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Estrogen receptor-alpha (ERα) regulates bone mass and is implicated in bone tissue's response to mechanical loading. The effects of ERα deletion in mice depend on sex, anatomical location, and the cellular stage at which ERα is removed. Few studies have investigated the effect of age on the role of ERα in skeletal maintenance and functional adaptation. We previously demonstrated that bone mass and adaptation to loading were altered in growing 10-week-old female and male mice lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO). Here our goal was to determine the effects of ERα and mechanical loading in skeletally-mature adult mice. We subjected 26-week-old skeletally-mature adult pOC-ERαKO and littermate control (LC) mice of both sexes to two weeks of in vivo cyclic tibial loading. ERα deletion in male mice did not alter bone mass or the response to loading. Adult female pOC-ERαKO mice had reduced cancellous and cortical bone mass and increased adaptation to high-magnitude mechanical loading compared to LC mice. Thus, ERα deletion from mature osteoblasts reduced the bone mass and increased the mechanoadaptation of adult female but not male mice. Additionally, compared to our previous work in young mice, adult female mice had greatly reduced mechanoadaptation and adult male mice retained most of their mechanoadaptation with age.

The coordinated spatial and temporal regulation of gene expression in the murine hindlimb determines the identity of mesenchymal progenitors and the development of diversity of musculoskeletal tissues they form. Hindlimb development has historically been studied with lineage tracing of individual genes selected a priori, or at the bulk tissue level, which does not allow for the determination of single cell transcriptional programs yielding mature cell types and tissues. To identify the cellular trajectories of lineage specification during limb bud development, we used single cell mRNA sequencing (scRNA-seq) to profile the developing murine hindlimb between embryonic days (E)11.5-E18.5. We found cell type heterogeneity at all time points, and the expected cell types that form the mouse hindlimb. In addition, we used RNA fluorescence in situ hybridization (FISH) to examine the spatial locations of cell types and cell trajectories to understand the ancestral continuum of cell maturation. This data provides a resource for the transcriptional program of hindlimb development that will support future studies of musculoskeletal development and generate hypotheses for tissue regeneration.

Objective Reduced subchondral bone mass and increased remodeling are associated with early stage OA. However, the direct effect of low subchondral bone mass on the risk and severity of OA development is unclear. We sought to determine the role of low bone mass resulting from a bone-specific loss of estrogen signaling in load-induced OA development using female osteoblast-specific estrogen receptor-alpha knockout (pOC-ERαKO) mice. Methods Osteoarthritis was induced by cyclic mechanical loading applied to the left tibia of 26-week-old female pOC-ERαKO and littermate control mice at peak loads of 6.5N, 7N, or 9N for 2 weeks. Cartilage damage and thickness, osteophyte development, and joint capsule fibrosis were assessed from histological sections. Subchondral bone morphology was analyzed by microCT. The correlation between OA severity and intrinsic bone parameters was determined. Results The loss of ERα in bone resulted in an osteopenic subchondral bone phenotype, but did not directly affect cartilage health. Following two weeks of cyclic tibial loading to induce OA pathology, pOC-ERαKO mice developed more severe cartilage damage, larger osteophytes, and greater joint capsule fibrosis compared to littermate controls. Intrinsic bone parameters negatively correlated with measures of OA severity in loaded limbs. Conclusions Subchondral bone osteopenia resulting from bone-specific loss of estrogen signaling was associated with increased severity of load-induced OA pathology, suggesting that reduced subchondral bone mass directly exacerbates load-induced OA development. Bone-specific changes associated with estrogen loss may contribute to the increased incidence of OA in post-menopausal women.

Mechanical loading is an anabolic stimulus that increases bone mass, and thus a promising method to counteract osteoporosis-related bone loss. The mechanism of this anabolism remains unclear, and needs to be established for both cortical and cancellous envelopes individually. We hypothesized that cortical and cancellous bone display different gene expression profiles at baseline and in response to mechanical loading. To test this hypothesis, the left tibiae of 10-week-old female C57Bl/6 mice were subjected to one session of axial tibial compression (9N, 1200 cycles, 4Hz triangle waveform) and euthanized 3 and 24 hours following loading. The right limb served as the contralateral control. We performed RNA-seq on marrow-free metaphyseal samples from the cortical shell and the cancellous core to determine differential gene expression at baseline (control limb) and in response to load. Differential expression was verified with qPCR. Cortical and cancellous bone exhibited distinctly different transcriptional profiles basally and in response to mechanical loading. More genes were differentially expressed with loading at 24 hours with more genes downregulated at 24 hours than at 3 hours in both tissues. Enhanced Wnt signaling dominated the response in cortical bone at 3 and 24 hours, but in cancellous bone only at 3 hours. In cancellous bone at 24 hours many muscle-related genes were downregulated. These findings reveal key differences between cortical and cancellous genetic regulation in response to mechanical loading. Future studies at different time points and multiple loading sessions will add to our knowledge of cortical and cancellous mechanotransduction with the potential to identify new targets for mouse genetic knockout studies and drugs to treat osteoporosis.

Estrogen receptor alpha (ERα) has been implicated in bone's response to mechanical loading in both males and females. ERα in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERα is deleted. We demonstrated previously that when ERα is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell–specific ERαKO mice. Therefore, we crossed ERα floxed (ERαfl/fl) and osteocalcin-Cre (OC-Cre) mice to generate animals lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro-CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ERα in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC-ERαKO mice had decreased cortical and cancellous bone mass, whereas male pOC-ERαKO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC-ERαKO female L5 vertebrae and with increased maximum moment in pOC-ERαKO male femora. Female pOC-ERαKO mice responded more to mechanical loading, whereas the response of pOC-ERαKO male animals was similar to their littermate controls. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.

Sclerostin, encoded by the Sost gene, is an important negative regulator of bone formation that has been proposed to have a key role in regulating the response to mechanical loading. To investigate the effect of long-term Sclerostin deficiency on mechanotransduction in bone, we performed experiments on unloaded or loaded tibiae of 10 week old female Sost−/− and wild type mice. Unloading was induced via 0.5U botulinum toxin (BTX) injections into the right quadriceps and calf muscles, causing muscle paralysis and limb disuse. On a separate group of mice, increased loading was performed on the left tibiae through unilateral cyclic axial compression of equivalent strains (+1200 µe) at 1200 cycles/day, 5 days/week. Another cohort of mice receiving equivalent loads (−9.0 N) also were assessed. Contralateral tibiae served as normal load controls. Loaded/unloaded and normal load tibiae were assessed at day 14 for bone volume (BV) and formation changes. Loss of BV was seen in the unloaded tibiae of wild type mice, but BV was not different between normal load and unloaded Sost−/− tibiae. An increase in BV was seen in the loaded tibiae of wild type and Sost−/− mice over their normal load controls. The increased BV was associated with significantly increased mid-shaft periosteal mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS), and endosteal MAR and BFR/BS. Notably, loading induced a greater increase in periosteal MAR and BFR/BS in Sost−/− mice than in wild type controls. Thus, long-term Sclerostin deficiency inhibits the bone loss normally induced with decreased mechanical load, but it can augment the increase in bone formation with increased load. © 2014 American Society for Bone and Mineral Research.

Reduced bioavailability of estrogen increases skeletal fracture risk in postmenopausal women, but the mechanisms by which estrogen regulates bone mass are incompletely understood. Because estrogen signaling in bone acts, in part, through estrogen receptor alpha (ERα), mice with global deletion of ERα (ERαKO) have been used to determine the role of estrogen signaling in bone biology. These animals, however, have confounding systemic effects arising from other organs, such as increased estrogen and decreased insulin-like growth factor 1 (IGF-1) serum levels, which may independently affect bone. Mice with tissue-specific ERα deletion in chondrocytes, osteoblasts, osteocytes, or osteoclasts lack the systemic effects seen in the global knockout, but show that presence of the receptor is important for the function of each cell type. Although bone mass is reduced when ERα is deleted from osteoblasts, no study has determined if this approach reduces whole bone strength. To address this issue, we generated female osteoblast-specific ERαKO mice (pOC-ERαKO) by crossing mice expressing a floxed ERα gene (ERα(fl/fl)) with mice transgenic for the osteocalcin-Cre promoter (OC-Cre). Having confirmed that serum levels of estrogen and IGF-1 were unaltered, we focused on relating bone mechanics to skeletal phenotype using whole bone mechanical testing, microcomputed tomography, histology, and dynamic histomorphometry. At 12 and 18 weeks of age, pOC-ERαKO mice had decreased cancellous bone mass in the proximal tibia, vertebra, and distal femur, and decreased cortical bone mass in the tibial midshaft, distal femoral cortex, and L5 vertebral cortex. Osteoblast activity was reduced in cancellous bone of the proximal tibia, but osteoclast number was unaffected. Both femora and vertebrae had decreased whole bone strength in mechanical tests to failure, indicating that ERα in osteoblasts is required for appropriate bone mass and strength accrual in female mice. This pOC-ERαKO mouse is an important animal model that could enhance our understanding of estrogen signaling in bone cells in vivo.

The effects of tears of the anterior cruciate ligament on knee kinematics and contact mechanics during dynamic everyday activities, such as gait, remains unclear. The objective of this study was to characterize anterior cruciate ligament–deficient knee contact mechanics and kinematics during simulated gait. Nine human cadaveric knees were each augmented with a sensor capable of measuring dynamic normal contact stresses on the tibial plateau, mounted on a load-controlled simulator, and subjected to physiological, multidirectional, dynamic loads to mimic gait. Using a mixed model with random knee identifiers, confidence intervals were constructed for contact stress before and after anterior cruciate ligament transection at two points in the gait cycle at which axial force peaked (14% and 45% of the gait cycle). Kinematic and contact mechanics changes after anterior cruciate ligament transection were highly variable across knees. Nonetheless, a statistically significant increase in contact stress in the posterior–central aspect of the medial tibial plateau at 45% of the gait cycle was identified, the location of which corresponds to the location of degenerative changes that are frequently found in patients with chronic anterior cruciate ligament injury. The variability in the contact stress in other regions of the medial plateau at 45% of the gait cycle was partly explained by the variations in osseous geometry across the nine knees tested. At 14% of gait, there was no significant change in peak contact stress after anterior cruciate ligament transection in any of the four quadrants, and none of the possible explanatory variables showed statistical significance. Understanding the variable effect of anterior cruciate ligament injury on contact mechanics based on geometric differences in osseous anatomy is of paramount clinical importance and may be invaluable to select the best reconstruction techniques and counsel patients on their individual risk of subsequent chondral degeneration.

Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the peri-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on peri-implant bone volume fraction. In this model, PTH enhanced peri-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced peri-implant bone volume, and surgery and PTH treatment had a strong combined effect. This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.

The tibial post in posterior-stabilized total knees is a potential source of polyethylene wear debris, but the relationship between the shape and location of the tibial post in relation to the tibiofemoral bearing surfaces and the subsequent wear damage patterns remains unknown.We used observations made on retrieved implant components from three contemporary posterior-stabilized knee designs to examine how differences in tibial post design affected wear damage on the post.We examined 113 retrieved Zimmer NexGen(®), 103 Exactech Optetrak(®), and 58 Smith and Nephew Genesis(®) II posterior-stabilized inserts using a subjective scale to grade post damage.All 274 inserts demonstrated wear damage. Total wear scores and scores for wear damage on the anterior post differed among designs: Optetrak(®) 20 ± 4 and 5 ± 1, NexGen(®) 13 ± 4 and 3 ± 1, and Genesis(®) II 8 ± 3 and 1 ± 1, respectively. The Optetrak(®) had predominantly anterior wear damage, the NexGen(®) had more global wear damage, and the Genesis(®) II had predominantly posterior wear damage. Tibial post wear damage and anterior post wear damage were primarily determined by implant design and to a lesser extent by length of implantation and revision diagnosis.Although tibial post wear damage is multifactorial, the primary determinant of wear damage, and specifically anterior wear damage, is implant design.The constraint provided by the posterior-stabilized post-cam contact in modern knee arthroplasties is reflected in the wear damage patterns that occur during in vivo use. Unintended constraint such as anterior impingement should be addressed through design modifications for future posterior-stabilized knee arthroplasties.

Mobile-bearing TKAs reportedly have no clinical superiority over fixed-bearing TKAs, but a potential benefit is improved polyethylene wear behavior.We asked whether extent of damage and wear patterns would be less severe on retrieved mobile-bearing TKAs than on fixed-bearing TKAs and if correlations with patient demographics could explain differences in extent or locations of damage.We performed damage grading and mapping of 48 mobile-bearing TKAs retrieved due to osteolysis/loosening, infection, stiffness, instability or malpositioning. Visual grading used stereomicroscopy to identify damage, and a grade was assigned based on extent and severity. Each damage mode was then mapped onto a photograph of the implant surface, and the area affected was calculated.Marked wear damage occurred on both surfaces, with burnishing, scratching, and pitting the dominant modes. Damage occurred over a large portion of both surfaces, exceeding the available articular borders in nearly 30% of implants. Wear of mobile-bearing surfaces included marked third-body debris. Damage on tibiofemoral and mobile-bearing surfaces was not correlated with patient BMI or component alignment. Damage on mobile-bearing surfaces was positively correlated with length of implantation and was greater in implants removed for osteolysis or instability than in those removed for stiffness or infection.Each bearing surface in mobile-bearing implants was damaged to an extent similar to that in fixed-bearing implants, making the combined damage score higher than that for fixed-bearing implants. Mobile-bearing TKAs did not improve wear damage, providing another argument against the superiority of these implants over fixed-bearing implants.

Biophysical stimuli may be an effective therapy to counteract age-related changes in bone structure that affect the primary stability of implants used in joint replacement or fracture fixation. The influence of controlled mechanical loading on osseointegration was investigated using an in vivo device implanted in the distal lateral femur of 12 male rabbits. Compressive loads (1 MPa, 1 Hz, 50 cycles/day, 4 weeks) were applied to a porous titanium foam implant and the underlying cancellous bone. The contralateral limbs served as nonloaded controls. Backscattered electron imaging indicated that the amount of bone ingrowth was significantly greater in the loaded limb than in the nonloaded control limb, whereas the amount of underlying cancellous periprosthetic bone was similar. No significant difference in the mineral apposition rate of the bone ingrowth or periprosthetic bone was measured in the loaded compared to the control limb. Histological analysis demonstrated newly formed woven bone in direct apposition to the implant coating, with a lack of fibrous tissue at the implant-periprosthetic bone interface in both loaded and nonloaded implants. The lack of fibrous tissue demonstrates that mechanical stimulation using this model significantly enhanced cancellous bone ingrowth without the detrimental effects of micromotion. These results suggest that biophysical therapy should be further investigated to augment current treatments to enhance long-term fixation of orthopedic devices. Additionally, this novel in vivo loading model can be used to further investigate the influence of biophysical stimulation on other tissue engineering approaches requiring bone ingrowth into both metallic and nonmetallic cell-seeded scaffolds.

Unicondylar knee arthroplasty (UKA) is considered an alternative to total knee arthroplasty for patients who have arthritis limited to one compartment of the knee. This study examined surface damage of 3 contemporary UKA designs that were retrieved at revision surgery. Two of the UKA designs were fixed bearing and one was mobile bearing. Demographic information was collected, as well as information about the implants used at revision surgery. Articular surface damage was greater in the fixed-bearing designs as compared to the mobile bearing, although the mobile-bearing implants had significantly shorter length of implantation. Backside damage was also graded for the mobile bearing and when combined with articular wear resulted in overall damage scores higher than both fixed-bearing designs. The fixed-bearing designs showed delamination and surface deformation, whereas the mobile bearing had no evidence of these damage modes. However, mobile-bearing components showed other types of wear, and significant wear damage was present on the bearing surfaces of the mobile-bearing implants despite a short time of implantation. At the time of conversion to a total knee arthroplasty, more than 50% of cases required the use of stems, augments, or constrained inserts for the tibial reconstruction. In conclusion, wear modes differed among UKA prosthesis designs. Revision of a UKA to a total knee arthroplasty remains complex with the tibial preparation more complicated than in the primary setting.

Background: The menisci are integral to normal knee function. The purpose of this study was to measure the contact pressures transmitted to the medial tibial plateau under physiological loads as a function of the percentage of the meniscus involved by the radial tear or repair. Our hypotheses were that (1) there is a threshold size of radial tears above which contact mechanics are adversely affected, and (2) partial meniscectomy results in increased contact pressure compared with that found after meniscal repair. Methods: A knee simulator was used to apply physiological multidirectional dynamic gait loads across human cadaver knees. A sensor inserted below the medial meniscus recorded contact pressures in association with (1) an intact meniscus, (2) a radial tear involving 30% of the meniscal rim width, (3) a radial tear involving 60% of the width, (4) a radial tear involving 90% of the width, (5) an inside-out repair with horizontal mattress sutures, and (6) a partial meniscectomy. The effects of these different types of meniscal manipulation on the magnitude and location of the peak contact pressure were assessed at 14% and 45% of the gait cycle. Results: The peak tibial contact pressure in the intact knees was 6 ± 0.5 MPa and 7.4 ± 0.6 MPa at 14% and 45% of the gait cycle, respectively. The magnitude and location of the peak contact pressure were not affected by radial tears involving up to 60% of the meniscal rim width. Radial tears involving 90% resulted in a posterocentral shift in peak-pressure location manifested by an increase in pressure in that quadrant of 1.3 ± 0.5 MPa at 14% of the gait cycle relative to the intact condition. Inside-out mattress suture repair of a 90% tear did not restore the location of the pressure peak to that of the intact knee. Partial meniscectomy led to a further increase in contact pressure in the posterocentral quadrant of 1.4 ± 0.7 MPa at 14% of the gait cycle. Conclusions: Large radial tears of the medial meniscus are not functionally equivalent to meniscectomies; the residual meniscus continues to provide some load transmission and distribution functions across the joint. Clinical Relevance: The results of this study support meniscal preservation and repair of medial radial tears.

Introduction of highly crosslinked polyethylene has increased interest in large femoral heads, because thin acetabular liners can be used while maintaining low wear rates and larger heads decrease the incidence of instability. However, crosslinking and subsequent thermal treatments can cause decreased mechanical properties that might obviate the reduced wear under extreme conditions. To examine whether increased contact pressures would adversely affect wear in thin liners, we tested thin and thick highly crosslinked liners (3.8 mm thickness/44-mm head and 7.9 mm thickness/36-mm head, respectively) to 5 million cycles on a hip simulator under near impingement conditions. Conventional polyethylene liners (7.9 mm thickness/36-mm head) served as controls. Large femoral heads with highly crosslinked polyethylene liners as thin as 3.8 mm in thickness do not wear at a higher rate than a thicker liner of the same material, even when subjected to large contact pressures such as occur under near-impingement conditions. Crosslinked polyethylene may allow for liners that are thinner than has been traditionally accepted. This conclusion, however, is based solely on wear test results with idealized cup position, no intentional edge loading, no head subluxation, and no artificial aging. Continued monitoring will be necessary to elucidate the clinical efficacy of these devices.

Despite the large loads placed upon constrained acetabular liners, little is known of their mechanical performance. We analyzed retrieved liners to determine wear and other damage modes and assess associations between types and severity of damage and clinical, radiographic, and implant variables. Outer rim impingement frequency and severity were higher than that for the inner rim. The 20 degrees elevation was most frequently affected by impingement. Inner rim impingement was more frequent with small heads. Outer bearing surface wear scores were higher than inner bearing scores. Liners removed for infection or stem failure had similar damage compared with other groups, demonstrating the complex relationship of impingement and wear with clinical performance. No association was found between liner damage and clinical and radiographic variables.

The high incidence of fragility fractures in cortico-cancellous bone locations, plus the fact that individual skeletal sites exhibit different responsiveness to load and disease, emphasizes the need to document separately gene expression in cortical and cancellous bone. A further confounding factor is marrow contamination since its high cellularity may effect gene expression measurements. We isolated RNA from cortical and cancellous bone of intact mouse tibiae, and also after marrow removal by flushing or centrifugation. RNA isolated from cancellous bone by each method was sufficient for gene expression analysis. Centrifugation removed contaminating cells more efficiently than flushing, as indexed by histology and decreased expression of Icam4, a highly expressed erythroid gene. In contrast, centrifuged cortical bone had 12- and 13- fold higher expression of the bone-related genes Col1a1 and Bglap, while levels in marrow-free cancellous bone were 30- and 31-fold higher when compared to bone where marrow was left intact. Furthermore, cortical bone had higher expression of Col1a1 and Bglap than cancellous bone. Thus, RNA isolated by this novel approach can reveal site-specific changes in gene expression in cortical and cancellous bone sites.

Estrogen receptor alpha (ERα) has been implicated in bone's response to mechanical loading in both males and females. ERα in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERα is deleted. We demonstrated previously that when ERα is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell-specific ERαKO mice. Therefore, we crossed ERα floxed (ERα(fl/fl)) and osteocalcin-Cre (OC-Cre) mice to generate animals lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro-CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ERα in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC-ERαKO mice had decreased cortical and cancellous bone mass, whereas male pOC-ERαKO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC-ERαKO female L(5) vertebrae and with increased maximum moment in pOC-ERαKO male femora. Female pOC-ERαKO mice responded more to mechanical loading, whereas the response of pOC-ERαKO male animals was similar to their littermate controls.

Reduced bioavailability of estrogen increases skeletal fracture risk in postmenopausal women, but the mechanisms by which estrogen regulates bone mass are incompletely understood. Because estrogen signaling in bone acts, in part, through estrogen receptor alpha (ERα), mice with global deletion of ERα (ERαKO) have been used to determine the role of estrogen signaling in bone biology. These animals, however, have confounding systemic effects arising from other organs, such as increased estrogen and decreased insulin-like growth factor 1 (IGF-1) serum levels, which may independently affect bone. Mice with tissue-specific ERα deletion in chondrocytes, osteoblasts, osteocytes, or osteoclasts lack the systemic effects seen in the global knockout, but show that presence of the receptor is important for the function of each cell type. Although bone mass is reduced when ERα is deleted from osteoblasts, no study has determined if this approach reduces whole bone strength. To address this issue, we generated female osteoblast-specific ERαKO mice (pOC-ERαKO) by crossing mice expressing a floxed ERα gene (ERα(fl/fl)) with mice transgenic for the osteocalcin-Cre promoter (OC-Cre). Having confirmed that serum levels of estrogen and IGF-1 were unaltered, we focused on relating bone mechanics to skeletal phenotype using whole bone mechanical testing, microcomputed tomography, histology, and dynamic histomorphometry. At 12 and 18 weeks of age, pOC-ERαKO mice had decreased cancellous bone mass in the proximal tibia, vertebra, and distal femur, and decreased cortical bone mass in the tibial midshaft, distal femoral cortex, and L5 vertebral cortex. Osteoblast activity was reduced in cancellous bone of the proximal tibia, but osteoclast number was unaffected. Both femora and vertebrae had decreased whole bone strength in mechanical tests to failure, indicating that ERα in osteoblasts is required for appropriate bone mass and strength accrual in female mice. This pOC-ERαKO mouse is an important animal model that could enhance our understanding of estrogen signaling in bone cells in vivo.

Large angular deformities can be a challenge when performing primary total knee replacement. Some investigators have advocated the use of increased component constraint in these settings. The goal of this study was to determine the location and extent of damage to a consecutive series of retrieved constrained tibial inserts used in primary arthroplasty. There was significant post and articular damage in retrieved implants. Reliance on the polyethylene post for implant stability was associated with post and articular surface damage and may be a potential source of failure. Attempts to achieve implant stability using soft tissue techniques seem justified.

Purpose To characterize the effect of radial tears (RTs) of the lateral meniscus and their subsequent treatment (inside-out repair, partial meniscectomy) on joint contact mechanics during simulated gait. Methods Six human cadaveric knees were mounted on a simulator programmed to mimic human gait. A sensor was inserted below the lateral meniscus to measure peak joint contact pressure location, magnitude, and contact area. The following conditions were compared: intact meniscus, 30% RT (at the popliteal hiatus), 60% RT, 90% RT, repair, and partial meniscectomy. Data were analyzed in the midstance phase of gait (14% and 45%) when axial force was at its highest (2,100 N). Results Intact knees had peak contact pressures of 5.9 ± 0.9 MPa and 6.4 ± 1.1 MPa at 14% and 45% of gait, respectively. RTs of up to and including 60% had no effect on pressure magnitude or location. RTs of 90% resulted in significantly increased peak pressure (8.4 ± 1.1 MPa) in the postero-peripheral aspect of the tibial plateau and reduced contact area versus the intact knee, at 45% of gait. Repair resulted in a significant decrease in peak pressure (7.7 ± 1.0 MPa) relative to 90% RT but had no effect on contact area. Partial lateral meniscectomy resulted in areas and pressures that were not significantly different from 90% tears (8.7 ± 1.5 MPa). Conclusions Simulated large RTs of the lateral meniscus in the region of the popliteal hiatus show unfavorable dynamic contact mechanics that are not significantly different from those resulting from a partial lateral meniscectomy. Pressure was significantly reduced with inside-out repair but was not affected by partial meniscectomy; contact area was not restored to that of the intact condition for either procedure. Clinical Relevance Large RTs in the region of the popliteal hiatus show unfavorable dynamic contact mechanics.

Highly crosslinked UHMWPE is associated with increased wear resistance in hip simulator and clinical studies. Laboratory and case studies, however, have described rim fracture in crosslinked acetabular liners. Controversy exists, therefore, on the relative merits of crosslinked liners over conventional liners in terms of wear performance versus resistance to fatigue cracking.We asked whether crosslinked liners would show less surface damage than conventional liners but would be more susceptible to fatigue damage.We examined 36 conventional UHMWPE and 39 crosslinked UHMWPE retrieved implants with similar patient demographics and identical design for evidence of wear damage, including articular surface damage, impingement, screw-hole creep, and rim cracks.We observed no difference in wear damage scores for the two liners. Conventional liners more frequently impinged but were more often elevated with smaller head sizes. We observed creep in approximately 70% of both types of liners. Incipient rim cracks were found in five crosslinked liners, and one liner had a rim fracture. Only one conventional liner had an incipient rim crack.Contrary to our expectation, damage was similar between crosslinked and conventional UHMWPE liners. Moreover, the 15% occurrence (six of 39) of incipient or complete fractures in crosslinked liners as compared with a 3% occurrence (one of 36) in conventional liners may have implications for the long-term performance of crosslinked liners. Longer-term studies will be necessary to establish the fate of rim cracks and thus the overall clinical fatigue performance of crosslinked liners.

Oxidized zirconium (OxZr) was introduced to serve as a ceramic surface for femoral components in TKA. The aim of this study was to compare retrieved OxZr components and corresponding PE inserts in matched comparison with conventional cobalt/chrome/molybdenum alloy (CoCrMo). Eleven retrieved posterior stabilized TKA with an OxZr femoral component were included. This included 6 implants from an earlier preliminary study. From a cohort of 56 retrieved TKA with conventional CoCrMo femoral components, pairs were matched according to duration of implantation, patient age, reason for revision, and BMI. Polyethylene inlays and femoral components were optically scored for in vivo damage. The average damage score of the tibial PE inserts was significantly lower with OxZr components (p=0.01). Mainly burnishing and scratches were found. The average wear score in the visual analysis of the femoral components was significantly lower for the OxZr as well (p=0.005). Femoral components made of OxZr were less sensitive to in vivo damage and corresponding PE inlays also showed less damage than CoCrMo components.

A novel porous titanium foam implant has recently been developed to enhance biological fixation of orthopaedic implants to bone. The aim of this study was to examine the mechanical and histological characteristics of bone apposition into two different pore sizes of this titanium foam (565 and 464 micron mean void intercept length) and to compare these characteristics to those obtained with a fully porous conventionally sintered titanium bead implant. Cylindrical implants were studied in a rabbit distal femoral intramedullary osseointegration model at time zero and at 3, 6, and 12 weeks. The amount of bone ingrowth, amount of periprosthetic bone, and mineral apposition rate of periprosthetic bone measured did not differ among the three implant designs at 3, 6, or 12 weeks. By 12 weeks, the interface stiffness and maximum load of the beaded implant was significantly greater than either foam implant. No significant difference was found in the interface stiffness or maximum load between the two foam implant designs at 3, 6, or 12 weeks. The lower compressive modulus of the foam compared to the more dense sintered beaded implants likely contributed to the difference in failure mode. However, the foam implants have a similar compressive modulus to other clinically successful coatings, suggesting they are nonetheless clinically adequate. Additional studies are required to confirm this in weight-bearing models. Histological data suggest that these novel titanium foam implants are a promising alternative to current porous coatings and should be further investigated for clinical application in cementless joint replacement.

s e9 Paper #9 Unicondylar Knee Implant Retrieval Theodore T. Manson, MD, Geoffrey H. Westrich, MD, Natalie Kelly, BS, Joseph Lipman, MS, Timothy M. Wright, PhD Introduction: Wear behavior of unicondylar knee arthroplasty (UKA) should be influenced by implant design. We compared wear patterns among 3 modern designs: Oxford mobile bearing (Biomet), Repicci fixed bearing with an all polyethylene tibia (Biomet), and Miller-Galante fixed bearing with a metal-backed tibia (Zimmer). Methods: Between 1999 and 2008, 44 tibial components were retrieved as part of an ongoing retrieval program. Wear damage was graded on a subjective 0 to 3 scale for 7 modes: scratching, pitting, burnishing, embedded debris, abrasion, and delamination. A cumulative score was assigned each component, in addition to scores for each mode. Results: Average patient age at implant removal was 61.7 years with no differences among the groups. Cumulative wear scores were higher for Repicci and Miller-Galante prostheses (34.8 and 33.6, respectively) than for Oxford prostheses (22.58; P b .01). However, the backside of the Oxford prostheses also showed wear damage with an average score of 16.3. Repicci and Miller-Galante had higher delamination scores (.89 and .75, respectively), while no Oxford prosthesis showed delamination. Likewise, Repicci and Miller-Galante had higher surface deformation scores (1.81 and 1.63) while the Oxford showed no surface deformation. Embedded debris was more common in the Repicci (0.6) than either the Oxford (0.19) or Miller-Galante (0.2) prostheses (P b .01). Conclusion: The Oxford prostheses showed less influence of shear-induced wear patterns (surface deformation and delamination) than the Repicci and Miller-Galante prostheses. Oxford prostheses revealed less overall wear on the bearing surfaces, though the presence of a mobile bearing provided another source for wear damage. The absence of delamination and surface deformation in the Oxford implants is consistent with the mobile bearing, providing less constraint to the bearing surfaces. The main types of wear present in our retrieval specimens could be minimized with a change to highly cross-linked polyethylene.

Introduction: Concern for stability and increased range of motion in THA has increased popularity of large femoral heads, while thin polyethylene liners have allowed acetabular component thickness to remain constant. Highly cross-linked polyethylene improves wear, but is accompanied by reduced toughness. Decreasing thickness may increase wear or cause gross fracture, especially at extremes of motion when contact between head and acetabulum nears the liner edge. We determined the effect of liner thickness on wear with large diameter heads in a near impingement model.