immobilization is a rare cause of hypercalcaemia that occurs particularly in children and adolescents because of their high bone turnover [ 1 , 2 ] . bisphosphonates are commonly used in the treatment of this condition [ 1 , 3 ] . however , in patients with advanced renal insufficiency [ glomerular filtration rate ( gfr ) < 30 ml / min ] , there is a possibility of renal toxicity . it is a human monoclonal antibody directed against receptor activator of nuclear factor-b ligand ( rankl ) that decreases osteoclast activity and bone resorption . as such , it could be an alternative for treatment of resorption - related hypercalcaemia particularly in patients with renal insufficiency . a 19-year - old male was admitted to the intensive care unit of our hospital for meningococcal meningitis complicated by multi - organ failure including acute renal insufficiency . amputation of the right lower leg had to be performed and there were significant neurological sequelae resulting in prolonged immobilization . during this admission , hypercalcaemia developed after 2 months with a maximum corrected serum calcium concentration of 3.4 mmol / l . the serum parathyroid hormone ( pth ) concentration was below the detection limit ( for laboratory values , see table 1 ) . the tentative diagnosis was immobilization - related hypercalcaemia . despite renal impairment [ estimated gfr ( egfr ) of 18 ml / min/1.73 m ] , a reduced dose of pamidronate ( 30 mg ) was administered intravenously with near normalization of the serum calcium concentration ( see figure 1 ) . three months later , the serum calcium concentration had increased again ( to 2.96 mmol / l ) and the same dose of pamidronate was administered . the serum calcium concentration again decreased to a near - normal level ( 2.70 mmol / l ) . the serum phosphate level was high , which is attributed to both impaired renal excretion and increased efflux from the bones . he had a persistent renal insufficiency with an egfr of 24 ml / min/1.73 m . unfortunately , 2 months later , the serum calcium concentration increased again to a corrected level of 3.9 mmol / l and the patient suffered from nausea and vomiting . he was readmitted to the hospital and hyper hydration was performed in combination with oral furosemide ( dose 125 mg twice daily ) , and calcitonin was administered subcutaneously ( dose 400 iu twice daily ) . , further analysis showed that both the serum 25-oh - vitamin d and 1,25-di - oh - vitamin d concentrations were low . urinary calcium excretion was high ( 9.4 mmol/24 h with a fractional calcium excretion of 9.8% ) . other rare causes of hypercalcaemia were excluded : urinary metanephrines and the serum thyroid stimulating hormone , cortisol and aluminium concentrations and the free light chain kappa / lambda ratio were all normal . a chest x - ray showed no lymphadenopathy and there were no signs of skeletal metastasis on magnetic resonance imaging of the vertebrae and the left leg that was performed earlier . a few weeks later , the serum calcium concentration had increased again to 3.02 mmol / l . because of the recurrent hypercalcaemia and lack of success of treatment with low - dose biphosphonate , we decided to treat the patient with a single subcutaneous dose of denosumab ( 60 mg ) . the serum phosphate level had decreased in parallel ( to 0.58 mmol / l ) suggesting effective inhibition of bone resorption . supplementation with both calciumcarbonate / colecalciferol and active vitamin d ( alfacalcidol ) was started after which the serum calcium concentration normalized . during the episode of hypocalcaemia , serum pth concentration increased to 47.8 pmol / l . after 2 months , the serum calcium level rose to 2.66 mmol / l . at that time , all vitamin d and calcium - supplementation was stopped . during a 2-month follow - up since then , the patient 's serum calcium concentration has remained within the normal range without further administration of denosumab . table 1.laboratory datavariablereference rangefebruary 2011february 2011march 2011may 2011may 2011june 2011july 2011august 2011september 2011october 2011november 2011november 2011december 2011january 2012january 2012february 2012march 2012march 2012calcium ( mmol / l)2.202.602.992.312.262.722.862.583.263.812.593.021.891.972.242.192.392.682.482.44albumin ( g / l)35.050.020.319.4162840344136.232.5404036363538413735corrected calcium ( mmol / l)2.202.603.382.722.742.962.862.73.243.892.743.021.892.052.322.292.432.662.542.54ionized calcium ( mmol / l)1.151.321.561.272.15phosphate ( mmol / l)0.801.501.751.191.32.51.731.11.641.661.011.160.580.640.85creatinin ( mol / l)74120393387406378376310337388348286231245240260266311337egfr mdrd ( ml / min/1.73 m)>601819182419212634313229282422alkalic phosphatase ( u / l)012014322618810625-oh vitamin d ( nmol / l)5010071261,25-di - oh - vitamin d ( pmol / l)50170<20<20pth ( pmol / l)1.07.0<0.60.40.991.447.80.6pth - related peptide ( pmol / l)<0.6<0.3 
 fig . after exclusion of other causes of hypercalcaemia , our patient was diagnosed with immobilization - induced hypercalcaemia . prolonged immobilization , e.g. after acute spinal cord injury , has long been known to result in hypercalciuria and hypercalcaemia combined with accelerated bone resorption and nephrolithiasis [ 57 ] . immobilization - related hypercalcaemia has been described in several clinical situations ( see table 2 ) . in this condition , an imbalance occurs in the bone - remodelling process with excessive osteoclastic bone resorption exceeding the rate of osteoblastic bone formation . increased bone resorption results in hypercalciuria within days and hypercalcaemia after a few weeks if the capacity of the kidneys to excrete calcium is exceeded . therefore , renal insufficiency increases the risk of immobilization - related hypercalcaemia [ 10 , 11 ] . children and adolescents are particularly vulnerable because of their high bone turnover [ 1 , 2 ] . according to a recent review , the exact pathogenesis of immobilization - related bone loss at the cellular level has not yet been resolved , although the rankl / rank / opg system is likely to be involved . the diagnosis is made in an appropriate clinical situation after exclusion of other causes of hypercalcaemia . limited data suggest that this type of hypercalcaemia can be treated successfully with bisphosphonates [ 1 , 3 , 14 ] . table 2.clinical situations associated with immobilization - related hypercalcaemiaacute spinal cord injury [ 3 , 5 , 7 , 9 , 2630]acute anterior poliomyelitis guillain  barr syndrome [ 3234]haemiplegia after stroke [ 3538]polyneuropathy ( critical illness , alcoholic   and acute intermittent porphyria ) extensive burns [ 10 , 4143]multiple fractures [ 4448]single limb fracture in children and adolescents [ 47 , 4954]sepsis [ 2 , 5557]liver transplantation polyarticular gout parkinson 's disease haemodialysis patients immobilized for fractures or coma [ 11 , 61 , 62 ] clinical situations associated with immobilization - related hypercalcaemia in agreement with this , the hypercalcaemia in our patient responded twice to administration of pamidronate , but the response was incomplete and of relatively short duration on both occasions . this may have been due to the fact that only a low dose of pamidronate was administered because of concerns about potential renal adverse effects . treatment with iv bisphosphonates has been associated with renal toxicity probably due to direct tubular injury . high peak levels seem to be a risk factor and consequently the dose of bisphosphonates should be decreased and the infusion time prolonged in patients with diminished renal function . if the egfr is above 30 ml / min/1.73 m , renal risk is low . very little is known about the safety of intravenous bisphosphonates in patients with stage 4 and 5 chronic kidney disease ( ckd ) ( egfr < 1530 ml / min ) [ 4 , 15 ] . administration of calcitonin also effectively decreased the serum calcium concentration in our patient but its effect is known to be limited to a few days because of development of tachyphylaxis . denosumab is a fully human antibody against rankl that inhibits binding of rankl to its receptor rank on osteoclasts . in adult bone remodelling , osteocytes are now known to be the primary rankl - producing cells , in contrast to the older paradigm that osteoblasts were the most important source of rankl . several other cell types , including endothelial cells , activated t lymphocytes and tumour cells , have been shown to express rankl . after binding to its receptor rank on osteoclasts and osteoclast precursors , rankl stimulates osteoclast formation , activation and survival , thus leading to increased bone resorption . after subcutaneous injection of denosumab , bone turnover decreases within 24 h as reflected by decreases in urinary and serum bone turnover markers , such as the urinary n - telopeptide / creatinin ratio and the serum n - telopeptide concentration . the maximum effect of denosumab is achieved after 24 weeks and lasts for several months depending on the dose . denosumab is registered both for treatment of post - menopausal osteoporosis and for prevention of skeletal - related events in bone metastasis in breast and prostate cancer . side effects are limited to sporadic cases of osteonecrosis of the jaw and mild hypocalcaemia in a small percentage of patients . denosumab is not excreted by the kidneys and dosing therefore does not have to be adjusted in patients with renal insufficiency . post hoc analysis of the freedom trial , which showed that denosumab reduces the risk of fractures in patients with osteoporosis , did not report a difference in side effects with increasing levels of renal insufficiency . however , no stage 5 ckd patients ( egfr < 15 ml / min ) were included in this study . interestingly , the renal excretion of calcium greatly increased in response to hypercalcaemia in our patient despite advanced renal insufficiency . this is in contrast to the situation in patients with ckd in general , in whom the calcium excretion is low   and does not readily increase when dietary calcium intake is increased . since the filtered load of calcium was greatly diminished in our patient despite the hypercalcaemia , hypercalciuria must have been caused by a reduced fractional tubular reabsorption of calcium . firstly , hypercalcaemia reduces the paracellular reabsorption of calcium in the thick ascending limb of henle 's loop ( talh ) by activating the basolateral calcium sensing receptor in this nephron segment . in this respect , secondly , pth secretion was appropriately suppressed in the presence of hypercalcaemia in our patient , whereas it usually increases in patients with advanced ckd . suppression of pth secretion will facilitate renal calcium excretion , since a function of this hormone is to stimulate calcium reabsorption in the talh and distal tubules . thirdly , the concentration of active vitamin d was low in our patient , which is relevant because active vitamin d increases calcium reabsorption in the distal tubules . in this respect , our patient may also differ from ckd patients , because most of them will receive active vitamin d supplements . volume expansion ( which suppresses calcium reabsorption in the proximal tubules ) and treatment with a loop diuretic ( which suppresses calcium reabsorption in the talh )   may have facilitated calcium excretion even further at the time of severe hypercalcaemia . this case of a patient with immobilization - related hypercalcaemia successfully treated with denosumab helps to remind us that immobilization is a cause of hypercalcaemia that should not be overlooked . the literature on the use of denosumab for hypercalcaemia is scarce and limited to malignancy - induced hypercalcaemia [ 24 , 25 ] . unlike bisphosphonates , the drug is not contraindicated in patients with renal insufficiency , and the effect is much more prolonged than that of calcitonin . however , clinicians should be aware that considerable hypocalcaemia may develop rapidly after administration of denosumab , and perhaps the initial dose of denosumab should be lower than the dose used for other indications .
we describe the case of a young adult with immobilization - related hypercalcaemia and advanced renal insufficiency . because of the uncertain safety profile of bisphosphonates in such patients , only a low dose of pamidronate was administered twice . 
 this did not result in a sufficient decrease in the serum calcium concentration nor was the decrease sustained . 
 we decided to administer a single dose of denosumab , a monoclonal antibody against the receptor activator of nuclear factor-b ligand , a new antiresorptive agent registered for use in osteoporosis . 
 this resulted in rapid and sustained decrease in the serum calcium concentration . 
 transient hypocalcaemia ensued with normalization after vitamin d supplementation . 
 furthermore , we summarize what is known about hypercalcaemia caused by immobilization .