Other Secondary Hyperparathyroid States

C H A P T E R

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Other Secondary Hyperparathyroid States Laila Tabatabai1, Suzanne M. Jan De Beur2 1Division

of Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, The Johns Hopkins University School of Medicine, and Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Parathyroid hormone (PTH) secretion is regulated by a complex interplay of circulating minerals and hormones that include extracellular calcium (via the calcium-sensing receptor, CaSR), plasma phosphate, 1,25-dihydroxyvitamin D (1,25(OH)2D), and fibroblast growth factor 23 (FGF23). The most common causes of secondary hyperparathyroidism are renal disease and vitamin D deficiency. These conditions and their effects on parathyroid function are discussed in detail elsewhere (see also Chapters 43–45). Although less common, other conditions that cause secondary hyperparathyroidism include disorders of calcium balance (deficiency, malabsorption, and excess excretion), disorders associated with FGF23 excess, persistent parathyroid disease after renal transplant, specific disorders of acid–base balance, and ingestion of certain medications.

DISORDERS OF CALCIUM BALANCE The serum calcium concentration is tightly regulated due to the importance of the calcium ion in numerous cellular and physiological functions. On the cellular level, these include cell division and adhesion, as well as plasma membrane structure and function. On the physiological level, calcium is necessary for muscle contraction (particularly important in cardiac myocytes), neuronal excitability, glycogen metabolism, and coagulation. The major function of the parathyroid gland is to act as a calciostat whereby the relationship between ionized calcium and PTH secretion is an inverse one with minute changes in ionized calcium resulting in significant changes in PTH secretion. PTH regulates circulating calcium through its actions on the bone, kidney, and intestinal tract. The major actions of PTH have been discussed extensively elsewhere in this book. To briefly summarize, when CaSR detects decreasing blood ionized calcium

The Parathyroids, Third Edition http://dx.doi.org/10.1016/B978-0-12-397166-1.00046-1

activity, PTH synthesis and secretion are augmented. PTH (and to a lesser extent 1,25(OH)2D) increases osteoclast resorption of calcium and phosphorus from bone, increases calcium reabsorption and phosphorus excretion from the proximal renal tubule, and enhances 1,25(OH)2D production by the kidneys. Consequently, 1,25(OH)2D increases calcium and phosphorus absorption in the intestine.1 The net effect is to increase serum calcium and maintain serum phosphorus concentrations. Changes in blood ionized calcium affect PTH by several mechanisms. In reaction to an increase in ionized calcium, these include the activation of calcium-sensitive proteases in secretory vesicles that increase PTH cleavage to inactive fragments and reduction of release of stored PTH. Responses to chronically reduced ionized calcium levels include increased PTH mRNA expression and increase in parathyroid cell proliferation.2 The G-protein linked, transmembrane CaSR, positioned on the parathyroid cell extracellular membrane, senses calcium with its large extracellular amino-terminal region.3 Increased ionized calcium activity suppresses PTH secretion and diminished ionized calcium levels increase PTH secretion. Binding of calcium to the CaSR activates heterotrimeric G-proteins Gq/G11 and Gi, stimulating phospholipase C and inhibiting cAMP, respectively. Intracellular free calcium is increased and cAMP is decreased resulting in suppression of the synthesis and secretion of PTH. In the kidney, the CaSR is located along the entire nephron, including the cortical thick ascending limb (CTAL) and distal convoluted tubule (DCT), where both PTHmediated and PTH-independent calcium reabsorption occurs. In the CTAL and DCT, PTH binds to its receptor and increases the activity of the Na/K/2Cl cotransporter that drives NaCl reabsorption and stimulates paracellular calcium and magnesium reabsorption.4,5 In the DCT, PTH regulates luminal calcium transfer via the transient receptor potential channel, TRPV5. PTH inhibits Na and

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2015 Published by Elsevier Inc.

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HCO3− reabsorption in the proximal renal tubule (PT) by inhibiting the apical type 3 Na+/H+ exchanger and the basolateral Na+/K+-ATPase. In the PT, PTH stimulates 1α-hydroxylase to make the active vitamin D metabolite 1,25(OH)2 vitamin D. In the intestinal tract, calcium absorption primarily occurs in the duodenum and jejunum, with some absorption also occurring in the ileum and colon. Reductions in dietary calcium result in increased PTH production. PTH enhances intestinal calcium absorption in an indirect manner, through renal production of the active 1,25(OH)2 vitamin D, which stimulates TRPV6, a channel-associated protein. The skeleton is the largest reservoir of calcium in the human body; 99% of total body calcium is located in the hydroxyapatite crystal in bone while the remaining 1% is located in the blood, extracellular fluid, and tissues. It has been established that a state of negative calcium balance leads to PTH-mediated osteoclastic bone resorption and liberation of calcium and phosphorus from the skeleton to maintain the serum calcium concentration within a narrow physiologic window.6

Increased Calcium Excretion Renal calcium excretion is regulated in part by PTH. Recall that one of the actions of PTH on the renal proximal tubule is to increase calcium reabsorption from the glomerular filtrate. Yet in primary hyperparathyroidism (PHPT), increased calcium excretion is frequently observed. In PHPT, the increased filtered load of calcium leads to urinary calcium losses in excess of intestinal calcium absorption, suggesting that skeletal resorption is the major contributor to the excess urine calcium. This is supported by studies showing loss in bone mineral density (BMD) in patients with PHPT7 (see also Chapter 10). Stone-forming patients with idiopathic hypercalciuria exhibit increased urine calcium excretion, intestinal calcium absorption, bone resorption, decreased renal tubular calcium reabsorption and BMD. In these patients, serum PTH concentrations are normal to reduced, and both 1,25(OH)2D values and vitamin D receptor number are normal or increased.8 There are two potential mechanisms that lead to increased urinary calcium excretion: absorptive hypercalciuria and renal hypercalciuria. It is important to distinguish between these two mechanisms. In absorptive hypercalciuria, intestinal calcium absorption exceeds urinary calcium loss, whereas in renal hypercalciuria, urinary calcium loss exceeds intestinal calcium absorption due to a primary defect in renal tubular reabsorption. In absorptive hypercalciuria, parathyroid function is normal or suppressed, while in renal hypercalciuria, there is a secondary hyperparathyroidism because the excess renal losses create negative calcium balance and

skeletal stores of calcium are required to maintain serum calcium levels within the tightly regulated physiological range.9 It is important to note that studies show reduced BMD in patients with idiopathic hypercalciuria, including both absorptive hypercalciuria and renal hypercalciuria. However, with subclassification, patients with renal hypercalciuria appear to have much greater BMD deficits than do patients with absorptive hypercalciuria, implying that the secondary hyperparathyroidism associated with renal hypercalciuria contributes to increased bone loss in this group.10 In renal hypercalciuria, intestinal absorption of calcium may also be elevated. This is likely secondary to the increased renal synthesis of 1,25(OH)2D that results from stimulation of CYP27B1(1α-hydroxylase) by PTH.11 Amelioration of excess calcium excretion is accomplished with thiazide diuretics, which is thought to be mediated by effects on the distal tubule calcium channel TRPV5 and calbindin expression. Thiazides also increase proximal tubular reabsorption of calcium.12 Thiazide diuretics correct renal hypercalciuria and decrease circulating PTH as evidenced by decreases in urinary calcium and cAMP excretion, respectively.13,14 In patients with renal hypercalciuria, thiazide therapy not only reduced fractional calcium absorption but also restored normal parathyroid function.9 Increased intestinal absorption of calcium in absorptive hypercalciuria does not correct with thiazide therapy and 1,25(OH)2D concentrations remain unchanged, indicating a distinct mechanism.15,16 Children with idiopathic hypercalciuria (with renal calculi and/or gross or microscopic hematuria) may also exhibit secondary hyperparathyroidism, which is similarly reversed with thiazide therapy.17 Osteoporosis has been documented in postmenopausal women with renal hypercalciuria and secondary hyperparathyroidism; histomorphometric analysis of bone biopsies from eight subjects revealed high fractional resorption surfaces and other indices of accelerated bone turnover. Treatment with thiazide diuretics corrected their secondary hyperparathyroidism and reduced the indices of bone resorption, suggesting that PTH-dependent osteoclastic resorption was partially responsible for osteoporosis in these women.18 In a study of 40 subjects with idiopathic hypercalciuria, 26 had persistent hypercalciuria and elevated PTH values, which normalized within 22 months of thiazide treatment.14 Male patients with idiopathic hypercalciuria also exhibit decreased BMD and have an increased risk of fracture.19 Thiazide treatment reduces stone recurrence in male patients with idiopathic hypercalciuria; data from a study of four male subjects suggest that thiazides may mediate this effect by increased proximal tubule reabsorption of sodium and calcium.12 In regard to the effect of thiazides on BMD, a study of 14 osteoporotic male subjects with idiopathic hypercalciuria treated

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Disorders of Calcium Balance

with thiazides showed no increase in their bone mass in comparison to osteoporotic male subjects without hypercalciuria who were treated with calcium and vitamin D supplementation alone.20 There is some controversy about whether secondary hyperparathyroidism is a feature of renal hypercalciuria. One study of 33 patients with nephrolithiasis showed that PTH concentrations were normal and did not increase when measured under low, normal, and high calcium intake.21 Another early study showed no difference between PTH concentrations and urinary cAMP excretion in patients with absorptive hypercalciuria and those with renal hypercalciuria.22 Recent trials have focused on differentiating subtypes of idiopathic hypercalciuria using prolonged dietary calcium restriction (300 mg/24 h for 3 weeks, 700–1000 mg/24 h for 4 weeks); this revealed that one subset of subjects responded to a low-calcium diet with increasing urinary calcium loss and compensatory rise in PTH, while another subset responded with normalized urinary calcium excretion.23 The molecular basis for these differences remains unclear. Studies of families with idiopathic hypercalciuria have revealed genetic loci that may be linked to hypercalciuric nephrolithiasis: chromosome 1q23.3-q24, which contains the human soluble adenylyl cyclase gene; chromosome 12q12-q14, which contains the vitamin D receptor gene; chromosome 9q33.3-q34.2, with candidate gene as yet undetermined.24–27

Decreased Calcium Intake For a variety of societal and other reasons, dietary intake of milk and milk products has steadily decreased over time. According to data from the Continuing Survey of Food Intakes by Individuals (CSFII) from 1994– 1996, more than 70% of adult men and women had low dietary calcium intake (defined as 400–800 mg per day), based on food intake alone.28 Furthermore, inadequate dietary calcium intake in the elderly has been implicated as a cause of secondary hyperparathyroidism, independent of vitamin D status.29 A trial of 60 female postmenopausal nursing-home residents in France showed that intake of vitamin D and calcium-fortified yogurt increased serum 25(OH)D levels and decreased serum PTH levels.30 Animal studies have demonstrated that severely calcium-deficient diets result in abnormalities in calciotropic hormones and bone metabolism. In one study, 5-week-old male rabbit pups were fed severely calciumrestricted diets (0.026%) until 30 weeks of age (skeletal maturity); controls received 0.45% calcium diets; and the calcium-replenished group was fed a 0.026% calcium diet until age 15 weeks and thereafter fed a 0.45% calcium diet. At baseline, calcidiol and calcitriol (1,25(OH)2D) levels were not significantly different in the groups; the

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pups began the study at age 5 weeks with 1,25(OH)2D levels of approximately 30 pg/mL. The animals fed the severely calcium-deficient diet developed hypocalcemia, hypophosphatemia, hypocalciuria, elevated serum alkaline phosphatase activity and 1,25(OH)2D levels, secondary hyperparathyroidism, and increased bone turnover.31 These animals gained less BMD than those fed a normal diet. Normalizing the animals’ calcium intake at age 15 weeks rapidly reversed these biochemical and bone densitometric changes by 30 weeks. This is in contrast to an earlier study by Peterson et al. in 1995, in which the effects of calcium deficiency were non-reversible. In that study, female rats were kept on a low-calcium diet (0.25%) for 20 weeks starting from age 4 weeks. The reversibility of the sequelae of calcium deficiency on peak bone mass was assessed after introducing 0.5 or 1% calcium diets at 12 weeks through 37 weeks of age. Results showed that low calcium diets through adolescence retard and prolong longitudinal bone growth; higher intakes of calcium promote greater peak bone mass. Furthermore, increasing calcium intake after adolescence (12 weeks of age) did not substantially alter the adult bone volume of the proximal tibia, therefore showing that low calcium intake through adolescence has permanent deleterious effects on peak bone mass.32 Vitamin D status was not assessed in that study. Vitamin D deficiency is considered the major cause of rickets in children in most countries, as breast milk is low in vitamin D and the climates may not allow adequate ultraviolet light exposure. However, in areas with high sun exposure, including Nigeria, South Africa, and the Indian subcontinent, vitamin D deficiency is less common and nutritional rickets in these areas is attributed to low dietary calcium intake.33 Multiple studies from India and African nations have observed rickets and osteomalacia in children with low dietary calcium intake, despite adequate vitamin D stores. Diets in these nations are heavily cereal and legume based, with relatively low intake of dairy products. Furthermore, these diets are rich in phytates and oxalates, which inhibit calcium absorption.34 In 1978, Pettifor et al. studied nine children in South Africa with rickets; they had mild hypocalcemia and secondary hyperparathyroidism with no evidence of vitamin D deficiency.35 A study of three South African children with rickets, low dietary intake of calcium (125 mg/day), and normal 25-hydroxyvitamin D (25(OH)D) levels (23–33 ng/mL) who were treated with 6 months of calcium and phosphorus supplements (no vitamin D) showed severe osteomalacia by bone histomorphometry at baseline, as evidenced by increased osteoid volume, surface, and thickness, a reduced calcification front, and a prolonged mineralization lag time.36 Calcium and phosphorus treatment significantly increased their calcified bone volume and normalized indices of bone mineralization. This study demonstrates

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that osteomalacia may be associated with pure calcium deficiency in children. A study of Bangladeshi children with active rickets showed that the majority did not have vitamin D deficiency; specifically, seven out of 10 subjects with active rickets (alkaline phosphatase>350 U/L) had 25(OH)D concentrations above 14 ng/mL with a mean of 20 ng/ mL.37 This suggests that dietary calcium deficiency in this population may be responsible for the observed rickets. Calcium and vitamin D deficiency may play different roles in the rachitic phenotype in children versus adolescents. A study of Indian children and adolescents with rickets showed that young children with rickets had lower calcium intake and similar 25(OH)D levels than controls, while adolescents with rickets had both lower calcium intake and lower vitamin D levels than controls at baseline.38 The subjects with rickets were randomized to 1 g calcium supplementation daily, with or without vitamin D. All children with rickets showed complete healing at 3 months, whether they received calcium alone or with vitamin D; however, adolescents with rickets showed no response to calcium alone, but had complete healing with calcium and vitamin D at 3–9 months.38 It is clear that both calcium deficiency and vitamin D deficiency contribute to nutritional rickets, albeit to varying degrees depending on the specific geographic population. In Nigerian children, calcium supplementation, with or without vitamin D, healed rickets.39,40 A study of 123 Nigerian children with low calcium intake (median intake of 203 mg daily) and rickets treated for 24 weeks with vitamin D, calcium, or a combination demonstrated that those on calcium alone or calcium plus vitamin D had a significant reduction in alkaline phosphatase and radiographic evidence of healed rickets compared to children treated with vitamin D alone.39 In this study, the children with rickets had lower 25(OH)D levels at baseline (13.9 ng/mL ± 10.2, mean ± SD) versus the control children (20.5 ng/mL ± 6.2). A study of 67 Indian children with rickets treated with vitamin D, calcium, and vitamin D plus calcium for 12 weeks showed radiological and biochemical evidence of healing of rickets after 6 and 12 weeks in all treatment groups, with best response in the vitamin D plus calcium group.41 All three groups had significant secondary hyperparathyroidism at baseline with normalization of PTH at 12 weeks. However, it is important to note that 82% of the participants enrolled in this study had vitamin D deficiency with 25(OH)D concentrations <20 ng/mL at baseline.

Decreased Calcium Absorption The amount of calcium absorbed from the human diet varies with age and amount of calcium ingested; it varies from 20 to 60%. Calcium absorption rates are high in

growing children and during pregnancy and lactation. Net calcium absorption declines with age in both sexes. About 90% of calcium absorption occurs in the duodenum and jejunum. Increased calcium requirements stimulate the epithelial calcium active transport system in the duodenum, ileum, and colon; with this increased demand, fractional calcium absorption increases from 20 to 45% in older adults, and from 55 to 70% in children and young adults. Active calcium absorption accounts for absorption of 10–15% of the dietary load. Intestinal absorption of calcium is limited by the epithelial calcium channel, which transfers luminal calcium into the intestinal cell. The channel-associated protein TRPV6, annexin2, calbindin-D9K, and basolateral extrusion system PMCA1b are also involved.42 Reduced calcium intake leads to increased PTH and 1,25(OH)2D, which in turn augment expression of TRPV6 and enhance fractional calcium absorption to compensate for reduced dietary calcium intake.43,44 Decreased intestinal calcium absorption occurs in conditions of decreased 1,25(OH)2D production, including vitamin D deficiency, chronic renal insufficiency, hypoparathyroidism, and aging. Glucocorticoid excess also results in decreased intestinal calcium absorption even with normal 1,25(OH)2D concentrations. Dietary protein intake affects calcium balance; most notably, high protein intake promotes urinary calcium excretion. Increasing dietary protein from 75 to 125 g/ day results in an increase in urinary calcium by about 1.6 mmol/day.45 If the additional calcium loss came entirely from the skeleton, it would result in a 1–2% annual loss in bone mass in an adult woman, which is comparable to the rate of bone loss in early menopause.28 However, increased intestinal calcium absorption accounts for the majority (approximately 80%) of the rise in urinary calcium, leaving the possibility that the skeleton is the source of the remaining 20%. In theory, high-protein diets can lead to increased PTH secretion; however, it is unclear if this results in frank secondary hyperparathyroidism. Conversely, dietary protein intakes at or below 0.8 g/kg/day have been associated with a reduction in intestinal calcium absorption sufficient to cause secondary hyperparathyroidism.28 Age-related decline in GFR (glomerular filtration rate) leads to secondary hyperparathyroidism by two mechanisms: (1) increased phosphate concentrations (see also Chapter 44); and (2) decreased 1,25(OH)2D levels, with resultant decreased intestinal calcium absorption.29 In the elderly, calcium malabsorption alone (without vitamin D deficiency) does not appear to cause secondary hyperparathyroidism. In a study of 482 postmenopausal women, older women had decreased radiocalcium absorption but did not have increased circulating PTH. There was no significant correlation between radiocalcium absorption and serum PTH values.46

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Phosphate-Wasting Disorders

Morbidly obese patients are at increased risk of secondary hyperparathyroidism after gastric bypass surgery; in one study, only 30% of post-gastric bypass patients with elevated PTH levels had vitamin D deficiency.47 This suggests that nutritional elements other than vitamin D may be related to post-gastric bypass secondary hyperparathyroidism and metabolic bone disease. Disruption of the small intestine (especially the duodenum and jejunum, where calcium absorption primarily occurs) in gastric bypass may lead to calcium malabsorption independent of vitamin D deficiency. In gastric bypass patients, African-American race and perimenopausal age (>45 years) were significantly associated with high postoperative PTH concentrations.47 Disorders of calcium balance, whether through diminished intake, altered intestinal absorption, or excess renal excretion, may result in secondary hyperparathyroidism. Similarly, altered phosphate homeostasis, primarily mediated by excess FGF23, may also result in secondary hyperparathyroidism.

PHOSPHATE-WASTING DISORDERS FGF23 is a circulating fibroblast growth factor made by osteocytes and osteoblasts that is an important physiological regulator of phosphate homeostasis. FGF23 has dual actions: (1) to promote urinary phosphate excretion via altered trafficking of renal sodium–phosphate cotransporters (NaPiIIa and NaPiIIc); and (2) to inhibit the synthesis and augment the catabolism of 1,25(OH)2D through decreased expression of 1α-hydroxylase and increased expression of 24 hydroxylase.48–50 FGF23 excess is the common pathway for the clinical and biochemical manifestations of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets types 1 and 2 (ARHR1, AHRH 2), and tumor-induced osteomalacia (TIO), which is manifested by hypophosphatemia, low 1,25(OH)2D, osteomalacia and fractures, and varying degrees of myopathy depending on the disorder.51 In each of these disorders, secondary hyperparathyroidism may be observed as a clinical feature; however, it is unclear whether the hyperparathyroidism is part of the pathophysiology of these disorders or an unintended result of treatment. The interrelationship of FGF23 and PTH is a complex and controversial topic.52,53 In some studies, PTH appears to increase FGF23 expression.54,55 FGF23 is elevated in some patients with primary hyperparathyroidism and in patients with Jansen’s metaphyseal chondrodysplasia in which the mutated PTHR1 is constitutively activated.56 Furthermore, in patients with chronic kidney disease (CKD) who undergo parathyroidectomy, FGF23 decreases postoperatively.57 In vitro, PTH directly stimulates FGF23 gene expression.58

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In other studies, PTH appears to have an inverse relationship with FGF23. In ROS 17/2.8 osteoblast cells and in calvarial cultures, stimulation with PTH failed to stimulate FGF23.59,60 In a variety of mouse models with secondary hyperparathyroidism, such as VDR-null mice and vitamin D deficiency mice, serum FGF23 is low.61,62 Interestingly, administration of vitamin D to PTH-null mice resulted in an increase in FGF23 independent of PTH.59 In another study, intermittent PTH administration resulted in lower FGF23 levels.63 Furthermore, in patients with hypoparathyroidism, FGF23 concentrations are elevated.64 Conversely, FGF23 directly suppresses PTH mRNA expression in vitro and decreases serum PTH in vivo.65 However, FGF23 does not appear to prevent the development of hyperparathyroidism in any clinical scenario. There is a strong association between elevated FGF23 levels and the severity of hyperparathyroidism in CKD (see also Chapter 44) and other disorders.66 This suggests that FGF23 may promote the development of hyperparathyroidism.66–68 Clearly, more research is needed to clarify the interplay between PTH and FGF23 in mineral ion homeostasis and bone mineralization.

Renal Hypophosphatemic Rickets: XLH, ADHR, ARHR, TIO The treatment of renal hypophosphatemic rickets, including XLH, ADHR, ARHR, and TIO, traditionally consisted of active vitamin D metabolites (calcitriol) and high doses of oral phosphate supplements. Treatment results in increased intestinal absorption of phosphate, increased serum phosphate levels, and improved osteomalacia. A common complication of high-dose phosphate treatment is a reduction in serum ionized calcium activity, leading to secondary hyperparathyroidism.69–72 In these patients, calcitriol is used to increase intestinal absorption of calcium and phosphorus, but it has a narrow therapeutic index and can lead to episodic hypercalciuria and hypercalcemia. Repeated episodes of hypercalciuria can lead to nephrolithiasis and reduced renal function. Older studies have shown that the adjunct use of diuretics (hydrochlorothiazide and amiloride) in patients with XLH results in increased serum phosphate levels, thus reducing the required dose of oral phosphate supplements. In patients with XLH and secondary hyperparathyroidism and hypercalciuria, the addition of diuretics allows higher doses of calcitriol and lower doses of phosphate to be administered, which results in suppression and normalization of PTH levels.73 X-linked hypophosphatemic rickets was first described in 1937 by Albright as a syndrome of growth retardation, rickets, skeletal deformities, and dental abscesses.74 XLH is caused by loss-of-function mutations in the “phosphate-regulating gene with homology

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to endopeptidase on the X chromosome” (PHEX), which results in elevation of FGF23 levels.75–79 Initially, FGF23 was thought to be a substrate for PHEX, but more recent data demonstrate that FGF23 is not a direct substrate for PHEX, but rather that PHEX appears to regulate FGF23 gene transcription in osteocytes by an unknown mechanism.79 FGF23 inhibits renal tubular reabsorption of phosphate, reduces synthesis, and increases catabolism of 1,25(OH)2D. This results in severe hypophosphatemia and low levels of 1,25(OH)2D, which lead to rickets and growth retardation in children and osteomalacia and fractures in adults. In patients with X-linked hypophosphatemic rickets, the use of calcitriol decreases serum PTH concentrations, increases tubular threshold for phosphate, and improves serum phosphate values.72 Recent studies have investigated the use of calcimimetics such as cinacalcet (Sensipar) as adjuvant therapy in XLH; calcimimetics act by allosterically modulating the calcium receptor in parathyroid chief cells, enhancing their sensitivity to calcium and therefore reducing PTH secretion. By suppressing PTH secretion, calcimimetics increase serum phosphate levels while allowing for lower doses of phosphate supplements and calcitriol, thus reducing the risk of secondary hyperparathyroidism and nephrocalcinosis.80 Furthermore, sustained decreases in circulating FGF23 have been observed in a case report of one patient with XLH and secondary hyperparathyroidism who was successfully treated with cinacalcet.81 Secondary hyperparathyroidism that arises from treatment of XLH with phosphate supplements may progress to tertiary hyperparathyroidism with autonomous hyperfunction of the parathyroids. This propensity for secondary and tertiary hyperparathyroidism has been reported in several hundred patients treated for XLH.82 XLH patients who developed tertiary hyperparathyroidism have, on average, earlier onset of XLH, higher doses of phosphate supplementation, and longer duration of treatment with phosphate supplements when compared to those who developed only secondary hyperparathyroidism.83 XLH patients with tertiary hyperparathyroidism have been successfully treated with parathyroidectomy with all patients achieving long-term normocalcemia. The most common complications are postoperative hypocalcemia and hungry bone syndrome. In one series of XLH patients with tertiary hyperparathyroidism who were treated with parathyroidectomy, the majority had parathyroid hyperplasia and a small number had one or more parathyroid adenomas.84 Parathyroid adenomas may be due to monoclonal expansion from diffuse hyperplasia in XLH patients with secondary hyperparathyroidism.85 However, another interesting possibility with a growing number of cases in the literature is XLH with primary hyperparathyroidism; this has most often been observed in patients with

untreated XLH who present with hyperparathyroidism, which points to a primary defect of the parathyroid gland in those with XLH rather than a result of treatment.82,85,86 Strikingly, XLH patients who develop secondary or tertiary hyperparathyroidism often subsequently develop hypertension (HTN). One study revealed that all the children with XLH and hypertension also had hyperparathyroidism.87 In patients with CKD, secondary hyperparathyroidism has long been implicated in the development of HTN.88,89 The mechanism linking hyperparathyroidism and HTN remains unclear; however, it has been postulated that chronic hyperparathyroidism causes intracellular calcium deposition in smooth muscle cells in the renal vasculature, leading to increases in plasma renin activity and blood pressure. The increased cardiovascular risk in patients with secondary hyperparathyroidism should highlight the necessity for early recognition and treatment of this condition, especially in young patients with hypophosphatemic rickets. Autosomal dominant hypophosphatemic rickets (ADHR) is due to missense mutations in the FGF23 gene that disrupt a furin protease recognition site, which renders FGF23 resistant to cleavage and inactivation. This stabilizes the protein and increases FGF23 levels, leading to phosphate wasting and the typical vitamin D synthetic defect. In this condition, it has been proposed that decreased calcitriol synthesis leads to hypocalcemia and resultant secondary hyperparathyroidism.90,91 ADHR results in a similar phenotype to XLH, including hypophosphatemia, rickets, and growth retardation; however, ADHR has variable penetrance with delayed onset of the disease and may even have spontaneous resolution of the biochemical defect. Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by high concentrations of FGF23 produced by benign mesenchymal tumors. TIO results in hyperphosphaturia, hypophosphatemia, inappropriately normal or low 1,25(OH)2 D levels, osteomalacia, fractures, and myopathy. Serum FGF23 values are typically elevated. TIO presents in adulthood with bone pain, pathological fractures, and proximal muscle weakness.92,93 TIO itself does not typically present with secondary hyperparathyroidism, as PTH concentrations are normal at presentation in most instances. However, as detailed above for XLH, the high doses of phosphate and calcitriol needed to heal osteomalacia and ameliorate symptoms can lead to secondary or even tertiary hyperparathyroidism in TIO patients.93 The mechanism for this is not well understood, but it has been proposed that high doses of phosphate transiently lower serum calcium levels, causing intermittent stimulation of the parathyroid glands and secondary hyperparathyroidism. With time, prolonged stimulation of the parathyroid glands with unopposed phosphate supplementation can lead to parathyroid autonomy and tertiary

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Post-Renal Transplant

hyperparathyroidism.93 As detailed above for XLH, the calcimimetic drug cinacalcet has also been used to treat TIO patients and has resulted in increased renal phosphate reabsorption, decreasing the need for phosphate supplementation, and bone healing in some patients.94

Vitamin D-dependent Rickets Vitamin D metabolism and its link to secondary hyperparathyroidism are discussed in detail elsewhere in this text (see also Chapter 43). Briefly, PTH is regulated by 1,25(OH)2D. Deficiency of 1,25(OH)2D leads to diminished intestinal calcium absorption and serum calcium levels, which in turn lead to increased PTH secretion which increases CYP27B1(1α-hydroxylase) activity hastening the conversion of 25(OH)D to 1,25(OH)2D. Conversely, 1,25(OH)2D can suppress PTH secretion by inhibiting transcription of the PTH gene itself through interaction of the VDR with the PTH gene promoter. Two rare forms of rickets, vitamin D-dependent rickets type 1 (VDDRI, OMIM #264700) and vitamin D-dependent rickets type 2 (VDDRII, OMIM #277440), are caused by disorders of vitamin D synthesis or of the vitamin D receptor. In each case, secondary hyperparathyroidism is a clinical feature. Vitamin D-dependent rickets type 2 is a rare autosomal recessive disorder caused by inactivating mutations in the vitamin D receptor (VDR) gene, which result in target tissue resistance to 1,25(OH)2D, the bioactive vitamin D metabolite.95–100 It was first recognized as a familial syndrome of vitamin D resistance in the late 1950s.101–103 VDDRII presents soon after birth and results in bone demineralization, fractures, growth delay, and alopecia in some patients, depending on the location of the VDR mutation.97 In severe cases, respiratory infections and compromise may occur. VDDRII leads to decreased intestinal absorption of calcium and hypocalcemia, secondary hyperparathyroidism, hypophosphatemia, high alkaline phosphatase, and extremely high levels of calcitriol.95 It has been proposed that secondary hyperparathyroidism is the cause of rachitic bone in VDDRII because hypophosphatemia prevents apoptosis of hypertrophic cells in the growth plate.104 VDDRII patients may require high doses of calcium to normalize PTH and alkaline phosphatase and heal bone demineralization.105 Some patients respond to high doses of vitamin D, 25(OH)D, or calcitriol plus calcium.106 Others are unresponsive to oral therapy and require high doses of intravenous calcium.96 It is important to note that hypophosphatemia in patients with VDDRII improves after calcium supplementation and does not require phosphate supplementation, indicating that hypophosphatemia in these patients was caused by secondary hyperparathyroidism. As in XLH and ADHR patients, cinacalcet has recently been used as an adjunctive

treatment for VDDRII.107 Cinacalcet leads to rapid suppression of PTH and resolution of radiological changes of rickets; this was further supported by reduction in bone turnover markers and evidence of increased mineralization on X-ray. This provides further evidence that secondary hyperparathyroidism with resultant hypophosphatemia may be the cause of rickets in VDDRII, since cinacalcet decreases PTH, improves hypophosphatemia, and improves rickets even though resistance to 1,25(OH)2D remains unaffected. Calcitriol is synthesized from 25(OH)D, the circulating hormone precursor, by the enzyme 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase). This enzyme is defective in vitamin D-dependent rickets type 1 (VDDR1) or pseudovitamin D deficiency rickets. VDDR1 is caused by mutations in the CYP27B1 gene that reduces 1α-hydroxylase activity. This disorder results in hypocalcemia, secondary hyperparathyroidism, extremely low to absent calcitriol levels, and early-onset rickets.96 Children with VDDR1 may also present with hypotonia, muscle weakness, growth failure, and hypocalcemic seizures. They respond well to physiologic doses of calcitriol but have no response to high doses of cholecalciferol. Vitamin D-dependent rickets type 1 can be differentiated from renal hypophosphatemic rickets in several ways. Patients with VDDR type 1 have symptomatic hypocalcemia, secondary hyperparathyroidism, increased nephrogenic cAMP excretion, and aminoaciduria. Low calcitriol levels and hypophosphatemia are observed in both disorders. It is possible to reverse hypocalcemia and hypophosphatemia in VDDR1 with physiologic amounts of calcitriol.70

POST-RENAL TRANSPLANT Secondary hyperparathyroidism is prevalent in CKD, as discussed in detail elsewhere in this text (see also Chapters 44 and 45). Even after renal transplantation, parathyroid autonomy may persist due to long-standing parathyroid stimulation. Up to 50% of transplant recipients exhibit elevated serum PTH concentrations at 1 year post-transplant. As renal function improves, posttransplant hyperparathyroidism results in mild hypercalcemia and hypophosphatemia.108 In many cases, the hyperplastic parathyroid glands gradually involute and return to normal size after renal transplantation, with subsequent normalization of PTH values.109 Recurrence of secondary hyperparathyroidism after successful renal transplantation has been widely reported, which can lead to nephrocalcinosis, vascular calcification, and graft dysfunction. Chronic allograft dysfunction is the most common etiology of recurrent secondary hyperparathyroidism post-renal transplantation; other causes include vitamin D deficiency and glucocorticoid administration

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for immunosuppression, which lead to decreased intestinal absorption and renal reabsorption of calcium, respectively.110,111 Persistence and severity of post-transplant hyperparathyroidism is related to pre-transplant serum PTH concentrations, parathyroid gland size, and parathyroid nodularity.112,113 In children who undergo renal transplantation, factors that predict persistent secondary hyperparathyroidism in the post-transplant period include pre-transplant PTH level, duration of dialysis, creatinine clearance, and hypophosphatemia.114 Both parathyroidectomy and percutaneous ethanol injection have been performed to treat both tertiary and recurrent secondary hyperparathyroidism after renal transplantation.115–118 Patients who discontinue cinacalcet at the time of renal transplantation may be more likely to develop rebound hyperparathyroidism and require parathyroidectomy in the early post-transplant period.119 Small studies have shown that cinacalcet is effective in treating post-renal transplant patients with parathyroid-mediated hypercalcemia and secondary hyperparathyroidism.120–124 A recent meta-analysis of 21 studies confirmed the efficacy of cinacalcet in post-transplant hyperparathyroidism.125 Metabolic bone disease in patients with CKD is a complex subject and secondary hyperparathyroidism plays a major role in its pathophysiology; it is covered elsewhere in this text (see also Chapter 45). In post-renal transplantation, multiple factors contribute to changes in BMD including mineral metabolism, immunosuppressive therapies, hormonal changes, renal tubular dysfunction, and nutrition, among others.126–129 The majority of renal transplant patients develop low-turnover bone disease or mixed renal osteodystrophy within 6 months.130,131 A study of post-transplant bone biopsies demonstrated a positive correlation between osteoblast surface and preand post-transplant PTH concentrations, suggesting that PTH may play a role in preserving osteoblast number and function after renal transplantation.130

ACID–BASE DISORDERS Jejunoileal bypass surgery for morbid obesity can result in malabsorption leading to hypocalcemia and vitamin D deficiency, both of which contribute to secondary hyperparathyroidism.132 Hyperchloremic acidosis is a known complication of intestinal bypass, due to both intestinal bicarbonate loss and renal tubular acidosis (RTA). Secondary hyperparathyroidism may play a role in RTA after jejunoileal bypass; correcting calcium and vitamin D deficiency resulted in restored ability to acidify urine, though the exact mechanism for this process remains unclear.133 Fanconi originally described a syndrome in children with glycosuria, aminoaciduria, hypophosphatemia,

and rickets; acquired forms of Fanconi’s syndrome in both adults and children have been described since then. Osteomalacia, with or without 1,25-dihydroxyvitamin D deficiency, has been documented in patients with Fanconi’s syndrome.134 This is a result of prolonged hypophosphatemia due to proximal renal tubular phosphate wasting and high fractional excretion of phosphorus, which can lead to secondary hyperparathyroidism.135–138 Dent’s disease was originally described in 1964 by Charles Dent and his colleagues.139 It is a rare, X-linked proximal renal tubular defect caused by a mutation in the CLCN5 gene. Dent’s disease is characterized by hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis with progressive renal failure, short stature, osteopenia, and rickets in children.140 The prolonged hypercalciuria can lead to secondary hyperparathyroidism. Distal RTA is characterized by persistent metabolic acidosis associated with inappropriately high urine pH, hypercalciuria, nephrocalcinosis, and nephrolithiasis.141 Hypercalciuria leads to secondary hyperparathyroidism and treatment of hypercalciuria with thiazide diuretics reduces serum PTH concentrations. In distal RTA patients, the use of alkali to treat acidosis also led to reduction in serum PTH levels by an unclear mechanism.142

Hyperaldosteronism Hyperaldosteronism is a state of chronic aldosterone elevation that is inappropriate for dietary sodium intake and has been linked to adverse remodeling of the heart and vasculature. Aldosterone excess leads to increased potassium excretion and sodium retention, as well as increased urinary and fecal losses of calcium and magnesium. The ensuing hypocalcemia stimulates PTH release.143,144 It has been recently proposed that aldosterone-induced secondary hyperparathyroidism leads to paradoxical intracellular calcium overload, oxidative stress, osmotic injury to mitochondria, and cell necrosis, which ultimately results in myocardial fibrosis.145 This mechanism was previously proposed and studied in parathyroidectomized rats treated with aldosterone.146 The role of PTH in pathologic cardiac remodeling warrants further study.

MEDICATIONS Lithium is widely used in the treatment of bipolar disease and has been linked to multiple endocrine disturbances including hyperparathyroidism and thyroid dysfunction. It has been observed clinically and reported in the literature that lithium-treated patients with normal renal function develop hypercalcemia,

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References

hypophosphatemia, and elevated serum PTH levels.147–150 In fact, in some series, up to 50% of patients treated with lithium develop hypercalcemia and hyperparathyroidism.151 Lithium-induced hyperparathyroidism appears to be unrelated to lithium concentration, duration of use, or cumulative dose.152 In this condition, serum calcium is mildly elevated, with PTH elevated or inappropriately normal, with normal serum phosphate and reduced urinary calcium excretion.153 The mechanism by which lithium affects the parathyroid glands remains unclear. It has been proposed that lithium blocks the CaSR, resulting in an increased threshold calcium level required for suppression of PTH release.154 Another possible mechanism is that lithium directly stimulates PTH release by the parathyroid glands.155 Others have postulated that lithium may unmask preexisting parathyroid pathology by affecting the calcium set point.156 Recently, it has been proposed that lithium may inhibit the action of glycogen synthase kinase 3b (GSK-3b), which in turn inhibits PTH transcription, thus leading to increased transcription and overproduction of PTH.157 Patients with lithium-associated hyperparathyroidism are more likely to have multiglandular hyperplasia than a distinct adenoma.156,158 It is important to monitor serum calcium levels and be aware of symptoms of hypercalcemia in patients treated with lithium; patients with a history of hypercalcemia or hyperparathyroidism should avoid treatment with lithium.159 Furosemide, a loop diuretic, in combination with salt loading has been shown to cause increased urinary calcium loss with unchanged total and ionized serum calcium levels. Subjects with furosemide-induced hypercalciuria exhibit increased urinary cAMP excretions, suggesting increased parathyroid activity. Consequently, secondary hyperparathyroidism leads to increased intestinal absorption of calcium in these hypercalciuric subjects, resulting in a state of net even calcium balance.160 Osteoblastic metastases in prostate cancer lead to calcium entrapment in bone and an increased demand for calcium, which results in secondary hyperparathyroidism.161–163 By contrast, osteolytic metastases tend to produce hypercalcemia by liberating calcium from the skeleton. Hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia have been reported in up to 50% of patients with prostate cancer and osteoblastic bone metastases.164 The calcium–phosphate product is reduced in patients with osteoblastic metastases, consistent with secondary hyperparathyroidism.165 Furthermore, elevated PTH levels may portend a negative prognosis in metastatic prostate cancer patients who are treated with zoledronic acid.166 Bisphosphonates are widely used to treat and prevent bone metastases in various cancers; bisphosphonate administration results in transient hypocalcemia and hyperparathyroidism, which resolves within 3–4

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weeks.167 Case reports describe profound hypocalcemia following bisphosphonate administration; this can result in secondary hyperparathyroidism with dramatic elevations in PTH levels that persist.168–172 Bisphosphonatemediated hypocalcemia can be secondary to a deficient compensatory mechanism, such as hypoparathyroidism from hypomagnesemia or previous parathyroidectomy, vitamin D deficiency, or PTH resistance. In patients with extensive bone metastases, calcium deposition into osteoblastic lesions can lead to a decline in serum calcium and limits the mobilization of calcium from the skeletal reservoir.168 Antiretroviral medications used to treat HIV may alter calcium–phosphate balance. Longitudinal studies have shown increased risk of low BMD, osteomalacia, and fractures in patients on antiretroviral therapy.173 Efavirenz and rifabutin have been linked to vitamin D deficiency, which often leads to secondary hyperparathyroidism.173,174 Tenofovir has been linked to secondary hyperparathyroidism, an entity that appears to be limited to HIV patients with 25(OH)D concentrations less than 20–30 ng/mL.175–178 Imatinib is now routinely used in the treatment of chronic myeloid leukemia. A cross-sectional study of patients treated with imatinib showed that some developed hypophosphatemia, low-normal calcium levels, elevated serum PTH concentrations, and low-normal bone turnover.179 A subsequent study showed that, after therapy with imatinib was initiated, patients exhibited increased markers of bone formation (osteocalcin and procollagen type I N-terminal propeptide [PINP]), while bone resorption (β-isomer of the C-terminal telopeptide of type I collagen [β-CTX]) remained stable. In addition, reduced serum calcium concentrations (potentially due to net flux of calcium from extracellular fluid to bone), leading to secondary hyperparathyroidism with resulting hyperphosphaturia and reduced serum phosphate levels,180 were observed. The long-term effects of imatinib on bone turnover and calcium–phosphate balance require further study.

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