Under development 2023, Jun, 26 | 12:00 am

How New Treatments for Rare Bone Disorders Are Changing the Landscape of Osteoporosis Care

Learn about three rare bone disorders and how they have inspired the development of new treatments for osteoporosis, a common bone disorder that affects millions of people worldwide.

MOHAMMAD HUTAIF, EMIAL

Introduction

  • Did you know that there are over 7,000 rare diseases in the world, affecting about 400 million people? Among them are rare bone disorders, which are conditions that affect the structure and function of the skeleton. Some examples of rare bone disorders are pycnodysostosis, sclerosteosis, and van Buchem disease.
  • These rare bone disorders have not only challenged the medical community to understand their causes and consequences, but also inspired the discovery of new treatments that target the molecular pathways of bone remodeling. Bone remodeling is the process by which old bone is replaced by new bone, and it is essential for maintaining bone health and strength.
  • In this blog post, we will explore three rare bone disorders and how they have led to the development of new treatments for osteoporosis, a common bone disorder that affects more than 200 million people worldwide. Osteoporosis is characterized by low bone mass and increased risk of fractures, and it can cause pain, disability, and reduced quality of life. We will review the new treatments that have emerged from the study of rare bone disorders and what they mean for the outcomes of osteoporosis patients.

Body

  • The first rare bone disorder we will discuss is pycnodysostosis
    • Pycnodysostosis is a genetic condition that affects the development and maturation of bone cells. It causes short stature, fragile bones, dental problems, and facial deformities. It affects about one in a million people worldwide.
    • Pycnodysostosis has revealed the role of cathepsin K, an enzyme that breaks down bone matrix. People with pycnodysostosis have a mutation in the gene that codes for cathepsin K, resulting in reduced bone resorption and increased bone density. However, this also leads to poor bone quality and increased fracture risk.
    • Cathepsin K inhibitors have been developed and tested for osteoporosis, a common bone disorder that involves increased bone resorption and decreased bone formation. By inhibiting cathepsin K, these drugs aim to reduce bone loss and preserve bone strength. They have shown promising results in clinical trials, demonstrating improved bone mineral density and reduced fracture risk in osteoporosis patients.
  • Pycnodysostosis is a genetic condition that affects the development and maturation of bone cells. It causes short stature, fragile bones, dental problems, and facial deformities. It affects about one in a million people worldwide.
  • Pycnodysostosis has revealed the role of cathepsin K, an enzyme that breaks down bone matrix. People with pycnodysostosis have a mutation in the gene that codes for cathepsin K, resulting in reduced bone resorption and increased bone density. However, this also leads to poor bone quality and increased fracture risk.
  • Cathepsin K inhibitors have been developed and tested for osteoporosis, a common bone disorder that involves increased bone resorption and decreased bone formation. By inhibiting cathepsin K, these drugs aim to reduce bone loss and preserve bone strength. They have shown promising results in clinical trials, demonstrating improved bone mineral density and reduced fracture risk in osteoporosis patients.
  • The second rare bone disorder we will discuss is sclerosteosis
    • Sclerosteosis is a genetic condition that affects the regulation of bone formation. It causes excessive bone growth, especially in the skull and jaw. It can lead to facial distortion, hearing loss, nerve compression, and increased intracranial pressure. It affects about one in 250,000 people worldwide.
    • Sclerosteosis has revealed the role of sclerostin, a protein that inhibits bone formation. People with sclerosteosis have a mutation or deletion in the gene that codes for sclerostin, resulting in increased bone formation and high bone density. However, this also leads to abnormal bone morphology and impaired function.
    • Sclerostin inhibitors have been developed and tested for osteoporosis, a common bone disorder that involves decreased bone formation and increased bone resorption. By inhibiting sclerostin, these drugs aim to stimulate bone formation and increase bone mass. They have shown promising results in clinical trials, demonstrating improved bone mineral density and reduced fracture risk in osteoporosis patients.
  • Sclerosteosis is a genetic condition that affects the regulation of bone formation. It causes excessive bone growth, especially in the skull and jaw. It can lead to facial distortion, hearing loss, nerve compression, and increased intracranial pressure. It affects about one in 250,000 people worldwide.
  • Sclerosteosis has revealed the role of sclerostin, a protein that inhibits bone formation. People with sclerosteosis have a mutation or deletion in the gene that codes for sclerostin, resulting in increased bone formation and high bone density. However, this also leads to abnormal bone morphology and impaired function.
  • Sclerostin inhibitors have been developed and tested for osteoporosis, a common bone disorder that involves decreased bone formation and increased bone resorption. By inhibiting sclerostin, these drugs aim to stimulate bone formation and increase bone mass. They have shown promising results in clinical trials, demonstrating improved bone mineral density and reduced fracture risk in osteoporosis patients.
  • The third rare bone disorder we will discuss is van Buchem disease
    • Van Buchem disease is a genetic condition that affects the regulation of bone formation. It causes excessive bone growth, especially in the skull and jaw. It can lead to facial distortion, hearing loss, nerve compression, and increased intracranial pressure. It affects about one in 50,000 people worldwide.
    • Van Buchem disease has revealed the role of sclerostin, a protein that inhibits bone formation. People with van Buchem disease have a mutation or deletion in a regulatory region of the gene that codes for sclerostin, resulting in reduced expression of sclerostin and increased bone formation and high bone density. However, this also leads to abnormal bone morphology and impaired function.
    • Sclerostin inhibitors have been developed and tested for osteoporosis, a common bone disorder that involves decreased bone formation and increased bone resorption. By inhibiting sclerostin, these drugs aim to stimulate bone formation and increase bone mass. They have shown promising results in clinical trials, demonstrating improved bone mineral density and reduced fracture risk in osteoporosis patients.
  • Van Buchem disease is a genetic condition that affects the regulation of bone formation. It causes excessive bone growth, especially in the skull and jaw. It can lead to facial distortion, hearing loss, nerve compression, and increased intracranial pressure. It affects about one in 50,000 people worldwide.
  • Van Buchem disease has revealed the role of sclerostin, a protein that inhibits bone formation. People with van Buchem disease have a mutation or deletion in a regulatory region of the gene that codes for sclerostin, resulting in reduced expression of sclerostin and increased bone formation and high bone density. However, this also leads to abnormal bone morphology and impaired function.
  • Sclerostin inhibitors have been developed and tested for osteoporosis, a common bone disorder that involves decreased bone formation and increased bone resorption. By inhibiting sclerostin, these drugs aim to stimulate bone formation and increase bone mass. They have shown promising results in clinical trials, demonstrating improved bone mineral density and reduced fracture risk in osteoporosis patients.

Conclusion

  • In conclusion, we have reviewed three rare bone disorders and how they have led to the development of new treatments for osteoporosis. These new treatments target the molecular mechanisms of bone remodeling and aim to improve the outcomes of osteoporosis patients by increasing bone mass and reducing fracture risk.
  • These new treatments represent a paradigm shift in the management of osteoporosis, as they offer novel and effective options for patients who have not responded well to conventional therapies or who have contraindications or intolerances to them. They also offer hope for patients who suffer from rare bone disorders, as they may provide a way to modulate their disease and improve their quality of life.
  • If you want to learn more about rare bone disorders and new treatments, or if you have any concerns about your bone health, please visit our website or contact us today. We are here to help you with your bone health needs.

Some other rare bone disorders and their treatments are:

●        Osteogenesis imperfecta: This is a genetic disorder that causes the bones to be brittle and prone to fractures. It can also affect other tissues such as skin, teeth, and blood vessels. It is caused by mutations in genes that code for type I collagen, a protein that provides strength and structure to bones. There are different types and severities of osteogenesis imperfecta, ranging from mild to lethal. The treatment for osteogenesis imperfecta may include medication, surgery, physical therapy, braces, splints, and lifestyle modifications. The goals of treatment are to prevent fractures, reduce pain, improve mobility, and enhance quality of life.

●        Fibrous dysplasia/McCune-Albright syndrome: This is a rare disorder that affects the development and growth of bones. It causes some bones to be replaced by fibrous tissue, which weakens them and makes them prone to deformity and fracture. It can affect any bone in the body, but most commonly affects the skull, ribs, spine, pelvis, and legs. It can also cause hormonal problems and skin pigmentation. It is caused by a random mutation in a gene that regulates cell growth and differentiation. There is no cure for fibrous dysplasia/McCune-Albright syndrome, but the treatment may include medication, surgery, radiation therapy, and supportive care. The goals of treatment are to control symptoms, prevent complications, and improve function and appearance.

●        X-linked hypophosphatemia: This is a genetic disorder that affects the metabolism of phosphate, a mineral that is essential for bone formation and maintenance. It causes low levels of phosphate in the blood and urine, which leads to rickets in children and osteomalacia in adults. These conditions cause softening and weakening of bones, resulting in bone pain, deformity, fracture, short stature, dental problems, and muscle weakness. It is caused by mutations in a gene that encodes a protein that regulates phosphate reabsorption in the kidneys. The treatment for X-linked hypophosphatemia may include oral phosphate supplements, vitamin D analogs, growth hormone therapy, and surgery. The goals of treatment are to correct phosphate levels, prevent bone loss, improve growth and development, and reduce complications.

References

Tosi LL, Warman ML. Mechanistic and therapeutic insights gained from studying rare skeletal diseases. Bone. 2015;76:67–75.

  1. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Gen Part A. 2015;167(12):2869–92.
  1. Yap P, Savarirayan R. Emerging targeted drug therapies in skeletal disorders. Am J Med Genet Part A. 2016;170(10):2596–604.
  1. Jelin AC, O'Hare E, Blakemore K, Jelin EB, Valle D, Hoover-Fong J. Skeletal disorders: Growing therapy for growing bones. Front Pharmacol. 2017;8:79.
  1. Nikkel SM. Skeletal Disorders: What Every Bone Health Clinician Needs to Know. Curr Osteoporosis Rep. 2017;15(5):419–24.
  1. Bacon S, Crowley R. Developments in rare bone diseases and mineral disorders. Ther Adv Chronic Dis. 2018;9(1):51–60.
  1. Yasoda A, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004;10(1):80–6.
  1. Duarte SP, Rocha ME, Bidondo MP, Liascovich R, Barbero P, Groisman B. Bone disorders in 1.6 million births in Argentina. Eur J Med Genet. 2018.
  2. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019;14(1):1.
  1. Unger S, Bonafé L, Gouze E. Current care and investigational therapies in achondroplasia. Curr Osteoporos Rep. 2017;15(2):53–60.
  1. Wynn J, King TM, Gambello MJ, Waller DK, Hecht JT. Mortality in achondroplasia study: A 42-year follow-up. Am J Med Genets Part A. 2007;143(21):2502–11.
  1. Arenas MA, del Pino M, Fano V. FGFR3-related hypochondroplasia: longitudinal growth in 57 children with the p. Asn540Lys mutation. J Pediatr Endocrinol Metab. 2018;31(11):1279–84.
  1. Pauli RM, Botto LD. Achondroplasia. In: Management of Genetic Syndromes. 4th ed. New York: Wiley; 2018.
  1. Mortier G, Nuytinck L, Craen M, Renard JP, Leroy JG, De Paepe A. Clinical and radiographic features of a family with hypochondroplasia owing to a novel Asn540Ser mutation in the fibroblast growth factor receptor 3 gene. J Med Genet. 2000;37(3):220–4.
  1. Peake NJ, Hobbs AJ, Pingguan-Murphy B, Salter DM, Berenbaum F, et al. Role of C-type natriuretic peptide signalling in maintaining cartilage and bone function. Osteoarth Cartilage. 2014;22(11):1800–7.
  1. Beyond Achondroplasia [internet]. 2018. Available from: https://www.beyondachondroplasia.org/en/health/treatments/emergent-treatments/22-vosoritide. [cited 2018 December 18].
  2. Noonberg S. BMN 111: vosoritide for achondroplasia. Biomarin R&D Day. 2016:98–135.
  3. Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019;381(1):25–35.
  1. Olney RC, Prickett TC, Espiner EA, Mackenzie WG, Duker AL, Ditro C, et al. C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia. J Clin Endocrinol Metab. 2015;100:E355–9.
  1. Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM, Peng J, et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3–related dwarfism. J Pharmacol Exp Ther. 2015;353:132–49.
  1. Therachon. [internet]. 2018. Available from: https://therachon.com/our-focus/achondroplasia/. [cited 2019 January 5].
  2. Webster MK, d'Avis PY, Robertson SC, Donoghue DJ. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol. 1996;16(8):4081–7.
  1. Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol. 2000;20(2):516–22.
  1. Daghlian M, Pfizer Pays $340 Million for Achondroplasia Therapy Developer Therachon. 2018. Available from: https://globalgenes.org/2019/05/08/pfizer-pays-340-million-for-achondroplasia-therapy-developer-therachon/. [cited on August 16 2019].
  1. Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med. 2013;5(203):203ra124.
  1. Pfizer. Product Pipeline. 2019. Available from: https://www.pfizer.com/science/rare-diseases/pipeline. [cited on August 16 2019].
  2. Matsushita M, Hasegawa S, Kitoh H, Mori K, Ohkawara B, Yasoda A, Masuda A, et al. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene. Endocrinology. 2014;156(2):548–54.
  1. Matsushita M. UMIN CTR Clinical Trial. 2018. Available from: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037683. [cited on December 5 2018].
  1. Kombla-Ebri D, et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest. 2016;126(5):1871–84.
  1. De Ridder R, Boudin E, Mortier G, Van Hul W. Human Genetics of Sclerosing Bone Disorders. Curr Osteoporos Rep. 2018;16(3):256–68.
  1. Bollerslev J, Henriksen K, Frost M, Brixen K, Van Hul W. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 2013;EJE-13.
  2. Radswiki. Sandwich vertebral body. 2018. Available from: https://radiopaedia.org/articles/sandwich-vertebral-body. [cited on December 16 2018].
  1. Thudium CS, Moscatelli I, Flores C, Thomsen JS, Brüel A, Gudmann NS, et al. A comparison of osteoclast-rich and osteoclast-poor osteopetrosis in adult mice sheds light on the role of the osteoclast in coupling bone resorption and bone formation. Calcif Tissue Int. 2014;95(1):83–93.
  1. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009;4(1):5.
  1. Key LL Jr, Rodriguiz RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, et al. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. 1995;332(24):1594–9.
  1. Key L, Carnes D, Cole S, Holtrop M, Bar-Shavit Z, Shapiro F, Arceci R, Steinberg J, Gundberg C, Kahn A, Teitelbaum S. Treatment of congenital osteopetrosis with high-dose calcitriol. N Engl J Med. 1984;310(7):409–15.
  1. Wu CC, Econs MJ, LA DM, Insogna KL, Levine MA, Orchard PJ, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines from the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017.
  2. Maurizi A, Capulli M, Patel R, Curle A, Rucci N, Teti A. RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development. Bone. 2018;110:343–54.
  1. Goessl C, Katz L, Dougall WC, et al. The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction. Ann N Y Acad Sci. 2012;1263:29–40.
  1. Chung PY, van Hul W. Paget's disease of bone: evidence for complex pathogenetic interactions. Semin Arthritis Rheum. 2012;41(5):619–41.
  1. Lo Iacono N, Pangrazio A, Abinun M, Bredius R, Zecca M, Blair HC, et al. RANKL cytokine: from pioneer of the osteoimmunology era to cure for a rare disease. Clin Dev Immunol. 2013;15:2013.
  1. Streeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, et al. Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone. 2008;43(3):584–90.
  1. Papapoulos SE. Bisphosphonates: how do they work? Best Pract Res Clin Endocrinol Metab. 2008;22(5):831–47.
  1. Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssière B, Belleville C, Estrera K, et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci. 2005;102(48):17406–11.
  1. Streeten E. Trial of Lithium Carbonate for Treatment of Osteoporosis-Pseudoglioma Syndrome. 2018. Available from: https://clinicaltrials.gov/ct2/show/study/NCT01108068. [cited 2018 December 5].
  1. Kedlaya R, Veera S, Horan DJ, Moss RE, Ayturk UM, Jacobsen CM, et al. Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome. Sci Transl Med. 2013;5(211):211ra158.
  1. Steiner RD, Adsit J, Basel D. COL1A1/2-related osteogenesis imperfect, Gene Reviews. 2014. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20301472. [cited December 8 2018].
  1. Xu XJ, Lv F, Song YW, Li LJ, Wei XX. Zhao XL, et al Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta. Clin Chim Acta. 2019;489:21–8.
  1. Sillence DO, Rimoin DL, Danks DM. Clinical variability in osteogenesis imperfecta- variable expressivity or genetic heterogeneity. Birth Defects Orig Artic Ser. 1979;15:113–29.
  1. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. Am J Med Genet Part A. 2014;164A:1470–81.
  1. Shapiro J. Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease. Academic Press. Chapter 2; 2014. p. 15–22.
  1. Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2016;10.
  2. Drake MT, Collins MT, Hsiao EC. The Rare Bone Disease Working Group: report from the 2016 American Society for Bone and Mineral Research Annual Meeting. Bone. 2017;102:80–4.
  1. Raulston S. Treatment of OI with PTH and Zoledronic acid. 2018. Available from: https://ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialNumber=ISRCTN15313991. [cited December 10 2018].
  1. Marini J, Smith SM. Osteogenesis Imperfecta. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext; 2015. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279109/. [cited February 14 2019].
  1. Kobayashi T, Nakamura Y, Suzuki T, Yamaguchi T, Takeda R, Takagi M, et al. Efficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis—Case Series. J Clin Med. 2018;7(12):479.
  1. Glorieux FH, Devogelaer JP, Durigova M, Goemaere S, Hemsley S. Jakob Fet al. BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J Bone Miner Res. 2017;32(7):1496–504.
  1. Wu M, Chen G, Li YP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009.
  1. Grafe I, Yang T, Alexander S, Homan EP, Lietman C, Jiang MM, Bertin T, Munivez E, Chen Y, Dawson B, Ishikawa Y. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med. 2014;20(6):670.
  1. Multicenter study to evaluate safety of freolimumab treatment in adults with moderate to severe OI. 2019. Available from: https://www.rarediseasesnetwork.org/cms/bbd/studies/7706. [cited December 20 2018].
  2. Le Blanc K, Gotherstrom C, Ringden O, Hassan M, McMahon R, Horwitz E, et al. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation. 2005;79(11):1607–14.
  1. Gotherstrom C, Westgren M, Shaw SW, Astrom E, Biswas A, Byers PH, et al. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl Med. 2014;3(2):255–64.
  1. The BOOSTB4 consortium. 2019. Available from: https://www.boostb4.eu/. [cited February 20 2019].
  2. Crouzin-Frankel J. The savior cells? Science. 2016;352(6283):284–7.
  1. Chevrel G, Cimaz R. Osteogenesis imperfecta: new treatment options. Curr Rheumatol Rep. 2006;8(6):474–9.
  1. Shapiro JR, Rowe DW. Genetic approach to treatment of osteogenesis imperfecta in Osteogenesis imperfecta. 1st ed. London: Elsevier Science and Technology; 2013.
  1. Berman AG, Wallace JM, Bart ZR, Allen MR. Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta. Matrix Biol. 2016;52:19–28.
  1. Whyte MP. Hypophosphatasia: an overview for 2017. Bone. 2017;102:15–25.
  1. Bowden SA, Foster BL. Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy. Drug Des Devel Ther. 2018;12:3147.
  1. Mornet E, Nunes ME. Hypophosphatasia. Gene Rev. 2016; Available from: https://www.ncbi.nlm.nih.gov/books/NBK1150/. [cited December 20 2018].
  2. Nishioka T, Tomatsu S, Gutierrez MA, Miyamoto KI, Trandafirescu GG, Lopez PL, et al. Enhancement of drug delivery to bone: characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol Genet Metab. 2006;88:244–55.
  1. Uçaktürk SA, Elmaogullari S, Ünal S, Gönülal D, Mengen E. Enzyme Replacement Therapy in Hypophosphatasia. J Coll Physicians Surg Pak. 2018;28(9):S198–200.
  1. Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res. 2017;32(10):1977–80.
  1. Iijima O, Miyake K, Watanabe A, Miyake N, Igarashi T. Kanokoda C, et al Prevention of lethal murine hypophosphatasia by neonatal ex vivo gene therapy using lentivirally transduced bone marrow cells. Hum Gene Ther. 2015;26(12):801–12.
  1. Kaunitz JD, Yamaguchi DT. TNAP, TrAP, ecto-purinergic signaling, and bone remodeling. J Cell Biochem. 2008;105(3):655–62.
  1. Seefried L, Baumann J, Hemsley S, Hofmann C, Kunstmann E, Kiese B, et al. Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia. J Clin Invest. 2017;127(6):2148–58.
  1. Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr J. 2015:EJ15–0275.
  2. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol. 2016;174(2):125–36.
  1. Sagnowsky E. U.K. cost watchdogs turn away rare disease med Crysvita. 2018. Available from: https://www.fiercepharma.com/pharma/u-k-cost-watchdogs-turn-away-rare-disease-med-crysvita. [cited November 13 2018].
  1. Mckee, S. NICE u-turn approves funding for rare disease therapy Crysvita. 2018. Available from: http://www.pharmatimes.com/news/nice_u-turn_approves_funding_for_rare_disease_therapy_crysvita_1251387. [cited November 13 2018].
  1. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–33.
  1. Squires LA, Prangley J. Neonatal diagnosis of Schwartz-Jampel syndrome with dramatic response to carbamazepine. Pediatr Neurol. 1996;15(2):172–4.
  1. Mullan LA, Mularczyk EJ, Kung LH, Forouhan M, Wragg JM, Goodacre R, et al. Increased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfism. J Clin Invest. 2017;127(10):3861–5.
  1. Meng Q, Chen X, Sun L, Zhao C, Sui G, Cai L. Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetylation of Hsp90. Mol Cell Biochem. 2011;348(1-2):165–71.
  1. MCDS Therapy. Towards treatment for this rare bone disease. https://mcds-therapy.eu/. Accessed 1 May 2019.
  2. Caja L, Bellomo C, Moustakas A. Transforming growth factor β and bone morphogenetic protein actions in brain tumors. FEBS Lett. 2015;589(14):1588–97.
  1. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):303ra137.
  1. Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci U S A. 2015;112(50):15438–43.
  1. Pacifici M. Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial. Bone. 2018;109:267–75.
  1. Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17(4):454–60.
  1. Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, et al. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) mutation. J Bone Miner Res. 2016;31(9):1666–75.
  1. Kaplan F. HE, Baujat G., Keen R., Grogan D., Pignolo R. Efficacy and Safety of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP): A Randomized, PlaceboControlled, Double-Blind Study. J Bone Miner Res. 2017. 32 (Suppl1).
  2. Wentworth KL, Masharani U, Hsiao EC. Therapeutic Advances for Blocking Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva. Brit J Clin Pharmacol. 2018.
  3. Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, et al. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone. 2018;109:276–80.
  1. Shrivats AR, Hollinger JO. The delivery and evaluation of RNAi therapeutics for heterotopic ossification pathologies. Biomimetics and Stem Cells. New York: Humana Press; 2013. p. 149–60.
  1. Fisher TJ, Williams N, Morris L, Cundy PJ. Metachondromatosis: more than just multiple osteochondromas. J Child Orthop. 2013;7(6):455–64.
  1. Pacifici M. Hereditary multiple exostoses: new insights into pathogenesis, clinical complications, and potential treatments. Curr Osteopor Rep. 2017;15(3):142–52.
  1. Mcfarlane J, Knight T, Sinha A, Cole T, Kiely N, Freeman R. Exostoses, enchondromatosis and metachondromatosis; diagnosis and management. Acta Orthop Belg. 2016;82(1).
  2. Burgetova A, Matejovsky Z, Zikan M, Slama J, Dundr P, Skapa P, et al. The association of enchondromatosis with malignant transformed chondrosarcoma and ovarian juvenile granulosa cell tumor (Ollier disease). Taiwan J Obstet Gyne. 2017;56(2):253–7.
  1. Fei L, Ngoh C, Porter DE. Chondrosarcoma transformation in hereditary multiple exostoses: A systematic review and clinical and cost-effectiveness of a proposed screening model. J Bone Oncol. 2018;13:114–22.
  1. Prokopchuk O, Andres S, Becker K, Holzapfel K, Hartmann D, Friess H. Maffucci syndrome and neoplasms: a case report and review of the literature. BMC Res Notes. 2016;9:126.
  1. Riou S, Morelon E, Guibaud L, Chotel F, Dijoud F, Marec-Berard P. Efficacy of rapamycin for refractory hemangioendotheliomas in Maffucci's syndrome. J Clin Oncol. 2012;30(23):e213–5.
  1. Li Z, Zhao B, Zhang Y, Tu C, Zheng Y, He X, Xiao S. Failure of rapamycin in the treatment of multiple haemangiomas associated with Maffucci syndrome. Clin Exp Dermatol. 2015;40(8):951–4.
  1. Clementia Pharmaceuticals. MO-Ped Trial for MO. 2018. Available from: https://clementiapharma.com/clinical-trials/#mo-ped-trial. [cited December 4 2018].
  1. Shih F, Inubushi T, Lemire I, Gossen R, Grogan D, Yamaguchi Y. Efficacy of palovarotene on prevention of osteochondroma formation in the Fsp1-Ext1 conditional knockout mouse model of Multiple Osteochondromas (MO). Poster presentation at the 13th meeting of ISDS, 2017. 2017. Available from: https://clementiapharma.com/our-pipeline/#palovarotene-mo. [cited December 4 2018].
  1. Silve C, Jüppner H. Ollier disease. Orphanet J Rare Dis. 2006;1(1):37.
  1. O’Neil MJF, McCusik V. Genochondromatosis. 2016. Available from: https://www.omim.org/entry/137360. [cited on February 2 2019].
  1. Wirth T, Parker N, Ylä-Herttuala S. History of gene therapy. Gene. 2013;525(2):162–9.
  1. Herper, M. Spark Therapeutics Sets Price Of Blindness-Treating Gene Therapy At $850,000. Forbes. 2018. [cited January 4 2019].
  1. Moschos, S. Gene therapy is now available but could cost millions over a lifetime, says scientist. The Independent. 2018. Available from: https://www.independent.co.uk/life-style/health-and-families/gene-therapy-cost-rare-genetic-diseases-treatment-expensive-research-a8275391.html accessed on 21.2.19. [cited January 2 2019].
  1. Personal Reference. Mooney P. Drug Development for Rare Disease [oral presentation]. Glaxosmith Kline, National Rare Disease Symposium, University of Birmingham. May17 2018.

 

  • rare bone disorders
  • osteoporosis
  • new treatments
  • bone remodeling
  • pycnodysostosis
  • sclerosteosis
  • van Buchem disease