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International Journal of Oral Science Oct 2023X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization...
X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) β-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.
Topics: Mice; Male; Female; Animals; Familial Hypophosphatemic Rickets; Bone and Bones; Tooth; Periodontal Ligament
PubMed: 37813865
DOI: 10.1038/s41368-023-00252-1 -
Hormone and Metabolic Research =... Oct 2023X-linked hypophosphatemia (XLH) associated with short stature during childhood are mostly referred to the hospital and diagnosed as vitamin D deficiency rickets and... (Review)
Review
X-linked hypophosphatemia (XLH) associated with short stature during childhood are mostly referred to the hospital and diagnosed as vitamin D deficiency rickets and received vitamin D before adulthood. A case is presented with clinical features of hypophosphatemia from childhood who did not seek medical care for diagnosis and treatment, nor did his mother or two brothers, who have short statures, bone pain, and fractures. The patient was assessed for sociodemographic, hematological, and biochemical parameters together with a genetic assessment. A DEXA scan and X-ray were done to determine the abnormalities and deformities of joints and bones despite clinical examination by an expert physician. All imaging, laboratory parameters, and the genetic study confirmed the diagnosis of XLH. A detailed follow-up of his condition was performed after the use of phosphate tablets and other treatments. X-linked hypophosphatemia needs a good assessment, care, and follow up through a complementary medical team including several specialties. Phosphate tablets in adulthood significantly affects clinical and physical improvement and prevention of further skeletal abnormality and burden on daily activity. The patients should be maintained with an adequate dose of phosphate for better patient compliance. More awareness is needed in society and for health professionals when conducting medical checkups during the presence of stress fractures, frequent dental and gum problems, rickets, short stature, or abnormality in the skeleton or walking to think of secondary causes such as hypophosphatemia. Further investigations including a visit to a specialist is imperative to check for the primary cause of these disturbances.
Topics: Adult; Humans; Male; Bone and Bones; Familial Hypophosphatemic Rickets; Hypophosphatemia; Phosphates; Vitamin D
PubMed: 37813097
DOI: 10.1055/a-2159-8429 -
Bone Reports Dec 2023Metabolic bone diseases (MBD) are typically diagnosed by non-invasive imaging and clinical biomarkers. However, imaging does not provide structural information, and...
BACKGROUND
Metabolic bone diseases (MBD) are typically diagnosed by non-invasive imaging and clinical biomarkers. However, imaging does not provide structural information, and biomarkers can be transiently affected by many systemic factors. Bone biopsy and pathologic evaluation is the gold standard for diagnosis of MBD, however, it is rarely utilized. We describe our technique for iliac crest tetracycline-labelled bone using a cannulated drill and assess the utility of bone biopsies to provide diagnostic and therapeutic guidance.
METHODS
In the 25-year period between March 1998 and January 2023, a total of 95 bone biopsies were performed on 94 patients for an osteological indication at Vanderbilt University Medical Center (VUMC). Patient demographics, bone biopsy indications, complications, diagnostic utility, and subsequent therapeutic guidance were retrospectively reviewed and analyzed.
RESULTS
The procedure had minimal complications and was well tolerated by patients. This technique provided good quality specimens for pathology, which helped establish a diagnosis and treatment change in most patients. Patients that had biopsy-guided treatment alterations showed significant increases in Dual-Energy X-ray Absorptiometry (DEXA) bone mineral density (BMD) scores post-biopsy and subsequent treatment.
CONCLUSION
Despite scientific and technological progress in non-invasive diagnostic imaging, clinical biomarkers, and procedures for MBD, there remains a small but significant subset of patients who may benefit from inclusion of tetracycline-labelled bone biopsy into the diagnostic and therapeutic picture. Future prospective comparison studies are warranted.
MINI ABSTRACT
Tetracycline-labelled bone biopsies are under-utilized. Biopsy led to a histological diagnosis and ensuing treatment alteration in most patients with significant increases in bone mineral density. The biopsy procedure used herein provided good specimens with low pain/adverse events. Bone biopsy remains a valuable tool in a small, though significant, subset of patients.
PubMed: 37811524
DOI: 10.1016/j.bonr.2023.101715 -
JBMR Plus Oct 2023Fibroblast growth factor (FGF)23 is one of the major regulators of phosphate homeostasis. Hypophosphatemia can lead to muscle weakness, fatigue, and osteomalacia. In the...
Fibroblast growth factor (FGF)23 is one of the major regulators of phosphate homeostasis. Hypophosphatemia can lead to muscle weakness, fatigue, and osteomalacia. In the setting of hypophosphatemia, serum FGF23 can be measured to differentiate between FGF23-mediated and non-FGF23-mediated renal phosphate wasting. C-terminal FGF23 (cFGF23) assays detect both cFGF23 and intact FGF23 (iFGF23). Circulating FGF23 is regulated by 1.25-dihydroxy-vitamin D, parathyroid hormone (PTH), serum phosphate, and serum calcium but also by, for example, iron status, inflammation, erythropoietin, and hypoxia-inducible-factor-1-α. We present the case of a 48-year-old woman with unexplained mild hypophosphatemia, very high cFGF23, and normal iFGF23. The patient proved to have an iron deficiency. Iron deficiency alters the iFGF23-to-cFGF23 ratio. After initiation of iron treatment, cFGF23 strongly decreased. This case report illustrates the limitation of cFGF23 assays and urges clinicians to be aware that cFGF23 concentrations do not necessarily reflect iFGF23 concentrations and that alternative causes for its elevation should be considered (eg, iron deficiency). © 2023 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
PubMed: 37808399
DOI: 10.1002/jbm4.10790 -
Patient Related Outcome Measures 2023Treatment process attributes can affect health state utilities associated with therapy. For intravenous iron, used to treat iron deficiency and iron deficiency anemia,...
PURPOSE
Treatment process attributes can affect health state utilities associated with therapy. For intravenous iron, used to treat iron deficiency and iron deficiency anemia, research into process attributes is still lacking. This study estimated utilities associated with process attributes for intravenous iron infusions.
METHODS
An online survey including seven health state vignettes and time trade-off tasks was administered to participants, who were not patients living with iron deficiency or iron deficiency anemia, from a Chinese online panel. Vignettes used an identical description of iron deficiency and iron deficiency anemia but differed in the annual number of infusions, infusion duration, and infusion-associated risk of hypophosphatemic osteomalacia. Disutilities and their rate of change as the number of infusions increased were examined using a power model.
RESULTS
The survey was completed by 1091 participants. The highest utilities were observed for one annual infusion of 15-30 minutes or 30-60 minutes, without risk of hypophosphatemic osteomalacia (0.754 and 0.746, respectively). In comparison, more infusions and infusions with a risk of hypophosphatemic osteomalacia were associated with lower utilities. Utility continued to decrease, but at a diminishing rate, as the annual number of infusions increased, with utility decrements of 0.006 and 0.002, respectively, when going from zero to one and from four to five infusions per year. All marginal disutilities were small (values <0.01).
CONCLUSION
This study suggested that treatment attributes of intravenous iron infusions affect health state utilities. Using intravenous iron formulations that allow for fewer and shorter infusions without the risk of hypophosphatemic osteomalacia can reduce the number of visits required and increase patients' quality of life.
PubMed: 37789883
DOI: 10.2147/PROM.S400389 -
European Journal of Medical Genetics Nov 2023Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and...
Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.
Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.
Topics: Child; Humans; Osteogenesis Imperfecta; Hypophosphatasia; Osteomalacia; Fractures, Multiple; Mutation; Alkaline Phosphatase; Calcinosis; Rickets
PubMed: 37758163
DOI: 10.1016/j.ejmg.2023.104856 -
Orphanet Journal of Rare Diseases Sep 2023X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and...
BACKGROUND
X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry.
RESULTS
The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH.
CONCLUSION
The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.
Topics: Child; Adult; Humans; Female; Child, Preschool; Male; Familial Hypophosphatemic Rickets; Genetic Diseases, X-Linked; Mutation; Registries; Demography
PubMed: 37752558
DOI: 10.1186/s13023-023-02882-4 -
Clinical Case Reports Sep 2023A thin patient with a history of eating disorders developed basicervical femoral neck fracture bilaterally and simultaneously due to vitamin D deficiency osteomalacia. A...
A thin patient with a history of eating disorders developed basicervical femoral neck fracture bilaterally and simultaneously due to vitamin D deficiency osteomalacia. A careful evaluation in thin patients with thigh pain, including bone biopsy, is required to avoid overlooking osteomalacia.
PubMed: 37744618
DOI: 10.1002/ccr3.7881 -
Journal of Bone Metabolism Aug 2023Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic...
Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.
PubMed: 37718900
DOI: 10.11005/jbm.2023.30.3.219 -
Transactions of the American Clinical... 2023Fibroblast growth factor 23 (FGF23) is an endocrine hormone that stimulates renal phosphate excretion and suppresses circulating concentrations of 1,25-dihydroxyvitamin...
Fibroblast growth factor 23 (FGF23) is an endocrine hormone that stimulates renal phosphate excretion and suppresses circulating concentrations of 1,25-dihydroxyvitamin D (1,25D). These effects of FGF23 are most evident in rare diseases that are characterized by FGF23-mediated hypophosphatemic rickets-osteomalacia. More commonly, elevated FGF23 is a ubiquitous, early consequence of chronic kidney disease (CKD) in which it helps to maintain normal serum phosphate levels but causes secondary hyperparathyroidism by suppressing 1,25D, and directly promotes cardiovascular disease and death. Elevated FGF23 is also a common complication of intravenous administration of ferric carboxymaltose (FCM), which is widely used to treat iron deficiency anemia. Among patients with normal kidney function who receive FCM, the resulting increase in FGF23 and subsequent FGF23-mediated reduction of 1,25D and secondary hyperparathyroidism promote hypophosphatemia that can be symptomatic, severe, and associated with musculoskeletal complications. Ongoing research is needed to design novel therapeutic approaches to mitigate FGF23-related illnesses.
Topics: Humans; Administration, Intravenous; Homeostasis; Kidney Diseases; Hyperparathyroidism, Secondary; Minerals; Phosphates
PubMed: 37701608
DOI: No ID Found