The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture-results of a large observational cohort study.

Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture; however, the mechanism is unclear. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users (OR 1.56, CI 1.08-2.23, p = 0.018). This highlights the importance of monitoring PPI use, especially in older adults. PURPOSE: Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture. Hyperparathyroidism may be implicated, but few studies have considered this relationship. This study evaluated the relationship between PPI use and hyperparathyroidism in older adults. METHODS: Participants were from the TUDA study, a large cross-sectional cohort of older Irish adults. Participants with an estimated glomerular filtration rate (eGFR) < 30 ml/min and serum calcium > 2.5 mmol/l were excluded to avoid hyperparathyroidism due to chronic renal disease and primary hyperparathyroidism. Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml. Multivariate regression models were used to analyse the relationship between PPI use and hyperparathyroidism. RESULTS: A total of 4139 participants met the inclusion criteria, of whom 37.8% (n = 1563) were taking PPI medication. PPI use was identified in 41.4% of calcium supplement users and 35.4% of non-calcium supplement users. Overall, compared to non-users of PPIs, those taking PPIs were older (74.8 vs 72.9 years, p < 0.001) and had a higher prevalence of hyperparathyroidism (17.8 vs 11.0%, p < 0.001). In those taking calcium supplements (but not in non-users), PPI use was significantly associated with hyperparathyroidism (OR 1.56, CI 1.08-2.23, p = 0.018) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, timed-up-and-go, dairy intake, medications, and comorbidities. DISCUSSION: The results are consistent with the hypothesis of PPIs reducing calcium absorption, leading to a rise in PTH which could mediate increased fracture risk. No relationship of PPI use with hyperparathyroidism was observed in non-users of calcium supplements, possibly owing to lower dietary calcium intake. These results highlight the importance of monitoring PPI use, especially in older adults at risk of fracture.

Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. CASE PRESENTATION: A 16-year-old female was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15-2.55), parathyroid hormone 2,151 pg/mL (15-65), and phosphate 1.07 mmol/L (1.45-1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient's condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological examination revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. CONCLUSION: Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.

Unusual case of chronic recurrent multifocal osteomyelitis.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory bone disorder that primarily affects young girls, with a mean age of 10 years at onset. Generally, it is a self-limited disease. However, recent data indicate that more than 50% of patients have a chronic persistent disease and about 20% a recurring course of this condition. Also, there are more cases reported with associated auto-inflammatory and autoimmune diseases. In this case report, we present a rare case of sporadic CRMO in which the patient eventually developed C-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies)-associated renal vasculitis and hyperparathyroidism. CASE PRESENTATION: A 14 year old female patient was brought to the emergency department with a sudden onset of left leg pain and oedema. After physical evaluation and initial investigation, she was diagnosed with femoral and pelvic deep vein thrombosis. While searching for possible thrombosis causes, osteomyelitis of the left leg was identified. Additional CT and MRI scans hinted at the CRMO diagnosis. Due to the multifocal lesions of CRMO, endocrinological evaluation of calcium metabolism was done. The results showed signs of hyperparathyroidism with severe hypocalcaemia. Moreover, when kidney damage occurred and progressed, a kidney biopsy was performed, revealing a C-ANCA associated renal vasculitis. Treatment was started with cyclophosphamide and prednisolone according to the renal vasculitis management protocol. Severe metabolic disturbances and hyperparathyroidism were treated with alfacalcidol, calcium and magnesium supplements. Secondary glomerulonephritis (GN) associated hypertension was treated with ACE (angiotenzine converting enzyme) inhibitors. Anticoagulants were prescribed for deep vein thrombosis. After 1.5 years of treatment, the patient is free of complaints. All microelement and parathormone levels are within normal range. Kidney function is now normal. To date, there are no clinical or diagnostic signs of deep vein thrombosis. CONCLUSIONS: This case report presents a complex immunodysregulatory disorder with both auto-inflammatory and autoimmune processes. We hypothesize that the long lasting active inflammation of CRMO may induce an autoimmune response and result in concomitant diseases like C-ANCA-associated vasculitis in our patient. Any potential specific pathogenic relationships between these two rare pathologies may need to be further studied. Furthermore, there is a lack of specific biomarkers for CRMO and more studies are necessary to identify CRMO's characteristic patterns and how to best monitor disease progression.

Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease.

BACKGROUND/AIMS: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. METHODS: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. RESULTS: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. CONCLUSION: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts.

The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

Propensity score matching and persistence correction to reduce bias in comparative effectiveness: the effect of cinacalcet use on all-cause mortality.

PURPOSE: The generalisability of randomised controlled trials (RCTs) may be limited by restrictive entry criteria or by their experimental nature. Observational research can provide complementary findings but is prone to bias. Employing propensity score matching, to reduce such bias, we compared the real-life effect of cinacalcet use on all-cause mortality (ACM) with findings from the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) RCT in chronic haemodialysis patients. METHODS: Incident adult haemodialysis patients receiving cinacalcet, recruited in a prospective observational cohort from 2007-2009 (AROii; n = 10,488), were matched to non-exposed patients regardless of future exposure status. The effect of treatment crossover was investigated with inverse probability of censoring weighted and lag-censored analyses. EVOLVE ACM data were analysed largely as described for the primary composite endpoint. RESULTS: AROii patients receiving cinacalcet (n = 532) were matched to 1790 non-exposed patients. The treatment effect of cinacalcet on ACM in the main AROii analysis (hazard ratio 1.03 [95% confidence interval (CI) 0.78-1.35]) was closer to the null than for the Intention to Treat (ITT) analysis of EVOLVE (0.94 [95%CI 0.85-1.04]). Adjusting for non-persistence by 0- and 6-month lag-censoring and by inverse probability of censoring weight, the hazard ratios in AROii (0.76 [95%CI 0.51-1.15], 0.84 [95%CI 0.60-1.18] and 0.79 [95%CI 0.56-1.11], respectively) were comparable with those of EVOLVE (0.82 [95%CI 0.67-1.01], 0.83 [95%CI 0.73-0.96] and 0.87 [95%CI 0.71-1.06], respectively). CONCLUSIONS: Correcting for treatment crossover, we observed results in the 'real-life' setting of the AROii observational cohort that closely mirrored the results of the EVOLVE RCT. Persistence-corrected analyses revealed a trend towards reduced ACM in haemodialysis patients receiving cinacalcet therapy.

Cinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is diagnosed by the presence of hypercalcemia and elevated or nonsuppressed parathyroid hormone (PTH) levels. Although surgery is usually curative, some individuals fail or are unable or unwilling to undergo parathyroidectomy. In such individuals, targeted medical therapy may be of value. Cinacalcet normalized calcium level and lowered PTH in patients with PHPT in several phase 2 and open-label studies. We compared cinacalcet and placebo in subjects with PHPT unable to undergo parathyroidectomy. DESIGN: Phase 3, double-blind, multi centere, randomized, placebo-controlled study. METHODS: Sixty-seven subjects (78% women) with moderate PHPT were randomized (1:1) to cinacalcet or placebo for ≤28 weeks. MAIN OUTCOME MEASURE: Achievement of a normal mean corrected total serum calcium concentration of ≤10.3 mg/dl (2.575 mmol/l). RESULTS: Baseline median (quartile 1 (Q1), Q3) serum PTH was 164.0 (131.0, 211.0) pg/ml and mean (s.d.) serum Ca was 11.77 (0.46) mg/dl. Serum Ca normalized (≤10.3 mg/dl) in 75.8% of cinacalcet- vs 0% of placebo-treated subjects (P<0.001). Corrected serum Ca decreased by ≥1.0 mg/dl from baseline in 84.8% of cinacalcet- vs 5.9% of placebo-treated subjects (P<0.001). Least squares mean (s.e.m.) plasma PTH change from baseline was -23.80% (4.18%) (cinacalcet) vs -1.01% (4.05%) (placebo) (P<0.001). Similar numbers of subjects in the cinacalcet and placebo groups reported adverse events (AEs) (27 vs 20) and serious AEs (three vs four). Most commonly reported AEs were nausea and muscle spasms. CONCLUSIONS: These results demonstrate that cinacalcet normalizes serum calcium in this PHPT population and appears to be well tolerated.

Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study.

CONTEXT: Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities. OBJECTIVE: The objective of the study was to suppress elevated PTH levels in XLH patients. DESIGN: This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later. SETTING: PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit. PATIENTS: Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less. INTERVENTION: The intervention for this study was the use of paricalcitol or placebo for 1 year. MAIN OUTCOME MEASURES: Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc-methylenediphosphonate bone scans. RESULTS: PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject. CONCLUSIONS: Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use.

Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease.

OBJECTIVE: It has been suggested that vitamin D may play a role in the pathogenesis of several endocrine diseases, such as hyperparathyroidism, type 1 diabetes (T1DM), type 2 diabetes (T2DM), autoimmune thyroid diseases, Addison's disease and polycystic ovary syndrome (PCOS). In this review, we debate the role of vitamin D in the pathogenesis of endocrine diseases. METHODS: Narrative overview of the literature synthesizing the current evidence retrieved from searches of computerized databases, hand searches and authoritative texts. RESULTS: Evidence from basic science supports a role for vitamin D in many endocrine conditions. In humans, inverse relationships have been reported not only between blood 25-hydroxyvitamin D and parathyroid hormone concentrations but also with risk of T1DM, T2DM, and PCOS. There is less evidence for an association with Addison's disease or autoimmune thyroid disease. Vitamin D supplementation may have a role for prevention of T2DM, but the available evidence is not consistent. CONCLUSIONS: Although observational studies support a potential role of vitamin D in endocrine disease, high quality evidence from clinical trials does not exist to establish a place for vitamin D supplementation in optimizing endocrine health. Ongoing randomized controlled trials are expected to provide insights into the efficacy and safety of vitamin D in the management of endocrine disease.

Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet.

BACKGROUND: NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice. OBJECTIVE: To describe a case of NSHPT unresponsive to cinacalcet. PATIENT AND RESULTS: A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation. CONCLUSION: The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial.

CONTEXT: Low 25-hydroxyvitamin D levels are common in patients with primary hyperparathyroidism (PHPT) and associated with higher PTH levels and hungry bone syndrome after parathyroidectomy (PTX). However, concerns have been raised about the safety of vitamin D supplementation in PHPT. OBJECTIVE: We aimed to assess safety and effects on calcium homeostasis and bone metabolism of supplementation with high doses of vitamin D in PHPT patients. DESIGN, SETTING: This was an investigator-initiated double-blind, randomized, placebo-controlled, parallel-group trial from a single center. PATIENTS: Forty-six PHPT patients were recruited, with a mean age of 58 (range 29-77) years, and 35 (76%) were women. INTERVENTIONS: Intervention included daily supplementation with 70 µg (2800 IU) cholecalciferol or identical placebo for 52 weeks. Treatment was administered 26 weeks before PTX and continued for 26 weeks after PTX. MAIN OUTCOME MEASURES: PTH, calcium homeostasis, and bone metabolism were evaluated. RESULTS: Preoperatively, 25-hydroxyvitamin D increased from 50 to 94 nmol/L in the treatment group and decreased from 57 to 52 nmol/L in the placebo group (P < .001). Compared with placebo, vitamin D decreased PTH significantly by 17% before PTX (P = .01), increased lumbar spine bone mineral density by 2.5% (P = .01), and decreased C-terminal ß-CrossLaps by 22% (P < .005). The trabecular bone score did not change in response to treatment, but improved after PTX. Postoperatively, PTH remained lower in the cholecalciferol group compared with the placebo group (P = .04). Plasma creatinine and plasma and urinary calcium did not differ between groups. CONCLUSIONS: Daily supplementation with a high vitamin D dose safely improves vitamin D status and decreases PTH in PHPT patients. The vitamin D treatment is accompanied by reduced bone resorption and improved bone mineral density before operation.

The effect of cholecalciferol for lowering albuminuria in chronic kidney disease: a prospective controlled study.

BACKGROUND: Growing evidence indicates that vitamin D receptor activation may have antiproteinuric effects. We aimed to evaluate whether vitamin D supplementation with daily cholecalciferol could reduce albuminuria in proteinuric chronic kidney disease (CKD) patients. METHODS: This 6-month prospective, controlled, intervention study enrolled 101 non-dialysis CKD patients with albuminuria. Patients with low 25(OH) vitamin D [25(OH)D] and high parathyroid hormone (PTH) levels (n = 50; 49%) received oral cholecalciferol (666 IU/day), whereas those without hyperparathyroidism (n = 51; 51%), independent of their vitamin D status, did not receive any cholecalciferol, and were considered as the control group. RESULTS: Cholecalciferol administration led to a rise in mean 25(OH)D levels by 53.0 ± 41.6% (P < 0.001). Urinary albumin-to-creatinine ratio (uACR) decreased from (geometric mean with 95% confidence interval) 284 (189-425) to 167 mg/g (105-266) at 6 months (P < 0.001) in the cholecalciferol group, and there was no change in the control group. Reduction in a uACR was observed in the absence of significant changes in other factors, which could affect proteinuria, like weight, blood pressure (BP) levels or antihypertensive treatment. Six-month changes in 25(OH)D levels were significantly and inversely associated with that in the uACR (Pearson's R = -0.519; P = 0.036), after adjustment by age, sex, body mass index, BP, glomerular filtration rate and antiproteinuric treatment. The mean PTH decreased by -13.8 ± 20.3% (P = 0.039) only in treated patients, with a mild rise in phosphate and calcium-phosphate product [7.0 ± 14.7% (P = 0.002) and 7.2 ± 15.2% (P = 0.003), respectively]. CONCLUSIONS: In addition to improving hyperparathyroidism, vitamin D supplementation with daily cholecalciferol had a beneficial effect in decreasing albuminuria with potential effects on delaying the progression of CKD.

Restoration of bone mineralization by cinacalcet is associated with a significant reduction in calcitriol-induced vascular calcification in uremic rats.

The present study investigated to what extent normalization of bone turnover goes along with a reduction of high-dose calcitriol-induced vascular calcifications in uremic rats. Five groups of male Sprague-Dawley rats were studied: sham-operated controls (n = 7), subtotally nephrectomized (SNX) uremic (CRF) animals (n = 12), CRF + calcitriol (vitD) (0.25 µg/kg/day) (n = 12), CRF + vitD + cinacalcet (CIN) (10 mg/kg/day) (n = 12), and CRF + vitD + parathyroidectomy (PTX) (n = 12). Treatment started 2 weeks after SNX and continued for the next 14 weeks. High-dose calcitriol treatment in hyperparathyroid rats went along with the development of distinct vascular calcification, which was significantly reduced by >50 %, in both CIN-treated and PTX animals. Compared to control animals and those of the CRF group, calcitriol treatment either in combination with CIN or PTX or not was associated with a significant increase in bone area comprising ±50 % of the total tissue area. However, whereas excessive woven bone accompanied by a dramatically increased osteoid width/area was seen in the CRF + vitD group, CIN treatment and PTX resulted in significantly reduced serum PTH level, which was accompanied by a distinct reduction of both the bone formation rate and the amount of osteoid. These data indicate that less efficient calcium and phosphorus incorporation in bone inherent to the severe hyperparathyroidism in vitamin D-treated uremic rats goes along with excessive vascular calcification, a process which is partially reversed by CIN treatment in combination with a more efficacious bone mineralization, thus restricting the availability of calcium and phosphate for being deposited in the vessel wall.

Metabolic bone disease of prematurity and secondary hyperparathyroidism.

AIM: To illustrate, via case histories, the importance of laboratory investigations for the early diagnosis and management of metabolic bone disease (MBD). METHODS: We report three cases of extreme premature infants with MBD. RESULTS: These three infants had several risk factors for MBD of prematurity: very low birthweight, delayed enteral feeds, cholestatic liver disease, intolerance of fortification, the use of glucocorticoids and diuretics. Serum alkaline phosphatase and parathyroid hormone (PTH) were elevated despite relatively normal calcium and phosphate levels. These parameters were corrected with additional supplementation of calcium, phosphate and vitamin D. CONCLUSIONS: Infants born extremely prematurely have significant calcium and phosphate depletion by the time they reach full term compared with the normal fetal accretion rate. This is exacerbated if there is poor tolerability to feeds where extra calcium and phosphate could not be added either by additives or via human milk fortifier. Serum calcium and phosphate levels may be normal despite inadequate intake or stores due to the counter-regulatory effect of PTH. In infants at risk of MBD, testing serum alkaline phosphatase, vitamin D and PTH with calcium and phosphate may assist in the monitoring and management of MBD.

The effect of cinacalcet on bone remodeling and renal function in transplant patients with persistent hyperparathyroidism.

BACKGROUND: Parathyroidectomy is associated with renal functional losses in transplant patients; cinacalcet offers an attractive alternative. METHODS: We performed a prospective observational study in 58 patients with persisting hyperparathyroidism after renal transplantation (Ca≥2.6 mmol/L) and impaired renal transplant function (estimated glomerular filtration rate [eGFR] <50 mL/min). The patients received 30 to 90 mg cinacalcet for 12 months with the target to normalize serum Ca. We measured parathyroid hormone (PTH), serum Ca, serum phosphorus, alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, and telopeptide at 0, 1, 2, 3, 6, 9, and 12 months of cinacalcet treatment. Fractional excretion of calcium and phosphorus (n=24) were monitored at 0 and 1 month. RESULTS: At inclusion, creatinine was 181±70 µmol/L, eGFR 43±19 mL/min, PTH 371±279 pg/mL, and Ca 2.73±0.22 mmol/L. We observed nephrocalcinosis in 58% of biopsied patients at enrollment. After cinacalcet, Ca decreased significantly and normalized at nearly any measurement. Phosphorus increased significantly at months 1, 9, and 12. PTH decreased significantly, but only at months 9 and 12 and did not normalize. Bone-specific alkaline phosphatase increased significantly (>normal) by month 12. eGFR decreased and serum creatinine increased at all time points. The Δ(creatinine) % increase correlated significantly with the Δ(PTH) % decrease at month 1 and 12. Telopeptide and alkaline phosphatase correlated with PTH and telopeptide also correlated with serum creatinine. CONCLUSION: Calcium-phosphorus homeostasis in hypercalcemic renal transplant patients normalizes under cinacalcet and PTH decreases, albeit not to normal. The renal functional decline could be PTH mediated, analogous to the effects observed after parathyroidectomy.

Hypercalcemia secondary to persistent hyperparathyroidism in kidney transplant patients: analysis after a year with cinacalcet.

INTRODUCTION: The most common cause of hypercalcemia in patients with transplanted kidneys is persistent hyperparathyroidism, which presents in 10%-30% of patients with functioning renal grafts. In these patients, the treatment of vitamin D-resistant hyperparathyroidism traditionally required parathyroidectomy. Calcimimetic agents represent a new therapeutic alternative; they inhibit parathyroid hormone (PTH) secretion, increasing the sensitivity of the calcium-sensitive receptor in the parathyroid gland. The objective of this study is to evaluate the efficacy of cinacalcet in renal transplant patients with persistent hyperparathyroidism. METHODS: Cinacalcet 30 mg/day was prescribed to 17 renal transplant patients (6 women, 11 men) with a mean age of 49 years and hypercalcemia secondary to persistent hyperparathyroidism. The treatment started 58.17 ± 35.16 months posttransplant, with 1 year of follow-up. RESULTS: Calcium in serum fell from 10.5 ± 0.74 to 9.4 ± 0.84 mg/dL (p<0.001), whereas phosphorous levels were not significantly altered. The fall in PTH was from 204.79 ± 78 to 148.55 ± 56 pg/mL (p<0.011). Kidney function remained stable, and immunosuppressant drug levels remained unchanged. The dose of cinacalcet was increased to 60 mg in 2 patients. No significant adverse effects were described, and none of the patients had to suspend the treatment. CONCLUSIONS: Calcimimetic agents represent a therapeutic alternative in transplant patients with persistent hyperparathyroidism, as they correct hypercalcemia and reduce PTH levels with no adverse effects on kidney function. Prospective, controlled studies should be designed to evaluate the long-term effects and evolution after suspension of the treatment.

Economic analysis of cinacalcet in combination with low-dose vitamin D versus flexible-dose vitamin D in treating secondary hyperparathyroidism in hemodialysis patients.

BACKGROUND: The ACHIEVE (Optimizing the Treatment of Secondary Hyperparathyroidism: A Comparison of Sensipar and Low Dose Vitamin D vs Escalating Doses of Vitamin D Alone) trial evaluated the efficacy of treatment with cinacalcet plus low-dose activated vitamin D analogues (Cinacalcet-D) compared with vitamin D analogues alone (Flex-D) in attaining KDOQI (Kidney Disease Outcomes Quality Initiative) targets for secondary hyperparathyroidism (SHPT). The economic implications of these treatment regimens have not been explored. STUDY DESIGN: Economic analysis of SHPT treatment in hemodialysis patients. SETTING & POPULATION: This analysis used data from the ACHIEVE trial, in which patients received either Cinacalcet-D or Flex-D. MODEL, PERSPECTIVE, & TIME FRAME: We assessed the relative cost-effectiveness of these regimens in treating SHPT during the 27-week ACHIEVE trial, using a US payer perspective, with medication costs valued in 2006 US dollars. INTERVENTION & OUTCOMES: Relative cost-effectiveness was assessed using cost-minimization analysis or incremental cost-effectiveness ratios. Effectiveness was measured using biochemical markers. RESULTS: Mean medication costs per patient were $5,852 and $4,332 for the Cinacalcet-D and Flex-D treatment arms, respectively. There were no significant differences for the primary end point (parathyroid hormone level of 150-300 pg/mL and calcium-phosphorus product < 55 mg²/dL²) and several of the secondary end points, rendering Cinacalcet-D more costly than Flex-D. For secondary end points, for which Cinacalcet-D was more effective, incremental cost-effectiveness ratios ranged from $2,957 (calcium < 9.5 mg/dL) to $22,028 (all KDOQI targets) per patient reaching target. Switching to generic calcitriol would have increased the cost difference between treatment arms ($2,079), whereas switching sevelamer to lanthanum decreased the difference ($1,426). LIMITATIONS: Costs and outcomes were derived from a short-term randomized controlled trial and were protocol driven. Clinical outcomes, such as mortality, were not available. Long-term economic conclusions cannot be drawn from these data. CONCLUSIONS: Cinacalcet combined with vitamin D analogues was no more effective than vitamin D analogues in achieving the primary ACHIEVE end point and incurred greater costs. This conclusion was not tempered substantially by the cost of vitamin D analogues or oral phosphate binders. Whether the additional costs of cinacalcet are warranted will require longer term models to determine whether changes in serum levels of mineral metabolic markers translate into lower morbidity, mortality, and downstream costs.

Cinacalcet effect on severe hyperparathyroidism.

To determine the efficacy and safety of cinacalcet, a calcimimetic drug that suppress parathyroid hormone (PTH) production, we studied its effect on 20 patients (13 males) on maintenance hemodialysis (HD), 80% of them have persistent high PTH levels (i.e. more than 80 pmol/L), the remaining patients had PTH levels more than 60 pmol/L. Five of 20 (25%) patients dropped out from the study (2 because of severe GIT upset, one showed severe myalgia and arthralgia, one patient due to non compliance and one died at home due to cardiac arrest). The remaining 15 patients (10 males) had a mean age of 40 ± 12.86 years and dialysis duration of 29.13 ± 18.27 months. The follow-up period on cinacalcet was 4 months with a single daily oral dose started with 30 mg/day and increased gradually according to the PTH levels. Nine (60%) patients were on concomitant active vitamin D during the study period with a mean dose of 7.33 ± 3.39 µg/week. There was a significant decrease in the serum PTH levels at the end the study compared to that at the start (46.4 ± 4.7 pmol/L versus 93.3 ± 25.6 pmol/L, respectively, P< 0.000), and the target PTH level (< 31.6 pmol/L) was achieved in 54% of patients. No significant changes in serum Ca and phosphorous levels were observed. We conclude that cinacalcet is an effective therapy to suppress the serum PTH levels and allows favorable management of the serum calcium and phosphorus levels in HD patients. The drug was well tolerated; however, GIT discomfort is a significant side effect that may necessitate drug withdrawal in some patients.

Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease.

Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.