Considerações sobre o uso dos bisfosfonatos intravenosos no tratamento da osteogenese imperfeita

• Ano de defesa: 2016
• Autor(a) principal: Oliveira, Telma Palomo de [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/48912/001300002gc3h
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Osteogeneses imperfecta; Bisphosphonate; Bisfosfonatos; Osteogeneses imperfeita
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3599791; http://repositorio.unifesp.br/handle/11600/47481

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that is mainly characterized by bone fragility, low bone mass and bone deformities. The intravenous bisphosphonate therapy, particularly the pamidronate, has been used widely for the treatment of children with moderate to severe OI. In the standard protocol, pamidronate is given over 4 h on 3 successive days. These infusion cycles are repeated every 2 to 4 months (according to the age group). In addition, many knowledge gaps remain in particular regarding long-term safety and efficacy of bisphosphonate treatment. Objectives: Evaluate the following specific aspects of intravenous bisphosphonate therapy in OI patients: 1- evaluated safety and efficacy of a simpler protocol with pamidronate. 2- Describe the long-term treatment outcomes with intravenous bisphosphonate. Patients and Methods: 1- This was a prospective study and comprised 18 patients with a clinical diagnosis of OI type I (n=9), III (n=4) and IV (n=5), who were seen in the Bone Fragility Clinic from the São Paulo Hospital, UNIFESP; patients received intravenous pamidronate infusion in a single dose of 2 mg per kg body weight over a 2-h period, every 4 months during 1 year. Biochemical profile, including serum levels of creatinine, sodium, potassium, calcium, phosphorus, microalbuminuria, urine volume and glomerular filtration rate (GFR) were performed during 1 week every each infusion. Kidney ultrasound, bone densitometry and X-ray films were performed during the study. The safety and efficacy data from this group were compared to historic controls, treated with standard protocol that received pamidronate treatment intravenously over 4 h at a dose of 1 mg per kg body weight on 3 consecutive days. Cycles were repeated every 4 months. 2- Restrospective chart review study reviewed 37 children with OI (OI type I, n=1; OI type III, n=14; and OI type IV, n=22) who were followed at the Shriners Hospital for Children?Canada, in Montreal and who started intravenous bisphosphonate therapy before 5 years of age and who had a subsequent follow-up period of at least 10 years (median 14.8 years), during which they had received intravenous pamidronate or zoledronic acid treatment for at least 6 years during growth. Anthropometry, lumbar spine densitometry, clinical-surgical parameters and markers of bone metabolism were performed during the follow-up period. Results: 1- The participants of the modified protocol had a mild transient post-infusion increases in serum creatinine between 8 and 24 hours after intravenous pamidronate infusion but it was recovered to baseline value 7 days after each infusion. At the end of the study, mean serum creatinine levels remained similar from baseline (baseline: 0.40 ± 0.13 mg/dl end of study: 0.41 ± 0.11 mg/dl; p=0.79). The two protocols led to similar changes in serum creatinine during the first pamidronate infusion (modified protocol: +2 % ± 21 %; standard protocol: -3 % ± 8 %; p= 0.32). Serum calcium and phosphorus decreased similarly in both protocols during the first 24 h of the first pamidronate infusion. Areal lumbar spine bone mineral density Z-scores increased similarly in both protocols (from -2.7 ± 1.5 to -1.8 ± 1.4 with the modified protocol, and from -4.1 ± 1.4 to -3.1 ± 1.1 with standard protocol, p= 0.68) 2- During the observation period, the mean lumbar spine areal bone mineral density Z-score (LS-aBMD) increased from ?6.6 ± 3.1 to ?3.0 ± 1.8 (p<0,001), and weight Z-score increased from ?2.3 ± 1.5 to ?1.7 ± 1.7 (p=0.008). At the time of the last assessment, patients with OI type IV had significantly higher height Z-scores than a control group of patients matched for age, gender, and OI type. Patients had a median of six femur fractures and five tibia fractures during the follow-up period. At baseline, 35% of vertebra were affected by compression fractures, whereas only 6% of vertebra appeared compressed at the last evaluation (p< 0.001), indicating vertebral reshaping during the treatment. Nevertheless, 43% of the pacients needed spinal fusion surgery for scoliosis treatment. Conclusions: 1- The modified pamidronate protocol with a shorter infusion (sigle dose, over 2-h period) for the treatment of children and adolescents with OI did not led to impairment in the renal function and showed an increase in LS-aBMD during the follow-up period, with similar effects on bone density as the standard pamidronate protocol. 2- The long-term intravenous bisphosphonate therapy was associated with higher Z-scores for lumbar spine areal bone mineral density, an improvement in vertebral reshaping and in the weight Z-score. In the patients with OI type IV, an addicional benefit could be seen on height Z-score. However, long-bone fracture rates were still high and some patients developed scoliosis progression.