Risk factors and clinical course of hungry bone syndrome after total parathyroidectomy in dialysis patients with secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), which might ultimately develop in nearly all patients with end-stage renal disease (ESRD) [1]. Despite aggressive medical therapy, parathyroidectomy continues to be necessary in those patients with severe SHPT. Hypocalcaemia is the most common medical complication following parathyroidectomy, which could be severe and prolonged in some situations, where a poorly defined entity called “hungry bone syndrome” (HBS) has been used to describe this phenomenon [2].

HBS was first described in 1948 in patients with prolonged hypocalcaemia after parathyroidectomy for primary hyperparathyroidism (HPT) [2]. Old age, size of resected parathyroid glands, preoperative serum parathyroid hormone (PTH) level, preoperative serum alkaline phosphatase (ALP) level, and serum urea nitrogen concentration were found to be risk factors [3‐6]. Nevertheless, the situation in SHPT should be more complicated, to which the above findings in HPT might not be applicable.

Renal osteodystrophy in patients with ESRD encompasses a wide range of bone abnormalities including osteitis fibrosa, adynamic bone disease, osteomalacia, and mixed uremic osteodystrophy [7]. The exact bone abnormality present in individual dialysis patients, which directly affects the bone and metabolic response as well as postoperative course, is highly variable and could not be reliably predicted by serum PTH level [7, 8]. In this context, there is, indeed, little data in the literature concerning the clinical course and risk factors of severe prolonged hypocalcemia or hungry bone syndrome in ESRD patients with SHPT undergoing total parathyroidectomy. In particular, there have been some new drugs, including paricalcitol and cinacalcet, recently available for the treatment of SHPT, and it would be interesting to know whether these drugs would impact on the postoperative course and development of HBS. We therefore did a study to examine the clinical course and risk factors of HBS in a cohort of dialysis patients undergoing total parathyroidectomy. The findings could be of substantial help in the prevention of HBS and perioperative management in this group of 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 90-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 2.1 mmol/L or below lasting for 4 or more days, that occurred anytime within 1 month following parathyroidectomy, despite standard postoperative supportive treatment of our unit. Patients developing HBS according to the definition were compared with those without HBS in terms of baseline characteristics, clinical course and length of hospitalization, and multivariate analysis was performed to evaluate the effect of age, sex, body weight, vintage on dialysis, Kt/V, size of the resected parathyroid glands, preoperative laboratory parameters including serum PTH, ALP, calcium, phosphate, hemoglobin and albumin as well as SHPT drug treatment for the development of HBS.

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 27.8 to 72%. 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.

With our case definition, hungry bone syndrome (HBS) was found to be present in 27.4% of cases in this study. The risk factors predisposing to its development were young age, high body weight, high preoperative ALP level, and low preoperative serum calcium level. Young age and low preoperative calcium have been reported in previous individual case series which employed various different case definitions [9‐11]. The role of preoperative serum ALP level, however, remained controversial. In a case series, high preoperative ALP was shown to be predictive of hypocalcemic problem as being represented by a prolonged hospital stay, whereas protective effect was found in another study which focused on early hypocalcemia within 24 h after operation [9, 13]. On the other hand, heavy body weight was, for the first time, being identified as a risk factor. While the exact underlying mechanism remains unknown, it is plausible that patients with high body weight might have a higher bone mass and hence higher total calcium deficit [16, 17].

Preoperative PTH level was not shown to be a risk factor in the current study. There are a few possible explanations for this. First, uraemic state is associated with resistance of bone cells to the actions of PTH [18‐20], and the relationship between serum iPTH levels and degree of bone remodeling is not always maintained. Second, iPTH assay not only measures the level of biologically active intact PTH (1-84), but also shows cross-reactivity with some smaller N-terminally truncated PTH fragments which have bone action opposite to intact PTH (1-84) [18‐20].

No significant difference was observed between patients with or without receiving active vitamin D sterols such as paricalcitol or cinacalcet preoperatively in terms of the risk of HBS and postoperative calcium requirement. This could either be due to our small sample size or be ascribed to an indirect effect of these drugs on bone healing instead of any direct effect on HBS. Nevertheless, with medications such as paricalcitol shown to have significant effect in suppressing serum ALP in the literature, it is possible that intensive treatment with this type of agents before operation might help mitigate the risk of severe postoperative hypocalcemia [21]. On the other hand, with low serum calcium being a risk factor for HBS, overzealous treatment with cinacalcet preoperatively should probably be avoided.

The present study had several limitations. First, it was retrospective and observational in nature. Thus, the results were subject to possible selection bias and limited by suboptimal data collection. Second, the sample size was relatively small and potential significant associations among variables could have been masked. A formal multicenter registry would provide more accurate estimate of epidemiology and better understanding of clinical features of HBS following parathyroidectomy in renal SHPT in our region. Third, due to the heterogeneous definitions of significant postoperative hypocalcemia or HBS, one must be cautious when comparing the results of the present study to other similar studies.

In addition, patients receiving PD and intermittent HD were pooled into a single study population in this study, where pre-dialysis serum concentrations of individual parameters in HD patients were compared with their PD counterparts being obtained by random blood sampling. With inherent fluctuations in serum concentrations, there might be a concern that pre-dialysis serum concentrations of dialyzable uremic retention molecules, in particular, phosphorus in patient on intermittent HD might not truly reflect the overall exposure, which could potentially affect the validity of comparison. For example, the time-averaged serum concentrations of phosphorus in HD patients were significantly lower despite having the pre-dialysis concentrations comparable with midmorning concentrations of PD [22, 23]. Nevertheless, with similar proportions of HD and comparable preoperative serum phosphate levels in patients with or without HBS in this study, we believe that it should not impact significantly on the results and our univariate and multivariate analyses in risk factor identification should remain valid.

HBS could be common after total parathyroidectomy. Serum calcium tended to fall soon after a successful total parathyroidectomy but the occurrence of severe hypocalcemia could be delayed up to 2 weeks after the operation. Patients should have their serum calcium, phosphate and ALP levels closely monitored in the following 2 weeks, especially for those at risk. Hopefully, with a better understanding of postoperative course and improvement of perioperative management, the occurrence of severe hypocalcemia could be avoided and any adverse consequence could be minimized.