Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. Osteoporotic fractures lead to considerable morbidity and mortality, making osteoporosis a major public health problem. While the diagnosis is usually made at adult age, the disease often has its onset in childhood. In addition to adverse lifestyle factors, genetic factors play an important role. Recent studies have identified new genes that are involved in bone mass accrual and pathogenesis of osteoporosis.

The aim of our group is to identify new genes involved in the development of osteoporosis and to study the role of previously characterized genes and their variation in osteoporosis. New information about the genetic causes of osteoporosis enables development of improved tools for effective screening and early treatment.
We have characterized several individuals and large families with childhood-onset osteoporosis, presenting with multiple spinal crush fractures by early adulthood. In one such family we identified WNT1 as the underlying gene for a new form of inherited osteoporosis. In several other individuals and families we have been able to show that skeletal fragility is caused by a mutation in a gene that plays a major role in skeletal homeostasis. Encouraged by these discoveries we continue to recruit from Finland and from international collaborators families with inherited early-onset osteoporosis of unknown cause to further expand our understanding of the molecular mechanisms underlying osteoporosis.

Skeletal dysplasias are a heterogeneous group of mostly monogenic disorders with various skeletal abnormalities. We have studied clinical characteristics and the underlying genetic defects in several conditions. Some skeletal dysplasias, including cartilage-hair hypoplasia (CHH), Shwachman-Diamond syndrome and CRMCC, associate with immune deficiency and can be used as models to explore the crosstalk between the immune system and the skeleton. We presently recruite patients with CHH to our studies on immune functions and anemia. In several skeletal dysplasias the underlying cause is unknown and our research aims to identify the disease-causing gene defect and molecular pathology in these disorders.   

A decade ago, vitamin D deficiency was common in pregnant women, infants, school children, and in children with chronic illness or frequent fractures. Vitamin D deficiency was associated with low bone mineral density (BMD), as measured by bone densitometry or peripheral quantitative CT (pQCT), even in newborns, and with unfavorable bone histology. However, based on our recent studies, vitamin D status has improved and is generally sufficient in pregnant women and newborns. This is mainly due to increased vitamin D food fortification, updated vitamin D recommendations and public awareness. We have carried out three vitamin D intervention studies. These studies provided pilot data for our large-scale vitamin D intervention in infants study (VIDI). VIDI 6 years follow-up study is ongoing, and in near future we will understand more about the impact of vitamin D in early childhood to later health outcomes.

Obesity is a complex disorder with various contributing genetic and environmental factors. Recent scientific discoveries show that the skeleton also plays an important role in whole-body homeostasis by secreting hormones that participate in energy metabolism and appetite regulation. The genetic causes and mechanisms for severe childhood obesity are still incompletely understood. It is acknowledged that obesity in some individuals and families could be a consequence of rare genetic variants with strong effect – these rare variants might be population specific. We aim to identify new obesity-related genetic variants and disease-causing gene mutations and determine their association with clinical manifestations in families with childhood-onset severe obesity. The study will increase our understanding of the pathogenesis of obesity and provide new tools for early diagnosis and targeted prevention.

Osteoporosis caused by an underlying illness and/or its treatment is defined as secondary. Any chronic illness or medication that impairs normal accrual of bone mass may have long-term effects on bone health. In addition, several other factors, such as chronic inflammation, impaired physical activity, genetic factors and hormonal or nutritional defects may predispose to impaired bone health. Due to the wide variety of potential risk factors, the incidence and prevalence of secondary osteoporosis depend on the diagnosis and age of onset of the underlying cause, its severity and duration, and on the applied therapeutic interventions and medications. In epidemiological and clinical studies, we have shown that osteoporosis is a common complication of chronic pediatric illnesses. For example, juvenile idiopathic arthritis, neuromuscular disorders and solid organ or stem cell transplantation have adverse skeletal effects that persist until adulthood.

Our ongoing studies aim to further characterize risk factors and treatment results in secondary osteoporosis and to explore the involved pathological processes on the tissue level using transilial bone biopsies. Understanding the underlying pathology enables development of targeted prevention and treatment strategies for pediatric osteoporosis. 

LELU Study

LELU project (LELU = Acronym from the Finnish words “Leukemia” and “Luu”, bone) is a prospective follow-up study investigating bone health in childhood leukemia.

Bone health is often compromised in children with leukemia, especially in acute lymphoblastic leukemia (ALL), the most common malignancy in childhood. The most important bone complications, osteoporosis and osteonecrosis, are well known, but their pathomechanisms in childhood leukemia remain incompletely understood. Therefore, this study aims to shed light on the tissue-level pathology underlying skeletal complications in childhood leukemia.

All children diagnosed with ALL or acute myeloid leukemia (AML) at Children’s Hospital, Helsinki University Hospital between 2019 and 2021 will be provided the opportunity to participate in the study. The patients will undergo initial clinical evaluation and sample collection at the time of diagnosis, and are then followed throughout until the end of treatment. Long-term follow up will continue at least 5 years after completion of leukemia treatment.

We will use innovative techniques to analyze the routine samples taken for diagnostic purposes: bone marrow aspirate, bone marrow biopsy and blood. Bone structural and functional characteristics will be studied with several novel methods, including quantitative backscattered electron imaging and microRNA panels. Bone characteristics and their changes during treatment are correlated with patient and disease characteristics.

Skeletal complications can significantly impair the quality of life in childhood leukemia survivors, despite the otherwise excellent outcome and high survival rate (up to 90 %). Therefore, the ultimate aim of the project is to gain better understanding of the tissue-level changes in bone structure and function to enable development of targeted prevention and treatment strategies for bone complications in childhood leukemia.

Principal investigator: Pauliina Utriainen