A Meta-analysis Of The Efficacy And Safety Of Vitamin K2 In The Treatment Of Postmenopausal Osteoporosis

Background and purpose: With the aging of population,osteoporosis(OP)has become a global public health problem.As a systemic metabolic bone disease,OP is characterized by low bone mass,damaged bone microstructure,increased bone fragility,and fracture can occur under slight external force.Osteoporosis includes primary osteoporosis and secondary osteoporosis,among which postmenopausal osteoporosis(PMOP)is the most common type of primary osteoporosis.According to statistics,the prevalence of OP in women over 50 years old in China is 32.1% and in women over 65 years old was 51.6%.Vitamin K2(VK2),namely menaquinone(MK),is an important nutrient for the human body.VK2 has been found to be a cofactor for the carboxylation of osteocalcin(OC),helping to convert undercarboxylated osteocalcin(uc OC)to carboxylated osteocalcin(c OC).c OC can combine with hydroxyapatite to promote bone mineralization,inhibit programmed cell death of osteoblasts,maintain the number of osteoblasts,and increase bone strength.However,the conclusions of relevant studies published at home and abroad on whether VK2 can effectively prevent PMOP and reduce the incidence of osteoporotic fractures in postmenopausal women by improving bone mineral density at common osteoporotic fracture sites in postmenopausal women are inconsistent.Therefore,the purpose of this study is to determine the efficacy and safety of VK2 in the prevention and treatment of PMOP,and to provide evidence-based medical evidence for the application of VK2 in PMOP.Methods: This study followed the PRISMA(preferred reporting items for systematic review and meta-analysis)statement to develop a relevant search strategy to search domestic and international literature databases(Pub Med,Embase,Cochrane Library,Web of Science,CNKI,Wanfang,VIP and CBM databases)for articles on VK2 in the prevention and treatment of PMOP published before March 31,2022.And then screened the randomized controlled trials(RCTs)that met the inclusion criteria.The quality of the included studies was assessed using the literature quality and risk of bias assessment tool provided by the Cochrane Library.According to the intervention measures,the subjects were divided into VK2 combination treatment subgroup and VK2 treatment alone subgroup.Subjects were divided into osteoporosis subgroup and non-osteoporosis subgroup according to whether they already had osteoporosis.Data indicators were extracted(all continuous variables in this study were percent change;if articles reported results at multiple follow-up points,the longest follow-up time data were used),and data were combined and analyzed using Rev Man5.3 software.And sensitivity analysis and publication bias detection were performed using Stata14.0software.Results: A total of 22 RCTs involving 7302 participants were included.BMD of lumbar spine,hip,femoral neck and forearm,incidence of fracture,serum uc OC,c OC levels and the ratio of serum uc OC to OC,and incidence of adverse reactions were selected for data analysis.The results of the pooled analysis of lumbar BMD showed that compared with the control group,the improvement of lumbar BMD in the VK2 group was more significant in postmenopausal women [MD=1.08,95%CI(0.21,1.95),P=0.01].The results of subgroup analysis of VK2 combined with other anti-OP drugs showed that compared with the control group,the improvement of lumbar BMD in postmenopausal women was more significant when VK2 was combined with other antiOP drugs [MD=1.43,95%CI(1.26,2.60),P=0.02].However,in the subgroup treated with VK2 alone,there was no significant difference between the two groups [MD=0.59,95%CI(-0.15,1.33),P=0.12].The results of the pooled analysis of the osteoporosis subgroup showed that the improvement of lumbar BMD in postmenopausal women in the VK2 group was more significant than that in the control group [MD=1.91,95%CI(0.36,3.43),P=0.02].However,in the subgroup without osteoporosis,there was no significant difference between the two groups [MD=0.51,95%CI(-0.20,1.21),P =0.16].There was no significant difference in BMD of the hip,femoral neck and forearm between the VK2 and control groups [MD=0.05,95%CI(-0.31,0.41),P=0.79],[MD=0.41,95%CI(-0.27,1.08),P=0.24],[MD=0.65,95%CI(-0.37,1.67),P=0.21].The result of meta-analysis of the incidence of fractures showed that the VK2 group had a significant effect on reducing the incidence of fractures compared with the control group [RR=0.53,95%CI(0.29,0.96),P=0.04].The results of the pooled analysis of serum uc OC and the ratio of uc OC to OC showed that the VK2 group could significantly reduce the serum uc OC levels and the ratio of uc OC to OC compared with the control group,and the differences were statistically significant [MD=-39.16,95%CI(-52.57,-25.76),P<0.00001],[MD=-49.41,95%CI(-64.03,-34.80),P<0.00001].However,the pooled analysis of serum c OC showed no significant difference between the two groups [MD=8.45,95%CI(-5.52,22.42),P=0.24].There was no significant difference in the incidence of adverse reactions between the VK2 and the control groups[RR=1.03,95%CI(0.88,1.21),P=0.72].Conclusions: According to the results of this meta-analysis,vitamin K2 improved lumbar vertebrae BMD in postmenopausal women,and its effect was more significant when combined with other anti-osteoporosis drugs,and postmenopausal women who already had osteoporosis benefited more from it.Vitamin K2 could reduce uc OC and decrease the risk of fracture without serious adverse reactions and with a high safety profile.More high-quality RCTs are needed in the future to further confirm the roles of vitamin K2 in postmenopausal osteoporosis.