To Treat or Not To Treat: Conclusions from the NIH Consensus Conferencea

Shonni J. Silverberg, John P. Bilezikian, Henry G. Bone, Gary B. Talpos, Mara J. Horwitz and Andrew F. Stewart

College of Physicians and Surgeons Columbia University New York, New York 10032


    Introduction
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 Introduction
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 To Treat Not To...
 The Future
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PARATHYROIDECTOMY remains the appropriate therapy for primary hyperparathyroidism when it presents as the syptomatic disease first described in the 1930’s. In the United States today, however, this classical form of primary hyperparathyroidism is rarely seen. Instead, we typically see a disorder that is asymptomatic in 80% of cases. Even in patients with "symptomatic" primary hyperparathyroidism (most often characterized by nephrolithiasis), marked hypercalcemia and overt skeletal involvement (osteitis fibrosa cystica) are uncommon. The evolution of primary hyperparathyroidism from a disabling disease to a largely asymptomatic one has led to uncertainty regarding appropriate therapy for this disorder. This, in turn, led in 1990 to a National Institutes of Health-sponsored Consensus Development Conference, which concluded that there were categories of patients over the age of 50 yr who can be safely followed without surgery. Since then, that view has been challenged and reports favoring surgery in all patients have appeared. We present the view, held by many, that although parathyroidectomy remains the only definitive therapy for primary hyperparathyroidism, surgical intervention is not necessary in all patients. The reasons for this view will be summarized.


    Clinical Presentation of Primary Hyperparathyroidism
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 Introduction
 Clinical Presentation of Primary...
 To Treat Not To...
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Classical primary hyperparathyroidism was formerly associated with nephrolithiasis in over one half of cases, and the bone disease, osteitis fibrosa cystica, in approximately one quarter. The latter, characterized by bone cysts and brown tumors of the long bones, subperiosteal resorption of the distal phalanges and clavicles, and "salt and pepper" demineralization of the skull, was easily detected by x-ray. Today, kidney stones are seen in fewer than 20% of patients with primary hyperparathyroidism. Even more drastic reductions have been noted in the incidence of osteitis fibrosa cystica, which is seen in less than 5% of patients. The clinical presentation of primary hyperparathyroidism has evolved from a symptomatic to an asymptomatic disorder.

Patients with primary hyperparathyroidism today present most commonly with mild elevations of the serum calcium concentration along with increased parathyroid hormone levels. With the more sensitive assays based on double antibody methods (immunoradiometric [IRMA] and immunochemiluminescent [ICMA] assays), parathyroid hormone levels are frankly elevated in 85–90% of patients with primary hyperparathyroidism. Even in patients whose parathyroid hormone levels are "normal," they are clearly inappropriate to the setting of hypercalcemia in which the parathyroid glands should be suppressed. In this era of cost consciousness, the immunoassay for parathyroid hormone is the standard diagnostic test in this disorder. Other biochemical characteristics are less important for their diagnostic value. Serum phosphorus concentration is generally in the lower range of normal (frankly low in only one quarter of all patients); urinary calcium excretion is in the higher range of normal (elevated in approximately 40%). Vitamin D concentrations tend to reflect the physiological actions of parathyroid hormone, which is to facilitate the renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. 25-hydroxyvitamin D levels tend to be in the lower end of the normal range, while 1,25-dihydroxyvitamin D levels are in the higher range of normal. Frank elevations of 1,25-dihydroxyvitamin D are found in one third of patients.

While osteitis fibrosa cystica is a rarity, there is ample evidence of skeletal involvement in patients with modern primary hyperparathyroidism. Biochemical markers of bone formation such as serum alkaline phosphatase activity and osteocalcin, and urinary markers of bone resorption such as hydroxypyridinium crosslinks of collagen, are typically increased. Bone densitometry at sites containing different amounts of cortical and cancellous bone shows the two skeletal compartments to be differently affected in primary hyperparathyroidism. Consistent with the proclivity of parathyroid hormone to be catabolic at endocortical bone surfaces, bone mass is diminished at the more highly cortical radius (distal one-third site). Conversely, bone mass is preserved at the mainly cancellous lumbar spine, consistent with anabolic properties of parathyroid hormone in cancellous bone. The femoral neck site, intermediate in composition between cortical and cancellous elements, is also intermediate in bone density as compared to the forearm and the spine. This profile of selective cortical involvement is also seen in the postmenopausal women who make up at least one half of all patients with primary hyperparathyroidism. This finding is of particular interest in view of the influence of menopause (i.e. estrogen deficiency) on diminishing bone density at cancellous sites. In this setting, therefore, the effects of parathyroid hormone on the skeleton appear to prevail over those of estrogen deficiency. These data have been confirmed on detailed histomorphometric analyses, which show cortical thinning and increased trabecular bone volume. Trabecular plates are more numerous, thinner, better connected, and are more closely spaced in primary hyperparathyroidism. It might be inferred that the clinical sequelae of these observations would translate into reduced vertebral fracture incidence, but no studies with sufficient numbers of patients have yet been conducted to confirm this expectation.

The involvement of organ systems other than the skeleton and the kidneys in modern day primary hyperparathyroidism has received less attention. The classic neuromuscular syndrome of primary hyperparathyroidism, with its attendant potential for myopathy, has virtually disappeared. A poorly characterized sense of weakness and easy fatigability, reported by a substantial number of patients, is clearly not related to classical neuromuscular disease. It has been difficult to quantitate such subjective reports, and no studies have clearly shown that they are pathophysiologically linked to primary hyperparathyroidism. Subjective improvement after parathyroidectomy may reflect features of the intervention (i.e. attention of the surgeon, relief of anxiety over surgery) rather than the curative effect of parathyroidectomy per se. Moreover, it is not clear that patients are consistently improved in this regard after successful parathyroid surgery. Other associated disorders, such as hypertension, peptic ulcer disease, gout and pseudogout, and depression, have been associated with primary hyperparathyroidism. But like the nonspecific weakness and easy fatigability, it is not clear that these disorders are associated with primary hyperparathyroidism more often than one would expect common disorders to be associated with each other. In addition, they too do not clearly improve following surgery.

It is generally agreed that, for the approximately 20–25% of patients who exhibit signs or symptoms of primary hyperparathyroidism, parathyroidectomy is indicated. This figure includes those with nephrolithiasis, as well as the unusual patient with osteitis fibrosa cystica, or classical neuromuscular symptoms of primary hyperparathyroidism. The National Institutes of Health Consensus Conference on the management of asymptomatic primary hyperparathyroidism addressed issues related to who among the asymptomatic should undergo parathyroid surgery. Identified as important risk factors for progressive disease were: significant hypercalcemia (>12 mg/dL), marked hypercalciuria (>400 mg/day) or unexplained renal insufficiency, or an episode of acute primary hyperparathyroidism. Included also on this list of recommendations for surgery were reduced cortical bone density (>2 SD below age-matched norms, as measured at the distal forearm, 1/3 site). Also those who are relatively young (less than 50 yr) were considered candidates for parathyroidectomy.


    To Treat Not To Treat: New Data 1990–1998. Persistent Controversy
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Recent interest has focused on identifying which patients with asymptomatic primary hyperparathyroidism can be safely followed without surgery. It is important to identify two groups of asymptomatic patients in this regard. First, there are patients who are at risk for complications of the disease and who thus would benefit from surgical intervention and cure. Second, there are patients with few or no risk factors for progression of their disease. This second group might be expected to do well with long-term conservative management without surgery. Much of the available information that addresses these questions is from an ongoing longitudinal study led by two of us (J.P.B., S.J.S.), sponsored by the National Institutes of Health.

If one applies National Institutes of Health Consensus Conference guidelines, as we have to our patients with primary hyperparathyroidism, the percentage of patients who are surgical candidates increases from the 20% who are symptomatic, to approximately one half of all patients with the diagnosis of primary hyperparathyroidism. Thus, about two-thirds of patients who are surgical candidates are asymptomatic. Surgery leads to restoration of normal serum calcium, as well as to normalization of all other biochemical indices, including parathyroid hormone levels and markers of bone turnover. In addition, bone mineral density increases, particularly at the lumbar spine and femoral neck, where a mean rise of 12% in bone mass is seen after parathyroidectomy.

Over the past decade we have recognized several additional groups of patients who may benefit from parathyroidectomy. Individuals who have vertebral osteopenia at the time of presentation constitute one such group. This is an unusual presentation because of the tendency of parathyroid hormone to preserve cancellous bone. Nevertheless, primary hyperparathyroidism can affect cancellous sites as well as cortical sites. In addition, menopausal women can have other reasons for experiencing vertebral bone loss. Longitudinal follow-up of these patients with vertebral osteopenia reveals dramatic improvement (up to 20%) in bone density after parathyroidectomy.

Consideration of parathyroidectomy should also be given to patients with primary hyperparathyroidism who are vitamin D deficient. Vitamin D deficiency may be associated with a worsening of primary hyperparathyroidism due to loss of the regulatory effects of 1,25-dihydroxyvitamin D on the parathyroid hormone gene. Efforts to correct this deficiency by vitamin D replacement in the face hypercalcemia and/or hypercalciuria can be risky. Parathyroidectomy becomes a more attractive option in such cases. Finally, preliminary data indicate that parathyroidectomy may protect women from perimenopausal bone loss that seems to accelerate, despite the presence of parathyroid hormone, at this time. If confirmed, this would support consideration of surgery in perimenopausal women with primary hyperparathy-roidism.

The clear benefit derived by patients who undergo parathyroidectomy raises some important questions. Can one be sure that patients who do not meet surgical guidelines are unharmed without surgery? Earlier data supporting an increase in cardiovascular mortality and recent reports from Steffenelli et al. on cardiac calcificatition in primary hyperparathyroidism must be considered. The increase in valvular and left ventricular calcification, along with septal and left ventricular hypertrophy seen in these patients, is not applicable to patients typically seen in the United States, where the disease is less severe than in those patients reported by Stefanelli et al. With regard to reports of increased overall mortality with cardiovascular etiologies assuming a prominent role, the recent study of Wermers et al. clearly dispells that notion. In this study of all residents of Rochester, Minnesota diagnosed with primary hyperparathyroidism between 1965 and 1992, many patients with mild hypercalcemia were observed with no intervention, thus allowing an assessment of risk of death. In this cohort, there was no evidence that primary hyperparathyroidism had any adverse effect on survival.

Data from our group and others show that biochemical and bone densitometric indices of primary hyperparathyroidism in asymptomatic patients who do not meet any guidelines for surgery are stable, in general, with up to a decade of observation. This suggests that those with very mild disease (i.e. serum calcium <1 mg/dL above normal, normal urinary calcium, and adequate bone density) can be followed safely.

While the population of patients with mild asymptomatic primary hyperparathyroidism can be safely followed without intervention, close follow-up is essential. Individual patients can have worsening hypercalciuria, and in a small percentage of patients, bone density may decrease over time. All patients should be evaluated at least twice yearly, including serum calcium levels. Urinary calcium excretion and bone mineral density should be assessed annually.

Patients who are followed without parathyroidectomy should also adhere to certain general medical principles. They must remain well hydrated and avoid immobilization. They should avoid thiazide diuretics, which can lead to further increases in serum calcium. There is no evidence that restricting dietary calcium intake has any effect on serum calcium levels in patients with primary hyperparathyroidism. Indeed, there is concern that low dietary calcium intake can be associated with further stimulation of the hyperparathyroid state. In a study of 71 patients with primary hyperparathyroidism, dietary calcium had no effect on serum calcium or parathyroid hormone levels, urinary calcium excretion, or bone mineral density at any site. However, concern about hypercalciuria in the subset of patients with frankly elevated levels of 1,25-dihydroxyvitamin D has led to the recommendation that standard recommendations for calcium intake (1200 mg daily in postmenopausal women) be reserved for patients with primary hyperparathyroidism whose levels of 1,25-dihydroxyvitamin D are normal.

At this time, options for management have been surgery or no surgery. Are there pharmacological approaches to patients with primary hyperparathyroidism? The use of oral phosphate has been limited by its lack of efficacy, risk of metastatic calcification, and gastrointestinal intolerance. Estrogen is useful in postmenopausal women with very mild primary hyperparathyroidism by lowering serum calcium by approximately 0.5 mg/dL, but estrogen has no effect on parathyroid hormone levels. There are no data on the effectiveness of Selective Estogen Receptor Modulators (such as raloxifene) on serum calcium or parathyroid hormone levels in this disorder. Bisphosphonates, such as etidronate and dichloromethylene diphosphonate, have not been useful in this disorder, and alendronate has not yet been evaluated systematically.

To date, there is no available medical therapy that specifically targets the abnormality in primary hyperparathyroidism, namely, hypersecretion of parathyroid hormone. The identification of molecules that act as calcium receptor-agonists in parathyroid cells has led to the development of a means of regulating hormone secretion from these cells. By mimicking the effect of extracellular calcium, these agents inhibit the secretion of parathyoid hormone. One such calcimimetic agent, R-568, has been studied in postmenopausal women with primary hyperparathyroidism. Administration of R-568 led to a decrease in both parathyroid hormone and serum calcium levels. This class of compounds holds significant promise for the future.


    The Future
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 Introduction
 Clinical Presentation of Primary...
 To Treat Not To...
 The Future
 References
 
When asymptomatic primary hyperparathyroidism was first recognized as a common condition nearly three decades ago, there was speculation, but no data, about the need for parathyroidectomy in this group. Although we now feel that it is safe to follow certain patients with mild disease, our knowledge remains incomplete. Longitudinal data are needed to allow a more complete understanding of which patients do or do not benefit from parathyroidectomy. Finally, the emerging importance of targeted and specific therapeutic agents for the treatment of primary hyperparathyroidism will raise new questions about the exclusive role of surgery as the only definitive way to treat this common endocrine disorder.


    Footnotes
 
Address all correspondence regarding these controversies and requests for reprints to: John P. Bilezikian, Department of Medicine, Columbus University College of Physicians and Surgeons, 630 W. 168th Street, PH-8 West, New York, New York 10032.

This work was supported in part by NIH Grants NIDDK 32333 and RR 00645.

Accepted March 9, 1999.


    References
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 Introduction
 Clinical Presentation of Primary...
 To Treat Not To...
 The Future
 References
 

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