Hungry bone syndrome following parathyroidectomy in patients with end-stage kidney disease

INTRODUCTION — Hypocalcemia is a common problem after parathyroidectomy. In patients with end-stage kidney disease (ESKD) and secondary or tertiary hyperparathyroidism, the degree of hypocalcemia after parathyroidectomy is proportionate to the severity of hyperparathyroidism and the extent of parathyroid-mediated high-turnover bone disease [1]. When high-turnover bone disease is suddenly corrected by the reduction in parathyroid hormone (PTH) after parathyroidectomy, reduced bone resorption and increased bone formation lead to a high net influx of calcium into bone, which can cause hypocalcemia.

Hypocalcemia after parathyroidectomy is generally transient when the bone disease is mild. However, in some patients with ESKD, postoperative hypocalcemia can be severe and prolonged, despite normal or elevated levels of PTH. This phenomenon is called the hungry bone syndrome. This syndrome is especially common among patients who have osteitis fibrosa, a bone disease associated with chronic increase in bone resorption [2,3]. (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis".)

In addition to low serum calcium, low phosphate, low magnesium, and high serum potassium levels may be observed in hungry bone syndrome. These electrolyte abnormalities likely reflect increased bone influx and efflux, respectively. (See 'Clinical features' below.)

Hungry bone syndrome has also been described after thyroidectomy in patients with hyperthyroidism [4,5]. In such patients, hypocalcemia is caused by the preoperative thyroid-hormone-induced high-turnover bone disease and by postoperative calcitonin release. A less common cause of hungry bone disease is estrogen therapy in patients with metastatic prostate cancer [6]. Rarely, hungry bone syndrome has been reported in patients with ESKD after starting calcimimetic therapy for secondary hyperparathyroidism [7].

Hungry bone syndrome following parathyroidectomy in patients with ESKD is discussed here. Other related topics are discussed elsewhere:

●Parathyroidectomy (see "Parathyroidectomy in end-stage kidney disease" and "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis")

●Nonsurgical hypoparathyroidism (see "Hypoparathyroidism")

●Management of secondary hyperparathyroidism (see "Management of secondary hyperparathyroidism in adult patients on dialysis" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease")

PATHOGENESIS — The postoperative hypocalcemia results from acute reversal of the parathyroid hormone (PTH)-induced contribution of bone to maintenance of the serum calcium concentration (figure 1). In the high turnover state associated with hyperparathyroidism, PTH increases both bone formation and resorption. Sudden reductions of circulating PTH after parathyroidectomy cause an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption and perhaps other changes affecting calcium fluxes, leading to a marked net increase in bone uptake of calcium, phosphate, and magnesium [3]. Thus, the hungry bone syndrome requires an abrupt decrease in PTH release that upsets the equilibrium between calcium efflux from bone and influx into the skeleton during bone remodeling.

Similar mechanisms may be responsible for the hypocalcemia occasionally seen in patients with metastatic prostate cancer who have been treated with estrogen [6]. The osteoblastic metastases act as a calcium sink, and bone resorption increases to maintain the serum calcium concentration. Inhibition of bone resorption with estrogen unmasks the underlying elevation in bone calcium uptake.

INCIDENCE — The lack of well-defined clinical criteria for the diagnosis of the hungry bone syndrome makes it difficult to determine its true incidence. In a report of 198 patients who underwent parathyroidectomy for primary hyperparathyroidism, the syndrome was considered present if the serum calcium concentration was below 8.5 mg/dL (2.13 mmol/L) and the serum phosphate concentration was below 3.0 mg/dL (0.96 mmol/L) on the third postoperative day [3]. Thirteen percent of the patients fulfilled these criteria, with a mean serum calcium of 8.2 mg/dL (2.05 mmol/L) and a mean serum phosphate concentration of 2.0 mg/dL (0.64 mmol/L).

The incidence of hungry bone syndrome following parathyroidectomy in patients with secondary hyperparathyroidism due to end-stage kidney disease (ESKD) has not been reliably established. In one study of 148 patients on dialysis who underwent parathyroidectomy, hungry bone syndrome occurred in 20 percent [8], whereas in another study of 130 such patients hungry bone syndrome occurred in 82 percent [9]. These widely disparate estimates likely are due to different definitions of hungry bone syndrome.

Risk factors — In the above report of patients with primary hyperparathyroidism, the following were identified as predictive factors for the development of hungry bone syndrome (in descending order of importance) [3]:

●Volume of the resected adenoma

●Preoperative blood urea nitrogen concentration

●Preoperative alkaline phosphatase concentration

●Older age

It is unclear whether these risk factors can be applied to patients with ESKD who undergo parathyroidectomy for secondary hyperparathyroidism. In contrast to studies of primary hyperparathyroidism, studies of ESKD-related secondary hyperparathyroidism have reported that younger patients are at higher risk for hungry bone syndrome [1,9,10]. This finding may be due to selection bias, since younger patients with ESKD are more likely to be referred for parathyroidectomy.

The postoperative fall in serum calcium has been correlated with the severity of bone disease seen on preoperative bone biopsy specimens [11]. The magnitude and chronicity of elevated parathyroid hormone (PTH) also correlates with the development of hungry bone syndrome.

CLINICAL FEATURES — The clinical features of hungry bone syndrome are largely due to hypocalcemia and, to a lesser degree, hypophosphatemia, hypomagnesemia, and hyperkalemia.

Hypocalcemia — Hypocalcemia, with or without its accompanying signs and symptoms, usually dominates the clinical picture. The serum calcium typically reaches a nadir two to four days postoperatively (figure 1) [3]. The duration of hypocalcemia is variable and may last three months or longer [12]. The clinical features of hypocalcemia are discussed at length elsewhere. (See "Clinical manifestations of hypocalcemia".)

Hypophosphatemia — The decrease in bone resorption and increase in bone formation that occurs after parathyroidectomy can also lead to hypophosphatemia. This primarily occurs in patients with primary rather than secondary hyperparathyroidism. In the latter disorder, the serum phosphorus falls from an initially high level to one that is usually still above the normal range (figure 2). The clinical manifestations of hypophosphatemia are discussed at length separately. (See "Hypophosphatemia: Clinical manifestations of phosphate depletion".)

Hypomagnesemia — Hypomagnesemia is also more prevalent among patients undergoing parathyroidectomy for primary hyperparathyroidism. The recognition and treatment of magnesium deficiency is important since hypomagnesemia can contribute to the development of refractory hypocalcemia by diminishing parathyroid hormone (PTH) secretion and inducing PTH resistance. The clinical features of hypomagnesemia are discussed at length separately. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

Hyperkalemia — Hyperkalemia occurs in up to 80 percent of dialysis patients undergoing parathyroidectomy [13,14]. The clinical manifestations of hyperkalemia are discussed elsewhere. (See "Clinical manifestations of hyperkalemia in adults".)

TREATMENT — Treatment is aimed at each of the abnormalities that can occur: hypocalcemia, hypomagnesemia, hypophosphatemia, and hyperkalemia.

Hypocalcemia — Careful monitoring is required to prevent and treat symptomatic hypocalcemia, which can be potentially catastrophic. Thus, the serum calcium concentration should be measured two to four times per day for the first few postoperative days, the time of greatest risk (figure 1). The measurement of ionized calcium is preferred to total serum calcium since the total serum calcium concentration may not reliably predict the ionized calcium concentration, especially among patients with chronic kidney disease.

Oral calcium supplementation (2 to 4 g of elemental calcium [50 to 100 mmol] per day) should be started as soon as the patient is able to swallow. If the serum phosphorus is normal or low, calcium should be administered between meals to maximize intestinal absorption and minimize phosphate binding.

Intravenous calcium is indicated if the patient develops a rapid and progressive reduction in serum calcium or symptoms related to hypocalcemia, including frank or latent tetany (Chvostek's or Trousseau's sign), seizures, cardiac arrhythmias, laryngeal spasm, or either an ionized calcium concentration below 1.0 mmol/L (4 mg/dL) or total serum calcium below 1.9 mmol/L (7.5 mg/dL), all which can be life-threatening. Some protocols would begin intravenous calcium expectantly in patients at high risk of developing hungry bone syndrome, defined by markedly elevated parathyroid hormone (PTH) and alkaline phosphatase levels, before ionized calcium levels decrease below 1.12 mmol/L [15].

Initially, intravenous calcium (1 to 2 g of calcium gluconate, equivalent to 90 to 180 mg elemental calcium, in 50 mL of 5 percent dextrose) can be infused over 10 to 20 minutes. The calcium should not be given more rapidly, because of the risk of serious cardiac dysfunction, including systolic arrest [16]. This dose of calcium gluconate will raise the serum calcium concentration for only two or three hours; as a result, it should be followed by a slow infusion of calcium in patients with persistent hypocalcemia.

Either 10 percent calcium gluconate (90 mg of elemental calcium per 10 mL) or 10 percent calcium chloride (270 mg of elemental calcium per 10 mL) can be used to prepare the infusion solution. Calcium gluconate is usually preferred because it is better tolerated through a peripheral intravenous line and less likely to cause tissue necrosis if extravasated. Local vein irritation can occur with calcium solutions >200 mg/dL.

An intravenous solution containing approximately 1 mg/mL of elemental calcium is prepared by adding 100 mL of 10 percent calcium gluconate (90 mg elemental calcium per 10 mL for a total of 900 mg elemental calcium) to 1000 mL of 5 percent dextrose in water. This solution is administered at an initial infusion rate of 50 mL/hour (equivalent to 50 mg/hour). The dose can be adjusted to maintain the ionized calcium concentration at the lower end of the normal range (normal ionized calcium 4.0 to 5.6 mg/dL [1.1 to 1.4 mmol/L]). Patients typically require 0.5 to 2.0 mg/kg of elemental calcium per hour.

The infusion should be prepared with the following considerations:

●The calcium should be diluted in dextrose and water or saline because concentrated calcium solutions are irritating to veins.

●The intravenous solution should not contain bicarbonate or phosphate, which can form insoluble calcium salts. If these anions are needed, another intravenous line (in another limb) should be used.

We also give active vitamin D (calcitriol) to all patients who are hypocalcemic following parathyroidectomy. Calcitriol increases intestinal absorption of oral calcium and also may slow calcium influx into bone. The typical dose of calcitriol is 0.5 mcg orally twice a day or 1 mcg intravenously daily, though depending on the response to therapy some clinicians escalate the dose in 1 mcg/day increments to a maximum of 2 mcg orally twice a day or to 4 mcg intravenously daily [17]. Calcitriol is continued until the serum calcium concentration is normal (usually two to four weeks). The only concern with the use of high-dose calcitriol is the potential to suppress the function and engraftment of autotransplanted parathyroid tissue.

There are no studies comparing the relative efficacy of oral and intravenous calcitriol administration in this setting. We generally use oral calcitriol since patients are usually discharged from the hospital on an oral regimen of calcitriol and calcium supplementation after the serum calcium has stabilized at a clinically safe level.

Dialysis is another method of correcting the hypocalcemia. A high-calcium bath (3.5 mEq/L [1.75 mmol/L]) can be used in patients undergoing hemodialysis. Alternatively, intravenous calcium can be administered during dialysis, thereby allowing an earlier switch to outpatient management. Similarly, one to three ampules of calcium gluconate can be added to each bag of peritoneal dialysate in patients treated with continuous ambulatory peritoneal dialysis [12].

Hypocalcemia may be prolonged or, in the event of nonadherence to the treatment regimen, recurrent. We check serum calcium weekly following hospital discharge until it is clear that the serum calcium is stable over 8.0 mg/dL [18].

Hypomagnesemia and hypophosphatemia — The serum magnesium and phosphate concentrations should also be monitored since hypomagnesemia and hypophosphatemia can occur. The hypomagnesemia can contribute to the development of refractory hypocalcemia by diminishing PTH secretion and inducing PTH resistance (see "Hypomagnesemia: Clinical manifestations of magnesium depletion"). Thus, raising the serum magnesium concentration may contribute to correction of the hypocalcemia.

In contrast, the administration of phosphate to reverse hypophosphatemia is generally avoided in patients with hungry bone syndrome since phosphate can combine with calcium and further reduce the plasma calcium concentration. Exceptions may be made for patients who have extremely low serum phosphate concentrations (ie, less than 0.5 to 1.0 mg/dL [0.16 to 032 mmol/L]) in the setting of symptoms of hypophosphatemia such as severe muscle weakness or heart failure. Even under such circumstances, the administration of phosphate should be considered potentially hazardous because of the rapidity with which symptoms of resulting hypocalcemia may develop. (See "Hypophosphatemia: Evaluation and treatment".)

Different changes in phosphate balance occur after parathyroidectomy in patients with primary hyperparathyroidism who do not have significant bone disease. These patients do not develop hungry bone syndrome and may have a rise in the plasma phosphate concentration due to reversal of PTH-induced phosphate loss in the urine.

Clinically significant hypomagnesemia and hypophosphatemia are uncommon in patients with chronic kidney failure undergoing parathyroidectomy. Serum phosphate values are typically elevated and fall toward the normal range after surgery (figure 2).

Hyperkalemia — The serum potassium concentration should be closely followed in patients with end-stage kidney disease (ESKD). Such patients should be dialyzed on the first or second postoperative day, preferably with a no-heparin protocol.

PREVENTION — Most clinicians recommend the administration of calcitriol preoperatively to prevent complications of hungry bone syndrome after parathyroidectomy. Oral calcitriol (0.5 mcg twice daily) or intravenous calcitriol (2 mcg at the end of each thrice weekly hemodialysis treatment) begun three to five days prior to surgery and continued postoperatively may be helpful in preventing marked hypocalcemia [19]. Such regimens increase intestinal absorption of oral calcium and also may slow calcium influx into bone, both of which can minimize the need for intravenous calcium postoperatively. Calcitriol is generally continued until the serum calcium concentration is normal (usually two to four weeks after surgery). Some authors also suggest starting oral calcium 2 to 3 grams per day two days prior to surgery, even in patients who are hypercalcemic [13].

Treatment with cinacalcet (alone or in combination with calcitriol) to suppress parathyroid hormone (PTH) levels and lower bone remodeling may attenuate the severity of hungry bone syndrome, but additional experience with this treatment is necessary before this is recommended.

A few case reports and several retrospective studies have suggested a possible role for the preoperative administration of bisphosphonates as another preventive measure [20]. In these reports, bisphosphonates were used to treat hypercalcemia in patients with severe primary and secondary hyperparathyroidism prior to parathyroidectomy [21,22].

Since bisphosphonates can reduce serum calcium levels, these anecdotal and apparently paradoxical observations require confirmation with a controlled, randomized study. The fact that these patients did not develop postoperative hypocalcemia does not constitute enough evidence to justify the use of bisphosphonates prior to parathyroidectomy. Use of the antiresorptive agent denosumab, which inhibits receptor activator of nuclear factor kappa-B ligand, can result in hypocalcemia in patients with end-stage kidney disease (ESKD) [23].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease-mineral and bone disorder".)

SUMMARY AND RECOMMENDATIONS

●Definition – The hungry bone syndrome refers to severe and prolonged hypocalcemia, which occurs after parathyroidectomy or less commonly, thyroidectomy, despite normal or even elevated levels of parathyroid hormone (PTH). A less severe hypocalcemic syndrome can occur in patients with end-stage kidney disease (ESKD) who are treated with calcimimetics. (See 'Introduction' above.)

●Risk factors – Risk factors include the volume of the resected parathyroid adenoma, preoperative blood urea nitrogen concentration, preoperative alkaline phosphatase concentration, and older age. It is unclear whether these risk factors can be applied to patients with ESKD who undergo parathyroidectomy for secondary hyperparathyroidism. (See 'Risk factors' above.)

●Clinical features – The clinical features of hungry bone syndrome are largely due to hypocalcemia and, to a lesser degree, hypophosphatemia, hypomagnesemia, and hyperkalemia. Symptoms of hypocalcemia include tetany, seizures, cardiac arrhythmias, and laryngeal spasm. The hypomagnesemia can contribute to the development of refractory hypocalcemia by diminishing PTH secretion and inducing PTH resistance. (See 'Clinical features' above.)

●Monitoring for hypocalcemia – Careful monitoring of serum calcium is required to prevent and treat symptomatic hypocalcemia. Among patients who have a parathyroidectomy, we suggest measuring the serum calcium concentration two to four times per day for the first few postoperative days. The measurement of ionized calcium is preferred to total serum calcium. (See 'Hypocalcemia' above.)

●Treatment

•Hypocalcemia – Hypocalcemia may be treated with oral or intravenous calcium supplementation or by dialysis. For patients who have undergone parathyroidectomy, we suggest the following approaches. (See 'Hypocalcemia' above.)

-Oral calcium supplementation (2 to 4 g of elemental calcium [50 to 100 mmol] per day) should be started as soon as the patient is able to swallow. If the serum phosphorus is normal or low, calcium should be administered between meals to maximize intestinal absorption and minimize phosphate binding.

-Intravenous calcium is indicated if the patient develops a rapid and progressive reduction in ionized serum calcium or symptoms related to hypocalcemia, including frank or latent tetany (Chvostek's or Trousseau's sign), seizures, cardiac arrhythmias, laryngeal spasm, or an ionized calcium concentration below 1.0 mmol/L (4 mg/dL), or total serum calcium below 7.5 mg/dL (1.9 mmol/L).

-We also give active vitamin D (calcitriol) to all patients who are hypocalcemic following parathyroidectomy. The typical dose of calcitriol is 0.5 mcg orally twice a day or 1 mcg intravenously daily.

-Dialysis may be used to correct hypocalcemia. The patient may be dialyzed against a high-calcium bath (3.5 mEq/L [1.75 mmol/L]), or intravenous calcium can be administered during dialysis. For patients who are on continuous ambulatory peritoneal dialysis, one to three ampules of calcium gluconate can be added to each bag of peritoneal dialysate.

-We check serum calcium weekly following hospital discharge until it is stable over 8.0 mg/dL.

•Hypomagnesemia and hypophosphatemia – Serum phosphate and magnesium concentrations should be closely followed after parathyroidectomy. The correction of hypomagnesemia may contribute to correction of the hypocalcemia. The administration of phosphate to reverse hypophosphatemia is generally avoided in patients with hungry bone syndrome since phosphate can combine with calcium and further reduce the plasma calcium concentration. (See 'Hypomagnesemia and hypophosphatemia' above.)

•Hyperkalemia – The serum potassium concentration should be closely followed in patients with ESKD. Such patients should be dialyzed on the first or second postoperative day, preferably with a no-heparin protocol. (See 'Hyperkalemia' above.)

●Prevention – For prevention of hungry bone syndrome, most clinicians recommend preoperative administration of calcitriol. Treatment with cinacalcet (alone or in combination with calcitriol) to suppress PTH levels and lower bone remodeling may attenuate the severity of hungry bone syndrome, but additional experience with this treatment is necessary before this is recommended. (See 'Prevention' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Berkoben, MD, who contributed to earlier versions of this topic review.