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Overview and Summary^c

Division of Endocrinology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15213

	Introduction

Top Introduction

 
THE MORE one learns, the more questions arise. The greater the precision with which one can ask questions, the more numerous and more subtle the questions become. The greater the amount of information accrued, the less useful are the broad guidelines to which we have adhered in the past. Or are they? These are the issues raised in the two position papers in this "Therapeutic Controversy" section of JCE&M.

It is now almost a full decade since the 1990 National Institutes of Health Consensus Conference on the evaluation and management of primary hyperparathyroidism. Those of us "in the trenches" trying to formulate optimal recommendations and treatment plans for our patients with primary hyperparathyroidism were never particularly satisfied with the Consensus Statement recommendations. Perhaps most disconcerting was the recommendation that the primary physician should use his or her own discretion in the most difficult patients who, of course, comprise the majority of affected patients we encounter. To be fair to the Consensus conferees, the Conference was held at the dawn of evidence-based or outcome-based medicine, and many of the important questions that needed to be answered simply could not be answered on the basis of data available in 1990. Moreover, many of the sensitive and reliable tools that were needed to fully and unequivocally evaluate patients with primary hyperparathyroidism were not available. During the decades of the 70’s and 80’s, we did not have access to sensitive and specific tools for investigating mineral metabolism that we now take for granted.

We don’t often reflect on the events that have overtaken a field over the course of a given decade. In the case of primary hyperparathyroidism, investigators and clinicians in this field might be rather astonished by the list of cumulative advances in the field over the past ten years. This remarkable decade has seen widespread application of sensitive and specific two-site PTH immunoassays, widespread use of high-precision bone densitometry techniques, and the unfolding of large scale clinical trials using vertebral and hip fractures as primary endpoints (in osteoporosis, not hyperparathyroidism). We have seen the cloning of the PTH/PTHrP receptor, and we have learned that it is expressed in almost every organ. We have seen the consequences of ablation of the PTH receptor (horrendous) or of PTH itself (not so bad) in gene "knockout" mice. Transgenic models of parathyroid adenoma/hyperplasia in mice have been developed and studied. We have seen the identification of a series of parathyroid adenoma/hyperplasia/carcinoma-associated oncogenes and tumor suppressor genes such as PRAD, ret, menin, p53, and Rb, and others. This decade has seen the cloning and characterization of the calcium-sensing receptor, the cell surface receptor that recognizes ambient calcium concentrations and thereby modulates parathyroid hormone secretion. We have learned an immense amount about parathyroid regulation and function at the cellular level.

There have been impressive accomplishments in the pharmaceutical arena over the past decade. New pharmaceuticals that may impact heavily on the management of primary hyperparathyroidsim have been developed and are now widely available. These include the newer generation bisphosphonates, such as alendronate, and the selective estrogen receptor modifiers (SERMs), such as raloxifene, with others to come. The discovery of the calcium sensor or receptor coincided with the unveiling of a new class of calcium receptor-targeted drugs that can either increase or decrease PTH secretion. Perhaps most surprisingly, after we had all learned that excessive concentrations of parathyroid hormone were bad for your skeleton, this decade has seen the rebirth of PTH as a therapeutic agent in osteoporosis: many companies currently have PTH or closely related compounds in late-phase clinical trials, and the results are impressive: one recent study reveals a near 35% increase in vertebral bone density after treatment with PTH for glucocorticoid-induced osteoporosis. We still have no clear idea at the cellular level as to how PTH can be at once both harmful and beneficial for the skeleton.

We have learned much in the areas of diagnostic imaging, bone histomorphometry, and epidemiology as they relate to primary hyperparathyroidism. Studies reported recently have shown that parathyroid adenomas can be readily localized using technetium-sestamibi imaging. Other studies have shown that parathyroidectomy in patients with hyperparathyroidism results in very substantial increases in bone density. On the other hand, other studies show that not operating on patients with mild hyperparathyroidism results in stable bone denisty. It is not clear which of these two outcomes will prove to be superior over the long term. Moreover, even if bone density declines at cortical sites with PTH treatment for osteoporosis, it is not a forgone conclusion that this is a negative outcome: PTH treatment in laboratory animals increases the number of struts and connections among trabeculae in bone and has been associated with increased bone tensile strength. Thus, even if bone density declines in trabecular or cortical sites, this is not necessarily an adverse outcome if the residual bone is of higher tensile strength. These considerations, of course, raise the issue of fracture incidence in primary hyperparathyroidism—do people with primary hyperparathyroidism have a higher than normal risk of vertebral, hip, or other fracture? Studies on sufficiently large populations are just beginning to accrue.

While these rather astonishing accomplishments have occurred, other things have not changed. Hyperparathyroidism is still common, although a recent study suggests that the incidence of primary hyperparathyroidism may be declining. In terms of soft surgical indications, while most investigators and clinicians agree on the negative "stone" and "bone" complications of primary hyperparathyroidism, we still argue over whether the "groan" features of hyperparathyroidism can truly be attributed to the disease. Silverberg et al. say "maybe no", while Bone would appear to argue "maybe yes".

The pace of investigation and access to research funding have increased markedly. During the past decade, funding by the National Institutes of Health for skeletal research has increased by a factor of approximately ten. Congress, women’s groups, densitometry companies, pharmaceutical companies, the lay press, and our patients are forcing scientists and clinical investigators to ask the difficult, large-scale outcome questions, and vitamin suppliers and health food product makers have jumped on the "bone health" bandwagon. Perhaps to the surprise of younger investigators and physicians, it was not always like this—widespread interest in bone health is a relatively new phenomenon.

So, at the conclusion of the decade that has passed since the last NIH Consensus Conference, where do we now stand with respect to optimal evaluation and management of primary hyperparathyroidism? We think it is time for two major events to occur, perhaps separately, perhaps together. First, we now have guidelines, endorsed by the National Osteoporosis Foundation (NOF) and by the American Society for Bone and Mineral Research Society (ASBMR), for the evaluation and management of postmenopausal osteoporosis. It is time to do the same for primary hyperparathyroidism.

Second, it is time for a new millennial NIH Consensus Conference with four goals in mind:

1. Develop Diagnosis and Treatment Guidelines. The Consensus Conferees should make another attempt at developing useful evaluation and management guidelines, as suggested above.
   
2. Provide Definition and Focus. The Conference should focus on the compelling questions that need to be answered in the current era. In our minds, some of these questions should be definitional, some operational, and some investigational: What exactly will the criteria be for asymptomatic vs. symptomatic primary hyperparathyroidism in the new millennium? Can we finally put to rest the arguments relating to peptic ulcer disease, hypertension, pancreatitis, marrow suppression, diabetes, and subtle mental changes as indications for surgery? If not, which of these should be studied and how? Which assays for PTH are best? Who should have bone mineral density measurements, and how often should they be performed if surgery is or is not performed? Is the under-50-yr-old cutoff still applicable? And what really are the risks of surgery—minimal (as Bone would have us believe), or more substantial (as our patients who would gladly trade their vocal cord paralysis for a 0.5% decrement in bone mineral density might advocate)? Are we ready for genetic testing in any forms of primary hyperparathyroidism such as the MEN syndromes or familial hypocalciuric hypercalcemic syndromes? And how does PTH increase or decrease bone mass and strength at the cellular level? Are there pharmacologic or gene therapeutic strategies that might be used to advantage in primary hyperparathyroidism, to take advantage of the osteoblastic, anabolic effects of PTH, while minimizing the osteoclastic, catabolic effects? Most importantly, perhaps, is it time for a multicenter large-scale trial to assess the risk of fracture and overall mortality in subjects with mild, subtle, or asymptomatic primary hyperparathyroidism?
   
3. Managed Care and Resource Allocation. The Consensus Conference could evaluate the data and guide the physician and patient through the confusing roadmap of managed care. Not surprisingly, a recent study reports that surgeons who have the most experience with parathyroid surgery generate the best outcomes. Yet, at the same time, managed care providers are modifying and controlling our referral channels. Should patients with hyperparathyroidism be steered by a primary physician to the surgeon recommended by the local health plan, or should the patient have access to a smaller number of highly skilled and experienced parathyroid surgeons? Or should certain patients be referred to an experienced parathyroid surgeon and others not? What will be the criteria for defining "the experienced parathyroid surgeon"? And, if only a cadre of approved parathyroid surgeons are permitted to do the surgery, how will others be trained and gain the obligate surgical training and experience? The Consensus Concerence should also provide guidance as to whether patients with suspected or documented primary hyperparathyroidism should be routinely referred to an endocrinologist. Should every patient see a specialist who is conversant with the issues raised above, and what are the economic consequences? Cost issues and technology deployment need to be addressed as they relate to measurements of bone mineral density in primary hyperparathyroidism, both pre- and post-op. What techniques and sites are optimal? How low is low enough to be a clear indication for surgery? And how often should it be measured post-op? Or if patients are not referred to surgery, what is the optimal management in terms of bone mineral density follow-up, serum creatinine, calcium and PTH determinations, and urinary calcium measurements? Similar issues pertain to PTH immunoassays. As economic decisions impact more and more heavily on assay and laboratory choice, how much information should be provided by clinical laboratories to clinicians who depend on these assay outcomes? Who should select the assays and the laboratories to which they are sent?
   
4. Define Opportunities for Future Research. Finally, the millenium NIH Consensus Conference should develop clear priorities for pressing unanswered questions, clinical and basic, that should be the focus of future Requests for Proposals. A number of questions have been raised above which require further study. For example, what really is the incidence of vertebral, hip, and forearm fracture in patients with primary hyperparathyroidism? What would be the impact on fracture of therapy with any of the new bisphosphonates such as alendronate, risedronate, or tiludronate in primary hyperparathyroidism? Or with estrogens? Or with the several new selective estrogen receptor modulators? Or with the calcimimetics? These would be ideal questions for large multicenter NIH- and industry-sponsored observational and interventional trials. The design of such trials, and planning the eventual funding thereof, would be excellent subjects for a Consensus Conference.
   

In the contributions by Silverberg and Bilezikian and by Bone and Talpos, many of the critical "gray areas" are fleshed out. We applaud the authors of the two viewpoints for having raised these important issues. Let’s see what guidance the new millennium brings for the evaluation and management of the complex, common, and confounding clinical conundrum of asymptomatic primary hyperparathyroidism.

	Footnotes

 
This work was supported by NIH Grant DK-51081.

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