Viral N. Shah*, Chirag S. Shah, Sanjay K. Bhadada and D. Sudhakar Rao

Transcription

1 Clinical Endocrinology (2014) 80, doi: /cen ORIGINAL ARTICLE Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature Viral N. Shah*, Chirag S. Shah, Sanjay K. Bhadada and D. Sudhakar Rao *Barbara Davis Center for Diabetes, University of Colorado, Denver, CO, USA, National Institute of Pharmaceutical Education and Research, Mohali, Postgraduate Institute of Medical Education & Research, Chandigarh, India and Bone and Mineral Metabolism, Henry Ford Hospital, Detroit, MI, USA Summary Context The safety of vitamin D replacement in subjects with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency is not well established. Objective To evaluate the safety of vitamin D replacement in PHPT. Data Source Data were searched from Medline, EMBASE, Cochrane CENTRAL and abstracts form annual scientific meetings of various international bone and mineral societies. Study Selection Studies examining the effect of preoperative vitamin D replacement in patients with PHPT and coexisting vitamin D deficiency, irrespective of year and language of the publication were included in the present meta-analysis. Data Extraction Data were extracted from text of the included publications or abstract of conferences. Data Synthesis Ten studies enrolling 3 subjects with PHPT were analysed in this meta-analysis. After vitamin D replacement, there was significant increase in 25(OH) D levels by 553 nmol/l (95% CI ), reduction in serum parathyroid hormone levels by 35 pmol/l (58 to 12) without change in serum calcium ( 008 mmol/l, 02 to+003) and urinary calcium levels (072 mmol/24 h, P = 02) compared to baseline. Conclusion Vitamin D replacement in subjects with PHPT and coexistent vitamin D deficiency increase 25 (OH) D and reduce serum PTH significantly without causing hypercalcaemia and hypercalciuria. The finding of the study needs to be confirmed by a large randomized trial in patient with PHPT and coexistent vitamin D deficiency. (Received 23 July 2013; returned for revision 18 August 2013; finally revised December 2013; accepted 23 December 2013) Correspondence: Dr. Viral N. Shah, Barbara Davis Center for Diabetes, University of Colorado, mail stop A14, room No 1318, Denver, CO, USA. Tel.: viral.shah@ucdenver.edu; viralshah_rational@yahoo.co.in Introduction The vitamin D deficiency is more common in patients with PHPT compared with the general population and is often associated with an aggravated form of the disease. 1,2 The higher incidence of vitamin D deficiency in patient with PHPT may be due to coexistent vitamin D deficiency, conversion of 25-hydroxyvitamin D [25(OH) D] to 1, 25 dihydroxyvitamin D [1,25 (OH) 2 D] by parathyroid hormone (PTH) and possibly accelerated catabolism of 25 (OH) D by 1, 25 (OH) 2 D. 3,4 Studies have shown that vitamin D deficiency in patients with PHPT has been associated with higher preoperative PTH levels, adenoma weight and severe bone disease and even paradoxical elevated serum calcium levels compared with vitamin D replaced or Vitamin D-sufficient PHPT patient. 1,5,6 The bone histomorphometry study by Stein and colleagues has shown that low levels of 25(OH) D in patients with PHPT are associated with higher concentrations of PTH and greater catabolic effects in cortical bone. 7 In addition, studies have also shown that vitamin D deficiency has been associated with a higher risk of developing postoperative hypocalcaemia, hungry bone syndrome 5 and persistent postoperative elevated serum PTH levels 8 and increased cardiovascular mortality. 9 There is a pervasive, but unfounded, practice of restricting both calcium and vitamin D supplements in PHPT for fear of aggravating hypercalcaemia, 10 which in most patients is stable over extended periods of time. 11 In addition, the recent guidelines encourage vitamin D replacement in vitamin D-deficient patients with PHPT. 12,13 There is no randomized controlled trial aimed to look for the safety of vitamin D replacement in patients with PHPT; hence, we undertook this meta-analysis. Materials and methods Study selection Medline, EMBASE and Cochrane CENTRAL were searched in February 2012, using terms primary hyperparathyroidism and 797

2 798 V. N. Shah et al. Vitamin D. Abstracts from annual scientific meeting (from 1990 forward) of the American Society for Bone and Mineral Research (ASBMR), the Society for Endocrinology (SfE) and the European Calcified Tissue Society (ECTS) were also searched. We also searched studies from cross-references of the included studies. The inclusion criteria were as follows: studies examining the effect of preoperative vitamin D replacement (D2, D3 or 25 hydroxylated vitamin D) in patients with PHPT, irrespective of year and language of the publication and studies reporting mean SD of serum 25 (OH) D, calcium and PTH at baseline and follow-up. Studies were excluded if vitamin D analogues or active vitamin D is used for replacement or vitamin D was replaced after parathyroidectomy. The case reports and case series with sample size of less than five subjects were also excluded for the meta-analysis. Primary hyperparathyroidism is defined as the elevation of PTH despite elevated serum calcium levels and mild PHPT defined as PHPT with serum calcium levels <3 mmol/l (<12 mg/dl). Vitamin D deficiency was defined as the mean 25 (OH) D level in the study is <20 ng/ml (50 nmol/l). Each of the potential studies was analysed independently by two authors (VNS & CSS), and a consensus was achieved regarding the suitability of each study by an expert in this field (DSR) without considering the results of the study. The study name, year of publication, sample size, patient demographics, disease characteristics, intervention (dose and duration of vitamin D replacement) and mean SD of biochemical parameters [e.g. serum calcium, PTH, 25(OH) D, creatinine, phosphate] at baseline and during follow-up were extracted from the each study. The biochemical parameters were converted into the SI units. The primary analysis was performed comparing the levels of serum 25(OH) D, calcium and PTH during the longest followup time of the study vs baseline. As the follow-up periods were different in each study, the last follow-up was considered as the longest follow-up. However, we have separately analysed the differences in these biochemical parameters between baseline and 2, 6 and 12 months. Secondary end-points were to examine differences in serum phosphate, alkaline phosphate, bone mineral density and 24-h urinary calcium excretion after vitamin D replacement. Statistical methods Data were analysed using REVMAN 5.2 software, Clinical Logistics, Oakland, CA, USA. Biochemical data (Serum calcium, phosphate, PTH and alkaline phosphatase) were expressed as pooled mean difference (with 95% CI) between follow-up periods and baseline. Z-test was used to find the significance of pooled mean difference. We also analysed P interaction of pooled mean difference between 3-, 6- and 12-month follow-up. We conducted sensitivity analysis after exclusion of studies reporting outlying data. The outlier is the value that has significant power to change the final estimation by its presence as well as absence in the calculation. We prespecified use of random-effects model for our analysis and tested for heterogeneity using the I 2 statistic, which estimates the percentage of total variation across studies that is due to heterogeneity rather than chance and I 2 values of 25 or less, 50 and at least 75% represents low, moderate and high inconsistency, respectively. Funnel plots were constructed to check each analysis for the publication bias. Data were presented as mean (95% CI) unless otherwise specified. All tests were two-tailed, and P-value <005 was considered significant. Results Study identification and characteristics The result of our search identified 310 publications and 90 abstracts from conferences of various societies. After the exclusion of unrelated studies, ten publications were eligible for meta-analysis (Fig. 1). All ten studies were observational in design There were two randomized control trial reporting the effect of vitamin D on various parameters in subjects with PHPT. One study used vitamin D analogues and the other used 24, 25(OH) 2 D3 and were excluded from the analysis. 24,25 Table 1 contains the name of first author, year of publication, study design, mean age of the study participants, sample size, study population (country), dose and duration of vitamin D replacement, mean 25(OH)D, PTH and calcium levels, and duration of follow-up of each study analysed in the present meta-analysis. The duration of vitamin D administration in these studies ranged from 125 to 12 months. Vitamin D2 was administered in four studies, 15,17,19,20 vitamin D3 in two studies, 16, two studies used 25-hydroxy vitamin D, 14,18 one study used different doses and forms of vitamin D, 23 and one study did not mention the type of vitamin D preparation. The doses of vitamin D Publications identified in search (n = 310) Publications included in analysis, 8 published studies + 2 abstracts (n = 10) Fig. 1 Flow of studies. Abstracts identified (n = 90) Publications excluded from analyses Reviews and editorials (n = 238) Case reports and case series (n = 53) Biochemical data not analysed (n = 3) Raw data not available (n = 1) Secondary and tertiary hyperparathyroidism (n = 90) Surgical treatment (n = 3) Studies using vitamin D analogues or active vitamin D (n = 2)

3 Safety of vitamin D replacement in PHPT 799 Table 1. Characteristics of included studies First author, year, ref no Study type Country Number of participants Mean age Intervention Duration and dose Mean pre/post 25(OH)D [nmol/l] Mean (SD) Serum PTH level [pmol/l] Mean (SD) Serum calcium level [mmol/l] Follow-up period LoCasicico, Obs. Italy 6 51* 25-OH-D3 50 µg/day for 1 month 383/ (809) (02) 4 weeks Kantorovich, Obs. USA 5 78 Vitamin D U/twice weekly for 5 week 4/ (25) 25 (02) 125 months Grey, Obs. New Zealand 683 Cholecalciferol U/week for month and thereafter once a month for 12 months Grubbs, Obs. USA Ergocalciferol U/tab. Dose and duration as per directed by surgeons. Median cumulative dose U / (71) (01) 12 months 459/ (99) (01) Median duration days Isidro, Obs. Spain 675 Calcifediol IU/day for 12 months 7/ (1) (01) 12 months Tucci, Obs. USA 636 Ergocalciferol U/week for 8 weeks followed by 800/day to U/month Velayoudomcephise, Obs. France 668 Ergocalciferol or cholecalciferol U/day for 3 months or U/month 364/ (51) (01) 34 weeks (85 months) 1/ (188) (02) 6 months Rathi, 2011 Obs. UK Cholecalciferol IU per week for 12 weeks 148/758 9 (110) NA 3 months Shkolnik, 2010 Obs. Israel 63 NA NA 385/ (36) 26 (01) NA Rao, Obs. UK 69 Various forms Variable dosage 3/ (13) 26 (003) 18 2 months Obs., observational; NA, information not available. *Mean age not available, data are in range.

4 800 V. N. Shah et al. were highly variable across the studies, which are mentioned in Table 1. The change in serum 25(OH) D, calcium and PTH levels after vitamin D replacement All ten studies reported the change in serum 25(OH) D levels from baseline after vitamin D replacement After vitamin D replacement, there was a significant increase in 25 (OH) D levels by 553 nmol/l (95% CI , P < ) compared to the baseline (Fig. 2a) There was a high heterogeneity across the studies (I 2 = 99%, P < ), and we did not find publication bias by visual assessment of the funnel plot which showed minimal asymmetry. In sensitivity analysis, after exclusion of the study by LoCasicio et al., 14 the pooled mean difference between longest follow-up and baseline 25 (OH) D was 485 nmol/l ( , Z = 4, P < 00001). Nine studies including a total of 317 subjects with mild PHPT were available for the calculation of difference in the mean for serum calcium levels before and after vitamin D replacement therapy ,,23 There was no change in serum calcium levels [reduction of 008 mmol/l ( 02, +003, P = 02)] after vitamin D replacement (Fig. 2b). There was a significant heterogeneity across the studies (I 2 = 97%, P < 00001), and no publication bias were detected. In a sensitivity analysis after excluding the study by Grubbs et al., 17 there was no change in serum calcium levels ( 004 mmol/l, 008, +001), Z = 167, P = 01). Of the 2 subjects with mild PHPT replaced with vitamin D in the six studies, five subjects developed significant hypercalcaemia (serum calcium >3 mmol/l). Therefore, the incidence of significant hypercalcaemia was % with vitamin D replacement in PHPT subjects. Three studies did not report any incidence of significant hypercalcaemia. 20 Those who developed significant hypercalcaemia were treated with either stoppage or reduction in their dose of vitamin D. There was not a single case of hypercalcaemic crisis reported in these studies. Although all ten studies reported the PTH levels before and after vitamin D replacement, the study by LoCasicico et al. 14 used old PTH assays and was excluded from the PTH analysis. Hence, a total nine studies were analysed for the PTH levels after vitamin D replacement. 15 There was a significant reduction in serum PTH levels by 35 pmol/l ( 58, 12, P = 0003) after vitamin D replacement (Fig. 2c). There was a high heterogeneity across the studies (I 2 = 87%) and no publication bias. We also analysed the difference in 25(OH) D, PTH and calcium levels at the end of 3, 6 and 12 months after vitamin D replacement. At the end of 3 and 6 months, there was significant (a) Kantorovich 2000 Grubbs 2008 Tucci 2009 Locascico 1985 Rathi % 10 4% 3 8% 10 8% [24 54, 37 68] [ 83, 57 17] [25 54, 76] [51 75, 64 45] [ 89, 71] 6 95 [136 87, ] [3 11, 19 83] [36 75, 52 25] [51 95, 70 05] [99 86, ] Year Z = % [33 33, 77 ] (P < ); I 2 = 99% Favour no vit. D replacement Favour vit. D replacement (b) Grubbs % 12 5% 0 03 [ 0 10, 0 04] 0 [ 0 44, 0 36] Kantorovich 2000 Locascico 1985 Tucci % 6 7% 7 9% 12 6% 12 5% 12 6% 10 9% 0 03 [ 0 03, 0 09] 0 02 [ 0 31, 0 ] 0 17 [ 0 07, 0 41] 0 07 [ 0 10, 0 04] 0 00 [ 0 04, 0 04] 0 03 [ 0 06, 0 00] 0 26 [ 0 38, 0 14] % Z = 1 42 (P = 0 16) 0 08 [ 0 19, 0 03] I 2 = 97% Favour vit. D replacement Favour no vit. D replacement (c) Grubbs 2008 Kantorovich 2000 Rathi 2011 Tucci % 14 0% 6 5% 10 5% 15 4% 9 2% 14 1% 12 9% 5 4% 3 20 [ 6 51, 0 11] 9 44 [ 11 39, 7 49] 2 30 [ 9 25, 4 65] 0 [ 4 35, 3 81] 2 60 [ 3 15, 2 05] 7 20 [ 12 14, 2 26] 0 [ 1 62, 2 16] 1 01 [ 3 66, 1 64] 8 45 [ 16 51, 0 39] % 3 49 [ 5 82, 1 16] I 2 = 87% Z = 2 94 (P = 0 003) Favour vit. D replacement Favour no vit. D replacement Fig. 2 Forest plots showing the mean differences between longest follow-up and baseline of serum 25(OH) D (a), calcium (b) and parathyroid levels (c). [Data are in SI units].

5 Safety of vitamin D replacement in PHPT 801 increase in 25(OH) D levels without change in serum calcium or PTH levels. And at the end of 12 months, except for the vitamin D and alkaline phosphatase, none of the other parameters of PHPT changed significantly. The details are provided in the Table S1. Effect of vitamin D replacement on serum phosphate, alkaline phosphate and 24-h urinary calcium excretion Four studies reported data on change in serum phosphate levels after vitamin D replacement therapy , There was no change in serum phosphate levels (00 mmol/l, 007, 007, P = 09) after vitamin D replacement. There was a high heterogeneity, but no publication bias (Fig. 3a). We analysed three studies that reported data about alkaline phosphatase after vitamin D replacement. 16,18,23 There was a reduction in serum alkaline phosphatase by 108 U/l ( 141, 77), P < 0001). There was neither heterogeneity nor publication bias among these three studies (Fig. 3b). Three studies reported data on change in 24-h urinary calcium after vitamin D replacement. 16,18,20 There was no change in urinary calcium excretion (072 mmol/24 h, 04 to +18, P = 02) after vitamin D replacement therapy. There was neither heterogeneity across the study (I = 24%) nor publication bias. (Fig. 3c). Discussion In the absence of the randomized controlled trial, this metaanalysis aimed to provide the evidences about the safety of vitamin D replacement in patients with primary hyperparathyroidism and coexistent vitamin D deficiency. There was a significant reduction in serum PTH levels after vitamin D replacement without the change in serum calcium or urinary calcium excretion. All the studies included in the present meta-analysis were observational studies. Though there were two randomized trial aimed to look for the effect of vitamin D on PHPT parameters. However, these studies 24,25 used vitamin D analogues and 24,25- (OH)2 D3 forms and were not included in the present meta-analysis. Therefore, the present meta-analysis included ten studies enrolling 3 subjects with mild PHPT and vitamin D deficiency. Many authors have expressed caution in recommending vitamin D replacement in PHPT due to the fear of worsening hypercalcaemia and hypercalciuria. 9,10,19 However, this fear was based on a few case reports and expert opinion rather than welldesigned studies and evidences. 10,26 Contrary to beliefs, this meta-analysis demonstrated a nonsignificant, but modest decline in serum calcium after vitamin D replacement which supports other studies. 1,5,6 This may be due to the reduction in serum PTH levels after vitamin D replacement therapy. Of the 2 patients with mild PHPT replaced with vitamin D in six studies, only % developed significant hypercalcaemia (serum calcium >12 mg/dl), which was successfully managed by either dose reduction or stopping vitamin D; there was not a single case reported of hypercalcaemic crisis in these studies. There was no significant change in 24-h calcium excretion after vitamin D replacement. However, there are only three studies that reported data on 24-h urinary calcium excretion; 16,18,20 hence, this result should be interpreted with caution. The study by Kantorovich et al. reported that three patients developed hypercalciuria but did not provide the baseline and follow-up 24-h urinary calcium excretion data, 15 while the study by Tucci et al. and Shkolnik et al. reported no change in urinary calcium/ creat ratio. 19, (a) Tucci % 23 2% 30 1% 3% 0 06 [ 0 14, 0 02] 0 00 [ 0 09, 0 09] 0 03 [ 0 08, 0 02] 0 13 [0 03, 0 23] Z = 0 09 (P = 0 93) 100 0% 0 00 [ 0 07, 0 07] I 2 = 70% Favour no vit. D replacement Favour vit. D replacement (b) 5 5% 1 0% 93 5% [ 32 46, 5 34] 0 90 [ 31 29, 33 09] [ 13 78, 7 ] I 2 = 0%, Z = 6 70 (P < ) 100 0% [ 14 02, 7 67] Fav vit. D replacement Fav no vit. D replacement Fig. 3 Forest plots showing the mean difference between longest follow-up and base line of serum phosphate (a), alkaline phosphatase (b) and 24-h urinary calcium excretion (c). [Data are in SI units]. (c) 47 5% 0% 25 6% Z = 1 (P = 0 20) 0 01 [ 1 63, 1 61] 2 20 [0 05, 4 35] 0 53 [ 1 68, 2 74] 100 0% 0 72 [ 0 39, 1 84] I 2 = 24% Favour vit. D replacement Favour no vit. D replacement

6 802 V. N. Shah et al. Although the information on renal stones after vitamin D replacement is not available from all studies, the studies by Kantorovich et al., Rao et al., Velayoudom-Cephise et al. and Grey et al. reported that their PHPT patients replaced with vitamin D did not develop renal stones despite few patients developed hypercalciuria. 15,16,23 Not all the patients with PHPT develop renal stones despite they have relative hypercalciuria. Therefore, many authors consider urinary calcium as poor predictor of renal stone formation in patients with PHPT. 16 However, until we have evidences from randomized trials, it is better to monitor 24-h urine calcium excretion in patients with PHPT on vitamin D replacement as per the recommendation by Third International Workshop on asymptomatic hyperparathyroidism. 12 Furthermore, we are unable to comment about the effect on renal function after vitamin D replacement in patients with PHPT because of unavailability of this information from these observational studies. However, the study by Rao et al. did not notice any change in serum creatinine and estimated glomerular filtration rate (egfr) 23 after vitamin D replacement. The recent study presented at ASBMR randomized 46 patients with PHPT and 25(OH) D levels <80 nmol/l to receive either 00 IU of cholecalciferol or placebo for 52 weeks. They noted significant rise in 25(OH)D and reduction in PTH levels without any change in urinary calcium or renal function. Severe hyperparathyroidism is known to be associated with decreased BMD and severe bone disease. However, the effect of vitamin D supplementation on BMD has been questioned recently. In a meta-analysis of 23 randomized controlled trial comprising more than 00 eucalcaemic subjects with mean age of 59 years, vitamin D supplements for 2 years did not reveal changes in BMD at four major sites with the exception of increase in BMD at femoral neck. 29 Nevertheless, the effect of vitamin D supplements in patients with PHPT may differ from normal osteoporotic subjects having normal PTH levels. Our meta-analysis indicates that vitamin D produces a significant decrease in PTH levels, and hence, preoperative vitamin D replacement in patients with mild PHPT may be helpful in reducing the severity of bone disease. The study by Kontorovich et al. showed improvement in BMD after vitamin D replacement in spite of persistent PHPT, but the sample size and duration of the follow-up was short. 15 The strength of this meta-analysis is that it has clinical as well as research implication. In absence of well-designed RCT, the data of the meta-analysis are important for the physicians. Furthermore, our findings support the recommendation by experts of Third International Workshop on asymptomatic primary hyperparathyroidism. However, the limitations are that all the studies were observational in design and hence may be subject to unrecognized bias. Furthermore, variations in dose, duration and type of vitamin D preparation used in these trials were different, making it difficult to be conclusive. The studies had only a short duration of follow-up, and hence, we cannot comment on long-term effect of vitamin D replacement in subjects with PHPT. In conclusion, vitamin D replacement in mild PHPT with coexistent vitamin D deficiency reduces parathyroid levels significantly without exhibiting hypercalcaemia or hypercalciuria. There is certainly a need for a large RCT with vitamin D replacement in asymptomatic PHPT with coexistent vitamin D deficiency with long-term follow-up to address the many questions that remain unanswered. Acknowledgements We acknowledge the help of M. Hassan Murad MD, Professor of Medicine, Mayo Clinic, Rochester, MN, for review and suggestion and Dr. Parth Ganatra, Bhavnagar, for help in editing the manuscript and Dr. Kapil Gudala, Ph.D student at NIPER, Mohali, for statistical help. Conflict of interest Nothing to declare. Financial disclosure Nothing to declare. References 1 Moosgaard, B., Vestergaard, P., Heickendorff, L. et al. (2005) Vitamin D status, seasonal variations, parathyroid adenoma weight and bone mineral density in primary hyperparathyroidism. 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