Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH)

Fratzl‐Zelman, Nadja; Gamsjaeger, Sonja; Blouin, Stéphane; Kocijan, Roland; Plasenzotti, Pia; Rokidi, Stamatia; Nawrot-Wawrzyniak, Kamilla; Roetzer, Katharina; Uyanık, Gökhan; Haeusler, Gabriele; Shane, Elizabeth; Cohen, Adi; Klaushofer, Klaus; Paschalis, Eleftherios P.; Roschger, Paul; Fratzl, Peter; Zwerina, Jochen; Zwettler, Elisabeth

doi:10.1016/j.jsb.2020.107556

Cited by 28 publications

(32 citation statements)

References 94 publications

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“…Other therapeutics targeting the FGF23 pathway e.g. suppressing the upregulation of osteopontin (170,171) are also under development. Inadvertent treatment with bisphosphonates or other osteoporosis drugs, e.g.…”

Section: Adjunctive Medical Therapiesmentioning

confidence: 99%

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

et al. 2021

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X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.

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Section: Adjunctive Medical Therapiesmentioning

confidence: 99%

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

et al. 2021

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“…In contrast to WT mice, which remain normocalcemic on the CD, VDR ∆/∆ mice on the CD suffer from severe hypocalcemia [9]. In dietary calcium deficiency or other conditions where calcium is needed, two mechanisms for calcium retrieval might be activated-one by osteoclastic resorption and the other by osteocytic osteolysis [6,8,16,[24][25][26]. Osteocytic osteolysis might result in a rapid calcium release from the mineralized bone matrix of the mineral around osteocytic lacunae, which would consequently increase the area of the sectioned lacunae in qBEI images, as was demonstrated in lactating mice [6].…”

Section: Discussionmentioning

confidence: 99%

“…Its link to PTHrP and PTH levels and its dependency on the PTHR1 receptor led to the hypothesis that osteocytic osteolysis might be stimulated in pathologic conditions with increased PTH. Indeed, osteocytic osteolysis has been found in rats treated with PTH [24], as well as in patients with sHPT [16,25]. Furthermore, an increased perilacunar area was also reported in growing mice with global [14] or targeted ablation of the VDR [12], as well as in WT mice after dietary calcium restriction after weaning [12].…”

Section: Discussionmentioning

confidence: 99%

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

Misof

Blouin

Hofstaetter

et al. 2020

IJMS

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Osteocytic osteolysis/perilacunar remodeling is thought to contribute to the maintenance of mineral homeostasis. Here, we utilized a reversible, adult-onset model of secondary hyperparathyroidism to study femoral bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging. Male mice with a non-functioning vitamin D receptor (VDRΔ/Δ) or wild-type mice were exposed to a rescue diet (RD) (baseline) and subsequently to a low calcium challenge diet (CD). Thereafter, VDRΔ/Δ mice received either the CD, a normal diet (ND), or the RD. At baseline, BMDD and OLS characteristics were similar in VDRΔ/Δ and wild-type mice. The CD induced large cortical pores, osteomalacia, and a reduced epiphyseal average degree of mineralization in the VDRΔ/Δ mice relative to the baseline (−9.5%, p < 0.05 after two months and −10.3%, p < 0.01 after five months of the CD). Switching VDRΔ/Δ mice on the CD back to the RD fully restored BMDD to baseline values. However, OLS remained unchanged in all groups of mice, independent of diet. We conclude that adult VDRΔ/Δ animals on an RD lack any skeletal abnormalities, suggesting that VDR signaling is dispensable for normal bone mineralization as long as mineral homeostasis is normal. Our findings also indicate that VDRΔ/Δ mice attempt to correct a calcium challenge by enhanced osteoclastic resorption rather than by osteocytic osteolysis.

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“…A quantitative assessment of bone mineralization is important as many metabolic diseases, and medication may affect mineralization. Examples include (high and low bone turnover) osteoporosis [9][10][11][12], osteogenesis imperfecta [13][14][15], melorheostosis [16,17], hypophosphatemia [18], hypophosphatasia [19,20] as well as bisphosphonate [21][22][23] or teriparatide [24] treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Other groups throughout the world have also used it to measure bone mineral content in pathological situations [33][34][35][36]. Recently, evaluation protocols were developed to also assess osteocyte lacunae number, size, and shape from qBE images [15,18,37,38]. However, it has to be emphasized that this method-in contrast to DXA and HR-pQCT-requires a bone biopsy sample.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source

et al. 2021

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Quantitative backscattered electron imaging is an established method to map mineral content distributions in bone and to determine the bone mineralization density distribution (BMDD). The method we applied was initially validated for a scanning electron microscope (SEM) equipped with a tungsten hairpin cathode (thermionic electron emission) under strongly defined settings of SEM parameters. For several reasons, it would be interesting to migrate the technique to a SEM with a field emission electron source (FE-SEM), which, however, would require to work with different SEM parameter settings as have been validated for DSM 962. The FE-SEM has a much better spatial resolution based on an electron source size in the order of several 100 nanometers, corresponding to an about $$10^5$$ 10 5 to $$10^6$$ 10 6 times smaller source area compared to thermionic sources. In the present work, we compare BMDD between these two types of instruments in order to further validate the methodology. We show that a transition to higher pixel resolution (1.76, 0.88, and 0.57 μm) results in shifts of the BMDD peak and BMDD width to higher values. Further the inter-device reproducibility of the mean calcium content shows a difference of up to 1 wt% Ca, while the technical variance of each device can be reduced to $$\pm 0.17$$ ± 0.17 wt% Ca. Bearing in mind that shifts in calcium levels due to diseases, e.g., high turnover osteoporosis, are often in the range of 1 wt% Ca, both the bone samples of the patients as well as the control samples have to be measured on the same SEM device. Therefore, we also constructed new reference BMDD curves for adults to be used for FE-SEM data comparison.

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Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH)

Cited by 28 publications

References 94 publications

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source

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