Hungry Bone Syndrome

Etiology

HBS typically develops in the postoperative period following parathyroidectomy for primary or secondary hyperparathyroidism, total thyroidectomy for thyrotoxicosis, or metastatic prostate cancer. In postsurgical cases, HBS arises after prolonged exposure to elevated parathyroid hormone (PTH) levels or thyrotoxicosis, which leads to high bone turnover and net bone resorption. Following the removal of the hormonal excess, there is a sudden and significant shift toward osteoblastic activity. Similarly, HBS can also occur in men with metastatic prostate cancer, where heightened osteoblastic activity leads to increased utilization of mineral building blocks for excessive bone formation.[1][2][4][5]

Epidemiology

The reported prevalence of HBS has varied over time. Historically, it was estimated to occur in approximately 13% of cases following parathyroidectomy for primary hyperparathyroidism. However, more recent case series report a lower prevalence, as low as 4%. A specific case from a population in Saudi Arabia likely reflects a rate closer to the current expectation in the United States. However, other data suggest a much higher rate, up to 87%, in a cohort of patients from an Asian population.[1] A possible explanation for this significant difference is that better access to care and earlier diagnosis, followed by timely treatment of hyperparathyroidism, may lead to a lower prevalence of HBS. 

In cases following parathyroidectomy for secondary hyperparathyroidism, the prevalence of HBS ranges from 20% to 70%.[1][2] Data regarding the prevalence of tertiary hyperparathyroidism are limited. However, a prospective study found that the prevalence of HBS in an Indian cohort of thyrotoxic patients after thyroidectomy was approximately 39%. A study involving postoperative patients in Singapore reported a 53% rate of hypocalcemia not attributed to postsurgical hypoparathyroidism following thyroidectomy. However, the study did not explicitly clarify or elucidate whether these cases were instances of HBS.[4][6] For HBS in metastatic prostate cancer, only case reports are available in the literature.[5]

Pathophysiology

To understand the pathophysiology underlying HBS in the post-parathyroidectomy state, it is important to initially review the actions of PTH. PTH is released from the parathyroid chief cells when the calcium-sensing receptor detects low serum calcium levels, triggering a cascade of reactions that stimulate both bone resorption and bone formation, ultimately aimed at raising serum calcium levels. Small or intermittent exposures to PTH promote net bone formation, while prolonged exposure, such as in hyperparathyroidism, leads to net bone resorption.[7]

A study by Ma et al investigated the catabolic effects of continuous PTH infusion in rodents.[8] Over time, steady PTH exposure led to increased levels of receptor activator of nuclear factor-kappa-B ligand (RANK-L) and decreased levels of osteoprotegerin. Normally, RANK-L promotes osteoclastogenesis, increasing osteoclast activity. As a counterregulatory mechanism, osteoprotegerin binds to RANK-L, reducing the differentiation of cells into osteoclasts and promoting net osteoblastic activity. This evidence suggests that prolonged exposure to PTH results in a predominance of bone resorption.[8]

Ge et al retrospectively assessed bone turnover markers in patients with HBS following parathyroidectomy for secondary hyperparathyroidism. The study found that, before parathyroidectomy, patients with HBS had significantly lower levels of osteocalcin—a marker of bone formation—and significantly higher levels of tartrate-resistant acid phosphatase-5b (TRAP-5b)—a bone resorption marker—compared to those without HBS.[9] Additionally, post-parathyroidectomy, all patients showed a statistically significant shift in bone markers, with an increase in markers of bone formation (osteocalcin, calcitonin, and C-terminal peptide) and a decrease in markers of bone resorption (TRAP-5b). During this process, the shift in bone metabolism from resorption to net formation leads to an influx of minerals into the bone, resulting in depleted levels of calcium and phosphate in the blood.[9]

Karunakaran et al prospectively evaluated the rate of HBS in the post-thyroidectomy state for thyrotoxicosis and suggested that the mechanism for HBS in these cases is related to increased bone turnover in the hyperthyroid state, which may take months to reverse, even if biochemical evidence of a euthyroid state is achieved before surgery.[4]

History and Physical

Patients with HBS, if symptomatic, will present with signs and symptoms of hypocalcemia, including seizures, tetany, paresthesias, and numbness or tingling in the perioral area, hands, or feet. Carpopedal spasms, arrhythmias, cardiomyopathy, and laryngospasm may also occur. Physical examination may reveal fractures, bone deformities depending on the duration of uncontrolled hyperparathyroidism, and a recent surgical scar following parathyroid or thyroid gland removal. In some cases, signs of nerve hyperexcitability due to hypocalcemia, such as prominent Trousseau or Chvostek signs, may also be observed.[1][2]

Evaluation

Multiple risk factors have been identified in retrospective studies, case reports, and case series reviews that correlate with HBS. These factors include elevated levels of PTH, alkaline phosphatase (ALK-P), body mass index (BMI), blood urea nitrogen (BUN), and the size of resected glands. Additionally, evidence of bone diseases such as brown tumors, fractures, and osteitis fibrosa cystica, along with higher osteoclast counts on bone biopsy, has been correlated with an increased risk of HBS.

On the other hand, divergent risk factors have been observed in the incidence of HBS. In primary hyperparathyroidism, older age and higher preoperative calcium levels are associated with HBS, while in secondary hyperparathyroidism, younger age and lower preoperative calcium levels have been linked to the condition.[1][2][3][10][11][12]

Unfortunately, no specific level of PTH has been identified where the risk for HBS is proportionate enough to suggest the development of a clinical calculator or indicator. However, in primary hyperparathyroidism, PTH levels are more often subtly elevated, ranging from 300 to 400 pg/mL, compared to the higher range of 700 to 1000 pg/mL seen in patients with secondary hyperparathyroidism. Summary of Risk Factors

Common risk factors include: 

• Elevated parathyroid hormone
• Elevated alkaline phosphatase
• Radiological evidence of bone disease
• Higher body mass index
• Larger volume or weight of removed parathyroid glands 
• Greater number of osteoclasts on bone biopsy
• Higher blood urea nitrogen levels

Divergent risk factors include:

• Primary hyperparathyroidism
  • Older age
  • Higher preoperative calcium levels
• Secondary hyperparathyroidism
  • Younger age
  • Lower preoperative calcium levels
• Thyrotoxicosis
  • Lower lumbar spine bone mineral density

Diagnosis relies on identifying a persistently low calcium level below 8.4 mg/dL (2.1 mmol/L) lasting more than 4 days postoperatively, accompanied by hypophosphatemia and normal PTH levels. Hypomagnesemia and hypocalciuria are frequently associated findings.[1][2][3]

Treatment / Management

Treatment with intravenous (IV) calcium is indicated if the serum calcium level falls below 7.6 mg/dL (1.9 mmol/L), if the patient exhibits symptoms, or if electrocardiogram changes such as QTc prolongation are observed. Calcium chloride and calcium gluconate are the 2 forms of calcium available for IV administration. Calcium gluconate is more commonly used, despite 1 g of calcium chloride containing three times more elemental calcium. This preference is due to the lower osmolality of calcium gluconate, which makes it less irritating and damaging if extravasation occurs into surrounding tissues during infusion. Calcium gluconate does not require a central line, unlike calcium chloride.[13][14] 

The treatment regimen should begin with a bolus of 10 to 20 mL of 10% calcium gluconate diluted in 50 to 100 mL of dextrose 5% (D5%) IV fluids, administered over 5 to 10 minutes. This provides approximately 100 to 200 mg of elemental calcium. Following the bolus, a continuous infusion can be initiated using a 100 cc dose of 10% calcium gluconate diluted in 1 liter of D5% in water (D5W), which delivers approximately 1 mg/mL of elemental calcium. The infusion can be initiated at 50 mL/h, with calcium, phosphorus, and magnesium levels monitored every 4 to 6 hours to adjust the rate as needed to achieve normal calcium levels. The target infusion rate is 0.5 to 1.5 mg of elemental calcium per kg/h. Concurrently, as the patient begins to tolerate oral medications, oral calcium supplementation should be initiated alongside IV calcium therapy.

Calcium citrate and calcium carbonate are the most commonly used oral calcium supplements. Calcium carbonate provides 400 mg of elemental calcium per gram, while calcium citrate provides 211 mg/g. Due to its higher elemental calcium content, calcium carbonate requires fewer pills to meet supplementation needs, making it the preferred choice for most patients. However, calcium citrate does not require an acidic environment for absorption, unlike calcium carbonate. Therefore, calcium citrate is a better option for individuals with hypochlorhydria, such as those using chronic proton-pump inhibitors or histamine-2 blockers, post-gastric bypass surgery, or older patients.

The daily calcium supplementation needed for patients with HBS can vary widely. Case reports have documented requirements ranging from as little as 800 mg of elemental calcium per day in a patient with a parathyroid adenoma to as much as 36 g/d in a patient with HBS following parathyroidectomy for secondary hyperparathyroidism.[15][16] Magnesium should be replenished as needed, as persistent hypomagnesemia can interfere with calcium replacement efforts by impairing PTH function, potentially leading to a state resembling hypoparathyroidism.(B3)

Hypophosphatemia should not be treated with repletion, as this can lead to calcium-phosphate precipitation, further decreasing calcium levels and complicating replacement efforts. While calcium and magnesium are being replenished, the patient should also receive active vitamin D. Calcitriol (0.25-1 mcg/d) can be used, keeping in mind that the effects of vitamin D may take several days to correlate with changes in calcium levels. 

Differential Diagnosis

The differential diagnoses include:

• Postsurgical devascularization of parathyroid glands.
• Accidental removal of all parathyroid glands, resulting in permanent postsurgical hypoparathyroidism.
• Long-term suppression of nonpathological parathyroid glands.

When considering the possible etiologies for hypocalcemia, specifically in the postoperative period, it is essential to assess the condition of the parathyroid glands. Possibilities include postsurgical devascularization or accidental destruction and removal of the remaining parathyroid glands. In other cases, the remaining parathyroid glands may require additional time to recover from the prolonged suppression of their PTH production caused by the hyperactive adenoma. In these instances, unlike in HBS, hypocalcemia will be present, but PTH levels will be low, and phosphorus levels will be elevated.[3]

Pertinent Studies and Ongoing Trials

Prevention

Research to date has explored the use of bisphosphonates and vitamin D supplementation as potential strategies for reducing the risk of HBS.

Bisphosphonates

The available data on bisphosphonate therapy are limited to retrospective studies, case series, and case reports. Lee et al conducted a retrospective analysis of primary hyperparathyroidism patients who received either clodronate or pamidronate 1 to 17 days preoperatively before parathyroidectomy. No instances of HBS were identified in the patients who received the bisphosphonates.[17]

A smaller retrospective study by Mayilvaganan et al evaluated the incidence of HBS in 19 primary hyperparathyroidism patients who received 4 mg of zoledronate 24 to 48 hours preoperatively. The study found a shorter duration of hospital stay and a nearly statistically significant reduction in the incidence of HBS compared to those who did not receive the bisphosphonate infusion. Researchers suggested that the sample size may not have been large enough to detect a statistically significant difference.[18] Other retrospective case series and a case report indicated that the use of bisphosphonates did not appear to increase the risk of HBS, with only a 4% incidence rate observed in a review of 46 patients.[1]

The available information suggests that bisphosphonates do not appear to increase the risk for HBS and may potentially have a protective effect, pending more robust and well-powered studies. However, a key question remains regarding the long-term impact on bone mineral density in patients who receive bisphosphonates before parathyroidectomy.

Vitamin D Supplementation

Vitamin D supplementation, whether with cholecalciferol or calcitriol, can help reduce the severity of the hyperparathyroid state in secondary hyperparathyroidism, particularly in the setting of end-stage renal disease. In patients with hypercalcemia awaiting parathyroidectomy for hyperparathyroidism, there may be concern and anxiety about administering vitamin D replacement due to fears of exacerbating the hypercalcemic state.

Rolighed et al conducted a double-blind, randomized controlled trial involving 46 patients at a single center to assess the effects of vitamin D replacement on preoperative PTH levels, serum and urinary calcium levels, and the rate of bone resorption.[19] They found that in patients with primary hyperparathyroidism compounded by vitamin D deficiency, vitamin D supplementation helped decrease preoperative PTH levels.

Additionally, the researchers observed that vitamin D replacement improved L-spine bone mineral density preoperatively and reduced bone resorption markers, specifically C-telopeptide. During the therapy, no statistically significant changes in plasma or 24-hour urinary calcium levels were found, suggesting that vitamin D supplementation did not lead to adverse effects.[19]

Prognosis

The overall prognosis for patients with HBS varies significantly, particularly in terms of the duration of the syndrome. In some case reports, the need for calcium and active vitamin D replacement can persist for up to 1 year postoperatively.[11][15][16][20]

Complications

HBS can lead to significant morbidity due to the consequences of hypocalcemia, with the most severe outcomes including seizures, cardiac arrhythmias, and cardiomyopathy, particularly in patients where the condition is not promptly recognized and treated.