There is a large individual variation in the bone remodelling markers (BRMs) osteocalcin (OC), procollagen 1 N-terminal propeptide (P1NP) and β-isomerized C-terminal telopeptide (β-CTx), as well as undercarboxylated osteocalcin (ucOC), at rest and in response to exercise. α-actinin-3 (ACTN3), a sarcomeric protein, is expressed in skeletal muscle and osteoblasts and may influence BRM levels and the cross-talk between muscle and bone. We tested the levels of serum BRMs in α-actinin-3 deficient humans (ACTN3 XX) at baseline, and following a single bout of exercise. Forty-three healthy Caucasian individuals were divided into three groups (ACTN3 XX, n=13; ACTN3 RX, n=16; ACTN3 RR, n=14). Participants completed a single session of High Intensity Interval Exercise (HIIE) on a cycle ergometer (8×2-min intervals at 85% of maximal power). Blood samples were taken before, immediately after, and three hours post exercise to identify the peak changes in serum BRMs. There was a stepwise increase in resting serum BRMs across the ACTN3 genotypes (XX>RX>RR) with significantly higher levels of tOC ~26%, P1NP ~34%, and β-CTX (~33%) in those with ACTN3 XX compared to ACTN3 RR. Following exercise BRMs and ucOC were higher in all three ACTN3 genotypes, with no significant differences between groups. Serum levels of tOC, P1NP and β-CTX are higher in men with ACTN3 XX genotype (α-actinin-3 deficiency) compared to RR and RX. It appears that the response of BRMs and ucOC to exercise is not explained by the ACTN3 genotype.

Lactation often affects calcium metabolism and induces bone loss. Calcium supplementation and a high calcium diet are recommended to prevent bone loss, especially during inadequate calcium intake. Our study aimed at determining bone loss in breastfeeding mothers, and if it occurred, whether it was site specific and there were correlations between serum bone turnover markers.

Since the 6-month exclusive breastfeeding is usually recommended in several countries, our study examined bone mineral density (BMD) in early (1-2 month), mid (3-4 month)-, and late (5-6 month) lactation compared with nonpregnant, nonlactating control women. Site-specific bone loss was monitored in lumbar vertebrae and femora. Bone turnover markers, that is, C-terminal telopeptide of type 1 collagen and N-terminal propeptide of type 1 collagen (P1NP), were determined by electrochemiluminescence immunoassays.

The onset of bone loss in exclusive breastfeeding mothers was site specific, for example, in the lumbar bone at mid-lactation and in the femoral bone in late lactation. Serum ionized calcium levels in late lactation were lower than the normal levels. In addition, a correlation was found between bone turnover marker, P1NP, and femoral BMD.

The onset of bone loss in exclusive breastfeeding mothers was site specific, and the lumbar bone was a vulnerable and perhaps better representative site for bone loss detection. It was suggested that the optimal starting time for calcium supplementation should be before the mid-lactation when the bone loss was observed. In addition, the biochemical marker that best predicted the onset of bone loss in lactating women was P1NP.

BACKGROUND

Global epidemic of diabetes is a serious health care concern because of its complications and consequently reduced life expectancy and increased morbidity. However, the bone turnover and thus bone health may be affected or even compromised by diabetes and its complications. The aim of this study was to assess whether bone turnover markers are associated with diabetes micro-vascular complications.

METHODS

A total of 204 type 2 diabetes patients (104 patients with diabetic micro-vascular complications (retinopathy and/or nephropathy) as a case group and 100 patients without retinopathy and/or nephropathy) as a control group were recruited in this case-control study. The biochemical and metabolic parameters and bone turnover markers were assessed in all patients.

RESULTS

Our findings showed serum levels of osteocalcin (OC) (p = 0.0001) and, carboxy-terminal collagen crosslinks (CTX) (p = 0.006) were higher in diabetic patients with both diabetic retinopathy and nephropathy compared with control group. However, there was no significant difference in serum levels of procollagen I aminoterminal propeptide (P1NP) between diabetic patients with diabetic retinopathy (DR) and/or diabetic nephropathy (DN) compared with control. In diabetes patients with complications, there were significant negative correlation between OC and CTX with estimated-glomerular filtration rate (e-GFR) and also positive correlation between each bone marker (OC and CTX) and PTH levels (p = 0.0001) and BUN (p = 0.0001). In a general linear model, after adjusting for age, sex and BMI, and microvascular complications, there was not any significant association between three bone turnover markers and metabolic markers including fasting glucose, insulin, and lipid profile. Among kidney markers, there were significant positive associations between serum levels of CTX and OC with BUN (p < 0.05) as well as PTH (p < 0.0001).

CONCLUSIONS

Our data suggest the possible role of PTH and BUN levels in modulating bone turnover markers in diabetic patients.

BACKGROUND

Current studies support the implication of metabolic changes associated with type 2 diabetes in altering bone metabolism, structure and resistance.

OBJECTIVE

We conducted a cross-sectional study on postmenopausal women aimed to analyze the differences in metabolic and bone profile in patients with and without type 2 diabetes Methods: We analyzed the metabolic and bone profile in postmenopausal women with and without type 2 diabetes(T2DM). Clinical, metabolic, hormonal parameters, along with lumbar, hip and femoral bone mineral density (BMD) and trabecular bone score (TBS) were evaluated.

RESULTS

56 women with T2DM(63.57±8.97 years) and 83 non-T2DM (60.21±8.77 years) were included. T2DM patients presented a higher value of body mass index (BMI) and BMD vs. control group (p 0.001; p=0.03-lumbar level, p=0.07-femoral neck and p=0.001-total hip). Also, BMI correlated positively with lumbar-BMD and glycated hemoglobin (HbA1c) (r=0.348, p=0.01; r=0.269, p=0.04), correlation maintained even after age and estimated glomerular filtration rate (eGFR) adjustment (r = 0.383, p = 0.005; r=0.237, p=0.08). Diabetic patients recorded lower levels of 25(OH)D(p=0.05), bone markers (p ≤0.05) and TBS(p=0.07). For the entire patient group we found a negative correlation between HbA1clevel and bone markers: r =-0.358, p = 0.0005-osteocalcin, r =-0.40, p = 0.0005-P1NP, r =-0.258, p = 0.005-crosslaps.

CONCLUSIONS

Our results indicate the presence of altered bone microarchitecture in T2DZ patients according to the TBS score, combined with lower levels of bone markers, with a statistically significant negative correlation between HbA1c level and bone markers.

HIV/hepatitis C virus (HCV) patients have a 3-fold increased fracture incidence compared to uninfected patients. The impact of HCV therapy on bone health is unclear. We evaluated bone turnover markers (BTM) in well-controlled (HIV RNA <50 copies/ml) HIV/HCV-coinfected patients who received pegylated interferon-α and ribavirin (PEG-IFN/RBV) in ACTG trial A5178. Early virologic responders (EVR: ≥2 log HCV RNA drop at week 12) continued PEG-IFN/RBV and non-EVRs were randomized to continuation of PEG-IFN alone or observation. We assessed changes in C-terminal telopeptide of type 1 collagen (CTX; bone resorption marker) and procollagen type I intact N-terminal propeptide (P1NP; bone formation marker), and whether BTM changes were associated with EVR, complete early virologic response (cEVR: HCV RNA <600 IU/ml at week 12), or PEG-IFN treatment. A total of 192 subjects were included. After 12 weeks of PEG-IFN/RBV, CTX and P1NP decreased: -120 pg/ml and -8.48 μg/liter, respectively (both p < 0.0001). CTX declines were greater in cEVR (N = 91; vs. non-cEVR (N = 101; p = 0.003). From week 12 to 24, CTX declines were sustained among EVR patients who continued PEG-IFN/RBV (p = 0.027 vs. non-EVR) and among non-EVR patients who continued PEG-IFN alone (p = 0.022 vs. Observation). Median decreases of P1NP in EVR vs. non-EVR were similar at weeks 12 and 24. PEG-IFN-based therapy for chronic HCV markedly reduces bone turnover. It is unclear whether this is a direct IFN effect or a result of HCV viral clearance, or whether they will result in improved bone mineral density. Further studies with IFN-free regimens should explore these questions.

BACKGROUND

Pathogenic role of TSH suppression in the damaged bone tissue, in contrast to increased concentrations of thyroid hormones is still unknown. The aim of study was to evaluate the relationship between serum TSH and biochemical bone turnover markers in postmenopausal women with normal thyroid function and to answer whether the differences in TSH concentration within reference range may affect bone metabolism.

METHODS

34 women (60-93 years old) admitted to the hospital after osteoporotic fracture participated in the study. Serum propeptide of type 1 procollagen (P1NP) as a bone formation marker and crosslinked C-terminal telopeptides (CTX-I), as a bone resorption marker and TSH were assayed.

RESULTS

Median P1NP (p=0,05) was significantly higher in the 1st tertile of TSH values (0,35-1,88 mlU/mL). In the 3rd tertile of TSH concentrations (3,42-4,94 mlU/mL), the highest CTX-I value was found that exceed the reference range for age. No differences were found in bone markers between a group of euthyroid and a group of subjects with TSH<0,35 mlU/mL. No relationship was observed between TSH and bone formation and resorption markers in the whole group of euthyroid postmenopausal women, however bone formation was found to be in the lower reference range for age in the euthyroid subjects as well as in these with decreased TSH. Weight and BMI correlated negatively with CTX (r=-0,68 p<0,03) in fractured women in the 1st tertile of TSH.

CONCLUSIONS

We found no consistent evidence that TSH concentrations within reference range was associated with changes in bone turnover markers.

Background: Epidural steroid injection (ESI) is widely used to manage low back pain. ESIs are commonly performed to treat pain accompanying intervertebral disc prolapse, spinal stenosis, facet joint pathologies, and other degenerative spinal pathologies. Corticosteroids for musculoskeletal conditions, regardless of the route of administration, can reduce bone mineral density (BMD) and increase the risk of fracture. With paraspinal administration of steroids, the severity of risk is enhanced as the steroid is being deposited in close proximity to bone. BMD and molecular markers of bone metabolism are the standard methods to assess the effect of any insult on bone strength and bone metabolism. Carboxy terminal crosslinked telopeptides of type 1 collagen (sCTX) and serum Procollagen Type I N-terminal propeptide (P1NP) are the reference markers of bone resorption and formation, respectively.

Objective: We conducted this study to determine the effect of ESI on BMD and bone turnover markers.

Study design: This was a prospective observational cohort study, involving a cohort of 264 patients between the ages of 40 to 60 years who were advised to undergo ESI at L3-4 or L4-5 by their pain physician.

Setting: Research was conducted at a tertiary care teaching hospital pain clinic in collaboration with the department of orthopaedics and radiodiagnosis.

Methods: Serum CTX-1, P1NP, and pre-ESI BMD of the spine, femur neck, and dual femur were evaluated at baseline; these same parameters were serially evaluated post ESI on follow-ups at 1, 3, and 6 months. Additional follow-up at 10 days post ESI was called for evaluation of bone turnover markers (BTMs). A paired t test was used to analyze changes in BMD and BTMs vs baseline within the group. Cumulative incidence and relative risk of moderate to markedly low BMD were calculated using standard formulas. Any fractures sustained during follow-ups were also evaluated thoroughly and quantified separately. A P value less than .05 was considered statistically significant.

Results: The proportion of pre-ESI moderately to markedly low BMD was 10.22% in the study population. There was a statistically significant increase in serum CTX 10 days post ESI which persisted at the one-month and 3-month follow-ups. There was no significant change in serum P1NP level post ESI after 7 days and at the one-month follow-up. The mean value of serum P1NP was, however, significantly higher at the 3-month follow-up. Statistical comparison of the mean BMD value at the spine and femur neck revealed statistically significant decline 3 months post ESI. There was no significant impact of ESI on the total femur BMD. The cumulative incidence of moderately low to markedly low BMD over a period of 6 months in the study population was 45 out of 223, i.e., 20.17%.

Limitations: The study's primary limitations included its high dropout rate, a larger reference range for BTMs, making them a less specific tool for comparison, and the absence of a control group. ESI has a negative impact on the BMD of the hip and spine. Reduced BMD should be considered as a potential side effect of ESI.

Keywords: Bone mineral density; bone turnover markers; epidural steroid injection; low back ache; steoporosis.

OBJECTIVE

To assess the relationship between total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC) and a range of markers of glucose homeostasis in type 1 diabetes.

METHODS

One hundred and eight community-based Caucasian adults (53 males, 55 females) without a history of osteoporosis and with a mean±SD age 39.1±15.1years and median [inter-quartile range] type 1 diabetes duration of 14.3 [6.6-20.4] years participated in a cross-sectional study of bone health. Fasting serum glucose and HbA1c, and serum tOC, ucOC, total adiponectin and procollagen type 1N-terminal propeptide (P1NP) were measured using validated assays, and daily insulin dose and estimated glucose disposal rate (eGDR) were calculated. Multiple linear regression was used to determine independent associates of markers of glucose homoeostasis (HbA1c, fasting serum glucose, daily insulin dose, eGDR and serum total adiponectin).

RESULTS

In sex-adjusted multivariable regression analyses, ln(serum P1NP) was independently and inversely associated with ln(HbA1c) and ln(serum adiponectin) (P≤0.013). Other associations included those between ln(serum vitamin D) and ln(HbA1c) (inversely), daily insulin dose (inversely) and eGDR (positively) (P≤0.035), as well as an inverse relationship between overweight by waist circumference and ln(serum adiponectin) (P<0.001). Ln(serum tOC) and ln(serum ucOC) were not independently associated with any glucose homoeostasis marker.

CONCLUSIONS

These data from well characterized community-based adults with type 1 diabetes do not suggest that there is a role for osteocalcin in the potentially complex interplay between the skeleton and energy homoeostasis in type 1 diabetes.

Baseline and on-treatment characteristics, including age, obesity, calcium intake, and bone turnover markers, may predict the bone mineral density (BMD) response in women with postmenopausal osteoporosis (PMO) to 1 to 2 years of antiresorptive therapy and/or vitamin D supplementation. This study aimed to explore clinical characteristics associated with 12-month BMD improvement in Chinese women with postmenopausal osteoporosis (PMO).In this post hoc analysis of a previous phase 3 multicenter, randomized controlled trial, Chinese PMO women who were treated with once weekly alendronate 70 mg/vitamin D3 5600 IU (ALN/D5600) or once daily calcitriol 0.25 mcg, and had measurements of 1-year lumbar spine BMD (LS-BMD) and on-treatment bone turnover markers (BTMs) were included in the analysis.In Chinese PMO patients on ALN/D5600, 1-year LS-BMD change was negatively correlated with age (β = -0.00084, P < .01), dietary calcium (β = -0.0017, P = .07), and procollagen type 1 N-terminal propeptide (P1NP) change at month 6 (β = -0.000469, P = .0016), but positively with body mass index (BMI) (β = 0.00128, P = .08); baseline P1NP above the median was associated with a significantly greater BMD percentage change at the lumbar spine (P = .02) and the total hip (P = .0001). In the calcitriol group, a significant 1-year LS-BMD increase was associated with BMI (β = 0.0023, P = .02), baseline P1NP (β = 0.00035, P = .0067), history of prior vertebral fracture(s) (β = 0.034, P < .0001) and baseline serum 25(OH)D level (β = -0.00083, P = .02).The presented findings from Chinese postmenopausal osteoporotic women suggested clinically meaningful baseline and on-treatment characteristics predicting BMD improvement after 1 year of ALN/D5600 treatment, which differed from calcitriol treatment with baseline identifiable associations. The study remained exploratory and further accumulation of evidence is needed.

OBJECTIVE

Menopause transition is associated with chronic conditions such as osteoporosis and cardiovascular disease. Concerns about the long-term safety of menopausal hormone therapy make alternative natural methods an appealing approach to management. The aim of this study was to examine the effect of royal jelly (RJ) on cardiovascular and bone turnover markers in clinically healthy postmenopausal women.

METHODS

A total of 36 postmenopausal healthy women were studied in a prospective follow-up study. Participants received 150 mg of RJ daily for three months. Circulating cardiovascular risk markers [lipid profile, antithrombin-III (ATIII), Protein C, Protein S, Plasminogen Activator Inhibitor-1 (PAI-1)] and bone turnover parameters [Total calcium, phosphate (P), parathormone (PTH), total type-1 Procollagen N-terminal (P1NP), Osteocalcin and serum collagen type 1 cross-linked C-telopeptide (CTX)] were compared between the baseline and the three-month visit.

RESULTS

The RJ used in this study was particularly rich in medium chain fatty acids, compounds with hypolipidemic properties, which comprised 63% of the dry weight fatty content. RJ treatment resulted in a significant increase in high density lipoprotein - cholesterol (HDL-C 60.2 mg/dL ± 12.3 versus 64.7 mg/dL ± 13.9, 7.7% increase, p = 0.0003), as well as in a significant decrease in low density lipoprotein - cholesterol (LDL-C, 143.9 ± 37.5 versus 136.2 ± 32, 4.1% decrease, p = 0.011) and in total cholesterol (224.4 ± 38.6 to 216.1 ± 36.5, 3.09% decrease, p = 0.018). No statistical significant changes were found in the remaining cardiovascular or the bone turnover parameters.

CONCLUSIONS

The intake of RJ 150 mg for three months is associated with significant improvements of the lipid profile of postmenopausal women. RJ supplementation may offer an alternative method of controlling the menopause - associated dyslipidemia.

OBJECTIVE

To examine how the development of obesity and the associated insulin resistance affect bone structural and material properties, and bone formation and resorption markers in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.

METHODS

This was a 36-week study of sedentary, hyperphagic, male OLETF rats (OLETF-SED), exercise-treated OLETF rats (OLETF-EX) and sedentary non-hyperphagic controls (LETO-SED) with data collection at 13, 20, and 40 weeks of age (n = 5-8 animals per group per timepoint).

RESULTS

Body mass and fat (%) were significantly greater in OLETF-SED versus controls. OLETF-SED were insulin resistant at 13 and 20 weeks, with overt diabetes by 40 weeks. At 13weeks, OLETF-SED had lower total body BMC and BMD and serum P1NP compared with LETO-SED. Differences in total body BMC and BMD between OLETF-SED and LETO-SED persisted at 20 weeks, with reductions in total and cortical BMD of the tibia. OLETF-SED also had lesser femur diameter, cross-sectional area, polar moment of area, and torque at fracture than LETO-SED. By 40 weeks, OLETF-SED had elevated bone resorption and reduced intrinsic bone strength. OLETF-EX did not show the excessive weight gain, obesity, insulin resistance or diabetes observed in OLETF-SED. OLETF-EX had greater BMD than OLETF-SED, and structural and material properties of the femur were significantly increased in OLETF-EX relative to OLETF-SED and LETO-SED.

CONCLUSIONS

The negative skeletal effects of excessive adiposity and insulin resistance were evident early in the progressive obesity with lasting negative impacts on intrinsic and extrinsic bone strength. Exercise protected against obesity-associated skeletal changes with marked benefits on the biomechanical properties of bone.

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) surgery of the right ureter. The left kidney (contralateral) was used as internal control. Six rats were sham operated and used as the control group. Rats were terminated two weeks after the surgery; the kidneys were excised and precision-cut kidney slices (PCKSs) were cultured for five days in serum-free medium. Markers of collagen type I formation (P1NP), collagen type I and III degradation (C1M and C3M), and α-smooth muscle actin (αSMA) were measured in the PCKS supernatants by enzyme-linked immunosorbent assay. P1NP, C1M, C3M, and α-SMA were increased up to 2- to 13-fold in supernatants of tissue slices from the UUO-ligated kidneys compared with the contralateral kidneys (P < 0.001) and with the kidneys of sham-operated animals (P < 0.0001). The markers could also reflect the level of fibrosis in different animals. The UUO PCKS ex vivo model provides a valuable translational tool for investigating the extracellular matrix remodeling associated with renal interstitial fibrosis.

HIV-infected adults have increased fracture risk.

To generate pilot data comparing bone density, structure, and strength between HIV-infected adults with and without a prior fracture.

Adults with and without a prior fracture after their HIV diagnosis were matched 1:1 based on age, sex, race, and smoking history. Participants underwent dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), hip structural analyses (HSA), vertebral fracture assessment (VFA), high-resolution peripheral quantitative tomography (HR-pQCT) and measurement of bone turnover markers. Results were compared between cases and controls, with differences expressed as percentages of control group values.

23 pairs were included. On DXA, cases had lower areal bone mineral density (aBMD) at the total hip (median difference in T-score -0.25, p = 0.04), but not the lumbar spine (median difference in T-score 0.10, p = 0.68). Cases had greater abnormalities in HSA and most HR-pQCT and HSA measures, by up to 15%. VFA revealed two subclinical fractures among cases but none among controls. TBS, CTX, and P1NP levels were similar between groups, with differences of 1.9% (p = 0.90), 9.7% (p = 0.55), and 10.0% (p = 0.24), respectively. For each parameter, we report the median and interquartile range for the absolute and relative difference between cases and controls, the correlation between cases and controls, and our recruitment rates, to inform the design of future studies.

These pilot data suggest potential differences in bone structure, estimated bone strength, and asymptomatic vertebral fractures among HIV-infected adults with and without fracture, warranting further study as markers of fracture risk in HIV.

Recent studies have shown that Dickkopf-related protein (DKK1) and sclerostin decrease when a complete response (CR) is obtained after chemotherapy in myeloma multiple (MM). To study variations in DKK1, sclerostin and P1NP in patients treated for MM, between complete response (CR) and relapse, we carried out a prospective study ancillary to the IFM 2009 protocol (IFM). The aim of IFM was to compare progression-free survival between patients treated with chemotherapy with or without transplantation. We selected 69 patients who reached CR and relapsed. We assayed by ELISA: DKK1, sclerostin and P1NP at 3 end points T1: CR, T2: 4 months before relapse and T3: relapse. There was a significant increase in DKK1 and sclerostin between T1, T2 and T3. (DKK1 medians (IQR): T1 = 30 pmol/l (20.4-41.1), T2 = 37.4 pmol/l (29.8-49.4), p < 0.0001, T3 = 42 pmol/l (33.8-55.5), p < 0.0001 sclerostin medians (IQR): T1 = 0.57 (0.47-0.69), T2 = 0.62 ng/ml (0.53-0.79), p < 0.0001, T3 = n0.64 ng/ml (0.56-0.79), p = 0.005). No significant variation was detected in the levels of P1NP. No association was observed between the characteristics of the MM, or the treatment received and the variation between T1-T3 for DKK1, sclerostin or P1NP. A significant increase in DKK1 and sclerostin was observed four months before relapse.

OBJECTIVE

To investigate the effects of calcium and vitamin D supplementation on bone turnover marker levels, muscle strength and quality of life in postmenopausal Chinese women.

METHODS

A total of 485 healthy postmenopausal Chinese women (63.44±5.04 years) were enrolled in this open-label, 2-year, prospective, community-based trial. The participants were divided into group A, B, C, which were treated with calcium (600 mg/d) alone, calcium (600 mg/d) and cholecalciferol (800 IU/d) or calcium (600 mg/d) and calcitriol (0.25 μg/d), respectively, for 2 years. Serum levels of 25-hydroxyvitamin D, parathyroid hormone, β-CTX and P1NP were measured, and the muscle strength and quality of life were assessed at baseline and at 12- and 24-month follow-ups.

RESULTS

Four hundred and sixty one participants completed this study. Serum levels of 25-hydroxyvitamin D were significantly increased in group C, but not changed in groups A and B at 24-month follow-up. Serum levels of parathyroid hormone, bone turnover marker β-CTX and bone formation marker P1NP were significantly decreased in group C, while serum levels of β-CTX were increased in group A at 24-month follow-up. The participants in group C maintained the grip strength, while those in groups A and B exhibited decreased grip strength at 24-month follow-up. The quality of life for the participants in groups B and C remained consistent, but that in group A was deteriorated at 24-month follow-up.

CONCLUSIONS

Supplementation with calcitriol and calcium modifies the bone turnover marker levels, and maintains muscle strength and quality of life in postmenopausal Chinese women, whereas supplementation with cholecalciferol and calcium prevents aging-mediated deterioration in quality of life.

Effects of the chemotherapeutic agent etoposide on the skeleton were determined in mice. Numbers of bone marrow cells were reduced and myeloid cells were increased. Bone volume was significantly decreased with signs of inhibition of bone formation. Etoposide after pre-treatment with zoledronic acid still reduced bone but overall bone volume was higher than with etoposide alone.

Chemotherapeutics target rapidly dividing tumor cells yet also impact hematopoietic and immune cells in an off target manner. A wide array of therapies have negative side effects on the skeleton rendering patients osteopenic and prone to fracture. This study focused on the pro-apoptotic chemotherapeutic agent etoposide and its short- and long-term treatment effects in the bone marrow and skeleton.

Six- to 16-week-old mice were treated with etoposide (20-25 mg/kg) or vehicle control in short-term (daily for 5-9 days) or long-term (3×/week for 17 days or 6 weeks) regimens. Bone marrow cell populations and their phagocytic/efferocytic functions were analyzed by flow cytometry. Blood cell populations were assessed by CBC analysis. Bone volume and area compartments and osteoclast numbers were measured by microCT, histomorphometry, and TRAP staining. Biomarkers of bone formation (P1NP) and resorption (TRAcP5b) were assayed from serum. Gene expression in bone marrow was assessed using qPCR.

Flow cytometric analysis of the bone marrow revealed short-term etoposide reduced overall cell numbers and B220+ cells, with increased marrow apoptotic (AnnexinV+PI-) cells, mesenchymal stem-like cells, and CD68+, CD45+, and CD11b+ monocyte/myeloid cells (as a percent of the total marrow). After 6 weeks, the CD68+, Gr1+, CD11b+, and CD45+ cell populations were still relatively increased in etoposide-treated bone marrow. Skeletal phenotyping revealed etoposide decreased bone volume, trabecular thickness, and cortical bone volume. Gene expression in the marrow for the leptin receptor and CXCL12 were reduced with short-term etoposide, and an increased ratio of RANKL/OPG mRNA was observed. In whole bone, Runx2 and osteocalcin gene expressions were reduced, and in serum, P1NP was significantly reduced with etoposide. Treatment with the antiresorptive agent zoledronic acid prior to etoposide increased bone volume and improved the etoposide-induced decrease in skeletal parameters.

These data suggest that etoposide induces apoptosis in the bone marrow and significantly reduces parameters of bone formation with rapid reduction in bone volume. Pre-treatment with an antiresorptive agent results in a preservation of bone mass. Preventive approaches to preserving the skeleton should be considered in human clinical studies.

Systemic infection and inflammation in men are associated with bone loss. Rodent studies have elucidated the pathways mediating the effects of bacterial lipopolysaccharide (LPS), activated immune cells and hormones on bone. Here we investigate the changes in biochemical parameters of bone turnover following human endotoxemia, an experimental model of self-limiting systemic infection and inflammation. Ten healthy men received in a randomised, placebo-controlled, cross-over trial once placebo and once 2 ng/kg Escherichia coli endotoxin (LPS). During the following 6 h we monitored parathyoid hormone (PTH) and osteopontin (OPN), a multifunctional protein related to bone pathophysiology, as well as biochemical markers of bone turnover: C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC). In LPS sessions there was a transient fall in PTH at 3 h (p=0.009) and a nearly two-fold increase in OPN levels after 6 h (LPS: 155+/-19 pg/ml; placebo: 85+/-13 pg/ml, p<0.001). LPS gradually reduced CTX levels (LPS: 0.44+/-0.4 pg/ml; placebo: 0.59+/-0.06 pg/ml, p=0.003), P1NP showed a peak at 4 h (LPS: 89.9+/-14.7 pg/ml; placebo: 75+/-9.7 pg/ml, p=0.028) and circulating OC did not change. The early human response to systemic endotoxemia boosts osteopontin levels and modifies bone biomarkers, indicating a decrease in the lytic activity of osteoclasts, accompanied by an increase in the activity of immature osteoblasts. These changes might present the acute phase response of immune and bone cells to bacterial stimuli in men.

Severe burn injury triggers massive alterations in stress hormone levels with a dose-dependent hypermetabolic status including increased bone resorption. This study evaluated bone microarchitecture measured by noninvasive high-resolution peripheral quantitative computed tomography (HR-pQCT). Changes of serum bone turnover markers (BTM) as well as regulators of bone signaling pathways involved in skeletal health were assessed. Standardized effect sizes as a quantitative measure regarding the impact of serum changes and the prediction of these changes on bone microarchitecture were investigated. In total, 32 male patients with a severe burn injury (median total body surface area [TBSA], 40.5%; median age 40.5 years) and 28 matched male controls (median age 38.3 years) over a period of 24 months were included. In patients who had sustained a thermal injury, trabecular and cortical bone microstructure showed a continuous decline, whereas cortical porosity (Ct.Po) and pore volume increased. Initially, elevated levels of BTM and C-reactive protein (CRP) continuously decreased over time but remained elevated. In contrast, levels of soluble receptor activator of NF-κB ligand (sRANKL) increased over time. Osteocalcin, bone-specific alkaline phosphatase (BALP), intact N-terminal type 1 procollagen propeptide (P1NP), and cross-linked C-telopeptide (CTX) acutely reflected the increase of Ct.Po at the radius (R2 = 0.41), followed by the reduction of trabecular thickness at the tibia (R2 = 0.28). In adult male patients, early and sustained changes of markers of bone resorption, formation and regulators of bone signaling pathways, prolonged inflammatory cytokine activities in conjunction with muscle catabolism, and vitamin D insufficiency were observed. These alterations are directly linked to a prolonged deterioration of bone microstructure. The probably increased risk of fragility fractures should be of clinical concern and subject to future interventional studies with bone-protective agents. © 2017 American Society for Bone and Mineral Research.

BACKGROUND

Diffuse idiopathic skeletal hyperostosis (DISH) and ossification of the posterior longitudinal ligament (OPLL) are both characterized as ossification in paravertebral ligaments and sometimes present simultaneously, however, the bone metabolism in patients with cervical OPLL accompanying/not accompanying DISH has not well been studied. Thus, a retrospective analysis was performed to understand any differences in bone metabolism in these patients.

METHODS

Male patients who underwent surgery for OPLL were divided into two groups based on the presence or absence of DISH (OD and O group, respectively). Patients with cervical spondylosis comprised the control group (CS group). Bone mineral density (BMD) and bone metabolism factors were compared among the groups.

RESULTS

The OD and O groups had significantly higher body mass indexes (BMIs) than did the CS group. Morphologically, the number of continuous type of OPLL was high in the OD group whereas that of segmental type was higher in the O group. The OD and O group had greater BMD than the CS group. Both TRACP-5b and P1NP were tended to be lower in the OD group whereas Ca and P concentrations were similar level among the groups. Intact parathyroid hormone in OD group was significantly higher than CS group.

CONCLUSIONS

Patients with OPLL accompanying DISH had significantly higher BMD whereas they tend to be lower in bone turnover. Significantly higher i-PTH levels was found in the OD group and would be the characteristic blood marker, but further research on the relationship between DISH and PTH was necessary.

Among ≥ 80 years old and under life self-care in the Beijing area, the prevalences of osteoporosis, falls, and fragility fracture were high; and these prevalences were even higher in women. The treatment rate of osteoporosis is very low. Therefore, comprehensive and standardized prevention and treatment should be promoted.

OBJECTIVE

The purpose of this study is to investigate prevalence of osteoporosis, falls, and fragility fractures in this population, and analyze related factors, in order to provide a basis for standardized prevention and treatment.

METHODS

From August 2015 to August 2016 in Beijing City, a total of 175 elderly individuals, who were ≥ 80 years old and had good self-care ability, were included into this study. The questionnaire, risk of falls, grip force, and walking speed were measured, and the Timed Up and Go test (TUG) and chair-rising test (CRT) were performed.

RESULTS

Compared to women, men have higher rates of smoking, drinking, drinking strong tea, longer outdoor activity time, as well as larger muscle strength and pace, and lower consumption of dairy products, fall risk assessment scale (FRA) score, 25OHD, administration rates of calcium and anti-osteoporosis drugs (P < 0.05, P < 0.01). Compared with men, women had higher bone turnover markers (P1NP, β-CTx, and OC) (P < 0.05, P < 0.01) and lower levels of sex hormones (E2, T) (P < 0.01). The overall prevalence of osteoporosis was 24.6%, and this was significantly higher in women than in men (52.5 vs. 9.6%, P < 0.01). Among these subjects, 62.9% had a history of fall after 80 years old, and this rate was higher in women than in men (77 vs. 55.3%, P < 0.01). The overall prevalence of fragility fractures was 25.1%, which was higher in women than in men (45.9 vs. 14.0%, P < 0.01). Risk factors included falls after age 80, high FRA score, and reduction in bone density of lumbar vertebrae 1-4, and odds ratio (OR) was 12.195, 1.339, and 0.076, respectively (P < 0.01). Anti-osteoporosis therapy was only performed on a small number of patients with fractures.

CONCLUSIONS

The prevalences of falls, prior fracture, and low BMD were high among ≥ 80 years old and under life self-care in the Beijing area. Therefore, a comprehensive approach to assessment and treatment should be promoted.

Antidiabetic drug metformin that improves insulin sensitivity and used in the treatment of nonalcoholic fatty liver disease (NAFLD), may affect the bone health. Our study was designed to investigate a possible effect of metformin on bone formation marker, procollagen type I N-terminal propeptide (P1NP) in patients with NAFLD.In a randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of 2 groups: Group 1 received daily metformin and Group 2 received placebo. Metabolic parameters, insulin resistance markers, and P1NP were determined.Although circulating P1NP levels did not differ significantly between the groups at baseline, at the end of the study, P1NP was significantly lower in patients treated with metformin than in the placebo group (p<0.007). Within-group analysis indicated that P1NP levels significantly decreased (p=0.023) in patients receiving metformin during 4-month follow-up period, while no change in P1NP was observed in placebo group (p=0.359). In general linear model metformin treatment was the only significant independent predictor of endpoint P1NP.Metformin treatment was associated with decrease in P1NP levels in patients with NAFLD. The effect on P1NP was independent of glucose lowering effect and caused from exposure to metformin per se.

OBJECTIVE

To evaluate the efficacy of conservative treatment with teriparatide for promoting bone fracture healing in patients with osteoporotic vertebral fracture.

METHODS

Twelve postmenopausal patients (aged 73±4.8 years) with osteoporotic spinal fracture confirmed by MRI or CT scanning received conservative treatment with teriparatidesc injection supplemented with calcium and analgesics for 6 months. At the beginning and at the end of the therapy, VAS score, Oswestry Disability Index (ODI), bone mass densitometry, and X-ray of the thoracic and lumbar spine, and serum P1NP and beta-CTX levels were measured. Six of the patients received a second MRI scan after the therapy to evaluate the bone healing.

RESULTS

All the 12 patients completed the treatment, during which no new fractures or adverse events occurred. At the end of the first month of treatment, analgesic was withdrawn for all the patients. The average VAS score decreased from 8±2 to 1±2 at 1 month during the therapy, and ODI was reduced from (76±12)% to (20±5)% at 1 month and further to (5±4)% at 6 month. After the 6-month therapy, the height of the fractured vertebrae (presented as the anterior to posterior wall height ratio) was insignificantly decreased from (75±20)% to (61±20)%, the BMD was increased by (20±5)%, P1NP increased significantly from 20.9±11.4 ng/mL to 80.0±41.2 ng/mL, and beta-CTX increased from 0.30±0.17 ng/mL to 0.51±0.3 ng/mL. The 6 patients re-examined with MRI demonstrated complete bone healing after the therapy.

CONCLUSIONS

Teriparatide is effective for conservative treatment of osteoporotic spinal fracture and can promote bone fracture healing, improve the quality of life, and prevents vertebral collapse, and can be therefore an alternative treatment to PVP or BV.

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research.

Aspects of bone remodeling have only been scarcely studied in X-linked hypophosphatemia (XLH). In this cross-sectional controlled study, we assessed biochemical indices of bone remodeling and sclerostin in 27 adult patients (median age 47 [range 24-79] years, 19 women, 8 men) with XLH matched with 81 healthy control subjects (1:3) with respect to age-, sex-, and menopausal status. Markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen, CTX) and formation (N-terminal propeptide of type 1 procollagen, P1NP) were higher in XLH patients compared to controls (median [IQR] 810 [500-1340] vs 485 [265-715] ng/l and 90 [57-136] vs 49 [39-65] ug/l, respectively, both p < 0.001) as well as sclerostin (0.81 [0.60-1.18] vs 0.54 [0.45-0.69] ng/ml, p < 0.001). Similar differences were found when comparing currently treated (with phosphate and alfacalcidol) (n = 11) and untreated (n = 16) XLH patients with their respective controls. We found no significant associations with treatment status and indices of bone remodeling or sclerostin although sclerostin tended to be increased in untreated versus treated (p = 0.06). In contrast to previous histomorphometric studies suggesting a low remodeling activity in XLH, these biochemical indices suggest high osteoblast and osteoclast activity. Further studies are needed to ascertain if the higher sclerostin level in XLH is related to osteocyte dysfunction or represents a secondary phenomenon.