Clin Physiol Funct Imaging (2018) doi: 10.1111/cpf.

12512

REVIEW ARTICLE

Effects of blood flow restriction exercises on bone

metabolism: a systematic review
S. T. Bittar , P. S. Pfeiffer, H. H. Santos and M. S. Cirilo-Sousa
Graduate Associate Programme in Physical Education, Federal University of Para
ıba (UFPB), Jo~ao Pessoa, Para
ıba, Brazil

Summary

Correspondence This study analysed the effect of low-intensity (LI) exercises with blood flow
Simoni Teixeira Bittar, Laboratory of Kinanthro-
restriction (BFR) on bone metabolism compared with high-intensity (HI) exer-
pometry and Human Performance, Associate
Graduate Program in Physical Education, Federal
cises without BFR. The following databases were searched using the keywords
University of Para
ıba (UFPB), Laboratory, Room therapeutic occlusion training OR BFR training OR vascular occlusion training OR
06 and 08, Castelo Branco, Jo~ao Pessoa KAATSU training OR ischaemia training AND osteogenesis OR bone biomarkers
58051-900, Brazil OR bone metabolic marker OR bone mass OR bone turnover OR osteoporosis OR
E-mail: [email protected] osteopenia: PubMed, Web of Science, SPORTDiscus, CINAHL, Science Direct,
Accepted for publication Cochrane and Google Scholar. Two researchers, independently and blindly,
Received 25 July 2017; selected the studies based on established inclusion and exclusion criteria. Elec-
accepted 15 January 2018
tronic and manual searches located 170 articles published in English; after screen-
Key words ing, only four studies showed that BFR training increases the expression of bone
biomarkers; blood flow restriction; ischaemia; formation markers (e.g. bone-specific alkaline phosphatase) and decreases bone
metabolic bone diseases; physical education and resorption markers (e.g. the amino-terminal telopeptides of type I collagen) after
training; therapeutic occlusion both aerobic and anaerobic exercise across several populations. The results of this
study show that few studies have confirmed the positive effect of exercise with
BFR on bone metabolism, formation and resorption. Furthermore, no method-
ological standardization of the samples, exercise type, intervention frequency or
duration was observed.

One study found that the use of the BFR without exercise
Introduction
during the postoperative period attenuated muscle atrophy
High-intensity strength training (ST) with more than 70% of compared with a control group (Takarada et al., 2000). In
one-repetition maximum (1RM) is associated with numerous addition, previous clinical studies using BFR (Inoue et al.,
positive effects in general populations; however, elderly peo- 2002; Odagiri, 2004) showed improved skeletal bone mass
ple and patients undergoing rehabilitation are often limited to patterns in people with certain diseases (e.g. avascular necrosis
low-intensity exercise (ACSM, 2009). of the femoral head and osteopenia or osteoporosis), and
The blood flow restriction (BFR) technique has been shown other papers (Loenneke et al., 2012a; Loenneke et al., 2012b)
to attenuate limb muscle atrophy and, when combined with showed that LI exercise combined with BFR may provide not
low-intensity (LI) exercises, increases muscle volume and only an increase in muscle adaptation, but also in bone and
strength across different age groups. BFR or KAATSU training consequently modification in its biomarkers.
is a technique created 50 years ago in Japan, in which the Studies analysed two biomarkers (bone alkaline phosphatase
blood flow for the individual’s lower or upper limbs is and amino-terminal telopeptides, respectively) and found that
restricted using cuffs. It is applied to decrease arterial and BFR training also accelerates bone metabolism (Beekley et al.,
occlude the venous blood flow of the muscle. When the nec- 2005; Bemben et al., 2007). The possible mechanisms respon-
essary precautions are taken, the possible risks to health are sible for this effect are as follows: increased intramedullary
the same as the high-intensity (HI) exercises, however, with pressure and interstitial fluid within the bone caused by
reduced mechanical effort of the joints (Loenneke et al., venous occlusion (Maher et al., 2003). In addition to these
2011). mechanisms, it was reported that BFR activates hypoxia-

© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 1
2 Blood flow restriction and bone metabolism: a systematic review, S. T. Bittar et al.

induced transcription factor (HIF), thereby increasing the To select the studies, two blinded and independent
expression of vascular endothelial growth factor (VEGF) and researchers (Bittar & Pfeiffer) who strictly complied with the
the formation of microblood vessels in bone tissue (Araldi & established inclusion and exclusion criteria evaluated the titles
Schipani, 2010). and abstracts identified in the initial search. When the title
The bone mass is the end product of two metabolic pro- and the abstract did not match (e.g. the title talks about
cesses (formation and resorption) that support the mechanical adults while on the abstract the subjects are elderly), the
load of the body and its maturation, can be influenced by the researchers took into account the guiding question of the
deposition of calcium and minerals. Blood and urinary mole- review to select or not the manuscript. Disagreements
cules (bone-specific alkaline phosphatase, osteocalcin, amino- between the two researchers were resolved via the opinion
terminal telopeptides of type I collagen, among others) had of a third evaluator.
been identified as bone formation or resorption markers. The
main advantage of these markers is that they can instanta-
Methodological quality: PEDro Scale
neously reveal the dynamics of bone metabolism in response
to exercise, depending on the exercise intensity (Seibel, 2005). Currently, the most used scale in the area of rehabilitation is
For improving bone health, the American College of Sports the PEDro scale (http://www.pedro.fhs.usyd.edu.au), which
Medicine (ACSM, 2009) recommends moderate-to-high-inten- was developed by the Physiotherapy Evidence Database for use
sity resistance exercises or high-impact exercises (e.g. jumps) with regard to experimental studies. This scale has a maxi-
to stimulate bone metabolism or to maintain it in the case of mum total score of 10 points and includes criteria concerning
the elderly. Therefore, it is essential to investigate the effects the evaluation of internal validity and the presentation of the
of LI exercises with BFR on bone metabolism because the statistical analysis used. For each criterion defined in the scale,
elderly, especially the ones in some special situations (e.g. one point (1
0) is attributed to the presence of indicators
chronic diseases, obesity, sedentary people and others) may regarding the quality of the evidence presented, and zero
not be able to perform HI exercises. points (0
0) are attributed to its absence.
Thus, this study aimed to analyse the effect of LI exercises The PEDro scale is composed of the following elements: (i)
with BFR compared with HI exercises without BFR on bone the specification of inclusion criteria (item not scored); (ii)
metabolism. random allocation; (iii) concealment of allocation; (iv) simi-
larity of the groups at baseline or the initial phase; (v) blind-
ing of all participants; (vi) blinding of all therapists; (vii)
Materials and methods blinding of all assessors; (viii) measures of at least one pri-
mary outcome obtained from more than 85% of participants
Identification and selection of studies
allocated; (ix) ‘intention to treat’ analysis; (x) between-group
The research was carried out on the following databases: comparisons of at least one primary outcome; and (xi) reports
PubMed, Web of Science, SPORTDiscus, CINAHL, Science of measures of variability and estimations of parameters con-
Direct, Cochrane and Google Scholar; in addition, manual cerning at least one primary variable (Maher et al., 2003). The
searches of the studies’ references were performed. The key- researchers used the PEDro scale independently. After its use,
words therapeutic occlusion training OR blood flow restriction they analysed their agreement using the Kappa (K) index.
training OR vascular occlusion training OR KAATSU training This study was conducted according to standardization of
OR ischaemia training AND osteogenesis OR bone biomarkers PRISMA scale (Liberati et al., 2009). Data analysis was carried
OR bone metabolic marker OR bone mass OR bone turnover out based on a critical review of content, using the following
OR osteoporosis OR osteopenia were used according to the criteria: title, abstract, rationale, objectives, protocol, risk of
Medical Subjects Headings (MeSH) using Boolean operators bias across studies, study characteristics, results of individual
(OR and AND), and the keywords that were not located in studies, limitations and conclusions.
the abstracts were located after reading the manuscripts that
referred to the same subject.
Results
The following inclusion criteria were considered for the
bibliographic research: (i) published between 1990 and 2016; The search in the seven databases (PubMed, Web of Science,
(ii) undefined target populations; (iii) the use of exercises SPORTDiscus, CINAHL, Science Direct, Cochrane and Google
associated with BFR as an intervention; (iv) outcomes of inter- Scholar), in addition to the manual search (i.e. the analysis of
est related to bone metabolism; (v) well-established method- references), revealed 170 articles. After discarding duplicate
ological criteria; (vi) published in English; and (vii) original articles and analysing whether the titles were consistent with
articles only. the object of study, nine articles remained for screening (eight
Articles were excluded if they (i) had scores lower than from the databases and one from the manual search). In the
three on the Physiotherapy Evidence Database (PEDro) scale; second step, the eligibility criteria for the manuscripts to be
(ii) had the same main text under a different title; and (iii) included in the systematic review were analysed, and five arti-
were repeated across other databases. cles were excluded as follows: one case study; one annals

© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
 Blood flow restriction and bone metabolism: a systematic review, S. T. Bittar et al. 3

abstract; one of which did not match the abstract (although The studies selected by the authors were evaluated using
the title was in accordance with the topic of this review); one the PEDro scale (http://www.pedro.fhs.usyd.edu.au), and the
duplicate; and one narrative review (Fig. 1). four articles selected received a score of 8 from the two evalu-
With respect to the four studies selected and included for ators (Beekley et al., 2005; Bemben et al., 2007; Karabulut
analysis, all were relatively recent (2005–2013) with hetero- et al., 2011; Kim et al., 2012). Table 2 demonstrates in detail
geneous samples (young and older adults including trained the individual scores of each item between each article.
and untrained, active and sedentary, and male and female par- None of the selected manuscripts were evaluated with the
ticipants). The interventions were based on strength and aero- maximum score on the PEDro Scale because they all failed on
bic training and varied in duration from a minimum of meeting the following criteria: blinding of all participants,
2 weeks (Bemben et al., 2007) to a maximum of 6 weeks blinding of all therapists and blinding of all assessors. After
(Karabulut et al., 2011) with frequency of at least one time the evaluation of methodological quality, the Kappa index was
(Bemben et al., 2007) and at most three times per week used to analyse the agreement between the scores given by
(Beekley et al., 2005; Karabulut et al., 2011; Kim et al., 2012). the evaluators, and perfect agreement was obtained
All of the articles specified the muscles worked during the (ICC = 1
00, P < 0
025).
training, the BFR method used, and the duration and type of
exercises performed (anaerobic or aerobic). Furthermore, it is
Discussion
important to highlight that all of the manuscripts selected for
the systematic review had as the major dependent variable the This is the first systematic review to address the effect of BFR
bone biomarkers (see Table 1). on bone metabolism in adults and the elderly. Regarding the

Title and Abstract Analysed (n = 170):

PubMed (n = 3)
Web of Science (n = 4)
SPORTDiscus (n = 3)
Identification

CINAHL (n = 0)
Science Direct (n = 2)
Cochrane (n = 1)
Google Scholar (150)
Manual Search (n = 7)
Screening

Articles selected by the two

reviewers (n = 9) Excluded articles (5):

Case study (1)

Annals abstract (1)

Did not fit the object of

study (1)
Elegibility

Articles selected after full-text Duplicate (1)

review (n = 4)
Narrative review (1)
Included

Articles analysed (n = 4)
Figure 1 Flow chart of the study selection
process.

© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
 Table 1 Studies that analysed BFR and bone biomarkers.

Author/Year Study sample Intervention type and duration Cuff pressure Experimental events Results Conclusion

Beekley n = 18 healthy men 15-min walk (50 m min 1) KAATSU Walk with KAATSU (n = 9) or Increased CSA (5
8%)**, Aerobic training combined
et al. (2005) (21–28 years old). on the treadmill, 2 9 /day, (160–230 mmHg) without (control n = 9). The 1RM strength (7
5%)b, and with BFR, increased the
(4-h interval between sessions) vascular restriction was in the most BAP levels (10
8%)* in the levels of BAP
for 3 weeks, 6 days week 1 proximal portion of the thighs and BFRG compared with the
was maintained during the protocol CG
of five sets of 2 min with 1-min
interval
Bemben n = 9 active men Two sessions of ST with BFR KAATSU ST with BFR: one session of 30 Decreased plasma volumea LI training combined with
et al. (2007) (18–30 years old). and control (ST without BFR): (140–180 mmHg) reps + three sessions of 15 reps immediately after exercise BFR decreased bone
20% 1RM for both groups with a 30-s interval between sets, in the BFRG. metabolism (NTx) during
with a 48-h interval in occlusion maintained for 10 min Time 9 training effect for an acute bout
random order throughout the protocol. Blood NTx levels (13
3%)*;
samples were obtained 30 min after exercise NTx
immediately, before and after levels decreased* compared
exercise, and 30 min after the end with baseline
of the exercise for the bone
biomarker analysis
Karabulut n = 37 healthy elderly ST: 3 9 /week for 6 weeks KAATSU HISTG (n = 13): three sets of eight Time 9 CTX decrease in the LISTG showed significant
et al. (2011) men (58
8  (120–180 mmHg) reps at 80% 1RM. LISTG + BFR exercise groups* changes in bone ALP
0
6 years old) (n = 13): one set of 30 reps + two Increase in BAP of 21% for concentrations and bone
sets of 15 reps at 20% 1RM, with the LISTG + BFR, 23% for ALP.
inflated cuffs for 6–8 min. CG the HISTG and 4
7% for CG
(n = 11). Blood samples were
collected 6 weeks before and after
4 Blood flow restriction and bone metabolism: a systematic review, S. T. Bittar et al.

to measure the concentrations of

bone biomarkers
Kim n = 30 healthy untrained ST: 3 9 /week for 3 weeks KAATSU Randomized (LISTG + BFR, n = 10): Increase in quadriceps CSA*, HISTG was most effective
et al. (2012) men (18–35 years old) (120 mmHg) 20% 1RM, (HISTG, n = 10): 80% but the HISTG had a greater than LISTG for eliciting
1RM and BFRG (n = 10). Both the increase (3
48%) compared bone formation and
LISTG + BFR and the HISTG with LISTG + BFR (1
15%). muscle hypertrophy
performed leg press, and isotonic The HISTG showed an responses.
knee extension–flexion exercises increase in fasting BAP after
(3 9 /week, two sets of 10 reps). training (50
91%)**
The BFRG was subjected to the
same procedure, without the
exercise protocol, for 10 min and
3 9 /week

CSA, cross-sectional area; BAP, bone-specific alkaline phosphatase (bone formation biomarker); BFRG, BFR group; CG, control group; ST with BFR, ST with BFR; NTx, bone resorption biomarker; HISTG,
HI ST group; LISTG + BFR, LI ST group with BFR; CTX, bone resorption biomarker; BFRG, group that only performs BFR; UL, upper limbs.
*P < 0
05.
**P < 0
01.

© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
 Blood flow restriction and bone metabolism: a systematic review, S. T. Bittar et al. 5

Table 2 PEDro Scale of quality for eligible randomized controlled the HI and LI combined with BFR (LI + BFR) groups, respec-
trial. tively. In the second study (Kim et al., 2012), 30 healthy
untrained men aged 18–35 years old were also divided into
Criteria
three randomized groups (ST + HI: 80% 1RM; ST + LI: 20%
Study 1 2 3 4 5 6 7 8 9 10 11 Total 1 RM combined with BFR; BFR only), but only the ST + HI:
80% 1RM group showed an increase (50
1  12
77%,
Beekley 1 1 1 1 0 0 0 1 1 1 1 8
P < 0
01) in their levels of bone-specific alkaline phosphatase.
et al. (2005)
Bemben 1 1 1 1 0 0 0 1 1 1 1 8 Although these two studies used ST as the variable of interest,
et al. (2007) the difference in their results may be caused by the differences
Karabulut 1 1 1 1 0 0 0 1 1 1 1 8 in participant characteristics, such as age and level of physical
et al. (2011) activity, or duration of intervention (3 and 6 weeks, respec-
Kim et al. 1 1 1 1 0 0 0 1 1 1 1 8
tively) (Karabulut et al., 2011; Kim et al., 2012).
(2012)
In addition to analysing the effects of BFR on bone forma-
1,eligibility criteria were specified; 2 – subjects were randomly allo- tion markers (e.g. bone-specific alkaline phosphatase), two
cated to groups; 3 – allocation was concealed; 4 – the groups were studies (Bemben et al., 2007; Karabulut et al., 2011) also
similar at baseline regarding the most important prognostic indicators; found significant results with regard to serum markers of bone
5 – there was blinding of all subjects; 6 – there was blinding of all resorption. The acute effect of ST ST + LI combined (or not)
therapists who administered the therapy; 7 – there was blinding of all
with BFR was analysed in nine physically active men
assessors who measured at least one key outcome; 8 – measures of at
least one key outcome were obtained from more than 85% of the (24
9  2
5 years old) who performed two training sessions
subjects initially allocated to groups; 9 – all subjects for whom out- with a 48-h interval between them (Bemben et al., 2007).
come measures were available received the treatment or control condi- These authors observed that NTx levels (amino-terminal
tion as allocated or, where this was not the case, data for at least one telopeptide of type I collagen) decreased (13
3  3
4%;
key outcome were analysed by ‘intention to treat’; 10 – the results of
P < 0
05) from baseline 30 min after ST + LI with BFR.
between-group statistical comparisons are reported for at least one key
outcome; 11 – the study provides both point measures and measures Although this marker responds faster to the stimulus of the
of variability for at least one key outcome. exercises than bone formation markers, it ensures that the
bone metabolism is under constant formation and resorption.
Then, while resorption biomarkers decrease with the practice
articles reviewed, three of them (Beekley et al., 2005; Karabu- of BFR exercise, there is a trend towards increasing bone for-
lut et al., 2011; Kim et al., 2012) evaluated the bone-specific mation (Bemben et al., 2007; Karabulut et al., 2011). This
alkaline phosphatase biomarker; these were measured with decrease in NTx can be explained by the increase in sub-
serum, whereas two of them (Bemben et al., 2007; Karabulut stances circulating in the blood, such as hormones and pro-
et al., 2011) analysed serum markers of bone resorption teins (Ahmadizad et al., 2006).
(telopeptides of type I collagen). In addition, a descriptive decrease was found in carboxy-
One study evaluated 18 healthy men ageing terminal telopeptide of type I collagen (CTX) concentration in
21
3  2
3 years (9 = control; 9 = BFR) for 3 weeks the exercise groups (7
7% for ST + LI 20% 1RM with BFR;
(6 days week 1, 2 times day 1, 4-h rest between sessions) 4
1% for ST + HI 80% 1RM), and a 3
3% increase for CON,
using treadmill-walking training at a speed of 50 m min 1 and after training for 6 weeks, 3 times a week; however, this
observed that BFR generated a 10
8% gain (P < 0
05) in serum difference between groups was not statistically significant
alkaline phosphatase levels, thereby demonstrating the effi- (Karabulut et al., 2011). Therefore, the results observed in
ciency of BFR when combined with aerobic training in relation different age groups, and intervention durations suggest
to this biomarker (Beekley et al., 2005). According to the that exercise is important for the prevention of diseases that
authors, these results may be due to the fact that RFS training weaken bone structure and might delay the osteopenia and
increases the levels of GH and IGF-1, which are responsible for osteoporosis caused by ageing.
bone turnover and show that even in healthy young subjects The results presented by the selected studies showed that both
practising low-intensity aerobic exercise, the use of BFR can be aerobic and anaerobic exercises combined with BFR can provide
feasible and applicable in relation to the bone formation bio- satisfactory results related to the bone biomarkers. Thus, this
marker. technique (BFR) is a feasible and applicable alternative to many
The effect of ST combined with BFR on bone-specific alka- population groups (elderly, young, physically active or not),
line phosphatase was analysed in two studies (Karabulut et al., that aim to treat or slow up the effects of bone diseases. Finally,
2011; Kim et al., 2012). In the first study (Karabulut et al., the current studies which approach this theme only show short-
2011), the authors divided 37 healthy elderly men term results justifying the use of biomarkers that reflect in a
(56
8  0
6 years old) into three randomized groups dynamic way the bone metabolism. However, it is believed that
(HI + ST, 80% 1RM; LI + ST, 20% 1RM combined with BFR; this technique combined with low-intensity training, can also
and a control group). After training three times a week for bring long-term satisfactory results that must be evaluated in
6 weeks, these authors found increases of 23% and 21% for the bone structure, showing that future studies are necessary to

© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
6 Blood flow restriction and bone metabolism: a systematic review, S. T. Bittar et al.

clarify these doubts related to the long-term effects of BFR over bone diseases. Furthermore, no methodological standardiza-
bone adaptations. tion was observed across these samples regarding exercise
The limitations of the present study include (i) the small type, intervention frequency or duration. Therefore, additional
number of articles; (ii) the lack of methodological standard- studies are needed to justify the quality of evidence regarding
ization (sample ‘n’; study design; intervention duration); and BFR studies on bone metabolism.
(iii) the divergences in the exercise protocols.

Acknowledgments
Conclusions
No financial assistance was obtained for this study.
The results of this study may assist future clinical research
with the method of RFS and bone metabolism (formation and
Conflict of interest
resorption) and show the positive effect of this technique
combined with exercise in the prevention and treatment of The authors have no conflict of interests.

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© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd