Hungry Bone Syndrome After Parathyroidectomy for Secondary Hyperparathyroidism: Pathogenesis and Contemporary Clinical Considerations
Abstract
1. Introduction
2. Parathyroid Hormone Physiology
3. Pathogenesis of Secondary Hyperparathyroidism in Chronic Kidney Disease
4. Molecular Targets and Signaling Pathways in Bone Tissue
4.1. The RANKL/RANK/OPG System
4.2. The Wnt/β-Catenin Signaling Pathway
4.3. Calcium-Sensing and Mineral Flux Dynamics
5. Bone Remodeling Dynamics Before and After Parathyroidectomy
6. Timeline and Clinical Evolution
7. Risk Factors and Predictive Modeling for Hungry Bone Syndrome in Secondary Hyperparathyroidism
7.1. Key Biochemical and Clinical Predictors
- Preoperative PTH Level: Very high iPTH represents a surrogate marker for severe SHPT and high bone turnover. Many studies report significantly higher pre-PTX PTH in HBS patients versus non-HBS [11]. In general, the risk of HBS rises sharply at the extreme PTH levels seen in dialysis patients (e.g., an iPTH >1000 pg/mL was reported as an independent HBS predictor in a 130-patient cohort [18]). However, some cohorts (see Table 2) did not find PTH an independent risk factor when controlling for ALP [30], likely because PTH and ALP are collinear.
- Bone Turnover Markers: Elevated serum ALP (especially bone-specific ALP) is one of the strongest and most consistent predictors of HBS. In multiple studies, pre-op ALP was significantly higher in those who developed HBS [11,18,30,114,129]. ALP reflects osteoblastic activity and overall bone turnover; values >3–4× the ULN (previously proposed cutoff of ALP >420 U/L [18]) carry high associated risk. Other predictive bone formation markers (OC, P1NP) and resorption markers (CTX, TRAP-5b) are currently being investigated and, when available, may prove useful [11,114]. Essentially, their dynamics reflect a very high bone turnover state pre-PTX, which sets the stage for dramatic post-op remineralization.
- Preoperative Calcium and Vitamin D: Paradoxically, lower pre-op serum calcium level (within the context of ESRD) portends a greater drop post-PTX. Patients with autonomous hypercalcemia from tertiary HPT (or adynamic bone) actually have less bone uptake capacity and thus lower HBS risk. Conversely, a normal or low calcium in a severe SHPT patient indicates suppressed bone mineralization despite high turnover—the body maintains normocalcemia by inhibiting calcium incorporation into an expanded but under-mineralized osteoid matrix. After PTX, this “hungry” skeleton rapidly mineralizes, causing profound hypocalcemia as calcium floods into bone. Indeed, absence of pre-op hypercalcemia was a significant risk factor in multiple studies, with meta-analyses showing an odds ratio of 0.19 (95% CI: 0.11–0.31) for severe post-op hypocalcemia [129]. Severe 25-hydroxyvitamin D deficiency (common in CKD) could theoretically exacerbate HBS by limiting baseline calcium stores, but most patients are repleted before PTX; studies on vitamin D status and HBS risk have shown mixed results [11].
- Patient Factors (Age, Body Mass, Sex, Dialysis Vintage): Younger patients tend to mount more robust osteoblastic responses and have more metabolically active bone, which increases HBS susceptibility [11,18]. Indeed, age ≤45 was an independent predictor in multiple series [18,30]. Higher body weight (and by extension, greater skeletal mass) has also been linked to HBS risk [30]. The influence of sex is less clear. Some reports suggest males are at higher risk (potentially due to larger bone mass and lower estrogen levels predisposing to high-turnover lesions), but this has not been consistently observed. Nutritional status may play a role as well—one recent systematic review found that low pre-PTX albumin correlates with HBS [11], possibly reflecting frailty or chronic inflammation. Finally, the duration of pre-PTX dialysis may influence HBS risk, as longer dialysis vintage is associated with more severe CKD-mineral bone disorder. Multiple investigations have corroborated this notion [11,116].
- Skeletal Burden of Disease: Patients with overt skeletal manifestations of SHPT (e.g., osteitis fibrosa cystica, subperiosteal bone resorption on X-ray, or brown tumors) inherently have very high bone turnover and large calcium deficits, predisposing them to severe HBS. In contrast, those with mixed uremic osteodystrophy or adynamic bone (often seen in longstanding diabetes or with calcimimetic overuse) have lower turnover and thus lower HBS risk. A bone biopsy (though rarely done pre-PTX) showing high turnover and abundant osteoid would strongly predict HBS. Similarly, very low pre-op bone mineral density could indicate high turnover bone loss.
- Surgical Factors: The extent and abruptness of PTH reduction at surgery significantly influence HBS development. Total PTX without autotransplantation causes the most complete and immediate PTH withdrawal, and thus confers the highest HBS risk [130]. Subtotal PTX or total PTX with a small autograft (e.g., forearm implant) theoretically leaves behind some PTH source to mitigate post-op hypocalcemia [131]. Even so, if the remnant tissue is insufficient or non-functioning, HBS can still occur. Thus, cohorts receiving autotransplant have shown inconsistent results: either marginally lower rates of severe HBS compared to those with solely total PTX [132], or no effect at all in any type of HPT patient [11]. The size and weight of resected parathyroid glands may also correlate with risk—larger glands (or higher total gland weight) theoretically indicate a greater burden of hyperactive tissue, which in turn implies more profound skeletal PTH effects pre-op [11]. Even so, results are scarce and inconsistent. Notably, in primary HPT, glands >1.7 cm had higher HBS occurrence risk [133], whereas in SHPT, removal of very large hyperplastic glands likewise portends HBS [117]. Concomitant thyroidectomy has been noted as a risk factor in primary HPT (likely due to longer associated operative time) [11], but in SHPT patients this is less common.
7.2. Emerging Predictive Models and Risk Scores
8. Prevention and Management Strategies
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ALP | Alkaline phosphatase |
BMU | Basic multicellular unit (anatomic bone remodeling unit) |
BTMs | Bone turnover markers |
CaSR | Calcium-sensing receptor |
CKD | Chronic kidney disease |
cAMP | Cyclic adenosine monophosphate |
CREB | cAMP-response element binding protein |
C-PTHR | C-terminal parathyroid hormone receptor |
CTX | C-terminal telopeptide of type I collagen (bone resorption marker) |
CYP24A1 | 25-hydroxyvitamin D-24-hydroxylase |
CYP27B1 | 25-hydroxyvitamin D-1α-hydroxylase |
ESRD | End-stage renal disease |
FGF-23 | Fibroblast growth factor-23 |
GFR | Glomerular filtration rate |
H&E | Hematoxylin and eosin (histological stain) |
HBS | Hungry bone syndrome |
HPT | Hyperparathyroidism |
iPTH | Intact parathyroid hormone (full-length 1–84 PTH) |
MCP-1 | Monocyte chemoattractant protein-1 |
MEF2 | Myocyte enhancer factor 2 |
MLR | Multivariate logistic regression |
NaPi-2a | Sodium-phosphate co-transporter type 2a |
NaPi-2c | Sodium-phosphate co-transporter type 2c |
NTX | N-terminal telopeptide of type I collagen (bone resorption marker) |
OC | Osteocalcin (osteogenesis marker) |
OPG | Osteoprotegerin |
PKA | Protein kinase A |
PKC | Protein kinase C |
PTH | Parathyroid hormone |
PTH1R | Type 1 parathyroid hormone receptor (classical PTH receptor) |
PTX | Parathyroidectomy |
P1NP | Procollagen type I N-terminal propeptide |
RANK | Receptor activator of nuclear factor-κB (osteoclast precursor receptor) |
RANKL | Receptor activator of nuclear factor-κB ligand |
SHPT | Secondary hyperparathyroidism |
TRACP5b | Tartrate-resistant acid phosphatase 5b (resorption marker) |
TRPV5 | Transient receptor potential vanilloid 5 (renal calcium channel) |
TRPV6 | Transient receptor potential vanilloid 6 (intestinal calcium channel) |
ULN | Upper limit of normal (reference range) |
VDR | Vitamin D receptor |
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Phase (Post-PTX) | Time Frame | Key Biochemical Changes | Clinical Features & Management Considerations |
---|---|---|---|
Immediate | 0–6 h | PTH drops >90% within minutes; Ca2+ initially stable (due to buffers). | Typically, asymptomatic [121,122]. Initiate calcium prophylaxis (e.g., IV calcium), especially if pre-op PTH was high [12]. Monitor Ca2+ q6h [27]. |
Early Acute | 12–72 h | Ca2+ starts to fall (notably by 18–24 h); PO43− rapidly falls by 24–48 h; PTH at nadir. | Subtle symptoms (perioral tingling, distal paresthesias, muscle cramps) may ensue. Positive Chvostek/Trousseau may be elicited [27]. Intensive Ca2+ monitoring (q6–8h) required; adjust IV/oral Ca2+ upwards as needed [27]. Ensure serum Mg2+ is normal [14]. Calcitriol analogues should be initiated [27]. |
Subacute | Day 3–14 | Ca2+ reaches nadir (often day 5–7); ALP peaks (2–3× pre-op); PO43− often <2 mg/dL; Mg2+ low as well. BTMs (CTX, TRAP5b) at nadir. | Severe hypocalcemia symptoms may appear: tetany, seizures, bronchospasm, laryngospasm, arrhythmias. Cardiac monitoring mandatory [15,16]. Highest IV Ca2+ requirements (oftentimes >10 g calcium gluconate/24 h) [12]. PO43− supplementation if <1.5 mg/dL [12]; administer IV Mg2+ as needed [14]. Calcitriol doses should be maximized [12]. |
Recovery | 2 weeks—12 months | Ca2+ gradually normalizes (weeks); ALP declines toward normal (months); PTH remains low (if total PTX) or low-normal (if subtotal/PTX+autograft). | Symptoms resolve. Taper IV Ca2+, then oral Ca2+ over weeks-months. High calcitriol dose continued until ALP normalizes and there is no hypocalcemia on minimal Ca2+ supplementation [15]. In ~10–15% of patients, oral Ca2+/vitamin D needed >1 year (“protracted HBS”) [16]. Endocrine follow-up for permanent hypoparathyroidism (if persistent) [27]. |
Study (Year) | Patient Population (n, Details) | HBS Incidence (Definition) | Significant Preoperative Risk Factors for HBS |
---|---|---|---|
Ho et al., 2017 [30] | 62 dialysis patients; tPTX(-)AT; 10-year single-center cohort. | 27.4% (corrected Ca2+ ≤ 2.1 mmol/L, lasting for ≥4 days, within 1st month post-PTX) | Younger age, higher body weight, higher ALP and lower Ca2+ predicted HBS in MLR analysis. iPTH was elevated in HBS vs. non-HBS, but not an independent predictor (when adjusted for ALP). |
Ge et al., 2019 [114] | 115 dialysis patients; tPTX(+)AT; 2.5-year single-center cohort. | 87.8% (total Ca2+ ≤ 2.1 mmol/L and/or hypocalcemia for ≥4 days post-PTX) | Higher ALP and lower Ca2+ predicted HBS in MLR analysis. Younger age, higher ALP and higher iPTH positively correlated with HBS severity. Specific bone metabolism dynamics were revealed (post-PTX: iPTH, CT, CTX and TRACP5b rapidly decreased, while OC and ALP increased more slowly). |
Kritmetapak et al., 2020 [18] | 130 dialysis patients; PTX technique at surgeons discretion; 6-year single-center cohort. | 82.3% (Ca2+ nadir <8.4 mg/dL within the first 3 days post-PTX and/or requiring IV Ca2+ for symptoms) | PTH >1000 pg/mL, ALP >420 U/L, age ≤45 years and absence of hypercalcemia (corrected Ca2+ <10.2 mg/dL) were significantly associated with HBS in MLR analysis. |
Phimphilai et al., 2022 [116] | 179 dialysis patients; mostly tPTX(+)AT (79.3%); 22- year single-center cohort. | 82.1% (corrected Ca2+ <8.5 mg/dL for >3 days post-PTX) | Longer dialysis vintage (≥5 years), higher PO43− (≥5 mg/dL); higher ALP (≥387 U/L) and mean difference between iPTH pre- and post-PTX (>97%) were independent risk factors for hypocalcemia in MLR analysis. |
Gao et al., 2022 [129] | 2990 ESRD patients with rSHPT (13 studies, from 2013–2021); variable PTX techniques (including ablation). | Not applicable (Meta-analysis of risk factors for post-PTX hypocalcemia) | Lower Ca2+, higher ALP and higher iPTH were associated with post-PTX hypocalcemia (i.e., Ca2+ <8.4 mg/dL within first 3 days post-PTX). Age was not significant. |
Mehta et al., 2024 [11] | 2598 patients undergoing PTX for primary, secondary and tertiary HPT (18 studies, from 2006–2021); variable PTX techniques. | 43.6% for SHPT cohort (Systematic review of risk HBS factors) | Younger age, larger glands, previous dialysis, longer dialysis vintage, Ca2+ close to normal, higher iPTH (i.e., >90% drop in PTH post-PTX), higher ALP, higher OC, lower albumin, and higher TRACP5b were HBS predictors in the SHPT cohort |
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Coman, A.; Tarta, C.; Marian, M.; Popa, D.I.; Olariu, S.; Rosu, M.; Utu, D.; Buleu, F.; Macovei-Oprescu, A.-M.; Novacescu, D.; et al. Hungry Bone Syndrome After Parathyroidectomy for Secondary Hyperparathyroidism: Pathogenesis and Contemporary Clinical Considerations. J. Clin. Med. 2025, 14, 7104. https://doi.org/10.3390/jcm14197104
Coman A, Tarta C, Marian M, Popa DI, Olariu S, Rosu M, Utu D, Buleu F, Macovei-Oprescu A-M, Novacescu D, et al. Hungry Bone Syndrome After Parathyroidectomy for Secondary Hyperparathyroidism: Pathogenesis and Contemporary Clinical Considerations. Journal of Clinical Medicine. 2025; 14(19):7104. https://doi.org/10.3390/jcm14197104
Chicago/Turabian StyleComan, Adina, Cristi Tarta, Marco Marian, Daian Ionel Popa, Sorin Olariu, Mihai Rosu, Diana Utu, Florina Buleu, Anca-Monica Macovei-Oprescu, Dorin Novacescu, and et al. 2025. "Hungry Bone Syndrome After Parathyroidectomy for Secondary Hyperparathyroidism: Pathogenesis and Contemporary Clinical Considerations" Journal of Clinical Medicine 14, no. 19: 7104. https://doi.org/10.3390/jcm14197104
APA StyleComan, A., Tarta, C., Marian, M., Popa, D. I., Olariu, S., Rosu, M., Utu, D., Buleu, F., Macovei-Oprescu, A.-M., Novacescu, D., Zara, F., & Murariu, M. (2025). Hungry Bone Syndrome After Parathyroidectomy for Secondary Hyperparathyroidism: Pathogenesis and Contemporary Clinical Considerations. Journal of Clinical Medicine, 14(19), 7104. https://doi.org/10.3390/jcm14197104