Glucocorticoids (GCs) are frequently used for common medical conditions, such as asthma, severe infection, nephrotic syndrome, inflammatory bowel disease, rheumatic and autoimmune-related diseases. Although GC therapy may well delay disease development and improve disease prognosis, it is generally acknowledged that GC use can result serious side effects on bones, which makes glucocorticoid-induced osteoporosis (GIOP) the most common cause of secondary osteoporosis, and greatly increase the risk of bone fracture. It is reported that 26% of the patients who receive long-term GC treatment had presumed GIOP, among which 30% to 50% of patients may suffer fractures, predominantly in the total hip (TH), femoral neck (FN), and the lumbar spine (LS). Meanwhile, GIOP and GC-induced fractures can reduce the quality of life of patients with primary disease. Thus, when using GCs to manage diseases, the early prevention of GIOP is very important. GIOP is a complex pathological process in which the mechanism can be summarized as follows: GCs increase the production of osteoclasts and stimulate osteoclastic bone resorption, reduce the number of osteoblasts and increase osteocyte apoptosis, thereby inhibiting bone growth. Vitamin D and calcium are usually used to prevent GIOP in clinic. Bisphosphonate, teriparatide and denosumab therapy are the primary treatments for GIOP patients, which as first-line and second-line treatment respectively. However, the efficacy and safety issues are controversial in recent years. Therefore, faced with the limitations of current treatment, a safer and more effective therapeutic strategy need to be explored.
Chinese herbal medicine (CHM) is widely used in the treatment of GIOP. In China, GIOP belongs to the category of “bone impotence.” According to traditional Chinese medicine (TCM) theory, bone is closely related to kidney, kidney deficiency can lead to bone loss. Based on the relationship between kidney and bone, tonifying kidney and strengthen bone (known as Bushen Jiangu, BSJG) is the classic TCM therapy for GIOP. For example, Chen found that when combined with BSJG therapy and western medicine (WM), it could improve the clinical treatment effect and improve the symptoms of patients. Tu also found that BSJG method could prevent bone loss and improve the bone pain symptoms of GIOP compared with placebo. Some clinical studies have evaluated the therapeutic effect of BSJG on GIOP and its positive effect on increasing bone mass and improving bone mineral density (BMD) in recent decades.[10–13] Therefore, to further confirm the clinical value of BSJG therapy for GIOP, we conducted this meta-analysis to lay a foundation for promoting the clinical application of this treatment modality.
2. Materials and methods
This study is a secondary study of the literature, and due to this type of research, ethical approval is not necessary.
2.1. Database searching
Two trained investigators (by authors SCZ and JX) independently searched randomized controlled trials (RCTs) of BSJG therapy for GIOP from 10 different databases (i.e., PubMed, EMBASE, Web of science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, China Biological Medicine Database, VIP Journals Database, Chinese Clinical Trial Register and ClinicalTrials.gov), which retrieved from their inception to June 20, 2022. On the other hand, ambiguous studies would be searched manually to avoid missing qualified studies. The search terms include: (bushen OR jiangu OR tonifying kidney OR strengthen bone) AND (Glucocorticoid induced osteoporosis OR Glucocorticoid-induced osteoporosis). For the Chinese databases, these strategies were translated into Chinese. If necessary, we would contact the original researcher to obtain more complete research data.
2.2. Inclusion criteria
Eligible studies were included if they fulfilled the following criteria: population: patients were individuals who were low BMD induced by GCs; intervention: combination treatment of BSJG therapy and WM (vitamin D, calcium, bisphosphonate or calcitonin); comparison: WM alone applied; outcome: the required outcomes were clinical effective rate, lumbar spine bone mineral density (LS-BMD), total hip bone mineral density (TH-BMD), femoral neck bone mineral density (FN-BMD), visual analogue scale (VAS) score, parathyroid hormone (PTH), N-terminal propeptide of type I precollagen (PINP), and number of adverse events (AEs); design: RCT, Including trials published in the form of dissertations, results were available in either Chinese or English.
2.3. Exclusion criteria
Articles were excluded if they fulfilled the exclusive criteria: study subjects did not meet GIOP diagnostic criteria (i.e., idiopathic osteoporosis, senile osteoporosis, and postmenopausal osteoporosis); both treatment and control groups contained CHM only therapy, or the control group was treated with other CHM; unavailable data studies or duplicated articles or animal experiments; reviews or comments or case reports or conference abstracts; non-RCT.
2.4. Quality assessment and data extraction
Two independent reviewers (SCZ and JX) extracted the relevant data according to predefined criteria. The collected data included the first author, publishing year, country, participant baseline characteristics (age, sex, and disease duration), sample size, intervention, comparison, treatment duration, and outcome parameters. Two reviewers (SCZ and JX) individually estimated the methodological quality of the included trials based on the bias risk assessment of the Cochrane collaboration tool. The tool had 6 domains: method of random allocation; allocation concealment; blinding method; integrity of data; selective reporting; other biases. Each domain was ranked as “Low,” “Unclear,” and “High.” If disagreements on the assessment were identified, the third author (NX) was asked for the final decisions.
2.5. Data analysis
RevMan v5.3 was used for this meta-analysis. For dichotomous data, risk ratio (RR) and a 95% confidence internal (CI) were calculated to express. For continuous data, weighted mean difference (WMD), standardized mean difference (SMD) and a 95% CI were calculated. Statistical heterogeneity was evaluated using the I2 and χ2 tests. When heterogeneity was identified (I2 ≥ 50%), a random-effects model was selected, otherwise a fixed-effects model was applied. The source of the heterogeneity was identified by sensitivity analysis when heterogeneity exists. When P < .05, statistically significant differences were considered. Funnel plot, Egger and Begg tests would be implemented using Stata v14.0 to evaluate the potential publication bias, when more than 10 studies were included in the meta-analysis.
3.1. Search results and study characteristics
As Figure 1 shown, we found 420 relevant records reporting on GIOP treatment using BSJG therapy in our initial search. 132 were discarded because of duplications, 109 were excluded due to non-human studies, and 38 were discarded because of reviews. A total of 108 records were excluded after going through the titles and abstracts due to irrelevant diseases, medicines, or clinical experience reports. Another 19 records were excluded because of they did not meet the inclusion criteria after going through the full-text. Finally, 14 RCTs[15–28] with 988 participants were considered eligible for our meta-analysis. Among them, 495 in the intervention group received BSJG + WM therapy and 493 in the control group received WM treatment. The general characteristics of these eligible studies were summarized in Table 1.
Table 1 -
The characteristics of the included studies.
||Sample size (T/C)
|Zhang and Su, 2016
||44.72 ± 5.47
||43.98 ± 4.36
||BSJG + WM
||b, c, e, f,
|Zeng et al, 2017
||33.07 ± 7.01
||32.33 ± 6.24
||BSJG + WM
||a, d, h
|Chen et al, 2022
||61.25 ± 12.47
||58.87 ± 12.81
||BSJG + WM
||e, g, h
|Tong et al, 2018
||30.26 ± 12.27
||34.42 ± 14.15
||BSJG + WM
||a, b, c, h
|Sun et al, 2016
||BSJG + WM
||b, d, e, g, h
|Leng et al, 2017
||48.15 ± 6.87
||48.48 ± 6.91
||BSJG + WM
||a, b, d, f,
|Liu et al, 2017
||42.14 ± 4.72
||42.73 ± 4.57
||BSJG + WM
||a, c, f,
|Lan and Chen, 2016
||34.76 ± 4.16
||34.54 ± 4.64
||BSJG + WM
||a, b, d,
||45.50 ± 6.53
||46.15 ± 4.91
||BSJG + WM
||a, b, d, e, h
||38.83 ± 8.71
||39.70 ± 8.36
||BSJG + WM
||a, c, f, h
|Yang et al, 2017
||55.03 ± 15.00
||51.60 ± 12.82
||BSJG + WM
||b, c, d, g, h
||32.36 ± 13.28
||34.43 ± 14.12
||BSJG + WM
||a, b, c, h
||27.60 ± 9.41
||36.07 ± 15.83
||BSJG + WM
||a, b, h
||40.03 ± 13.24
||40.97 ± 12.60
||BSJG + WM
||a, c, f, h
Outcomes: a, clinical efficacy; b, LS-BMD; c, TH-BMD; d, FN-BMD; e, VAS score; f, PTH; g, PINP; h, AEs.
BSJG = Bushen Jiangu, C = control group, M/F = male/female, NA = not available, T = treatment group, WM = western medicine.
3.2. Risk of bias
As Figures 2 and 3 shown, the potential sources of bias and the included articles methodological quality were outlined. All included trials claimed randomized, however, only 5 reported the randomization method.[15,16,21,23,28] One described allocation concealment. Two mentioned the blinding of participant and personnel, the blinding of outcome assessment.[19,27] All studies had the complete outcome data, none of them had selective reporting or other biases.
3.3. Effects of intervention
3.3.1. Clinical efficacy rate.
Ten studies[16,18,20–24,26–28] with totaling 667 patients (334 in the BSJG therapy group, 333 in the control group) reported Clinical efficacy rates. We adopted the fixed effect model due to heterogeneity was not found (I2 = 0%) (Fig. 4). Pooled analysis showed that the BSJG therapy group clinical efficacy rates were higher than the control group (RR = 1.22, 95% CI: 1.14, 1.30, P < .00001).
3.3.2. BMD of lumbar spine.
Nine studies[15,18–20,22,23,25–27] provided LS-BMD, among them, 2 studies[15,18] were expressed by T value, and 7 studies[19,20,22,23,25–27] were expressed by BMD value. Qualitative analysis showed that the improvement of LS-BMD in the BSJG therapy group was better than that in the control group. 7 studies with totaling 504 patients (253 in the BSJG therapy group, 251 in the control group) were combined for quantitative analysis. We adopted the random effect model due to large heterogeneity (I2 = 96%) (Fig. 5). Pooled analysis showed that the BSJG therapy group could increase the LS-BMD compared with the controls (WMD = 0.21, 95% CI: 0.08, 0.33, P = .001).
3.3.3. BMD of total hip.
Seven studies[15,18,21,24–26,28] provided TH-BMD, among them, 4 studies[15,18,24,28] were expressed by T value, and 3 studies[21,25,26] were expressed by BMD value. Qualitative analysis showed that the improvement of TH-BMD in the BSJG therapy group was better than that in the control group. Since there were more studies related to T value, we used it to reflect the TH-BMD. 4 studies with totaling 228 patients (the BSJG therapy group and the control group were 114) were combined for quantitative analysis. We adopted the fixed effect model due to heterogeneity was not found (I2 = 13%) (Fig. 6). Pooled analysis showed that compared with the control group, the BSJG therapy group could improve the T value of total hip, suggesting that the BSJG therapy group could increase the TH-BMD (WMD = 0.16, 95% CI: 0.09, 0.24, P < .0001).
3.3.4. BMD of femoral neck.
Six studies[16,19,20,22,23,25] provided FN-BMD, among them, 1 study was expressed by T value, and 5 studies[19,20,22,23,25] were expressed by BMD value. Qualitative analysis showed that the improvement of FN-BMD in the BSJG therapy group was better than that in the control group. Five studies with totaling 432 patients (the BSJG therapy group and the control group were 216) were combined for quantitative analysis. We adopted the random effect model due to large heterogeneity (I2 = 70%) (Fig. 7). Pooled analysis showed that the BSJG therapy group could increase the FN-BMD compared with the controls (WMD = 0.07, 95% CI: 0.03, 0.10, P = .0001).
3.3.5. VAs score.
Four studies[15,17,19,23] with totaling 297 patients (149 in the BSJG therapy group, 148 in the control group) reported VAS score. We adopted the random effect model due to large heterogeneity (I2 = 60%) (Fig. 8). Pooled analysis showed that the BSJG therapy group VAS scores were lower than the control group (WMD = −0.60, 95% CI: −0.97, −0.23, P = .002).
3.3.6. Parathyroid hormone.
Five studies[15,20,21,24,28] with totaling 406 patients (the BSJG therapy group and the control group were 203) reported PTH. We adopted the random effect model due to large heterogeneity (I2 = 89%) (Fig. 9). Pooled analysis showed that the BSJG therapy group PTH was lower than the control group (SMD = −0.93, 95% CI: −1.58, −0.27, P = .006).
3.3.7. N-terminal propeptide of type I precollagen.
Three studies[17,19,25] with totaling 256 patients (129 in the BSJG therapy group, 127 in the control group) reported PINP. We adopted the fixed effect model due to heterogeneity was not found (I2 = 0%) (Fig. 10). Pooled analysis showed that the BSJG therapy group PINP were higher than the control group (SMD = 0.69, 95% CI: 0.44, 0.95, P < .00001).
3.4. AE reporting
Ten studies[16–19,23–28] provided AEs, among them, 5 studies[16,18,24–26] mentioned that there were no AEs in both groups, the remaining 5 studies[17,19,23,27,28] with totaling 332 patients (the BSJG therapy group and the control group were 166) reported AEs. We adopted the fixed effect model due to heterogeneity was not found (I2 = 20%) (Fig. 11). Compared BSJG therapy group with control group, there was no difference in AEs (RR = 1.45, 95% CI: 0.63, 3.31, P = .38). In the BSJG therapy group, the main AEs were stated as gastrointestinal discomfort (n = 6), muscle soreness (n = 1), sore throat (n = 3), and acne (n = 2). In the control group, the main AEs were stated as gastrointestinal discomfort (n = 4), muscle soreness (n = 2), hypertension (n = 1), and hypotension (n = 1). These AEs were transient and improved without special treatment. Because oral bisphosphate has obvious gastrointestinal reactions, the above AEs may be related to WM treatment. Thus, BSJG therapy seems to be safe, and the AEs does not increase compared with control group.
3.5. Sensitivity analysis
The reliability of the LS-BMD, FN-BMD, VAS score, and PTH results were affected by the huge heterogeneity, the source of that heterogeneity was investigated by the sensitivity analysis. After removing trials one by one, we were not found the source of the heterogeneity, which demonstrated that our results were robust (Fig. 12).
3.6. Publication bias
We used the clinical efficacy rate funnel plot to assess publication bias. The result revealed a slight asymmetry. The Begg regression (P = .032) and Egger regression tests (P = .004) showed possible publication bias (Fig. 13).
GIOP is one of the serious complications of GC use, which has been a challenging disorder. Nowadays, CHM is widely used in the treatment of GIOP to improve its symptoms and signs, and to control disease progression. According to the TCM theory, the pathogenesis of GIOP is related to kidney and bone deficiency, which belong to mingled with excess and deficiency syndromes or pure deficiency syndrome. Therefore, the principle for CHM treatment of GIOP is BSJG therapy. In recent years, more and more RCTs have used BSJG therapy to treat GIOP, which provides an opportunity for comprehensive and objective evaluation of this method.
In this meta-analysis of 14 RCTs, the efficacy and safety of BSJG therapy for GIOP were evaluated. We found that BSJG therapy combined with WM (vitamin D, calcium, bisphosphonate or calcitonin) was superior to monotherapy with WM. Previous meta-analyses showed that CHM could treat osteoporosis, improving symptoms and BMD, but most of the subjects were primary osteoporosis, postmenopausal osteoporosis or senile osteoporosis, and the intervention method was single decoction or Chinese patent medicine,[33,34] and only Wan study involved GIOP. However, our study varies from the research of Wan, the included RCTs in her study contained the patients who were diagnosed with GIOP and might have GIOP after long-term use of GC. At the same time, the intervention method in her study was not strictly limited to the type of CHM, and there was a direct comparison between CHM and WM. In addition, the effect of BSJG therapy on PTH and PINP in her study was not discussed. So strictly speaking, this is the first study of BSJG therapy in the treatment of GIOP.
Our meta-analysis found the following: BSJG combined with WM therapy could improve the clinical efficacy rate compared with the WM alone; BSJG combined with WM therapy could improve LS-BMD, TH-BMD and FN-BMD compared with the WM alone; adjunctive treatment with BSJG therapy decreased VAS score and PTH in GIOP patients; adjunctive treatment with BSJG therapy increased PINP in GIOP patients; BSJG combined with WM therapy did not increase AEs compared with the WM alone. These results suggest that BSJG therapy can be considered a potentially valid and safe drug in the management of GIOP patients.
Relevant studies have shown that the increase of PTH can inhibit osteoblasts, transform large monocytes into osteoclasts, and then promote bone absorption. At the same time, osteoblasts express cytokines such as interleukin-6 (IL-6), which together supplement and activate osteoclasts, leading to osteoporosis. From the above results, BSJG therapy can inhibit PTH and improve osteoporosis. In addition, osteoblasts contain large type I procollagen. During bone formation, type I procollagen is secreted outside the cells and cleaved into fragments such as PINP. Therefore, PINP can reflect the level of bone formation. From the above results, BSJG therapy can increase PINP and treat osteoporosis. In the included studies, the most commonly used CHM in BSJG was Epimedium sagittatum (Siebold & Zucc.) Maxim. (Yin yang huo), Rehmannia glutinosa (Gaertn.) DC. (Shu di huang), and Eucommia ulmoides Oliv. (Du zhong), which all have the function of tonifying the kidney. These kidney tonifying herbs can treat osteoporosis by regulating Runx2 gene and OPG/RANKL/RANK signaling pathway.
Several limitations in the meta-analysis should also be considered. First, the included subjects were Chinese, which may present selection bias. Second, given that the methodological quality of some enrolled studies might be generally low, making it prone to produce false negative or false positive results. Moreover, although sensitivity analysis showed that our conclusions were reliable and stable, heterogeneity among the studies, possibly owing to different treatment duration, different anti-osteoporosis WM and different GIOP primary disease should be considered seriously when interpreting the results. Finally, in the clinical efficacy rate there was a publication bias, which may be because of the lack of small studies with published negative results or the flawed small research design. Our study showed that BSJG therapy demonstrates good potential in treating GIOP. However, the possible mechanisms of BSJG therapy in the treatment of GIOP need to be explored in the future, and the strict trial design is also necessary to further validate our findings.
In general, for GIOP patients, compared with the WM alone, BSJG combined with WM therapy can increase the clinical efficacy rates and PINP, improve the LS-BMD, TH-BMD and FN-BMD, reduce the VAS score and PTH, without an increased AEs incidence. However, because the quality of the included literature is relatively poor, our conclusions should be interpreted with some caution. Therefore, we also need large-scale and more multi-center RCTs to objective and comprehensive evaluation of the effectiveness and safety of BSJG in patients with GIOP in future.
We would like to thank the tutor (NX) for her selfless help and inculcation. We thank the reviewer useful comments, which greatly improved this article quality.
Conceptualization: Xietian Yin.
Data curation: Shichao Zhao, Jun Xu.
Formal analysis: Jidong Chen, Yudan Zhang.
Methodology: Xietian Yin, Nan Xiang.
Writing – original draft: Xietian Yin.
Writing – review & editing: Shichao Zhao.
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