Objectives: Permanent hypoparathyroidism is a lifelong condition and characterized by chronic hypocalcemia and dependence on calcium and active vitamin D therapy. Parathyroid cell transplantation has emerged as a potential restorative treatment, yet standardized tools for assessment of posttransplant recovery are lacking. This study aimed to evaluate clinical recovery following parathyroid cell transplant using a novel functional scoring system.
Materials and Methods: This retrospective, single-center (in Istanbul, Türkiye), longitudinal study included 40 consecutive parathyroid cell transplants performed between 2019 and 2024 in patients with permanent hypoparathyroidism. A 5-level recovery scoring system (score 0 to 4) integrating serum calcium levels, medication requirements, and hypocalcemia-related symptoms was developed to assess outcomes. Patients were followed for up to 4 years. Clinically meaningful recovery was defined as score ≥3, corresponding to a ≥50% reduction in calcium and/or active vitamin D supplementation.
Results: Recovery scores improved progressively over time posttransplant. Most patients demonstrated early biochemical benefit within the first 2 months, followed by stabilization and sustained improvement. By 6 months, a substantial proportion achieved clinically meaningful recovery (score ≥3), characterized by marked reduction in supplementation requirements and symptomatic improvement. A limited subset of patients achieved score 4, indicating complete independence from replacement therapy. Serum calcium levels showed a significant time-dependent increase, although interindividual variability in response persisted.
Conclusions: Parathyroid cell transplant can provide sustained functional improvement in patients with permanent hypoparathyroidism. The proposed recovery scoring system offers a practical, clinically meaningful tool that integrates biochemical parameters, medication dependence, and symptoms, enabling standardized monitoring of posttransplant outcomes. This approach may facilitate long-term treatment management strategies for this challenging disease.

Key words : Composite tissue, Hypoparathyroidism, Parathyroid, Parathyroid allotransplantation, Scoring

Introduction
Permanent hypoparathyroidism (PH) is one of the possible complications following thyroid surgery and usually results from accidental removal of the parathyroid glands or vascular damage. This disorder is characterized by chronic hypocalcemia, hyperphosphatemia, neuromuscular irritability, and impaired quality of life. Despite advances in surgical techniques, PH is a life-limiting disease that typically requires lifelong treatment and follow-up, including oral calcium, anti-phosphate, and active vitamin D supplementation, frequent laboratory monitoring, and occasional hospitalization for intravenous calcium therapy.^1-3 Recombinant parathyroid hormone (PTH) preparations are used as a hormone replacement strategy. This treatment can improve calcium balance and reduce the need for supplementation; however, its use is limited by high cost, daily injections, and a relatively short half-life.^4,5 As a result, most patients worldwide continue their lives with symptomatic treatment rather than routine PTH replacement. Parathyroid cell transplant (PcT) is considered the only therapeutic alternative for PH.⁶ Conventional treatment targets symptoms but cannot replace the physiological effects of PTH and has significant limitations, such as fluctuating calcium levels, hypercalciuria, nephrocalcinosis, and chronic symptoms. Even if specific biochemical targets are achieved, many patients continue to experience a decline in quality of life, cognitive dysfunction, fatigue, and neuromuscular symptoms.^7-9 These challenges highlight the need for definitive treatments that can restore physiological calcium homeostasis. Parathyroid cell transplantation has emerged as a promising therapeutic modality for individuals afflicted with severe, refractory hypoparathyroidism. Empirical and clinical investigations have substantiated that transplanted parathyroid tissue or cells possess the capacity to restore endogenous PTH secretion and enhance calcium homeostasis.^10-12 Nonetheless, this surgical intervention is performed at a limited number of medical centers worldwide, and there is a lack of standardized criteria for assessing posttransplant recovery. The evaluation of treatment outcomes in hypoparathyroidism has traditionally relied on biochemical parameters, particularly serum calcium, PTH, magnesium, and phosphorus levels. However, it has been observed that biochemical follow-up parameters alone do not adequately reflect the clinical condition.^9,13 Patients may show symptomatic improvement and reduced medication dependency before systemic PTH levels normalize. Some patients may maintain acceptable laboratory values despite their symptom burden.^3,14,15 Similarly, methods based on scoring systems that evaluate disease-specific symptoms and patient-reported outcomes have been developed. However, their integration into routine clinical decision-making is still minimal.^1,16 With heterogeneity of clinical responses and lack of standardized monitoring tools, practical approaches that capture functional improvement are needed rather than a focus solely on biochemical values. A clinically meaningful definition of success should reflect a reduction in medication requirements for calcium and phosphorus homeostasis and an improvement in symptoms related to hypocalcemia and hyperphosphatemia.^17,18 Given these differences and limitations, beyond laboratory parameters, clinically meaningful interpretations and measurements reflecting improvement are needed. In routine practice, patients often report gradual improvement in symptoms and reduced dependence on supplements, but it is difficult to measure these changes using current biochemical endpoints. Therefore, a combined approach that integrates biochemical trends, medication requirements, and patient-reported symptoms may provide a more accurate assessment of therapeutic benefit. Our center has been performing PcT with official approval since 2013 and has accumulated extensive long-term clinical experience. During follow-up of transplant recipients, we observed heterogeneous changes that serum PTH levels alone could not adequately reflect. Based on these observations, we developed a new recovery scoring system designed to measure functional clinical improvement after transplantation. The present study aimed to evaluate recovery patterns following PcT using this newly developed scoring system in a consecutive cohort of patients with permanent hypoparathyroidism. We sought to characterize the time course of clinical improvement, the durability of response, and the relationship between clinical recovery and biochemical changes in serum calcium levels.

Materials and Methods
Parathyroid cell transplant was conducted with the permission of the Turkish Ministry of Health, National Scientific Board for Transplantation. Our PcT unit is the first officially permitted center to conduct PcT since 2013.

Study design
This study represents a retrospective longitudinal clinical analysis of patients who underwent PcT between January 2019 and December 2024 at the Organ Transplant Center of Bezmialem Vakıf University Hospital (Istanbul, Türkiye). The recovery scoring system was developed based on cumulative real-world clinical observations obtained during routine follow-up of transplanted patients. Following its formulation, all cases were retrospectively re-evaluated and categorized according to the defined scoring framework.

Development of the recovery scoring system
During longitudinal follow-up of transplanted patients, recovery patterns were heterogeneous and were not adequately captured by serum PTH measurements alone. In many cases, patients demonstrated symptomatic improvement and reduced medication dependency despite persistently low systemic PTH levels. An earlier version of this scoring approach was preliminarily applied in a smaller cohort of patients (n = 23) in our previous study, primarily to evaluate the contribution of the omentum as a transplantation site.¹⁹ The present study builds on this initial framework by expanding the cohort size (n = 40) and refining the scoring system to include a broader range of clinical and biochemical parameters. Based on these cumulative clinical observations and patient-reported outcomes, a 5-level recovery scoring system (score of 0 to 4) was developed to integrate biochemical trends and functional clinical status. Score 0 indicated no change in serum calcium levels, medication requirement, or symptoms. Score 1 indicated increase in serum calcium levels without change in medication or symptoms. Score 2 indicated increase in serum calcium levels with partial improvement in symptoms and/or reduction in supplementation of <50%. Score 3 indicated reduction of calcium and/or active vitamin D supplementation by approximately 50% to 75%. Score 4 indicated complete discontinuation of calcium and active vitamin D supplementation with maintenance of normocalcemia. The scoring system was formulated after systematic evaluation of the accumulated dataset of 40 transplant cases. Subsequently, all cases were retrospectively reclassified according to this framework to assess recovery trajectories over time.

Patient population
Our analyses included 40 consecutive PcT procedures performed for PH patients. All patients had biochemical evidence of hypocalcemia and low PTH levels prior to transplant. We included follow-up data of patients of at least 1 year posttransplant, with some cases reaching up to 4 years of follow-up.

Parathyroid cell transplant procedure
Parathyroid glandular tissue was obtained and processed under sterile laboratory conditions. After donor tissue retrieval, parathyroid cells were isolated using standardized mechanical dissociation techniques in the Parathyroid Transplantation Laboratory (patent number 201815244).¹³ After recipient preparation, isolated parathyroid cells were transplanted over omentum, which was selected as the implantation site due to its rich vascularization and favorable engraftment characteristics.¹⁹ In this study, we did not analyze donor-recipient immunological matching parameters, immunosuppression protocols, or HLA compatibility, as the primary objective was to evaluate clinical recovery dynamics rather than immunological outcomes.

Posttransplant monitoring
Patients were monitored longitudinally after PcT. Follow-up visits included (1) serum total calcium measurements, (2) assessment of calcium and active vitamin D supplementation dose, and (4) evaluation of hypocalcemia-related symptoms (eg, muscle cramps, tetany). Notably, systemic PTH levels were recorded but were not used as the primary determinant of recovery, as clinical observations indicated that symptomatic and biochemical stabilization could occur without measurable systemic PTH normalization. Monitoring was performed at regular intervals, particularly during the early phase (0-2 months), intermediate phase (3-5 months), at 6 months, and during long-term follow-up (≥2 years).

Outcomes
The primary outcome of the study was achievement of clinically meaningful recovery following PcT, as defined by the novel recovery scoring system. Clinically meaningful recovery was defined as attainment of score ≥3, corresponding to a ≥50% reduction in calcium and/or active vitamin D supplementation, with biochemical stabilization and symptomatic improvement. Secondary outcomes included time to reach score ≥3, proportion of patients achieving score 4 (complete discontinuation of supplementation), sustainability of recovery at long-term follow-up (≥24 months), and longitudinal trends in serum calcium levels. Of note, normalization of systemic serum PTH levels was not considered a prerequisite for treatment success. Based on cumulative clinical observations, recovery was defined by functional stabilization of calcium metabolism and reduced medication dependency rather than biochemical PTH normalization alone.

Statistical analyses
We used descriptive statistics to summarize patient characteristics and the distribution of recovery scores at each follow-up interval. We presented continuous variables as mean ± SD and categorical variables as frequency and percentage. To analyze changes in serum calcium levels over time, we used the Friedman test for repeated measures, followed by Dunn’s multiple comparisons test with baseline as the reference. We analyzed recovery scores descriptively to characterize the trajectory of clinical improvement. We used GraphPad Prism version 10.5 for statistical analyses. A 2-tailed P < .⁰⁵ was considered statistically significant.

Results
Among the 40 PcTs with adequate follow-up included in the study, at baseline, all patients had a recovery score of 0, reflecting symptomatic hypocalcemia and ongoing dependence on calcium and active vitamin D therapy. A time-dependent increase in recovery scores was observed during follow-up (Figure 1A). By 2 months, most patients transitioned from score 0 to scores 1 to 2, indicating early clinical benefit with partial symptom relief and/or reduced supplement requirements. By 6 months, the distribution shifted predominantly toward scores 2 to 3 (Figure 1A), consistent with substantial clinical improvement and reduced medication needs in a large proportion of recipients. At 12 months, this improvement was generally maintained, with most patients remaining at scores 2 to 3 and a minority demonstrating decline or persistently limited response. At the last available follow-up, the cohort continued to demonstrate heterogeneous trajectories; most patients maintained clinically meaningful benefit (score ≥2), whereas a smaller subset achieved sustained high-level recovery compatible with score 4. Overall, our findings demonstrated progressive clinical improvement following PcT, with interindividual variability in the magnitude and durability of response. Serum calcium levels increased progressively after PcT (Figure 1B). Individual measurements showed wide variability at each time point, yet the overall trend indicated an upward shift toward the lower end of the normal range during follow-up. Because pretransplant calcium measurements were obtained under active calcium and vitamin D therapy (and, in some cases, shortly after intensive supplementation), preoperative values were excluded from statistical comparisons to avoid non-steady-state bias. Longitudinal analysis of posttransplant serum calcium values (2 months, 6 months, 12 months, and last available follow-up) demonstrated a significant time-dependent change (Friedman test, P = .⁰²¹³). These biochemical findings were concordant with the temporal shift in recovery score distribution, supporting sustained clinical benefit in most recipients. Serum calcium and phosphorus values at predefined follow-up intervals are summarized in Table 1. Phosphorus measurements were incomplete across the cohort and therefore are presented descriptively without formal statistical comparison. When exact time-point measurements were unavailable, the closest available laboratory value within the corresponding follow-up interval was used. Overall, phosphorus levels demonstrated heterogeneous changes without a consistent temporal pattern across patients. Across the cohort, 3 qualitative response patterns were observed: sustained response with improvement, partial response with persistent but incomplete benefit, and limited/nonresponders with minimal change over time. Fluctuating changes were also observed in some patients, with intermittent supplement requirements despite overall symptomatic improvement.

Discussion
The time-dependent improvement observed in recovery scores suggested that PcT can restore partial physiological regulation of calcium metabolism. Most patients demonstrated early biochemical benefit followed by stabilization, whereas a subset showed delayed or limited responses, reflecting interindividual variability in graft survival, vascularization, immune interactions, and host metabolic factors. Such heterogeneous trajectories are consistent with observations in both transplant biology and chronic hypoparathyroidism management, where treatment response has been shown to vary widely among individuals.^20,21 Notably, a substantial proportion of patients achieved marked reduction in calcium and active vitamin D supplementation, and some attained complete independence from replacement therapy. Medication reduction represents a clinically meaningful endpoint because conventional therapy does not replicate physiological PTH activity and is associated with long-term complications, including renal impairment, hypercalciuria, and persistent symptom burden.^8,22 Even when serum calcium levels are maintained within the target range, many patients continue to experience reduced quality of life and neurocognitive symptoms, underscoring the limitations of conventional treatment approaches.^3,7,23 Our study introduced a novel, clinically oriented recovery scoring system to evaluate outcomes after PcT and demonstrated that most patients with permanent hypoparathyroidism experience progressive, sustained functional improvement over long-term follow-up. Rather than relying solely on biochemical normalization, this framework captured clinically meaningful recovery, reflected by stabilization of calcium metabolism, reduced supplementation requirements, and improvement in hypocalcemia-related symptoms. A preliminary version of a clinical scoring approach based on symptom relief and medication reduction was previously used in our earlier studies¹⁹; however, the present study introduces an expanded and more comprehensive scoring system that integrates biochemical parameters and provides a higher-resolution assessment of recovery. To our knowledge, standardized tools specifically designed to assess posttransplant recovery in hypoparathyroidism are lacking, making this approach a valuable addition to current monitoring strategies. The proposed scoring system offers several practical advantages over existing assessment methods. This system integrates biochemical trends, medication dependency, and symptom changes into a single clinically interpretable metric, facilitating longitudinal monitoring in routine practice. Unlike the use of complex patient-reported outcomes, which may be difficult to implement outside research settings, this framework is simple and reproducible. The system can be used by endocrinologists and surgeons even in centers without dedicated transplant expertise, addressing a significant gap in posttransplant follow-up. A key finding of our analysis is that clinically significant improvement frequently occurred without normalization of systemic PTH levels. This observation supports the notion that graft function may not be adequately reflected in circulating hormone measurements alone. Local paracrine effects, intermittent hormone release, partial graft activity, or peripheral sensitivity to PTH may contribute to improved calcium homeostasis despite persistently low systemic concentrations. Previous studies have similarly emphasized that biochemical markers do not always correlate with symptom burden or quality of life in PH.^3,23 Moreover, predictive models based solely on laboratory parameters have shown limited ability to capture real-world treatment control, highlighting the need for multidimensional outcome assessment.^14,17 Long-term sustainability of improvement is another notable finding. Patients who reached higher recovery scores generally maintained stable outcomes for years, suggesting durable graft function. Nevertheless, a minority exhibited fluctuating courses or limited benefit, indicating that transplant outcomes are not uniform and that individualized follow-up remains essential. Identifying predictors of response, including immunological compatibility, graft characteristics, and recipient factors, represents an important area for future research. From a broader perspective, this approach aligns with contemporary trends in hypoparathyroidism management that prioritize functional disease control and patient-centered outcomes over strict biochemical normalization. Recent advances in long-acting PTH replacement therapies similarly aim to reduce treatment burden and improve quality of life rather than merely correct laboratory abnormalities.^7,24 The present findings suggest that PcT may achieve comparable goals by restoring endogenous regulatory mechanisms. This study had several limitations. First, its retrospective design and single-center setting may limit generalizability. However, given the rarity of PcT worldwide, single-center cohorts provide important evidence. Second, immunological matching parameters, immunosuppressive regimens, and detailed graft characteristics were not analyzed, as the primary objective was to evaluate clinical recovery dynamics. Third, the scoring system was developed based on observational data and therefore requires prospective validation in independent and larger cohorts. Despite these limitations, the relatively large number of cases and extended follow-up period strengthen the reliability of the findings.

Conclusions
Our results demonstrated that PcT can produce durable clinical benefit in patients with PH and that recovery can be meaningfully quantified using a structured functional framework. Future studies should focus on external validation of the scoring system, identification of predictors of treatment success, integration with immunological and mechanistic data, and correlation with objective measures of graft viability and quality of life. Such efforts may facilitate broader adoption of PcT as a therapeutic option and improve long-term management of this challenging condition.