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1.  Vitamin D Deficiency Rickets Mimicking Pseudohypoparathyroidism 
Vitamin D deficiency rickets (VDDR) is a disorder biochemically characterized by elevated serum alkaline phosphatase (ALP) activity, normal or decreased serum calcium (Ca) and inorganic phosphate concentrations, secondary hyperparathyroidism and decreased serum 25−hydroxyvitamin D (25(OH)D) levels. In stage 1 VDDR, urinary amino acid and phosphate excretion are normal with minimal or no findings of rickets on radiographs. Pseudohypoparathyroidism (PHP) is an inherited disorder characterized by end−organ resistance to parathormone (PTH). VDDR occasionally resembles PHP type 2 in clinical presentation and biochemical features, creating difficulties in the differential diagnosis of these two entities. Here we report an infant diagnosed with VDDR. In addition to inadequate vitamin D intake, usage of antiepileptic drugs (AED) may have led to the worsening of the vitamin D deficiency. The patient presented with a history of febrile convulsions, for which he received phenobarbital treatment. The initial findings of hypocalcemia, hyperphosphatemia and normal tubular reabsorption of phosphate, mimicking PHP 2, responded well to vitamin D and oral Ca treatment with normalization of serum Ca, phosphorus (P), ALP and PTH levels
Conflict of interest:None declared.
doi:10.4274/jcrpe.v2i4.173
PMCID: PMC3005691  PMID: 21274319
Vitamin D deficiency rickets; Pseudohypoparathyroidism; antiepileptic drugs
2.  Serum Alkaline Phosphatase Levels in Healthy Children and Evaluation of Alkaline Phosphatasez-scores in Different Types of Rickets 
Objective: Serum alkaline phosphatase (ALP) levels show great variation with age and sex in children and adolescents. Additionally, different buffers used even in the same method cause variable results. This detail is not usually taken into account in the evaluation. We aimed to study pediatric age- and sex-specific reference ranges for ALP by colorimetric assay using p-nitrophenyl phosphate as substrate and diethanolamine as buffer and also to compare the ALP levels in patients with different types of rickets.
Methods: 1741 healthy children and adolescents (904 girls) were included in the study for normative data. 77 different ALP measurements from 38 nutritional rickets (NR), 7 vitamin D-dependent rickets (VDDR) and 8 hypophosphatemic rickets (HR) patients were included.
Results: Reference values for ALP were constructed. ALP levels demonstrated a tetraphasic course with two peaks at infancy and puberty. There was no difference in ALP levels between boys and girls until puberty. However, higher ALP levels were noted at 10-11 years in girls (p=0.02) and at 12-13, 14-15, 16-17 years in boys (p<0.001). ALP levels start to decline after age 12 and 14 in girls and boys, respectively. Serum ALP levels were highest in the VDDR group and lowest in the HR group (median z-score values in HR, VDDR and NR were 3.6, 10.4 and 6.5, respectively; p<0.001). Similarly, plasma parathormone(PTH) levels ranged from highest to lowest in the VDDR, NR and HR groups (median values: 525, 237 and 98 pg/mL, respectively; p<0.001).
Conclusions: This normative data will provide a basis for better evaluation of ALP levels determined by the described method. Furthermore, use of z-scores gives a more precise assessment of changes in ALP levels in rickets and other bone disorders.
Conflict of interest:None declared.
doi:10.4274/jcrpe.v3i1.02
PMCID: PMC3065317  PMID: 21448327
Alkaline phosphatase; children; reference values; rickets
3.  Circulating Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) is not Regulated by Parathyroid Hormone and Vitamin D in vivo: Evidence from Children with Rickets 
Objective: Insulin-like growth factor binding protein-4 (IGFBP-4), inhibits IGF actions under a variety of experimental conditions. Parathyroid hormone (PTH), 1.25-hydroxy(OH)vitamin D, IGF-I, IGF-II and transforming growth factor (TGF)-b are the major regulators of IGFBP-4 production in vitro. However, little is known about the in vivo regulation of circulating IGFBP-4 in humans.
Methods: We measured serum concentrations of calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), PTH, vitamin D, IGF-I, IGFBP-3, and IGFBP-4 in infants (n=22) with nutritional rickets before and after treatment of rickets with vitamin D (300 000 U single dose po).
Results: The mean±SD age of the patients was 1.3±1.6 years (range 0.2-3). Serum Ca and P increased, whereas ALP and PTH decreased after treatment (Ca from 6.6±1.4 to 9.5±1.6 mg/dL, P from 3.9±1.4 to 5.4±0.8 mg/dL, ALP from 2590±2630 to 1072±776 IU/mL and PTH from 407±248 to 27.4±20.8 ng/dL, respectively). Vitamin D levels were low (7.8±2.5 ng/mL) and increased after treatment (18.1±4.0 ng/mL, p<0.001). Serum IGF-I and IGFBP-3 levels both increased after treatment (IGF-I: 13.5±12.2 vs. 23.7±14.2 ng/mL, p<0.001 and IGFBP-3: 1108±544 vs. 1652±424 ng/mL, p<0.001). However, serum IGFBP-4 levels did not change significantly after treatment (18.8±8.0 vs. 21.5±4.8 ng/mL). No correlation between PTH and IGF-I, IGFBP-3 or IGFBP-4 was detected. Significant correlations were observed between PTH and ALP (r=0.53, p<0.05), and between IGF-I and IGFBP-3 (r=0.46, p<0.05).
Conclusion: The results demonstrate that contrary to in vivo studies, circulating IGFBP-4 levels are not influenced by secondary hyperparathyroidism in vitamin D deficiency rickets since IGFBP-4 levels did not change after normalization of PTH with vitamin D treatment.
Conflict of interest:None declared.
doi:10.4274/jcrpe.v2i1.17
PMCID: PMC3005664  PMID: 21274331
Vitamin D; rickets; IGF-I; IGFBP-3; IGFBP-4; PTH; Bone
4.  Familial vitamin D resistant rickets: End-organ resistance to 1,25-dihydroxyvitamin D 
Rickets is softening of bones due to defective mineralization of cartilage in the epiphyseal growth plate, leading to widening of ends of long bones, growth retardation, and skeletal deformities in children. The predominant cause is deficiency or impaired metabolism of vitamin D. The observation that some forms of rickets could not be cured by regular doses of vitamin D, led to the discovery of rare inherited abnormalities of vitamin D metabolism or vitamin D receptor. Vitamin D dependent rickets (VDDR) is of two types: Type I is due to defective renal tubular 25-hydroxyvitamin D 1-α hydroxylase and type II is due to end-organ resistance to active metabolite of vitamin D. Typical signs are observed from the first month of life. The patient with rickets described below had markedly increased serum alkaline phosphatase and 1,25-dihydroxyvitamin D. We attribute these abnormalities to impaired end-organ responsiveness to 1,25-dihydroxyvitamin D.
doi:10.4103/2230-8210.119579
PMCID: PMC3830312  PMID: 24251166
End-organ resistance; rickets; vitamin D; vitamin D dependent rickets; 1,25-dihydroxyvitamin D
5.  Serum 25-hydroxy-vitamin D levels in malnourished children with rickets. 
Archives of Disease in Childhood  1980;55(4):285-287.
Serum levels of calcium, phosphorus, alkaline phosphatase, and 25 hydroxy-vitamin D (25-OH-D3) were measured in normal and malnourished children with and without rickets. Children with rickets had clinical, biochemical, and x-ray evidence of the disease; most of them were malnourished. 25-OH-D3 levels were lower than in normal children. After treatment with vitamin D their condition improved. 25-OH-D3 levels were also found to be reduced in malnourished children without rickets. These studies show that rickets is common in malnourished children. Inadequate exposure to sunlight appears to be the factor mainly responsible for the high incidence of the disease. In addition, malnutrition perhaps contributes to the development of rickets.
PMCID: PMC1626835  PMID: 6774669
6.  Renal rickets-practical approach 
Rickets/osteomalacia is an important problem in a tropical country. Many cases are due to poor vitamin D intake or calcium deficient diets and can be corrected by administration of calcium and vitamin D. However, some cases are refractory to vitamin D therapy and are related to renal defects. These include rickets of renal tubular acidosis (RTA), hypophosphatemic rickets, and vitamin D dependent rickets (VDDR). The latter is due to impaired action of 1α-hydroxylase in renal tubule. These varieties need proper diagnosis and specific treatment.
doi:10.4103/2230-8210.119503
PMCID: PMC3830358  PMID: 24251212
Hypophosphatemic rickets; osteomalacia; renal rickets; rickets; renal tubular acidosis; vitamin D rickets
7.  Primary Hyperparathyroidism Masquerading as Rickets: Diagnostic Challenge and Treatment Outcomes 
Primary hyperparathyroidism (PHPT) is extremely uncommon among children and is more likely to be associated with genetic syndromes, multiglandular involvement, and more severe symptoms. Rickets can very rarely be the presenting feature of PHPT in children. Rickets was diagnosed in a 12-year-old girl presenting with short stature, genu valgum, eversion deformity at the ankle joints, and flat feet. Radiograms showed generalized osteopenia, widening of the distal ends of the long bones along with splaying, cupping and fraying. Biochemical evaluation revealed low serum calcium (7.8 mg/dL), low phosphorus (1.4 mg/dL), vitamin-D deficiency [25-hydroxy-vitamin-D (25(OH)D): 8.7 ng/mL], and elevated intact parathyroid hormone (PTH, 811 pg/mL). Re-evaluation due to lack of clinical improvement following vitamin-D and calcium supplementation revealed hypercalcemia 11.9 mg/dL, normal 25(OH)D 41 ng/mL, persistence of elevated PTH 632 pg/mL. A 99mTc-sestamibi scan showed increased uptake at the lower pole of the right lobe of the thyroid. A right inferior parathyroidectomy was performed. Histopathology revealed chief cell type parathyroid adenoma. Last evaluated 4 months after surgery, the bone pains and proximal weakness had resolved, with significant improvement in the patient’s quality of life. Rickets in the setting of PHPT often masks the classical phenotype of PHPT. In a child with rickets, lack of improvement following vitamin-D supplementation, hypercalcemia at presentation or following vitamin-D supplementation are warning signs which necessitate further evaluation to rule out PHPT.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.1060
PMCID: PMC3890227  PMID: 24379038
primary hyperparathyroidism; rickets; Parathyroid adenoma
8.  Relationships between radiological and biochemical evidence of rickets in Asian schoolchildren. 
Postgraduate Medical Journal  1985;61(714):307-312.
One hundred Asian schoolchildren provided evidence of the relationships between radiological and biochemical evidence of rickets in a vitamin D-deficient population. In a retrospective study of the X-rays of 56 children the variables serum alkaline phosphatase, inorganic phosphorus and age provided a discriminant function which correctly classified 10 of 11 children with radiological evidence of rickets and 44 of 45 children with negative or marginally abnormal X-rays. When the discriminant function was applied to a prospective study of 44 children, three children with radiological evidence of rickets were correctly classified together with 38 of the remaining 41 children with negative or marginally abnormal X-rays. Serum alkaline phosphatase was the most important variable in the discriminant analysis, followed by serum inorganic phosphorus and age. Low levels of serum 25-hydroxy vitamin D (25-OHD) are of little value in predicting the severity of radiological evidence of rachitic bone disease in a vitamin D-deficient population.
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PMCID: PMC2418223  PMID: 4022859
9.  A novel CYP27B1 mutation causes a feline vitamin D-dependent rickets type IA 
A 12-week-old domestic cat presented at a local veterinary clinic with hypocalcemia and skeletal abnormalities suggestive of rickets. Osteomalacia (rickets) is a disease caused by impaired bone mineralization leading to an increased prevalence of fractures and deformity. Described in a variety of species, rickets is most commonly caused by vitamin D or calcium deficiencies owing to both environmental and or genetic abnormalities. Vitamin D-dependent rickets type 1A (VDDR-1A) is a result of the enzymatic pathway defect caused by mutations in the 25-hydroxyvitamin D3-1-alpha-hydroxylase gene [cytochrome P27 B1 (CYP27B1)]. Calcitriol, the active form of vitamin D3, regulates calcium homeostasis, which requires sufficient dietary calcium availability and correct hormonal function for proper bone growth and maintenance. Patient calcitriol concentrations were low while calcidiol levels were normal suggestive of VDDR-1A. The entire DNA coding sequencing of CYP27B1 was evaluated. The affected cat was wild type for previously identified VDDR-1A causative mutations. However, six novel mutations were identified, one of which was a nonsense mutation at G637T in exon 4. The exon 4 G637T nonsense mutation results in a premature protein truncation, changing a glutamic acid to a stop codon, E213X, likely causing the clinical presentation of rickets. The previously documented genetic mutation resulting in feline VDDR-1A rickets, as well as the case presented in this research, result from novel exon 4 CYP27B1 mutations, thus exon 4 should be the initial focus of future sequencing efforts.
doi:10.1177/1098612X12446637
PMCID: PMC3541000  PMID: 22553308
10.  Oral Calcium-loading Test in Rickets and in Neonatal Tetany: Effect of Vitamin D 
British Medical Journal  1969;3(5663):150-152.
In an oral calcium-loading test performed on 10 infants with vitamin-D deficiency rickets and low fasting calcium levels, a comparison of results before and after therapy showed that vitamin D raised the serum calcium level at each stage of the test and altered the response so that a more rapid and substantial rise and fall in serum calcium occurred.
The effects of vitamin D therapy on newborn infants with hypocalcaemic hyperphosphataemic tetany in another study suggests that these infants should be treated in this way to make them more responsive to oral calcium therapy.
PMCID: PMC1983908  PMID: 5792914
11.  Serum Alkaline Phosphatase and Rickets in Urban Schoolchildren 
British Medical Journal  1973;1(5849):324-327.
Among 569 schoolchildren (386 boys and 183 girls) aged 14-17 years, 233 had serum alkaline phosphatase values of 30 K.A. units or greater. There was no significant difference in the results in Asian, white, or West Indian children. The mean values were significantly greater in boys than girls and both showed a fall in mean values with increasing age. Radiological rickets occurred in at least 4% of the survey, and was more common in Asians. Low calcium and high hydroxyproline excretion in most of those investigated and the response to vitamin D therapy suggests that most children with alkaline phosphatase levels above 30 K.A. units have rickets.
Since the decline of the widespread supplementation of the diet with vitamin D, the demands of the physiological growth spurt for extra vitamin D in adolescents already on a borderline intake may be responsible for the great increase in “biochemical” rickets. Once the growth spurt is over the condition subsides but the results of impaired growth or permanent pelvic deformity will not necessarily be eradicated.
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PMCID: PMC1588178  PMID: 4685622
12.  Dental Problems in Hypophosphatemic Rickets, a Cross Sectional Study 
Iranian Journal of Pediatrics  2012;22(4):531-534.
Objective
Hypophosphatemic rickets is an uncommon metabolic bone disorder which affects all ages and both sexes. It is characterized by low concentration of serum phosphate levels, impairment of mineralization of bone matrix and teeth with variable etiology. Dental problems in this disorder have not been described well in previous studies.
Methods
All hypophosphatemic rickets patients who came to a referral clinic during 2008-2010 enrolled in this study. All patients had low phosphorous and high ALP, normal PTH and 25-hydroxy-vitamin D and normal or low level of serum calcium. After diagnosis all patients were examined by a dentist for enamel hypoplasia, taurodontism, dental abscess, gingivitis, dental caries, and dentition delay.
Findings
Nineteen patients were enrolled in this study. The average age of the patients was 10 (±4.23) years (range 3-17). Seventy-nine percent of patients had regular follow-up after diagnosis of background disease. Dental caries and delay in the dentition were most prevalent (each one 47.7%) followed by enamel hypoplasia in 42.1% of the patients. Other problems were taurodontism in 15.8% patients, dental abscess and gingivitis in 10.9%.
Conclusion
Hypophosphatemic rickets is a disease with different clinical features; one of them is dental problem, dental caries is the most common problem.
PMCID: PMC3533156  PMID: 23430969
Dental caries; Hypophosphatemia; Rickets; Enamel hypoplasia
13.  Resurrection of vitamin D deficiency and rickets 
The Journal of Clinical Investigation  2006;116(8):2062-2072.
The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sun exposure and the fortification of milk with vitamin D resulted in almost complete eradication of the disease. Vitamin D (where D represents D2 or D3) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorus, and bone metabolism. Vitamin D deficiency has again become an epidemic in children, and rickets has become a global health issue. In addition to vitamin D deficiency, calcium deficiency and acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolism cause rickets. This review summarizes the role of vitamin D in the prevention of rickets and its importance in the overall health and welfare of infants and children.
doi:10.1172/JCI29449
PMCID: PMC1523417  PMID: 16886050
14.  Comparison of Metabolism of Vitamins D2 and D3 in Children With Nutritional Rickets 
Journal of Bone and Mineral Research  2010;25(9):1988-1995.
Children with calcium-deficiency rickets may have increased vitamin D requirements and respond differently to vitamin D2 and vitamin D3. Our objective was to compare the metabolism of vitamins D2 and D3 in rachitic and control children. We administered an oral single dose of vitamin D2 or D3 of 1.25 mg to 49 Nigerian children—28 with active rickets and 21 healthy controls. The primary outcome measure was the incremental change in vitamin D metabolites. Baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations ranged from 7 to 24 and 15 to 34 ng/mL in rachitic and control children, respectively (p < .001), whereas baseline 1,25-dihydroxyvitamin D [1,25(OH)2D] values (mean ± SD) were 224 ± 72 and 121 ± 34 pg/mL, respectively (p < .001), and baseline 24,25-dihydroxyvitamin D [24,25(OH)2D] values were 1.13 ± 0.59 and 4.03 ± 1.33 ng/mL, respectively (p < .001). The peak increment in 25(OH)D was on day 3 and was similar with vitamins D2 and D3 in children with rickets (29 ± 17 and 25 ± 11 ng/mL, respectively) and in control children (33 ± 13 and 31 ± 16 ng/mL, respectively). 1,25(OH)2D rose significantly (p < .001) and similarly (p = .18) on day 3 by 166 ± 80 and 209 ± 83 pg/mL after vitamin D2 and D3 administration, respectively, in children with rickets. By contrast, control children had no significant increase in 1,25(OH)2D (19 ± 28 and 16 ± 38 pg/mL after vitamin D2 and D3 administration, respectively). We conclude that in the short term, vitamins D2 and D3 similarly increase serum 25(OH)D concentrations in rachitic and healthy children. A marked increase in 1,25(OH)2D in response to vitamin D distinguishes children with putative dietary calcium-deficiency rickets from healthy children, consistent with increased vitamin D requirements in children with calcium-deficiency rickets. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.99
PMCID: PMC3153403  PMID: 20499377
metabolic bone; vitamin D; calcium; pediatric; nutrition
15.  Rickets, Growth, and Alkaline Phosphatase in Urban Adolescents 
British Medical Journal  1974;2(5914):293-297.
Calciferol therapy for 12 months in white, Asian, and West Indian schoolchildren resulted in a highly significant increase in height and weight when compared with schoolchildren not so treated. The rate of fall of serum alkaline phosphatase was similar in both the treated and untreated schoolchildren and in other children treated in hospital for rickets. Dietary studies on 9% of the total survey by weighed inventory methods showed a low average intake of vitamin D, while random estimates of 25-hydroxycalciferol levels on 6% of the children were less than 3·8 ng/ml in 40% of those studied (principally Asian). It was concluded that there was a significant problem of vitamin D deficiency among Asian and West Indian teenagers and that white children were also affected to a less degree.
PMCID: PMC1610982  PMID: 4545274
16.  Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. 
Journal of Clinical Investigation  1986;77(5):1661-1667.
We report the beneficial effects of calcium infusions in a child with hereditary resistance to 1,25(OH)2D and alopecia. This patient after transient responsiveness to vitamin D derivatives became unresponsive to all therapy despite serum 1,25(OH)2D concentrations maintained at levels approximately 100-fold normal. A 7-mo trial with calcium infusions led to correction of biochemical abnormalities and healing of rickets. Bone biopsies (n = 3) showed a normal mineralization and the disappearance of the osteomalacia. Cultures of bone-derived cells demonstrated a lack of activation of 25-hydroxyvitamin D 24-hydroxylase and osteocalcin synthesis by 1,25(OH)2D3 (10(-9) and 10(-6) M). These results demonstrate that even in the absence of a normal 1,25(OH)2D3 receptor-effector system in bone cells, normal mineralization can be achieved in humans if adequate serum calcium and phosphorus concentrations are maintained; and calcium infusions may be an efficient alternative for the management of patients with this condition who are unresponsive to large doses of vitamin D derivatives.
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PMCID: PMC424571  PMID: 3009551
17.  Vitamin D Deficiency in Children and Adolescents with Type 1 Diabetes 
Objective: To investigate the frequency and effects of vitamin D deficiency in children with type 1 diabetes (T1D) in a region which is known to have a high rate of vitamin D deficiency among adolescents.
Methods: In this prospective cross-sectional study, 120 children and adolescents with T1D (55 girls and 65 boys) aged 3-20 years were evaluated. Serum 25-hydroxyvitamin D [25(OH)D], parathormone (PTH), and alkaline phosphatase (ALP) levels were measured. Hemoglobin A1c levels and daily insulin requirement were also evaluated. Classification of vitamin D status was made according to the American Academy of Pediatrics (AAP)/LWEPS’s recommendations. The patients were divided into 2 groups according to their vitamin D status and also according to the season of the year in which 25(OH)D sampling was done.
Results: Serum 25(OH)D levels revealed vitamin D deficiency or insufficiency in 38% of the patients. Higher PTH levels were found in the patient group whose mean 25(OH)D level was <20 ng/mL as compared to the group whose mean 25(OH)D level was >20 ng/mL (p<0.05). Only 11% of patients had secondary hyperparathyroidism. The 25(OH)D levels of patients whose serum samples were taken in summer and spring months were significantly different (p<0.05). There were no significant correlationsbetween 25(OH)D level and daily insulin dose.
Conclusion: Although we could not show a significant association between vitamin D deficiency and metabolic parameters, the frequency of vitamin D deficiency in T1D children is substantial. Vitamin D status should be assessed also in patients who do not have signs of rickets.
Conflict of interest:None declared.
doi:10.4274/jcrpe.430
PMCID: PMC3245490  PMID: 22155459
Vitamin D; type 1 diabetes; children and adolescents
18.  Nutritional Rickets among Children in a Sun Rich Country 
Objective. This study describes the magnitude and characteristics of nutritional rickets and associated risk factors among children in Qatar. Subjects. A consecutive sample of 730 healthy subjects who visited the primay health care clinics were approached and 540 (73.9%) subjects gave consent. Mehods. Nutritional rickets diagnosis was based on clinical radiologic and biochemical parameters and normalization of alkaline phosphatase level after 6 weeks course of daily vitamin D therapy. Results. The study revealed that 23.9% of the studied children had nutritional rickets. The mean ± SD age of those with rickets (3.76 years ± 1.51) was slightly higher than those without rickets (3.57 years ± 1.45). Family history of vitamin D deficiency (44.2%; P = .001) and diabetes mellitus (53.5%; P = .002) were significantly higher in rachitic children than in nonrachitic children. The children with rickets spent a significantly shorter average duration (26.86 minutes ± 19.94) under the sun than those without rickets (30.59 minutes ± 15.72; P < .001). A significantly larger proportion of rachitic children was afflicted with vitamin D deficiency (75.2% versus 62.2%; P < .001), secondary hypothyroidism (100% versus 7.5%; P = .009) and muscular weakness (56.6% versus 26.3%; P < .001). Conclusion. The most important risk factors were low vitamin D and calcium intakes, lack of exposure to sunlight, prolonged breast feeding without supplementation of vitamin D.
doi:10.1155/2010/410502
PMCID: PMC2965426  PMID: 21048925
19.  Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. 
Journal of Clinical Investigation  1985;75(6):1858-1868.
Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.
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PMCID: PMC425542  PMID: 3839245
20.  Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy. 
Archives of Disease in Childhood  1981;56(6):446-449.
An epidemiological study on vitamin D-dependent rickets was carried out in severely handicapped institutionalised children on long-term anticonvulsant therapy. Nine (10%) of 94 patients had overt rickets on the basis of roentgenological bone changes and biochemical indices, but 46 patients in hospital without medication, and 50 epileptic patients attending an outpatient clinic and taking anticonvulsants had no sign of rickets. Causative factors for the development of rickets were evaluated. Administration of anticonvulsive drugs depressed the serum 25-hydroxyvitamin D (25-OHD) level, but this was not the major factor in the development of rickets. Vitamin D intake seemed to be about average in these patients and its supplementation increased their serum 25-OHD level. This serum 25-OHD level was not maintained by supplemental vitamin D, unless the children were exposed to sunlight. These results indicate that although several factors--such as anticonvulsants, low vitamin D intake, and inactivity--are concerned in the development of rickets, the main cause is lack of sun in institutionalised handicapped children.
PMCID: PMC1627455  PMID: 6973324
21.  Low serum levels of 1.25-dihydroxyvitamin D and histomorphometric evidence of osteomalacia after jejunoileal bypass for obesity. 
Gut  1980;21(7):624-631.
Twenty-seven unselected patients were investigated three to eight years after jejunoileal bypass for morbid obesity. The serum levels of calcium, magnesium, and phosphorus, and the renal excretions of calcium and magnesium were reduced. The serum alkaline phosphatase levels were increased. The serum levels of the two vitamin D metabolites 25-hydroxyvitamin D (25-OHD) and 1.25-dihydroxyvitamin D (1.25-(OHD)2D) were reduced and inversely related to the increased serum levels of immunoreactive parathyroid hormones (iPTH). Serum 1.25-(OH)2D correlated positively and serum iPTH inversely with serum concentrations and renal excretion rates of calcium. Iliac crest bone biopsies after in vivo tetracycline double-labelling showed a reduced bone turnover with an increased amount of osteoid due to an increase in both surface extent and mean width of osteoid seams. The increased volume of osteoid was caused by a decreased osteoblastic function with a longer life-span of bone-forming sites and a prolongation of the mineralisation lag time. The amount of trabecular bone was normal. The results indicate an impaired vitamin D metabolism with osteomalacia and secondary hyperparathyroidism.
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PMCID: PMC1419901  PMID: 7429327
22.  Therapeutic Use of Oral Sodium Phosphate (Phosribbon® Combination Granules) in Hereditary Hypophosphatemic Rickets 
Oral sodium phosphate formulations indicated for hypophosphatemia are commercially available worldwide. In Japan, however, many medical institutes have used hospital dispensary or foreign over-the-counter formulations because no such medication with an indication covered by the health insurance system is domestically available. To address this problem, we initiated the development of Phosribbon®. The present study evaluated the efficacy and safety of Phosribbon® in 16 patients with hereditary hypophosphatemic rickets. The optimal dosage and an administration pattern were also investigated. Administration of the agent resulted in an increase in the level of serum phosphorus in all patients, which implied that the employed dosage was appropriate. The dosage and administration pattern were adjusted based on comprehensive considerations, including changes in clinical laboratory values such as serum phosphorus, alkaline phosphatase and intact PTH, the dosage of a concomitantly administered activated vitamin D formulation and characteristics of individual patients. Adverse drug reactions were observed in 2 patients, neither of which were serious or necessitated therapy dose reduction or discontinuation. We conclude that Phosribbon® is a safe and effective treatment for patients with hypophosphatemic rickets and that dose adjustment in this therapy can be guided by the results of regular clinical examination and renal ultrasonography. (ClinicalTrials.gov Identifier: NCT01237288)
doi:10.1292/cpe.23.9
PMCID: PMC3924172  PMID: 24532956
oral sodium phosphate; hypophosphatemic rickets/osteomalacia; hypophosphatemia; FGF23
23.  Radiological and biochemical resolution of nutritional rickets with calcium 
Archives of Disease in Childhood  2003;88(9):812-817.
Aims: To determine the response to oral calcium in Nigerian children with rickets.
Methods: In a teaching hospital in Western Nigeria, 26 children (13 boys, 13 girls, aged 2–5 years) with confirmed rickets received calcium lactate (2.7 g/day).
Results: Within one month of treatment leg pain was relieved and the children were more active. The mean x ray score improved from 3.3 at baseline to 1.7 at three months and 0.9 at six months (arbitrary scoring system, 0–6). Twelve cases were healed radiologically after six months, 11 others improved considerably, two showed no significant improvement, and a non-compliant patient was worse. There was progressive reversal of biochemical features. Median plasma alkaline phosphatase fell from 519 (range 178–1078) to 283 (209–443) IU/l (p = 0.04) in four months, while mean 1,25-dihydroxyvitamin D fell from 473 (251–1057) to 281 (155–481) pmol/l (p = 0.04), and mean plasma calcium increased from 2.26 (1.63–2.54) to 2.37 (2.06–2.54) mmol/l (p = 0.13). Parathyroid hormone fell from 5.3 (0.4–21.5) to 1.7 (0.45–7.4) pmol/l. Type I collagen carboxy terminal cross linked telopeptide was very high at baseline (20 (7.2–103) to 14 (11–24) µg/l) (p = 0.03) and fell promptly to normal.
Conclusion: Calcium supplementation alone effected healing of rickets in most of these Nigerian children and may provide sufficient treatment in this environment.
doi:10.1136/adc.88.9.812
PMCID: PMC1719645  PMID: 12937108
24.  Diagnosis of subclinical rickets. 
Archives of Disease in Childhood  1980;55(2):155-157.
44 randomly selected infants under age one year with suspected lower respiratory infections were investigated for the presence of subclinical rickets. Seven infants had metaphyseal changes at the wrist compatible with a diagnosis of rickets and all of these infants had 25-hydroxy-vitamin D (25-OHD) concentrations less than 12 ng/ml. Serum calcium and phosphorus concentrations were normal in all 44 children. Alkaline phosphatase concentrations did not correlate with the presence of metaphyseal changes. The clinical presence of craniotabes or splaying and loss of definition of the anterior ends of the ribs on x-rays did not correlate with metaphyseal changes at the wrist or with 25-OHD concentrations. An x-ray of the wrist is essential to confirm the presence of subclinical rickets and the at-risk infant can be detected by measuring serum 25-OHD concentrations.
PMCID: PMC1626677  PMID: 7377839
25.  Vitamin D deficiency rickets presenting as pseudotumor cerebri 
Pseudotumor cerebri is a condition of elevated intracranial pressure in the absence of clinical, laboratory or radiological evidence of an intracranial space-occupying lesion. Various associations with pseudotumor cerebri have been made in literature. We report the case of a five-month-old female infant with vitamin D deficiency rickets, who presented with pseudotumor cerebri. Her cerebrospinal fluid examination was normal, with a high opening pressure of 330 mmH2O. Her computed tomography scan was normal. After lumbar puncture the anterior fontanelle came at level. Her investigations revealed vitamin D deficiency. She was started on acetazolamide, calcitriol sachets, and calcium supplements. She became asymptomatic in three days and was discharged. Through this case we wish to highlight this unusual presentation of vitamin D deficiency rickets appearing as pseudotumor cerebri.
doi:10.4103/0976-3147.120210
PMCID: PMC3858774  PMID: 24347962
Acetazolamide; increased intracranial pressure; papilledema; pseudotumor cerebri; vitamin D deficiency

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