Effects of resistance training on microcirculation of bone tissue and bone turnover markers in postmenopausal women with osteopenia or osteoporosis: A systematic review

Abstract

After menopause, there is an imbalance between bone formation and resorption activity, which could lead to postmenopausal osteopenia or osteoporosis. Resistance training (RT) can induce mechanical stress on bone which is necessary for bone remodeling and angiogenic-osteogenic response. This systematic review aims to assess the effects of RT on bone microcirculation and bone turnover markers (BTMs) in postmenopausal women with osteopenia or osteoporosis.

We conducted a comprehensive search for related studies published up to April 2023 to identify eligible articles. Out of 316 articles identified, the full texts of 69 articles were screened. There is not any study which consider the effect of resistance exercises on bone microcirculation in PMOP women, but four articles aseess the effect of RT on BTMs and were reviewed. The quality of the articles was assessed by using the Physiotherapy Evidence Database (PEDro) scale.

In one study, after 6 and 12 months of RT, bone formation and bone resorption biomarkers decreased not significantly. According to another study, bone formation and resorption biomarkers increased significantly after 3-months RT. Two other studies reported increases in biomarkers of bone formation along with decreases of biomarkers in bone resorption after 6-months of RT, but these were not significant.

However, these results suggest that RT had some beneficial effects on BTMs but it is not an effective tool for modifying BTMs in women with osteoporosis or osteopenia. This may be due to the site-specific skeletal stimulation that RT provides. In addition considering the effect of RT on microcirculation of bone are important. So, there is a need for further, high-quality studies in this field.

Keywords

Resistance training microcirculation of bone tissue bone turnover markers osteopenia osteoporosis postmenopausal women

1 Introduction

According to the World Health Organization (WHO), osteoporosis is defined as a bone mineral density (BMD) >2.5 standard deviations below the mean normal value, and osteopenia is defined as a BMD between 1 and 2.5 standard deviations below the mean normal value. Postmenopausal women account for 80% of patients with osteoporosis and osteopenia [1, 2]. After menopause, bone resorption exceeds bone formation throughout the menopausal transition, with a decrease in serum estradiol and estrone levels. Increased bone resorption, could lead to an increased risk of bone fracture. In addition to causing disabilities and high medical costs, these fractures may even lead to mortality [3, 4].

Exercise has been reported to improve bone health due to the mechanical load sensitivity of bones. Weight-bearing exercises (such as hopping or jogging) and progressive resistance training, alone or in combination with each other, are beneficial in stimulating and promoting osteogenic responses in bone [5, 6]. Resistance training involves different muscle contractions (isotonic, isokinetic, and isometric) against different resistances (i.e., free weight, weight machines, medicine balls, elastic bands, and different movement velocities) to improve fitness, health, and sports performance. The optimal bone response to resistance training occurs when muscle contraction encounters progressive resistance during dynamic activity [6, 7]. The effect of resistance training on BMD in postmenopausal women with osteoporosis has been assessed by the dual X-ray absorptiometry (DXA), and findings revealed different results depending on the duration of exercise [8, 9]. Also, contrast enhanced ultra-sonography or [18F]-positron emission tomography can be used to assess bone microcireculation [10, 11].

Some researchers found that the blood supply in people with osteoporosis or osteopenia is relatively lower than in the people with normal bone mass, and indicating that bone blood supply and bone mineral density are highly correlated [12, 13]. Furthermore, enhancing bone microcirculation, especially capillarization in the bone microenvironment, is essential for bone growth and development and the preservation of normal bone health [14, 15].

Bone turnover markers (BTMs) are indicators of bone remodelling process [16, 17]. Some blood and urine molecules have been identified as BTMs in detecting bone turnover dynamics. These molecules are ideal means to assess the true metabolic status of the bone and are sensitive to either short-term or long-term therapeutic intervention periods [18, 19]. BTMs fall in the categories of bone formation and bone resorption; the former are direct or indirect products of active osteoblasts, secreted by osteoblasts at different stages with different characteristics of osteoblast function and bone growth. Researchers measure all bone formation markers using blood serum. The majority of the bone resorption markers are the product of bone collagen degradation, and their levels are detected in blood serum and urine [4, 20]. The possible variation in the concentration of BTMs may indicate the status of bone metabolism; therefore, their use continues to expand [21, 22].

Among the beneficial effects of resistance training on bone health, little is known about the effect of resistance training on microcirculation of bone tissue and bone turnover markers. Indeed, some authors have argued that exercises may have no effect on BTMs. Since, under typical circumstances, any increase in bone formation is accompanied by an increase in bone loss [23, 24]. Monitoring BTMs in clinical practice may help to elucidate physiological mechanism responsible for the osteogenic effect of therapeutic intervention. So, this systematic review aims to investigate the effectiveness of resistance training on microcirculation of bone tissue and BTMs in postmenopausal women with osteopenia or osteoporosis.

2 Methods

2.1 Searching method

The present study is based on a comprehensive review of the effects of resistance training on BTMs in postmenopausal women with osteopenia or osteoporosis. This systematic review strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. The study is registered in PROSPERO, the international prospective register of systematic reviews (ID CRD42023411238).

We searched the three electronic databases, PubMed, Scopus and Web of Science, to identify potentially relevant published studies. The primary search was performed in April 2023 and updated in December 2023. To identify the appropriate keywords, postmenopausal osteoporosis women, resistance exercise, microcirculation of bone tissue and bone turnover were searched in the Medical Subject Heading (MeSH), and their synonyms were used for database searching. The selected keywords consist of: (“Osteoporosis Postmenopausal” OR “Post-Menopausal Osteoporoses” OR “Post-Menopausal""Osteoporosis” OR “Postmenopausal Osteoporoses” OR “Perimenopausal Bone Losses” OR “Postmenopausal Bone Loss”) AND (“Resistance Training” OR “Strength Training” OR “Weight-Lifting Strengthening Program” OR “Weight-Lifting Exercise Program” OR “Weight-Bearing Strengthening Program” OR “Weight-Bearing Strengthening Program” OR “Weight-Bearing Exercise Program” OR “Circuit weight training”) AND (“Microvascular Blood Flow” OR “Blood Flow, Microvascular” OR “Flow, Microvascular Blood” OR “Microvascular Blood Flows” OR “Microvascular Circulation” OR “Circulation, Microvascular” OR “Microvascular Circulations”) AND (“Remodeling, Bone” OR “Bone Turnover” OR “Bone Turnovers” OR “Turnover, Bone” OR “Bone Turnover Markers”).

2.2 Selection of studies

The two authors (F.S. and H.CH.) of this review first independently screened the titles and abstracts of all selected primary research articles; next, they reviewed the full texts to determine inclusion and exclusion criteria, then provided a list of possible relevant studies, and finally critically appraised the selected studies using the Physiotherapy Evidence Database (PEDro).

2.3 Inclusion/exclusion criteria

Inclusion criteria: a) the published randomized control trials (RCTs) in any language that report the effect of resistance training on bone turnover markers; b) with at least one resistance training group as an intervention vs. a control group with no exercise, with sham exercise, or with other intervention; c) women with postmenopausal osteopenia or osteoporosis status based on the BMD report at baseline; d) intervention of at least four weeks; and e) the BTMs (bone-specific biomarkers) or bone microcirculation reported as outcome measures at baseline or follow-up assessment(s).

Exclusion criteria: a) mixed sex subjects; b) women undergoing hormone therapy, chemotherapy, and/or radiotherapy; c) double or multiple publications one of a study and preliminary data from subsequently published studies; and d) review articles, case reports, editorials, conference abstracts, and letters were not considered.

2.4 Data extraction

For this purpose, a data extraction form was developed that included the publication characteristics, methodology (e.g., design, blinding, sample size), participant characteristics (e.g., age, weight, BMD), exercise characteristics (e.g., frequency, intensity, and duration, progression), outcome measures, and final results.

2.5 Outcome measures

The change in bone microcirculation (capillarization of tissue or blood flow) or bone turnover biomarkers (BTMs), were the outcome of this study.

2.6 Quality assessment

The selected articles were clinically appraised using the Physiotherapy Evidence Database PEDro scale and the quality of each study was scored [25, 26]. During the consensus meeting, the authors resolved any disputes and determined the final scores. The methodological quality of the selected studies was graded on the PEDro scale as ≥7 = high, 5-6 = moderate and 5< = low. Table 1 presents the tabulated details of the quality score for the selected studies.

Table 1
Quality assessment of included articles based on the PEDro Scale

Item Study ID

Waltman et al. Linero et al. Mosti et al. Basat et. al

Eligibility criteria Yes Yes Yes Yes

Random allocation Yes Yes Yes Yes

Allocation concealment Yes No No No

Intergroup homogeneity Yes Yes Yes Yes

Blinding subjects No No No No

Blinding therapist No No No No

Blinding assessor No No No No

Participants >85% allocation No No No No

Intention to treat analysis Yes No No No

Between-group comparison Yes Yes Yes Yes

Point measures and measures of variability Yes Yes Yes Yes

Total score 7 5 5 5

Item	Study ID
Eligibility criteria	Yes	Yes	Yes	Yes
Random allocation	Yes	Yes	Yes	Yes
Allocation concealment	Yes	No	No	No
Intergroup homogeneity	Yes	Yes	Yes	Yes
Blinding subjects	No	No	No	No
Blinding therapist	No	No	No	No
Blinding assessor	No	No	No	No
Participants >85% allocation	No	No	No	No
Intention to treat analysis	Yes	No	No	No
Between-group comparison	Yes	Yes	Yes	Yes
Point measures and measures of variability	Yes	Yes	Yes	Yes
Total score	7	5	5	5

2.7 Studies characteristics

From these studies, the 4 eligible studies were identified, including seven exercises, four control groups, and one bisphosphonate intervention [27 –30]. The flowchart for searching and screening is shown in Fig. 1.

Fig. 1

Flow diagram of search process according to PRISMA.

In these studies, 139 and 123 women are considered for the exercise and control groups and 91 for the bisphosphonate group. The sample size in the exercise group ranges from the 6 to 91 per group. The average BMI of all group members ranges from 22.28±1.23 to 27.5±3.7. One study followed the two parallel RCT design resistance exercise and the control groups [29]. Two other studies used three parallel RCT designs [27, 30]. One compared the effectiveness of resistance training and high-impact exercises with the control group [30]. Another compared a resistance training group, a bisphosphonates group, and a control group [27]. Another study compared four RT groups: moderate-to-high-intensity exercise (MHIRT), low-intensity blood flow restriction (LIBFR), low-intensity exercise (LIRT) and a control group [28].

Two studies included women with postmenopausal osteopenia [27, 30], and other two studies included postmenopausal women with postmenopausal osteoporosis and osteopenia [28, 29]. The studies were conducted in the USA [27], South Korea [28], Turkey [30] and Norway [29].

The baseline characteristics of the participants in the selected studies are tabulated in Table 2. Note: The selected articles are in English.

Table 2

Baseline features of the subject studies’s participants (n:4)

Author. year	Initial sample size (n)	Age Mean (SD)	BMI Mean (SD)	Osteoporosis statue
Waltman et al. (2022)	RG:92	RG:54.4(3.1)	EG:25.9(4.3)	Osteopenia
	BG:91	BG:54.3(3.3)	BG:25.2(4.3)
	CG:93	CG:54.3(3.3)	CG:25.9(5.2)
Linero et al.(2020)	MHIRG:7	MHIRT:56.43(0.72)	MHIRT:24.96(0.94)	Osteopenia and osteoporosis
	LIBFG:7	LIBFR:55.71(0.52)	LIBFR:22.5(1.02)
	LIRG:6	LIRT:56.50(0.99)	LIRT:22.5(0.97)
	CG:6	CG:56.83(0.70)	CG:22.28(1.23)
Mosti et al. (2013)	EG:10	EG:61.9(5.0)	EG:25.3(2.9)	Osteoporosis and osteopenia
	CG:11	CG:66.7(7.4)	CG:24.9(2.5)
Basat et al. (2013)	RG:14	RG:55.9(4.9)	RG:25.0(4.7)	Osteopenia
	HI:14	HI:55.6(2.9)	HI:26.4(3.5)
	CG:14	CG:56.2(4)	CG:27.5(3.7)

RG: resistance training group, BG: bisphosphonates group, CG: control group, RT: resistance training, MHIRT: Moderate to high RT, LIBFRTG: low- intensity with blood flow restriction RT, LIRT: low intensity RT, HI: High-impact.

2.8 Intervention characteristics

2.8.1 Medical intervention

All intervention and control groups in three studies had daily vitamin D and calcium supplements [27 , 30]. One study did not mention the use of supplements [28]. According to [31 –33] the consumption of risedronate as an intervention in the bisphosphonate group was considered by the researchers in [27].

2.8.2 Exercises

Table 3 presents the exercise protocol of the selected studies. The resistance training machines or free weights are applied with a focus on all or most of the major muscles. The studies were conducted over a period of 3–12 months. The training frequency in all four studies was three sessions per week. The setting of the progression of exercises is evident in all included study. The exercise program is supervised in two studies [29, 30].

Table 3
Exercise features of the selected studies (n = 4)

Author (s) (Year) Length (month) session Type of exercise, amount of exercise Resistance training intensity Progression of exercise Supervised/rest

Waltman et al. (2022) 12 months3sessions/per week Resistance exercise, (all main muscles group) on machines and with free weighted, jogging 5 min slow walking for warm-up, 6 EXS, 1-2 sets of 40% 1RM-8-12 Rep, the load will be added using a weighted vest for some exercise based on BW. progression up to 1-2 set 70–80% 1 RM 8–12 rep not supervise /2 min rest between sets

Linero et al. (2000) 3month3session/per Week Bilateral leg-press-leg extension-dumbbel biceps curl, Triceps extention 10 min warm up, for MHIRT followed by 60% 1-RM at 1st and 2nd week 3 set,10 Reps for LIBFRT, 30% of 1-RM,3 set,20 Reps Only in MHIRTG progression setting was done – 70% 1RM3rd – 4th and 80% 1RM5th – 12th W not mention /30 s rest between sets 90 s rest between each workout

Mosti et al. (2013) 4 months3sessions/per Week Resistance squat (lower extremely muscle) with squat machine 1 EXS,2 warm-up sets,8–12 Reps 50% and 4 sets 3–5 Reps,85–90% 1RM After performing >5 rep training load was increased by 2.5 kg Supervised/2-3 min rest between sets

Basat et al. (2013) 6 months3sessions/per Week Isometric resistance training, (all main muscles group) on machines 15 min warm-up, followed by 9 Isometric resistance exercises, 1 set 10 Reps. Isometric exercise will progress according to the patient’s tolerance Supervised/not mention

Author (s) (Year)	Length (month) session	Type of exercise, amount of exercise	Resistance training intensity	Progression of exercise	Supervised/rest
Waltman et al. (2022)	12 months3sessions/per week	Resistance exercise, (all main muscles group) on machines and with free weighted, jogging	5 min slow walking for warm-up, 6 EXS, 1-2 sets of 40% 1RM-8-12 Rep, the load will be added using a weighted vest for some exercise based on BW.	progression up to 1-2 set 70–80% 1 RM 8–12 rep	not supervise /2 min rest between sets
Linero et al. (2000)	3month3session/per Week	Bilateral leg-press-leg extension-dumbbel biceps curl, Triceps extention	10 min warm up, for MHIRT followed by 60% 1-RM at 1st and 2nd week 3 set,10 Reps for LIBFRT, 30% of 1-RM,3 set,20 Reps	Only in MHIRTG progression setting was done – 70% 1RM3rd – 4th and 80% 1RM5th – 12th W	not mention /30 s rest between sets 90 s rest between each workout
Mosti et al. (2013)	4 months3sessions/per Week	Resistance squat (lower extremely muscle) with squat machine	1 EXS,2 warm-up sets,8–12 Reps 50% and 4 sets 3–5 Reps,85–90% 1RM	After performing >5 rep training load was increased by 2.5 kg	Supervised/2-3 min rest between sets
Basat et al. (2013)	6 months3sessions/per Week	Isometric resistance training, (all main muscles group) on machines	15 min warm-up, followed by 9 Isometric resistance exercises, 1 set 10 Reps.	Isometric exercise will progress according to the patient’s tolerance	Supervised/not mention

EXS: exercise, 1RM:one-Repetition Maximum, BW: Body-weight, min: minute, Reps: repetitions, MHIRT: Moderate to high resistance training, LIBFRT: low intensity with blood flow restriction.

2.8.3 Outcome measurement and results for biomarkers

The five bone biomarkers: 1) bone-specific alkaline phosphatase (BSALP), 2) procollagen type 1 N-terminal propeptide (P1NP), 3) osteocalcin (OC) as a bone formation biomarker, 4) carboxy-terminal cross-linked telopeptide of type 1 collagen (CTX) and 5) N-terminal telopeptide of type 1 collagen (NTX), as bone resorption biomarker. Only in one study [30], a 5-day delay exists between the end of the intervention and the BTMS assessed, while the same is assessment in the morning after an overnight fast [28, 29].

CTX and P1NP were assessed in two studies [28, 29]. In both studies, P1NP (as a bone formation biomarker) increased after RT; this increase was significant in the MHIRT and the LIBFR subgroups in [28], but it was not significantly increased in [29]. CTX (as a bone resorption biomarker) did not decrease significantly after RT in the study by Mosti [29] and in the LIBFR subgroup of the study by Linero et al. [28]. Surprisingly, CTX increased significantly after RT in the MHIRTG subgroup of the Linero et al. study [28]. The other common biomarker, NTX, is assessed in [27, 30], and did not decrease significantly after RT.

The volume of P1NP and CTX extracted from [28, 29] and NTX extracted from [27, 30] after RT are tabulated in Table 4 respectivly.

Table 4
Average measures of serum P1NP, CTX and NTX of studies by Mosti et al. Linero et al. Waltman et al. and Basat et al.

Study Groups P1NP(ng/ml) CTX(ng/ml)

Pre-test Post-test Pre-test Post-test

Linero et al. (2020) MHIRT 59.47(10.32) 68.70(12.24) 0.46(0.10) 0.56(0.10)

LIBFR 60.48(10.21) 67.53(9.85) 0.52(0.07) 0.46(0.06)

LIRT 57.65(10.71) 57.50(8.70) 0.40(0.05) 0.40(0.05)

CONT 66.48(7.65) 70.76(8.69) 0.58(0.10) 0.58(0.10)

Mosti et al. (2013) RG 54.25(15.36) 59.13(17.84) 0.743(0.200) 0.709(0.257)

CG 51.67(12.36) 48.50(10.45) 0.576(0.051) 0.582(0.121)

Study Groups NTX(nmol BCE/L)

Before 6-months 12-months

Waltman et al. (2023) RG 15.03(5.45) 13.36(5.83) 13.92(5.84)

BG 14.31(4.44) 10.30(3.93) 11.42(4.71)

CG 13.99(4.22) 12.16(3.84) 12.36(3.84)

Basat et al(2013) RG 31.7(6.9) 26.9(5.6)

HG 27.8(7.2) 20.3(6.1)

CG 27.8(5.2) 29.6(8.9)

Study	Groups	P1NP(ng/ml)	CTX(ng/ml)
Linero et al. (2020)	MHIRT	59.47(10.32)	68.70(12.24)	0.46(0.10)	0.56(0.10)
	LIBFR	60.48(10.21)	67.53(9.85)	0.52(0.07)	0.46(0.06)
	LIRT	57.65(10.71)	57.50(8.70)	0.40(0.05)	0.40(0.05)
	CONT	66.48(7.65)	70.76(8.69)	0.58(0.10)	0.58(0.10)
Mosti et al. (2013)	RG	54.25(15.36)	59.13(17.84)	0.743(0.200)	0.709(0.257)
	CG	51.67(12.36)	48.50(10.45)	0.576(0.051)	0.582(0.121)

RG: resistance training group, BG: bisphosphonates group, CG: control group, MHIRTG: Moderate to high Resistance training, LIBFRTG: low- intensity resistance training with blood flow restriction, LIRT: low intensity resistance training, HI: High-impact group.

Table 5

Summary of results and findings of the included studies

Author. year	Outcome measurement	Time of assessment	Main results
Waltman et al. (2022)	BSALPNTX	Before, 6th and 12th months	RG: 12-month change in BSALP was – 6/7%BG: 12-month change in BSALP was – 20/3%CG: 12-month change in BSALP was – 6/3%RG: 12-month change in NTX was – 7/0%BG: 12-month change in NTX was – 19/0%CG: 12-month change in NTX was – 9/0%Significantly decreased of BSAL and NTX in BG compare to RG and CG.
Linero et al. (2020)	P1NPCTX	Before and after three months	MHIRT: 3-month change in P1NP was +15.5%LIBFR: 3-month change in P1NP was +11.66%.LIRT: 3-month change in P1NP was – 0.2%.CG: 3-month change in P1NP was +13.3%MHIRT: 3-month change in CTX was +21.7%.LIBFR: 3-month change in CTX was – 11.5%.LIRT: 3-month change in CTX was 0%.CG:3-month change in CTX was – 0.03%CTX significantly increased in MHIRT.No significant difference was determined between the groups on post P1NP value.
Mostti et al. (2013)	P1NPCTX	Before and 6th months	RG: No significant changes occurred in the serum levels of P1NP and CTX.The ratio of P1NP/CTX increased in the RG compared to CG but not significant.
Basat et al. (2013)	OCNTX	Before and after 6th months	RG: 6-month change in OC was +31.1%.HG: 6-month change in OC was +30.2%.CG: 6-month change in OC was +4.7 %.RG: 6-month change in NTX was – 12.7%.HG: 6-month change in NTX was – 25.7%.CG: 6-month change in NTX was +8.7%.Significantly increased of OC and significantly decreased in NTX in HG compared to RG and CG.

Researchers [30], next to NTX, applied OC assessment as a bone formation at the end of 4 months of resistance training and did not find any significant increase in OC in the resistance group, while NTX decreased and OC increased significantly in the high-impact exercise group.∥Researchers [27] used BSALP as the formation biomarker and found no increase in the resistance training group after 6 and 12 months of intervention, instead they reported a slight decrease inBSALP.∥All bone biomarkers were measured using the ELISA detection method in these four included studies [27 –30].

3 Discussion

This study was designed as a systematic review to assess the effects of resistance training on bone microcirculation (capillarization of tissue or blood flow) and bone turnover biomarkers in postmenopausal women with osteopenia and osteoporosis. Many articles included in the preliminary full-text analysis from database research involving postmenopausal women without a diagnosis of osteoporosis or osteopenia [34 –37]. On the other hand there is not any study which investigated the effect of resistance training on bone microcirculation (capillarization of tissue or blood flow) in postmenopausal women with osteopenia or osteoporosis. About BTMS, In [38, 39], the total alkaline phosphatase (ALP) was already assessed; this biomarker was not appropriate as a bone-specific formation biomarker; consequently, it did not meet this inclusion criteria. The lack of an RCT design [23, 40] was another reason for excluding some articles. For the above reasons, our finding only focused on the data from four studies which consider effect of resistance training on BTMs.

About the effect of resistance training on blood flow many studies have done in rat’s bone tissue so they are not include in this studies [41 –43]. However these studies mentioned possible mechanisms of effect of resistance exercise on bone blood flow, like stimulating angiogenic-osteogenic response in bone [42] and leading to an increase in periosteal vascularity and regionsal bone area [43]. Many factors, such as Vascular endothelial growth factor (VEGF), Hypoxia-inducible factor-1 (HIF-1) and Notch ligands, which are induced by exercise could regulate proliferation and differentiation of endothelial cells and promote bone vascularization, as well as an angiogenic and osteogenic coupling in the bone local environment [44].

During resistance training, a variety of musclular forces induce an anabolic effect through mechanotransduction. The piezoelectric effect and the vascular effect are two well-known theories in this area, although the exact mechanism underlying the effect of resistance training on bone remodelling is not yet fully understood. Based on this, it is expected that resistance training will lead to stimulation of bone formation [45 –47].

In [30] an isometric resistance training programme applied for 4 months & in [29], maximal strength training (MST) for 6 months, indicated that bone formation was stimulated, as a the result of a slight decrease in bone resorption biomarkers and a slight increase in bone formation biomarkers. There were no adverse effects (AEs) associated with resistance training during the intervention periods in these two studies.

Similar to these two studies, in [28], an increase in the bone formation biomarker with a decrease in bone resorption was reported after LIBFR, in contrast, in MHIRTG, a significant increase in the bone formation biomarker and an unexpectedly significant increase in bone resorption biomarker was reported. We should mention that each group has a small sample size (<10) in thisstudy.

After 6 and 12 weeks of bone-loading exercise (combination of resistance exercises with two high-impact exercise) in the Waltman study, there was a slight decrease in the bone resorption and the bone formation biomarkers. This study reported adverse events (AEs) of the interventions without mentioning their presence in the given intervention’s bisphosphonate or resistance exercise[27].

Recently, P1NP (bone formation) and CTX (bone resorption) have been reported, to be the most specific and sensitive biomarkers for measuring bone formation and bone resorption in osteoporosis [48, 49]. Researchers in two studies have investigated these two biomarkers [28, 29].

In two other study NTX was assessed as a promising marker of bone resorption [27, 30]. There is evidence that to reduce the likelihood of fracture, interventions should concentrate on reducing the blood serum levels of NTX down to 12.6 nMBCE or below (the mean value for premenopausal) [50, 51]. This serum NTX level was not reported after resistance training in the two studies mentioned.

In addition to NTX, BSALP and OC were evaluated as bone formation biomarker [27, 30]. The BSALP biomarker was widely used as an adjunctive biomarker in managing osteoporosis. In contrast serum OC has been considered a specific biomarker of osteoblast function for the assessment of bone formation in osteoporosis. It plays an important role in metabolic regulation, bone mineralization and calcium ion homeostasis [23, 52]. The variety of the assessed biomarkers has hindered a robust evaluation of the findings so far.

Some authors have suggested that it would be better to consider a delay between the end of the intervention and the assessment of BTMs [36, 53]. This would reduce any effect of fluctuation in BTMs that might be due to their last intervention session. This delay is only considered in the research of [30].

In terms of quality assessment, 3 RCTs were rated as “moderate quality” [28 –30] and 1 as “high quality” [27]. Three studies of moderate quality did not consider intention to treat and cannot understand attribution blinding. In all four included studies, neither the therapist nor the rater were blinded. Despite these limitations, the study by Waltman et al. was considered the most relevant [27].

Most researchers reported that exercises and physical activity, are effective in modifying and improving BTMs, and introduced BTMs as a useful evaluation tool for measuring the effectiveness of exercise [17, 18]. In contrast, few articles [27, 54] reported that BTMs are more useful for measuring the effects of medication than for exercise. This is because BTMs reflect the changes in the whole skeletal system, and these studies assumed that exercises such as resistance exercises are targeted at specific skeletal sites, and their stimulation of bone metabolism is likely to be at the sites that have suffered from muscle-tendon forces. Therefore, their effectiveness is better measured by changes in bone mineral density at these sites. All of the above studies have reported significant increases in BMD.

On the other hand, the mechanism of action of drugs such as bisphosphonate appears to be different from that of exercise. Biophosphonates reduce the bone turnover rate by decreasing both formation and resorption biomarkers. In contrast, some studies have shown that resistance exercise is able to increase bone formation biomarkers while stimultaneously decreasing bone resorption biomarkers [23, 55].

However a high emphasis on the importance of doing resistance training and increasing the stimulus to reduce bone loss is suggested [5 , 56]. There is no consensus on the intensity, frequency, and setting of exercises that are optimal for women with osteopenia and osteoporosis. According to the literature, the best bone response to resistance training occurs when the muscle contraction is isotonic [56], but researchers in [30] applied the isometric muscle contraction in their RT program.

Although evidence suggested that high intensity resistance training (≥80% 1 repetition maximum (1-RM)) is superior to moderate (65≤80% 1RM) or low intensity exercise (<65% 1RM) for stimulating bone formation [57, 58]. In [29], the exercise programme started at low intensity and progressed to moderate intensity, whereas in Waltman et al. [27] and the MHIRT group in Libero et al. study, the exercise programme started at moderate intensity and progressed to high intensity. No intensity progression was considered in the low-intensity groups in the Libero et al. study [28].

Regarding exercise frequency, it is beliefed that, aside from the impact of frequency on bone, the feasibility of the exercise programme and participant compliance with the program should not be neglected. The most recent review shows that lower training frequency (<2 sessions per week) has a significantly greater impact on BMD than higher training frequency (> = 2 session per week) [8]. The frequency of resistance training in the four included studies was three sessions per week. The limited number and lack of diversity of the articles in this review precludes making any recommendations regarding the intensity or frequency of resistance exercise.

The other related consequences of osteoporosis, such as kyphotic postural changes, decreased muscle strength and balance, are important for the management of osteoporosis patients [59, 60]. Only two included studies considered these complication and reported an increae in quality of life and improvement in balance after RT [27, 30]. Therefore, in this review, the researchers are not able to assess this complication of osteoporosis as a secondary outcome.

Although there is a limited number of articles on this subject, we aim to summarize the available findings in this field. It is necessary to run more high-quality RCT studies with an enlarged sample size in this context, with a high focus on postmenopausal osteoporosis women. Future studies should considering blood flow changes after Resistence ecercise in postmenopausal women and also assess BTMs with a few days’ delay after intervention cessation and considering the most sensitive and specific bone biomarkers (P1NP, CTX,). Assessing other important complications of osteoporosis such as kyphotic postural angle, balance, fear of falling in addition to BTMs is suggested here, and finally, future systematic reviews should be avoided until more studies are conducted.

4 Conclusion

The results obtained indicate that RT had some beneficial effects on BTMs in women with osteopenia and osteoporosis. but it could not effectively improve BTMs. There is a need for further, high quality studies with using the most sensitive BTMs in this area..The limited number of studies and the different bone biomarkers assessed therein did not allow these researchers to provide a meta-analysis accordingly.

Footnotes

Acknowledgment

Appreciations are extended to the Research Deputy of Tehran University of Medical Sciences for supporting this study. This study project is financially supported by a grant from Tehran University of medical sciences (grant number: 1402-4-103-65068).

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Item	Study ID
	Waltman et al.	Linero et al.	Mosti et al.	Basat et. al
Eligibility criteria	Yes	Yes	Yes	Yes
Random allocation	Yes	Yes	Yes	Yes
Allocation concealment	Yes	No	No	No
Intergroup homogeneity	Yes	Yes	Yes	Yes
Blinding subjects	No	No	No	No
Blinding therapist	No	No	No	No
Blinding assessor	No	No	No	No
Participants >85% allocation	No	No	No	No
Intention to treat analysis	Yes	No	No	No
Between-group comparison	Yes	Yes	Yes	Yes
Point measures and measures of variability	Yes	Yes	Yes	Yes
Total score	7	5	5	5

Study	Groups	NTX(nmol BCE/L)
		Before	6-months	12-months
Waltman et al. (2023)	RG	15.03(5.45)	13.36(5.83)	13.92(5.84)
	BG	14.31(4.44)	10.30(3.93)	11.42(4.71)
	CG	13.99(4.22)	12.16(3.84)	12.36(3.84)
Basat et al(2013)	RG	31.7(6.9)	26.9(5.6)
	HG	27.8(7.2)	20.3(6.1)
	CG	27.8(5.2)	29.6(8.9)