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A Osteogênese Imperfeita (OI) é uma doença genética do tecido conjuntivo caracterizada por fragilidade óssea e susceptibilidade à fratura sob mínimo ou nenhum trauma. O objetivo deste trabalho foi estudar características clínicas e moleculares de crianças e adultos com Osteogênese Imperfeita e analisar o efeito do tratamento medicamentoso com bifosfonados em relação aos biomarcadores metabólicos e ósseos em pacientes adultos. Esta tese se dividiu em dois capítulos onde 1) foi realizado um estudo retrospectivo sobre as características clínicas no momento do diagnóstico de OI, com ênfase nas características clínicas, especialmente em relação às fraturas ósseas; 2) avaliação clínica e análise da mutação c.-14C>T no gene IFITM5 foi estuda em uma população com características sugestivas de OI tipo V; e 3) estudo retrospectivo em adultos com OI divididos em 2 grupos tratados com bifosfonados e não tratados. Em relação ao tratamento com bifosfonados foram avaliados os seguintes parâmetros: tipo de droga e duração do tratamento, valores de biomarcadores metabólicos e ósseos por um período de 5 anos, incidência de fraturas num de período de 5 ou 10 anos e densidade mineral óssea da coluna lombar, quadril total e colo femural no início e no final do tratamento. Nossos resultados mostraram que 1) no momento do diagnósico de OI características como escleras azuladas, dentinogênese imperfeita, ossos wormianos e fraturas de membros inferiores e superiores podem ser observadas. Pacientes com formas mais graves de OI foram diagnosticados mais precocemente quando comparados com pacientes com formas leves. Nenhuma criança com OI apresentou fraturas posteromediais das costelas, fratura de escápula ou lesões metafisárias. Essas informações associadas a história da saúde da criança são relevantes para a realização do diagnóstico diferencial. 2) OI tipo V correspondeu a 4% dos casos de OI atendidos no Centro de Referência para OI do HCPA. Indivíduos com OI V associada a mutação c.-14C> T no gene IFITM5 apresentaram características clínicas distintas como formação de calo hiperplásico, calcificação das membranas interósseas, deslocamento da cabeça radial e deformidade de coluna, porém a expressão da doença é variável. 3) Observamos que o tratamento de adultos com OI a longo prazo não foi associado com redução na incidência das fraturas e não se refletiu de forma significativa nos níveis de biomarcadores metabólicos e ósseos, porém houve uma melhora significativa na densidade mineral óssea da coluna lombar associada à terapia. Por ser uma doença rara com prevalência variável e ampla variabilidade fenotípica e genotípica, estudos clínicos e moleculares bem como estudos sobre o efeito do tratamento medicamentoso são imprescindíveis, contribuindo no melhor entendimento da doença, aconselhamento genético acurado e propiciando melhores estratégias de prevenção e tratamento para esta população. / Osteogenesis Imperfecta (OI) is a genetic connective tissue disease characterized by bone fragility and susceptibility to fracture under minimal or no trauma. The aim of this study was to evaluate clinical and molecular features of children and adults with OI and analyze the effect of the drug treatment with bisphosphonates in regarding to metabolic and bone biomarkers in adult patients. This thesis was divided by two chapters: 1) a retrospective study was performed where the clinical characteristic at the moment of diagnosis of OI, the clinical characteristics specially related to bone fractures was evaluated; 2) clinical evaluation and mutation analysis of c.-14C>T in the IFITM5gene was studied in a population with clinical charcteristics suggestive of OI type V; and 3) retrospective study in adults with OI divided in two groups treated with biphosphonates and not treated. Bisphosphonate treatment was evaluated according to the parameters: type of drug and duration of treatment, metabolic and bone biomarkers values for a period of 5 years, incidence of fractures in a period of 5 or 10 years and bone mineral density of the lumbar spine, total hip and femoral neck at baseline and at the end of treatment. Our results showed that 1) at the time of OI diagnosis features such as bluish slerae, dentinogenis imperfecta, wormian bones, and fractures of upper and lower limbs can be observed. Patients with more severe forms of OI were diagnosed earlier when compared with patients with mild forms. No OI children presented posteromedial fractures of the ribs, scapula fracture or metaphyseal lesions. This information associated with the child's health history are relevant for carrying out the differential diagnosis. This information is relevant for carrying out the differential diagnosis. 2) OI type V corresponds to 4% of OI cases at the Reference Center for OI at HCPA. Subjects with OI V associated to the mutation c.-14C> T in the IFITM5 gene presented distinctives clinical features as hyperplastic callus formation, calcification of interosseous membranes, dislocation of the radial head and spinal deformity, but the expression of the disease is variable. 3) We observed that long-term treatment with bisphosphonates (BP) for adults with OI was not associated with reduced incidence of fractures and was not reflected significantly in the levels of metabolic and bone biomarkers, but there was a significant improvement in bone mineral density of the lumbar spine associated to the therapy. Because it is a rare disease with a prevalence variable and wide phenotypic and genotypic variability, clinical and molecular studies and studies of the effect of drug treatment are essential, contributing to the better understanding of the disease, accurate genetic counseling and providing better strategies for prevention and treatment for this population.

A Osteogênese Imperfeita (OI) é uma doença genética do tecido conjuntivo caracterizada por fragilidade óssea e susceptibilidade à fratura sob mínimo ou nenhum trauma. O objetivo deste trabalho foi estudar características clínicas e moleculares de crianças e adultos com Osteogênese Imperfeita e analisar o efeito do tratamento medicamentoso com bifosfonados em relação aos biomarcadores metabólicos e ósseos em pacientes adultos. Esta tese se dividiu em dois capítulos onde 1) foi realizado um estudo retrospectivo sobre as características clínicas no momento do diagnóstico de OI, com ênfase nas características clínicas, especialmente em relação às fraturas ósseas; 2) avaliação clínica e análise da mutação c.-14C>T no gene IFITM5 foi estuda em uma população com características sugestivas de OI tipo V; e 3) estudo retrospectivo em adultos com OI divididos em 2 grupos tratados com bifosfonados e não tratados. Em relação ao tratamento com bifosfonados foram avaliados os seguintes parâmetros: tipo de droga e duração do tratamento, valores de biomarcadores metabólicos e ósseos por um período de 5 anos, incidência de fraturas num de período de 5 ou 10 anos e densidade mineral óssea da coluna lombar, quadril total e colo femural no início e no final do tratamento. Nossos resultados mostraram que 1) no momento do diagnósico de OI características como escleras azuladas, dentinogênese imperfeita, ossos wormianos e fraturas de membros inferiores e superiores podem ser observadas. Pacientes com formas mais graves de OI foram diagnosticados mais precocemente quando comparados com pacientes com formas leves. Nenhuma criança com OI apresentou fraturas posteromediais das costelas, fratura de escápula ou lesões metafisárias. Essas informações associadas a história da saúde da criança são relevantes para a realização do diagnóstico diferencial. 2) OI tipo V correspondeu a 4% dos casos de OI atendidos no Centro de Referência para OI do HCPA. Indivíduos com OI V associada a mutação c.-14C> T no gene IFITM5 apresentaram características clínicas distintas como formação de calo hiperplásico, calcificação das membranas interósseas, deslocamento da cabeça radial e deformidade de coluna, porém a expressão da doença é variável. 3) Observamos que o tratamento de adultos com OI a longo prazo não foi associado com redução na incidência das fraturas e não se refletiu de forma significativa nos níveis de biomarcadores metabólicos e ósseos, porém houve uma melhora significativa na densidade mineral óssea da coluna lombar associada à terapia. Por ser uma doença rara com prevalência variável e ampla variabilidade fenotípica e genotípica, estudos clínicos e moleculares bem como estudos sobre o efeito do tratamento medicamentoso são imprescindíveis, contribuindo no melhor entendimento da doença, aconselhamento genético acurado e propiciando melhores estratégias de prevenção e tratamento para esta população. / Osteogenesis Imperfecta (OI) is a genetic connective tissue disease characterized by bone fragility and susceptibility to fracture under minimal or no trauma. The aim of this study was to evaluate clinical and molecular features of children and adults with OI and analyze the effect of the drug treatment with bisphosphonates in regarding to metabolic and bone biomarkers in adult patients. This thesis was divided by two chapters: 1) a retrospective study was performed where the clinical characteristic at the moment of diagnosis of OI, the clinical characteristics specially related to bone fractures was evaluated; 2) clinical evaluation and mutation analysis of c.-14C>T in the IFITM5gene was studied in a population with clinical charcteristics suggestive of OI type V; and 3) retrospective study in adults with OI divided in two groups treated with biphosphonates and not treated. Bisphosphonate treatment was evaluated according to the parameters: type of drug and duration of treatment, metabolic and bone biomarkers values for a period of 5 years, incidence of fractures in a period of 5 or 10 years and bone mineral density of the lumbar spine, total hip and femoral neck at baseline and at the end of treatment. Our results showed that 1) at the time of OI diagnosis features such as bluish slerae, dentinogenis imperfecta, wormian bones, and fractures of upper and lower limbs can be observed. Patients with more severe forms of OI were diagnosed earlier when compared with patients with mild forms. No OI children presented posteromedial fractures of the ribs, scapula fracture or metaphyseal lesions. This information associated with the child's health history are relevant for carrying out the differential diagnosis. This information is relevant for carrying out the differential diagnosis. 2) OI type V corresponds to 4% of OI cases at the Reference Center for OI at HCPA. Subjects with OI V associated to the mutation c.-14C> T in the IFITM5 gene presented distinctives clinical features as hyperplastic callus formation, calcification of interosseous membranes, dislocation of the radial head and spinal deformity, but the expression of the disease is variable. 3) We observed that long-term treatment with bisphosphonates (BP) for adults with OI was not associated with reduced incidence of fractures and was not reflected significantly in the levels of metabolic and bone biomarkers, but there was a significant improvement in bone mineral density of the lumbar spine associated to the therapy. Because it is a rare disease with a prevalence variable and wide phenotypic and genotypic variability, clinical and molecular studies and studies of the effect of drug treatment are essential, contributing to the better understanding of the disease, accurate genetic counseling and providing better strategies for prevention and treatment for this population.

A Osteogênese Imperfeita (OI) é uma doença genética do tecido conjuntivo caracterizada por fragilidade óssea e susceptibilidade à fratura sob mínimo ou nenhum trauma. O objetivo deste trabalho foi estudar características clínicas e moleculares de crianças e adultos com Osteogênese Imperfeita e analisar o efeito do tratamento medicamentoso com bifosfonados em relação aos biomarcadores metabólicos e ósseos em pacientes adultos. Esta tese se dividiu em dois capítulos onde 1) foi realizado um estudo retrospectivo sobre as características clínicas no momento do diagnóstico de OI, com ênfase nas características clínicas, especialmente em relação às fraturas ósseas; 2) avaliação clínica e análise da mutação c.-14C>T no gene IFITM5 foi estuda em uma população com características sugestivas de OI tipo V; e 3) estudo retrospectivo em adultos com OI divididos em 2 grupos tratados com bifosfonados e não tratados. Em relação ao tratamento com bifosfonados foram avaliados os seguintes parâmetros: tipo de droga e duração do tratamento, valores de biomarcadores metabólicos e ósseos por um período de 5 anos, incidência de fraturas num de período de 5 ou 10 anos e densidade mineral óssea da coluna lombar, quadril total e colo femural no início e no final do tratamento. Nossos resultados mostraram que 1) no momento do diagnósico de OI características como escleras azuladas, dentinogênese imperfeita, ossos wormianos e fraturas de membros inferiores e superiores podem ser observadas. Pacientes com formas mais graves de OI foram diagnosticados mais precocemente quando comparados com pacientes com formas leves. Nenhuma criança com OI apresentou fraturas posteromediais das costelas, fratura de escápula ou lesões metafisárias. Essas informações associadas a história da saúde da criança são relevantes para a realização do diagnóstico diferencial. 2) OI tipo V correspondeu a 4% dos casos de OI atendidos no Centro de Referência para OI do HCPA. Indivíduos com OI V associada a mutação c.-14C> T no gene IFITM5 apresentaram características clínicas distintas como formação de calo hiperplásico, calcificação das membranas interósseas, deslocamento da cabeça radial e deformidade de coluna, porém a expressão da doença é variável. 3) Observamos que o tratamento de adultos com OI a longo prazo não foi associado com redução na incidência das fraturas e não se refletiu de forma significativa nos níveis de biomarcadores metabólicos e ósseos, porém houve uma melhora significativa na densidade mineral óssea da coluna lombar associada à terapia. Por ser uma doença rara com prevalência variável e ampla variabilidade fenotípica e genotípica, estudos clínicos e moleculares bem como estudos sobre o efeito do tratamento medicamentoso são imprescindíveis, contribuindo no melhor entendimento da doença, aconselhamento genético acurado e propiciando melhores estratégias de prevenção e tratamento para esta população. / Osteogenesis Imperfecta (OI) is a genetic connective tissue disease characterized by bone fragility and susceptibility to fracture under minimal or no trauma. The aim of this study was to evaluate clinical and molecular features of children and adults with OI and analyze the effect of the drug treatment with bisphosphonates in regarding to metabolic and bone biomarkers in adult patients. This thesis was divided by two chapters: 1) a retrospective study was performed where the clinical characteristic at the moment of diagnosis of OI, the clinical characteristics specially related to bone fractures was evaluated; 2) clinical evaluation and mutation analysis of c.-14C>T in the IFITM5gene was studied in a population with clinical charcteristics suggestive of OI type V; and 3) retrospective study in adults with OI divided in two groups treated with biphosphonates and not treated. Bisphosphonate treatment was evaluated according to the parameters: type of drug and duration of treatment, metabolic and bone biomarkers values for a period of 5 years, incidence of fractures in a period of 5 or 10 years and bone mineral density of the lumbar spine, total hip and femoral neck at baseline and at the end of treatment. Our results showed that 1) at the time of OI diagnosis features such as bluish slerae, dentinogenis imperfecta, wormian bones, and fractures of upper and lower limbs can be observed. Patients with more severe forms of OI were diagnosed earlier when compared with patients with mild forms. No OI children presented posteromedial fractures of the ribs, scapula fracture or metaphyseal lesions. This information associated with the child's health history are relevant for carrying out the differential diagnosis. This information is relevant for carrying out the differential diagnosis. 2) OI type V corresponds to 4% of OI cases at the Reference Center for OI at HCPA. Subjects with OI V associated to the mutation c.-14C> T in the IFITM5 gene presented distinctives clinical features as hyperplastic callus formation, calcification of interosseous membranes, dislocation of the radial head and spinal deformity, but the expression of the disease is variable. 3) We observed that long-term treatment with bisphosphonates (BP) for adults with OI was not associated with reduced incidence of fractures and was not reflected significantly in the levels of metabolic and bone biomarkers, but there was a significant improvement in bone mineral density of the lumbar spine associated to the therapy. Because it is a rare disease with a prevalence variable and wide phenotypic and genotypic variability, clinical and molecular studies and studies of the effect of drug treatment are essential, contributing to the better understanding of the disease, accurate genetic counseling and providing better strategies for prevention and treatment for this population.

Globally, ~17 million women and ~2.1 million children are living with HIV. Sub-Saharan Africa accounts for 70% of HIV-infected (HIV+) persons. Mother-To-Child Transmission of HIV (MTCT) during pregnancy, delivery and breastfeeding, is the main route of HIV infection in children. The World Health Organisation recommends lifelong antiretroviral therapy (ART) for all HIV+ pregnant and breastfeeding mothers to prevent MTCT, and breastfeeding for ≥24 months for optimal child health in resource limited settings (Option B+ strategy). Initiation of ART in HIV+ adults is associated with a 2-6% decrease in areal bone mineral density (aBMD) regardless of ART regimen, but data are limited in pregnant and lactating women. Tenofovir, a preferred first-line drug in Option B+ ART regimen, is associated with 1-2% greater decreases in aBMD. Pregnancy and lactation are associated with physiological changes in maternal bone mineral density, but most evidence shows that this is recovered after cessation of breastfeeding. The hypothesis of this thesis is that ART may accentuate the normal process of bone mobilisation during pregnancy and lactation, leading to bone loss that is not recovered in the mother and/or compromised infant growth and bone mineral accretion. The primary objective of this research was to investigate if HIV+ women experience greater reductions in bone mineral compared to HIV-uninfected (HIV-) counterparts. Two groups of pregnant women, 95 HIV+ on ART (Tenofovir-Lamivudine-Efavirenz, previously ART naïve) and 96 HIV- were followed prospectively in Kampala, Uganda. Data were collected at 36 wks gestation (PG36), 2 (PP2) and 14 wks postpartum (PP14). Dual-energy x-ray absorptiometry was used to measure bone phenotype (aBMD, bone mineral content (BMC), bone area (BA), and size-adjusted BMC (SA-BMC, adjusted for height or length, weight and BA) of the whole body (WB) and lumbar spine (LS) in mother-baby pairs, and total hip (TH) in mothers. The primary outcome was the difference between groups in % change (± SE) in maternal LS aBMD between PP2 and PP14. Secondary outcomes included changes in maternal markers of bone formation (P1NP and BAP) and resorption (CTX), serum 25-hydroxy vitamin D (25(OH)D), parathyroid hormone (PTH), plasma and urine concentrations of creatinine (Cr), calcium (Ca), phosphate (PO4) and magnesium (Mg), urine mineral:creatinine ratios, TmCa/GFR and TMP/GFR, respectively), breastmilk mineral composition (Ca, P, Na, K and Na/K ratio); and infant growth Z-scores and bone mineral. Statistical models were adjusted for potential confounders. Median maternal age was 24.5 (IQR 21.1, 26.9) yrs. Mean gestation was 40.9±1.8 wks and not significantly different between groups. All women were breastfeeding at PP2 and PP14. More HIV+ women reported exclusive breastfeeding (PP2: 82.9% v 58.7%, p=0.0008; PP14: 86.7% v 66.2%, p=0.002). Body weight was 4-5% lower in HIV+ women. By PP14, mean duration of ART was 29.3±5.1 wks, adherence was > 95%, and the median CD4 count was 403 (IQR 290-528) cells/mm3. Maternal aBMD decreased between PP2 and PP14 at all skeletal sites in both groups as expected in lactation. Reductions in LS aBMD were not significantly different between groups (-1.8±0.4% vs -2.5±0.4%, p=0.3). However, HIV+ women had a significantly greater reduction in TH aBMD which persisted after adjustment for body size (-3.7±0.3% vs -2.7±0.3%, p=0.04). Median serum 25(OH)D was 67.4 nmol/L (IQR 54.8, 83.7) at PG36 and 57.6 nmol/L (48.7, 70.1) at PP14 with no significant difference between groups. Changes in 25(OH)D and PTH from PG36 to PP14 were not significantly different between groups (25(OH)D: -13.9±4.1% vs -11.1±3.1%; PTH: +60.0±6.4% vs +57.6±6.4%; both p > 0.05). However, HIV+ women had 33-35% greater plasma PTH concentrations at both PG36 and PP14. Bone formation and resorption markers increased in both groups between PG36 and PP14. HIV+ women had greater increases (CTX: +74.6±5.9% vs +56.2±5.9%; P1NP: +100.3±5.0% vs +72.6±5.0%; BAP: +67.2±3.6% vs +57.1±3.6%, all p < 0.05). They also had a greater decrease in plasma Ca (-6.6±0.5% vs-3.8±0.5%, p≤0.0001) and greater increase in plasma phosphate (+14.4±2.0% vs +7.7±2.0%, p=0.02). Changes in plasma Cr and Mg, TmP/GFR and urine mineral:creatinine ratios were not significantly different between the groups. However, at both PG36 and PP14, HIV+ had significantly lower mean plasma Ca (PG36: -1.0±0.5%; PP14: -4.1±0.6%) and TmP/GFR (PG36: -11.4±3.1%; PP14: -7.2±3.0%) but higher PTH (PG36: +33.0±7.0%; PP14: +35.3±7.6%) compared to HIV- women (all p < 0.05). Mean breastmilk Ca decreased between PP2 and PP14, and the changes were not different between the groups (-19.9±3.0% vs -24.2±3.1%, p=0.3). There were no significant changes in breastmilk phosphorus (P) in both groups, but HIV+ women had significantly higher concentrations (PP2: +9.7±3.8%, p=0.01; PP14:+9.6±3.5 %, p=0.007). Breastmilk P was significantly correlated with maternal plasma [CTX] in a separate ANCOVA model (β = +0.13±0.04% per 1% increase in CTX, p=0.0003). Mean breastmilk Na, K concentrations and Na/K decreased between PP2 and PP14 in both groups. However, HIV+ women had a smaller decrease in breastmilk Na (-44.3±8.9% vs -72.6±9.0%, p=0.03). They also had a trend towards smaller reduction in Na/K ratio (-22.2±9.3% vs -46.6.6±9.5%, p=0.07). Babies born to HIV+ mothers (HIV-exposed infants, HEI) had significantly lower gains in weight +53.0±1.4% vs +57.5±1.4%, p=0.02) compared to HIV-unexposed infants (HUI), and also lower weight-for-age (-0.47±0.16, p=0.003) and length-for-age (-0.53±0.18, p=0.005) Z-scores at PP14. HEI had a slower gain in WB BMC (+51.2±1.9% vs +57.3±1.9%, p=0.02), but the difference was not significant after adjustment for body size (-6.0±3.5% vs -7.6±3.8%, p=0.2); showing that the bone mineral accretion was appropriate for achieved infant size. In contrast, HEI had a greater increase in LS BMC (+29.5±1.7% vs +24.4±1.7%, p=0.03), a difference which remained after size-adjustment (+9.4±5.8% vs +4.3±6.2%, p=0.02). This is the first study to compare changes in maternal aBMD and bone metabolism between HIV+ mothers on Option B+ ART and HIV- counterparts. The results show a greater reduction in TH aBMD in Ugandan HIV+ women on Option-B+ ART compared to HIV- in the first three months of lactation, consistent with their greater increases in bone turnover markers, lower TmP/GFR and plasma phosphate, and higher breastmilk phosphorus concentration. Also, HEI have slower growth and whole body bone mineral accretion compared to HUI. It is important to determine if these changes are temporary or have long-term consequences for the bone health of the mother and child.