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INTRODUCTION
Hyperparathyroidism (HPT) is a condition characterized by excessive secretion of parathyroid hormone (PTH), leading to disturbances in calcium (Ca) and phosphorus (P) metabolism [1]. Secondary HPT (SHPT) and tertiary HPT (THPT) commonly develop in patients with chronic kidney disease, particularly those undergoing long-term dialysis [23]. In these patients, chronic elevations in PTH drive high bone turnover, leading to compromised bone quality and an increased risk of fractures. If left untreated, HPT can contribute to severe bone disease, vascular calcifications, and cardiovascular complications [14].
Parathyroidectomy (PTX) is the definitive treatment for refractory SHPT and THPT, particularly when medical management fails [56]. Surgical approaches include subtotal PTX (SubPTX) and total PTX with or without autotransplantation [7]. However, PTX is associated with significant postoperative metabolic disturbances, including hungry bone syndrome (HBS), a well-recognized complication characterized by profound and prolonged hypocalcemia [8910]. HBS occurs due to a rapid influx of calcium and phosphorus into bones following the removal of hyperfunctioning parathyroid tissue, driven by enhanced osteoblastic activity and accelerated bone remineralization [111213]. This results in increased calcium and vitamin D demand, necessitating vigilant perioperative management. Failure to properly manage HBS can lead to serious morbidity, including neuromuscular symptoms, cardiac arrhythmias, and even life-threatening complications, highlighting the need for intensive perioperative monitoring and management [14].
Despite its clinical significance, the precise predictive factors for HBS remain poorly defined [1516171819202122]. This study aimed to enhance the understanding of HBS pathophysiology and its predisposing factors by analyzing key biochemical markers—calcium, PTH, phosphorus, and ALP, alongside preoperative and postoperative bone mineral density (BMD). Developing a reliable risk assessment model will facilitate early identification of high-risk patients and enable tailored perioperative interventions, ultimately reducing complications and enhancing recovery. Furthermore, the impact of different surgical techniques on postoperative outcomes will be evaluated to refine patient management strategies.
This study aimed to identify clinical predictors of HBS and assess its impact on bone mineral density after PTX.
METHODS
Ethics statement
The study protocol was approved by the Institutional Review Board of Asan Medical Center (No. 2024-0820), which waived the requirement for informed consent due to the retrospective nature of the study. All methods were performed according to relevant guidelines and regulations.
Patient selection
This retrospective study involved patients who underwent surgery for SHPT and THPT at Asan Medical Center from 2010 to 2022. We identified 206 patients aged ≥ 18 years who underwent SubPTX or total PTX with autotransplantation (TPTX + AT) (Fig. 1). To ensure a homogenous study cohort, patients were excluded based on the following criteria: (1) insufficient intact PTH (iPTH) decrease after surgery, with surgical success defined as ([preoperative iPTH – postoperative iPTH]/preoperative iPTH) ≥0.7 or postoperative iPTH ≤60 pg/mL); (2) previous PTX history (to ensure a more accurate assessment of postoperative changes); (3) preoperative hypocalcemia (Ca <8 mg/dL) or calcium supplementation; (4) loss to follow-up; and (5) missing data.
Data collection
Clinical data, including age, sex, type of operation, laboratory parameters, and postoperative calcium supplementation, were collected. Laboratory values, including iPTH, calcium, phosphorus, and ALP, were measured at multiple time points: preoperatively, postoperatively, 3 months postoperatively, and 1 year postoperatively. The iPTH level was measured using an immunoradiometric assay. Postoperative iPTH levels were assessed at their nadir before patient discharge. HBS was defined as profound hypocalcemia of less than 8.4 mg/dL (2.1 mmol/L) or prolonged hypocalcemia lasting for >4 days after PTX [11]. Among the 91 selected patients, 32 had preoperative and postoperative BMD measurements, which were obtained using dual-energy X-ray absorptiometry at the lumbar spine and femur.
Statistical analysis
Descriptive statistics were used to summarize baseline characteristics. Continuous variables are presented as means with standard deviations, and categorical variables are presented as frequencies and percentages. Comparisons between groups were performed using the Pearson chi-square test for categorical variables and the Mann-Whitney U-test or the Student t-test, depending on data distribution, for continuous variables. To identify risk factors associated with HBS, univariate and multivariate logistic regression analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Statistical analysis was conducted using IBM SPSS Statistics ver. 26.0 for Windows (IBM Corp.). A P-value <0.05 was considered statistically significant.
RESULTS
A total of 91 patients met the inclusion criteria, with 18 patients (19.8%) diagnosed with SHPT and 73 (80.2%) with THPT (Table 1). The mean follow-up duration was 68.3 ± 33.5 months (range, 7–150 months). The mean age of the study population was 48.8 ± 10.6 years, with no significant age difference between the SHPT and THPT groups (P = 0.071). The sex distribution was similar, with males comprising 53.8% of the total population (P = 0.795).
Clinical characteristics of hungry bone syndrome
Patients with HBS were younger at the time of surgery compared to those without HBS (42.9 ± 12.3 years vs. 51.8 ± 8.16 years, P < 0.001) (Table 2). HBS was diagnosed in 31 patients (34.1%), with a significantly higher incidence in SHPT patients compared to that in THPT patients (72.2% vs. 24.7%, P < 0.001).
Surgical techniques and hungry bone syndrome incidence
Among the 91 patients, 80 (87.9%) underwent SubPTX, and 11 (12.1%) underwent TPTX+AT. The 2 surgical procedures were performed equally in the SHPT group, whereas most patients with THPT (97.3%) underwent SubPTX (P < 0.001). All patients who underwent TPTX + AT developed HBS, compared to 25.0% of those who underwent SubPTX (P < 0.001).
Calcium supplementation
Patients with HBS required significantly more postoperative calcium supplementation than those without HBS. Among patients with HBS, 83.9% required calcium supplementation, compared to 43.3% of non-HBS patients (P < 0.001). The duration of calcium supplementation was significantly longer in the HBS group than in the non-HBS group (14.3 ± 22.4 months vs. 2.1 ± 6.6 months, P < 0.001). The maximum calcium dose was significantly higher in the HBS group compared to that in the non-HBS group (1,700.0 ± 1,584.7 mg vs. 411.7 ± 550.2 mg, P < 0.001).
Biochemical parameters
Preoperative iPTH levels were significantly higher in patients with HBS than in those without HBS (1,352.2 ± 1,289.0 pg/mL vs. 407.9 ± 408.7 pg/mL, P < 0.001) (Fig. 2). Postoperative iPTH levels decreased in both groups, with no significant difference between them (P = 0.145).
Calcium levels were consistently lower in the HBS group at all measured time points (Fig. 3). The mean preoperative calcium level in the HBS group was 10.4 ± 1.4 mg/dL, which dropped to a nadir of 7.1 ± 1.1 mg/dL postoperatively and slightly recovered to 8.9 ± 1.0 mg/dL at 1 year (P < 0.001 for all comparisons).
Phosphorus levels were higher in the HBS group than in the non-HBS group preoperatively (3.7 ± 2.1 mg/dL vs. 2.5 ± 0.9 mg/dL, P < 0.001) (Fig. 4). Postoperatively, phosphorus levels decreased in both groups, but at 1 year, the HBS group exhibited higher phosphorus levels compared to the non-HBS group (3.8 ± 1.6 mg/dL vs. 3.0 ± 0.9 mg/dL, P = 0.006).
ALP levels
Preoperative ALP levels were significantly elevated in the HBS group compared to the non-HBS group (411.6 ± 455.1 IU/L vs. 97.5 ± 51.0 IU/L, P < 0.001) (Fig. 5). Postoperatively, ALP levels peaked higher in the HBS group compared to the non-HBS group (432.4 ± 556.2 IU/L vs. 85.8 ± 46.3 IU/L, P < 0.001) and remained higher at all time points: immediately, 3 months, and 1 year postoperatively (P < 0.001 for all comparisons). The mean ALP reduction time was significantly longer in HBS patients (2.1 ± 1.4 months vs. 0.8 ± 2.6 months, P < 0.001).
Bone mineral density
Measurements of BMD revealed significant differences between patients with and those without HBS (Table 3). Preoperative spine BMD was comparable between the 2 groups (P = 0.910), but postoperative spine BMD showed a trend toward improvement in the HBS group compared to the non-HBS group (0.978 ± 0.243 g/cm2
vs. 0.897 ± 0.138 g/cm2, P = 0.136). The increase in spine BMD from pre- to postoperation was greater in the HBS group than in the non-HBS group (17.065% ± 16.325% vs. 5.619% ± 6.321%, P = 0.059).
Femoral BMD significantly improved in the HBS group, increasing from 0.685 ± 0.167 g/cm2 preoperatively to 0.779 ± 0.210 g/cm2 postoperatively (P = 0.005). Contrastingly, the non-HBS group demonstrated only a modest improvement (1.623% ± 5.866%, P = 0.005).
Risk factors for hungry bone syndrome
Univariate logistic regression analysis identified several significant predictors of HBS (Table 4). Younger age was significantly associated with an increased risk of HBS, with an adjusted OR of 3.422 (95% CI, 1.350–8.673; P = 0.010). SHPT diagnosis was also a strong predictor of HBS, with patients diagnosed with SHPT being significantly more likely to develop HBS compared to those with THPT (adjusted OR, 7.944; 95% CI, 2.489–25.358; P = 0.001). Among biochemical markers, higher preoperative ALP levels were strongly correlated with the occurrence of HBS, with each 100 IU/dL increase in ALP levels associated with an adjusted OR of 6.632 (95% CI, 2.638–16.674; P = 0.001). Similarly, higher preoperative iPTH levels were associated with an increased risk of HBS, with each 100 pg/mL increase in iPTH corresponding to an adjusted OR of 1.219 (95% CI, 1.103–1.347; P = 0.001).
Multivariate analysis confirmed that higher preoperative ALP levels remained an independent predictor of HBS, with an adjusted OR of 7.381 (95% CI, 2.751–19.801; P = 0.001).
DISCUSSION
This study demonstrates significant differences in clinical and biochemical characteristics between patients with and without HBS following PTX. Patients who developed HBS required prolonged calcium supplementation, exhibited persistently elevated ALP levels, and experienced greater postoperative BMD recovery. These findings emphasize the profound metabolic and skeletal changes associated with HBS and provide valuable insights for improving perioperative and postoperative management strategies.
Analysis of clinical and biochemical parameters identified younger age, SHPT, and elevated preoperative ALP and iPTH levels as significant risk factors for HBS. These results align with previous studies investigating SHPT patients [171819202122]. The strong association between elevated preoperative iPTH and ALP levels and the development of HBS suggests that high bone turnover plays a crucial role in its pathogenesis. Increased osteoblastic activity and accelerated bone mineralization following PTX result in greater calcium and phosphorus demand, leading to severe and prolonged hypocalcemia [1213]. This study confirmed that postoperative calcium levels remained significantly lower in patients with HBS, while ALP persisted at elevated levels across all measured time points. These findings support the hypothesis that intense bone remodeling and excessive calcium uptake contribute to the pathophysiology of HBS. By systematically identifying these predictors, this study contributes to improved perioperative risk stratification for patients undergoing PTX for SHPT and THPT.
BMD recovery was significantly greater in HBS patients, particularly in the femur, suggesting that patients with higher preoperative bone turnover may experience more pronounced postoperative bone remodeling. Additionally, the variability in BMD recovery emphasizes the need for individualized postoperative monitoring and tailored calcium supplementation strategies. This study further contributes to the understanding of BMD recovery following PTX, demonstrating that surgical intervention has the potential to reverse the deleterious effects of chronic HPT.
Regarding surgical technique, TPTX + AT was associated with a significantly higher incidence of HBS than SubPTX. The abrupt decline in PTH levels following complete gland removal likely triggers more pronounced metabolic shifts, exacerbating calcium demand. Contrastingly, SubPTX may allow a more gradual normalization of calcium metabolism, potentially reducing the severity of postoperative hypocalcemia [23]. These findings emphasize the importance of individualized surgical planning based on patient-specific risk profiles. Specifically, understanding the impact of surgical technique and preoperative biochemical markers enables more precise risk stratification, ensuring that high-risk patients receive early and appropriate interventions to prevent complications.
These results reinforce the necessity of a multidisciplinary approach in managing patients with complex metabolic disorders. Close collaboration among endocrinologists, nephrologists, and surgeons is essential in optimizing the perioperative plan, including biochemical assessments, perioperative monitoring, and individualized supplementation protocols. Implementing standardized management strategies for high-risk patients may enhance long-term outcomes and overall quality of life.
While this study contributes to a comprehensive understanding of HBS following PTX, it has certain limitations. The retrospective nature of the study introduces the potential for selection bias, and the relatively small sample size necessitates further validation in larger, multicenter, prospective studies. In addition, other risk factors being studied related to HBS need to be comprehensively investigated. Future research should focus on establishing predictive models for HBS, integrating both biochemical and clinical risk factors, to facilitate early identification and targeted perioperative management for high-risk patients.
In conclusion, this study identified elevated preoperative ALP and iPTH levels, younger age, and SHPT as significant risk factors for HBS following PTX. Furthermore, TPTX+AT was associated with a higher incidence of HBS compared to SubPTX, emphasizing the impact of surgical technique on postoperative metabolic outcomes. BMD significantly improved after PTX, particularly in the femur, highlighting the potential benefit of surgical intervention in reversing bone loss associated with chronic HPT. Recognizing these risk factors and understanding postoperative bone metabolism patterns in HBS will enable clinicians to optimize perioperative management strategies to reduce severe hypocalcemia and enhance skeletal integrity.
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