Hypercalcaemia associated with malignancy (HCM) is the most common cause of PTH- independent hypercalcaemia and is responsible of the majority of cases of hypercalcaemia in hospitalized patients. HCM can be distinguished in humoral hypercalcaemia of malignancy (HHM), the most common form due to endocrine or paracrine effects on bone of tumour- produced molecules, and local osteolytic hypercalcaemia (LOH) that is mainly, but not only, due to the direct invasion of bone by tumour cells.
HCM can be associated at any type of cancer. It generally occurs at endstage of the disease, is associated with severe gastrointestinal, renal, neuropsychic, and cardiovascular symptoms and is predictive of a poor prognosis. In some patients serum calcium may increase over a short period of time and hypercalcaemia may be of difficult control leading to fatal hypercalcaemic crisis.
Lung and breast cancers and multiple myeloma account for more than half of all cases of HCM. Other cancers frequently associated with HCM are squamous cells carcinoma of the head and neck, and renal and kidney cancers.
Humoral hypercalcaemia of malignancy. HHM is due to the paracrine or endocrine actions of molecules secreted by the tumour cells, mainly the PTH- related peptide (PTHrP) (Figure 1). The hypothesis that a factor similar to PTH could be responsible for hypercalcaemia in cancer patients was firstly proposed by Albright in 1940, but it was only in 1980s that PTHrP was identified and shown to be similar to native PTH in its N- terminal end. PTH and PTHrP are encoded by the same gene, but the two molecules have different structure and mechanism of control, even if they share the same PTH1 receptor. PTHrP mimics most of the actions of PTH: it increases bone resorption and distal tubular calcium reabsorption, and inhibits proximal tubular phosphate transport. Conversely, PTHrP does not stimulate the production of 1,25(OH)2 vitamin D and has no effect on intestinal calcium ab sorption. Despite the use of the same cellular receptor, PTHrP and PTH act in a different way on bone, likely because of the activation of different intracellular signal pathways. PTH induces a high, but still coupled bone turnover, whereas PTHrP produces an un coupling of bone remodelling (non- equilibrium hypercalcaemia) and a negative bone balance. Moreover, However, PTHrP- induced hypercalcaemia is also and largely caused by its action of on the renal tubule with increased calcium reabsorption and phosphate excretion. PTHrP production is common in patients with adeno carcinomas of breast, prostate, and ovary. An epidemiological follow- up study demonstrated a strong association between ovarian cancer and hypercalcaemia, with a 63% increased risk of mortality when hypercalcaemia occurs [32]. HHM can also occur in patients with squamous cell carcinoma (lung, cervix, oesophagus), renal carcinomas, and lymphomas, although in the latter cases overproduction of 1,25(OH)2 vitamin D may also play an important role.
Fig1. Mechanism involved in the humoral hypercalcaemia of malignancy (HHM). PTH: parathormone; PTHrP, PTH- related peptide; OAF, osteoclast activating factors; Ca2+, ionized serum calcium; UCa, urinary calcium; 1,25 (OH)2 VitD, 1,25 didroxy vitamin D.
Local osteolytic hypercalcaemia. Since the 1940s, it has been recognized that some solid tumours (e.g. breast cancer) and haematological malignancies (e.g. myeloma, lymphoma, and leukaemia) may led to hypercalcaemia due to a widespread skeletal involvement (LOH). In these patients an extensive bone marrow invasion by the tumour was found at pathology and the initial understanding was that hypercalcaemia was due to the extensive bone marrow destruction by osteolytic tumours. Subsequently, it was clear that some tumours produced factors that could act in a paracrine way, inducing calcium mobilization from bone. The current understanding is that tumour cells, after their interaction with the bone marrow microenvironment, produce different factors with activating (osteo clast activating factors, OAFs) or inhibitory (osteoblast inhibitory factors, OIFs) effects. OAFs, namely interleukin (IL)1, IL6, IL11, macrophage inflammatory protein 1 a (MIP1a) and, particularly PTHrP, directly increase maturation and activity of osteoclasts. This effect is mediated by an increased production by osteoblasts and stromal cells of RANK ligand (RANKL), associated with and inhibition of osteoprotegerin (OPG) production by the same cells. RANKL transduction signal induces osteoclast maturation by the mitogen activated protein kinase (MAPK) pathway, thus leading to bone re sorption. The bone matrix destruction releases some growth factors such as TGFβ, FGF, PDGF, and IGF1 that stimulates tumour cells growth in a vicious cycle. At the same time, the Wnt/ dikkopf- 1 pathway is inhibited, leading to a decreased osteoblast activation. The final effect is an uncoupling of bone remodelling, with prevalent bone destruction and calcium release. Clinical features of LOH are hypercalcaemia, bone pain, bone loss, and fragility fractures.
