Recombinant Human Parathyroid Hormone Therapy (1-34) In an Adult Patient with a Gain-of-Function Mutation in the Calcium-Sensing Receptor-a Case Report

ObjectiveTo describe a case of hypocalcemia in a patient with a gain-of-function mutation in the calcium-sensing receptor that was undetected until adulthood and successfully treated with recombinant parathyroid hormone.MethodsThe clinical findings, laboratory data, and a review of the pertinent literature are presented.ResultsA 55-year-old woman was hospitalized and seen by the endocrinology consult service for hypocalcemia that was refractory to repeated doses of intravenous calcium gluconate. She expressed concern about chronic leg muscle cramps and paresthesias of the lips and fingertips. In addition, she had no history of neck surgery, neck irradiation, or any autoimmune disease. She was a well-appearing female with no dysmorphic features or skin changes. Laboratory tests revealed hypocalcemia, hyperphosphatemia, hypomagnesemia, and hypovitamino-sis D. Her parathyroid hormone concentration (PTH) was low at 14.2 pg/mL. Her PTH and calcium concentrations remained low despite repletion of magnesium and treatment with calcitriol and oral calcium replacement. A 24-hour collection for urinary calcium showed inappropriate hypercalciuria. Medical records showed her hypocalcemia to be chronic. Additionally, several family members had also complained of muscle cramps. A congenital cause of her hypoparathyroidism was considered, and genetic testing confirmed heterozygosity for a gain-of-function mutation in the calcium-sensing receptor gene associated with autosomal dominant familial isolated hypoparathyroidism (ADH). Treatment with subcutaneous recombinant human parathyroid hormone teriparatide (rhPTH [1-34]) 20 mcg twice daily for three days normalized her calcium and phosphorus concentrations.ConclusionrhPTH (1-34) is an effective treatment for patients with hypoparathyroidism due to gain-of-function mutations in the calcium-sensing receptor. ADH can be insidious in presentation and the diagnosis can be missed unless there is a high index of suspicion. (Endocr Pract. 2013;19:e24-e28)     

An Open-Label Extension Study of Parathyroid Hormone Rhpth(1-84) in Adults with Hypoparathyroidism

Objective: Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and bone abnormalities. Adults with hypoparathyroidism treated with recombinant human PTH, rhPTH(1-84), in the 24-week, phase III REPLACE study maintained serum calcium despite reductions in oral calcium and active vitamin D. This study assessed the long-term efficacy and safety of rhPTH(1-84) for hypoparathyroidism.Methods: This was a 24-week, open-label, flexible-dose extension study of REPLACE (REPEAT) conducted in 3 outpatient centers in Hungary. Patients who previously completed or enrolled in REPLACE received 50 μg/day rhPTH(1-84), escalated to 75 and then to 100 μg/day, if needed, to reduce active vitamin D and oral calcium. The primary endpoint was ≥50% reduction in oral calcium (or ≤500 mg/day) and active vitamin D (or calcitriol ≤0.25 μg/day or alfacalcidol ≤0.50 μg/day) with normocalcemia.Results: Twenty-four patients (n = 16 previously treated with rhPTH[1-84]; n = 8 rhPTH[1-84]-naïve) were enrolled and completed the study. At Week 24, 75% of patients (95% confidence interval [CI], 53.3–90.2%) achieved the study endpoint; 58% eliminated oral calcium and active vitamin D. Urinary calcium, serum phosphate, and calcium × phosphate (Ca × P) product decreased by Week 24. Mean serum bone turnover markers increased with rhPTH(1-84). Treatment-emergent adverse events (TEAEs) were reported by 92% of patients. No serious adverse events (AEs) occurred.Conclusion: This study used a simplified treatment algorithm intended to better mimic typical clinical practice and demonstrated the extended efficacy and safety of rhPTH(1-84) in patients with hypoparathyroidism and confirmed the REPLACE findings. Sustained rhPTH(1-84) efficacy up to 48 weeks was observed despite treatment interruption between studies.Abbreviations:AE = adverse eventBMD = bone mineral densityBSAP = bone-specific alkaline phosphataseBTM = bone turnover markerCa × P product = calcium × phosphate productCTX = cross-linked C-telopeptide of type 1 collagenOCN = osteocalcin25(OH)D = 25-hydroxyvitamin DP1NP = aminoterminal propeptide of type 1 collagenPTH = parathyroid hormonerhPTH(1-84) = recombinant human parathyroid hormoneTEAE = treatment-emergent adverse eventULN = upper limit of normal     

Effect of hydrochlorothiazide on calcium metabolism in postoperative hypoparathyroidism

Vitamin D3 administered to patients with postoperative hypoparathyroidism increases calcium absorption from the gut and calcium blood levels but leads to hypercalciuria and may produce renal lithiasis. Thiazides decrease calcium excretion with the urine. Therefore, an effect of combined therapy with hydrochlorothiazide, vitamin D3 and calcium on hypoparathyroidism was investigated. Twenty one women were selected out of 135 patients with postoperative hypoparathyroidism. These women were constantly given vitamin D3 (30,000-225,000 IU daily) and calcium. Normocalcemia, hyperphosphatemia and hypercalciuria were noted before the treatment with hydrochlorothiazide. Therapy normalized hypercalciuria but did not change mean differences in calcemia, phosphatemia, magnesemia, blood alkaline phosphatase and phosphates and magnesium clearance factors. Hypercalcemia and necessity to withdraw hydrochlorothiazide together with change of either doses or preparation of vitamin D3 were noted in three patients, including one patient in whom both hypercalcemia and hypercalciuria with the symptoms of vitamin D3 poisoning were observed. The author suggests that combined therapy with hydrochlorothiazide, vitamin D3 and calcium prevents hypercalciuria but may require changes in vitamin D3 dosage and withdrawal of hydrochlorothiazide in some patients.     

1,25-(OH)2-16ene-23yne-D3 reduces secondary hyperparathyroidism in uremic rats with little calcemic effect

OBJECTIVES: To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels. METHODS: Biological activity of 4 vitamin D analogs, 1,25-(OH)(2)-16ene- D(3) (RO(1)), 1,25-(OH)(2)-16ene-23yne-D(3) (RO(2)), 1,25-(OH)(2)-26,27-hexafluoro-16ene-23yne-D(3) (RO(3)) and 1,25-(OH)(2)-16ene-23yne-26,27-hexafluoro-19nor-D(3) (RO(4)) was tested vs. calcitriol in parathyroidectomized rats. In a second set of experiments, the effects of RO(2), RO(4) and calcitriol were studied in 5/6 nephrectomized rats with secondary hyperparathyroidism. RESULTS: In parathyroidectomized rats, all analogs (250 pmol/day) led calcemia to rise after 7 days. In uremic rats, all treatments reduced PTH levels. RO(4) revealed toxicity. RO(2) was as effective as calcitriol in suppressing PTH in a dose dependent manner. Mean plasma ionized calcium did not change from baseline to day 14 and day 28 on RO(2) (250 or 500 pmol/day) whereas it increased significantly on RO(2) (1,000 pmol/day) and calcitriol (125 or 250 pmol/day). Increasing the dose of calcitriol led Ca x P to rise more dramatically than increasing the dose of RO(2), which appears to have a wider therapeutic window than calcitriol. CONCLUSION: 1,25-(OH)(2)-16ene-23yne-D(3) (RO(2)) may represent a novel candidate for the treatment of renal osteodystrophy in humans.     

Renal handling of calcium in hypoparathyroidism.

Treatment of hypoparathyroidism usually requires the use of pharmacological doses of parent vitamin D or near physiological amounts of the hydroxylated metabolites, calcitriol or alphacalcidol. Vitamin D intoxication and hypercalcaemia may be a problem but can be minimised by the use of small doses of vitamin D or its metabolites combined with large amounts of oral calcium. The response to treatment can be easily monitored by measuring serum and urinary calcium and creatinine concentrations. This allows the derivation of two simple indices reflecting calcium load presented to the kidney (calcium excretion in mmol/l glomerular filtrate) and renal tubular calcium reabsorption (TmCa/GFR). These can be used to predict the requirement of calcium supplements and also identify those patients at particular risk of hypercalcaemia.     

Tumor-induced osteomalacia: pre- and postoperative biochemical findings

A patient with late-onset hypophosphatemic osteomalacia was treated with oral supplements of phosphate (1.5 g/day) and calcitriol (1.5-3.0 micrograms/day) for 17 months, before a slowly growing tumor in the first metatarsal space became evident. Before treatment concentrations of inorganic phosphate (Pi) and calcitriol in serum and tubular reabsorption of phosphate (TRP) were very low, calcium and parathyroid hormone (PTH) in serum were normal, urinary cyclic adenosine monophosphate (cAMP) was strongly elevated. During the first weeks of conservative treatment urinary cAMP returned to normal; concomitantly there was a transient slight fall in PTH. Serum calcium was in the low normal range and did not significantly change during conservative therapy. During the further course PTH rose to pretreatment values, but urinary cAMP remained normal. When the dose of calcitriol was elevated to 3 x 1.0 micrograms/day, leading to slightly elevated serum concentrations of this substance, Pi in serum rose to the low normal range, but TRP remained low and bone pain, although improved, did not subside. The tumor was locally excised. Postoperatively calcitriol concentration became elevated within 48 hours and remained so for several weeks. The rise in calcitriol concentration preceded the elevation of Pi in serum, not, however, the increase of TRP. The elevation of urinary cyclic AMP before therapy may have been due to a direct action of the substance secreted by the tumor.     

Combined therapies in osteoporosis: bisphosphonates and vitamin D-hormone analogs

During the last two decades, the development of new, highly effective therapeutics (e.g. bisphosphonates, SERMs, strontium ranelate and PTH) has significantly extended the spectrum of osteoporosis therapy. However, the interest of combining bone-active agents and/or Vitamin D and calcium is still being debated, and is restricted to a very marginal set of compounds (Alendronate and native Vitamin D). On the other hand, Vitamin D-hormone analogs, calcitriol, and alfacalcidol, have repeatedly demonstrated their effectiveness in being valuable alternatives compared to native Vitamin D in this setting. A growing amount of data documents the pre-clinical and clinical efficacies of combinations of bisphosphonates with calcitriol, or with alfacalcidol in primary and secondary osteoporosis. This exhaustive review of the available animal and clinical data aimed at comparing the theoretical with demonstrated absolute and relative benefits of those therapeutic approaches. Most of the pre-clinical and clinical data in PMOP suggest significant, clinical improvements in response to combination therapies versus monotherapies in postmenopausal osteoporosis. As a investigated by most of the currently available trials, a daily dose of alendronate 10 mg or a weekly dose of Alendronate 70 m plus alfacalcidol 0.5-1.0 microg daily plus alfacalcidol 0.5 microg seems to surpass other combinations when BMD and bone metabolism markers are considered. A synergy with bisphosphonates in reducing the fracture episodes may lie in the pleiotropic effects of D-hormone analogs on musculoskeletal, immunological and neurological systems. Negative interactions between both drugs have not yet been reported, while a reduction of hypercalcuria episodes has been noted in combination therapies, as compared to monotherapies involving high doses of Vitamin D, calcitriol, or alfacalcidol. Based on the possible reduction of periodic safety checks of calcemia, an improved compliance could then be expected, which would, in turn, generate a better end result. However, to document this, long-term, high quality comparative studies with factorial designs are needed to determine which role this alternative should play in the management of postmenopausal, male, and glucocorticoid-induced osteoporosis.     

Toxicity and antineoplastic effect of (24R)-1,24-dihydroxyvitamin D3 (PRI-2191)

Many efforts have been made to obtain active and less toxic Vitamin D analogs for new clinical applications. The results of previous studies demonstrated the efficacy and safety of topical treatment of psoriasis with one of these analogs, 1,24-dihydroxyvitamin D(3), tacalcitol (1,24-(OH)(2)D(3)). In the present study, we evaluated the toxicity and antitumor effect of this analog. Lethal toxicity of 1,24-(OH)(2)D(3) after s.c. injection was significantly lower than that of calcitriol. No significant differences were observed in the toxicity of the analogs when administered p.o. Calcium levels in the serum of mice treated with calcitriol were significantly higher (111%) than those in mice treated with 1,24-(OH)(2)D(3) (89%) at 5 day after the first s.c. (10 microg/kg/day) administration in comparison to the control (healthy, untreated animals). Oral administration increased the calcium level by 78% for calcitriol and only to 47% over the control for 1,24-(OH)(2)D(3). Parallel administration of clodronate prevented the calcitriol- and 1,24-(OH)(2)D(3)-induced lethal toxicity and also prevented increase in calcium levels. Single therapy with calcitriol did not affect tumor growth in the 16/C mouse mammary cancer model. In contrary, 1,24-(OH)(2)D(3) alone reduced tumor volume to 41% of control. Cisplatin alone did not affect growth of 16/C tumor in these conditions. The growth of tumors in the presence of cisplatin was inhibited by 1,24-(OH)(2)D(3) but not by calcitriol. Interestingly, the inhibition of tumor growth in cisplatin-treated mice by 1,24-(OH)(2)D(3) was greater, than that observed in mice treated with this analog alone. In conclusion, 1,24-(OH)(2)D(3) revealed higher antitumor and lower calcemic activity and toxicity than calcitriol. Application of biphosphonates along with Vitamin D analogs is sufficient to overcome the calcemic and toxic side effects of the proposed treatment.     

Proton Pump Inhibitor-Induced Hypocalcemic Seizure in A Patient with Hypoparathyroidism

ObjectiveTo report a case of proton pump inhibitor-induced hypocalcemic seizure in a patient with hypoparathyroidism.MethodsWe describe the clinical history, physical examination findings, and laboratory values of the patient and briefly review the relevant literature.ResultsA 48-year-old woman with a history of postsurgical hypoparathyroidism who was taking calcium carbonate, 1500 mg 3 times daily, and cholecalciferol, 1200 IU daily, presented with a generalized seizure in the setting of hypocalcemia 12 days after initiating therapy with the proton pump inhibitor lansoprazole. Physical examination revealed a positive Chvostek sign. Electrocardiogram was notable for a prolonged QT_c interval of 576 milliseconds. Laboratory data were notable for the following values: total serum calcium, 5.3 mg/dL; ionized calcium, 2.51 mg/dL; and intact parathyroid hormone, 5.8 pg/mL. The patient’s condition responded to therapy with intravenous calcium gluconate, oral calcium carbonate, and calcitriol. As an outpatient she remained asymptomatic off lansoprazole, treated with calcium carbonate and calcitriol.ConclusionsCaution should be exercised in prescribing proton pump inhibitors to patients with a history of hypoparathyroidism treated with calcium carbonate supplementation because severe hypocalcemia is a potential adverse effect. (Endocr Pract. 2011;17:104-107)     

An investigation into a possible relationship between vitamin D, parathyroid hormone, calcium and magnesium in a normally pigmented and an albino rural black population in the Northern Province of South Africa

Vitamin D levels are important in the management of patients with various disorders of calcium metabolism associated with rickets, osteomalacia, osteodystrophy osteoporosis and hypoparathyroidism. 82 albinos and 58 normally pigmented children resident at the Siloe School for the Visually Impaired were sampled. Blood samples of fasting subjects were collected over a two-day period and analyzed for vitamin D, parathyroid hormone, plasma calcium and both plasma and red blood cell magnesium measurements. The height and weight of each subject was also recorded. The results are discussed in relation to the different skin pigmented groups, for specific age groups, sex and visual status. Statistical outliers were excluded from the results. It appears that the Albino group has significantly (p = 0.06) higher vitamin D levels against the background of a similar dietary intake and similar exposure to sunlight/day length. Thus black children/subjects require a significantly higher intake of vitamin D to attain the same level as their Albino counterparts. In spite of significantly higher vit D levels, the other homeostatic control mechanisms were not altered (i.e., PTH levels are similar in both groups). This study supports the postulate that a dark complexion predisposes to sub-optimal vit D status.     

Decreased Calcitriol Requirement During Pregnancy and Lactation With A Window of Increased Requirement Immediately Post Partum

ObjectiveTo describe the changes in calcium and cal- citriol requirements during pregnancy and lactation in a pa- tient with hypoparathyroidism due to autosomal dominant hypocalcemia.MethodsWe summarize the clinical presentation and treatment of the patient and review the pertinent literature.ResultsCalcitriol requirements disappeared during pregnancy in a 34-yearold woman with autosomal dominant hypoparathyroidism secondary to an activating mutation in the calciumsensing receptor gene. Within hours after delivery, her serum calcium concentration dropped to 4.7 mg/dL (albumin, 3.2 g/dL), and she required intravenous calcium and reinstitution of calcitriol. When lactation began a few days later, her calcitriol requirement again disappeared. As has occasionally been described in the literature, this patient with hypoparathyroidism required no calcitriol during late pregnancy and lactation to maintain a normal serum calcium level.ConclusionsTo our knowledge, this is the first reported case documenting a period of time between pregnancy and lactation when calcitriol requirements reappeared, likely due to a parathyroid hormone-related protein “window” between delivery, when placental production of parathyroid hormone-related protein stops, and lactation, when mammary gland production begins. (Endocr Pract. 2010:16:459-462)     

Characterization of Vitamin D insensitive prostate cancer cells

The antitumor effects of 1,25-dihydroxyvitamin D₃ (calcitriol) are being exploited for prevention and treatment of prostate cancer (CaP). These studies examined the antiproliferative effects of calcitriol in primary cell cultures derived from transgenic adenocarcinoma of mouse prostate (TRAMP) mice chronically treated with calcitriol (20 μg/kg) or vehicle 3×/week from 4 weeks-of-age until palpable tumors developed. This is a report on the response of two representative control (Vitamin D naïve, naïve) and calcitriol-treated (Vitamin D insensitive, VDI) cells to calcitriol. VDI cells were less sensitive to calcitriol based on less cell growth inhibition and less inhibition of DNA synthesis as measured by MTT and BrdU incorporation assays. Similarly, VDI cells were less sensitive to growth inhibition by the vitamin analog, 19-nor-1,25-dihydroxyvitamin D₂ (paricalcitol). There was no change in apoptosis following treatment of naïve and VDI cells with calcitriol. Vitamin D receptor (VDR) expression was up-regulated by calcitriol in both naïve and VDI cells. In addition, calcitriol induced the Vitamin D metabolizing enzyme, 24-hydroxylase (cyp24) mRNA and enzyme activity similarly in naïve and VDI cells as measured by RT-PCR and HPLC, respectively. In summary, VDI cells are less responsive to the antiproliferative effects of calcitriol. Understanding Vitamin D insensitivity will further clinical development of Vitamin D compounds for prevention and treatment of CaP.     

Hypoparathyroidism after surgery on thyroid cancer: is there a delayed chance for recovery after a prolonged period of substitutive therapy?

INTRODUCTION: Transient and persistent hypoparathyroidism (HPT) belong to the well known complications of total thyroidectomy performed because of thyroid carcinoma. The true frequency of persistent hypoparathyroidism is often higher than estimated in the reports published by the specialized centers with low rate of complications. THE AIM OF THE STUDY: Investigation whether the repeated check-up, performed over 2 years post thyroidectomy, reveals some cases of recovery in patients diagnosed with persistent HPT post thyroid cancer surgery. MATERIAL AND METHODS: In total, 115 patients were included into the study, all of them treated with vitamin D derivatives and calcium supplementation. In 17 of them a diagnosis of transient hypoparathyroidism was made on the basis of evaluation performed 6 months after surgery, the remaining 98 were diagnosed with persistent HPT. Parathyroid (PTH) function was reevaluated after withdrawal of active vitamin D derivatives for 10 days and of calcium carbonate for two days during the hospital stay in patients admitted for radioiodine scan, thus after thyroxine withdrawal. The control group consisted of 123 DTC (differentiated thyroid carcinoma) patients without parathyroid dysfunction. On the basis of intact PTH serum level and calcium and phosphorus estimations HPT was unequivocally confirmed in 49 patients (50%). The remaining 49 patients exhibited normal PTH level and in 43 (86%) of them Ca(2+) level was also within normal range, thus delayed, recovery from HPT was stated. RESULTS: Our results indicate that reevaluation of hypoparathyroidism post total thyreoidectomy is necessary, as delayed recover of parathyroid dysfunction is a frequent phenomenon. We also propose criteria of reevaluation of HTP in patients on chronic substitutive therapy.     

Postoperative hypoparathyroidism: long term observation and therapy]

Hundred thirty patients with surgical hypoparathyroidism were followed up. Group I involved 45 patients with mild and group II--85 patients with severe surgical hypoparathyroidism. A delay in vitamin D3 therapy was X +/- SD = 4.2 +/- 8.1 years. A delay in introducing vitamin D3 therapy correlated with the duration of hypoparathyroidism (r = 0.93; 8.9 +/- 9.6 years). Follow up period lasted for 15 years and was 4.3 +/- 3.8 years out of which the attempts to establish ultimate and effective dose of vitamin D3 lasted 1.8 +/- 2.4 years. Dose of vitamin D3 was adjusted 5 times, on the average. Effective daily dose was 4,200-22,500 IU (9,311 +/- 7,252) in group I, and 30,000-195,000 IU (51,385 +/- 32,978) in group II whereas maximum daily dose was 75,000 and 250,000 IU respectively (p < 0.001). Some patients were given 25-OH-D3 in daily doses of 50-225 micrograms or 25(OH)2-D3 in daily dose of 0.10-0.75 micrograms. Calcium oral doses of 400-1600 mg daily were administered to 115 patients. In case of high hypercalciuria (over 350 mg/24 h) hydrochlorothiazide (43 +/- 17 mg a day) or chlorthalidone (60 +/- 22 mg a day) normalized calciuria. Low phosphate diet and aluminium oxide (4.4 +/- 1.7 g a day) were more frequently used in group II. Period of time necessary to establish an effective dose of vitamin D3 is long in patients with surgical hypoparathyroidism. Several dose adjustments are required. Maximum daily vitamin D3 dose required for normocalcemia is approximately higher by 1/3 in the early period of the treatment than the effective maintenance dose. A decrease in diet phosphate content, inhibition of phosphates absorption in the gut or blocking increased calcium loss with the urine are necessary in some patients, only.     

Management of Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease

ObjectiveTo review approved treatment options for secondary hyperparathyroidism (SHPT) in patients with stages 3 and 4 chronic kidney disease (CKD).MethodsRecently published data on the diagnosis and treatment of SHPT in patients with CKD were critically assessed.ResultsEarly detection of SHPT is critical for effective treatment. Approximately 40% of patients with stage 3 CKD and 80% of patients with stage 4 have SHPT due to low serum 1,25-dihydroxyvitamin D levels. Appropriate treatment involves suppression of parathyroid hormone (PTH) to normal levels with active vitamin D therapy and phosphate binders. Ergocalciferol or cholecalciferol should be used to correct 25-hydroxyvitamin D levels either before or during active vitamin D therapy. Active vitamin D analogues include calcitriol, doxercalciferol, and paricalcitol. Calcitriol is effective, but has a narrow therapeutic window at higher doses because of hypercalcemia and hyperphosphatemia, which require frequent monitoring. Doxercalciferol is also effective, but has been associated with significant elevations in serum phosphorus requiring greater use of oral phosphate binders. Paricalcitol effectively suppresses PTH with minimal impact on serum calcium and phosphorus. Limited data exist on the use of cinacalcet in treating SHPT in stages 3 and 4 CKD, and it is only approved for use in patients receiving dialysis.ConclusionSHPT is an early and major complication of CKD. Treatment involves suppression of PTH to prevent metabolic bone disease, bone loss, and metabolic complications that may result in marked morbidity and mortality. Early detection of elevated PTH levels with appropriate intervention using active vitamin D therapy, even in the absence of elevated serum phosphorus and reduced serum calcium, is critical. (Endocr Pract. 2008;14:18-27)     

Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis

Vitamin D, especially its most active metabolite 1,25-dihydroxyvitamin D₃ or calcitriol, is essential in regulating a wide variety of biologic processes, such as calcium homeostasis, immune modulation, cell proliferation and differentiation. Clinical studies show that the circulating level of calcitriol is substantially reduced in patients with chronic renal insufficiency. Administration of active Vitamin D results in significant amelioration of renal dysfunction and fibrotic lesions in various experimental models of chronic kidney diseases. Active Vitamin D elicits its renal protective activity through multiple mechanisms, such as inhibiting renal inflammation, regulating renin–angiotensin system and blocking mesangial cell activation. Recent studies indicate that calcitriol induces anti-fibrotic hepatocyte growth factor expression, which in turn blocks the myofibroblastic activation and matrix production in interstitial fibroblasts. Furthermore, in vivo and in vitro studies demonstrate that active Vitamin D effectively blocks tubular epithelial to mesenchymal transition (EMT), a phenotypic conversion process that plays a central role in the evolution of renal interstitial fibrosis. Together, it is becoming increasingly clear that a high level of active Vitamin D may be obligatory in the maintenance of normal kidney structure and function. Thus, supplementation of active Vitamin D could be a rational strategy for the therapeutics of chronic kidney diseases.     

No association between the vitamin D pathway gene polymorphisms and bone biomarkers response to calcium and low dose calcitriol supplementation in postmenopausal Chinese women: a one-year prospective study

Abstract

Introduction: The aim of the study was to explore the association between the vitamin D pathway gene variations and the bone biomarkers response to calcium and low dose calcitriol supplementation in postmenopausal Chinese women.

Methods: A total of 110 healthy postmenopausal Chinese women (61.51?±?6.93?years) were enrolled. The participants were supplemented with calcium (600?mg/d) and calcitriol (0.25?μg/d), for 1?year. Four biomarkers, serum levels of beta C-terminal cross-linked telopeptides of type I collagen (β-CTX), amino-terminal propeptide of type I collagen (P1NP), parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] were measured at baseline and 12-month follow-up. Multivariate regression models were established to explore the statistical association between the change rate of the four biomarkers and 15?key genes within the vitamin D metabolic pathway.

Results: This exclusion process left 98 participants for analysis. Serum levels of P1NP, β-CTX and PTH were significantly decreased at the 12-month follow-up (all p?<?0.05). Serum 25(OH)D level had no significant change (p?>?0.05). No association was found between the vitamin D pathway gene polymorphisms and bone biomarkers response to calcium and low dose calcitriol supplementation.

Conclusions: Genetic background of postmenopausal Chinese women might not influence supplemental response of the biomarkers to calcium and low dose calcitriol.     

Prolonged Vitamin D Intoxication in a Patient with Hypoparathyroidism

Pitfalls in the management of hypoparathyroidism are illustrated by the case of a patient who developed hypervitaminosis D while receiving doses of calciferol and of calcium in amounts commonly recommended for treatment. Either the patient was very slow to obtain maximum vitamin D effect or else her sensitivity to vitamin D increased, because she did not become hypercalcemic until two years after treatment was started. The dose of vitamin D was halved to 50,000 units per day and the dose of calcium was lowered to 0.26 g. daily. She failed to remain under medical supervision for the next four years and presented with hypercalcemia and evidence of renal impairment. After vitamin D was discontinued she remained hypercalcemic for nine months.These findings are discussed in the light of current knowledge concerning the actions of parathyroid hormone and vitamin D. The influence of adrenocortical hormones on calcium metabolism is considered. The need to follow up hypoparathyroid patients closely, and to check the level of calcium in the serum, is emphasized.     

Determinants of parathormone secretion in primary hyperparathyroidism

We studied the effects of acute modifications in plasma calcium on parathormone (PTH) secretion in 23 patients with primary hyperparathyroidism (PHPT). In 12 patients, PTH hypersecretion was autonomous, and basal plasma calcium concentration was positively correlated with maximal serum PTH(1-84) reached during Na2EDTA infusions. In 11 patients, PTH hypersecretion remained suppressible, but with elevated set point value, and basal plasma calcium concentration was positively correlated with set point. Thus, the degree of hypercalcemia seems mainly determined by the magnitude of maximal PTH secretion and set point error in autonomous and suppressible PHPT, respectively. We have previously suggested that high serum calcitriol levels might chronically inhibit PTH hypersecretion in PHPT. We showed that hyperparathyroid patients with renal stone presentation exhibited an abnormally high value of circulating calcitriol and a moderately elevated PTH activity, while patients with severe bone disease presentation displayed a low to normal calcitriol value and a dramatically increased PTH activity. The hypothesis was supported by a recent study from our Unit in one hyperparathyroid patient with severe bone disease and normal serum calcitriol level. Increment of serum calcitriol after daily intravenous Rocaltrol for 5 days directly suppressed PTH hypersecretion without change in plasma ionized calcium.     

Which circulating level of 25-hydroxyvitamin D is appropriate?

Moderate Vitamin D deficiency causes secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures. Controversy exists which circulating level of 25-hydroxyvitamin D (25OH)D is appropriate. The high incidence of hip fractures at northern latitudes suggest a relationship with Vitamin D deficiency. However, international studies show lower serum 25(OH)D levels in southern than in northern Europe. Serum 25(OH)D was not a risk factor for hip fractures in several epidemiological studies. The required serum 25(OH)D is usually established by assessing the point where serum parathyroid hormone (PTH) starts to rise. This point varied in several studies between 30 and 78 nmol/l. However, interlaboratory variation may also influence the apparent required serum 25(OH)D level. Dietary calcium intake influences serum PTH and serum PTH may influence the turnover of Vitamin D metabolites. A low calcium intake causes an increase of serum PTH and serum 1,25(OH)2D thereby decreasing the half life of serum 25(OH)D. While a low calcium intake may aggravate Vitamin D deficiency, a high calcium intake may have a Vitamin D sparing effect. With current knowledge, a global estimate for the appropriate serum 25(OH)D is 50 nmol/l.