Hypophosphatemic Rickets: Effect of 1α, 25-Dihydroxyvitamin D3 on Growth and Mineral Metabolism

Growth retardation nearly invariably accompanies hypophosphatemic rickets. Studies were conducted in an adolescent male with this disorder as follows. Protocol I: age, 6 to 16 years; treatment per day, 5,000 to 80,000 units vitamin D2, 1,760 to 2,200 mg phosphorus, orally as buffered phosphate; growth velocity, 5 to 6 cm/year. Protocol II: age 16 to 17 years; treatment per day, 1α,25-dihydroxyvitaniin D3, 1 µg; 2,200 mg of phosphorus, orally as buffered phosphate; growth velocity, 14 cm/year. The height improved from less than third percentile for the decade during study protocol I to the 25th percentile during protocol II. Mineral balance studies showed a reduction of urinary and stool phosphorus during treatment protocol II, while the patient was receiving metabolic diet. The serum phosphorus improved from 2.2 to 4.3 mg/dl and radiologic healing of rickets was documented. No hypercalcemic episode was encountered. The data support the contention that lα,25-dihydroxyvitamin D3 is the treatment of choice for hypophosphatemic rickets.

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Questions on the Use of Vitamin D3

PEDIATRICS ◽

10.1542/peds.66.3.483 ◽

1980 ◽

Vol 66 (3) ◽

pp. 483-484

Author(s):

Sonia Balsan ◽

Robert Steendijk

Keyword(s):

Growth Velocity ◽

Point Of View ◽

Hypophosphatemic Rickets ◽

Growth Spurt ◽

Vitamin D2 ◽

Pubertal Growth Spurt ◽

Dihydroxyvitamin D3 ◽

Pubertal Growth ◽

Careful Scrutiny ◽

Late Maturer

From their observations in a boy with hypophosphatemic rickets Chan and Bartter1 conclude that administration of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is the treatment of choice for this disease. Since this point of view is not shared by everybody, it demands careful scrutiny. The conclusion rests on the increased growth velocity, the radiologic healing of the rachitic lesions, and the increase in serum phosphorus which occurred when treatment was changed from vitamin D2 to 1,25-(OH)2D3. From the growth curve of this boy it appears that the increase in growth velocity could represent the pubertal growth spurt in a late maturer.

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Syringe service program-based telemedicine linkage to opioid use disorder treatment: protocol for the STAMINA randomized control trial

BMC Public Health ◽

10.1186/s12889-021-10669-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dennis P. Watson ◽

James A. Swartz ◽

Lisa Robison-Taylor ◽

Mary Ellen Mackesy-Amiti ◽

Kim Erwin ◽

...

Keyword(s):

Study Protocol ◽

Randomized Control Trial ◽

Treatment Protocol ◽

Opioid Use Disorder ◽

Additional Treatment ◽

Initial Assessment ◽

Opioid Use ◽

Structured Interviews ◽

Randomized Control ◽

Opioid Users

Abstract Background A key strategy for mitigating the current opioid epidemic is expanded access to medications for treating opioid use disorder (MOUD). However, interventions developed to expand MOUD access have limited ability to engage opioid users at higher levels of overdose risk, such as those who inject opioids. This paper describes the study protocol for testing STAMINA (Syringe Service Telemedicine Access for Medication-assisted Intervention through NAvigation), an intervention that engages high-risk opioid users at community-based syringe service programs (SSP) and quickly links them to MOUD using a telemedicine platform. Methods This randomized control trial will be conducted at three SSP sites in Chicago. All participants will complete an initial assessment with a provider from a Federally Qualified Health Center who can prescribe or refer MOUD services as appropriate. The control arm will receive standard referral to treatment and the intervention arm will receive immediate telemedicine linkage to the provider and (depending on the type of MOUD prescribed) provided transportation to pick up their induction prescription (for buprenorphine or naltrexone) or attend their intake appointment (for methadone). We aim to recruit a total of 273 participants over two years to provide enough power to detect a difference in our primary outcome of MOUD treatment linkage. Secondary outcomes include treatment engagement, treatment retention, and non-MOUD opioid use. Data will be collected using structured interviews and saliva drug tests delivered at baseline, three months, and six months. Fixed and mixed effects generalized linear regression analyses and survival analysis will be conducted to compare the probabilities of a successful treatment linkage between the two arms, days retained in treatment, and post-baseline opioid and other drug use. Discussion If successful, STAMINA’s telemedicine approach will significantly reduce the amount of time between SSP clients’ initial indication of interest in the medication and treatment initiation. Facilitating this process will likely lead to stronger additional treatment- and recovery-oriented outcomes. This study is also timely given the need for more rigorous testing of telemedicine interventions in light of temporary regulatory changes that have occurred during the COVID-19 pandemic. Trial registration ClinicalTrials.gov (Clinical Trials ID: NCT04575324 and Protocol Number: 1138–0420). Registered 29 September 2020. The study protocol is also registered on the Open Science Framework (DOI 10.17605/OSF.IO/4853 M).

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Pathogenic role of Fgf23 in Dmp1-null mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90201.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. E254-E261 ◽

Cited By ~ 96

Author(s):

Shiguang Liu ◽

Jianping Zhou ◽

Wen Tang ◽

Rochelle Menard ◽

Jian Q. Feng ◽

...

Keyword(s):

Growth Retardation ◽

Matrix Protein ◽

Serum Levels ◽

Serum Phosphate ◽

Hypophosphatemic Rickets ◽

Null Mouse ◽

Matrix Mineralization ◽

Severe Growth ◽

Inactivating Mutations

Autosomal recessive hypophosphatemic rickets (ARHR), which is characterized by renal phosphate wasting, aberrant regulation of 1α-hydroxylase activity, and rickets/osteomalacia, is caused by inactivating mutations of dentin matrix protein 1 ( DMP1). ARHR resembles autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH), hereditary disorders respectively caused by cleavage-resistant mutations of the phosphaturic factor FGF23 and inactivating mutations of PHEX that lead to increased production of FGF23 by osteocytes in bone. Circulating levels of FGF23 are increased in ARHR and its Dmp1-null mouse homologue. To determine the causal role of FGF23 in ARHR, we transferred Fgf23 deficient/enhanced green fluorescent protein (eGFP) reporter mice onto Dmp1-null mice to create mice lacking both Fgf23 and Dmp1. Dmp1−/− mice displayed decreased serum phosphate concentrations, inappropriately normal 1,25(OH)2D levels, severe rickets, and a diffuse form of osteomalacia in association with elevated Fgf23 serum levels and expression in osteocytes. In contrast, Fgf23−/− mice had undetectable serum Fgf23 and elevated serum phosphate and 1,25(OH)2D levels along with severe growth retardation and focal form of osteomalacia. In combined Dmp1−/−/Fgf23−/−, circulating Fgf23 levels were also undetectable, and the serum levels of phosphate and 1,25(OH)2D levels were identical to Fgf23−/− mice. Rickets and diffuse osteomalacia in Dmp1-null mice were transformed to severe growth retardation and focal osteomalacia characteristic of Fgf23-null mice. These data suggest that the regulation of extracellular matrix mineralization by DMP1 is coupled to renal phosphate handling and vitamin D metabolism through a DMP1-dependent regulation of FGF23 production by osteocytes.

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Metabolism of vitamin D in patients with primary biliary cirrhosis and alcoholic liver disease

Clinical Science ◽

10.1042/cs0690561 ◽

1985 ◽

Vol 69 (5) ◽

pp. 561-570 ◽

Cited By ~ 42

Author(s):

E. Barbara Mawer ◽

H. J. Klass ◽

T. W. Warnes ◽

Jacqueline L. Berry

Keyword(s):

Vitamin D ◽

Liver Disease ◽

Primary Biliary Cirrhosis ◽

Alcoholic Liver Disease ◽

Vitamin D3 ◽

Control Group ◽

Biliary Cirrhosis ◽

Vitamin D2 ◽

Dihydroxyvitamin D3 ◽

Poor Renal Function

1. The metabolism of isotopically labelled vitamin D2 and D3 has been investigated in eight patients with primary biliary cirrhosis and in five controls. The concentration of labelled vitamin D2 was lower than that of vitamin D3 in serum of patients with primary biliary cirrhosis on days 1 and 2 after intravenous injection (P < 0.005 and P < 0.05, respectively) but no difference was seen in controls. 2. Similar amounts of labelled 25-hydroxyvitamin D2 and D3 were seen in serum of the control group; the same pattern was observed in the primary biliary cirrhosis group, and no significant differences were observed between the two groups. 3. In both control and primary biliary cirrhosis groups, the serum concentration of labelled 24,25-dihydroxyvitamin D2 exceeded that of 24,25-dihydroxyvitamin D3 (significant for controls on day 2, P < 0.02) but concentrations in the two groups were not different. 4. Concentrations of labelled 25,26-dihydroxyvitamin D3 were significantly higher than those of 25,26-dihydroxyvitamin D2 in the primary biliary cirrhosis group at all times and in the control group on days 2 and 3. Both 25,26-dihydroxyvitamin D2 and D3 were higher in the serum of patients with primary biliary cirrhosis than in controls (significant on day 1, P < 0.05). 5. Urinary excretion over days 0–3 of radioactivity from both vitamins D2 and D3 was significantly higher in the primary biliary cirrhosis group than in controls: 12.03 vs 1.80% for vitamin D2 and 8.98 vs 1.76% for vitamin D3(P < 0.005). Vitamin D2-derived urinary radioactivity in primary biliary cirrhosis correlated strongly with serum bilirubin (P = 0.005). 6. The metabolism of labelled vitamin D3 was studied in seven patients with alcoholic liver disease, three of whom showed low serum concentrations of labelled 25-hydroxyvitamin D3 suggesting impaired hepatic synthesis. The 25-hydroxylation response was quantified as the relative index of 25-hydroxylation and was significantly related to two other indices of liver function. It is concluded that impaired 25-hydroxylation of vitamin D may occur in alcoholic liver disease and results from hepatocellular dysfunction. 7. Less than the predicted amounts of 1,25-dihydroxyvitamin D3 were produced in four of the seven patients with alcoholic liver disease; this defect may be attributable in part to decreased precursor 25-hydroxyvitamin D and to poor renal function.

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INFECTIOUS STUNTING SYNDROME ASSOCIATED WITH DISTURBANCES OF MINERAL METABOLISM AND BONE DEVELOPMENT IN BROILER CHICKENS

Acta Veterinaria Hungarica ◽

10.1556/avet.47.1999.3.10 ◽

1999 ◽

Vol 47 (3) ◽

pp. 361-378 ◽

Cited By ~ 3

Author(s):

Glávits ◽

G. Sályi ◽

R. Glávits

Keyword(s):

Growth Retardation ◽

Broiler Chickens ◽

Neuronal Degeneration ◽

Bone Development ◽

Mineral Metabolism ◽

Digestive Enzyme ◽

Small Intestinal Mucosa ◽

Vacuolar Degeneration ◽

Leg Weakness ◽

Small Intestinal

On a broiler farm with a rearing capacity of about 200,000 chickens, a disease characterised by growth retardation, variability in chick size, 'leg weakness', diarrhoea and increased mortality at 3 weeks of age occurred repeatedly, in several successive broiler flocks. Gross and histopathological findings were dominated by widening of the hypertrophic and ossification layers of the physes of long bones as well as by thickening, unevenness and defective calcification of the cartilage trabeculae. In the parathyroid gland, vacuolar degeneration of the cytoplasm of glandular epithelial cells, connective tissue proliferation and, here and there, cyst formation were seen. Additional findings included severe cerebellar oedema and neuronal degeneration. The pancreatic, myocardial and intestinal changes typical of infectious stunting syndrome (ISS) occurred only in a mild form. Four-week-old chickens exhibiting 'leg weakness' had significantly lower blood inorganic phosphate concentration and tibial ash content as compared to healthy chickens. The disease was successfully transmitted by oral administration of small intestinal homogenate from affected chickens. In a second experiment, however, the disease could not be transmitted with intestinal homogenate sterilized by irradiation. Large doses of vitamin D3reduced the rate of growth retardation and defective calcification of bones. The digestive enzyme activities of the pancreas and small intestinal mucosa of 'infected' chickens were decreased as is typical of ISS.

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Hypercalcemia in Children with Disorders of Calcium and Phosphate Metabolism During Long-Term Treatment with 1,25-Dihydroxyvitamin-D3

PEDIATRICS ◽

10.1542/peds.72.2.225 ◽

1983 ◽

Vol 72 (2) ◽

pp. 225-233

Author(s):

James C. M. Chan ◽

Reuben B. Young ◽

Uri Alon ◽

Peter Mamunes

Keyword(s):

Renal Function ◽

Calcium Phosphate ◽

Renal Insufficiency ◽

Hypophosphatemic Rickets ◽

Phosphate Metabolism ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Renal Function Deterioration ◽

Calcium And Phosphate Metabolism ◽

1,25 Dihydroxy Vitamin D3

Forty-two children received 1,25-dihydroxy-vitamin-D3 for treatment of disorders in calcium and phosphate metabolism secondary to chronic renal insufficiency (n = 29), sex-linked dominant hypophosphatemic rickets (n = 9), hypoparathyroidism (n = 2), and pseudohypoparathyroidism (n = 2). Serum calcium, phosphate, and creatinine concentrations were measured monthly for a mean of 26 months and a total of 1,079.5 patient-months. Patients with renal osteodystrophy manifested hypercalcemia (>11 mg/dL) once in every 13 months of treatment on the average. Of three children with hypophosphatemic rickets who experienced hypercalcemia, two proved to have tertiary hyperparathyroidism. Among children with hypoparathyroidism and pseudohypoparathyroidism, three episodes of hypercalcemia were observed during 124.5 patient-months, an incidence of one hypercalcemic episode per 39 treatment months. Renal function, as represented by reciprocals of serum creatinine determined retrospectively for a mean of 22 months before and prospectively for a mean of 26 months after initiation of 1,25-dihydroxyvitamin-D3 treatment, underwent no significant changes except in seven of 29 children with chronic renal insufficiency, six of whose rate of renal function deterioration increased on the treatment and one whose rate decreased. With one exception, hypercalcemia was associated in all cases with accelerated renal function deterioration. Before and after initiation of treatment with 1,25-dihydroxyvitamin-D3 the mean calcium x phosphate solubility products were 42.9 and 47.2, respectively. Values less than 60 are accepted as normal. Hypercalcemia is an occasional concomitant of such treatment and a more rapid deterioration of renal function may occur in some of the patients treated with 1,25-dihydroxyvitamin-D3. Thus, careful monitoring of concentrations of serum calcium, phosphate, and creatinine must accompany 1,25-dihydroxy-vitamin-D3 therapy.

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SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

BMJ Open ◽

10.1136/bmjopen-2019-029808 ◽

2019 ◽

Vol 9 (8) ◽

pp. e029808 ◽

Cited By ~ 2

Author(s):

Leon de Wit ◽

Doortje Rademaker ◽

Daphne N Voormolen ◽

Bettina M C Akerboom ◽

Rosalie M Kiewiet-Kemper ◽

...

Keyword(s):

Cost Effectiveness ◽

Glycaemic Control ◽

Study Protocol ◽

Controlled Trial ◽

Treatment Protocol ◽

Large For Gestational Age ◽

Secondary Outcome ◽

Oral Glucose ◽

Open Label ◽

Randomised Controlled

IntroductionIn women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM.MethodsThe SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals.Trial registration numberNTR6134; Pre-results.

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