Mitochondrial dysfunction is associated with several clinical manifestations including diabetes mellitus (DM), neurological disorders, renal and hepatic diseases, and myopathy. Although mitochondrial dysfunction is associated with increased bone resorption and decreased bone formation in mouse models, effects of alterations in mitochondrial function on bone remodeling and mass have not been investigated in humans. We recruited 45 carriers (29 females, 16 males) with the m.3243A>G mutation and healthy controls matched for gender, age, height, and menopausal status. DXA and HRpQCT scans were performed, and bone turnover markers (BTMs) P1NP and CTX were measured. Cases and controls were well matched except for body weight, which was lower in cases (63.6 ± 18.1 kg versus 74.6 ± 14.8 kg, p < 0.01), and manifest DM was present in 25 of 45 cases (none in controls). Bone scans showed lower BMD at the lumbar spine, total hip, and femoral neck in cases. Mean lumbar spine, total hip, and femoral neck T-scores were -1.5, -1.3, and -1.6 in cases, respectively, and -0.8, -0.3, and -0.7 in controls (all p < 0.05). The m.3243A>G mutation was associated with lower BMD, cortical but not trabecular density, cortical thickness, and estimated bone strength. Furthermore, BTMs were lower in the m.3243A>G group before but not after adjustment for DM. The mitochondrial point mutation m.3243A>G was associated with decreased bone mass and strength. Although the coexistence of DM may have influenced bone turnover, the bone phenotype observed in m.3243A>G cases appeared to mirror age-related deterioration in bone, suggesting that mitochondrial dysfunction may cause a premature aging of bone. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

The current study examined the relationship between vitamin D status and muscle strength in young healthy adults: residents (>6 months) and newcomers (0-3 months), originally from sunny climate countries but currently living in the northeast of Scotland. Our longitudinal data found a positive, albeit small, relationship between vitamin D status and knee extensor isometric strength.

Vitamin D has been suggested to play a role in muscle health and function, but studies so far have been primarily in older populations for falls prevention and subsequent risk of fractures.

Vitamin D status was assessed in a healthy young adults from sunny climate countries (n = 71, aged 19-42 years) with 56% seen within 3 months of arriving in Aberdeen [newcomers; median (range) time living in the UK = 2 months (9-105 days)] and the remainder resident for >6 months [residents; 23 months (6-121 months)]. Participants attended visits every 3 months for 15 months. At each visit, fasted blood samples were collected for analysis of serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type I collagen (P1NP). Maximal voluntary contractions (MVC) were performed for grip strength (both arms) and for maximal isometric strength of the knee extensors (right knee).

There were small seasonal variations in 25(OH)D concentrations within the newcomers and residents, but no seasonal variation in bone turnover markers. There was a positive, albeit small, association between 25(OH)D and knee extensor maximal isometric strength. Mixed modelling predicted that for each 1 nmol/L increase in 25(OH)D, peak torque would increase by 1 Nm (p = 0.04).

This study suggests that vitamin D may be important for muscle health in young adults migrating from sunnier climates to high latitudes, yet the potential effect is small.

Long-term glucocorticoid therapy is known to induce increased bone fragility and impaired skeletal regeneration potential. Growing evidence suggests that pulsed electromagnetic fields (PEMF) can accelerate fracture healing and increase bone mass both experimentally and clinically. However, how glucocorticoid-treated bone and bone cells respond to PEMF stimulation remains poorly understood. Here we tested the effects of PEMF on bone quantity/quality, bone metabolism, and porous implant osseointegration in rabbits treated with dexamethasone (0.5 mg/kg/day, 6 weeks). The micro-CT, histologic and nanoindentation results showed that PEMF ameliorated the glucocorticoid-mediated deterioration of cancellous and cortical bone architecture and intrinsic material properties. Utilizing the new porous titanium implant (Ti2448) with low toxicity and low elastic modulus, we found that PEMF stimulated bone ingrowth into the pores of implants and enhanced peri-implant bone material quality during osseous defect repair in glucocorticoid-treated rabbits. Dynamic histomorphometric results revealed that PEMF reversed the adverse effects of glucocorticoids on bone formation, which was confirmed by increased circulating osteocalcin and P1NP. PEMF also significantly attenuated osteocyte apoptosis, promoted osteoblast-related osteocalcin, Runx2 and Osx expression, and inhibited osteocyte-specific DKK1 and Sost expression (negative regulators of osteoblasts) in glucocorticoid-treated skeletons, revealing improved functional activities of osteoblasts and osteocytes. Nevertheless, PEMF exerted no effect on circulating bone-resorbing cytokines (serum TRAcP5b and CTX-1) or skeletal gene expression of osteoclast-specific markers (TRAP and cathepsin K). PEMF also significantly upregulated skeletal gene expression of canonical Wnt ligands (Wnt1, Wnt3a and Wnt10b), whereas PEMF did not alter non-canonical Wnt5a expression. This study demonstrates that PEMF treatment improves bone mass, strength and porous implant osseointegration in glucocorticoid-treated rabbits by promoting potent bone-anabolic action, which is associated with canonical Wnt-mediated improvement in osteoblast and osteocyte functions. This study provides a new treatment alternative for glucocorticoid-related bone disorders in a convenient and non-invasive manner.

UNASSIGNED

The purpose of the present controlled cross-sectional study was to investigate proximal femur and whole-body bone mineral density (BMD), as well as bone turnover profile, in lifelong trained elderly male football players and young elite football players compared with untrained age-matched men.

UNASSIGNED

One hundred and forty healthy, non-smoking men participated in the study, including lifelong trained football players (FTE, n = 35) aged 65-80 years, elite football players (FTY, n = 35) aged 18-30 years, as well as untrained age-matched elderly (UE, n = 35) and young (UY, n = 35) men. All participants underwent a regional dual-energy X-ray Absorptiometry (DXA) scan of the proximal femur and a whole-body DXA scan to determine BMD. From a resting blood sample, the bone turnover markers (BTMs) osteocalcin, carboxy-terminal type-1 collagen crosslinks (CTX-1), procollagen type-1 amino-terminal propeptide (P1NP), and sclerostin were measured.

UNASSIGNED

FTE had 7.3%-12.9% higher (p < 0.05) BMD of the femoral neck, wards, shaft, and total proximal femur in both legs compared to UE, and 9.3%-9.7% higher (p < 0.05) BMD in femoral trochanter in both legs compared to UY. FTY had 24.3%-37.4% higher (p < 0.001) BMD in all femoral regions and total proximal femur in both legs compared to UY. The whole-body DXA scan confirmed these results, with FTE showing similar whole-body BMD and 7.9% higher (p < 0.05) leg BMD compared to UY, and with FTY having 9.6% higher (p < 0.001) whole-body BMD and 18.2% higher (p < 0.001) leg BMD compared to UY. The plasma concentration of osteocalcin, CTX-1, and P1NP were 29%, 53%, and 52% higher (p < 0.01), respectively, in FTY compared to UY.

UNASSIGNED

BMD of the proximal femur and whole-body BMD are markedly higher in lifelong trained male football players aged 65-80 years and young elite football players aged 18-30 years compared to age-matched untrained men. Elderly football players even show higher BMD in femoral trochanter and leg BMD than untrained young despite an age difference of 47 years.

Melatonin is the primary circadian output signal from the brain and is mainly synthesized in pinealocytes. The rhythm and secretion of melatonin is under the control of an endogenous oscillator located in the SCN or the master biological clock. Disruptions in circadian rhythms by shift work, aging, or light at night is associated with bone loss and increased fracture risk. Restoration of nocturnal melatonin peaks to normal levels or therapeutic levels through timed melatonin supplementation has been demonstrated to provide bone-protective actions in various models. Melatonin is a unique molecule with diverse molecular actions targeting melatonin receptors located on the plasma membrane or mitochondria or acting independently of receptors through its actions as an antioxidant or free radical scavenger to stimulate osteoblastogenesis, inhibit osteoclastogenesis, and improve bone density. Its additional actions on entraining circadian rhythms and improving quality of life in an aging population coupled with its safety profile makes it an ideal therapeutic candidate for protecting against bone loss in susceptible populations. The intent of this review is to provide a focused discussion on bone loss and disorders of the bone as it relates to melatonin and conditions that modify melatonin levels with the hope that future therapies include those that include melatonin and correct those factors that modify melatonin levels like circadian disruption.

Keywords: CTx; P1NP; circadian; clock proteins; melatonin; mesenchymal stem cells; osteoblasts; osteoclasts; osteopenia; osteoporosis; oxidative stress; rheumatoid arthritis.

Introduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two years. The longer-term effects, however, of zoledronate treatment are unknown. We aimed to study the effect of a single zoledronate infusion during the third year following denosumab discontinuation, in initially treatment-naive postmenopausal women who became osteopenic after 2.4 ± 0.2 years of denosumab therapy.

Methods: We report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in lumbar spine bone mineral density (LS-BMD); secondary endpoints were changes in femoral neck (FN)-BMD and markers of bone turnover (BTM) during the 3rd year from the zoledronate infusion. Changes are presented as mean and SEM.

Results: LS-BMD did not change significantly at year 3 compared to year 2 (-1.35 ± 1.1%, p = 1.00) and compared to baseline (-1.96 ± 1.44%, p = 1.00). FN-BMD values did not change while serum P1NP values decreased and CTX values remained unchanged during the third-year of the follow-up. In 4 of the 23 studied women BMD values returned to the osteoporotic range at 3 years.

Conclusions: A single i.v. infusion of zoledronate 5 mg, given 6 months after the last injection of denosumab therapy maintains for three years BMD gains in the majority of patients previously treated with denosumab for an approximate period of 2.5 years. Follow-up of patients is, however, recommended because about one-fifth of treated women will require additional antiosteoporotic treatment.

Keywords: Bone mineral density; Bone turnover markers; Denosumab; Postmenopausal osteoporosis; Zoledronate.

We assessed the potential of Calcium (Ca) isotope fractionation measurements in blood (δ^44/42Ca_Blood) and urine (δ^44/42Ca_Urine) as a new biomarker for the diagnosis of osteoporosis. One hundred post-menopausal women aged 50 to 75 years underwent dual-energy X-ray absorptiometry (DXA), the gold standard for determination of bone mineral density. After exclusion of women with kidney failure and vitamin D deficiency (<25 nmol/l) 80 women remained in the study. Of these women 14 fulfilled the standard diagnostic criteria for osteoporosis based on DXA. Both the δ^44/42Ca_Blood (p < 0.001) and δ^44/42Ca_Urine (p = 0.004) values were significantly different in women with osteoporosis (δ^44/42Ca_Blood: -0.99 ± 0.10‰, δ ^44/42Ca_Urine: +0.10 ± 0.21‰, (Mean ± one standard deviation (SD), n = 14)) from those without osteoporosis (δ^44/42Ca_Blood: -0.84 ± 0.14‰, δ^44/42Ca_Urine: +0.35 ± 0.33‰, (SD), n = 66). This corresponded to the average Ca concentrations in morning spot urine samples ([Ca]_Urine) which were higher (p = 0.041) in those women suffering from osteoporosis ([Ca]_{Urine-Osteoporosis}: 2.58 ± 1.26 mmol/l, (SD), n = 14) than in the control group ([Ca]_Urine-_Control: 1.96 ± 1.39 mmol/l, (SD), n = 66). However, blood Ca concentrations ([Ca]_Blood) were statistically indistinguishable between groups ([Ca]_Blood, control: 2.39 ± 0.10 mmol/l (SD), n = 66); osteoporosis group: 2.43 ± 0.10 mmol/l (SD, n = 14) and were also not correlated to their corresponding Ca isotope compositions. The δ^44/42Ca_Blood and δ^44/42Ca_Urine values correlated significantly (p = 0.004 to p = 0.031) with their corresponding DXA data indicating that both Ca isotope ratios are biomarkers for osteoporosis. Furthermore, Ca isotope ratios were significantly correlated to other clinical parameters ([Ca]_Urine, ([Ca]_Urine/Creatinine)) and biomarkers (CRP, CTX/P1NP) associated with bone mineralization and demineralization. From regression analysis it can be shown that the δ^44/42Ca_Blood values are the best biomarker for osteoporosis and that no other clinical parameters need to be taken into account in order to improve diagnosis. Cut-off values for discrimination of subjects suffering from osteoporosis were - 0.85‰ and 0.16‰ for δ^44/42Ca_Blood and δ^44/42Ca_Urine, respectively. Corresponding sensitivities were 100% for δ^44/42Ca_Blood and ~79% for δ^44/42Ca_Urine. Apparent specificities were ~55% for δ^44/42Ca_Blood and ~71%. The apparent discrepancy in the number of diagnosed cases is reconciled by the different methodological approaches to diagnose osteoporosis. DXA reflects the bone mass density (BMD) of selected bones only (femur and spine) whereas the Ca isotope biomarker reflects bone Ca loss of the whole skeleton. In addition, the close correlation between Ca isotopes and biomarkers of bone demineralization suggest that early changes in bone demineralization are detected by Ca isotope values, long before radiological changes in BMD can manifest on DXA. Further studies are required to independently confirm that Ca isotope measurement provide a sensitive, non-invasive and radiation-free method for the diagnosis of osteoporosis.

<AbstractText>To measure type 1 serum amino-terminal propeptide procollagen (<em>P1NP</em>) and type 1 cross-linked C-terminal telopeptide collagen (CTX) before parathyroidectomy (PTX) in PHPT patients, correlating these measurements with bone mineral density (BMD) changes.</AbstractText><AbstractText>31 primary hyperparathyroidism (HPTP) were followed from diagnosis up to 12-18 months after surgery. Serum levels of calcium, parathyroid hormone (PTH) vitamin D, CTX, <em>P1NP</em>, and BMD were measured before and 1 year after surgery.</AbstractText><AbstractText>One year after PTX, the mean BMD increased by 8.6%, 5.5%, 5.5%, and 2.2% in the lumbar spine, femoral neck (FN), total hip (TH), and distal third of the nondominant radius (R33%), respectively. There was a significant correlation between BMD change 1 year after the PTX and CTX (L1-L4: r = 0.614, p < 0.0003; FN: r = 0.497, p < 0.0051; TH: r = 0.595, p < 0.0005; R33%: r = 0.364, p < 0.043) and <em>P1NP</em> (L1-L4: r = 0,687, p < 0,0001; FN: r = 0,533, p < 0,0024; TH: r = 0,642, p < 0,0001; R33%: r = 0,467, p < 0,0079) preoperative levels. The increase in 25(OH)D levels has no correlation with BMD increase (r = -0.135; p = 0.4816). On linear regression, a minimum preoperative CTX value of 0.331 ng/mL or <em>P1NP</em> of 37.9 ng/mL was associated with a minimum 4% increase in L1-L4 BMD. In TH, minimum preoperative values of 0.684 ng/mL for CTX and 76.0 ng/mL for <em>P1NP</em> were associated with a ≥ 4% increase in BMD.</AbstractText><AbstractText>PHPT patients presented a significant correlation between preoperative levels of turnover markers and BMD improvement 1 year after PTX.</AbstractText>

OBJECTIVE

Growing evidence suggests the presence of a complex interplay between hypertension as well as type 2 diabetes mellitus (DM) and osteoporosis. The present study was designed to investigate a possible effect of type 2 DM on bone remodelling markers such as osteoprotegerin and N-terminal propeptide of type 1 collagen (P1NP) in hypertensive patients.

METHODS

The 100 study participants were divided into three groups according to the presence of DM and hypertension: group one included diabetic hypertensive subjects, group 2 included hypertensive subjects without diabetes and group 3 included subjects without hypertension and without DM (controls). Blood sampling for metabolic parameters, including osteoprotegerin, P1NP, adiponectin, fasting glucose, HbA1c , CRP, homeostasis model assessment-insulin resistance, homeostasis model assessment-beta function was performed.

RESULTS

Circulating P1NP increased from group 1 to group 3 in a continuous fashion. P1NP was significantly lower in hypertensive subjects with DM (group 1), than in groups 2 and 3 (p < 0.0001). P1NP, was marginally lower in diabetic hypertensive subjects as compared with nondiabetic subjects with hypertension (p = 0.079). Circulating osteoprotegerin did not differ significantly between groups (p = 0.593).

CONCLUSIONS

In the present study, bone formation marker, P1NP, was significantly lower in diabetic hypertensive subjects as compared with nondiabetic subjects with and without hypertension. P1NP was inversely associated with parameters of glucose homeostasis such as fasting glucose, HbA1c and positively with homeostasis model assessment-beta cell function. Type 2 DM was associated with an adverse effect on bone formation independently of age, sex and exposure to anti-diabetic drugs.

OBJECTIVE

Orthosiphon stamineus (OS) or Misai Kucing (Java tea) is a popular herbal supplement from Southeast Asia for various metabolic, age-related diseases. This study investigated the potential use of OS leaf extracts to ameliorate osteoporosis in ovariectomized rats.

METHODS

Fifty-six female Sprague-Dawley rats were randomly allocated into eight groups (n = 7): SHAM (healthy sham control); OVX (ovarietomized) nontreated rats (negative control); OVX + Remifemin (100 mg/kg body weight), and 2% green tea extract (positive controls); OVX + OS 50% ethanolic and aqueous extracts, both at either 150 or 300 mg/kg. After 16 weeks, the rats' bones and blood were evaluated for osteoporosis indicators (protein and mRNA expressions), micro-computed tomography for bone histomorphometry, and three-point bending test for tibia mechanical strength.

RESULTS

The extracts dose-dependently and significantly (P < 0.05) improved bone strength and flexibility, bone mineral density, bone formation protein markers (P1NP), and bone histomorphometry. All extracts reduced the inflammation biomarker (interleukin-6). The extracts up-regulated osteoblastogenesis (bone morphogenetic protein-2) and collagen-1 synthesis (collagen type 1 alpha-1) mRNA expressions, and down-regulated bone resorption (TNFSF11 and nuclear factor-kappa B) mRNA expressions. Both the water and 50% ethanolic extract were effective. The effective dose is equivalent to 25 to 50 mg/kg extract for humans.

CONCLUSIONS

The extract showed bone-protective and antiosteoporotic effects (improving bone strength, flexibility, bone density, and bone morphometry) by reducing inflammation and the bone resorption biomarkers, while enhancing bone formation biomarkers and collagen synthesis.

The present study investigates the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) in male patients with ankylosing spondylitis (AS). We demonstrated that monocytes from these patients display a lower capacity to generate osteoclasts compared to cells from healthy controls, and osteoclastogenesis was negatively correlated with disease duration.

BACKGROUND

Ankylosing spondylitis (AS) is a disease characterized by new bone growth that leads to syndesmophyte formation but AS patients frequently present with low bone mineral density/fractures. Osteoclastogenesis in AS patients is poorly studied and controversial. The aim of this study is to determine if the osteoclastogenic capacity of PBMCs is different in AS patients compared to controls and the relationship between osteoclastogenesis and clinical/laboratory parameters.

METHODS

PBMCs from 85 male AS patients and 59 controls were tested for CD16+ cells and induced to differentiate into osteoclasts over 3 weeks in vitro. Serum levels of RANKL, osteoprotegerin (OPG), C-terminal telopeptide of type I collagen (CTX), and amino-terminal pro-peptide of type I collagen (P1NP) were also evaluated.

RESULTS

PBMCs from AS patients had fewer CD16+ cells and produced fewer osteoclasts compared to controls. Apoptosis occurred less frequently in osteoclasts obtained from AS patients than in osteoclasts from the controls. A lower RANKL/OPG and CTX/P1NP were observed in AS patients compared to controls. AS patients taking NSAIDs presented no difference regarding the number of OCs produced and the percentage of CD16+ cells compared to controls. However, patients taking TNF inhibitors (TNFi) presented lower OC numbers than controls. A negative correlation was demonstrated between the number of osteoclasts generated from PBMCs of AS patients and disease duration.

CONCLUSIONS

Monocytes from male AS patients display a lower capacity to generate osteoclasts in vitro compared to cells from controls. Osteoclastogenesis was negatively correlated with disease duration. This finding supports the idea that osteoclasts play a role in the physiopathology of bone disease in AS patients.

Type 2 diabetes (T2DM) is associated with increased risk of fractures. Soy supplementation has been shown to have a beneficial effect on bone turnover markers (BTM) in postmenopausal women. However, the effect of soy supplementation on BTM in T2DM and particularly in men is unclear. We performed an analysis of a randomized double blind parallel study of 200 men with T2DM treated with soy, either with or without isoflavones. Outcome measures were type I collagen crosslinked beta C-telopeptide (βCTX), and type 1 procollagen-N-propeptide (P1NP). The men, with a total testosterone <12 nmol/L, were treated with 15 g soy protein containing 66 mg of isoflavones (SPI) or 15 g soy protein alone without isoflavones (SP) daily for three months. There was a 15% reduction in βCTX after three months of SPI compared to SP supplementation. There was no significant difference in P1NP with either SPI or SP supplementation. There was a significant linear correlation between the reduction in βCTX in the SPI group with the reduction in HbA1c (r2 = 0.42; p = 0.04) and HOMA-IR (r2 = 0.54; p = 0.02). Our study indicates that there was a significant reduction in bone resorption following 3 months of SPI supplementation that correlated with an improvement of glycemic control in men with T2DM.

METHODS

Retrospective observational study.

OBJECTIVE

We investigated whether bone turnover markers could be a useful indicator for prediction of nonunion.

BACKGROUND

Nonunion is a major complication of lumbar spinal fusion surgery. The involvement of bone turnover in the process of bony union in spinal fusion surgery is, however, poorly understood.

METHODS

Of the 74 patients analyzed, 13 were diagnosed with nonunion. We evaluated the significance of the following risk factors: age, sex, number of fused segments, serum levels of total alkaline phosphatase, procollagen type 1 amino-terminal propeptide (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and albumin, and history of diabetes mellitus, cigarette smoking, or alcohol use. We also defined the bone turnover ratio (BTR) as a value that equals serum TRACP-5b concentration divided by serum P1NP concentration to evaluate patients' individual bone turnover balance and investigated the significance of BTR as a risk factor.

RESULTS

Univariate analysis showed that older age, malnutrition, and lower P1NP are risk factors for nonunion. Stepwise logistic regression analysis revealed that in the presence of lower P1NP, higher TRACP-5b becomes a risk factor. Furthermore, we identified BTR as the most significant risk factor for nonunion. The optimum cut-off value of BTR by receiver-operating characteristic curve was 11.74.

CONCLUSIONS

These findings show a relation between bone turnover and nonunion after spinal fusion surgery. The measurement of bone turnover markers could potentially be used to predict nonunion after spinal fusion surgery.

METHODS

4.

OBJECTIVE

Parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) are elevated in secondary hyperparathyroidism. In hemodialysis, higher dialysate calcium (1.5 mmol/L) induces intradialytic suppression of iPTH, whereas its impact on FGF23 and markers of bone metabolism is unknown. We assessed the time course of FGF23 and markers of bone metabolism in relationship to dialysate calcium.

METHODS

In this prospective cohort study of 19 patients on maintenance hemodialysis, we measured serum calcium (sCa), inorganic phosphate (iP), blood urea nitrogen (BUN), β2-microglobulin (ßMG), iPTH, FGF23, aminoterminal propeptide type 1 procollagen (P1NP), C-telopeptide of type I collagen for bone degradation (CTX-I), osteocalcin (OC), bone specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP5b) during a single hemodialysis session at baseline, 1, 2, and 3h of dialysis. The time course of measured parameters was compared according to groups of prescribed dialysate calcium of 1.25 mmol/L and 1.5 mmol/L.

RESULTS

iPTH declined in the 1.5 mmol/L dialysis group as serum calcium increased whereas it tended to increase in the 1.25 mmol/L group without significant changes in serum calcium. Patients on long-term dialysate calcium of 1.5 mmol/L had significantly lower CTX-I levels and tended to lower levels of iPTH, FGF23, OC, P1NP and TRAP5b at the start of dialysis compared to those on 1.25 mmol/L. CTX-I, FGF23 and OC but not BALP, P1NP and TRAP5b decreased during dialysis independent of dialysate calcium.

CONCLUSIONS

In spite of immediate effects on iPTH, dialysate calcium does not acutely affect other parameters of bone and mineral metabolism.

OBJECTIVE

Dialysate calcium concentration is known to have both immediate and longer-term impact on parathyroid hormone levels in hemodialysis patients. Little is known about the acute impact of dialysate calcium on bone metabolism. In this cross-sectional study of prevalent hemodialysis patients, we found no evidence of immediate short-term dialysate calcium-induced changes of fibroblast growth factor 23 or anabolic and catabolic markers of bone turnover during hemodialysis. However, differences in CTX-I and to a lesser extent other parameters between groups of higher and lower dialysate calcium suggest a longer-term effect that remains to be validated.

CONCLUSIONS

Predictors of bone mineral density (BMD) loss are additional tools in the management of osteoporosis in premenopausal women with systemic lupus erythematosus (SLE). This study provides original evidence that N-terminal propeptide of type 1 collagen (P1NP), the most specific bone formation marker, is a predictor of BMD loss in this group of women.

BACKGROUND

SLE is associated with a high risk of low bone mass/fractures but this risk is still controversial in premenopausal women. Our aim was to determine the 1 year incidence of BMD loss in premenopausal SLE women and the value of bone turnover markers as predictors of this complication.

METHODS

This study enrolled a convenience sample of 63 premenopausal SLE patients. BMD was evaluated by dual X-ray absorptiometry at lumbar spine and hip at baseline and after 12 months. BMD changes above the least significant change were considered significant. Serum levels of P1NP and CTX (electrochemiluminescence), OPG, and RANKL (ELISA) were determined at baseline.

RESULTS

Mean age was 31.1±6.8 years, and disease duration was 5.25±3.8 years. 36.5 % of patients presented BMD loss and 17.5 % BMD gain at lumbar spine and/or hip. Patients were divided in three groups: BMD loss (BL), no BMD change (NC), and BMD gain (BG). Patients with BL and NC received similar cumulative/mean/maximum glucocorticoid doses during the study, but patients with BG received lower doses (p<0.05). Baseline P1NP levels were different in the groups (BL: 36.95±23.37 vs. NC: 54.63±30.82 vs. BG: 84.09±43.85 ng/mL; p=0.031 BL vs. NC, p<0.001 BL vs. BG, and p=0.039 NC vs. BG). There was no difference in CTX, OPG, or RANKL levels. After multivariate analysis, P1NP remained as an independent risk factor for BMD loss (p<0.03).

CONCLUSIONS

This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of BMD loss over 12 months in premenopausal SLE patients.

Context: The correlation between Fibrous Dysplasia/McCune-Albright syndrome (FD/MAS) skeletal disease burden on Na[18F]F-PET-CT and serum bone turnover markers (BTMs) was recently described. The effect of treatment on lesional fluoride burden in FD/MAS is unknown.

Objective: To investigate treatment response measurements in FD/MAS patients who underwent Na[18F]F-PET-CT and treatment with antiresorptives.

Design: Observational case series.

Setting: Academic center of expertise for rare bone diseases.

Patients: 15 consecutive patients with FD/MAS with baseline and follow-up Na[18F]F-PET-CT-parameters of healthy bone and FD lesions, BTMs and pain scores at start of denosumab (n=8) and non-denosumab patients (n=7).

Main outcome(s): On Na[18F]F-PET-CT the Volumetric measures of FD-burden (FTV) and 'Fraction affected skeleton' (FAS), represented the portion of the skeleton affected. This was correlated with BTMs and pain.

Results: Disease activity decreased significantly, with FTV 361cm 3 to 97cm 3, p=0.018 in denosumab-treated patients, not in non-denosumab patients (p=0.249). Serum P1NP and Alkaline Phosphatase (ALP) decreased significantly: 82ng/mL vs 55ng/mL, p=0.023 and 119 IU/L vs 84 IU/L, p=0.020, respectively. In denosumab-treated patients pain scores improved leading to pain medication reduction. This correlated with lesional uptake whilst healthy bone activity did not change. BTMs and FTV correlated positively, P1NP r=0.730; p<0.001 and ALP r=0.406; p=0.006, as dis change in BTMs and FTV: P1NP (p=0.032) and ALP (p=0.024). FAS strongly correlated with treatment-induced decrease in ALP (p=0.027) and P1NP (p=0.009).

Conclusion: Na[18F]F-PET-CT captured treatment-induced lesional changes which correlated with BTMs and pain reduction. Therefore Na[18F]F-PET-CT can be used as an objective local parameter of response to denosumab treatment in FD/MAS.

Keywords: McCune Albright; Sodium Fluoride PET-CT; bisphosphonates; denosumab; fibrous dysplasia; follow-up.

This study evaluated the levels of bone turnover markers (BTMs) and investigated relationships between them and bone mineral density (BMD) in postmenopausal women in China suburban district. The prevalence of osteoporosis was 25.03 % at lumbar spine and 6.23 % at femoral neck, and BTMs were negatively correlated with BMDs.

The aims of this study were to evaluate the levels of bone turnover markers (BTMs), including serum N-terminal procollagen of type I collagen (P1NP), beta C-terminal cross-linked of type I collagen (β-CTX), 25-hydroxyvitamin D [25(OH)D], and parathyroid hormone (PTH), and to investigate relationships between these markers and bone mineral density (BMD) as well the prevalence of osteoporosis in postmenopausal women of suburban district.

A population of 4822 postmenopausal women aged 55-69 years old (62.22 ± 6.75) from the suburban district was recruited voluntarily. BMD was measured at the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry; 2251 women in this group had the serum BTMs 25(OH)D and PTH tested.

The prevalence of osteoporosis was 25.03 % at lumbar spine and 6.23 % at femoral neck. The median (interquartile range) values of serum P1NP, β-CTX, 25(OH)D, and PTH were 59.3 ng/mL (44.7-75.52), 0.370 ng/mL (0.280-0.490), 23.0 ng/mL (17.1-30.5), and 31.4 pg/mL (24.9-39.7), respectively. Serum P1NP and β-CTX levels presented significantly negative correlations with BMDs at the all the sites (Betastd = -0.098 to -0.208, respectively, P < 0.001), whereas PTH levels were negatively correlated with BMDs of the femoral neck and total hip (Betastd = -0.062 and -0.054, P < 0.01, respectively). Serum 25(OH)D had positive associations with BMDs at total hip (Betastd = 0.051, P < 0.01).

The BMD of postmenopausal women in China suburban area is higher than that in downtown area, and over 60 % of the participants had their serum 25(OH)D level over 20 ng/mL. BTMs were negatively correlated with BMDs, suggesting that BTMs are reliable factors for early declines in BMD.

Sustained hypoxia inhibits osteogenesis and osteoblast differentiation by downregulating the expression of runt-related transcription factor 2 (Runx2). MicroRNAs (miRNAs) have been shown to regulate osteogenesis and osteoblast differentiation. In the present study, we profiled miRNAs, with microRNA array and quantitative real-time polymerase chain reaction (RT-PCR) methods, in mouse osteoblast (MC3T3-E1) cells under hypoxia. Then, we investigated regulation by miRNA-21-5p on the expression of Runx2 and other osteoblast differentiation-associated markers via gain-of-function and loss-of-function strategies. We found that expression of miRNA-21-5p, miRNA-210-5p, and other eight miRNAs was upregulated significantly in hypoxia-treated MC3T3-E1 cells. miRNA-21-5p overexpression downregulated the expression of the mRNA and protein of suppressor of mothers against decapentaplegic (SMAD7) markedly, the 3'-untranslated region (3'-UTR) of which was highly homologous with the miRNA-21-5p sequence. miRNA-21-5p overexpression upregulated the protein expression of Runx2 in hypoxia-treated MC3T3-E1 cells, although mRNA expression of Runx2 and other osteoblast differentiation-associated molecules (eg, osteocalcin, procollagen type 1 amino-terminal propeptide, P1NP) were not regulated by it; such upregulation was SMAD7-dependent. In conclusion, hypoxia-responsive miRNA-21-5p promoted Runx2 expression (at least in part) by targeting the 3'-UTR and downregulating SMAD7 expression. Our study suggests a protective role of miRNA-21-5p in promoting osteoblast differentiation under hypoxia.

Bone disorders are common in children with end-stage liver diseases, especially those associated with cholestasis. Abnormal hepatocyte function, disordered vitamin D metabolism and calcium-phosphorous homeostasis, malnutrition, and immunosuppressive treatment are potential risk factors of bone tissue pathology before and after transplantation. The aim of the study was to analyze the long-term effect of successful living-related liver transplantation (LRLTx) on skeletal status and bone metabolism in cholestatic children. Eighteen cholestatic children (1.4±0.5yr old; 12 females [F]/6 males [M]) qualified for LRLTx were analyzed; 16 (5F/11M) of them participated in long-term observation (V4). Serum levels of osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), cross-linked telopeptide of type 1 collagen (CTx), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3), parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) were assayed before (V0) and 6mo (V1), 12mo (V2), 18mo (V3), and 4.4yr (V4) after LRLTx. Total body bone mineral content (TBBMC) and total body bone mineral density (TBBMD) were measured by dual-energy X-ray absorptiometry (DXA) at the same pattern. Before LRLTx, the OC, P1NP, CTx, IGF-I, and IGFBP-3 levels as well as TBBMC and TBBMD were decreased compared with age-matched control group. The mean serum levels of 25(OH)D and 1,25(OH)(2)D were within reference ranges from V0 to V4. After LRLTx, the OC, P1NP, CTx, IGF-I, and IGFBP-3 as well as TBBMC and TBBMD reached the age-matched reference values. At V4, the level of P1NP decreased below and the PTH increased above the reference range that coincided with reduced Z-scores of both TBBMC (-1.11±1.24) and TBBMD (-1.00±1.19). P1NP and CTx, both measured at V3, correlated with IGF-I at V2 (R=0.86, p=0.014 and R=0.78, p=0.021, respectively) and PTH at V3 for P1NP and V1 for CTx (R=0.64, p=0.048 and R=0.54, p=0.038, respectively). The TBBMC changes between V0 and V4 correlated with IGF-I (R=0.68, p=0.015) and 1,25(OH)(2)D (R=0.54, p=0.025), both assayed at V1. The change of TBBMC Z-scores between V0 and V4 correlated with P1NP at V1 (R=0.69, p=0.002). The TBBMD changes between V0 and V4 correlated with CTx at V1 (R=0.54, p=0.027) and P1NP change between V0 and V1 (R=0.51, p=0.038). In short-term observation, successful LRLTx led to bone metabolism normalization triggered by probable anabolic action of IGF-I and PTH and manifested by TBBMC and TBBMD increases. In long-term horizon, moderately impaired DXA assessed bone status coincided with disturbances in bone metabolism. Bone metabolism markers, especially P1NP and CTx, appeared to be good predictors of changes in bone status evaluated by DXA.

Previous studies indicate that human immunodeficiency virus (HIV)-infection and combination antiretroviral therapy (cART) can affect bone turnover. Furthermore, HIV-infected patients have lower bone mineral density (BMD) compared to a healthy reference population.

To evaluate the longitudinal effect of HIV-infection and cART on bone turnover markers (BTMs) and BMD in men with primary HIV-infection (PHI).

Thirty-five PHI-men were divided into two groups, those that received cART for the first time (n = 26) versus no-cART (n = 9). Dual-energy X-ray absorptiometry (DXA) was performed on femoral neck (FN), total hip (TH) and lumbar spine (LS) and BTMs (P1NP, alkaline phosphatase, osteocalcin, ICTP and CTX) were measured at baseline and follow-up.

At baseline, the median CD4+ T-cell count was 455 cells/mm3 (IQR 320-620) and plasma viral load 5.4 log10 copies/mL (IQR 4.7-6.0) in the cART treated group, compared to 630 (IQR 590-910) and 4.8 (IQR 4.2-5.1) in the untreated group. The median follow-up time was 60.7 weeks (IQR 24.7-96.0). All BTMs, except ICTP, showed a significant increase during cART versus no changes of BTMs in the untreated group. FN and TH BMD showed a significant decrease in both groups. LS BMD did not change in both groups.

Bone turnover increased in PHI-men treated with cART which was accompanied by a decrease in FN and TH BMD. No increase of bone turnover was seen in untreated PHI-men. Our study suggests that cART results in increased bone turnover and decreased BMD of the hip in PHI-men.

Introduction: Bone turnover markers (BTMs) can be used to monitor bone metabolism, while the actual clinical changing in hip fracture had not been certified to evaluate the changes of BTMs during the healing process after surgery of elderly hip fractures; and to get the effects of operation type, gender, serum 25(OH)D level, and age on bone turnover markers.

Materials and methods: A total of 100 elderly cases with hip fracture were selected, including 74 females and 26 males, and the patients were followed to 180-230 days after surgery. Serum levels of N-propeptide of type 1 collagen (P1NP), C-terminal crosslinking telopeptides of type 1 collagen (CTX), Osteocalcin (OC), and 25 hydroxy vitamin D (25OHD) were investigated. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry (DXA).

Results: (1) P1NP and CTX showed peak time at 30-60 days after operation, while OC keep going even at 180-230 days; P1NP showed less than 4 times elevation during healing, CTX and OC only had less than 2 times rise. (2) Female had higher serum CTX and OC than male, intramedullary nailing for intertrochanteric fracture patients had higher P1NP than hip replacement for femoral neck fracture patients, and both the degrees of increase were less than 50%. (3) Serum average 25(OH)D level had no effect on BTMs during the fracture healing; different from the young old (65-84 years), serum OC level of eldest older patients(≥ 85 years) decreased early in the process of fracture healing.

Conclusions: BTMs reached the peak level in 30-60 days after surgery, P1NP showed less than 4 times elevation, and CTX and OC had less than 2 times rise. It was not necessary to take gender into account when observing P1NP, and it was not necessary to take fracture and operation type into account when observing CTX and OC.

Keywords: Bone turnover markers; Fracture healing; Hip fracture; Osteoporosis.