Osteoporos Int (2009) 20:519–526 DOI 10.1007/s00198-008-0724-x

REVIEW

Phytotherapy versus hormonal therapy for postmenopausal bone loss: a meta-analysis

M. Xu & C. Qi & B. Deng & P. X. Deng & C. W. Mo

Received: 2 January 2008 /Accepted: 31 July 2008 / Published online: 17 September 2008 # International Foundation and National Osteoporosis Foundation 2008

Abstract This meta-analysis included 14 randomized con- commonly used herbs in the included trials were identified. trolled trials involving 780 patients to compare phytotherapy Phytotherapy may not show effects beyond hormonal with hormonal therapy in the treatment of postmenopausal therapy, but may be safer than hormonal therapy in the bone loss. Current evidence suggests that phytotherapy may treatment of postmenopausal bone loss. Further trials with possess a similar effect on bone mineral density (BMD) high-quality study designs should be conducted in this values but clinically is not associated with a high incidence field. of uterine bleeding and breast pain as is hormonal therapy. Clinical trials indicate that phytotherapy may be a potential Keywords Hormonal therapy. Meta-analysis . treatment for postmenopausal osteoporosis. The objective of Phytotherapy. Postmenopausal osteoporosis this meta-analysis was to compare the efficacy and safety of phytotherapy with that of hormonal therapy, to assess the quality of phytotherapy trials, and to identify herbs used Introduction commonly in the treatment of postmenopausal bone loss. A total of 43 electronic databases were searched. The quality of Osteoporosis is a rapidly growing health problem world- eligible trials was assessed using Jadad’s scale. Outcome wide [1]. Postmenopausal osteoporosis that typically affects measures were BMD values and adverse events. Revman 5.0 elderly women after the is associated with software was used for data syntheses and meta-analyses. The fractures that result in a high morbidity and mortality and a database search revealed 14 randomized controlled trials large expenditure of health-care resources. As gonadal involving 780 patients that met the inclusion criteria, and hormone deficiency plays a key role in the pathogenesis four trials were graded as high quality (score 3–5). There was of postmenopausal osteoporosis, hormonal therapy (HT) no significant difference in lumbar, femoral or forearm BMD was regarded as the first choice in past decades for the values between subjects treated with phytotherapy and those treatment of this disease [2]. However, using HT has treated with hormonal therapy (P>0.05), but the incidence become an international concern, since results of the trials of uterine bleeding and breast pain was significantly lower of the Women’s Health Initiative showed that the overall in those treated with phytotherapy than in those treated with risks of HT exceed its benefits to postmenopausal women hormonal therapy (P=0.002 and P=0.01). The six most [3]. Finding safer therapies and remains an important aim in osteoporosis research. Phytotherapy (PT) is becoming popular globally. Natural * : : : M. Xu ( ) C. Qi B. Deng P. X. Deng herbs have been widely used in orthopedic clinical practice School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, in China and other countries since ancient times. Certain Kowloon, Hong Kong, China natural herbs have potential effects in promoting gonadal e-mail: [email protected] function and fracture healing [4, 5] and therefore are suitable reagents in further research to treat and prevent C. W. Mo Guangzhou University of Chinese Medicine, postmenopausal osteoporosis. During the last 10 years, Guangzhou, China some unique clinical trials focused on PT in the treatment 520 Osteoporos Int (2009) 20:519–526 of postmenopausal osteoporosis have been conducted. It Proceedings of Conference Databases, and China Doctorate/ would be valuable to evaluate the quality of these trials and Master Dissertations Full Text Databases. The reference lists assess the efficacy and safety data provided by the trials in of retrieved papers were further scanned for any possible terms of the principles and measurements of evidence- titles matching the inclusion criteria. Particular attention was based medicine. In this study, a systematic review and given to relevant journals on osteoporosis, bone disease, meta-analysis of randomized trial evidence was performed women’s health, complementary and alternative medicine, to compare PT with HT and to identify herbs commonly and Chinese medicine. In order to indentify further trials used in the clinical treatment of postmenopausal bone loss. matching the inclusion criteria, periodicals, journals, and We hypothesized that the eligible trials would provide symposium abstracts found in the libraries of Hong Kong evidence of the effect of PT on bone mineral density Baptist University and Guangzhou University of Chinese (BMD) and the therapeutic benefits of PT in patients with Medicine up to the most recent issues available were also postmenopausal bone loss. searched manually.

Data extraction Materials and methods Full-text articles of each potential eligible trial were retrieved Inclusion and exclusion criteria and assessed by two independent reviewers (Min Xu and Chen Qi) to determine if they met the inclusion and All randomized controlled trials (RCTs) comparing the exclusion criteria. Missing information was sought by efficacy and/or safety of PT and HT for the treatment of contacting the authors of the articles. A data extraction form postmenopausal women with osteoporosis or osteopenia was used to summarize key information from the included were included. The diagnostic criteria for osteoporosis or trials, and key information was extracted by one reviewer osteopenia in the trials were required to be in accordance and confirmed by another reviewer. Any disagreement was with the criteria of the World Health Organization. Subjects resolved by discussion. could not be suffering from secondary osteoporosis or other bone diseases such as osteomalacia, myeloma, bone cancer Data analysis and metastasis, Paget’s bone disease or thyroid disease, diabetes, or severe cardiac, pulmonary, hepatic, gastroin- A meta-analysis was carried out using Revman 5.0 software testinal or renal diseases. There was no restriction on race (Cochrane Collaboration) to combine and analyze the data or duration of menopause. The intervention was required to from individual trials. The statistical validity of combining be oral administration of any kind of herbal preparation various trials was assessed by examining the homogeneity of used alone or in combination with other herbs for subjects outcomes from trials using a Q-test (Mantel-Haenszel chi- in treatment groups and any kind of by individual squared test). Overall results of combined trials were drug or mixed with other hormones for subjects in the calculated with fixed or random effect models. The mea- control groups. Concurrent administration of calcium and/ surement and category data were evaluated in terms of or vitamin D was acceptable if both groups received the weighted mean difference (WMD) and odds ratio (OR), same dose and formulation. The outcome measures includ- respectively, and 95% confidence intervals (95%CI). The ed changes in lumbar, femoral, and forearm BMD values, methodological quality of all included trials was assessed as well as the incidence of adverse events after treatment using the Jadad scale that assesses randomization, double with PT or HT. blinding, and the dropout rate of trials by ranking them on a scale of 1–5. The trials that scored 1 or 2 points were Search strategy considered low-quality trials, and those that scored 3–5 were considered high-quality trials [7]. The herbs used in the A search strategy was developed by modifying a strategy used included trials to treat postmenopausal osteoporosis were for herbal medicines in a Cochrane review [6] to retrieve all ranked according to their reported frequency of use [8]. the literatures of relevant clinical trials by electronic searching and hand searching regardless of language or publication status. A total of 43 electronic databases were searched Results including the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, AMED, China National Knowledge Excluded and included trials Infrastructure, VIP, Chinese BioMedical disc, Chinese Med- ical Current Contents, Wanfang Chinese Scientific Journal The literature search revealed 63 RCTs conducted in China Database, Traditional Chinese Medicine Database, China in which postmenopausal bone loss was treated by oral Osteoporos Int (2009) 20:519–526 521 administration of PT. However, 49 of these trials were Meta-analysis of safety excluded from the analysis as they did not meet the inclusion criteria; the reasons were (1) PT and HT not compared (37 Of the 14 included trials, 3 [12, 13, 19] reported the trials) and (2) BMD not measured or reported unclearly (12 incidences of both uterine bleeding and breast pain, while trials). Finally, a total of 14 trials that met the criteria were one trial [10] reported the incidence of uterine bleeding included [9–22]. Of a total of 780 subjects, 419 were treated alone during treatment. Using the fixed-effect model, Fig. 2 with PT, and the treatment durations of the included trials shows the results of the meta-analysis to compare the ranged from 1 to 6 months (Table 1). In 11 out of the 14 incidences of uterine bleeding and breast pain between the trials the PT groups were treated with patent herbal two treatment groups. The incidences of both uterine formulae including Qiang-Gu capsules, Mi-Gu tablets, bleeding and breast pain were significantly lower in the Xian-Gu-Ning powder, and in the other 3 trials herbal PT groups than in the HT groups (OR 0.09; 95% CI 0.02, decoctions were used. The HT control groups were treated 0.41; P=0.002; and OR 0.11; 95% CI 0.02, 0.62; P=0.01). with nilestriol in five trials [11, 13, 15, 17, 20], combined No statistically significant heterogeneity was found in the estrogen– in four trials [9, 12, 14, 19], analysis (P=0.88 and 0.96). in three trials [10, 16, 18], and in two trials [21, 22]. Quality assessment

Outcome measurement The Jadad scale was used for evaluation of the quality of the 14 included trials. Four of the trials [12, 14, 15, 19] For evaluating therapeutic and adverse effects of the two were assessed as high quality (score 3–5), and the rest as treatments, the outcome assessment of this study was low quality (score 1 or 2) owing to poor descriptions of the focused on BMD values and uterine bleeding and breast methods of randomization and blinding. The reports of all pain events in the subjects. Five of the included trials trials mentioned randomization and the dropout rate, but reported both lumbar and femoral BMD values, four trials only three [12, 15, 19] described the method of randomi- reported lumbar or femoral BMD values alone, and five zation. In addition, the reports of three trials mentioned trials reported forearm BMD values. The subjects’ lumbar double blinding [12, 14, 19], and the report of one trial [17] and femoral BMD was determined by a dual-energy X-ray mentioned single blinding in their methodological design. absorptiometry (DEXA) scan, while forearm BMD was determined by a single-photon absorptiometry (SPA) scan. Identification of herbs Although all included trials presented BMD data for both pre- and posttreatment time points, only the study of Xu A total of 28 natural herbs were reported in the 14 included reported mean differences and standard deviations in trials, and the six most frequently used herbs were Herba relation to baseline [19]. Thus, according to the recom- epimedii, Fructus psoraleae, Radix rehmanniae, Rhizoma mendation of the Cochrane handbook for systematic drynariae, Herba cistanches,andCortex eucommiae reviews of interventions [23], we used the means of (Fig. 3). posttreatment BMD values for comparing WMD between the two treatment groups. In addition, four of the included trials reported the incidence of uterine bleeding and/or Discussion breast pain in subjects after treatment. This meta-analysis is the first to compare the efficacy and Meta-analysis of efficacy safety of PT and HT including estrogen and progestogen preparations. Our systematic assessment indicated that PT Figure 1 shows the results of the meta-analysis of lumbar, had therapeutic benefits in the treatment and prevention of femoral, and forearm BMD values to compare the thera- postmenopausal bone loss. Our analysis was based on 14 peutic effects of PT and HT. There were no statistically trials that were conducted in Chinese menopause patients significant differences in lumbar BMD (WMD 0.00; 95% during the past decade. The strengths of this meta-analysis CI −0.02, 0.03; P=0.82), femoral BMD (WMD 0.00; 95% include acceptable standard and methodology and consider- CI −0.01, 0.01; P=0.77), or forearm BMD (WMD 0.03; able sample size, by which we may obtain current evidence 95% CI −0.01, 0.07; P=0.12) values between subjects on the research target. Moreover, additional evidence on the treated with PT and those treated with HT. Heterogeneity efficacy of PT was obtained from many observational trials was not found in the analysis of lumbar BMD (P=0.37) and even though they were excluded before data synthesis. These femoral BMD (P=0.45), but was statistically significant in large-scale observational data generally supported the results the analysis of forearm BMD (P=0.007). of the RCTs included in the meta-analysis. 522 Osteoporos Int (2009) 20:519–526

Table 1 Trials included in the meta-analysis

Reference Treatment Treatment No. of Treatment BMD change (g/cm2) Adverse events (%) duration group subjects (site) (months)

9 6PT48Rhizoma drynariae +0.024 (femur) – HT 42 valerate, medroxyprogesterone +0.015 (femur) 10 6PT34Rhizoma drynariae +0.005 (lumbar); – +0.025 (femur) HT 35 Tibolone +0.043 (lumbar); Uterine bleeding (8.6%) +0.051 (femur) 11 6PT40Herba epimedii, Radix astragali, Rhizoma drynariae, +0.038 (femur) – Radix rehmanniae, Radix salviae miltiorrhiae HT 40 Nilestriol +0.039 (femur) 12 6PT32Cortex eucommiae, Fructus ligustri lucidi, −0.001 (lumbar); – Fructus psoraleae, Herba epimedii +0.001 (femur) HT 34 Conjugated , medroxyprogesterone −0.019 (lumbar); Uterine bleeding (7.7%), +0.050 (femur) breast pain (12.8%) 13 6PT22Cortex eucommiae, Herba cistanches, Poria +0.095 (forearm) – cocos (Schw.) Wolf, Rhizoma alismatis, Rhizoma dioscoreae, Radix rehmanniae, Semen cuscutae HT 18 Nilestriol +0.136 (forearm) Uterine bleeding (5.6%), breast pain (11.1%) 14 3PT15Herba epimedii +0.036 (lumbar) – HT 10 , medroxyprogesterone +0.087 (lumbar) 15 6PT23Flos carthami, Fructus psoraleae, Herba cistanches, +0.016 (lumbar); – Herba dendrobii, Herba epimedii, Radix aucklandiae, +0.008 (femur) Radix angelicae sinensis, Radix polygoni multiflori HT 23 Nilestriol +0.021 (lumbar); +0.010 (femur) 16 6PT20Acanthopanax obovatus Hoo, Cortex cinnamomi, +0.050 (lumbar); – Fructus ligustri lucidi, Herba cistanches, Radix +0.122 (femur) rehmanniae, Semen cuscutae HT 20 Tibolone +0.045 (lumbar); +0.109 (femur) 17 3PT50Herba epimedii, Radix codonopsis, +0.103 (forearm) – Radix dipsaci, Rhizoma drynariae HT 30 Nilestriol +0.056 (forearm) 18 6PT36Cortex eucommiae, Fructus psoraleae, +0.030 (lumbar); – Herba epimedii, Radix achyranthis bidentatae, +0.008 (femur) Radix rehmanniae, walnut HT 36 Tibolone +0.006 (lumbar); +0.017 (femur) 19 4PT26Fructus psoraleae, Herba epimedii, Radix astragali, +0.003 (lumbar) – Radix puerariae, Radix salviae miltiorrhiae HT 26 Piperazine sulfate, medroxyprogesterone +0.001 (lumbar) Uterine bleeding (28%), breast pain (12%) 20 6PT30Cortex eucommiae, Fructus psoraleae, +0.140 (forearm) – Herba epimedii, Radix achyranthis bidentatae, Radix rehmanniae, walnut HT 20 Nilestriol −0.003 (forearm) 21 6PT30Flos chrysanthemi, Fructus psoraleae, +0.011 (forearm) – Herba cistanches, Radix achyranthis bidentatae, Rhizoma atractylodis macrocephalae, Radix polygoni multiflori, Semen cuscutae HT 20 Diethylstilbestrol +0.011 (forearm) 22 1PT13Cortex cinnamomi, Rhizoma alismatis, Rhizoma +0.030 (forearm) – dioscoreae, Radix rehmanniae, Poria HT 7 Diethylstilbestrol +0.018 (forearm) Osteoporos Int (2009) 20:519–526 523

Fig. 1 Meta-analyses of effica- cy (PT vs. HT)

Accelerated bone loss secondary to loss of ovarian estrogen alone or estrogen plus progestogen and other function after the menopause has been well recognized as a hormones. Clinical studies have demonstrated that HT can major risk factor for osteoporosis, and an approach to significantly reduce the incidence of fractures in elderly treating postmenopausal bone loss is via HT that uses women, and they may regain the lost bone during treatment

Fig. 2 Meta-analyses of safety (PT vs. HT) 524 Osteoporos Int (2009) 20:519–526

Fig. 3 The six most frequently used herbs. a Herba epimedii, b Fructus psoraleae, c Radix rehmanniae, d Rhizoma drynariae, e Herba cistanches, and f Cortex eucommiae

[24]. The reports of 7 of the 14 included trials provided data such as , , and can reduce bone on the changes in lumbar and femoral BMD in HT loss [30, 31]. In RCTs these have shown treatment groups. HT resulted in an increase of 0.026± positive effects in both inhibiting bone resorption and 0.035 g/cm2 in lumbar BMD and 0.042±0.034 g/cm2 in improving bone formation [32, 33]. The therapeutic effects femoral BMD compared with baseline values (Table 1). of phytoestrogens might be more marked among meno- The changes in BMD caused by HT in the included RCTs pausal Chinese patients with lower calcium intake and body were in accordance with the findings of other RCTs weight [34, 35]. conducted in different countries [25, 26]. Phytochemical analyses have revealed that the six most Preliminary studies showed similar pharmacological commonly used herbs ranked in this analysis contain effects between PT and HT in the regulation of bone turnover. various effective components such as icariin in Herba In a study of the effects of PT and HT in ovariectomized rats epimedii and isopsoralen in Fructus psoraleae [28]. These we found that both PT and HT significantly improve spinal effective components have estrogen-like effects and may be and femoral BMD, the mechanical properties of the tibia, and new phytoestrogens for future research. Thus, further urinary pyridinoline/creatinine and deoxypyridinoline/creati- laboratory studies and clinical trials focusing on these nine ratios [27]. In this study, we systematically reviewed herbs and their effective components undoubtedly will clinical trials, and synthesized data from 14 trials that contribute more direct evidence for understanding the examined 28 kinds of herbs as different preparations and beneficial effects of PT in the treatment of postmenopausal the review indicated the potential of PT for the treatment of bone loss. In addition, recent data from RCTs show a postmenopausal bone loss. It is postulated that some significant effect of simultaneous administration of bio- effective components in these herbs were responsible for chanin A, , genistein, and for 1-year the estrogen-like activities in clinical treatment. treatment [36]. This suggests that evaluating possible No matter how many effective components herbs and synergistic effects of herbal phytoestrogens may also be a herbal formulae may have and how complex their action new topic for future research. mechanisms, it is phytoestrogens in herbal preparations, HT has undesirable side effects. In particular, it causes including certain flavones, isoflavones, flavanones, flavo- an unacceptable increase in the risk of endometrial cancer nols, , , that definitely play an important and breast cancer. Uterine bleeding and breast pain role in the amelioration of postmenopausal bone loss [28]. commonly occur in women during HT. In our analysis, The effects of phytoestrogens have been reported in both four included trials reported the incidence of uterine laboratory studies and clinical trials [29]. Studies in bleeding, which ranged from 6% to 28%, and three trials ovariectomized rats suggest that known phytoestrogens reported the incidence of breast pain, which ranged from 11% Osteoporos Int (2009) 20:519–526 525 to 13%, in subjects receiving HT. In contrast, we are uncertain breast pain than those treated with HT. PT is therefore a about the adverse effects of PT due to paucity in reporting in possible approach to the management of postmenopausal the included trials (Table 1). In previous animal studies, we bone loss. As the data from primary trials for this meta- did not find any negative impact of a herbal preparation on analysis were limited, more clinical trials with high-quality histopathological examination of the uterus, and the effects study designs should be conducted. Further long-term of the herbal preparation on bone resembled those of the clinical trials with a large sample size followed by a new selective modulators (SERMs) [27]. RCTs meta-analysis would be valuable to verify the evidence have also shown that the effects on bone of PT from this study. are equipotent to those of HT and SERMs, but that PT does not exert uterotrophic effects [37]. Acknowledgements This project was supported by a grant under the The quality of the study designs and descriptions of the 973 Plan of the Chinese Government (2005CB523502) and a Faculty Research Grant from Hong Kong Baptist University (FRG/0304/I57). original trials are critical issues for meta-analyses. It is a matter The authors acknowledge the assistance of Professor Zhao Zhongzhen of concern that 14 RCTs included in this study were assessed and Dr. Ou Tong at Hong Kong Baptist University in providing herbal by the Jadad scale, and only four were accepted as high- pictures. quality trials. In 2004 we reported a study evaluating the Conflicts of interest None. quality of clinical trials on the treatment of postmenopausal osteoporosis with PT [38]. 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