20.500.12556/RUL-184951 ​Zoledronska kislina in denosumab za zdravljenje osteoporoze pri pomenopavznih bolnicah s primarnim hiperparatiroidizmom Zoledronic Acid and Denosumab for Treatment of Osteoporosis in Postmenopausal Women with Primary Hyperparathyroidism Uvod in pričakovani rezultati: Primarni hiperparatiroidizem (PHPT) je relativno pogosta endokrina bolezen, ki večinoma poteka s hiperkalcemijo in je posledica avtonomnega izločanja paratiroidnega hormona (PTH) iz obščitnic. Med najpomembnejšimi zapleti bolezni je osteoporoza, ki nastane zaradi povečane razgradnje kosti. Kadar vzročno operativno zdravljenje (paratiroidektomija) ni možno, skušamo zmanjšati razgradnjo kosti z zdravili (antiresorptivi). Dva učinkovita antiresorptiva, ki se uporabljata za zdravljenje primarne osteoporoze, sta zoledronska kislina oziroma zoledronat (intravenski bisfosfonat) in denosumab (inhibitor sistema RANK/RANKL). Glede na to, da PHPT povzroča razgradnjo kosti predvsem zaradi prekomerne aktivacije sistema RANK/RANKL, pričakujemo, da bo denosumab, ki ciljano zavira ta sistem, bolj zvišal mineralno kostno gostoto (MKG), bolj znižal serumski kalcij in močneje zavrl kostno prenovo kot zoledronat. Metode: Vključili smo 40 pomenopavznih bolnic s PHPT z osteoporozo, ki niso primerne kandidatke za operacijo. V izhodišču smo določili osnovne laboratorijske parametre in označevalce kostne prenove (angl. bone turnover markers – BTM), in sicer C-terminalni telopeptid kolagena tipa 1 (CTX), N-terminalni propeptid prokolagena tipa 1 (P1NP), kostno specifično alkalno fosfatazo (angl. bone specific alkaline phosphatase- BAP) ter izmerili MKG. Naključno smo jih razdelili v enaki skupini in zdravili z zoledronatom 5 mg intravensko enkrat letno (skupina ZOL) ali s podkožno injekcijo denosumaba 60 mg vsakih 6 mesecev (skupina DMAB). Primerjali smo učinek obeh zdravil na MKG po 12 in 24 mesecih zdravljenja ter njun učinek na osnovne laboratorijske parametre in BTM po 3, 6, 12, 18 in 24 mesecih zdravljenja. Vse bolnice so prejemale tudi vitamin D3 800 do 1000 IE dnevno. Svetovali smo jim vnos do 1000 mg kalcija dnevno s hrano. Srednjo vrednost številskih spremenljivk smo med skupinama primerjali s testom t oz. testom Manna in Whitneya ter z mešanim modelom ANOVA za analizo ponovljenih meritev znotraj obeh skupin in za primerjavo med skupinama s pomočjo statističnega programa SPSS. Rezultati: V prvih dveh letih zdravljenja ni bilo razlik v porastu MKG med skupinama, DMAB torej ni bolj zvišal MKG kot ZOL. Po enem letu zdravljenja je bila MKG na ledveni hrbtenici (angl. lumbar spine - LS) v obeh skupinah bistveno višja (∆DMAB LS (0M-12M) 0,038 g/cm2; p<0,001 in ∆ZOL LS (0M-12M) 0,040 g/cm2; p=0,003). MKG na celotnem kolku (angl. total hip - TH) je bila značilno višja le v skupini DMAB (∆DMAB TH (0M-12M) 0,036 g/cm2; p=0,006), medtem ko se MKG na vratu stegnenice (angl. femoral neck - FN) in podlakti (angl. one third radius - 1/3R) v prvem letu ni spremenila v nobeni od skupin. Po dveh letih zdravljenja je MKG ostala višja kot v izhodišču na LS v obeh skupinah in na TH v skupini DMAB. Pomembnega dodatnega porasta v drugem letu ni bilo. Tri mesece (3M) po zdravljenju se je v obeh skupinah statistično značilno zmanjšal serumski celokupni kalcij (S-Ca) (∆DMAB S-Ca (0M-3M) –0,07 mmol/L; p=0,045, ∆ZOL S-Ca (0M-3M) –0,08 mmol/L; p<0,01), razlik med skupinama ni bilo. Tudi po šestih mesecih (6M) je celokupni kalcij ostal nižji kot v izhodišču (F(1, 37) = 5,0904, p=0,03), v kasnejših časovnih točkah (12M, 18M, 24M) se raven celokupnega kalcija ni več značilno razlikovala od izhodišča, statistično pomembnih razlik med skupinama ni bilo. Raven iPTH se je značilno povišala po prvi aplikaciji obeh zdravil: 3M F(1, 37) = 10,4848, p=0,003), 6M F(1, 37) = 7,4644, p=0,01, pri čemer ni bilo razlik med skupinama. Ob drugi in nadaljnjih aplikacijah obeh zdravil raven iPTH ni porasla. Ravni CTX, P1NP in BAP so se pri 3M v obeh skupinah znatno znižale (CTX 3M ΔDMAB –0,952 (0,639) in ΔZOL –0,556 (0,439) μg/L; p=0,03; P1NP 3M ΔDMAB –75,45 (33, 9) in ΔZOL –54,06 (32,06) μg/L; p=0,003; BAP 3M ΔDMAB –19,72 (8,12) in ΔZOL –13,68 (9,55) μg/L; p=0,685), absolutne vrednosti CTX in P1NP so bile pri 3M bistveno nižje v skupini DMAB, relativno znižanje je bilo višje v skupini DMAB tudi pri BAP (58 vs 50%, p=0,0242). V nadaljnjih časovnih točkah so bile CTX vrednosti vedno nižje od izhodišča v obeh skupinah, pri čemer ni bilo razlik med skupinama, relativno znižanje P1NP je bilo v vseh obdobjih višje v skupini DMAB. Absolutne vrednosti BAP so bile v skupini DMAB nižje pri 24M (p=0,0425), upad BAP od izhodišča pa je bil višji v skupini DMAB še pri 12M in 24M. Zaključek: Po dveh letih zdravljenja ni bilo razlik v porastu MKG med skupinama, je pa MKG v obeh skupinah porasla na LS, v skupini DMAB tudi na TH. Prav tako ni bilo razlik v upadu serumskega kalcija, ki je bil bistveno nižji od izhodišča pri treh mesecih v obeh skupinah. Denosumab je bolj zavrl kostno prenovo kot zoledronat, razgradnjo predvsem v prvih treh mesecih, izgradnjo pa tudi v kasnejših obdobjih zdravljenja. Introduction: Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by autonomous secretion of parathyroid hormone (PTH), most often presenting with hypercalcemia. One of its most important complications is osteoporosis, which results primarily from increased bone resorption. When curative surgical treatment (parathyroidectomy) is not feasible, pharmacological therapy aimed at reducing bone resorption is indicated. Two potent antiresorptive agents used in the treatment of primary osteoporosis are zoledronic acid (zoledronate), an intravenous bisphosphonate, and denosumab, a monoclonal antibody that inhibits the RANK/RANKL pathway. Because bone loss in PHPT is largely driven by excessive activation of the RANK/RANKL system, we hypothesized that denosumab, as a targeted inhibitor of this pathway, would lead to greater increases in bone mineral density (BMD), more pronounced reductions in serum calcium, and stronger suppression of bone turnover compared with zoledronate. Methods: We enrolled 40 postmenopausal women with PHPT and osteoporosis who were not eligible for surgical treatment. At baseline, we assessed routine biochemical parameters and bone turnover markers (BTMs), including C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I procollagen (P1NP), and bone-specific alkaline phosphatase (BAP), and measured BMD. Participants were randomly assigned in equal numbers to receive either zoledronate 5 mg intravenously once yearly (ZOL group) or denosumab 60 mg subcutaneously every 6 months (DMAB group). BMD was evaluated at baseline and after 12 and 24 months. Laboratory parameters and BTMs were measured at 3, 6, 12, 18, and 24 months. All participants received vitamin D₃ supplementation (800–1000 IU daily) and were advised to maintain a daily calcium intake of up to 1000 mg from dietary sources. Between-group comparisons of continuous variables were performed using the independent-samples t-test or the Mann–Whitney test, as appropriate. Changes over time and between-group differences in repeated measurements were analyzed using a mixed ANOVA model. Statistical analyses were conducted using SPSS. Results: Over the two-year treatment period, increases in BMD did not differ significantly between the two groups. After 12 months, lumbar spine (LS) BMD increased significantly in both groups (DMAB: +0.038 g/cm², p < 0.001; ZOL: +0.040 g/cm², p = 0.003). Total hip (TH) BMD increased significantly only in the DMAB group (+0.036 g/cm², p = 0.006). No significant changes were observed at the femoral neck (FN) or one-third radius (1/3R) in either group during the first year. At 24 months, BMD remained significantly above baseline at the LS in both groups and at the TH in the DMAB group. No additional significant increases were observed during the second year of treatment. At 3 months, serum total calcium decreased significantly in both groups (DMAB: −0.07 mmol/L, p = 0.045; ZOL: −0.08 mmol/L, p < 0.01), with no difference between treatments. At 6 months, calcium levels remained lower than baseline (F (1,37) = 5.09, p = 0.03). However, at 12, 18, and 24 months, calcium levels no longer differed significantly from baseline, and no between-group differences were observed at any time point. Intact PTH (iPTH) increased significantly after the first administration of both drugs (3 months: F (1,37) = 10.48, p = 0.003; 6 months: F (1,37) = 7.46, p = 0.01), without differences between groups. No further increases were observed following subsequent administrations. At 3 months, CTX, P1NP, and BAP decreased significantly in both groups. The reductions in CTX and P1NP were greater in the DMAB group (CTX: −0.952 vs −0.556 μg/L, p = 0.03; P1NP: −75.45 vs −54.06 μg/L, p = 0.003). Although BAP decreased in both groups, the relative reduction was greater with DMAB (58% vs 50%, p = 0.024). Absolute CTX and P1NP values at 3 months were significantly lower in the DMAB group. At later time points, CTX remained suppressed below baseline in both groups, without significant differences between treatments. The relative reduction in P1NP remained consistently greater in the DMAB group throughout follow-up. Absolute BAP values were lower in the DMAB group at 24 months (p = 0.0425), and reductions from baseline were greater with DMAB at 12 and 24 months. Conclusion: After two years of treatment, denosumab and zoledronate produced comparable increases in BMD. LS BMD improved significantly in both groups, while TH BMD increased significantly only with denosumab. Both treatments resulted in a modest, short-term reduction in serum calcium, with no sustained differences between groups. Denosumab produced a more pronounced suppression of bone turnover; resorption was particularly suppressed during the first three months of treatment, and formation was also suppressed in the later stages of treatment. Primarni hiperparatiroidizem osteoporoza denosumab zoledronska kislina mineralna kostna gostota označevalci kostne prenove hiperkalcemija Primary hyperparathyroidism Osteoporosis Denosumab Zoledronic acid Bone mineral density Bone turnover markers Hypercalcemia true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2026-07-18 07:16:37 2026-07-18 07:16:54 2026-07-19 04:03:09 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 39412 10255.pdf 10255.pdf 1 B3BE85BF1EA020425036DA275D011EE0 955f9ea0871040fb9666abae10c3a110a89aaa419eaa9b0848f023edbad36251 b23b4c30-8267-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240408 10256.pdf 10256.pdf 1 0FB462A0644C95E9A1F460C49AF9BF09 16290089db19c88b279a1ff8ea8f2e52687d417450347ba79599e33e5220a770 b23c5185-8267-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240409 10257.pdf 10257.pdf 1 F02C60F563AB194F274D0CE089728263 d13f5caa6de1068ebfcdc8cce5ca8eb69b320e19c610e0cd2e57b8b64768fb03 b23cce2e-8267-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240410 10258.pdf 10258.pdf 1 F03A2EA9E371C219B440FF19CEFFD25F 44f165864292dd241506d7eb4efa04cb480948ca7017ff01e61ec73621b8f4d7 b23d2b6f-8267-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240411 10259.pdf 10259.pdf 1 67FE6F3F9EAB91CB95E3B77649D9DDA9 ab3885949783473a25b13459043f6c5a57955c1dc6735fc2386392e222e9488a b24fbb81-8267-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240412 Medicinska fakulteta 0 0 0