Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - Postępy Nauk Medycznych 1/2017, s. 27-30
*Marta Toboła, Magdalena Osińska, Ada Sawicka
Diabetes mellitus, osteoporosis and bone fractures
Cukrzyca, osteoporoza i złamania kości
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
Streszczenie
Częstość osteoporozy i cukrzycy (DM) jest alarmująca. Obie choroby mają zbliżone mechanizmy molekularne i predyspozycje genetyczne. Pacjenci z cukrzycą typu 1 (T1DM) charakteryzują się obniżoną gęstością mineralną kości (BMD), co częściowo tłumaczy zwiększone ryzyko złamań. Większość pacjentów z cukrzycą typu 2 (T2DM) ma normalną lub podwyższoną BMD, ale wyższe ryzyko złamań kości. Konwencjonalne metody diagnostyczne wykorzystywane u pacjentów podejrzewanych o osteoporozę, takie jak ocena ryzyka złamań (FRAX) i pomiary przy pomocy DXA, są niewystarczające u pacjentów z DM.
Leki przeciwcukrzycowe mogą dodatkowo zwiększyć lub zmniejszyć częstość złamań niskoenergetycznych. Tiazolidinediony redukują tworzenie tkanki kostnej oraz zwiększają jej resorpcję. Leki zwiększają ryzyko złamań, które wzrasta w miarę wydłużania czasu terapii. Insulina nieznacznie zwiększa częstość złamań, prawdopodobnie z powodu większej liczby epizodów hipoglikemii, która sprzyja upadkom. Metformina wywiera korzystny wpływ na różnicowanie się osteoblastów i zmniejsza częstość złamań u pacjentów z T2DM. Ważne jest, aby weryfikować obecność czynników ryzyka złamań u każdego pacjenta z cukrzycą i uwzględnić wyniki tej oceny przy wyborze terapii przeciwcukrzycowej.
Summary
The prevalence of osteoporosis and diabetes mellitus (DM) is alarming. Both diseases have similar molecular mechanisms and genetic predispositions. Patients with type-1 DM (T1DM) have reduced bone mineral density (BMD), which may partly explain increased fracture risk. Most patients with type-2 DM (T2DM) show normal or increased BMD but higher risk of fractures. Conventional diagnostic methods used in patients suspected for osteoporosis, such as the fracture risk assessment tool (FRAX) and DXA measurements are not sufficient in patients with DM.
Anti-diabetic therapies can additionally enhance fracture risk or reduce the incidence of low energy fractures. Thiazolidinediones reduce bone formation, and increase bone resorption. The drugs increase risk of fractures, that is further increased with duration of treatment. Insulin slightly increases fracture rate, possibly due to frequent episodes of hypoglicemia resulted in falls. Metformin has a positive effect on osteoblast differentiation and decreases fracture rate in T2DM patients. It is important to verify all risk factors for fracture in every individual diabetic patient and take into account this assessment when anti-diabetic therapy is chosen.
INTRODUCTION
The prevalence of osteoporosis and diabetes mellitus is alarming. In the United States, 50% of elderly individuals are osteoporotic and 20% of population have either diabetes or prediabetic condition. It was found that both diseases had similar features including molecular mechanisms and genetic predispositions (1). Bone and energy homeostasis are under the control of the same regulatory factors, including insulin, bone derived hormone – osteocalcin, peroxisome proliferator-activated receptor-γ (PPAR-γ), as well as gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP).
Insulin exerts an anabolic effect on bone tissue due to its structural homology to insulin-like growth factor-I (IGF-I), interacting with the IGF-I receptor present on osteoblasts (2). It was shown that lower serum IGF-I concentrations are associated with a higher number of vertebral fractures in postmenopausal women with type 2 diabetes (3, 4). On the other hand insulin increases bone resorption by reducing an expression of osteoprotegerin (OPG) – a decoy receptor for receptor activator of nuclear factor kB ligand (RANKL) and stimulates bone turnover (5-8).
PATOPHYSIOLOGY OF OSTEOPOROSIS IN DIABETES MELLITUS
A complex and heterogenous molecular pathophysiology seems to underlie osteoporosis and fracture risk in diabetes-related bone disease. Diabetes mellitus (DM) was found to induce the overexpression of many cytokines and hormones, such as sclerostin, gremlin, angiotensin II (Ang-II), parathyroid hormone (PTH), interleukin-6 (IL-6) and tumor necrosis factors (TNFs) but it also sequesters the over expression of vitamin D and neurotransmitters required for growth of osteoblasts (1). DM is responsible for the upregulation of PPAR-γ, fatty acid binding protein, tumor necrosis factor-α (TNF-α) and for increased availability of mesenchymal stem cells for adipocyte formation at the cost of osteoblast formation (9-12). For this reason DM is considered responsible for the deposition of lipids in the bone marrow, expansion of marrow cavity, diminishing of bone microcirculation, and the reduction of osteoblast number available for bone formation (13-15).
Serum osteocalcin concentration has been reported to be negatively correlated with hemoglobin A1c (HbA1c) level (16). In patients with DM osteocalcin, both in bone and serum, has been found to be incompletely carboxylated, and undercarboxylated osteocalcin has been negatively implicated in energy metabolism and glucose control (17, 18). Higher levels of undercarboxylated osteocalcin were suggested to be linked to increased risk of hip fractures (19).
Recent human cross-sectional studies confirm that bone turnover is attenuated in type 2 diabetes mellitus (T2DM). Sclerostin, an inhibitor of bone formation, was shown to be increased in patients with T2DM, independent of gender and age. Positive correlation was documented between sclerostin level and both duration of T2DM and HbA1c, and negative correlations between sclerostin and bone turnover markers (13).
Decreased bone quality in patients with T2DM is partly combined with advanced glycation end products (AGEs) – highly reactive glucose metabolites, which are implicated in forming additional cross-links between collagen fibres in bone. It results in excessive stiffness and in fragility of bone tissue (20, 21). AGEs accumulate in various tissues including bone, interfere with normal tissue function, as well as increase inflammation and cellular damage. AGEs have been identified as a biomarkers of increased fracture risk. Accumulation of pentosidine, one of the AGEs, in cortical and trabecular bone tissues was reported to exert negative impact on bone strength (22-24), while higher levels of the endogenous secretory receptor for AGEs (esRAGE) – a decoy AGE receptor – have protective effects on fracture risk in diabetes (25).
DIABETES MELLITUS AND RISK OF FRACTURES
Significant associations between diabetes mellitus and fracture risk were documented. Patients with T1DM are characterized by reduced BMD, which may partly explain increased fracture risk. Most patients with T2DM show normal or increased BMD (at the spine and femoral neck) but, in spite of this, higher fracture risk (26). The meta-analysis of the published data showed that younger age, higher body mass index, male gender, and higher HbA1c were positively associated with higher BMD values in patients with T2DM (27). The results of 16 studies performed in the US and Europe revealed that T2DM was associated with over two-fold increase in risk of hip fractures in men (relative risk [RR] = 2.8) and women (RR = 2.1) (1). Studies conducted on a Japanese population indicated that T2DM patients, both men and women have increased rate of vertebral fractures (28). The results of Rotterdam Study documented that individuals with T2DM were characterized by 69% higher risk of non-vertebral fractures compared to those without diabetes, despite having higher BMD at the femoral neck and lumbar spine (29). It was shown that glycemic control at the HbA1c level of 7.5% was associated with higher BMD but also with higher risk of all types of osteoporotic fractures (30). Obese Japanese men with T2DM and HbA1C of 9% and above had three times increased risk of vertebral fractures compared with men with diabetes and normal BMI, despite equal or even higher BMD values (16). Human histomorphometric studies revealed that bone turnover in older T2DM patients was diminished. Low bone turnover could result in higher BMD together with decreased bone quality (31).

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otrzymano: 2016-12-07
zaakceptowano do druku: 2016-12-28

Adres do korespondencji:
*Marta Toboła
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases Centre of Postgraduate Medical Education
Czerniakowska 231, 00-416 Warszawa
tel. +48 (22) 584-11-47
kl.geriatrii@szpital-orlowskiego.pl

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