Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.

https://eje.bioscientifica.com/downloadpdf/journals/eje/168/3/R45.pdf

Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature.

Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT.

https://www.aem-sbem.com/wp-content/uploads/articles_xml/0004-2730-abem-58-5-0553/0004-2730-abem-58-5-0553.pdf

Bone disease in primary hyperparathyroidism

Before the introduction of routine measurements of serum calcium in ambulatory services, PHTP (primary hyperparathyroidism) was symptomatic with classic bone disease (known as osteitis fibrosa cystica) nephrolithiasis, and acute neuropsychiatric syndrome with severe hypercalcemia. Currently, PHPT presents few unspecific symptoms. This cross-sectional study was conducted from December 1, 2007, through August 31, 2008 to estimate the prevalence of primary hyperparathyroidism and to describe the clinical and laboratory characteristics of patients receiving ambulatory care. From 4207 patients, we found a prevalence of PHTP of 0.78 (95% confidence interval [CI], 0.52–1.04) of which 81.8% were asymptomatic and 18.2% symptomatic. The female:male ratio was 7.2:1, and 89.7% of the women were postmenopausal. Mean age was 61.12 ± 15.73 years, mean serum calcium was 10.63 ± 1.33 mg/dL, and mean serum parathyroid hormone (PTH) was 182.48 ± 326.51 pg/mL. We found a high prevalence of PHTP at reference centers and a high prevalence of hypertension and type 2 diabetes.

https://journals.sagepub.com/doi/pdf/10.4137/CMED.S13147

Epidemiology of Primary Hyperparathyroidism and its Non-classical Manifestations in the City of Recife, Brazil

The presentation of primary hyperparathyroidism (PHPT) has changed globally and most patients do not usually suffer from its overt skeletal complications. The clinical phenotype of normocalcemic PHPT has been considered the most noteworthy change in the presentation of PHPT in the United States over the past 10 years. In Europe, asymptomatic PHPT has been the predominant form of presentation as well. In most Latin American countries available data on primary hyperparathyroidism are from case reports or small case series with the majority of patients being presented in the symptomatic form. Conversely, in Brazil, the clinical presentation has been shifting toward asymptomatic PHPT. Recently, changing clinical patterns of PHPT have been reported in Chinese patients. In contrast, data from other Asian countries, like India, Iran, Saudi Arabia and Thailand, still report a predominance of symptomatic disease with overt skeletal manifestations.

Clinical Presentation of Primary Hyperparathyroidism: A Global Perspective

It has been proposed to cautiously supplement with vitamin D to any patient with asymptomatic primary hyperparathyroidism (PHTP) and a plasma 25-hydroxyvitamin D [25(OH)D] concentration <50 nmol/l. Evidence about the safeness of this intervention is limited to two studies. Our aim was to prospectively assess the biochemical effects of one-year 25(OH)D supplementation in this context. Twenty-seven patients were included in this study. Calcifediol was started at a dose of 480–960 IU/24 h (8–16 μg/24 h) and adjusted up to a maximum of 960 IU/24 h (16 μg/24 h). Basal calcium, phosphate, albumin, total alkaline phosphatase (ALP), creatinine, 24 h calcium urinary excretion, intact PTH (iPTH) and 25(OH)D were measured before and during vitamin D supplementation. The mean basal 25(OH)D was 28.7 ± 8.0 nmol/l, and at 12 months was 71.5 ± 32.5 nmol/l (P = 0.00 vs. baseline). After 3, 6 and 12 months iPTH levels were 141.7 ± 108.4 ng/l (P = 0.00 vs. baseline), 131.1 ± 95.7 ng/l (P = 0.03 vs. baseline) and 162.2 ± 139.3 ng/l (P = ns vs. baseline). Mean calcium did not change. Mean urinary calcium excretion increased significantly (basal: 5.7 ± 2.9 mmol/24 h, 12 months: 7.9 ± 4.9 mmol/24 h, P = 0.02). Cautious calcifediol supplementation significantly increased mean 25(OH)D and temporarily reduced mean iPTH. It did not change mean serum calcium, but urinary calcium excretion increased significantly. We suggest that serum calcium and 24 h calciuria be measured at regular intervals in patients with PHTP, while on calcifediol supplementation.

Biochemical effects of calcifediol supplementation in mild, asymptomatic, hyperparathyroidism with concomitant vitamin D deficiency

OBJECTIVE: To assess the effect of bisphosphonates on post-parathyroidectomy hypocalcemia in patients with osteitis fibrosa cystica. METHODS: Review of the medical records of six patients using bisphosphonates preoperatively. RESULTS: Mean age was 35.6 ± 10.5 years; serum calcium = 13.51 + 0.87 mg/dL; iPTH = 1,389 + 609 pg/mL. The mean value of urine deoxypyridinoline (UDPD) of three patients was 131 ± 183 nmol/mmol Cr, and of C-telopeptide (CTX), 2,253 ± 1,587 pg/mL. The mean values of bone densitometry (T score) were as follows: 0.673 ± 0.150 g/cm2 (-4.42 ± 1.23) in lumbar spine (L2-L4); 0.456 ± 0.149 g/cm2 (-5.58 ± 1.79) in the femoral neck; and 0.316 ± 0.055 g/cm2 (-5.85 ± 0.53) in radius 33. Patient 1 received oral alendronate, 30 mg/day for four weeks; his calcium decreased from 14 to 11.6 mg/dL, and his UDPD from 342 to 160 nmol/mmol Cr. Patient 2 received oral alendronate, 20 mg/day for six weeks; his calcium decreased from 14 to 11.0 mg/dL and his UDPD from 28.8 to 14 nmol/mmol Cr. Patient 3 received intravenous pamidronate, 90 mg prior to surgery. Patient 4 received oral alendronate, 140 mg/week for six weeks; her calcium decreased from 13.7 to 12.3 mg/dL and her CTX from 2,160 to 1,340 pg/mL. Patient 5 received oral alendronate, 140 mg/ week for six weeks; her calcium levels dropped from 14.3 to 14.1 mg/dL; her CTX did not change. Patient 6 received ibandronate, 150 mg, ten days prior to surgery; his CTX reduced by 62%. No patient developed severe hypocalcemia in the first postoperative week. One year after surgery, the mean gain in bone mineral density was 40% ± 29% in L2-L4, 86 ± 39% in the femoral neck, and 22% ± 11% in radius 33. CONCLUSION: The preoperative use of bisphosphonates seems to attenuate bone hunger without preventing a significant increase in bone mass in the follow-up of parathyroidectomy.

Jorge Pinho

Papers

Bisphosphonates can reduce bone hunger after parathyroidectomy in patients with primary hyperparathyroidism and osteitis fibrosa cystica.

Prevalence of Cortical Osteoporosis in Mild and Severe Primary Hyperparathyroidism and its Relationship With Bone Markers and Vitamin D Status