Pharmacological management of X‐linked hypophosphataemia

Imel, Erik A.; White, Kenneth E.

doi:10.1111/bcp.13763

Cited by 25 publications

(47 citation statements)

References 96 publications

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“…This reinforces the importance of the stroma, and in conjunction with our results, the Ocys, in the progression of tumors that grow in bone such as MM. Fgf23-targeting drugs, like Burosumab, might be efficacious in treating MMBD and reducing marrow neo-vascularization associated with its development 65 . Although the in vivo data presented in this manuscript supports the hypothesis that osteocytes are pro-angiogenic in MM microenvironment, these models have limitations and do not recapitulate all aspects of the human pathophysiology of MM 10,13,16,17,22 .…”

Section: Discussionmentioning

confidence: 99%

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

Mulcrone

Edwards

Petrusca

et al. 2020

Sci Rep

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Multiple Myeloma (MM) induces bone destruction, decreases bone formation, and increases marrow angiogenesis in patients. We reported that osteocytes (Ocys) directly interact with MM cells to increase tumor growth and expression of Ocy-derived factors that promote bone resorption and suppress bone formation. However, the contribution of Ocys to enhanced marrow vascularization in MM is unclear. Since the MM microenvironment is hypoxic, we assessed if hypoxia and/or interactions with MM cells increases pro-angiogenic signaling in Ocys. Hypoxia and/or co-culture with MM cells significantly increased Vegf-a expression in MLOA5-Ocys, and conditioned media (CM) from MLOA5s or MM-MLOA5 co-cultured in hypoxia, significantly increased endothelial tube length compared to normoxic CM. Further, Vegf-a knockdown in MLOA5s or primary Ocys co-cultured with MM cells or neutralizing Vegf-a in MM-Ocy co-culture CM completely blocked the increased endothelial activity. Importantly, Vegf-a-expressing Ocy numbers were significantly increased in MM-injected mouse bones, positively correlating with tumor vessel area. Finally, we demonstrate that direct contact with MM cells increases Ocy Fgf23, which enhanced Vegf-a expression in Ocys. Fgf23 deletion in Ocys blocked these changes. These results suggest hypoxia and MM cells induce a pro-angiogenic phenotype in Ocys via Fgf23 and Vegf-a signaling, which can promote MM-induced marrow vascularization.

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Section: Discussionmentioning

confidence: 99%

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

Mulcrone

Edwards

Petrusca

et al. 2020

Sci Rep

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“…(40,41) Therapy with calcitriol and phosphate salts is often limited by gastrointestinal side effects, as well as by more serious complications, including development of hypercalcemic hyperparathyroidism and nephrocalcinosis. (69) Furthermore, the hyperparathyroidism involves multigland disease, which may be difficult to manage even with surgery. Limited data suggest that cinacalcet, a calcimimetic, may be able to ameliorate the hyperparathyroidism in some patients with XLH.…”

Section: Medical Therapy Of Fgf23-mediated Skeletal Disordersmentioning

confidence: 99%

FGF23, Hypophosphatemia, and Emerging Treatments

2019

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FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co‐receptor Klotho, it modulates phosphate reabsorption and both 1α‐hydroxylation and 24‐hydroxylation in the renal proximal tubules. The most common FGF23‐mediated hypophosphatemia is X‐linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23‐mediated forms of hypophosphatemia are characterized by phosphaturia and low or low‐normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23‐mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor‐induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23‐mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…As such, conventional therapy presents only a limited effectiveness in the management of XLH, often rendering the skeletal deformities irreversible. Furthermore, conventional therapy is associated with safety and tolerability issues, and involves complex posology schemes requiring multiple daily intakes, which undermines the adherence to treatment and poses another barrier to treatment success [3][4][5][6][7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Value-based decision-making for orphan drugs with multiple criteria decision analysis: burosumab for the treatment of X-linked hypophosphatemia

Vandewalle¹,

Amorim²,

Ramos³

et al. 2021

Current Medical Research and Opinion

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Objective: Burosumab is an orphan medicinal product (OMP) approved in Europe for the treatment of X-linked hypophosphatemia (XLH). The aim of this study was to assess the value of burosumab versus conventional therapy for the treatment of paediatric XLH, through a multi-criteria decision analysis (MCDA) framework for health technology assessment (HTA) of OMPs in Portugal. Methods: The MCDA framework considered 14 criteria related to disease burden, therapeutic value and economic burden. A multidisciplinary panel of national stakeholders participated in a two-phase exercise. In the first phase, relative weights and part-worth utilities for the criteria and their levels were elicited and a reimbursement likelihood function was calibrated through adaptive conjoint analysis. In the second phase, burosumab and conventional therapy were assessed against the criteria, providing a global value score (0-100) and reimbursement likelihood (0-100%) for both. Results: Of the 14 criteria, disease burden, therapeutic value and economic burden criteria represented 27.29%, 57.17% and 15.53% of the total weight in the decision, respectively. All disease burden and some therapeutic value criteria, typically not included in traditional HTA, represented 47.88% of the total weight. Burosumab was unanimously considered superior to conventional therapy, with an average (range) global value score of 84.96 (82.48-86.54) against 48.06 (43.37-57.68), and reimbursement likelihood of 97.50% (96.78%-98.32%) against 43.66% (31.48%-68.73%), respectively. Conclusions: MCDA represents a powerful tool in HTA decision-making for OMPs. The results of this MCDA acknowledge burosumab as a disease-modifying drug, deemed superior to conventional therapy for the treatment of paediatric XLH.

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Pharmacological management of X‐linked hypophosphataemia

Cited by 25 publications

References 96 publications

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

FGF23, Hypophosphatemia, and Emerging Treatments

Value-based decision-making for orphan drugs with multiple criteria decision analysis: burosumab for the treatment of X-linked hypophosphatemia

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