[Association between preoperative cholecalciferol therapy and hypocalcemia after parathyroidectomy in patients with primary hyperparathyroidism].

BACKGROUND: Primary hyperparathyroidism (PHPT) is a endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) from parathyroid gland tumors. Parathyroidectomy (PTE) is the main treatment for PHPT, but it can lead to hypocalcemia in up to 46% of cases. Hypocalcemia is associated with seizures and life-threatening cardiac arrhythmias, and vitamin D deficiency can exacerbate PHPT severity and contribute to «hungry bones syndrome,¼ resulting in severe and persistent postoperative hypocalcemia. AIM: To evaluate the association and determine the strength of the relationship between preoperative cholecalciferol therapy and the occurrence of hypocalcemia within 1-3 days after PTE in patients with PHPT. MATERIALS AND METHODS: The study was conducted at the Endocrinology Research Centre, during the periods of 1993-2010 and 2017-2020. The inclusion criteria consisted of patients diagnosed with PHPT who required PTE, had a serum 25-hydroxyvitamin D (25(OH)D) level below 20 ng/mL, and a serum total calcium level below 3 mmol/L. The exclusion criterion was the use of medications that affect calcium-phosphorus metabolism, including cinacalcet, denosumab, or bisphosphonates, either as monotherapy or as part of combination therapy. RESULTS: There were 117 patients, including 110 (94%) females and 7 (6%) males. The median age and interquartile range were 58 [49; 65] years. Among the participants, 21 (18%) received cholecalciferol supplementation for a duration of 2 weeks to 2 months prior to PTE, aiming to address vitamin D deficiency. The remaining 96 (82%) participants did not receive -cholecalciferol supplementation. Both groups, i.e., participants receiving cholecalciferol and those who did not, were similar in terms of anthropometric factors (sex and age at the time of surgery), preoperative clinical characteristics (BMD decrease), and laboratory parameters (PTH, total calcium, phosphorus, ALP, OC, CTX-1, and 25(OH)D levels). The occurrence of postoperative hypocalcemia was significantly lower in participants who received cholecalciferol supplementation (10% vs. 63%, p<0,001, FET2). Cholecalciferol intake showed a negative association with hypocalcemia development (RR=0,15, 95% CI (0,03; 0,51)). CONCLUSION: Preoperative cholecalciferol supplementation for 2 weeks to 2 months before PTE reduces the risk of postoperative hypocalcemia in patients with PHPT by 2-33 times.

Levels of bioavailable, and free forms of 25(OH)D after supplementation with vitamin D3 in primary hyperparathyroidism.

The 25 hydroxyvitamin D [25(OH)D] is the major metabolite for ascertaining vitamin D status, which circulates bound to a specific carrier (vitamin D-binding protein - VDBP). A portion that circulates unbound vary according to the VDBP genotype. This study evaluates the behavior of different forms of 25(OH)D, before and after supplementation with 14,000 IU of vitamin D3, weekly for 12 weeks, in individuals with primary hyperparathyroidism and controls. Fifty-six patients with active primary hyperparathyroidism (PHPT) and 64 paired controls (CTRL), not taking vitamin D3 for the last three months, were enrolled. The genetic isotypes of VDBP were determined to calculate bioavailable and free 25(OH)D. A p < 0.05 was considered significant. There were no statistical differences in free, bioavailable, and total 25(OH)D levels between PHPT and CTRL groups at baseline. The distribution of VDBP haplotypes 1s/1s, 1f/1f, 1s/1f, 2/2, 1s/2, and 1f/2 was similar between groups. After supplementation, all three forms of 25(OH)D proportionally increased within each group, although the percentage increment was lower in the PHPT group (p < 0.05). Total 25(OH)D is better correlated with PTH in the PHPT group than bioavailable and free 25(OH)D (r = -0.41; p < 0.05). The concentrations of total, free, and bioavailable 25(OH)D were similar in both PHPT and CTRL groups, and all forms increased proportionally after supplementation, although this increment percentage was higher in the CTRL group, with a subsequent reduction of PTH and AP. Total 25(OH)D correlated better with PTH than other forms, suggesting no advantages in measuring free or bioavailable 25(OH)D in these situations.

[Vitamin D metabolite and calcium phosphorus metabolism in in patients with primary hyperparathyroidism on the background of bolus therapy with colecalciferol].

BACKGROUND: Vitamin D (25-hydroxyvitamin D [25(ОН)D]) deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common in primary hyperparathyroidism (PHPT), but data regarding the vitamin D metabolism in this population is limited. AIM: The aim of this study is to estimate the vitamin D metabolites and their relationship with the main parameters of phosphorus-calcium metabolism in patients with PHPT at baseline and on the background of a single dose of cholecalciferol 150,000 IU. MATERIALS AND METHODS: A single-center interventional, dynamic, prospective, comparative study has been carried out. The study included 54 participants, divided into two groups: the 1st group included 27 patients with confirmed PHPT, the 2nd control group (n = 27), matched on gender (p = 0.062). The study included 4 visits; the baseline laboratory examination and a bolus dose of cholecalciferol were performed at the visit 1, the subsequent visits included a dynamic laboratory examination. RESULTS: Vitamin D deficiency (<20 ng/ml) was detected in 69% of patients with PHPT. In the PHPT group (before cholecalciferol therapy), there was a direct association of 1.25(OH)2 D3 with albumin-corrected and ionized calcium, as well as between the 25(OH)D3 /24.25(OH)2 D3 ratio with PTH and magnesium. After taking of cholecalciferol, the levels of 1.25(OH)2 D3 and 25(OH)D3 /24.25(OH)2 D3 were significantly increased, and the levels of 25(OH)D3 /1.25(OH)2 D3 were significantly declined at all visits among patients with PHPT. The common 25(OH)D level was comparable to the control group, however the levels of 1,25(OH)2 D3 in patients with PHPT were 55% higher at baseline, and after taking of cholecalciferol 150,000 IU. They remained increased by 3-7 days by an additional 23-36%, significantly higher than those in the control group: 44%, 74% and 65%, at visits 2, 3 and 4, respectively (p<0.05). The taking of 150,000 IU cholecalciferol in the PHPT group did not lead to a significant increase in hypercalcemia and hypercalciuria, which indicates the safety of this dose in patients with mild hypercalcemia (albumin corrected calcium <3 mmol/l). None of the study participants experienced any side effects. CONCLUSION: The completely comprehensive assessment of vitamin D metabolites was carried out for the first time in patients with PHPT before and after using a bolus dose of cholecalciferol. The results confirmed the differences of vitamin D metabolism in chronic excessive secretion of PTH compared to control group, which is new data in the pathogenesis of the disease, and can be used to develop optimal regimens for cholecalciferol taking in this population.

Cinacalcet-Associated Resolution of Primary Hyperparathyroidism in a Patient With Normal Kidney Function.

Cinacalcet use is associated with risk of hypocalcemia; however, this risk has been mostly demonstrated in patients with chronic kidney disease. In this article, we describe a case of a 59-year-old male with primary hyperparathyroidism (PHPT), hypercalciuria, osteopenia, and normal kidney function who was started on cinacalcet for the management of recurrent hypercalcemia following prior unsuccessful parathyroidectomy. Within 6 months following cinacalcet commencement, he developed symptomatic and biochemical hypocalcemia requiring discontinuation of the medication and initiation of calcium supplementation. Over more than 3 years of follow-up, his calcium supplementation was gradually tapered off and then discontinued. He is presently eucalcemic and euparathyroid off calcium supplements while also demonstrating normalization of hypercalciuria and bone mineral density. These data indicate that our patient has experienced resolution of PHPT after brief exposure to cinacalcet. We recommend that low starting cinacalcet doses should be considered for treatment of hypercalcemia in patients with PHPT who underwent unsuccessful parathyroidectomy along with close clinical and biochemical follow-up.

Effect of vitamin D replacement in primary hyperparathyroidism with concurrent vitamin D deficiency: a systematic review and meta-analysis.

INTRODUCTION: We conducted a meta-analysis to assess the effects of vitamin D replacement on biochemical and skeletal parameters in subjects with mild primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency. EVIDENCE ACQUISITION: A systematic search of all English-language medical literature published from 1980 till May 2016 using PubMed, Embase and Ovid was performed. Nine observational studies were evaluated after fulfilling the inclusion and exclusion criteria. EVIDENCE SYNTHESIS: A total of 547 patients were examined. All studies used vitamin D2/D3 or calcifediol (25-hydroxyvitamin D3), There was significant improvement of serum 25(OH)D with unchanged serum iPTH level after vitamin D replacement, with pooled d+: 3.10 (95% CI 2.25 to 3.95), P<0.01 and pooled d+: 0.82 (95% CI -0.35 to 1.98), P=0.16 respectively. There was neither worsening of the pre-existing hypercalcemia (pooled d+: -0.27 [95% CI -1.09 to 0.64, P=0.56]) nor hypercalciuria (pooled d+: 3.64 [95% CI -0.55 to 7.83, P=0.09]). Two studies assessed in this meta-analysis reported unchanged bone density with vitamin D replacement. CONCLUSIONS: Vitamin D replacement in subjects with mild PHPT and coexistent vitamin D deficiency improved serum 25(OH)D level without worsening of pre-existing hypercalcemia or hypercalciuria. Well-designed multicenter randomized controlled trials examining pre- and postoperative outcomes of vitamin D therapy in patients with different severities of PHPT and vitamin D inadequacy are warranted to elucidate the most appropriate vitamin D treatment protocol and determine the long-term safety concerns.

The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An Observational Study.

BACKGROUND: The comparative effectiveness of surgical and medical treatments on fracture risk in primary hyperparathyroidism (PHPT) is unknown. OBJECTIVE: To measure the relationship of parathyroidectomy and bisphosphonates with skeletal outcomes in patients with PHPT. DESIGN: Retrospective cohort study. SETTING: An integrated health care delivery system. PARTICIPANTS: All enrollees with biochemically confirmed PHPT from 1995 to 2010. MEASUREMENTS: Bone mineral density (BMD) changes and fracture rate. RESULTS: In 2013 patients with serial bone density examinations, total hip BMD increased transiently in women with parathyroidectomy (4.2% at <2 years) and bisphosphonates (3.6% at <2 years) and declined progressively in both women and men without these treatments (-6.6% and -7.6%, respectively, at >8 years). In 6272 patients followed for fracture, the absolute risk for hip fracture at 10 years was 20.4 events per 1000 patients who had parathyroidectomy and 85.5 events per 1000 patients treated with bisphosphonates compared with 55.9 events per 1000 patients without these treatments. The risk for any fracture at 10 years was 156.8 events per 1000 patients who had parathyroidectomy and 302.5 events per 1000 patients treated with bisphosphonates compared with 206.1 events per 1000 patients without these treatments. In analyses stratified by baseline BMD status, parathyroidectomy was associated with reduced fracture risk in both osteopenic and osteoporotic patients, whereas bisphosphonates were associated with increased fracture risk in these patients. Parathyroidectomy was associated with fracture risk reduction in patients regardless of whether they satisfied criteria from consensus guidelines for surgery. LIMITATION: Retrospective study design and nonrandom treatment assignment. CONCLUSION: Parathyroidectomy was associated with reduced fracture risk, and bisphosphonate treatment was not superior to observation. PRIMARY FUNDING SOURCE: National Institute on Aging.

No beneficial effects of vitamin D supplementation on muscle function or quality of life in primary hyperparathyroidism: results from a randomized controlled trial.

CONTEXT: Impairments of muscle function and strength in patients with primary hyperparathyroidism (PHPT) are rarely addressed, although decreased muscle function may contribute to increased fracture risk. OBJECTIVE: We aimed to assess the changes in muscle strength, muscle function, postural stability, quality of life (QoL), and well-being during treatment with vitamin D or placebo before and after parathyroidectomy (PTX) in PHPT patients. DESIGN: A randomized placebo-controlled trial. PATIENTS: We included 46 PHPT patients, mean age 58 (range 29-77) years and 35 (76%) were women. INTERVENTIONS: Daily treatment with 70 µg (2800 IU) cholecalciferol or placebo for 52 weeks. Treatment was administered 26 weeks before PTX and continued for 26 weeks after PTX. MAIN OUTCOME MEASURES: Changes in QoL and measures of muscle strength and function. RESULTS: Preoperatively, 25-hydroxyvitamin D (25OHD) increased significantly (50-94 nmol/l) compared with placebo (57-52 nmol/l). We did not measure any beneficial effects of supplementation with vitamin D compared with placebo regarding well-being, QoL, postural stability, muscle strength, or function. In all patients, we measured marked improvements in QoL, well-being (P<0.01), muscle strength in the knee flexion and extension (P<0.001), and muscle function tests (P<0.01) after surgical cure. Postural stability improved during standing with eyes closed (P<0.05), but decreased with eyes open (P<0.05). CONCLUSIONS: Patients with PHPT and 25OHD levels around 50 nmol/l did not benefit from vitamin D supplementation concerning muscle strength, muscle function, postural stability, well-being, or QoL. Independent of preoperative 25OHD levels, PTX improved these parameters.

Health-related quality of life after successful surgery for primary hyperparathyroidism: no additive effect from vitamin D supplementation: results of a double-blind randomized study.

OBJECTIVE: Vitamin D insufficiency is common in primary hyperparathyroidism (pHPT). Patients with pHPT frequently have a reduced health-related quality of life (HRQoL). Our objectives were to evaluate whether HRQoL in pHPT is associated with vitamin D insufficiency and whether vitamin D supplementation after parathyroidectomy (PTX) could improve HRQoL. DESIGN: A randomized, double-blind study (ClinicalTrials.gov identifier: NCT00982722). METHODS: The study included 150 pHPT patients randomized, 6 weeks after PTX, to daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D+) or calcium carbonate alone (D-). HRQoL was estimated with SF-36 before and after PTX and after 12 months of study medication. RESULTS: Three-quarters (77%) of the pHPT patients had vitamin D insufficiency, defined as 25OHD <50 nmol/l. The pHPT patients scored lower than a reference population in all domains of SF-36. A total of 135 patients completed the entire study period. Improvements in nearly all domains were registered at the follow-up 6 weeks after PTX. At the end of the study medication period, the D+ group had a significantly higher median serum (s-) 25OHD concentration (76 (65; 93) (lower; upper interquartile ranges) vs 48 (40; 62) nmol/l, P<0.001) and a lower plasma (p-) parathyroid hormone concentration (40 (34; 52) vs 49 (38; 66) ng/l, P=0.01) than the D- group. The improvements in HRQoL remained unchanged at the follow-up 1 year after PTX. Postoperative vitamin D supplementation had no obvious effect on HRQoL. CONCLUSION: PTX resulted in significant improvements in HRQoL. Despite a high prevalence of vitamin D insufficiency, 1 year of postoperative vitamin D supplementation had no obvious beneficial effect on HRQoL.

Medical management of primary hyperparathyroidism: proceedings of the fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism.

OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The only available definitive therapy is parathyroidectomy, which is appropriate to consider in all patients. The purpose of this report is to provide an update on calcium and vitamin D supplementation and medical management for those patients with PHPT who cannot or do not want to undergo surgery. METHODS: Questions were developed by the International Task Force on PHPT. A comprehensive literature search was undertaken, and relevant articles published between 2008 and 2013 were reviewed in detail. The questions were addressed by the panel of experts, and consensus was established at the time of the workshop. CONCLUSIONS: The recommended calcium intake in patients with PHPT should follow guidelines established for all individuals. It is not recommended to limit calcium intake in patients with PHPT who do not undergo surgery. Patients with low serum 25-hydroxyvitamin D should be repleted with doses of vitamin D aiming to bring serum 25-hydroxyvitamin D levels to ≥ 50 nmol/L (20 ng/mL) at a minimum, but a goal of ≥75 nmol/L (30 ng/mL) also is reasonable. Pharmacological approaches are available and should be reserved for those patients in whom it is desirable to lower the serum calcium, increase BMD, or both. For the control of hypercalcemia, cinacalcet is the treatment of choice. Cinacalcet reduces serum calcium concentrations to normal in many cases, but has only a modest effect on serum PTH levels. However, bone mineral density (BMD) does not change. To improve BMD, bisphosphonate therapy is recommended. The best evidence is for the use of alendronate, which improves BMD at the lumbar spine without altering the serum calcium concentration. To reduce the serum calcium and improve BMD, combination therapy with both agents is reasonable, but strong evidence for the efficacy of that approach is lacking.

Impact of cinacalcet hydrochloride in clinical management of primary hyperparathyroidism in multiple endocrine neoplasia type 1.

AIM: Primary hyperparathyroidism (PHPT) is one of main cause of morbidity in patients with multiple endocrine neoplasia type 1 (MEN1). Medical therapy with cinacalcet-hydrochloride may modify the therapeutic strategy of MEN1 related PHPT. We present an experience with cinacalcet-hydrochloride in two patients with MEN1 PHPT. METHODS: The study included two MEN1 patients belonging to the same family (a 50-year-old woman and her daughter aged 20 years) with PHPT secondary to multiple involvement of parathyroid glands and other MEN1 related tumors. As both patients refused to undergo parathyroid surgery, we decided to start medical treatment with cinacalcet at the dose of 30 mg/day, which was the first treatment for the youngest patient, while the oldest had already been treated with partial parathyroidectomy. Serum concentrations of PTH, calcium and phosphorus, 24-h urine calcium-to-creatinine ratio and renal-threshold-phosphate concentration were evaluated before and after therapy. RESULTS: Serum calcium and PTH levels were normalized after 1 and 6 months of therapy, respectively, and 60 and 54 months after the beginning of cinacalcet remained normal. Hypercalciuria, hypophosphoremia and renal-threshold-phosphate normalized during therapy with cinacalcet. At ultrasonography, parathyroid nodular lesion remained unchanged. Cinacalcet was well tolerated without occurrence of side effects. CONCLUSION: Cinacalcet seems to be highly effective in controlling PHPT in patients with MEN1 either in naïve patients or in those with postsurgical recurrence. If cinacalcet will be confirmed to ensure a long-time control of PHPT or even to prevent the development and progression of PHPT, this may led to modify the therapeutic strategy of MEN1 PHPT.

Safety of vitamin D replacement in patients with primary hyperparathyroidism and concomitant vitamin D deficiency.

OBJECTIVE: To evaluate the safety of vitamin D replacement in patients with vitamin D deficiency and primary hyperparathyroidism. METHODS: Retrospective chart review of 35 patients from our endocrine clinic, age 22 to 89 years, diagnosed with primary hyperparathyroidism and vitamin D deficiency, and treated with either 1,000 to 2,000 international units (IU) of vitamin D daily or 50,000 IU of vitamin D weekly for 5 months. Data were collected before and after treatment on serum calcium, 25-hydroxyvitamin D (25-OH D), intact parathyroid hormone (iPTH), phosphorus, alkaline phosphatase, nephrolithiasis, fractures, and osteoporosis. RESULTS: 25-OH D increased significantly, from a baseline of 14.65 ± 6.57 ng/mL to 42.17 ± 12.98 ng/mL after weekly treatment with 50,000 IU of vitamin D (P<.0001), and from 22.42 ± 5.47 ng/mL to 33.33 ± 6.39 ng/mL following daily treatment with 1,000 to 2,000 IU of vitamin D (P<.0001). Pre- and posttreatment unadjusted serum calcium remained stable in the high-dose group (10.80 ± 0.43 mg/dL vs. 10.72 ± 0.67 mg/dL; P = .47), but decreased slightly in the low-dose group (10.76 ± 0.58 mg/dL vs. 10.11 ± 0.54 mg/dL; P = .0007). After adjusting for age, sex, vitamin D, and PTH levels, the small calcium difference in the low-dose group became statistically insignificant. Treatment with either high or low doses of vitamin D did not significantly change iPTH levels. Creatinine remained stable in all patients, and no new cases of nephrolithiasis were reported. CONCLUSION: Replacing vitamin D in mild primary hyperparathyroidism is safe, effective, and does not increase calcium to dangerous levels.

Over-supplementation of vitamin D in two patients with primary hyperparathyroidism.

OBJECTIVE: To describe the biochemical effects of an over-supplementation of vitamin D3 in two patients with primary hyperparathyroidism (PHPT). DESIGN: Two patients (A and B) with PHPT took erroneously 2,400,000 U (300,000 U/day for 8 days) and 4,500,000 U (300,000 U/day for 15 days) of cholecalciferol, respectively. They were followed for 4 months and ionized calcium, creatinine, PTH, 25 hydroxy-vitamin D, 1,25(OH)2D and urinary calcium/creatinine levels were measured. Finally, the patients were operated on and a parathyroid adenoma was removed in both. RESULTS: One week after the last dose of vitamin D, serum ionized calcium (iCa) rose from 1.35 to 1.41 mMol/L (n.r. 1.14-1.31) for patient A, and from 1.43 to 1.62 for patient B, while fasting urinary Calcium/Creatinine (uCa/Cr) augmented from 0.31 to 0.50 mg/mg, and from 0.32 to 0.55, respectively. During the follow-up, the average levels of iCa were 1.37 ± 0.03 and 1.48 ± 0.07 mMol/L, while those of uCa/Cr were 0.29 ± 0.13 and 0.32 ± 0.13, both iCa and uCa/Cr levels returning to baseline values within 4 months. CONCLUSIONS: The unintentional over-supplementation of vitamin D in the two PHPT patients caused a moderate and temporary increase of hypercalcemia and hypercalciuria and was not associated with clinical signs of toxicity.

Effects of strontium ranelate administration on calcium metabolism in female patients with postmenopausal osteoporosis and primary hyperparathyroidism.

We investigated possible changes of parameters of calcium metabolism induced by strontium ranelate (SR). Twenty-three patients with postmenopausal osteoporosis (PO) and 14 with primary hyperparathyroidism (PHPT) were studied while taking 2 g/day of SR. Women with PO and 10 healthy age-matched control women were also daily supplemented with 1,000 mg calcium and 800 IU vitamin D. All subjects were studied at baseline and after 7 and 30 days; PO women and controls were also investigated at 180 and 360 days of treatment. Serum ionized calcium (iCa), phosphate (sP), magnesium, creatinine, 25-hydroxycholecalciferol (25[OH]D), 1,25-dihydroxycholecalciferol (1,25[OH](2)D), serum parathyroid hormone (PTH) were measured. In spot urine, we assessed calcium and phosphate over creatinine ratios (uCa/Cr, uP/Cr), calcium excretion (Ca ex) and renal phosphate threshold (TmP/GFR); in 24-h urine, calcium and magnesium over creatinine clearance ratios (CaCl/CrCl and MgCl/CrCl). In PO, SR administration was associated with a significant decrease of PTH and 1,25(OH)(2)D levels but an increase of sP (p < 0.001). SR also significantly increased Ca/Cr, Ca ex, and TmP/GFR in spot urine and CaCl/CrCl in both spot and 24-h urine (p = 0.004 to <0.001). In PHPT, SR significantly decreased iCa and increased sP, slightly modifying PTH, 25(OH)D, and 1,25(OH)(2)D values. Also in PHPT, Ca ex and CaCl/CrCl of spot and 24-h urine, as TmP/GFR, significantly increased (all p < 0.02). SR influenced the main parameters of calcium homeostasis, probably through the calcium-sensing receptor.

A mathematical model of calcium and phosphorus metabolism in two forms of hyperparathyroidism.

Parathyroid hormone (PTH) plays a critical role in calcium and phosphorus metabolism. Interestingly, in two forms of hyperparathyroidism (excessive amount of PTH in the serum), the metabolic disturbances in patients with chronic kidney disease (CKD) significantly differ from those with primary hyperparathyroidism (PHP). Since an intuitive understanding of these PTH-linked regulatory mechanisms are hardly possible, we developed a mathematical model using clinical data (1586 CKD and 40 PHP patients). The model was composed of a set of ordinary differential equations, in which the regulatory mechanism of PTH together with other key factors such as 1,25-Dihydroxyvitamin D (1,25(OH)2D) and calcium was described in the tissues including bone, the kidney, the serum, and the parathyroid glands. In this model, an increase in PTH was induced by its autonomous production in PHP, while PTH in CKD was elevated by a decrease in feedback inhibition of 1,25(OH)2D in the serum, as well as an increase in stimulation by phosphorus in the serum. The model-based analysis revealed characteristic differences in the outcomes of hyperparathyroidism in CKD and PHP. The calcium exchange in bone, for instance, was predicted significantly higher in PHP than CKD. Furthermore, we evaluated the observed and predicted responses to the administration of calcimimetics, a recently developed synthetic drug that modulated efficacy of calcium-sensing receptors. The results herein support the notion that the described model would enable us to pose testable hypotheses about the actions of PTH, providing a quantitative analytical tool for evaluating treatment strategies of PHP and CKD.

Current evidence for recommendation of surgery, medical treatment and vitamin D repletion in mild primary hyperparathyroidism.

Management of patients with mild primary hyperparathyroidism (PHPT) has been widely discussed because most patients today do not have specific symptoms. While surgery is always an option, the recommendations for treatment have shifted, which mostly reflects changes in clinical practice. In this study, we aimed to evaluate evidence for the current recommendations concerning operation vs observation, repletion with vitamin D (VitD) and alternative medical management. Surgery is followed by normalisation of calcium and parathyroid hormone (PTH) and a decrease in bone turnover followed by an increase in bone mass. It is not known what the consequences would be for the frequency of fractures. Randomised studies have indicated beneficial effects of operation on quality of life (QoL), but the effects have been minor and inconsistent. Operation seems not to be superior to observation for cardiovascular risk factors. Although PHPT patients in average have slightly decreased plasma 25OH VitD, severe symptomatic VitD deficiency seems not to be a characteristic of PHPT patients in Europe. However, if present, we recommend VitD substitution before final decision on surgical treatment. It is unknown whether routine VitD supplementation should be offered preoperatively to all patients with mild PHPT or as part of long-term medical treatment. Targeted medical management could be an option for patients with contraindications to surgery. Antiresorptive therapy might be appropriate for patients with a low bone mass to prevent further bone loss. Calcimimetics could be tried to control serum calcium levels although there is no evidence of an effect on the hypercalcaemic symptoms or the QoL. Combined therapy with calcimimetics and alendronate could be considered for patients with hypercalcaemia and overt bone disease.

Different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls.

CONTEXT: In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 µg/day) increases the serum levels of both 25(OH)D and 1,25(OH)(2)D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH). OBJECTIVE: To evaluate the different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls. DESIGN: We evaluated the main physiological regulators of 1α-hydroxylase and the substrate-product relationship of 25(OH)D and 1,25(OH)(2)D in 20 patients with PH, 25 with FBH, and 122 healthy sex- and age-matched controls before and after administration of 25(OH)D for 2 weeks. RESULTS: 25(OH)D increased significantly in all subjects, whereas 1,25(OH)(2)D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate-product relationship of 25(OH)D-1,25(OH)(2)D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups. CONCLUSIONS: The lack of 1,25(OH)(2)D increase in FBH may be due to a direct inhibitory effect on 1α-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH)(2)D, or a decreased stimulus of 1α-hydroxylase related to persistently low levels of hCT.

Hiperparatiroidismo primario con normocalcemia, una asociación de diagnóstico complejo: a propósito de un caso clínico / Normocalcemic hyperparathyroidism: report of one case

We report a 59 years old female with a history of nephrolithiasis and progressive worsening of her bone mineral density. High serum PTH levels were detected, with normal serum calcium. Causes of secondary hyperparathyroidism were discarded. The patient was followed during six years, period in which she maintained elevated serum PTH and normal serum calcium. During the second year of follow up, hydrochlorothiazide was indicated. Serum calcium raised progressively and after six years, it became abnormally high. The patient was subjected to a total left lobe and subtotal right lobe thyroidectomy. The surgeon found a 1.6 mm diameter left parathyroid nodule. After surgery the patient is asymptomatic and is receiving levothyroxine supplementation.

Vitamin D therapy in patients with primary hyperparathyroidism and hypovitaminosis D.

OBJECTIVE: To determine whether vitamin D repletion of patients with primary hyperparathyroidism (PHPT) and vitamin D deficiency or insufficiency (hypovitaminosis D) has deleterious clinical and/or biochemical effects. DESIGN: Prospective audit of the effect of vitamin D repletion on biochemical data in 56 patients with PHPT. Patients were treated with 50,000 units of vitamin D2 weekly for 8 weeks with biochemical measurements at 5 and 10 weeks, and subsequently after 12 weeks on 800 units of vitamin D3 daily, and in those with hypovitaminosis D after 12 weeks of up to 100 000 units of vitamin D(2) monthly. METHODS: Serum calcium, albumin, phosphorus, 25-OHD, intact parathyroid hormone (PTH) and urine calcium/creatinine (Ca/Cr) ratios were measured before and during vitamin D therapy. RESULTS: Patients treated with 50,000 units of vitamin D2 weekly for 8 weeks resulted in a significant increase in serum 25-OHD levels from 36.4 to 89.4 nmol/l at 5 weeks (P<0.0001) and 88.6 nmol/l at 10 weeks (P<0.0001). There were no significant changes in serum calcium. At 10 weeks, there was a non-significant decrease in serum PTH and in urine Ca/Cr ratios. None of the patients developed any calcium-related adverse events. Subsequently, patients with subnormal 25-OHD levels on 800 units of vitamin D daily were treated for the next 12 weeks with up to 100,000 units of vitamin D2 monthly with normalization of serum 25-OHD in all but 4 patients. CONCLUSION: These data fail to demonstrate any adverse effects of vitamin D repletion in PHPT.

Surgical and calcium outcomes in 427 patients treated prospectively in an image-guided and intraoperative PTH (IOPTH) supplemented protocol for primary hyperparathyroidism: outcomes and opportunities.

UNLABELLED: Unilateral exploration based upon preoperative imaging has become increasingly applied in the management of patients with primary hyperparathyroidism. Unilateral surgical exploration purportedly has high rates of disease control, limited morbidity, and shortened operative time. Unfortunately, significant cohorts of patients with primary hyperparathyroidism are unable to have abnormal glands localized on preoperative imaging evaluation. AIM: The aim of our study was to evaluate the efficacy of Tc(99m) sestamibi preoperative imaging, intraoperative Tc(99m) sestamibi with gamma probe, and intraoperative parathyroid hormone (IOPTH) assessment in a large cohort of patients with primary hyperparathyroidism. RESULTS: A total of 427 patients were prospectively evaluated who were deemed surgical candidates for the treatment of primary hyperparathyroidism. Of these patients, 240 (56%) presented with positive Tc(99m) sestamibi imaging. Another 105 (25%) presented with equivocal Tc(99m) sestamibi imaging. Finally, 82 (19%) presented with negative Tc(99m) sestamibi imaging. Intraoperative rapid assessment of parathyroid hormone was performed at the time of surgical exploration in all patients with negative and equivocal preoperative imaging. All 240 patients with positive preoperative imaging underwent unilateral surgical exploration utilizing intraoperative Tc(99m) sestamibi with gamma probe. The most common finding in the positive Tc(99m) sestamibi scan group was single adenoma in 235 (98%). Normocalcemia was achieved in 233 (97%) of these patients, although in 25 (10%) this was normocalcemia with a persistent elevation in parathyroid hormone (PTH). The most common surgical finding in the equivocal Tc(99m) sestamibi scan group was single adenoma in 85 (81%). Additionally 85 (81%) of these equivocal patients were able to undergo unilateral exploration limited by IOPTH assessment. Normocalcemia was achieved in 101/105 (96%) of patients; although, 10 patients were normocalcemic with persistently elevated PTH and 2 patients had normocalcemia with low PTH. All patients with negative Tc(99m) sestamibi scan underwent bilateral cervical exploration plus IOPTH; 52/82 (63%) were found to have a single adenoma which was the most common surgical finding. Normocalcemia was achieved in 77/82 (94%) of the negative Tc(99m) sestamibi cohort; although 5 patients had normocalcemia with persistently elevated PTH and 2 had normocalcemia with low PTH. Only 3 (0.7%) overall recurrent laryngeal nerve injuries were encountered, and only 1 (0.2%) was permanent. Wound complication rates are reported in detail and were low and comparable for all three Tc(99m) sestamibi imaging based cohorts. CONCLUSIONS: Tc(99m) sestamibi preoperative imaging, intraoperative Tc(99m) sestamibi with gamma probe, IOPTH, and combinations of these strategies allow for excellent opportunities for targeted excision of pathologic parathyroid tissue with the least dissection necessary while achieving excellent long-term calcium control and low rates of complication.

New strategies for the treatment of hyperparathyroidism incorporating calcimimetics.

BACKGROUND: Hyperparathyroidism (HPT), characterised by increased parathyroid hormone (PTH) secretion and parathyroid hyperplasia, can be caused by physiologic defects in the parathyroid gland (primary HPT [PHPT]) or as a consequence of declining renal function (secondary HPT [SHPT]). OBJECTIVE: To review the safety and efficacy of cinacalcet in the treatment of SHPT and PHPT. METHODS: Studies indexed in NLM/PubMed investigating the safety, efficacy, and pharmacokinetics of cinacalcet for PHPT and SHPT and supporting preclinical evidence. RESULTS/CONCLUSION: Recent evidence has demonstrated the efficacy of the calcimimetic cinacalcet in the treatment of PHPT and SHPT. Compared with traditional therapies such as vitamin D sterols and phosphate binders, cinacalcet treatment can allow an increased proportion of patients with SHPT to improve Kidney Disease Outcomes Quality Initiative (KDOQI) Bone Metabolism and Disease laboratory parameter target attainment. Recent evidence suggests that improvements in these biochemical parameters with cinacalcet can translate into improved morbidity and mortality. Cinacalcet lowers PTH and calcium in patients following renal transplantation, and also normalises serum calcium in patients with PHPT. Ongoing studies are focusing and future studies are likely to focus on the effect of cinacalcet on clinical outcomes and on novel strategies for the integration of cinacalcet with traditional therapies to improve serum PTH and mineral metabolism control.