Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Moxibustion treatment for primary osteoporosis: A systematic review of randomized controlled trials

  • Fanping Xu,

    Affiliation Department of Orthopaedics, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

  • Minghua Huang,

    Affiliation Department of Orthopaedics, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

  • Yi Jin,

    Affiliation Department of Orthopaedics, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

  • Qingzhe Kong,

    Affiliation Department of Orthopaedics, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

  • Zhongmin Lei ,

    lzm136@sohu.com (ZL); weixu.007@163.com (XW)

    Affiliation Department of Orthopaedics, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

  • Xu Wei

    lzm136@sohu.com (ZL); weixu.007@163.com (XW)

    Affiliation Department of Scientific Research, Wangjing hospital, China Academy of Chinese Medical Sciences, Beijing, China

    ORCID http://orcid.org/0000-0001-6723-9604

Moxibustion treatment for primary osteoporosis: A systematic review of randomized controlled trials

  • Fanping Xu, 
  • Minghua Huang, 
  • Yi Jin, 
  • Qingzhe Kong, 
  • Zhongmin Lei, 
  • Xu Wei
PLOS
x

Abstract

Primary osteoporosis (POP) has a serious impact on quality of life for middle-aged and elderly, which particularly increase the risk of fracture. We conducted the systematic review to evaluate the effects of moxibustion for POP in randomized controlled trials (RCTs).Eight databases were searched from their inception to July 30, 2016. The RCTs reporting the moxibustion as a monotherapy or in combination with conventional therapy for POP were enrolled. The outcomes might be fracture incidence, quality of life, clinical symptoms, death attributed to osteoporosis, adverse effect, bone mineral density (BMD), and biochemical indicators. Literature selection, data abstraction, quality evaluation, and data analysis were in accordance with Cochrane standards.Thirteen trials including 808 patients were included. Meta-analysis was not conducted because of the obvious clinical or statistical heterogeneity. Limited evidence suggested that moxibustion plus anti-osteoporosis medicine might be more effective in relieving the pain (visual analogue scale scores average changed 2 scores between groups, 4 trials), increasing the BMD of femoral neck (average changed 0.4 g/cm2 between groups, 3 trials), and improving the level of bone gla protein, osteoprotegerin and bone alkaline phosphatase (2 trials) compared with anti-osteoporosis medicine alone. However, the quality of previous studies was evaluated as generally poor. The safety evidence of moxibustion was still insufficient. Due to the paucity of high-quality studies, there was no definite conclusion about the efficacy and safety of moxibustion treating POP although parts of positive results were presented. Future research should pay attention to the dose-response relation and fracture incidence of moxibustion for POP.

Introduction

Primary osteoporosis (POP) is a disease particularly occurred in senile population and postmenopausal women [1]. In Asia countries, Europe and the United States, POP has become a major health issue because of its high prevalence, serious complications and heavy economic burden [24]. This disease often causes significant harm, such as decreased quality of life [5] and increasing mortality risk within a year after a hip fracture [6]. In China, take for example, recently published data indicates that the median of the per-admission inpatient costs for osteoporotic fractures is ¥18,587 [7]. After post-discharge, the average direct medical cost, indirect medical cost, and caregiver lost income associated with osteoporosis-related fracture still totaled ¥7,886 [8]. Therefore, treatment of osteoporosis has positive significance to prevent fractures, especially for POP patients. With a growing number of senior citizens in the total population, the problem of POP management relatively lagging has been emerged [9] and will become more and more serious. In recent years, the management of POP gained more and more attention in many nations of the world [1012].

Anti-osteoporosis medicine is recommended as the first-line treatment for POP in the clinical practice guidelines [13, 14]. Evidence from clinical trials supports the use of bisphosphonates for POP [15, 16]. However, the long-term use of bisphosphonates may be associated with adverse effects; for instance, pyrexia, arthralgia myalgia [17], osteonecrosis of the jaw, atrial fibrillation [18]. In China and some other countries, the clinical doctors and patients are looking for complementary and alternative therapies to treat osteoporosis [19, 20]. As a Chinese traditional treatment, moxibustion has been commonly used in several chronic musculoskeletal disease states, including cervical spondylosis [21], lumber disc herniation [22], knee osteoarthritis [23], and POP [24]. Like the acupuncture, moxibustion also need to choose specific acupoints in the body, such as Zusanli (ST 36), Shenshu (BL 23). Moxibustion therapy has the properties of warming the body, eliminating cold, regulating energy metabolism and relieving pain [25]. According to the theory of traditional Chinese medicine, moxibustion is thought to regulate qi and the blood, improving physical fitness to eliminate pathogenesis by means of warming [26].

Based on the available literature, some clinical trial reports were found on moxibustion therapy for POP. In addition, the recommendation on moxibustion in the clinical practice guideline of traditional medicine for POP still depends on the literatures before 2011. So far there is no critical appraisal of the evidence on the clinical efficacy and safety of the alternative treatment for POP. Therefore, this systematic review reporting moxibustion treating POP contributes to complement and update the evidence of treatment.

Materials and methods

Study registration

This protocol of systematic review was registered at PROSPERO (registration number: CRD42016047944; http://www.crd.york.ac.uk/PROSPERO). This systematic review was conducted in accordance with the PRISMA guidelines [27].

Inclusion criteria

Randomized controlled trial (RCT) designs that compared moxibustion intervention targeting POP patients with either non-moxibustion intervention or a group that did not receive any intervention were enrolled. In order to be included, the RCTs need to report the effectiveness of the moxibustion as a monotherapy or in combination with conventional therapy with at least one of the outcomes of interest. For instance: moxibustion vs. antiosteoporosis drug, (moxibustion + antiosteoporosis drug) vs. (antiosteoporosis drug), moxibustion vs. no treatment, moxibustion vs. exercise. The outcomes at the end of treatment or at maximal follow-up might be fracture incidence, quality of life, clinical symptoms (such as pain, muscle fatigue, and limited mobility), death directly or indirectly attributed to osteoporosis, adverse effect, bone mineral density (BMD), and biochemical markers of bone turnover [28].

Database and search strategy

Two independent authors performed a systematic electronic search in PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journals Database (VIP), Chinese Biomedical Literature Database (CBM) were retrieved. The search terms used were “moxibustion”, “osteoporosis”, and “random” from their inception to July 30, 2016. The keywords were combined applying the Boolean logic operation AND. The search statement applied in the PubMed database was presented as ((moxibustion) AND osteoporosis) AND random. The search was restricted to RCTs published in English or Chinese. In addition, we performed a search of bibliographies of identified RCTs. For those grey literatures, we searched trial registries (e.g., http://www.chictr.org.cn and http://clinicaltrials.gov), conference proceedings or abstracts, and dissertation databases. The electronic search would be repeated for two months before the final manuscript submission.

Study selection

Two independent reviewers screened the potential studies. Titles and abstracts from the initial search were first scanned, and then the full papers of possible eligible studies were evaluated. The records of ineligible articles would be saved in a separate document. PRISMA flow diagram was formed to demonstrate the search and screening process.

Data extraction and quality assessment

The following information was extracted: study characteristics (The author, year, and sample size), patient characteristics (age, sex, and days of disease), intervention details (doses, administration forms), treatment and follow-up duration, outcome measures (mean and standard deviation or standard errors per arm, number of events). For RCTs with more than one follow-up point, we selected the longest period. Two reviewers extracted the data independently. In case of disagreements that could not be resolved by discussion, a third author would be consulted. We would contact authors of primary studies to obtain any missing information.

Two authors independently evaluated risk of bias in the included RCTs by using the Cochrane Collaboration’s risk of bias tool [29]. Each domain will be confirmed as ‘low risk’, ‘high risk’ or ‘unclear risk’. These articles were then rated according to methodological quality: low, high or unclear risk of bias.

Data synthesis

Continuous outcomes were pooled to obtain a mean difference (MD) or Standardized mean difference (SMD) with its 95% confidence interval (CI). Inter-study heterogeneity among the trials was assessed by the Cochran's Q test and I2 statistic. For Q test, p<0.10 indicated statistically significant heterogeneity. For the I2 statistic, I2 > 50% indicated large heterogeneity. In case of statistical heterogeneity, the subgroup or sensitivity analyses would be used to explain this reason with a random effect model. In the light of the obvious clinical and statistical heterogeneity, the results were unable to be synthesized, so the description analysis for the single study was presented. A two-tailed p value<0.05 was considered to indicate statistical significance. If we could retrieve at least ten studies, a funnel plot would be constructed for each outcome to assess the potential publication bias. All statistical analyses were performed using the software Review Manager 5.2 software by the Cochrane Collaboration (Copenhagen: The Nordic Cochrane Centre, Cochrane Collaboration, 2011).

Strength of evidence

In the systematic review, the strength of the body of evidence was assessed by the grading of recommendations assessment, development, and evaluation (GRADE) tool.

Results

Process of literature search

All the electronic databases resulted in 418 retrieved references in S1 Fig. After removing the duplicates, the titles and abstracts of 224 records were screened for further evaluation. And then full-text was obtained and eligibility was evaluated for 25 publications. Eleven publications were excluded on the basis of the PICO question. Finally 14 articles were enrolled in the systematic review [3043]. However, two articles reported a same trial but just different outcomes [33, 34]. Thus, 13 RCTs were included. The studies were published in 2010 or later, with a large proportion (69%, 9/13) published in 2013 or later, signaling a recent rise in attention to this issue. All of the trials were conducted in China and published in Chinese.

Characteristics of included trials

The 13 included studies, which evaluated the effect of moxibustion as an add-on therapy, are depicted in Table 1. They included 406 cases in the treatment group and 402 cases in the control group. All the studies were from the single centers, and the largest sample size in the previous studies was less than 100 cases. The average age of patients within the groups was above 50 years old. According to the classification criteria of disease, POP included senile osteoporosis and postmenopausal osteoporosis [1]. In this systematic review, 2 trials paid attention to senile osteoporosis [30, 33, 34], 5 trials just studied postmenopausal osteoporosis [37, 38, 4042], 6 trials focused on both [31, 32, 35, 36, 39, 43].

Moxibustion included heat-sensitive moxibustion (5 trials), mild moxibustion (4 trials), du-moxibustion (4 trials) based on the specific acupoints. The frequency of moxibustion covered in the included trials was varied, but the majority of studies chose to moxibustion treatment once daily [3036, 41]. Specific acupoints of the moxibustion were shown in Table 2.

All the treatment groups were moxibustion plus the interventions based on the control group. The control groups only used conventional treatments, including alendronate sodium [30, 33, 34], calcium supplementation [31, 32, 3639], salmon calcitonin [35], calcium supplementation, alendronate sodium, α-D3, combined with resistance training [40], calcium supplementation and alendronate sodium [41, 42], calcium supplementation, alendronate sodium and calcitriol [43]. However, the type of study design such as moxibustion vs. no treatment or waiting-list was not found.

The treatment duration ranged from 14 days to 12 months, but most of studies (62%, 8/13) designed a 3-month treatment program in clinical trials. For the outcome evaluation, fracture incidence and death directly or indirectly attributed to osteoporosis were not reported in all the previous studies. Quality of life [36, 40], pain and functional activities rating [32, 38, 39, 43], bone mineral density (BMD) [30, 31, 35, 3942], biochemical indicators [3034, 36, 37, 4043] and adverse effect [31, 38, 42] were recorded. In addition, none of studies mentioned follow-up observation.

Risk of bias in included studies

Methodological quality of the included studies was presented in S2 and S3 Figs. The risk of bias was assessed as high for all the studies. Of the 13 studies, 7 trials used random number table for the generation of the allocation sequence [30, 31, 33, 34, 36, 3840]. In the review, only 1 trial described the detail of allocation concealment [40]. No trials implemented the blinding of participants and personnel. In addition, we did not found any information to identify the blinding of outcome assessment.

The items of quality assessment were described in Table 3. Only 3 trials provided information about withdrawals or drop-outs [37, 38, 40]. No study protocol was registered or published in public, so it was difficult to judge the reporting bias. Other biases were considered in two aspects: sample size calculation and comparability of baseline data. None of the trials reported a pre-trial estimation of sample size, though analysis of the baseline was complete in every single study. Therefore, the reviewers evaluated all of the trials at an unclear risk of other bias.

Effects of the interventions

The outcomes were summarized as follows.

Quality of life.

Two trials reported the improvement of quality of life [36, 40]. The medical outcome study item short form health survey (SF-36) [36] and osteoporosis quality of life scale [40] were used to evaluate the quality of life, respectively. One trial [36] demonstrated that heat-sensitive moxibustion plus calcium D was better than calcium D alone in improving the physical functioning (MD -3.59, 95%CI -5.73 to -1.45), role limitations because of physical health problems (MD -7.54, 95%CI -13.43 to -1.65), bodily pain (MD -4.29, 95%CI -8.33 to -0.25), vitality (MD -4.38, 95%CI -7.69 to -1.07), general mental health (MD -2.97, 95%CI -5.82 to -0.12), and general health perceptions (MD -2.62, 95%CI -4.86 to -0.38). However, the other trial [40] did not show significant difference between the combination therapy and calcium supplementation, alendronate sodium, α-D3, combined with resistance training alone.

Pain measurement.

Four trials described the pain score evaluated by visual analogue scale (VAS) [32, 38, 39, 43]. Meta-analysis was not conducted because of the obvious clinical and statistical heterogeneity. The first one showed a better effect of mild moxibustion as add-on therapy for calcium D alone in reducing the VAS scores (MD -3.90, 95%CI -4.64 to -3.16). The other two trials showed positive effect of du-moxibustion plus calcium D treatment for postmenopausal osteoporosis (MD -1.15, 95%CI -1.74 to -0.56) [38] or for POP (MD -2.16, 95%CI -2.36 to -1.96) [39] compared with calcium D alone. The last one found a better add-on benefit of du-moxibustion in improving the rest pain (MD -1.25, 95%CI -1.74 to -0.76), turn-over pain (MD -1.53, 95%CI -1.92 to -1.14), flexion-extension pain (MD -1.34, 95%CI -1.69 to -0.99) when calcium D, alendronate sodium and calcitriol were applied as basic treatment [43].

Functional activities assessment.

Only one trial observed functional activities using Oswestry disability index (ODI) pre and post treatment [38]. The result showed that du-moxibustion plus calcium D was better than calcium D alone in reducing the ODI scores (MD -7, 95%CI -10.20 to -3.80).

BMD in different anatomical region.

Seven trials mentioned the BMD in lumbar [30, 31, 35, 39, 4042]. Based on the available trials, the data was not able to be pooled due to the variations of study population, the type of moxibustion and control interventions that were studied. Of these trials, four trials [30, 39, 41, 42] found a significant effect of moxibustion combined with conventional therapy, while the other three trials [31, 35, 40] showed no difference between groups in improving the lumbar BMD. Three trials mentioned the BMD in femoral neck [30, 39, 41]. All of the studies demonstrated that moxibustion plus conventional drug therapy (alendronate sodium, calcium supplementation, calcium supplementation and alendronate sodium, respectively) significantly increased the BMD of the femoral neck compared with conventional drug alone. Two trials mentioned the BMD in ward area [30, 42]. One trial showed a statistically significant increase in BMD of the ward area in the combination therapy group compared to alendronate sodium [30], while the other one showed no significant difference between the groups [42]. Estimate effect for moxibustion in improving the lumbar, femoral neck, and ward area BMD were showed in Table 4.

thumbnail
Table 4. Estimate effect for moxibustion in improving the bone mineral density (BMD).

https://doi.org/10.1371/journal.pone.0178688.t004

The group treated with heat-sensitive moxibustion plus alendronate sodium also had a statistically significant increase in femoral great trochanter BMD compared to alendronate sodium alone (MD 0.07 g/cm2, 95%CI 0.02 g/cm2 to 0.12 g/cm2) [30]. In addition, the combination therapy could not dramatically improve the average BMD of hip joint (MD 0.00 g/cm2, 95%CI -0.03 g/cm2 to 0.03 g/cm2) [40], but could improve the femoral trochanter BMD (MD 0.03 g/cm2, 95%CI 0.00 g/cm2 to 0.06 g/cm2) [42].

Biochemical indicators.

Ten trials evaluated the biochemical indicators [3034, 36, 37, 4043]. For bone gla protein (BGP), heat-sensitive moxibustion plus alendronate sodium was better than alendronate sodium (MD -0.30 μg/mL, 95%CI -0.59 μg/mL to -0.01 μg/mL) [30]. Du-moxibustion as adjuvant therapy was superior to calcium D and alendronate sodium alone (MD -1.37 μg/mL, 95%CI -2.62 μg/mL to -0.12 μg/mL) [42]. For osteoprotegerin (OPG), mild moxibustion (MD 10.43 pg/ml, 95%CI 7.48 pg/ml to 13.38 pg/ml) [32] or heat-sensitive moxibustion (MD 3.16 pg/ml, 95%CI 0.81 pg/ml to 5.51 pg/ml) [36] had a better add-on benefit compared with anti-osteoporosis medicine alone. At the same time, there was no significant difference for serum estradiol (E2) between the groups (MD -0.82 pg/ml, 95%CI -3.79 pg/ml to 2.15 pg/ml) [40].

Two trials evaluated bone alkaline phosphatase (BALP) [33, 37]. One trial found a significant benefit of heat-sensitive moxibustion as add-on treatment for alendronate sodium (MD -38 U/L, 95%CI -41.46 U/L to -34.54 U/L) in senile osteoporosis patients [33]. The other one showed significant effect of mild moxibustion plus calcium D compared with calcium D alone (MD 9.16 U/L, 95%CI 4.62 U/L to 13.70 U/L) in postmenopausal osteoporosis patients [37]. Meanwhile, heat-sensitive moxibustion plus alendronate sodium could improve the level of amino-terminal procollagen of type 1 collagen (P1NP) (MD 33.10 μg/L, 95%CI 2.75 μg/L to 63.45 μg/L) compared to alendronate sodium alone [33]. For tartrate-resistant acid phosphatase-5b (TRAP-5b), two trials reported the outcome [37, 40]. Positive results were still found in the mild moxibustion plus calcium D (MD 0.44 U/L, 95%CI 0.09 U/L to 0.79 U/L) [37], while the other trial showed no difference between the groups (MD 0.17 U/L, 95%CI -0.45 U/L to 0.79 U/L) [40].

Three trials reported blood calcium (Ca) [4143]. Based on the anti-osteoporosis medicine therapy, mild moxibustion (MD -1.04 mmol/L, 95%CI -1.77 mmol/L to -0.31 mmol/L) [41] and du-moxibustion (MD 0.09 mmol/L, 95%CI 0.01 mmol/L to 0.17 mmol/L) [42] could change the level of Ca compared to medicine alone. However, the third trial found no difference between du-moxibustion plus medicine and medicine alone (MD 0.01 mmol/L, 95%CI -0.08 mmol/L to 0.10 mmol/L) [43]. And four trials reported alkaline phosphatase (ALP) [31, 40, 41, 43]. There was no significant difference for ALP in two trials [31, 40]. The remaining two trials suggested that mild moxibustion plus medicine (MD -6.27 IU/L, 95%CI -12.43 IU/L to 0.01 IU/L) [41] or du-moxibustion plus medicine (MD 10.89 IU/L, 95%CI 8.97 IU/L to 12.81 IU/L) [43] was better than medicine alone separately. Additionally, heat-sensitive moxibustion for ratio of urinary calcium /Creatinine (MD -0.16 μmol/L, 95%CI -0.34 μmol/L to 0.02 μmol/L) [31] or mild moxibustion for blood phosphate (P) (MD 0.06 mmol/L, 95%CI -0.23 mmol/L to 0.35 mmol/L) [41] had no better add-on benefit compared with anti-osteoporosis medicine alone.

Adverse effect.

Two of 13 trials observed the adverse drug reaction (ADR) [31, 38], and only one trial reported the liver and renal function [42]. The first trial did not found any ADR in the heat-sensitive moxibustion group [31]. Nevertheless, 6 cases from du-moxibustion group appeared the blister in the second trial, but not serious [38]. The third trial demonstrated that no patients underwent the abnormal liver function and renal function after du-moxibustion treatment [42]. No adverse effects were recorded in the other trials.

Publication bias

The number of trials was too limited to conduct any sufficient additional analysis of publication bias.

Strength of evidence

According to the GRADE tool, low quality to very low quality evidence was evaluated to identify the add-on effect of moxibustion for POP.

Discussion

Summary of evidence

Medication and functional exercise remains the mainstay for the treatment of osteoporosis [4448]. In the included 13 trials, different type of moxibustion is almost applied as a complementary treatment method. To the best of our knowledge, this will be the first systematic review that synthesizes information on the effectiveness and safety of moxibustion treating POP. Based on the current evidence, we cannot determine the add-on effect of moxibustion for enhancing the quality of life, alleviating disability, increasing BMD in some anatomical regions (including BMD of lumbar, ward area, femoral trochanter and average BMD of hip joint), improving biochemical indicators (including E2, TRAP-5b, Ca, P, ALP, ratio of urinary calcium /Creatinine). Limited evidence suggest that moxibustion plus anti-osteoporosis medicine may be more effective in reducing the pain (VAS scores average changed 2 scores between groups, 4 trials), increasing the BMD of femoral neck (average changed 0.4 g/cm2 between groups, 3 trials), and improving the level of BGP, OPG and BALP (2 trials) compared with anti-osteoporosis medicine alone. However, all of the trials were assessed to be low quality due to the high risk of bias.

One trial found that du-moxibustion plus calcium D may be able to relieve the low back dysfunction (NDI score, MD -7) compared to calcium D alone [38]. Another trial demonstrated that heat-sensitive moxibustion plus alendronate sodium was better than alendronate sodium alone in enhancing femoral great trochanter BMD (MD 0.07 g/cm2) [30]. Additionally, heat-sensitive moxibustion plus alendronate sodium was been shown to improve the level of P1NP (MD 33.10 μg/L) compared to alendronate sodium alone [33]. Nevertheless, the results were still inconclusive because of the small sample size and poor quality of the previous studies.

The majority of trials did not report the safety of moxibustion. We could not draw any conclusion on the adverse effect of moxibustion in terms of existing evidence. But from the published literatures, the most frequently reported adverse events are allergy, burn and infection [49].

Limitations of the review

There are several methodological limitations in the present review. In the first place, seven databases which are related to our topic have been retrieved, but it is possible that not all relevant RCTs are enrolled in these databases. We included RCTs published in English and Chinese only. In the second place, the results are based on the trials with small sample size (no more than 100 cases), and the calculation method of sample size is not provided.

In the third place, the method of randomization, measurement and evaluation are insufficient which will influence the internal validity of the results. Also, there are discrepant results regarding the efficacy of moxibustion interventions treatment for POP using the different measuring instruments, such as quality of life. Due to the clinical and statistical heterogeneity, it is hard to synthesize the current data using meta-analysis or conduct the subgroup analysis.

Implications for the clinical practice

The common type of moxibustion in management of POP is heat-sensitive moxibustion, mild moxibustion, and du-moxibustion. The treatment period lasted at least 3 months in the available RCTs. The most frequently used meridians or acupoints are Du Meridian including from Dazhui (GV14) to Yaoshu (GV2), Bladder Meridian of Foot-Taiyang such as Shenshu (BL23), Pishu (BL20), Guanyuanshu (BL26) and Stomach Meridian of Foot-Yangming (Zusanli, ST36) etc. Moxibustion in specific acupoints were thought to strengthen the body of middle-aged and elderly patients [50].

In this review, the preliminary result suggests that moxibustion plus conventional anti-osteoporosis medicine may have better effect on alleviating the pain and increasing the BMD of femoral neck though the insufficient evidence was seen. There are various anti-osteoporosis medications to choose, for instance, calcium supplementation, alendronate sodium or calcitriol.

Implications for the future research

With ever-growing interest in complementary and alternative treatments for chronic disease, there has increasingly been attention directed at moxibustion for POP practices. However, the quality of the previous studies on moxibustion needs to be improved in methodological aspects. In the 13 eligible RCTs, no studies conducted the clinical trial registration and sample size calculation. All of the trials are a positive-control design, absolute effect of moxibustion is not determined. In the future, the control program should add to the intervention similar to ‘placebo moxibustion’ on the basis of conventional treatment. Moreover, an important problem from future research is the choice of moxibustion treatment frequency. How is the frequency of moxibustion? To some extent, the dose-response relation is uncertain.

Last but not the least, to the question if moxibustion plus conventional therapy will affect fracture incidence attributed to osteoporosis, the answer is unknown. As fracture incidence is the endpoint outcome of POP, the long-term follow up will be crucial [51]. Obviously, future research should pay attention to this key point.

Conclusion

Due to the paucity of high-quality studies, there was no definite conclusion about the efficacy and safety of moxibustion treating POP although parts of positive results were presented. Future research should pay attention to the dose-response relation and fracture incidence of moxibustion for POP.

Supporting information

S2 Fig. Risk of bias graph for 13 included trials.

https://doi.org/10.1371/journal.pone.0178688.s002

(TIF)

S3 Fig. Risk of bias summary for 13 included trials.

https://doi.org/10.1371/journal.pone.0178688.s003

(TIF)

S1 Table. Characteristics of 13 included trials.

https://doi.org/10.1371/journal.pone.0178688.s004

(DOC)

S2 Table. Specific acupoints of moxibustion in 13 included trials.

https://doi.org/10.1371/journal.pone.0178688.s005

(DOC)

S3 Table. Quality assessment of included randomized controlled trials.

https://doi.org/10.1371/journal.pone.0178688.s006

(DOC)

S4 Table. Estimate effect for moxibustion in improving the bone mineral density.

https://doi.org/10.1371/journal.pone.0178688.s007

(DOC)

Acknowledgments

We also would like to thank Di Wu for designing the database of literature data collection.

Author Contributions

  1. Conceptualization: ZML XW.
  2. Data curation: ZML XW.
  3. Formal analysis: FPX XW.
  4. Funding acquisition: ZML XW.
  5. Investigation: MHH FPX.
  6. Methodology: FPX XW.
  7. Project administration: FPX.
  8. Resources: YJ QZK.
  9. Software: FPX.
  10. Supervision: ZML.
  11. Validation: XW.
  12. Visualization: FPX.
  13. Writing – original draft: FPX.
  14. Writing – review & editing: FPX XW.

References

  1. 1. Xie YM, Yuwen Y, Dong FH, Sun SC, Wang HM, Liu QS, et al. Clinical practice guideline of traditional medicine for primary osteoporosis. Chin J Integr Med. 2011; 17: 52–63. pmid:21258898.
  2. 2. Jang EJ, Lee YK, Choi HJ, Ha YC, Jang S, Shin CS, et al. Osteoporotic Fracture Risk Assessment Using Bone Mineral Density in Korean: A Community-based Cohort Study. J Bone Metab. 2016; 23:34–39. pmid:26981519.
  3. 3. Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos. 2013; 8: 136. pmid:24113837.
  4. 4. Guillemin F, Martinez L, Calvert M, Cooper C, Ganiats T, Gitlin M, et al. Fear of falling, fracture history, and comorbidities are associated with health-related quality of life among European and US women with osteoporosis in a large international study. Osteoporos Int. 2013; 24: 3001–3010. pmid:23754200.
  5. 5. Salaffi F, Cimmino MA, Malavolta N, Carotti M, Di Matteo L, Scendoni P, et al. The burden of prevalent fractures on health-related quality of life in postmenopausal women with osteoporosis: the IMOF study. J Rheumatol. 2007; 34: 1551–1560. pmid:17516618.
  6. 6. D'Amelio P, Isaia GC. Male Osteoporosis in the Elderly. Int J Endocrinol. 2015; 2015: 907689. pmid:26457082.
  7. 7. Yang Y, Du F, Ye W, Chen Y, Li J, Zhang J, et al. Inpatient cost of treating osteoporotic fractures in mainland China: a descriptive analysis. Clinicoecon Outcomes Res. 2015; 7: 205–212. pmid:25926747.
  8. 8. Xie Z, Burge R, Yang Y, Du F, Lu T, Huang Q, et al. Posthospital Discharge Medical Care Costs and Family Burden Associated with Osteoporotic Fracture Patients in China from 2011 to 2013. J Osteoporos. 2015; 2015: 258089. pmid:26221563.
  9. 9. Rice P, Mehan U, Hamilton C, Kim S. Screening, assessment, and treatment of osteoporosis for the nurse practitioner: key questions and answers for clinical practice—a Canadian perspective. J Am Assoc Nurse Pract. 2014; 26: 378–385. pmid:24911524.
  10. 10. Gehlbach S, Hooven FH, Wyman A, Diez-Perez A, Adachi JD, Luo X, et al. Patterns of anti-osteoporosis medication use among women at high risk of fracture: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). PLoS One. 2013; 8: e82840. pmid:24376589.
  11. 11. McLeod KM, Johnson S, Charturvedi R, St Onge J, Lionel A, Verma A. Bone mineral density screening and its accordance with Canadian clinical practice guidelines from 2000–2013: an unchanging landscape in Saskatchewan, Canada. Arch Osteoporos. 2015; 10: 227. pmid:26173601.
  12. 12. Barnard K, Lakey WC, Batch BC, Chiswell K, Tasneem A, Green JB, et al. Recent Clinical Trials in Osteoporosis: A Firm Foundation or Falling Short? PLoS One. 2016; 11: e0156068. pmid:27191848.
  13. 13. Khan SN, Craig L, Wild R. Osteoporosis: therapeutic guidelines. Guidelines for practice management of osteoporosis. Clin Obstet Gynecol. 2013; 56: 694–702. pmid:24177062.
  14. 14. Compston J, Bowring C, Cooper A, Cooper C, Davies C, Francis R, et al. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas. 2013; 75: 392–396. pmid:23810490.
  15. 15. Hagino H, Yoshida S, Hashimoto J, Matsunaga M, Tobinai M, Nakamura T. Increased bone mineral density with monthly intravenous ibandronate contributes to fracture risk reduction in patients with primary osteoporosis: three-year analysis of the MOVER study. Calcif Tissue Int. 2014; 95: 557–563. pmid:25377907.
  16. 16. Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. Denosumab or Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates. J Clin Endocrinol Metab. 2016; 101: 3163–3170. pmid:27270237.
  17. 17. Kotian P, Boloor A, Sreenivasan S. Study of Adverse Effect Profile of Parenteral Zoledronic Acid in Female Patients with Osteoporosis. J Clin Diagn Res. 2016; 10: OC04–6. pmid:26894105.
  18. 18. McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med. 2013; 126: 13–20. pmid:23177553.
  19. 19. Lin X, Xiong D, Peng YQ, Sheng ZF, Wu XY, Wu XP, et al. Epidemiology and management of osteoporosis in the People's Republic of China: current perspectives. Clin Interv Aging. 2015; 10: 1017–1033. pmid:26150706.
  20. 20. Yen L, Jowsey T, McRae IS. Consultations with complementary and alternative medicine practitioners by older Australians: results from a national survey. BMC Complement Altern Med. 2013; 13: 73. pmid:23548137.
  21. 21. Xu SJ, Liang ZH, Fu WB. Chronic neck pain of cervical spondylosis treated with acupuncture and moxibustion in terms of the heart and kidney theory: a randomized controlled trial. Zhongguo Zhen Jiu. 2012; 32: 769–775. pmid:23227676.
  22. 22. Xie XJ, Chen RX, Fu Y, Jiao L, Zhang B, Xiong J, et al. Efficacy comparison of lumber disc herniation treated with mild moxibustion at Yaoyangguan (GV 3) under different conditions. Zhongguo Zhen Jiu. 2014; 34: 1077–1080. pmid:25675566.
  23. 23. Kim TH, Kim KH, Kang JW, Lee M, Kang KW, Kim JE, et al. Moxibustion treatment for knee osteoarthritis: a multi-centre, non-blinded, randomised controlled trial on the effectiveness and safety of the moxibustion treatment versus usual care in knee osteoarthritis patients. PLoS One. 2014; 9: e101973. pmid:25061882.
  24. 24. Zhao Y. The present state and perspective in treatment of primary osteoporosis by acupuncture and moxibustion. J Tradit Chin Med. 2002; 22: 67–72. pmid:11977527.
  25. 25. Run-Ming Y. The origin and development of Chinese acupuncture and moxibustion. Anc Sci Life. 1985; 4: 224–228. pmid:22557484.
  26. 26. Sun YJ, Yuan JM, Yang ZM. Effectiveness and safety of moxibustion for primary insomnia: a systematic review and meta-analysis. BMC Complement Altern Med. 2016; 16: 217. pmid:27411310.
  27. 27. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009; 339: b2535. pmid:19622551.
  28. 28. Liu Y, Liu JP, Xia Y. Chinese herbal medicines for treating osteoporosis. Cochrane Database Syst Rev. 2014; (3): CD005467. pmid:24599707.
  29. 29. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The CochraneCollaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. pmid:22008217.
  30. 30. Tu GQ, Zou LY. Effect of Heat-sensitive Moxibustion on Bone Mineral Density and Serum Bone Gla Protein of Senile Osteoporosis Patients. Xin Zhong Yi. 2010; 42: 97–98.
  31. 31. Li F, He ZG, Tu GQ, Meng Y, Cao YX, Huang XP. Effect of heat-sensitive point moxibustion on BMD, S-AKP, U-Ca/Cr in patients with primary osteoporosis. Zhongguo Zhen Jiu. 2011; 31: 223–226. pmid:21644308.
  32. 32. Ouyang JJ, Liu QS, Xu XY, Pang XH. The influence of mild moxibustion treatment for primary osteoporosis on bone pain (visual analogue scale score) and serum osteoprotegerin. Zhongguo Kang fu Yi Xue Za Zhi. 2012; 27: 971–972.
  33. 33. Tu GQ, Zou LY. Effect of heat-sensitive moxibustion for senile osteoporosis patients on bone alkaline phosphatase. Shi Zhen Guo Yi Guo Yao. 2012; 23: 481–482.
  34. 34. Tu GQ, Zou LY, Zhu YH. Effect of heat-sensitive moxibustion for senile osteoporosis patients on amino-terminal procollagen of type 1 collagen. Guang Ming Zhong Yi. 2012; 27: 520–521.
  35. 35. Xiong DL, Peng H, Li BY, Yi J, Xiong RH. The clinical effect observation of heat-sensitive moxibustion plus salmon calcitonin in the treatment of osteoporosis. The Second Academic Conference Proceeding for Endocrine professional committee of Jiangxi province Association of Chinese Integrative Medicine. 2013; 172–174.
  36. 36. Ouyang JJ, Liang DB, Pang XH. Effects of heat-sensitive moxibustion therapy on secretion of osteoprotegerin and quality of life in patients with primary osteoporosis. Zhongguo Zhong Yi Ji Chu Yi Xue Za Zhi. 2013; 19: 812–813, 816.
  37. 37. Ouyang JJ, Xu XY. Effect of Mild Moxibustion on Thermal Infrared Temperature Value and Bone Turnover Markers in Patients with Postmenopausal Osteoporosis. Liaoning Zhong Yi Yao Da Xue Xue Bao. 2013; 15: 152–154.
  38. 38. Lin HB, Li AQ, Liu CM, Qiu JH. Clinical research of governor vessel moxibustion on treating the low back Pain in postmenopausal osteoporosis of spleen-kidney-yang deficiency. Zhong Yi Lin Chuang Yan Jiu. 2013; 5: 49–51.
  39. 39. Yang K, Cai SC, Zhu CF, Fei AH, Qin XF, Xia JG. Clinical study on primary osteoporosis treated with spreading moxibustion for warming yang and activating blood circulation. Zhongguo Zhen Jiu. 2014; 34: 555–558. pmid:25112087.
  40. 40. Pan SJ. Effect of Resistance Training Combined with Moxibustion Treatment on Bone Mineral Density and Quality of Daily Life in Patients with Postmenopausal Osteoporosis. Dissertation for Master Degree of Nanjing University of Chinese Medicine. 2015.
  41. 41. Yu Z. Clinical effect of aconite cake-separated moxibustion treatment on postmenopausal osteoporosis. Zhong Xi Yi Jie He Yan Jiu. 2015; 7: 72–75.
  42. 42. Li ZM, Yang D, Ma XM. The clinical observation of du-moxibustion combined with alendronate sodium for postmenopausal osteoporosis (spleen-kidney-yang deficiency). Zhong Yi Yao Dao Bao. 2016; 22: 61–63.
  43. 43. Wang YH, Xie T. Thirty-six cases clinical observation of ginger-separated moxibustion combined with calcium supplementation treating low back pain osteoporosis. Zhejiang Zhong Xi Yi Jie He Za Zhi. 2016; 26: 132–133.
  44. 44. Zhang ZL, Liao EY, Xia WB, Lin H, Cheng Q, Wang L, et al. Alendronate sodium/vitamin D3 combination tablet versus calcitriol for osteoporosis in Chinese postmenopausal women: a 6-month, randomized, open-label, active-comparator-controlled study with a 6-month extension. Osteoporos Int. 2015; 26: 2365–2374. pmid:25929192.
  45. 45. Paschalis EP, Gamsjaeger S, Hassler N, Fahrleitner-Pammer A, Dobnig H, Stepan JJ, et al. Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality. Bone. 2016; 95: 41–46. pmid:27826025.
  46. 46. Beck BR, Daly RM, Singh MA, Taaffe DR. Exercise and Sports Science Australia (ESSA) position statement on exercise prescription for the prevention and management of osteoporosis. J Sci Med Sport. 2016 Oct 31. pii: S1440-2440(16)30217-1. pmid:27840033.
  47. 47. Zhao C, Hou H, Chen Y, Lv K. Effect of aerobic exercise and raloxifene combination therapy on senile osteoporosis. J Phys Ther Sci. 2016; 28: 1791–1794. pmid:27390417.
  48. 48. Wei X, Xu A, Yin Y, Zhang R. The potential effect of Wuqinxi exercise for primary osteoporosis: A systematic review and meta-analysis. Maturitas. 2015; 82: 346–354. pmid:26386831.
  49. 49. Park JE, Lee SS, Lee MS, Choi SM, Ernst E. Adverse events of moxibustion: a systematic review. Complement Ther Med. 2010; 18: 215–223. pmid:21056845.
  50. 50. Zhang L, Qin YM, Zheng LX, Zhang M, Guo HJ, Xu LR, et al. Governor vessel moxibustion: Ancient Chinese medical technology with new vitality. Chin J Integr Med. 2015 Jul 4. [Epub ahead of print]. pmid:26142338.
  51. 51. Benzvi L, Gershon A, Lavi I, Wollstein R. Secondary prevention of osteoporosis following fragility fractures of the distal radius in a large health maintenance organization. Arch Osteoporos. 2016; 11: 20. pmid:27142832.