Endoscopy-assisted dacryocystorhinostomy in a dog.

OBJECTIVE: To describe the use of an endoscope to assist in performing minimally invasive dacryocystorhinostomy in a dog to successfully manage a nasolacrimal duct cyst (dacryocyst). ANIMAL STUDIED: A 4-year-old female spayed American Staffordshire Terrier with chronic epiphora and swelling ventromedial to the nasal canthus of the right eye and reverse sneezing. PROCEDURES: Computed tomography revealed a fluid-filled cystic lesion of the right nasolacrimal duct with extensive nasal extension and secondary obstructive frontal sinusitis. Aspiration of serosanguinous fluid with no growth of microbial organisms and histopathology confirmed the cystic nature of the structure. A 2.7 mm, 30 deg, 11 cm foreward-oblique endoscope with arthroscopic cannula was passed through a mucosal stab incision in the dorsal buccal recess into the cyst to allow for exploration. A separate instrument portal was placed in the center of the cyst through the skin which allowed for transcutaneous dacryocystorhinostomy with a meniscal probe to be performed. No clear communication was evident caudodorsally into the frontal sinus on endoscope examination. A small frontal sinus trephination was performed and lavage flowed easily into the cystic cavity and out of the nostril. RESULTS: Follow-up at 10 days and 17 months postoperatively showed complete resolution of clinical signs with an excellent cosmetic outcome. CONCLUSION: Endoscopy-assisted dacryocystorhinostomy demonstrated an effective minimally invasive technique to treat a functionally obstructive dacryocyst of the right nasolacrimal duct in a dog.

Caudoventral hip luxation in 160 dogs (2003-2023): A multicenter retrospective case series.

OBJECTIVE: To describe patient characteristics, etiology, treatment outcomes and complications of caudoventral hip luxation (CvHL) in a large cohort of dogs and investigate factors associated with nonsurgical treatment outcomes. STUDY DESIGN: Multicenter retrospective case series. ANIMAL POPULATION: A total of 160 client-owned dogs (170 limbs). METHODS: Medical records from 2003 to 2023 were reviewed for signalment, history, treatment outcomes and complications. Logistic regression was performed to investigate factors associated with nonsurgical treatment outcome. RESULTS: Low-trauma accidents accounted for 82.9% of cases. Over-represented breeds included poodles (38.1%) and poodle crosses (11.3%). On a per-treatment basis, success rates of closed reduction alone, closed reduction/Ehmer sling, closed reduction/hobbles were 9.1%, 15.2% and 48.8%, respectively. When accounting for repeated attempts using closed reduction alone, Ehmer sling, or hobbles, eventual success rate increased to 10.3%, 18.5% and 61.8%, respectively. Success rate for toggle rod stabilization was 88.2%. Complication rate of hobbles was 31.9% versus 60.6% for Ehmer slings. Use of hobbles (OR:7.62, p = .001, CI:2.23-26.05), treatment by specialist surgeons (OR:2.68, p = .047, CI: 1.01-7.08) and increasing age (OR:1.15, p < .005, CI: 1.08-1.23) were associated with successful nonsurgical treatments. CONCLUSION: Low-trauma etiology, and poodles and their crosses were over-represented in cases of CvHL. Success rate of nonsurgical treatments was lower than previously reported. Hobbles were 7.6 times more likely to be successful when compared to dogs treated without hobbles and remains a viable noninvasive first-line treatment. CLINICAL SIGNIFICANCE/IMPACT: Hobbles are recommended as a low-morbidity first-line treatment for CvHL. An Ehmer sling is not recommended. Toggle rod stabilization is an effective surgical treatment for CvHL.

Cortical bone adaptation response is region specific, but not peak load dependent: insights from µ CT image analysis and mechanostat simulations of the mouse tibia loading model.

The two major aims of the present study were: (i) quantify localised cortical bone adaptation at the surface level using contralateral endpoint imaging data and image analysis techniques, and (ii) investigate whether cortical bone adaptation responses are universal or region specific and dependent on the respective peak load. For this purpose, we re-analyse previously published µ CT data of the mouse tibia loading model that investigated bone adaptation in response to sciatic neurectomy and various peak load magnitudes (F = 0, 2, 4, 6, 8, 10, 12 N). A beam theory-based approach was developed to simulate cortical bone adaptation in different sections of the tibia, using longitudinal strains as the adaptive stimuli. We developed four mechanostat models: universal, surface-based, strain directional-based, and combined surface and strain direction-based. Rates of bone adaptation in these mechanostat models were computed using an optimisation procedure (131,606 total simulations), performed on a single load case (F = 10 N). Subsequently, the models were validated against the remaining six peak loads. Our findings indicate that local bone adaptation responses are quasi-linear and bone region specific. The mechanostat model which accounted for differences in endosteal and periosteal regions and strain directions (i.e. tensile versus compressive) produced the lowest root mean squared error between simulated and experimental data for all loads, with a combined prediction accuracy of 76.6, 55.0 and 80.7% for periosteal, endosteal, and cortical thickness measurements (in the midshaft of the tibia). The largest root mean squared errors were observed in the transitional loads, i.e. F = 2 to 6 N, where inter-animal variability was highest. Finally, while endpoint imaging studies provide great insights into organ level bone adaptation responses, the between animal and loaded versus control limb variability make simulations of local surface-based adaptation responses challenging.

Cortical thickness adaptation to combined mechanical loading and parathyroid hormone treatments is site specific and synergistic in the mouse tibia model.

In this study, we aimed to quantify the localised effects of mechanical loading (ML), low (20 µg/kg/day), moderate (40 µg/kg/day) or high (80 µg/kg/day) dosages of parathyroid hormone (PTH), and combined (PTHML) treatments on cortical bone adaptation in healthy 19-week old female C57BL/6 mice. To this end, we utilise a previously reported image analysis algorithm on µCT data of the mouse tibia published by Sugiyama et al. (2008) to measure changes in cortical area, marrow cavity area and local cortical thickness measures (ΔCt.Ar, ΔMa.Ar, ΔCt.Th respectively), evaluated at two cross-sections within the mouse tibia (proximal-middle (37 %) and middle (50 %)), and are compared to a superposed summation (P + M) of individual treatments to determine the effectiveness of combining treatments in vivo. ΔCt.Ar analysis revealed a non-linear, synergistic interactions between PTH and ML in the 37 % cross-section that saturates at higher PTH dosages, whereas the 50 % cross-section experiences an approximately linear, additive adaptation response. This coincided with an increase in ΔMa.Ar (indicating resorption of the endosteal surface), which was only counteracted by combined high dose PTH with ML in the middle cross-section. Regional analysis of ΔCt.Th changes reveal localised cortical thinning in response to low dose PTH treatment in the posteromedial region of the middle cross-section, signifying that PTH does not provide a homogeneous adaptation response around the cortical perimeter. We observe a synergistic response in the proximal-middle cross-section, with regions of compressive strain experiencing the greatest adaptation response to PTHML treatments, (peak ΔCt.Th of 189.32, 213.78 and 239.30 µm for low, moderate and high PTHML groups respectively). In contrast, PTHML treatments in the middle cross-section show a similar response to the superposed P + M group, with the exception of the combined high dose PTHML treatment which shows a synergistic interaction. These analyses suggest that, in mice, adding mechanical loading to PTH treatments leads to region specific bone responses; synergism of PTHML is only achieved in some regions experiencing high loading, while other regions respond additively to this combined treatment.

Cystoscopic-guided scissor transection of intramural ectopic ureters as a novel alternate minimally invasive treatment option to laser ablation in female dogs: 8 cases (2011-2020).

OBJECTIVE: To evaluate the safety and efficacy of cystoscopic-guided scissor transection of ectopic ureters (CST-EU) in female dogs. ANIMALS: 8 incontinent female dogs with intramural ectopic ureters. PROCEDURES: For this retrospective case series, data were collected from medical records of dogs that underwent CST-EU to relocate the ectopic ureteral orifice to an anatomically normal trigonal location between June 2011 and December 2020. Outcome after hospital discharge was determined using owner telephone questionnaires. RESULTS: Ectopic ureters were bilateral in 4 of the 8 dogs, and all dogs had other urogenital tract anomalies. Owner questionnaire follow-up was available for 7 dogs, and results indicated 6 dogs had improved urinary continence immediately following the procedure. At the last follow-up (44 to 3,384 days after CST-EU), 3 of the 7 dogs were completely continent with CST-EU alone, 3 others became continent or were markedly improved with the addition of medications for urethral sphincter mechanism incompetence, and 1 required ureteroneocystostomy, colposuspension, and an artificial urethral sphincter to become fully continent. Owners of 5 of the 7 dogs reported that they considered the outcome of CST-EU as good to excellent, and all owners reported that they would consider having CST-EU performed again should they have another incontinent dog. Complications were minor, and only 3 dogs showed transient lower urinary tract signs after CST-EU. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated CST-EU could provide a safe, effective, minimally invasive alternative in the absence of laser technology for the treatment of intramural ectopic ureters in female dogs.

Beam theory for rapid strain estimation in the mouse tibia compression model.

The mouse tibia compression model is a leading model for studying bone's mechanoadaptive response to load. In studying this mechanoadaptive response, (FE) modelling is often used to determine the stress/strain within the tibia. The development of such models can be challenging and computationally expensive. An alternate approach is to use continuum mechanics based analytical theories, such as beam theory (BT). However, applying BT to the mouse tibia requires the fibula be neglected, introducing error in the stress/strain distribution. While several studies have applied BT to the mouse tibia, no study has explored the accuracy of this approach. To address these questions, this work investigates the use of BT in determining stress/strain within the mouse tibia. By comparing BT against FE modelling, it was found that BT can accurately predict tibial stress/strain if correction factors are applied to account for the effect of the fibula. The 25, 37, 50 and 75% cross sections are studied. Focusing on the 37% cross section, without correction, BT can have errors of approximately 21.6%. With correction, this is reduced to 6.6%. Such correction factors are presented. The developed BT model is applicable in the diaphysis and distal metaphysis, where the assumptions of BT are valid. This work verifies BT for determining localised strains in a mouse tibia compression model. This is anticipated to provide efficiency dividends, allowing for high throughput modelling of the mouse tibia, advancing study of bone's mechanoadaptive response.

Cortical Thickness Adaptive Response to Mechanical Loading Depends on Periosteal Position and Varies Linearly With Loading Magnitude.

The aim of the current study was to quantify the local effect of mechanical loading on cortical bone formation response at the periosteal surface using previously obtained µCT data from a mouse tibia mechanical loading study. A novel image analysis algorithm was developed to quantify local cortical thickness changes (ΔCt.Th) along the periosteal surface due to different peak loads (0N ≤ F ≤ 12N) applied to right-neurectomised mature female C57BL/6 mice. Furthermore, beam analysis was performed to analyse the local strain distribution including regions of tensile, compressive, and low strain magnitudes. Student's paired t-test showed that ΔCt.Th in the proximal (25%), proximal/middle (37%), and middle (50%) cross-sections (along the z-axis of tibia) is strongly associated with the peak applied loads. These changes are significant in a majority of periosteal positions, in particular those experiencing high compressive or tensile strains. No association between F and ΔCt.Th was found in regions around the neutral axis. For the most distal cross-section (75%), the association of loading magnitude and ΔCt.Th was not as pronounced as the more proximal cross-sections. Also, bone formation responses along the periosteum did not occur in regions of highest compressive and tensile strains predicted by beam theory. This could be due to complex experimental loading conditions which were not explicitly accounted for in the mechanical analysis. Our results show that the bone formation response depends on the load magnitude and the periosteal position. Bone resorption due to the neurectomy of the loaded tibia occurs throughout the entire cross-sectional region for all investigated cortical sections 25, 37, 50, and 75%. For peak applied loads higher than 4 N, compressive and tensile regions show bone formation; however, regions around the neutral axis show constant resorption. The 50% cross-section showed the most regular ΔCt.Th response with increased loading when compared to 25 and 37% cross-sections. Relative thickness gains of approximately 70, 60, and 55% were observed for F = 12 N in the 25, 37, and 50% cross-sections. ΔCt.Th at selected points of the periosteum follow a linear response with increased peak load; no lazy zone was observed at these positions.

Outcome after surgical management of canine insulinoma in 49 cases.

Canine insulinoma has historically been associated with a poor prognosis; however, prolonged survival times have recently been reported. Prognostic indicators that are available preoperatively are of limited predictive accuracy, and consensus on post-operative treatment recommendations is lacking. The objectives of this study were to describe outcomes in dogs with insulinoma treated surgically, and to assess whether selected potential risk factors are strongly associated with outcomes after surgery. Medical records of two institutions were searched for dogs with insulinoma that were treated surgically. Forty-nine dogs were included. Thirty-nine dogs (80%) had immediate resolution of hypoglycaemia and 10 (20%) remained persistently hypoglycaemic postoperatively. The median survival time (MST) for all dogs was 561 days. The MST for dogs that had resolution of hypoglycaemia was 746 days. The median of the overall euglycaemic time (times from surgery to first detection of hypoglycaemia at any time point after surgery) for all dogs was 424 days. Forty-four percent of those that had resolution of hypoglycaemia experienced recurrence of hypoglycaemia by 2 years postoperatively. Pathological stage was a predictor of persistent post-operative hypoglycaemia which, in turn, was a predictor of survival time. These results show that dogs with insulinoma can have prolonged survival, and that pathological stage is a predictor of outcome.

Mapping Regional Cortical Bone Responses to Local Changes in Loading and Systemic Stimuli.

Quantification of cortical bone mass and architecture using µCT is commonplace in osteoporosis and osteoarthritis research. Different groups often report substantially divergent mouse cortical bone responses to nominally comparable interventions. In the case of studies assessing bones' responses to externally applied loading, these differences are commonly associated with methodological differences in the loading regime. This chapter describes a widely published, standardized method of in vivo mouse tibia axial loading to produce lamellar bone formation. Despite uniform application of axial loading, changes in bone mass are highly site-specific within individual bones. For example, the mouse proximal tibia rapidly accrues new bone following axial loading, but this osteogenic response tapers to produce undetectable differences distally. Consequently, the bone sites selected for comparisons substantially influence the magnitude of differences observed. Application of the freely available Site Specificity software allows site-specific responses to be identified by rapidly quantifying cortical bone mass at each 1% site along the bone's length. This high-content screening tool has been informatively applied to study the local effects of changes in loading as well as systemic interventions including hormonal treatment and aging. Automated multisite analyses of cortical mass is increasingly identifying site-specific effects of "systemic" interventions such as global gene deletions. Biological mechanisms underlying this apparent regionalization of cortical responses are largely unknown but may start to be elucidated by increasingly widespread application of Site Specificity methods.

Estimation of load conditions and strain distribution for in vivo murine tibia compression loading using experimentally informed finite element models.

The murine tibia compression model, is the gold standard for studying bone adaptation due to mechanical loading in vivo. Currently, a key limitation of the experimental protocol and associated finite element (FE) models is that the exact load transfer, and consequently the loading conditions on the tibial plateau, is unknown. Often in FE models, load is applied to the tibial plateau based on inferences from micro-computed tomography (µCT). Experimental models often use a single strain gauge to assess the three-dimensional (3D) loading state. However, a single strain gauge is insufficient to validate such FE models. To address this challenge, we develop an experimentally calibrated method for identifying the load application region on the tibial plateau based upon measurements from three strain gauges. To achieve this, axial compression was conducted on mouse tibiae (n=3), with strains gauges on three surfaces. FE simulations were performed to compute the strains at the gauge locations as a function of a variable load location. By minimising the error between experimental and FE strains, the precise load location was identified; this was found to vary between tibia specimens. It was further shown that commonly used FE loading conditions, found in literature, did not replicate the experimental strain distribution, highlighting the importance of load calibration. This work provides critical insights into how load is transferred to the tibial plateau. Importantly, this work develops an experimentally informed technique for loading the tibial plateau in FE models.

Bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice.

The primary aim of osteoanabolic therapies is to strategically increase bone mass in skeletal regions likely to experience high strains. In the young healthy skeleton, this is primarily achieved by bone's adaptation to loading. This adaptation appears to fail with age, resulting in osteoporosis and fractures. We previously demonstrated that prior and concurrent disuse enhances bone gain following loading in old female mice. Here, we applied site specificity micro-computed tomography analysis to map regional differences in bone anabolic responses to axial loading of the tibia between young (19-week-old) and aged (19-month-old), male and female mice. Loading increased bone mass specifically in the proximal tibia in both sexes and ages. Young female mice gained more cortical bone than young males in specific regions of the tibia. However, these site-specific sex differences were lost with age such that bone gain following loading was not significantly different between old males and females. To test whether disuse enhances functional adaption in old male mice as it does in females, old males were subjected to sciatic neurectomy or sham surgery, and loading was initiated four days after surgery. Disuse augmented tibial cortical bone gain in response to loading in old males, but only in regions which were load-responsive in the young. Prior and concurrent disuse also increased loading-induced trabecular thickening in the proximal tibia of old males. Understanding how diminished background loading rejuvenates the osteogenic loading response in the old may improve osteogenic exercise regimes and lead to novel osteoanabolic therapies.

Student Perceptions of Sectional CT/MRI Use in Teaching Veterinary Anatomy and the Correlation with Visual Spatial Ability: A Student Survey and Mental Rotations Test.

Diagnostic imaging technology is becoming more advanced and widely available to veterinary patients with the growing popularity of veterinary-specific computed tomography (CT) and magnetic resonance imaging (MRI). Veterinary students must, therefore, be familiar with these technologies and understand the importance of sound anatomic knowledge for interpretation of the resultant images. Anatomy teaching relies heavily on visual perception of structures and their function. In addition, visual spatial ability (VSA) positively correlates with anatomy test scores. We sought to assess the impact of including more diagnostic imaging, particularly CT/MRI, in the teaching of veterinary anatomy on the students' perceived level of usefulness and ease of understanding content. Finally, we investigated survey answers' relationship to the students' inherent baseline VSA, measured by a standard Mental Rotations Test. Students viewed diagnostic imaging as a useful inclusion that provided clear links to clinical relevance, thus improving the students' perceived benefits in its use. Use of CT and MRI images was not viewed as more beneficial, more relevant, or more useful than the use of radiographs. Furthermore, students felt that the usefulness of CT/MRI inclusion was mitigated by the lack of prior formal instruction on the basics of CT/MRI image generation and interpretation. To be of significantly greater use, addition of learning resources labeling relevant anatomy in tomographical images would improve utility of this novel teaching resource. The present study failed to find any correlation between student perceptions of diagnostic imaging in anatomy teaching and their VSA.

Parathyroid hormone's enhancement of bones' osteogenic response to loading is affected by ageing in a dose- and time-dependent manner.

Decreased effectiveness of bones' adaptive response to mechanical loading contributes to age-related bone loss. In young mice, intermittent administration of parathyroid hormone (iPTH) at 20-80µg/kg/day interacts synergistically with artificially applied loading to increase bone mass. Here we report investigations on the effect of different doses and duration of iPTH treatment on mice whose osteogenic response to artificial loading is impaired by age. One group of aged, 19-month-old female C57BL/6 mice was given 0, 25, 50 or 100µg/kg/day iPTH for 4weeks. Histological and µCT analysis of their tibiae revealed potent iPTH dose-related increases in periosteally-enclosed area, cortical area and porosity with decreased cortical thickness. There was practically no effect on trabecular bone. Another group was given a submaximal dose of 50µg/kg/day iPTH or vehicle for 2 or 6weeks with loading of their right tibia three times per week for the final 2weeks. In the trabecular bone of these mice the loading-related increase in BV/TV was abrogated by iPTH primarily by reduction of the increase in trabecular number. In their cortical bone, iPTH treatment time-dependently increased cortical porosity. Loading partially reduced this effect. The osteogenic effects of iPTH and loading on periosteally-enclosed area and cortical area were additive but not synergistic. Thus in aged, unlike young mice, iPTH and loading appear to have separate effects. iPTH alone causes a marked increase in cortical porosity which loading reduces. Both iPTH and loading have positive effects on cortical periosteal bone formation but these are additive rather than synergistic.

Old age and the associated impairment of bones' adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle.

In old animals, bone's ability to adapt its mass and architecture to functional load-bearing requirements is diminished, resulting in bone loss characteristic of osteoporosis. Here we investigate transcriptomic changes associated with this impaired adaptive response. Young adult (19-week-old) and aged (19-month-old) female mice were subjected to unilateral axial tibial loading and their cortical shells harvested for microarray analysis between 1h and 24h following loading (36 mice per age group, 6 mice per loading group at 6 time points). In non-loaded aged bones, down-regulated genes are enriched for MAPK, Wnt and cell cycle components, including E2F1. E2F1 is the transcription factor most closely associated with genes down-regulated by ageing and is down-regulated at the protein level in osteocytes. Genes up-regulated in aged bone are enriched for carbohydrate metabolism, TNFα and TGFß superfamily components. Loading stimulates rapid and sustained transcriptional responses in both age groups. However, genes related to proliferation are predominantly up-regulated in the young and down-regulated in the aged following loading, whereas those implicated in bioenergetics are down-regulated in the young and up-regulated in the aged. Networks of inter-related transcription factors regulated by E2F1 are loading-responsive in both age groups. Loading regulates genes involved in similar signalling cascades in both age groups, but these responses are more sustained in the young than aged. From this we conclude that cells in aged bone retain the capability to sense and transduce loading-related stimuli, but their ability to translate acute responses into functionally relevant outcomes is diminished.

Wnt16 Is Associated with Age-Related Bone Loss and Estrogen Withdrawal in Murine Bone.

Genome Wide Association Studies suggest that Wnt16 is an important contributor to the mechanisms controlling bone mineral density, cortical thickness, bone strength and ultimately fracture risk. Wnt16 acts on osteoblasts and osteoclasts and, in cortical bone, is predominantly derived from osteoblasts. This led us to hypothesize that low bone mass would be associated with low levels of Wnt16 expression and that Wnt16 expression would be increased by anabolic factors, including mechanical loading. We therefore investigated Wnt16 expression in the context of ageing, mechanical loading and unloading, estrogen deficiency and replacement, and estrogen receptor α (ERα) depletion. Quantitative real time PCR showed that Wnt16 mRNA expression was lower in cortical bone and marrow of aged compared to young female mice. Neither increased nor decreased (by disuse) mechanical loading altered Wnt16 expression in young female mice, although Wnt16 expression was decreased following ovariectomy. Both 17ß-estradiol and the Selective Estrogen Receptor Modulator Tamoxifen increased Wnt16 expression relative to ovariectomy. Wnt16 and ERß expression were increased in female ERα-/- mice when compared to Wild Type. We also addressed potential effects of gender on Wnt16 expression and while the expression was lower in the cortical bone of aged males as in females, it was higher in male bone marrow of aged mice compared to young. In the kidney, which we used as a non-bone reference tissue, Wnt16 expression was unaffected by age in either males or females. In summary, age, and its associated bone loss, is associated with low levels of Wnt16 expression whereas bone loss associated with disuse has no effect on Wnt16 expression. In the artificially loaded mouse tibia we observed no loading-related up-regulation of Wnt16 expression but provide evidence that its expression is influenced by estrogen receptor signaling. These findings suggest that while Wnt16 is not an obligatory contributor to regulation of bone mass per se, it potentially plays a role in influencing pathways associated with regulation of bone mass during ageing and estrogen withdrawal.

Quantification of Alterations in Cortical Bone Geometry Using Site Specificity Software in Mouse models of Aging and the Responses to Ovariectomy and Altered Loading.

Investigations into the effect of (re)modeling stimuli on cortical bone in rodents normally rely on analysis of changes in bone mass and architecture at a narrow cross-sectional site. However, it is well established that the effects of axial loading produce site-specific changes throughout bones' structure. Non-mechanical influences (e.g., hormones) can be additional to or oppose locally controlled adaptive responses and may have more generalized effects. Tools currently available to study site-specific cortical bone adaptation are limited. Here, we applied novel site specificity software to measure bone mass and architecture at each 1% site along the length of the mouse tibia from standard micro-computed tomography (µCT) images. Resulting measures are directly comparable to those obtained through µCT analysis (R (2) > 0.96). Site Specificity analysis was used to compare a number of parameters in tibiae from young adult (19-week-old) versus aged (19-month-old) mice; ovariectomized and entire mice; limbs subjected to short periods of axial loading or disuse induced by sciatic neurectomy. Age was associated with uniformly reduced cortical thickness and site-specific decreases in cortical area most apparent in the proximal tibia. Mechanical loading site-specifically increased cortical area and thickness in the proximal tibia. Disuse uniformly decreased cortical thickness and decreased cortical area in the proximal tibia. Ovariectomy uniformly reduced cortical area without altering cortical thickness. Differences in polar moment of inertia between experimental groups were only observed in the proximal tibia. Aging and ovariectomy also altered eccentricity in the distal tibia. In summary, site specificity analysis provides a valuable tool for measuring changes in cortical bone mass and architecture along the entire length of a bone. Changes in the (re)modeling response determined at a single site may not reflect the response at different locations within the same bone.

Androgens inhibit the osteogenic response to mechanical loading in adult male mice.

Androgens are well known to enhance exercise-induced muscle hypertrophy; however, whether androgens also influence bone's adaptive response to mechanical loading remains unclear. We studied the adaptive osteogenic response to unilateral in vivo mechanical loading of tibia in adult male mice in both a long- and a short-term experimental set-up. Mice were divided into four groups: sham operated, orchidectomized (ORX), T (ORX+T), or nonaromatizable dihydrotestosterone (ORX+DHT) replacement. Significant interactions between androgen status and osteogenic response to mechanical loading were observed. Cortical thickness increased by T (0.14 vs 0.11 mm sham, P<.05) and DHT (0.17 vs 0.11 mm sham, P<.05). However, T partially (+36%) and DHT completely (+10%) failed to exhibit the loading-related increase observed in sham (+107%) and ORX (+131%, all P<.05) mice. ORX decreased periosteal bone formation, which was restored to sham levels by T and DHT. However, both androgens completely suppressed the loading-related increase in periosteal bone formation. Short-term loading decreased the number of sclerostin-positive osteocytes in sham, whereas in control fibulas, ORX decreased and T increased the number of sclerostin-positive osteocytes. Loading no longer down-regulated sclerostin in the ORX or T groups. In conclusion, both T and DHT suppress the osteogenic response to mechanical loading.

Planar cell polarity aligns osteoblast division in response to substrate strain.

Exposure of bone to dynamic strain increases the rate of division of osteoblasts and also influences the directional organization of the cellular and molecular structure of the bone tissue that they produce. Here, we report that brief exposure to dynamic substrate strain (sufficient to rapidly stimulate cell division) influences the orientation of osteoblastic cell division. The initial proliferative response to strain involves canonical Wnt signaling and can be blocked by sclerostin. However, the strain-related orientation of cell division is independently influenced through the noncanonical Wnt/planar cell polarity (PCP) pathway. Blockade of Rho-associated coiled kinase (ROCK), a component of the PCP pathway, prevents strain-related orientation of division in osteoblast-like Saos-2 cells. Heterozygous loop-tail mutation of the core PCP component van Gogh-like 2 (Vangl2) in mouse osteoblasts impairs the orientation of division in response to strain. Examination of bones from Vangl2 loop-tail heterozygous mice by µCT and scanning electron microscopy reveals altered bone architecture and disorganized bone-forming surfaces. Hence, in addition to the well-accepted role of PCP involvement in response to developmental cues during skeletal morphogenesis, our data reveal that this pathway also acts postnatally, in parallel with canonical Wnt signaling, to transduce biomechanical cues into skeletal adaptive responses. The simultaneous and independent actions of these two pathways appear to influence both the rate and orientation of osteoblast division, thus fine-tuning bone architecture to meet the structural demands of functional loading.