Effekt von additivem körperlichem Training zur Bisphosphonat-Therapie auf die Knochendichte: Eine systematische Übersichtsarbeit und Meta-Analyse

Zusammenfassung

Hintergrund Körperliches Training und antiresorptive pharmakologische Therapie wirken über unterschiedliche Mechanismen auf den Knochenstoffwechsel ein. Die vorliegende Arbeit beschäftigt sich mit dem Ansatz, ob eine Bisphosphonat-Behandlung durch zusätzliches körperliches Training additive Effekte auf die Knochendichte (BMD) an Lendenwirbelsäule (LWS) und/oder Schenkelhals (SH) ausübt.

Methoden Unsere systematische Literaturrecherche von fünf elektronischen Datenbanken gemäß PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) schloss kontrollierten Studien mit einer Dauer von mehr als 6 Monaten und mindestens zwei Studienarmen: (a) Bisphosphonate (B), (b) Bisphosphonate und körperliches Training (B+E) bis zum 26. August 2021, ein. Studien mit anderen pharmazeutischen Therapien oder Krankheiten mit relevanten Auswirkungen auf den Knochenstoffwechsel wurden ausgeschlossen. Die vorliegende Analyse wurde als random-effects Meta-Analyse durchgeführt. Ergebnismaße waren standardisierte mittlere Differenzen (SMD) für BMD-Änderungen an LWS und Schenkelhals (SH).

Ergebnisse Unsere Suche identifizierte vier geeignete Studien mit insgesamt 247 Teilnehmern. Zusammenfassend zeigte die kombinierte Intervention (B+E) verglichen mit der isolierten Bisphosphonat-Therapie keine signifikant höheren Effektstärken an LWS (SMD: 0,66, 95%-CI: − 0,63 bis 1,94) oder SH-BMD (0,49 − 0,42 bis 1,40). Wir beobachteten für beide Studienendpunkte (BMD-LWS, BMD-SH) eine sehr hohe Heterogenität der Ergebnisse der eingeschlossenen Studien (I²: 89 bzw. 92%). Die Wahrscheinlichkeit eines „small study“ bzw. Publikations-Bias liegt in beiden Fällen ebenfalls recht hoch.

Schlussfolgerung Wir konnten keinen signifikant überlegenen Effekt einer kombinierten Intervention aus Bisphosphonaten und körperlichem Training im Vergleich zu isolierter Bisphosphonat-Therapie auf die BMD an LWS oder SH erfassen. Allerdings zeigten die vorliegenden Einzelstudien eine hohe Heterogenität, die wir primär auf unterschiedlichen Trainingsprotokolle der Studien zurückführen.

Schlüsselworte körperliches Training, Bisphosphonate, Knochendichte, Meta-Analyse

Abstract

Background Physical exercise and antiresorptive pharmacological therapy affect bone metabolism through different mechanisms. The present study addresses the question of whether bisphosphonate treatment with additional exercise training has additive effects on bone density (BMD) at the lumbar spine (LS) and/or femoral neck (SH).

Methods Our systematic literature search of five electronic databases according to PRISMA included controlled trials with a duration of≥6 months with at least two study arms: (a) bisphosphonates (B), (b) bisphosphonates and exercise (B+E) published up to 26 August 2021. Studies including other pharmaceutical therapies or diseases with relevant effects on bone metabolism were excluded. The analysis was conducted as a random-effects meta-analysis. Outcome measures were standardized mean differences (SMD) for BMD changes at LS and SH.

Results Our search identified four eligible studies with a total of 247 participants. In summary, compared with bisphosphonate therapy alone, the combined intervention did not demonstrate significantly higher effect sizes at LS- (SMD: 0.66, 95%-CI: − 0.63 to 1.94) or SH-BMD (0.49, − 0.42 to 1.40). We observed very high heterogeneity among the results of the included studies for both, BMD-LWS and BMD-SH (I²: 89 and 92%, respectively). The evidence for a “small study” or publication bias is also quite high for both outcomes.

Conclusion We could not detect a significantly superior effect of a combined intervention (B+E) compared to isolated bisphosphonate therapy on BMD at LS and/or SH. However, the eligible studies indicate a high heterogeneity, which we primarily refer to the different training protocols of the trials.

Schlüsselwörter

körperliches Training - Bisphosphonate - Knochendichte - Meta-Analyse

Key words

Exercise - Bisphosphonates - Bone Mineral Density - Meta-Analysis

Publication History

Received: 13 May 2022

Accepted: 19 July 2022

Article published online:
08 September 2022

• Literatur

• 1 Liu J, Curtis EM, Cooper C. et al. State of the art in osteoporosis risk assessment and treatment. J Endocrinol Invest 2019; 42: 1149-1164 DOI: 10.1007/s40618-019-01041-6.
• 2 Hadji P, Klein S, Gothe H. et al. The epidemiology of osteoporosis--Bone Evaluation Study (BEST): an analysis of routine health insurance data. Dtsch Arztebl Int 2013; 110: 52-57 DOI: 10.3238/arztebl.2013.0052.
• 3 Oryan A, Sahvieh S. Effects of bisphosphonates on osteoporosis: Focus on zoledronate. Life Sci 2021; 264: 118681 DOI: 10.1016/j.lfs.2020.118681.
• 4 Langdahl BL. Overview of treatment approaches to osteoporosis. Br J Pharmacol 2021; 178: 1891-1906 DOI: 10.1111/bph.15024.
• 5 Reid IR, Billington EO. Drug therapy for osteoporosis in older adults. Lancet 2022; 399: 1080-1092 DOI: 10.1016/S0140-6736(21)02646-5.
• 6 Russell LB, Fike JR, Cann CE. et al. Dual energy CT scanning for analysis of brain damage due to X-irradiation. Ann Biomed Eng 1984; 12: 15-28
• 7 Iconaru L, Baleanu F, Charles A. et al. Which treatment to prevent an imminent fracture?. Bone Reports 2021; 15: 101105
• 8 Jensen PR, Andersen TL, Chavassieux P. et al. Bisphosphonates impair the onset of bone formation at remodeling sites. Bone 2021; 145: 115850 DOI: 10.1016/j.bone.2021.115850.
• 9 Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2016; 8: 225-235 DOI: 10.1177/1759720X16670154.
• 10 Mages M, Shojaa M, Kohl M. et al. Exercise Effects on Bone Mineral Density in Men. Nutrients 2021; 13: 4244 DOI: 10.3390/nu13124244.
• 11 Shojaa N, von Stengel S, Schoene D. et al. Effect of exercise training on bone mineral density in postmenopausal women: A systematic review and meta-analysis of intervention studies. Front Physiol 2020; 11: 1427-1444 DOI: 10.3389/fphys.2020.00652.
• 12 Chilibeck PD, Davison KS, Whiting SJ. et al. The effect of strength training combined with bisphosphonate (etidronate) therapy on bone mineral, lean tissue, and fat mass in postmenopausal women. Can J Physiol Pharmacol 2002; 80: 941-950
• 13 Uusi-Rasi K, Kannus P, Cheng S. et al. Effect of alendronate and exercise on bone and physical performance of postmenopausal women: a randomized controlled trial. Bone 2003; 33: 132-143
• 14 Maher CG, Sherrington C, Herbert RD. et al. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther 2003; 83: 713-721
• 15 Cochrane Cochrane Handbook for Systematic Reviews of Interventions. In: Higgins J, Green S eds, The Cochrane Collaboration. 2016
• 16 Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. J Stat Softw 2010; 36: 1-48 DOI: 10.18637/jss.v036.i03.
• 17 R_Development_Core_Team. R: A language and environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2020
• 18 Doi SA, Barendregt JJ, Khan S. et al. Advances in the meta-analysis of heterogeneous clinical trials I: The inverse variance heterogeneity model. Contemp Clin Trials 2015; 45: 130-138 DOI: 10.1016/j.cct.2015.05.009.
• 19 Higgins JP, Altman DG, Gotzsche PC. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928 DOI: 10.1136/bmj.d5928.
• 20 Duval SJ, Tweedie RL. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. JASA 2000; 95: 89-98
• 21 Furuya-Kanamori L, Barendregt JJ, Doi SAR. A new improved graphical and quantitative method for detecting bias in meta-analysis. Int J Evid Based Healthc 2018; 16: 195-203 DOI: 10.1097/XEB.0000000000000141.
• 22 Borba-Pinheiro CJ, Dantas EH, Vale RG. et al. Resistance training programs on bone related variables and functional independence of postmenopausal women in pharmacological treatment: A randomized controlled trial. Arch Gerontol Geriatr 2016; 65: 36-44 DOI: 10.1016/j.archger.2016.02.010.
• 23 Fu W, Fan J. Intervention effect of exercise rehabilitation therapy on patients with type 2 diabetic osteoporosis. American Journal of Translational Research 2021; 13: 3400
• 24 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71 DOI: 10.1136/bmj.n71.
• 25 Kemmler W, Stengel V. Hrsg. The Role of Exercise on Fracture Reduction and Bone Strengthening. London: Avademic Press; 2019: 433-448
• 26 Mori T, Crandall CJ, Ganz DA. Cost-effectiveness of combined oral bisphosphonate therapy and falls prevention exercise for fracture prevention in the USA. Osteoporos Int 2017; 28: 585-595 DOI: 10.1007/s00198-016-3772-7.
• 27 Suzuki T, Harada A, Shimada H. et al. Assessment of eldecalcitol and alendronate effect on postural balance control in aged women with osteoporosis. J Bone Miner Metab 2020; 38: 859-867 DOI: 10.1007/s00774-020-01118-w.
• 28 Zhou J, Liu B, Qin MZ. et al. Fall Prevention and Anti-Osteoporosis in Osteopenia Patients of 80 Years of Age and Older: A Randomized Controlled Study. Orthop Surg 2020; 12: 890-899 DOI: 10.1111/os.12701.
• 29 Caristia S, Campani D, Cannici C. et al. Physical exercise and fall prevention: A systematic review and meta-analysis of experimental studies included in Cochrane reviews. Geriatr Nurs 2021; 42: 1275-1286 DOI: 10.1016/j.gerinurse.2021.06.001.
• 30 Sherrington C, Michaleff ZA, Fairhall N. et al. Exercise to prevent falls in older adults: an updated systematic review and meta-analysis. Br J Sports Med 2017; 51: 1750-1758 DOI: 10.1136/bjsports-2016-096547.
• 31 Sun M, Min L, Xu N. et al. The Effect of Exercise Intervention on Reducing the Fall Risk in Older Adults: A Meta-Analysis of Randomized Controlled Trials. Int J Environ Res Public Health 2021; 18 DOI: 10.3390/ijerph182312562.
• 32 Mandema JW, Zheng J, Libanati C. et al. Time course of bone mineral density changes with denosumab compared with other drugs in postmenopausal osteoporosis: a dose-response-based meta-analysis. J Clin Endocrinol Metab 2014; 99: 3746-3755 DOI: 10.1210/jc.2013-3795.
• 33 Xu Z. Alendronate for the Treatment of Osteoporosis in Men: A Meta-Analysis of Randomized Controlled Trials. Am J Ther 2017; 24: e130-e138 DOI: 10.1097/MJT.0000000000000446.
• 34 Appelman-Dijkstra NM, Papapoulos SE. Sclerostin Inhibition in the Management of Osteoporosis. Calcif Tissue Int 2016; 98: 370-380 DOI: 10.1007/s00223-016-0126-6.
• 35 Sugiyama T, Meakin LB, Galea GL. et al. Risedronate does not reduce mechanical loading-related increases in cortical and trabecular bone mass in mice. Bone 2011; 49: 133-139 DOI: 10.1016/j.bone.2011.03.775.
• 36 Naruse K, Uchida K, Suto M. et al. Alendronate does not prevent long bone fragility in an inactive rat model. J Bone Miner Metab 2016; 34: 615-626 DOI: 10.1007/s00774-015-0714-y.
• 37 Bajaj D, Geissler JR, Allen MR. et al. The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate. Bone 2014; 64: 57-64 DOI: 10.1016/j.bone.2014.03.045.
• 38 Stadelmann VA, Bonnet N, Pioletti DP. Combined effects of zoledronate and mechanical stimulation on bone adaptation in an axially loaded mouse tibia. Clin Biomech (Bristol, Avon) 2011; 26: 101-105 DOI: 10.1016/j.clinbiomech.2010.08.014.
• 39 Correa CB, Camargos GV, Chatterjee M. et al. Can the alendronate dosage be altered when combined with high-frequency loading in osteoporosis treatment?. Osteoporos Int 2017; 28: 1287-1293 DOI: 10.1007/s00198-016-3859-1.
• 40 Hatori K, Camargos GV, Chatterjee M. et al. Single and combined effect of high-frequency loading and bisphosphonate treatment on the bone micro-architecture of ovariectomized rats. Osteoporos Int 2015; 26: 303-313 DOI: 10.1007/s00198-014-2857-4.
• 41 Kranenburg G, de Jong PA, Bartstra JW. et al. Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum. J Am Coll Cardiol 2018; 71: 1117-1126 DOI: 10.1016/j.jacc.2017.12.062.
• 42 Kistler-Fischbacher M, Yong JS, Weeks BK. et al. A Comparison of Bone-Targeted Exercise With and Without Antiresorptive Bone Medication to Reduce Indices of Fracture Risk in Postmenopausal Women With Low Bone Mass: The MEDEX-OP Randomized Controlled Trial. J Bone Miner Res 2021; 36: 1680-1693 DOI: 10.1002/jbmr.4334.
• 43 Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc 2009; 84: 632-637 quiz 638. DOI: 84/7/632 [pii]10.4065/84.7.632
• 44 Das De S, Setiobudi T, Shen L. et al. A rational approach to management of alendronate-related subtrochanteric fractures. J Bone Joint Surg Br 2010; 92: 679-686 DOI: 10.1302/0301-620X.92B5.22941.
• 45 Rizzoli R. Bisphosphonates for post-menopausal osteoporosis: are they all the same. QJM 2011; 104: 281-300 DOI: 10.1093/qjmed/hcq259.
• 46 Erben RG. Hypothesis: Coupling between Resorption and Formation in Cancellous bone Remodeling is a Mechanically Controlled Event. Front Endocrinol (Lausanne) 2015; 6: 82 DOI: 10.3389/fendo.2015.00082.
• 47 Eriksen EF. Cellular mechanisms of bone remodeling. Rev Endocr Metab Disord 2010; 11: 219-227 DOI: 10.1007/s11154-010-9153-1.
• 48 Kemmler W, Riedel H. Einfluß eines intensiven 9monatigen körperlichen Trainings auf Knochendichte, Gesamtkalzium und Wirbelkörperbreite bei Frauen mit Osteoporose, Osteopenie und Knochengesunden. Osteologie 1998; 7: 203-210