Treatment of hypophosphataemic vitamin D-resistant rickets and adult presenting hypophosphataemic vitamin D-resistant osteomalacia

Summary The results of the treatment of 12 patients with hypophosphataemic vitamin D-resistant rickets, 4 similar patients who were first diagnosed in adulthood, and 2 adult patients with hypophosphataemic vitamin D-resistant osteomalacia are presented.Treatment with a high dosage of Vitamin D2 was begun between 1 1/2 and 7 years of age. The dose of Vitamin D2 required for the treatment of rickets varied widely depending on the severity of the process and the age of the patient. Four patients with leg deformities required osteotomy or other operations. In other patients deformities improved with medical treatment alone.Dwarfism and severe deformity of the legs were characteristic features in rickets first diagnosed in adulthood. Radiographic features were Looser's zones, a coarse trabecular pattern, increased bone density and ligamentous calcification. These patients presented several difficult orthopaedic problems.Two brothers with hypophosphataemic vitamin Dresistant osteomalacia presented with bone pains, muscle weakness, limitation of motion in the back and height loss. Treatment with oral phosphate supplements in addition to high doses of Vitamin D2 was dramatic, with complete disappearance of muscle weakness and bone pain.

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Résumé Présentation des résultats du traitement de 12 malades atteints de rachitisme vitamino-résistant hypophosphatémique, de 4 autres malades chez qui le diagnostic ne fut porté qu'à l'âge adulte, et de 2 malades atteints d'ostéomalacie vitamino-résistante hypophosphatémique de l'adolescent.Le traitement par de hautes doses de vitamine D₂ a été commencé entre 1 an et demi et 7 ans. La dose de vitamine D₂ nécessaire au traitement du rachitisme varie considérablement selon la sévérité de l'affection et l'âge des malades. Quatre malades présentant des déformations des jambes ont eu besoin d'une ostéotomie ou d'un autre traitement chirurgical. Chez les autres malades, les déformations furent améliorées par le seul traitement médical.Le nanisme et les déformations sévères des jambes sont caractéristiques du rachitisme vitamino-résistant découvert à l'âge adulte. Radiologiquement il est caractérisé par la présence de zones de Looser, d'une trabéculation lâche, d'une accentuation de la densité osseuse et de calcifications ligamentaires. Ces malades posaient de nombreux et difficiles problèmes orthopédiques.Deux frères atteints d'ostéomalacie vitamino-résistante présentaient des douleurs osseuses, une faiblesse musculaire, une limitation de la mobilité du rachis et une diminution de taille. Le traitement par phosphate associé à de hautes doses de vitamine D₂ fut spectaculaire, avec disparition complète de la faiblesse musculaire et des douleurs osseuses.

     

Comparison of two assays for fibroblast growth factor (FGF)-23

FGF-23 was recently shown to be involved in the development of several hypophosphatemic diseases, including X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia (TIO). FGF-23 is processed between Arg¹⁷⁹ and Ser¹⁸⁰, and only full-length FGF-23 was shown to cause hypophosphatemia. Two assays for FGF-23 have been reported. One assay detects only full-length FGF-23. In contrast, the C-terminal assay recognizes both full-length and processed C-terminal fragment of FGF-23. However, discrepant results concerning circulatory levels of FGF-23 in patients with TIO and XLH have been reported using these two assays. We simultaneously measured FGF-23 levels in 13 patients with adult-onset hypophosphatemic osteomalacia and 29 patients with XLH by these two assays. The full-length assay indicated that FGF-23 was above the upper limit of the reference range in all patients with osteomalacia and in 24 of 29 patients with XLH. However, the C-terminal assay in dicated that FGF-23 was within the reference range in 3 of 13 patients with osteomalacia and 16 of 29 patients with XLH. In addition, there was no correlation between FGF-23 levels measured by these assays in patients with XLH whose FGF-23 was within the reference range by C-terminal assay. These results indicate that FGF-23 within the reference range by C-terminal assay does not rule out an increase in full-length FGF-23. In addition, because FGF-23 was high in most of these hypophosphatemic patients, these results support the notion that FGF-23 plays a major role in the development of hypophosphatemia in patients with TIO and XLH.     

Distribution of the perilacunar hypomineralized areas in cortical bone from patients with familial hypophosphatemic (vitamin D-resistant) rickets

Summary The perilacunar areas of low mineral density in microradiographs from cortical bone of patients with hypophosphatemic (vitamin D-resistant) rickets are not evenly distributed throughout the bone tissue. Their frequency and distribution were determined in bone from 9 patients with this disease. It was found that the lesion was more frequent in haversian bone than in interstitial bone, and along the inner circumference of growing haversian systems as compared with the outer circumference. These findings indicate that the lesion is the result of retarded mineralization, and that mineralization slowly proceeds in these areas as the bone becomes older. A relatively high frequency of the lesion was also found in osteons with an elliptical cross section along the long axis of the ellipse. The cause of the abundance of the lesion at these sites is not clear, but it is possible to explain the uneven distribution in elliptical osteons by assuming an unequal rate of bone formation in these structures.     

Exacerbation of rickets and osteomalacia by maize: A study of bone histomorphometry and composition in young baboons

Summary Three groups of young baboons were fed for 16 months on one of three diets. The first group was given a well-tried semisynthetic formula, the second group the same diet save that vitamin D had been omitted, and the third group was given the vitamin D-free diet in which maize replaced the dextrin normally used. Although both groups fed the vitamin D-free diets developed rickets and osteomalacia, the group receiving maize did so far more rapidly and to a much greater degree of severity, as evidenced by clinical, radiological, biochemical, and histological signs. The mechanism by which maize acts remains unclear, but this report serves to emphasize the extremely detrimental effects that might be expected in populations who are deficient in vitamin D and who have predominantly cereal diets.     

Changes in bone mineral in experimentally induced rickets in the rat: Electron microprobe and chemical studies

Summary The elemental composition of trabecular bone was compared for: (a) rats made rachitic on a low phosphorus, vitamin D-deficient diet; (b) rats fed the same diet but supplemented with vitamin D; (c) normal rats fed a standard laboratory diet with normal phosphorus and vitamin D levels. Quantitative energy dispersive X-ray microanalysis was performed on mineralized bone matrix at four sites: (1) clusters of mineral crystals in osteoid; (2) bone matrix adjacent to osteoid containing mineralization clusters; (3) peri-lacunar bone matrix; and (4) deep bone matrix distant from osteocytes. Estimations were also made of serum calcium, phosphorus, and 25-hydroxy-vitamin D, and of calcium, phosphorus, and hydroxyproline in whole bone. At bone sites 2, 3, and 4, the mineral content was greater in the normal group than in the other two groups. At each site, the mineral content of the rachitic bone matrix was greater than that from the vitamin D-treated group. A normal pattern of increasing mineral content with distance into the bone from a recently mineralized border was found in the normal and vitamin D-treated groups but was notably absent in the rachitic bones. Microprobe measurements of Ca:P molar ratios in hydroxyapatite standards and in normal rat bone were approximately 1.7. In both rachitic and vitamin D-treated bones, the Ca:P molar ratio was significantly higher than that in normal bones and correlated with serum Ca:P ratios. It is suggested that the increased Ca:P ratios in the rachitic and vitamin D-treated bones may be explained by an increased carbonate deposition.     

Renal phosphate loss in hereditary and acquired disorders of bone mineralization

Three metabolic bone diseases display similar characteristics such as hypophosphatemia due to chronically elevated renal phosphate clearance, inappropriately low 1,25 (OH)₂ vitamin D serum levels, and variable bone disease (rickets and osteomalacia). X-linked dominant hypophosphatemic rickets (XLH), also called vitamin D-resistant rickets and autosomal dominant hypophosphatemic rickets (ADHR) represent two inherited diseases, whereas oncogenic hypophosphatemia (OHO), also known as tumor induced osteomalacia (TIO), is an acquired paraneoplastic syndrome that, in certain aspects, has much in common with XLH and ADHR. Although the primary causes for these disorders are distinct and well established, their similar features suggest a unifying pathophysiological basis.

This review summarizes what is known about the mechanisms that underlie these diseases and includes most up-to-date information about recently introduced factors that might be involved in the regulation of phosphate homeostasis and skeletal mineralization.     

Antacid and sucralfate-induced hypophosphatemic osteomalacia: A case report and review of the literature

Summary A 42-year-old woman presented to our institution with a 2-week history of bone pain in the lower extremities. Her history was remarkable for duodenal ulcer and long-term treatment with a magnesium-aluminum hydroxide antacid (Maalox) and sucralfate. Initial laboratory studies showed severe hypophosphatemia and elevated alkaline phosphatase and serum 1,25-dihydroxyvitamin D levels. Bone scan showed multiple areas of increased uptake consistent with osteomalacia and microfractures. The patient recovered completely following withdrawal of antacids and sucralfate and shortterm treatment with phosphate. Although hypophosphatemia induced by aluminum-containing antacids is rare, treatment of peptic ulcer disease with a combination of two aluminum-containing agents may increase the risk of clinically significant hypophosphatemia. Awareness of this condition is important, because early recognition can prevent morbidity and lead to safe and effective treatment.     

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors

Tumor‐induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D₃ metabolism and is caused by fibroblast growth factor 23 (FGF‐23)–producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF‐23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF‐23‐secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF‐23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF‐23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF‐23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47–0.99] and a specificity of 0.71 (95% CI 0.29–0.96). Selective venous sampling for FGF‐23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies. © 2011 American Society for Bone and Mineral Research.     

Resurgence of vitamin D: Old wine in new bottle

There are early references of it in ancient text and physicians have discussed its importance and features of its deficiency in the past. Vitamin D has again regained interest with recent dramatic rise in the incidence of deficiency in the developing as well as developing world. In this review article, we discuss the biochemical and role of vitamin D in the skeletal system. We also discuss the recommended dietary requirements and features of skeletal deficiency. Extra-skeletal roles of vitamin D deficiency have been a matter of debate lately and it has also been discussed in detail in this article. In conclusion, it would not be wrong to label vitamin D as one of the most important vitamin involved in the metabolism of the musculoskeletal system and any clinician, especially the orthopaedician, should be well versed with its overall mechanism and roles in the human body.     

Oncogenic osteomalacia: two case reports with surprisingly different outcomes

Oncogenic osteomalacia is a rare paraneoplastic syndrome of acquired hypophosphatemic osteomalacia, resulting from a deficit in renal tubular phosphate reabsorption, in which fibroblast growth factor 23 (FGF23) seems to be implicated. This condition is usually associated with a phosphaturic mesenchymal tumor of mixed connective tissue located in the bone or soft tissue. The clinical and the radiologic findings are the same as those seen in osteomalacia, and the biochemical features include renal phosphate loss, low serum phosphate and 1,25-(OH)₂ vitD₃ levels, increased alkaline phosphatase, and normal calcium, PTH, calcitonin, 25-OH-vitD₃ and 25,25-(OH)₂ vitD₃. We present two cases of oncogenic osteomalacia associated with phosphaturic mesenchymal tumors, which were histologically similar, but presented a completely different evolution. In the first patient, the tumor developed on the sole of the foot. Following removal of the mass, the symptoms resolved and biochemical and radiological parameters returned to normal. However, in the second patient, a liver tumor developed and resection did not resolve the disease. Multiple lesions appeared in several locations during follow-up. This disease usually remits with complete tumor resection. Nevertheless, if this is not possible, oral treatment with phosphate, calcium and calcitriol can improve the symptoms. If scintigraphy of the tumor shows octreotide receptors, patients may respond partially to therapy with somatostatin analogs, with stabilization of the lesion.     

A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene

X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets/osteomalacia (ARHR1 or ARHR2) are hereditary fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets showing similar clinical features. We here show a patient with hypophosphatemic rickets and widespread ossification of posterior longitudinal ligament (OPLL). The proband is a 62-year-old female. Her parents are first cousins and showed no signs of rickets or osteomalacia. She showed hypophosphatemic rickets with elevated FGF23 level and had been clinically considered to be suffering from XLH. However, direct sequencing of all coding exons and exon–intron junctions of phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX), FGF23 and dentin matrix protein 1 (DMP1) genes, responsible genes for XLH, ADHR and ARHR1, respectively, showed no mutation. A novel homozygous splice donor site mutation was found at the exon–intron junction of exon 21 of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene responsible for ARHR2 (IVS21 + 1_3(GTA > CACC)). Subsequent analysis of mRNA revealed that this mutation caused skipping of exon 21 which created a premature stop codon in exon 22. These results indicate that genetic analysis is mandatory for the correct diagnosis of hereditary FGF23-related hypophosphatemic rickets. Because Enpp1 knockout mouse is a model of OPLL, this case also suggests that OPLL is associated with ARHR2.     

Reduced absorption of45calcium from isolated duodenal segmentsin vitro in juvenile but not adult X-linked hypophosphatemic mice

Summary In juvenile X-linked hypophosphatemic (Hyp) mice, whole body calcium balances are significantly lower than in genetically normal mice. This is associated with low duodenal vitamin D-dependent calcium-binding protein and a failure of skeletal mineralization. To seek more specific evidence of an intestinal defect in these mice, absorption of⁴⁵Ca was measured in isolated duodenal segmentsin vivo in mice from 2–13 weeks of age. The duodenum was isolated by sutures and⁴⁵Ca was injected into the lumen in 150 mM NaCl and 2 mM CaCl₂ at pH=7.2. Absorption was measured by the amount of isotope remaining in the lumen and by the plasma isotope level. HemizygousHyp male and heterozygousHyp female mice absorbed significantly less⁴⁵Ca at 4 and 7 weeks of age than genetically normal mice whileHyp mice at 2, 10, and 13 weeks of age were not significantly affected. At 4 and 7 weeks of age, theHyp mice also had significantly reduced plasma radioactivity midway through the collection period as well as at the end of the period. To explore a possible mechanism for this malabsorption, 1,25(OH)₂-vitamin D receptors were measured in cytosol prepared from 4-week-old normal andHyp duodenum. There were non-significant differences between the normal andHyp mice in both binding affinity, K_d, and the number of receptors, n_max. In conclusion, juvenileHyp mice at 4 and 7 weeks of ages malabsorbed calcium from their duodenum.Hyp mice younger than this period were not affected nor were adultHyp mice. This delay in the development of calcium absorption was not caused by a delay in the appearance of intestinal receptors for 1,25(OH)₂D.     

Hemodialysis-Induced Hypophosphatemia in a Normophosphatemic Patient Dialyzed for Ethylene Glycol Poisoning: Treatment with Phosphorus-Enriched Hemodialysis

It is the goal of this section to publish material that provides information regarding specific issues, aspects of artificial organ application, approach, philosophy, suggestions, and/or thoughts for the future.
Hypophosphatemia developed in a normophosphatemic patient after 9 h of hemodialysis therapy (using a phosphate-free dialysate) administered for the treatment of ethylene glycol poisoning. The hypophosphatemia was promptly improved with additional hemodialysis treatment using a phosphorus-enriched dialysate.     

Thoracic spinal cord compression caused by hypopbosphataemic rickets: a case report and review of the world literature

Vitamin D resistant hypophosphataemic rickets is a rare cause of spinal cord compression. The compression is caused by a combination of thickening of the laminae and calcification of the ligamentum flavum. Modern imaging techniques including CT and MRI provide excellent detail of both the level and degree of compression. MRI is particularly useful for examining the rest of the spinal cord for areas of impending compression and for postoperative follow-up. With careful surgical decompression a full neurological recovery can be achieved.     

Familial hypophosphatemic rickets: Bone mass measurements in children following therapy with calcitriol and supplemental phosphate

Summary Familial hypophosphatemic rickets is characterized by defective skeletal mineralization resulting in abnormal growth and development. The pathologic and radiologic correlates of this syndrome have been given some investigation, but the effect of this mineralization defect on bone mineral density has not been adequately assessed. We measured axial and appendicular bone mineral in 17 children (mean age 5.59±4.87) with familial hypophosphatemia at baseline and at 6-month intervals after initiation of therapy with vitamin D₃ (calcitriol) and phosphate supplementation. Noninvasive quantitative techniques included single photon absorptiometry (SPA) of the radius, combined cortical thickness (CCT) of the second metacarpal, and quantitative computed tomography (QCT) of vertebral trabecular bone. Thoraco-lumbar and hand/wrist radiographs were qualitatively assessed for the prevalence and severity of osteosclerosis, rickets, and other parameters indicative of metabolic bone disease as well as skeletal age. Quantitative determinations of bone mineral by each technique were compared with normal values for age and sex, and individual standardized scores (z-scores) were calculated at each measurement interval. Standard scores were also calculated for bone age-adjusted mineral values. At baseline, spinal trabecular bone by QCT was not significantly different from normal values; however, measurements of peripheral cortical bone by either SPA or CCT were significantly lower than values for normal children of the same age and sex (P=0.05 andP=0.01, respectively). Following therapy with calcitriol and phosphate, peripheral bone mass was not shown to improve significantly when contiguous standard scores were compared even when values were adjusted for bone age. Comparison of noncontiguous standard scores between longer measurement intervals also failed to achieve significance. In spite of a general increase in bone mass over time, we found that peripheral bone mass expressed as a standard score remained significantly low. To the contrary, vertebral trabecular bone density generally remained in the normal range. However, concomitant and persistent vertebral osteosclerosis, with a prevalence of greater than 50% throughout the study, may mimic these “normal” values. Though the treatment regimen under investigation may be effective in preventing and ameliorating the osseous lesions associated with this syndrome, it appears to have limited short-term value in improving abnormal bone density development.     

Deformity correction for vitamin D-resistant hypophosphatemic rickets of adults

We performed correction for bowing deformity of the lower extremities due to vitamin D-resistant hypophosphatemic rickets of three adults, six segments. The operative method was gradual correction and lengthening using distraction osteogenesis by Ilizarov external fixator or Heidelberg external fixator. The orders of the corrections were simultaneous correction of the bilateral femur for one patient, simultaneous correction of the ipsilateral leg for one patient, and diagonal correction of the bilateral leg for one patient. The mean correction angle was 30.5°. The mean external fixation period was 146 days. Each orders of the corrections had its merits and demerits. All patients obtained a physiological alignment and good bone formation by taking Vitamin D and oral phosphate supplements even an adult patient. All the patients had articular pain, such as hip, knee, and ankle, however, these pains healed up. All the patients were satisfied with the outcomes at the time of the final follow-up interview in terms of their cosmetic improvement. Distraction osteogenesis for bowing deformity of the lower extremities due to vitamin D-resistant hypophosphatemic rickets was very effective method and could be applied to adult patients. However, the order of the corrections should be considered carefully depending on each patient.     

Metabolic and orthopedic management of X-linked vitamin D-resistant hypophosphatemic rickets

Purpose  Therapy of vitamin D-resistant hypophosphatemic rickets (VDXLR) consists of oral phosphate and vitamin D supplements. Bone deformities, pain, and small stature can occur even in children with good compliance, requiring surgical correction and bone lengthening. However, only few surgical reports are available. Methods  Twelve patients (three males) with VDXLR were followed at our institution. Median age at diagnosis was 3 9/12 years (range, birth to 11 10/12) with a follow-up period of 7 8/12 years (1 9/12–30) and age at last follow-up of 13 6/12 years (2–30). Eight patients underwent surgical correction, three of them in combination with bone lengthening. The corrections were performed at the end of growth in three patients. Clinical endpoints were height, leg axis, and pain. Results  Single bilateral surgical correction was performed in six patients; one patient each had three and five corrections. Bone lengthening was performed in three patients. At last follow-up, the height of seven operated patients was within normal range. In addition, leg axis was normalized in six patients with mild genua vara in two. Only one patient complained of intermittent pain. Bone healing was excellent; surgical complications were rare. There was no radiological evidence of degenerative arthropathy. Conclusions  Medical treatment remains the main pillar of therapy in children with VDXLR. In case of bone deformity, surgery can safely be performed, independent of age or bone maturation. All patients were satisfied with the results of axial corrective surgery and bone lengthening, and in the majority only one corrective intervention was needed.