An Up-Date of the Muscle Strengthening Exercise Effectiveness in Postmenopausal Women with Osteoporosis: A Qualitative Systematic Review

Background: Osteoporosis (OP) is a systemic disease that is characterized by decreased bone density and quality. Purpose: The purpose of this systematic review was to determine the effects of muscle strengthening exercise in postmenopausal women with OP. Methods: A literature search was conducted systematically in MEDLINE, CINAHL, EMBASE databases for human studies up to 31 March 2021. Two researchers screened the articles against predefined inclusion criteria; a third resolved discrepancies. Articles were included if they assessed the effects of muscle strengthening exercise in postmenopausal women with OP. The protocol for this systematic review was registered on PROSPERO (CRD42021207917) and a qualitative systematic review was carried out following the PRISMA statement. Methodological quality was evaluated through the scientific validity scales PEDro. Finally, RTCs and NRCTs risk of bias was assessed with the Cochrane risk of bias tool (Risk of Bias-ROB 2.0) and ROBINS-1, respectively. Results: A total of 16 studies (1028 subjects) that met the different eligibility criteria previously established were selected. There is evidence of good methodological quality and a low to moderate risk of bias that supports that muscle strengthening exercise alone or in combination with other therapeutic modalities improves BMD (9, n = 401) in proximal femur and lumbar vertebra body, muscle strength (10, n = 558), balance (4, n = 159), functionality (7, n = 617), and quality of life (5, n = 291). Conclusions: Exercise programs focused on muscle strengthening have benefits for all variables studied in postmenopausal women with OP.


Introduction
Osteoporosis (OP) represents a pathology of important health implications, which identifies its clinical significance in the fracture that occur as a consequence of increased bone fragility [1]. In 2010, it was estimated that 22 million women aged over 50 years old in the EU had osteoporosis using the diagnostic criterion of the WHO [1]. The high societal and personal cost of osteoporosis pose challenges to publich health and physician, particularly since most patients with osteoporosis remain untreated [2].
The standard treatment is fundamentally pharmacological and aims to reduce the incidence of fractures through the interruption of the resolution mechanism [3]. It appears that although the benefits outweigh the risks, the association between the combination of sequential antiresorptive/anabolic pharmacotherapeutic cycles and the reduction of fracture risk using aminobisphosphonates, selective estrogen receptor modulators, denosumab and teriparatide has not been demonstrated. However, when combined with exercise this would help maintain bone architecture thanks to increased bone mass and muscle strength [4,5]. Muscle strengthening exercise would be effective because it is believed to increase muscle mass and decrease fat mass, especially in osteoporotic menopausal women in whom, by stimulating osteogenesis, it would reduce falls and fractures [6,7].
In contrast, Ashe et al. [8], Sanudo et al. [9] and Asikainen et al. [10] have respectively highlighted the lack of efficacy of resistance exercise in elderly women, pointing out a nonsignificant positive effect on body loss in resistance protocols alone and showing how even the combination of aerobic and resistance training does not lead to improvements in terms of BMD, muscle strength, flexibility and coordination, even in programs lasting more than one year. In addition, Benedetti et al. [4] has reported the low efficacy of long-term muscle strengthening exercise in elderly women in terms of cortical volumetric bone mineral density when performed with own body weight or resistance. Perhaps this is due to the diversity of the exercise used in the research detailed in the existing literature, and to the different nomenclatures used: physical exercise, exercise, resistance training, strength training, weight-bearing exercise training, resistance training programs, land exercise program, aquatic exercise program, physical activity program, circuit training, high-intensity resistance and impact training, adapted physical activity exercise protocol, progressive load training, strengthening exercises and multicomponent training.
Due to the diversity of studies found in the literature that clearly indicate the effects of muscle strengthening exercise on bone architecture, but also the existence of other studies that deny a positive effect, the purpose of this systematic review was to present an update of studies assessing the effects of muscle strengthening exercise in postmenopausal women with OP.

Data Source and Search Strategy
This is a systematic literature review of studies investigating or updating the effects of muscle strengthening exercise in postmenopausal women with OP Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were followed during the design, search and reporting stages of this systematic review. The protocol for this systematic review was registered on PROSPERO (CRD42021207917).

Search Strategy
Independent researchers (J.L.A.P., S.M.P. and A.B.) conducted a qualitative systematic review following the PRISMA statement by introducing the keywords "Osteoporosis, Postmenopausal", "Resistance Training", "Exercise", and "Isometric Contraction" as well as the free terms "Strength Training", "Musculoskeletal", "Exercise" and "Strength" combined with the Booleans "AND" and "OR" in metasearch engines Cochrane Library Plus and TripDataBase and electronic databases Pubmed (MEDLINE) and Physiotherapy Database (PEDro), Table 1, search equations.

Eligibility Criteria
Eligibility criteria were: (1) Randomized and non-randomized clinical trials, (2) published full text, (3) without restriction in language (4) between 1 January 2005 and 31 March 2021, (5) in which participate postmenopausal women with OP over 40 years (6) in an exercise program based on muscle strengthening exercise combined or not with other modalities.

Data Extraction
All relevant articles from the aforementioned datasets were identified by two reviewers who conducted the data extraction independently (J.L.A.P. and S.M.P.). A third author (A.B.) resolved discrepancies. Reviewers were not masked to any pieces of information regarding the authors, the journal or the outcomes for each article reviewed. A standardized form was used to extract data concerning study design, number and mean age of participants, year and country of publication, setting, exercise program involved, follow-up timing, clinical outcome measures and reported findings. The form was developed according to the directions of the Cochrane Handbook for Systematic Reviews of Interventions-Version 5.1.0. This form was pilot-tested for reliability using a representative sample of the studies to be reviewed.

Outcome Measure
The primary outcomes was the change of BMD at lumbar spine and femoral bone regions, muscle strength, balance, functionality and quality of life between baseline and follow-up.

Quality Assessment
All the articles that met the eligibility criteria were independently assessed by two independent authors (J.L.A.P. and S.M.P.) for methodological quality with the Physiotherapy Evidence Database (PEDro) Scale and for risk of bias using Cochrane Collaboration's Risk of Bias (ROB.2.0) for RCTs and Risk of Bias in Non-randomized Studies of Interventions (ROBINS-1) for NRCTs. Disagreements were solved by discussion including a third author (A.B.) until a consensus was reached. We classified the methodological quality as follows: ≥ 7 = high, 5-6 = moderate, and <5 = low and RCTS risk of bias as "high" risk of bias, "unclear" or "low" and NRCTs as "low", "moderate", "serious" and "critical".

Study Selection
Via the databases search, 172 articles have been identified. Of these, after first screening based on title, abstracts and duplicates, 46 articles have been submitted to a second screening. After the full text reading, according to out exclusion criteria, 16 studies were eligibility for this review, with a total amount of 1028 patient ( Figure 1).

Study Characteristics and Quality Assessment
The review included 14 RCCTs and 2 NRCCTs, whose characteristics are collected in Table 1. The methodological quality evaluation, based on PEDro Scale, reports an average score of 6/10 (PEDro Table). The risk of bias analysis, using RoB 2.0 for RCTs and ROBINS-1 for NRCTs, showed a low to moderate risk and a critical risk respectively.

Association between Exercise Therapy and Bone Quality
Nine of the 16 studies included in this review investigated the effects of exercise on bone quality. In the tested districts (femoral neck, lumbar spine, tibia) were found a statistically significant correlation between Bone Mineral Density and BMC with a 10 to 52 week exercise protocol (Table 1) [11][12][13][14][15][16][17][18][19]. However, Brentano and Ashe report absence of modifications and changes not statistically significant in this outcome measure [8,20].

Association between Exercise Therapy and Muscular Strength
In the included trials, muscle strength was evaluated at the level of back extensor strength, lower limb strength using leg press 45 • , knee extension/flexion, ankle dorsiflexion, quadriceps strength (QS) and grip strength in the upper limb. The results agree in highlighting a significant correlation between an exercise protocol ( Table 1) and muscle strength in all districts evaluated [14,15,23,24,26].

Association between Exercise Therapy and Balance
The dynamic balance was evaluated, within the trials, using the Tinetti Scale and the Berg Balance Scale; the static one was evaluated using a stabilometric platform (Stabilometric platform E.P.S./R/LorAn Engineering, Bologna, Italy), analyzing the stakinesiogram and the stabiligram. For both components (dynamic and static) a significant correlation between exercise and balance improvements was found [12,14,15,18,21,27], (Table 1).

Association between Exercise and Quality of Life
Koevska et al [22] and Cergel et al [23] investigated this outcome using QUALEFFO-41; Borba-Pinheiro et al [18] used in both studies the OPAQ questionnaire, an instrument to measure the quality of life in patients with low BMD levels. In the other two trials in which this outcome was evaluated, the EQ-5D questionnaire was used, with the addition, in the study of Marini et al [21] of the ECOS-16, a specific tool for osteoporosis in assessing quality of life.
With the exception of Koevska et al [22], who reported only statistically significant changes within the sample study groups, the results of the other authors agree on a significant correlation between the execution of an exercise protocol (Table 1) and improvements in quality of life compared to those who do not perform any exercise program.

Association between Exercise Therapy and Functionality
The evaluation of physical performance was measured using different types of tests: time up-and-go test, 5 time sit-to-stand, 6-min walking test, functional reach test (FRT), bend reach performance test (BRPT), vertical jump (VJ) and chair sit-and-reach; then SF-36 in its physical function component and Tinetti's Scale were used.
The results report a statistically significant increase in performance in the evaluation tools used, with superiority of the groups performing an exercise protocol (Table 1) over the control groups [12,15,21,[23][24][25]27].

Discussion
The purpose of this systematic review had to analyze the actual evidence about the muscle strengthening exercise and its efficacy in postmenopausal women suffering osteoporosis/osteopenia. The results of the studies analyzed, despite the wide range of years of publication, agree on the association between resistance exercise and its positive effect on the population examined in this review. However, the moderate-low level of methodological quality and the lack of homogeneity of the training programs analyzed suggest that there is contradictory evidence.
Strength training aims to promote osteogenesis in women diagnosed with OP, however, no significant changes are observed in vitamin-D levels, but significant changes are observed in bone architecture in both protein matrix and bone (p = 0.00177, p = 0.00031) as well as in BMD. It seems that these changes would be more pronounced if the strength programs had a duration of 12 months [28,29]. However, the studies included in the present review presented a wide range of exercise duration (from 12 weeks for the program of Mosti et al. to 13 months for the program of Borba-Pinheiro et al.) with inconsistency in the positive impact on bone quality, which does not allow a firm conclusion on the optimal durability of the programs [14].
Muscle strengthening exercise improves other capacities such as isometric and isotonic strength of large neuromuscular complexes of both the lower and upper limbs that seem to be key in the primary prevention of falls [30]. Furthermore, these improvements are related to work intensity, showing that interventions are required that work at least at an intensity of 80 to 85% 1RM to achieve the desired effects. Effects on balance are also observed, although these improvements do not seem to extend beyond 10 months, so we believe it is necessary that this ability be introduced as early as possible in training programs, especially if the intensity is high at a lower frequency. However, this last aspect has not been rigorously demonstrated because for many researchers it would be difficult to justify the use of high intensity in frail women diagnosed with OP To overcome this procedural obstacle, Watson et al. proposed in their LIFTMOR study to divide the program into two mesocycles of 6 months duration, avoiding that excessive load accumulation ends up putting these patients at risk [24].
Regarding the topic of exercise parameters, a 2020 review and meta-analysis by Shojaa et al., aiming to analyse the effects of dynamic muscle strengthening exercise on BMD in postmenopausal women [31], showed no significant difference in BMD between protocols with different duration of intervention and between different exercise intensities. On the contrary, it showed a significant difference with a positive effect on bone quality, in favour of training with free weights and a low net training frequency (<2 sessions/week).
On the other hand, it has been widely demonstrated that physical activity is able to promote bone formation, stimulating bone metabolism and its remodeling through mechanical loading (compression, tension and tissue shear) [32,33], improve hormonal regulation (estrogens, parathyroid hormone and glucocorticoids) [34][35][36][37] (with mimetic effect to hormone replacement therapy in postmenopausal women [38]), facilitate the regulation of signaling pathways [39][40][41][42][43][44], and stimulation of angiogenic-osteogenic responses [45]. However, and only from a clinical point of view, working in an aquatic environment may be a good approach to work in early phases due to the ease of working on the psychological and behavioral aspects associated with fear of movement.
Although not investigated in this review, considering the complexity and multifactorial nature of postmenopausal osteoporosis, further research is needed to investigate the possible synergistic effect of pharmacotherapy with certain exercise modalities, as highlighted in the study by Zhao et al. [46], who demonstrated that the combination of hormone replacement therapy (HRT) and a mixed-modality exercise protocol (high-impact activity in combination with high-intensity progressive muscle strengthening exercise was able to generate greater beneficial effects on hip and spine BMD in postmenopausal women than single-modality exercise.
With the results of this work, and given the absence of studies that address this question of clinical relevance, it is convenient to deepen the role of muscle strength training in the primary prevention of osteoporotic fracture in patients with osteopenia and even with delayed diagnosis of OP.
Furthermore, from a methodological point of view, differences have been detected in the proposed interventions, in the sample size and in the initial clinical status of the participants, which vary not only in issues such as age but also in the prognosis of their disease. Therefore, the existing variability and the lack of uniformity make it difficult to interpret and relate the different results, so it seems necessary to carry out more studies that assess suitability and promote the unification of criteria to achieve maximum effectiveness in therapeutic proposals to help us resolve the clinical question.

Conclusions
Muscle strengthening exercise in postmenopausal women with OP produces favorable results in terms of bone mineral density, strength, functionality, and quality of life. However, the benefits produced can be increased when combined with other therapeutic exercise modalities such as aerobic, balance and coordination. Funding: The publication of this work has been financed by the Universidad Europea de Canarias, C/Inocencio García 1 38300 La Orotava, 38300 Tenerife, Canary Islands, Spain.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available on request from the corresponding authors.

Conflicts of Interest:
The authors certify that they have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the article.