Background In the United States, most patients with primaryhyperparathyroidism have few or no symptoms. The need for parathyroidectomyto treat all patients with this disorder has therefore beenquestioned.
Methods We studied the clinical course and development of complicationsfor periods of up to 10 years in 121 patients with primary hyperparathyroidism,101 (83 percent) of whom were asymptomatic. There were 30 menand 91 women (age range, 20 to 79 years). During the study,61 patients (50 percent) underwent parathyroidectomy, and 60patients were followed without surgery.
Results Parathyroidectomy in patients with or without symptomsled to normalization of serum calcium concentrations and a mean(±SE) increase in lumbar-spine bone mineral density of8±2 percent after 1 year (P=0.005) and 12±3 percentafter 10 years (P=0.03). Bone mineral density of the femoralneck increased 6±1 percent after 1 year (P=0.002) and14±4 percent after 10 years (P=0.002). Bone mineral densityof the radius did not change significantly. The 52 asymptomaticpatients who did not undergo surgery had no change in serumcalcium concentration, urinary calcium excretion, or bone mineraldensity. However, 14 of these 52 patients (27 percent) had progressionof disease, defined as the development of at least one new indicationfor parathyroidectomy. All 20 patients with symptoms had kidneystones. None of the 12 who underwent parathyroidectomy had recurrentkidney stones, whereas 6 of the 8 patients who did not undergosurgery did have a recurrence.
Conclusions In patients with primary hyperparathyroidism, parathyroidectomyresults in the normalization of biochemical values and increasedbone mineral density. Most asymptomatic patients who did notundergo surgery did not have progression of disease, but approximatelyone quarter of them did have some progression.
Primary hyperparathyroidism in the Western world has evolvedfrom a disease of "bones, stones, and groans" to a disorderthat is asymptomatic in most patients.1,2,3,4,5 As a result,common questions include the following: When is surgery —the definitive therapy for this disorder — indicated inpatients with primary hyperparathyroidism who have no symptoms,6,7,8and what is the natural history of the disease in such patients?
Early studies of patients with primary hyperparathyroidism donot help to answer these questions, because many of the patientshad symptomatic disease. In a 1981 study of 197 patients, forexample, 51 percent had nephrolithiasis and 24 percent had radiographicevidence of bone involvement.9 Today, only about 20 percentof patients have nephrolithiasis, and radiographically detectablebone disease is rare.5 To address some of these issues, in 1990the National Institutes of Health Consensus Development Conferenceon the Diagnosis and Management of Asymptomatic Primary Hyperparathyroidismrecommended criteria for surgery, while recognizing that prospectivedata were needed to "define this disease's multisystem effects"and to "assess the long-term incidence and progression of complications"in asymptomatic patients.10
Fifteen years ago, we initiated a prospective study of primaryhyperparathyroidism to define the biochemical, bone densitometric,and histomorphometric features of the disorder; to determineits natural history; and to assess the results of surgery. Inthis report, we describe our findings during 10 years of follow-upin two cohorts of patients: one treated by successful parathyroidectomyand the other observed without intervention.
Methods
Patients
Over a seven-year period we enrolled 137 patients in a prospectivestudy of primary hyperparathyroidism. Of these patients, 121(88 percent) participated for at least one year and are includedin this report (Figure 1). The study was approved by the institutionalreview board of Columbia–Presbyterian Medical Center,and all patients gave written informed consent. These patientswere also included in earlier cross-sectional11,12 and longitudinal13,14studies conducted by our group. Primary hyperparathyroidismwas diagnosed when the patient had hypercalcemia and high serumparathyroid hormone concentrations. Patients who were receivingthiazide or lithium therapy were excluded.
Figure 1. Base-Line Characteristics and Outcome in 121 Patients with Primary Hyperparathyroidism.
All patients with symptomatic disease had kidney stones. In patients with disease progression, either an indication for surgery (according to NIH Consensus Conference guidelines10) developed or an overt complication of hyperparathyroidism (such as kidney stones, fracture, or osteitis fibrosa cystica) occurred during follow-up.
The decision to recommend parathyroidectomy was based on guidelinesadopted by the NIH Consensus Conference.10 Thus, all patientswith signs of hyperparathyroidism — osteitis fibrosa cystica,nephrolithiasis, classic neuromuscular symptoms (proximal muscleweakness, atrophy, hyperreflexia, and gait disturbances),12,15and hyperparathyroid crisis (a discrete episode of life-threateninghypercalcemia) — were referred for surgery. Nephrolithiasiswas documented by a review of the medical records. Screeningradiography for nephrolithiasis or nephrocalcinosis was notroutinely performed. A complete neurologic evaluation was performedfor the first 42 patients enrolled12 and as needed for subsequentpatients. Some patients described vague constitutional symptomsthat are often associated with primary hyperparathyroidism,including fatigue, weakness with no objective signs, and constipation.However, since such symptoms are common and are not clearlycaused by either mild hypercalcemia or high serum parathyroidhormone concentrations, these patients were not considered tohave symptoms.
We recommended surgery for patients without symptoms if theymet at least one of the following criteria10: a serum calciumconcentration of greater than 12 mg per deciliter (3 mmol perliter), marked hypercalciuria (urinary calcium excretion, greaterthan 400 mg per day [10 mmol per day]), markedly reduced corticalbone density (z score for the distal third of the radius, lessthan –2; the z score reflects the standard deviation fromthe mean for a sex-matched and age-matched reference population),an unexplained reduction in creatinine clearance, and an ageof less than 50 years. Moderate calcium intake without vitaminD supplementation was recommended for patients who did not undergosurgery. No particular recommendations were made with regardto exercise. Five postmenopausal women took estrogen–progestintherapy for at least one year during follow-up.
Although 75 patients (62 percent) met the criteria for parathyroidectomyat enrollment, 29 did not undergo surgery, for the followingreasons: previous parathyroid surgery that was not curative(5 patients), an intercurrent medical condition or advancedage (4 patients), and the patient's choice (20 patients). Fifteenof the 46 patients (33 percent) who did not meet the criteriafor parathyroidectomy elected to undergo the procedure. Elevenpatients, six of whom met guidelines for surgery at enrollment,underwent parathyroidectomy after follow-up for 2 to 11 years(mean, 5 years). This group of 11 patients included 6 of the14 patients in whom an indication for surgery, which was notpresent at base line, developed during follow-up.
Study Protocol
All patients underwent biochemical studies at base line andevery four months thereafter if they were followed with no intervention,or every six months thereafter if they underwent parathyroidectomy.Serum calcium, phosphorus, and alkaline phosphatase were measuredby automated techniques (Technicon Instruments, Tarrytown, N.Y.).Serum parathyroid hormone was measured by immunoradiometricassay (interassay coefficient of variation, 5.6 percent),16and serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D weremeasured as previously described (interassay coefficients ofvariation, 9.6 percent and 9.8 percent, respectively).11 Serumosteocalcin was measured by radioimmunoassay (interassay coefficientof variation, 4.8 percent).17 Urinary pyridinoline and deoxypyridinolinewere measured by high-performance liquid chromatography,18 andurinary calcium by atomic absorption spectrophotometry.
The bone mineral density of the lumbar spine (L2, L3, and L4),femoral neck, and distal third of the nondominant radius wasmeasured at enrollment and yearly thereafter. Before 1991, weused single-photon and dual-photon absorptiometry (SP2 and DP3scanners, respectively; Lunar Radiation, Madison, Wis.), andthereafter we used dual-energy x-ray absorptiometry (model QDR-1000bone densitometer, Hologic, Waltham, Mass.). The coefficientof variation of these measurements on a phantom spine was 0.4percent. The data on bone density are reported both as absolutemeasurements and as z scores.19 The results obtained with thetwo densitometric techniques were compared by means of a seriesof equations we developed,13 and all measurements are presentedin terms of dual-energy x-ray absorptiometry values (in gramsper centimeter squared). The contrast between the increase inbone mineral density in the patients who underwent parathyroidectomyand the lack of change in patients who did not argues againstsystematic errors resulting from the conversion to the use ofdual-energy x-ray absorptiometry.
Statistical Analysis
For each patient, we determined the change in bone mineral densityfrom base line at each site during each year of follow-up andthen averaged the changes for all the patients for each yearof follow-up. Student's paired t-tests were used to evaluatechanges in biochemical values and bone mineral density overtime, and Student's unpaired t-tests were used to compare biochemicalvalues and changes in bone mineral density between the groupthat underwent surgery and the group that received no intervention.Logistic-regression analysis was used to identify factors associatedwith loss of bone mineral density.
Results
Characteristics of the Patients
The cohort of 121 patients was made up of 29 premenopausal women(24 percent), 62 postmenopausal women (51 percent), and 30 men(25 percent) with mild primary hyperparathyroidism. Only 20patients (17 percent) had symptoms of hyperparathyroidism —specifically, a history of kidney stones. None of the 121 patientshad clinical bone disease or fractures, neuromuscular symptoms,or hyperparathyroid crisis. Because there is little debate aboutthe importance of surgery in symptomatic patients with primaryhyperparathyroidism, a central goal of this study was to characterizethe course of the disease and its complications in the 101 patientswho were asymptomatic. Therefore, patients were studied accordingto treatment and according to the presence or absence of symptomsreferable to their hyperparathyroidism (Figure 1 and Table 1).
Table 1. Base-Line Characteristics of the Patients with Primary Hyperparathyroidism.
The 61 patients who underwent parathyroidectomy were youngerand had higher serum calcium concentrations and urinary calciumexcretion than the 60 who did not undergo surgery (Table 1).The patients who underwent surgery also had significantly lowerz scores for bone mineral density at the lumbar spine and femoralneck, but not at the radius. The serum parathyroid hormone,alkaline phosphatase, and vitamin D concentrations were similarin these two groups.
Course of Disease among Patients Who Underwent Parathyroidectomy
Of the 61 patients who underwent parathyroidectomy, 49 (80 percent)had an adenoma, 7 (11 percent) had hyperplasia, and 5 (8 percent)had a mixture of adenomatous and hyperplastic disease. All hadnormal biochemical values after surgery (Table 2).
Table 2. Effect of Parathyroidectomy in 61 Patients with Primary Hyperparathyroidism.
Increases in bone mineral density at the lumbar spine and femoralneck in these patients have previously been reported for a four-yearperiod after parathyroidectomy.14 During the 10-year follow-up,the increases in bone density at these sites, as compared withbase-line (preoperative) values, in this group were prompt andsustained (Figure 2), although the trend toward a further increaseafter year 1 was significant only for the femoral-neck values(P=0.02 after 4 years and P=0.03 after 7 and after 10 years,by paired t-tests). Bone mineral density of the lumbar spineand femoral neck increased to the same extent in the 28 postmenopausalwomen who underwent surgery as in premenopausal women and menwho underwent surgery (data not shown). There was no significantchange in the bone mineral density of the radius.
Figure 2. Mean (±SE) Change in Bone Mineral Density at Three Sites in Patients with Primary Hyperparathyroidism, According to Treatment.
Data shown are the cumulative percent changes from base line at each site after 1, 4, 7, and 10 years of follow-up in patients who did not undergo parathyroidectomy and in those who underwent parathyroidectomy. There were no significant changes from base line in radial bone mineral density.
Among the 61 patients who underwent parathyroidectomy, 49 wereasymptomatic and 12 were symptomatic (all had kidney stones)(Figure 1). After surgery, the increases in bone mineral densityat the lumbar spine and femoral neck in the patients withoutsymptoms were similar to those in the patients with symptoms(data not shown). None of the 12 patients with symptoms whounderwent parathyroidectomy had recurrence of kidney stonespostoperatively (Table 2).
Course of Disease among Patients Who Did Not Undergo Parathyroidectomy
Of the 60 patients who did not undergo parathyroidectomy, 52were asymptomatic (Figure 1). The eight symptomatic patients,all of whom had kidney stones, either refused surgery or hadpreviously undergone unsuccessful surgery.
There were no significant changes from base-line values in serumcalcium, parathyroid hormone, or alkaline phosphatase concentrations;urinary calcium excretion (Table 3); or bone mineral densityat any site during the 10-year period in these 52 asymptomaticpatients. There also were no significant changes in biochemicalvalues or bone mineral density from base line in the subgroupof 29 postmenopausal women who had asymptomatic disease anddid not undergo surgery (data not shown).
Table 3. Biochemical Values in 52 Asymptomatic Patients with Primary Hyperparathyroidism Who Did Not Undergo Parathyroidectomy.
However, 11 of these 52 patients (21 percent) had a decreaseof more than 10 percent in bone density at one or more sitesover the 10-year period. All but 1 of these 11 patients werewomen, and 5 became menopausal during follow-up. These 11 patientshad higher mean (±SD) serum calcium concentrations atbase line than those in whom bone density did not change (10.7±0.5vs. 10.3±0.4 mg per deciliter [2.68±0.12 vs. 2.58±0.10mmol per liter], P=0.03); 4 met criteria for surgery at baseline and thus had more severe disease than those in whom bonedensity did not change. Other than the base-line serum calciumconcentration, onset of menopause during follow-up was the onlyfactor identified in the logistic-regression analysis as havingan association with a risk of loss of bone mineral density (P=0.006).
Fourteen of the 52 asymptomatic patients (27 percent) who didnot undergo surgery had evidence of disease progression (Figure 1),defined as the development of one or more new indicationsfor parathyroidectomy during follow-up. Marked hypercalcemia(serum calcium concentration of more than 12 mg per deciliter)developed in two patients, marked hypercalciuria (urinary calciumexcretion of more than 400 mg per day) in eight, and low corticalbone density (z score for the distal third of the radius, lessthan –2) in six. These patients were younger at base linethan those with no disease progression (52±12 vs. 60±10years old, P=0.02), and six became menopausal during follow-up.Their serum calcium and parathyroid hormone concentrations,urinary calcium excretion, and bone mineral density at baseline were similar to those of the asymptomatic patients in whomthere was no progression of disease. None of these 14 patientshad nephrolithiasis, an unexplained decrease in creatinine clearance,a fracture, or hyperparathyroid crisis. Six of the 14 underwentparathyroidectomy after the development of an indication forsurgery. In addition, four asymptomatic patients who did notmeet criteria for surgery chose to have surgery after severalyears of follow-up.
Among the eight patients who had kidney stones at base linebut who did not undergo parathyroidectomy, all eight had atleast one sign of progression: six had a recurrence of kidneystones and three had new indications for surgery during follow-up(Figure 1). Only one of these eight patients eventually underwentparathyroidectomy. In contrast, none of the 12 patients withkidney stones who underwent surgery initially had a recurrence(Table 2).
Discussion
The questions underlying this study were clearly delineatedat the NIH Consensus Conference in 1990: What are the benefitsof curing primary hyperparathyroidism? What are the consequencesof nonintervention? On the basis of our results we can now commenton the long-term course of treated and untreated asymptomaticprimary hyperparathyroidism.
In the 61 patients who underwent surgery, biochemical valuesnormalized and bone density increased. These results, whichextend those of previous studies,14,20 reveal that successfulsurgery leads to sustained increases in bone mineral densityat sites rich in cancellous bone (such as the lumbar spine andfemoral neck) in patients with primary hyperparathyroidism,including postmenopausal women. A satisfactory explanation forthis sustained increase in bone mineral density remains elusive.One hypothesis attributes the increase to mineralization ofthe expanded remodeling space that is characteristic of primaryhyperparathyroidism.21 This hypothesis, however, does not explainwhy the increase in bone mineral density is sustained. A secondhypothesis is that surgery restores normal pulsatility to thesecretion of parathyroid hormone, which is thought to stimulatethe formation of cancellous bone.22,23 Paradoxically, althoughcortical bone is more vulnerable than cancellous bone to thecatabolic effects of parathyroid hormone,24 parathyroidectomyis not followed by an increase in radial bone mineral density.Our results substantiate earlier observations that corticalbone loss in patients with primary hyperparathyroidism is notreadily reversible.25,26,27,28
Our data are in agreement with those of previous, shorter-termstudies that found that asymptomatic patients who did not undergoparathyroidectomy had stable bone mineral density.13,26,29,30,31In one study, however, bone density at the radius did decreaseduring follow-up.26 Although age-related decreases in bone mineraldensity are expected during middle age, bone mineral densityin most of our patients who did not undergo surgery remainedstable during a decade of observation. Our inability to detectdecreases in bone mineral density could be due to limitationsrelated to sample size or the presence of vertebral degenerativejoint disease, which can alter bone mineral density values atthe lumbar spine, but the finding that femoral-neck bone mineraldensity was stable makes the latter explanation less likely.Alternatively, the stable bone mineral density could reflectour finding that patients with primary hyperparathyroidism donot have the expected age-related changes on bone histomorphometry,perhaps because of the continued anabolic effect of parathyroidhormone on cancellous bone.32,33,34
Bone density was not stable in all our patients. Those who enteredmenopause during follow-up were at risk for bone loss, as arenormal women at the onset of menopause. The absence of reliablepredictors of bone loss in most patients makes regular measurementof bone density mandatory in patients who do not undergo parathyroidectomy.
Although no symptomatic complications such as fractures or kidneystones developed during follow-up in any of the patients withasymptomatic primary hyperparathyroidism who did not undergosurgery, hypercalcemia and hypercalciuria did worsen and bonemineral density decreased in approximately one quarter of thissubgroup. On the other hand, the majority of patients who initiallyhad symptoms of primary hyperparathyroidism (kidney stones)but did not undergo surgery had recurrent kidney stones duringfollow-up.
Our results suggest that patients with symptomatic primary hyperparathyroidismshould undergo surgery. In both patients with and those withoutsymptoms, parathyroidectomy can be expected to result in biochemicalcure and increases in bone mineral density at the lumbar spineand femoral neck. Thus, surgery can be a particularly suitabletreatment option for patients who have low bone mineral densityat these sites at the time of diagnosis.
This study has several limitations. First, our results are observational.Second, we did not include the nonspecific manifestations ofhyperparathyroidism in our criteria for symptomatic disease,because validated, quantitative measures of these manifestationsare not yet available.
In conclusion, biochemical test results and bone mineral densitydid not change significantly during follow-up in most patientswith asymptomatic primary hyperparathyroidism who do not undergosurgery. Since women with hyperparathyroidism seem to be atrisk for the progression of disease at the time of menopause,they should consider parathyroidectomy. Because some asymptomaticpatients have progression of disease over time, biannual measurementsof serum calcium concentrations and annual measurements of urinarycalcium excretion and bone mineral density should be performedin all patients who do not undergo surgery. These tests willpermit the timely recognition of any indications for surgeryas they develop and should allow most patients with asymptomaticprimary hyperparathyroidism to be monitored safely without surgery.
Supported in part by grants (NIDDK 32333 and RR 00645) fromthe National Institutes of Health.
We are indebted to Don McMahon for statistical advice; to MarkusSeibel, M.D., for the collagen cross-link assays; and to TaeSook Kim, R.N., Flore Locker, R.N., Ed.D., and Ijeoma Brown,R.N., for help with patient care and data management.
Source Information
From the Departments of Medicine (S.J.S., E. Shane, T.P.J., E. Siris, J.P.B.) and Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York.
Address reprint requests to Dr. Silverberg at the Department of Medicine, College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032.
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A correction has been published: N Engl J Med 2000;342(2):144.
