Immobilization-induced Hypercalcemia Research Articles

Immobilization-induced Hypercalcemia in a Critically Ill Adult: A Case Report

Immobilization-induced Hypercalcemia in a Critically Ill Adult: A Case Report

Denosumab in Immobilization-Induced Hypercalcemia

Denosumab in Immobilization-Induced Hypercalcemia

Immobilization-induced hypercalcemia in a patient with renal failure.

SummaryImmobilization-induced hypercalcemia is an uncommon cause of elevated calcium which is usually diagnosed following extensive systemic workup and exclusion of more common etiologies. Previously reported cases have largely described this phenomenon in adolescents and young adults a few weeks to months after the initial onset of immobilization. Metabolic workup tends to demonstrate hypercalcemia, hypercalciuria, and eventual osteoporosis. While the exact mechanism remains largely unclear, a dysregulation between bone resorption and formation is central to the pathogenesis of this disease. Decreased mechanical loading from prolonged bedrest tends to increase osteoclast induced bone resorption while promoting osteocytes to secrete proteins such as sclerostin to reduce osteoblast mediated bone formation. We describe the case of an 18-year-old male who was admitted following intraabdominal trauma. He underwent extensive abdominal surgery including nephrectomy resulting in initiation of dialysis. After 6 months of hospitalization, the patient gradually began developing uptrending calcium levels. Imaging and laboratory workup were unremarkable for any PTH-mediated process, malignancy, thyroid disorder, adrenal disorder, or infection. Workup did reveal significant elevated bone turnover markers which in combination with the clinical history led the physicians to arrive at the diagnosis of immobilization induced hypercalcemia. In order to prevent decreased rates of bone loss, the patient was administered denosumab for treatment. Hypocalcemia followed treatment expectedly and was repleted with supplementation via the patient’s total parenteral nutrition.Learning pointsImmobilization-induced hypercalcemia should remain as a differential diagnosis of patients with prolonged hospitalizations with hypercalcemia.Extensive workup of common etiologies of hypercalcemia should be considered prior to arriving at this diagnosis.Denosumab, while off-label for this usage, offers an effective treatment option for immobilization-induced hypercalcemia though it carries a risk of hypocalcemia especially among patients with renal disease.

Immobilization-Induced Hypercalcemic Nephropathy Associated with Acute Kidney Injury

Hypercalcemia commonly occurs because of primary hyperparathyroidism and metastatic malignancies, such as multiple myeloma, breast cancer and lung cancer; these causes account for 90% of cases. The other causes of hypercalcemia are numerous, and immobilization is an under-appreciated etiology. The mechanisms underlying immobilization-induced hypercalcemia are uncertain. However, an overall increased osteoclastic bone resorption and decreased osteoblastic bone formation can induce hypercalciuria and hypercalcemia. Additionally, hypercalcemia can induce and be associated with acute kidney injury, but it is rarely reported in immobilization hypercalcemia. We report here a 58-year-old man with suspected immobilization hypercalcemia associated with acute kidney injury and treated successfully with glucocorticoids. (Korean J Med 2012;82:744-748)

Immobilization and hip fracture

Hip fracture is among the most common causes of acute immobilization in elderly patients, and elderly patients with hip fracture are at high risk for a subsequent hip fracture. At baseline, both groups had high serum concentrations of ionized calcium, high urinary deoxypyridinoline (DPD) concentrations, suggesting immobilization-induced hypercalcemia. We previously showed deficiency of vitamins D and K(1) causes reduced bone mineral density (BMD) in female Alzheimer's disease (AD) patients. In a random and prospective study of AD patients, 100 patients received 45 mg menatetrenone, 1,000 IU ergocalciferol and 600 mg calcium daily for 2 years, and the remaining 100 (untreated group) did not. Treatment with MK-4 and vitamin D(2) with calcium supplements increases the BMD in elderly female patients with AD and leads to the prevention of nonvertebral fractures. The risk of hip fracture after stroke is 2 to 4 times as high as that in age-matched healthy controls. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly persons. Randomized, controlled, double-blinded study of 628 consecutive elderly hemiplegic patients at least 1 year following first ischemic stroke. Patients were assigned to daily oral treatment with 5 mg of folate and 1,500 microg of mecobalamin or double placebos, and 559 completed the 2 year follow up. Plasma homocysteine levels in the decreased by 38% in the treatment group and increased by 31% in the placebo group. The number of the hip fractures per 1,000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (p<0.001). In this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B(12) is safe and effective in reducing the risk of a hip fracture in elderly stroke patients. Because of limited study power, the relative risk reduction may only be around 0.5.

RETRACTED: Abnormal calcium homeostasis in disabled stroke patients with low 25-hydroxyvitamin D

Disabled elderly stroke patients occasionally have very low serum 25-hydroxyvitamin D (25-OHD), which may be due to sunlight deprivation and malnutrition. Many of such patients have very low level of serum 1, 25-dihydroxyvitamin D (1, 25-[OH]2D; calcitriol), and immobilization-induced hypercalcemia may be responsible for inhibition of renal synthesis of calcitriol. To elucidate determinants of serum 1, 25-[OH]2D levels in elderly poststroke patients, we measured serum indices of bone and calcium metabolism and metacarpal bone mineral density (BMD). Patients whose serum 1, 25-[OH]2D concentration was below the mean-3 SD of normal control subjects were defined as the low 1, 25-[OH]2D group and the rest of the patients were designated as the normal group. Mean illness duration was 59 months in the normal group and 20 months in the low group. The Barthel index (BI), which predicts the degree of immobilization, was significantly lower in the low group than in the normal group. Mean serum 1, 25-[OH]2D and 25-OHD concentrations in the normal group were 36.7 pg/ml and 4.4 ng/ml, respectively; and those in the low group were 14.2 pg/ml and 1.8 ng/ml, respectively. Multiple regression analysis identified illness duration and calcium level as independent determinants of 1, 25-[OH]2D in both groups, and PTH in the normal group and 25-OHD in the low group were additional independent determinants. BMD in stroke patients was significantly lower than that in controls, and BMD in the normal group was lower as compared to the low group. BMD correlated negatively with 1, 25-[OH]2D and PTH in the normal group, and hyperparathyroidism may contribute to reduced BMD. These results suggest that treatment of decreased bone mass in stroke patients has to be individualized according to vitamin D status and calcium homeostasis.

RETRACTED: Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency

Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.

RETRACTED: Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients

Significant reduction in bone mineral density (BMD) occurs in stroke patients on the hemiplegic and contralateral sides, correlating with the degree of paralysis and vitamin D and K deficiency due to malnutrition, and increasing the risk of hip fracture. We evaluated the efficacy of vitamin K2 (menatetrenone: menaquinone-4; MK-4) in maintaining BMD by comparing serum biochemical indices of bone metabolism between treated and untreated patients. In a random and prospective study, of 108 hemiplegic patients following stroke, 54 received 45 mg menatetrenone daily (MK-4 group, n = 54) for 12 months, and the remaining 54 (untreatment group) did not. Nine patients excluded from the study. The BMD in the second metacarpals and serum indices of bone metabolism were determined. BMD on the hemiplegic side increased by 4.3% in the MK-4 group and decreased by 4.7% in the untreated group (p < 0.0001), while BMD on the intact side decreased by 0.9% in the MK-4 group and by 2.7% in the untreated group (p < 0.0001). At baseline, patients of both groups showed vitamin D and K1 deficiencies, high serum levels of ionized calcium, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), and low levels of parathyroid hormones (PTH) and bone Gla proteins (BGP), indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D) and compensatory PTH secretion. Both vitamins K1 and K2 increased by 97.6% and 666.9%, respectively, in the MK-4 group. Correspondingly, a significant increase in BGP and decreases in both ICTP and calcium were observed in the MK-4 group, in association with a simultaneous increase in both PTH and 1, 25-[OH]2D. One patient in the untreated group suffered from a hip fracture, compared with none in the MK-4 group. The treatment with MK-4 can increase the BMD of disused and vitamin D- and K-deficient hemiplegic bone by increasing the vitamin K concentration, and it also can decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1, 25-[OH]2D concentration.

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High prevalence of vitamin D deficiency and reduced bone mass in Parkinson's disease [RETRACTED

Despite excessive hip fractures in patients with Parkinson's disease (PD), little is known about bone changes in these patients. We measured bone mineral density (BMD; Z scores) in PD patients and analyzed its relation to serum biochemical indices and sunlight exposure. We measured BMD in 71 patients in the second metacarpals and divided the patients into two groups according to functional independence; group 1, Hoehn and Yahr stages 1 and 2; and group 2, stages 3 to 5. In four of 20 patients in group 1 (20%), the Z score was less than -1.0, indicating osteopenia. In 51 patients in group 2, 31 (61%) had a Z score less than -1.0. The group 1 patients showed a normal mean serum level of 25-hydroxyvitamin D (25-OHD; 21.7 ng/ml), while most group 2 patients were in a deficiency range (group mean 8.9 ng/ml). Many group 2 patients were sunlight deprived. Both groups had elevated serum ionized calcium levels correlating positively with Hoehn and Yahr stage and markedly depressed serum 1,25-dihydroxyvitamin D (1,25-[OH]2D) concentrations, indicating that immobilization-induced hypercalcemia had inhibited 1,25-[OH]2D production. Z scores correlated positively with 25-OHD levels and negatively with parathyroid hormone concentration and Hoehn and Yahr stage. Vitamin D deficiency due to sunlight deprivation and hypercalcemia induces compensatory hyperparathyroidism, which contributes to reduced BMD in PD patients, particularly those who are functionally dependent. Low BMD increases risk of hip fractures in patients with PD but may be improved by vitamin D supplementation.

Immobilization-induced hypercalcemia in a renal transplant recipient with persistent hyperparathyroidism

Immobilization-induced hypercalcemia in a renal transplant recipient with persistent hyperparathyroidism

Immobilization-induced Hypercalcemia and Regional Osteoporosis

Immobilization hypercalcemia accompanied by unusual hormonal and bony changes complicated the Guillain-Barré syndrome in a 21-year-old woman. Metaphyseal rarefaction appeared in many sites and was severe in the lower limbs. A bone scan showed increased uptake of 99mTc methylene diphosphonate at these sites and throughout the axial skeleton. The literature on experimental metaphyseal rarefaction suggests that osteoclastic resorption and enhanced regional blood flow are associated with immobilization. Suppression of this osteoclastic component of the increased bone turnover, especially if it is widespread, was the rationale for treatment with calcitonin (CT). The patient also became amenorrheic, with low plasma gonadotropin and estrogen levels. Estrogen therapy coincided with a return of plasma calcium to normal.

Urinary Tract Stones in Immobilized Children

Urinary tract stones in children are uncommon in the absence of structural abnormalities or metabolic disorders. Prolonged immobilization is a recognized precursor of hypercalcemia and other disturbances in mineral metabolism. The authors describe 3 children (7, 9, and 11 years of age) who were found to have stones in the upper urinary tract following prolonged immobilization for treatment of orthopedic abnormalities. Hypercalcemia was documented in 2 patients and hypercalciuria in 1. The mechanism of immobilization-induced hypercalcemia and hypercalciuria is discussed.