Markers of bone turnover after 12 months of exercise in patients with chronic kidney disease 3-5: a sub-study of RENEXC – a randomized controlled trial

Markers of bone turnover after 12 months of exercise in patients with chronic kidney disease 3-5: a sub-study of RENEXC – a randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Markers of bone turnover after 12 months of exercise in patients with chronic kidney disease 3-5: a sub-study of RENEXC – a randomized controlled trial Vaida Petrauskiene¹, Matthias Hellberg¹, Philippa Svensson¹, Naomi Clyne¹ This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6785539/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Oct, 2025 Read the published version in BMC Nephrology → Version 1 posted 14 You are reading this latest preprint version Abstract Background Bone and mineral disorders are common in patients with chronic kidney disease (CKD), leading to poor quality of life, high fracture risk, and increased morbidity and cardiovascular mortality. Parathyroid hormone (PTH) and bone-specific alkaline phosphatase (bALP) are frequently used to assess bone turnover, but markers such as procollagen type I N-terminal propeptide (intact PINP) and tartrate-resistant acid phosphatase isoform 5b (TRAP5b), which reflect bone formation and resorption, may provide more specific insights into bone remodeling. This study aims to investigate the effects of balance and strength exercises on bone turnover markers in patients with CKD not undergoing kidney replacement therapy. Methods This study is a sub-analysis of the RENEXC trial, a randomized controlled exercise intervention lasting 12 months. A total of 151 CKD stage 3–5 patients were randomly assigned to either strength or balance exercise, both combined with endurance exercise. Exercise intensity was monitored using the Borg Rating of Perceived Exertion (RPE) scale. Bone turnover markers, including intact PINP and TRAP5b, were measured at baseline and after 12 months. Results After 12 months of exercise both groups significantly improved physical performance, no significant changes were observed in intact PINP or TRAP5b across the entire cohort. However, subgroup analysis revealed that women in the balance group experienced a significant reduction in TRAP5b, indicating a potential decrease in bone resorption. Additionally, both exercise groups showed an increase in the proportion of patients with TRAP5b values indicative of low bone turnover, suggesting a protective effect on bone resorption. Higher phosphate and PTH levels were associated with positive Δ intact PINP as well as positive Δ TRAP5b, while higher 25(OH)D levels were associated with negative Δ TRAP5b values. Conclusions While no significant changes in bone turnover markers were observed in the overall cohort, the results suggest that balance exercise may reduce bone resorption in women with CKD. Additionally, both strength and balance exercises appeared to diminish bone resorption as indicated by TRAP5b levels. These findings warrant further investigation into the long-term effects of exercise on bone health in CKD, with a particular focus on the mechanisms underlying these responses. Trial registration NCT02041156 at www.ClinicalTrials.gov. Date of registration January 20, 2014. Retrospectively registered. bone markers chronic kidney disease exercise procollagen type I N-terminal propeptide tartrate-resistant acid phosphatase isoform 5b Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Bone and mineral disorders are common complications in patients with chronic kidney disease (CKD) resulting in poor quality of life, high fracture risk, increased morbidity and cardiovascular mortality. Parathyroid hormone (PTH) has long been the preferred surrogate biomarker of bone turnover together with bone specific alkaline phosphatase (bALP) and is recommended for routine clinical use in the most recent Kidney Disease-Improving Global Outcomes (KDIGO) guidelines [ 1 ]. Markers of bone turnover, which are released from bone cells, could be superior in understanding bone remodelling processes in contrast to PTH, which is a regulator of bone metabolism [ 2 ]. They show acceptable diagnostic accuracy for bone turnover and in everyday clinical practice could be seen as an accessible alternative to bone biopsy, which is still considered to be the gold standard, in diagnosing renal osteodystrophy [ 2 ]. Nonetheless, bone turnover markers, which are released during the bone remodelling cycle and reflect bone remodelling rate, need to be selected with care due to decreased renal excretion in CKD. Monomeric fragments of procollagen type I N-terminal propeptide (PINP) is a reference marker of bone formation as it is released as collagen and is deposited in the bone matrix [ 3 ]. Monomeric fragments accumulate in CKD, necessitating the use of specific assays for the intact, trimeric form of PINP (intact PINP) in this specific group of patients [ 4 ]. Tartrate-resistant acid phosphatase isoform 5b (TRAP5b) is released from osteoclasts and is considered a highly specific marker of bone resorption [ 5 ]. Very few studies, mostly with small sample sizes and examining patients on dialysis, studied the relationship of exercise and changes in bone specific biomarkers and did not show significant associations [ 6 , 7 ]. Although positive effects of resistance exercise on the regulation of bone formation and resorption biomarkers in healthy subjects has been described [ 8 , 9 ], there are to our knowledge no studies which have examined the influence of exercise on changes in bone specific biomarkers in patients with CKD not on kidney replacement therapy (KRT). In a previous sub-study of RENEXC, a randomised controlled head-to-head trial examining two different exercise regimes, balance or strength both in combination with endurance exercise, during 12 months of intervention, we explored the possible effects of exercise on bone mineral density in patients with CKD stages 3 to 5 not on KRT. We showed that balance exercise seemed to be superior in maintaining and improving whole body bone mineral density compared with strength exercise [ 10 ]. We concluded that balance exercise in combination with endurance exercise appeared to influence bone metabolism processes positively in these patients. The aim of this study is to investigate the effects of balance- and strength exercise (both in combination with endurance exercise) on markers of bone metabolism in patients with CKD stages 3–5 not on KRT. Materials and Methods Study design This study is a prespecified sub-study of the RENEXC trial, a prospective randomized controlled exercise trial, with an intervention period of 12 months. There were no changes to protocol after the trial began. Complete study design and primary analysis of RENEXC data have been reported previously [ 11 ]. Some information on study design and methods is repeated here for clarity. All incident and prevalent patients at the Department of Nephrology in Lund, Skåne University Hospital with an estimated GFR < 30 ml/min/1.73m², age ≥ 18 years, all kidney diseases and any number of comorbidities were eligible for participation in the study. Orthopaedic impediment, severe neurological dysfunction, inability to understand patient information and instructions, estimated start of KRT within 12 months of study start were exclusion criteria. The study was approved by the Regional Ethical Review Board in Lund (registration number 2011/369) and adhered to the Helsinki Declaration. All participants gave informed consent prior to inclusion after having received written and oral information. Intervention 151 patients were randomised to either strength or balance exercise both together with endurance exercise. The exercises were individually prescribed, monitored by a physiotherapist, and self-administered at home or at a nearby gym. The Borg Rating of Perceived Exertion scale (RPE) was used to prescribe exercise intensity and to monitor progress [ 12 ]. The prescribed weekly exercise duration was 150 minutes, comprising 60 minutes per week of endurance exercise at a RPE of 13–15 for both groups combined with 90 minutes per week of either strength or balance exercise at a RPE of 13–17 per exercise set. All patients were tested at baseline (T0) and after 12 months (T12). Measures of physical performance were the primary outcomes. Predetermined secondary outcome was changes in non-invasive bone turnover markers. Physical performance Overall endurance was tested with the 6-minute walk test (6-MWT) [ 13 ]. Muscular endurance and fatigability in the proximal leg muscles were tested with the 30-seconds sit-to-stand test (30-STS) [ 14 ]. Balance was tested with functional reach (FR) [ 15 , 16 ]. Neuromuscular function and strength in the lower extremities were tested with isometric quadriceps strength (ISQ) [ 15 , 16 ]. Comorbidity score Comorbidity was assessed with the Davies Comorbidity Score [ 17 ] at baseline. Laboratory analyses Plasma 25 hydroxyvitamin D (25(OH)D) was analysed using liquid chromatography-mass spectrometry. Glomerular filtration rate (GFR) was measured using iohexol clearance. Calcium, phosphate, parathyroid hormone (PTH), alkaline phosphatase (ALP) were measured using standard laboratory techniques and performed at the Department of Clinical Chemistry, Laboratory Medicine Skåne, which is accredited by SWEDAC (ISO 15189:2012). Trimeric procollagen- type I N-propeptide (intact PINP, assay range 2.0-4600 µg/L) and tartrate-resistant acid phosphatase isoform 5b (TRAP5b, assay range 0.9–56 U/L) were measured with ImmunoDiagnostic System iSYS instrument (IDS, Boldon, UK). The plasma was collected fasting and stored at − 80°C. Values of intact PINP above upper limit of quantification of the assay were determined after dilution. For intact PINP the intra and inter assay variations are both at maximum 8%. For TRAcp-5b the intra and inter assay variations are both at maximum 12%. Evaluation of bone turnover markers To define between group changes after the study period Δ intact PINP and Δ TRAP5b values (T12 value – T0 value) were calculated. For more detailed analyses after the study period, we used calculated cutoffs for high and low turnover reported by Jørgensen et al [ 2 ]. Thresholds of intact PINP > 120.7 µg/L and TRAP5b > 5.05 U/L have been suggested as indicative of high bone turnover. Conversely, values of intact PINP < 49.8 µg/L and TRAP5b < 3.44 U/L are consistent with low turnover and due to their high negative predictive value, may be particularly informative for excluding high turnover states. Randomisation Patients were randomized using ProcPlan in SAS, SAS Institute Cary NC. The statistician generated the random allocation sequence, the nephrologist enrolled patients and the physiotherapist assigned participants to intervention. Patients were included and allocated sequential treatment according to a list that only the research physiotherapist had access to. Both interventions comprised endurance exercise. The difference between the treatment arms was that one group was allocated strength exercise and one group balance exercise. Statistical analyses Statistical analyses were performed using the SPSS for Windows software program version 24.0. Per-protocol analysis was employed including only patients who completed the treatment originally allocated. Variables were expressed as frequencies, percentages for discrete factors. Continuous factors are presented as means ± standard deviations or medians [minimum and maximum]. The two-tailed chi-square and Wilcoxon tests was used for categorical variables. The two-tailed Student’s t-test or Mann-Whitney test for continuous variables, according to data distribution. The paired sample T-test was used for parametric variables. For all comparisons a p value < 0.05 was considered significant. Results A total of 217 patients were screened and 151 patients were randomized. 112 patients completed the whole exercise period of whom 11 patients were excluded from this study because of missing blood samples. Consequently, results from 101 (73 men, 28 women) patients (mean age 68 ± 12.8 years) were analysed. Most of the patients were in CKD stage 4 (n = 67, 66%), 17 patients (17%) were in CDK 3 and 17 (17%) in CKD stage 5. 49 patients (37 men, 12 women) participated in the strength group, and 52 (36 men, 16 women,) in the balance group. The Consolidated Standards of Reporting Trials (CONSORT) flow diagram is presented in Fig. 1. Some clinical characteristics and laboratory data are presented in Table 1 . Table 1 Some clinical characteristics at baseline Units Strength group Balance group Whole group Age years 71 [23–84] 70 [27–87] 71 [23–87] Male n (%) 37 (76) 36 (69) 73 (72) Weight kg 83.7 ± 18.0 79.6 ± 16.7 81.6 ± 17.6 Height m 1.7 ± 0.1 1.7 ± 0.1 1.7 ± 0.1 BMI kg/m² 27.9 ± 5.2 27.0 ± 4.9 27.4 ± 5.0 Diuretics* 35 (71) 36 (70) 71 (70) PPI 14 (29) 13 (25) 27 (27) Cinacalcet 1 (2) 0 (0) 1 (1) Active vit D 28 (57) 34 (65) 62 (61) Native vit D 3 (6) 6 (12) 9 (9) Calcium based phosphate binders • Calcium carbonate • Calcium acetate 11 (23) 1 (2) 19 (37) 1 (2) 30(30) 2 (2) Non-calcium-based phosphate binders • Sevelamer • Lanthanum 6 (12) 1 (2) 1 (2) 3 (6) 7 (7) 4 (4) Malignancy 4(8) 7 (14) 11 (12) Ischemic heart disease 8 (16) 13 (25) 21 (22) Peripheral vascular disease 11 (22) 9 (17) 20 (21) Left ventricular dysfunction 4 (8) 6 (12) 10 (10) Diabetes mellitus 15 (31) 10 (19) 25 (26) Systemic collagen vascular disease 3 (6) 5 (10) 8 (8) Other (e.g. hypertension) 33 (67) 38 (73) 71 (74) Data are presented as mean ± SD or median [minimum- maximum]. BMI- body mass index, PPI- proton pump inhibitors, vit D- vitamin D. * 9 patients received hydrochlorothiazide, all others received loop diuretics. Whole group The effects of 12 months of exercise on physical performance have been presented in detail previously and shall not be repeated here. Both groups improved overall endurance (6MWT), muscular endurance(30-STS), strength (IQS) and balance (FR) significantly, with no between group differences [ 10 , 11 ]. No significant differences were observed in values of intact PINP (T0: 75 [22–414] vs T12: 72 [19–257], p = 0.797) and TRAP5b (T0:1.9 [0.9–2.54] vs T12:1.8 [0.9–7.4], p = 0.072) after the 12-month study period in the whole group. Values of intact PINP and TRAP5b are statistically significantly lower (p = 0.001) compared with values reported earlier by Jørgensen et al [ 2 ]. The strength group showed a non-significant increase in intact PINP (T0: 71.8 [21.8-169.5] and T12:79.7 [26.8-174.2], p = 0.20) and non-significant decrease in TRAP5b (T0: 2.2 [0.9–7.1] and T12: 1.9 [0.9–4.7], p = 0.26). The balance group showed a non-significant decrease in intact PINP value (T0: 80.8 [23.8-413.6] and T12: 63.8 [19.1-256.9], p = 0.15) and no change in TRAP5b (T0: 1.60 [0.9–9.4] and T12: 1.7 [0.9–7.4], p = 0.16). When stratified for CKD stage, patients with CKD stage 3 in the strength group showed a significant decrease in TRAP5b after 12 months of exercise (Table 2 ). Women in the balance group had a significant decrease in TRAP5b after the study period (Table 3 ). Table 2 Bone markers at baseline (T0) and after 12 months of exercise (T12) stratified for CKD stages Strength group Balance group Whole group T0 T12 P T0 T12 P T0 T12 P Intact PINP (pg/mL) CKD 3 51 [22–170] 83 [40–151] 0.18 61 [39–156] 90 [60–124] 0.90 55 [22–170] 84 [40–150] 0.40 CKD 4 76 [32–120] 75 [27–174] 0.56 84 [26–414] 64 [19–257] 0.25 76 [22–414] 70 [19–257] 0.84 CKD 5 74 [33–114] 80 [38–160] 0.89 52 [23–345] 56 [25–247] 0.67 80 [24–345] 72 [25–247] 0.79 TRAP5b (U/L) CKD 3 2.1 [0.9–7.1] 1.6 [0.9–3.0] 0.04 3.4 [1.3–9.4] 2.4 [0.9–7.4] 0.50 2.9 [0.9–7.1] 2.0 [0.9–7.4] 0.89 CKD 4 2.2 [0.9–6.0] 2.2 [1.0–4.1] 0.53 1.6 [0.9–5.7] 1.7 [0.9–2.1] 0.40 1.8 [0.9–9.4] 1.8 [0.9–4.3] 0.158 CKD 5 2.4 [0.9–4.7] 1.1 [0.9–4.7] 0.18 1.3 [0.9–4.1] 1.5 [0.9–2.7] 0.67 2.0 [0.9–5.7] 1.5 [0.9–4.7] 0.18 Data are presented as median [minimum- maximum]. Intact PINP- N-terminal propeptide of type I procollagen, intact, TRAP5b - tartrate-resistant acid phosphatase 5b, CKD- chronic kidney disease. Table 3 Bone markers at baseline (T0) and after 12 months of exercise (T12) stratified for sex Strength group Balance group Whole group T0 T12 P T0 T12 P T0 T12 P Intact PINP (pg/mL) Female 75 [22–169] 70 [31–174] 0.79 84 [24–414] 64 [19–124] 0.06 83 [22–414] 65 [1.9–174] 0.09 Male 70 [22–125] 82 [27–162] 0.10 69 [26–399] 64 [22–257] 0.58 70 [22–399] 74 [22–257] 0.47 TRAP5b (U/L) Female 1.9 [0.9–7.1] 1.6 [1–4.1] 0.45 2.2 [1–9.4] 1.7 [0.9–2.8] 0.03 2.1 [0.9–9.4] 1.6 [0.9–4.1] 0.03 Male 2.3 [0.9–6.0] 2.0 [0.9–4.7] 0.33 1.5 [0.9–5.7] 1.7 [0.9–7.4] 0.90 1.8 [0.9–6.0] 1.8 [0.9–7.4] 0.59 Data are presented as median [minimum- maximum]. Intact PINP- N-terminal propeptide of type I procollagen, intact, TRAP5b - tartrate-resistant acid phosphatase 5b. There were no overall significant between group differences for Δ intact PINP or Δ TRAP5b. Δ intact PINP was positive in the strength group and negative in the balance group (12.8 [-89-112] vs -5.9 [-349-152], p = 0.07). Δ TRAP5b showed a slight negative trend in both groups (-0.1 [-5.5-2.6] vs -0.3 [-6.6-3.7], p = 0.82). Significantly higher levels of phosphate and parathyroid hormone after 12 months were observed in patients with positive Δ intact PINP as well as positive Δ TRAP5b. Higher 25(OH)D was observed in participants with negative Δ TRAP5b values (Table 4 ). No differences were observed in prescription of active vitamin D in patients with positive vs negative Δ intact PINP (59% vs 65% accordingly, p = 0.66). There were no statistically significant differences in frequency of prescription of active vitamin D in patients with negative vs positive Δ TRAP5b values in either group (65% vs 60%, p = 0.66). Proportion of values of intact PINP that could indicate a high bone turnover (intact PTH > 120.7 µg/L) showed a tendency to increase in the strength group (T0: 4% vs T12: 14%, p = 0.54) and decrease in the balance group (T0: 27% vs T12: 10%, p = 0.07) but did not reach statistical significance. Figures 2 and 3. Proportion of TRAP5b values that could show congruence with low bone turnover (TRAP5b < 3.44 U/L) increased significantly in both groups: strength group (T0: 79% vs T12: 91%, p = 0.03) and balance group (T0: 80% vs T12: 94%, p = 0.05). Figures 4 and 5. Table 4 Changes in some laboratory analyses according to changes in delta values of measured markers of bone turnover T0 T12 P Δ intact PINP decreased P-calcium (mmol/L) 2.3 ± 0.1 2.3 ± .0.1 0.44 P-phosphate (mmol/L) 1.2 ± 0.2 1.2 ± 0.2 0.47 P-PTH (pmol/L) 11 [3–135] 13.5 [1.7–59] 0.25 P-ALP (µkat/L) 1.4 ± 0.5 1.3 ± 0.3 0.17 P-25(OH)D (nmol/L) 59.2 ± 25 66.8 ± 30 0.14 Δ intact PINP increased P-calcium (mmol/L) 2.3 ± 0.1 2.3 ± 0.1 0.21 P-phosphate (mmol/L) 1.1 ± 0.2 1.2 ± 0.3 0.01 P-PTH (pmol/L) 11 [2.6–26] 11 [1.8–36] 0.03 P-ALP (µkat/L) 1.3 ± 0.5 2.4 ± 6.6 0.3 P-25(OH)D (nmol/L) 68.4 ± 26 71.9 ± 28 0.35 Δ TRAP5b decreased P-calcium (mmol/L) 2.3 ± 0.1 2.3 ± 0.1 0.99 P-phosphate (mmol/L) 1.2 ± 0.2 1.1 ± 0.23 0.62 P-PTH (pmol/L) 11 [4–133] 12 [1.7–48] 0.30 P-ALP (µkat/L) 1.3 ± 0.4 2.2 ± 6.1 0.33 P-25(OH)D (nmol/L) 62.0 ± 28 69.3 ± 27.0 0.03 Δ TRAP5b increased P-calcium (mmol/L) 2.3 ± 0.1 2.3 ± 0.1 0.70 P-phosphate (mmol/L) 1.1 ± 0.2 1.2 ± 0.3 0.02 P-PTH (pmol/L) 11 [2.6–45] 12.5 [3.5–59] 0.01 P-ALP (µkat/L) 1.4 ± 0.5 1.4 ± 0.4 0.99 P-25(OH)D (nmol/L) 64.8 ± 21.9 68.2 ± 31.1 0.55 Data presented as mean ± SD or median with minimal - maximal values. P- plasma, PTH– parathyroid hormone, ALP- alkaline phosphatase, 25(OH)D- 25 -hydroxy-vitamin D, Intact PINP- N-terminal propeptide of type I procollagen, intact, TRAP5b - tartrate-resistant acid phosphatase 5b Discussion To the best of our knowledge, this is the first study to investigate possible effects of exercise on bone markers representing bone formation and resorption. Neither the balance- nor the strength group showed any significant differences for Δ intact PINP nor Δ TRAP5b after the 12-month exercise period. However, when examining the results by subgroup, women in the balance group had a significant decrease in TRAP5b, indicating that balance exercise could have a positive effect on decreasing bone resorption in women with CKD. Few studies have examined changes in bone specific markers in relation to exercise. All of them were observational, only comprising patients on hemodialysis and were of small sample size [ 6 , 7 ]. No study found changes in bone specific markers after exercise despite finding effects on bone mineral density. Although, in a study in young healthy males Fujimura et al showed that resistance exercise increased markers of bone formation, while it transiently suppressed a marker of bone resorption [ 18 ]. A notable finding was the significant increase in the proportion of TRAP5b values consistent with low bone turnover (TRAP5b < 3.44 U/L) in both the strength and balance groups. This increase suggests that both interventions may have effectively contributed to reducing bone resorption. Our results are in line with the findings of studies in healthy men or patients with osteoporosis linking exercise to increased markers of bone formation, while transiently suppressing a marker of bone resorption [ 18 , 21 ]. Low bone turnover is typical in the early stages of CKD and slowly proceeds to high turnover in the later stages of CKD. Thus, our findings showing an increase in TRAP5b values, which are consistent with low turnover, could be considered a sign of a protective effect of exercise from a bone perspective. The positive relationship between phosphate and PTH both with Δ intact PINP and Δ TRAP5b could suggest that in the presence of increasing phosphate and PTH, bone turnover increases, potentially reflecting a shift towards high-turnover bone disease. This is especially notable as the patients in this study had phosphate values within reference values and acceptable levels of PTH. Findings from the literature on this subject are not uniform. Direct effects of PTH on osteoblasts and osteocytes and indirect actions on osteoclasts promote both bone formation and bone resorption. Bone resorption predominates in response to continuous exposure to high levels of circulating PTH [ 22 ]. A previous study has reported that higher phosphate levels may induce osteoblast apoptosis and reduce bone formation as well as inhibit bone resorption [ 23 ]. One could speculate that this direct effect of high phosphate could be ameliorated by an indirect stimulating effect on PTH secretion as well as suppressing 1-alpha-hydroxylase activity contributing to calcitriol deficiency [ 23 ]. On the other hand, a recent study in patients on hemodialysis revealed that high serum phosphate was consistently associated with an increased risk of bone fractures, regardless of other factors such as previous fractures, age, sex, time on hemodialysis, serum calcium and PTH [24]. According to our data, increasing 25(OH)D levels could be associated with a decrease in the bone resorptive process. It is notable that despite a significant increase in 25(OH)D levels after 12 months the recommended levels of 75nmol/L were not reached. Direct effects of vitamin D on bone include activities on both formation and resorption. Conflicting data suggest that these actions may differ by skeletal site and dietary calcium intake [25]. In the case of a sufficient calcium supply, vitamin D and its metabolites can improve calcium balance and facilitate mineral deposition in bone matrix largely without direct effects on bone cells, although some beneficial effects may occur via mature osteoblasts, as demonstrated in mice with osteoblast-specific overexpression of VDR or 1α-hydroxylase [25]. In the setting of calcium deficiency, however, calcitriol enhances bone resorption, whereas simultaneously inhibiting bone mineralization, to maintain serum calcium homeostasis at the expense of bone mass [25]. The levels of both markers in our study are significantly lower compared with the levels presented by Jørgensen et al [ 2 ]. Salam et al reported higher TRAP5b levels but similar levels of intact PINP levels as in our study [ 19 ]. These differences can at least partly be explained by differences in study population. In Jørgensen’s et al study 18% of the patients were in CKD stages 4–5, the rest were on KRT [ 2 ]. In Salam’s et al study 63% of the patients were in stages 4–5 of CKD and 27% were on KRT [ 19 ]. Salam and al have also showed that patients with CKD had significantly higher marker levels compared with controls which could not only be explained by accumulation due to decreased kidney function as both the markers tested are known not to be influenced by decreased excretion. One could speculate that there are different patterns of bone turnover as CKD progresses. Evidence suggests that in the early stages of CKD, low bone turnover is often the earliest detectable alteration in bone remodelling. [ 20 ]. This may be due to a predominance of factors that inhibit bone turnover, such as resistance to PTH, low calcitriol levels, sex hormone deficiency, diabetes, and uremic toxins. These factors contribute to the suppression of osteocyte Wnt/b-catenin signalling and the increased expression of Wnt antagonists like sclerostin, Dickkopf-1, and sFRP4. High turnover bone disease typically emerges at later stages of CKD, when serum PTH levels can overcome peripheral PTH resistance and other inhibitors of bone formation [ 20 ]. There are several strengths in this study. The participants represent a typical cohort of patients with CKD stages 3 to 5 not on KRT and, to our knowledge, this is the first study to compare effects of strength versus balance exercise on bone specific markers in patients with CKD not on KRT. Patients maintained levels for calcium and phosphate within the reference values. This study also has limitations such as the absence of a sedentary control group, but the reasons for that have been discussed and explained previously [ 10 ]. Additionally, the short follow-up period could be considered a significant limitation as the intervention that lasted 12 months is acceptable for investigating effects of exercise in patients with CKD but may be insufficient to capture meaningful changes in bone metabolism in this group. Bone remodelling is a slow process, and longer observation periods are likely necessary to detect significant shifts in bone metabolism reflecting markers. Moreover, we were unable to examine bALP, a key marker of bone formation and skeletal mineralization which limits the comprehensiveness of the bone status assessment. This limitation at least partly was compensated by analysis of total ALP which did not reveal any significant differences. In conclusion, while 12 months of exercise did not produce significant overall changes in bone turnover markers across the whole group or in either of the exercise groups, women in the balance group, showed significant reductions in TRAP5b indicating decreased bone resorption. The mechanism and the importance of this finding remains elusive necessitating further studies for elucidation. Further studies are also needed to explore the finding that the proportion of patients whose TRAP5b value could be consistent with low turnover increased in both exercise groups after 12 months of exercise. Associations of increasing phosphate and PTH with changes in bone turnover markers as well as effects of vitamin D were interesting but require more detailed study. While no significant changes in bone turnover markers were observed in the overall cohort, the results suggest that balance exercise may reduce bone resorption in women with CKD. Additionally, both strength and balance exercises appeared to diminish bone resorption as indicated by TRAP5b levels. These findings warrant further investigation into the long-term effects of exercise on bone health in CKD, with a particular focus on the mechanisms underlying these responses. Abbreviations CKD - Chronic Kidney Disease PTH - Parathyroid Hormone bALP - Bone Specific Alkaline Phosphatase KDIGO - Kidney Disease-Improving Global Outcomes PINP - Procollagen Type I N-terminal Propeptide TRAP5b - Tartrate-Resistant Acid Phosphatase Isoform 5b KRT - Kidney Replacement Therapy RENEXC – RENal EXerCise RPE - Borg Rating of Perceived Exertion 6-MWT - 6-Minute Walk Test 30-STS - 30-Seconds Sit-to-Stand Test FR - Functional Reach ISQ - Isometric Quadriceps Strength GFR - Glomerular Filtration Rate ALP - Alkaline Phosphatase SWEDAC - Swedish Board for Accreditation and Conformity Assessment 25(OH)D - Plasma 25-Hydroxyvitamin D SPSS - Statistical Package for the Social Sciences CONSORT - Consolidated Standards of Reporting Trials ISO - International Organization for Standardization Declarations Acknowledgements For practical assistance, we would like to thank kidney failure nurses Carina Holmesson and Marianne Liljenborg, medical secretary Ann-Charlotte Malmberg and biomedical analyst Åsa Pettersson. Conflict of interest statement None declared. The results presented in this paper have not been published previously in whole or part. Authors contribution Research idea and study design: VP, NC, MH, data acquisition: MH, PS, data analysis and interpretation: VP, statistical analysis: VP, supervision and mentorship: NC. Each author contributed important intellectual content during manuscript drafting and revision and accepts accountability for the overall work. Funding This study was supported by grants from Birgit and Sven-Håkan Ohlsson’s Trust, Skåne University Hospital’s Research Foundation, the Kidney Trust (Njurstiftelsen), the Swedish Society of Nephrology, the Southern Health Care Region in Sweden and Anna-Lisa and Sven Eric Lundgren’s Trust. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This randomized controlled trial is registered as NCT02041156 at www.ClinicalTrials.gov approved by the Regional Ethical Review Board in Lund (Ref 2011/369) and adheres to the Helsinki declaration. All patients received written and oral information and have given written informed consent. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Ketteler M, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and why it matters. Kidney Int. 2017;92(1):26–36. 10.1016/j.kint.2017.04.003 . Jørgensen HS, Behets G, Viaene L, Bammens B, Claes K, Meijers B, Naesens M, Sprangers B, Kuypers D, Cavalier E, D'Haese P, Evenepoel P. Diagnostic accuracy of noninvasive bone turnover markers in renal osteodystrophy. Am J Kidney Dis. 2022;79(5):667–e6761. 10.1053/j.ajkd.2021.07.027 . Koivula MK, Risteli L, Risteli J. Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem. 2012;45(12):920–7. 10.1016/j.clinbiochem.2012.03.023 . Melkko J, Hellevik T, Risteli L, Risteli J, Smedsrød B. Clearance of NH2-terminal propeptides of types I and III procollagen is a physiological function of the scavenger receptor in liver endothelial cells. J Exp Med. 1994;179(2):405–12. 10.1084/jem.179.2.405 . Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Väänänen HK. Tartrate-resistant acid phosphatase 5b: A novel serum marker of bone resorption. J Bone Miner Res. 2000;15(7):1337–43. 10.1359/jbmr.2000.15.7.1337 . Morishita Y, Kubo K, Miki A, Ishibashi K, Kusano E, Nagata D. Positive association of vigorous and moderate physical activity volumes with skeletal muscle mass but not bone density or metabolism markers in hemodialysis patients. Int Urol Nephrol. 2014;46(3):633–9. 10.1007/s11255-014-0662-9 . Ota S, Takahashi K, Taniai K, Makino H. Bone metabolism and daily physical activity in women undergoing hemodialysis. Nihon Jinzo Gakkai Shi. 1997;39(4):441–6. Maïmoun L, Sultan C. Effects of physical activity on bone remodeling. Metabolism. 2011;60(3):373–88. 10.1016/j.metabol.2010.03.001 . Fujimura R, Ashizawa N, Watanabe M, Mukai N, Amagai H, Fukubayashi T, Hayashi K, Tokuyama K, Suzuki M. Effect of resistance exercise training on bone formation and resorption in young male subjects assessed by biomarkers of bone metabolism. J Bone Miner Res. 1997;12(4):656–62. 10.1359/jbmr.1997.12.4.656 . Petrauskiene V, Hellberg M, Svensson P, Zhou Y, Clyne N. Bone mineral density after exercise training in patients with chronic kidney disease stages 3 to 5: A sub-study of RENEXC - a randomized controlled trial. Clin Kidney J. 2023;17(1):sfad287. 10.1093/ckj/sfad287 . Hellberg M, Hoglund P, Svensson P, et al. Randomized controlled trial of exercise in CKD: The RENEXC Study. Kidney Int Rep. 2019;4(7):963–76. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377–81. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med. 1998;158(5):1384–7. Csuka M, McCarty DJ. Simple method for measurement of lower extremity muscle strength. Am J Med. 1985;78(1):77–81. Hellberg M, Wiberg EM, Simonsen O, et al. Small distal muscles and balance predict survival in end-stage renal disease. Nephron Clin Pract. 2014;126(3):116–23. Wiberg E, ZE. Bedømning av funktionell kapacitet hos njursjuka-reliabilitetsprøving av ett testbatteri. Nordisk Fysioterapi. 1997;1(3):127. Davies SJ, Phillips L, Naish PF, et al. Quantifying comorbidity in peritoneal dialysis patients and its relationship to other predictors of survival. Nephrol Dialysis Transplantation. 2002;17(6):1085–92. Fujimura R, Ashizawa N, Watanabe M, Mukai N, Amagai H, Fukubayashi T, Hayashi K, Tokuyama K, Suzuki M. Effect of resistance exercise training on bone formation and resorption in young male subjects assessed by biomarkers of bone metabolism. J Bone Miner Res. 1997;12(4):656–62. Salam S, Gallagher O, Gossiel F, Paggiosi M, Khwaja A, Eastell R. Diagnostic accuracy of biomarkers and imaging for bone turnover in renal osteodystrophy. J Am Soc Nephrol. 2018;29(5):1557–65. 10.1681/ASN.2017050584 . Drüeke TB, Massy ZA. Changing bone patterns with progression of chronic kidney disease. Kidney Int. 2016;89(2):289–302. 10.1016/j.kint.2015.12.004 . Marini S, Barone G, Masini A, Dallolio L, Bragonzoni L, Longobucco Y, Maffei F. The effect of physical activity on bone biomarkers in people with osteoporosis: A systematic review. Front Endocrinol (Lausanne). 2020;11:585689. 10.3389/fendo.2020.585689 . Evenepoel P, Bover J, Ureña Torres P. Parathyroid hormone metabolism and signaling in health and chronic kidney disease. Kidney Int. 2016;90(6):1184–90. 10.1016/j.kint.2016.06.041 . Fusaro M, Holden R, Lok C, Iervasi G, Plebani M, Aghi A, Gallieni M, Cozzolino M. (2021). Phosphate and bone fracture risk in chronic kidney disease patients. Nephrology Dialysis Transplantation , 36(3), 405–412. DOI: [10.1093/ndt/gfz196](https. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6785539","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":470606044,"identity":"12a75542-6ef1-41af-8378-d9942bf18d3f","order_by":0,"name":"Vaida Petrauskiene¹","email":"data:image/png;base64,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","orcid":"","institution":"Lund University","correspondingAuthor":true,"prefix":"","firstName":"Vaida","middleName":"","lastName":"Petrauskiene¹","suffix":""},{"id":470606045,"identity":"5099bc0f-bae2-4a71-867d-50c2b5dd0be5","order_by":1,"name":"Matthias Hellberg¹","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Hellberg¹","suffix":""},{"id":470606046,"identity":"35b5ac03-c9f4-4f91-a613-c7e42fb2e346","order_by":2,"name":"Philippa Svensson¹","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Philippa","middleName":"","lastName":"Svensson¹","suffix":""},{"id":470606047,"identity":"f57fccd6-5234-47f5-8dc3-128b381895e1","order_by":3,"name":"Naomi Clyne¹","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Naomi","middleName":"","lastName":"Clyne¹","suffix":""}],"badges":[],"createdAt":"2025-05-30 14:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6785539/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6785539/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04501-9","type":"published","date":"2025-10-13T15:58:36+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84818707,"identity":"0624c63a-8578-4f00-b599-8e34cc12c45d","added_by":"auto","created_at":"2025-06-17 15:54:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18563,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6785539/v1/bf916b9b0471f84097fb66e3.png"},{"id":84818661,"identity":"ffbbf9f1-fa50-40a6-9a65-06b55b60a412","added_by":"auto","created_at":"2025-06-17 15:53:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12747,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of intact PINP levels after 12 months of exercise in the strength group\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6785539/v1/f5e5cdf3cf828762a0df2c37.png"},{"id":84818666,"identity":"27d89d56-028c-4cb6-8738-f57d5de22b45","added_by":"auto","created_at":"2025-06-17 15:53:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13135,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of intact PINP levels after 12 months of exercise in the balance group\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6785539/v1/527f47609f478b65a754eb9f.png"},{"id":84818665,"identity":"10b5872f-1f41-4952-9b04-f88f60ca7273","added_by":"auto","created_at":"2025-06-17 15:53:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":12402,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of TRAP5b levels after 12 months of exercise in the strength group\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6785539/v1/1493f539bc5d1e0a92e29899.png"},{"id":84818695,"identity":"c570b2c3-000f-4876-b6ed-c71d7e713a4a","added_by":"auto","created_at":"2025-06-17 15:54:00","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":11746,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of TRAP5b levels after 12 months of exercise in the balance group\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6785539/v1/970aa7565052578e8f61f54b.png"},{"id":93956076,"identity":"739405a6-ee4e-47ad-93a1-f9a8ade5cd4e","added_by":"auto","created_at":"2025-10-20 16:10:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":946649,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6785539/v1/f11cb00d-0a79-439d-9ab3-752e3ff5a602.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Markers of bone turnover after 12 months of exercise in patients with chronic kidney disease 3-5: a sub-study of RENEXC – a randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eBone and mineral disorders are common complications in patients with chronic kidney disease (CKD) resulting in poor quality of life, high fracture risk, increased morbidity and cardiovascular mortality. Parathyroid hormone (PTH) has long been the preferred surrogate biomarker of bone turnover together with bone specific alkaline phosphatase (bALP) and is recommended for routine clinical use in the most recent Kidney Disease-Improving Global Outcomes (KDIGO) guidelines [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Markers of bone turnover, which are released from bone cells, could be superior in understanding bone remodelling processes in contrast to PTH, which is a regulator of bone metabolism [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. They show acceptable diagnostic accuracy for bone turnover and in everyday clinical practice could be seen as an accessible alternative to bone biopsy, which is still considered to be the gold standard, in diagnosing renal osteodystrophy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNonetheless, bone turnover markers, which are released during the bone remodelling cycle and reflect bone remodelling rate, need to be selected with care due to decreased renal excretion in CKD. Monomeric fragments of procollagen type I N-terminal propeptide (PINP) is a reference marker of bone formation as it is released as collagen and is deposited in the bone matrix [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Monomeric fragments accumulate in CKD, necessitating the use of specific assays for the intact, trimeric form of PINP (intact PINP) in this specific group of patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTartrate-resistant acid phosphatase isoform 5b (TRAP5b) is released from osteoclasts and is considered a highly specific marker of bone resorption [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVery few studies, mostly with small sample sizes and examining patients on dialysis, studied the relationship of exercise and changes in bone specific biomarkers and did not show significant associations [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although positive effects of resistance exercise on the regulation of bone formation and resorption biomarkers in healthy subjects has been described [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], there are to our knowledge no studies which have examined the influence of exercise on changes in bone specific biomarkers in patients with CKD not on kidney replacement therapy (KRT).\u003c/p\u003e \u003cp\u003eIn a previous sub-study of RENEXC, a randomised controlled head-to-head trial examining two different exercise regimes, balance or strength both in combination with endurance exercise, during 12 months of intervention, we explored the possible effects of exercise on bone mineral density in patients with CKD stages 3 to 5 not on KRT. We showed that balance exercise seemed to be superior in maintaining and improving whole body bone mineral density compared with strength exercise [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. We concluded that balance exercise in combination with endurance exercise appeared to influence bone metabolism processes positively in these patients.\u003c/p\u003e \u003cp\u003eThe aim of this study is to investigate the effects of balance- and strength exercise (both in combination with endurance exercise) on markers of bone metabolism in patients with CKD stages 3\u0026ndash;5 not on KRT.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study is a prespecified sub-study of the RENEXC trial, a prospective randomized controlled exercise trial, with an intervention period of 12 months. There were no changes to protocol after the trial began. Complete study design and primary analysis of RENEXC data have been reported previously [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Some information on study design and methods is repeated here for clarity.\u003c/p\u003e \u003cp\u003eAll incident and prevalent patients at the Department of Nephrology in Lund, Sk\u0026aring;ne University Hospital with an estimated GFR\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/min/1.73m\u0026sup2;, age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, all kidney diseases and any number of comorbidities were eligible for participation in the study. Orthopaedic impediment, severe neurological dysfunction, inability to understand patient information and instructions, estimated start of KRT within 12 months of study start were exclusion criteria.\u003c/p\u003e \u003cp\u003e The study was approved by the Regional Ethical Review Board in Lund (registration number 2011/369) and adhered to the Helsinki Declaration. All participants gave informed consent prior to inclusion after having received written and oral information.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003e151 patients were randomised to either strength or balance exercise both together with endurance exercise. The exercises were individually prescribed, monitored by a physiotherapist, and self-administered at home or at a nearby gym. The Borg Rating of Perceived Exertion scale (RPE) was used to prescribe exercise intensity and to monitor progress [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The prescribed weekly exercise duration was 150 minutes, comprising 60 minutes per week of endurance exercise at a RPE of 13\u0026ndash;15 for both groups combined with 90 minutes per week of either strength or balance exercise at a RPE of 13\u0026ndash;17 per exercise set.\u003c/p\u003e \u003cp\u003eAll patients were tested at baseline (T0) and after 12 months (T12).\u003c/p\u003e \u003cp\u003eMeasures of physical performance were the primary outcomes. Predetermined secondary outcome was changes in non-invasive bone turnover markers.\u003c/p\u003e\n\u003ch3\u003ePhysical performance\u003c/h3\u003e\n\u003cp\u003eOverall endurance was tested with the 6-minute walk test (6-MWT) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Muscular endurance and fatigability in the proximal leg muscles were tested with the 30-seconds sit-to-stand test (30-STS) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Balance was tested with functional reach (FR) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Neuromuscular function and strength in the lower extremities were tested with isometric quadriceps strength (ISQ) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eComorbidity score\u003c/h3\u003e\n\u003cp\u003eComorbidity was assessed with the Davies Comorbidity Score [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] at baseline.\u003c/p\u003e\n\u003ch3\u003eLaboratory analyses\u003c/h3\u003e\n\u003cp\u003ePlasma 25 hydroxyvitamin D (25(OH)D) was analysed using liquid chromatography-mass spectrometry. Glomerular filtration rate (GFR) was measured using iohexol clearance. Calcium, phosphate, parathyroid hormone (PTH), alkaline phosphatase (ALP) were measured using standard laboratory techniques and performed at the Department of Clinical Chemistry, Laboratory Medicine Sk\u0026aring;ne, which is accredited by SWEDAC (ISO 15189:2012). Trimeric procollagen- type I N-propeptide (intact PINP, assay range 2.0-4600 \u0026micro;g/L) and tartrate-resistant acid phosphatase isoform 5b (TRAP5b, assay range 0.9\u0026ndash;56 U/L) were measured with ImmunoDiagnostic System iSYS instrument (IDS, Boldon, UK). The plasma was collected fasting and stored at \u0026minus;\u0026thinsp;80\u0026deg;C. Values of intact PINP above upper limit of quantification of the assay were determined after dilution. For intact PINP the intra and inter assay variations are both at maximum 8%. For TRAcp-5b the intra and inter assay variations are both at maximum 12%.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of bone turnover markers\u003c/h2\u003e \u003cp\u003eTo define between group changes after the study period Δ intact PINP and Δ TRAP5b values (T12 value \u0026ndash; T0 value) were calculated. For more detailed analyses after the study period, we used calculated cutoffs for high and low turnover reported by J\u0026oslash;rgensen et al [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Thresholds of intact PINP\u0026thinsp;\u0026gt;\u0026thinsp;120.7 \u0026micro;g/L and TRAP5b\u0026thinsp;\u0026gt;\u0026thinsp;5.05 U/L have been suggested as indicative of high bone turnover. Conversely, values of intact PINP\u0026thinsp;\u0026lt;\u0026thinsp;49.8 \u0026micro;g/L and TRAP5b\u0026thinsp;\u0026lt;\u0026thinsp;3.44 U/L are consistent with low turnover and due to their high negative predictive value, may be particularly informative for excluding high turnover states.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRandomisation\u003c/h3\u003e\n\u003cp\u003ePatients were randomized using ProcPlan in SAS, SAS Institute Cary NC. The statistician generated the random allocation sequence, the nephrologist enrolled patients and the physiotherapist assigned participants to intervention. Patients were included and allocated sequential treatment according to a list that only the research physiotherapist had access to. Both interventions comprised endurance exercise. The difference between the treatment arms was that one group was allocated strength exercise and one group balance exercise.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eStatistical analyses were performed using the SPSS for Windows software program version 24.0. Per-protocol analysis was employed including only patients who completed the treatment originally allocated. Variables were expressed as frequencies, percentages for discrete factors. Continuous factors are presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations or medians [minimum and maximum]. The two-tailed chi-square and Wilcoxon tests was used for categorical variables. The two-tailed Student\u0026rsquo;s t-test or Mann-Whitney test for continuous variables, according to data distribution. The paired sample T-test was used for parametric variables. For all comparisons a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 217 patients were screened and 151 patients were randomized. 112 patients completed the whole exercise period of whom 11 patients were excluded from this study because of missing blood samples. Consequently, results from 101 (73 men, 28 women) patients (mean age 68\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8 years) were analysed. Most of the patients were in CKD stage 4 (n\u0026thinsp;=\u0026thinsp;67, 66%), 17 patients (17%) were in CDK 3 and 17 (17%) in CKD stage 5. 49 patients (37 men, 12 women) participated in the strength group, and 52 (36 men, 16 women,) in the balance group. The Consolidated Standards of Reporting Trials (CONSORT) flow diagram is presented in Fig.\u0026nbsp;1. Some clinical characteristics and laboratory data are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSome clinical characteristics at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnits\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStrength group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBalance group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWhole group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eyears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 [23\u0026ndash;84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 [27\u0026ndash;87]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71 [23\u0026ndash;87]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73 (72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ekg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.7\u0026thinsp;\u0026plusmn;\u0026thinsp;18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e81.6\u0026thinsp;\u0026plusmn;\u0026thinsp;17.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003em\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ekg/m\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiuretics*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71 (70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 (27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCinacalcet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActive vit D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62 (61)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNative vit D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium based phosphate binders\u003c/p\u003e \u003cp\u003e\u0026bull; Calcium carbonate\u003c/p\u003e \u003cp\u003e\u0026bull; Calcium acetate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (23)\u003c/p\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (37)\u003c/p\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30(30)\u003c/p\u003e \u003cp\u003e2 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-calcium-based phosphate binders\u003c/p\u003e \u003cp\u003e\u0026bull; Sevelamer\u003c/p\u003e \u003cp\u003e\u0026bull; Lanthanum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12)\u003c/p\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (7)\u003c/p\u003e \u003cp\u003e4 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschemic heart disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral vascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft ventricular dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic collagen vascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther (e.g. hypertension)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71 (74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median [minimum- maximum]. BMI- body mass index, PPI- proton pump inhibitors, vit D- vitamin D. * 9 patients received hydrochlorothiazide, all others received loop diuretics.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eWhole group\u003c/h2\u003e \u003cp\u003eThe effects of 12 months of exercise on physical performance have been presented in detail previously and shall not be repeated here. Both groups improved overall endurance (6MWT), muscular endurance(30-STS), strength (IQS) and balance (FR) significantly, with no between group differences [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo significant differences were observed in values of intact PINP (T0: 75 [22\u0026ndash;414] vs T12: 72 [19\u0026ndash;257], p\u0026thinsp;=\u0026thinsp;0.797) and TRAP5b (T0:1.9 [0.9\u0026ndash;2.54] vs T12:1.8 [0.9\u0026ndash;7.4], p\u0026thinsp;=\u0026thinsp;0.072) after the 12-month study period in the whole group. Values of intact PINP and TRAP5b are statistically significantly lower (p\u0026thinsp;=\u0026thinsp;0.001) compared with values reported earlier by J\u0026oslash;rgensen et al [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe strength group showed a non-significant increase in intact PINP (T0: 71.8 [21.8-169.5] and T12:79.7 [26.8-174.2], p\u0026thinsp;=\u0026thinsp;0.20) and non-significant decrease in TRAP5b (T0: 2.2 [0.9\u0026ndash;7.1] and T12: 1.9 [0.9\u0026ndash;4.7], p\u0026thinsp;=\u0026thinsp;0.26).\u003c/p\u003e \u003cp\u003eThe balance group showed a non-significant decrease in intact PINP value (T0: 80.8 [23.8-413.6] and T12: 63.8 [19.1-256.9], p\u0026thinsp;=\u0026thinsp;0.15) and no change in TRAP5b (T0: 1.60 [0.9\u0026ndash;9.4] and T12: 1.7 [0.9\u0026ndash;7.4], p\u0026thinsp;=\u0026thinsp;0.16).\u003c/p\u003e \u003cp\u003eWhen stratified for CKD stage, patients with CKD stage 3 in the strength group showed a significant decrease in TRAP5b after 12 months of exercise (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Women in the balance group had a significant decrease in TRAP5b after the study period (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBone markers at baseline (T0) and after 12 months of exercise (T12) stratified for CKD stages\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eStrength group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eBalance group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eWhole group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eIntact PINP (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 [22\u0026ndash;170]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 [40\u0026ndash;151]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61 [39\u0026ndash;156]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e90 [60\u0026ndash;124]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55 [22\u0026ndash;170]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e84 [40\u0026ndash;150]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 [32\u0026ndash;120]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 [27\u0026ndash;174]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84 [26\u0026ndash;414]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64 [19\u0026ndash;257]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e76 [22\u0026ndash;414]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e70 [19\u0026ndash;257]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 [33\u0026ndash;114]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 [38\u0026ndash;160]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52 [23\u0026ndash;345]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56 [25\u0026ndash;247]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e80 [24\u0026ndash;345]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e72 [25\u0026ndash;247]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eTRAP5b (U/L)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1 [0.9\u0026ndash;7.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6 [0.9\u0026ndash;3.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.4 [1.3\u0026ndash;9.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.4 [0.9\u0026ndash;7.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.9 [0.9\u0026ndash;7.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.0 [0.9\u0026ndash;7.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.2 [0.9\u0026ndash;6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2 [1.0\u0026ndash;4.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.6 [0.9\u0026ndash;5.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.7 [0.9\u0026ndash;2.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.8 [0.9\u0026ndash;9.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.8 [0.9\u0026ndash;4.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.158\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.4 [0.9\u0026ndash;4.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1 [0.9\u0026ndash;4.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.3 [0.9\u0026ndash;4.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.5 [0.9\u0026ndash;2.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.0 [0.9\u0026ndash;5.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.5 [0.9\u0026ndash;4.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as median [minimum- maximum]. Intact PINP- N-terminal propeptide of type I procollagen, intact, TRAP5b - tartrate-resistant acid phosphatase 5b, CKD- chronic kidney disease.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBone markers at baseline (T0) and after 12 months of exercise (T12) stratified for sex\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eStrength group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eBalance group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eWhole group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eIntact PINP (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 [22\u0026ndash;169]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 [31\u0026ndash;174]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84 [24\u0026ndash;414]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64 [19\u0026ndash;124]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e83 [22\u0026ndash;414]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e65 [1.9\u0026ndash;174]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 [22\u0026ndash;125]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 [27\u0026ndash;162]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69 [26\u0026ndash;399]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64 [22\u0026ndash;257]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e70 [22\u0026ndash;399]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e74 [22\u0026ndash;257]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eTRAP5b (U/L)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 [0.9\u0026ndash;7.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6 [1\u0026ndash;4.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.2 [1\u0026ndash;9.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.7 [0.9\u0026ndash;2.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.1 [0.9\u0026ndash;9.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.6 [0.9\u0026ndash;4.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3 [0.9\u0026ndash;6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0 [0.9\u0026ndash;4.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.5 [0.9\u0026ndash;5.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.7 [0.9\u0026ndash;7.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.8 [0.9\u0026ndash;6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.8 [0.9\u0026ndash;7.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as median [minimum- maximum]. Intact PINP- N-terminal propeptide of type I procollagen, intact, TRAP5b - tartrate-resistant acid phosphatase 5b.\u003c/p\u003e \u003cp\u003eThere were no overall significant between group differences for Δ intact PINP or Δ TRAP5b. Δ intact PINP was positive in the strength group and negative in the balance group (12.8 [-89-112] vs -5.9 [-349-152], p\u0026thinsp;=\u0026thinsp;0.07). Δ TRAP5b showed a slight negative trend in both groups (-0.1 [-5.5-2.6] vs -0.3 [-6.6-3.7], p\u0026thinsp;=\u0026thinsp;0.82).\u003c/p\u003e \u003cp\u003eSignificantly higher levels of phosphate and parathyroid hormone after 12 months were observed in patients with positive Δ intact PINP as well as positive Δ TRAP5b. Higher 25(OH)D was observed in participants with negative Δ TRAP5b values (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNo differences were observed in prescription of active vitamin D in patients with positive vs negative Δ intact PINP (59% vs 65% accordingly, p\u0026thinsp;=\u0026thinsp;0.66). There were no statistically significant differences in frequency of prescription of active vitamin D in patients with negative vs positive Δ TRAP5b values in either group (65% vs 60%, p\u0026thinsp;=\u0026thinsp;0.66).\u003c/p\u003e \u003cp\u003eProportion of values of intact PINP that could indicate a high bone turnover (intact PTH\u0026thinsp;\u0026gt;\u0026thinsp;120.7 \u0026micro;g/L) showed a tendency to increase in the strength group (T0: 4% vs T12: 14%, p\u0026thinsp;=\u0026thinsp;0.54) and decrease in the balance group (T0: 27% vs T12: 10%, p\u0026thinsp;=\u0026thinsp;0.07) but did not reach statistical significance. Figures\u0026nbsp;2 and 3.\u003c/p\u003e \u003cp\u003eProportion of TRAP5b values that could show congruence with low bone turnover (TRAP5b\u0026thinsp;\u0026lt;\u0026thinsp;3.44 U/L) increased significantly in both groups: strength group (T0: 79% vs T12: 91%, p\u0026thinsp;=\u0026thinsp;0.03) and balance group (T0: 80% vs T12: 94%, p\u0026thinsp;=\u0026thinsp;0.05). Figures\u0026nbsp;4 and 5.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in some laboratory analyses according to changes in delta values of measured markers of bone turnover\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eΔ intact PINP decreased\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-calcium (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;.0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-phosphate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-PTH (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 [3\u0026ndash;135]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.5 [1.7\u0026ndash;59]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-ALP (\u0026micro;kat/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-25(OH)D (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.2\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.8\u0026thinsp;\u0026plusmn;\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eΔ intact PINP increased\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-calcium (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-phosphate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-PTH (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 [2.6\u0026ndash;26]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 [1.8\u0026ndash;36]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-ALP (\u0026micro;kat/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-25(OH)D (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.4\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.9\u0026thinsp;\u0026plusmn;\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eΔ TRAP5b decreased\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-calcium (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-phosphate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-PTH (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 [4\u0026ndash;133]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 [1.7\u0026ndash;48]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-ALP (\u0026micro;kat/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-25(OH)D (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.0\u0026thinsp;\u0026plusmn;\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.3\u0026thinsp;\u0026plusmn;\u0026thinsp;27.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eΔ TRAP5b increased\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-calcium (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-phosphate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-PTH (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 [2.6\u0026ndash;45]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5 [3.5\u0026ndash;59]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-ALP (\u0026micro;kat/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-25(OH)D (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.8\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.2\u0026thinsp;\u0026plusmn;\u0026thinsp;31.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median with minimal - maximal values. P- plasma, PTH\u0026ndash; parathyroid hormone, ALP- alkaline phosphatase, 25(OH)D- 25 -hydroxy-vitamin D, Intact PINP- N-terminal propeptide of type I procollagen, intact, TRAP5b - tartrate-resistant acid phosphatase 5b\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first study to investigate possible effects of exercise on bone markers representing bone formation and resorption. Neither the balance- nor the strength group showed any significant differences for Δ intact PINP nor Δ TRAP5b after the 12-month exercise period. However, when examining the results by subgroup, women in the balance group had a significant decrease in TRAP5b, indicating that balance exercise could have a positive effect on decreasing bone resorption in women with CKD.\u003c/p\u003e \u003cp\u003eFew studies have examined changes in bone specific markers in relation to exercise. All of them were observational, only comprising patients on hemodialysis and were of small sample size [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. No study found changes in bone specific markers after exercise despite finding effects on bone mineral density. Although, in a study in young healthy males Fujimura et al showed that resistance exercise increased markers of bone formation, while it transiently suppressed a marker of bone resorption [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA notable finding was the significant increase in the proportion of TRAP5b values consistent with low bone turnover (TRAP5b\u0026thinsp;\u0026lt;\u0026thinsp;3.44 U/L) in both the strength and balance groups. This increase suggests that both interventions may have effectively contributed to reducing bone resorption. Our results are in line with the findings of studies in healthy men or patients with osteoporosis linking exercise to increased markers of bone formation, while transiently suppressing a marker of bone resorption [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Low bone turnover is typical in the early stages of CKD and slowly proceeds to high turnover in the later stages of CKD. Thus, our findings showing an increase in TRAP5b values, which are consistent with low turnover, could be considered a sign of a protective effect of exercise from a bone perspective.\u003c/p\u003e \u003cp\u003eThe positive relationship between phosphate and PTH both with Δ intact PINP and Δ TRAP5b could suggest that in the presence of increasing phosphate and PTH, bone turnover increases, potentially reflecting a shift towards high-turnover bone disease. This is especially notable as the patients in this study had phosphate values within reference values and acceptable levels of PTH. Findings from the literature on this subject are not uniform. Direct effects of PTH on osteoblasts and osteocytes and indirect actions on osteoclasts promote both bone formation and bone resorption. Bone resorption predominates in response to continuous exposure to high levels of circulating PTH [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A previous study has reported that higher phosphate levels may induce osteoblast apoptosis and reduce bone formation as well as inhibit bone resorption [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. One could speculate that this direct effect of high phosphate could be ameliorated by an indirect stimulating effect on PTH secretion as well as suppressing 1-alpha-hydroxylase activity contributing to calcitriol deficiency [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. On the other hand, a recent study in patients on hemodialysis revealed that high serum phosphate was consistently associated with an increased risk of bone fractures, regardless of other factors such as previous fractures, age, sex, time on hemodialysis, serum calcium and PTH [24].\u003c/p\u003e \u003cp\u003eAccording to our data, increasing 25(OH)D levels could be associated with a decrease in the bone resorptive process. It is notable that despite a significant increase in 25(OH)D levels after 12 months the recommended levels of 75nmol/L were not reached. Direct effects of vitamin D on bone include activities on both formation and resorption. Conflicting data suggest that these actions may differ by skeletal site and dietary calcium intake [25]. In the case of a sufficient calcium supply, vitamin D and its metabolites can improve calcium balance and facilitate mineral deposition in bone matrix largely without direct effects on bone cells, although some beneficial effects may occur via mature osteoblasts, as demonstrated in mice with osteoblast-specific overexpression of VDR or 1α-hydroxylase [25]. In the setting of calcium deficiency, however, calcitriol enhances bone resorption, whereas simultaneously inhibiting bone mineralization, to maintain serum calcium homeostasis at the expense of bone mass [25].\u003c/p\u003e \u003cp\u003eThe levels of both markers in our study are significantly lower compared with the levels presented by J\u0026oslash;rgensen et al [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Salam et al reported higher TRAP5b levels but similar levels of intact PINP levels as in our study [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These differences can at least partly be explained by differences in study population. In J\u0026oslash;rgensen\u0026rsquo;s et al study 18% of the patients were in CKD stages 4\u0026ndash;5, the rest were on KRT [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In Salam\u0026rsquo;s et al study 63% of the patients were in stages 4\u0026ndash;5 of CKD and 27% were on KRT [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Salam and al have also showed that patients with CKD had significantly higher marker levels compared with controls which could not only be explained by accumulation due to decreased kidney function as both the markers tested are known not to be influenced by decreased excretion. One could speculate that there are different patterns of bone turnover as CKD progresses. Evidence suggests that in the early stages of CKD, low bone turnover is often the earliest detectable alteration in bone remodelling. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This may be due to a predominance of factors that inhibit bone turnover, such as resistance to PTH, low calcitriol levels, sex hormone deficiency, diabetes, and uremic toxins. These factors contribute to the suppression of osteocyte Wnt/b-catenin signalling and the increased expression of Wnt antagonists like sclerostin, Dickkopf-1, and sFRP4. High turnover bone disease typically emerges at later stages of CKD, when serum PTH levels can overcome peripheral PTH resistance and other inhibitors of bone formation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are several strengths in this study. The participants represent a typical cohort of patients with CKD stages 3 to 5 not on KRT and, to our knowledge, this is the first study to compare effects of strength versus balance exercise on bone specific markers in patients with CKD not on KRT. Patients maintained levels for calcium and phosphate within the reference values. This study also has limitations such as the absence of a sedentary control group, but the reasons for that have been discussed and explained previously [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, the short follow-up period could be considered a significant limitation as the intervention that lasted 12 months is acceptable for investigating effects of exercise in patients with CKD but may be insufficient to capture meaningful changes in bone metabolism in this group. Bone remodelling is a slow process, and longer observation periods are likely necessary to detect significant shifts in bone metabolism reflecting markers.\u003c/p\u003e \u003cp\u003eMoreover, we were unable to examine bALP, a key marker of bone formation and skeletal mineralization which limits the comprehensiveness of the bone status assessment. This limitation at least partly was compensated by analysis of total ALP which did not reveal any significant differences.\u003c/p\u003e \u003cp\u003eIn conclusion, while 12 months of exercise did not produce significant overall changes in bone turnover markers across the whole group or in either of the exercise groups, women in the balance group, showed significant reductions in TRAP5b indicating decreased bone resorption. The mechanism and the importance of this finding remains elusive necessitating further studies for elucidation.\u003c/p\u003e \u003cp\u003eFurther studies are also needed to explore the finding that the proportion of patients whose TRAP5b value could be consistent with low turnover increased in both exercise groups after 12 months of exercise. Associations of increasing phosphate and PTH with changes in bone turnover markers as well as effects of vitamin D were interesting but require more detailed study.\u003c/p\u003e \u003cp\u003eWhile no significant changes in bone turnover markers were observed in the overall cohort, the results suggest that balance exercise may reduce bone resorption in women with CKD. Additionally, both strength and balance exercises appeared to diminish bone resorption as indicated by TRAP5b levels. These findings warrant further investigation into the long-term effects of exercise on bone health in CKD, with a particular focus on the mechanisms underlying these responses.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eCKD - Chronic Kidney Disease\u003c/p\u003e\n\u003cp\u003ePTH - Parathyroid Hormone\u003c/p\u003e\n\u003cp\u003ebALP - Bone Specific Alkaline Phosphatase\u003c/p\u003e\n\u003cp\u003eKDIGO - Kidney Disease-Improving Global Outcomes\u003c/p\u003e\n\u003cp\u003ePINP - Procollagen Type I N-terminal Propeptide\u003c/p\u003e\n\u003cp\u003eTRAP5b - Tartrate-Resistant Acid Phosphatase Isoform 5b\u003c/p\u003e\n\u003cp\u003eKRT - Kidney Replacement Therapy\u003c/p\u003e\n\u003cp\u003eRENEXC \u0026ndash; RENal EXerCise\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRPE - Borg Rating of Perceived Exertion\u003c/p\u003e\n\u003cp\u003e6-MWT - 6-Minute Walk Test\u003c/p\u003e\n\u003cp\u003e30-STS - 30-Seconds Sit-to-Stand Test\u003c/p\u003e\n\u003cp\u003eFR - Functional Reach\u003c/p\u003e\n\u003cp\u003eISQ - Isometric Quadriceps Strength\u003c/p\u003e\n\u003cp\u003eGFR - Glomerular Filtration Rate\u003c/p\u003e\n\u003cp\u003eALP - Alkaline Phosphatase\u003c/p\u003e\n\u003cp\u003eSWEDAC - Swedish Board for Accreditation and Conformity Assessment\u003c/p\u003e\n\u003cp\u003e25(OH)D - Plasma 25-Hydroxyvitamin D\u003c/p\u003e\n\u003cp\u003eSPSS - Statistical Package for the Social Sciences\u003c/p\u003e\n\u003cp\u003eCONSORT - Consolidated Standards of Reporting Trials\u003c/p\u003e\n\u003cp\u003eISO - International Organization for Standardization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor practical assistance, we would like to thank kidney failure nurses Carina Holmesson and Marianne Liljenborg, medical secretary Ann-Charlotte Malmberg and biomedical analyst \u0026Aring;sa Pettersson.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared. The results presented in this paper have not been published previously in whole or part.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch idea and study design: VP, NC, MH, data acquisition: MH, PS, data analysis and interpretation: VP, statistical analysis: VP, supervision and mentorship: NC. Each author contributed important intellectual content during manuscript drafting and revision and accepts accountability for the overall work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from Birgit and Sven-H\u0026aring;kan Ohlsson\u0026rsquo;s Trust, Sk\u0026aring;ne University Hospital\u0026rsquo;s Research Foundation, the Kidney Trust (Njurstiftelsen), the Swedish Society of Nephrology, the Southern Health Care Region in Sweden and Anna-Lisa and Sven Eric Lundgren\u0026rsquo;s Trust.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis randomized controlled trial is registered as NCT02041156 at www.ClinicalTrials.gov approved by the Regional Ethical Review Board in Lund (Ref 2011/369) and adheres to the Helsinki declaration. All patients received written and oral information and have given written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKetteler M, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease\u0026ndash;Mineral and Bone Disorder (CKD-MBD) Guideline Update: what\u0026rsquo;s changed and why it matters. 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DOI: [10.1093/ndt/gfz196](https.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"bone markers, chronic kidney disease, exercise, procollagen type I N-terminal propeptide, tartrate-resistant acid phosphatase isoform 5b","lastPublishedDoi":"10.21203/rs.3.rs-6785539/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6785539/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBone and mineral disorders are common in patients with chronic kidney disease (CKD), leading to poor quality of life, high fracture risk, and increased morbidity and cardiovascular mortality. Parathyroid hormone (PTH) and bone-specific alkaline phosphatase (bALP) are frequently used to assess bone turnover, but markers such as procollagen type I N-terminal propeptide (intact PINP) and tartrate-resistant acid phosphatase isoform 5b (TRAP5b), which reflect bone formation and resorption, may provide more specific insights into bone remodeling. This study aims to investigate the effects of balance and strength exercises on bone turnover markers in patients with CKD not undergoing kidney replacement therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study is a sub-analysis of the RENEXC trial, a randomized controlled exercise intervention lasting 12 months. A total of 151 CKD stage 3\u0026ndash;5 patients were randomly assigned to either strength or balance exercise, both combined with endurance exercise. Exercise intensity was monitored using the Borg Rating of Perceived Exertion (RPE) scale. Bone turnover markers, including intact PINP and TRAP5b, were measured at baseline and after 12 months.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAfter 12 months of exercise both groups significantly improved physical performance, no significant changes were observed in intact PINP or TRAP5b across the entire cohort. However, subgroup analysis revealed that women in the balance group experienced a significant reduction in TRAP5b, indicating a potential decrease in bone resorption. Additionally, both exercise groups showed an increase in the proportion of patients with TRAP5b values indicative of low bone turnover, suggesting a protective effect on bone resorption. Higher phosphate and PTH levels were associated with positive Δ intact PINP as well as positive Δ TRAP5b, while higher 25(OH)D levels were associated with negative Δ TRAP5b values.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWhile no significant changes in bone turnover markers were observed in the overall cohort, the results suggest that balance exercise may reduce bone resorption in women with CKD. Additionally, both strength and balance exercises appeared to diminish bone resorption as indicated by TRAP5b levels. These findings warrant further investigation into the long-term effects of exercise on bone health in CKD, with a particular focus on the mechanisms underlying these responses.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eNCT02041156 at www.ClinicalTrials.gov. Date of registration January 20, 2014. Retrospectively registered.\u003c/p\u003e","manuscriptTitle":"Markers of bone turnover after 12 months of exercise in patients with chronic kidney disease 3-5: a sub-study of RENEXC – a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-17 15:53:38","doi":"10.21203/rs.3.rs-6785539/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-10T12:21:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-10T12:12:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52100970212728867329383456731623240439","date":"2025-07-01T09:10:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-30T09:56:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237026620166670960181130461517988683819","date":"2025-06-28T11:23:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"101884003055810690678307106903962818021","date":"2025-06-26T10:47:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"100019609242076807787401243369105571796","date":"2025-06-23T12:15:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-23T05:50:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217124570251157429967923338069482020282","date":"2025-06-12T06:17:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-12T05:38:56+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-03T06:52:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-31T07:27:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-31T07:26:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-05-30T14:13:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fd943011-e6bb-4a36-b9c4-3946585f021e","owner":[],"postedDate":"June 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:04:42+00:00","versionOfRecord":{"articleIdentity":"rs-6785539","link":"https://doi.org/10.1186/s12882-025-04501-9","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-10-13 15:58:36","publishedOnDateReadable":"October 13th, 2025"},"versionCreatedAt":"2025-06-17 15:53:38","video":"","vorDoi":"10.1186/s12882-025-04501-9","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04501-9","workflowStages":[]},"version":"v1","identity":"rs-6785539","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6785539","identity":"rs-6785539","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}