The kidney is a central organ in ensuring calcium balance and PTH has a major role in fine-tuning this renal function (18-20). PTH has little effect on modulating calcium fluxes in the proximal tubule where 65% of the filtered calcium is reabsorbed, coupled to the bulk transport of solutes such as sodium and water (19). Nevertheless, in this region PTH binds (21), to its cognate receptor, the type I PTH/PTHrP receptor (PTHR) a 7-transmembrane-spanning G protein-coupled protein which is linked to both the adenylate cyclase system and the phospholipase C system (22-24). Stimulation of adenylate cyclase is believed to be the major mechanism whereby PTH causes internalization of the type II Na+/Pi- (inorganic phosphate) co-transporter leading to decreased phosphate reabsorption and phosphaturia (25).

In this nephron region, PTH can, after binding to the PTHR, also stimulate the 25(OH)D3-1a hydroxylase [1a(OH)ase], leading to increased synthesis of 1,25(OH)2D3 (26). A reduction in ECF calcium can itself stimulate 1,25(OH)2D3 production but whether this occurs via the CaSR is presently unknown. Finally PTH can also inhibit Na+ and HC03- reabsorption in the proximal tubule by inhibiting the apical type 3 Na+/H+ exchanger (27), and the basolateral Na+/K+-ATPase (28) as well as by inhibiting apical Na+/Pi- cotransport.

About 20% of filtered calcium is reabsorbed in the cortical thick ascending limb of the loop of Henle (CTAL) and 15% in the distal convoluted tubule (DCT) and it is here that PTH also binds to the PTHR (23) and again by a cyclic AMP-mediated mechanism (29), enhances calcium reabsorption. In the CTAL, at least, this appears to occur by increasing the activity of the Na/K/2Cl cotransporter that drives NaCl reabsorption and also stimulates paracellular calcium and magnesium reabsorption (30). The CaSR is also resident in the CTAL (31) and can respond to an increased ECF calcium by activating phospholipase A2, reducing the activity of the Na/K/2Cl cotransporter and of an apical K channel, and diminishing paracellular calcium and magnesium reabsorption. Consequently a raised ECF calcium antagonizes the effect of PTH in this nephron segment and ECF calcium can in fact participate in this way in the regulation of its own homeostasis. Furthermore the inhibition of NaCl reabsorption and loss of NaCl in the urine that results may contribute to the volume depletion observed in severe hypercalcemia. ECF calcium may therefore act in a manner analogous to "loop" diuretics such as furosemide.

In the DCT, PTH can also influence transcellular calcium transport (31a). This is a multistep process involving transfer of luminal Ca ⁺²into the renal tubule cell via the transient receptor potential channel (TRPV5), translocation of Ca+ ⁺²across the cell from apical to basolateral surface a process involving proteins such as calbindin-D28K, and finally active extrusion of Ca+ ⁺²from the cell into the blood via a Na+/Ca+ ⁺²exchanger, designated NCX1. PTH markedly stimulates Ca2+ reabsorption in the DCT primarily by augmenting NCX1 activity via a cyclic AMP-mediated mechanism.

In bone, the PTHR is localized on cells of the osteoblast phenotype which are of mesenchymal origin (32) but not on osteoclasts which are of hematogenous origin. Nevertheless in the postnatal state the major physiologic role of PTH appears to be to maintain normal calcium homeostasis by enhancing osteoclastic bone resorption and liberating calcium into the ECF. This effect of PTH on increasing osteoclast stimulation is indirect, with PTH binding to the PTHR on pre-osteoblastic stromal cells (33) and enhancing the production of the cytokine RANKL (receptor activator of NFkappaB ligand), a member of the tumor necrosis factor (TNF) family (34). Simultaneously, levels of a soluble decoy receptor for RANKL, termed osteoprotegerin, are diminished facilitating the capacity for increased stromal cell-bound RANKL to interact with its cognate receptor, RANK, on cells of the osteoclast series. Multinucleated osteoclasts are derived from hematogenous precursors which commit to the monocyte/macrophage lineage, and then proliferate and differentiate as mononuclear precursors, eventually fusing to form multinucleated osteoclasts (35). These can then be activated to form bone-resorbing osteoclasts. RANKL can drive many of these proliferation/differentiation/fusion/activation steps although other cytokines, notably monocyte-colony stimulating factor (M-CSF) may participate in this process (35).

It has been noted that continuous administration of PTH in vivo can lead to enhanced bone resorption and hypercalcemia whereas intermittent administration can lead to a net anabolic effect by increasing bone formation (36). PTH has been reported to increase growth factor production, notably insulin-like growth factor-1 (IGF-1) production, which may contribute to this (37), however the precise mechanism of the anabolic effect remains elusive. PTH has been suggested to elicit both increases in osteoblast production and activity and decreases in osteoblast apoptosis (38) although which mechanisms predominate is unclear. It is conceivable that different modes of anabolic action occur depending on the stage of development of the organism. Endogenous  PTH has also been shown to exert a physiologic anabolic effect on trabecular bone formation in both the fetus and neonate (39, 39a)

Primary sporadic hyperparathyroidism is generally (at least 85-90% of cases) associated with a single parathyroid adenoma which overproduces PTH. Although 10-15% of cases may be associated with multigland hyperplasia, it seems prudent to consider that at least some if not most of these cases represent familial rather than sporadic disease. The presence of "multiple adenomas" should also suggest the possibility that all glands are involved as part of a familial syndrome. Primary malignant sporadic hyperparathyroidism may occur as a consequence of parathyroid carcinoma, but is a relatively rare event (about 1% of cases).

To date, the only genes definitively implicated in primary sporadic benign hyperparathyroidism are cyclin D1, an oncogene that encodes a key regulator of the cell cycle and MEN1, a tumor suppressor gene, also implicated in familial multiple endocrine neoplasia type I (97a). HRPT2, a tumor suppressor gene associated with the Hyperparathyroidism-Jaw Tumor syndrome (97b), has also been implicated in most sporadic parathyroid carcinomas (97c). Other important parathyroid regulatory pathways that may play a role in the pathogenesis of hyperparathyroidism are those related to the principal regulators or parathyroid cell proliferation and PTH secretion i.e. 1,25(OH)2D3, Ca ⁺²and phosphate. Rarely, sporadic hyperparathyroidism with hypocalciuria may occur, caused by antibodies to the calcium-sensing receptor. This syndrome has been termed Autoimmune Hypocalciuric Hypercalcemia (97d).

The clinical manifestations of these disorders are caused by the overproduction of PTH and its effect on bone resorption and formation, on its capacity to stimulate renal 1,25(OH)2D3 production and on the resultant effect on ECF calcium which can modify the filtered renal load of calcium (Fig. 4). Thus, in the most common form of primary hyperparathyroidism ie primary benign sporadic hyperparathyroidism, excess PTH production can produce significant bone loss manifested by discrete lesions including subperiosteal bone resorption of the distal phalanges, osteitis fibrosa cystica characterized by bone cysts and "brown tumors" (ie collections of osteoclasts intermixed with poorly mineralized woven bone), and ultimately fractures. These manifestations are rarely seen in Western nations (2% of cases) but were common manifestations in the past and appear to be very common in the East (80-100%) (98-101). Whether this severe bone disease reflects a delay in detecting primary hyperparathyroidism early in the East, or as seems equally plausible, is a manifestation of excess PTH action in the face of marginal or deficient vitamin D and calcium intake (102), remains to be determined. The more common skeletal manifestation of excess circulating PTH in the West now appears to be demineralization of cortical bone, reflecting the "catabolic bone activity" of PTH, with relative preservation of trabecular bone, reflecting its "anabolic activity" (103). Consequently the severity of bone disease in the West appears considerably diminished. Possibly as a consequence of less severe bone disease, hypercalcemia is also less marked in the West, the filtered load of renal calcium is lower and the incidence of kidney stones and particularly of nephrocalcinosis has declined as well. Nevertheless hypercalciuria still occurs in 35-40% of patients with primary benign sporadic hyperparathyroidism in the West and kidney stones occurs in 15-20% (104). In the East, where relative or absolute vitamin D deficiency may limit the severity of hypercalcemia and therefore the filtered load of calcium, the incidence of nephrolithiasis (10-40%) does not appear to be as different as is the incidence of bone disease. The higher incidence in the West of primary benign sporadic hyperparathyroidism in women and in an older age group (105) also distinguishes the presentation of this disorder in the West relative to the East.

Figure 4. Disordered mineral homeostasis in hyperparathyroidism. In primary sporadic hyperparathyroidism PTH is generally overproduced by a single parathyroid adenoma. Increased PTH secretion leads to a net increase in skeletal resorption with release of Ca+2 and Pi (inorganic phosphate) from bone. PTH also increases renal 1(OH)ase activity leading to increased production of 1,25(OH)2D3 from 25(OH)D3 and increased Ca+2 and Pi absorption from the small intestine. PTH also enhances renal Ca+2 reabsorption and inhibits Pi reabsorption resulting in increased urine Pi excretion. The net result is an increase in ECF calcium and a decrease in ECF phosphate.

Abnormalities other than skeletal and renal have been associated with primary benign sporadic hyperparathyroidism. These include gastrointestinal manifestations including peptic ulcer, which is now believed to suggest the presence of multiple endocrine neoplasia type I (MENI) and acute pancreatitis which may be a manifestation of hypercalcemia per se. Neuromuscular abnormalities manifested by weakness and fatigue and accompanied by EMG changes may occur although the pathophysiology is uncertain. The relationship of hypertension and neuropsychiatric symptoms to the hyperparathyroidism remains unclear inasmuch as the former is generally not reversible when the hyperparathyroidism is treated and the latter is quite common in the population at large and difficult to ascribe to hyperparathyroidism. Rarely, primary benign sporadic hyperparathyroidism may present with severe acute hypercalcemia (parathyroid crisis) (106).

Although estrogen therapy has been advocated for the treatment of primary hyperparathyroidism in postmenopausal women (107) and trials of bisphosphonates (108) and calcimimetic agents (those that mimic or potentiate the action of calcium at the CaSR) (109) have been reported there is no ideal long-term medical management for primary hyperparathyroidism at the present time.

Surgical removal of the parathyroid adenoma currently remains the treatment of choice if the ECF calcium is greater than 1mg/dL above normal, if there is overt bone disease or nephrolithiasis, if severe acute hypercalcemia has occurred, if urine calcium is greater than 400 mg/day, if cortical bone mass is greater than 2SD below controls or if the patient is less than 50 (110). Where more than one gland is enlarged it is reasonable to assume that this is multiple glandular disease and removal of 3½ glands or total parathyroidectomy with or without a parathyroid autograft is indicated. Severe, chronic hypercalcemia is more commonly associated with parathyroid carcinoma. Complete resection of the primary lesion is urgent in this case.

Tertiary hyperparathyroidism appears to represent the autonomous function of parathyroid tissue that develops in the face-of-long-standing secondary hyperparathyroidism (126). This may occur with monoclonal expansion of nodular areas of the parathyroid gland. These in turn can be associated with decreased VDR and decreased CaSR expression which may lead to an increased set point for PTH secretion. The most common circumstance in which this occurs is in chronic renal failure where 1,25(OH)2D3 deficiency, hyperphosphatemia and hypocalcemia produce chronic stimulation of the parathyroid glands. However, hypercalcemic hyperparathyroidism has also been described in some cases of hypophosphatemic osteomalacia after long-term treatment with supplemental phosphate which induces intermittent slight decreases in ECF calcium and stimulation of PTH secretion. In symptomatic patients, surgical treatment, ie either removal of about 5/8 of the parathyroid mass or total parathyroidectomy with autografting of parathyroid tissue fragments into the muscle of the forearm, is indicated.

Hypercalcemia has been reported in as many as 50% of patients with thyrotoxicosis (127). Due to direct effects of increased triiodothyronine on bone, bone turnover and resorption are increased (128,129). The liberated calcium appears to suppress PTH release so that 1,25(OH)2D3 levels are reduced and renal calcium reabsorption is diminished. Therapy of the hyperthyroidism reverses the hypercalcemia (130,131).

Although both primary and secondary hypoadrenalism have been associated with hypercalcemia (132,133), the underlying etiology is unclear. Ionized calcium appears to be elevated and PTH and 1,25(OH)2D3 are suppressed. The hypercalcemia is reversed by volume expansion and glucocorticoids.

Jansen's Syndrome is a rare autosomal dominant form of short-limbed dwarfism in which neonates presents with metaphyseal chondro-dysplasia, hypercalcemia and hypophosphatemia which is lifelong (134). PTH and PTHrP levels in serum are undetectable but renal tubular reabsorption of phosphate is decreased and urinary cyclic AMP is increased. An activating mutation of the PTHR has been described in such patients. A variety of skeletal abnormalities have been noted which reflect the overactivity of PTH and PTHrP during development, growth and in the adult skeleton.

The association between hypercalcemia and neoplastic disease was first reported in the 1920's and the suggestion was made that the direct osteolytic action of malignant cells was responsible for the release of calcium from bone, resulting in hypercalcemia (135). An association between neoplasia and hypercalcemia was later reported in the English medical literature (136). In 1941 Fuller Albright, while discussing a case of a patient with a renal cell carcinoma, who in fact had a bone metastasis, noted that hypophosphatemia should not have accompanied the hypercalcemia if the tumor was simply producing hypercalcemia by causing osteolysis (137). He suggested that the tumor might be secreting a hypercalcemic substance which was also phosphaturic. Consequently the concept of "ectopic" PTH production by tumors arose and lead to the terms ectopic hyperparathyroidism (138) or pseudohyperparathyroidism. Nevertheless immunoreactive PTH could not be detected in the circulation of these patients (139) and PTH mRNA could not be detected in their tumors (140). To circumvent these issues, bioassays sensitive to PTH were employed to identify PTH-like bioactivity in blood and tumor extracts (141,142) and eventually to identify a novel protein (143), PTHrP. Despite the limited homology of PTH and PTHrP within the NH2-terminal 13 amino acids, PTH(1-34) and PTHrP(1-34) exhibited similar effects on raising blood calcium and lowering blood phosphorus, reducing renal calcium clearance and inhibiting the renal tubular reabsorption of phosphate. The molecular basis of these effects was subsequently shown to be cross-reactivity at the PTHR. In animals models of MAH associated with high PTHrP secretion, passive immunization with PTHrP antiserum reduced hypercalcemia (144,145). Initially after passive immunization, urine calcium increased reflecting reduction in PTHrP induced renal calcium reabsorption; only subsequently did urine calcium decline as bone resorption was neutralized and the filtered load of calcium fell (145). Consequently, the hypercalcemia induced by PTHrP involved a renal mechanism as well as an osseous one. Other similarities were noted between PTHrP and PTH including similar capacities to raise 1,25(OH)2D3 levels (146) and effects on bone characterized, for both PTHrP and PTH, by enhanced bone turnover and increased bone formation as well as resorption (147).

The classic neoplasms associated with hypercalcemia and excess PTHrP have few or no skeletal metastases, and are solid tumors (Fig. 6). This constellation has been termed humoral hypercalcemia of malignancy (HHM). The availability of assays to detect PTHrP demonstrated a broad spectrum of tumors that produce the peptide (148-152). Hypercalcemia is notably associated with squamous cell tumors arising in most sites including esophagus, cervix, vulva, skin and head and neck, but especially in lung. Renal cell carcinomas are also commonly associated with the syndrome as are bladder and ovarian carcinomas. On the other hand patients with colon, gastric, prostate, thyroid and oat cell lung cancers manifest hypercalcemia much less commonly. Islet cell tumors such as VIPomas are frequently associated with hypercalcemia and pheochromocytomas occasionally. PTHrP may be the mediator of hypercalcemia in these cases.

Figure 6. Growth factor-regulated PTHrP production in tumor states. Tumor cells at a distance from bone may be stimulated by autocrine growth factors (GF) to increase production of PTHrP which can then travel to bone via the circulation and enhance bone resorption. Tumor cells metastatic to bone (inset) may secrete PTHrP which can resorb bone and release growth factors which in turn can act in a paracrine manner to further enhance PTHrP production.

Inasmuch as PTHrP is broadly distributed in normal tissues, PTHrP secretion by tumors likely represents eutopic overproduction rather than ectopic PTHrP production. Although demethylation of the PTHrP promoter (153) and gene amplification (154) have been involved as mechanisms responsible for PTHrP overproduction by malignancies, it seems likely that in most cases overproduction of PTHrP is driven by enhanced gene transcriptions of tumor growth factors and by oncogenes which are signalling molecules in the growth factor pathways.

Patients who manifest hypercalcemia usually present with advanced disease. These tumors are generally obvious clinically, and carry a poor prognosis. Elevated PTHrP per se may be an independent prognostic factor signaling a poor prognosis(154a).

Hypercalcemia in association with malignancy is generally more acute and severe than in association with primary hyperparathyroidism. Nevertheless, as in primary hyperparathyroidism hypercalcemia is accompanied by hypophosphatemia, reduced tubular reabsorption of phosphorus, enhanced tubular reabsorption of calcium and increased excretion of nephrogenous cyclic AMP, reflecting the PTH-like actions of PTHrP. Nevertheless serum 1,25(OH)2D3 concentrations which are generally high or high normal in hyperparathyroidism are frequently low or low normal in HHM (155). This may reflect the higher levels of ambient calcium observed in HHM which may directly inhibit the renal 1a(OH)ase enzyme. In hyperparathyroidism, bone resorption is increased but osteoblastic bone formation is also accelerated reflecting a relatively balanced increase in turnover. However, in HHM, osteoclastic bone resorption is markedly increased and osteoblastic bone formation may be reduced (156). The reasons for this uncoupling is unclear and could reflect the action of osteoblast inhibitory cytokines co-released from the tumor or in the bone microenvironment or perhaps the effect of the very high levels of calcium per se.

Several studies have indicated that elevated PTHrP correlates better with hypercalcemia than does the presence or absence of skeletal metastases (148,150,152). This appears particularly relevant to certain neoplasms such as breast cancer which is commonly-associated with hypercalcemia but is even more commonly associated with osteolytic skeletal metastases. Elevated circulating PTHrP concentrations (150,151) may contribute to the development of hypercalcemia in these cases in part through augmented bone resorption and in part through increased renal calcium reabsorption. contribute to the pathogenesis of local osteolytic lesions (157,158). Thus, breast tumors that are metastatic to bone may release PTHrP in the bone microenvironment which will resorb bone and release growth factors such as TGFb (159); released TGFb can then stimulate further PTHrP release from the tumor, thus setting up a positive feedback loop (Fig. 6, see above). Consequently, the presence of skeletal metastases in association with a malignancy is not mutually exclusive with high circulating PTHrP which can contribute to the hypercalcemia, through both osseous and renal mechanisms; at the same time, locally released PTHrP may contribute to the focal osteolysis. It is in fact uncertain whether local osteolysis per se ever effectively raises ECF calcium in the absence of some cause of reduced renal calcium excretion.

Hematologic malignancies that may cause hypercalcemia (160,161) include non-Hodgkin's lymphoma, chronic myeloid and lymphoblastic leukemia, adult T cell leukemia/lymphoma (ATL) and multiple myeloma.

ATL is an aggressive malignancy that develops after 20-30 years of latency in about 5% of individuals infected with human T-cell lymphotrophic virus type I (HTLV-I). This tumor can be associated with hypercalcemia and increased PTHrP production (162). The mechanism of PTHrP production appears to be stimulation of the PTHrP promoter by the viral protein TAX in the infected lymphoid cells, causing increased PTHrP gene transcription.

Non-Hodgkin's lymphoma may also be associated with increased PTHrP secretion and hypercalcemia and this appears to occur predominantly in patients with late-stage disease and high-grade pathology (161). Multiple Myeloma, although frequently associated with hypercalcemia (about 30% of cases) is rarely associated with increased PTHrP production.

PTHrP assays that recognize NH2-terminal regions or mid-regions of the molecule, and two-site assays detecting two molecular epitopes have been developed. These assays have generally been quite sensitive and specific and successful in detecting PTHrP in MAH where PTHrP overproduction occurs. Circulating levels in normal individuals are generally low or undetectable. Studies have also shown that PTHrP levels do not fall after treatment of the hypercalcemia of MAH but do fall after reducing the tumor burden (150,163). Consequently the assays may prove useful to track PTHrP as a tumor marker to monitor the course of therapy. Detection of elevated serum PTHrP concentrations in malignancy may, however, predict a poor prognosis (163a). Nevertheless further work is necessary to understand the identity of PTHrP fragments which circulate in order to produce even more useful assays. In most reported NH2-terminal or mid-region assays, PTHrP levels may be elevated in some normocalcemic cancer patients. Whether this represents the detection of bioinert fragments which might be useful as tumor markers or the detection of bioactive PTHrP which presages the development of hypercalcemia and therefore also has predictive value needs to be clarified.

Although concentrations of 1,25(OH)2D3 are generally normal or low in most patients with MAH, elevated serum concentrations have been reported in some cases of non-Hodgkin's and Hodgkin's lymphoma in association with hypercalcemia (164-166). In view of the fact that extra-renal production of 1,25(OH)2D3 has been shown in various cell types and that renal impairment accompanied several of the reported lymphoma cases it seems likely that synthesis was occurring in the tumor tissue. This would be analogous to expression of a 1a(OH)ase enzyme in granulomatous tissue. Although it is likely that elevated 1,25(OH)2D3 contributed to the hypercalcemia, co-production of PTHrP has also been reported in some cases (160). Consequently production of 1,25(OH)2D3, lymphoid cytokines and PTHrP individually or in concert might all contribute to disordered skeletal and calcium homeostasis in these tumor states.

A variety of manifestations of malignancy including anorexia, cachexia and dehydration may be due to tumor-produced circulating proinflammatory cytokines. Cytokines such as Il-1, IL-6, TNF, and RANKL which are produced in the bone microenvironment have been identified as physiological regulators of bone turnover. PTHrP released from tumors may increase the local production of several of these cytokines however animal studies have reported that tumor activity can increase systemic levels of certain cytokines such as IL-6 and IL-1 which may contribute along with PTHrP to skeletal lysis and hypercalcemia. Some studies of tumor models have implicated a soluble form of RANKL as contributing to MAH (167), and this remains an intriguing possibility. Finally, circulating concentrations of IL-6 have been reported to correlate with tumor burden in a patient with a squamous carcinoma, a protypical malignancy associated with hypercalcemia and elevated PTHrP (168).

Overall therefore it seems likely that other modulators of skeletal and calcium metabolism may be secreted by malignancies and, generally in the presence but occasionally in the absence of PTHrP, may contribute to the dysregulation of bone and mineral homeostasis occurring with MAH.

Inasmuch as PTH per se is expressed mainly in the parathyroid gland, the secretion of PTH by non-parathyroid tumors constitutes true ectopic hyperparathyroidism. A number of such cases of MAH with true PTH production have now been well documented by immunological and molecular biological techniques (169,170). These tumors include ovarian, lung, thyroid and thymus malignancies. Consequently true ectopic hyperparathyroidism may occur as a cause of MAH but is rare.

Unlike other hematologic malignancies, multiple myeloma appears to have a special predilection to grow in bone (171). This may be related to production of growth factors, notably IL-6, by osteoblastic and osteoclastic cells, which facilitate its growth and factors such as MIP-1a which may promote its adherence to bone. In order to grow in bone, myeloma cells must secrete bone-resorbing factors. A number of such factors have been implicated including IL-1, IL-6, TNF-b (lymphotoxin) and hepatocyte growth factor (HGF). More recently, increased RANKL expression by stromal cells with decreased OPG expression has been reported in multiple myeloma and this correlates with the extent of the bone resorption (171b). Although bone resorption is stimulated there is little active new bone formation. Consequently the serum alkaline phosphatase, a marker of osteoblast function is usually normal and bone scans may be negative. Production by myeloma cells of  Dickkopf-1 (DKK-1) protein, a soluble inhibitor of signalling via the Wnt pathway, an important growth factor  pathway for osteoblasts , has been implicated in the suppression of osteoblast differentiation (171c). All patients with myeloma therefore have extensive bone destruction which may be discrete and focal or diffuse throughout the axial skeleton. Consequently bone pain is a frequent complaint (80% of cases) and pathological fractures are a disabling consequence.

Although all patients develop osteolysis, hypercalcemia occurs in only about 30% of patients. It is likely that as long as renal function is intact and no circulating factor is produced which enhances renal calcium re-absorption (PTHrP is rarely produced by myeloma cells), increased renal excretion of calcium can accommodate the increased filtered load consequent to bone resorption. Impairment of renal function can occur however due to Bence Jones nephropathy or "myeloma kidney" (in which free light chain fragments of immunoglobulins are filtered and damage glomerular and tubular function), or due to amyloidosis, uric acid nephropathy or recurrent infections. At this time hypercalcemia may become evident and be associated, because of the renal damage, with hyperphosphatemia rather than the hypophosphatemia occurring in other disorders causing MAH. Therapy aimed at inhibiting bone resorption (eg bisphosphonates) may therefore have a special effect in Myeloma, not only in reducing hypercalcemia but also in limiting tumor growth.

Therapy of MAH should be directed primarily at treating the hypercalcemia, which may be of acute onset and considerable magnitude, and at treating the underlying tumor burden. Several approaches have been directed at reducing PTHrP production by those tumors in which PTHrP hypersecretion occurs. These include immunoneutralization (145), antisense inhibition, inhibition of growth factor stimulation through farnesyl transferase inhibition (64), inhibition of gene transcription with low calcemic vitamin D analogs (69), and convertase inhibition (71). To date these remain experimental but if PTHrP contributes to the local growth of the tumor, which some studies have reported, reduction of PTHrP levels may contribute not only to the long-term amelioration of skeletal and calcium homeostasis but also to a reduction in tumor burden.