J Endocrinol Invest (2014) 37:467–471 DOI 10.1007/s40618-014-0056-y
ORIGINAL ARTICLE
Management of hypovitaminosis D in patients with primary hyperparathyroidism M. S. Rathi • S. Gonzalez • D. Wright N. R. Ellis • S. R. Peacey
•
Received: 29 November 2013 / Accepted: 21 January 2014 / Published online: 11 February 2014 Ó Italian Society of Endocrinology (SIE) 2014
Abstract Aim Epidemiological studies suggest that vitamin D deficiency is common in patients with primary hyperparathyroidism (PHPT). They have higher levels of serum parathyroid hormone (PTH) and markers of bone turnover and fractures are more frequent than vitamin D-replete patients. However, there are concerns that Vitamin D repletion might exacerbate pre-existent hypercalcaemia. Therefore, we aimed to determine if vitamin D replacement improved biochemical indices of calcium metabolism without worsening underlying hypercalcaemia. Subjects and methods This is a prospective, observational study based on routine clinical practice, set up in a secondary care centre. 45 consecutive patients with mild biochemical hypercalcaemia due to PHPT and hypovitaminosis D were enrolled. The mean age of the cohort was 61 years (range 25–85 years), predominately Asian (32 patients) and female (41 patients). They received 20,000 IU of oral cholecalciferol, once a week, for 3 months. Calcium, phosphate, alkaline phosphatase and PTH were measured at baseline, 4, 8 and 12 weeks following treatment. Vitamin D levels were obtained at baseline and at 12 weeks, after they completed their treatment. Results Vitamin D levels normalised at week 12 (mean ± SD, 18.8 ± 9.4 versus 76 ± 20 nmol/L, p = 0.0001) and PTH levels improved following treatment
M. S. Rathi (&) S. Gonzalez D. Wright N. R. Ellis S. R. Peacey Department of Diabetes and Endocrinology, Bradford Teaching Hospitals NHS Foundation Trust, Duckworth Lane, Bradford BD9 6RJ, UK e-mail: [email protected]; [email protected]
completion (21.2 ± 10 versus 16.2 ± 6 pmol/L, p = 0.026). There was no significant increase in serum calcium levels during vitamin D supplementation. Conclusions High doses of oral cholecalciferol normalised vitamin D levels without worsening underlying hypercalcaemia in individuals with PHPT. Keywords Hypovitaminosis D Primary hyperparathyroidism Vitamin D insufficiency Vitamin D deficiency
Introduction Primary hyperparathyroidism (PHPT) is a common endocrine disorder, with an estimated prevalence rate ranging from 0.1 to 0.7 % and rising up to 3 % in selected cohorts such as postmenopausal women [1, 2]. Epidemiological studies suggest that the prevalence of hypovitaminosis D (an inclusive term for both vitamin D deficiency and insufficiency) is more common in patients with primary hyperparathyroidism (PHPT) than in the general population and this is independent of age, sex and season [3]. In the Danish study, vitamin D insufficiency (plasma 25OHD \ 50 nmol/ l) was observed in 81 % of the PHPT patients compared with 60 % of the sex-, age- and season-matched controls (p \ 0.001) and vitamin D deficiency (25OHD \ 25 nmol/ l) was found in one-third of their PHPT population compared with one-fifth of the control population [3]. The reason for the frequent co-existence of vitamin D insufficiency and PHPT is not fully understood but several plausible mechanisms have been proposed in the literature: the conversion of 25OHD to 1,25OHD by the high PTH level may lead to depletion of 25OHD stores [4], the demonstration of inverse correlation between plasma
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elimination half time of 25OHD and serum 1,25OHD may support this hypothesis [5]. Clements et al. [6] have detected increased excretion of vitamin D-derived products in the faeces of patients with PHPT suggesting an enhanced hepatic inactivation of 25OHD. Subjects with PHPT being aware of their high serum calcium tend to avoid consumption of foods rich in vitamin D and avoid taking vitamin D supplements [4]. There is a trend towards an increased risk of osteoporotic fractures in patients with mild PHPT and low plasma 25OHD3 and it has been suggested that chronic vitamin D deficiency may accelerate parathyroid adenoma growth and PTH secretion and thereby aggravate bone catabolism, turnover and bone loss [4, 7–10]. Furthermore, Vitamin D deficient patients undergoing parathyroidectomy for primary hyperparathyroidism are at increased risk of postoperative hypocalcaemia and ‘‘hungry bone syndrome’’ [11]. Kantorovich et al. [12] demonstrated that vitamin D repletion was associated with significant increase in bone mineral density at both lumbar spine and femoral neck even in patients with vitamin D insufficiency and PHPT. In contrast to these study findings. Carnevale et al. [13] found that PTH concentration, age, and BMI had the predominant effects on bone mass, whereas 25OHD levels had no independent effect on BMD at any site. Similarly, Yamashita et al. [14] did not find an association between BMD and plasma 25OHD either. To summarise, the concomitant presence of hypovitaminosis D in PHPT can cause a delay in diagnosis, presentation with more severe disease and occasionally diagnostic uncertainty separating it from secondary hyperparathyroidism (SHPT). Therefore, treatment with Vitamin D would be advantageous and it should be considered in those patients with mild PHPT who are found to have hypovitaminosis D, regardless of whether surgical intervention is planned. However, there is reluctance in clinical practice to prescribe vitamin D supplementation in PHPT because of concerns that vitamin D repletion might exacerbate preexistent hypercalcaemia and possibly hypercalciuria, although recent literature suggests this is uncommon [15– 18]. Our aim was to determine the effects of vitamin D replacement on biochemical indices of calcium metabolism in patients with combined PHPT and hypovitaminosis D in a predominantly Asian cohort, as this population makes up a significant part of our clinical work.
J Endocrinol Invest (2014) 37:467–471
hypovitaminosis D were studied. All the subjects met the diagnostic criteria of PHPT and hypovitaminosis D (vitamin D: deficiency 25OHD3 \ 20 nmol/L or insufficiency 25OHD3; 20–59 nmol/L) before enrolment. Of these patients, 32 patients of Asian and 13 were of Caucasian ethnic origin. Mean age of study population was 61 years (range 25–85 years). Mean age of the Asian population was 57 years (range 25–76 years). None of these patients were taking antiresorptive agents or vitamin D supplements. Design This is a prospective, observational study based on previously published clinical evidence and routine clinical practice and set up in a secondary care centre. Methods All subjects had basal measurement of corrected calcium, phosphate, alkaline phosphatase, creatinine, PTH and 25OHD3. Each patient received oral 20,000 IU cholecalciferol once per week for 12 weeks. Serum corrected calcium, phosphate, alkaline phosphatase, PTH were measured at weeks four, eight and twelve. 25OHD3 was measured at 12 weeks. Laboratory assays Serum 25OHD3 was determined by tandem mass spectrometry (CV 6 %), serum PTH was measured using an immune-chemiluminometric assay on Advia Centaur XP (CV 10 %). Calcium (CV 3 %), phosphate (CV 2 %) and alkaline phosphatase (CV 2 %) were determined by Siemens 2400 immunoassay. Statistical analysis Biochemical values were compared pre and post vitamin D supplementation using paired t test for Vitamin D levels and ANOVA for the other parameters, using SPSS version 19. All parameters except PTH were normally distributed when checked with the Homogeneity of Variances Test. Results are reported in mean ± standard deviation (SD). Significance was reached if p \0.05. Post hoc comparisons using Dunnet T3 were made for PTH. The statistical relationship between 25OHD3 and PTH was explored using Pearson’s correlation.
Subjects and methods Subjects
Results
A total of 45 consecutive patients (41 females and 4 males) with PHPT, mild hypercalcaemia and coexistent
Basal levels of corrected serum calcium, phosphate, alkaline phosphatase, PTH and total vitamin D (25OHD3) are
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469
Table 1 Biochemical values, total cohort of patients Baseline
4 weeks
8 weeks
12 weeks
p value
Adjusted Calcium (2.20–2.60 mmol/L)
2.63 ± 0.1
2.64 ± 0.1
2.64 ± 0.1
2.65 ± 0.1
0.83
Phosphate (0.8–1.3 mmol/L)
0.87 ± 0.2
0.92 ± 0.2
0.93 ± 0.1
0.91 ± 0.2
0.57
Alkaline phosphatase (70–300 IU/L)
267 ± 88.5
264 ± 98
254 ± 102
256 ± 89.1
0.89
PTH (1.5–7.6 pmol/L)
21.2 ± 10
20.4 ± 17
15.8 ± 6*
25OHD3 (nmol/L)
18.8 ± 9.4
16.2 ± 6**
0.018*, 0.026**
76 ± 20
0.0001
Values represent mean ± standard deviation (SD) Normal reference range: Calcium, 2.20–2.60 mmol/L; phosphate, 0.8–1.3 mmol/L; alkaline phosphatase, 70–300 IU/L; PTH, 1.5–7.6 pmol/L; 25OHD3, [60 nmol/L; vitamin D deficiency \10 nmol/L; vitamin D insufficiency, 10–59 nmol/L * p values 8 weeks versus baseline, ** 12 weeks versus baseline
Table 2 Biochemical values, Asian subgroup Baseline
4 weeks
8 weeks
12 weeks
p value
Adjusted Calcium (2.20–2.60 mmol/L)
2.62 ± 0.1
2.61 ± 0.1
2.62 ± 0.1
2.63 ± 0.1
0.86
Phosphate (0.8–1.3 mmol/L)
0.89 ± 0.1
0.91 ± 0.2
0.93 ± 0.1
0.90 ± 0.1
0.73
Alkaline phosphatase (70–300 IU/L)
263 ± 71.2
258 ± 75.3
242 ± 86.7
250 ± 79.1
0.72
PTH (1.5–7.6 pmol/L)
20.9 ± 10
21.8 ± 19
15.5 ± 6
15.2 ± 5*
0.04
Vit D (nmol/L)
17.3 ± 9
72.7 ± 19
0.0001
* p values baseline versus 12 weeks
shown in Table 1 (for the total cohort) and Table 2 (for the Asian subgroup). All the patients completed the treatment, it was tolerated without any side effects and no patient developed symptomatic renal stones during the study. Serum 25OHD3 levels significantly improved following completion of vitamin D therapy (baseline versus 12 weeks 18.8 ± 9.4 versus 76 ± 20 nmol/L, p = 0.0001), rendering the majority of patients vitamin D replete. A significant reduction in PTH levels was observed at week 8 when compared with baseline levels (baseline versus 8 weeks 21.2 ± 10 versus 15.8 ± 6 pmol/L, p = 0.018) and maintained at week 12 (baseline versus 12 weeks 21.2 ± 10 versus 16.2 ± 6 pmol/L, p = 0.026). Basal vitamin D levels were inversely correlated with the degree of PTH reduction at 3 months (r = -0.33, p = 0.02). No significant changes in calcium, phosphate or alkaline phosphatase levels were observed and serum calcium did not exceed 2.78 mmol/L in any of these patient groups. When the Asian cohort was examined separately (n = 32), similar findings were observed (Table 2).
Discussion Physiologically, parathyroid hormone and vitamin D are involved in homeostatic mechanisms controlling serum calcium ion activity. In response to decreased serum calcium ion, feedback loops increase PTH secretion, thereby increasing renal resorption of calcium, mobilising calcium
from bone, and stimulating renal 1a-hydroxylation of 25-OHD (with subsequent increased gastrointestinal absorption of calcium). The net effect is an increase in serum calcium ion activity, and subsequent reduced PTH secretion. Therefore, it seems plausible that vitamin D replacement in patients with primary hyperparathyroidism might trigger an increase in gastrointestinal calcium absorption hence exacerbating the underlying hypercalcaemia and hypercalciuria. However, there is some limited evidence in the literature that might indicate otherwise. Four separate studies [15– 18] using different types of vitamin D supplementation in patients with mild PHPT reported stable calcium levels without any cases of severe hypercalcaemia. Two of these studies noted a small but statistically significant increase in mean urinary calcium excretion, although no urolithiasis was reported [15, 18]. In all of them, repletion of hypovitaminosis D led to a significant reduction in PTH levels. These studies also highlight the different approaches utilised within the scientific community to achieve vitamin D repletion and an ongoing debate continues to determine the optimal serum vitamin D levels and the best replacement options for these patients. The US Institute of Medicine-recommended Dietary Allowance of vitamin D is 600 IU per day for adults up to 70 years and 800 IU per day for older adults, and target level of serum 25-hydroxyvitamin D 25OHD of 50 nmol/L (20 ng/ml) or more whereas the US Endocrine Society’s Clinical Practice Guidelines recommend 1,500–2,000 IU Vitamin D per day
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for adults aged 19 years or more to maintain 25OHD above the level of 75 nmol/l (30 ng/ml) [19, 20]. Following the 3rd workshop on the Management of Asymptomatic PHPT, the panel proposed cautious vitamin D supplementation in asymptomatic patients with PHPT and 25OHD3 \ 50 nmol/l, before making any medical or surgical management decision [21]. Our current practice is in line with those recommendations and shows that vitamin D replacement with oral cholecalciferol using our routine replacement protocol is effective improving vitamin D levels in patients with PHPT and mild hypercalcaemia, and more importantly, it appears to be a safe practice since corrected calcium levels were stable during the duration and completion of treatment. Additionally, we report a reduction in serum PTH levels of approximately 25 % similar to the study performed by Grey et al. [15] but without significant changes in total alkaline phosphate in response to vitamin D therapy after 3 months of treatment. Perhaps total ALP might not have been a sensitive enough marker to detect subtle changes in bone turnover, especially in patients with very limited bone disease in relation to the mild primary hyperparathyroidism or that significant changes in alkaline phosphate levels lag behind Vitamin D correction, since reductions were observed by Grey et al. 6 and 12 months after initiation of therapy but earlier changes were not reported. Urinary calcium excretion was not monitored during the period of vitamin D supplementation in our cohort because levels [10 mmol/24 h should no longer be considered as an indication for surgical treatment, hence there is little need to measure it during the follow-up [21]. In addition, the significance of any increase in urinary calcium excretion reported with Vitamin D supplementation is uncertain. The strength of our study is that we describe similar effects in both our Asian and Caucasian patients irrespectively of their age or gender which has not been reported previously. This is relevant in our daily practice due to the local rich mix of ethnic groups, in particular people with Asian heritage (20 %). Vitamin D deficiency is highly prevalent in Asians living in the UK, especially in women, due to dietary, cultural habits and possibly due to genetic predisposition causing abnormal vitamin D metabolism in response to an increased activity of 25-OHD, 24 hydroxylase that might be responsible for the low 25-hydroxyvitamin D3 levels observed in this population [22]. Primary care practitioners are increasingly aware of widespread vitamin D deficiency in patients of Asian ethnicity and our data will help to emphasise the positive aspects of vitamin D replacement in PHPT associated with mild hypercalcaemia while demonstrating repletion is safe in both in Asians and Caucasians. A limitation of this study is that our observations cannot be readily extrapolated to different subgroups of patients
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with primary hyperparathyroidism especially if the degree of baseline hypercalcaemia is more severe or their disease is particularly symptomatic.
Conclusion We conclude that weekly vitamin D supplementation with 20,000 IU of cholecalciferol for 12 weeks in patients with mild PHPT lowers serum PTH, improves vitamin D levels and appears to be safe without any deleterious clinical or biochemical effects on serum calcium levels, in both an Asian and Caucasian population and it might help improving diagnostic separation between primary and secondary hyperparathyroidism and reduce the severity of the disease. Acknowledgments We thank Dr. Helen Field and Dr. Julian Barth, Leeds Teaching Hospitals for measuring serum Vitamin D levels. Conflict of interest M. S. Rathi, S. Gonzalez, D. Wright, N. R. Ellis and S. R. Peacey declare they have no conflict of interest.
References: 1. Fraser WD (2009) Hyperparathyroidism. Lancet 374:145–158 2. Lundgren E, Hagstro¨m EG, Lundin J et al (2002) Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago. World J Surg 26:931–936 3. Moosgaard B, Vestergaard P, Heickendorff L et al (2005) Vitamin D status, seasonal variations, parathyroid adenoma weight and bone mineral density in primary hyperparathyroidism. Clin Endocrinol 63:506–513 4. Silverberg SJ, Shane E, Dempster DW et al (1999) The effects of vitamin D insufficiency in patients with primary hyperparathyroidism. Am J Med 107:561–567 5. Clements MR, Davies M, Hayes ME et al (1992) The role of 1, 25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol (Oxf) 137:17–27 6. Clements MR, Davies M, Fraser DR et al (1987) Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci (Lond) 73:659–664 7. Nordenstrom E, Westerdahl J, Lindergard B et al (2002) Multifactorial risk profile for bone fractures in primary hyperparathyroidism. World J Surg 26:1463–1467 8. Rao DS, Honasoge M, Divine GW et al (2000) Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J Clin Endocrinol Metab 85:1054–1058 9. Rao DS, Agarwal G, Talpos GB et al (2002) Role of vitamin D and calcium nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective. J Bone Miner Res 17:N75–N80 10. Lumb GA, Stanbury SW (1974) Parathyroid function in human vitamin D deficiency and vitamin D deficiency in primary hyperparathyroidism. Am J Med 56:833–839 11. Silverberg SJ (2007) Vitamin D deficiency and primary hyperparathyroidism. J Bone Miner Res 22(S2):100–104 12. Kantorovich V, Gacad M, Seeger LL, Adams JS (2000) Bone mineral density increases with vitamin D repletion in patients
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with coexistent vitamin D insufficiency and primary hyperparathyroidism. J Clin Endocrinol Metab 85:3541–3543 Carnevale V, Manfredi G, Romagnoli E et al (2004) Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage? Clin Endocrinol 60:81–86 Yamashita H, Noguchi S, Uchno S et al (2002) Vitamin D status in Japanese patients with hyperparathyroidism. World J Surg 26:937–941 Grey A, Lucas J, Horne A et al (2005) Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. J Clin Endocrinol Metab 90:2122–2126 Grubbs EG, Rafeeq S, Jimenez C et al (2008) Preoperative vitamin D replacement therapy in primary hyperparathyroidism: safe and beneficial? Surgery 144:852–858 Tucci JR (2009) Vitamin D therapy in patients with primary hyperparathyroidism and hypovitaminosis D. Eur J Endocrinol 161:189–193
471 18. Isidro ML, Ruano B (2009) Biochemical effects of calcifediol supplementation in mild, asymptomatic, hyperparathyroidism with concomitant vitamin D deficiency. Endocrine 36:305–310 19. IOM (Institute of Medicine) (2011) Dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington, DC, pp 260–262 20. Holick MF, Binkley NC, Bischoff-Ferrari HA et al (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930 21. Eastell R, Arnold A, Brandi ML et al (2009) Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2:340–350 22. Awumey EM, Mitra DA, Hollis BW et al (1998) Vitamin D metabolism is altered in Asian Indians in the southern United States: a clinical research center study. J Clin Endocrinol Metab 83:169–173
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ORIGINAL ARTICLE
Management of hypovitaminosis D in patients with primary hyperparathyroidism M. S. Rathi • S. Gonzalez • D. Wright N. R. Ellis • S. R. Peacey
•
Received: 29 November 2013 / Accepted: 21 January 2014 / Published online: 11 February 2014 Ó Italian Society of Endocrinology (SIE) 2014
Abstract Aim Epidemiological studies suggest that vitamin D deficiency is common in patients with primary hyperparathyroidism (PHPT). They have higher levels of serum parathyroid hormone (PTH) and markers of bone turnover and fractures are more frequent than vitamin D-replete patients. However, there are concerns that Vitamin D repletion might exacerbate pre-existent hypercalcaemia. Therefore, we aimed to determine if vitamin D replacement improved biochemical indices of calcium metabolism without worsening underlying hypercalcaemia. Subjects and methods This is a prospective, observational study based on routine clinical practice, set up in a secondary care centre. 45 consecutive patients with mild biochemical hypercalcaemia due to PHPT and hypovitaminosis D were enrolled. The mean age of the cohort was 61 years (range 25–85 years), predominately Asian (32 patients) and female (41 patients). They received 20,000 IU of oral cholecalciferol, once a week, for 3 months. Calcium, phosphate, alkaline phosphatase and PTH were measured at baseline, 4, 8 and 12 weeks following treatment. Vitamin D levels were obtained at baseline and at 12 weeks, after they completed their treatment. Results Vitamin D levels normalised at week 12 (mean ± SD, 18.8 ± 9.4 versus 76 ± 20 nmol/L, p = 0.0001) and PTH levels improved following treatment
M. S. Rathi (&) S. Gonzalez D. Wright N. R. Ellis S. R. Peacey Department of Diabetes and Endocrinology, Bradford Teaching Hospitals NHS Foundation Trust, Duckworth Lane, Bradford BD9 6RJ, UK e-mail: [email protected]; [email protected]
completion (21.2 ± 10 versus 16.2 ± 6 pmol/L, p = 0.026). There was no significant increase in serum calcium levels during vitamin D supplementation. Conclusions High doses of oral cholecalciferol normalised vitamin D levels without worsening underlying hypercalcaemia in individuals with PHPT. Keywords Hypovitaminosis D Primary hyperparathyroidism Vitamin D insufficiency Vitamin D deficiency
Introduction Primary hyperparathyroidism (PHPT) is a common endocrine disorder, with an estimated prevalence rate ranging from 0.1 to 0.7 % and rising up to 3 % in selected cohorts such as postmenopausal women [1, 2]. Epidemiological studies suggest that the prevalence of hypovitaminosis D (an inclusive term for both vitamin D deficiency and insufficiency) is more common in patients with primary hyperparathyroidism (PHPT) than in the general population and this is independent of age, sex and season [3]. In the Danish study, vitamin D insufficiency (plasma 25OHD \ 50 nmol/ l) was observed in 81 % of the PHPT patients compared with 60 % of the sex-, age- and season-matched controls (p \ 0.001) and vitamin D deficiency (25OHD \ 25 nmol/ l) was found in one-third of their PHPT population compared with one-fifth of the control population [3]. The reason for the frequent co-existence of vitamin D insufficiency and PHPT is not fully understood but several plausible mechanisms have been proposed in the literature: the conversion of 25OHD to 1,25OHD by the high PTH level may lead to depletion of 25OHD stores [4], the demonstration of inverse correlation between plasma
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468
elimination half time of 25OHD and serum 1,25OHD may support this hypothesis [5]. Clements et al. [6] have detected increased excretion of vitamin D-derived products in the faeces of patients with PHPT suggesting an enhanced hepatic inactivation of 25OHD. Subjects with PHPT being aware of their high serum calcium tend to avoid consumption of foods rich in vitamin D and avoid taking vitamin D supplements [4]. There is a trend towards an increased risk of osteoporotic fractures in patients with mild PHPT and low plasma 25OHD3 and it has been suggested that chronic vitamin D deficiency may accelerate parathyroid adenoma growth and PTH secretion and thereby aggravate bone catabolism, turnover and bone loss [4, 7–10]. Furthermore, Vitamin D deficient patients undergoing parathyroidectomy for primary hyperparathyroidism are at increased risk of postoperative hypocalcaemia and ‘‘hungry bone syndrome’’ [11]. Kantorovich et al. [12] demonstrated that vitamin D repletion was associated with significant increase in bone mineral density at both lumbar spine and femoral neck even in patients with vitamin D insufficiency and PHPT. In contrast to these study findings. Carnevale et al. [13] found that PTH concentration, age, and BMI had the predominant effects on bone mass, whereas 25OHD levels had no independent effect on BMD at any site. Similarly, Yamashita et al. [14] did not find an association between BMD and plasma 25OHD either. To summarise, the concomitant presence of hypovitaminosis D in PHPT can cause a delay in diagnosis, presentation with more severe disease and occasionally diagnostic uncertainty separating it from secondary hyperparathyroidism (SHPT). Therefore, treatment with Vitamin D would be advantageous and it should be considered in those patients with mild PHPT who are found to have hypovitaminosis D, regardless of whether surgical intervention is planned. However, there is reluctance in clinical practice to prescribe vitamin D supplementation in PHPT because of concerns that vitamin D repletion might exacerbate preexistent hypercalcaemia and possibly hypercalciuria, although recent literature suggests this is uncommon [15– 18]. Our aim was to determine the effects of vitamin D replacement on biochemical indices of calcium metabolism in patients with combined PHPT and hypovitaminosis D in a predominantly Asian cohort, as this population makes up a significant part of our clinical work.
J Endocrinol Invest (2014) 37:467–471
hypovitaminosis D were studied. All the subjects met the diagnostic criteria of PHPT and hypovitaminosis D (vitamin D: deficiency 25OHD3 \ 20 nmol/L or insufficiency 25OHD3; 20–59 nmol/L) before enrolment. Of these patients, 32 patients of Asian and 13 were of Caucasian ethnic origin. Mean age of study population was 61 years (range 25–85 years). Mean age of the Asian population was 57 years (range 25–76 years). None of these patients were taking antiresorptive agents or vitamin D supplements. Design This is a prospective, observational study based on previously published clinical evidence and routine clinical practice and set up in a secondary care centre. Methods All subjects had basal measurement of corrected calcium, phosphate, alkaline phosphatase, creatinine, PTH and 25OHD3. Each patient received oral 20,000 IU cholecalciferol once per week for 12 weeks. Serum corrected calcium, phosphate, alkaline phosphatase, PTH were measured at weeks four, eight and twelve. 25OHD3 was measured at 12 weeks. Laboratory assays Serum 25OHD3 was determined by tandem mass spectrometry (CV 6 %), serum PTH was measured using an immune-chemiluminometric assay on Advia Centaur XP (CV 10 %). Calcium (CV 3 %), phosphate (CV 2 %) and alkaline phosphatase (CV 2 %) were determined by Siemens 2400 immunoassay. Statistical analysis Biochemical values were compared pre and post vitamin D supplementation using paired t test for Vitamin D levels and ANOVA for the other parameters, using SPSS version 19. All parameters except PTH were normally distributed when checked with the Homogeneity of Variances Test. Results are reported in mean ± standard deviation (SD). Significance was reached if p \0.05. Post hoc comparisons using Dunnet T3 were made for PTH. The statistical relationship between 25OHD3 and PTH was explored using Pearson’s correlation.
Subjects and methods Subjects
Results
A total of 45 consecutive patients (41 females and 4 males) with PHPT, mild hypercalcaemia and coexistent
Basal levels of corrected serum calcium, phosphate, alkaline phosphatase, PTH and total vitamin D (25OHD3) are
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Table 1 Biochemical values, total cohort of patients Baseline
4 weeks
8 weeks
12 weeks
p value
Adjusted Calcium (2.20–2.60 mmol/L)
2.63 ± 0.1
2.64 ± 0.1
2.64 ± 0.1
2.65 ± 0.1
0.83
Phosphate (0.8–1.3 mmol/L)
0.87 ± 0.2
0.92 ± 0.2
0.93 ± 0.1
0.91 ± 0.2
0.57
Alkaline phosphatase (70–300 IU/L)
267 ± 88.5
264 ± 98
254 ± 102
256 ± 89.1
0.89
PTH (1.5–7.6 pmol/L)
21.2 ± 10
20.4 ± 17
15.8 ± 6*
25OHD3 (nmol/L)
18.8 ± 9.4
16.2 ± 6**
0.018*, 0.026**
76 ± 20
0.0001
Values represent mean ± standard deviation (SD) Normal reference range: Calcium, 2.20–2.60 mmol/L; phosphate, 0.8–1.3 mmol/L; alkaline phosphatase, 70–300 IU/L; PTH, 1.5–7.6 pmol/L; 25OHD3, [60 nmol/L; vitamin D deficiency \10 nmol/L; vitamin D insufficiency, 10–59 nmol/L * p values 8 weeks versus baseline, ** 12 weeks versus baseline
Table 2 Biochemical values, Asian subgroup Baseline
4 weeks
8 weeks
12 weeks
p value
Adjusted Calcium (2.20–2.60 mmol/L)
2.62 ± 0.1
2.61 ± 0.1
2.62 ± 0.1
2.63 ± 0.1
0.86
Phosphate (0.8–1.3 mmol/L)
0.89 ± 0.1
0.91 ± 0.2
0.93 ± 0.1
0.90 ± 0.1
0.73
Alkaline phosphatase (70–300 IU/L)
263 ± 71.2
258 ± 75.3
242 ± 86.7
250 ± 79.1
0.72
PTH (1.5–7.6 pmol/L)
20.9 ± 10
21.8 ± 19
15.5 ± 6
15.2 ± 5*
0.04
Vit D (nmol/L)
17.3 ± 9
72.7 ± 19
0.0001
* p values baseline versus 12 weeks
shown in Table 1 (for the total cohort) and Table 2 (for the Asian subgroup). All the patients completed the treatment, it was tolerated without any side effects and no patient developed symptomatic renal stones during the study. Serum 25OHD3 levels significantly improved following completion of vitamin D therapy (baseline versus 12 weeks 18.8 ± 9.4 versus 76 ± 20 nmol/L, p = 0.0001), rendering the majority of patients vitamin D replete. A significant reduction in PTH levels was observed at week 8 when compared with baseline levels (baseline versus 8 weeks 21.2 ± 10 versus 15.8 ± 6 pmol/L, p = 0.018) and maintained at week 12 (baseline versus 12 weeks 21.2 ± 10 versus 16.2 ± 6 pmol/L, p = 0.026). Basal vitamin D levels were inversely correlated with the degree of PTH reduction at 3 months (r = -0.33, p = 0.02). No significant changes in calcium, phosphate or alkaline phosphatase levels were observed and serum calcium did not exceed 2.78 mmol/L in any of these patient groups. When the Asian cohort was examined separately (n = 32), similar findings were observed (Table 2).
Discussion Physiologically, parathyroid hormone and vitamin D are involved in homeostatic mechanisms controlling serum calcium ion activity. In response to decreased serum calcium ion, feedback loops increase PTH secretion, thereby increasing renal resorption of calcium, mobilising calcium
from bone, and stimulating renal 1a-hydroxylation of 25-OHD (with subsequent increased gastrointestinal absorption of calcium). The net effect is an increase in serum calcium ion activity, and subsequent reduced PTH secretion. Therefore, it seems plausible that vitamin D replacement in patients with primary hyperparathyroidism might trigger an increase in gastrointestinal calcium absorption hence exacerbating the underlying hypercalcaemia and hypercalciuria. However, there is some limited evidence in the literature that might indicate otherwise. Four separate studies [15– 18] using different types of vitamin D supplementation in patients with mild PHPT reported stable calcium levels without any cases of severe hypercalcaemia. Two of these studies noted a small but statistically significant increase in mean urinary calcium excretion, although no urolithiasis was reported [15, 18]. In all of them, repletion of hypovitaminosis D led to a significant reduction in PTH levels. These studies also highlight the different approaches utilised within the scientific community to achieve vitamin D repletion and an ongoing debate continues to determine the optimal serum vitamin D levels and the best replacement options for these patients. The US Institute of Medicine-recommended Dietary Allowance of vitamin D is 600 IU per day for adults up to 70 years and 800 IU per day for older adults, and target level of serum 25-hydroxyvitamin D 25OHD of 50 nmol/L (20 ng/ml) or more whereas the US Endocrine Society’s Clinical Practice Guidelines recommend 1,500–2,000 IU Vitamin D per day
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for adults aged 19 years or more to maintain 25OHD above the level of 75 nmol/l (30 ng/ml) [19, 20]. Following the 3rd workshop on the Management of Asymptomatic PHPT, the panel proposed cautious vitamin D supplementation in asymptomatic patients with PHPT and 25OHD3 \ 50 nmol/l, before making any medical or surgical management decision [21]. Our current practice is in line with those recommendations and shows that vitamin D replacement with oral cholecalciferol using our routine replacement protocol is effective improving vitamin D levels in patients with PHPT and mild hypercalcaemia, and more importantly, it appears to be a safe practice since corrected calcium levels were stable during the duration and completion of treatment. Additionally, we report a reduction in serum PTH levels of approximately 25 % similar to the study performed by Grey et al. [15] but without significant changes in total alkaline phosphate in response to vitamin D therapy after 3 months of treatment. Perhaps total ALP might not have been a sensitive enough marker to detect subtle changes in bone turnover, especially in patients with very limited bone disease in relation to the mild primary hyperparathyroidism or that significant changes in alkaline phosphate levels lag behind Vitamin D correction, since reductions were observed by Grey et al. 6 and 12 months after initiation of therapy but earlier changes were not reported. Urinary calcium excretion was not monitored during the period of vitamin D supplementation in our cohort because levels [10 mmol/24 h should no longer be considered as an indication for surgical treatment, hence there is little need to measure it during the follow-up [21]. In addition, the significance of any increase in urinary calcium excretion reported with Vitamin D supplementation is uncertain. The strength of our study is that we describe similar effects in both our Asian and Caucasian patients irrespectively of their age or gender which has not been reported previously. This is relevant in our daily practice due to the local rich mix of ethnic groups, in particular people with Asian heritage (20 %). Vitamin D deficiency is highly prevalent in Asians living in the UK, especially in women, due to dietary, cultural habits and possibly due to genetic predisposition causing abnormal vitamin D metabolism in response to an increased activity of 25-OHD, 24 hydroxylase that might be responsible for the low 25-hydroxyvitamin D3 levels observed in this population [22]. Primary care practitioners are increasingly aware of widespread vitamin D deficiency in patients of Asian ethnicity and our data will help to emphasise the positive aspects of vitamin D replacement in PHPT associated with mild hypercalcaemia while demonstrating repletion is safe in both in Asians and Caucasians. A limitation of this study is that our observations cannot be readily extrapolated to different subgroups of patients
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with primary hyperparathyroidism especially if the degree of baseline hypercalcaemia is more severe or their disease is particularly symptomatic.
Conclusion We conclude that weekly vitamin D supplementation with 20,000 IU of cholecalciferol for 12 weeks in patients with mild PHPT lowers serum PTH, improves vitamin D levels and appears to be safe without any deleterious clinical or biochemical effects on serum calcium levels, in both an Asian and Caucasian population and it might help improving diagnostic separation between primary and secondary hyperparathyroidism and reduce the severity of the disease. Acknowledgments We thank Dr. Helen Field and Dr. Julian Barth, Leeds Teaching Hospitals for measuring serum Vitamin D levels. Conflict of interest M. S. Rathi, S. Gonzalez, D. Wright, N. R. Ellis and S. R. Peacey declare they have no conflict of interest.
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