Secondary hyperparathyroidism (SHPT), a common complication of end-stage renal disease, promotes high-turnover bone disease and extensive vascular calcification, thereby substantially increasing mortality risk [1, 2, 3]. Parathyroidectomy (PTX) is the definitive treatment for medically refractory cases, as it effectively normalizes biochemical parameters and alleviates symptoms [4]. Although PTX corrects hyperparathyroidism, the abrupt withdrawal of parathyroid hormone (PTH) often induces severe hypocalcemia (SH), defined by a serum calcium level 1.9 mmol/L [5]. This metabolic shift leads to a rapid decline in serum calcium, typically peaking on the first postoperative day [6].

Despite the high incidence of postoperative hypocalcemia, its severity cannot be reliably predicted preoperatively at the individual level. Although previous studies have associated preoperative PTH, alkaline phosphatase (ALP), and serum calcium levels with hypocalcemia risk, their predictive performance remains inconsistent across the literature [7, 8]. Additionally, the contribution of specific bone turnover markers, which directly reflect underlying bone pathology, has not been fully incorporated into comprehensive predictive models. For example, a model integrating a sensitive bone formation marker such as procollagen type I N-terminal propeptide (PINP), with a specific bone resorption marker, such as C-terminal cross-linked telopeptide of type I collagen (CTX), may improve prediction of postoperative calcium decline severity. These preoperative markers may capture the extent of uncoupling between bone formation and resorption, a key mechanism in the development of hungry bone syndrome.

This study aimed to develop and validate a linear predictive model for SH on the first postoperative day in SHPT patients undergoing PTX. A clinically applicable nomogram was developed for risk stratification, personalized perioperative care, and prevention of SH-related complications.

SHPT is a common complication in patients with end-stage renal disease. Patients with SHPT typically exhibit parathyroid hyperplasia and excessive PTH secretion, leading to disruption of bone and mineral metabolism [1]. High PTH levels mobilize bone calcium and promote ectopic calcium and phosphate deposition in vascular, cutaneous, and cardiac tissues, ultimately causing osteoporosis, fractures, pruritus, and poor clinical outcomes [2, 3]. Although PTX effectively lowers serum calcium and phosphorus levels and improves prognosis [17, 18], this procedure may cause various complications, among which hypocalcemia is one of the most severe. Hypocalcemia manifests as numbness, pain, seizures, low blood pressure, and potentially life-threatening conditions [19]. The reported incidence of postoperative hypocalcemia in SHPT patients ranges from 27.4% to 100% [20, 21, 22], typically occurring on the first postoperative day. Similar results were observed in our study: 341 (49.78%) of 685 patients developed hypocalcemia, and 195 (28.47%) experienced SH after the first postoperative day. Thus, close collaborative monitoring and postoperative management by thyroid surgeons, nephrologists, intensivists, and otolaryngologists are essential. However, the lack of established methods for identifying patients at high risk of hypocalcemia before surgery complicates management, highlighting the need for early SH risk stratification to improve therapeutic outcomes and reduce complications.

Currently, PTH is the most common index used to evaluate SHPT severity. PTH promotes bone resorption exceeding bone formation [23], thereby increasing circulating calcium concentrations [24]. Consequently, this effect reverses immediately after PTX, causing calcium to shift abruptly from circulation into bone tissue [25, 26]. Our results corroborate earlier studies linking elevated PTH levels to increased risk of hypocalcemia [27, 28]. However, several other retrospective studies did not identify PTH as a significant factor for hypocalcemia development [29, 30, 31]. This discrepancy may reflect the advanced disease stage and markedly elevated PTH levels characteristic of Chinese SHPT patients undergoing delayed PTX.

The role of serum calcium as a risk factor for PTX remains controversial. In SHPT patients, lower serum calcium levels may reflect a higher baseline bone-remodeling status [32]. After PTX, patients with lower-normal calcium levels experience a more precipitous and severe drop in serum calcium. Our findings align with prior reports demonstrating a positive correlation between serum calcium and POD1 Ca [33]. Nevertheless, a separate study by Mittendorf et al. [34] found no correlation between preoperative and postoperative serum calcium levels. This inconsistency may be attributed to the use of corrected calcium values rather than original total serum calcium values.

Although numerous studies have reported an association between preoperative ALP levels and postoperative hypocalcemia, a consensus has not been reached regarding the predictive utility of ALP for this outcome [35]. For example, Sun et al. [36] reported that preoperative ALP was a risk factor for hypocalcemia and recommended its use in postoperative management. In Torer et al.’s study [37], high serum ALP even exerted a positive effect in preventing postoperative hypocalcemia. These discrepancies may result from variations in bone disease severity and study sample sizes. Our analysis confirms preoperative ALP as an independent predictor of hypocalcemia following PTX.

Previous research has selected CTX as a preferred marker for bone resorption due to its well-characterized assay [38]. Theoretically, higher preoperative ALP levels reflect a more active bone remodeling state, leading to a higher incidence of hypocalcemia after PTX. However, few studies indicate that CTX independently predicts hypocalcemia after PTX. Parshina et al. [39] demonstrated CTX as an independent risk factor for SH development following SHPT surgery, while Liu et al. [40] confirmed its predictive value through univariate logistic regression. In our study, CTX was included in the regression equations. If possible, preoperative CTX levels should be assessed to reflect the effect of PTX on bone turnover.

The optimal surgical approach for PTX remains controversial. According to a large meta-analysis, postoperative hypocalcemia rates are similar regardless of the type of operation; however, patients undergoing TPTX-AT might need longer periods of calcium and vitamin D supplementation [41]. Ho et al. [42] reported a higher incidence of hypocalcemia following TPTX, attributing this result to a more rapid postoperative decline in serum calcium levels. Surprisingly, our data indicated a lower rate of hypocalcemia after TPTX compared with TPTX-AT. These discrepancies likely reflect variations in baseline patient characteristics and differences in sample sizes. Additionally, our analysis did not include established preoperative risk factors such as gender, age, and BMI, previously associated with hypocalcemia [43]. Interestingly, despite vitamin D’s well-known role in calcium and bone metabolism, our analysis did not identify preoperative 25(OH)D levels as significant predictors of postoperative hypocalcemia. This finding could be due to consistently low vitamin D levels observed in most patients with severe SHPT, thus limiting its predictive usefulness. Further studies are necessary to clarify the influence of these factors on hypocalcemia development.

The primary aim of this study is to provide clinicians with a practical tool for enhancing patient care. A key strength supporting its feasibility is that the model includes five predictive factors routinely available or easily obtainable during preoperative evaluations for PTX. Serum calcium, PTH, and ALP are standard laboratory tests. Although the CTX assay is more specialized, it is a widely recognized marker for bone turnover, increasingly used in managing severe renal bone disease. We propose embedding this assessment tool into hospital electronic health record (EHR) systems. Clinicians could utilize the nomogram in real-time during perioperative care. The EHR could automatically extract the required laboratory data, compute the risk score, and issue alerts for patients at high risk, prompting clinical teams to adjust postoperative management plans accordingly. It should be emphasized that the nomogram serves as a risk stratification tool to assist, but not replace, clinical judgment.

This study introduces a novel nomogram to predict postoperative hypocalcemia, developed using linear regression analysis. Additional strengths of the study include the following: the linear regression model provides richer, more actionable information; the sample size (n = 685) is adequate; ten-fold cross-validation and leave-one-out cross-validation were performed, confirming the reliability of the nomogram; and patients with a total score of $\le$106.5 were identified as a high-risk subgroup for SH.

However, this study has several limitations. Firstly, the data were collected from a single institution, limiting the generalizability of the results. Secondly, this research was retrospective. Although surgical procedures were selected based on intraoperative anatomical findings, the possibility of subtle selection biases inherent in retrospective designs cannot be completely ruled out. Thirdly, despite excluding patients with over 30% missing data and employing multiple imputation for features with less than 20% missing values, residual confounding effects may persist. Finally, other unmeasured factors potentially associated with postoperative hypocalcemia, such as parathyroid gland weight and bone mineral density, were not evaluated. Incorporating these variables should be a primary goal for future prospective studies.

In conclusion, this model demonstrates strong predictive capability by integrating preoperative hypocalcemia status, ALP, CTX, PTH, and surgical procedures. Clinicians can use this tool preoperatively to evaluate hypocalcemia risk in patients with SHPT, enabling timely interventions and improved outcome predictions.

• This study developed and validated a nomogram to predict severe hypocalcemia on the first postoperative day in patients with secondary hyperparathyroidism undergoing parathyroidectomy.

• Multivariable linear regression identified preoperative serum calcium, parathyroid hormone, alkaline phosphatase, CTX, and surgical procedures (TPTX vs. TPTX-AT) as independent predictors.

• The model showed good calibration and internal validation, with AUCs of 0.75 for hypocalcemia and 0.81 for severe hypocalcemia.

• This nomogram enables individualized risk stratification and supports tailored perioperative calcium management to improve outcomes in SHPT patients.

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

WTL: Conceptualization, Methodology, Data curation, Formal analysis, Visualization, Writing—original draft. YW: Data curation, Investigation, Writing—original draft. JX: Investigation, Data curation. ZHL: Formal analysis. PZ: Conceptualization, Supervision, Funding acquisition. QQH: Conceptualization, Methodology, Supervision, Funding acquisition. All authors contributed to revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study adhered to the ethical principles for medical research involving human subjects set forth in the Declaration of Helsinki. The research protocol was reviewed and approved by the Research Ethics Committee of the 960th Hospital of the PLA Joint Logistics Support Force (Approval No. 2025-090). As a retrospective study using de-identified data, informed consent was waived. The privacy rights of all human subjects were strictly observed, with all data handled in an anonymized manner to prevent disclosure of personal information.

This study was generously supported by Jingding Medical Tech, to whom we extend our sincere gratitude. We especially thank them for providing authorization and technical support for the JD-LCPM software (V2.10, Jingding Medical Technology Co., Ltd., Hefei, China). The team at Jingding Medical Tech offered invaluable assistance in data processing. They provided valuable assistance in data processing and technical support, and did not influence or interfere with the objectivity of the results.

This work was supported by the Key Medical Discipline Project of Joint Logistics Support Force of the People’s Liberation Army of China.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/BJHM50726.