Zastosowanie technologii interferencji RNA w medycynieApplication of RNA interference in medicineMarta Gabryelska1, Eliza Wyszko1, Stanis³aw Nowak2, Ryszard ¯ukiel2, Jan Barciszewski12 z Katedry i Kliniki Neurochirurgii i Neurotraumatologiigenny RNA, np. wirusowy (18). Dlatego w³anie RNAiInterferencja RNA nale¿y do technik anty-mRNA ada-mo¿e funkcjonowaæ jako specyficzny stra¿nik ge
Bardzo tanie apteki z dostawą w całej Polsce kupic levitra i ogromny wybór pigułek.
Osteoporoz 2010-Original Investigation / Orijinal Araﬂt›rma 17
Effect of Weekly Alendronate on Knee Symptoms in Patients
with Osteoporosis and Knee Osteoarthritis Coexistence
Osteoporoz ve Diz Osteoartritinin Birlikte Bulundu¤u Hastalarda Diz Semptomlar› Üzerine Haftal›k Alendronat›n Etkinli¤i Levent Ediz, Özcan H›z, Murat Toprak*, ‹brahim Tekeo¤lu**
Yüzüncü Y›l Üniversitesi T›p Fakültesi, Fiziksel T›p ve Rehabilitasyon Anabilim Dal›, Van, Türkiye *Sa¤l›k Bakanl›¤› Van E¤itim ve Araﬂt›rma Hastanesi, Fizik Tedavi ve Rehabilitasyon Bölümü, Van, Türkiye **Yüzüncü Y›l Üniversitesi T›p Fakültesi, Romatoloji Anabilim Dal›, Van, Türkiye Summary
Aim: The aim of this study was to examine the effect of alendronate 70 mg weekly on knee symptoms in elderly women with
osteoporosis and knee OA coexistence.
Material and Methods: Elderly women who diagnosed as osteoporosis between 60-75 years old, underwent radiography of
the knee if they reported symptoms of knee OA. Radiographs were read for Kellgren and Lawrence grade and individual fea-
tures of OA. Osteoporotic patients with Knee OA treated with 70 mg alendronate once weekly for one year. Knee symptoms
were assessed by interview before the treatment and 6 and 12 months after the treatment, and knee pain severity was eval-
uated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequense index, VAS at rest and
Results: Alendronate 70 mg once weekly use was associated with less severity of knee pain as assessed by WOMAC scores,
Lequense index, VAS at rest and at movement at 6th and 12th month assessments.
Conclusion: This current study has shown that Alendronate 70 mg once weekly use was associated with less severity of knee
symptoms in elderly women with osteoporosis and knee OA coexistence. Additional long-term randomised, placebo controlled
clinical trials are needed to confirm this effect of weekly Alendronate. (From the World of Osteoporosis 2010;16:17-21)
Key words: Alendronate, osteoporosis, knee osteoarthritis
Amaç: Bu çal›ﬂman›n amac›, Osteoporoz ve diz osteoartritinin birlikte bulundu¤u yaﬂl› kad›nlarda diz semptomlar› üzerine haf-
tal›k alendronat 70 mg’›n etkinli¤ini araﬂt›rmak idi.
Gereç ve Yöntemler: Altm›ﬂ-Yetmiﬂ beﬂ yaﬂ aras› osteoporoz tan›s› alan yaﬂl› kad›nlara, e¤er diz semptomlar› bildirmiﬂlerse,
Kellgren-Lawrence evrelemesi ve diz osteoartritinin di¤er bulgular› için diz radyografisi çektirildi. 1 y›l süre ile, diz osteoartriti ve
osteoporoz birlikteli¤i olan hastalar Alendronat 70 mg haftada bir gün ile tedavi edildiler. Hastalar diz semptomlar› için tedavi
baﬂlang›c›nda, 6. ayda ve 12. ayda WOMAC, Lequense index, istirahat ve harekette VAS skorlar› ile de¤erlendirildiler.
Bulgular: Alendronat 70 mg haftal›k kullan›m›, WOMAC skoru, Lequense index ve istirahatte ve harekette VAS skorlar› ile
de¤erlendirilen diz semptomlar› ﬂiddetinde 6. ve 12. aylarda anlaml› derecede azalma sa¤lad›.
Sonuç: Bu çal›ﬂma, Alendronat 70 mg haftal›k kullan›m›n›n, osteoporoz ve diz osteoartriti birlikteli¤i olan yaﬂl› kad›nlarda, diz
semptomlar›n› hafifletti¤ini göstermektedir. Haftal›k alendronat›n bu etkisini de¤erlendirmek için, randomize, plasebo kontrol-
lü çal›ﬂmalara ihtiyaç vard›r. (Osteoporoz Dünyas›ndan 2010;16:17-21)
Anahtar kelimeler: Alendronat, osteoporoz, diz osteoartriti
Address for Correspondence/Yaz›ﬂma Adresi: Dr. Levent Ediz, Yüzüncü Y›l Üniversitesi T›p Fakültesi, Fiziksel T›p ve Rehabilitasyon Anabilim Dal›, Van, Türkiye Phone: +90 432 226 90 07 Gsm: +90 507 995 17 32 E-mail: [email protected] Received/Geliﬂ Tarihi: 26.01.2010 Accepted/Kabul Tarihi: 15.03.2010 Osteoporoz Dünyas›ndan Dergisi, Galenos Yay›nevi taraf›ndan bas›lm›ﬂt›r. / World of Osteoporosis, published by Galenos Publishing. 18
Alendronate in Symptoms of Knee Osteoarthritis Introduction
Materials and Methods
Knee Osteoarthritis is the most common form of joint Of the total 47 osteoporosis female patients referred for disease which is characterized by degradation, loss of the first assessment, 7 did not meet the inclusion criteria joint cartilage which results in pain and physical disabil- and 2 subjects refused to participate; 38 female patients ity in the elderly (1). Osteoporosis is characterized by (age 60-75 years, ≥5 years since menopause), who admit-
reduced bone mass and alteration in bone architecture, ted to rehab clinic and diagnosed as postmenopausal or resulting in increased fracture risk. These fractures are a senile osteoporosis with mean lumbar spine (L2-L4) major cause of morbidity and mortality in the elderly (2).
BMD T-score < -2.5 and ≥-5.0 coexistence with knee OA
Osteoarthritis (OA) and osteoporosis (OP) are diseases of according to the clinical and radiographic osteoarthritis increasing incidence and prevalence with age. Although criteria (all patients had Grade I, II to III knee data from cross-sectional studies suggest that OA might osteoarthritis confirmed radiologically according to the be associated with less OP (3,4). Osteoarthritis does not Kellgren-Lawrence grading system) of the American seem to protect a patient from generalized primary College of Rheumatology and no other inflammatory osteoporosis. In a study the majority (74%) of the diseases, were included the trial (Table 1). female hip OA patients were osteopenic or osteoporot- Exclusion criteria included significant medical disease, ic with signs of increased bone turnover (5). Patients hypersensitivity to bisphosphonates, contraindications with knee osteoarthritis (OA) generally complain of for calcium or vitamin D therapy, renal impairment (GFR insidious throbbing arthralgias with activity. Although <30 ml/min), history of major upper gastrointestinal dis- initially, resting relieves the pain, the patient eventually ease, any active disease known to influence bone begins to suffer pain even at rest (6). A low BMD does metabolism, or recent treatment with drugs known to not preclude osteoarthritic change in the knee, more- affect bone and cartilage (such as glucosamine-chon- over Terauchi M et al found a low level of BMD was droitin)metabolism. All participants gave written associated with varus deformity originating at the prox- imal tibia and a low BMD predisposes to trabecular The objective of the study was to test the effects of microfractures and consequently increased stress on the antiresorptive osteoporosis drug alendronate 70 mg articular cartilage (7). Osteoporosis is also common in weekly on symptoms of knee osteoarthritis with the the osteoarthritic arthroplasty population, with a preva- prior hypothesis that biphosphonates may have disease lence at least equal to that in the general population.
modifying effects on knee osteoarthritis consequently The prevalence of osteoporosis in osteoarthritic patients would decrease the symptoms from initial of treatment. is 26%. 37% of these patients reported current treat- The study was conducted in accordance with the princi- ment with biphosphonates (8). At the subchondral level ples of the Declaration of Helsinki or with the laws and of osteoarthritis, affected joints have decreased bone regulations of the country concerned, whichever provid- mineral content and quality. In addition, increased bone ed greater protection to the individual. The study pro-tocol was also approved by the ethical board of our turnover has been observed at levels similar to those in patients with osteoporosis (9). Bisphosphonates are All patients received vitamin D 400 IU/day and elemen- analogues of inorganic pyrophosphate and are tal calcium 500 mg/day as dietary supplements through- inhibitors of bone resorption. Bisphosphonates may out the study, irrespective of dietary intake. BMD was have disease-modifying effects in patients with knee measured by a single DXA scan of the proximal femur OA. Clear trends towards improvement were observed and lumbar spine (mean BMD of at least two vertebrae by Spector et al in both joint structure and symptoms (pain, WOMAC scores) in patients with primary knee OA This study was an open labelled, prospective study with treated with biphosphonates (10). In a study, biphos- a 1 year follow-up period. All patients received alen- phonates considered an adjunctive therapy in the pain dronate 70 mg weekly. All patients received also vitamin D 400 IU/day and elemental calcium 500 mg/day as Many derivatives have been developed for the treat-ment of enhanced bone resorption; several reportsreveal that treatment with bisphosphonates is able to Table 1. Demographic properties of the patients reduce the pain associated with different painful dis- This study examined and compared knee symptoms (WOMAC scores, Lequense index, VAS at rest and atmovement) of patients with osteoporosis and knee osteoarthritis coexistence before and after six months, and one year of the treatment with weekly alen-dronate 70 mg.
Alendronate in Symptoms of Knee Osteoarthritis 19
dietary supplements throughout the study, irrespective patients showed a significant improvement in WOMAC of dietary intake. The patients were allowed to use scale, Lequesne index and significant reduction in the paracetamol (to a maximum of 3 gr daily) during the VAS score during standing and walking (Table 3, Figure 1).
study period as considered appropriate by the physician.
There was no statistically significant difference in However, no paracetamol use was permitted for at least WOMAC scale, Lequense index and VAS scores between 48 hours before each clinical assessment. Patients were 6. month and 12. month values (Table 3, Figure 1). There not allowed to use of NSAID’s, opiades, slow-acting were no serious adverse effects reported. drugs such as glucosamine-chondroitin sulphate used totreat osteoarthritis. Discussion
Primary efficacy outcome was Western Ontario-McMaster University Osteo-Arthritis Index (WOMAC), In this current study, we evaluated the symptom modi- Lequesne index and secondary outcome parameters fying effects of Alendronate in female osteoporotic included VAS at rest and at movement, global judge- patients with knee osteoarthritis. We found statistically ment. The clinical assessment was made by a study physi- significant improvements in knee symptoms of osteo- cian using the study parameters at baseline, at month 6, porotic female patients at 6. and 12. months assessed by WOMAC scores, Lequense index, VAS at movement and Statistical analysis was performed using SPSS ver 13.0 statistical package. The efficacy parameters were statis- Knee OA has been considered a disease of the cartilage, tically analysed using the values measured at baseline, but literature evidence suggests that subchrondral bone at month 6, and at month 12. After the variance analy- is also involved in the pathogenesis, in both disease ini- sis in repeated measures, paired t-test was performed to tiation and progression. Increased local bone turnover, compare differences at evaluation times of the study decreased bone mineral content and stiffness, and parameters. Statistical significance for comparisons was decreased trabecular numbers have been observed in knee OA subchondral bone structure compared withnormal bone (13). A higher rate of subchondral bone turnover, as indicated by increased uptake of scinti-graphic tracer in subarticular bone, is associated withmore rapid progression of knee OA (14). A total of 38 female osteoporosis patients (mean age of We suggest symptom modifying effect of alendronate 67.3 (60-75) years) with knee osteoarthritis included the on knee osteoarthritis in this current study due to study. Kellgren-Lawrence distribution was 5 patientsgrade 1, 22 patients grade 2, 11 patients grade 3. The improving periarticular bone changes of osteoarthritis.
mean L2-L4 BMD was 0.816±0.156 gm/cm2. The mean Drugs used to prevent or treat osteoporosis, including knee osteoarthritis duration of patients was 7.4±5.7 bisphosphonates, may influence the periarticular bone years. 31 patients completed the study. 7 patients Table 2. Reasons for dropping out of study of 7 patients dropped out the study (1 patient did not use the studydrug regularly because of gastrointestinal complaints, 4 Reasons for
Time of drop-out
patients because of contact lacking, 1 patient died dropping out
because of myocard infarctus, 1 patient because of glu- cosamine intake. Demographic data of the patients were given in the table 1 and reasons of dropping out 31 female patients completed the study. While study parameters at 6th month and at the end of the study (12th month) compared with the initial parameters, Table 3. Study parameters values of 31 patients who completed the study at baseline, at month 6, and at month 12 Parameters
Baseline (Mean±SD) 6. month (Mean±SD) 12. month (Mean±SD)
Visual Analog Scale (VAS), (pain at movement) 100 mm Visual Analog Scale (VAS), (pain at rest) 100 mm a p<0.05, Comparison of WOMAC values at baseline versus at 6. and 12. monthsb p>0.05, Comparison of WOMAC values at 6. month versus at 12. monthc p<0.05, Comparison of Lequesne index values at baseline versus at 6. and 12. monthsd p>0.05, Comparison of Lequesne index values at 6. month versus at 12. monthe p<0.05, Comparison of VAS values (at movement and at rest) at baseline versus at 6. and 12. monthsf p>0.05, Comparison of VAS values at (at movement and at rest) 6. month versus at 12. month 20
Alendronate in Symptoms of Knee Osteoarthritis changes of OA and could, therefore, have an effect on inhibitory effect of which on the each level of P13-Akt- the course of the disease, including the possibility of NFkappaB pathway (22). Because inhibition of NF- slowing its development and progression (15-17).
kappaB nuclear signalling in dorsal root ganglia reduces We found use of alendronate was associated with less severity of knee pain assessed by WOMAC scores and The biases of this study were a small number of patients, Lequense index. Carbone et al found that use of alen- an open labelled study and the absence of a control dronate was associated with less severity of knee pain as group. So long-term randomised, placebo controlled assessed by WOMAC scores and significantly less sub- clinical trials are needed to assess symptom modifying chondral bone attrition and bone marrow edema-like effects on knee osteoarthritis in osteoporotic female abnormalities in the knee as assessed by MRI, as com- pared with women who had not received this medica-tion (18). Conclusion
Spector TD et al observed in both joint structure andsymptoms in patients with primary knee OA treated In this current study, Alendronate 70 mg once weekly with risedronate. Risedronate 15 mg once daily (but not use was associated with less severity of knee pain as 5 mg once daily) significantly reduced markers of carti- assessed by WOMAC scores, Lequense index, VAS at lage degradation and bone resorption. Both doses of movement and at rest in patients with osteoporosis and risedronate were well tolerated in this study (10). knee osteoarthritis coexistence after six months, and We also suggest that symptom modifying effects of one year of the treatment. Additional long-term ran- alendronate in this study may be depend on anti-inflam- domised, placebo controlled clinical trials are needed to matory and analgesic properties of it. The anti-inflam- assess this effect of weekly Alendronate. matory and analgesic properties of different bisphos-phonates have been demonstrated in both animal and References
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PUBLIKATIONSVERZEICHINS Prof. Dr. Dr. med. habil. Josef Niebauer Dissertation für Dr. med. Niebauer J : Effects of 3,4,5-trimethoxybenzoic acid -8- diethylamino-octylester (TMB-8) and ruthenium red on vasopressin release of isolated rat neurohypophysis. Universität Mainz, Abteilung für Pharmakologie, 1991. Dissertation für Ph.D. Niebauer J : Metabolic abnormalitie