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

Characterization and Evaluation of Asymptomatic Primary Hyperparathyroidism JOHN P. BILEZIKIAN,'~' SHONNI J. SILVERBERG,' ELIZABETH SHANE,' MAY PARISIEN,''4 and DAVID W. DEMPSTER3,4

ABSTRACT Data are presented on 97 patients with primary hyperparathyroidism who constitute a representative cohort of the disease seen today. The average calcium (11.1 f 0.1 mg/dl; normal 8.7-10.7), phosphorus (2.8 f 0.1 mg/dl; normal 2.5-4.5), and parathyroid hormone level by immunoradiometric assay (119 f 7 pg/ml; normal 10-65) are typical of the modern presentation of primary hyperparathyroidism. Most patients were asymptomatic in that there was evidence for nephrolithiasis in only 18% and for radiologically evident bone disease in only 1 % of patients. Nevertheless, when patients were evaluated with bone densitometry and with histomorphometric analysis of the bone biopsy specimen, evidence for the hyperparathyroid process could be shown in the majority of patients. Selective reduction of cortical bone and preservation of cancellous bone were apparent. Among patients with nephrolithiasis, no particular feature distinguished them from patients without nephrolithiasis. All biochemical data were similar between both stone and non-stone formers. The selective reduction in cortical bone was seen to the same extent among those with stones as among those without stones. The average 1,25-dihydroxyvitamin D level was not increased among those with stones. When the population was divided into groups with elevated or normal 1,25-dihydroxyvitamin D levels, the incidence of nephrolithiasis was unchanged. The results indicate that bone involvement can be demonstrated among most patients with asymptomatic primary hyperparathyroidism and that no pathophysiologic mechanisms are yet apparent to account for nephrolithiasis in primary hyperparathyroidism.

INTRODUCTION REVIOUS SESSIONS of the consensus development conference, devoted to the diagnosis and clinical spectrum of primary hyperparathyroidism, established that it is now relatively easy to make the diagnosis of this common metabolic bone disease. The greater incidence of primary hyperparathyroidism in the general population and its predominant clinical presentation, namely asymptomatic hypercalcemia, were emphasized. The asymptomatic aspect of primary hyperparathyroidism has raised anew questions of the natural history and the management of this disorder. To develop guidelines for management of primary hyperparathyroidism, it is important to reassess our methods of evaluation to gain as much information as we can about

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the natural history of the disease. This presentation covers the available information in these areas and attempts to identify additional information needed over the next decade to make our approach to primary hyperparathyroidism more certain and more rational. The metabolic bone diseases group at the College of Physicians and Surgeons and at the Helen Hayes Hospital is in the midst of a long-term prospective study of the evaluation, natural history, and pathophysiology of primary hyperparathyroidism. This paper focuses upon the detailed characterization of this group of patients, whom we believe to be representative of the hyperparathyroid population in the United States today. Information about the natural history of the disease as monitored by longitudinal studies is covered in the papers to follow.

Departments of Medicine,' Pharmacology* and P a t h ~ l o g y College ,~ of Physicians and Surgeons, New York, New York. 'Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York.

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RESULTS AND DISCUSSION

General characteristics of the population Data are presented for 97 patients enrolled in our study. The group includes 74 women and 23 men, with a mean age of 55 f 1 years. Analysis of data at sequential points in the enrollment process has shown that in the first 52, 62, or 97 patients, the mean serum calcium has been remark0.1 mg/dl ably constant and mildly elevated at 11.1 (normal 8.7-10.7). The serum phosphorus is at the lower 0.1 mg/dl (normal 2.5limits of the normal range, 2.8 4.5). The mean parathyroid hormone level is elevated by three different immunoassays: N-terminal (30.0 f 1.5 pg/ml; normal 8-24); midmolecule (771 f 64 pg/ml; nor7 pg/ml; normal 10-65). The mal 50-330); IRMA (119 immunoradiometric assay (IRMA) and the midmolecule radioimmunoassay for parathyroid hormone are the two most useful assays, showing elevations in over 90% of patients. 25-Hydroxyvitamin D (25-OHD) is 19 l ng/ml, in the lower range of normal (9-52 ng/ml), but the 1,25dihydroxyvitamin D [ 1,25-(OH),D] level is 54 f 2 pg/ml, in the upper range of normal (16-60 pg/ml). Alkaline phosphatase is elevated (1 14 f 5 IU/liter; normal < 100). Urinary calcium excretion in the entire group is 240 f 11 mg/g Cr (Table 1). The only difference between women and men is a slight but significantly increased value for the serum alkaline phosphatase: 119 f 6 versus 98 f 5 IU liter, respectively. Of all women 58% had an elevated alkaline phosphatase level in comparison to 43% of all men. When the women were subdivided into premenopausal ( n = 23; age 44 f 2 years) and postmenopausal ( n = 51; age 62 f 1 years)

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groups, no differences were noted in any index in Table 1. Of additional interest, however, are observations related to the serum alkaline phosphatase. Premenopausal women and men showed indistinguishable values (102 + 13 versus 98 f 5 ) , whereas the difference between postmenopausal women and men was even more apparent (126 f 6 versus 98 f 5 ; p < 0.01). Of all postmenopausal women 67% had elevations in alkaline phosphatase in comparison to only 39% of premenopausal women. We documented nephrolithiasis in 11 patients and radiologically evident bone disease in only 1 patient. Although some patients report other features of primary hyperparathyroidism, such as easy fatigability and vague neuromuscular and neuropsychiatric complaints, it is difficult to attribute these potential complicating aspects of the disease as specific to it. Even in patients for whom such symptoms as easy fatigability are prominent, it is very difficult to ascertain by objective criteria that this problem is specifically due to the hyperparathyroid state. Among 42 patients from this cohort who underwent detailed neuromuscular testing, no patient showed typical findings previously observed in primary hyperparathyroidism, such as muscular weakness, atrophy, hyperreflexia, abnormal gait, tongue fasciculations, or objective changes in mental status.''.*] The lack of objective manifestations of neuromuscular disease, however, does not allow one to conclude that the nonspecific manifestations of primary hyperparathyroidism are unimportant or not in fact related to the disease. Sometimes one only knows in retrospect, after successful parathyroid surgery, that the constellation of symptoms was or was not due to primary hyperparathyroidism. Much more information is needed in this area.

TABLE1. BASELINE INDICES IN 97 PATIENTS WITH PRIMARY HYPER PARATHYROID ISM^ All patientsb

Normal range

Serum index Calcium, mg/dl Phosphorus, mg/dl Alkaline phosphatase, IU/liter Magnesium, mg/dl N-PTH, pg/ml MM-PTH, pg/ml IRMA-PTH, pg/ml 25-OHD, ng/ml 1,25-(OH),D, pg/ml

11.1 f 0.1 2.8 f 0.1 114 5 2.0 f 0.1 30.0 f 1.5 771 f 64 119 f 7 19 f 1 54 f 2

8.7-10.7 2.5-4.5 < 100 1.8-2.4 8-24 50-330 10-65 9-52 16-60

Urine index Calcium, mg/dl Calcium mg/g creatinine Phosphorus, mg/dl Cyclic AMP, nmol/dl Hydroxyproline, mg/day

248 240 753 3.9 39

aAll data shown are mean f SEM. bMean age 55 1 year.

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34 0.2 2

< 250 3.9

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EVALUATION OF ASYMPTOMATIC HYPERPARATHYROIDISM

Skeletal involvement in primary hyperparathyroidism

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The increased incidence of asymptomatic primary hyperparathyroidism has magnified the need to determine target organ involvement with greater sensitivity. In our cohort, conventional radiographic assessment demonstrated specific signs of hyperparathyroid bone disease in only one patient. We have taken advantage of more sensitive methodologies, such as bone densitometry and quantitative histomorphometric analysis of bone biopsy specimens, to learn whether involvement of the skeleton by the hyperparathyroid process can be demonstrated in these patients. Bone density was measured at three skeletal sites to evaluate sites enriched in cortical bone (distal radius), cancellous bone (vertebral spine), and a mixture of both (the hip region).‘31At the distal radius, 58qo of our patients had reductions greater than 80% of age- and sex-matched control values. The actual value at this site (0.54 0.1 g/cm) 2% of the expected mean value. In conwas only 79 trast, at the lumbar spine, bone mineral density was relatively well preserved. Only 13% of patients showed a loss greater than 80% of age- and sex-matched control values. The actual mean value (1.07 f 0.03 g/cm’) was within 5% of the expected mean. Not surprisingly, values for the hip were midway between data obtained for the spine and those for the distal radius (Fig. 1). The results indicate that this group of patients with primary hyperparathyroidism shows a selective reduction in cortical bone and relative preservation of cancellous bone, consistent with the physiologic actions of parathyroid hormone, which are believed to be directed toward cortical bone. To evaluate further the presence and extent of hyperparathyroid bone involvement among this group of patients, most of whom were asymptomatic, we obtained a specimen of bone from the iliac crests of 27 patients via the percutaneous bone b i o p ~ y . ‘ ~The . ~ ’ subset of patients who underwent bone biopsy was representative of the entire cohort with respect to all serum and urinary indices, bone densitometry, and incidence of nephrolithiasis. Static parameters indicated elevated values for osteoid surface, osteoid volume, and eroded surface compared to normal values for men and women. Dynamic parameters showed that mineral apposition rate was unchanged. However, mineralizing surface was increased. Structural indices of cortical and cancellous bone in the biopsies from hyperparathyroid subjects were significantly different from those in normal subjects.l6I In general, subjects showed thinned cortices and a striking maintenance of trabecular architecture (Fig. 2). Cortical thickness was significantly lower; cancellous bone volume was significantly greater in hyperparathyroid patients than in control subjects. In fact, 26% of our patients had values for cancellous bone volume that were greater than 2 standard deviations (SD) above mean control values. The increase in cancellous bone volume appears to be due to greater trabecular number rather than a change in trabecular thickness. In 37% of our patients, trabecular number was greater than 2 SD above control values. No patient had a value for trabecular number below normal limits. Consis-

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FIG. 1. Bone densitometry in primary hyperparathyroidism. Three different sites - radius (solid), femoral neck (dotted), and lumbar spine (open)-are shown in comparison to expected values for age- and sex-matched normal subjects. Divergence from expected values is different at each site (p < 0.OOOl). (Reprinted with permission from Ref. 3.)

tent with these observations, trabecular separation was reduced in primary hyperparathyroidism. Total bone density was unchanged as a result of the opposing effects of reduced cortical and increased cancellous bone. The regression line describing trabecular number as a function of age in the control population ( r = -0.476; p < 0.05) lost its significance in primary hyperparathyroidism ( r = -0.22; p > 0.05). One could interpret this observation to mean that the age-related loss of trabecular number is markedly reduced in primary hyperparathyroidism. This may be a particularly relevant observation in the postmenopausal group of hyperparathyroid subjects in whom loss of trabecular plates and connectivity is believed to bc important in the pathophysiology of osteoporosis. In this regard, postmenopausal women and age-matched men with primary hyperparathyroidism have bone mineral density of the lumbar spine that is not significantly different (women, 1.07 + 0.02 g/cm’, n = 74, versus men, 1.12 f 0.04 g/cm2, n = 23; p = NS). Under normal circumstances, one would expect a difference to exist between women and men in this age group. It is premature at this time to speculate on the clinical implications of these observations in patients with asymptomatic primary hyperparathyroidism. We can say that the majority of patients who are asymptomatic by conventional criteria nevertheless have evidence for the metabolic

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Bone and stone disease in primary hyperparathyroidism

FIG. 2. Scanning electron micrographs of iliac crest biopsies of a patient with primary hyperparathyroidism (bottom) and a control subject (top). The test sample was obtained from a 38-year-old woman with primary hyperparathyroidism. The normal sample was obtained at autopsy from a 27-year-old woman who had no evidence of bone disease and who died suddenly. The cortices of the hyperparathyroid sample are markedly thinned, but cancellous bone and trabecular connectivity appear to be well preserved. (Reprinted with permission from Ref. 4.)

bone disease of primary hyperparathyroidism.(3.4.61 However, we lack important longitudinal information. We do not know yet whether there will be progression of these findings over time. If morphologic markers of the skeleton show progressive disease, is this a general observation, or is there a subgroup of patients at risk? Or are we, as suggested by Rao et aI.,(’) observing a phase of primary hyperparathyroidism that may not be progressive? We also do not understand the implications of the observation that the hyperparathyroid process may protect the cancellous elements of the skeleton, in particular the vertebral spine. This last point is of special relevance to postmenopausal women with primary hyperparathyroidism, who constitute the majority of patients with the disease. The ongoing longitudinal aspects of our study will help to address these points.

Past experience with primary hyperparathyroidism has taught that bone and stone disease rarely occur in the same patient. (’-‘‘I Broadus and his colleagues provided evidence that patients with primary hyperparathyroidism predisposed to stone disease had elevated levels of 1,25-dihydroxyvitamin D.(91This observation gave support to the hypothesis that stone formers tended to hyperabsorb calcium from the gastrointestinal tract. It also implied that those who did not hyperabsorb calcium from the gastrointestinal tract might be predisposed to developing bone disease. However, subsequent studies by Pak and his associates were unable to identify a subgroup of patients predisposed to stone disease.(1o’In particular, 1,25-hydroxyvitamin D levels were identical among stone and non-stone formers. In our study group, we sought biochemical distinctions among stone formers to account for their predisposition to stone disease.‘”) We found no differences in serum calcium, phosphorus, parathyroid hormone levels, 25-hydroxyvitamin D, or 1,25-dihydroxyvitarnin D. Urinary calcium excretion was higher among stone formers (329 f 42 versus 246 + 17 mg daily excretion). When urinary calcium excretion was normalized to the creatinine, however, the differences between the two groups were no longer apparent (258 f 24 versus 247 f 15 mg/g Cr). The stone formers were much heavier (76 f 5 kg) than the non-stone formers (69 f 2 kg). Hypercalciuria was seen in the same proportion of stone formers (29%) and non-stone formers (33%). Calcium excretion correlated positively with 1,25dihydroxyvitamin D ( r = 0.32; p c 0.05). 1,25-Dihydroxyvitamin D was elevated in the same proportion of those with nephrolithiasis (27%) as those without nephrolithiasis (31To). Further blurring of the distinction between those with bone disease and stone disease came from our comparison among both populations with regard to bone mineral densitometry.(”) Cortical demineralization occurred to the same extent and with the same frequency in patients with and without nephrolithiasis (Fig. 3). We observed the same preferential pattern of skeletal demineralization at cortical sites in stone formers as we did among the entire cohort. Furthermore, urinary calcium excretion correlated negatively with forearm bone mineral density ( r = -0.34; p < 0.05),suggesting that a component of urinary calcium may reflect, in part, events occurring at the level of bone. These observations do not provide support for the hypothesis that stone formers can be conveniently distinguished from non-stone formers on the basis of these indices of parathyroid function. Detailed evaluation of the skeleton in our population fails to confirm the classic teaching that bone disease and stone disease are mutually exclusive manifestations of primary hyperparathyroidism. The population, however, has not yet been studied with more sophisticated methods to analyze urinary composition. It is entirely possible that when these studies are performed, additional data will be more revealing. Our study is about to enter a second phase, which will concentrate on the longitudinal aspects of these observa-

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EVALUATION OF ASYMPTOMATIC HYPERPARATHYROIDISM

REFERENCES

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1. Turken SA, Cafferty M, Silverberg SJ, de la Cruz L, Cimino C , Lange DJ, Lovelace RE, Bilezikian J P 1989 Neuromuscu>

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FIG. 3. Bone mineral density in primary hyperparathyroidism in those with or without nephrolithiasis. Data are shown for all patients (left), stone formers (middle group), and non-stone formers (right) for the radius (solid bars, g/cm); for the femoral neck (crosshatched bars, g/cm*) and for the lumbar spine (striped bars, g/cm*). Values are SEM. (Reprinted with permission from shown as mean Ref. 11.)

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tions. The database thus generated should help to identify a set of risk factors associated with the development of complications of the disease, as well as a set of factors that may be associated with protection from major complications. Our study will also examine the question of the reversibility of the metabolic bone disease among those who have undergone successful parathyroid surgery.

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lar involvement in mild, asymptomatic primary hyperparathyroidism. Am J Med 87:553-557. Patten BM, Bilezikian J P , Mallette LE, Prince AP, Engk WK, Aurbach G D 1974 Neuromuscular disease of primary hyperparathyroidism. Ann Intern Med 80:187-193. Silverberg SJ, Shane E, De La Cruz L, Dempster DW, Feldman F, Seldin D, Jacobs T P , Siris ES, Cafferty M, Parisien MV, Lindsay R, Clemens T L , Bilezikian JP 1989 Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 4: 283-291. Parisien M, Silverberg SJ, Shane E, Dempsler DW, Hilezikian J P 1990 Bone disease in primary hyperparathyroidism. Endocrinol Metab North Am Clin 19:19-34. Rao DS, Wilson RJ, Kleerekoper M, Parfitt AM 1988 Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism; evidence for a biphasic disease course. J Clin Endocrino1 Metab 109:959-962. Parisien M, Silverberg SJ, Shane E, de la Cruz L, Lindsay R, Bilezikian J P , Dempster DW 1990 The histornorphometry of bone in primary hyperparathyroidism: Preservation of cancellous bone structure. J Clin Endocrinol Metab 70:930-938. Albright F, Aub JC, Bauer W 1934 Hyperparathyroidism: A common and polymorphic condition as illustrated by 17 proven cases from one clinic. JAMA 102:1276-1287,. Albright F, Reifenstein E C 1948 The Parathyroid Glands and Metabolic Bone Disease. Williams & Wilkins, Baltimore. Broadus AE, Horst RL, Lang R, Littlcdike ET, Rasmussen H 1980 The importance of circulating 1,25(OH),D in the pathogenesis of hypercalciuria and renal stone formation in primary hyperparathyroidism. N Engl J Med 302:421-426. Pak CYC, Nicar MJ, Peterson R, Zerwekh JE, Snyder W 1981 Lack of unique pathophysiologic background for nephrolithiasis in primary hyperparathyroidism. J Clin Endocrinol Metab 53536-542. Silverberg SJ, Shane E, Jacobs T P , Siris ES, Gartenberg F, Seldin D, Clemens TL, Bilezikian J P 1990 Nephrolithiasis and bone in involvement in primary hyperparathyroidism, 1985-1990. Am J Med 89:327-334.

ACKNOWLEDGMENTS A substantial portion of this work was supported by NIH Grants No. NIDDK 32333, and NIAMDS 39191, 35647, and RR00645. We acknowledge with gratitude the untiring work of Flore Gartenberg, R.N. and Tae Sook Kim, R.N.

Address reprint requests to: John P. Bilezikian Department of Medicine 9-410 College of Physicians and Surgeons 630 W. 168th Street New York, N Y 10032

Characterization and evaluation of asymptomatic primary hyperparathyroidism.

Data are presented on 97 patients with primary hyperparathyroidism who constitute a representative cohort of the disease seen today. The average calci...
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