Primary Hyperparathyroidism

ABSTRACT

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and elevated or inappropriately normal parathyroid hormone (PTH) levels. PHPT results from excessive secretion of PTH from one or more of the parathyroid glands. The clinical presentation of PHPT has evolved since the 1970’s with the advent of the routine measurement of serum calcium at that time. Classical PHPT, with its associated severe hypercalcemia, osteitis fibrosa cystica, nephrolithiasis, and neuropsychological symptoms, once common is now infrequent. Today most patients are asymptomatic and have mild hypercalcemia, but may have evidence of subclinical skeletal and renal sequelae such as osteoporosis and hypercalciuria as well as vertebral fractures and nephrolithiasis both of which may be asymptomatic. Parathyroidectomy is the only curative treatment for PHPT and is recommended in patients with symptoms and those with asymptomatic disease who have evidence of end-organ sequelae. Parathyroidectomy results in an increase in BMD and a reduction in nephrolithiasis. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and elevated or inappropriately normal parathyroid hormone (PTH) levels. The disorder today bears few similarities to the severe condition described by Fuller Albright and others as a “disease of stones, bones, and groans” in the 1930s (1-3). The skeletal hallmark of PHPT was osteitis fibrosa cystica, radiographically characterized by brown tumors of the long bones, subperiosteal bone resorption, distal tapering of the clavicles and phalanges, and “salt-and-pepper” erosions of the skull (4). Nephrocalcinosis and nephrolithiasis were present in the majority of patients, and neuromuscular dysfunction with muscle weakness was also common. With the advent of the automated serum chemistry autoanalyzer in the 1970s, the diagnosis of PHPT was increasingly recognized, leading to a four- to five-fold increase in incidence (5-7). Classic symptomatology, concomitantly, became much less frequent. In the United States and elsewhere in the developed world, symptomatic PHPT is now the exception and more than three fourths of patients having no symptoms attributable to their disease, making PHPT a disease that has “evolved” from its classic presentation (Table 1) (8). Symptomatic nephrolithiasis is still observed, although much less frequently than in the past. Now, radiologically evident bone disease is rare, but subclinical skeletal involvement can be readily detected by bone densitometry (9). This chapter describes the modern presentation, diagnosis and management of PHPT.

Table 1.

Changing Clinical Profile of Primary Hyperparathyroidism

RISK FACTORS, PATHOLOGY, AND ANATOMICAL LOCATION

PHPT results from excessive secretion of PTH from one or more of the parathyroid glands. The underlying cause of sporadic PHPT is unknown in most cases. While external neck radiation and lithium therapy are risk factors for the development of sporadic PHPT, most patients do not report these exposures (10-12). Chronically low calcium intake and higher body weight have also been recently described to be risk factors (13,14). The genetic pathogenesis of sporadic PHPT is unclear in most patients but genes regulating the cell cycle are thought to be important given the clonal nature of sporadic parathyroid adenomas.

By far the most common pathological finding in patients with PHPT is a solitary parathyroid adenoma, occurring in 80% of patients (15). In 2-4% of patients, PHPT is due to multiple adenomas (16). In approximately 15% of patients, all four parathyroid glands are involved (15,17). Parathyroid carcinoma accounts for <1% of all cases of PHPT(18). The etiology of four-gland parathyroid hyperplasia is multifactorial. There are no clinical features that definitively differentiate single versus multiglandular disease, but risk factors include inherited genetic syndromes such as multiple endocrine neoplasia (MEN) type 1 or type 2a and lithium exposure (17).

Parathyroid adenomas can be found in many unexpected anatomic locations. Parathyroid tissue embryonal migration patterns account for a plethora of possible sites of ectopic parathyroid adenomas. The most common atypical locations are within the thyroid gland, the superior mediastinum, and within the thymus (19). Occasionally, adenomas are identified in the retroesophageal space, the pharynx, the lateral neck, and even in the alimentary submucosa of the esophagus (20-22). On histologic examination, most parathyroid adenomas are encapsulated and are composed of parathyroid chief cells. Adenomas containing mainly oxyphilic or oncocytic cells are rare, but can give rise to clinical PHPT (23). Very rarely, PHPT may be due to parathyromatosis. This refers to an uncommon condition in which benign hyperfunctioning parathyroid tissue is scattered throughout the neck and/or in the superior mediastinum (see Unusual Presentations) (24).

EPIDEMIOLOGY

The incidence of PHPT has changed dramatically over the last half century (5,6,25,26). Before the advent of the multichannel autoanalyzer in the early 1970s, Heath et al reported an incidence of 7.8 cases per 100,000 persons in Rochester, Minnesota (5). With the introduction of routine calcium measurements in the mid-1970s, this rate rose dramatically to 51.1 cases per 100,000 in the same community. After prevalent cases were diagnosed, the incidence declined to approximately 27 per 100,000 persons per year in the United States until 1998, at which time another sharp increase was noted (25,27,28). This second peak has been attributed to the introduction of osteoporosis screening guidelines and targeted testing in those with osteoporosis (28). Recent works shows the incidence of PHPT increases with age and is higher in women and African-Americans than in men and other racial groups, respectively (29).

Greater appreciation of the catabolic potential of PTH in postmenopausal women with osteoporosis has led to measurement of PTH even in subjects who do not have hypercalcemia. This trend has led to the emergence of a new entity, normocalcemic PHPT or NPHPT(30). This condition is characterized by normal serum calcium, elevated PTH, and exclusion of known causes of secondary hyperparathyroidism. The incidence of NPHPT is unknown, but recent studies suggest a prevalence ranging from 0.2-3.1% (31,32).

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of PHPT is made when hypercalcemia and elevated PTH levels are present.

PTH levels that are inappropriately normal are also consistent with the diagnosis. The other major cause of hypercalcemia, malignancy, is readily discriminated from PHPT by a suppressed PTH level. Further, both the clinical presentation and biochemical profile of PHPT and hypercalcemia of malignancy help distinguish them. Patients with hypercalcemia of malignancy typically have severe and symptomatic hypercalcemia and advanced cancers that are clinically obvious. On the other hand, in PHPT most patients are asymptomatic and the serum calcium level is typically mildly elevated (within 1 mg/dl of the upper limit of normal). Extremely rarely, a patient with malignancy will be shown to have elevated PTH levels resulting from ectopic secretion of native PTH from the tumor itself (33). Much more commonly, the malignancy is associated with the secretion of parathyroid hormone–related protein (PTHrP), a molecule that does not cross-react in intact PTH assay (discussed below). Finally, it is possible that a malignancy is present in association with PHPT. When the PTH level is elevated in someone with a malignancy, this is more likely to be the case than a true ectopic PTH syndrome.

While ninety percent of patients with hypercalcemia have either PHPT or malignancy, the differential diagnosis of hypercalcemia includes a number of other etiologies such as vitamin D intoxication, granulomatous disease, and others (33). With the exception of lithium and thiazide use and familial hypocalciuric hypercalcemia (FHH), virtually all other causes of hypercalcemia are associated with suppressed levels of PTH. If lithium and/or thiazides can be safely withdrawn, serum calcium and PTH levels that continue to be elevated 3-6 months later, confirm the diagnosis of PHPT. FHH, on the other hand, is differentiated from PHPT by family history, typically (but not always) low urinary calcium excretion, and mutations in the calcium sensing receptor (CASR) or more recently associated GNA11 and AP2S1 genes (34-36). In addition, virtual complete genetic penetrance leads to its clinical appearance typically before the age of 30. It is extremely unusual for FHH to present without an antecedent history after the age of 50.

To distinguish PTH-mediated from non-PTH mediated causes of hypercalcemia, PTH should be measured with an intact immunoradiometric (IRMA) or immunochemiluminometric (ICMA) assay, which readily discriminates between PHPT and hypercalcemia of malignancy. In PHPT, PTH concentrations are usually frankly elevated, but most often within 2 times the upper limit of normal. A minority may have PTH levels in the normal range, typically in the upper range of normal. In PHPT, such values, although within the normal range, are clearly abnormal in a hypercalcemic setting. Several factors affect the PTH level in those with and without PHPT, including age, vitamin D levels, and renal function. Because PTH levels normally rise with age, the broad normal range (typically 10-65 pg/mL) reflects values for the entire population. In the younger individual (< 45 years), one expects a narrower and lower normal range (10-45 pg/mL). Occasionally, the PTH level as measured will be as low as 20-30 pg/mL. Such unusual examples require a more careful consideration of other causes of hypercalcemia, but such individuals will usually be shown to have PHPT because hypercalcemia that is not PTH-mediated suppresses the PTH concentration to levels that are either undetectable or at the lower limits of the reference range. Souberbielle et al (37) have illustrated that the normal range is dependent on whether or not the reference population is or is not vitamin D deficient. When vitamin D–deficient individuals were excluded, the upper limit of the PTH reference interval decreased. Patients with PHPT and vitamin D deficiency have a “heightened” PTH levels compared to those who are vitamin D sufficient (38).

On the other hand, renal dysfunction tends to elevate PTH levels via a number of mechanisms, including reduced clearance and degradation of PTH. Indeed, patients with PHPT and severe renal dysfunction (glomerular filtration rate < 30ml/min), may also have higher PTH levels compared to those with better renal function (39). In addition, the “intact” IRMA for PTH overestimates the concentration of biologically active PTH, particularly in renal failure. In 1998, Lepage et al (40) demonstrated a large non-(1–84) PTH fragment that comigrated with a large aminoterminally truncated fragment (PTH[7–84]) and showed substantial cross-reactivity in commercially available IRMAs. This large, inactive moiety constituted as much as 50% of immunoreactivity by IRMA for PTH in individuals with chronic renal failure (41). Recognition of this molecule led to the development of a new IRMA using affinity-purified polyclonal antibodies to PTH (39–84) and to the extreme N-terminal amino acid regions, PTH (1–4) (42,43). This “whole PTH” or third generation assay detects only the full-length PTH molecule, PTH (1–84). This assay has clear utility in uremic patients, but in PHPT, both assays are equally useful (40,44-46). Using the third-generation assay for PTH (1-84), a second molecular form of PTH(1-84) that is immunologically intact at both extremes has been identified. This molecule reacts only poorly in second-generation PTH assays. It represents less than 10% of the immunoreactivity in normal individuals and up to 15% in renal failure patients. In a limited number of patients with a severe form of PHPT or with parathyroid cancer, it may be over-expressed (47).

PHPT can be discriminated from secondary and tertiary hyperparathyroidism by its different biochemical profile. Secondary hyperparathyroidism is associated with an appropriate elevation in PTH in response to a hypocalcemic provocation and either a frankly low or normal serum calcium level. Secondary hyperparathyroidism is often due to vitamin D deficiency. Other causes include malabsorption, kidney disease, or hypercalciuria. Infrequently, patients with secondary hyperparathyroidism may become hypercalcemic, and will ultimately be found to have PHPT, when the underlying condition (for example, vitamin D deficiency) is corrected (48). In these cases, the hypercalcemia of PHPT was ‘masked’ by the co-existing condition. On the other hand, tertiary hyperparathyroidism describes a condition in which prolonged, severe secondary hyperparathyroidism (as in end-stage renal disease) evolves into a hypercalcemic state due to the development of autonomous functioning of one or more of the hyperplastic parathyroid glands. This can be observed in patients on dialysis or after renal transplant. Tertiary hyperparathyroidism is usually obvious from the history.

Normocalcemic primary hyperparathyroidism (NPHPT) describes a condition characterized by normal serum albumin-corrected calcium levels and ionized calcium values with an elevated PTH level. This condition can only be diagnosed when all known causes of secondary hyperparathyroidism have been excluded. Patients with NPHPT typically are diagnosed when PTH is measured in the course of an evaluation for low bone mass. NPHPT may represent the earliest manifestations of PHPT, a “forme fruste” of the disease. Several reports have appeared describing these individuals, with some patients progressing to overt hypercalcemia while under observation (30,32,49,50).

Although the term “normocalcemic PHPT” has been in use for decades, there has been considerable controversy concerning the accuracy of this designation. In many cases, the increases in PTH levels were attributable to the limitations of available assay technology. The older midmolecule radioimmunoassay for PTH, previously in common use, measured hormone fragments in addition to the intact molecule. Spuriously elevated PTH levels, particularly in those with renal insufficiency in whom clearance of hormone fragments is impaired, were seen. Alternative explanations for hyperparathyroidism with NPHPT have been discovered, including medications, hypercalciuria, renal insufficiency, and certain forms of liver and gastrointestinal disease. In recent years, it has become clear that many patients designated as having NPHPT were vitamin D deficient. Vitamin D deficiency with coexisting PHPT can give the semblance of normal calcium levels when in fact they would have been hypercalcemic if the vitamin D levels were normal. Since a possible view of NPHPT is a condition fostered by an element of vitamin D resistance, it is important to ensure vitamin D sufficiency. While the Institute of Medicine states that normal levels of vitamin D, as measured by 25-hydroxyvitamin D, are 20 ng/ml, it did not address conditions of abnormal mineral metabolism, such as PHPT. In particular, in NPHPT, we and others recommend that levels of 25-hydorxyvitamin D be raised, if necessary, to > 30 ng/mL for at least 3 months in order to rule out an element of vitamin D insufficiency in this population. Biochemical profiles for the various causes of hypercalcemia and hyperparathyroidism are shown in Table 2.

Table 2.

Biochemical Profiles for Various Causes of Hypercalcemia and Hyperparathyroidism

OTHER BIOCHEMICAL FEATURES

In PHPT, serum phosphorus tends to be in the lower range of normal, but frank hypophosphatemia is present in less than one fourth of patients. Hypophosphatemia, when present, is due to the phosphaturic actions of PTH. Average total urinary calcium excretion is at the upper end of the normal range, with about 40% of all patients experiencing hypercalciuria. Serum 25-hydroxyvitamin D levels tend to be in the lower end of the normal range. Although mean values of 1,25-dihydroxyvitamin D are in the high-normal range, approximately one third of patients have frankly elevated levels of 1,25-dihydroxyvitamin D (51). This pattern is a result of the actions of PTH to increase expression of the 1-alpha hydroxylase that converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. A typical biochemical profile is shown in Table 3.

Table 3.

Biochemical Profile in Primary Hyperparathyroidism (n = 137)

CLINICAL PRESENTATION

PHPT typically occurs in individuals in their middle years, with a peak incidence between ages 50 and 60 years. However, the condition can occur at any age. Women are affected more frequently than men, in a ratio of approximately 3-4:1. Several different presentations of PHPT are possible and were originally described successively in time (2,30,52). The classical symptomatic presentation was described first; later, asymptomatic PHPT emerged due to biochemical screening, and most recently the normocalcemic variant was discovered as described above. However, these three forms of PHPT contemporaneously exist today. Which presentation predominates depends upon population- and geographic-specific screening practices. It is also postulated that vitamin D deficiency may affect clinical presentation. Vitamin D deficiency heightens PTH elevations and this can worsen the hyperparathyroid process (53). In regions of the world and populations where biochemical screening is not routine and incidentally where vitamin D deficiency is endemic, symptomatic PHPT is the most common form and PHPT will appear to be uncommon because it is only discovered when symptomatic (54-64). In areas and populations where screening is routine, asymptomatic PHPT will predominate and the incidence of PHPT is higher (52,65).

This chapter focuses on asymptomatic PHPT, as it is the predominant form in the United States and in most of the developed world. At the time of diagnosis, most patients with PHPT do not exhibit classic symptoms or signs associated with disease. Clinically overt kidney stones and fractures are rare (66). Constitutional complaints such as weakness, easy fatigability, depression, and intellectual weariness are seen with some regularity (see later discussion) (67). The physical examination is generally unremarkable. Band keratopathy, a hallmark of classic PHPT, occurs because of deposition of calcium phosphate crystals in the cornea, but is virtually never seen grossly. Even by slit-lamp examination, this finding is rare. The neck shows no masses. The neuromuscular system is normal. The sections below provide a detailed description of the multi-systemic manifestations of PHPT.

Diseases associated epidemiologically with PHPT have included hypertension (68-70), peptic ulcer disease, gout, or pseudogout (71,72). More recently celiac disease has been associated with PHPT (73). Some concomitant disorders such as hypertension are commonly seen, but it is not established that any of these associated disorders are etiologically linked to the disease.

The Skeleton

The classic radiologic bone disease of PHPT, osteitis fibrosa cystica, is rarely seen today in the United States. Most series place the incidence of osteitis fibrosa cystica at less than 2% of patients with PHPT. The absence of classic radiographic features (salt-and-pepper skull, tapering of the distal third of the clavicle, subperiosteal bone resorption of the phalanges, brown tumors) does not mean that the skeleton is not affected. With more sensitive techniques, it has become clear that skeletal involvement in the hyperparathyroid process is actually quite common. This section reviews the profile of the skeleton in PHPT as it is reflected in assays for bone markers, bone densitometry, bone histomorphometry, and new skeletal imaging techniques.

BONE TURNOVER MARKERS

PTH stimulates both bone resorption and bone formation. Markers of bone turnover, which reflect those dynamics, provide clues to the extent of skeletal involvement in PHPT (74).

Bone Formation Markers

Osteoblast products, including bone-specific alkaline phosphatase activity, osteocalcin, and serum amino-terminal propeptide of type I collagen (P1NP), reflect bone formation (74). In PHPT, alkaline phosphatase levels, the most widely clinically available marker, can be mildly elevated, but in many patients, total alkaline phosphatase values are within normal limits (75,76). In a small study from our group (77), bone-specific alkaline phosphatase activity correlated with PTH levels and BMD at the lumbar spine and femoral neck. Osteocalcin is also generally increased in patients with PHPT (77-79). Sclerostin is an important regulator of bone formation. Patients with PHPT have low sclerostin levels, suggesting PTH down regulates sclerostin (80). As expected the bone formation marker, serum amino-terminal propeptide of type I collagen (P1NP), is negatively associated with sclerostin in PHPT (81). In a small series of 27 patients followed for up to a year post-PTX, circulating sclerostin increases shortly after post-surgery but return to the age reference range within 10 days (82).

Bone Resorption Markers

Markers of bone resorption include the osteoclast product, tartrate-resistant acid phosphatase (TRAP), and collagen breakdown products such as hydroxyproline, hydroxypyridinium cross-links of collagen, and N- and C-telopeptides of type 1 collagen (NTX and CTX) (74). Urinary hydroxyproline, once the only available marker of bone resorption, no longer offers sufficient sensitivity or specificity to make it useful. Although urinary hydroxyproline was frankly elevated in patients with osteitis fibrosa cystica, in mild asymptomatic PHPT it is generally normal. Hydroxypyridinium cross-links of collagen, pyridinoline (PYD), and deoxypyridinoline (DPD), on the other hand, are often elevated in PHPT. They return to normal after parathyroidectomy (83). DPD and PYD both correlate positively with PTH concentrations. Studies of NTX, CTX and TRAP are limited, although levels of the latter have been shown to be elevated (48). Thus, sensitive assays of bone formation and bone resorption are both elevated in mild PHPT.

Longitudinal Bone Turnover Marker Studies

Studies of bone turnover markers in the longitudinal follow-up of patients with PHPT indicate a reduction in these markers following parathyroidectomy. Information from our group (83,84), Guo et al (85), and Tanaka et al (86) all report declining levels of bone markers following surgery. The kinetics of change in bone resorption versus bone formation following parathyroidectomy provide insight into skeletal recovery. We have found that markers of bone resorption decline rapidly following successful parathyroidectomy, whereas indices of bone formation follow a more gradual decrease (83). Urinary PYD and DPD decreased significantly as early as 2 weeks following parathyroid surgery, preceding reductions in alkaline phosphatase. Similar data were reported from Tanaka et al (86), who demonstrated a difference in time course between changes in NTX (reflecting bone resorption) and osteocalcin (reflecting bone formation) following parathyroidectomy, and Minisola et al (87), who reported a drop in bone resorptive markers and no significant change in alkaline phosphatase or osteocalcin. The persistence of elevated bone formation markers coupled with rapid declines in bone resorption markers indicate a shift in the coupling between bone formation and bone resorption toward an accrual of bone mineral postoperatively. More recent data indicate that levels of preoperative markers of bone turnover (formation and resorption) are positively associated with the extent of bone accrual after parathyroidectomy, though some of the patients included in this study had more severe PHPT than is typically seen in the United States today (88).

BONE DENSITOMETRY

The advent of bone mineral densitometry as a major diagnostic tool for osteoporosis occurred at a time when the clinical profile of PHPT was changing from a symptomatic to an asymptomatic disease. This fortuitous timing allowed questions about skeletal involvement in PHPT to be addressed when specific gross radiologic features of PHPT had all but disappeared. Observations of skeletal health in PHPT made by bone densitometry have established the importance of this technology in the evaluation of all patients with PHPT. The Consensus Development Conference on Asymptomatic Primary Hyperparathyroidism in 1990 implicitly acknowledged this point when bone mineral densitometry was included as a separate criterion for clinical decision making (89). Since that time, bone densitometry has become an indispensable component of both evaluating the patient and establishing clinical guidelines for management and monitoring.

The known physiologic proclivity of PTH to be catabolic at sites of cortical bone make a cortical site essential to any complete densitometric study of PHPT. By convention, the distal third of the radius is the site used. The early densitometric studies in PHPT also showed another physiologic property of PTH, namely, to preserve bone at cancellous sites. The lumbar spine is an important site to measure not only because it is predominantly cancellous bone, but also because postmenopausal women are at risk for cancellous bone loss. In PHPT, bone density at the distal third of the radius is diminished (90,91) while at the lumbar spine it is only minimally reduced (Figure 1). The hip region, containing relatively equal amounts of cortical and cancellous elements, shows bone density intermediate between the cortical and cancellous sites. The results support not only the notion that PTH is catabolic for cortical bone but also the view that PTH is generally protective against bone loss in cancellous bone (92-94). In postmenopausal women, the same pattern was observed (91). Postmenopausal women with PHPT, therefore, show a reversal of the pattern typically associated with postmenopausal bone loss. Rather than preferential loss of cancellous bone at the lumbar spine, the cortical site of the distal radius is more often affected in postmenopausal women with PHPT.

Figure 1.

The pattern of bone loss in primary hyperparathyroidism. A typical pattern of bone loss is seen in asymptomatic patients with primary hyperparathyroidism. The lumbar spine is relatively well preserved while the distal radius (1/3 site) is preferentially affected. (Reprinted with permission from Silverberg SJ, Shane E, DeLaCruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Mineral Res 1989;4:283-291).

The bone density profile in which there is relative preservation of skeletal mass at the vertebrae and reduction at the more cortical distal radius is not always seen in PHPT. Although this pattern is evident in the vast majority of patients, small groups of patients show evidence of vertebral osteopenia at the time of presentation. In our natural-history study, approximately 15% of patients had a lumbar spine Z score of less than –1.5 at the time of diagnosis (95). Only half of these patients were postmenopausal women, so not all vertebral bone loss could be attributed entirely to estrogen deficiency. These patients are of interest with regard to changes in bone density following parathyroidectomy and are discussed in further detail later. The extent of vertebral bone involvement will vary as a function of disease severity. In the typical mild form of the disease, the pattern described earlier is seen. When PHPT is more advanced, there will be more generalized involvement, with involvement of the lumbar bone. When PHPT is severe or more symptomatic, all bones can be extensively involved. Vitamin D deficiency in mild asymptomatic PHPT seems to have minimal effect on BMD with only slightly reduced BMD at the 1/3 radius in those with low vitamin D (96,97).

BONE HISTOMORPHOMETRY

Analyses of percutaneous bone biopsies from patients with PHPT have provided direct information that could only be indirectly surmised by bone densitometry and by bone markers. Both static and dynamic parameters present a picture of cortical thinning, maintenance of cancellous bone volume, and a very dynamic process associated with high turnover and accelerated bone remodeling. Cortical thinning, inferred by bone mineral densitometry, is clearly documented in a quantitative manner by iliac crest bone biopsy (98,99). Van Doorn et al (100) demonstrated a positive correlation between PTH levels and cortical porosity. These findings are consistent with the known effect of PTH to be catabolic at endocortical surfaces of bone. Osteoclasts are thought to erode more deeply along the corticomedullary junction under the influence of PTH.

Histomorphometric studies have also contributed information about cancellous bone in PHPT (100). Again, as suggested by bone densitometry, cancellous bone volume is well preserved in PHPT. This is seen as well among postmenopausal women with PHPT. Several studies have shown that cancellous bone is actually increased in PHPT as compared to normal subjects (101,102). When cancellous bone volume is compared among age- and sex-matched subjects with PHPT or postmenopausal osteoporosis, a dramatic difference is evident. Whereas postmenopausal women with osteoporosis have reduced cancellous bone volume, women with PHPT have higher cancellous bone volume (101). The region(s) of bone loss in PHPT is (are) directed toward the cortical bone compartment, with good maintenance of cancellous bone volume unless the PHPT is unusually active.

In PHPT, age-related bone loss appears to be mitigated. In a study of 27 patients with PHPT (10 men and 17 women), static parameters of bone turnover (osteoid surface, osteoid volume, and eroded surface) were increased, as expected, in patients relative to control subjects (103). However, in control subjects, trabecular number varied inversely with age, whereas trabecular separation increased with advancing age. These observations are expected concomitants of aging. In marked contrast, in the patients with PHPT, no such age dependency was seen. There was no relationship between trabecular number or separation and age in PHPT, suggesting that the actual plates and their connections were being maintained over time more effectively than one would have expected by aging per se. Thus, PHPT seems to retard the normal age-related processes associated with trabecular loss.

In PHPT, indices of trabecular connectivity are greater than expected, whereas indices of disconnectivity are decreased. When three matched groups of postmenopausal women were assessed (a normal group, a group with postmenopausal osteoporosis, and a group with PHPT), women with PHPT were shown to have trabeculae with less evidence of disconnectivity compared with normal, despite increased levels of bone turnover (102,103). Thus, cancellous bone is preserved in PHPT through the maintenance of well-connected trabecular plates. To determine the mechanism of cancellous bone preservation in PHPT, static and dynamic histomorphometric indices were compared between normal and hyperparathyroid postmenopausal women. In normal postmenopausal women, there is an imbalance in bone formation and resorption, which favors excess bone resorption. In postmenopausal women with PHPT, on the other hand, the adjusted apposition rate is increased. Bone formation, thus favored, may explain the efficacy of PTH at cancellous sites in patients with osteoporosis (92,104-106). Assessment of bone remodeling variables in patients with PHPT shows increases in the active bone-formation period (101) (Table 4). The increased bone formation rate and total formation period may explain the preservation of cancellous bone seen in this disease.

Table 4.

Wall Width and Remodeling Variables in PHPT and Control Groups (Mean ± SEM)

More recently, further analysis of trabecular microarchitecture has taken advantage of newer technologies that have largely been confirmatory. In a three-dimensional analysis of transiliac bone biopsies using microCT technology, a highly significant correlation was observed with the conventional histomorphometry described earlier (107). In comparison to age-matched control subjects without PHPT, postmenopausal women with PHPT had higher bone volume (BV/TV), higher bone surface area (BS/TV), higher connectivity density (Conn.D), and lower trabecular separation (Tb.Sp.). There were also less marked age-related declines in BV/TV and Conn.D as compared to controls, with no decline in BS/TV. Using the technique of backscattered electron imaging (qBEI) to evaluate trabecular BMD distribution (BMDD) in iliac crest bone biopsies, Roschger et al (108) showed reduced average mineralization density and an increase in the heterogeneity of the degree of mineralization, consistent with reduced mean age of bone tissue. Studies of collagen maturity using Fourier Transform Infrared Spectroscopy provide further support for these observations (109). Bone strength, therefore, in PHPT has to take into account a number of factors related to skeletal properties of bone besides BMD (110).

NEW IMAGING TECHNIQUES

Newer non-invasive skeletal imaging technologies offer new insight into the skeletal manifestations of PHPT beyond observations made by DXA and radiography. The trabecular bone score or TBS provides an indirect assessment of trabecular microstructure from the DXA image. In those without PHPT, it has been shown to predicts fracture independently of BMD (111). In PHPT, TBS reveals trabecular microstructural deterioration at the spine, despite preserved BMD by DXA at this site (112). High resolution peripheral quantitative CT (HRpQCT) is a technology that noninvasively and directly measures skeletal microstructure at the distal radius and tibia. Utilizing this technology, studies in patients with PHPT indicate not only cortical thinning, but additionally trabecular deficits at the radius and tibia (Figure 2) (113-115). At the radius, trabeculae were fewer, thinner, more widely and heterogeneously spaced. At the tibia, trabeculae were more heterogeneously spaced (116). These deficits led to reduced stiffness when images were analyzed using microfinite element analysis, a technique that integrates structural and denisitometric information from the HRpQCT image into an estimated of mechanical competence. These recent findings, pointing to abnormalities in the trabecular compartment of bone, help to account for the increased risk of vertebral fractures (see below) observed in PHPT that had remained unexplained prior to the advent of such technologies (117-120). The difference in microskeletal abnormalities between the iliac crest bone biopsy data and HRpQCT may well reflect site-specific sampling differences.

Figure 2.

High-resolution peripheral quantitative CT images of the radius in a patient with primary hyperparathyroidism (PHPT; left) and a normal control (right). Trabecular deterioration is evident in PHPT. Image from Stein EM, Silva BC, Boutroy S, et al. Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. J Bone Miner Res 2012

FRACTURES

Fractures were a common clinical event in classic PHPT. In modern PHPT, one would anticipate, based on the BMD patterns observed with DXA, an increased risk of peripheral fractures, but a reduction in vertebral fractures. While not all studies are consistent and much of the data is retrospective and/or cross-sectional, the majority of studies suggest an increased risk for vertebral fractures in patients with PHPT (117-123). Moreover, recent data indicates that many vertebral fractures are in fact clinically silent (118,124). The paradox of increased vertebral fracture risk despite preserved lumbar spine BMD in PHPT had remained unclear until the advent of TBS and HRpQCT, which clearly document trabecular deficits in addition to previously recognized cortical skeletal deterioration. Using the Danish National Patient registry and a nested case-control design, Ejlsmark-Svensson et al. recently showed that vertebral fractures in patients with PHPT occur at a higher BMD than in patients without PHPT, again pointing to the importance of other elements of bone quality in PHPT (125). In one recent study, among asymptomatic PHPT patients, only those who met surgical guidelines showed a higher incidence of vertebral fractures compared with controls (118).

The risk for hip fracture is not clearly increased in PHPT. In a study that focused on hip fracture, a population-based prospective analysis (mean of 17 years’ duration; 23,341 person years) showed women with PHPT in Sweden not to be at increased risk (126). The Mayo Clinic experience with PHPT and risk of fracture reviewed 407 cases of PHPT recognized during the 28-year period between 1965 and 1992 (117). Fracture risk was assessed by comparing fractures at a number of sites with numbers of fractures expected based on gender and age from the general population. The clinical presentation of these patients with PHPT was typical of the mild form of the disease, with the serum calcium being only modestly elevated at 10.9 ± 0.6 mg/dL. The data from this retrospective epidemiologic study indicate that overall fracture risk was significantly increased at many sites such as the vertebral spine, the distal forearm, the ribs, and the pelvis. There was no increase in hip fractures. One might expect to see an increased incidence of distal forearm fractures as seen in the May study, because the hyperparathyroid process tends to lead to a reduction of cortical bone (distal forearm) in preference to cancellous bone (vertebral spine). Unfortunately, there were no densitometric data provided in this study, so one could not relate bone density to fracture incidence.

The impact of PHPT on fracture incidence appears complex and may be site-specific. This relationship is likely influenced by site-specific changes in areal bone density, bone size, and microstructure. Excess PTH would induce cortical thinning due to endosteal bone resorption but would also increase periosteal apposition, thus increasing bone diameter. Decreased areal bone density would increase fracture risk, while increased bone diameter and preserved microstructure at certain sites, might protect against fractures. Prospective studies are needed to elucidate the site-specific risk of fracture in PHPT.

EVALUATION

The diagnosis of PHPT is confirmed by demonstrating an elevated or inappropriately normal PTH level in the face of hypercalcemia. Further biochemical assessment should include serum phosphorus, alkaline phosphatase activity, vitamin D metabolites, albumin, and creatinine. A morning 2-hour or 24-hour urine collection should be obtained for calcium and creatinine. A urinary bone resorption marker such as serum CTX or urinary N-telopeptide can be helpful. Bone densitometry is performed in all patients. It is important to obtain densitometry at three sites: the lumbar spine, the hip, and the distal third of the radius. Because of the differing amounts of cortical and cancellous bone at the three sites and the different effects of PTH on cortical and cancellous bone, measurement at all three sites gives the most accurate clinical assessment of skeletal involvement in PHPT. Bone biopsy is not routinely obtained in the evaluation of PHPT, but is essential in research. In the most recent guidelines, spinal imaging is recommended to assess for clinically silent vertebral fractures (137). This can be vertebral X-rays, vertebral fracture assessment or TBS score, the latter two obtained by the DXA image. While symptomatic kidney stones are present in 15% to 20% of patients by history, the finding that many more have clinically silent nephrolithiasis has led to the recommendation to obtain renal ultrasound, CT, or abdominal x-ray to assess for either nephrolithiasis or nephrocalcinosis.

NATURAL HISTORY

Since the early 1990s, new knowledge of the natural history of PHPT with or without surgery has been very helpful in guiding decisions regarding surgery in patients with asymptomatic PHPT. The authors and their colleagues have conducted the longest prospective observational trial (52,241). This project began in 1984 in an effort to define the natural history of asymptomatic PHPT. The study included detailed analyses of pathophysiologic, densitometric, histomorphometric, and other skeletal features of PHPT (52,241). Much of the information gleaned from that study has been summarized already in this chapter. The 15-year follow-up to this study constitutes the longest natural-history study of this disorder (241).

Recommendations for surgery or observation were made based on the 1990 set of National Institutes of Health guidelines, but both groups included patients who did or did not meet surgical guidelines. This is because some patients opted for surgery even if they did not meet the guidelines, whereas others opted for a conservative approach even if they did meet guidelines for surgery. As will be described in the following sections, this imperfect design was followed by three studies that were truly randomized but were of much shorter duration. The results with regard to natural history from all studies are remarkably concordant.

Natural History with Surgery

Successful parathyroidectomy results in permanent normalization of the serum calcium and PTH levels. Postoperatively, there is a marked improvement in BMD at all sites (lumbar spine, femoral neck, and distal one-third radius) amounting to gains greater than 10% (52) (Figure 3), The improvement is most rapid at the lumbar spine, followed by gains at the hip regions and the distal 1/3 radius during the 15-year follow-up (241). The improvements were seen in those who met and did not meet surgical criteria at study entry, confirming the salutary effect of parathyroidectomy in this regard on all patients.

Figure 3.

Improvement in bone density after parathyroid surgery. Data shown are the cumulative percentage changes from baseline over 15 years of follow-up in patients who underwent parathyroidectomy.

GUIDELINES FOR PARATHYROIDECTOMY

Parathyroidectomy remains the only currently available option to cure PHPT. As the disease profile has changed, questions have arisen concerning the advisability of surgery in asymptomatic patients. If asymptomatic patients have a benign natural history, the surgical alternative is not an attractive one. On the other hand, asymptomatic patients may display levels of hypercalcemia or hypercalciuria that cause concern for the future. Similarly, bone-mass measurements can be frankly low. In an effort to address such issues, there have been four consensus development conferences (in 1991, 2002, 2008, and 2013) on the management of asymptomatic PHPT (89,137,244-247). The most recent guidelines that emerged from the 2013 conference are helpful to the clinician faced with the asymptomatic hyperparathyroid patient: All symptomatic patients are advised to undergo parathyroidectomy. Surgery is advised in asymptomatic patients with (1) serum calcium greater than 1 mg/dL higher than the upper limit of normal; (2) renal guidelines: reduction in creatinine clearance to less than 60 mL/min; urinary calcium excretion >400 mg/24 h with increased stone risk; or presence of nephrolithiasis or nephrocalcinosis on renal imaging; (3) skeletal guidelines: reduced bone density T-score < –2.5 at any site; or vertebral compression fracture on an imaging study; and (4) age younger than 50 years. The most recent guidelines are shown in Table 5. A noteworthy change in the guidelines reflects the fact that asymptomatic kidney stones and vertebral compression fractures are now considered as indications for parathyroidectomy.

Table 5.

Comparison of New and Old Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidism

A number of points were discussed that did not lead to specific recommendations, including the issues of the neurocognitive and cardiovascular aspects of PHPT. The workshop panel also acknowledged a potential role of vitamin D deficiency in fueling processes associated with abnormal parathyroid glandular activity. Finally, the panel also reaffirmed the entity of normocalcemic PHPT, but noted that there are insufficient data to provide evidence-based guidelines for management.

SURGERY

A large percentage of those patients who meet the surgical guidelines listed in Table 5 are asymptomatic. Some asymptomatic patients who meet surgical guidelines elect not to have surgery for varying reasons including personal choice, intercurrent medical conditions, and previous unsuccessful parathyroid surgery. Conversely, there are patients who meet none of the NIH guidelines for parathyroidectomy but opt for surgery nevertheless. Physician and patient input remain important factors in the decision regarding parathyroid surgery.

MEDICAL MANAGEMENT

Patients who do not meet any surgical guidelines are often followed without intervention. The most recent guidelines for management of asymptomatic PHPT restated the position that it is reasonable to pursue a nonsurgical course of management for those who do not meet criteria for surgery, at least for a period of years. In those patients who are not going to have parathyroid surgery, the Workshop (137) suggested a set of monitoring steps that are summarized in Table 6. This includes annual measurements of the serum calcium concentration, a calculated creatinine clearance, and regular monitoring of BMD.

Table 6.

Comparison of New and Old Management Guidelines for Patients with Asymptomatic Primary Hyperparathyroidism Who Do Not Undergo Parathyroid Surgery

Ideal medical therapy of PHPT would provide the equivalent to a medical parathyroidectomy. Such an agent would normalize serum calcium and PTH levels as well as urinary calcium excretion, increase BMD and lower fracture risk, and reduce the risk of kidney stones. Unfortunately, no currently available single drug meets all these criteria. The following medications can achieve some of these goals and might be considered in patients not having surgery in whom it is desirable to lower serum or urinary calcium levels or increase BMD.

General Measures

Patients should be instructed to remain well hydrated and to avoid, if possible, medications that can increase serum calcium (e.g. thiazide diuretics). Prolonged immobilization, which can raise the serum calcium concentration further and induce hypercalciuria, should also be avoided.

DIET AND SUPPLEMENTS

Dietary management of PHPT has long been an area of controversy. Many patients are advised to limit their dietary calcium intake because of the hypercalcemia. However, it is well known that low dietary calcium can lead to increased PTH levels in normal individuals (268-270). In patients with PHPT, even though the abnormal PTH tissue is not as sensitive to slight perturbations in the circulating calcium concentration, it is still possible that PTH levels will rise when dietary calcium is tightly restricted. Conversely, diets enriched in calcium could suppress PTH levels in PHPT, as shown by Insogna et al (271). Dietary calcium could also be variably influenced by ambient levels of 1,25-dihydroxyvitamin d. In patients with normal levels of 1,25-dihydroxyvitamin d, Locker et al (272) noted no difference in urinary calcium excretion between those on high (1000 mg/day) and low (500 mg/day) calcium intake diets. On the other hand, in those with elevated levels of 1,25-dihydroxyvitamin d, high calcium diets were associated with worsening hypercalciuria. This observation suggests that dietary calcium intake in patients can be liberalized to 1000 mg/day if 1,25-dihydroxyvitamin d levels are not increased but should be more tightly controlled if 1,25-dihydroxyvitamin d levels are elevated. Although calcium supplements are not specifically recommended in those with PHPT and osteoporosis, small doses do not seem to exacerbate hypercalcemia or hypercalciuria if the diet is deficient (273). Most experts recommend that patients with PHPT who are going to be followed without surgery have an intake of calcium that is consistent with nutritional guidelines for a normal population.

Recent guidelines recommend maintaining 25-hydroxyvitamin D to levels of 21–30 ng/ml with conservative doses of vitamin D (600–1000 IU daily) based on data showing that vitamin D repletion lowers PTH levels (274). Higher levels of vitamin D might be beneficial. A 2014 RCT of cholecalciferol (2,800 IU daily versus placebo) indicated that treatment increased 25-hydroxyvitamin d levels from 20 ng/ml to 37.8 ng/ml, lowered levels of PTH, and increased lumbar spine BMD without having a deleterious effect on serum or urinary calcium levels (275).

PHARMACEUTICALS

Phosphate

Oral phosphate can lower the serum calcium by up to 1 mg/dL (276,277). A complex interplay of mechanisms leads to this moderating effect of oral phosphate. First, calcium absorption falls in the presence of intestinal phosphorus. Second, concomitant increases in serum phosphorus will tend to reduce circulating 1,25-dihydroxyvitamin d levels. Third, phosphate can be an antiresorptive agent. Finally, increased serum phosphorus reciprocally lowers serum calcium. Problems with oral phosphate include limited gastrointestinal tolerance, possible further increase in PTH levels, and the possibility of soft-tissue calcifications after long-term use. It is essentially not used any longer in the management of PHPT.

Estrogens and Selective Estrogen-Receptor Modulators

The earliest studies on the use of estrogen replacement therapy in PHPT date back to the early 1970s. A 0.5 to 1.0 mg/dL reduction in total serum calcium levels in postmenopausal women with PHPT who received estrogen was seen along with a lowering of urinary calcium (278,279). Most studies indicated no change in PTH (279-281). A randomized controlled trial of conjugated estrogen (0.625 mg daily plus medroxyprogesterone 5 mg daily) versus placebo indicated that hormone-replacement therapy effectively increases BMD at all skeletal sites in patients with PHPT, with the greatest increases at the lumbar spine (281). This randomized controlled trials, however, did not confirm the calcium-lowering effect of earlier uncontrolled studies (274). In view of concerns expressed about chronic estrogen use in the Women’s Health Study, estrogen use is not often recommended for medical management of hyperparathyroidism.

Raloxifene, a selective estrogen-receptor modulator, has been studied in PHPT, but the data are sparse. In a short-term (8-week) trial of 18 postmenopausal women, raloxifene (60 mg/day) was associated with a statistically significant although small (0.5 mg/dL) reduction in the serum calcium concentration and in markers of bone turnover (282). No long-term data or data on bone density are available.

Bisphosphonates and Denosumab

Bisphosphonates are conceptually attractive in PHPT because they are antiresorptive agents with an overall effect of reducing bone turnover. Although they do not affect PTH secretion directly, bisphosphonates could reduce serum and urinary calcium levels. Early studies with the first-generation bisphosphonates were disappointing. Etidronate has no effect (283). Clodronate use was associated in several studies with a reduction in serum and urinary calcium (284), but the effect was transient.

Alendronate has been studied most extensively in PHPT. Studies by Rossini et al (285) and Hassani et al (286) were followed by those of Chow et al (287), Parker et al (288), and Kahn et al (289). These studies were all characterized by a randomized, controlled design. Typically, BMD of the lumbar spine and hip regions increases along with reductions in bone turnover markers (Figure 4). Except for the study of Chow et al (287), serum calcium was unchanged. These results suggest that bisphosphonates may be useful in patients with low bone density in whom parathyroid surgery is not to be performed. One small study suggests that denosumab increases BMD in women with PHPT to a greater extent than patients without PHPT but with osteoporosis (290).

Figure 4.

The effect of alendronate on bone mineral density in primary hyperparathyroidism. With alendronate, bone mineral density increases significantly after 1 year, while the placebo group shows no change until it is crossed over to alendronate in year 2. (Modified from reference Khan AA, Bilezikian JP, Kung AWC, et al: Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:3319-3325).

Inhibition of Parathyroid Hormone

The most specific pharmacologic approach to PHPT is to inhibit the synthesis and secretion of PTH from the parathyroid glands, such as those that act on the parathyroid cell calcium-sensing receptor. This G protein–coupled receptor recognizes calcium as its cognate ligand (291-293). When activated by increased extracellular calcium, the calcium-sensing receptor signals the cell via a G protein–transducing pathway to raise the intracellular calcium concentration, which inhibits PTH secretion. Molecules that mimic the effect of extracellular calcium by altering the affinity of calcium for the receptor could activate this receptor and inhibit parathyroid cell function. The phenylalkylamine (R)-N(3-methoxy-a-phenylethyl)-3-(2-chlorophenyl)-1-propylamine (R-568) is one such calcimimetic compound. R-568 was found to increase cytoplasmic calcium and to reduce PTH secretion in vitro, as well as in normal postmenopausal women (294,295). This drug was also shown to inhibit PTH secretion in postmenopausal women with PHPT (296). A second-generation ligand, cinacalcet, has been the subject of more extensive investigations in PHPT and is now approved for the treatment of severe hypercalcemia in PHPT when surgery cannot be pursued. Studies conducted by the authors and their colleagues (297-299) indicate that this drug can reduce the serum calcium concentration to normal in PHPT, but despite normalization of the serum calcium concentration, PTH levels do not return to normal; they do fall by 35% to 50% after administration of the drug. Urinary calcium excretion does not change; serum phosphorus levels increase but are maintained in the lower range of normal; and 1,25-dihydroxyvitamin D levels do not change. The average BMD does not change, even after 5 years of administration of cinacalcet (300). Marcocci et al (299) have shown that cinacalcet is effective in subjects with intractable PHPT. Silverberg et al (301) have shown that cinacalcet reduces calcium levels effectively in inoperable parathyroid carcinoma.

Hydrochlorothiazide

Though avoiding agents that exacerbate hypercalcemia is generally recommended in patients with PHPT, a recent study has recently reexamined the role of thiazides in patients with PHPT. This retrospective analysis of 72 patients suggested that thiazides might not increase serum levels of calcium in PHPT as they can do in normal individuals. Hydrochlorothiazide (12.5–50 mg daily for 3.1 years on average) was associated with a decrease in urinary calcium excretion but no change in serum levels of calcium (302). Smaller and cross-sectional studies have suggested similar results, although it is unclear if hydrochlorothiazide reduces the risk of nephrolithiasis (303,304). Given the heterogeneity of doses used, and the absence of larger, (preferably) randomized trial data, recommending thiazide use routinely in PHPT is premature. However, thiazides could be considered in those who refuse surgery or are poor surgical candidates but at high risk of nephrolithiasis in whom the benefit is thought to outweigh the risk as long as serum levels of calcium are monitored regularly.

TREATMENT OF PARATHYROID CANCER

Surgery is the only effective therapy currently available for parathyroid cancer. The greatest chance for cure occurs with the first operation. After the disease recurs, cure is unlikely, although the disease may smolder for many years thereafter. The tumor is not radiosensitive, although there are isolated reports of tumor regression with localized radiation therapy. Traditional chemotherapeutic agents have not been useful. When metastasis occurs, isolated removal is an option, especially if only one or two nodules are found in the lung. Such isolated metastasectomies are never curative but they can lead to prolonged remissions, sometimes lasting for several years. Similarly, local debulking of tumor tissue in the neck can be palliative, although malignant tissue is invariably left behind.

Chemotherapy has had a very limited role in this disease. Bradwell and Harvey (305) have attempted an immunotherapeutic approach by injecting a patient who had severe hypercalcemia resulting from parathyroid cancer with antibodies raised to their own circulating PTH. Coincident with a rise in antibody titer to PTH, previously refractory hypercalcemia fell impressively. A more recent report (306) provided evidence of the antitumor effect in a single case of PTH immunization in metastatic parathyroid cancer.

Attention has been focused instead on control of hypercalcemia. Intravenous bisphosphonates have been used to treat severe hypercalcemia. Although efficacious in the short term, they do not provide an approach that allows long-term outpatient normalization of serum calcium levels. Denosumab has more recently been reported to treat resistant hypercalcemia in patients with parathyroid carcinoma (307,308).

The calcimimetic agents offer a newer approach. Our group (309) reported on a single patient treated with the calcimimetic, R-568; despite widely metastatic disease, the patient showed serum calcium levels that were maintained within a range that allowed him to return to normal functioning for nearly 2 years. A wider experience by Silverberg et al (301) showed that cinacalcet is useful in the management of parathyroid cancer. The U.S. Food and Drug Administration approved this calcimimetic for the treatment of hypercalcemia in patients with parathyroid cancer. Use of this agent in parathyroid cancer led to improvement in serum calcium levels and a decrease in symptoms of nausea, vomiting, and mental lethargy, which are common concomitants of marked hypercalcemia. There are no data on the effect of cinacalcet on tumor growth in parathyroid cancer. Similarly, there are no data on the use of a combination of cinacalcet and bisphosphonates in parathyroid cancer, the former used to decrease PTH secretion from the cancer, and the latter used to decrease release of calcium from the skeleton. Cinacalcet offers an option for control of intractable hypercalcemia when surgical removal of cancerous tissue is no longer an option.

SUMMARY

This chapter has presented a comprehensive summary of the modern-day presentation of PHPT. Typically, an asymptomatic disorder in countries that are economically more developed, the disorder’s presentation has raised issues regarding the extent to which such patients may nevertheless show subclinical target organ involvement, who should be recommended for parathyroid surgery, who can be safely followed without surgical intervention, as well as questions regarding the role of medical therapy. Questions about the natural history and pathophysiology of the disorder continue to be of great interest. Inasmuch as this disorder continues to evolve, it is clear that additional careful studies are required continually to gain new insights into this disease.

ACKNOWLEDGEMENTS

This work was supported in part by National Institutes of Health grants NIDDK 32333, DK084986, RR 00645, and R21DK104105. With permission, this chapter is adapted from:

Walker MD, Bilezikian JP. Primary hyperparathyroidism. IN: Endocrinology, 8^th edition (Jameson JL, Robertson P, eds) Saunders, Elsevier (in press), 2021.

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