Bone mineral density and blood pressure in patients with asymptomatic hyperparathyroidism. The Tromsù Study

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1 Journal of Internal Medicine 2000; 247: 325±330 Bone mineral density and blood pressure in patients with asymptomatic hyperparathyroidism. The Tromsù Study R. JORDE 1,3 & J. SUNDSFJORD 2 From the Departments of 1 Internal Medicine and 2 Clinical Chemistry, University Hospital of Tromsù, Tromsù, Norway, and 3 Centre for Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, University of Newcastle, Newcastle, Australia Abstract. Jorde R, Sundsfjord J (University Hospital of Tromsù, Tromsù, Norway). Bone mineral density and blood pressure in patients with asymptomatic hyperparathyroidism. The Tromsù Study. J Intern Med 2000; 247: 325±330. Objective. To evaluate bone mineral density and blood pressure in asymptomatic hyperparathyroidism. Design. A case-control study. Setting. The participants obtained from an epidemiological survey in Tromsù 1994±95, that included more than subjects. The reexamination in 1998 was performed at the University Hospital of Tromsù, Norway. Participants. Thirty-nine subjects with hyperparathyroidism and 72 control subjects were studied. Main outcome measures. Bone mineral density measurements of the lumbar spine and the proximal femur (femoral neck, Ward's triangle, and trochanter). Systolic and diastolic blood pressure. Results. In the hyperparathyroidism group bone mineral density was significantly lower measured at the lumbar spine ( vs g cm 22, mean 6 SD, P, 0.01) and at the femoral neck ( vs g cm 22, P, 0.05). In the females, but not in the males, blood pressure was significantly higher in the hyperparathyroidism group than in the control group [systolic blood pressure vs mmhg (P, 0.05) and diastolic blood pressure vs mmhg (P, 0.05)]. In the females the number of subjects on antihypertensive medication was significantly higher in the hyperparathyroidism group than in the control group (32.1% and 16.6%, respectively, P, 0.01). Conclusions. Subjects with asymptomatic hyperparathyroidism have moderately reduced bone mineral density. In females with hyperparathyroidism there is an increase in blood pressure. Keywords: blood pressure, bone mineral density, hypertension, primary hyperparathyroidism. Introduction Bone disease and hypertension have traditionally been associated with hyperparathyroidism. Originally, bone disease in the form of osteitis fibrosa cystica was a common part of the disease presentation [1], whereas today this is seldom seen. On the other hand, several recent studies have shown a reduced bone mineral density in patients with hyperparathyroidism [2±4], and measurement of bone density has been recommended as part of the clinical evaluation before deciding upon surgical treatment [5]. Similarly, hypertension is a well known part of hyperparathyroidism [6±8]. However, the cause of hypertension in hyperparathyroidism is uncertain, and there appears to be no effect of surgery on the blood pressure [9, 10]. Most studies on hyperparathyroidism have been performed on patients diagnosed because of specific clinical symptoms, or discovered by chance through multichannel biochemical screening where hyperparathyroidism originally was not suspected. Only a few are based on epidemiological studies [11], and therefore cohorts of patients with truly asymptomatic hyperparathyroidism are rare. In Tromsù, Northern Norway, there have been four large health surveys since In the last one in 1994±95, serum calcium was measured in all subjects, and those with a value above 2.59 mmol L 21 were re-examined. Those fulfilling our criteria for hyperparathyroidism were re-exam- # 2000 Blackwell Science Ltd 325

2 326 R. JORDE & J. SUNDSFJORD ined every year, and if clinically indicated, surgery was recommended. Thus a group of subjects with asymptomatic hyperparathyroidism was established, suitable for examining the presence of reduced bone density as well as hypertension in the mild form of the disease. Materials and methods Subjects A total of men and women were included in the Tromsù study in 1994±95. All subjects had blood samples drawn for serum calcium measurements. If the serum calcium was greater than 2.59 mmol L 21, and the subject was below the age of 76 and living within reasonable distance from the city centre, the subject was asked to come for new blood samples for measurement of serum calcium, creatinine, and parathyroid hormone. In order to include subjects with mild hyperparathyroidism, a diagnosis of hyperparathyroidism was made if serum calcium was greater than 2.49 mmol L 21 and serum parathyroid hormone greater than 5.9 pmol L 21 ; or serum calcium was greater than 2.54 mmol L 21 and serum parathyroid hormone greater than 5.4 pmol L 21 ; or serum calcium was greater than 2.59 mmol L 21 and serum parathyroid hormone greater than 4.9 pmol L 21, provided the serum creatinine was below 150 mmol L 21. Subjects fulfilling these criteria were then re-examined annually at the outpatient clinic at the Medical Department, University Hospital of Tromsù. If the serum calcium was above 2.80 mmol L 21, and/or the patient had symptoms that could be ascribed to hypercalcaemia, operation was advised. In 1998 the subjects with hyperparathyroidism were invited to have a bone mineral density measurement in addition to the routine follow-up. An age- and sex-matched control group of 72 subjects was recruited from the cohort that in 1994/95 had a serum calcium level lower than 2.60 mmol L 21. Subjects using oestrogen or bisphosphonates were not included in the control group. Measurements The follow-up study was performed at the Clinical Research Unit at the University Hospital of Tromsù. After a general health examination a medical history was taken and present medication recorded. All subjects filled out a questionnaire on dietary habits that included questions on consumption of milk, cheese, yoghurt, bread, butter, and fat fish. Furthermore, they were asked for daily use of calcium and vitamin D tablets, and cod liver oil supplementation. Using a Norwegian food table [12] the daily intake of calcium and vitamin D from these products was calculated. Height and weight were measured in light clothing without shoes. Body mass index was calculated as weight in kilograms divided by the square of the height in meters. Blood pressure was measured with an automatic device (Propaq S/W version 6.0; Protocol systems, Beaverton, Oregon, USA). The subjects were seated for 5 min before the first of three measurements, 1 min apart. The mean of the two last measurements was used in the analysis. The subjects were not requested to fast. Bone mineral density was measured using a Lunar DPX-L dual-energy X-ray absorptiometer (Lunar Radiation Corporation, Madison, Wisconsin, USA). Separated scans for the lumbar spine in the posteroanterior (L1±L4) projection and the proximal femur (femoral neck, Ward's triangle, and trochanter) were carried out and analysed with the manufacturer's software version 1.3. Blood samples were drawn and analysed for serum calcium, phosphate, creatinine, albumin, and ALP on Hitachi 917 with reagents from Boehringer Mannheim (Mannheim, FRG). Serum ionized calcium was measured with an ion-selective electrode (Ciba Corning 288; Chiron Diagnostics Corporation, USA). The measurements were carried out in serum samples collected anaerobically, and the samples were centrifuged and analysed within 1 h. The actual measured serum ionized calcium levels, without ph adjustments, were used. Intact parathyroid hormone was measured on Immulite (Diagnostic Products Corporation, Los Angeles, USA) based on a two-site chemiluminescent immunocompetitive assay. Statistical analyses Comparisons between the subjects with hyperparathyroidism and the control group were made using the Student's t-test. For bone mineral density and blood pressure the groups were in addition com-

3 BMD AND BP IN PATIENTS WITH HPT 327 pared using linear regression with bone mineral density or blood pressure as dependent variable and body mass index and age as covariables. A comparison of the number of subjects on antihypertensive medication in the two groups was made using the x 2 -test. With regard to blood pressure, possible interactions between hyperparathyroidism or control group status, use of antihypertensive medication, and gender were tested with linear regression using blood pressure as a dependent variable and the other variables in question as fixed factors. Possible associations between blood pressure and bone mineral density were tested with linear regression using blood pressure as a dependent variable, the same fixed factors as above, and bone mineral density, age and body mass index as independent variables. All tests were performed two-sided, and P, 0.05 was considered statistically significant; the data are presented as mean 6 SD. Statistical analyses were carried out using SPSS version 8.0 (SPSS Inc., Chicago). Ethics The study was approved by the Regional Ethics Committee, and all subjects gave their written informed consent to participate. Results Subjects A total of 366 subjects had serum calcium above 2.59 mmol L 21. Of these, 282 subjects had a second set of blood samples. One subjects was diagnosed with gastric cancer, 217 had normal serum calcium and parathyroid hormone levels, and 64 fulfilled our criteria for hyperparathyroidism. Surgery was performed in eight, and three subjects died during the follow-up period. Of the remaining 53 subjects, one had moved, nine dropped out during the follow-up period, and four did not want to participate in the present examination. Thus, 39 subjects (11 males) with hyperparathyroidism attended the extended examination in None of them were using oestrogen substitution or were taking bisphosphonates. The characteristics of the two study groups appear from Table 1; the sex distribution was almost identical, but the hyperparathyroidism group had a slightly lower mean age. The hyperparathyroidism Table 1 Characteristics of the hyperparathyroidism (HPT) group and the control group and results of the examinations (mean SD) Normal range HPT group Control group Males/females 11/28 18/54 Age (years) Serum calcium (mmol L 21 ) 2.20± c Serum ionized calcium (mmol L 21 ) 1.10± c Serum PTH (pmol L 21 ) 1.1±6.8 f c Serum phosphate (mmol L 21 ) 0.75± c Serum albumin (g L -1 ) 35.0± Serum alkaline phosphatase (U L 21 ) 80±275 g c Serum creatinine (mmol L 21 ) 70±120 h BMI (kg m 22 ) Calcium intake (mg day 21 ) Vitamin D intake (mg day 21 ) Bone mineral density (g cm 22 ) Lumbar spine ae Femoral neck d Ward's triangle Trochanter Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) a P < 0.05; 2 P < 0.01; c P < vs. control group (Student's t-test). d P < 0.05; e P < 0.01 vs. control group (linear regression). f >50 years: 1.1±7.5; g >70 years: 100±400; h Females: 55±100.

4 328 R. JORDE & J. SUNDSFJORD group had significantly higher (P, 0.001) serum total calcium, ionized calcium, parathyroid hormone, and serum alkaline phosphatase (ALP). There were no significant differences regarding serum levels of creatinine and albumin, nor for the intakes of calcium and vitamin D. Body mass index was nonsignificantly higher in the hyperparathyroidism group. Bone mineral density The bone mineral density measured at the lumbar spine was significantly lower in the hyperparathyroidism group than in the control group (P, 0.05). When controlling for age and body mass index this was also seen for the femoral neck (P, 0.05; Table 1). When looking at men and women separately, the differences in bone mineral density between the hyperparathyroidism and the control group were present in both sexes. However, it reached statistical significance only for the females (Table 2). Blood pressure Both the systolic and diastolic blood pressure were higher in the hyperparathyroidism group, but for both sexes taken together the differences were not statistically significant (Table 1). However, in this regard males and females behaved differently. Thus, for the males, the blood pressure was slightly lower in those with hyperparathyroidism, whereas in the females it was significantly higher (P, 0.05) in the hyperparathyroidism group, both for systolic and diastolic blood pressure (Table 2). There was a difference in use of blood pressure medication in the two groups; 14 of the 39 subjects with hyperparathyroidism (35.9%) used blood pressure medication, whereas this was the case in only 14 of the 72 controls (19.4%; P, 0.01). For males separately the corresponding figures were five out of 11 subjects with hyperparathyroidism (45.5%), and five out of 18 in the control group (27.8%) (NS). In the females the figures were nine out of 28 in the hyperparathyroidism group (32.1%), and nine out of 54 in the control group (16.6%) (P, 0.01). If excluding those on blood pressure medication, there was still a difference in blood pressure between females with hyperparathyroidism and the control group, but the difference did not reach statistical significance (Table 2). Regarding blood pressure, there were no significant interactions between gender, hyperparathyroidism or control group, and use of antihypertensive medication; neither was there any significant association with bone mineral density. Discussion In the present study we looked at a group of subjects with hyperparathyroidism that were recruited from an epidemiological survey. When diagnosed by us, Table 2 Bone mineral density (BMD) and blood pressure (BP) in relation to gender in the hyperparathyroidism (HPT) group and the control group (mean SD) Males Females HPT group Control group HPT group Control group Number of subjects Bone mineral density (g cm 22 ) Lumbar spine ac Femoral neck b Ward's triangle b Trochanter Systolic BP (mm Hg) b Diastolic BP (mm Hg) ab Subjects not on medication for BP Number of subjects Systolic BP (mm Hg) Diastolic BP (mm Hg) a P < 0.05 vs. control group (Student's t-test); b P < 0.05 and c P < 0.01 vs. control group (linear regression).

5 BMD AND BP IN PATIENTS WITH HPT 329 none of them were aware they had hypercalcaemia. Those with symptoms that could be ascribed to hyperparathyroidism, or those with serum calcium persistently above 2.80 mmol L 21, were referred to surgery. The others were followed for 3 to 4 years before the present follow-up, and it is therefore fair to say that our patients were as asymptomatic as a clinical study group can be. Furthermore, our definition of hyperparathyroidism, which was similar to that used by Lundgren et al. [13], included subjects with combinations of serum calcium and serum parathyroid hormone in the upper normal range. Most of our patients therefore had a very mild form of the disease, which was documented by their mean serum calcium being only 2.56 mmol L 21 at the present follow-up. In this respect our hyperparathyroidism subjects differ from those previously reported, where the patients with hyperparathyroidism have frequently been recruited from those referred to surgical treatment [4, 14, 15]. It was remarkable that out of the 282 subjects that had a second set of blood samples, hyperparathyroidism was only confirmed in 64. However, it must be recalled that our subjects were recruited from an epidemiological survey, and the number of `false positive tests' is therefore bound to be large when the cut off was set as low as 2.60 mmol L 21. Our control group was well matched to those with hyperparathyroidism. However, the hyperparathyroidism group was slightly younger and had a slightly higher body mass index than the controls, which could affect both the bone mineral density and the blood pressure. Therefore, this was controlled for in the statistical analysis. Furthermore, the groups were similar regarding intake of calcium and vitamin D, although the calcium intake was lower than expected (probably due to the food frequency questionnaire mainly covering dairy products and not fully including the dinner meal). None of the subjects were taking drugs for the treatment of osteoporosis, but considerably more of those with hyperparathyroidism were on medication for hypertension. However, this could not increase the difference between the groups with regard to blood pressure. Accordingly, our study groups were well suited for disclosing differences regarding bone mineral density and blood pressure. As expected, we did find a reduced bone mineral density in the subjects with hyperparathyroidism; this was seen in both sexes, but most pronounced in the females. Depending on sex and site of measurement the difference between the two groups was from 3.5% to 10.2%. As the effect of parathyroid hormone has traditionally been claimed to be most profound on cortical bone [16] it was somewhat surprising that the difference was largest for the lumbar spine, which in contrast to the femoral neck has more cancellous than cortical bone. The reduction in bone mineral density has repeatedly been described in subjects with hyperparathyroidism [2±4, 17, 18]. Generally, the effect of parathyroid hormone on the skeleton is to increase both bone resorption and bone formation, and, as in other studies [4, 15], we found an increased serum ALP level in the hyperparathyroidism group, reflecting increased bone turn-over. In our study blood pressure was higher in those with hyperparathyroidism, but surprisingly, the difference was only seen in females, being 10 mmhg higher for the systolic and 6 mmhg higher for the diastolic blood pressure. This sex difference has, to our knowledge, not been commented on before. Furthermore in our study, far more subjects with hyperparathyroidism than controls had been diagnosed as hypertensive and were taking drugs to reduce the blood pressure. Accordingly, without medication the difference between the two groups would have been even greater. There are several previous reports on an increased blood pressure in patients with hyperparathyroidism [6±8, 10]. However, there does not appear to be a clear cause and effect relationship between hyperparathyroidism and hypertension. Thus, in the study by Salahudeen et al. [9], parathyroidectomy did not result in any change in blood pressure when the subjects were restudied half a year after surgery. Similarly, in a study by Lind et al. [10], mild hyperparathyroidism was associated with increased blood pressure, both in subjects that were left unoperated as well as in those successfully treated surgically. The apparent lack of effect of surgery on hypertension in hyperparathyroidism is puzzling. It could indicated that the development of hypertension is unrelated to hypercalcaemia or to the increased parathyroid hormone levels, and is instead caused by an as yet unknown factor. Another explanation could be that the hyperparathyroidism is diagnosed and treated too late. Most likely, as the disease process is very slow [19], subjects with

6 330 R. JORDE & J. SUNDSFJORD hyperparathyroidism have had the disease for years before diagnosis, which might have initiated an irreversible process leading to manifest hypertension. In hypertensive subjects an increased urinary calcium loss has been described [20]. If this applies to patients with hyperparathyroidism and hypertension as well, it could, at least in theory, add to the effect of hyperparathyroidism on the loss of calcium from the skeleton. However, in our study we did not find any inverse relation between hypertension and bone mineral density. In conclusion, subjects with asymptomatic hyperparathyroidism have moderately reduced bone mineral density. In females, but not in males, there is also an increased blood pressure. Acknowledgements The study was supported by a grant from The Norwegian Research Council. The assistance by the staff, in particular Annika Gustafsson, at the Clinical Research Unit, University Hospital of Tromsù, is gratefully acknowledged. References 1 Albright F, Aub JC, Bauer W. Hyperparathyroidism: a common and polymorphic condition as illustrated by seventeen cases from one clinic. JAMA 1934; 102: 1276± McDermott MT, Perloff JJ, Kidd GS. Effects of mild asymptomatic primary hyperparathyroidism on bone mass in women with and without estrogen replacement therapy. J Bone Miner Res 1994; 9: 509±14. 3 Gou C-Y, Thomas WEG, Al-Dehaimi AW, Assiri AMA, Eastell R. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81: 3487±91. 4 Christiansen P, Steiniche T, Brixen K, et al. Primary hyperparathyroidism: biochemical markers and bone mineral density at multiple skeletal sites in Danish patients. Bone 1997; 21: 93±9. 5 NIH, Consensus Conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991; 114: 593±7. 6 HellstroÈm J, Birke G, Edvall CA. Hypertension in hyperparathyroidism. Br J Urol 1958; 30: 13±24. 7 Rosenthal FD, Roy S. Hypertension, hyperparathyroidism. Br Med J 1972; 4: 396±7. 8 Lind L, Hvarfner A, PalmeÂr M, Grimelius L, AÊ kerstroèm G, Ljunghall S. Hypertension in primary hyperparathyroidism in relation to histopathology. Eur J Surg 1991; 157: 457±9. 9 Salahudeen AK, Thomas TH, Sellars L, et al. Hypertension and renal dysfunction in primary hyperparathyroidism: effect of parathyroidectomy. Clin Sci 1989; 76: 289± Lind L, Jacobsson S, PalmeÂr M, Lithell H, Wengle B, Ljunghall S. Cardiovascular risk factors in primary hyperparathyroidism: a 15-year follow-up of operated and unoperated cases. J Intern Med 1991; 230: 29± PalmeÂr M, Adami H-O, BergstroÈm R, Jakobsson S, AÊ kerstroèm G, Ljunghall S. Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet 1987; i: 59± Rimestad AH, Blaker B, FlaÊten A-M, Nordbotten A. Statens ernñringsraêd. Den Store Matvaretabellen. Oslo: Universitetsforlaget, Lundgren E, Rastad J, Thurfjell E, AÊ kerstroèm G, Ljunghall S. Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women. Surgery 1997; 121: 287± Martin P, Bergmann P, Gillet C, et al. Partially reversible osteopenia after surgery for primary hyperparathyroidism. Arch Intern Med 1986; 146: 689± Pfeilschifter J, Siegrist E, WuÈster C, Blind E, Ziegler R. Serum levels of intact parathyroid hormone and alkaline phosphatase correlate with cortical and trabecular bone loss in primary hyperparathyroidism. Acta Endocrinol 1992; 127: 319± Bilezikian JP, Silverberg SJ, Shane E, Parisien M, Dempster DW. Characterization and evaluation of asymptomatic primary hyperparathyroidism. J Bone Miner Res 1991; 6: S85±9. 17 Block MA, Dailey GE, Muchmore DE. Bone demineralization, a factor of increasing significance in the management of primary hyperparathyroidism. Surgery 1989; 106: 1063±8. 18 Hesp R, Tellez M, Davidson L, Elton A, Reeve J. Trabecular and cortical bone in the radii of women with parathyroid adenoma: a greater trabecular deficit, with a preliminary assessment of recovery after parathyroidectomy. Bone Miner 1987; 2: 301± Corlew DS, Bryda SL, Bradley EL, DiGirolamo M. Observations on the course of untreated primary hyperparathyroidism. Surgery 1985; 98: 1064± Young EW, Morris CD, McCarron DA. Urinary calcium excretion in essential hypertension. J Lab Clin Med 1992; 120: 624±32. Received 3 March 1999; accepted 14 September Correspondence: Dr R. Jorde, Department of Internal Medicine, University Hospital of Tromsù, 9038 Tromsù, Norway (fax: ; medrj@rito.no).