Calcified Tissue International

, Volume 104, Issue 4, pp 355–363 | Cite as

Annual Injection of Zoledronic Acid Improves Bone Status in Children with Cerebral Palsy and Rett Syndrome

  • Arnaud WiedemannEmail author
  • Emeline Renard
  • Magali Hernandez
  • Brigitte Dousset
  • François Brezin
  • Laetitia Lambert
  • Georges Weryha
  • François Feillet
Original Research


Osteoporosis is a common complication of cerebral palsy and Rett’s syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett’s syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett’s syndrome. 27 children under 18 years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1 mg/kg (max 4 mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. One year after injection of ZA, we observe an increase of Lumbar spine BMD from − 2.99 to − 2.14 SD (p < 0.0001) and femoral BMD from − 4.26 to − 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from − 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.



The authors would like to thank Mrs. Henrion-Felter for her help to regroup medical records, to Mrs. Saunier for her work on the ethic agreement of the study, and the families for their agreement.

Compliance with Ethical Standards

Conflict of interest

Arnaud Wiedemann, Emeline Renard, Magali Hernandez, Brigitte Dousset, François Brezin, Laetitia Lambert, Georges Weryha, and François Feillet declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

A written information with adverse events related to ZA utilization was given to every parents or legal guardians. Clinical trial has been approved by the Ethical Review Committee of the University Hospital of Nancy and is registered with the CNIL (French Institutional Ethics Committee of Protection and Liberties registration number: R2017-03). All clinical investigations were conducted in accordance to the Declaration of Helsinki.


  1. 1.
    Mergler S et al (2009) Epidemiology of low bone mineral density and fractures in children with severe cerebral palsy: a systematic review. Dev Med Child Neurol 51:773–778CrossRefGoogle Scholar
  2. 2.
    Jefferson A et al (2016) Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence. PLoS ONE 11:e0146824CrossRefGoogle Scholar
  3. 3.
    Lambert A-S et al (2017) Lower incidence of fracture after IV bisphosphonates in girls with Rett syndrome and severe bone fragility. PLoS ONE 12:e0186941CrossRefGoogle Scholar
  4. 4.
    Bishop N et al (2014) Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions. J Clin Densitom 17:275–280CrossRefGoogle Scholar
  5. 5.
    Henderson RC et al (2002) Bisphosphonates to treat osteopenia in children with quadriplegic cerebral palsy: a randomized, placebo-controlled clinical trial. J Pediatr 141:644–651CrossRefGoogle Scholar
  6. 6.
    Reid IR et al (2018) Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med. Google Scholar
  7. 7.
    Ward L et al. Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Cochrane Database Syst Rev (2007). Google Scholar
  8. 8.
    August KJ et al (2011) The use of zoledronic acid in pediatric cancer patients. Pediatr Blood Cancer 56:610–614CrossRefGoogle Scholar
  9. 9.
    Sezer RG et al (2012) Comparison of oral alendronate versus prednisolone in treatment of infants with vitamin D intoxication. Acta Paediatr 101:e122–e125CrossRefGoogle Scholar
  10. 10.
    Baroncelli GI, Bertelloni S (2014) The use of bisphosphonates in pediatrics. Horm Res Paediatr 82:290–302CrossRefGoogle Scholar
  11. 11.
    Simm PJ et al (2011) Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis. Bone 49:939–943CrossRefGoogle Scholar
  12. 12.
    Munns CF et al (2007) Acute phase response and mineral status following low dose intravenous zoledronic acid in children. Bone 41:366–370CrossRefGoogle Scholar
  13. 13.
    Bowden SA, Mahan JD (2017) Zoledronic acid in pediatric metabolic bone disorders. Transl Pediatr 6:256–268CrossRefGoogle Scholar
  14. 14.
    Jefferson A et al (2015) Longitudinal bone mineral content and density in Rett syndrome and their contributing factors. Bone 74:191–198CrossRefGoogle Scholar
  15. 15.
    Otaify GA et al (2016) Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study. Osteoporos Int 27:81–92CrossRefGoogle Scholar
  16. 16.
    Favia G, Tempesta A, Limongelli L, Crincoli V, Maiorano E (2016) Medication-related osteonecrosis of the jaw after once-a-year intravenous zoledronic acid infusion for osteoporosis: report of eight cases. Quintessence Int 47:433–440Google Scholar
  17. 17.
    Pirbhai A et al (2015) Bisphosphonate-induced orbital inflammation: a case series and review. Orbit 34:331–335CrossRefGoogle Scholar
  18. 18.
    Trivedi S et al (2016) Severe non-infective systemic inflammatory response syndrome, shock, and end-organ dysfunction after zoledronic acid administration in a child. Osteoporos Int 27:2379–2382CrossRefGoogle Scholar
  19. 19.
    Riley A, Vadeboncoeur C (2012) Nutritional differences in neurologically impaired children. Paediatr Child Health 17:e98–e101CrossRefGoogle Scholar
  20. 20.
    Coppola G et al (2009) Bone mineral density in children, adolescents, and young adults with epilepsy. Epilepsia 50:2140–2146CrossRefGoogle Scholar
  21. 21.
    Fehlings D et al (2012) Informing evidence-based clinical practice guidelines for children with cerebral palsy at risk of osteoporosis: a systematic review. Dev Med Child Neurol 54:106–116CrossRefGoogle Scholar
  22. 22.
    Johnston CC et al (1992) Calcium supplementation and increases in bone mineral density in children. N Engl J Med 327:82–87CrossRefGoogle Scholar
  23. 23.
    Budden SS, Gunness ME (2001) Bone histomorphometry in three females with Rett syndrome. Brain Dev 23(Suppl 1):S133–S137CrossRefGoogle Scholar
  24. 24.
    Motil KJ, Schultz RJ, Abrams S, Ellis KJ, Glaze DG (2006) Fractional calcium absorption is increased in girls with Rett syndrome. J Pediatr Gastroenterol Nutr 42:419–426CrossRefGoogle Scholar
  25. 25.
    Motil KJ, Barrish JO, Neul JL, Glaze DG (2014) Low bone mineral mass is associated with decreased bone formation and diet in girls with Rett syndrome. J Pediatr Gastroenterol Nutr 59:386–392CrossRefGoogle Scholar
  26. 26.
    Blue ME et al (2015) Osteoblast function and bone histomorphometry in a murine model of Rett syndrome. Bone 76:23–30CrossRefGoogle Scholar
  27. 27.
    Mergler S et al (2012) Lumbar spine and total-body dual-energy X-ray absorptiometry in children with severe neurological impairment and intellectual disability: a pilot study of artefacts and disrupting factors. Pediatr Radiol 42:574–583CrossRefGoogle Scholar
  28. 28.
    Mergler S et al (2016) Automated radiogrammetry is a feasible method for measuring bone quality and bone maturation in severely disabled children. Pediatr Radiol 46:1017–1022CrossRefGoogle Scholar
  29. 29.
    Palomo T et al (2015) Intravenous bisphosphonate therapy of young children with osteogenesis imperfecta: skeletal findings during follow up throughout the growing years. J Bone Miner Res 30:2150–2157CrossRefGoogle Scholar
  30. 30.
    Bianchi ML et al (2000) Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: a prospective multicenter study. Arthritis Rheum 43:1960–1966CrossRefGoogle Scholar
  31. 31.
    Lee JM, Kim JE, Bae SH, Hah JO (2013) Efficacy of pamidronate in children with low bone mineral density during and after chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Res 48:99–106CrossRefGoogle Scholar
  32. 32.
    Iwasaki T et al (2008) Secondary osteoporosis in long-term bedridden patients with cerebral palsy. Pediatr Int 50:269–275CrossRefGoogle Scholar
  33. 33.
    Bachrach SJ, Kecskemethy HH, Harcke HT, Hossain J (2010) Decreased fracture incidence after 1 year of pamidronate treatment in children with spastic quadriplegic cerebral palsy. Dev Med Child Neurol 52:837–842CrossRefGoogle Scholar
  34. 34.
    Sees JP et al (2016) Pamidronate treatment to prevent reoccurring fractures in children with cerebral palsy. J Pediatr Orthop 36:193–197CrossRefGoogle Scholar
  35. 35.
    Strampel W, Emkey R, Civitelli R (2007) Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Saf 30:755–763CrossRefGoogle Scholar
  36. 36.
    Silverman SL et al (2011) Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid. Osteoporos Int 22:2337–2345CrossRefGoogle Scholar
  37. 37.
    Kreutle V et al (2014) Bisphosphonate induced hypocalcaemia—report of six cases and review of the literature. Swiss Med Wkly 144:w13979Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Arnaud Wiedemann
    • 1
    • 2
    • 4
    Email author
  • Emeline Renard
    • 3
    • 4
  • Magali Hernandez
    • 5
  • Brigitte Dousset
    • 6
  • François Brezin
    • 3
  • Laetitia Lambert
    • 7
  • Georges Weryha
    • 8
  • François Feillet
    • 1
    • 3
    • 4
  1. 1.Centre de référence des erreurs innées du métabolisme, Hôpital d’EnfantsCHRU NancyNancyFrance
  2. 2.Réanimation pédiatrique spécialisée, Hôpital d’enfantsCHRU NancyNancyFrance
  3. 3.Service de Médecine Infantile, Hôpital d’enfantsCHRU NancyNancyFrance
  4. 4.Faculté de médecineINSERM U-1256Vandoeuvre les NancyFrance
  5. 5.Service d’OdontologieCHU NancyNancyFrance
  6. 6.Service de BiochimieCHU NancyNancyFrance
  7. 7.Service de Génétique CliniqueCHU NancyNancyFrance
  8. 8.Service d’EndocrinologieCHU NancyNancyFrance

Personalised recommendations