Vpliv dolžine telomer v levkocitih pri bolnikih s hudo osteoporozo na zdravljenje s teriparatidom

Camloh, Eva (author), Ostanek, Barbara (mentor)

S staranjem prebivalstva se povečuje tudi število bolezni, ki so povezane s staranjem. Obstaja več kazalcev za določanje biološke starosti organizma, največkrat se uporablja dolžina telomer. Telomere so heterokromatinske strukture na koncu kromosomov, ki se skrajšajo z vsako celično delitvijo, občutljive pa so tudi na oksidativni stres in vnetje. Nekaj študij je dokazalo povezavo med krajšimi telomerami in osteoporozo. Osteoporoza je presnovna bolezen kosti, za katero sta značilni nizka kostna masa in porušena mikroarhitektura kostnega tkiva, kar vodi do povečane lomljivosti kosti. Obstaja več zdravil, ki se uporabljajo za preprečevanje izgube kostne mase, eno od novejših je osteoanabolno zdravilo teriparatid, ki se v Sloveniji predpiše le bolnikom s hudo obliko bolezni. V magistrski nalogi smo preučevali vpliv dolžine telomer v levkocitih na uspešnost terapije s teriparatidom. To je prva študija, ki preučuje to povezavo. Iz polne krvi preiskovank odvzete pred začetkom zdravljenja smo izolirali DNA in s kvantitativno verižno reakcijo s polimerazo v realnem času določili relativno dolžino telomer v levkocitih. S korelacijo smo dokazali negativno povezavo med kronološko starostjo in dolžino telomer v levkocitih (p = 0,019), mejno statistično značilna negativna korelacija pa je med dolžino telomer v levkocitih in razliko v mineralni kostni gostoti po 24 mesecih terapije na mestu ledvenih vretenc (p = 0,060) in celotnega kolka (p = 0,073). Z linearno regresijo smo ugotavljali vplive relativne dolžine telomer v levkocitih, kronološke starosti, starosti ob menopavzi, terapije z vitaminom D in kalcijem, indeksom telesne mase, časa zdravljenja s teriparatidom, vpliv mineralne kostne gostote (MKG) pred začetkom zdravljenja ter prekinitve zdravljenja na uspešnost terapije s teriparatidom, ki smo jo opredelili s spremembo v MKG na različnih mestih. Po 24 mesecih terapije je na spremembo na predelu vrata stegnenice značilno vplivala začetna MKG (p = 0,013), na predelu ledvenih vretenc mejno statistično značilno vpliva starost ob menopavzi (p = 0,084), na predelu celotnega kolka pa ima značilen vpliv vnos kalcija (p = 0,049) in mejno statistično značilen vpliv dolžina telomer v levkocitih (p = 0,064). Primerjali smo kakšne so dolžine telomer v levkocitih pri bolnicah z uspešnim in bolnicah z neuspešnim odzivom na zdravljenje ter ugotovili, da imajo bolnice, ki se niso odzvale na zdravljenje, daljše telomere v levkocitih. Na podlagi rezultatov sklepamo, da z enkratno meritvijo dolžine telomer v levkocitih ne moremo napovedati uspešnosti terapije s teriparatidom, saj imajo mlajše bolnice daljše telomere in večjo mineralno kostno gostoto, za zdravljenje s teriparatidom pa je značilno, da imajo boljši prirast v mineralni kostni gostoti bolnice z nižjo začetno mineralno kostno gostoto.

• Language: Slovenian
• Keywords: Dolžina telomer v levkocitih, staranje, osteoporoza, teriparatid, kvantitativna verižna reakcija s polimerazo v realnem času.
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-116769
• Publication date in RUL: 10.06.2020

Secondary language

• Language: English
• Title: The influence of leukocyte telomere lenght on teriparatide treatment response in patients with severe osteoporosis

Abstract

Aging of the world's population is associated with increasing number of age-related diseases. The biological age of an organism can be determined by many markers, the most common is telomere length. Telomere is a heterochromatin structure on the chromosome end which gets shorter with every cell division and is susceptible to oxidative stress and inflammation. Some studies report association between shortened telomere length and osteoporosis. Osteoporosis is a metabolic bone disease, determined by low bone mass and microarchitectual deterioration which leads to higher incidence of fractures. There are many drugs to prevent bone loss, including the osteoanabolic drug teriparatide. In Slovenia, it is prescribed only to patients with the most severe cases of osteoporosis. In our research we studied the effect of leukocyte telomere length on teriparatide treatment. This is the first study to evaluate this relationship. We isolated DNA from whole blood which was taken before treatment, measured the leukocyte telomere length by using real-time polymerase chain reaction, and statistically analysed the association. The results show negative correlation between chronological age and leukocyte telomere length (p = 0,019), and week negative correlation between leukocyte telomere length and changes in bone mineral density in lumbar spine (p = 0,060) and in total hip (p = 0,073). We evaluated the effects of leukocyte telomere length, chronological age, age at the menopause, vitamin D and calcium intake, body mass index, time of teriparatide treatment, bone mineral density (BMD) before the treatment and at the termination time of the treatment on therapy outcome with linear regression. The success of treatment was determined by changes in BMD at different sites. After 24 months of therapy the changes in BMD at the femoral neck are affected by the BMD before treatment (p = 0,013), at lumbar spine by age at the beginning of menopause (p = 0,084) and at total hip by calcium intake (p = 0,049) as well as leukocyte telomere length (p = 0,064). The leukocyte telomere length was compared between patients with good response to teriparatide therapy and those with no response. Longer telomeres were observed in patients with no response to the treatment. We conclude that one-time measurement of leukocyte telomere length cannot be used to predict the outcome of teriparatide treatment. Teriparatide is more efficient in patients with lower bone mineral density at the beginning of the therapy. In our case, the patients with longer telomeres were younger and therefore had better bone mineral density which resulted in lower response to teriparatide therapy.

• Keywords: Leukocyte telomere length, aging, osteoporosis, teriparatide, real-time polymerase chain reaction.