PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.
HMGCR
Mendelian randomization
Osteoporosis
PCSK9
Journal
BMC musculoskeletal disorders
ISSN: 1471-2474
Titre abrégé: BMC Musculoskelet Disord
Pays: England
ID NLM: 100968565
Informations de publication
Date de publication:
16 Jul 2024
16 Jul 2024
Historique:
received:
16
09
2023
accepted:
08
07
2024
medline:
16
7
2024
pubmed:
16
7
2024
entrez:
15
7
2024
Statut:
epublish
Résumé
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.
Sections du résumé
BACKGROUND
BACKGROUND
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis.
METHODS
METHODS
Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis.
RESULTS
RESULTS
The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I
CONCLUSION
CONCLUSIONS
PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.
Identifiants
pubmed: 39010016
doi: 10.1186/s12891-024-07674-w
pii: 10.1186/s12891-024-07674-w
doi:
Substances chimiques
PCSK9 protein, human
EC 3.4.21.-
PCSK9 Inhibitors
0
HMGCR protein, human
EC 1.1.1.-
Proprotein Convertase 9
EC 3.4.21.-
Hydroxymethylglutaryl CoA Reductases
EC 1.1.1.-
Types de publication
Journal Article
Meta-Analysis
Langues
eng
Sous-ensembles de citation
IM
Pagination
548Subventions
Organisme : Natural Science Foundation of Fujian Province
ID : No. 2020J011244
Informations de copyright
© 2024. The Author(s).
Références
Hu L, Yin C, Zhao F, Ali A, Ma J, Qian A. Mesenchymal stem cells: cell fate decision to osteoblast or adipocyte and application in osteoporosis treatment. Int J Mol Sci. 2018;19(2):360. https://doi.org/10.3390/ijms19020360 .
doi: 10.3390/ijms19020360
pubmed: 29370110
pmcid: 5855582
Föger-Samwald U, Kerschan-Schindl K, Butylina M, Pietschmann P. Age related osteoporosis: Targeting Cellular Senescence. Int J Mol Sci. 2022;23(5):2701. https://doi.org/10.3390/ijms23052701 .
doi: 10.3390/ijms23052701
pubmed: 35269841
pmcid: 8910503
Laskou F, Fuggle NR, Patel HP, Jameson K, Cooper C, Dennison E. Associations of osteoporosis and sarcopenia with frailty and multimorbidity among participants of the Hertfordshire Cohort Study. J Cachexia Sarcopenia Muscle. 2022;13(1):220–9. https://doi.org/10.1002/jcsm.12870 . Epub 2021 Dec 6.
doi: 10.1002/jcsm.12870
pubmed: 34873876
Anagnostis P, Florentin M, Livadas S, Lambrinoudaki I, Goulis DG. Bone Health in patients with Dyslipidemias: an underestimated aspect. Int J Mol Sci. 2022;23(3):1639. https://doi.org/10.3390/ijms23031639 .
doi: 10.3390/ijms23031639
pubmed: 35163560
pmcid: 8835770
Duan Y, Gong K, Xu S, Zhang F, Meng X, Han J. Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Signal Transduct Target Ther. 2022;7(1):265. https://doi.org/10.1038/s41392-022-01125-5 .
doi: 10.1038/s41392-022-01125-5
pubmed: 35918332
pmcid: 9344793
Grześk G, Dorota B, Wołowiec Ł, Wołowiec A, Osiak J, Kozakiewicz M, et al. Safety of PCSK9 inhibitors. Biomed Pharmacother. 2022;156:113957. https://doi.org/10.1016/j.biopha.2022.113957 . Epub 2022 Nov 8.
doi: 10.1016/j.biopha.2022.113957
pubmed: 36411665
Gallego-Colon E, Daum A, Yosefy C, Statins. PCSK9 inhibitors: a new lipid-lowering therapy. Eur J Pharmacol. 2020;878:173114. https://doi.org/10.1016/j.ejphar.2020.173114 . Epub 2020 Apr 14.
doi: 10.1016/j.ejphar.2020.173114
pubmed: 32302598
Sabatine MS. PCSK9 inhibitors: clinical evidence and implementation. Nat Rev Cardiol. 2019;16(3):155–65. https://doi.org/10.1038/s41569-018-0107-8 .
doi: 10.1038/s41569-018-0107-8
pubmed: 30420622
Tian L, Yu X. Lipid metabolism disorders and bone dysfunction–interrelated and mutually regulated (review). Mol Med Rep. 2015;12(1):783–94. https://doi.org/10.3892/mmr.2015.3472 . Epub 2015 Mar 11.
doi: 10.3892/mmr.2015.3472
pubmed: 25760577
pmcid: 4438959
Ruscica M, Tokgözoğlu L, Corsini A, Sirtori CR. PCSK9 inhibition and inflammation: a narrative review. Atherosclerosis. 2019;288:146–55. https://doi.org/10.1016/j.atherosclerosis.2019.07.015 . Epub 2019 Jul 17.
doi: 10.1016/j.atherosclerosis.2019.07.015
pubmed: 31404822
Newman CB. Safety of statins and nonstatins for treatment of Dyslipidemia. Endocrinol Metab Clin North Am. 2022;51(3):655–79. https://doi.org/10.1016/j.ecl.2022.01.004 . Epub 2022 Jul 8.
doi: 10.1016/j.ecl.2022.01.004
pubmed: 35963634
Hummelgaard S, Vilstrup JP, Gustafsen C, Glerup S, Weyer K. Targeting PCSK9 to tackle cardiovascular disease. Pharmacol Ther. 2023;249:108480. https://doi.org/10.1016/j.pharmthera.2023.108480 . Epub 2023 Jun 17.
doi: 10.1016/j.pharmthera.2023.108480
pubmed: 37331523
Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol. 2004;43(4):642–8. https://doi.org/10.1016/j.jacc.2003.07.049 .
doi: 10.1016/j.jacc.2003.07.049
pubmed: 14975476
Alehagen U, Benson L, Edner M, Dahlström U, Lund LH. Association between use of statins and outcomes in heart failure with reduced ejection fraction: prospective propensity score matched cohort study of 21 864 patients in the Swedish Heart failure Registry. Circ Heart Fail. 2015;8(2):252–60. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001730 . Epub 2015 Jan 9.
doi: 10.1161/CIRCHEARTFAILURE.114.001730
pubmed: 25575580
Wang Z, Li Y, Zhou F, Piao Z, Hao J. Effects of statins on Bone Mineral density and fracture risk: a PRISMA-compliant systematic review and Meta-analysis. Med (Baltim). 2016;95(22):e3042. https://doi.org/10.1097/MD.0000000000003042 .
doi: 10.1097/MD.0000000000003042
Liu J, Zhu LP, Yang XL, Huang HL, Ye DQ. HMG-CoA reductase inhibitors (statins) and bone mineral density: a meta-analysis. Bone. 2013;54(1):151–6. https://doi.org/10.1016/j.bone.2013.01.044 . Epub 2013 Feb 4.
doi: 10.1016/j.bone.2013.01.044
pubmed: 23388418
Alam S, Ueki K, Nakagawa K, Marukawa K, Hashiba Y, Yamamoto E, Sakulsak N, Iseki S. Statin-induced bone morphogenetic protein (BMP) 2 expression during bone regeneration: an immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107(1):22–9. https://doi.org/10.1016/j.tripleo.2008.06.025 . Epub 2008 Aug 28.
doi: 10.1016/j.tripleo.2008.06.025
pubmed: 18755616
Wang W, Nyman JS, Moss HE, Gutierrez G, Mundy GR, Yang X, Elefteriou F. Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts. J Bone Min Res. 2010;25(7):1658–67. https://doi.org/10.1002/jbmr.42 .
doi: 10.1002/jbmr.42
Goes P, Lima AP, Melo IM, Rêgo RO, Lima V. Effect of atorvastatin in radiographic density on alveolar bone loss in Wistar rats. Braz Dent J. 2010;21(3):193–8. https://doi.org/10.1590/s0103-64402010000300003 .
doi: 10.1590/s0103-64402010000300003
pubmed: 21203699
Parhami F, Mody N, Gharavi N, Ballard AJ, Tintut Y, Demer LL. Role of the cholesterol biosynthetic pathway in osteoblastic differentiation of marrow stromal cells. J Bone Min Res. 2002;17(11):1997–2003. https://doi.org/10.1359/jbmr.2002.17.11.1997 .
doi: 10.1359/jbmr.2002.17.11.1997
Parhami F. Possible role of oxidized lipids in osteoporosis: could hyperlipidemia be a risk factor? Prostaglandins Leukot Essent Fat Acids. 2003;68(6):373–8. https://doi.org/10.1016/s0952-3278(03)00061-9 .
doi: 10.1016/s0952-3278(03)00061-9
Chen M, Chen Q, Xiao XY, Feng SJ, Wang XY, Tang TC, et al. Genetically proxied inhibition of tumor necrosis factor and the risk of colorectal cancer: a drug-target mendelian randomization study. Front Pharmacol. 2022;13:1079953. https://doi.org/10.3389/fphar.2022.1079953 .
doi: 10.3389/fphar.2022.1079953
pubmed: 36618924
pmcid: 9816472
Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, Holmes MV. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable mendelian randomisation analysis. PLoS Med. 2020;17(3):e1003062. https://doi.org/10.1371/journal.pmed.1003062 .
doi: 10.1371/journal.pmed.1003062
pubmed: 32203549
pmcid: 7089422
Lewis RG, Simpson B, Genetics AD. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.
D’Onofrio N, Prattichizzo F, Marfella R, Sardu C, Martino E, Scisciola L, et al. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. Theranostics. 2023;13(2):531–42. https://doi.org/10.7150/thno.80289 .
doi: 10.7150/thno.80289
pubmed: 36632236
pmcid: 9830434
Ding Z, Pothineni NVK, Goel A, Lüscher TF, Mehta JL. PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovasc Res. 2020;116(5):908–915. https://doi.org/10.1093/cvr/cvz313 . Erratum in: Cardiovasc Res. 2022;118(8):2031.
Adler RA. Osteoporosis in men: a review. Bone Res. 2014;2:14001. https://doi.org/10.1038/boneres.2014.1 .
doi: 10.1038/boneres.2014.1
pubmed: 26273515
pmcid: 4472130
Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I. Immunology of osteoporosis: a Mini-review. Gerontology. 2016;62(2):128–37. https://doi.org/10.1159/000431091 . Epub 2015 Jun 17.
doi: 10.1159/000431091
pubmed: 26088283
Jeong TD, Lee W, Choi SE, Kim JS, Kim HK, Bae SJ, et al. Relationship between serum total cholesterol level and serum biochemical bone turnover markers in healthy pre- and postmenopausal women. Biomed Res Int. 2014;2014:398397. https://doi.org/10.1155/2014/398397 . Epub 2014 May 15.
doi: 10.1155/2014/398397
pubmed: 24949440
pmcid: 4052088
Esposito K, Capuano A, Sportiello L, Giustina A, Giugliano D. Should we abandon statins in the prevention of bone fractures? Endocrine. 2013;44(2):326–33. https://doi.org/10.1007/s12020-013-9924-z . Epub 2013 Mar 24.
doi: 10.1007/s12020-013-9924-z
pubmed: 23526261
Almeida M, Laurent MR, Dubois V, Claessens F, O’Brien CA, Bouillon R, et al. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev. 2017;97(1):135–87. https://doi.org/10.1152/physrev.00033.2015 .
doi: 10.1152/physrev.00033.2015
pubmed: 27807202
Gambacciani M, Levancini M. Management of postmenopausal osteoporosis and the prevention of fractures. Panminerva Med. 2014;56(2):115–31. Epub 2014 Jun 19.
pubmed: 24942322
Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314–29. https://doi.org/10.1016/j.jacc.2018.04.054 . Epub 2018 Jul 9.
doi: 10.1016/j.jacc.2018.04.054
pubmed: 30012326
Jefcoate C. High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex. J Clin Invest. 2002;110(7):881–90. https://doi.org/10.1172/JCI16771 .
doi: 10.1172/JCI16771
pubmed: 12370263
pmcid: 151162
Zhang X, Li J, Zhou X, Guan Q, Zhao J, Gao L, SIMVASTATIN DECREASES SEX HORMONE LEVELS IN MALE RATS, et al. Endocr Pract. 2017;23(2):175–81. .OR. Epub 2016 Nov 16.
doi: 10.4158/EP161274.OR
pubmed: 27849375
Guldvang A, Hansen CH, Weisser JJ, Halling-Sørensen B, Styrishave B. Simvastatin decreases steroid production in the H295R cell line and decreases steroids and FSH in female rats. Reprod Toxicol. 2015;58:174–83. https://doi.org/10.1016/j.reprotox.2015.10.005 . Epub 2015 Oct 23.
doi: 10.1016/j.reprotox.2015.10.005
pubmed: 26476359
de Keyser CE, de Lima FV, de Jong FH, Hofman A, de Rijke YB, Uitterlinden AG, et al. Use of statins is associated with lower serum total and non-sex hormone-binding globulin-bound testosterone levels in male participants of the Rotterdam Study. Eur J Endocrinol. 2015;173(2):155–65. https://doi.org/10.1530/EJE-14-1061 . Epub 2015 Jun 1.
doi: 10.1530/EJE-14-1061
pubmed: 26034077
Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. J Pharm Pharmacol. 2006;58(1):3–18. https://doi.org/10.1211/jpp.58.1.0002 .
doi: 10.1211/jpp.58.1.0002
pubmed: 16393459
Melsen WG, Bootsma MC, Rovers MM, Bonten MJ. The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses. Clin Microbiol Infect. 2014;20(2):123–9. https://doi.org/10.1111/1469-0691.12494 .
doi: 10.1111/1469-0691.12494
pubmed: 24320992
Stogiannis D, Siannis F, Androulakis E. Heterogeneity in meta-analysis: a comprehensive overview. Int J Biostat. 2023;20(1):169–99. https://doi.org/10.1515/ijb-2022-0070 .
doi: 10.1515/ijb-2022-0070
pubmed: 36961993
Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA. Limits to causal inference based on mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol. 2006;163(5):397–403. https://doi.org/10.1093/aje/kwj062 . Epub 2006 Jan 12.
doi: 10.1093/aje/kwj062
pubmed: 16410347
Gill D, Walker VM, Martin RM, Davies NM, Tzoulaki I. Comparison with randomized controlled trials as a strategy for evaluating instruments in mendelian randomization. Int J Epidemiol. 2020;49(4):1404–6. https://doi.org/10.1093/ije/dyz236 .
doi: 10.1093/ije/dyz236
pubmed: 31764983