Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism

Abstract

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community’s attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients’ characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified.

Key words

asfotase alfa - burosumab - X-linked hypophosphatemia - tumor-induced osteomalacia - hypophosphatasia - FGF 23

Publication History

Received: 06 May 2022

Accepted after revision: 24 July 2022

Article published online:
01 September 2022

• References

• 1 Kinoshita Y, Fukumoto S. X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases: prospect for new treatment. Endocr Rev 2018; 39: 274-291
• 2 Fukumoto S. FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment. J Mol Endocrinol 2021; 66: R57-R65
• 3 Heijboer AC, Cavalier E. The measurement and interpretation of fibroblast growth factor 23 (FGF23) concentrations. Calcif Tissue Int 2022;
• 4 Athonvarangkul D, Insogna KL. New therapies for hypophosphatemia-related to FGF23 Excess. Calcif Tissue Int 2021; 108: 143-157
• 5 Acar S, Demir K, Shi Y. Genetic causes of rickets. J Clin Res Pediatr Endocrinol 2017; 9: 88-105
• 6 Addison WN, Masica DL, Gray JJ. et al. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Miner Res 2010; 25: 695-705
• 7 Barros NMT, Hoac B, Neves RL. et al. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. J Bone Miner Res 2013; 28: 688-699
• 8 Kocijan R, Haschka J, Feurstein J. et al. New therapeutic options for bone diseases. Wien Med Wochenschr 2021; 171: 120-125
• 9 Lewiecki EM, Bilezikian JP, Kagan R. et al. Proceedings of the 2019 Santa Fe bone symposium: new concepts in the care of osteoporosis and rare bone diseases. J Clin Densit 2020; 23: 1-20
• 10 Florenzano P, Hartley IR, Jimenez M. et al. Tumor-induced osteomalacia. Calcif Tissue Int 2021; 108: 128-142
• 11 Crotti C, Bartoli F, Coletto LA. et al Tumor induced osteomalacia: a single center experience on 17 patients. Bone 2021; 152: 116077
• 12 Dahir K, Zanchetta MB, Stanciu I. et al. Diagnosis and management of tumor-induced osteomalacia: perspectives from clinical experience. J Endocr Soc 2021; 5 bvab099
• 13 Fratzl-Zelman N, Gamsjaeger S, Blouin S. et al. Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH). J Struct Biol 2020; 211: 107556
• 14 Schindeler A, Biggin A, Munns CF. Clinical evidence for the benefits of burosumab therapy for X-linked hypophosphatemia (XLH) and other conditions in adults and children. Front Endocrinol (Lausanne) 2020; 11: 338
• 15 Li X, Jiang Y, Huo L. et al. Nonremission and recurrent tumor-induced osteomalacia: a retrospective study. J Bone Miner Res 2020; 35: 469-477
• 16 Mishra SK, Kuchay MS, Sen IB. et al. Successful management of tumor-induced osteomalacia with radiofrequency ablation: a case series. JBMR Plus 2019; 3: 10178
• 17 Tarasova VD, Trepp-Carrasco AG, Thompson R. et al. Successful treatment of tumor-induced osteomalacia due to an intracranial tumor by fractionated stereotactic radiotherapy. J Clin Endocrinol Metab 2013; 98: 4267-4272
• 18 Hoyer-Kuhn H, Schönau E. Pharmacotherapy in rare skeletal diseases. In: Handbook of Experimental Pharmacology. Springer; 2020: 87-104
• 19 Minisola S, Peacock M, Fukumoto S. et al. Tumour-induced osteomalacia. Nat Rev Disease Primers 2017; 3: 17044
• 20 Jiang Y, Li X, Huo L. et al. Consensus on clinical management of tumor-induced osteomalacia. Chin Med J 2021; 134: 1264-1266
• 21 Goetz R, Nakada Y, Hu MC. et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci 2010; 107: 407-412
• 22 Zhang MYH, Ranch D, Pereira RC. et al. Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology 2012; 153: 1806-1816
• 23 Wöhrle S, Henninger C, Bonny O. et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 2013; 28: 899-911
• 24 Aono Y, Yamazaki Y, Yasutake J. et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 2009; 24: 1879-1888
• 25 Aono Y, Hasegawa H, Yamazaki Y. et al. Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res 2011; 26: 803-810
• 26 Carpenter TO, Imel EA, Ruppe MD. et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest 2014; 124: 1587-1597
• 27 Imel EA, Zhang X, Ruppe MD. et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab 2015; 100: 2565-2573
• 28 Carpenter TO, Whyte MP, Imel EA. et al. Burosumab therapy in children with X-linked hypophosphatemia. N Eng. J Med 2018; 378: 1987-1998
• 29 Imel EA, Glorieux FH, Whyte MP. et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019; 393: 2416-2427
• 30 Whyte MP, Carpenter TO, Gottesman GS. et al. Efficacy and safety of burosumab in children aged 1–4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol 2019; 7: 189-199
• 31 Martín Ramos S, Gil-Calvo M, Roldán V. et al. Positive response to one-year treatment with burosumab in pediatric patients with X-linked hypophosphatemia. Front Pediatr 2020; 8: 48
• 32 Insogna KL, Briot K, Imel EA. et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res 2018; 33: 1383-1393
• 33 Portale AA, Carpenter TO, Brandi ML. et al. Continued beneficial effects of burosumab in adults with X-linked hypophosphatemia: results from a 24-week treatment continuation period after a 24-week double-blind placebo-controlled period. Calcif Tissue Int 2019; 105: 271-284
• 34 Insogna KL, Rauch F, Kamenický P. et al. Burosumab improved histomorphometric measures of osteomalacia in adults with X-linked hypophosphatemia: a phase 3, single-arm, international trial. J Bone Miner Res 2019; 34: 2183-2191
• 35 Jan de Beur SM, Miller PD, Weber TJ. et al. Burosumab for the treatment of tumor-induced osteomalacia. J Bone Miner Res 2021; 36: 627-635
• 36 Imanishi Y, Ito N, Rhee Y. et al. Interim analysis of a phase 2 open-label trial assessing burosumab efficacy and safety in patients with tumor-induced osteomalacia. J Bone Miner Res 2021; 36: 262-270
• 37 Haffner D, Emma F, Eastwood DM. et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019; 15: 435-455
• 38 Wöhrle S, Henninger C, Bonny O. et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 2013; 28: 899-911
• 39 Hartley IR, Miller CB, Papadakis GZ. et al. Targeted FGFR blockade for the treatment of tumor-induced osteomalacia. N Engl J Med 2020; 383: 1387-1389
• 40 Villa-Suárez JM, García-Fontana C, Andújar-Vera F. et al. Hypophosphatasia: a unique disorder of bone mineralization. Int J Mol Sci 2021; 22: 4303
• 41 Tournis S, Yavropoulou M, Polyzos S. et al. Hypophosphatasia. J Clin Med 2021; 10: 5676
• 42 Vimalraj S. Alkaline phosphatase: structure, expression and its function in bone mineralization. Gene 2020; 754: 144855
• 43 Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med School 2010; 77: 4-12
• 44 Waymire KG, Mahuren JD, Jaje JM. et al. Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nat Genet 1995; 11: 45-51
• 45 Simon S, Resch H, Klaushofer K. et al. Hypophosphatasia: from diagnosis to treatment. Curr Rheumatol Rep 2018; 20: 69
• 46 Millán JL, Plotkin H. Hypophosphatasia – pathophysiology and treatment. Actual Osteol 2012; 8: 164-182
• 47 Whyte MP. Hypophosphatasia: enzyme replacement therapy brings new opportunities and new challenges. J Bone Miner Res 2017; 32: 667-675
• 48 Vaisman DN, McCarthy AD, Cortizo AM. Bone-specific alkaline phosphatase activity is inhibited by bisphosphonates: role of divalent cations. Biol Trace Elem Res 2005; 104: 131-140
• 49 Sutton RAL, Mumm S, Coburn SP. et al. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res 2012; 27: 987-994
• 50 Schalin-Jäntti C, Mornet E, Lamminen A. et al. Parathyroid hormone treatment improves pain and fracture healing in adult hypophosphatasia. J Clin Endocrinol Metab 2010; 95: 5174-5179
• 51 Doshi KB, Hamrahian AH, Licata AA. Teriparatide treatment in adult hypophosphatasia in a patient exposed to bisphosphonate: a case report. Clin Cases Miner Bone Metab 2009; 6: 266-269
• 52 Laroche M. Failure of teriparatide in treatment of bone complications of adult hypophosphatasia. Calcif Tissue Int 2012; 90: 250-250
• 53 Gagnon C, Sims NA, Mumm S. et al. Lack of sustained response to teriparatide in a patient with adult hypophosphatasia. J Clin Endocrinol Metab 2010; 95: 1007-1012
• 54 Choida V, Bubbear JS. Update on the management of hypophosphatasia. Ther Adv Musculoskelet Dis 2019; 11: 1759720X19863997
• 55 Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 2014; 6: 48-57
• 56 Li X, Ominsky MS, Niu Q-T. et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008; 23: 860-869
• 57 McClung MR, Grauer A, Boonen S. et al. Romosozumab in postmenopausal women with low bone mineral density. N Eng. J Med 2014; 370: 412-420
• 58 Seefried L, Baumann J, Hemsley S. et al. Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia. J Clin Invest 2017; 127: 2148-2158
• 59 Fedde KN, Blair L, Silverstein J. et al. Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 1999; 14: 2015-2026
• 60 Millán JL, Narisawa S, Lemire I. et al. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res 2008; 23: 777-787
• 61 McKee MD, Nakano Y, Masica DL. et al. Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia. J Dent Res 2011; 90: 470-476
• 62 Whyte MP, Greenberg CR, Salman NJ. et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 2012; 366: 904-913
• 63 Whyte MP, Simmons JH, Moseley S. et al. Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diabetes Endocrinol 2019; 7: 93-105
• 64 Hofmann CE, Harmatz P, Vockley J. et al. Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study. J Clin Endocrinol Metab 2019; 104: 2735-2747
• 65 Whyte MP, Madson KL, Phillips D. et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight 2016; 1: e85971
• 66 Schroth RJ, Long C, Lee VHK. et al. Dental outcomes for children receiving asfotase alfa for hypophosphatasia. Bone 2021; 152: 116089
• 67 Kishnani PS, Rockman-Greenberg C, Rauch F. et al. Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 2019; 121: 149-162
• 68 Stürznickel J, Schmidt FN, von Vopelius E. et al. Bone healing and reactivation of remodeling under asfotase alfa therapy in adult patients with pediatric-onset hypophosphatasia. Bone 2021; 143: 115794
• 69 Seefried L, Rak D, Petryk A. et al. Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa. Osteoporos Int 2021; 32: 2505-2513
• 70 Kishnani PS, del Angel G, Zhou S. et al. Investigation of ALPL variant states and clinical outcomes: An analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa. Mol Genet Metab 2021; 133: 113-121
• 71 Klidaras P, Severt J, Aggers D. et al. Fracture healing in two adult patients with hypophosphatasia after asfotase alfa therapy. JBMR Plus 2018; 2: 304-307
• 72 Rolvien T, Schmidt T, Schmidt FN. et al. Recovery of bone mineralization and quality during asfotase alfa treatment in an adult patient with infantile-onset hypophosphatasia. Bone 2019; 127: 67-74
• 73 Freitas TQ, Franco AS, Pereira RMR. Improvement of bone microarchitecture parameters after 12 months of treatment with asfotase alfa in adult patient with hypophosphatasia: Case report. Medicine 2018; 97: e13210
• 74 Genest F, Rak D, Petryk A. et al. Physical function and health-related quality of life in adults treated with asfotase alfa for pediatric-onset hypophosphatasia. JBMR Plus 2020; 4: e10395
• 75 Magdaleno AL, Singh S, Venkataraman S. et al. Adult-onset hypophosphatasia: before and after traetment with asfotase alfa. AACE Clin Case Rep 5: e344-e348
• 76 Kitaoka T, Tajima T, Nagasaki K. et al. Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial. Clin Endocrinol (Oxf) 2017; 87: 10-19
• 77 Kishnani PS, Rush ET, Arundel P. et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab 2017; 122: 4-17
• 78 Bowden SA, Adler BH. Reappearance of hypomineralized bone after discontinuation of asfotase alfa treatment for severe childhood hypophosphatasia. Osteoporos Int 2018; 29: 2155-2156
• 79 Khan AA, Josse R, Kannu P. et al. Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int 2019; 30: 1713-1722