SciCombinator

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Journal: Bone

29

Many surgical procedures use metal implants in bone. The clinical results depend on the strength of the bone holding these implants. Our objective was to show that a drug released from the implant surface can improve parameters reflecting the quality or amount of this bone. Sixteen patients received paired dental titanium implants in the maxilla, in a randomized, double-blinded fashion. One implant in each pair was coated with a thin fibrinogen layer containing 2 bisphosphonates. The other implant was untreated. Fixation was evaluated by measurement of resonance frequency (implant stability quotient; ISQ) serving as a proxy for stiffness of the implant-bone construct. Increase in ISQ at 6months of follow-up was the primary variable. None of the patients had any complications. The resonance frequency increased 6.9 ISQ units more for the coated implants (p=0.0001; Cohen’s d=1.3). The average difference in increase in ISQ, and the effect size, suggested a clinically relevant improvement. X-ray showed less bone resorption at the margin of the implant both at 2months (p=0.012) and at 6months (p=0.012). In conclusion, a thin, bisphosphonate-eluting fibrinogen coating might improve the fixation of metal implants in human bone. This might lead to new possibilities for orthopedic surgery in osteoporotic bone and for dental implants.

Concepts: Osteoporosis, Improve, Surgery, Dental implant, Titanium, Dentistry, Resonance Frequency Analysis, Implant stability quotient

29

Methylphenidate (MP) is a psychostimulant widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD). Although generally well tolerated, growth deficits have been reported in children and adolescents undergoing MP treatment. This study was designed to elucidate the skeletal effects of chronic MP administration in adolescent rats. Male, 4-week-old rats received one of two doses of MP (MP-Low or MP-High) delivered for 8 h a day via drinking water, or were untreated (water only). After 13 weeks, half were sacrificed (N=12/group) and the remaining rats were left to recover, untreated for 5 additional weeks. Femora, tibiae, and L5 vertebra were analyzed using calipers, DXA, and mechanical testing. Immediately following treatment, MP decreased femoral anterior-posterior diameter (5% and 9% for MP-Low and MP-High, respectively), femoral and tibial bone mineral density (BMD) (6% and 5% for MP-High femora and tibiae, respectively), and bone mineral content (BMC) (9% for MP-High femora and tibiae). In addition, femora from MP treated rats had reduced ultimate force (20% for MP-High) and energy to failure (20% and 33% for MP-Low and MP-High, respectively). However, after recovery, there were no statistically significant differences for any measured parameters. Despite these effects on the appendicular skeleton, no differences were identified between vertebral samples at either time-point. In summary, MP treatment resulted in smaller, less mineralized, and weaker bones at appendicular sites, but did not affect the axial site. Although these effects were ameliorated within 5 weeks, these data suggest that adolescents undergoing MP treatment may be at an increased risk for long bone fractures.

Concepts: Osteoporosis, Bone, Attention, Skeletal system, Attention-deficit hyperactivity disorder, Hyperactivity, Stimulant, Methylphenidate

28

In metabolic bone diseases, the alterations in fibrillar level bone-material quality affecting macroscopic mechanical competence are not well-understood quantitatively. Here, we quantify the fibrillar level deformation in cantilever bending in a mouse model for hereditary rickets (Hpr). Microfocus in-situ synchrotron small-angle X-ray scattering (SAXS) combined with cantilever bending was used to resolve nanoscale fibril strain in tensile- and compressive tissue regions separately, with quantitative backscattered scanning electron microscopy used to measure microscale mineralization. Tissue-level flexural moduli for Hpr mice were significantly (p<0.01) smaller compared to wild-type (~5 to 10-fold reduction). At the fibrillar level, the fibril moduli within the tensile and compressive zones were significantly (p<0.05) lower by ~3- to 5-fold in Hpr mice compared to wild-type mice. Hpr mice have a lower mineral content (24.2±2.1Cawt.% versus 27.4±3.3Ca wt.%) and its distribution was more heterogeneous compared to wild-type animals. However, the average effective fibril modulus did not differ significantly (p>0.05) over ages (4, 7 and 10weeks) between tensile and compressive zones. Our results indicate that incompletely mineralized fibrils in Hpr mice have greater deformability and lower moduli in both compression and tension, and those compressive and tensile zones have similar moduli at the fibrillar level.

Concepts: Electron, Dietary mineral, Mineral, X-ray crystallography, Scanning electron microscope, Young's modulus, X-rays, Small-angle X-ray scattering

28

Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of- function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre; Lrp5(f/f)) would alter responses to ulna loading. Loading was applied to the right ulna for 3 min (360 cycles at 2 Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young’s modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young’s modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young’s modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass.

Concepts: DNA, Bone, Mutation, Natural selection, Bone density, Density, Skeletal system, Young's modulus

28

Recent studies suggest that patients with sickle cell disease (SCD) have profound vitamin D (VD) deficiency. Limited data exist on the effect of VD deficiency on bone fragility in these patients.

Concepts: Cohort study, Vitamin D, Epidemiology, Clinical trial, Vitamins, Sickle-cell disease, Sickle

28

Bone fragility depends on its post-yield behavior since most energy dissipation in bone occurs during the post-yield deformation. Previous studies have investigated the progressive changes in the post-yield behavior of human cortical bone in tension and compression using a novel progressive loading scheme. However, little is known regarding the progressive changes in the post-yield behavior of bone in shear. The objective of this short study was to address this issue by testing bone specimens in an inclined double notch shear configuration using the progressive loading protocol. The results of this study indicated that the shear modulus of bone decreased with respect to the applied strain, and the rate of degradation was about 50% less than those previously observed in compression and tension tests. In addition, a quasi-linear relationship between the plastic and applied strains was observed in shear mode, which is similar to those previously reported in tension and compression tests. However, the viscous responses of bone (i.e. relaxation time constants and stress magnitude) demonstrated slight differences in shear compared with those observed in tension and compression tests. Nonetheless, the results of this study suggest that the intrinsic mechanism of plastic deformation of human cortical bone may be independent of loading modes.

Concepts: Continuum mechanics, Cortical bone, Shear stress, Fluid, Young's modulus, Elasticity, Solid mechanics, Shear strain

28

Adequate blood supply and circulation to the bones is required to maintain a healthy skeleton. Inadequate blood perfusion is associated with numerous bone pathologies and a decrease in bone mineral density, yet bone hemodynamics remains poorly understood. This study aims to 1) quantify bone hemodynamic responses to changes in external pressure, and 2) identify the predominant mechanisms regulating bone hemodynamic responses to pressure changes. Photoplethysmography was used to measure bone and skin perfusion in response to changes in external pressure. Single-limb pressure chamber experiments were performed over a pressure range of -50 to +50mm Hg. Bone perfusion is decreased at all negative pressures, and larger decrements in perfusion are observed at the more extreme pressure differences. At positive pressures we observed an initial increase in perfusion followed by activation of intramuscular pressure receptors at +30mm Hg, which overrides the initial response and results in decreased perfusion at the highest positive pressure levels. The myogenic effect is observed and is shown to be the predominant control mechanism in bone over a wide range of pressure exposures. Greater understanding of these hemodynamic mechanisms may be important in developing new drugs and therapies to treat various bone disorders.

Concepts: Bone, Blood, Heart, Skeletal system, Photoplethysmograph, Hemodynamics, Perfusion, Knowledge

28

Fluoroquinolones (FQs) are a class of antibiotics with a broad spectrum of activity, known to disturb bone metabolism. The aim of this work was to characterize the cellular and molecular effects of five FQs (ofloxacin, norfloxacin, ciprofloxacin, levofloxacin and moxifloxacin) in unstimulated and stimulated human osteoclast precursors. Peripheral blood mononuclear cells (PBMC) were cultured in the absence (unstimulated) or in the presence of osteoclastogenic factors (M-CSF and RANKL, stimulated), and were treated with FQs (0.3×10(-9)-10(-3) M), for 21 days. In unstimulated PBMC cultures, FQs (excepting moxifloxacin) exhibited a high osteoclastogenic potential, as shown by a significant increase in the expression of osteoclastic genes, TRAP activity and, specially, number of TRAP-positive multinucleated cells and calcium phosphate resorbing ability, suggesting the presence of mature and functional osteoclasts. Norfloxacin and levofloxacin induced the higher effect, followed by ciprofloxacin and ofloxacin. A decrease on apoptosis and an increase on M-CSF expression might have a possible contribution in the observed cellular behavior. In stimulated PBMC cultures, FQs further increase the osteoclastogenic response induced by M-CSF and RANKL (except ofloxacin). However, the osteoclastogenic response was much lower than that observed in unstimulated PBMC cultures. Both in unstimulated and stimulated PBMC cultures, for most of the FQs, the osteoclastogenic effects were observed in a wide range of concentrations, representative of plasmatic and tissue levels attained in several clinical settings. The various FQs differed on the stimulatory concentration range, the extent of the induced osteoclastogenic response and, also, on the dose- and time-dependent profile. Nevertheless, at high concentrations all the FQs seemed to elicit an increase on apoptosis. Additionally, some differences were noted in the intracellular signaling pathways tested, namely NFkB, MEK and PGE2 production. Results suggest that, considering the inter-individual variability of the FQs pharmacokinetics, the detailed biological profile of each FQ on bone cells is of utmost importance to clarify the effects of these compounds on bone metabolism.

Concepts: Bone, Signal transduction, Ciprofloxacin, Quinolone, Moxifloxacin, Ofloxacin, Levofloxacin, Norfloxacin

28

We aimed to investigate the epidemiological determinants, clinical features, and genetic pattern of FOP in our country by evaluating the entire population of patients identified according to a combination of methods. To achieve this, 24 individuals were confirmed as FOP cases, 17 of whom were alive at the end of 2011 (point prevalence=0.36 × 10(-6)). The gender distribution (male/female ratio=13/11) and the concurrent range of ages (from 4 to 53 years; mean ± SD: 30.2 ± 13.8) are in agreement with similar reports. Twenty-one (87.5%) had characteristic congenital malformations of the big toe, and short thumbs were found in 65.2% of cases. In addition, other skeletal malformations such us fusion of the posterior elements of the cervical spine (89.0%), knee osteochondromas (71%), scoliosis (54.5%), and short and broad femoral neck (52.6%) were observed. All had developed mature ossicles of heterotopic bone in typical anatomic and temporal patterns, ranging in number from 1 to 17 (9.5 ± 3.9). Age at appearance of first ossifying lesion varied from 3 months to 15 years. Mean age at diagnosis was 7.3 ± 5.1 years and the average delay in reaching the correct diagnosis after the onset of heterotopic ossification was 2.7 years (range=0-12 years). Biopsy of the pre-osseous lesions was performed in 11 of 20 (55.0%), providing no useful information for the diagnosis of FOP. Seven of 18 (38.9%) reported some hearing loss, and 5 (27.8%) experienced diffuse thinning of the hair or were bald. No patient had relatives with a typical FOP clinical picture. Fourteen of the 16 cases which were genetically investigated displayed the single heterozygous mutation c.617G>A in exon 4 of the ACVR1 gene. One of the two patients who did not present with the canonical ACVR1 mutation showed a heterozygous mutation c.774G>C in exon 5 leading to the substitution of Arginine 258 with a serine. The other patient had a heterozygous c.774G>T substitution in exon 5 leading to the same amino acid change (p.Arg258Ser). These two patients had only nonspecific abnormalities of the great toe, lacked the typical anatomic and developmental pattern of heterotopic ossification, and shared a trend toward uncommon clinical features. These results provide new insight on the epidemiological and clinical traits of FOP, reinforcing the notion of its worldwide homogeneity. The molecular characterization of ACVR1 sequence variation will contribute to the understanding of the genetic profile of this devastating disease in different geographical areas.

Concepts: DNA, Genetics, Amino acid, Hallux, Fibrodysplasia ossificans progressiva, Congenital disorders, Toe, Heterotopic ossification

28

It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis.

Concepts: Bisphosphonate, Osteoporosis, Vitamin D, Menopause