Original. Se Hwa Kim 1), Tae Ho Kim 1) and Soo-Kyung Kim 2)

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1 Endocrine Journal 2014 Original Advance Publication doi: /endocrj. EJ Effect of high parathyroid hormone level on bone mineral density in a vitamin D-sufficient population: Korea National Health and Nutrition Examination Survey Se Hwa Kim 1), Tae Ho Kim 1) and Soo-Kyung Kim 2) 1) Division of Endocrinology, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary s Hospital, Incheon, Republic of Korea 2) Division of Endocrinology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea Abstract. The detrimental effect of high parathyroid hormone (PTH) on bone has not been adequately evaluated in vitamin D-sufficient Koreans. The aim of this study was to investigate the effect of high PTH on bone mineral density (BMD) in such a population. A total of 5,403 subjects (2,644 men and 2,759 postmenopausal women; 50 years old) were selected from the Korea National Health and Nutrition Examination Survey (KNHANES). Subjects were divided into four groups according to vitamin D status (<20 and 20 ng/ml) and PTH levels ( 65 and >65 pg/ml). Total hip and spine BMD were evaluated in each group. High PTH level was found in 50% of vitamin D-deficient subjects and 35% of vitamin D-sufficient subjects. In the vitamin D-deficient group, subjects with normal PTH level had higher total hip and spine BMD than those with high PTH after adjusting for multiple confounding factors, regardless of gender. In the vitamin D-sufficient group, only women with high PTH showed lower total hip and spine BMD than those with normal PTH. Multivariable linear regression analysis found that PTH level was independently associated with total hip BMD in vitamin D-sufficient women as well as vitamin D-insufficient women, but no association was found in men. In conclusion, high serum PTH level has an additive detrimental effect on BMD in postmenopausal women even though they had sufficient vitamin D levels. Key words: Bone mineral density, Parathyroid hormone, Vitamin D IT IS WELL known that vitamin D deficiency decreases intestinal calcium absorption, leads to secondary hyperparathyroidism, and accelerates bone loss [1]. In addition, vitamin D deficiency is associated with decreased muscle strength and increased fall risk [2, 3]. Many studies have shown a positive association between serum 25-hydroxyvitamin D [25(OH) D] and bone mineral density (BMD) [4]. Also, several cohort studies have reported that low serum 25(OH)D is associated with osteoporotic fractures in the elderly [5]. On the other hand, high serum parathyroid hormone (PTH) level has been associated with increased bone remodeling and increased fracture risk [6]. One Submitted Jun. 25, 2014; Accepted Aug. 21, 2014 as EJ Released online in J-STAGE as advance publication Sep. 20, 2014 Correspondence to: Soo-Kyung Kim, M.D., Ph.D., Division of Endocrinology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, Korea. imdrksk@chollian.net The Japan Endocrine Society recent study showed that serum PTH, but not 25(OH) D, predicts bone loss rate during a four-year follow-up study in the elderly [7]. Interestingly, not all patients with vitamin D deficiency develop secondary hyperparathyroidism. A previous study by Sahota et al. [8] found that only onethird of vitamin D-deficient patients had a secondary hyperparathyroidism. These patients had a lower hip BMD compared to vitamin D-deficient patients with normal PTH level and to vitamin D-sufficient patients. On the contrary, it is unclear if all subjects with vitamin D sufficiency have a normal PTH level except for those with primary hyperparathyroidism or chronic kidney disease. The authors of the present study hypothesized that a high PTH level has detrimental effects on BMD even in vitamin D-sufficient subjects. The results show that a substantial proportion of vitamin D-sufficient subjects had a high serum PTH level. Also, high PTH

2 2 Kim et al. level had detrimental effects on BMD in postmenopausal women, but not in men, even though the women were vitamin D-sufficient. Materials and Methods Study participants This study is based on data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted from 2008 to The KNHANES is a cross-sectional study regularly conducted by the Division of Chronic Disease Surveillance, Korea Centers for Disease Control and Prevention of the Ministry of Health and Welfare to examine the general health and nutritional status of the population of South Korea. The KNHANES database is publicly available at the KNHANES website ( cdc.go.kr, available in Korean). A total of 10,238 subjects 50 years of age participated in the KNHANES surveys from 2008 to Of these 10,238 participants, 2,975 individuals were excluded from the present study because of incomplete BMD, serum PTH, or serum 25(OH)D data. Additionally, 1,860 individuals were excluded because they were premenopausal or had a history of osteoporosis medication, rheumatoid arthritis, asthma, cancer, serum PTH 150 or <10 pg/ ml, or estimated glomerular filtration rate (egfr) <60 ml/min/1.73m 2. Finally, 2,644 men and 2,759 women were included in the study analysis (Fig. 1). All participants provided written informed consent. Measurements of anthropometric parameters and bone mineral density Height and body weight were measured using standard methods while the participants were wearing light-weight clothes. Body mass index (BMI) was calculated as weight divided by height squared (kg/m 2 ). BMD values for the lumbar spine (L1-L4) and total hip were measured using dual-energy X-ray absorptiometry (DXA, Discovery QDR 4500; Hologic Inc., Waltham, MA, USA). The coefficients of variations (CVs) of the lumbar spine and total hip were 1.9%, and 1.8%, respectively. Biochemistry assessment As part of the KNHANES survey, blood samples were collected after an 8-hour fast and then immediately processed, refrigerated, and transported in cold storage to the central laboratory (Neodin Medical N=29,235 assessed for eligibility KNHANES IV-2 (2008, n=9744) KNHANES IV-3 (2009, n=10533) KNHANES V-1 (2010, n=8958) N=10,238 men (n=4384), women (n=5854) N=7,263 men (n=3146), women (n=4117) Excluded < 50 years old Excluded due to missing data serum 25(OH)D, n=1332 serum PTH, n=2534 BMD, n=2344 Excluded due to following conditions any cancer history, n=329 egfr <60 ml/min/1.73m 2, n=341 serum PTH 150 or 10pg/mL, n=116 premenopausal women, n=245 osteoporosis medication, n=373 History of rheumatoid arthritis, n=193 History of asthma, n=260 N=5,403 men (n=2644), women (n=2759) Fig. 1 Schematic flow diagram of study subject selection and exclusion. 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone; BMD, bone mineral density Institute, Seoul, South Korea). All blood samples were analyzed within 24 hours of collection. Serum 25(OH) D concentration was measured with a radioimmunoassay (DiaSorin Inc., Stillwater, MN, USA) using a gamma counter (1470 Wizard; PerkinElmer, Turku, Finland). According to an Endocrine Society Guideline for evaluation of vitamin D deficiency, vitamin D deficiency was defined as a 25(OH)D level below 20 ng/ ml [9]. A previous report using KNHANES data [10] demonstrated that only 13.2% of men and 6.7% of women had a serum 25(OH)D level greater than 30 ng/ ml. Therefore, we arbitrarily defined vitamin D sufficiency as a 25(OH)D greater than 20 ng/ml in the present study. Serum intact PTH was analyzed using a chemiluminescence assay (DiaSorin Inc., Stillwater, MN, USA). Serum creatinine was determined using a Hitachi automatic analyzer (Hitachi, Tokyo, Japan). Estimated GFR was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. Lifestyle questionnaires and nutrition assessment Subjects were classified as regular exercisers if they exercised moderately for more than 30 min per session

3 PTH and BMD in vitamin D-sufficiency 3 more than five sessions per week or if they exercised strenuously for more than 20 min per session more than three sessions per week. Current smokers were defined as those who had smoked more than five packs of cigarettes during their life and were a current smoker. Alcohol consumption was defined as consuming more than one unit of alcohol per month. Daily calcium intake was assessed with a 24-hour dietary recall questionnaire administered by a trained dietician. Fracture history was defined as having a history of clinical vertebral, hip, or forearm fracture. Statistical analyses Participants were classified into four groups according to vitamin D status and PTH level. Participant characteristics were compared using one-way analysis of variance (ANOVA) for continuous variables and Chi-square test for categorical variables. Mean BMD values of the four groups were compared by analysis of covariance (ANCOVA) after adjusting for age, BMI, smoking status, alcohol consumption, exercise habits, egfr, history of hormone replacement therapy (HRT, for women), daily calcium intake, and fracture history. Separate multivariable logistic regression analysis was also performed for vitamin D-sufficient and -insufficient subjects in order to identify independent factors for total hip BMD. Multivariable regression model included age, BMI, smoking, alcohol consumption, exercise, daily calcium intake, fracture history, 25(OH) D, PTH, egfr, and history of HRT (for women). A P value <0.05 was considered significant. Statistical analyses were carried out using SPSS (version 19.0; SPSS Inc., Chicago, IL, USA). Results Characteristics of study participants Clinical and biochemical characteristics of study subjects were shown in Table 1 and Table 2. Mean age was 62.9 ± 8.4 years and 51% of the subjects were women. Mean serum 25(OH)D concentrations were 20.6 ± 7.4 ng/ml and mean PTH levels were 64.3 ± 21.9 pg/ml. There were significant inverse correlations between serum 25(OH)D and PTH levels in men (r = , p < 0.001) and women (r = , p < 0.001) (Fig. 2). To determine the effect of high PTH levels on BMD according to the vitamin D status, subjects were first divided into groups according to vitamin D status [deficient - 25(OH)D < 20ng/mL or sufficient - 25(OH)D 20ng/mL]. Subjects were further divided into groups according to PTH level (PTH 65pg/mL vs. PTH > 65pg/mL). Characteristics of study subjects according to vitamin D and PTH status were shown in men (Table 1) and women (Table 2). Forty three percent of men and 60% of women were classified as vitamin D-insufficient. Nearly half of the subjects in the vitamin D insufficiency group had normal PTH level ( 65pg/mL) (50.3%, n=572 in men and 50.3%, n=838 in women). Approximately 35% of the subjects in the Table 1 Characteristics of male study subjects according to vitamin D status and PTH level 25(OH)D < 20 ng/ml 25(OH)D 20 ng/ml All subjects (n=2644) PTH >65 pg/ml PTH 65 pg/ml PTH >65 pg/ml PTH 65 pg/ml (n=563) (n =572) (n=543) (n=966) P value Age (years) 62.6 ± ± ± ± ± BMI (kg/m 2 ) 23.7 ± ± ± ± ± egfr (ml/min/1.73m 2 ) 86.3 ± ± ± ± ± Total 25(OH)D (ng/ml) 22.1 ± ± ± ± ± 5.8 <0.001 PTH (pg/ml) 63.7 ± ± ± ± ± 10.8 <0.001 Calcium intake (mg/day) 545 ± ± ± ± ± Current smoker (%) Alcohol (%) Regular exercise (%) Hypertension (%) Diabetes (%) Fracture history (%) Values are presented as the means ± SD or proportion (percent). BMI, body mass index; egfr, estimated glomerular filtration rate; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone

4 4 Kim et al. Table 2 Characteristics of female study subjects according to vitamin D status and PTH level Variable 25(OH)D < 20 ng/ml 25(OH)D 20 ng/ml All subjects (n=2759) PTH >65 pg/ml PTH 65 pg/ml PTH >65 pg/ml PTH 65 pg/ml (n=828) (n=838) (n=355) (n=738) P value Age (years) 63.1 ± ± ± ± ± 8.1 <0.001 BMI (kg/m 2 ) 24.2 ± ± ± ± ± 3.0 <0.001 egfr (ml/min/1.73m 2 ) 89.4 ± ± ± ± ± Total 25(OH)D (ng/ml) 19.0 ± ± ± ± ± 5.0 <0.001 PTH (pg/ml) 64.8 ± ± ± ± ± 10.5 <0.001 Calcium intake (mg/day) 410 ± ± ± ± ± Current smoker (%) Alcohol (%) Regular exercise (%) Hypertension (%) <0.001 Diabetes (%) HRT (%) Fracture history (%) Values are presented as the means ± SD or proportion (percent). BMI, body mass index; egfr, estimated glomerular filtration rate; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone; HRT, hormone replacement therapy Parathyroid hormone [pg/ml] Men Men r=-0.189, P P < Women Women r=-0.223, P < P < (OH)D [ng/ml] 25(OH)D [ng/ml] Fig. 2 Relationship between serum 25-hydroxyvitamin D [25(OH)D] and PTH concentration in men and women. vitamin D-sufficient group had high PTH level (36.0%, n=563 in men and 32.5%, n=355 in women). The percentage of subjects with hypertension was higher in subjects with high PTH than in those with normal PTH regardless of vitamin D status (Tables 1, 2). Relationships between BMD, vitamin D, and PTH concentration Subjects who were vitamin D-deficient with high PTH had the lowest BMD, while subjects who were vitamin D-sufficient with normal PTH level had the highest BMD at each site. In the vitamin D-deficient group, subjects with normal PTH had higher total hip BMD than those with high PTH, even after adjusting for age, history of HRT (for women), BMI, smoking status, alcohol consumption, exercise habits, daily calcium intake, a history of fracture, and egfr in both men (0.925±0.005 vs ±0.005 g/cm 2, p=0.009) (Fig. 3a) and women (0.785±0.003 vs ±0.003 g/cm 2, p=0.002) (Fig. 3b). Furthermore, there was a significant difference in total hip BMD according to PTH status among vitamin D-sufficient women (0.792±0.003 vs ±0.005 g/cm 2, p=0.033) (Fig. 3b). However, in men who were vitamin D-sufficient, there was no

5 PTH and BMD in vitamin D-sufficiency 5 (a) Total hip BMD (g/cm 2 ) P < (b) 0.82 P =0.001 P = ns P = P = ns PTH >65 PTH 65 PTH >65 PTH 65 Vitamin D deficiency Vitamin D sufficiency P < P = ns P = P = P = ns PTH >65 PTH 65 PTH >65 PTH 65 Vitamin D deficiency Vitamin D sufficiency (c) Lumbar spine BMD (g/cm 2 ) P = P = P = P = ns P = ns PTH >65 PTH 65 PTH >65 PTH 65 PTH >65 PTH 65 PTH >65 PTH 65 Vitamin D deficiency Vitamin D sufficiency Vitamin D deficiency Vitamin D sufficiency Fig. 3 Bone mineral densities according to serum 25-hydroxyvitamin D and parathyroid hormone concentrations in men (a, c) and women (b, d). These data are adjusted for age, BMI, estimated glomerular filtration rate, smoking, alcohol consumption, exercise, history of HRT (for women), calcium intake, and previous fracture history. Error bar represents standard error. (d) P = P = ns P =0.023 P = P = difference in total hip BMD according to PTH status (0.937±0.004 vs ±0.005 g/cm 2, p=0.341) (Fig. 3a). Similar results for lumbar spine BMD were seen in both men (Fig. 3c) and women (Fig. 3d). Multiple linear regression analysis A multiple linear regression analysis was performed to identify independent factors for total hip BMD in all subjects. As expected, age, BMI, exercise, serum 25(OH)D, daily calcium intake, previous fracture history, serum PTH, and egfr were independent factors in men and women (Table 3). Use of HRT was an additional independent factor for total hip BMD in women. This study also explored whether PTH was independently associated with total hip BMD in subjects based on vitamin D status. Therefore, we analyzed our data separately for subjects with vitamin D-sufficiency and -deficiency. PTH was not an independent factor for total hip BMD in men with vitamin D-sufficiency as well as vitamin D-deficiency (Table 3). On the other hand, PTH was independently associated with total hip BMD in women, regardless of vitamin D status. These data suggest that the detrimental effects of high PTH on BMD are more prominent in postmenopausal women than in men. Furthermore, serum 25(OH)D was not an independent factor for total hip BMD among vitamin D-sufficient men as well as vitamin D-sufficient women (Table 3). This result suggest that further increase of serum 25(OH)D may not have additional benefit on BMD in vitamin D-sufficient population. Discussion Both men and women with vitamin D deficiency and normal PTH level had higher BMD compared to those with vitamin D deficiency and high PTH. Interestingly, vitamin D-sufficient women with high PTH level had lower BMD compared to those with

6 6 Kim et al. Table 3 Multivariable linear regression analysis to identify factors associated with total hip BMD in men and women Subjects with 25(OH)D < Subjects with 25(OH)D 20 ng/ml 20 ng/ml All subjects β P value β P value β P value I. Men Model R Age (year) < < <0.001 BMI (kg/m 2 ) < < <0.001 Smoking (yes/no) Alcohol (yes/no) Exercise (yes/no) Daily calcium intake (mg) <0.001 Fracture history (yes/no) (OH)D (ng/ml) <0.001 PTH (pg/ml) egfr (ml/min/1.73m 2 ) II. Women Model R Age (year) < < <0.001 BMI (kg/m 2 ) < < <0.001 Smoking (yes/no) Alcohol (yes/no) Exercise (yes/no) Daily calcium intake (mg) Fracture history (yes/no) (OH)D (ng/ml) PTH (pg/ml) < <0.001 egfr (ml/min/1.73m 2 ) HRT (yes/no) BMI, body mass index; egfr, estimated glomerular filtration rate; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone normal PTH. However, there was no significant difference in BMD according to PTH status in men with vitamin D sufficiency. It is well known that vitamin D deficiency causes secondary hyperparathyroidism and bone loss [1]. However, some studies have shown that patients with vitamin D deficiency can have a normal PTH level [7, 8]. Sahota et al. [8] reported that normal serum PTH was present in 67% of subjects with hypovitaminosis D (defined as a 25OHD 12 ng/ml). They also found that patients with hypovitaminosis D and normal PTH level had higher BMD compared to those with hypovitaminosis D and secondary hyperparathyroidism. Similarly, Arabi et al. [7] conducted a study of elderly men and women that included a four-year follow-up and found that the rate of bone loss was higher in subjects who were vitamin D-insufficient (<20ng/mL) and had high PTH level, compared to subjects who were vitamin D-insufficient and had normal PTH level. These findings were consistent with results from both genders in the present study, which showed that nearly 50% of subjects with vitamin D deficiency (<20ng/mL) had normal PTH level. Our study also found that subjects with vitamin D deficiency and normal PTH level had higher total hip and lumbar spine BMD than those with vitamin D deficiency and high PTH level, even after adjusting for multiple confounding factors. In the vitamin D-sufficient population, there were differences in BMD response between men and women according to PTH level. Women with high PTH had significantly lower total hip BMD compared to those with normal PTH. Moreover, serum PTH was an independent factor for total hip BMD in vitamin D sufficient women after adjusting for confounding factors. On the other hand, there was no significant difference in total hip BMD according to PTH level in men. These data suggest that the detrimental effects of high PTH on BMD are more prominent in postmenopausal women than in men; however, the reason for the observed variation in these results remains unclear.

7 PTH and BMD in vitamin D-sufficiency 7 Sahota et al. [8] did not compare BMD according to PTH level among vitamin D-sufficient patients because only a few of these patients had high serum PTH level. In the present study, 35% of the population with vitamin D sufficiency ( 20ng/mL) showed high PTH concentration (>65 pg/ml). When the cut-off value for vitamin D sufficiency is defined as 30ng/mL, 32% of the population showed high PTH levels in our study (data not shown). The causes of this high prevalence of increased serum PTH levels in vitamin D-sufficient population are unknown. Firstly, very low dietary calcium intake may lead to secondary hyperparathyroidism despite vitamin D sufficiency. Mean dietary calcium intake was 545 mg/day for men and 410 mg/day for women. These values are substantially lower than values reported by other studies conducted in populations of different ethnicities [11, 12]. Secondly, subjects with primary hyperparathyroidism may be included in the study. Because we exclude CKD stage 3 or more, renal dysfunction could not be a factor for high prevalence of increased PTH. Interestingly, the percentage of subjects with hypertension was higher in groups with high PTH than in those with normal PTH regardless of vitamin D status in our study. Previous studies have shown that serum PTH concentration is associated with hypertension, high cardiovascular morbidity and mortality [13-15]. PTH receptors are expressed in the vessel wall and myocardium and may be involved in the pathological process of cardiovascular disease. An important limitation of this study was that serum calcium and phosphorus levels were not measured. Thus, subjects with primary hyperparathyroidism may be included in the study. However, recent study reported the incidence of primary hyperparathyroidism was 66 per 100,000 person-years among women, and 25 per 100,000 person-years among men [16]. The incidence of primary hyperparathyroidism was highest among blacks, followed by whites, Asians, and Hispanics. Therefore, these findings suggest the potential for bias in our study would be minimal. In conclusion, serum PTH is a significant determinant of BMD in subjects with vitamin D sufficiency as well as vitamin D deficiency, especially in postmenopausal women. Measuring serum PTH level may help identify individuals who are at risk of osteoporosis even if they have normal renal function and are vitamin D-sufficient, especially in postmenopausal Korean women. Disclosure Summary The authors have nothing to declare. References 1. Lips P (2001) Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 22: Pfeifer M, Begerow B, Minne HW, Schlotthauer T, Pospeschill M, et al. (2001) Vitamin D status, trunk muscle strength, body sway, falls and fractures among 237 postmenopausal women with osteoporosis. Exp Clin Endocrinol Diabetes 109: Gerdhem P, Ringsberg KAM, Obrant KJ, Akesson K (2005) Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of elderly women. Osteoporos Int 16: Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson- Hughes B (2004) Positive association between 25-hydroxyvitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med 116: Van Schoor NM, Visser M, Pluijm SMF, Kuchuk N, Smit JH, et al. (2008) Vitamin D deficiency as a risk factor for osteoporotic fractures. Bone 42: Mosekilde L (2008) Primary hyperparathyroidism and the skeleton. Clin Endorinol 69: Arabi A, Baddoura R, El-Rassi R, El-Hajj Fuleihan G (2012) PTH level but not 25(OH)vitamin D level predicts bone loss rates in the elderly. Osteoporos Int 23: Sahota O, Mundey MK, San P, Godber IM, Lawson N, et al. (2004) The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis. Bone 35: Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine society clinical practice guideline. J Clin Endocrinol Metab 96: Choi HS, Oh HJ, Choi H, Choi WH, Kim JG, et al. (2011) Vitamin D insufficiency in Korea-a greater threat to younger generation: the Korea National Health and

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