Alterations In Calcium Metabolism Research Articles

Abnormal extraosseous activity in both lungs and stomach in pre-transplant 99mTc-MDP bone scan disappearing after renal transplant

A chronic kidney disease male patient presenting with bone pains, fever, weakness, and clinically ascites was subjected to four technetium-99m-methylene diphosphonate (Tc99m-MDP) bone scans, two before renal transplant and two after renal transplants. Pretransplant bone scan revealed metabolic bone disease with focal insufficiency fractures. Marked extraosseous activity in both lungs and stomach was also visualized. On regular hemodialysis (HD) after 4 months, repeat pretransplant bone scan showed persistent uptake in lungs and stomach, representing altered calcium metabolism with microcalcifications. He underwent human leukocyte antigen (HLA) matched live donor renal transplantation, started on immune-suppression and steroids. Posttransplant bone scan at 20 days revealed no definite interval change, but bone scan performed approximately 17 months posttransplant showed resolving metabolic bone disease and the tracer uptake in the lungs and stomach was no more visualized. Patient clinically followed-up until the date (February 2013) is asymptomatic with serum creatinine of 1.5 mg/dl, no bone scan done.

Proton pump inhibitors do not induce change in bone mineral density in a long-term observational study

Commentary on: Targownik LE, Leslie WD, Davison KS, et al. the CaMos Research Group. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based...

An update on calcium metabolism alterations and cardiovascular risk in patients with chronic kidney disease: questions, myths and facts

In 2006, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines introduced, for the first time, the definition and diagnostic and therapeutic criteria for a systemic complication of the mineral metabolism dysfunction, such as vascular calcification, caused by chronic renal insufficiency. Abdominal x-ray and echocardiography rather than the more complex CT scan is suggested to make the diagnosis. This condition is associated with high cardiovascular risk and consequent poor prognosis. An alteration in total body calcium (Ca) content is one of the key factors in the cardiovascular complications observed in uremic subjects. In the general population, the addition of Ca to the diet has been to shown to improve bone mineral density (BMD) compared to controls, but it does not appear to reduce the risk of bone fractures. In patients with CKD, there are certainly some theoretical justifications for administering calcium salts: vitamin D deficiency, which reduces the intestinal absorption of Ca; hypocalcemia, which increases the risk of hyperparathyroidism; and hyperphosphatemia, which justifies the use of Ca-based P binders. There is already a large body of evidence pointing against the use of Ca-based binding agents, when there is a positive Ca balance because of the development of vascular calcification.

Linear skin atrophy preceding calcinosis cutis in pseudo-pseudohypoparathyroidism

Albright hereditary osteodystrophy (AHO) is a syndrome caused by inactivating mutations in the GNAS (guanine nucleotide-binding protein, alpha-stimulating) gene. Patients with AHO have short stature, obesity, brachydactyly and subcutaneous calcifications. AHO can be associated with pseudohypoparathyroidism type IA (PHP-IA) with upregulation of parathyroid hormone, whereas in pseudo-pseudohypoparathyroidism (PPHP), an endocrinopathy is not present. We report the case of a 5-month-old male infant who presented with slowly progressive linear atrophic skin lesions. The histological findings showed evidence of dermal hypoplasia. The child's father had PHP-IA. Four months after presentation, the infant developed calcifications within the pre-existent atrophic lesions. No alterations in calcium metabolism were noted. Analysis of the GNAS gene identified a short duplication leading to a frameshift mutation. We conclude that linear atrophic skin lesions may be an early sign of imminent cutaneous calcifications in AHO.

Incidental Diagnosis of Carcinoma of the Bladder Due to Uptake of (99m)Tc-MDP.

An 80-year-old male patient presented to the orthopaedist for evaluation of low backache. A bone scan was performed using 740 MBq (20 mCi) 99mTc-MDP. Whole-body planar images were acquired 3 h after injection (Fig. 1). The scan revealed normal physiological tracer uptake in skeletal system but irregular and heterogenous accumulation of tracer in the bladder (Fig. 2). To evaluate this abnormal accumulation further, the patient was given a dose of 40 mg furosemide and asked to drink plenty of water. He was instructed to void three to four times within 2–3 h. After 3 h, the urine became less radioactive. An SPECT-CT image of pelvis was acquired, and the images revealed intense multifocal uptake in multiple bladder polyps (Figs. 3, ​,4).4). Urine cytology was done, which subsequently revealed malignant cells. Further evaluation with cystoscopic biopsy confirmed transitional cell carcinoma (TCC) of the bladder. Intraoperatively multiple broad based polyps were seen in the dome of the bladder. Transurethral resection of the bladder tumors was done, and histopathology revealed arborizing islands and cords of atypical urothelial cells dissecting and infiltrating the bladder musculature (Fig. 5a, b). H&E photomicrograph at higher magnification (×200) showed mitosis and focal squamous differentiation (Fig. 5c). Fig. 1 Anterior and posterior whole-body bone scan showing physiological uptake in skeleton but irregular accumulation in bladder Fig. 2 99mTc-MDP bone scan of anterior and posterior pelvic spot views highlighting the irregular accumulation in the bladder Fig. 3 CT showing multiple bladder polyps; SPECT showing uptake in those polyps and the fused SPECT/CT image Fig. 4 Transaxial SPECT-CT images showing intense 99mTc-MDP uptake in the bladder polyps and less radioactive urine. Corresponding CT images showing multiple bladder polyps Fig. 5 a, b H&E photomicrograph at low magnification (×40) showing arborizing islands and cords of atypical urothelial cells dissecting and infiltrating the bladder musculature. c Photomicrograph at higher magnification (×200) showing ... Soft tissue uptake of 99mTc-MDP is described in various benign and malignant conditions [1–4]. It is known to accumulate in adenocarcinoma of lung, primary breast cancer, and colonic carcinoma among others. The actual mechanism of uptake in the malignant lesion is not known. The postulated causes of 99mTc-MDP uptake in extraosseous neoplasms are numerous and include tumor vascularity, inflammation, local pH factors, altered calcium metabolism, hormonal influences and cell wall damage [4, 5]. Our case shows that TCC of the bladder was incidentally diagnosed due to MDP uptake in multiple bladder polyps detected on a bone scan done for low backache in an 80-year-old man. This report also shows the importance of delayed imaging after diuretic administration.

Low concentration amino‐bisphosphonates stimulate human keratinocyte proliferation and in vitro wound healing

Amino-bisphosphonates (N-BPs) are widely used to treat a great variety of clinical conditions involving altered calcium metabolism, as well as to prevent bone metastases. The use of N-BPs, however, display well-known side effects, including cellular toxicity, mainly at soft tissue and mucosal level, that arise from N-BPs ability to induce cell apoptosis when administered at clinically relevant concentrations. The aim of this study was to evaluate, in an in vitro wound healing model, the effect of N-BPs low concentration (10 nM-10 µM) stimulation on keratinocyte cellular behaviour. Human keratinocytes were treated with neridronate and zoledronate, two N-BPs with different chemical structure and clinical potency, but sharing a common pharmacological target: farnesyl pyrophosphate (FPP) synthase. Surprisingly, at the tested concentrations, both drugs stimulated keratinocytes proliferation, upregulating cytokeratin 5 while downregulating filaggrin expression, and wound healing ability, without any significant effect on matrix metalloproteinase (MMP)-9 activity. The lack of N-BPs effect on MMP-9 activity indicates that wound closure, in our experimental model, is mainly due to an increase in cell proliferation rather than to an increase in cell migration. Therefore, it can be hypothesised that the observed wound healing results could be ascribed to an N-BPs mediated reduction of FPP endogenous levels, thus suggesting new possible clinical applications for these compounds.

Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients

Familial idiopathic bilateral strio-pallido-dentate calcinosis is a rare autosomal dominant disorder characterized by massive symmetric calcification, detectable by CT, into the globus pallidus and striatum, with or without the involvement of the dentate nucleus, thalamus and white matter in the absence of alterations of calcium metabolism. Clinically, it has been associated with movement and/or neuropsychiatric disorders with age at onset typically in the fourth or fifth decade. Other sporadic or familial diseases can be responsible for brain calcifications with a similar anatomic strio-pallidal or strio-pallido-dentate pattern and, a restricted number of them, for neurological symptoms with onset in adulthood. Moreover, physiological age-related basal ganglia calcifications are often incidentally found, although with a far different CT aspect, in elderly patients with movement disorders. Indentifying familial and idiopathic cases may offer the opportunity to study the molecular mechanisms underlying this minerals deposition.

W1901 Role of Klotho/Trpv5 Dysfunction in Altered Calcium Metabolism Associated With Aging

W1901 Role of Klotho/Trpv5 Dysfunction in Altered Calcium Metabolism Associated With Aging

Correlation of serum-adjusted calcium with ionized calcium over a 24-h period in patients with adult growth hormone deficiency before and after growth hormone replacement

Difficulties associated with measuring ionized calcium in clinical practice have led to the use of total calcium, with or without adjustment for albumin concentration, as an estimate of calcium metabolism. We examined the correlation between ionized and total/adjusted calcium over a 24-h period in patients with adult growth hormone deficiency (AGHD), a group of patients with previously reported alterations in calcium metabolism. Four patients with AGHD were consented to the study. They were hospitalized for 24 h where half-hourly blood samples were collected for ionized calcium, total calcium, albumin and creatinine, before and one month after the commencement of growth hormone replacement. Total calcium concentration was adjusted for serum albumin. Strong correlations were found between ionized calcium and adjusted calcium (r(2) = 0.840 and 0.766 for visits 1 and 2, respectively, P < 0.001), and between ionized calcium and total calcium (r(2) = 0.828 and 0.731 for visits 1 and 2, respectively, P < 0.001). Correlations remained significant during the day (ionized versus adjusted calcium: r(2) = 0.847 and 0.780 for visits 1 and 2, respectively; ionized versus total calcium: r(2) = 0.860 and 0.792 for visits 1 and 2, respectively, all P < 0.001) and at night (ionized versus adjusted calcium: r(2) = 0.831 and 0.802 for visits 1 and 2, respectively; ionized versus total calcium: r(2) = 0.767 and 0.722 for visits 1 and 2, respectively, all P < 0.001). The results of our study suggest that total calcium and serum-adjusted calcium can be used in place of ionized calcium as a reliable indicator of calcium metabolism over a 24-h period in patients with AGHD.

Oxidative stress inhibits Klotho activation of TRPV5 and TRPV6 in intestinal epithelial cells

Calcium is an essential ion in all organisms. We have shown that calcium metabolism is disregulated during chronic inflammation and aging. Klotho is a major player in cell senescence and is associated with calcium metabolism. We hypothesized that oxidative stress in intestinal epithelial cells may cause disregulated calcium balance in the gastrointestinal tract via Klotho disfunction. Caco‐2 and HT29/cl 19A cells were exposed to oxidative stress (H2O2, 100 nM) for 24–72 hr. The cells were then tested for Klotho, TRPV5, TRPV6 mRNA and protein expression, and for calcium transport. H2O2 treatment significantly decreased expression and activity of Klotho vs controls in a time‐dependent manner (1‐, 3‐, 1‐fold decrease at 24, 48, 72 hr, respectively). In parallel, TRPV5 and TRPV6 activity was decreased. Calcium transport was significantly reduced at 24–48 hr, and completely inhibited at 72 hr. H2O2 treatment reversed the co‐immunprecipitation of Klotho and the calcium channels by western blot, and co‐localization by confocal microscopy. We conclude that oxidative stress is in part responsible for the altered calcium metabolism observed in chronic inflammatory diseases through inhibition of Klotho activation of the major intestinal epithelial cell calcium channels. (NIH‐DK062096, SR).

Imbalance and Vertigo: The Aging Human Vestibular Periphery

Dizziness, vertigo, and imbalance are likely the most common presenting complaints among patients 75 years and older in office practices. Although the cause of falls among the aging population is multifactorial, several studies have implicated senescence of the vestibular periphery. It is imperative that clinicians correctly diagnose and treat dizziness and vertigo in the geriatric population, as vestibular impairment is quite responsive to specifically designed rehabilitation. One of the most common causes of vertigo in older adults is benign positional vertigo. The aging otolithic membrane, alterations in calcium metabolism, and microvascular ischemia may all play a role. An age-related deterioration of vestibular function on quantitative testing has been documented, and the age of onset correlates with the age-related cellular loss in the vestibular periphery. Furthermore, longitudinal tests of decline in vestibular function correlate with decline in gait and balance on testing. It is likely that senescence of both the central and peripheral vestibular pathways plays a role in age-related decline in balance. Vestibular disorders in the older patient are associated with a diminished level of independent activities, an increased incidence of falls, and possibly also clinical depression. The author's laboratory is delineating the immunohistochemical expression of proteins in the basement membrane of the vestibular system in older adults as a potential cause of the age-related decline in sensory cell and neuronal number.

UP-3.142: Bone Mass Study in Patients with Upper Urinary Tract Calcium Urolithiasis in Ghaem Hospital from 23.9.2005 to 4.4.2006

Bone loss is one of the main complications seen in urolithiasis patients. One of the explanations for this finding could be the alterations in calcium metabolism, leading to excessive resorption of calcium. In this study we evaluate the bone mineral density (BMD) among patients with urolithiasis.

Association of proton pump inhibitor use with altered calcium metabolism and bone fractures

Association of proton pump inhibitor use with altered calcium metabolism and bone fractures

Altered calcium metabolism: the probable major biochemical lesion in many pathological and clinical states of lead toxicity

The study was designed to provide evidence for altered calcium metabolism in lead toxicity and its pathological and clinical implications, which are incompletely elucidated in humans. Eighty-six lead (Pb) workers and 51 age, sex, dietary and anthropometric indices matched controls participated in this study. Blood lead level (BLL), serum total and ionized calcium, inorganic phosphate, serum albumin, total alkaline phosphatase (ALP) and the Bone form (isoenzyme) of alkaline phosphatase (B- ALP) and indices of renal function were evaluated in both lead workers and controls. The result showed blood lead level was higher in Pb workers than in controls (P0.05) respectively. Nineteen percent (19%) of Pb workers demonstrated calcium level below the lower limit of reference range (0.05; P>0.05) respectively. Urinary protein related to creatinine was significantly higher in Pb workers than in controls (P0.05; P>0.05) respectively. These data are suggestive of altered calcium metabolism impairing cell membrane stabilization, the vasorelaxing effect of calcium and cell signaling. Altered calcium metabolism may be the major biochemical lesion underlying many pathological and clinical states of lead toxicity.Journal of Biomedical Investigation Vol. 5 (1) 2007: pp. 9-16

Bone Metabolism in Celiac Disease

To investigate the prevalence of both calcium metabolism alterations and bone defects in children with celiac disease (CD). We studied 54 untreated patients with CD (mean age, 7 years). We compared the serum concentration of calcium, magnesium, 25(OH)vitamin D3, alkaline phosphatase, and parathyroid hormone (PTH) of patients with CD with those of 60 healthy children. Children with CD with 2 laboratory alterations underwent DEXA examination, which was evaluated after 6 months of a gluten-free diet (GFD). The calcium and the 25(OH)vitamin D3 levels were lower in children with CD than in control subjects, and the PTH level was higher in children with CD than in control subjects (P < .001). Hyperparathyroidism was found in 29 children with CD. Twenty patients tested positive for 2 laboratory alterations, and 10 of them were osteopenic. After 6 months of GFD calcium, 25(OH)vit.D3 and PTH levels normalized, with the improvement of bone mineral density. Calcium metabolism defects are common in untreated children with CD, and they returned to normal after GFD. A detailed, time-consuming, and expensive study of bone metabolism is not necessary in children with CD shortly exposed to gluten who follow the GFD.

Vitamin D, PTH, and the Metabolic Syndrome in Severely Obese Subjects

The objective of this study was to evaluate the association between the metabolic syndrome (MS) and vitamin D [25(OH)D] or parathyroid hormone (PTH) levels in severely obese subjects. Cross-sectional study in 298 severely obese patients [body mass index (BMI) 46.7 +/- 5.3 kg/m2; women/men, 70.4/29.6%; age 42.9 +/- 10.6 years]. Logistic and stepwise regression models were fit to estimate the odds for the MS (revised ATPIII criteria) and each of its individual components across quartiles of 25(OH)D and PTH after adjusting for age (years), gender, BMI, %FM, and season of blood sample collection. Insufficient 25(OH)D and elevated PTH plasma levels were encountered, respectively, in 64.3 and 47.4% of the studied subjects. The prevalence of MS was 79.5%. In the unadjusted analysis, those in the highest quartile of 25(OH)D were less likely to present the MS [0.42 (95% CI 0.19-0.96)], hyperglycemia [0.47, (0.24-0.92)], high triglycerides [0.48 (0.25-0.95)], low HDL-cholesterol [1.51 (0.76-2.98)], and high blood pressure [0.35 (0.16-0.77)]. Nonetheless, these odds ratios lost significance after adjustment for age, gender, BMI, fat mass, and season. Backward stepwise regression analysis showed that only male gender [2.66 (1.16-6.10)] and age [1.07 (1.03-1.10)] were predictive variables for the MS. We did not find an association between the PTH quartiles and the MS or its individual components. Our data are consistent with previous reports on the high prevalence of alterations in calcium metabolism in severely obese subjects. However, our data do not support an independent contribution of 25(OH)D or PTH in the pathogenesis of the MS in severely obese subjects.

Effects of calcitonin and parathyroid hormone on the regulation of cabindin‐D9k in the uterus, placenta, and fetal membrane of rats related to blood calcium level during late gestation

Calbindin-D(9k) (CaBP-9k) gene is expressed in the uterus of pregnant rats, which is regulated by steroid hormones during estrous cycle or gestation. We hypothesized that there is a positive correlation between altered CaBP-9k expression and change in one or more of the hormones to provide a clue to the mechanism responsible for the altered calcium levels in the uterus, placenta, and fetal membrane during late gestation. Thus, in the present study, we investigated the effects of the hormones including estradiol (E2), calcitonin (CT), and parathyroid hormone (PTH) on the regulation of CaBP-9k in these tissues. There was an increase in the level of CaBP-9k in the uterus, placenta, and extra-embryonic membrane at late gestation, as blood calcium level increased. The protein level of CaBP-9k remained lower in the uterus at two-thirds of pregnancy, and then it rebounded abruptly during late pregnancy. During late gestation, E2 is postulated to be a dominant factor in the regulation of uterine CaBP-9k gene expression. Furthermore, we assumed that there is a positive correlation between altered expression of CaBP-9k and blood calcium level during pregnancy. The present study demonstrated the regulation of CaBP-9k mRNA in the uterus, placenta, and fetal membrane of rats, implying a role for CaBP-9k gene in the control of blood calcium in placenta and the calcium passing from maternal blood to fetal circulation. Taken together, these results suggest that major alterations in calcium metabolism caused by maternal thyroparathyroidectomy (TPTX), are sufficient to affect the changes in reproductive tissues during late pregnancy. In addition, an increase of blood calcium level is one of the most significant factors in the regulation of CaBP-9k at the transcriptional and/or translational levels in the reproductive tissues during late pregnancy.

Alterations in calcium metabolism in patients on long-term bisphosphonate therapy for metastatic breast cancer (MBC): A potential therapeutic target?

1044 Background: The effect of long-term potent BP use on calcium homeostasis in MBC pts is poorly understood. These effects and the need for calcium and Vitamin D supplementation may have significant implications for pt management in both the metastatic and adjuvant settings. Methods: We evaluated serum calcium (sCa), PTH, and 25(OH)D levels and their inter-relationships in 30 MBC pts after prolonged BP use for bone metastases (BM), compared with a control group (CG) of 1484 normal women without bone or mineral disease (JCEM 2003;88:185). The MBC pts were prescribed oral calcium (1g/d) and vitamin D (400IU/d) for 1 month prior to analysis. To determine whether MBC pts differed from CG with respect to the sCa-PTH correlation, logistic regression was performed with sCa, log-transformed PTH and an interaction term (Ca × lnPTH). Results: Mean age of the two groups did not differ [MBC group (58.5 ± 2.0 yr) vs. CG (55.2 ± 0.4 yr, p &gt;.05)]. VitD-deficiency (25vitD &lt; 40 nM) was equally prevalent in the two groups [MBC (23%) vs. CG (25%)]. sCa was significantly higher in MBC pts (2.473 ± 0.019 mM) compared to CG (2.377 ± 0.003, p &lt;0.001). However, PTH was not decreased in MBC pts (4.60 ± 0.36 pM), compared to CG (4.56 ± 0.06, t-test, p=0.91). Logistic regression was highly significant (p&lt;0.0001), as were coefficients for both explanatory variables (sCa, p &lt;0.0001 and lnPTH, p = 0.009) and their interaction (p=0.011). Conclusion: In pts with BM and prolonged BP use there appears to be a shift in the calcium set-point such that PTH release is activated by higher levels of sCa than in controls. We are currently studying whether prophylaxis for relative vit D deficiency in this population can not only correct this shift but also improve pt symptoms No significant financial relationships to disclose.

Preliminary study on the effect of parenteral naloxone, alone and in association with calcium gluconate, on bone healing in an ovine "drill hole" model system

BackgroundSeveral diseases affect bone healing and physiology. Many drugs that are commonly used in orthopaedics as "analgesics" or anti-inflammatory agents impair bone healing. Stressful conditions are associated with decreased serum osteocalcin concentration. High endorphin levels alter calcium metabolism, blocking the membrane channels by which calcium normally enters cells. The consequent decrease of intracellular calcium impairs the activities of calcium-related enzymes. Naloxone is a pure opioid antagonist. Morphine-induced osteocalcin inhibition was abolished when osteoblasts were incubated with naloxone. Naloxone restored the altered cellular and tissue physiology by removing β-endorphins from specific receptors. However, this is only possible if the circulating Ca concentration is adequate. The aim of the present study was to evaluate the efficacy of parenteral naloxone administration in inducing fast mineralization and callus remodelling in a group of sheep with a standardised bone lesion.MethodsTwenty ewes were randomly assigned to 4 treatment groups. Group A acted as control, group B received a solution of calcium gluconate, group C a solution of naloxone, and group D a solution of calcium gluconate and naloxone. A transverse hole was drilled in the left metacarpus, including both cortices, then parenteral treatment was administered intramuscularly, daily for four weeks. Healing was evaluated by weekly radiographic examination for eight weeks. For quantitative evaluation, the ratio of the radiographic bone density between the drill area and the adjacent cortical bone was calculated. After eight weeks the sheep were slaughtered and a sample of bone was collected for histopathologyResultsGroup D showed a higher radiographic ratio than the other groups. Sheep not treated with naloxone showed a persistently lower ratio in the lateral than the medial cortex (P < 0.01). Histopathology of bone samples showed more caverns and fewer osteoblasts in group D than in the other groups (P ≤ 0.001).ConclusionA low-dose parenteral regimen of naloxone enhances mineralization and remodelling of the callus in healing cortical defects in sheep, especially if associated with calcium gluconate.

The Bitter End

Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process. Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.