JOURNAL OF BONE AND MINERAL RESEARCH Volume 6, Supplement 2, 1991 Mary Ann Liebert, Inc., Publishers

Discussion Section V

Panel Members: Robert Marcus, M.D., Ph.D., Elizabeth Shane, M.D., Orlo H. Clark, M.D., and Samuel A. Wells, Jr., M.D.

R. COBURN asked whether there might be specific D drugs, particularly calcium channel blockers, that would be more efficacious in the management of hyperten- sion associated with primary hyperparathyroidism. Dr. Shane replied that any hypertensive patient with primary hyperparathyroidism should have appropriate therapy but that there is no special advantage to using calcium channel blockers. Dr. Marcus added that hypertensive patients given estrogen may require a modest change in their dos- age of antihypertensive medication. Dr. Coburn empha- sized that the reason for being particularly diligent in the treatment of a hypertensive hyperparathyroid patient is the dual risk of progression of a mild renal disease due to the elevated diastolic pressure as well as the hyperparathyroid- ism.

Dr. Ackerman asked Dr. Shane if she was using estro- gens or etidronate or both in her patients with asympto- matic hyperparathyroidism. Dr. Shane reviewed her ap- proach, which is to use estrogens if she thinks patients are reasonable candidates for this form of therapy. In general, however, if a patient needs to have calcium lowered, sur- gery is a more attractive alternative. Dr. Ackerman pointed out that such agents as estrogens or etidronate may be indicated with respect to the hyperparathyroid pro- cess in bone, especially in postmenopausal woman. Dr. Marcus has approximately 25 patients in addition to the 14 he formerly studied who are being followed long term on estrogen replacement therapy. He said that the lumbar spine densities in these patients as followed either by quan- titative CT or by dual-energy x-ray absorptiometry ap- peared to be stable for as long as 5 years. He did not have any data to report on hip density. Dr. Marcus noted data presented at the ASBMR meeting in August 1990 by Dr. Gallagher showing that standard estrogen replacement doses of 0.625 mg may not be adequate to protect against bone loss at the hip.

Dr. Raisz asked if Dr. Marcus reduces the dose of estro- gen from 1.25 to 0.625 mg in those who respond. In Dr. Marcus’ experience, the serum and urine calcium both in- crease somewhat if the estrogen dose is lowered from 1.25 to 0.625 mg. Dr. Marcus added that another important ob- jective of estrogen therapy is to protect against ischemic heart disease. There is no evidence that the serum or urine calcium must be fully controlled to achieve this objective.

In fact, epidemiologic studies are based primarily on the dose of 0.625 mg or its equivalent.

Finally, Dr. Shane said that she had not used etidronate in patients with primary hyperparathyroidism. The poten- tial effect of etidronate to inhibit bone mineralization has dampened enthusiasm for this agent in this disease.

Drs. Clark and Wells then focused upon surgery for pri- mary hyperparathyroidism. First, Dr. Potts clarified com- ments made earlier about the level of calcium above which one would be inclined to operate. One certainly does not have to wait until the calcium reaches 12 mg’dl before op- erating. Dr. Raisz asked Dr. Clark to expand on his com- ment that the profile of psychological symptoms was dif- ferent in hyperthyroidism and hyperparathyroidism. Dr. Clark pointed out that one of his control groups was not hyperthyroid patients but patients with nontoxic goiter or solitary thyroid nodules. He agreed that psychological problems can be present in patients with hyperthyroidism. He said that control groups are difficult to study because nonspecific symptoms can occur independent of whether they have a disease.

Dr. Hui asked Dr. Wells about the paucity of control groups in the surgical literature. She wanted to know how one could rule out a placebo effect. Dr. Wells agreed it is difficult to interpret studies in which patients are evaluated pre- and postoperatively. He thought that the only way to accomplish the task would be to take an age-matched group of patients who underwent an operation other than parathyroidectomy and to follow them for a similar period of time. Few studies in the literature include such control groups.

Dr. Bone emphasized the importance of the excellent re- sults of surgery performed in the hands of expert surgeons and thought it may be appropriate for the panel to recom- mend that parathyroidectomy be performed only by exper- ienced surgeons who perform the operation regularly. Dr. Purnell strongly agreed with Dr. Bone’s comment and added a comment on cardiovascular mortality in hyper- parathyroidism. Of the 142 patients in the Mayo Clinic study, 12 of 36 unoperated patients died. At that time, in the mid-l970s, this mortality, compared with age- and sex- matched control subjects, was not thought to be signifi- cant. Dr. Clark cited several European studies and one by Reinhoff in the United States that suggest that patients

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with hyperparathyroidism have a higher death rate, but that this seems to be altered by successful parathyroidec- tomy. This issue needs further investigation.

Dr. Palmieri emphasized a point made by Dr. Clark about the relative importance of the serum calcium. Since parathyroid hormone affects calcium transport, the neuro- muscular manifestations of hyperparathyroidism may be due to intracellular calcium accumulation, resulting in cell damage. Thus, the actions of parathyroid hormone at the cellular level may be more important than the extracellular calcium concentration per se.

Dr. Barker asked what factors affect surgical results, in- cluding single- versus multiple-gland disease. Dr. Wells re- plied that he did not think that success depended upon whether patients had mild or severe disease. Most surgical investigators have documented success rates above 90- 95%. Patients with multiple-gland disease d o less well than patients with single-gland disease. The recurrence rate of hypercalcemia in four-gland disease ranges from 25 to 50%. Dr. Wells thought that there is not a good operation for multiple-gland disease. He added that if patients are followed long enough, especially with MEN-I syndrome, recurrent hypercalcemia may be as high as 8O-90%. Even patients with two- and three-gland disease have higher re- currence rates.

Dr. Potts asked how important was the expertise and ex- perience of the operating surgeon in the overall result. Dr. Clark emphasized the dilemma by stating “you need an ex- perienced surgeon” and questioning, “how d o you become an experienced surgeon?” Dr. Clark thought that endo- crine surgery was not exceedingly difficult if you under- stood the disease process and had been trained by someone who was experienced in the field, and that one can learn how to d o endocrine surgery without having to put pa-

tients at a disadvantage. As a curious and perhaps ironic note, he said that preoperative localization studies may have led to more failed cases in this country. An inexperi- enced surgeon is likely to think, “we know where the hot spot is; we’ll just go take it out.” If localization tests were so reliable, this approach would be fine, but they are not.

Dr. Nussbaum asked about selection bias. Since the re- ferral pattern is likely to be through internists or endocri- nologists, a surgical experience is likely to be weighted in favor of patients with signs or symptoms of hyperparathy- roidism, and studies from these populations may show more impressive benefit from surgery. Dr. Wells agreed that there was probably some selection in surgical series.

Dr. Parfitt alluded to data presented by Dr. Melton that 10,OOO parathyroid operations are currently performed in the United States each year. If the incidence rates are accu- rate, and if all patients were to undergo parathyroid sur- gery, Dr. Parfitt estimated an increase to approximately 100,OOO operations per year. He asked whether those addi- tional 90,OOO operations would be carried out by members of the American Association of Endocrine Surgeons. Dr. Wells said that members of the American Association of Endocrine Surgeons perform a large number of parathy- roidectomies but most parathyroid surgery is performed by general surgeons and that there are some excellent sur- geons who d o not belong to that society.

Dr. Neer commented on long-term improvement in understanding hyperparathyroidism and suggested that it would be desirable to compare the effects of surgical inter- vention with no treatment or treatment with a bisphospho- nate in asymptomatic patients in a prospective clinical trial. Dr. Wells did not think there was any other way to solve the problem than a prospective randomized trial but did not know what would be the appropriate medical arm.