Observations: We report three cases of hungry bone syndrome developed after parathyroidectomy for hyperparathyroidism. Hypocalcaemia was objectified immediately on postoperative with a generalized tetanus attack in the two patients. One patient has developed cramps and tingling of the limbs. An oral calcium supplement was prescribed. The tingling disappeared on postoperative with a normalization of the calcium serum level in the three cases. Conclusion: HBS is a serious complication after parathyroidectomy for hyperparathyroidism.
All risk factors should be indentified in PHP patients. A strategy to prevent its occurrence must be done. The hungry bone syndrome HBS is an important complication often under diagnosed that occurs essentially after parathyroidectomy for primary hyperparathyroidism PHP or secondary hyperparathyroidism SHPT.
It is defined as a prolonged hypocalcaemia with hypophosphataemia hat exacerbated by suppressed parathyroid hormone PTH levels [1,2]. Indeed, intensive bone turn-over and excessive greed for calcium is developed during the HBS [3]. Many risk factors had been identified to predict HBS in HPT such as old age, size of resected parathyroid glands, preoperative serum parathyroid hormone PTH level, preoperative serum alkaline phosphatase ALP level and serum urea nitrogen concentration [2,].
Unfortunately, only few publications found that young age, high body weight, high preoperative serum ALP level, and low preoperative serum calcium level predicted the development of HBS [2]. The aim of this study is to alert physician that this serious complication could be seen in both SHPT and HPT even if bone abnormality is quiet different between the two populations. Among them, three patients developed a HBS. A year-old female patient was admitted with complaints of bone pain and exploration of multiple renal lithiasis.
Clinical examination found a thyroid goiter without any compression sign. The biological analysis demonstrated: a preoperative serum calcium level at 2. Her neck ultrasound showed a multinodular goiter at the expense of two lobes, the MIBI scintigraphy revealed hyperfixation of the right inferior parathyroid. Bone densitometry recorded indicated a bone demineralization. She was referred to otolaryngologist for neck exploration.
Preoperatively, the left superior parathyroid was large with a goiter. The patient had superior left parathyroidectomy associated to thyroidectomy. The anatomopathologist confirmed the presence of an adenoma in both parathyroid and thyroid. Hypocalcaemia was objectified immediately on postoperative when she developed a generalized tetanus attack.
A year-old male patient with a medical history of pathological fracture of the lower limb. He was complaining about bone pain. The biological analysis showed: a preoperative serum calcium level at 2.
Both neck ultrasound and MIBI scintigraphy had demonstrated an abnormal right inferior parathyroid. The neck exploration found a huge right inferior parathyroid that was addressed to the anatomopathological examination. The presence of adenoma in parathyroid was confirmed.
The patient has developed a generalized tetanus attack with severe Hypocalcaemia immediately on postoperative. A normalization of the calcium serum level 2. On any tentative of supplements degression tingling appears associated to hypocalcaemia. A year-old male patient with a medical history of chronic kidney disease and dialysis since nineteen years old. Clinical examination of the neck was normal. The presence of hyperplasia in the 3.
The patient has developed cramps and tingling of the limbs immediately on postoperative. The serum calcium level attended 1. The serum phosphataemia level was collapsed. Flowchart of articles included in the systematic review. Citation: European Journal of Endocrinology , 3; Bone remodelling consists of a series of cellular events on the bone surface, the function of which is to remove damaged bone through the process of osteoclastic bone resorption, and replacing it with new bone through the process of osteoblastic bone formation.
The process of bone resorption, which lasts about 2 weeks is followed by a reversal phase of 2—3 weeks duration, before new bone is formed, which lasts about 3 months. The remodelling space is the total amount of bone that at any time has been resorbed by osteoclasts but not yet reformed by osteoblasts during the coupled remodelling process because of the delay between resorption and formation.
This space depends on the activation frequency of new remodelling sites, which is considerably increased in PHPT, leading to mineral depletion of bone and significantly contributing to the hypercalcaemia of PHPT 10 , 11 , 12 , 13 , In those patients with preoperative high rates of bone turnover, successful parathyroidectomy curbs osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space leading to a consequent gain in bone mass.
This is believed to be the cause of the rapid, profound and sometimes prolonged decrease in serum calcium, phosphate and magnesium levels.
The duration of the HBS is defined as the duration of post-operative hypocalcaemia or time required for normalisation of serum calcium following successful parathyroidectomy, which parallels normalisation of bone turnover and may last for up to 9 months, but exceptionally longer in cases of parathyroid carcinoma following radical excision of the tumour.
In our experience, the duration of the hypocalcaemia is determined by the height of the increased bone turnover preoperatively as well as by the time required for recovery of normal function of residual non-pathologic parathyroid tissue N A T Hamdy, , unpublished personal observations.
Patients can also develop generalised convulsions, which can lead to pathological fractures 27 , 28 , and ultimately if remaining uncorrected to coma and even death. Congestive heart failure, which is reversible after normalisation of serum calcium concentration, has also been reported 15 , Older age at time of surgery is a risk factor for HBS 1.
Patients who developed HBS had higher preoperative levels of serum calcium, and almost two-fold increased levels of PTH and alkaline phosphatase compared with patients who had an uncomplicated post-operative course Table 1 1 , 4 , However, Lee et al.
Serum magnesium and albumin levels were found to be significantly decreased in patients who subsequently developed HBS Table 1 1. Preoperative laboratory data in patients with primary hyperparathyroidism who developed HBS following parathyroidectomy compared with those who did not. Radiological evidence of PHPT-related bone disease has been reported to be an important risk factor for the development of HBS 4 , 16 , 17 , 26 , 27 , 31 , Fourteen of 18 case reports on HBS indeed report skeletal abnormalities, such as subperiostal erosions, lytic lesions, brown tumours and multiple fractures 15 , 16 , 17 , 18 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 40 , 41 , 42 , 43 , There are no available data on the relationship between histological characteristics of the resected pathological glands adenoma vs hyperplasia and the development of HBS.
A rapid decrease in serum PTH levels to a mean of 1. Serum phosphate levels decrease post-operatively and remain so for the duration of the syndrome 1 , 17 , 27 , 31 , 37 , 38 , 40 , 45 , Hypomagnesaemia is frequently encountered Serum alkaline phosphatase levels increase significantly post-operatively and remain elevated sometimes for up to 9 months after surgery 1 , 17 , 27 , 31 , 38 , 39 , 40 , 42 , 43 , Agarwal et al. In three of 51 patients with extreme osteopenia, bone turnover markers remained elevated for 1 year after successful parathyroidectomy Removal of the excessive circulating levels of PTH shuts off bone-resorptive activity and leads to a rapid increase in bone mineral density.
Follow-up radiographs show recovery of subperiosteal resorption and remineralisation of brown tumours, osteolytic lesions and fracture sites 7 , 16 , 27 , A moderately increased uptake can still be seen 8 months after parathyroidectomy 18 and a decrease in the number of lesions and a normalisation of uptake in the remaining lesions 1 year after parathyroidectomy The treatment of HBS is aimed, in the short term, primarily at replenishing the depleted skeletal calcium stores.
The first case reports of a HBS, which appeared in the late s, described the difficulties encountered in the management of this severe complication of parathyroidectomy before active metabolites of vitamin D and their synthetic analogues became available for use in the clinic 15 , 22 , 26 , These management difficulties are, however, still being observed today, despite widespread availability of active vitamin D preparations The amount of magnesium required to correct hypomagnesaemia has not always been reported, and supplementation has been variably given intravenously as magnesium chloride or sulphate or orally as magnesium sulphate 15 , 17 , 19 , 22 , 26 , 38 , In 11 of 18 cases, serum magnesium level was not mentioned, and in one of 18 cases serum magnesium level was within the normal range 16 , 18 , 21 , 23 , 24 , 25 , 27 , 29 , 40 , 41 , 42 , Depleted vitamin D status has been postulated to be a risk factor for the development of HBS and it has generally been recommended to supplement vitamin D to normalise 25 OH vitamin D levels, although there are so far no available data to support the premise that this would contribute to the prevention or blunting of HBS 1 , Two case reports of patients with extensive hyperparathyroid bone disease demonstrated that preoperative treatment with i.
In a retrospective study, Lee et al. There was no significant difference in preoperative mean serum calcium 3. A retrospective case series of 46 patients with severe bone disease, who were treated with i.
Boyle et al. In contrast, Heath et al. HBS is a relatively uncommon complication of parathyroidectomy for severe PHPT associated with preoperative high bone turnover.
It is characterised by a rapid, profound and persistent hypocalcaemia associated with hypophosphataemia, hypomagnesaemia and is exacerbated by suppressed PTH levels. The duration of the HBS is the time taken to remineralise the skeleton, which is also mirrored by normalisation of bone turnover markers, by healing of radiological features of osteitis fibrosa cystica and brown tumours and by significant gains in bone mass.
Our literature search suggests that the prevalence of HBS has decreased in the Western World over the last two decades, most likely due to the early detection of still asymptomatic PHPT by routine calcium screening before the effects of high circulating levels of PTH on the skeleton, such as high bone turnover, osteoporosis or osteitis fibrosa cystica, become evident 38 , 45 , although exact numbers are missing.
One of the identified risk factors for a post-operative HBS is older age at the time of surgery. A testable hypothesis for the development of bone disease, and for the development of HBS, relates to the possibility that low circulating levels of 1,25 OH 2 D with resultant decreased fractional absorption of calcium, leads to undermineralisation of the skeleton 1 , 4. Low levels of 1,25 OH 2 D may thus represent a measurable risk factor for the development of HBS, independently of age, although 25 OH D deficiency has been proposed to be the more significant risk factor Preoperative serum alkaline phosphatase levels reflect the state of bone turnover and, therefore, the degree of osteoclast activity and bone resorption.
It has been suggested that preoperative serum alkaline phosphatase concentrations may predict the degree and duration of hypocalcaemia after successful parathyroidectomy Other risk factors for the development of HBS include evidence of bone disease, such as osteitis fibrosa cystica, subperiostal bone erosions or bone cysts 4 , 15 , 16 , 17 , 26 , 27 , 31 , 39 and the volume and weight of the removed hyperactive parathyroid gland s 1 , 3.
Treatment of the HBS is aimed in the short term primarily at replenishing the circulating calcium deficit, and in the longer term, at normalising bone turnover and remineralising the skeleton. Doses of calcium and active vitamin D preparations required and duration of treatment is guided by serum calcium and bone turnover marker levels, aiming at normalisation of bone turnover 3 , 15 , 20 , 26 , 27 , 28 , 45 , which may sometimes last in excess of 12 months after successful surgery.
In the early stages of HBS, the doses of calcium supplements necessary to increase and maintain serum calcium concentrations within the normal range are too large to be tolerated orally, and i.
When calcium-containing solutions are given intravenously, administration into large veins or via a central venous catheter is recommended to minimise the risk of local irritation or tissue necrosis by accidental extravasation in surrounding tissues.
Electrocardiographic monitoring is recommended as dysrhythmias may occur in case of too rapid correction of the hypocalcaemia In prescribing oral calcium preparations, it is important to realise that different calcium preparations contain different amounts of elemental calcium. If high doses of magnesium are required for the treatment of hypomagnesaemia, this should only be given intravenously in adequate dilutions of magnesium sulphate, and not intramuscularly or orally.
Lower doses of magnesium can be supplemented as magnesium oxide orally or magnesium sulphate intramuscularly Hypocalcaemia does not resolve until the magnesium deficiency has been corrected 3 , 15 , 26 , 27 , 28 , Depleted vitamin D status has been postulated to be associated with an increased risk of developing post-operative hypocalcaemia and HBS 55 , 56 , 57 , Preliminary data suggest that preoperative correction of vitamin D deficiency may decrease levels of PTH and bone turnover, without exacerbating hypercalcaemia 55 , 58 , Although the effect of preoperative vitamin D treatment on post-operative hypocalcaemia has not been evaluated by randomised controlled intervention studies in PHPT, it is our experience that a preoperative replete vitamin D status is associated with a decreased likelihood of a severe or prolonged HBS 1 , Bisphosphonates are antiresorptive agents, widely used in the management of osteoporosis and bone disorders associated with increased bone turnover, such as Paget's disease of bone or metastatic bone disease.
In hyperparathyroid bone disease these agents inhibit osteoclastic bone resorption and decrease activation frequency of remodelling sites, thus resulting in refilling of remodelling space and increasing mineralisation of bone 38 , 60 , 61 , In this context, preoperative bisphosphonate treatment would have a potential beneficial effect on the severity and duration of HBS by significantly decreasing or normalising bone turnover before surgery is attempted 38 , In contrast, short term preoperative treatment may exacerbate post-operative hypocalcaemia by just reducing bone resorption, without allowing time for a coupled decrease in bone formation.
There are as yet no prospective studies or randomised control trials addressing the use of bisphosphonates in the prevention or limitation of duration of HBS.
Data from case reports and small case series on the beneficial effect of preoperative treatment with bisphosphonates on the HBS in patients with hyperparathyroid bone disease 7 , 35 , 37 , 51 or with longstanding severe PHPT 49 are conflicting 23 , 27 , 35 , 36 , Some cases thus report failure of preoperative bisphosphonates to prevent HBS, although this was believed to be due to short duration of treatment or low dosage used, as serum alkaline phosphatase levels had not normalised before surgery 23 , 38 , 42 , 43 , Because low levels of 1,25 OH 2 D are a risk factor for the development of post-operative HBS 1 , 4 , it has also been hypothesised that preoperative supplementation of 1,25 OH 2 D could shorten symptomatic hypocalcaemia and hospital course 1 , 7 , HBS is a relatively uncommon but serious complication of parathyroidectomy for PHPT associated with high bone turnover.
There are no clear guidelines for the management of the HBS, but treatment is aimed at replenishing the severe calcium deficit and at restoring normal bone turnover with the use of high doses of calcium and active metabolites or analogues of vitamin D. Adequate preoperative treatment with bisphosphonates may reduce the severity and duration of post-operative hypocalcaemia. Further prospective studies are needed to optimise pre- and post-operative treatment strategies in patients with PHPT and skeletal manifestations at high risk for HBS.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery.
American Journal of Medicine 84 — Relation of postoperative hypocalcemia to operative techniques: deleterious effect of excessive use of parathyroid biopsy. Surgery 92 — Zamboni WA , Folse R. Adenoma weight: a predictor of transient hypocalcemia after parathyroidectomy.
American Journal of Surgery — BMJ 1 — Prospective study of perioperative factors predicting hypocalcemia after thyroid and parathyroid surgery. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism. Archives of Surgery — Inhibition of 1,25 OH 2 D production by hypercalcemia in osteitis fibrosa cystica: influence on parathyroid hormone secretion and hungry bone disease.
Bone and Mineral 23 15 — The findings could be of substantial help in the prevention of HBS and perioperative management in this group of patients. It was a retrospective study on 62 consecutive dialysis patients who underwent parathyroidectomy because of SHPT between January 1, , and February 28, , in a regional hospital with a program of about prevalent peritoneal dialysis PD and hemodialysis HD patients.
The medical records were reviewed and data including patient gender, age at the time of surgery, and operative-, laboratory-, medication-, and dialysis-related data were collected.
The serial results of the following laboratory parameters preoperatively and, for multiple time points, postoperatively were identified: hemoglobin, serum albumin, calcium, phosphate, alkaline phosphatase ALP , and intact parathyroid hormone PTH levels.
Except for the early postoperative period when frequent and close monitoring of serum calcium was required, blood sampling was performed immediately before the commencement of individual dialysis session in HD patients. In addition, detailed information about preoperative medications, including daily doses of phosphate-binding drugs, active vitamin D analogs and calcimimetics were recorded.
For active vitamin D analogs and calcimimetics, the exposure to such agents was counted only if the patients had taken the drug for 30 days or more within the day period preceding the surgery. Cumulative doses of calcium and vitamin D supplements at 14 days, 1 month, 3 months and 12 months after surgery were calculated. Hungry Bone Syndrome was defined as profound and prolonged hypocalcaemia with corrected serum calcium level of 2. All patients underwent bilateral neck exploration with an attempt to identify all parathyroid glands.
When four or more glands were identified at the time of surgery, total parathyroidectomy was intended without doing any autotransplantation. If fewer than four glands were found, all identifiable parathyroid glands were removed. All patients undergoing parathyroidectomy were started on oral alfacalcidol 2 micrograms twice daily for 2 days before surgery if they were not receiving any form of active vitamin D analog before the surgery.
After surgery, all patients received a normal calcium dialysis bath. Serum calcium levels were monitored every 6 h starting from the time immediately after surgery. If serum calcium level was 2. Cinacalcet or paricalcitol therapy was stopped if present. When they were fully awake, patients were prescribed with oral calcium supplements and vitamin D analogs alfacalcidol or calcitriol with the dosage titrated against the serum calcium levels to allow cessation of calcium infusion.
The frequency of serum calcium level monitoring and the dosage of intravenous calcium infusion were adjusted by the attending physician the next day after operation. Patients were discharged when calcium levels remained stable in the normal range.
Statistical analyses of collected data were performed using SPSS version Continuous variables were compared using independent samples T -test or Mann-Whitney U test for data of non-normal distribution. There were 46 female and 16 male patients with a mean age of There was no predominant primary renal diagnosis in these patients. At the time of surgery, 17 Mean vintage on dialysis was 5.
The pathology revealed parathyroid hyperplasia in The mean serum calcium level of the 62 patients decreased from 2. There were 17 patients However, they all suffered no symptom of hypocalcaemia. While the serum calcium levels of patients without HBS appeared to stabilize after the first few days, the fall of serum calcium in patients with HBS tended to last longer with the trough occurring at about 2 weeks after the operation.
The serum calcium levels of patients with HBS remained significantly lower throughout the following up period up to 1 year after operations when compared with patients without HBS. Serum calcium level before and after parathyroidectomy. The mean serum phosphate level of the 62 patients decreased from 2. The serum phosphate level tended to stabilize between 4 and 14 days after the operation.
There was no significant difference in the serum phosphate level between patients with and without HBS. The change in serum phosphate level over time was shown in Fig. Serum phosphate level before and after parathyroidectomy. Generally, serum ALP level increased progressively after surgery in both groups, attaining their peak levels at 2 weeks postoperatively and then decreased gradually Fig.
By 3 months, In addition to having a higher preoperative level, patients with HBS also showed a significantly higher serum ALP level at day 5, day 7 and 1 month after the operation as compared with patients without HBS.
Serum ALP level before and after parathyroidectomy. At 1-year follow-up, 12 Table 2 summarized the results on postoperative use of calcium and vitamin D supplementation in the 62 patients divided into the two outcome groups. Average daily doses of calcium supplementation were significantly higher in the group with HBS compared to the group without HBS up to 1 year postoperatively.
Similarly, average daily doses of vitamin D supplementation postoperatively were higher in HBS group as compared with the group without HBS throughout the study period. For patients who received active vitamin D analogs preoperatively, the requirement of calcium and vitamin D supplementation after surgery tended to be lower than those who did not receive active vitamin D analogs, but the difference did not reach statistical significance Table 3a.
For patients who received cinacalcet preoperatively, the requirement of calcium and vitamin D supplementation after surgery appeared to be higher than those who did not receive cinacalcet, but the difference did not reach statistical significance Table 3b. Preoperative use of active vitamin D analogs had no significant effect on the development of HBS. The proportion of patients with preoperative use of cinacalcet appeared to be higher in HBS group compared with the group without HBS but the difference did not reach statistical significance With the significant findings in univariate analysis, factors including gender, age, body weight, serum preoperative ALP and serum preoperative calcium levels were further evaluated using multivariate logistic regression analysis, and it showed that that young age, high body weight, high preoperative serum ALP level, and low preoperative serum calcium level independently predicted the development of HBS Table 5.
Additional analyses forcing preoperative iPTH levels into the model yielded no change in the results. Although there are a few retrospective studies in the literature examining the problem of post-operative hypocalcemia in dialysis patients undergoing parathyroidectomy, there was marked heterogeneity in the case definition and reported incidence ranging from Most studies merely focused on individual aspect such as the occurrence of early hypocalcemia immediately after the operation whereas other studies addressed the problem from other perspectives such as the length of hospital stay after operation, hospital readmission and total calcium requirement [ 9 — 13 ].
Since these studies just concentrated on a particular area in the postoperative course, the data might not be able to reflect the whole situation.
In addition, parathyroid procedures were rather variable in these studies. The majority underwent subtotal parathyroidectomy or total parathyroidectomy with auto-transplantation while total parathyroidectomy merely accounted for a minority. Indeed, there has not been any study that could clearly delineate the postoperative course in patients with total parathyroidectomy for SHPT.
In this context, this study examined multiple aspects related to the postoperative care in patients suffering from SHPT undergoing total parathyroidectomy without autotransplantation. They included serial changes in serum calcium, phosphate and alkaline phosphatase levels, calcium and active vitamin D requirement and length of hospitalization in addition to risk factor identification for postoperative occurrence of HBS.
Indeed, this study showed that in patients undergoing total parathyroidectomy, although the serum calcium level and phosphate level tended to fall immediately after the operation, there might be a delay up to 2 weeks after the operation before it reached its lowest level. At the same time, serum ALP level also increased progressively after the operation, reflecting the state of increased bone formation [ 14 , 15 ], and peaked at week 2.
These findings should carry important implications. First, the severity of hypocalcemia and demand of calcium replacement resulting from accelerated bone formation might not be fully reflected by the serum calcium level early after operation. In other words, patients might develop severe hypocalcemia in the later time despite a modest drop in serum calcium early postoperatively. Therefore, patients undergoing total parathyroidectomy should have their serum calcium and phosphate levels closely monitored in the following 2 weeks to safeguard against the development of severe hypocalcemia and to provide guidance on the intensity of calcium supplementation.
At the same time, it appeared that the rise of serum alkaline phosphate correlated well with the decline in serum calcium and probably increasing demand of calcium replacement. Serum ALP level might therefore serve as a biomarker indicating the intensity of bone formation and the likely calcium requirement of individual patients. In practical terms, a rising serum alkaline phosphatase might portend an increasing demand for calcium supplementation and should prompt for a dose escalation whereas a declining serum ALP level would warrant consideration of dose tapering in active vitamin D and calcium to avoid overzealous replacement and inadvertent hypercalcemia.
Second, this postoperative calcium dynamic with delayed drop in serum calcium level also challenges the validity of those case definition adopted by some previous studies in examining the problem, which solely focused on serum calcium level immediately after operation.
In contrast, by including all those cases having profound and prolonged hypocalcaemia lasting for 4 days or more that occurred anytime within 1 month following parathyroidectomy, it is highly unlikely that any case of significant postoperative hypocalcemia would have been missed and misclassified in this study. In other words, we believe that our definition of HBS in this study should be appropriate which could allow us to identify a particular group of patients who would likely require intensive monitoring and aggressive calcium supplementation.
It follows that the risk factors found in this study should also be highly relevant and be of help in accurately identifying those high risk individuals.
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