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If the guidelines offered by the expert panel convened after the Workshop on Aymptomatic Primary Hyperparathyroidism are followed, about 40-50 percent of patients with primary hy- perparathyroidism in the United States will fit into the non-sur­gical, conservative management category. The natural history of this cohort indicates that over a 10-year period, patients in general are remarkably stable. The group data show that serum and urine biochemical parameters are stable. Simi­larly, in the majority of patients, bone mineral density is un­changed at lumbar spine, hip and distal radius after 10 years. When these data for the group as a whole are reviewed more closely, however, it is clear that some patients who are fol­lowed without surgery will show changes and thus meet criteria for surgery. In about 25 percent of these patients followed with­out surgery over 10 years, guidelines for surgery were met eventually by virtue of an increasing serum or urinary calcium or declining bone mineral density. The fact that an appre­ciable number of asymptomatic patients will progress to meet criteria for surgery emphasizes the need for all these patients to be monitored.

Monitoring asymptomatic patients who are not to undergo surgery

The Panel of the 2002 Workshop on Asymptomatic Primary Hyperparathyroidism recommended a plan for monitoring pa­tients who are not to undergo parathyroid surgery (Table II). The serum calcium measurement should be made every six months, while it is not considered necessary to monitor the uri­nary calcium excretion on a regular basis. Renal function can be monitored by the yearly serum creatinine concentration and the Cockcroft-Gault relationship. The panel emphasized the utility of measuring annually bone density at the lumbar spine, hip and distal 1/3 radius site.

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In the hands of an expert parathyroid surgeon, parathyroidec- tomy is a highly successful procedure with infrequent complica­tions. Both the classic approach of neck exploration, usually with efforts to examine all four parathyroid glands and the in­creasingly popular minimimally invasive parathyroidectomy that uses local rather than general anesthesia are associated with cure in over 95 percent of cases.

The minimally invasive procedure requires successful preoper­ative localization of the abnormal parathyroid gland and capa­bility to measure PTH rapidly in the operating room. Pre­operative blood is obtained for comparison of the PTH concen­tration with an intraoperative sample obtained minutes after re­moval of the “abnormal” parathyroid gland. If the level falls by more than 50 percent immediately following resection, the gland that has been removed is considered to be the sole source of overactive parathyroid tissue and the operation is ter­minated. If the PTH level does not fall by more than 50 per­cent, the operation is extended to a more traditional one in a search for other overactive parathyroid tissue. There is a risk (albeit small) that the minimally invasive procedure may miss other overactive gland(s) that are less active in the presence of a dominant gland. With advances in imaging technology and growing experience with minimally invasive parathyroid surgery, it is likely that these newer approaches will become more widely used.

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This discussion is focused entirely upon the patient with asymptomatic primary hyperparathyroidism. Patients with symptoms or signs such as fractures, renal stones and the classic neuromuscular manifestations of primary hyper- parathyroidism should have surgery. Since many patients, however, are not symptomatic, it is important to consider how best to treat these individuals. For example, it is quite reason­able to question the advisability of surgery in all patients with asymptomatic disease. Since many patients with primary hy- perparathyroidism are known to have the disease only be­cause an incidental serum calcium determination was ob­tained, it is possible the disease would have remained unrec­ognized without the serum calcium measurement. In fact, in their long-term natural history study of asymptomatic primary hyperparathyroidism, Silverberg and Bilezikian have shown that in some patients with asymptomatic primary hyper­parathyroidism, the course is benign. Given the observa­tion that some of these individuals do have an uneventful nat­ural history, non-surgical approaches would appear to be a reasonable alternative. On the other hand, some patients, al­though asymptomatic, may have levels of serum and/or uri­nary calcium that are sufficiently above normal to give concern as to the wisdom of following them long term. In these asymp­tomatic individuals, bone mineral density measurements that are low could be a clue that they are at increased fracture risk, especially given the uncertainty about the effects of PTH ex­cess on skeletal fragility.

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Although the incidence of nephrolithiasis is much less common than its incidence in the classic, older presentation of primary hyperparathyroidism, kidney stones remain the most common manifestation of primary hyperparathyroidism, with estimates placing the incidence of kidney stones now at 15 to 20 percent. Other renal manifestations of primary hyperparathy­roidism include hypercalciuria, which is seen in approximately 40 percent of patients, and nephrocalcinosis, the frequency of which is unknown.

Other organ involvement

Neurologic and cognitive signs or symptoms. Perhaps the most common nonspecific complaints of patients with primary hyper­parathyroidism are those of weakness and easy fatigability. These complaints do not reflect the classic neuromuscu­lar syndrome, in which type II muscle cell are dysfunctional.

In asymptomatic primary hyperparathyroidism, this specif­ic neuromuscular disorder is rarely seen. Nevertheless, the nonspecific complaints of patients in this regard are note­worthy. They often report some degree of constitutional, be­havioral and/or psychiatric symptomatology and, in some stud­ies, such symptoms have been documented by psychometric testing. Reports exist in which there is apparent improve­ment after successful parathyroid surgery, while others have not been able to document changes postoperatively. This issue remains unsettled.

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Skeletal manifestations

The demonstration of skeletal involvement in asymptomatic pri­mary hyperparathyroidism depends upon dual energy X-ray absorptiometry (DXA). Classical radiographic features are rarely seen. DXA shows classic pathophysiological effects of PTH in terms of a reduction in bone density of the distal third of the radius, a site of cortical bone. The proclivity of PTH to be catabolic for cortical bone is in constrast to its protective ef­fect on cancellous bone (Fig. 1). Thus, at a site enriched in cancellous bone, namely the lumbar spine, bone mineral den­sity tends to be reasonably normal. At a site that contains a more even admixture of cortical and cancellous elements, namely the hip region, bone mineral density is intermediate be­tween the cortical and cancellous sites. This pattern is seen not only in unselected cohorts of subjects with primary hyper­parathyroidism but also in postmenopausal women, in whom one might expect to see selective reductions in lumbar spine bone density because of the estrogen deficiency. Al­though this classic densitometric profile is most commonly seen, a distinctive pattern characterized by vertebral osteope­nia can also be detected at the time of diagnosis. Histomorphometric analysis of the bone biopsy in primary hy­perparathyroidism shows cortical thinning, maintenance of can­cellous bone volume, and accelerated bone remodeling. Other features emphasize the point that the cortical bone compartment is at risk in primary hyperparathyroidism. The biopsy studies have also shown that indices of trabecular con­nectivity are actually greater than expected. Even the expected age-dependent loss of cancellous bone is not seen in primary hyperparathyroidism. Based upon the densitomet­ric data, it might be expected that the cortical skeleton would be at greater risk than the cancellous skeleton for fracture. The data are conflicting, however, with some studies showing an in­crease and other studies no increase in incidence of vertebral fractures.

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Diagnosis

The diagnosis of primary hyperparathyroidism is generally very straightforward, even though there are many causes of hyper­calcemia. Since in primary hyperparathyroidism, parathyroid hormone (PTH) is oversecreted, a PTH immunoassay that reli­ably detects this increased PTH production is a cornerstone of diagnosis. PTH levels by currently available immunoradiomet- ric assay (IRMA) have the requisite sensitivity and specificity; they reveal PTH levels that are either frankly elevated or in the upper range of normal despite hypercalcemia. In malignancy, the other most common cause of hypercalcemia, the PTH level will be suppressed, even if the cause of the hypercalcemia in malignancy is parathyroid hormone related protein (PTHrP). The IRMA in general use in the United States for over 20 years, however, has recently been shown to detect not only the full-length amino acid molecule, but also amino terminal­ly truncated forms of PTH. Recent studies report a mixture of peptides similar in size to PTH but with three to 14 amino acids deleted from the amino terminus; PTH is the most prominent of these species. These forms consti­tute up to 50 percent of the circulating species of PTH in nor­mal subjects. In secondary hyperparathyroidism in renal failure and in primary hyperparathyroidism these forms consti­tute a higher percentage in the circulation than in normal sub­jects. An IRMA for PTH that measures only the biologi­cally active, full-length molecule [PTH] has become avail­able. The newer IRMA does not detect the large PTH fragment. It remains to be seen whether this newer assay will be shown to have more diagnostic utility in primary hyper­parathyroidism. Silverberg et al. compared this newer assay with the older IRMA and a mid-molecule-specific radioimmunoassay (RIA) in 56 subjects with primary hyper­parathyroidism. The newer assay was shown to be elevated in 96 percent of subjects as compared to 73 percent and 63 per­cent using the older IRMA and the RIA, respectively. However, in chronic renal failure and secondary hyperparathyroidism where the newer IRMA assays might be expected to more dis­criminant, results appear similar. The presumptive diagno­sis of primary hyperparathyroidism in subjects whose calcium and PTH levels are elevated has to take into account other sit­uations in which the serum calcium and PTH levels can be ele­vated. Drug-induced hypercalcemia due to lithium or thiazide diuretics is readily apparent because of the history. In familial hypocalciuric hypercalcemia (FHH), the PTH can also be ele­vated, but it is distinguished from primary hyperparathyroidism by family history and exceedingly low urinary calcium excre­tion. If needed in the management of families suspected of FHH, detection of a specific gene abnormality in the calcium receptor can be sought (see other article in this series). Although most patients with primary hyperparathyroidism have elevated serum calcium levels, a subgroup has been charac­terized with normal serum calcium levels. Patients with normocalcemic primary hyperparathyroidism are distinct from patients with primary hyperparathyroidism and abnormal PTH levels in whom the serum calcium level is intermittently elevated. The key consideration in this setting in which PTH levels are elevat­ed when the serum calcium is normal, however, is not primary hyperparathyroidism but secondary hyperparathyroidism in which the parathyroid glands are appropriately responding to a hypocalcemic stimulus. It is particularly important to rule out vit­amin D insufficiency because it is so common in the popula­tion. The initial descriptions of normocalcemic primary hyper- parathyroidism included a requirement that 25-hydroxyvitamin D (25(OH)D) levels had to be greater than 20 ng/ml. Maruani et al. and Silverberg and Bilezikian have described pa­tients in whom this situation exists. With a revision upwards in the definition of sufficient vitamin D levels, it is important to be sure that these patients are truly vitamin D sufficient. Vita­min D repletion to levels of 25(OH)D that are greater than 30 ng/ml without an alteration in the elevated PTH levels is neces­sary to sustain the diagnosis. Patients with normocalcemic pri­mary hyperparathyroidism may represent the earliest manifes­tations of primary hyperparathyroidism.

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One meta-analysis addressed the effect of vitamin D on the risk of falling in older persons. Based on 5 RCTs (n = 1237), vitamin D reduced the risk of falling by 22% (pooled cor­rected OR = 0.78; 95% CI [0.64, 0.92]) compared to calcium or placebo (10, 16, 20-22). Subgroup analyses suggested that the reduction in risk was independent of the type of vitamin D, du­ration of therapy, and gender. However, the results from one trial suggested that 400 IU of vitamin D may not be clinically ef­fective in preventing falls in the elderly, while two trials that used 800 IU of vitamin D per day plus calcium reduced the risk of falling. For the two trials with 259 subjects using 800 IU of cholecalciferol, the corrected pooled OR was 0.65 (95% CI [0.40, 1.00]). A recent double-blind RCT testing the long-term effect of 700 IU vitamin D plus 500 mg calcium com­pared to placebo confirmed a benefit on falls among communi­ty-dwelling older women (n = 246) with a 46% reduction in the odds of falling (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.30-0.97) (23). Fall reduction was most pronounced in less active women (OR, 0.35; 95% CI, 0.15-0.81), while the ef­fect in community-dwelling older men was neutral (OR, 0.93; 95% CI, 0.50-1.72, n = 199). The neutral effect in men maybe explained by higher physical activity and higher 25-hydroxyvit- amin D [25(OH)D] levels among men in this trial compared to women.

Furthermore, the data suggested a possible benefit of vitamin D on the risk of falling among less active men. A threshold for optimal 25(OH)D and lower extremity function has been addressed recently examining the association between serum 25(OH)D levels and lower-extremity function in NHANES III including 4100 ambulatory older adults. Func­tional assessment included the 8-foot-walk test and sit-to-stand test. Both tests depend on lower extremity strength, and mirror functions needed in everyday life. For the 8-foot walk test, compared to the lowest quintile of 25(OH)D, the highest quintile showed an average decrease by 5.6% (test for trend: p < 0.001). For the sit-to-stand test, compared to the lowest quintile of 25(OH)D the highest quintile showed an aver­age decrease by 3.9% (test for trend: p = 0.017). In the regression plots of the NHANES III analysis, perfor­mance speed continued to increase throughout the reference range of 25(OH)D (22.5 to 94 nmol/l) with most of the improve­ment occurring in 25(OH)D levels going from 22.5 to approxi­mately 40 nmol/l. Further improvement was seen in the range of 40-94 nmol. These results were similar for subgroups of active and inactive individuals, men and women, three eth­nic groups (Caucasians, African Americans and Mexican Americans), and persons with higher (> 500 mg/day) and lower calcium intakes ( 500 mg/day).

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