Calcitonin inhibits osteoclasts, but its effects are transitory
Calcitonin is a 32–amino-acid peptide hormone made by the clear or C cells of the thyroid gland. C cells (also called parafollicular cells) are derived from neural crest cells of the fifth branchial pouch, which in humans migrate into the evolving thyroid gland. Although it is located within the thyroid, calcitonin's major, if not sole, biological action relates to the regulation of mineral metabolism and bone turnover. The incidental nature of its relationship with the major functions of the thyroid is emphasized by the finding that, in many nonhuman species, C cells are found in a body called the ultimobranchial gland and not in the thyroid at all.
Calcitonin is synthesized in the secretory pathway (see pp. 34–35) by post-translational processing of a large procalcitonin. As illustrated in Figure 52-11, alternative splicing of the calcitonin gene product gives rise to several biologically active peptides. In the C cells, calcitonin is the only peptide made in biologically significant amounts. Within the central nervous system, calcitonin gene–related peptide (CGRP) is the principal gene product, and it appears to act as a neurotransmitter in peptidergic neurons (see Table 13-1). Calcitonin is stored in secretory vesicles within the C cells, and its release is triggered by a rise in the extracellular [Ca2+] above normal. Conversely, a lowering of the extracellular [Ca2+] diminishes calcitonin secretion. The threshold [Ca2+] for enhancing calcitonin secretion is in the midphysiological range. In principle, this secretory profile would leave calcitonin well poised to regulate body Ca2+ homeostasis.
FIGURE 52-11 Synthesis of calcitonin and CGRP. A common primary RNA transcript gives rise to both calcitonin and CGRP. In the thyroid gland, C cells produce a mature mRNA that they translate to procalcitonin. They then process this precursor to produce an N-terminal peptide, calcitonin (a 32–amino-acid peptide), and calcitonin C-terminal peptide (CCP). In the brain, neurons produce a different mature mRNA and a different “pro” hormone. They process the peptide to produce an N-terminal peptide, CGRP, and a C-terminal peptide. AA, amino acids.
The precise role of calcitonin in body Ca2+ homeostasis has been difficult to define. This difficulty was first apparent from the simple clinical observation that, after complete thyroidectomy with removal of all calcitonin-secreting tissue, plasma [Ca2+] remains normal (provided the parathyroid glands are not injured). Conversely, patients with a rare calcitonin-secreting tumor of the C cells frequently have plasma calcitonin concentrations that are 50 to 100 times normal, yet they maintain normal plasma levels of Ca2+, vitamin D, and PTH. Nevertheless, several lines of evidence suggest that calcitonin does have biologically important actions. First, although calcitonin appears to have a minimal role in the minute-to-minute regulation of plasma [Ca2+] in humans, it does play an important role in many nonmammalian species. This role is particularly clear for teleost fish. The [Ca2+] in seawater (and therefore in food) is relatively high, and calcitonin, secreted in response to a rise in plasma [Ca2+], decreases bone resorption, thus returning the plasma [Ca2+] toward normal. Salmon calcitonin, which differs from human calcitonin in 14 of its 32 amino-acid residues, is roughly 10-fold more potent on a molar basis in inhibiting human osteoclast function than is the human hormone.
The second line of evidence that calcitonin may have biologically important actions is the presence of calcitonin receptors. Like PTH receptors, the calcitonin receptor is a GPCR that, depending on the target cell, may activate either adenylyl cyclase (see p. 53) or phospholipase C (see pp. 53–56). Within bone, the osteoclast—which lacks PTH receptors—appears to be the principal target of calcitonin. Indeed, the presence of calcitonin receptors may be one of the most reliable methods of identifying osteoclasts. In the osteoclast, calcitonin raises [cAMP]i, which activates effectors such as protein kinases. Calcitonin inhibits the resorptive activity of the osteoclast, thus slowing the rate of bone turnover. It also diminishes osteocytic osteolysis, and this action—together with its effect on the osteoclast—is responsible for the hypocalcemic effect after the acute administration of pharmacological doses of calcitonin. The hypocalcemic action of calcitonin is particularly effective in circumstances in which bone turnover is accelerated, as occurs in rapidly growing young animals and in humans with hyperparathyroidism. The antiosteoclastic activity of calcitonin is also useful in treating Paget disease of bone (Box 52-3). However, within hours of exposure to high concentrations of calcitonin, osteoclasts desensitize. This “escape” from the hypocalcemic effect of calcitonin has limited the use of calcitonin in the clinical treatment of hypercalcemia. The transitory nature of the action of calcitonin appears to result, in part, from rapid downregulation of calcitonin receptors.
Approximately 25 million Americans, mostly postmenopausal women, are affected by osteoporosis, and every year between 1 and 2 million of these individuals experience a fracture related to osteoporosis. The cost in economic and human terms is immense. Hip fractures are responsible for much of the morbidity associated with osteoporosis, but even more concerning is the observation that as many as 20% of women with osteoporotic hip fracture will die within 1 year of their fracture.
The major risk factor for osteoporosis is the postmenopausal decline in estrogen levels in aging women. Rarely, other endocrine disorders such as hyperthyroidism, hyperparathyroidism, androgen deficiency, and Cushing disease (hypercortisolism) are responsible. Other risk factors include inadequate dietary Ca2+ intake, alcoholism, cigarette smoking, and a sedentary lifestyle.
Strategies to prevent the development of osteoporosis begin in the premenopausal years. High Ca2+ intake and a consistent program of weight-bearing exercises are widely recommended.
Pharmacological agents are now available for preventing or at least retarding the development of osteoporosis and for treating the disease once it has become established. These agents can be broadly classified into two groups: antiresorptive drugs and anabolic drugs that stimulate bone formation.
Among the antiresorptive drugs, estrogen is the most widely used. It is most effective when started at the onset of menopause, although it may offer benefits even in patients who are 20 or more years past menopause. However, possible increased risk of breast and endometrial cancer from postmenopausal estrogen limit use of this treatment. Another class of drugs—the bisphosphonates—are effective inhibitors of bone resorption and have become a mainstay for the treatment of osteoporosis in both men and women. The newer bisphosphonates, which have a much greater potency, can be given either orally or as a once-a-year intravenous treatment.
Agents that can stimulate bone formation include vitamin D—often given as 1,25-dihydroxyvitamin D (calcitriol)—which is combined with Ca2+ therapy to increase the fractional absorption of Ca2+ and to stimulate the activity of osteoblasts. PTH is also now available as an injectable treatment for osteoporosis (see p. 1063), and when given intermittently, it potently stimulates osteoblast formation and increases bone mass. PTH also appears to decrease the rate of vertebral fractures. As mentioned on pages 1057–1058, denosumab—a monoclonal antibody to RANKL—is another antiresorptive therapy. It is also being used in some cases of bone resorption associated with metastatic disease. Now in clinical trials are agents that promote Wnt signaling by interfering with either sclerostin or dickkopf1; the hope is that these agents will have both prosynthetic and antiresorptive actions.
Calcitonin and the bisphosphonates have also been used successfully to treat Paget disease of bone, a disorder characterized by localized regions of bone resorption and reactive sclerosis. The level of bone turnover at sites of active Paget disease can be extremely high. Although it remains asymptomatic in many individuals, the disease can cause pain, deformity, fractures, and (if bony overgrowth occurs in the region of the eighth cranial nerve) vertigo and hearing loss. The cause of Paget disease is not known.
In the kidney, calcitonin, like PTH, causes a mild phosphaturia by inhibiting proximal-tubule phosphate transport. Calcitonin also causes a mild natriuresis and calciuresis. These actions may contribute to the acute hypocalcemic and hypophosphatemic actions of calcitonin. However, these renal effects are of short duration and do not appear to be important in the overall renal handling of Ca2+, phosphate, or Na+.
Sex steroid hormones promote bone deposition, whereas glucocorticoids promote resorption
Although PTH and 1,25-dihydroxyvitamin D are the principal hormones involved in modulating bone turnover, other hormones participate in this process. For example, the sex steroids testosterone and estradiol are needed for maintaining normal bone mass in males and females, respectively. The decline in estradiol that occurs postmenopausally exposes women to the risk of osteoporosis; that is, a decreased mass of both cortical and trabecular bone caused by a decrease in bone matrix (see Box 52-3). Osteoporosis is less common in men because their skeletal mass tends to be greater throughout adult life and because testosterone levels in men decline slowly with age, unlike the abrupt menopausal decline of estradiol in women.
Glucocorticoids also modulate bone mass. This action is most evident in circumstances of glucocorticoid excess, which leads to osteoporosis, as suggested by the effects of glucocorticoids on the production of OPG (see pp. 1057–1058) and RANKL (see p. 1057).
The precise cellular mechanisms that mediate the action of androgens, estrogens, or glucocorticoids on bone have not been well defined. Despite the loss of bone that occurs with androgen or estrogen deficiency or glucocorticoid excess, in each case the coupling of bone synthesis to degradation is qualitatively preserved. Synthesis of new bone continues to occur at sites of previous bone resorption, and no excess of unmineralized osteoid is present. Presumably, the decline in bone mass reflects a quantitative shift in which the amount of new bone formed at any site is less than what was resorbed. Because this shift occurs at multiple sites, the result is a decline in overall bone mass.
PTHrP, encoded by a gene that is entirely distinct from that for PTH, can cause hypercalcemia in certain malignancies
Unlike PTH, which is synthesized exclusively by the parathyroid gland, a peptide called PTH-related protein (PTHrP) is made in many different normal and malignant tissues. The PTH1R receptor (see p. 1061) in kidney and bone recognizes PTHrP with an affinity similar to that for intact PTH. PTHrP mimics each of the actions of PTH on kidney and bone. Thus, when present in sufficient concentrations, PTHrP causes hypercalcemia. PTHrP exists in three alternatively spliced isoforms of a single gene product. The gene encoding PTHrP is completely distinct from that for PTH. The similar actions of PTHrP and PTH arise from homology within the first 13 amino acids of PTHrP and native PTH. Only weak homology exists between amino acids 14 and 34 (three amino acids are identical), and essentially none beyond amino acid 34. This situation is an unusual example of mimicry among peptides that are structurally quite diverse.
The normal physiological roles of PTHrP are largely in regulating endochondral bone and mammary-gland development. The lactating breast also secretes PTHrP, and this hormone is present in very high concentrations in milk. PTHrP may promote the mobilization of Ca2+ from maternal bone during milk production. In nonlactating humans, the plasma PTHrP concentration is very low, and PTHrP does not appear to be involved in the day-to-day regulation of plasma [Ca2+]. It appears likely that under most circumstances, PTHrP acts in a paracrine or autocrine, rather than in an endocrine, regulatory fashion.
Many tumors are capable of manufacturing and secreting PTHrP, among them the following: squamous cell tumors of the lung, head, and neck; renal and bladder carcinomas; adenocarcinomas; and lymphomas. Patients with any of these tumors are subject to severe hypercalcemia of fairly abrupt onset. N52-3
Parathyroid Hormone–Related Protein
Contributed by Emile Boulpaep, Walter Boron
PTHrP was discovered at Yale University as the factor responsible for humeral hypercalcemia of malignancy (HHM). Andrew Stewart, Karl Insogna, Arthur Broadus, and their colleagues first demonstrated that this factor stimulates adenylyl cyclase activity. They later showed that this activity was inhibited by PTH antagonists and finally identified the 17-kDa protein.
Burtis WJ, Wu T, Bunch C, et al. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase–stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987;262:7151–7156.
Rodan SB, Insogna KL, Vignery AM, et al. Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells. J Clin Invest. 1983;72:1511–1515.
Stewart AF, Insogna KL, Goltzman D, Broadus AE. Identification of adenylate cyclase–stimulating activity and cytochemical glucose-6-phosphate dehydrogenase–stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy. Proc Natl Acad Sci U S A. 1983;80:1454–1458.