The American Journal of Surgery (2012) 203, 357–360

Midwest Surgical Association -lowering medications in patients with primary hyperparathyroidism: intraoperative findings and postoperative

David F. Schneider, M.D., M.S.a,*, Gregory M. Day, M.D.a,b, Steven A. De Jong, M.D., F.A.C.S.a aDepartment of Surgery, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153, USA; bDepartment of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

KEYWORDS: Abstract Hyperparathyroidism; BACKGROUND: We analyzed how calcium-lowering medications (CLMs) influenced surgical find- Calcium; ings in patients with primary hyperparathyroidism. Medications; METHODS: A retrospective review was conducted of 281 patients undergoing surgery for primary ; hyperparathyroidism. Logistic regression evaluated the relationship between CLM and surgical find- ings. A mixed-effects model determined the influence of CLMs on these curves. RESULTS: We found that CLM (P ϭ .018) and a higher serum calcium level (P ϭ .018) were variables making 4-gland hyperplasia less likely. Analysis of intraoperative parathyroid hormone (IOPTH) plots revealed that CLMs altered the kinetics (P ϭ .043). However, the 2 groups did not differ in the number of measurements necessary for a 50% decrease in IOPTH levels. Multivariate logistic regression also revealed that patients taking more than one CLM had an increased association with postoperative hypocalcemia (P ϭ .018). CONCLUSIONS: Although CLM contributed to differences in IOPTH curves, their use does not require changing standard IOPTH protocol but should alert the surgeon to the risk of postoperative hypocalcemia. © 2012 Elsevier Inc. All rights reserved.

In the United States, 100,000 new cases of primary heartburn, , and . Neuropsychi- hyperparathyroidism (HPTH) are diagnosed annually.1 This atric symptoms such as fatigue and also are com- disease is characterized by inappropriately increased para- mon.2,3 Surgery remains the only definitive treatment for hormone levels. The resultant hypercalcemia dis- HPTH with cure rates of 95% or better.4–6 Recently, the rupts bone metabolism, leading to /, number of medications that alter serum calcium levels has nephrolithiasis, renal dysfunction, gout, or . Other grown, and patients with primary hyperparathyroidism often symptoms include gastrointestinal manifestations such as are prescribed these medications. Some, such as the calcimi- metics, are marketed specifically to treat hyperparathyroidism. act by stimulating the calcium-sensing receptor, ϩ ϩ * Corresponding author. Tel.: 1-608-263-1387; fax: 1-608-263- thereby decreasing PTH secretion and decreasing serum cal- 7652. E-mail address: [email protected] cium. Others, such as bisphosphonates or selective estrogen Manuscript received July 6, 2011; revised manuscript September 25, receptor modulators, prevent . Postmenopausal 2011 women often are prescribed hormone replacement therapy

0002-9610/$ - see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2011.09.014 358 The American Journal of Surgery, Vol 203, No 3, March 2012 whereas younger women take various formulations of estrogen these curves were compared with one another by the mixed- and progesterone as oral contraceptives. These estrogen/pro- effects model. This model is useful in settings where re- gesterone compounds are antiresorptive, preventing bone turn- peated measurements are made on the same patient, such as over and decreasing serum calcium levels.7 Many patients with intraoperative PTH testing. Furthermore, we chose this HPTH suffer from gastroesophageal reflux disease and take model because we were comparing curves from regres- proton pump inhibitors (PPIs). These medications interfere sion analysis and needed to account for the effects of this with intestinal calcium absorption, resulting in lower serum previous statistical transformation.11,12 For this analysis, calcium levels. Specifically, a slightly acidic environment fa- each medication class was considered individually and as cilitates liberation of calcium from the food matrix and absorp- a group. Statistical analysis was performed using STATA tion of calcium within the proximal duodenum.8,9 software, version 10.0 (StataCorp, College Station, TX). With such an array of calcium-lowering medications A P value of less than .05 was considered statistically (CLMs) available, the purpose of this report was to describe significant. their occurrence in a single-institution, retrospective study of patients presenting for surgical treatment of HPTH. Spe- cifically, we analyzed the influence of CLMs on intraoper- ative findings such as 4-gland hyperplasia and intraopera- Results tive PTH (IOPTH) kinetics. Finally, we show that CLMs are Of the 281 patients undergoing surgery for HPTH, 118 associated with postoperative hypocalcemia. (42%) were taking CLMs at the time of surgery, and 34 patients (12%) were taking more than one of these medica- tions (Table 1). The frequencies of the various CLMs pre- scribed to these patients are shown in Table 1. Thirty-three Methods patients also were taking , but vitamin D was not considered a CLM because its overall effect is to increase We performed a retrospective chart review of 281 con- serum calcium levels (Table 1). It is interesting to note that secutive patients undergoing surgery for HPTH at our in- 38 patients (14%) in this series of patients with HPTH were stitution from 2006 to 2008. Patients with secondary or taking calcimimetics such as (Table 1). tertiary hyperparathyroidism were excluded from this study. We analyzed the relationship between the use of these Patients whose hyperparathyroidism was found to be part of CLMs and surgical findings, specifically the number of a hereditary syndrome also were excluded from this study. adenomas or abnormal glands, by multivariate logistic re- Patient demographics, comorbidities, symptoms, medica- gression analysis. Although there was no overall relation- tions, preoperative studies, surgical findings, and IOPTH ship between CLM and multigland disease, we did find that levels were recorded in a database. PPIs, estrogen/proges- a higher preoperative calcium level (odds ratio, .4; 95% terone, selective estrogen receptor modulators, bisphospho- confidence interval, .2–.9; P ϭ .018) and CLM (odds ratio, nates, calcitonin, and calcimimetics were considered CLMs. .33; 95% confidence interval, .1–.9; P ϭ .018) were signif- All surgeries were performed by a single surgeon (S.A.D.). icant variables making 4-gland hyperplasia less likely. As part of the preoperative work-up, each patient underwent technetium-99m-sestamibi scanning and neck ultrasonogra- phy. Patients with localized sestamibi scans underwent a lim- Table 1 Calcium-altering medications in patients with ited, unilateral exploration whereas those whose imaging stud- primary hyperparathyroidism ies were non-localizing or who had discordant imaging underwent a bilateral neck exploration. IOPTH monitoring Variable Number (%) was performed using a modified protocol as first described by Patients on calcium-altering medications 118 (41.99) 10 Irvin et al. In cases in which the PTH did not decrease into Mean number of calcium-altering 1.10 (.59) the normal range or poor renal function dampened the PTH medications (SD) decline, additional PTH levels (beyond 10 minutes) also were Patients on Ͼ1 calcium-altering medication 34 (12.10) sent. Calcium levels were drawn on the morning of the first Medication class Estrogen/progesterone* 10 (3.56) postoperative day, and a level less than 8.5 mg/dL was con- SERMs* 4 (1.42) sidered postoperative hypocalcemia. Bisphosphonates* 34 (12.1) The Loyola University Medical Center Institutional Re- Calcitonin* 6 (2.14) view Board approved this study. Calcimimetics* 38 (13.5) Multivariate logistic regression was used to analyze the PPI* 38 (13.5) Vitamin D 33 (11.4) relationship between CLMs and intraoperative findings (sin- gle vs multigland disease) in addition to postoperative hy- Incidence and distribution of calcium-altering medications among pocalcemia. the 281 patients undergoing surgery for primary hyperparathyroidism. SD ϭ standard deviation, SERM ϭ selective estrogen receptor To determine the effect of CLMs on IOPTH kinetics, modulator. each patient’s series of IOPTH values was plotted against *Considered CLMs. time. Regression was used to fit curves to these values, and D.F. Schneider et al. CLMs and HPTH 359

with postoperative hypocalcemia (odds ratio, 1.59; 95% confidence interval, 1.11–2.26; P ϭ .010).

Comments

Here we have reported a series of 281 consecutive pa- tients undergoing surgery for HPTH and found that 42% of these patients were taking a CLM at the time of surgery. The most frequent CLMs prescribed to this patient cohort were PPIs and calcimimetics. It is striking that 13.5% of these patients were prescribed cinacalcet even though the Food and Drug Administration–approved indication is for pa- tients with secondary hyperparathyroidism. This was a de- Figure 1 Fitted quadratic plot of intraoperative PTH values. Re- tailed analysis of how CLM influences intraoperative and gression was used to fit curves for intraoperative PTH. A mixed- postoperative findings. Much has been written about the effects model was used to determine that the IOPTH curves between impact of vitamin D supplementation on localization studies those taking (gray) and not taking CLM (black) were significantly and IOPTH kinetics.13,14 We did not consider vitamin D as different from one another with the P value shown. *P ϭ .04. a CLM because its overall effect is to increase, not decrease, serum calcium level, and its influence on IOPTH kinetics 14 To analyze the influence of CLM on IOPTH kinetics, we already has been studied. Kandil et al13 found that patients with lower 25- plotted IOPTH values versus time, and found that a qua- hydroxyvitamin D levels were more likely to have posi- dratic function best described these curves by regression tive sestamibi scan results. We did not find that CLM analysis (Fig. 1). When comparing these fitted curves, we influenced localization studies, however, our multivariate found that CLM significantly altered IOPTH kinetics with a analysis did reveal that CLM was a significant factor steeper decline in PTH with less recovery at later time making 4-gland hyperplasia less likely. Our group and points (Fig. 1). Although the fitted curves were significantly others have found that a higher preoperative calcium level is different from one another (P ϭ .04), the presence or ab- a key feature that predicts single adenoma.15 Kandil et al13 sence of CLMs did not change the number of IOPTH reported that patients with hypovitaminosis D present with measurements needed to achieve a 50% decrease in PTH more severe laboratory indexes of HPTH. We believe that after resection of the enlarged gland(s). When considering patients taking CLMs also have a more severe biochemical each class of CLMs individually, we found that the form of the disease. Although vitamin D supplementation IOPTH curves for patients taking bisphosphonates or exacerbates the laboratory indexes (serum calcium and in- calcimimetics were significantly different from patients tact PTH), CLM masks or ameliorates these laboratory not taking these medications and followed the overall findings, and our findings are consistent with the existing pattern described earlier. literature on vitamin D and HPTH. Because CLMs did alter IOPTH kinetics when compared CLMs do alter the shape of IOPTH curves when com- with the IOPTH kinetics of patients not taking CLMs, we pared with patients not taking CLMs (Fig. 1). Impor- hypothesized that CLMs might lead to postoperative hy- tantly, this did not require a change in the standard pocalcemia. It is our practice to measure calcium levels on IOPTH protocol because the number and timing of mea- all patients undergoing parathyroidectomy on the first post- surements needed to achieve a 50% decrease in PTH operative day before their discharge. There were no differ- values did not differ between the 2 groups. Those taking ences in calcium levels when comparing those patients a CLM showed a steeper decline in IOPTH with less taking CLMs with those patients not taking these medica- recovery at the final measurements when compared with tions. As noted earlier, some patients were taking more than those not taking these medications. one CLM, and multivariate logistic regression to predict This finding led us to investigate the relationship be- postoperative hypocalcemia revealed that patients taking tween CLM and postoperative hypocalcemia. Although a more than one CLM had a significantly increased associa- single CLM did not change postoperative serum calcium tion with postoperative hypocalcemia (odds ratio, 3.06; 95% values, patients taking more than one CLM did have post- confidence interval, 1.21–7.75; P ϭ .018). No single agent operative hypocalcemia. Our data were limited in that we alone had a significant impact on postoperative hypocalce- could not directly attribute the effects of any single agent to mia, but the combination of calcimimetics and bisphospho- postoperative hypocalcemia, but we did find that more than nates were associated with the greatest decrease in calcium one medication was associated with postoperative hypocal- after the surgery. This analysis also identified the number of cemia; the worst combination was a and a glands removed as another factor significantly associated bisphosphonate. The subset of patients taking more than one 360 The American Journal of Surgery, Vol 203, No 3, March 2012

CLM were more likely to require activated vitamin D in the 14. Adler JT, Sippel RS, Chen H. 25-hydroxyvitamin D status does not postoperative period, although our decision to use activated affect intraoperative parathyroid hormone dynamics in patients with vitamin D in combination with calcium carbonate was mul- primary hyperparathyroidism. Ann Surg Oncol 2010;17:2958–62. 15. Kebebew E, Hwang J, Reiff E, et al. Predictors of single-gland vs tifactorial and not driven by formula or protocol. We believe multigland in primary hyperparathyroidism: a sim- that this represents transient postoperative hypocalcemia ple and accurate scoring model. Arch Surg 2006;141:777–82. and not permanent , but we did not collect long-term data. Furthermore, we do not have data on the symptoms of hypocalcemia that patients may have ex- Discussion perienced after hospital discharge. Another limitation of this retrospective study was that we also do not have long-term Dr Scott M. Wilhelm (Cleveland, OH): I have several data on our cure rates, and it would be interesting to know questions. Did you check whether PTH levels were a marker of if CLMs ultimately influenced cure rates for HPTH. multigland disease? Did you find an impact of any of the In the short term, we believe that a CLM may serve as a individual calcium-lowering medications on the impact of bio marker for the severity of HPTH. We have tried to control PTH level or your postoperative calcium levels? Have you for this by including preoperative calcium and PTH levels in made any changes to your overall clinical practices as a result all of our multivariate analyses. Nonetheless, the pattern of of the study? If patients are taking more than one calcium- IOPTH kinetics and postoperative hypocalcemia seen lowering medication preoperatively, do you automatically start among patients taking CLMs might reflect a more severe them on or calcium supplementation immediately form of HPTH or a subset of patients with long-standing after surgery? And, finally, can you speculate as to why you HPTH whose surgical treatment has been delayed in favor think any of these calcium-lowering medications taken preop- of medical management. Even if these medications are only eratively decrease the rate of multigland disease? a marker for disease severity or duration, we believe that a Dr David F. Schneider (Madison, WI): Regarding PTH CLM should alert the surgeon to which patients will need levels, there was an insignificant trend towards slightly extra calcium or activated vitamin D supplementation in the increased both calcium and PTH in the group that was on immediate postoperative period. these medications. Regarding specific medications in a sub- group analysis, it turns out that both the bisphosphonates and the calcium medicines fit this overall pattern. You asked References what we do in our practice now for patients taking these, and, most of the time, patients stay 1 night in the hospital, 1. Coker LH, Rorie K, Cantley L, et al. Primary hyperparathyroidism, and do not have problems until a day or two later. So we cognition, and health-related quality of life. Ann Surg 2005;242:642–50. give them higher doses of calcium supplementation to go 2. Kukora JS, Zeiger MA, Clark OH, et al. The American Association of home on if they are taking more than one of these medica- Clinical Endocrinologists and the American Association of endocrine tions. Calcitriol use is based more on what their calcium and surgeons position statement on the diagnosis and management of phosphorous look like and whether or not we think they primary hyperparathyroidism. Endocrinol Pract 2005;11:49–54. 3. Rodgers SE, Lew JI, Solorzano CC. Primary hyperparathyroidism. truly are hypoparathyroid. I do not think these medications Curr Opin Oncol 2008;20:52–8. change the underlying patho-biology of primary hypopara- 4. Doppman JL, Miller DL. Localization of parathyroid tumors in pa- thyroidism, but are a marker for patients with a higher tients with asymptomatic hyperparathyroidism and no previous sur- calcium and a higher PTH. Those patients on these medi- gery. J Bone Miner Res 1991;6:S153–9. cations are more likely to have single-gland disease. 5. Grant CS, Thompson G, Farley D, et al. Primary hyperparathyroidism surgical management since the introduction of minimally invasive para- Dr Tracy Wang (Milwaukee, WI): I have 2 questions. thyroidectomy: Mayo Clinic experience. Arch Surg 2005;140:472–8. Did you look at the duration that the patients were on any of 6. Chen H, Zeiger MA, Gordon TA, et al. Parathyroidectomy in Mary- these medications prior to surgery and see if that related to land: effects of an endocrine center. Surgery 1996;120:948–52. the degree of postoperative hypocalcemia? With respect to 7. Vestergaard P. Current pharmacological options for the management vitamin D, did you look at vitamin D levels preoperatively of primary hyperparathyroidism. Drugs 2006;66:2189–211. 8. Insogna KL. The effect of proton pump-inhibiting drugs on mineral and relate that to postoperative hypocalcemia? metabolism. Am J Gastroenterol 2009;104:S2–4. Dr Schneider: As to length of time that they were on 9. Wright MJ, Proctor DD, Insogna KL, et al. Proton pump-inhibiting drugs, these medications, many of our patients got referred from other calcium , and bone health. Nutr Rev 2008;66:103–8. institutions so we simply just did not have that data. Vitamin D 10. Irvin GL, Prudhomme DL, Deriso GT, et al. A new approach to levels were not available for all patients, and the focus of this parathyroidectomy. Ann Surg 1994;219:574–81. 11. Freedman DA. Statistical Models: Theory and Practice. Cambridge, study was the medications, since there has already been a lot UK: University Press; 2005. published on vitamin D and intraoperative PTH. 12. Lindstrom ML, Bates DM. Newton-Raphson and EM algorithms for Dr Arthur M. Carlin (Detroit, MI): Did you look at linear mixed-effects models for repeated-measures data. J Am Stat bone-specific or urinary N-telopeptide Assoc 1988;83:1014–21. to determine if there is any correlation with postoperative 13. Kandil E, Tufaro AP, Carson KA, et al. Correlation of plasma 25- hydroxyvitamin D levels with severity of primary hyperparathyroid- hypocalcemia? ism and likelihood of localization on sestamibi Dr Schneider: We did not. We do not routinely measure scan. Arch Otolaryngol Head Neck Surg 2008;134:1071–5. those, so I did not have data on those markers.