patients (7%), while family preference or sibling use of teriparatide was noted in 2 patients (2%). In the majority of cases, initiation was study protocol-driven or the rationale was not clearly reported (56 patients, 60%).

Outcomes with Intermittent Teriparatide Injection and Continuous Subcutaneous Teriparatide Infusion (CSPI)

Calcium Homeostasis

Among studies evaluating intermittent teriparatide injections, 6 studies with sufficient data were included in the pooled analysis of total serum calcium [13, 15–19]. There was no significant difference between teriparatide and conventional therapy (WMD −0.02, 95% CI −0.10 to 0.07). Heterogeneity was low (I² = 0.0%) and not statistically significant (p = 0.44) (Fig. 2A). Serum calcium levels were generally stable in observational cohorts and randomized controlled trials, and improved in case reports following initiation of teriparatide therapy [23, 24, 26–28].

Fig. 2.

Calcium homeostasis outcomes comparing teriparatide and conventional therapy. Squares represent study estimates with 95% confidence intervals (CIs), and the diamond represents the pooled estimate. A Total serum calcium (mmol/L). Negative values favor teriparatide. The pooled WMD was −0.02 (95% CI −0.10 to 0.07). Heterogeneity was low (I² = 0.0%, p = 0.44). B Urine calcium (mmol/24 h). Negative values favor teriparatide. The pooled WMD was −1.05 (95% CI −5.53 to 3.42). Heterogeneity was substantial (I² = 72.9%, p = 0.02). C Urine calcium-to-creatinine ratio (mmol/mmol). Negative values favor teriparatide. The pooled WMD was −0.73 (95% CI −2.63 to 1.18). Heterogeneity was substantial (I² = 89.7%, p < 0.01)

Three studies with sufficient data were included in the pooled analysis of urinary calcium excretion (mmol/24 h) [13, 15, 17]. There was no significant difference between teriparatide and conventional therapy (WMD −1.05, 95% CI −5.53 to 3.42), with substantial heterogeneity (I² = 72.9%; p = 0.02) (Fig. 2B). Three studies with sufficient data were included in the pooled analysis of urine calcium-to-creatinine ratio (mmol/mmol) [16, 18, 19]. There was no significant difference between teriparatide and conventional therapy (WMD −0.73, 95% CI −2.63 to 1.18), with substantial heterogeneity (I² = 89.7%; p < 0.01) (Fig. 2C).

Urinary calcium excretion was generally stable or decreased with teriparatide. Observational studies with long-term follow-up from Matarazzo et al. (2014) [16], Winer et al. (2018) [17], and Tuli et al. (2020) [18], in which all patients were followed for more than 2 years, showed reduced urinary calcium excretion compared with baseline levels during conventional therapy.

Regarding CSPI, Linglart et al. (2011) [21], Saraff et al. (2018) [22], Sastre et al. (2021) [20], and Lindsay Mart et al. (2023) [29] reported improved serum calcium, fewer hypocalcemia-related hospitalizations, and decreased hypocalcemic seizures. In a randomized crossover study, Winer et al. (2015) [14] found that CSPI achieved near-normal serum calcium with less fluctuation compared with twice-daily injections, which demonstrated a biphasic pattern in serum and urinary calcium.

Phosphate Homeostasis

Six studies evaluating intermittent teriparatide injections with sufficient data were included in the pooled analysis of serum phosphate (mmol/L) [13, 15–19]. Teriparatide was associated with lower serum phosphate compared with conventional therapy (WMD −0.28, 95% CI −0.45 to −0.12). Heterogeneity was moderate (I² = 40.4%) and not statistically significant (p = 0.14) (Fig. 3A).

Fig. 3.

Phosphate homeostasis outcomes comparing teriparatide and conventional therapy. Squares represent study estimates with 95% confidence intervals (CIs), and the diamond represents the pooled estimate. A Serum phosphate (mmol/L). Negative values favor teriparatide. The pooled WMD was −0.28 (95% CI −0.45 to −0.12). Heterogeneity was moderate (I² = 40.4%, p = 0.14). B Urine phosphate (mmol/24 h). Negative values favor teriparatide. The pooled WMD was −0.30 (95% CI −9.77 to 9.18). Heterogeneity was low (I² = 0.0%, p = 0.42)

Three studies with sufficient data were included in the pooled analysis of urine phosphate (mmol/24 h) [13, 15, 17]. There was no significant difference between teriparatide and conventional therapy (WMD −0.30, 95% CI −9.77 to 9.18), with low heterogeneity (I² = 0.0%; p = 0.42) (Fig. 3B).

Regarding CSPI, Sastre et al. (2021) [20] reported a reduction in mean serum phosphate in all patients. Winer et al. (2015) [14] reported higher mean 24-h serum phosphate during CSPI compared with twice-daily injections, while 8 AM fasting serum phosphate and 24-h urinary phosphate excretion were not different between groups.

Skeletal and Growth Outcomes

Six studies evaluating intermittent teriparatide injections were included in the pooled analysis of alkaline phosphatase (U/L) [13, 15–19]. Teriparatide was associated with higher alkaline phosphatase compared with conventional therapy (WMD 54.59, 95% CI 19.05 to 90.14), with low heterogeneity (I² = 0.0%; p = 0.50) (Fig. 4A).

Fig. 4.

Skeletal and growth outcomes comparing teriparatide and conventional therapy. Squares represent study estimates with 95% confidence intervals (CIs), and the diamond represents the pooled estimate. A Alkaline phosphatase (U/L). Negative values favor teriparatide. The pooled WMD was 54.59 (95% CI 19.05 to 90.14), with low heterogeneity (I² = 0.0%, p = 0.50). B Height standard deviation (SD) (Z-score). Negative values favor teriparatide. The pooled WMD was −0.24 (95% CI −1.42 to 0.94), with low heterogeneity (I² = 0.0%, p = 0.46)

Winer et al. (2008, 2010) [13, 15] also reported increases in osteocalcin, urine pyridinoline, and deoxypyridinoline during teriparatide therapy, whereas Winer et al. (2018) [17] reported bone turnover markers were associated with teriparatide treatment dose. For CSPI, Winer et al. (2015) [14] reported significantly lower bone turnover markers compared with intermittent teriparatide injection.

BMD outcomes were reported in several studies but could not be quantitatively synthesized due to heterogeneity in imaging modalities and skeletal sites. Winer et al. (2010) [15] reported no significant differences in BMD Z-scores over time or between treatment groups across multiple skeletal sites. In a longitudinal analysis, Winer et al. (2018) [17] found that bone accrual velocities at the lumbar spine, whole body, and femoral neck remained within the normal range, with a transient reduction at the distal radius. Reported findings were variable but generally remained within normal range during teriparatide therapy.

Three studies evaluating teriparatide injections were included in the pooled analysis of height standard deviation (SD) [16, 19, 26]. There was no significant difference between teriparatide and conventional therapy (WMD −0.24, 95% CI −1.42 to 0.94), with low heterogeneity (I² = 0.0%; p = 0.46) (Fig. 4B). Several studies also reported normal growth velocity during treatment [15, 17], with linear growth remaining within the normal range.

Among studies evaluating CSPI, Linglart et al. (2011) [21] and Sastre et al. (2021) [20] reported normal growth and BMD within reference range during treatment with CSPI.

Renal Complications

Renal outcomes during teriparatide therapy were variable. Several studies reported stable or absent nephrocalcinosis without new or progressive findings on follow-up imaging [16, 20, 26], whereas others described incident or progressive nephrocalcinosis, including new cases after treatment initiation. Tuli et al. (2020) [18] reported progression in 2 of 6 patients after 9 years of follow-up, and Winer et al. (2018) [17] observed progression in 5 of 12 patients over a mean follow-up of 6.9 years. In a case reported by Lindsay Mart et al. (2023) [29], renal ultrasound performed shortly after CSPI initiation demonstrated medullary nephrocalcinosis, which remained stable over 2 years of follow-up.

PTH Dose

Among 14 studies that reported teriparatide dosing in mcg/kg/day [14–17, 19–23, 26, 28, 30], initial doses ranged from approximately 0.5 to 1.8 mcg/kg/day. Maintenance doses were generally lower and more narrowly distributed, typically ranging from 0.26 to 0.8 mcg/kg/day.

Winer et al. (2015) [14] reported that CSPI required a lower daily PTH dose compared with twice-daily injections (0.32 ± 0.04 vs. 0.85 ± 0.11 mcg/kg/day).

Concomitant Active Vitamin D and Calcium Supplementation

Requirements for concomitant active vitamin D during teriparatide therapy varied considerably across studies. While several studies reported discontinuation of calcitriol and/or calcium supplementation at or shortly after teriparatide initiation, others reported dose reductions only or did not describe changes in concomitant therapy. Bernador et al. (2021) [19] and Bhatt et al. (2022) [28] reported calcitriol reintroduction. Festa Silva et al. (2021) [27], and Thambundit et al. (2024) [30] reported continued calcitriol use with dose reduction, with Festa Silva et al. (2021) [27] demonstrating a > 50% reduction in calcitriol requirements. Mittelman et al. (2006) [23] reported successful discontinuation. Requirements for calcium supplementation also varied. Mittelman et al. (2006) [23] and Bhatt et al. (2022) [28] reported reductions in calcium supplementation, whereas Dayal et al. (2021) [26] and Festa Silva et al. (2021) [27] reported discontinuation. Matarazzo et al. (2014) [16] and Tuli et al. (2020) [18] reported that some patients required temporary calcium supplementation during intercurrent illnesses. Among studies evaluating CSPI, active vitamin D and calcium supplementation were generally discontinued following treatment initiation. Saraff et al. (2018) [22] reported that one patient remained on a reduced dose of oral calcium supplementation, whereas no additional active vitamin D or calcium supplementation was required in the remaining patients when reported.

Discussion

In this systematic review, we evaluated the existing literature on teriparatide in children with chronic hypoparathyroidism, focusing on outcomes compared with conventional therapy. Due to heterogeneity in study design and outcome reporting, meta-analysis was limited to outcomes with sufficient comparable data, while other findings were summarized descriptively.

In children with chronic hypoparathyroidism, teriparatide appears to provide a physiologic approach to calcium regulation and may be particularly beneficial in patients with suboptimal control or adherence on conventional therapy. However, in patients who were already well controlled on conventional therapy, serum calcium levels remained within the normal range without significant improvement on teriparatide.

Although pooled analysis using WMDs did not demonstrate a significant difference in urinary calcium excretion, the effect may be time-dependent, as longer-term studies suggest a decline in urinary calcium excretion with teriparatide therapy [16–18]. Serum phosphate levels generally decreased across studies. Although part of the observed reduction may reflect physiological age-related changes, as serum phosphate declines during childhood toward adult reference ranges [31], lower serum phosphate was also observed in studies with relatively short treatment durations, suggesting that aging alone is unlikely to fully explain this finding. Urinary phosphate has generally remained stable. Overall, teriparatide may improve phosphate homeostasis and promote longer-term reductions in urinary calcium excretion.

Skeletal effects remain less well defined. Long-term use of teriparatide raises theoretical concerns in pediatric populations, given that intermittent exogenous PTH has anabolic effects on bone, whereas continuous PTH exposure is associated with increased bone resorption and reduced bone density, as seen in hyperparathyroidism [32]. Among the available studies, teriparatide was generally associated with higher bone turnover markers compared with conventional therapy, while remaining within the normal range. CSPI may be associated with lower bone turnover markers compared with intermittent injection. Despite these differences, BMD was generally maintained within the normal range during treatment with both intermittent teriparatide and CSPI.

Teriparatide was initially associated with a black box warning for osteosarcoma based on rat studies using supraphysiologic doses, however, this warning has been removed in adults after large surveillance studies showed no increased risk [33–35]. Nevertheless, the long-term risk in children remains uncertain due to open epiphyses and higher baseline bone turnover. Notably, no cases of osteosarcoma have been reported in pediatric patients treated with teriparatide to date, including studies with follow-up up to 13.5 years [25, 34]. Growth data have also been overall reassuring, with stable or improved height SD and normal growth velocity reported.

Patients with chronic hypoparathyroidism had significantly increased risk of nephrolithiasis and nephrocalcinosis compared with patients without hypoparathyroidism [36]. Conventional therapy contributes to this risk by increasing the calcium-phosphate product and urinary calcium excretion, creating conditions favorable for renal calcium deposition [37, 38]. Renal outcomes with teriparatide remain variable. While some studies demonstrated stable nephrocalcinosis during long-term follow-up, others reported incident or worsening nephrocalcinosis in a subset of patients. Therefore, continued renal imaging surveillance is warranted during therapy.

CSPI may provide additional benefit for selected patients because it more closely replicates physiologic hormone secretion, although its use is limited by technical and device-related challenges. A recently published long-term observational study by Vincent et al. (2026) [39] of five children with follow-up of up to 11 years further supports the potential benefits of CSPI, demonstrating improved mineral homeostasis and appropriate growth, although nephrocalcinosis progressed in some patients, highlighting the importance of continued renal monitoring. As this study was published after completion of the literature search, it was not eligible for inclusion in the systematic review.

Teriparatide dosing varied across studies, but a consistent reduction from initial to maintenance dosing suggests that lower doses may be sufficient once calcium levels are stabilized. CSPI appears to achieve similar biochemical control at lower daily doses compared with intermittent injections, likely reflecting more physiologic hormone delivery. Optimal dosing strategies remain to be defined.

Although teriparatide reduces reliance on adjunctive therapies such as calcitriol and calcium supplementation, these agents may still be required in some patients. Ongoing use with dose adjustment [26–28, 30], or reintroduction [18, 19] of supplementation observed in some studies suggests that teriparatide may not fully replace physiological calcium homeostasis in all cases. This underscores the need for continued biochemical monitoring after treatment initiation.

A key limitation of this study is the limited number of available studies and substantial heterogeneity in study design, and reported outcomes, which limited formal analysis of several clinically relevant endpoints. In addition, there was heterogeneity in the underlying etiologies of hypoparathyroidism included in the analysis, as individuals with CaSR mutations are predisposed to hypercalciuria due to activation of renal CaSR independent of PTH status, while those with APS-1 or genetic/syndromic etiologies may have additional comorbidities affecting calcium and mineral metabolism that could contribute to variability in biochemical outcomes during treatment [40, 41]. However, given the rarity of pediatric chronic hypoparathyroidism, inclusion of diverse etiologies was necessary to capture the available evidence, especially since many studies reported pooled data without separate subgroup analyses. Furthermore, the predominance of observational studies may increase the potential for publication bias.

A strength of this review is the comprehensive and updated synthesis of available evidence in pediatric population. By integrating data on biochemical outcomes, growth, and safety, this study provides a useful overview and serves as a resource for clinicians considering teriparatide in patients refractory to standard care. In addition, in the context of emerging PTH-based replacement therapies, these findings provide relevant insights into the potential role of physiologic PTH replacement strategies in children.

In conclusion, current evidence suggests that teriparatide may be a promising alternative for selected children with chronic hypoparathyroidism who have persistent symptoms, treatment-related complications, or difficulty achieving adequate control with conventional therapy. However, given the limited and heterogeneous data and the need for additional long-term pediatric safety data, routine use cannot yet be recommended, and conventional therapy should remain the standard of care. Teriparatide may be considered in selected patients with persistent symptoms, treatment-related complications, or challenges with adherence to conventional therapy.

Supplementary Material

The online version contains supplementary material available at https://doi.org/10.1007/s00223-026-01582-y.

Data Availability

All data analyzed in this study were derived from published articles. The extracted study data used for the analyses are available from the corresponding author upon reasonable request.