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Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7877
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Abstract |
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 Top Abstract I. IntroductionII. Normal Calcium and...III. Humoral Mechanisms by...IV. Local Mechanisms by...References |
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I. Introduction |
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TopAbstractI. IntroductionII. Normal Calcium and...III. Humoral Mechanisms by...IV. Local Mechanisms by...References |
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Since the time of Paget, it has become clear that cancer affects bone in several ways: 1) indirectly through elaboration of factors that act systemically on target organs of bone and kidney to disrupt normal calcium homeostasis; 2) locally and directly via secondary spread of tumor to bone; and 3) via direct involvement by primary bone tumors. As primary bone tumors comprise a small minority of all tumors affecting bone, this review will focus on the aspects of cancer and bone related to the former only.
The three most common neoplasms in humans, breast, prostate, and lung cancer, frequently affect the skeleton. Since the majority of patients dying of cancer have bone involvement either through metastatic spread or as a result of the systemic effects of tumor-produced factors on bone and kidney, this is not a trivial problem. In 1996 alone, the estimated number of new cancer cases in men included 317,000 cases of prostate cancer and 98,900 cases of lung cancer while 184,300 cases of breast cancer and 78,100 cases of lung cancer were diagnosed in women (2). Furthermore, in the same year, prostate and lung cancer were responsible for 41,400 and 94,400 deaths, respectively, in men while breast and lung cancer deaths in women totaled 44,300 and 64,300 individuals, respectively (2). Despite advances in cancer therapy, cancer statistics indicate that the mortality rate of lung cancer is still rising for women, even though 1996 is the first year that it has leveled off for men. Additionally, the age-adjusted death rates of prostate cancer continue to rise, and although 1996 was the first year that a slight decrease in mortality due to breast cancer was observed, the age-adjusted death rate for breast cancer remains similar to that of 1930 (2). Thus, to improve therapy and prevention, it is important to understand the pathophysiology of the effects of cancer on bone as it will be a continued source of morbidity for years to come. Although the topic is an expansive one, this review will attempt to detail scientific advances in this area regarding the pathophysiology of the effects of cancer on bone.
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II. Normal Calcium and Bone Homeostasis |
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TopAbstractI. IntroductionII. Normal Calcium and...III. Humoral Mechanisms by...IV. Local Mechanisms by...References |
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A. Bone remodeling
Bone is unique among target tissues affected by cancer as it is
being continually remodeled under the influence of systemic hormones
and local bone-derived growth factors. Bone consists of two physically
and biologically distinctive structures. The outer cortical bone is
hard mineralized matrix in which cellular and metabolic activities are
relatively low. Cortical bone makes up 85% of the total bone in the
body and is most abundant in the long bones of the appendicular
skeleton. The volume of cortical bone is regulated by the formation of
periosteal bone, by remodeling within Haversian systems, and by
endosteal bone resorption. Cancellous or trabecular bone constitutes
the remaining 15% of the skeleton and is most abundant in the
vertebral bodies. The adult skeleton is in a dynamic state as the
coordinated actions of osteoclasts and osteoblasts on trabecular
surfaces and in Haversian systems result in continual bone resorption
and formation. The normal mineralization of bone matrix is contingent
upon adequate amounts of vitamin D, calcium, and phosphate. The
mineralized bone matrix contains abundant amounts of growth factors,
transforming growth factor-ß (TGFß) and insulin-like growth factor
II (IGF-II) comprising the majority (3, 4). Such growth factors are
released from the bone matrix as a result of osteoclastic bone
resorption (5), a component of the normal remodeling process necessary
to maintain the structural integrity of bone. The inner portion of bone
consists of multicellular bone marrow in which hematopoietic stem
cells, stromal cells, and immune cells reside. The hematopoietic stem
cells have the potential to differentiate into the blood-forming
elements and bone-resorbing osteoclasts, while the stromal cells
support the differentiation of the hematopoietic cells as well as from
bone-producing osteoblasts. Cells in the bone marrow, stromal and
immune in particular, produce cytokines and growth factors that mediate
cell-to-cell interactions in autocrine, paracrine, and/or juxtacrine
fashions (6). Thus, tumor secretion of hormones that act systemically
on bone may disrupt normal calcium homeostasis and bone remodeling to
result in hypercalcemia and bone loss while tumor-produced phosphaturic
factors may result in osteomalacia. Likewise, once cancer cells arrest
in bone, the high concentrations of growth factors and cytokines in the
bone microenvironment provide a fertile soil on which the cells can
grow. Furthermore, when the tumor cells stimulate osteoclastic bone
resorption, this bone microenvironment is even more enriched with
bone-derived growth factors that enhance survival of the cancer and
similarly disrupt normal bone remodeling to result in bone destruction.
B. Calcium homeostasis
Blood-ionized calcium concentrations are remarkably stable in
normal individuals due to a complex regulatory system involving the
actions of three calciotropic hormones on the target organs of bone,
gut, and kidney. Calcium exchanged between the extracellular fluid and
these target organs normally remains in zero balance (Fig. 1
). Normal calcium homeostasis is
dependent on the interactions of PTH,
1,25-(OH)2D3, and calcitonin on these organs to
maintain the ionized calcium concentration within a very narrow range.
Regulation of normal calcium homeostasis has been extensively reviewed
by Chattopadhyay et al. (7) as well as by Parfitt (8, 9).
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) and represents a simple negative
feedback loop (10). Similar to other endocrine hormones, such as those
secreted by the anterior pituitary, PTH is secreted in a pulsatile
fashion in the normal state as well as in states of primary
hyperparathyroidism (12). The calcium-sensing receptor that mediates
this negative feedback has been cloned from bovine parathyroid cells
(13) and is mutated in the disorders of familial benign hypocalciuric
hypercalcemia (13, 14, 15, 16, 17, 18, 19) and autosomal dominant hypocalcemia (20, 21).
Active vitamin D metabolites decrease PTH synthesis in vitro
and in vivo (22, 23) as well.
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Metabolism of PTH is complex, and the intact and biologically active peptide has a half-life of less than 4 min (29). Intact PTH is cleared rapidly by kidney and liver (30, 31, 32, 33, 34). Carboxy-terminal fragments circulate significantly longer than the intact hormone, mainly because they are cleared exclusively by glomerular filtration (35, 36). Highly sensitive and specific immunoradiometric assays for intact PTH are now widely available (37) and are extremely useful when employed in the differential diagnosis of hypercalcemia.
2. Calcitonin. Plasma-ionized calcium concentration is the most important regulator of calcitonin secretion (38). Increases in plasma-ionized calcium result in an increase in calcitonin secretion and, conversely, a fall in the ambient calcium concentration inhibits calcitonin secretion. These changes are likely mediated through the calcium-sensing receptor, as the parafollicular cells of the thyroid gland express the same calcium-sensing receptor that is expressed in the parathyroid and kidney (39). Gastrointestinal peptide hormones, gastrin in particular, are potent calcitonin secretagogues. Although the physiological significance of this observation remains unclear, it is the basis for the pentagastrin stimulation test, a provocative test to determine the capacity of a patient to secrete calcitonin (40).
The precise biological role of calcitonin in the overall schema of calcium homeostasis is uncertain. Calcitonin directly inhibits osteoclastic bone resorption (41), and the effect is rapid, occurring within minutes of administration. This inhibition is accompanied by the production of cAMP (42), as well as an increase in cytosolic calcium (43) in the osteoclast, and results in contraction of the osteoclast cell membrane (44). These effects are transient and likely have little role in chronic calcium homeostasis. Clinical observations support this since neither calcitonin-deficient patients (athyroid) nor patients with medullary thyroid cancer and excess calcitonin production experience alterations in calcium homeostasis. The calcitonin receptor (45) is a G protein-coupled receptor with seven-transmembrane domains that is structurally similar to the PTH/PTHrP and secretin receptors. The half-life of calcitonin is measured in minutes and metabolism occurs predominantly in the kidney (38). Clinical abnormalities of calcitonin secretion include medullary thyroid carcinoma, small cell lung cancer, and carcinoids and islet cell tumors of the pancreas.
3. Calcitriol. The steroid hormone calcitriol or
1,25-(OH)2D3 is the major biologically active
metabolite of the vitamin D sterol family. Vitamin D precursor
(previtamin D3) is either ingested in the diet or
synthesized in the skin from 7-dehydrocholesterol through exposure to
sunlight (46, 47). Hydroxylation occurs in the liver at the C-25
position to form 25-hydroxyvitamin D [25(OH)D], the precursor of the
more potent metabolite, 1,25-(OH)2D3. 25(OH)D
is hydroxylated at the C-1 position in the kidney by 1
-hydroxylase,
a complex cytochrome P450 mitochondrial enzyme system
located in the proximal nephron (48), to form
1,25-(OH)2D3 (49, 50, 51). The renal
1-hydroxylation of 25(OH)D is the major recognized control point in
vitamin D metabolism, responding to ambient phosphorus, PTH, and
calcium concentrations. PTH and low serum phosphate concentrations
independently increase 1,25-(OH)2D3 production,
while hypercalcemia and 1,25-(OH)2D3 inhibit
renal 1-hydroxylase activity. Under physiological conditions, the
kidney is the sole source of 1,25-(OH)2D3. The
other known important extrarenal sites of
1,25-(OH)2D3 production are the placenta and
granulomatous tissue (52, 53, 54). The half-life of
1,25-(OH)2D3 in the circulation is
approximately 5 h in humans. Fifteen percent is excreted as
urinary metabolites and 50% as fecal metabolites.
1,25-(OH)2D3 increases plasma calcium and
phosphate concentrations by increasing the absorption of calcium and
phosphate from the gastrointestinal tract (51). It also increases bone
resorption (55) and enhances the capacity for PTH to promote renal
tubular calcium reabsorption in the nephron. It is a powerful
differentiation agent for committed osteoclast precursors (56, 57),
causing their maturation to multinucleated cells that are capable of
resorbing bone. Thus, 1,25-(OH)2D3 ensures a
supply of calcium and phosphate available at bone surfaces for the
mineralization of bone matrix. Deficiency of
1,25-(OH)2D3 or of 1-hydroxylase results in
osteomalacia or rickets, as does resistance to
1,25-(OH)2D3, caused by mutations in the
vitamin D receptor (58, 59, 60, 61). Although the function of other vitamin D
metabolites has been unclear, recent evidence from mice deficient in
the 24-hydroxylase gene indicate that such metabolites have a role in
normal bone metabolism. Deficiency of 24-hydroxylase results in lack of
the vitamin D metabolites hydroxylated at the 24 position and abnormal
bone structure consisting of accumulation of osteoid at sites of
intramem-branous ossification (62).
C. Defenses against hyper- and hypocalcemia
The normal physiological defenses against hypercalcemia and
hypocalcemia are listed in Table 1. The
majority of these defense mechanisms are mediated through the hormonal
actions of PTH and 1,25-(OH)2D3. Although the
role of endogenous calcitonin is relatively modest in comparison to PTH
and 1,25-(OH)2D3, pharmacological calcitonin
therapy can be beneficial as discussed later.
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In the converse situation, a rise in ionized calcium concentration results in decreased PTH secretion from the parathyroid glands. Thus, renal tubular calcium reabsorption is decreased, as is osteoclastic bone resorption. Synthesis of 1,25-(OH)2D3 and, subsequently, gastrointestinal absorption of dietary calcium and phosphate are decreased. Thus, the normal response to increases in ionized calcium is an increase in renal calcium excretion and a decrease in intestinal absorption of calcium.
In general, these hormonal responses are more effective in protecting against hypocalcemia than hypercalcemia. Perturbations in these mechanisms, as exemplified by excessive increases in bone resorption, deficiencies or excess of PTH or 1,25-(OH)2D3, and defects in renal capacity to handle calcium and phosphate, will result in either hypercalcemia or hypocalcemia.
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III. Humoral Mechanisms by Which Solid Tumors Affect the Skeleton |
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TopAbstractI. IntroductionII. Normal Calcium and...III. Humoral Mechanisms by...IV. Local Mechanisms by...References |
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1. Clinical features of hypercalcemia. The clinical features
of hypercalcemia are listed in Table 2.
Symptoms may vary in individual patients and are related both to the
absolute concentration of serum calcium and to the rate of rise in
serum calcium. Symptoms also reflect the underlying cause of the
hypercalcemia as well as intercurrent medical conditions. In older or
critically ill patients, symptoms of hypercalcemia may be more
prominent with relatively small increases in serum calcium
concentration. Hypercalcemia most often results in neuromuscular,
gastrointestinal, and renal manifestations. Severe hypercalcemia is
likely the result of a vicious cycle. The hypercalcemic effects of
anorexia, nausea, vomiting, and impaired renal concentrating ability
lead to dehydration and, subsequently, altered mental status. This, in
turn, may promote immobilization and lead to worsening hypercalcemia.
In addition to the symptoms of hypercalcemia, clinical features of
hypercalcemia of malignancy include signs and symptoms of the
underlying cancer. Generally, the cancer is well advanced when
hypercalcemia occurs, and the prognosis is poor. Survival beyond 6
months is uncommon (64, 65, 66).
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(67). Hypercalcemia occurring in the
setting of malignancy may be due to 1) humoral factors secreted by
tumors that act systemically on target organs of bone, kidney, and
intestine to disrupt normal calcium homeostasis; 2) local factors
secreted by tumors in bone, either metastatic or hematological, which
directly stimulate osteoclastic bone resorption; and 3) coexisting
primary hyperparathyroidism.
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a. PTHrP.
Although cancer has been associated with
hypercalcemia since the 1920s, it wasn’t until 1941 that Fuller
Albright first proposed the syndrome of ectopic hormone production in a
patient with hypercalcemia, renal carcinoma, and a solitary bone
metastasis (68). As the patient had normal parathyroid glands at the
time of the neck operation, Albright postulated that the tumor
produced PTH but when he had Collip assay the tumor for PTH, it
was not detected. Thereafter, the syndrome was often referred to as
"pseudohyperparathyroidism" or "ectopic hyperparathyroidism."
When more sensitive PTH assays became available, it was clear that the
offending factor was not PTH, but rather an immunologically distinct
factor that had PTH-like biological activity (69).
Biochemical features of malignancy-associated hypercalcemia share some similarities to those seen in primary hyperparathyroidism (1oHPT). Specifically, in addition to the hypercalcemia, hypophosphatemia can occur (depending on the patient’s renal function) as well as hypercalciuria, hyperphosphaturia, and increased excretion of nephrogenous cAMP (69). Plasma-intact PTH concentrations are suppressed in this syndrome except in rare cases of ectopic PTH production or concomitant primary hyperparathyroidism. Plasma 1,25-(OH)2D3 concentrations are generally low except in certain hematological malignancies when the humoral mediator is 1,25-(OH)2D3.
Almost 50 yr after Albright’s observations, this PTHrP was purified
from human lung cancer (70), breast cancer (71), and renal cell
carcinoma (72) simultaneously by several independent groups and was
cloned shortly thereafter (73). It is now evident that PTHrP, and not
PTH, is a major mediator of humoral hypercalcemia of malignancy (74, 75), although four cases of authentic tumor-produced PTH have been
reported (76, 77, 78, 79). PTHrP has 70% homology to the first 13 amino acids
of the N-terminal portion of PTH (73), binds to PTH receptors (80), and
shares similar biological activity to PTH (81). Specifically, it
stimulates adenylate cyclase in renal and bone systems (71, 72, 81, 82, 83), increases renal tubular reabsorption of calcium and
osteoclastic bone resorption (82, 83), decreases renal phosphate uptake
(81, 82, 84), and stimulates 1-hydroxylase (81). PTHrP has been
found in a variety of tumor types associated with hypercalcemia
including squamous, breast, and renal carcinoma (85, 86). Although the
majority of squamous cell carcinomas produce PTHrP (87), the capacity
to cause hypercalcemia may depend on the level of PTHrP gene
expression, which in turn may be determined by differential
transcription of the PTHrP gene promoters (88). The regulation of PTHrP
is complex, and factors such as PRL (89), epidermal growth factor (EGF)
(90, 91, 92, 93), insulin (91), IGF-I (91, 94) and II (91), TGF (95), TGFß
(93, 96, 97, 98), angiotensin II (99), stretch (100), and the
src protooncogene (101) have been shown to increase
expression, while glucocorticoids (91, 94, 102, 103) and
1,25-(OH)2D3 (90, 91) decrease it. Estrogen has
been shown to increase PTHrP expression in uterine tissue, and
in vitro studies suggest that an estrogen response
element is present in the PTHrP gene (104, 105). Mutations in codons
248 and 273 of the p53 tumor suppressor gene repress PTHrP gene
expression in some squamous cell carcinomas (106). The cell death
inhibitor, Bcl-2, is downstream in a signaling pathway that is required
for normal skeletal development (107).
The human PTHrP gene is much larger and more complex than the human PTH gene. It spans approximately 15 kb of genomic DNA and has nine exons and three promoters. Three PTHrP isoforms of 139, 141, or 173 amino acids as well as multiple PTHrP mRNA species exist (93). There is considerable sequence homology across species up to amino acid 111 (108). Cell line-specific utilization of the promoters and of the 3'-alternative splicing pathways among bone, breast, kidney, and lung cell lines have been demonstrated (93). In this study, dexamethasone decreased while EGF and TGFß increased abundance of each of the alternative mRNA species. Furthermore, EGF treatment increased transcription from promoters 1 and 2 and stabilized exon VII- and IX-containing transcripts in various cell lines (93).
Like PTH and other endocrine peptides, PTHrP undergoes endoproteolytic posttranslational processing that results in several secretory forms: 1) an amino-terminal PTHrP-(1–36); 2) a midregion species that begins at amino acid 38 that has an undefined carboxyl terminus (109, 110); and 3) a carboxyl-terminal species that is recognized by an antibody directed against the 109–138 region (110, 111, 112). The preponderance and arrangement of basic residues in the protein sequence suggest that members of the subtilisin family of endoproteases, such as furin (113), PC 1/3, PC-2, PACE-4, and PC8 (114), are responsible for such processing (109, 115, 116). Posttranslational modification of PTHrP also occurs as glycosylation of an amino-terminal PTHrP species produced by keratinocytes has been reported (117). The subject of posttranslational processing of PTHrP, as well as the receptor and signal transduction pathways employed by the mature secretory forms of PTHrP, has been extensively reviewed by Orloff et al. (115). Regulation of PTHrP secretion may be cell specific as PTHrP expressed in neuroendocrine cells is secreted in a regulated fashion as compared with a constitutive secretion when expressed in nonneuroendocrine cell types such as squamous cell carcinoma (116). Although PTHrP mediates its calcemic effects through the classic PTH/PTHrP receptor, there is evidence for a separate PTHrP receptor (118). However, the function of such a receptor remains unclear.
PTHrP has been detected in a variety of tumor types as well as in normal tissue (85, 86). The widespread expression of PTHrP in normal tissue was the first evidence that the hormone had a role in normal physiology. In addition to the PTH-like effects, emerging work testifies to the fact that PTHrP has an important role in normal physiology. Such a topic is beyond the scope of this review, but suffice it to say that PTHrP appears to be important in 1) the regulation of cartilage differentiation and bone formation through endochondral ossification (119, 120, 121); 2) growth and differentiation of skin (122), mammary gland (123, 124), and pancreatic islets (125); 3) cardiovascular function (126); 4) transepithelial calcium transport in the distal nephron, mammary epithelia, and the placenta (124, 127); 5) relaxation of smooth muscle in uterus, bladder, arteries, stomach, and ileum (99, 128, 129, 130); and 6) host immune function (131, 132, 133). Bone perichondrial cell production of PTHrP regulates cartilage cell differentiation and has been linked to expression of Indian Hedgehog gene (134). Indian Hedgehog protein expressed by prehypertrophic cartilage cells inhibited cartilage differentiation, and this inhibitory effect was mediated by PTHrP. The normal physiological functions of PTHrP have been extensively reviewed elsewhere (135, 136).
The role of PTHrP in normal breast physiology (137, 138) sheds light on its potential importance in the pathophysiology of hypercalcemia and bone metastasis associated with breast cancer, which is discussed in later portions of this review. PTHrP is expressed in lactating mammary tissue (139) and secreted into milk at concentrations 10,000–100,000 times greater than plasma concentrations of humans with malignancy-associated hypercalcemia (140, 141, 142, 143, 144). Increased plasma PTHrP concentrations have been documented in at least two patients with the rare syndrome of lactational hypercalcemia (145, 146, 147) in addition to some breast-feeding mothers (148). Thus, PTHrP may be responsible for mobilizing calcium from maternal bone for use in milk production, and it may mediate lactation-associated bone loss.
In addition to the diverse and accumulating normal physiological functions of PTHrP, it likely has a multifunctional role in cancer as well. Such identified functions include 1) mediating hypercalcemia; 2) aiding in the development and progression of osteolytic bone metastasis in breast cancer; 3) regulating growth of cancer cells (149, 150, 151); and 4) acting as a cell survival factor (107).
The hypercalcemia of malignancy syndrome was the first identified consequence of the PTHrP effects in cancer. In this syndrome, tumor-produced PTHrP interacts with PTH receptors in bone and kidney to cause hypercalcemia, osteoclast-mediated bone resorption, and increased nephrogenous cAMP and phosphate excretion. The PTH-like properties of PTHrP, and specifically increasing osteoclastic bone resorption and renal tubular calcium reabsorption, appear to be responsible for the hypercalcemia. Approximately 80% of hypercalcemic patients with solid tumors have detectable or increased plasma PTHrP concentrations (111). Plasma PTHrP concentrations, as measured by a sensitive two-site immunoradiometric assay, are low or undetectable in the plasma of normals (152), but as is the situation with PTH, the C-terminal fragment is increased in patients with chronic renal failure (111). In fact, the plasma C-terminal PTHrP concentration increases as the glomerular filtration rate decreases (112).
i. Humoral hypercalcemia of malignancy (HHM) vs.
1oHPT.Despite similarities between HHM and
1oHPT and the similar biological actions of PTHrP and PTH,
respectively, unexplained differences between these syndromes exist.
First, patients with PTHrP-mediated HHM have low serum concentrations
of 1,25-(OH)2D3 compared with patients with
1oHPT (153), even though both proteins stimulate renal
1-hydroxylase activity. Clinical studies in which normal humans
received short-term infusions of PTHrP-(1–34) (154) or PTHrP-(1–36)
(155) revealed increased serum 1,25-dihydroxyvitamin D concentrations
comparable to those who had received a similar infusion of PTH-(1–34).
Animal studies have revealed similar findings (156, 157). Female nude
mice infused with synthetic PTHrP-(1–40) for 7 days developed
hypercalcemia, hypophosphatemia, and increased serum
1,25-dihydroxyvitamin D concentrations (157). Likewise, male nude mice
bearing Chinese hamster ovarian (CHO) cell tumors transfected with the
cDNA for human prepro-PTHrP or prepro-PTH developed similar
hypercalcemia and increased plasma concentrations of
1,25-dihydroxyvitamin D when compared with control animals bearing
untransfected CHO tumors (158). Additionally, similar increases in
blood ionized calcium and 1,25-dihydroxyvitamin D concentrations were
observed in nude mice bearing CHO tumors that were engineered to
secrete PTHrP mutants truncated at the carboxyl terminus (156).
Second, human studies using either quantitative bone histomorphometry (159) or biochemical markers of bone turnover (160) have demonstrated that although patients with either HHM or 1oHPT have increased osteoclastic bone resorption, many patients with HHM do not have the coupled increase in osteoblastic bone formation that those with 1oHPT have. Serum osteocalcin concentrations, a marker for bone formation, were significantly increased in patients with 1oHPT compared with normals (161). In the same study, serum osteocalcin concentrations in hypercalcemic patients with bone metastasis were significantly lower compared with those of normal controls, while normocalcemic patients with bone metastases had values similar to normal humans. These osteocalcin concentrations correlated with histomorphometric parameters of bone formation but not bone resorption (161). In the studies by Fraher et al. (154) and Everhart-Caye et al. (155), in which normal humans received infusions of PTH or PTHrP, bone histomorphometry or biochemical markers of bone turnover were not measured. Such studies done with PTHrP infusions in rodents have revealed increased osteoclastic bone resorption, as well as increased bone formation, as assessed by dynamic bone histomorphometry (157). In contrast, nude mice bearing a PTHrP-secreting human squamous cell carcinoma demonstrated increased bone resorption and decreased bone formation as assessed by dynamic bone histomorphometry (162). Thus, whether PTHrP alone is responsible for the uncoupling of bone formation from bone resorption is an issue that remains controversial.
Unlike the metabolic acidosis seen in patients with primary
hyperparathyroidism, patients with malignancy-associated hypercalcemia
often have a metabolic alkalosis with a low plasma chloride and high
plasma bicarbonate concentration. Although many explanations have been
postulated for the discrepancies between HHM and 1oHPT,
such as differences between the pulsatile secretion of PTH and the
presumed continuous secretion of PTHrP, suppression of bone formation
and 1-hydroxylase activity by other tumor-associated factors,
biologically active PTHrP fragments, or hypercalcemia per se
(163), the reasons for these differences have not been adequately
elucidated.
ii. Modulation of PTHrP effects by other tumor-associated
factors. Regardless of the reasons for the clinical differences
between HHM and 1oHPT, there is clear evidence that other
tumor-produced factors can modulate the end-organ effects of PTHrP as
well as its secretion from tumors. Using an in vivo model of
PTH and PTHrP-mediated hypercalcemia, Uy et al. (164)
demonstrated that both proteins, when produced by tumors in which the
corresponding genes were transfected and then inoculated into nude
mice, caused similar hypercalcemia as well as increases in osteoclastic
bone resorption, more committed marrow mononuclear osteoclast
precursors, and mature osteoclasts. No stimulatory effects were seen on
the multipotent osteoclast precursors, the granulocyte/macrophage
colony-forming unit. In a similar model system, IL-6 potentiated the
hypercalcemia and bone resorption mediated by PTHrP in vivo
by stimulating production of early osteoclast precursors (165).
Likewise, TGF has been shown to enhance the hypercalcemic effects of
PTHrP in an animal model of malignancy-associated hypercalcemia (166)
as well as to modulate the renal and bone effects of PTHrP (167, 168).
Sato et al. (169) demonstrated that IL-1 and PTHrP may
have synergistic effects in vivo, and others have shown that
IL-1 may modulate the renal effects of PTHrP (170). Finally, Uy
et al. have demonstrated that tumor necrosis factor-
(TNF) enhanced the hypercalcemic effect of PTHrP by increasing the
pool of committed osteoclast progenitors with a subsequent increase in
osteoclastic bone resorption. Bone formation parameters in these nude
mice indicate that TNF did not inhibit the new bone formation
stimulated by PTHrP (171).
Such tumor-associated factors also appear to be important regulators of
PTHrP expression and secretion by tumors. EGF has been shown to
stimulate PTHrP expression in a keratinocyte cell line (172) as well as
a mammary epithelial line (91) while TGF enhanced PTHrP expression
in a human squamous cell carcinoma of the lung (173). Interleukin-6
(IL-6), TNF, IGF-I, and IGF-II increased the production of PTHrP
in vitro by a human squamous cell carcinoma (94). TGFß,
which is abundant in bone, released in active form by resorbing bone
and expressed by some breast cancers (174, 175) and cancer-associated
stromal cells (176), has been shown to enhance secretion of and
stabilize the message for PTHrP in a renal cell carcinoma (96) as well
as in a squamous cell carcinoma (97, 98). Other data (177, 178)
demonstrate that this relationship also exists in a human breast
adenocarcinoma cell line, MDA-MB-231.
iii. PTHrP in hypercalcemia associated with breast cancer. Hypercalcemia in breast cancer represents a special situation. Although it is clear that the predominant way in which breast cancer affects bone is through metastatic mechanisms, there is sufficient evidence to support the notion that breast cancers may secrete factors that act systemically to stimulate osteoclastic bone resorption and to increase renal tubular reabsorption of calcium (179, 180, 181). Hypercalcemia is associated with breast cancer, occurring in approximately 10% of afflicted women during the course of their disease (182). It is likely more common in those with advanced breast cancer. Osteoclast-mediated skeletal destruction by metastatic tumor is a major mechanism responsible for hypercalcemia, as increased osteoclastic bone resorption has been documented histologically in areas surrounding breast cancer metastases (183, 184, 185, 186). However, humoral mechanisms may contribute in 10–60% of cases of breast cancer-associated hypercalcemia as evidenced by increased nephrogenous cAMP and plasma PTHrP in some patients (186, 187, 188, 189, 190).
PTHrP is clearly a significant factor in mediating hypercalcemia in breast cancer (191). Since PTHrP is expressed in normal breast tissue and appears to play an important role in normal breast physiology, its overproduction in breast cancer is not surprising. One of the three tumors from which PTHrP was originally purified was a breast cancer from a patient with humoral hypercalcemia of malignancy (70). PTHrP was detected by immunohistochemical staining in 60% of 102 invasive breast tumors removed from normocalcemic women, but not in normal breast tissue (192). At least four other studies have confirmed these percentages (193, 194, 195, 196), and one of these has demonstrated immunoreactive PTHrP within the cytoplasm of lobular and ductal epithelial cells in normal and fibrocystic breast tissues (193). Furthermore, 65–92% of hypercalcemic breast cancer patients (with and without bone metastasis) had detectable plasma PTHrP concentrations by RIA similar to those documented in patients with humoral hypercalcemia of malignancy due to nonbreast tumors (180, 195). Not only is PTHrP an important mediator of hypercalcemia in breast cancer, it may have a significant role in the pathophysiology of breast cancer metastasis to bone as evidenced by the clinical studies indicating that PTHrP expression by the primary breast cancer is more commonly associated with the development of bone metastasis and hypercalcemia (195). This topic will be discussed in a later section.
iv. PTHrP in hypercalcemia associated with hematological malignancies. The mechanisms responsible for hypercalcemia associated with hematological malignancies are multifactorial and include secretion of local bone-active cytokines, such as IL-6, IL-1, and lymphotoxin or TNFß, from tumor in bone or from systemic effects of tumor-produced factors such as 1,25-(OH)2D3 (discussed below). Recent data from a clinical study of 76 patients with various hematological malignancies demonstrate that PTHrP also may be an important pathogenetic factor in the development of hypercalcemia in some patients (197). In this study, eight of the 14 hypercalcemic patients had non-Hodgkin’s lymphoma and, of these, 62% had significant increases in plasma PTHrP concentrations. The serum 1,25-(OH)2D3 concentrations, when measured, were low in the hypercalcemic non-Hodgkin’s lymphoma patients who had increased plasma PTHrP concentrations (197). Additionally, one of two hypercalcemic patients with Hodgkin’s disease and one of four hypercalcemic patients with multiple myeloma had increased plasma PTHrP concentrations. Also of interest in this study is the fact that several normocalcemic patients with non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, multiple myeloma, and Waldenstrom’s macroglobulinemia had increased plasma PTHrP concentrations as measured by an amino-terminal PTHrP assay (197). Using a sensitive two-site immunoradiometric assay, other investigators have noted increased plasma PTHrP concentrations in patients with adult T cell leukemia and B cell lymphoma (198). Finally, circulating concentrations of PTHrP, comparable to those in humoral hypercalcemia of malignancy, were present in two of four hypercalcemic patients with non-Hodgkin’s lymphoma, in three of nine with myeloma (199), and in a patient with myeloid blast crisis of chronic myeloid leukemia (200). Thus, the humoral mediators in the hypercalcemia associated with hematological malignancies include both 1,25-(OH)2D3 and PTHrP.
b. 1,25-(OH)2D3.
In the setting of
hypercalcemia, serum concentrations of
1,25-(OH)2D3 are normally suppressed unless an
autonomous source of PTH is the cause, such as a parathyroid adenoma.
Lack of 1,25-(OH)2D3 suppression in this
situation is evidence of disordered regulation of
1,25-(OH)2D3 synthesis and indicates extrarenal
production such as that observed in the hypercalcemia associated with
granulomatous disease. Less commonly, tumors may secrete other humoral
factors responsible for hypercalcemia. A major mediator of
hypercalcemia in Hodgkin’s disease, non-Hodgkin’s lymphoma, and other
hematological malignancies appears to be extrarenal production of
1,25-(OH)2D3 (201). The mechanism is similar to
that observed in hypercalcemia associated with granulomatous disease in
which activated macrophages within the granuloma synthesize
1,25-(OH)2D3 (52, 202, 203). In this scenario,
patients usually have increased plasma
1,25-(OH)2D3 concentrations in addition to low
or normal plasma PTH and urinary cAMP concentrations (204) in the
absence of bone involvement. In similar studies, affected patients have
also been shown to have increased fasting urinary calcium excretion
(204) as well as increased intestinal calcium (47Ca)
absorption (205). Increased 1,25-(OH)2D3
concentrations were noted in 12 of 22 hypercalcemic patients with
non-Hodgkin’s lymphoma. In addition, 71% of 22 normocalcemic patients
with non-Hodgkin’s lymphoma were hypercalciuric, and 18% had
increased serum 1,25-(OH)2D3 concentrations.
These findings led the investigators to conclude that dysregulated
1,25-(OH)2D3 production is common in patients
with diffuse large cell lymphoma (201).
Thus, the mechanisms responsible for hypercalcemia in this setting
appear to be multifactorial and include increased intestinal calcium
absorption as well as increased osteoclastic bone resorption.
Additionally, many of the reported patients had altered renal function,
a finding that suggests that impaired renal calcium clearance may also
be contributing to the hypercalcemia in certain patients. The low serum
PTH and urinary cAMP concentrations indicate that neither PTH nor PTHrP
mediates the hypercalcemia in this setting. Prostaglandins, when
measured, have been low, and selected patients had no calcium-lowering
effect from indomethacin therapy (199). It is likely that the lymphoma
tissue itself hydroxylates 25-hydroxyvitamin D to the active
1,25-(OH)2D3 similar to the situation in
hypercalcemia associated with granulomatous disease (52, 203). One
-hydroxylase activity has been demonstrated in human T cell
lymphotrophic virus type I-transformed lymphocytes (206). None of the
reported patients with 1,25-(OH)2D3-mediated
hypercalcemia had concomitant granulomatous disease, and hypercalcemia
often improved with medical or surgical therapy that resulted in a
decrease in serum 1,25-(OH)2D3 concentrations.
Recurrence of hypercalcemia and increased plasma
1,25-(OH)2D3 concentrations has been documented
with recurrence of disease (207).
c. PTH.
After Fuller Albright’s observations in 1941, it was
postulated that malignancy-associated hypercalcemia was due to tumor
production of PTH. This notion was strengthened by the early PTH RIA
data in hypercalcemic patients with malignancy, which suggested that
tumors produced factors recognized in these PTH RIAs (208, 209, 210, 211).
Although, for many years, malignancy-associated hypercalcemia was
attributed to ectopic tumor-produced PTH, it is now clear that PTHrP is
responsible for most cases. Analysis of 13 human and three animal
nonparathyroid tumors of diverse origin associated with hypercalcemia
did not detect PTH RNA transcripts (212). Since that time, four cases
of authentic tumor-produced PTH have been convincingly demonstrated in
a small cell carcinoma of the lung (78), an ovarian cancer (77), a
widely metastatic primitive neuroectodermal tumor (76), and a thymoma
(79). Molecular analysis of the ovarian carcinoma revealed both DNA
amplification and rearrangement in the upstream regulatory region of
the PTH gene (77). Interestingly, the primitive neuroectodermal tumor
produced both PTH and PTHrP that resulted in severe hypercalcemia (76).
These reported patients did not have coexisting primary
hyperparathyroidism since the parathyroid glands were normal at the
time of neck exploration or at autopsy in all cases. However, the fact
remains that ectopic production of PTH is a rare event, and it is
clearly documented that most patients with malignancy-associated
hypercalcemia have suppressed plasma PTH concentrations (69). It should
be emphasized that the most likely cause of hypercalcemia in the
setting of malignancy that is associated with a normal or increased
serum PTH concentration is coexisting primary hyperparathyroidism.
d. Other tumor-associated factors.
There is accumulating
evidence that solid tumors may produce other factors, alone or in
combination with PTHrP, that have the capacity to stimulate
osteoclastic bone resorption and cause hypercalcemia (213). These
factors include IL-1, IL-6, TGF, and tumor necrosis factor (TNF).
Administration of IL-1 injections to mice caused mild hypercalcemia
(214, 215), and this IL-1-induced hypercalcemia has been effectively
blocked by the IL-1 receptor antagonist (216). Mice bearing CHO tumors
transfected with the cDNA for IL-6 developed mild hypercalcemia (217)
as did mice bearing a renal carcinoma that cosecreted IL-6 and PTHrP
(218). Human TGF and TNF have been demonstrated to stimulate
osteoclastic bone resorption in vitro and cause
hypercalcemia in vivo (219, 220, 221, 222, 223, 224). TNF also caused
hypercalciuria, without an increase in nephrogenous cAMP, and increased
osteoclastic bone resorption in vivo in a mouse model
(225). In addition, as noted in the previous section, some of these
factors have been shown to modulate the end-organ effects of PTHrP on
bone and kidney. In some instances, factors such as TGF, IL-1, IL-6,
and TNF enhance the hypercalcemic effects of PTHrP. The ability of IL-6
to enhance PTHrP-mediated hypercalcemia appears to be due to increased
production of the early osteoclast precursor, granulocyte macrophage
colony forming units, by IL-6 in combination with increased production
of the more committed osteoclast precursors stimulated by PTHrP (165).
Figure 3 summarizes the known effect of
various tumor-produced factors on stages of the osteoclast lineage as
determined in bone marrow cultures from mice treated with respective
factors (164, 165, 171, 226).
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3. Treatment of hypercalcemia associated with malignancy. Treatment of hypercalcemia due to malignancy should always involve treating the underlying tumor. Unfortunately, since this is often not effective or cannot be accomplished with the rapidity needed when the patient is faced with life-threatening hypercalcemia, therapy should also be directed against the mechanisms responsible for the hypercalcemia. In essentially all patients with hypercalcemia of malignancy, there is an increase in osteoclastic bone resorption, and in many there is also an increase in renal tubular calcium reabsorption, even in malignancies that are not associated with PTHrP production (230). Medical therapy is therefore aimed at inhibiting bone resorption and promoting renal calcium excretion. Because hypercalcemia associated with cancer is often accompanied by dehydration, volume expansion with isotonic saline is essential. This serves to increase the glomerular filtration rate and reduces the fractional reabsorption of both sodium and calcium. Since hydration alone will normalize serum calcium concentrations only transiently (231), inhibitors of bone resorption such as the bisphosphonates or calcitonin should be administered as well. When possible, mechanism-specific treatment should be attempted (232). Glucocorticoids, for example, are more effective in reducing the serum calcium concentration in hematological malignancies and 1,25-(OH)2D3-mediated hyper-calcemia than in solid tumors. Dietary calcium restriction is ineffective in reducing serum calcium concentrations except in cases of vitamin D-mediated hypercalcemia. In these cases, dietary calcium should be restricted to 400 mg daily until the underlying disorder is corrected. It is not desirable or advantageous to reduce calcium intake in hypercalcemia due to malignancy.
Bisphosphonates, analogs of pyrophosphate, have become the most useful antiresorptive agents among the currently available armamentarium for the treatment of hypercalcemia. They have a high affinity for hydroxyapatite in bone and concentrate in areas of high bone turnover. The mechanisms by which bisphosphonates inhibit bone resorption are not clearly understood, but potentially include induction of osteoclast apoptosis, inhibition of osteoclast formation and recruitment, or stimulation of osteoblasts to produce an inhibitor of osteoclast formation (233, 234). Another mechanism by which bisphosphonates might affect bone resorption is by decreasing the function of the osteoclast with respect to attachment and ruffled border formation (233). Recent in vitro findings using rodent marrow cultures suggest that tyrosine phosphatase activity is important in osteoclast formation and function and is a potential molecular target of bisphosphonate action (235). Bisphosphonates also inhibit axenic growth of amoebe of the slime mold Dictyostelium discoideum, and this property of growth inhibition paralleled the potency of inhibition of bone resorption (236). These findings indicate that bisphophonates may have a mechanism of action that is similar in both the osteoclast and Dictyostelium discoideum.
Bisphosphonates vary in potency but, in general, are poorly absorbed and are most effective in treating hypercalcemia when given intravenously. Bisphosphonates are concentrated in bone and remain there until the bone is resorbed. Etidronate, the first available bisphosphonate in the United States, is the least potent. Intravenous etidronate, given in doses of 7.5 mg/kg iv over 3 consecutive days normalized calcium concentration in 30%–40% of patients (237, 238, 239). Oral etidronate is generally ineffective in treating hypercalcemia (229), and at sustained dosages of 25 mg/kg per day for more than 6 months, it can cause bone mineralization defects (234). Etidronate can also cause hyperphosphatemia which, in addition to hypercalcemia, may lead to a high calcium-phosphate solubility product.
Pamidronate is a potent aminobisphosphonate available for the treatment of hypercalcemia of malignancy. The drug combines high efficacy with low toxicity profile and thus has become the current bisphosphonate of choice for the treatment of hypercalcemia of malignancy. It is highly effective in normalizing serum calcium concentrations and, when used in dosages recommended for hypercalcemia of malignancy, is not associated with bone mineralization defects. Pamidronate, administered as a single 24-h infusion, normalized serum calcium concentrations in 30% of patients who received 30 mg, 61% of patients who received 60 mg, and 100% of patients who received 90 mg (66). Successful therapy with bisphosphonates is associated with an increase in the plasma PTH and 1,25-(OH)2D3 concentrations as well as a decrease in the biochemical markers of bone resorption (66, 153, 190). Clinical studies of pamidronate treatment in patients with hypercalcemia of malignancy indicate that the calcium-lowering response to bisphosphonates correlates positively with the presence of bone metastases (240, 241, 242) and correlates negatively with plasma PTHrP concentrations (65, 240, 241). Such a relationship has also been demonstrated with clodronate, an oral bisphosphonate (243). This is presumably due to the effects of PTHrP to increase renal tubular reabsorption of calcium, which are not blocked by bisphosphonates. Nonetheless, pamidronate compares favorably to other inhibitors of bone resorption such as plicamycin, calcitonin, and gallium nitrate and is well tolerated. Pamidro-nate should be delivered as an intravenous infusion over 4–24 h. Clinical studies using 90 mg infusion of pamidronate over 4 h indicate that the mean time to achieve normocalcemia is approximately 4 days while the mean duration of normocalcemia is 28 days (244). Similarly, intravenous pamidronate, 60 mg every 2 weeks, maintained normocalcemia in a majority of patients with malignancy-associated hypercalcemia (245). An effective method for achieving more rapid reduction of the serum calcium is to use the combination of calcitonin and pamidronate (246). Calcitonin acts rapidly to lower the serum calcium, although usually its effects are only transient. Although escape from calcitonin therapy may occur within 48 h, by that time pamidronate is beginning to exert its maximal effects. Calcitonin can be administered either intramuscularly or subcutaneously every 12 h in doses of 200–400 MRC units. Reported side effects of pamidronate include transient low-grade fever and asymptomatic mild hypocalcemia (66). Bone mineralization defects have been reported only in patients receiving high-dose pamidronate at weekly intervals for the treatment of Paget’s disease (247). It is possible that other bisphosphonates, such as alendronate, risedronate, and tiludronate, will be effective oral therapy for hypercalcemia of malignancy. Due to its propensity to cause mouth ulcers, oral pamidronate, although effective, is not likely to be approved for such use in the United States.
Calcitonin inhibits osteoclastic bone resorption and renal tubular reabsorption of calcium. The main advantages of calcitonin are its rapid onset of action and its relative lack of serious side effects. Unfortunately, calcitonin alone only transiently normalizes the calcium concentration in patients with hypercalcemia of malignancy. Tachyphylaxis, probably due to down-regulation of calcitonin receptors, frequently develops with calcitonin administration, although this can be delayed with concomitant glucocorticoid treatment (248). However, calcitonin use can be particularly effective in the setting of severe hypercalcemia while waiting for the more sustained hypocalcemic effect of administered bisphosphonates to occur. Calcitonin use with bisphosphonates lowers calcium concentrations more quickly and effectively than either alone (249). Although human calcitonin is available, salmon calcitonin is generally used. If salmon calcitonin is used, a test dose of 1 MRC unit should be administered first, since rare anaphylactic reactions have been reported (250).
Plicamycin, or mithramycin, an antineoplastic agent used in the treatment of certain embryonal cancers (251), is also a potent inhibitor of bone resorption. Plicamycin inhibits DNA-dependent RNA synthesis (252) in tumor cells by binding to the promoter regions on DNA, thus preventing transcription (253). Presumably, osteoclastic bone resorption is inhibited by this mechanism as well. The dosage used to treat hypercalcemia (25 µg/kg) is one-tenth of the usual chemotherapeutic dose and should be infused over 4 h. Although plicamycin is almost invariably effective in lowering serum calcium concentrations, its considerable toxicity has limited its use in more recent years as more potent bisphosphonates have become available. Plicamycin has serious hepato- and nephrotoxicity in addition to local irritation and thrombocytopenic effects, which can limit its use in cancer patients as well as in those with renal impairment.
Gallium nitrate is another antineoplastic agent that, like plicamycin, was found to induce hypocalcemia in normocalcemic cancer patients receiving it (254). It inhibits osteoclastic bone resorption and appears to be more effective in lowering serum calcium concentration than calcitonin (255) and etidronate. Gallium is administered as a continuous infusion over 5 days, making it somewhat less convenient than some other antihypercalcemic agents. Gallium is excreted unchanged by the kidneys and has significant nephrotoxicity. Thus, it should not be administered to patients with renal impairment or to those receiving other nephrotoxic drugs (256).
About 30% of patients treated with glucocorticoids for hypercalcemia associated with nonparathyroid malignancy respond with a fall in calcium concentration (229). However, the response is often not complete and the responsiveness to glucocorticoids is unpredictable (229). Glucocorticoids are most effective in hypercalcemic patients with hematological malignancies, multiple myeloma in particular, as well as in vitamin D-associated disorders such as lymphomas. In hematological malignancies, glucocorticoids inhibit osteoclastic bone resorption by decreasing tumor production of locally active cytokines in addition to having direct tumorolytic effects (257). Glucocorticoids in dosage equivalents of prednisone, 40 to 60 mg daily, should be given for 10 days. If the calcium has not decreased in this period, glucocorticoids should be discontinued. Long-term adverse effects of glucocorticoids, such as osteopenia and Cushing’s syndrome, occur with continued administration over several months. This is usually not a consideration in patients with widespread malignancy, who have a very limited prognosis.
B. Oncogenic osteomalacia
Oncogenic osteomalacia is a rare tumor-associated disorder, first
recognized in 1947 (258, 259), that is characterized by
hypophosphatemia, phosphaturia, normocalcemia, and osteomalacia in the
absence of a family history of rickets, heavy metal poisoning, or
Fanconi’s syndrome. The serum alkaline phosphatase concentration is
increased and the serum 1,25-(OH)2D3
concentration is decreased. Affected patients typically present with
bone pain, proximal muscle weakness, and fractures. The disorder may
manifest as rickets if it occurs before fusion of the growth plate.
Tumors associated with this disorder are generally of mesenchymal
origin, small, and benign, although it has occasionally been associated
with malignant tumors. Reported tumor types include sclerosing
hemangioma (260, 261), paraganglioma (262), prostate cancer (263, 264),
oat cell carcinoma of the lung (265), fibrous dysplasia,
hemangiopericytoma, osteosarcoma, chondroblastoma, chondromyxoid
fibroma, malignant fibrous histiocytoma, giant cell tumor (266), and a
metaphyseal fibrous defect (267). Oncogenic osteomalacia associated
with metastatic prostate cancer comprises about 10% of all reported
cases (264). Regardless of the origin, tumors causing oncogenic
osteomalacia are often small and difficult to locate. Some reported
locations include the groin, nasopharynx, and the popliteal region.
Biochemical abnormalities resolve after complete tumor resection and
recur with tumor regrowth. Serum phosphate concentrations increase
immediately in the postoperative period while alkaline phosphatase
concentrations may take more than 1 yr to normalize with healing of the
osteomalacia (260, 262). In one patient, the bone mineral density
measurement increased from a preoperative value of 0.627
g/cm2 to 1.097 g/cm2 198 days postoperative
(262).
Phosphaturia may contribute to the osteomalacia in affected patients as does the apparent decrease in plasma 1,25-(OH)2D3 concentrations, both of which presumably lower the concentrations of available phosphate ions at the mineralizing bone site. The responsible phosphaturic factor has not been identified, but does not appear to be PTH or PTHrP since calcium and nephrogenous cAMP concentrations are normal in affected patients. Conditioned medium from cell culture of oncogenic osteomalacia tumors has been shown to inhibit phosphate uptake in cultured epithelial opossum kidney cells (260, 262). In one report, there was no measurable immunoactive PTH or PTHrP in the conditioned media from a paraganglioma (262). Another report found that conditioned media from a hemangioma inhibited phosphate uptake in opossum kidney cells without increasing cellular concentrations of cAMP. The media contained PTH-like immunoreactivity without PTHrP immunoreactivity, and the inhibition of phosphate transport was not blocked by a PTH antagonist (260). This putative factor appeared to be heat sensitive and of a molecular mass between 8 and 25 kDa (260).
Serum 1,25-(OH)2D3 concentrations are low in
patients with oncogenic osteomalacia, despite the presence of
hypophosphatemia, which normally increases
1,25-(OH)2D3 production by stimulating renal
1-hydroxylase activity independent of PTH. Additionally, most
reported cases of oncogenic osteomalacia have normal serum
25-hydroxyvitamin D concentrations. Deficient production of
1,25-(OH)2D3 could be a contributing factor to
the pathogenesis of oncogenic osteomalacia in these patients as the
clinical and biochemical abnormalities improve during calcitriol
therapy in some patients. The pathophysiology of the vitamin D
derangement is not well understood, but the clinical features have led
investigators to hypothesize that tumor-produced factors inhibit
1-hydroxylase activity. In one study, tumor extracts from a
hemangiopericytoma inhibited the formation of
1,25-(OH)2D3, and transplantation of this tumor
into athymic mice resulted in renal phosphate wasting and decreased
1,25-(OH)2D3 concentrations (268).
C. Tumor lysis syndrome
Another disorder of calcium homeostasis associated with malignancy
is the tumor lysis syndrome, which may occur as a consequence of
successful therapy of neoplastic disease (269). The syndrome often
occurs during therapy of hematological malignancies, particularly
high-grade lymphomas, in which a large number of tumor cells are lysed
in a short period of time. It has also been reported during therapy of
small cell carcinoma of the lung (270), breast cancer, and
medulloblastoma as well as during immunotherapy for sarcoma (271) and
therapy with TNF and monoclonal antibody against GD3 ganglioside in
metastatic melanoma (272). Rare reports of spontaneous tumor lysis have
also been reported (273). The release of tumoral intracellular ions,
such as phosphate and potassium, into the extracellular fluid result in
hyperphosphatemia. Hypocalcemia, hyperuricema (due to uric acid release
from lysed cells), and renal failure are a consequence.
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IV. Local Mechanisms by Which Tumors Affect the Skeleton |
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TopAbstractI. IntroductionII. Normal Calcium and...III. Humoral Mechanisms by...IV. Local Mechanisms by...References |
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A. Clinical manifestations
Both solid tumors and hematological malignancies frequently affect
the most vascular areas of the skeleton, specifically in the red bone
marrow of the axial skeleton, the proximal ends of the long bones,
ribs, and the vertebral bodies. The most common way in which cancer
affects the skeleton is directly through local tumor-mediated
stimulation of osteoclastic bone resorption. Such osteolytic bone
lesions are typical of breast and lung carcinoma as well as
hematological malignancies such as multiple myeloma. Although breast
cancer cells have been shown to resorb bone directly in
vitro (278), most evidence [scanning electron microscopic
examination of adjacent bone surfaces (184) and response to osteoclast
inhibitors] is consistent with the notion that factors secreted by
cancer cells can activate osteoclasts locally. This is illustrated in
Fig. 4, a photomicrograph of an
osteolytic lesion due to the human breast cancer cell line MDA-MB-231.
Thus, local and systemic effects of cancer on bone are mediated through
one common final pathway, the osteoclast. The resulting osteolytic bone
destruction can lead to pain, pathological fractures, nerve compression
syndromes, and hypercalcemia.
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Hypercalcemia associated with metastatic bone disease or hematological malignancies has been referred to as local osteolytic hypercalcemia, as clinical studies have demonstrated that many patients with bone involvement and hypercalcemia did not have the increase in plasma PTHrP or nephrogeneous cAMP concentration observed in patients with humoral hypercalcemia of malignancy (69, 111). The mechanism of hypercalcemia in this situation was postulated to be local tumor production of factors that stimulate osteoclastic bone resorption, such as TNFß, IL-6, and IL-1 as in the case of myeloma. However, it is now clear that humoral mediators of hypercalcemia, such as PTHrP, may mediate local osteolysis, even in the absence of hypercalcemia and increased plasma PTHrP concentrations (282). Additionally, if tumor burden in bone is great enough, tumor-produced factors in bone may be produced in enough quantity locally to reach the systemic circulation and have effects on sites distant from affected bone.
B. Pathophysiology of the metastatic process to bone
Breast and prostate cancer are the most common malignancies in
which bone metastases occur. Breast cancer is most often associated
with osteolytic metastasis while osteoblastic metastases are more often
manifest in prostate cancer. Mixed osteolytic and osteoblastic lesions
are often evident in both breast and prostate cancer. The remainder of
the review will focus on general principles of metastasis to bone,
followed by mechanisms specific to osteolytic and osteoblastic
metastasis, citing examples from current research in breast and
prostate cancer, respectively. This will be followed by a review of
bone involvement in myeloma. The reader should understand that breast
and prostate cancer, although predominantly lytic and blastic,
respectively, often have components of both osteolysis and
osteosclerosis. In this review, delineation of osteolytic and
osteoblastic mechanisms of bone metastasis to breast and prostate
cancer, respectively, is by no means meant to be exclusive. It is
likely that both mechanisms are often operative in the same patient.
1. Anatomical. Tumor metastasis to bone is not a random event, but rather a result of anatomical factors, tumor cell phenotype, and suitability of the metastatic site for tumor growth. Blood flow from the primary site is a significant determinant of the site of metastasis. Studies by Batson (283) describe in detail a low-pressure, high-volume system of valveless vertebral veins that communicate between the spine and intercostal veins independently of the pulmonary, caval, or portal systems. Batson accessed this plexus in cadavers via dye injection into the dorsal vein of the penis, an integral part of the prostatic venous plexus. Through these extensive injection studies of the prostatic plexus and venules of the breast in male and female cadavers, as well as in animals, Batson described this vertebral vein system as 1) consisting of the epidural veins, the perivertebral veins, the veins of the thoraco-abdominal wall, the veins of the head and neck, and the veins of the walls of blood vessels of the extremities; 2) valveless vessels that carry blood under low pressure; 3) subject to arrest and reversal of blood flow; 4) parallels, connects with, and provides bypasses for the portal, pulmonary, and caval systems. This plexus may serve as a major channel by which certain malignancies, such as prostate and breast cancer, metastasize to bone.
This concept that the vertebral system of veins acts as a direct conduit in the spread of prostatic carcinoma to the skeletal system was refuted by Dodds et al. (284), who analyzed 99mtechnetium bone scans in patients with skeletal metastases from assorted primary tumors. They found that the distribution of metastases was virtually identical in patients with prostatic and nonprostatic tumors. Of the patients with prostatic carcinoma, 25% had bone scan lesions exclusively outside the region of the sacrum, pelvis, and lumbar spine. The distribution of skeletal metastases from prostatic carcinoma did not support the concept that the vertebral veins have a substantial role in the dissemination of this tumor.
2. Seed and soil. Regardless of whether or not blood flow or
anatomic considerations are important determinants of the site of
metastasis, they are not the only ones. The distribution of metastases
to various organs are not predicted by anatomic considerations alone in
approximately 40% of tumors (285). Thus, other determinants of the
site of metastasis, such as properties of both the tumor cell and the
metastatic site, are important. Metastasis is an extremely complex
event that involves a cascade of linked sequential events that must be
completed before a tumor cell successfully establishes a secondary
tumor in bone (Fig. 5). Specifically, a
tumor cell must 1) detach from the primary site; 2) enter tumor
vasculature to reach the circulation; 3) survive host immune response
and physical forces in the circulation; 4) arrest in distant capillary
bed; 5) escape the capillary bed; and 6) proliferate in the metastatic
site. The events involved in entering the tumor vasculature are similar
to those involved with exiting the vasculature in the bone marrow
cavity. These include 1) attachment of tumor cells to the basement
membrane; 2) tumor cell secretion of proteolytic enzymes to disrupt the
basement membrane; and 3) migration of tumor cells through the basement
membrane. Attachment of tumor cells to basement membranes and to other
cells are mediated through cell adhesion molecules such as laminin and
E-cadherin. Tumor cell secretion of substances such as
metalloproteinases facilitate disruption of the basement membranes and
enhance invasion. Inherent tumor cell motility or motility in response
to chemotactic stimuli are also important factors for tumor cell
invasion to the secondary site.
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