https://orcid.org/0000-0003-2154-9468
Figures
Abstract
Objective
To examine the effectiveness and safety of non-pharmacological interventions to reduce bone loss among post-stroke adult patients.
Data sources
Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database for Systematic Reviews, MEDLINE, CINAHL, ScienceDirect, Scopus, PubMed and PeDRO databases were searched from inception up to 31st August 2021.
Methods
A systematic review of randomized controlled trials, experimental studies without randomization and prospective cohort studies with concurrent control of non-pharmacological interventions for adult stroke patients compared with placebo or other stroke care. The review outcomes were bone loss, fall and fracture. The Cochrane Risk of Bias Tools were used to assess methodological quality, and Grading of Recommendations, Assessment, Development and Evaluations Framework to assess outcome quality. Synthesis Without Meta-Analysis (SWiM) was used for result synthesis.
Results
Seven studies (n = 453) were included. The methodological and outcome qualities varied from low to moderate. There were statistically significant changes between the intervention and parallel/placebo group in bone mineral density, bone mineral content, cortical thickness and bone turnover markers with specific physical and vibration therapies (p<0.05). Falls were higher in the intervention group, but no fracture was reported.
Conclusion
There was low to moderate evidence that physical and vibration therapies significantly reduced bone loss in post-stroke patients at the expense of a higher falls rate. The sample size was small, and the interventions were highly heterogeneous with different duration, intensities and frequencies. Despite osteoporosis occurring with ageing and accelerated by stroke, there were no studies on vitamin D or protein supplementation to curb the ongoing loss. Effective, high-quality non-pharmacological intervention to improve post-stroke bone health is required.
Citation: Sallehuddin H, Ong T, Md. Said S, Ahmad Tarmizi NA, Loh SP, Lim WC, et al. (2022) Non-pharmacological interventions for bone health after stroke: A systematic review. PLoS ONE 17(2): e0263935. https://doi.org/10.1371/journal.pone.0263935
Editor: Gausal A. Khan, Fiji National University, FIJI
Received: November 13, 2021; Accepted: January 30, 2022; Published: February 23, 2022
Copyright: © 2022 Sallehuddin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files.
Funding: There is no financial support or funding for this review. The publication of this manuscript is partially funded by the Universiti Putra Malaysia Publication Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
The risk for hip fracture is quadrupled in stroke survivors compared to healthy individuals [1, 2], attributable mainly to falls and disuse osteoporosis in the paretic side [3–5]. A study by Ramnemark et al. [5] showed that fracture risk increased from 4% in the first year after stroke to 15% and 24% after 5 and 10 years, respectively. Among stroke patients with unilateral persisting paresis at the time of fracture, up to two-thirds had their fractures on the paretic side [2]. Bone loss was significant in the paretic limb due to loss of muscle tensile strength and immobility. However, it is also present, albeit at a lesser degree, in the non-paretic limb [6]. A recent study showed that milder stroke and osteoporosis, but not stroke type, to be significantly associated with fracture risk [7]. Despite this evidence since 1957, patients with recent strokes were still not adequately screened for osteoporosis [8].
Stroke patients with osteoporosis were found to have a poorer Modified Rankin Score (MRS 2 or more) at three months than those without [9]. From an inversed U-shaped relationship found between fall and MRS, those with MRS ≥2 were more likely to fall than those with lower or higher functional status. This scenario can be due to the low physical activity in the lower functional status group and intact motor-sensory function in the higher functional status group [10]. Therefore, stroke survivors with underlying osteoporosis were more likely to have MRS 2 or more (poor function) and at increased risk of fall, leading to injuries and fractures. Osteoporosis itself lowers the quality of life, increases disability-adjusted life span, and cause a substantial financial burden to the country’s health system [11].
Bone loss started in the early days post-stroke and progressively worsened until the 3rd-4th month before plateauing off afterwards [12, 13]. This loss is probably due to sudden immobility and reduced muscle function, leading to disuse atrophy. Osteoporosis is equally distributed in men, women and younger patients with stroke [14, 15]. It is a concern as many developing countries report strokes occurring in a younger cohort [16]. The medical fraternity has highlighted this risk post-stroke and has recommended assessing fall and fracture risk for all adult stroke patients [17–19]. However, it does not make a firm recommendation on the interventions to prevent the bone loss that occurs post-stroke.
Non-pharmacological management remains the mainstay for bone health until osteoporosis or fragility fractures occur. Exercise benefits in preventing falls and fractures among the general population [20–22]. However, findings may not necessarily translate to the stroke cohort, and it is uncertain whether such non-pharmacological interventions are feasible and effective. A meta-analysis found that no strong recommendation can be made on daily Vitamin D and calcium intake for fracture prevention, due to methodological problems, with unknown efficacy or safety of high dose Vitamin D in high-risk individuals [23]. Therefore, this review aimed to examine the effectiveness and safety of non-pharmacological interventions (physical therapy, nutrition and vitamin supplements) that has been done previously to prevent bone loss among post-stroke individuals.
Methods
Search strategy and selection of studies
A systematic review of the literature was carried out. The following online databases were searched for articles published from inception to 31st August 2021: Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database for Systematic Reviews, MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ScienceDirect, Scopus, PubMed and PeDRO. The search was initially performed from 24th November 2020 until 1st December 2020, and a search re-run was done from 29th September 2021 till 30th September 2021. We also searched the reference lists of primary studies included in the review.
Search terms were stroke, cerebral infarct, hemiplegia, cerebrovascular accident, osteoporosis, bone resorption, bone density, bone loss, exercise, nutrition, vitamin, multifactorial. The search terms used for each database were described in S1 File. Due to limited translation resources, searches were limited to human studies and the English language. The protocol for this systematic review was registered in PROSPERO (CRD42021231970).
The first reviewer (HMS) downloaded all retrieved studies into a reference manager software (EndNote 20), removed the retracted articles and duplicates. According to the eligibility criteria, the titles and abstracts were screened for full-text review by two reviewers (NAT, LSP). All retrieved full text articles were reviewed by two independent reviewers (LHT, LWC), with the exclusion criteria documented. The discrepancy between the two reviewers was resolved at each stage by a discussion with a third reviewer (TO) and recorded in a table form, with reasons for exclusion stated.
Eligibility criteria
The review question was built on the PICOS (Participants, Interventions, Comparisons, Outcome and Study Design) framework, as shown in Table 1.
Any pharmacological interventions including anti-osteoporotic medications, hormonal treatment and traditional, complementary medicine were excluded. Case reports, grey literature, case-control studies, studies with historical controls and cross-sectional studies were also excluded as these were regarded to be of lower evidence in assessing intervention effectiveness.
Evaluation of methodological quality
Two review authors (HMS, YYH) independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions [24]. Randomized trials were evaluated using the ROB-I tool, while non-randomized trials used ROBINS-I. Disagreement between two reviewers was resolved by discussion with a third reviewer (TO). The data were analyzed using RevMan 5.4.
Effect measures
Synthesis without meta-analysis (SWiM) [25] was carried out because the interventions and outcome measures were too diverse to yield a meaningful summary effect estimate.
Data extraction and synthesis
Data extraction from included studies was performed independently using a standardized form piloted by two reviewers (NH/RN). Disagreement between two reviewers was resolved by discussion with a third reviewer (TO). Studies were analyzed separately according to their type of interventions. Continuous data were presented as mean differences between groups. Heterogeneity between studies in each type of intervention was tabulated, and included modifiers were gender, age, type and duration of a stroke, baseline bone health, mobility status and settings (recruitment and intervention).
Certainty of synthesis
All studies had their characteristics and their outcome qualities assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [26] by two reviewers (HMS, YYH). Any discrepancies were resolved by discussion with a third reviewer (SSG). Data were analyzed using the online GRADEpro GDT software. Certainty of evidence assessed using the GRADE framework is shown in S1 Table. We included all selected studies in the synthesis regardless of the methodological or outcome quality because of the few articles available on this particular topic.
Results
Our initial online database yielded 40,764 publications, of which seven articles were included in this systematic review. The PRISMA flowchart of the search and selection of studies included in this review are presented in Fig 1.
Description of included studies
Participants.
This review included 453 participants from Canada, Japan, Hong Kong and China. Two-thirds of the participants were men (63.6%, n = 288). Recruitment was mainly from the community [27–32] and only one study included hospitalized stroke patients [33]. The mean age of participants in all studies was 62 years (ranging between 46 and 74 years old). The sample size of included trials ranged from 11 to 129 participants. The median sample size was 63 participants in total. The stroke diagnosis to recruitment duration ranged from one week to 9.3 years, with an average of 5 years. Six studies reported the type of stroke [27, 28, 30–33], with 251 out of 432 participants (58.1%) having an ischemic stroke. Five studies reported participants’ mobility upon recruitment and stroke severity [27–30, 32], whereby all participants could walk independently, with or without walking aids. In addition, they were also required to stand for more than 1.5 minutes [30], pedal a stationary cycling ergometer at least 60% heart rate [27] and be able to walk for at least 10 meters [27–29]. Thirty-six out of 63 participants (57%) in two studies respectively have a stroke severity of American Heart Association (AHA) Stroke Functional Class II [27, 28]. One study [29] included those with a moderate to severe impairment in the paretic lower limb, while another study [30] included those with Chedoke McMaster Stroke Assessment (CMSA) paretic leg score 4 out of 7. Three studies [28, 29, 31] reported baseline bone health status of the participants, with 47 out of 95 (49.5%) participants having osteopenia and 20 (21.1%) having osteoporosis. All participants in these studies underwent DXA before the interventions, and no study reported falls or fracture history at baseline. The main characteristics of participants are summarised in Table 2.
Study design and intervention.
Included studies were 4 RCTs [27, 28, 30, 31], two randomized, parallel groups without control studies [32, 33] and one quasi-experimental study [29]. The studies were published between 2002–2021. The methodological quality was found to be low to moderate. Fig 2(a) and 2(b) summarise the risk of bias (ROB) for each study and across studies, respectively.
(a). Risk of Bias (ROB) analysis for each study. (b). Summary of risk of bias across the studies.
The interventions to prevent post-stroke bone loss were physical and whole-body vibration (WBV) therapies. The studies employed a substantial variety of physical therapy interventions, intensity, frequency, and duration. Resistance exercises in the lower limbs by sit-to-stand, weight-bearing activities and partial squats [27–29, 33] and upper limb by squeezing a ball [31] were employed. Balance exercises by alternate stepping onto low risers, standing on a balance disc, standing up with bodyweight support harness and progressive toe rises [27–29] as well as aerobic exercises using a treadmill, brisk walking and increasing speed of movement were also carried out [27–29]. Two studies used a specific device that emitted vibration frequencies (20-30Hz) [30, 32]. One study [33] had required all study participants to have essential lifestyle modifications such as adequate protein, vitamin D and calcium intake. The study designs and interventions are summarised in Table 3.
Intervention effects
Measurement tools and results of the included studies are summarised in Table 4.
Bone mineral density.
Two [28, 33] out of 4 studies [28, 29, 31, 33] that measured this outcome using DXA demonstrated a significantly reduced bone loss or improved bone mineral density (BMD) in post-stroke subjects following the specified interventions. An hour of three-times-weekly community-based fitness and mobility exercise program for 19 weeks [28] was able to reduce bone mineral density loss in the intervention group, in the paretic lower limb (-0.00 (CI -0.02–0.01) vs -0.02 (CI -0.03 to -0.01),p = 0.043), but not in the non-paretic limb. It was also shown that standing weight training of a minimum of 60min/day and 90min/day for three months was needed for males and females, respectively, for a statistically significant BMD improvement as measured by DXA in the lumbar spine (p<0.05) and femur (p<0.05) [33]. Treadmill exercises with bodyweight support did not statistically improve BMD in the paretic leg [29]. Home exercise by squeezing a ball did not result in a statistical difference in BMD in the arms of osteoporotic post-stroke patients [31]. Two studies [27, 29] that measured this outcome using pQCT at 4% area (BMDtrab), 50% area(BMDcort) [27] and 66% area(BMDcort) [29] of the paretic lower limb did not show any significant difference.
Bone mineral content.
Two studies reported this outcome [27, 31] using pQCT and DXA, respectively. An hour, three sessions a week of weight-bearing activities and aerobic exercises, static and dynamic balance exercises, as well as functional and muscle strengthening exercises during weight-bearing for 19 weeks, resulted in a significant increase in bone mineral content (BMC) at 4% area of the paretic leg (BMCtrab,5.6±6.7 vs -0.5±10.8,p<0.05), but not in the non-paretic leg and at 50% area (BMCcort,p = 0.21) [27]. No statistical difference in the BMC in the upper limb after a home exercise was found [31].
Cortical thickness.
Two studies measured this outcome by using pQCT [27, 29]. Weight-bearing activities, aerobic exercises, balance exercises, and strengthening exercises during weight-bearing for 19 weeks [27] led to a significant change in mean difference between the two groups at 50% area of the paretic leg (0.4±2.2 vs -0.9±1.9, p = 0.026). A treadmill exercise with bodyweight support for six months [29] led to a significant change in mean difference between the two groups at 66% area of the paretic leg (0.1 ± 0.1 versus -0.0 ± 0.1,p = 0.018).
Bone turnover markers.
Two studies reported on bone turnover markers [30, 32]. There was no significant effect of WBV (20-30Hz) administered for eight weeks on C-Telopeptide of Type-1 collagen cross-link (CTX) and Bone-specific Alkaline Phosphatase (BAP) [30]. However, there was a significant reduction of bone loss assessed by serum Cross-linked N-telopeptides of Type I collagen (NTx) in both 20Hz and 30Hz vibration frequency groups after eight weeks (−2.2±3.4 and −2.7±4.0, respectively,p<0.001) [32].
Falls.
Six studies [27–32] reported adverse incidents. Two studies [27, 28] specifically mentioned fall incidents, while four studies [29–32] mentioned no adverse effects in general, without specifying falls incidents. One study [33] did not report on the adverse incident at all. Among the six studies (n = 324) that assessed adverse effects, there were ten falls in the intervention group (4.9%,n = 204) and one in the control group (0.8%, n = 120). None of the falls resulted in serious injury. The cause of falls was not mentioned.
Other adverse events.
One study reported other adverse events apart from falls, where two participants in the arm (control) group reported soreness in the shoulder region of the paretic side, which was alleviated after reducing the weight lifted and modifying the exercise [27].
Certainty of evidence
The quality of evidence regarding bone mineral density, bone mineral content, cortical thickness, bone turnover markers, and falls ranged from low to moderate across the five comparisons in the GRADE Framework, as depicted in S1 Table. This means that we have a low to moderate level of certainty in these results.
Discussion
From the low to moderate-quality evidence that we gathered, we could not make a firm recommendation on the best approach to prevent bone loss in post-stroke patients. The positive and significant findings of bone loss reduction were found in the bone mineral density, bone mineral content and cortical thickness of the lower extremities among those who underwent upright weight-bearing, balance and aerobic exercises. This finding suggests the potential benefit of physical therapy and exercise in bone loss reduction among post-stroke patients, as previously evidenced among postmenopausal women [22].
The interventions were substantially heterogeneous, mainly included a small number of participants and only one study included acutely hospitalized stroke patients during recruitment [33]. Exercise type, frequency, duration, intensity, and methods were highly heterogeneous. The populations studied also differed widely, from immediate post-stroke to many years post-stroke, with variable functional ability.
Whole-body vibration induced osteogenic effects against age-associated bone mass alteration in older adults via mechanical stimulation [34]. It was shown to reduce bone resorption in postmenopausal women [35, 36]. Among post-stroke patients, vibration therapy at 20-30Hz frequencies reduced bone resorption only when assessed by NTx, but not CTX and BAP [30, 32]. Bone turnover markers could be time-specific and related to nutritional intake before, during and after exercise [37]. For example, CTX should be taken in the early morning in a fasted state, while P1NP is more stable for these changes [38].
An exercise that needs special equipment (for example, a WBV device) may not be feasible to replicate and expand in larger-scale studies without adequate funding [30, 32]. The device usage may be suitable in the research setting. However, from the requirement of having a therapist to ensure an accurate frequency and amplitude used and proper knee flexion of 60o while standing on the vibration platform, it can be cumbersome for home or community setting in the long run [32]. The two studies were carried out using the same vibration device, but patients’ functional status was assessed using different tools at baseline. The study designs were different in which one of them did not have a control group.
The existing studies only mentioned the effects of physical therapies to prevent post-stroke bone loss. Other aspects such as nutrition and vitamin supplements in optimizing bone health were not explored. Nutritional factor plays a role in moderating the bone metabolic response to exercise [37]. Only one study by Han et al [33] employed adequate protein, vitamin D and calcium intake for all its participants. However, monitoring the intake (for example, pill counts and food diary) was not mentioned. The level of serum 25(OH)D was also not monitored in any of the included studies to assess vitamin D deficiency, which is an important aspect of bone health. A study in a developing country [39] showed that a low vitamin D level was prominent among its general population. In the Rotterdam study, Vitamin D deficiency was found to be the consequence of stroke itself [40], a condition found to accelerate bone loss in the proximal femur of post-stroke patients [41]. The risk factors attributed to post-stroke osteoporosis, which are low physical activity and poor nutrition, compounded by multimorbidity and ageing, will increase the risk of falls and fractures. Bone and muscle act as one functional unit, of which muscle strength/mass deterioration after an acute stroke must be intervened early to maintain bone density/strength index [42]. Acute stroke induces muscle hypercatabolism, where protein degradation is higher than protein synthesis. Studies have shown that post-stroke amino acid supplementation could reverse this process. However, the amino acid supplementation effect on bone properties was not measured [43, 44]. Therefore, to have optimum prevention against bone loss, a multi-domain intervention comprising adequate protein, calcium and vitamin D, and individually tailored physical therapy is proposed for acute stroke patients.
Strength and limitations
This systematic review has identified the evidence so far in improving bone health among post-stroke patients. The comprehensive search strategy employed here would have identified all pertinent published literature on the topic. However, the study had no translation service and was only able to include English language articles. There are limitations with this study as it does not take into consideration the effect of comorbidity, gender, frailty, vitamin D deficiency, and other factors that affect bone loss to determine the effect of these interventions on post-stroke bone health. Postmenopausal women consist 36% of the study population, which means the effect of postmenopausal bone density loss could be underestimated. Another limitation is that most included studies are from the same author, Pang et al, which may influence our findings.
Implications of the results for practice, policy, and future research
There is a need for further larger-scale studies with cost-effective interventions to be carried out in the future, which may be applicable in developing countries where expert resources and financial support are limited. The intervention may include a combination of aerobic, balance and resistance exercises, with protein and vitamin supplementation that is easy to replicate in multiple centres internationally. Given the complex, multifactorial, and heterogeneous nature of post-stroke bone loss among the global ageing population, interventions simultaneously targeting several risk factors and mechanisms may be required for optimal preventive effects. The risk factors may be shared between the osteoporosis mechanism in general, and loss of muscle strength, balance, and sensory impairment that increase the risk of fall in stroke. Methodological harmonization may be possible, for example, if all participants have a known bone health status at baseline, using validated measuring tools such as DXA and bone turnover markers as well as Modified Rankin Score (MRS) as the basis of functional status. Future studies may include the impact of an intervention on the quality of life as this is an essential aspect of ageing research. Finally, health economic studies alongside clinical trials should be carried out in the future to determine the cost-effectiveness of any intervention for stakeholders’ interest in the long-term implementation of a programme.
Conclusion
There is low to moderate evidence that specific physical and vibration therapies significantly reduce bone loss in post-stroke patients at the expense of a higher falls rate. However, the small sample size and lack of sub-analysis on comorbidity, gender (except Han et al), frailty, vitamin D deficiency, and other factors that may affect bone loss on the intervention outcomes may limit its applicability and generalizability. An extensive search found no published evidence on the effects of vitamins or protein in preventing post-stroke bone loss. In addition, the interventions were highly heterogeneous. With the global population ageing, a more well-designed randomized controlled trial that involves early post-stroke multi-domain intervention may further establish the value of non-pharmacological intervention in reducing post-stroke bone loss.
Supporting information
S1 File. This is the S1 File on search terms used for each online database.
https://doi.org/10.1371/journal.pone.0263935.s001
(PDF)
S1 Table. This is the S1 Table on summary of certainty of evidence using GRADE system.
https://doi.org/10.1371/journal.pone.0263935.s002
(TIF)
References
- 1. Lau EMC, Suriwongpaisal P, Lee JK, Das De S, Festin MR, Saw SM, et al. Risk Factors for Hip Fracture in Asian Men and Women: The Asian Osteoporosis Study. Journal of Bone and Mineral Research. 2001;16(3):572–80. pmid:11277276
- 2. Ramnemark A, Nilsson M, Borssén B, Gustafson Y. Stroke, a major and increasing risk factor for femoral neck fracture. Stroke. 2000;31(7):1572–7. pmid:10884456
- 3. Peszczynski M. The fractured hip in hemiplegic patients. Geriatrics. 1957;12(12):687–90. pmid:13480487
- 4. Mulley G, Espley AJ. Hip fracture after hemiplegia. Postgraduate Medical Journal. 1979;55(642):264–5. pmid:471862
- 5. Ramnemark A, Nyberg L, Borssén B, Olsson T, Gustafson Y. Fractures after Stroke. Osteoporosis International. 1998;8(1):92–5. pmid:9692083
- 6. Liu M, Tsuji T., Higuchi Y., Domen K., Tsujiuchi K., & Chino N. Osteoporosis in Hemiplegic Stroke Patients as Studied with Dual-Energy X-ray Absorptiometry. Archives of Physical Medicine and Rehabilitation. 1999;80:1219–26. pmid:10527077
- 7. Wang H-P, Sung S-F, Yang H-Y, Huang W-T, Hsieh C-Y. Associations between stroke type, stroke severity, and pre-stroke osteoporosis with the risk of post-stroke fracture: A nationwide population-based study. Journal of the Neurological Sciences. 2021;427:117512. pmid:34082148
- 8. Kapoor E, Austin PC, Alibhai SMH, Cheung AM, Cram P, Casaubon LK, et al. Screening and Treatment for Osteoporosis After Stroke. Stroke. 2019;50(6):1564–6. pmid:31018778
- 9. Lee SB, Cho AH, Butcher KS, Kim TW, Ryu SY, Kim YI. Low bone mineral density is associated with poor clinical outcome in acute ischemic stroke. Int J Stroke. 2013;8(2):68–72. pmid:22151871
- 10. Wei WE, De Silva DA, Chang HM, Yao J, Matchar DB, Young SHY, et al. Post-stroke patients with moderate function have the greatest risk of falls: a National Cohort Study. BMC Geriatrics. 2019;19(1). pmid:31878876
- 11. Sözen T, Özışık L, Başaran NÇ. An overview and management of osteoporosis. Eur J Rheumatol. 2017;4(1):46–56. pmid:28293453
- 12. Hamdy RC, Moore SW, Cancellaro VA, Harvill LM. Long-term effects of strokes on bone mass. Am J Phys Med Rehabil. 1995;74(5):351–6. pmid:7576411
- 13. Takamoto S, Masuyama T, Nakajima M, Sekiya K, Kosaka H, Morimoto S, et al. Alterations of bone mineral density of the femurs in hemiplegia. Calcified Tissue International. 1995;56(4):259–62. pmid:7767834
- 14. Brown DL, Morgenstern LB, Majersik JJ, Kleerekoper M, Lisabeth LD. Risk of fractures after stroke. Cerebrovasc Dis. 2008;25(1–2):95–9. pmid:18057878
- 15.
Zhang L, Zhang H, Wang R, Su J, Lu Y, Zhang L, et al. Stroke and osteoporosis: a Taiwan cohort study. 2019:6.
- 16.
Abdul Aziz Z, Sidek,Norsima Nazifah. Annual Report of The Malaysian Stroke Registry 2009–2016. National Neurology Registry. 2016.
- 17.
Stroke Council M. Clinical Practice Guidelines: Management of Ischemic Stroke 3rd Edition. 2020.
- 18. SIGN118 SIGN. Management of Patients with Stroke: A national clinical guideline. NHS Healthcare Improvement Scotland. 2010:48.
- 19.
SIGN142 SIGN. Management of osteoporosis and the prevention of fragility fractures: A National Clinical Guideline. NHS Healthcare Improvement Scotland. 2020.
- 20. Sherrington C, Fairhall NJ, Wallbank GK, Tiedemann A, Michaleff ZA, Howard K, et al. Exercise for preventing falls in older people living in the community. Cochrane Database of Systematic Reviews. 2019;2019(1).
- 21. Pinheiro MB, Oliveira J, Bauman A, Fairhall N, Kwok W, Sherrington C. Evidence on physical activity and osteoporosis prevention for people aged 65+ years: a systematic review to inform the WHO guidelines on physical activity and sedentary behaviour. International Journal of Behavioral Nutrition and Physical Activity. 2020;17(1). pmid:33239014
- 22. Howe TE, Shea B, Dawson LJ, Downie F, Murray A, Ross C, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2011(7):Cd000333. pmid:21735380
- 23. Yao P, Bennett D, Mafham M, Lin X, Chen Z, Armitage J, et al. Vitamin D and Calcium for the Prevention of Fracture. JAMA Network Open. 2019;2(12):e1917789. pmid:31860103
- 24.
Higgins JPT SJ, Page MJ, Elbers RG, Sterne JAC. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor. Cochrane Handbook for Systematic Reviews of Interventions version 62 (updated February 2021): Cochrane; 2021.
- 25. Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ. 2020:l6890. pmid:31948937
- 26. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. pmid:18436948
- 27. Pang MY, Ashe MC, Eng JJ, McKay HA, Dawson AS. A 19-week exercise program for people with chronic stroke enhances bone geometry at the tibia: a peripheral quantitative computed tomography study. Osteoporos Int. 2006;17(11):1615–25. pmid:16896509
- 28. Pang MY, Eng JJ, Dawson AS, McKay HA, Harris JE. A community-based fitness and mobility exercise program for older adults with chronic stroke: a randomized, controlled trial. J Am Geriatr Soc. 2005;53(10):1667–74. pmid:16181164
- 29. Pang MYC, Lau RWK. The Effects of Treadmill Exercise Training on Hip Bone Density and Tibial Bone Geometry in Stroke Survivors: A Pilot Study. Neurorehabilitation and Neural Repair. 2010;24(4):368–76. pmid:19959830
- 30. Pang MYC, Lau R.W.K., Yip S.P. The effects of whole-body vibration therapy on bone turnover, muscle strength, motor function, and spasticity in chronic stroke. European Journal of Physical and Rehabilitation Medicine. 2013;49(4):439–50. pmid:23486302
- 31. Shimizu ME, Ishizaki Fumiko., Nakamura Shigenobu. Results of a Home Exercise Program for Patients with Osteoporosis Resulting from Neurological Disorders. Hiroshima J Med Sci. 2002;51(1):15–22. pmid:11999456
- 32. Yang Z, Miller T, Xiang Z, Pang MYC. Effects of different vibration frequencies on muscle strength, bone turnover and walking endurance in chronic stroke. Scientific reports. 2021;11(1):121. pmid:33420277
- 33. Han L, Li SG, Zhai HW, Guo PF, Chen W. Effects of weight training time on bone mineral density of patients with secondary osteoporosis after hemiplegia. Exp Ther Med. 2017;13(3):961–5. pmid:28450926
- 34. Liu P-Y, Brummel-Smith K, Ilich JZ. Aerobic Exercise and Whole-Body Vibration in Offsetting Bone Loss in Older Adults. Journal of Aging Research. 2011;2011:1–9. pmid:21253515
- 35. Marín-Cascales E, Alcaraz PE, Ramos-Campo DJ, Martinez-Rodriguez A, Chung LH, Rubio-Arias JÁ. Whole-body vibration training and bone health in postmenopausal women: A systematic review and meta-analysis. Medicine. 2018;97(34):e11918. pmid:30142802
- 36. Turner S, Torode M, Climstein M, Naughton G, Greene D, Baker MK, et al. A Randomized Controlled Trial of Whole Body Vibration Exposure on Markers of Bone Turnover in Postmenopausal Women. Journal of Osteoporosis. 2011;2011:1–10. pmid:21772975
- 37. Dolan E, Varley I, Ackerman KE, Pereira RMR, Elliott-Sale KJ, Sale C. The Bone Metabolic Response to Exercise and Nutrition. Exercise and Sport Sciences Reviews. 2020;48(2):49–58. pmid:31913188
- 38. Szulc P, Naylor K, Hoyle NR, Eastell R, Leary ET. Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. Osteoporosis International. 2017;28(9):2541–56. pmid:28631236
- 39. Leiu KH, Chin YS, Mohd Shariff Z, Arumugam M, Chan YM. High body fat percentage and low consumption of dairy products were associated with vitamin D inadequacy among older women in Malaysia. PLOS ONE. 2020;15(2):e0228803. pmid:32053636
- 40. Berghout BP, Fani L, Heshmatollah A, Koudstaal PJ, Ikram MA, Zillikens MC, et al. Vitamin D Status and Risk of Stroke. Stroke. 2019;50(9):2293–8. pmid:31390971
- 41. Levendoglu F, Ugurlu H, Gürbilek M, Akkurt E, Karagözolu E. Increased Bone Resorption in the Proximal Femur in Patients with Hemiplegia. American Journal of Physical Medicine & Rehabilitation. 2004;83(11):835–41. pmid:15502736
- 42. Yang FZ, Jehu DAM, Ouyang H, Lam FMH, Pang MYC. The impact of stroke on bone properties and muscle-bone relationship: a systematic review and meta-analysis. Osteoporosis International. 2020;31(2):211–24. pmid:31720713
- 43. Aquilani R, Boselli M, D’Antona G, Baiardi P, Boschi F, Viglio S, et al. Unaffected Arm Muscle Hypercatabolism in Dysphagic Subacute Stroke Patients: The Effects of Essential Amino Acid Supplementation. BioMed Research International. 2014;2014:1–17. pmid:25431770
- 44. Ramasamy DK, Dutta T, Kannan V, Chandramouleeswaran V. Amino acids in post-stroke rehabilitation. Nutritional Neuroscience. 2021;24(6):426–31. pmid:31328694