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Calcium is the most represented bivalent cation in the organism, and it is essential for a variety of actions. It supports the body, and works as a second messenger, modulating different intracellular and extracellular processes. The balance of parathyroid hormone (PTH), calcitonin, and vitamin D has long been considered the main regulator of calcium metabolism, but the function of other “actors”, such as fibroblast growth factor-23 (FGF-23), Klotho gene, and transient receptor potential cation channel, subfamily V, member 5 (TPRV5) should be considered. Hypercalcemia may cause renal damage both temporary (alteration of renal tubular function for instance) and persisting (relapsing nephrolithiasis, especially with high kidney stones) by different ways, leading to a progressive loss of renal function, and ultimately the end stage renal disease with subsequent need of renal replacement therapy. A worsened renal function stimulates further alterations of calcium metabolism, and renal osteodistrophy may result. Hypercalcemia is a common problem also in renal transplant recipients, although in most cases spontaneous resolution occurs, and a modification of the PTH set up, unrelated with extracellular calcium levels, appears very often. In any case, hypercalcemia can lead to alteration of almost the whole renal tubules, modifying the glomerular filtration rate both in direct (vasoconstriction) and indirect (modification of filtration coefficient) ways. Nephrological therapies can treat both acute and chronic hypercalcemia, and it seems to be effective also in secondary hyperparathyroidism (HPT), but in other situations, such as posttransplantation HPT, a surgical approach is often needed.

Primary hyperparathyroidism (HPT) is the most common cause of hypercalcemia in nonhospitalized patients. Benign sporadic primary HPT is caused by a solitary adenoma in 80-85%, by multiglandular disease (multiple adenoma, parathyroid hyperplasia) in 12-14%, and parathyroid carcinoma in 1-2% of the cases. Parathyroid carcinoma is an uncommon finding, and its etiology remains unclear. Primary HPT can also occur in familial syndromes, such as multiple endocrine neoplasia type 1 (MEN 1), MEN 2A, hyperparathyroidism-jaw tumor (HPT-JT) syndrome, and familial isolated primary HPT, which seems to be an early stage of MEN 1 or HPT-JT. Most of the patients with primary HPT are diagnosed because of asymptomatic hypercalcemia, and both signs and symptoms of the disease, when present, are nonspecific, mainly depending on serum calcium concentration. Some patients, however, are diagnosed because of having osteopenia, osteoporosis, or unjustified recurrent bilateral nephrolithiasis. Primary HPT can be discovered by a simultaneous increase of both serum calcium and parathyroid hormone (PTH) levels, and thus the diagnosis can be obtained by inclusion rather than by excluding all the other causes of hypercalcemia. Indeed, the PTH measurement represents the keystone for differential diagnosis between primary HPT and malignancy-associated hypercalcemia. Other benign causes of hypercalcemia are drug-induced (vitamins A & D intoxication, thiazides, lithium, estrogens), endocrine (thyrotoxicosis), posttransplant and tertiary HPT, and familial benign hypocalciuric hypercalcemia. Virtually, all symptomatic patients with confirmed primary HPT should be referred for surgery, while more restrictive criteria have been suggested for the management of those with asymptomatic HPT.

Hypercalcemia arising in cancer patients is usually referred to as malignancy-associated hypercalcemia (MAH). It may complicate early or, more often, late phases of the disease with a prevalence of around 5-30% of all patients with different types of cancer. However, the prophylactic use of bisphosphonates to prevent skeletal events in patients with bone metastases, has probably reduced the occurrence of clinically symptomatic MAH. The most frequent cause of MAH is abnormal production of a parathyroid hormone-related protein (PTHrP), which mimics the effects of parathyroid hormone, increasing bone resorption and, especially, renal tubular calcium reabsorption. Other causes may be bone lysis due to several cytokines and mediators released by the cancer cells in the bone or the ectopic production of 1,25(OH)2 vitamin D3 in tumor tissue. Periodical monitoring of serum ions in cancer patients usually unveils the onset of MAH before the appearance of the classical symptoms (headache, confusion, de-hydration), prompting adequate treatment consisting in hydration, diuretics, bisphosphonates and, whenever possible, treatment of the underlying cancer (usually with systemic chemotherapy). Bisphosphonates are a class of compounds which have all shown to decrease serum calcium levels primarily by inhibition of PTH-dependent osteoclast activation. Although, the antiresorptive potency is higher with late generation compounds (pamidronate, zolendronate, ibandronate) compared to older oral compounds. Agents able to interfere with the receptor activator of nuclear actor-κ ligand (RANKL) pathway such as the monoclonal antibody denosumab represent novel and promising strategies for the treatment of MAH which are currently undergoing experimental and clinical assessment.

Hypercalcemia is a frequent condition, especially in cancer patients, sometimes difficult to diagnose because of its clinical presentation, mimicking other diseases. Severe elevation of serum calcium generally gives mild and non-specific symptoms, ranging from fatigue, nausea, vomiting, abdominal pain, and up to mental status deterioration and cardiac arrhythmias. It is crucial to recognize acute hypercalcemia soon, and treat it aggressively. The severity of clinical findings depends on both the calcium level and the rate at which it develops. The first line treatment is massive rehydration with intravenous saline 0.9% to reach normovolemia, using invasive or noninvasive monitoring. This helps eliminating calcium excretion in the urine. When hemodynamic status or renal function is impaired, dialysis should be considered. Only when normovolemic status is achieved and renal function restored, furosemide administration can help to further increase urinary excretion of calcium. The second step is to inhibit osteoclastic bone resorption, which is possible with both bisphosphonate and non-bisphosphonate drugs. After the emergency treatment, it is important to diagnose and treat the underlying disease, such as hematological malignancy or other malignancies, while patients with primary hyperparathyroidism should be considered for surgery within a few days.

Hypercalcemia, defined as serum total calcium “adjusted” for the serum albumin concentration above the upper limit of the population reference interval, can develop either in a context of a known disease (renal failure, malignancy, or endocrine diseases) or an unexpected result in a routine biochemical testing. The first step is confirming that it is “true” hypercalcemia, excluding pre-analytical, biological, and analytical interferences. A serum calcium value >2.65-2.70 mmol/L (10.8 mg/dL) is very unlikely to be due to analytic variations. However, only ionized calcium correctly assesses the calcium balance and should be the test of choice. In the diagnostic algorithm, which requires assessment of renal function by serum creatinine or estimated glomerular fraction rate, the key step is the determination of intact parathyroid hormone (PTH), together with 25-hydroxyvitamin D [25(OH)]D, for differential diagnosis between PTH-mediated and non-PTHmediated hypercalcemia. In primary hyperparathyroidism, laboratory findings related to calcium balance and renal function, together with bone mineral density, are important guideline elements in patients with symptomatic primary HPT. In those undergoing parathyroidectomy, the intraoperative measurement of PTH by a quick assay may predict operative outcome. In familial hyperparathyroidism, genetic sequencing can provide useful information and it is necessary for a definitive diagnosis, and adequate management of relatives. In severe malignancy-associated hypercalcemia, calcium-phosphate balance and renal function tests are useful for monitoring the course of disease, and the effects of medical therapy. In differential diagnosis with granulomatous disorders, 25(OH)D measurement is suggested, while PTH-related protein assay is not recommended as a routine test.

In patients with hypercalcemia the usefulness and indications of imaging studies depend on the pathological condition causing the disease. The main causes of hypercalcemia are primary hyperparathyroidism (HPT) and malignancy, but an increased serum calcium level can also be the consequence of several diseases affecting different organs, being the object of specific imaging studies. Unfortunately, they are not able to confirm or exclude all those disorders, having the purpose to examine the morphology of each organ involved in the pathogenesis of hypercalcemia, such as parathyroid glands, kidneys and urinary tract, bones and other organs. In patients with HPT the aim of imaging studies is to localize the enlarged PT glands, both in patients with single PT adenoma, and in those with multiple glands disease. The first studies should be neck ultrasonography and sestamibi scintigraphy. If they are negative or discordant, ectopic PT glands are suspected, and computed tomography (CT) scan, magnetic resonance imaging (MR) and more recently positron emission tomography (PET) should be suggested. Ultrasonography has a good accuracy in the detection of renal stones, but unenhanced CT has the best sensitivity. In patients with bone metastases the first imaging technique to be used is whole body bone scintigraphy, followed by plan x-ray of single sites, while CT and MRI may complete the differential diagnosis. CT is usually suggested for mineralized and rib lesions, MRI is preferable for bone marrow lesions, while 18F-fluoro-2-deoxyglucose (FDG)- PET is useful in the detection of soft tissue or bone metastases.

In patients with hypercalcemia the surgical treatment is likely limited to those with primary hyperparathyroidism (HPT), which represents the most frequent cause of this biochemical alteration. Hypercalcemia may also occur in up to 30% of patients with cancer, but unfortunately they are usually unsuitable for surgery. Surgery of parathyroid glands is particularly challenging, because PT anatomy is one of the variables of our organism. The treatment of choice for patients with symptomatic primary HPT is removal of the affected parathyroid(s), that can be achieved both by surgical and non-surgical techniques. The latter is used only in selected patients, when surgery is contraindicated. In asymptomatic patients, surgical parathyroidectomy is usually suggested to prevent complications, but its role is controversial. Bilateral cervical exploration has been the procedure of choice for decades, and it is still mandatory in case of suspicion of multiglandular disease or malignancy, and multiple endocrine neoplasia or familial syndromes. Recent advances in preoperative localization studies, and intraoperative adjuncts, such as quick parathyroid hormone assay, encouraged as a less invasive surgery. Currently, minimally invasive parathyroidectomy is widely performed, both videoassisted and radioguided. Considering the significant improvements of clinical features of the disease after surgery, and the effectiveness and safety of minimally invasive surgical techniques, parathyroidectomy should be suggested both in symptomatic patients and in those with minimally symptomatic primary HPT. However, each patient should be referred to an experienced parathyroid surgeon or endocrinologist, with the aim of having a better definition of the disease, and the best recommendation for treatment.

Hypercalcemia is a relatively common disorder. Primary hyperparathyroidism and malignancy-associated hypercalcemia (MAH) are responsible for more than 90% of all causes of hypercalcemia. General measures of treatment include rehydration and loop diuretics, when renal insufficiency or heart failure is associated. Calcitonin is indicated for the short-term control of severe hypercalcemia, while bisphosphonates are required in the long-term management. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Both clodronate and pamidronate have been widely used in the past. Recently controlled clinical trials demonstrated the superiority of zoledronate compared with previous treatments. The use of calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of primary hyperparathyroidism. They are used when patients do not meet surgical criteria or surgery is not possible or accepted. Recent studies on cancer-induced bone disease have highlighted the role of receptor activator of nuclear factor-κ ligand (RANKL) as a critical effector of skeletal complications of malignancy. RANKL inhibitors may reduce bone resorption in patients with bone metastases and multiple myeloma. Malignancyassociated hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The former refers to the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). A humanized monoclonal antibody against human PTHrP has been generated. It is able to neutralize the PTHrP effects, reducing hypercalcemia in human tumor xenograft animal models.