endocrine and metabolic disorders
Hypercalcemia
Treatment of Hypercalcemia
Oral phosphate for serum calcium<11.5 mg/dL (< 2.9 mmol/L) with mild symptoms and no kidney disease IV saline andfurosemidefor more rapid correction of elevated serum calcium<18 mg/dL (< 4.5 mmol/L) Bisphosphonates or other calcium-lowering medications for serum calcium 11.5 to 18 mg/dL (3.7 to 5.8 mmol/L) and/or moderate symptoms Hemodialysis for serum calcium>18 mg/dL (> 5.8 mmol/L) Surgical removal of parathyroid glands for moderate, progressive primary hyperparathyroidism and sometimes for mild hyperparathyroid disease Phosphate restriction and phosphate binders and sometimescalcitriolfor secondary hyperparathyroidism There are 4 main strategies for lowering serum calcium: Decrease intestinal calcium absorption Increase urinary calcium excretion Decrease bone resorption Remove excess calcium through dialysis The treatment used depends on both the degree and the cause of hypercalcemia. Volume repletion with saline is an essential element of care. In mild hypercalcemia (serum calcium<11.5 mg/dL [<2.9 mmol/L]), in which symptoms are mild or absent, treatment is deferred pending definitive diagnosis. After diagnosis, the underlying disorder is treated. When symptoms are significant, treatment aimed at lowering serum calcium is necessary. Oral phosphate can be used. When taken with meals, phosphate binds some calcium, preventing its absorption. A starting dose is 250 mg of elemental phosphate (as sodium or potassium salt) 4 times a day. The dose can be increased to 500 mg 4 times a day as needed unless diarrhea develops. 20 to 40 mg IV every 2 to 4 hours is given as needed to maintain a urine output of roughly 250 mL/hour (monitored hourly). Care must be taken to avoid volume depletion. Potassium and magnesium are monitored as often as every 4 hours during treatment and replaced IV as needed to avoid Hypokalemia and Moderate hypercalcemia (serum calcium>11.5 mg/dL [> 2.88 mmol/L] and<18 mg/dL [<4.51 mmol/L]) can be treated with isotonic saline and a loop diuretic as is done for mild hypercalcemia or, depending on its cause, with medications that decrease bone resorption (usually bisphosphonates,calcitonin, or infrequently plicamycin or gallium nitrate), corticosteroids, orchloroquine. Bisphosphonatesinhibit osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia.Zoledronic acidcan be given as a one-time dose of 4 to 8 mg IV and lowers serum calcium very effectively for an average of>40 days. Pamidronatecan be given for cancer-associated hypercalcemia as a one-time dose of 30 to 90 mg IV, repeated only after 7 days. It lowers serum calcium for≤2 weeks. Ibandronateas a one-time dose of 4 to 6 mg IV can be given for cancer-associated hypercalcemia; it is effective for about 14 days. Etidronate7.5 mg/kg IV once a day for 3 to 5 days is used to treat Paget disease and cancer-associated hypercalcemia. Maintenance dosage is 20 mg/kg orally once a day, but the dose must be reduced when glomerular filtration rate is low. Repetitive use of IV bisphosphonates to treat hypercalcemia associated with metastatic bone disease or myeloma has been associated with Medication-Related Osteonecrosis of the Jaw (MRONJ) . Some reports suggest this finding may be more common with Denosumab,120 mg subcutaneously every 4 weeks with additional doses on days 8 and 15 of the first month of treatment, is a monoclonal antibody inhibitor of osteoclastic activity that can be used for cancer-associated hypercalcemia that does not respond to bisphosphonates. Calcium andvitamin Dare given as needed to avert hypocalcemia. Calcitonin(thyrocalcitonin) is a rapidly acting peptide hormone normally secreted in response to hypercalcemia by the C cells of the thyroid.Calcitoninappears to lower serum calcium by inhibiting osteoclastic activity. A dosage of 4 to 8 IU/kg subcutaneously every 12 hours of salmoncalcitoninis safe.Calcitonincan lower serum calcium levels by 1 to 2 mg/dL within a few hours. Its usefulness in the treatment of cancer-associated hypercalcemia is limited by its short duration of action with the development of tachyphylaxis (often after about 48 hours) and by the lack of response in≥40% of patients. However, the combination of salmoncalcitoninandprednisonemay control serum calcium for several months in some patients with cancer. Ifcalcitoninstops working, it can be stopped for 2 days (whileprednisoneis continued) and then resumed. Corticosteroids(eg,prednisone20 to 40 mg orally once a day) can help control hypercalcemia as adjunctive therapy by decreasingcalcitriolproduction and thus intestinal calcium absorption in most patients withvitamin Dtoxicity, idiopathic hypercalcemia of infancy, and sarcoidosis. Some patients with myeloma, lymphoma, leukemia, or metastatic cancer require 40 to 60 mg ofprednisoneonce a day. However,>50% of such patients fail to respond to corticosteroids, and response, when it occurs, takes several days; thus, other treatment usually is necessary. Chloroquinephosphate500 mg orally once a day inhibits 1,25(OH)2D synthesis and reduces serum calcium concentration in patients with sarcoidosis. Routine ophthalmologic surveillance (eg, retinal examinations every 6 to 12 months) is mandatory to detect dose-related retinal damage. Plicamycin25 mcg/kg IV once a day in 50 mL of 5%dextrosein water over 4 to 6 hours is effective in patients with hypercalcemia due to cancer but is rarely used because other treatments are safer. 4.5 mmol/L] or with severe symptoms), hemodialysis with low-calcium dialysate may be needed in addition to other treatments. Although there is no completely satisfactory way to correct severe hypercalcemia in patients with renal failure, Hemodialysis is probably the safest and most reliable short-term treatment. IV phosphate(disodium phosphate or monopotassium phosphate) should be used only when hypercalcemia is life threatening and unresponsive to other methods and when short-term hemodialysis is not possible. No more than 1 g should be given IV in 24 hours; usually 1 or 2 doses over 2 days lower serum calcium for 10 to 15 days. Soft-tissue calcification and acute renal failure may result. (NOTE: IV infusion of sodium sulfate is even more hazardous and less effective than phosphate infusion and should not be used.) can be added if hypercalcemia remains unresponsive. Hemodialysis is needed to lower calcium level acutely if other treatments are not successful ( Treatment reference ). Treatment for hyperparathyroidism depends on severity. Patients withasymptomatic primary hyperparathyroidismwith no indications for surgery may be treated conservatively with methods to ensure that serum calcium concentrations remain low. Patients should remain active (ie, avoid immobilization that could exacerbate hypercalcemia), follow a low-calcium diet, drink plenty of fluids to minimize the chance of nephrolithiasis, and avoid drugs that can raise serum calcium, such as thiazide diuretics. Serum calcium level and renal function are monitored every 6 months. Bone density is monitored every 12 months. However, subclinical bone disease, hypertension, and longevity are concerns. Osteoporosis is treated with bisphosphonates. Inpatients with symptomatic or progressive hyperparathyroidism,surgery is indicated. The indications for surgery in patients with asymptomatic, primary hyperparathyroidism are controversial. Surgical parathyroidectomy increases bone density and may have modest effects on some quality of life symptoms, but most patients do not have progressive deterioration in biochemical abnormalities or bone density. Still, concerns about hypertension and longevity remain. Many experts recommend surgery in the following circumstances: Serum calcium 1 mg/dL (0.25 mmol/L) greater than the upper limits of normal Calciuria>400 mg/day (>10 mmol/day) Creatinine clearance < 60 mL/minute Peak bone density at the hip, lumbar spine, or radius 2.5 standard deviations below controls (T score=−2.5) Age<50 years The possibility of poor adherence with follow-up Surgery consists of removal of adenomatous glands.Parathyroid hormoneconcentration can be measured before and after removal of the presumed abnormal gland using rapid assays. A fall of ≥ 50% 10 minutes after removal of the adenoma indicates successful treatment. In patients with disease of>1 gland, several glands are removed, and often a small portion of a normal-appearing parathyroid gland is reimplanted in the belly of the sternocleidomastoid muscle or subcutaneously in the forearm to prevent hypoparathyroidism. Parathyroid tissue is also occasionally preserved using cryopreservation to allow for later autologous transplantation in case persistent hypoparathyroidism develops. When hyperparathyroidism is mild, the serum calcium concentration drops to just below normal within 24 to 48 hours after surgery; serum calcium must be monitored. In patients with severe osteitis fibrosa cystica, prolonged, symptomatic hypocalcemia may occur postoperatively unless 10 to 20 g elemental calcium is given in the days before surgery. Even with preoperative calcium administration, large doses of Treatment are needed while bone calcium is repleted. In patients with severe hypercalcemia with primary hyperparathyroidism who are unable to undergo parathyroidectomy, medical treatment is indicated.Cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to extracellular calcium, may lowerparathyroid hormoneand calcium levels. Hyperparathyroidism in patients with renal failureis usually secondary. Measures used for treatment can also be used for prevention. One aim is to prevent hyperphosphatemia. Treatment combines dietary phosphate restriction and phosphate binding agents, such ascalcium carbonateorsevelamer. Despite the use of phosphate binders, dietary restriction of phosphate is needed. Aluminum-containing compounds have been used to limit phosphate concentration, but they should be avoided, especially in patients receiving long-term dialysis, to prevent aluminum accumulation in bone resulting in severe osteomalacia.Vitamin Dadministration is potentially hazardous in renal failure because it can increase phosphate absorption and contribute to hypercalcemia; administration requires frequent monitoring of calcium and phosphate levels. Treatment should be limited to patients with any of the following: Symptomatic osteomalacia (unrelated to aluminum) Secondary hyperparathyroidism Postparathyroidectomy hypocalcemia Although oralcalcitriolis often given along with oral calcium to suppress secondary hyperparathyroidism, the results are variable in patients with end-stage renal disease. The parenteral form ofcalcitriol, orvitamin Danalogs such asparicalcitol, may better prevent secondary hyperparathyroidism in such patients, because the higher attained serum concentration of 1,25(OH)2D directly suppresses PTH release. Simple osteomalacia may respond tocalcitriol0.25 to 0.5 mcg orally once a day, whereas correction of postparathyroidectomy hypocalcemia may require prolonged administration of as much as 2 mcg ofcalcitriolorally once a day and≥2 g of elemental calcium/day. The calcimimetic,cinacalcet, modulates the set point of the calcium-sensing receptor on parathyroid cells and decreases PTH concentration in dialysis patients without increasing serum calcium. In patients with osteomalacia caused by having taken large amounts of aluminum-containing phosphate binders, removal of aluminum withdeferoxamineis necessary beforecalcitrioladministration reduces bone lesions. Although FHH results from histologically abnormal parathyroid tissue, the response to subtotal parathyroidectomy is unsatisfactory. Because overt clinical manifestations are rare, treatment, other than calcium supplementation, is usually not required. 1.El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab2023;108(3):507-528. doi:10.1210/clinem/dgac621 