Bone and Mineral Metabolism

Functional disuse initiates medullary endosteal micro-architectural impairment in cortical bone characterized by nanoindentation Abstract In this study, we evaluated the effect of functional disuse-induced bone remodeling on its mechanical properties, individually at periosteum and medullary endosteum regions of the cortical bone. Left middle tibiae were obtained from 5-month-old female Sprague–Dawley rats for the baseline control as well as hindlimb suspended (disuse) groups. Micro-nano-mechanical elastic moduli (at lateral region) was evaluated along axial (Z), circumferential (C) and radial (R) orientations using nanoindentation. Results indicated an anisotropic microstructure with axial orientation having the highest and radial orientation with the lowest moduli at periosteum and medullary endosteum for both baseline control as well as disuse groups. Between the groups: at periosteum, an insignificant difference was evaluated for each of the orientations (p > 0.05) and at endosteum, a significant decrease of elastic moduli in the radial (p < 0.0001), circumferential (p < 0.001) and statistically insignificant difference in axial (p > 0.05) orientation. For the moduli ratios between groups: at periosteum, only significant difference in the Z/R (p < 0.05) anisotropy ratio, whereas at endosteum, a statistically significant difference in Z/C (p < 0.001), and Z/R (p < 0.001), as well as C/R (p < 0.05) anisotropy ratios, was evaluated. The results suggested initial bone remodeling impaired bone micro-architecture predominantly at the medullary endosteum with possible alterations in the geometric orientations of collagen and mineral phases inside the bone. The findings could be significant for studying the mechanotransduction pathways involved in maintaining the bone micro-architecture and possibly have high clinical significance for drug use against impairment from functional disuse.

A meta-analysis of bone morphogenetic protein-2 versus iliac crest bone graft for the posterolateral fusion of the lumbar spine Abstract The impact of autologous iliac crest bone graft versus BMP-2 to improve fusion rates for posterolateral fusion (PLF) of the lumbar spine remains unanswered. Single-institution-centered data dominate the literature, providing results that may be contradictory or inconclusive. The aim of this paper is to analyze data pooled from multiple well-controlled studies that examined both ICBG and BMP-2 for use in PLF. This meta-analysis also provides details of success in different subsets of patients with variable risk factors for delayed and non-unions. Six high-quality randomized clinical trials were selected. Efficacy, morbidity, quality of life, and safety were compared between the BMP-2 group and the ICBG group. A total of 908 patients were included in the study. At 24 months, 94% of patients achieved fusion in the BMP-2 group and 83% in the ICBG group. At 6 and 12 months, the fusion was also greater in the BMP-2 group (86% vs. 60% and 88% vs. 80%, respectively). Surgical time, intraoperative blood loss, and hospitalization days also showed significant differences in favor of the experimental group (p < 0.01). There were no differences between two groups in the Oswestry Disability Index, 36-Item Short Form Health Survey and Back Pain Score, whereas a greater number of additional surgical procedures were performed in the ICBG group (p = 0.001). In conclusion, the use of BMP-2 in PLF reduced the surgical morbidity and had more beneficial effects on the fusion rate. The quality of life based on clinical scores was the same in both groups.

Urolithiasis increases the risk of subsequent onset of osteoporosis Abstract Urolithiasis and osteoporosis are two different pathological entities, but are both important public health issues in older patients. Moreover, the two diseases may share some similar pathogenesis pathway. Currently, few studies focus on the relationship between urolithiasis and osteoporosis. Furthermore, whether the common mobilities influence the long-term osteoporosis rate in urolithiasis patients has never been studied. In the present study, we used the Taiwan National Health Insurance Database (LHID 2000) compiled by the NHI from 1996 to 2013 to determine whether urolithiasis influenced long-term osteoporosis; controls were matched for age, sex, and other comorbidities (including hypertension, diabetes mellitus, dyslipidemia, liver disease, and cardiovascular disease). We included a total of 91,254 patients, including 22,575 patients with urolithiasis and 68,679 control patients. There was a significant difference between the incidence of osteoporosis between the urolithiasis and control groups (adjusted hazard ratio 1.34, 95% CI 1.19–1.79, p < 0.001) during the follow up. The incidence rate of osteoporosis during the follow-up period was 8.87 per 1000 person-years in the urolithiasis group and 6.37 per 1000 person-years in the control group. Based on our results, it is evident that urolithiasis significantly increases the subsequent osteoporosis rate. Though the clinical mechanisms are not fully understood, patients who have a history of urolithiasis may need regular follow-up assessment of bone marrow density.

Maternal 25-hydroxycholecalciferol during lactation improves intestinal calcium absorption and bone properties in sow-suckling piglet pairs Abstract Lower maternal vitamin D status during lactation is a common health problem. The objectives of this study were to investigate the effects of maternal 25-hydroxycholecalciferol (25-OH-D3) supplementation during lactation on maternal and neonatal bone health in a sow model. 32 Large White × Landrace sows were assigned randomly to one of two diets supplemented with 2000 IU/kg vitamin D3 (ND) or 50 μg/kg 25-OH-D3 (25-D). The experiment began on day 107 of gestation and continued until weaning on day 21 of lactation. Maternal 25-OH-D3 supplementation significantly decreased milk n-6:n-3 PUFA ratio, which supported bone formation of piglets. Supplementation with 25-OH-D3 altered bone turnover rate of sows and piglets, as evidenced by higher bone-specific alkaline phosphatase (BALP) concentration in serum. 25-D sows had significantly higher bone density and mechanical properties of tibias and femurs than ND sows. Calcium (Ca) absorption rate was higher in 25-D sows than ND sows, which was caused partially by the increased mRNA expressions of renal 1α-hydroxylase (CYP27B1) and duodenal vitamin D receptor (VDR), transient receptor potential vanilloid 6 (TRPV6), and calcium-binding protein D9k (CaBP-D9k). Maternal 25-OH-D3 supplementation increased tibial and femoral Ca content by up-regulating Ca-related gene expression in kidney (CYP27B1), ileum (VDR and claudin-2), and colon (VDR and CaBP-D9k), thus, activating 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3]-dependent Ca transport in piglets. In conclusion, improved milk fatty acids and higher mRNA expressions of calcitropic genes triggered by maternal 25-OH-D3 supplementation would be the potential mechanism underlying the positive effects of 25-OH-D3 on maternal and neonatal bone health.

Clinical characteristics of patients with thoracic myelopathy caused by ossification of the posterior longitudinal ligament Abstract Although ossification of the posterior longitudinal ligament (OPLL) commonly develops in the cervical spine, it also occurs, albeit less commonly, in the thoracic spine. However, data are scarce regarding the characteristics of patients with thoracic OPLL. In the current study, we performed a cross-sectional study on a total of 133 patients with OPLL to clarify the clinical characteristics of patients with thoracic OPLL compared with those of patients with cervical OPLL. The subjects were divided into four groups according to the main region of OPLL and treatment type: C-OPLL-C, cervical OPLL treated conservatively; C-OPLL-S, cervical OPLL treated via surgery; T-OPLL-C, thoracic OPLL treated conservatively; and T-OPLL-S, thoracic OPLL treated via surgery. Symptoms developed at an earlier age in the T-OPLL-S group than in the C-OPLL groups. Current body mass index (BMI), maximum lifetime BMI, and BMI at the age of 20 years were significantly higher in the T-OPLL-S group than in the C-OPLL groups. Yearly weight gain from the age of 20 years to the age at which maximum body weight was attained was significantly greater in the T-OPLL-S group than in the C-OPLL groups. The T-OPLL group showed a higher rate of co-existence of OPLL at other regions or ossification of the ligamentum flavum compared to the C-OPLL groups. Our findings demonstrate that severe obesity, early-onset of symptoms, and diffuse ossification of spinal ligaments are distinct features of patients with myelopathy caused by thoracic OPLL.

Correction to: Re‑fracture and correlated risk factors in patients with osteoporotic vertebral fractures In the Original publication of the article, the funding ID has been incorrectly published as (815602390) in the Acknowledgements.

Effect of CBX7 deficiency on the socket healing after tooth extractions Abstract CBX7 is shown to down-regulate the expression of osteopontin (OPN) that is associated with osteoblast function. Here, we studied the role of CBX7 in the wound healing of tooth extraction socket in which osteoblast activity is critical via comparison between CBX7-knockout (CBX7−/−) mice and their wild-type (WT) counterparts of 6 weeks old with maxillary first molar extracted. Mice were euthanized at 7, 14, and 21 days after extractions, and alveolar sockets were assessed by semi-quantitative histomorphometry for hard tissue healing, including new bone fill (Masson's trichrome staining), osteoblast activity (OPN/osterix, Osx), osteoclast activity (tartrate-resistant acid phosphatase, TRAP), and for soft tissue healing, including blood vessels (alpha smooth muscle actin, α-SMA). Also, the bone microarchitecture was evaluated by micro-CT. In radiological analysis, CBX7−/− mice increased bone mass significantly more than WT mice did. Consistently, both the amount of new bone fill and OPN/Osx-immunopositive cells in the extraction sockets were significantly increased in CBX7−/− mice at each time point with respect to their WT siblings, while osteoclast number exhibited a trend of more increase in CBX7−/− mice at all time points as well. In agreement with enhanced bone formation during socket healing, significantly elevated α-SMA-immunopositive area was noted in CBX7−/− mice in contrast to WT mice. Taken together, these data suggest that CBX7 deficiency has a positive effect on tooth extraction socket healing.

Efficacy and safety of once-monthly risedronate in osteoporosis subjects with mild-to-moderate chronic kidney disease: a post hoc subgroup analysis of a phase III trial in Japan Abstract Limited data are available on the safety and efficacy of anti-resorptive agents, particularly once-monthly bisphosphonates, for use in osteoporotic patients with chronic kidney disease (CKD). We conducted a post hoc analysis of data from a 12-month, randomized, double-blind, phase III study to evaluate the safety and efficacy of once-monthly risedronate (RIS-OM) 75 mg tablets in Japanese osteoporosis patients with mild-to-moderate CKD. Patients who received RIS-OM 75 mg were stratified by baseline estimated glomerular filtration rate (eGFR; ≥ 90, ≥ 60 to < 90, or ≥ 30 to < 60 mL/min/1.73 m2). Safety endpoints were incidence of adverse events (AEs) and percent change from baseline in eGFR, serum creatinine, calcium, and phosphorus. Efficacy endpoints were percent change from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers (BTMs). In 420 patients included (age 67.7 ± 6.7 years, women 98.8%), the incidence of all AEs, gastrointestinal disorders, acute phase reaction, non-vertebral fractures, and renal and urinary disorders was not significantly different among subgroups. Interaction between subgroups and time was significant for eGFR (p = 0.010) and serum creatinine (p = 0.001) but considered to be regression to the mean and clinically insignificant. BMD significantly increased while BTMs significantly decreased from baseline with a similar degree of change among the subgroups. In conclusion, RIS-OM 75 mg showed consistent safety and efficacy in suppressing bone turnover and increasing BMD in Japanese primary osteoporosis patients with mild-to-moderate CKD. These results should, however, be interpreted with caution because the number of patients with moderate CKD was limited.

The effect of testosterone itself and in combination with letrozole on bone mineral density in male rats Abstract Testosterone is an essential hormone to maintain bone integrity; however, the effect of aromatase enzyme in androgen-induced bone maintenance remains somewhat unclear. The present study evaluated the effect of testosterone itself and combined with letrozole, an aromatase inhibitor, on bone mineral density of male rats. Total of 48 male rats were divided into 4 equal groups (n = 12/group); sham group, O: orchiectomy, O + T: orchiectomized rats treated with testosterone, O + T + L: orchiectomized rats treated with combination of testosterone and letrozole. Bone density (BMD), bone markers, and vitamin D metabolism parameters were checked in all groups before and after the study. There was no significant difference in baseline values of these parameters, but at the end of the study there was a significant decrease in delta BMD at both lumbar and femor in orchiectomized rats in comparison with the sham group (p < 0.001, p < 0.001, respectively). Both testosterone and its combination with letrozole increased lumbar and femoral BMD of orchiectomized rats, with a higher increase in lumbar BMD in O + T group. CTX were higher in O group rats. The present study showed a major role for testosterone on BMD maintenance in male rats. However, testosterone has a potent effect on lumbar BMD, by the aromatization to estradiol.

Cortical bone mineral density is increased by the cathepsin K inhibitor ONO-5334, which leads to a robust increase in bone strength: results from a 16-month study in ovariectomised cynomolgus monkeys Abstract This study evaluated the long-term effects of the cathepsin K inhibitor ONO-5334 on bone mass and strength in ovariectomised (OVX) cynomolgus monkeys. Animals were assigned to one of the following six groups: Sham (non-OVX), OVX control treated with vehicle, ONO-5334 1.2, 6 or 30 mg/kg/day, p.o., or alendronate (ALN) 0.05 mg/kg/2 weeks, i.v. for 16 months. Peripheral quantitative computed tomography (pQCT) analysis revealed that ONO-5334 increased not only trabecular bone mineral density (BMD) but also cortical BMD in the distal radius and the lumbar vertebra. ONO-5334 and ALN suppressed the deterioration of trabecular architecture by micro-CT analysis in the distal radius. Assessments of bone strength showed that ONO-5334 increased maximum load at the distal and midshaft radius. The linear regression lines between bone mass and strength in the lumbar vertebra were tended to be shifted towards increasing bone strength in the ONO-5334 6 and 30 mg/kg groups compared with the ALN groups. This indicated that bone strength was higher in the ONO-5334 groups than the ALN group, even though bone mineral content (BMC) and BMD were comparable. Subpopulation analysis revealed that, at similar integral BMC or BMD level, cortical bone mass for ONO-5334 was higher than for ALN; the opposite effects were observed for trabecular bone. In conclusion, ONO-5334 preferentially increased cortical bone, which may provide a greater contribution to bone strength. Since these results support a different mode of action for ONO-5334 compared with that of ALN, ONO-5334 may offer new therapeutic options to patients with osteoporosis.

Alexandros Sfakianakis
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alsfakia@gmail.com