World J Surg (2014) 38:1268–1273 DOI 10.1007/s00268-014-2555-6

Predictors of Bone Mineral Density Improvement in Patients Undergoing Parathyroidectomy for Primary Hyperparathyroidism Jyotirmay Sharma • Dina S. Itum • Lewis Moss Christine Chun-Li • Collin Weber

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Published online: 18 April 2014 Ó Socie´te´ Internationale de Chirurgie 2014

Abstract Introduction Primary hyperparathyroidism (PHPT) results in increased bone turnover, resulting in bone mineral density (BMD) reduction and a predisposition towards fractures. Parathyroidectomy (PTX) is the only definitive cure. Objective The primary goals of this study were to investigate the impact of PTX on BMD in patients with PHPT and to identify factors associated with post-operative BMD improvement using a multivariate model. Methods Between 1999 and 2010, a total of 757 patients underwent PTX for treatment of PHPT; 123 patients had both a pre- and a post-operative dual-energy X-ray absorptiometry (DEXA) scan. A prospective database was queried to obtain information about patient demographics, medications, comorbidities, and pre- and post-operative laboratory values. A Cox regression model was used to stratify patients and to identify factors that independently predict BMD response following PTX in this patient population. Results Overall, mean percent change in BMD was ?12.31 % at the spine, ?8.9 % at the femoral neck (FN), and ?8.5 % at the hip, with a mean follow-up of 2.3 ± 1.5 years. A total of 101 (82.1 %) patients had BMD improvement at their worst pre-operative site. In patients who improved, 69.9 % (n = 86) had [5 % increase. Factors associated with BMD improvement at the worst preoperative site were as follows: male gender (hazard ratio [HR] 2.29; 95 % confidence interval [CI] 1.54–4.21); preoperative BMD with T-score less than -2.0 (HR 1.89; J. Sharma (&)
D. S. Itum
L. Moss
C. Chun-Li
C. Weber Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA e-mail: [email protected]

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95 % CI 1.11–2.39); age \55 years (HR 1.74; 95 % CI 1.14–2.25); BMD DEXA scan at [2.5 years post-operatively (HR 1.71; 95 % CI 1.09–2.17); history of previous fracture (HR 1.24; 95 % CI 1.05–1.92); and private insurance (HR 1.18; 95 % CI 1.06–2.1). The use of bisphosphonates, estrogens, vitamin D supplementation, or tobacco; obesity; history of previous PTX, serum calcium or parathyroid hormone levels were not independently associated with post-operative BMD improvement. Conclusion Osteoporosis is one of the established National Institutes of Health criteria for PTX in asymptomatic patients with PHPT, but BMD improvement is not consistently seen during the post-operative period. Gender, age, more severe pre-operative bone disease, and insurance status were all predictors for greater BMD improvement following PTX. Further studies with a rigorous post-operative BMD regimen are needed in order to validate these results.

Introduction Primary hyperparathyroidism (PHPT) results in increased bone turnover, resulting in a reduction in bone mineral density (BMD) and a predisposition towards fractures. PHPT affects up to 1 % of the adult population, overwhelmingly the most frequent being women [1]. After menopause, there is a decrease in estrogen levels, with resultant bone loss [2]. In PHPT, elevated parathyroid hormone (PTH) increases osteoclastic activity and leads to a further decrease in BMD, resulting in osteopenia and osteoporosis. Osteoporosis, defined by the World Health Organization as a reduction in BMD of -2.5 standard deviations below peak bone mass (T-score -2.5) and osteopenia (T-score between -1 and -2.5) are associated

World J Surg (2014) 38:1268–1273

with increased fracture risk. There is a high correlation between BMD, bone health, and fracture risk. [3] BMD is routinely measured with dual-energy X-ray absorptiometry (DEXA); and, in patients with PHPT and mild hypercalcemia, DEXA is often used to select patients for parathyroidectomy (PTX). [4] Patients with PHPT who remain untreated experience an ongoing decrease in BMD. [5] PTX has been found to improve BMD, but this improvement is not universal and is inconsistent across different populations. [6] [7] The goal of this study was to assess improvement in BMD after PTX in PHPT and stratify the change in BMD based upon patient factors such as gender, race, age, and other comorbidities.

Methods Between 1999 and 2009, a total of 757 patients underwent PTX for treatment of PHPT at Emory University Hospital, Atlanta, GA, USA; 374 patients had a preoperative DEXA within 2 years of surgery and 154 patients had both a preoperative and a post-operative DEXA scan (range 9 months to 8.2 years). After Institutional Review Board (IRB) approval, a prospective database was queried to obtain information about patient demographics, medications, comorbidities, and pre-operative and post-operative laboratory values (Table 1). BMD was measured at lumbar spine, femur, and total hip and recorded in absolute g/cm2 and as T-scores. DEXA scans were performed on a Hologic

1269 Table 2 Frequency of comorbidities, medication, and lab values in 123 patients Factor

N

%

Calcium and PTH at follow-up

113

91.9

Hypertension

74

60.16

Vitamin D supplementation at follow-up

69

56.10

Symptomatic?

49

39.84

Levothyroxine

38

30.89

Dyslipidemia

38

30.89

Anti-lipid meds Chronic PPI use

36 31

29.27 25.20

Bisphosphonates

30

24.39

BMI [ 30 kg/m2

28

22.8

Reoperative PTX

21

17.07

Anti-depressant use

21

17.07

Diabetes

19

15.45

Tobacco use

18

14.63

Steroids

15

12.20

Estrogen Agonists

14

11.38

Vitamin D deficiency

14

11.38

History of fracture pre-op

14

11.38

CAD/CHF

12

9.76

Regular NSAID use

10

8.13

Anti-estrogen (tamoxifen)

4

3.25

Parathyroidectomy failure

1

0.81

BMI body mass index, CAD coronary artery disease, CHF congestive heart failure, NSAID non-steroidal anti-inflammatory drug, PPI protein pump inhibitor, PTH parathyroid hormone, PTX parathyroidectomy

Table 1 Variables in 123 patients undergoing parathyroidectomy Serum labs

Ca, parathyroid hormone, phosphorus, albumin, creatinine,

Demographics

Age, race, gender

Comorbidities

Hypertension Symptoms Diabetes mellitus Alcohol Smoking Fracture CAD/CHF

Medications

Disability Vitamin D Bisphosphonates Estrogen agonists Estrogen antagonists Steroids NSAIDs/PPIs Antidepressants Anti-lipid

CAD coronary heart disease, CHF congestive heart failure, NSAID non-steroidal anti-inflammatory drug, PPI protein pump inhibitor

QDR4500 (Hologic, Bedford, MA, USA) for 94 % of patients and Lunar Prodigy Advance (General Electric, Fairfield, CT, USA) for 6 % of patients. BMD comparisons were only performed if the patient had a postoperative DEXA on the same machine as the initial preoperative DEXA. Due to missing data, only 123 patients were included in the final analysis, and the frequency of analyzed variables is displayed in Table 2. An initial comparison was performed between the patients with only a pre-operative DEXA (n = 374) and patients who underwent both a pre-operative and post-operative DEXA (n = 123) (Table 3). Body mass index (BMI) was calculated in kg/m2, and glomerular filtration rate (GFR) was calculated using MDRD based upon age, race, gender, and serum creatinine. BMD improvement was classified as a [5 % improvement in absolute BMD, and it was examined at lumbar spine, total hip, and femur. All continuous variables between the groups were analyzed by a t test, and categorical variables were analyzed by a Fisher exact test. A Cox regression model was used to stratify patients and to identify factors that independently

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Table 3 Comparison of factors between patients with pre-operative DEXA and patients with both pre-operative and post-operative DEXA Pts with preoperative bone density (n = 374)

Pts with pre- and post-operative bone density (n = 123)

p value

Age, (years)

53.1 ± 16.2

57.9 ± 13.6

0.0214*

Age [55 y or postmenopause [n (%)]

147 (39.3)

61 (49.6)

0.0462*

Race (% C:AA:O)

59.1:33.7:7.2

68.2:27.6:4.2

0.0654

Gender (% M:F)

24.4:75.6

25.2:74.8

0.879

Pre-operative calcium (mg/dL)

10.9 ± 0.92

11.3 ± 0.85

0.549

Pre-operative PTH (pg/ mL)

166 ± 171

173 ± 165

0.327

Serum phosphorus (md/dL)

3.8 ± 0.16

3.6 ± 0.24

0.845

Creatinine clearance

142 ± 42

126 ± 53

0.174

BMI (kg/m2)

29.8 ± 5.2

28.9 ± 6.1

0.371

Mean BMD (T-score all sites)

-2.2 ± 0.98

-2.08 ± 1.11

0.148

AA African-American, BMD bone mineral density, BMI body mass index, C Caucasian, F female, M male, O other, PTH parathyroid hormone * p \ 0.05

predict BMD improvement of 5 % following PTX in this patient population. Significance was defined as p value \ 0.05. Statistical analysis was carried out with SPSS Statistics 17.0 (IBM, Armonk, NY, USA) and SAS Version 9.2 for Windows (SAS Institute, Cary, NC, USA).

a preoperative DEXA only (53.1 ± 16.2) (p value = 0.0214) (Table 3). A total of 82.1 % (n = 101) of patients had an improvement in BMD; 12.2 % (n = 15) had 0–5 % improvement, 26.8 % (n = 33) had 5–10 % improvement, 23.6 % (n = 29) had 10–15 % improvement, and 19.5 % (n = 24) had [15 % improvement. The distributions in percent change in BMD from preoperative DEXA to postoperative DEXA at lumbar spine, femur, and total hip were -59 to 111 %, -53 to 158 %, and -20 to 74 %, respectively (Fig. 1). A total of 86.2 % (n = 106) of patients had a repeat BMD within 3 years of PTX; improvement in T-scores and absolute BMD was noted at years 1, 2, 3, 7, and 8 (Figs. 2 and 3). In the other years, there was either lack of improvement or the standard error of the mean was not substantive. A linear regression model was used to compare the worst site of BMD in a patient with its respective change after PTX. Patients who presented with a lower BMD trended towards more improvement in BMD after PTX than patients who presented with a higher T-score (Fig. 4). This was observed in both T-score improvement and absolute BMD improvement. On univariate analysis, BMD improvement after PTX was associated with male gender; worst preoperative T-score; age \55 years; a DEXA performed [2.5 years after PTX; history of previous fracture; private insurance; use of bisphosphonates, estrogen agonists, and vitamin D supplementation. Tobacco use, BMI [ 30, reoperative PTX, preoperative serum calcium, or PTH were not associated with BMD improvement. Based upon clinical value, due to missing data or a prevalence of \10 % in the dataset, the following variables were excluded from univariate analysis: chronic protein pump inhibitor (PPI) use, vitamin D deficiency, non-steroidal anti-inflammatory drug (NSAID) use, estrogen antagonist use, alcohol intake, steroid use, heart disease, and PTX failure. On multivariate analysis, BMD improvement was associated with male gender, worst preoperative T-score, age \55, a DEXA performed [2.5 years after PTX, history of previous fracture, and private insurance (Table 4).

Results PTX was successful in 99.2 % (n = 122) of patients, with a mean age of 57.9 ± 13.6 years. At follow-up (range 9 months–8.2 years), mean serum calcium was 9.2 ± 0.62 md/dL and PTH 52 ± 17 pg/mL (normal reference range 10–65 pg/mL). The patients receiving a postoperative DEXA were similar to patients receiving preoperative DEXA only in gender, race, BMI, GFR, BMD, serum calcium, serum PTH, and serum phosphorus. However, patients receiving a postoperative DEXA had a mean age of 57.9 ± 13.6 compared with patients who had

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Discussion Bone density improves after PTX in [80 % of patients. In this study, we observed that bone density improvement is also associated with age, gender, severity of bone disease, and insurance status. This improvement was observed in spine, hip, and femoral head for up to 4 years post-PTX. Unique aspects of this study are the duration of follow-up (range 1–8 years) and the continued improvement in bone density for each year of follow-up.

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200%

25 20

Percent Change

Percent BMD Change (%)

150%

100%

50%

-50%

Femoral Neck

Hip

0.2

Absolute BMD (g/cm2)

Spine

A

0.15 0.1 0.05 0 -0.05