hyperparathyroidism case.pdf

EBM Instructions

The purpose of this exercise is to employ some of the principles of evidence based medicine into a critical appraisal of a journal article. You will be given a generic patient scenario, (a) journal article(s) addressing the treatment issue raised in that scenario, and several questions to answer regarding the article. You will meet with a faculty member as a group to discuss the answers to these questions. Your answers should be an evaluation of the research (as opposed to an in depth discussion of the patient condition), looking at whether the results of the paper are valid, what they results are, and are the results applicable to the patient in the scenario. The discussion session with the faculty will be scheduled for you and posted on Learn@UW.

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Hyperparathyroidism Case #2

A 50 year old woman is found to have an elevated serum calcium of 11.0 mg/dl ( normal 8.5 - 10.2) and a high PTH level of 90 pg/ml (normal < 65) during a routine physical exam. The diagnosis is primary hyperparathyroidism. The patient's bone density score is -2.5, consistent with osteoporosis. She has symptoms of fatigue and constipation but is otherwise healthy. She has no history of kidney stones. She is referred for possible parathyroid surgery. She wants to know what operation you would recommend.

This was a recent topic of discussion among your colleagues, and you have been studying the following articles as a result of the discussion (articles found under content section at Learn@UW):

Bergenfelz A, Lindblom P, Tibblin S, et. al. Unilateral versus bilateral neck expoloration for primary hyperparathyroidism. A prospective randomized controlled trial. Ann Surg 2002.

Rubin M, Bilezikian, J, McMahon D, et. al. The Natural History of Primary Hyperparathyroidism with or without Parathyroid Surgery after 15 Years. J Clin Endocrinol Metab. September 2008, 93(9):34623470.

Be prepared to answer the following questions related to the scenario and articles youve read.

1. What is the study design? 2. What are the limitations of the study design? 3. What are some potential sources of bias? 4. How does the study design affect the validity of the study? 5. If you wanted to design a better study to address the same question(s)

how would you do it? 6. Briefly discuss the statistical analysis used is it appropriate? Do you

have any concerns about the statistical analysis used or how the statistics were reported or interpreted?

7. If you were the patients physician, how would you apply this study to the treatment of this patient?

TISSOTSticky NoteUse the Bookmarks links to the left to navigate to the articles

Unilateral Versus Bilateral Neck Exploration forPrimary HyperparathyroidismA Prospective Randomized Controlled Trial

Anders Bergenfelz, MD, PhD, Pia Lindblom, MD, PhD, Sten Tibblin, MD, PhD, and Johan Westerdahl, MD, PhD

From the Department of Surgery, Lund University Hospital, Lund, Sweden

ObjectiveTo compare unilateral and bilateral neck exploration for pri-mary hyperparathyroidism in a prospective randomized con-trolled trial.

Summary Background DataBased on the assumption that unilateral neck exploration for asolitary parathyroid adenoma should reduce operating timeand morbidity, a variety of minimally invasive procedures havechallenged the idea that bilateral neck exploration is the goldstandard for the surgical treatment of primary hyperparathy-roidism. However, to date, no open prospective randomizedtrial has been published comparing unilateral and bilateralneck exploration.

MethodsNinety-one patients with the preoperative diagnosis of primaryhyperparathyroidism were randomized to unilateral or bilateralneck exploration. Preoperative scintigraphy and intraoperativeparathyroid hormone measurement guided the unilateral ex-ploration. Gross morphology and frozen section determinedthe extent of parathyroid tissue resection in the bilateral

group. The primary end-point was the use of postoperativemedication for hypocalcemic symptoms.

ResultsEighty-eight patients (97%) were cured. Histology and curerate did not differ between the two groups. Patients in thebilateral group consumed more oral calcium, had lower serumcalcium values on postoperative days 1 to 4, and had ahigher incidence of early severe symptomatic hypocalcemiacompared with patients in the unilateral group. In addition, forpatients undergoing surgery for a solitary parathyroid ade-noma, unilateral exploration was associated with a shorteroperative time. The cost for the two procedures did not differ.

ConclusionsPatients undergoing a unilateral procedure had a lower inci-dence of biochemical and severe symptomatic hypocalcemiain the early postoperative period compared with patients un-dergoing bilateral exploration. Unilateral neck exploration withintraoperative parathyroid hormone assessment is a valid sur-gical strategy in patients with primary hyperparathyroidismwith distinct advantages, especially for patients with solitaryparathyroid adenoma.

Primary hyperparathyroidism (pHPT) is today recognizedas a common disease.1,2 Bilateral neck exploration withidentification of at least four parathyroid glands and re-moval of all hyperfunctioning tissue yields excellent re-sults35 and has thus evolved as the gold standard for thesurgical treatment of the disease.6 However, it is known that80% to 90% of patients with pHPT have a solitary parathy-roid adenoma.7,8 In these patients, only one gland requiresexcision for cure. To reduce the risk for postoperative

hypocalcemia and to simplify the surgical procedure, theunilateral approach to the solitary parathyroid adenoma wasadvocated by Wang9 and later refined by Tibblin et al.10Good results have been claimed, with a decreased risk ofhypocalcemia1114 and vocal cord injury.11 Since then, bet-ter localization modalities such as high-resolution ultra-sonography,1517 scintigraphy,1820 and intraoperative nu-clear scanning2123 have prompted several groups to modifythe original unilateral approach. Furthermore, intraoperativemeasurement of parathyroid hormone (PTH) has beenshown to be a valid method for confirming complete re-moval of hyperfunctioning parathyroid tissue.2430 Mostrecently, endoscopic or video-assisted unilateral parathy-roidectomy,3134 as well as focused exploration in local orregional anesthesia,15,17,24,25 is proposed to improve cosme-

Correspondence: Anders Bergenfelz, MD, PhD, Department of Surgery,Lund University Hospital, S-221 85 Lund, Sweden.

E-mail: [email protected] for publication April 2, 2002.

DOI: 10.1097/01.SLA.0000032949.36504.C3

ANNALS OF SURGERYVol. 236, No. 5, 543551 2002 Lippincott Williams & Wilkins, Inc.

THIS MONTHS FEATURE

543

sis and reduce postoperative pain.3134 However, from aprinciple point of view, the main difference is still betweenbilateral and unilateral neck exploration.

A recent systemic review comparing unilateral with bi-lateral neck exploration indicated a tendency to favor theunilateral procedure.35 To the best of our knowledge, noopen prospective randomized controlled trial has been pub-lished comparing these two surgical strategies for the treat-ment of pHPT. Therefore, we designed the present study.We focused on the impact of surgical strategy on earlypostoperative hypocalcemia.

METHODS

Study Population

Ninety-one patients (18 men, 73 women), referred to theDepartment of Surgery, Lund University Hospital, Lund,Sweden, for first-time surgery for pHPT between September1996 and March 2001, were enrolled in the study afterwritten and oral information was given. The exclusion cri-teria for entering the study were a family history of pHPT(MEN 1, MEN 2, hereditary pHPT), previous neck surgery,other planned operations during the surgical procedure (in-cluding thyroid surgery), pregnancy and breast-feeding,emergency operation due to hypercalcemic crisis, and in-ability to understand information or to comply with sched-uled follow-up.

Eight eligible patients were operated on outside the study.Six patients entered a prospective trial for video-assisted

surgery of pHPT due to their own preference. Two patientscould not be randomized during a short time period whenintraoperative PTH analysis was not available due to tech-nical problems. Thus, the 91 randomized patients repre-sented 92% of eligible individuals during the study period.

Informed consent was obtained in all cases. The EthicalCommittee of the Medical Faculty, Lund University, ap-proved the study. The preoperative biochemical diagnosisof pHPT was based on a serum calcium level of more than2.60 mmol/L and a serum PTH level of more than 3.5pmol/L, with a serum creatinine level of less than 200mol/L. The mean age ( SD) of the patients was 67 15years. The mean ( SD) preoperative serum level of cal-cium was 2.77 0.15 mmol/L. The mean ( SD) serumPTH level of 10.1 5.2 pmol/L. The mean preoperativeserum calcium level of the eight patients operated on out-side the study was 2.80 0.16 mmol/L.

Preoperative symptoms and signs were recorded. Thir-teen patients were considered asymptomatic.

Planned Intervention

A flow chart summarizing the study is shown in Figure 1.During the outpatient visit, eligible patients were ran-

domized to either unilateral neck exploration (study group)or bilateral neck exploration (control group). After random-ization, patients in the unilateral group underwent preoper-ative sestamibi subtraction scintigraphy; no localizationprocedure was performed in the bilateral group.

Figure 1. Flowchart summarizing this prospective randomized trial comparing unilateral with bilateral neckexploration for patients with primary hyperparathyroidism.

544 Bergenfelz and Others Ann. Surg. November 2002

Preoperatively, all patients underwent indirect laryngos-copy. Biochemical variables reflecting calcium metabolismand renal function were assessed.

Surgery was performed by three of the authors (A.B.,P.L., J.W.), all experienced endocrine surgeons, each per-forming one third of the operations.

In both groups, surgery was performed through a short(5 cm) standard Kocher incision. The strap muscles weredissected in the midline and not divided.

In the unilateral group, surgery was started on the sideindicated by the preoperative scintigram. If no enlargedparathyroid gland was visualized on the scintigram, the leftside was first explored. After finding the first enlargedparathyroid gland, blood samples were drawn for intraop-erative measurement of PTH before and at 5 and 15 minutesafter gland excision. Surgery was terminated if the PTHlevels declined more than 50% after 5 minutes30 or morethan 60% after 15 minutes.28 No attempts were made per seto visualize normal parathyroid glands.

If no enlarged parathyroid gland was found on the firstexplored side, or the decline of PTH was insufficient for thediagnosis of a solitary parathyroid adenoma, comprehensivebilateral exploration was performed. Frozen section was notused.

In the bilateral group, surgery was started on the left sideand comprehensive bilateral exploration was performed. Anattempt was made to visualize four parathyroid glands. Theenlarged parathyroid glands were removed for frozen sec-tion. The decision to terminate surgery was based on thegross morphology of visualized and excised parathyroidglands in combination with frozen section. Normal parathy-roid glands were not routinely biopsied.

Evaluation

Follow-up was done on postoperative days 1 to 4 and 6weeks after surgery with biochemistry and with a patientquestionnaire focusing on the incidence, frequency, andseverity of hypocalcemic symptoms. After the first postop-erative day, the patients were kept in the patient hotel of thehospital and made individual visits on postoperative days 2to 4. Patients were given thorough information regardingthe specific items on the questionnaire by a registered nurse.The patients were similarly informed by the nurse abouthypocalcemic symptoms and were instructed to medicatewith oral calcium (T. Kalcitena 250 mg; ACO, Stockholm,Sweden) up to a maximum of 3 g/24 hours when symptom-atic. No patient was placed on oral calcium by the surgeonimmediately postoperatively. Calcium ingestion and com-plications were recorded in the study protocol. Indirectlaryngoscopy was done before discharge if possible; other-wise, it was performed within 3 weeks postoperatively.

The primary outcome measure was postoperative medi-cation for hypocalcemia during the first 4 postoperativedays. The secondary outcome measures were symptomatichypocalcemia, serum levels of calcium (severe hypocalce-

mia defined as serum calcium 2.00 mmol/L), persistenthyperparathyroidism, complications, operative time, andcost.

Sample Size

We previously showed that bilaterally explored patientswith pHPT due to a solitary parathyroid adenoma have anincreased risk for symptomatic hypocalcemia compared tounilaterally explored patients. They also had lower calciumlevels during the first 4 postoperative days.14 In a pilot studywe found that unilaterally explored patients differed in theingestion of oral calcium during the first 4 postoperativedays. Thus, with a type 1 error of 0.05 (two-tailed) and apower of 0.80, it was determined that 44 patients in eacharm would be sufficient to detect a difference in 1.0 g oralcalcium ingestion in the unilateral group versus 1.75 gcalcium in the bilateral group. The difference in calciummedication was considered important since it reflects theseverity of early postoperative hypocalcemia.

Statistics

Analysis of outcome for the unilateral and bilateral groupwas done on an intention-to-treat basis. For numeric data,differences between groups were analyzed with an unpairedt test, except for data with skewed distribution of numbers,when the Mann-Whitney test was used. For categorical data,statistical significance was analyzed using the chi-squaredtest and the Fisher exact test when expected frequencieswere less than 5. A probability level of a random differenceof P .05 was considered significant. Results for contin-uous variables are reported as mean SD if not statedotherwise. For categorical data, absolute numbers in addi-tion to percentage are given.

To estimate early biochemical hypocalcemia, the areaunder the curve (AUC) for serum calcium concentrationsduring the first 4 postoperative days was used according tothe equation: AUC T (0.5f0 f1 f2 . . . fn-1 0.5fn), where T equals the days between sampling and f thecalcium concentration of the consecutive samples.

Pain during the first 4 postoperative days, as reported bythe patients on a visual analogue scale, was also calculatedas the AUC.

Stopping Rules

No particular stopping rules were applied, since previousretrospective comparative studies have not shown the curerate to differ between unilaterally and bilaterally exploredpatients.

Assignment

Patients were randomized in blocks of 10 with a sealedenvelope to either unilateral or bilateral neck exploration

Vol. 236 No. 5 Surgery for Primary Hyperparathyroidism 545

(1:1) during the outpatient visit at the Department of Sur-gery, Lund University Hospital.

Histopathology

The diagnosis of a parathyroid adenoma and hyperplasiawas established by conventional histologic criteria,37 aidedby gross morphology in the bilateral group and in theunilateral group by the perioperative decrease in the serumlevel of intact PTH.

Sestamibi Scintigraphy

Sestamibi subtraction scintigraphy was performed with30 MBq 99mTc and 500 MBq 99mTc sestamibi.38 A resultwas classified as true positive only if it clearly correspondedto an enlarged parathyroid gland found at the same locationat neck exploration.

Renal Function

Glomerular filtration rate was measured using a methodfor the calculation of plasma clearance of the contrast agentiohexol.39 The reference values are 20 to 50 years, 80 to 125mL/min; 51 to 65 years, 60 to 110 mL/min; and 66 to 80years, 50 to 90 mL/min.

Biochemical Variables

Preoperative blood samples were drawn after an over-night fast the day before surgery. Serum levels of PTH weremeasured with the intact PTH assay (Incstar, Stillwater,MN). The sensitivity of this assay is 0.13 pmol/L. Theinterassay coefficient of variation (CV) is less than 11% andthe intraassay variation less than 6%. The method has a CVof 2.2% at a value of 5 pmol/L. The reference range is 1.0to 5.0 pmol/L. To shorten the time for intraoperative anal-ysis, the assay was modified as previously described.28 The

within-assay variation between 0.8 and 10 pmol/L is lessthan 8% for the rapid method. The correlation between thetwo methods is 0.99.

High-performance liquid chromatography was used forassessment of 25-hydroxycholecalciferol (25 (OH) D3) and1.25-dihydroxycholecalciferol (1,25(OH) 2 D3) with a ra-dioreceptor assay (Incstar). Serum levels of calcium, alka-line phosphatase, phosphate, and creatinine were analyzedwith a routine autoanalyzer (Kodak Ektachem, 700xR-C,Eastman Kodak Co., Rochester, NY).

Costs

The costs for the operative procedure for the two groupsof patients were calculated from official in-hospital chargesfor services performed by different departments. The costfor sestamibi scintigraphy (in U.S. dollars) was $134, intra-operative PTH $126, frozen section $155, and time foranesthesia $12/min.

RESULTS

Forty-seven patients were randomized to the unilateralgroup and 44 patients to the bilateral group. The preopera-tive clinical and biochemical data as well as renal functionwere well balanced and did not differ between the twogroups (Table 1). There was no difference in clinical signsand symptoms between the two groups (data not shown).Six patients in the unilateral group and seven patients in thebilateral group were considered asymptomatic (P .67).The eight patients operated on outside the study all had asolitary parathyroid adenoma. They were normocalcemic atthe 6-week follow-up.

Analysis of the Whole Group of Patients

At surgery, 40 patients in the bilateral group had a solitaryadenoma and 4 patients multiglandular disease. In the unilat-

Table 1. PREOPERATIVE CLINICAL DATA, RENAL FUNCTION, AND BIOCHEMICALVARIABLES

Variable

UnilateralGroup Mean

( SD)

BilateralGroup Mean

( SD) P Value Normal Range

Age (years) 66 14 67 15 .96Sex (male/total) 8/47 10/44 .50Serum-calcium (mmol/L) 2.79 0.16 2.75 0.12 .17 2.202.60Serum-phosphate (mmol/L) 0.81 0.03 0.80 0.02 .86 0.701.30Serum-PTH (pmol/L) 9.7 4.4 10.5 6.0 .46 1.05.025 (OH) vitamin D3 (nmol/L) 53 19 50 22 .60 201001,25 (OH)2 vitamin D3 (pmol/L) 83 33 88 33 .52 36120Serum-alkaline phosphatase (kat/L) 3.7 1.5 3.5 1.2 .68 0.84.6Serum-creatinine (mol/L) 77 25 74 19 .54 Male: 55116

Female: 45100GFR (mL/min) 73 21 77 21 .34 See Methods section


eral group, 41 patients had a solitary adenoma and 5 patientsmultiglandular disease (P .99). The mean ( SD) weight ofthe parathyroid adenoma in the unilateral group was 1.24 1.12 g; in the bilateral group it was 1.04 1.29 g (P .48).In 21 patients, the adenoma weighed less than 500 mg. In onepatient in the unilateral group (explored bilaterally, see below),no enlarged parathyroid gland was found at neck exploration.Three patients had persistent hyperparathyroidism at 6weeks after surgery, two in the unilateral group and one inthe bilateral group. Clinical and biochemical data on thesepatients are shown in Table 2. Thus, the overall cure ratewas 97%. There was no difference between the mean( SD) time for operation in the unilateral group comparedwith the bilateral group (72 42 minutes vs. 82 37minutes, P .22). The costs for the surgical procedure wereslightly but not significantly higher in the unilateral group($2,258 509 vs. $2,097 505, P .13).

In the unilateral group, 29 of 47 patients were unilaterallyexplored (62%). Sestamibi subtraction scintigraphy visual-ized one enlarged parathyroid gland in 35 of 47 patients(74%); in 12 patients (26%) the scan was negative. Incomparison, had the same surgical strategy been used in thebilateral group (remove large gland, check PTH, no frozensection) and the left side first explored, 19 of 44 patients(44%) could have had a unilateral dissection.

The median weight of nonlocalized glands was 0.43 g(range 0.202.55 g) versus 0.87 g (range 0.205.85 g) forlocalized glands (P .05, Mann-Whitney U test). Of thepatients with negative scans, 1 patient had asymmetric hy-perplasia with three enlarged glands and 10 patients had asolitary parathyroid adenoma; in 1 patient with four normalparathyroid glands identified during surgery, no enlargedgland was found. Of the 35 positive scans, a solitary para-thyroid adenoma at the suggested location was confirmed in29 patients. Thus, the sensitivity to localize a solitary para-thyroid adenoma in the unilateral group was 71% (29 of 41

parathyroid adenomas) and the positive predictive value foran adenoma was 83%. In the six patients with incorrectscans, two patients with solitary parathyroid adenoma werenot correctly lateralized and four patients had asymmetrichyperplasia with two enlarged glands each. Thus, in nopatient was multiglandular disease predicted by the scan.

The mean ( SD) decline of PTH after excision of thefirst enlarged parathyroid gland was 54 25% after 5minutes (n 44, three tests missing due to technical prob-lems) and 69 25% after 15 minutes. Fifteen minutes afterexcision of the enlarged parathyroid gland, 35 patients(74%) declined by more than 60%. These patients werecured by surgery (solitary parathyroid adenoma). Twelvepatients (36%) declined by less than 60%. Five of thesepatients were found to have multiglandular disease duringneck exploration, and they were cured. In one patient, a3.5-gland resection was performed due to suspicion of dif-fuse hyperplasia macroscopically as well as on frozen sec-tion (protocol violation). However, histology showed nor-mal parathyroid glands. The patient has persistenthyperparathyroidism, and therefore a solitary parathyroidadenoma in a fifth gland is suspected (see Table 2, patient49). One patient declined by more than 50% at 5 minutesafter surgery, and thus the operation was terminated. How-ever, this patient has persistent HPT as predicted by thePTH level 15 minutes after gland excision (see Table 2,patient 38).

In three patients, no other enlarged gland was founddespite comprehensive bilateral exploration. These patientsare cured (serum calcium 2.21, 2.46, and 2.48 mmol/L at 1year after surgery, with normal levels of intact PTH).

Thus, the sensitivity for a solitary parathyroid adenoma at15 minutes was 92%, the specificity 100%, the positive pre-dictive value 100%, and the negative predictive value 75%.

During the first 4 postoperative days, patients in theunilateral group consumed significantly less oral calcium

Table 2. PATIENTS WITH PERSISTENT HYPERPARATHYROIDISM AFTER NECK SURGERY

PatientNo.

Randomizedto Comments

2 Bilateral Preoperative serum-calcium 2.63 mmol/L, serum-PTH 9.0 pmol/L. Four glands identified at neckexploration. Right upper gland removed. Histology showed parathyroid adenoma (weight 0.57g). At 1 year after surgery, serum-calcium 2.74 mmol/L, serum-PTH 14 pmol/L. GFR 35 mL/min.Urinary-calcium 1.2 mmol/L.

38 Unilateral Preoperative serum-calcium 2.74 mmol/L, serum-PTH 5.5 pmol/L. Negative sestamibiscintigraphy. Bilateral explored. Three glands identified (right lower missing). Right upperremoved. The decline of PTH was 55% after 5 min and 54% after 15 min. Histology showedparathyroid adenoma. At 1 year after surgery, serum-calcium 2.97 mmol/L, serum-PTH 7.1pmol/L. GFR 66 mL/min. Urinary-calcium 4.9 mmol/L.

49 Unilateral Preoperative serum-calcium 2.80 mmol/L, serum-PTH 13 pmol/L. Sestamibi scintigraphy negative.Bilateral exploration. Four glands identified during surgery. On gross morphology and frozensection (protocol violation), suspected diffuse hyperplasia. Subtotal parathyroidectomy wasperformed. The decline of PTH was 0% 15 min after excision of first gland and 16% afterexcision of second gland. Histology showed normal parathyroid glands (weight 0.70 g, 0.70 g,0.37 g, 0.10 g). At 1 year after surgery, serum-calcium 2.84 mmol/L, serum-PTH 10.0 pmol/L.GFR 107 mL/min. Urinary-calcium 3.2 mmol/L.


(0.78 1.07 g) compared to patients in the bilateral group(1.94 2.69 g, P .01).

On the first postoperative day, 19 of 39 patients in thebilateral group (49%) and 12 of 43 patients (28%) in theunilateral group reported mild hypocalcemic symptoms (tin-gling in the lips, fingers, and toes) (P .052). Furthermore,4 of 39 patients (10%) in the bilateral group versus zero of43 patients in the bilateral group reported severe symptoms(i.e., muscle cramps) (P .05). No difference was found inthe frequency of self-reported hypocalcemic symptoms onpostoperative days 2 to 4. There was no significant differ-ence between the two groups in terms of postoperative painrecorded by the patients (Fig. 2).

The serum calcium levels during the first 4 postoperativedays for the patients in the unilateral and the bilateral groupare shown in Figure 3. On the second postoperative day, theserum calcium concentration was significantly lower in thebilateral group compared with the unilateral group (2.15 0.14 mmol/L vs. 2.26 0.17 mmol/L, P .01). Further-more, the AUC for serum calcium during the first 4 post-operative days was smaller in the bilateral group (6.53 0.42 vs. 6.71 0.44, P .05). During the first 6 weeksafter surgery (excluding the first 4 postoperative days),patients in the bilateral group consumed more oral calcium(4.20 6.67 g) than patients in the unilateral group (1.923.86 g, P .05), although self-reported hypocalcemicsymptoms did not differ between the two groups. There wasno difference in the biochemical variables measured at 6weeks after surgery (Table 3).

Three patients had vocal cord palsy on indirect laryngos-copy after surgery, two in the unilateral and one in thebilateral group (P .99); all were temporary.

Two patients with a solitary parathyroid adenoma andone patient with multiglandular disease experienced post-operative hypoparathyroidism with vitamin D substitution

therapy, all in the bilateral group (P .11). In two of thesecases (one patient with adenoma and one patient with mul-tiglandular disease), the medication was temporary, whereasone patient with adenoma still requires vitamin D substitu-tion 1 year after surgery. Three other significant complica-tions were recorded, all in the bilateral group (Table 4).Thus, 5 of 44 patients (11%) in the bilateral group and 2 of47 patients (4%) in the unilateral group had a significantcomplication (P .27; Fishers exact test).

Analysis of Patients With SolitaryParathyroid Adenoma

The mean ( SD) operative time was significantlyshorter in the unilateral group compared to the bilateralgroup (62 29 minutes vs. 84 38 minutes, P .01).During the first 4 postoperative days, patients in the unilat-eral group consumed significantly less oral calcium (0.66 0.89 g) compared to patients in the bilateral group (1.85 2.77 g, P .01). On the first postoperative day, 4 of 35patients in the bilateral group (11%) and zero of 38 patients

Figure 2. Postoperative pain, as estimated on a visual analogue scale(VAS), during the first 4 days after surgery in patients with unilateral orbilateral neck exploration for primary hyperparathyroidism. Bilateralgroup,; unilateral group. Mean ( SD) is shown. No difference wasfound between the two groups of patients (AUC; P .24).

Figure 3. Serum calcium values (S-Ca) for the first 4 postoperativedays in patients enrolled in a prospective randomized trial comparingunilateral with bilateral neck exploration for patients with primary hyper-parathyroidism. Bilateral group, ; unilateral group, . Mean ( SD) isshown.

Table 3. BIOCHEMICAL DATA AT6 WEEKS FOLLOW-UP

Variable

UnilateralGroup

(n 47)

BilateralGroup

(n 44)P

Value

Serum-calcium (mmol/L) 2.37 0.12 2.35 0.12 .40Serum-PTH (pmol/L) 5.7 3.0 6.0 3.3 .60Serum-Phosphate (mmol/L) 1.03 0.19 1.05 0.16 .5625 (OH) vitamin D3 (nmol/L) 54 21 59 24 .321,25 (OH)2 vitamin D3 (pmol/L) 69 33 68 21 .90


in the unilateral group reported severe hypocalcemic symp-toms (i.e., muscle cramps) (P .05). Self-reported hypocal-cemic symptoms did not differ day 2 to 4. Patients with asolitary parathyroid adenoma in the bilateral group hadlower serum levels of calcium on the second postoperativeday compared to patients in the unilateral group (2.15 0.14 mmol/L vs. 2.25 0.15 mmol/L, P .01). Further-more, the nadir of serum calcium during the first 4 postop-erative days was lower in the bilateral group (2.09 0.15mmol/L) compared with the unilateral group (2.15 0.12,P .05). In 10 of 40 patients in the bilateral group (25%)and 3 of 41 patients (7%) in the unilateral group, severebiochemical hypocalcemia (2.00 mmol/L) was recordedduring the first 4 postoperative days (P .04).

The AUC for serum calcium levels during the first 4postoperative days was significantly smaller for patients inthe bilateral group compared to the unilateral group (6.5 0.42 vs. 6.7 0.39, P .05). At the 6-week follow-up,there was no difference in the biochemical variables mea-sured or in self-reported hypocalcemic symptoms and oralcalcium medication.

DISCUSSION

During the past decade, new surgical procedures haveevolved for the treatment of pHPT. From a principle pointof view, the main difference is still between bilateral andunilateral neck exploration. The latter could be performedusing a variety of forms of general and local anesthesia. Themain claim of the proponents of unilateral neck explorationis that compared with bilateral exploration, the unilateralapproach carries a decreased risk for temporary and perma-nent hypocalcemia,1013,40 without an increased risk forpersistent or recurrent pHPT.13 To the best of our knowl-

edge, the present trial is the first prospective randomizedstudy analyzed on an intention-to-treat basis between uni-lateral and bilateral neck exploration.

The results from the present study are quite clear. Al-though only 29 of 47 patients (62%) in the unilateral groupultimately underwent focused adenoma excision, the unilat-eral approach offered some distinct benefits. Patients oper-ated on using a unilateral approach consumed less oralcalcium during the first 4 postoperative days. They also hadless incidence and severity of symptomatic and biochemicalhypocalcemia. For patients with a solitary parathyroid ade-noma, we also found that the operative time was shorter inthe unilateral group. Furthermore, there was no difference incure rate between the two patient groups. The complicationswere found mainly in the bilaterally explored patients (seeTable 4).

Our trial raises a number of possible questions.Although the costs for the operative procedures did not

differ between the two groups, the moderate sensitivity fora solitary parathyroid adenoma by the sestamibi scintigra-phy, in this study 71%, is a cause of concern. A highsensitivity of the preoperative localization procedure is ofgreat importance for a successful focused neck exploration.Furthermore, in agreement with previous investigations, weconfirmed that preoperative sestamibi scintigraphy does notreliably predict multiglandular disease.38,41 We have previ-ously reported a high sensitivity for solitary parathyroidadenoma,38 but the results were not reproduced in thepresent trial. Since gland weight has been shown to be oneof the chief determinants of sestamibi sensitivity,42 onereason could be the relatively high incidence of small ade-nomas. In the present study the adenoma weight was lessthan 500 mg in 21 patients, and the mean weight fornonlocalized glands was lower than the weight for glands

Table 4. COMPLICATIONS

PatientNo. Randomized Operated Histology Complication and Comments

12 Bilateral Bilateral Adenoma Vitamin D substitution therapy at 1 year after surgery22 Bilateral Bilateral Adenoma Patient with rheumatic arthritis

1. Postoperative acute tracheal edema with no response toconservative treatment. Emergency operation withtracheostomy.

2. Temporary paresis of the recurrent laryngeal nerve3. Temporary vitamin D substitution therapy due to

hypocalcemia26 Bilateral Bilateral Adenoma Refused surgery for large goiter. On first postoperative day,

tracheal edema. Emergency operation with totalthyroidectomy.

44 Unilateral Bilateral Adenoma Temporary paresis of the recurrent laryngeal nerve. Scintigraphyneg.

47 Unilateral Unilateral Adenoma Temporary paresis of the recurrent laryngeal nerve. Scintigraphytrue positive.

90 Bilateral Bilateral Adenoma Operated due to rebleeding95 Bilateral Bilateral Hyperplasia Temporary vitamin D substitution therapy due to hypocalcemia


localized by sestamibi scintigraphy. Another possibility isthat the previous study was confounded by a referral bias;that is, patients tend to be referred for surgery more often ifsestamibi scintigraphy is positive.

To optimize the cost-effectiveness of the unilateralmethod, the accuracy of sestamibi scintigraphy clearlyneeds to be improved. By adding delayed sestamibi scansbased on differential washout kinetics43 and single photonemission computed tomography (SPECT)44 or obliqueviews with a higher-dose 99mTc sestamibi,45 an increasedsensitivity might be possible. However, this remains to beproven in prospective controlled trials.

The incidence of multiglandular disease has previouslybeen estimated to be about 15% of patients being operatedon due to pHPT.7,8 However, the incidence of multiglandu-lar disease in a patient cohort in which intraoperative PTHguided the extent of tissue resection was recently found tobe as low as 5%.46 In this study, histologically provenmultiglandular disease was found in 5 of 47 patients in theunilateral group and in 4 of 44 patients in the bilateralgroup. One patient in each group had persistent hyperpara-thyroidism despite one enlarged gland being excised. Thus,the true incidence of multiglandular disease was 13% in theunilateral group and 11% in the bilateral group. The datatherefore strongly suggest that the incidence of multiglan-dular disease was not underestimated in the unilateral group.

One patient in whom the PTH level declined by morethan 50% 5 minutes after excision of an enlarged parathy-roid gland was not cured. This finding is in agreement withprevious investigations4749 suggesting that a 50% decreasein PTH level is not an entirely reliable predictor for post-operative normocalcemia.

To enhance the accuracy of the intraoperative PTH mea-surement, we have developed a rigid protocol. First, bloodsamples are always drawn in a peripheral vein. Second, thebaseline sample should be obtained when the first enlargedparathyroid gland is visualized, since we have shown thatafter general anesthesia the levels of ionized calcium de-crease and the levels of PTH increase.50 Third, the dissec-tion of the enlarged parathyroid gland must be extremelyprecise, without pressure on the gland and with clipping ofthe vascular pedicle as the last measure. Fourth, we havepreviously shown that a decline of PTH by more than 60%at 15 minutes after excision of an enlarged parathyroidgland is highly specific in predicting cure of patients withpHPT.29 In agreement, in the present investigation a declineby more than 60% at 15 minutes after gland excision pre-dicted cure in all patients.

In the present investigation, the cure rate was 97%. Threepatients, two in the unilateral group (both bilaterally ex-plored according to the study protocol) and one in thebilateral group, had persistent hyperparathyroidism. Inagreement, retrospective comparative studies have not shownan increased incidence of persistent or recurrent pHPT forpatients explored with a unilateral approach.11,13,40

In summary, in this prospective randomized trial, patients

operated on according to a unilateral approach consumedless oral calcium and had a lower incidence of biochemicaland early severe symptomatic hypocalcemia compared withpatients explored bilaterally, with no difference in cure rate.Whether endoscopic or video-assisted surgery or other min-imally invasive techniques could provide additional benefitsin terms of early ambulation and less local discomfort andpain compared to the classical open unilateral methodneeds to be answered in future randomized trials.

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The Natural History of Primary Hyperparathyroidismwith or without Parathyroid Surgery after 15 Years

Mishaela R. Rubin, John P. Bilezikian, Donald J. McMahon, Thomas Jacobs, Elizabeth Shane,Ethel Siris, Julia Udesky, and Shonni J. Silverberg

Departments of Medicine (M.R.R., J.P.B., D.J.M., T.J., E.Sh., E.Si., J.U., S.J.S.) and Pharmacology (J.P.B.), Columbia University, College ofPhysicians and Surgeons, New York, New York 10032

Context: Primary hyperparathyroidism (PHPT) often presents without classical symptoms such asovert skeletal disease or nephrolithiasis.Wepreviously reported that calciotropic indices and bonemineral density (BMD) are stable in untreated patients for up to a decade, whereas after para-thyroidectomy, normalization of biochemistries and increases in BMD ensue.

Objective: The objective of the study was to provide additional insights in patients with andwithout surgery for up to 15 yr.

Design: The study had an observational design.

Setting: The setting was a referral center.

Patients: Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic.

Intervention: Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were fol-lowed up without surgery.

Main Outcome Measure: BMD was measured.

Results: Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical siteseven before 10 yr, ultimately decreasing by 10 3% (mean SEM; P 0.05) at the femoral neck,and 35 5%; P 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-sevenpercent of asymptomatic patients showed disease progression (one or more new guidelines forsurgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict whowould have progressive disease. BMD increases in patientswhounderwent surgerywere sustainedfor the entire 15 yr.

Conclusions: Parathyroidectomy led to normalization of biochemical indices and sustained in-creases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meetingsurgical criteria at the outset did not predict this progression. Cortical bone density decreased inthe majority of subjects with additional observation time points and long-term follow-up. Theseresults raise questions regarding how long patients with PHPT should be followed up withoutintervention. (J Clin Endocrinol Metab 93: 34623470, 2008)

Introduction of the multichannel screening test in the early1970s signaled a marked change in the incidence and in theclinical profile of primary hyperparathyroidism (1, 2). The most

common presentation, namely classical symptoms and signs ofskeletal and renal involvement, was replaced by one in whichpatients were discovered incidentally during a routine medical

0021-972X/08/$15.00/0

Printed in U.S.A.

Copyright 2008 by The Endocrine Society

doi: 10.1210/jc.2007-1215 Received May 31, 2007. Accepted May 29, 2008.

First Published Online June 10, 2008

For editorial see page 3302

Abbreviations: BMD, Bonemineral density; DXA, dual-energy x-ray absorptiometry; PHPT,primary hyperparathyroidism.

O R I G I N A L A R T I C L E

E n d o c r i n e C a r e

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at Ebling Library, University of Wisconsin-Madison on October 19, 2009 jcem.endojournals.orgDownloaded from

evaluation. Secure clinical recommendations for managementof this asymptomatic disorder required access to a cohort ofpatients who could be followed long term, both with regard tothose who would undergo surgery or be managed withoutintervention (3).

In 1984 we initiated a prospective study to define the naturalhistory, pathophysiology, densitometric, and other skeletal ab-normalities of primary hyperparathyroidism (PHPT) in themul-tichannel screening era (3). In terms of that natural history com-ponent of this study, we previously reported on this cohort at theconclusion of the first 10 yr of observation. In this report, mixedmodel analysis (see Statistical analysis below) allows amore sta-tistically efficient attempt at detecting systematic patterns thanthe methods we previously used. This has permitted an analysisof all the data, which now includes more time points within the10 yr and extends to 15 yr of prospective longitudinal follow-up.The longer follow-up period has led to new observations thathave implications for decision-making and for management ofthis disorder.

Patients and Methods

PatientsThe study, which began in 1984, enrolled 116 subjects with PHPT

who had at least one follow-up bone mineral density test (Fig. 1). Theprotocol was approved by the Institutional Review Board of ColumbiaUniversity Medical Center, and all patients gave written informedconsent.

The decision to recommend parathyroidectomy was based on guide-lines adopted by the 1990National Institutes of Health Consensus Con-ference on the Management of Asymptomatic PHPT (4). Criteria forsurgery included complications of PHPT (osteitis fibrosa cystica, neph-rolithiasis (documented by a review of the medical records and/or by adiscrete event), classic neuromuscular symptomsorparathyroid crisis) or

one or more of the following criteria (4): serum calcium concentrationgreater than 12 mg/dl (3 mmol/liter), 24-h urinary calcium excretiongreater than 400 mg (10 mmol), bone density Z score at the distal onethird radius less than 2, an unexplained reduction in creatinine clear-ance, or age younger than 50 yr. Although these guidelines were used asthe basis for recommendations for or against surgery, some patientschose to have surgery, even though they did not meet any guidelines,whereas others who met criteria refused intervention. All patients in-cluded in the surgical group were operated on within a year of studyentry. As previously reported (5) calcium intake at presentation wasoften low (mean600mg/d). Intake of nomore than 1000mg (withoutcalcium supplementation) was generally recommended for patients whodid not undergo surgery; compliance with this recommendation was notspecifically monitored.

Study protocolAll patients underwent biochemical studies at baseline and every

4 months if they were followed up with no intervention, or every 6months if they had parathyroid surgery Serum calcium, phosphorus,and alkaline phosphatase activity were measured by automated tech-niques (Technicon Instruments, Tarrytown, NY). Serum PTH wasmeasured by immunoradiometric assay (interassay coefficient of vari-ation, 5.6%) (6), urinary calcium by atomic absorption spectropho-tometry, and serum 25-hydroxyvitamin D and 1,25-dihydroxyvita-minD as previously described (interassay coefficients of variation, 9.6and 9.8%, respectively) (7).

Bone mineral density (BMD) of the lumbar spine, femoral neck, anddistal third of the nondominant radius was measured at baseline andyearly thereafter. The short-term in vivo precision error (root meansquare SD) was 0.026 g/cm2 for L1-L4, 0.032 g/cm2 for the total hip,0.041 g/cm2 for the femoral neck, and 0.033 g/cm2 for the forearm. Thedata on bone density are reported both as absolute measurements and asZ scores (8).

During the first 5 yr of the study, densitometric data were obtainedusing single- and dual-photon absorptiometry techniques (SP2 andDP3;Lunar Radiation Corp., Madison, WI), whereas data for virtually theentire past 20 yr were obtained using dual-energy x-ray absorptiometry(DXA). Twenty-six subjects who did not undergo parathyroidectomyswitched densitometers (mean time from study entry was 3 yr; range

116 patients 99 with asymptomatic disease (85%) 17 with symptomatic disease (15%)

Surgery in 59 patients (51%)50 with asymptomatic disease 9 with symptomatic disease

Normalization of biochemical values and increased bone

mineral density in 59 patientsa (100% of symptomatic and

asymptomatic patients)

No surgery in 57 patients (49%) 49 with asymptomatic disease

20 with surgical criteria; 29 without surgical criteria 8 with symptomatic disease

Disease progression in 22 patients 18 with asymptomatic disease

7 with surgical criteriab; 11 without surgical criteriac

(37% of asymptomatic patients) 8 with symptomatic disease

(100% of symptomatic patients)

Stable disease in 31 patients 31 with asymptomatic disease

13 with surgical criteria; 18 without surgical criteriad

(63% of asymptomatic patients)

FIG. 1. Baseline characteristics and outcomes in 116 patients with PHPT. All patients with symptomatic disease had kidney stones. In patients with disease progression,either an indication for surgery, according to National Institutes of Health Consensus Conference guidelines (4, 25) developed, or an overt complication ofhyperparathyroidism (such as kidney stones or fracture) occurred during follow-up. a, Fifteen patients remaining at 15 yr; b, three patients remaining at 15 yr; c, onepatient remaining at 15 yr; d, two patients remaining at 15 yr.

J Clin Endocrinol Metab, September 2008, 93(9):34623470 jcem.endojournals.org 3463


16 yr). Of the 11 patients followed up beyond 10 yr, eight switcheddensitometers (mean timeof switch fromstudyentrywas4yr).When thistransition occurred, the different machines were cross-calibrated byscanning 60 people on both machines within a fewweeks. Subjects wereselected to represent the range of bone densities that represented ourcohort. Regression modeling was used to create the predictive equationsthat allowed interconversion of the data to the newer instrumentation.Data obtained on the cohorts followed for 20 yr with the DXA technol-ogy were essentially identical with the data that spanned the transitionto DXA, giving assurance that an artifact of measurement was not in-troduced into the monitoring process.

Quality control included reading phantoms daily that were analyzedby Shewhart criteria for process stability (9, 10).

Statistical analysisIndependent t tests were used to compare baseline characteristics of

the medical and surgical groups. All data were transformed to percentchange from baseline before analysis and descriptive statistics examinedfor distributional characteristics. No measure exceeded a range of 3orders of magnitude, and all mean and median percent changes frombaseline were within 30% of each other on all measures. Whereas our10-yr report used ANOVA for comparison among surgical and nonsur-gical cohorts, and paired t tests to measure changes over time, a moreprecise tool was chosen for this report. Linear mixed model analysis forrepeated measures was used to estimate within-subject changes in BMDand biochemical parameters. Identical models with a fixed effect of time(annual years of follow-up), random effects of subject, time and error,and an empirically determined block diagonal autoregressive [1] covari-ance structure were created for each bone measurement site and bio-chemical parameter (11). Estimated within-subject change in outcomebetween specific time points was taken from the differences betweenmodel estimated means for each time, after adjustment of the degrees offreedom, to test the statistical significance of the comparison (12). Ad-justments for multiple comparisons were not used because the mixedmodel adjusted degrees of freedom for the calculation of the confidenceinterval for the difference. All models were run under restricted maxi-mum likelihood.

Separate models were performed for medically managed subjectsfrom the time of enrollment, with andwithout patientswhowere treatedwith antiresorptivemedications andwith andwithoutpatientswhocom-pleted the 15 yr of the study and for surgical subjects starting with theirlast available presurgical evaluation. The proportion of subjects meeting

surgical criteria at baseline that went on to have surgery was assessedwith Fishers exact test. Data are presented as mean SEM.

Results

Baseline characteristicsThe cohort of 116patientswithPHPT included66postmeno-

pausal women (56%), 25 premenopausal women (22%), and 25men (22%). Although 17 patients (15%) had a history of kidneystones, none had osteitis fibrosa cystica or classical neuromus-cular symptoms. Patients were followed up according to theirtreatment category (with or without surgery) and according tothe presence or absence of PHPT symptoms (Fig. 1 and Table 1).Patientswho underwent parathyroidectomy (n 59) had higherserum calcium and PTH concentrations than those (n 57)whodid not undergo surgery (Table 1). Patients who underwent sur-gery also had significantly lower BMD Z-scores at the lumbarspine and femoral neck but not at the radius. In both groups, atypical pattern of skeletal involvement was seen with greaterreductions at the distal one third radius (cortical site) than thelumbar spine (cancellous site). Urinary calcium excretion, alka-line phosphatase activity, and vitamin D concentrations weresimilar between the surgical and nonsurgical groups.

Clinical course over 15 yr: no parathyroid surgeryFifty-seven subjects with PHPT were followed without inter-

vention for up to 15 yr. The vast majority (n 49; 86%) wereasymptomatic. During this period of time, 11 patients died. Fourof the 11 subjects who died had increased risk factors for car-diovascular disease at study entry, such as diabetes mellitus andhypertension. The causes of death included myocardial infarc-tion (n 2), complications of diabetes mellitus (n 2), con-gestive heart failure (n 1), stroke (n 1), aortic aneurysmrupture (n1), gall bladder cancer (n1), andunknown causes(n 3). The subjects who died did not have higher serum

TABLE 1. Baseline characteristics of patients with primary hyperparathyroidism

CharacteristicNo surgery(n 57)

Surgery(n 59) Normal range P value

Age (yr) 57 2 55 2 NSSex (n) NSPostmenopausal 32 34Premenopausal 13 12men 12 13

Kidney stones (n) 8 9 NSSerum calcium (mg/dl) 10.5 0.1 10.8 0.1 8.410.2 0.01Serum PTH (pg/ml) 116 7 144 13 1065 0.05Urinary calcium (mg/g creatinine) 236 17 262 17 300 NSSerum total alkaline phosphatase (U/liter) 98 6 98 6 100 NSSerum 25-hydroxyvitamin D (ng/ml) 21 1 21 1 952 NSSerum 1,25-dihydroxyvitamin D (pg/ml) 57 2 58 3 1560 NSBMD Z score lumbar spine 0.03 0.2 0.80 0.2 0.02BMD Z score femoral neck 0.63 0.1 1.22 0.1 0.002BMD Z score distal one third radius 0.98 0.2 1.30 0.2 NS

Values are shown as means SEM. To convert values for serum calcium to millimoles per liter, multiply by 0.25; to convert values for PTH to picomoles per liter, divideby 9.5; to convert values for urinary calcium to millimoles per liter, multiply by 0.025; to convert values for 25-hydroxyvitamin D to nanomol/liter, multiply by 2.496; toconvert values for 1,25-dihydroxyvitamin D to picomoles per liter, multiply by 2.6. NS, Non-significant.

3464 Rubin et al. Natural History of Primary Hyperparathyroidism J Clin Endocrinol Metab, September 2008, 93(9):34623470


calcium levels at baseline (10.3 0.1 mg/dl) than the remain-der of the asymptomatic medical subjects but did have higherinitial PTH levels (161 25 vs. 107 8 pg/ml, P 0.05).Eight subjects were unable to comply with regular study visitsand five were eventually lost to follow-up. None of the demo-graphic variables available to predict duration of follow (age atstudy enrollment, sex, and race) achieved statistical significance.Nearly half of the nonintervention group (20 of 57) ultimatelyhad successful surgery. Of these, one was symptomatic at base-line but had initially refused surgery, sixmet surgical criteria butdeferred intervention initially, six had disease progression, andseven no longer wished to be followed up without intervention.

Biochemical changesOf the 49 asymptomatic subjects, 29 (59%) did not meet

surgical criteria at baseline, whereas 20 (41%) did meet criteriabut refused intervention. There were no significant changes inPTH, total alkaline phosphatase activity, or urinary calcium ex-cretion (Table 2) among the asymptomatic patients who did nothave surgery, for as long as 15 yr of follow-up. However, in thesubjects who were followed up conservatively for up to 15 yr,serum calcium concentrations rose to levels, beginning at yr 13,that were slightly but significantly higher than their individualbaseline values. In the11patientswhocompleted10yrof follow-up, neither the serum calcium nor the PTH changed significantlyover yr 0, 5, and 10 (serum calcium: 10.5 0.1, 10.7 0.1,10.8 0.2 mg/dl; PTH: 109 13, 102 13, 110 14 pg/ml).In the six patients who completed 15 yr of follow-up, the serumcalciumchanged significantly only at yr 15, comparedwith base-line (yr 0, 5, 10, and 15were 10.6 0.2, 10.7 0.2, 11.1 0.3,and 11.1 0.2 mg/dl, respectively). PTH did not change signif-icantly (yr 0, 5, 10, and 15 were 98 12, 81 12, 74 14, and89 12 pg/ml, respectively). Longitudinal biochemical profileswere similar among those asymptomatic subjectswhomet or didnot meet surgical criteria.

Densitometric changesBMDdid not change at any measurement site during the first

8 yr of follow-up (Fig. 2) in the 49 asymptomatic patients. Thelumbar spine BMD was stable for the entire 15 yr of follow-up,in both the overall cohort and the 28 postmenopausal women.

However, even before the 10-yr time point, the femoral neck, asite containing a substantial amount of cortical bone, and thedistal one third radius, a site containing a predominance of cor-tical bone, showed significant reductions in BMD.Overall, 29 ofthe 49 asymptomatic patients (59%) had more than a 10% de-cline in BMD at one or more sites over the 15-yr period. Elevenof the 29 subjects were patients who had been previously foundto have declined within 10 yr (3); eight other patients, with theavailability of additional time points, were now found to alsohave declined within 10 yr, whereas 10 other patients declinedafter 10 yr of observation.

Of the 11 patients followed beyond 10 yr, eight switcheddensitometers early in the study (mean time of switch from studyentry was 4 yr). In that subgroup of eight patients, before theswitch, BMD increased on average 4% at the lumbar spine anddecreased 2% at the femoral neck and 1% at the distal radius.After the switch (using the first BMD after the switch as a newbaseline), there were further declines in average BMD of 1% atthe lumbar spine, 2% at the femoral neck, and 10% at the distalradius.

The six asymptomatic subjects who completed the 15-yr periodof monitoring did not differ from the rest of the asymptomaticsubjects (n 43) in terms of age, baseline biochemistries (serumcalcium, PTH, urinary calcium excretion, total alkaline phos-phatase, 25-hydroxyvitamin D, or 1,25-dihydroxyvitamin D),or baseline Z-scores. However, even before year 10, BMD at thedistal one third radius site showed accelerated losses. Linearmixed-model analyses for repeatedmeasures were performed,comparing BMD changes in the first 10 yr of study among thosefollowedup for less than10yr, and those followedup fora longerperiod. At the lumbar spine or femoral neck, the rates ofchange between these groups did not differ (P 0.85, lumbarspine; P 0.09, femoral neck). However, after yr 10, BMDdeclined significantly at the distal one third radius (P 0.001).The slope of BMD loss therefore differed at the distal radius(there was an accelerated rate of loss after 10 yr) but not at thefemoral neck (there was the same rate of loss continuing frombefore 10 yr).

Thirteen asymptomatic subjects who were followed upwithout surgery received antiresorptive therapy at some timepoint in the study (off protocol). The median duration of

TABLE 2. Biochemical changes in asymptomatic patients followed up without parathyroidectomy (n 49)

VariableBaseline(n 49)

Yr 5(n 25)

Yr 10(n 11)

Yr 13(n 9)

Yr 15(n 6)

Serum calcium (mg/dl) 10.5 0.1 10.7 0.1 10.8 0.2 11.0 0.2a 11.1 0.2a

PTH (pg/ml) 122 10 119 12 123 14 124 16 121 18Serum creatinine (mg/dl) 1.0 0.1 1.0 0.1 1.0 0.1 1.0 0.2 0.8 0.1Urinary calcium (mg/dl) 238 19 215 23 185 32 247 36 202 36Serum 25-(OH) vitamin D (ng/ml) 21 1 22 2 22 3 21 3 19 4Serum 1,25-(OH)2 vitamin D (pg/ml) 56 2 58 3 54 5 40 5

a 48 7

Values are shown as means SEM. Pair-wise comparisons are shown at each time point with respect to the retained subjects baseline values. To convert values forserum calcium to millimoles per liter, multiply by 0.25; to convert values for PTH to picomoles per liter, divide by 9.5; to convert values for serum creatinine tomicromoles per liter, multiply by 76.26; to convert values for urinary calcium to millimoles per liter, multiply by 0.025; to convert values for 25-hydroxyvitamin D tonanomoles per liter, multiply by 2.496; to convert values for 1,25-dihydroxyvitamin D to picomoles per liter, multiply by 2.6. 25-(OH) vitamin D, 25-hydroxyvitamin D;1,25-(OH)2 vitamin D, 1,25-dihydroxyvitamin D.a P 0.01 for the comparison with the individual baseline values for these groups.



antiresorptive drug use was 4 yr (range 111 yr), whereas themedian observation time in the remaining 36 asymptomaticsubjects was 5 yr (range 115 yr). However, linear mixed-model analyses for repeated measures, comparing BMDchanges in those who did and did not receive antiresorptivetherapy, showed no differences in terms of the densitometricmeasurements over the 15 yr at any site.

Disease progressionMost of the 49 asymptomatic patients did not develop densito-

metric or other surgical guidelines. However, 18 patients (37%)did develop new surgical criteria at any time point over the 15 yr ofobservation.Meeting surgical criteria at study baseline did not pre-dictwhowouldhaveprogressivedisease.Of the 20 asymptomaticsubjects who met surgical criteria at baseline (5 yr, n 10; 10

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FIG. 2. A, Mean ( SEM) changes in BMD at three sites in patients with PHPT. Data shown are cumulative percent changes from baseline at each site in subjects whodid not undergo parathyroidectomy after 115 yr of follow-up. *, P 0.05, compared with baseline. B, Mean ( SEM). Changes in BMD at three sites in patients withPHPT are shown only in subjects who completed 10 yr of follow-up. Eleven subjects were followed up for a total of 10 yr. C, Mean ( SEM). Changes in BMD at threesites in patients with PHPT are shown only in subjects who completed 15 years of follow-up. Six subjects were followed up for a total of 15 yr.



yr, n 5; 15 yr, n 3), seven had disease progression (35%);likewise, of the 29 asymptomatic subjects who did not meetsurgical criteria at baseline (5 yr, n 15; 10 yr, n 12; 15 yr,n 3), 11 had disease progression (38%), a similar proportion.Changes in bone density over time were also similar among theasymptomatic subjects, regardless of whether they met surgicalcriteria at baseline.

All eight of the patients who had nephrolithiasis, and weretherefore symptomatic, but refused surgery, showed progressionby at least one criterion: six had recurrent kidney stones, onesustained a fracture, and one developed marked hypercalcemia.Despite these further complications, only one of these patientsagreed to undergo parathyroidectomy.

Clinical course over 15 yr in subjects who underwentparathyroidectomy

All 59 patients had successful surgery as evidenced by normalserum calcium and PTHvalues postoperatively. Only nine of the

59 subjects (15%) who underwent surgery were symptomaticwith kidney stones. At 15 yr, serum calciumwas 9.8 0.2mg/dl(2.5 0.1 mmol/liter), PTH 34 21 pg/ml (3.6 2 pmol/liter),and urinary calcium excretion 138 36mg/dl (3.5 0.9mmol/liter), all significantly lower (P 0.01) in comparison with theindividual subjects baseline values and all well within normallimits. Postoperative increases in BMD were sustained withBMD remaining significantly above baseline for the entire 15 yrof follow-up at all three skeletal sites (Fig. 3). Pre- and post-menopausalwomen andmen, and thosewith andwithout symp-toms, all had similar increases in BMD. Assessment of postop-erative changes in BMD in those subjects who were initiallyfollowedupwithout intervention, but ultimately underwent par-athyroidectomy (n 20), demonstrated similar increases inBMD to those who had parathyroidectomy at the outset (at yr 1,5, and 10, the lumbar spine increased 9, 6, and 12%; the femoralneck 1, 7, and 10%; the distal radius 4, 8, and 7%). There wereno recurrent kidney stones in any of the nine symptomatic pa-tients with kidney stones who underwent parathyroid surgery.

Discussion

This report, the longest prospective follow-upofmild PHPTeverconducted, provides data on the long-term natural history of thetreated and untreated disorder. In our previous report, coveringthe first 10 yr, we showed that most asymptomatic patients whodid not have surgery did well, although 25% did show evidenceof progressive disease (3). Average serum levels of calcium andPTH did not change and hypercalciuria, if present, did notworsen. Average BMD asmeasured by DXAwas stable. Amongthe 25% who did show evidence for progression, worseninghypercalcemia, hypercalciuria, and reductions in BMDwere themost common complications. In the earlier report, we also de-scribed patients who underwent successful surgery. In additionto normalization of serum calcium and PTH levels, BMD im-proved significantly at the lumbar spine and hip regions (3). Thecurrent report, which extends findings on this same cohort to 15yr, provides new information that may well influence treatmentdecisions in this disease.

In those who did not undergo surgery, lumbar spine BMDcontinued to be relatively stable during yr 1015. Although pro-gressive osteoarthritic changes at this site could have contributedto the stable lumbar spine findings, it is also consistent with ourprior observations that the lumbar spine is a site that is relativelyprotected from bone loss in PHPT. Thus, despite histomorpho-metric evidence for increased bone turnover in PHPT (13), can-cellous bone appears to be relatively well preserved, even aftermany years. Potentialmechanisms for preservation of cancellousbone mass are suggested by quantitative histomorphometry ofbone biopsies from patients with PHPT (1315). Although ac-tivation frequency is increased, resorptionpits are relatively shal-low such that increased osteoblast activity is likely to ensurereasonably well-balanced remodeling units. As a result, the ex-pected age-associated loss of trabecular plates is not regularlyseen in PHPT (16).

In contrast to the stability at the lumbar spine, declines in

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FIG. 2. (Continued).



BMD became apparent before yr 10 at the femoral neck anddistal one third radius sites in the few remaining patients whowere followed up without surgery. The detection of statistically

significant declines in cortical bonedensity before yr 10 is a result of boththe additional observation points inthe time line as well as the more pow-erful statistical mixed model ap-proach, in that variance attributableto within-subject covariance amongrepeated measures no longer inflatesthe error term (3).

This observation suggests thatthe catabolic effects of PTH at thefemoral neck and distal radius,which contain more cortical bonethan the lumbar spine, might beginto emerge with prolonged exposureto PTH excess. Cortical bone is morevulnerable than cancellous bone tothe catabolic effects of PTH (17).The possibility that cortical bonedensity is eventually compromised inPHPT has been suggested by some(18, 19) but not all studies (20, 21).Why so much time is required beforethese changes manifest themselvesmay relate to the low turnover rate ofcortical bone, requiring years of ex-posure to demonstrate the negativeeffect. Alternatively, the process bywhich excess PTH leads to resorp-tion of cortical bone may be com-pensated initially but not sustainedover time.

The declines in cortical bone den-sity were observed regardless ofwhether the patients taking antire-sorptive therapy were excluded. In-cluding those on antiresorptive ther-apy might have potentially masked aneven greater bone loss than what wasobserved. However, the importantpoint is that use of antiresorptives didnot alter the natural history of theeventual cortical reductions after 10yr or the prolonged maintenance ofbone density at the lumbar spine.

Concepts of bone loss in mildPHPTmay need to be re-examined inlight of these new observations. It iscurrently hypothesized (22, 23) thatcortical BMD is lost early in the dis-ease before hypercalcemia brings thedisorder to clinical attention. Al-though some patients may have hadPHPT for years before diagnosis, for

most patients, as demonstrated in this study, BMD remainsstable for several years after coming to medical attention. Thenewsteady statemaybe sustained for an even longerperiodat the

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n= 46 38 24 15

Years of Follow-UpFIG. 3. Mean ( SEM) changes in BMD at three sites in patients with PHPT after parathyroidectomy. Datashown are cumulative percent changes from surgery at each site after 115 yr of follow-up. *, P 0.05,compared with baseline.



cancellous lumbar spine but may not be at sites in which corticalbone is more prominent. The loss of bone mass in the hip anddistal one third radius suggests that cortical bone might not re-main stable over time.

Over the 15-yr follow-up period, 37% of asymptomatic pa-tients showed evidence for disease progression at some timepoint, a substantial increaseover the25%progressionduring thefirst 10 yr.Meeting surgical criteria at study entry did not predictwho would have worsening disease. In asymptomatic patientswho did not undergo parathyroidectomy, there were no reliablepredictors of bone loss, the development of symptomatic com-plications, or other surgical criteria. This point, along with theeventual decline in cortical bone density, highlights the impor-tanceof regularmonitoring inasymptomaticpatientswithPHPTwho do not undergo parathyroid surgery.

Meeting surgical guidelines at the time of diagnosis did notpredict a worse outcome in asymptomatic patients who werefollowed upwithout surgery, raising questions as to whether theguidelines for surgery in asymptomatic patients with PHPT aresufficient to support appropriate decisionmaking (24). Since thisstudy began, surgical criteria were revised after a National In-stitutes of Health-sponsored workshop on asymptomatic PHPTin 2002 (25). Surgical recommendations were expanded to in-cludea serumcalciumconcentrationgreater than1.0mg/dl (0.25mmol/liter) above normal or a marked reduction in BMD at anysite (T scorebelow2.5).Using thesenewmore stringent criteriawould, in all likelihood, have uncovered evidence for evengreater disease progression. In addition, a larger group of lessseverely affected individuals would have met surgical criteria atbaseline.

Fifteen years after successful parathyroid surgery, patientssustained their postoperative increases in BMD both at cancel-lous and cortical sites despite the expectation of age-related boneloss. Most likely, the early increase in cancellous BMD resultsfrom mineralization of the expanded remodeling space that ischaracteristic of PHPT (26, 27). Although the increase in BMDat themore highly cortical distal one third radiuswas not as greatas that at cancellous sites, these data suggest that cortical boneloss in patients with PHPT is at least partially reversible. Thisnew observation contrasts with data from previous reports (19,28) and is most likely explained by the longer period ofobservation.

A limitation of this study is the small number of asymptomaticparticipants who remained in the nonsurgical group at the conclu-sion of the 15 yr of observation, a byproduct of this type of verylong-term natural history study. Nevertheless, the six asymptom-atic subjects who completed the 15-yr period of monitoring didnot differ from the rest of the asymptomatic subjects in terms ofage, baseline biochemistries, or baseline BMD Z-scores. An ad-ditional limitationwas the change indensitometers in someof thepatients in the early years of the study. However, the contrastbetween the increase in BMD in the patients who underwentparathyroidectomy (manyofwhomwere also studiedbefore andafter change in equipment) and the lackof change inpatientswhodid not argues against any widespread systematic error.

A further limitation is that the study was not randomized or

controlled. The patients who underwent surgery were differentat the outset from those who were managed conservatively. De-spite this point, the presence within each group (surgical andnonsurgical) of patients who did or did not meet criteria forsurgery has allowed us to gain some insights thatwould not havebeen possible with a more rigorous experimental design. More-over, it is noteworthy that data from short-term studies in whichidentically matched PHPT subjects were randomized to a surgi-cal or nonsurgical group are virtually indistinguishable from thefindings we currently present (29, 30). Like the randomized trialofRao et al. (30),manyofourmedical subjects eventually electedto undergo parathyroidectomy. Most recently, randomized 1-(31) and 2-yr (32) trials of surgery have also corroborated ourearly densitometric observations. These studies, together withours, seem to raise the question as to whether long-termfollow-up without intervention is the best option in PHPT.

The clinical significance of densitometric changes in PHPTneeds to be considered along with other indices of bone strength(33). For example, the decreases in cortical BMD in the groupfollowed up medically might be due to increased cortical diam-eter, which itself might counteract the apparent BMD reductionand thus reduce fracture risk by virtue of size-related improve-ments in biomechanical indices (34). It is also unclear whetherpostoperative improvements in cortical BMD are associatedwith improved bone strength. Assessment of bone geometry,microarchitecture, and material properties of bone (33, 35, 36),as well as fractures per se, is necessary for a complete descriptionof fracture risk in PHPT (37, 38).

Whether mortality is increased in mild PHPT, as it clearly is inmore severedisease, is controversial (39,40). Inour study, thenum-ber of deaths in the surgical group is unknown because many sub-jects were lost to follow-up, but 11 of the nonsurgical subjects(19%) died over the 15 yr of follow-up. The observations that themajority of these deaths were related to cardiovascular causes, andthat baseline PTH levels in these subjects were significantly higher,is consistent with the observation that more severe PHPT and/orhigher sustainedPTHlevelsmight be associatedwith increased car-diovascularmortality.Nevertheless, it is important to reiterate thatthis study was not powered to allow us to comment on this issue.Only epidemiological studies can address the issue of mortality inPHPTandwhether there isadifferencebetween thosewhoundergoparathyroid surgery and those who do not.

These results indicate that there is evidence of progressivedisease in individuals with mild PHPT, particularly with regardto declines in cortical bone density. Although the study was lim-ited by its observational design and the small number of patientswho completed 15 yr of observation, these new data raise thequestion as towhether conservative, nonsurgicalmanagement ofPHPT, among those deemed not to be surgical candidates,should be limited to a decade of follow-up. Decisions about fur-ther conservativemanagement dependon continueddensitomet-ric stability. These results also emphasize the need for continuedlong-term surveillance of biochemical indices and bone densi-tometry in all patients with mild disease who do not undergoparathyroid surgery.



Acknowledgments

Address all correspondence and requests for reprints to: Shonni J.Silverberg, M.D., Department of Medicine, Columbia University,College of Physicians and Surgeons, 630 West 168th Street, NewYork, New York 10032. E-mail: [email protected].

This work was supported by Grant 32333 from the National Insti-tutes of Health, National Institute of Diabetes and Digestive and KidneyDiseases. S.J.S. is supported in part by Grant K24 DK074457 from theNational Institutes of Health, National Institute of Diabetes and Diges-tive Kidney Diseases.

Disclosure Statement: M.R.R., J.P.B., D.J.M., T.J., E.Sh., E.Si., J.U.,and S.J.S. have nothing to declare.

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