Telemedicine delivery of patient education in remote Ontario communities: feasibility of an Advanced Clinician Practitioner in Arthritis Care (ACPAC)-led inflammatory arthritis education program.

OBJECTIVE: Telemedicine-based approaches to health care service delivery improve access to care. It was recognized that adults with inflammatory arthritis (IA) living in remote areas had limited access to patient education and could benefit from the 1-day Prescription for Education (RxEd) program. The program was delivered by extended role practitioners with advanced training in arthritis care. Normally offered at one urban center, RxEd was adapted for videoconference delivery through two educator development workshops that addressed telemedicine and adult education best practices. This study explores the feasibility of and participant satisfaction with telemedicine delivery of the RxEd program in remote communities. MATERIALS AND METHODS: Participants included adults with IA attending the RxEd program at one of six rural sites. They completed post-course program evaluations and follow-up interviews. Educators provided post-course feedback to identify program improvements that were later implemented. RESULTS: In total, 123 people (36 in-person and 87 remote, across 6 sites) participated, attending one of three RxEd sessions. Remote participants were satisfied with the quality of the video-conference (% agree/strongly agree): could hear the presenter (92.9%) and discussion between sites (82.4%); could see who was speaking at other remote sites (85.7%); could see the slides (95.3%); and interaction between sites adequately facilitated (94.0%). Educator and participant feedback were consistent. Suggested improvements included: use of two screens (speaker and slides); frontal camera angles; equal interaction with remote sites; and slide modifications to improve the readability on screen. Interview data included similar constructive feedback but highlighted the educational and social benefits of the program, which participants noted would have been inaccessible if not offered via telemedicine. CONCLUSION: Study findings confirm the feasibility of delivering the RxEd program to remote communities by using telemedicine. Future research with a focus on the sustainability of this and other models of technology-supported patient education for adults with IA across Ontario is warranted.

A prospective comparison of telemedicine versus in-person delivery of an interprofessional education program for adults with inflammatory arthritis.

Introduction We evaluated two modes of delivery of an inflammatory arthritis education program ("Prescription for Education" (RxEd)) in improving arthritis self-efficacy and other secondary outcomes. Methods We used a non-randomized, pre-post design to compare videoconferencing (R, remote using telemedicine) versus local (I, in-person) delivery of the program. Data were collected at baseline (T1), immediately following RxEd (T2), and at six months (T3). Self-report questionnaires served as the data collection tool. Measures included demographics, disorder-related, Arthritis Self-Efficacy Scale (SE), previous knowledge (Arthritis Community Research and Evaluation Unit (ACREU) rheumatoid arthritis knowledge questionnaire), coping efficacy, Illness Intrusiveness, and Effective Consumer Scale. Analysis included: baseline comparisons and longitudinal trends (R vs I groups); direct between-group comparisons; and Generalized Estimating Equations (GEE) analysis. Results A total of 123 persons attended the program (I: n = 36; R: n = 87) and 111 completed the baseline questionnaire (T1), with follow-up completed by 95% ( n = 117) at T2 and 62% ( n = 76) at T3. No significant baseline differences were found across patient characteristics and outcome measures. Both groups (R and I) showed immediate effect (improved arthritis SE, mean change (95% confidence interval (CI)): R 1.07 (0.67, 1.48); I 1.48 (0.74, 2.23)) after the program that diminished over six months (mean change (95% CI): R 0.45 (-0.1, 0.1); I 0.73 (-0.25, 1.7)). For each of the secondary outcomes, both groups showed similar trends for improvement (mean change scores (95% CI)) over time. GEE analysis did not show any meaningful differences between groups (R vs I) over time. Discussion Improvements in arthritis self-efficacy and secondary outcomes displayed similar trends for I and R participant groups.

Symptom Resolution and Patient-Perceived Recovery Following Ankle Arthroplasty and Arthrodesis.

BACKGROUND: Patients' perception of outcomes is not always defined by the absence of limitations/symptoms (resolution), but can also be characterized by behavioral adaptation and cognitive coping arising in cases with residual deficits. Patient-reported outcome measures (PROs) are designed to measure levels of function or symptoms, largely missing whether patients are coping with ongoing limitations. This study aimed to broaden the conventional definition of a "satisfactory" outcome following ankle reconstruction by comparing patient-reported outcomes of patients with and without residual symptoms and limitations. METHODS: The study consisted of a cross-sectional survey of ankle arthroplasty (n = 85) and arthrodesis (n = 15) patients. Outcome measures included the Ankle Osteoarthritis Scale, Short Musculoskeletal Function Assessment, Short Form-12, and EuroQol-5 Dimension. Patients also completed measures of pain (0-10), stiffness (0-10), satisfaction (0-3), and ability to complete activities of daily living (ADL) (0-6). Based on a self-reported question regarding recovery and coping, patients were categorized as "Recovered-Resolved" (better with no symptoms or residual effects), "Recovered, not Resolved" (RNR, better with residual effects), or "Not Recovered" (not better). Recovery groups were compared across measures. RESULTS: Only 15% of patients were categorized Recovered-Resolved. Most were RNR (69%), leaving 14% Not Resolved. Recovered-Resolved experienced lower rates of pain (1.4 ± 2.3), stiffness (1.1 ± 2.6), and difficulty performing ADLs (0.9 ± 1.2). Overall, outcome measure scores were high (ie, better health) for Recovered-Resolved patients, midrange for RNR patients, and low for Not Recovered patients, thus confirming predefined hypotheses. Recovered-Resolved and RNR patients had similarly high satisfaction summary scores (3.0 ± 0.0 vs 2.6 ± 0.6). CONCLUSION: Most patients reported positive outcomes, but few (15%) experienced resolution of all symptoms and limitations. Current PROs focus on achieving low levels of symptoms and limitations, but miss an important achievement when patients are brought to a level of residual deficits with which they can cope. Patients' perceptions of satisfactory outcomes were not predicated on the resolution of all limitations; thus, the conventional definition of "satisfactory" outcomes should be expanded accordingly. LEVEL OF EVIDENCE: Level II, prospective cohort study.

The patient perspective: arthritis care provided by Advanced Clinician Practitioner in Arthritis Care program-trained clinicians.

OBJECTIVE: To assess patient satisfaction with the arthritis care services provided by graduates of the Advanced Clinician Practitioner in Arthritis Care (ACPAC) program. MATERIALS AND METHODS: This was a cross-sectional evaluation using a self-report questionnaire for data collection. Participants completed the Patient-Doctor Interaction Scale, modified to capture patient-practitioner interactions. Participants completed selected items from the Group Health Association of America's Consumer Satisfaction Survey, and items capturing quality of care, appropriateness of wait times, and a comparison of extended-role practitioner (ERP) services with previously received arthritis care. RESULTS: A total of 325 patients seen by 27 ERPs from 15 institutions completed the questionnaire. Respondents were primarily adults (85%), female (72%), and living in urban areas (79%). The mean age of participants was 54 years (range 3-92 years), and 51% were not working. Patients with inflammatory (51%) and noninflammatory conditions (31%) were represented. Mean (standard deviation) Patient-Practitioner Interaction Scale subscale scores ranged from 4.50 (0.60) to 4.63 (0.48) (1 to 5 [greater satisfaction]). Overall satisfaction with the quality of care was high (4.39 [0.77]), as was satisfaction with wait times (referral to appointment, 4.27 [0.86]; in clinic, 4.24 [0.91]). Ninety-eight percent of respondents felt the arthritis care they received was comparable to or better than that previously received from other health care professionals. CONCLUSION: Patients were very satisfied with and amenable to arthritis care provided by graduates of the ACPAC program. Our findings provide early support for the deployment and integration of ACPAC ERPs into the Ontario health care system and should inform future evaluation at the patient level.

Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice.

Bone loss associated with microgravity exposure poses a significant barrier to long-duration spaceflight. Osteoprotegerin-Fc (OPG-Fc) is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor that causes sustained inhibition of bone resorption after a single subcutaneous injection. We tested the ability of OPG-Fc to preserve bone mass during 12 days of spaceflight (SF). 64-day-old female C57BL/6J mice (n=12/group) were injected subcutaneously with OPG-Fc (20mg/kg) or an inert vehicle (VEH), 24h prior to launch. Ground control (GC) mice (VEH or OPG-Fc) were maintained under environmental conditions that mimicked those in the space shuttle middeck. Age-matched baseline (BL) controls were sacrificed at launch. GC/VEH, but not SF/VEH mice, gained tibia BMD and trabecular volume fraction (BV/TV) during the mission (P<0.05 vs. BL). SF/VEH mice had lower BV/TV vs. GC/VEH mice, while SF/OPG-Fc mice had greater BV/TV than SF/VEH or GC/VEH. SF reduced femur elastic and maximum strength in VEH mice, with OPG-Fc increasing elastic strength in SF mice. Serum TRAP5b was elevated in SF/VEH mice vs. GC/VEH mice. Conversely, SF/OPG-Fc mice had lower TRAP5b levels, suggesting that OPG-Fc preserved bone during spaceflight via inhibition of osteoclast-mediated bone resorption. Decreased bone formation also contributed to the observed osteopenia, based on the reduced femur periosteal bone formation rate and serum osteocalcin level. Overall, these observations suggest that the beneficial effects of OPG-Fc during SF are primarily due to dramatic and sustained suppression of bone resorption. In growing mice, this effect appears to compensate for the SF-related inhibition of bone formation, while preventing any SF-related increase in bone resorption. We have demonstrated that the young mouse is an appropriate new model for SF-induced osteopenia, and that a single pre-flight treatment with OPG-Fc can effectively prevent the deleterious effects of SF on mouse bone.

Reliability and validity of 6 measures of pain, function, and disability for ankle arthroplasty and arthrodesis.

BACKGROUND: Patient-reported outcome measures are increasingly used evaluating clinical care. Many measures used to assess operative hindfoot interventions vary in content, and some have not been psychometrically validated in this population. The purpose of this study was to compare measurement properties of 6 lower-extremity patient-reported outcome measures, and to evaluate their reliability and validity in light of patients' preferences. METHODS: Cross-sectional survey of 42 preoperative and 100 postoperative patients completed 6 lower-extremity outcome measures on 2 occasions: Foot Function Index (FFI), Ankle Osteoarthritis Scale (AOS), patient-reported items of the American Orthopaedic Foot & Ankle Society Questionnaire (AOFAS), Lower Extremity Functional Scale (LEFS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Short Musculoskeletal Function Assessment (SMFA), as well as measures of preference, and symptoms. RESULTS: Internal consistency was good to excellent for all scales and subscales (α = .84-.97; ICC [2,1] = .81-.96). Correlations between scales ranged from .50 (WOMAC(Stiffness) and FFI(Activity) Limitations) to .92 (LEFS and SMFA(Overall), WOMAC(Pain) and AOS(Overall), FFI(Overall) and AOFAS(Overall)). Higher correlations occurred within instruments (r = .97 AOS(Pain) and AOS(Overall)) and between similar subscales from different instruments (r = .91 WOMAC(Pain) and AOS(Pain)). Construct validity showed moderate to high correlations to global ratings of Pain, Stiffness, and difficulty performing Daily Activities. The highest correlations (r > .75) occurred between Pain and AOS(Overall) (r = .84), stiffness and WOMAC(Stiffness) (r = .81), and Daily Activities and AOS(Disability) (r = .87). Patients rated instruments by preference. FFI, WOMAC, LEFS, and SMFA rated favorably for length. FFI, WOMAC, LEFS, and AOFAS rated high for understandability. FFI was rated by postoperative patients as most likely to capture change due to surgery. SMFA rated the best overall. CONCLUSIONS: Direct comparison of instruments revealed similarity between scales in construct validity and reliability. Patient preferences supported the use of these scales. Foot-specific instruments offered no clear advantage over lower-extremity instruments. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Progressive increases in bone mass and bone strength in an ovariectomized rat model of osteoporosis after 26 weeks of treatment with a sclerostin antibody.

The effects of up to 26 weeks of sclerostin antibody (Scl-Ab) treatment were investigated in ovariectomized (OVX) rats. Two months after surgery, 6-month-old osteopenic OVX rats were treated with vehicle or Scl-Ab (25 mg/kg, sc, one time per week) for 6, 12, or 26 weeks. In vivo dual-energy x-ray absorptiometry analysis demonstrated that the bone mineral density of lumbar vertebrae and femur-tibia increased progressively through 26 weeks of Scl-Ab treatment along with progressive increases in trabecular and cortical bone mass and bone strength at multiple sites. There was a strong correlation between bone mass and maximum load at lumbar vertebra, femoral neck, and diaphysis at weeks 6 and 26. Dynamic histomorphometric analysis showed that lumbar trabecular and tibial shaft endocortical and periosteal bone formation rates (BFR/BS) increased and peaked at week 6 with Scl-Ab-treatment; thereafter trabecular and endocortical BFR/BS gradually declined but remained significantly greater than OVX controls at week 26, whereas periosteal BFR/BS returned to OVX control levels at week 26. In the tibia metaphysis, trabecular BFR/BS in the Scl-Ab treated group remained elevated from week 6 to week 26. The osteoclast surface and eroded surface were significantly lower in Scl-Ab-treated rats than in OVX controls at all times. In summary, bone mass and strength increased progressively over 26 weeks of Scl-Ab treatment in adult OVX rats. The early gains were accompanied by increased cortical and trabecular bone formation and reduced osteoclast activity, whereas later gains were attributed to residual endocortical and trabecular osteoblast stimulation and persistently low osteoclast activity.

System integration and clinical utilization of the Advanced Clinician Practitioner in Arthritis Care (ACPAC) Program-Trained Extended Role Practitioners in Ontario: a two-year, system-level evaluation.

BACKGROUND: The Advanced Clinician Practitioner in Arthritis Care (ACPAC) program was developed in 2005 to prepare experienced physical and occupational therapists to function as extended role practitioners (ERPs) within models of arthritis care across Ontario, Canada. PURPOSE: To examine the system-level integration and clinical utilization of the ACPAC program-trained ERP. METHOD: A longitudinal survey was administered to all ACPAC graduates over a two-year period (n=30). RESULTS: The majority of ERPs were physical therapists working in urban settings. Family physicians or physician specialists referred the majority of patients. The longest median wait time to access ERPs' services was 22 days. Half of the ERPs triaged patients, and most of those who did triage (75%) worked under medical directives. Approximately half (51.6%) of the patients seen had a diagnosis of osteoarthritis, followed by rheumatoid arthritis (14.7%). CONCLUSION: Understanding the system-level impact of this unique human resource can help to shape healthcare planning and delivery of care.

Evaluation of perceived collaborative behaviour amongst stakeholders and clinicians of a continuing education programme in arthritis care.

Successful implementation of new extended practice roles which transcend conventional boundaries of practice entails strong collaboration with other healthcare providers. This study describes interprofessional collaborative behaviour perceived by advanced clinician practitioner in arthritis care (ACPAC) graduates at 1 year beyond training, and relevant stakeholders, across urban, community and remote clinical settings in Canada. A mixed-method approach involved a quantitative (survey) and qualitative (focus group/interview) evaluation issued across a 4-month period. ACPAC graduates work across heterogeneous settings and are on teams of diverse size and composition. Seventy per cent perceived their team as actively working in an interprofessional care model. Mean scores on the Bruyère Clinical Team Self-Assessment on Interprofessional Practice subjective subscales were high (range: 3.66-4.26, scale: 1-5 = better perception of team's interprofessional practice), whereas the objective scale was lower (mean: 4.6, scale: 0-9 = more interprofessional team practices). Data from focus groups (ACPAC graduates) and interviews (stakeholders) provided further illumination of these results at individual, group and system levels. Issues relating to ACPAC graduate role recognition, as well as their deployment, integration and institutional support, including access to medical directives, limitation of scope of practice, remuneration conflicts and tenuous funding arrangements were barriers perceived to affect role implementation and interprofessional working. This study offers the opportunity to reflect on newly introduced roles for health professionals with expectations of collaboration that will challenge traditional healthcare delivery.

The ability of outcome questionnaires to capture patient concerns following ankle reconstruction.

BACKGROUND: The objective of this study was to compare questions from outcome questionnaires with items generated by preoperative and postoperative ankle reconstruction patients (using the open-ended questions of self-reported Patient-Specific Index [PASI]) to determine whether existing questionnaires address patients' concerns. METHODS: Patients (n = 142) completed the PASI. Questions from 6 standardized questionnaires (American Academy of Orthopaedic Surgeons Foot and Ankle Questionnaire [AAOS], patient-reported portion of the American Orthopaedic Foot and Ankle Society Clinical Rating System Ankle-Hindfoot Scale [AOFAS], Foot Function Index [FFI], Lower Extremity Functional Scale [LEFS], Short Musculoskeletal Function Assessment [SMFA], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) and PASI were matched by 3 reviewers to corresponding categories in the International Classification of Functioning, Disability and Health (ICF). Standardized questionnaires were then compared with the patient responses produced by the PASI. RESULTS: Patients identified 690 items corresponding to 45 ICF categories. Most PASI concepts fell into Activities and Participation (60.3%) and Body Functions (29.0%) components, including the categories "walking" (19.1%), "pain" (16.5%), and "recreation and leisure" (15.4%); 237 items were identified in questionnaires and linked to 39 ICF categories. Core issues in questionnaires ("pain," "walking," "stairs") were important concerns for patients, but other key patient concerns ("swelling," "recreation and leisure," "sports") were seldom included in questionnaires. CONCLUSION: No single questionnaire captured all patient concerns, and standardized questionnaires differed largely in content. This analysis may help guide development of a more comprehensive instrument for evaluating outcomes following ankle reconstruction. CLINICAL RELEVANCE: When choosing an outcome questionnaire, clinicians and researchers should consider the targeted outcome because no one questionnaire captures the full patient experience.

Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury.

OBJECTIVE: Sclerostin plays a major role in regulating skeletal bone mass, but its effects in articular cartilage are not known. The purpose of this study was to determine whether genetic loss or pharmacologic inhibition of sclerostin has an impact on knee joint articular cartilage. METHODS: Expression of sclerostin was determined in articular cartilage and bone tissue obtained from mice, rats, and human subjects, including patients with knee osteoarthritis (OA). Mice with genetic knockout (KO) of sclerostin and pharmacologic inhibition of sclerostin with a sclerostin-neutralizing monoclonal antibody (Scl-Ab) in aged male rats and ovariectomized (OVX) female rats were used to study the effects of sclerostin on pathologic processes in the knee joint. The rat medial meniscus tear (MMT) model of OA was used to investigate the pharmacologic efficacy of systemic Scl-Ab or intraarticular (IA) delivery of a sclerostin antibody-Fab (Scl-Fab) fragment. RESULTS: Sclerostin expression was detected in rodent and human articular chondrocytes. No difference was observed in the magnitude or distribution of sclerostin expression between normal and OA cartilage or bone. Sclerostin-KO mice showed no difference in histopathologic features of the knee joint compared to age-matched wild-type mice. Pharmacologic treatment of intact aged male rats or OVX female rats with Scl-Ab had no effect on morphologic characteristics of the articular cartilage. In the rat MMT model, pharmacologic treatment of animals with either systemic Scl-Ab or IA injection of Scl-Fab had no effect on lesion development or severity. CONCLUSION: Genetic absence of sclerostin does not alter the normal development of age-dependent OA in mice, and pharmacologic inhibition of sclerostin with Scl-Ab has no impact on articular cartilage remodeling in rats with posttraumatic OA.

Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats.

Clinical studies have revealed a blunting of the bone anabolic effects of parathyroid hormone treatment in osteoporotic patients in the setting of pre- or cotreatment with the antiresorptive agent alendronate (ALN). Sclerostin monoclonal antibody (Scl-Ab) is currently under clinical investigation as a new potential anabolic therapy for postmenopausal osteoporosis. The purpose of these experiments was to examine the influence of pretreatment or cotreatment with ALN on the bone anabolic actions of Scl-Ab in ovariectomized (OVX) rats. Ten-month-old osteopenic OVX rats were treated with ALN or vehicle for 6 wk, before the start of Scl-Ab treatment. ALN-pretreated OVX rats were switched to Scl-Ab alone or to a combination of ALN and Scl-Ab for another 6 wk. Vehicle-pretreated OVX rats were switched to Scl-Ab or continued on vehicle to serve as controls. Scl-Ab treatment increased areal bone mineral density, volumetric bone mineral density, trabecular and cortical bone mass, and bone strength similarly in OVX rats pretreated with ALN or vehicle. Serum osteocalcin and bone formation rate on trabecular, endocortical, and periosteal surfaces responded similarly to Scl-Ab in ALN or vehicle-pretreated OVX rats. Furthermore, cotreatment with ALN did not have significant effects on the increased bone formation, bone mass, and bone strength induced by Scl-Ab in the OVX rats that were pretreated with ALN. These results indicate that the increases in bone formation, bone mass, and bone strength with Scl-Ab treatment were not affected by pre- or cotreatment with ALN in OVX rats with established osteopenia.

Prescription for education: development, evaluation, and implementation of a successful interprofessional education program for adults with inflammatory arthritis.

OBJECTIVE: To assess the feasibility of recruitment and standardize care delivery for an interprofessional program for inflammatory arthritis education (Prescription for Education, or RxEd), and to explore outcomes relevant to arthritis patient education. METHODS: A patient-based needs assessment and ongoing patient feedback guided program development. An interprofessional team was involved in developing program content and delivering and adapting the program to patient needs. A quasiexperimental, waitlisted control with crossover design was used to evaluate the program. Data were collected at baseline, immediately following intervention, at 6 months (when the crossover control group received intervention), and at 1 year. Self-report measures included demographics, disorder-related data, Arthritis Self-efficacy Scale, arthritis knowledge, coping efficacy, and illness intrusiveness. Analysis included baseline comparisons and longitudinal trends; direct between-group comparison at 6 months; and generalized estimating equations (GEE) analysis to evaluate the main effect of the intervention on the primary outcome (arthritis self-efficacy) and secondary outcomes. RESULTS: Program modifications based on patient input made recruitment possible. Forty-two persons participated (including 19 controls), with 93% followup at 1 year. Comparison of change shows moderate effect sizes (standardized effect size 0.5 to 0.7). GEE analysis showed significant main effect, before to after the program, in both groups for primary outcome (arthritis self-efficacy) and most secondary outcomes. CONCLUSION: Program feasibility was dependent on patient feedback. Our pilot study provides evidence that the RxEd program is feasible and improves arthritis self-efficacy and other outcomes.

Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats.

The purpose of this study was to evaluate the effects of sclerostin inhibition by treatment with a sclerostin antibody (Scl-AbII) on bone formation, bone mass, and bone strength in an aged, gonad-intact male rat model. Sixteen-month-old male Sprague-Dawley rats were injected subcutaneously with vehicle or Scl-AbII at 5 or 25 mg/kg twice per week for 5 weeks (9-10/group). In vivo dual-energy X-ray absorptiometry (DXA) analysis showed that there was a marked increase in areal bone mineral density of the lumbar vertebrae (L(1) to L(5) ) and long bones (femur and tibia) in both the 5 and 25 mg/kg Scl-AbII-treated groups compared with baseline or vehicle controls at 3 and 5 weeks after treatment. Ex vivo micro-computed tomographic (µCT) analysis demonstrated improved trabecular and cortical architecture at the fifth lumbar vertebral body (L(5) ), femoral diaphysis (FD), and femoral neck (FN) in both Scl-AbII dose groups compared with vehicle controls. The increased cortical and trabecular bone mass was associated with a significantly higher maximal load of L(5) , FD, and FN in the high-dose group. Bone-formation parameters (ie, mineralizing surface, mineral apposition rate, and bone-formation rate) at the proximal tibial metaphysis and tibial shaft were markedly greater on trabecular, periosteal, and endocortical surfaces in both Scl-AbII dose groups compared with controls. These results indicate that sclerostin inhibition by treatment with a sclerostin antibody increased bone formation, bone mass, and bone strength in aged male rats and, furthermore, suggest that pharmacologic inhibition of sclerostin may represent a promising anabolic therapy for low bone mass in aged men.

Increased RANK ligand in bone marrow of orchiectomized rats and prevention of their bone loss by the RANK ligand inhibitor osteoprotegerin.

Orchiectomized (ORX) rats were used to examine the extent to which their increased bone resorption and decreased bone density might relate to increases in RANKL, an essential cytokine for bone resorption. Serum testosterone declined by >95% in ORX rats 1 and 2 weeks after surgery (p<0.05 versus sham controls), with no observed changes in serum RANKL. In contrast, RANKL in bone marrow plasma and bone marrow cell extracts was significantly increased (by approximately 100%) 1 and 2 weeks after ORX. Regression analyses of ORX and sham controls revealed a significant inverse correlation between testosterone and RANKL levels measured in marrow cell extracts (R=-0.58), while marrow plasma RANKL correlated positively with marrow plasma TRACP-5b, an osteoclast marker (R=0.63). The effects of RANKL inhibition were then studied by treating ORX rats for 6 weeks with OPG-Fc (10 mg/kg, twice/week SC) or with PBS, beginning immediately after surgery. Sham controls were treated with PBS. Vehicle-treated ORX rats showed significant deficits in BMD of the femur/tibia and lower trabecular bone volume in the distal femur (p<0.05 versus sham). OPG-Fc treatment of ORX rats increased femur/tibia BMD and trabecular bone volume to levels that significantly exceeded values for ORX or sham controls. OPG-Fc reduced trabecular osteoclast surfaces in ORX rats by 99%, and OPG-Fc also prevented ORX-related increases in endocortical eroded surface and ORX-related reductions in periosteal bone formation rate. Micro-CT of lumbar vertebrae from OPG-Fc-treated ORX rats demonstrated significantly greater cortical and trabecular bone volume and density versus ORX-vehicle controls. In summary, ORX rats exhibited increased RANKL protein in bone marrow plasma and in bone marrow cells, with no changes in serum RANKL. Data from regression analyses were consistent with a potential role for testosterone in suppressing RANKL production in bone marrow, and also suggested that soluble RANKL in bone marrow might promote bone resorption. RANKL inhibition prevented ORX-related deficits in trabecular BMD, trabecular architecture, and periosteal bone formation while increasing cortical and trabecular bone volume and density. These results support the investigation of RANKL inhibition as a strategy for preventing bone loss associated with androgen ablation or deficiency.

One year of transgenic overexpression of osteoprotegerin in rats suppressed bone resorption and increased vertebral bone volume, density, and strength.

RANKL is an essential mediator of bone resorption, and its activity is inhibited by osteoprotegerin (OPG). Transgenic (Tg) rats were engineered to continuously overexpress OPG to study the effects of continuous long-term RANKL inhibition on bone volume, density, and strength. Lumbar vertebrae, femurs, and blood were obtained from 1-yr-old female OPG-Tg rats (n = 32) and from age-matched wildtype (WT) controls (n = 23). OPG-Tg rats had significantly greater serum OPG (up to 260-fold) and significantly lower serum TRACP5b and osteocalcin compared with WT controls. Vertebral histomorphometry showed significant reductions in osteoclasts and bone turnover parameters in OPG-Tg rats versus WT controls, and these reductions were associated with significantly greater peak load in vertebrae tested through compression. No apparent differences in bone material properties were observed in OPG-Tg rat vertebrae, based on their unchanged intrinsic strength parameters and their normal linear relationship between vertebral bone mass and strength. Femurs from OPG-Tg rats were of normal length but showed mild osteopetrotic changes, including reduced periosteal perimeter (-6%) and an associated reduction in bending strength. Serum OPG levels in WT rats showed no correlations with any measured parameter of bone turnover, mass, or strength, whereas the supraphysiological serum OPG levels in OPG-Tg rats correlated negatively with bone turnover parameters and positively with vertebral bone mass and strength parameters. In summary, low bone turnover after 1 yr of OPG overexpression in rats was associated with increased vertebral bone mass and proportional increases in bone strength, with no evidence for deleterious effects on vertebral material properties.

Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL.

RANKL is a TNF family member that mediates osteoclast formation, activation, and survival by activating RANK. The proresorptive effects of RANKL are prevented by binding to its soluble inhibitor osteoprotegerin (OPG). Recombinant human OPG-Fc recognizes RANKL from multiple species and reduced bone resorption and increased bone volume, density, and strength in a number of rodent models of bone disease. The clinical development of OPG-Fc was discontinued in favor of denosumab, a fully human monoclonal antibody that specifically inhibits primate RANKL. Direct binding assays showed that denosumab bound to human RANKL but not to murine RANKL, human TRAIL, or other human TNF family members. Denosumab did not suppress bone resorption in normal mice or rats but did prevent the resorptive response in mice challenged with a human RANKL fragment encoded primarily by the fifth exon of the RANKL gene. To create mice that were responsive to denosumab, knock-in technology was used to replace exon 5 from murine RANKL with its human ortholog. The resulting "huRANKL" mice exclusively express chimeric (human/murine) RANKL that was measurable with a human RANKL assay and that maintained bone resorption at slightly reduced levels versus wildtype controls. In young huRANKL mice, denosumab and OPG-Fc each reduced trabecular osteoclast surfaces by 95% and increased bone density and volume. In adult huRANKL mice, denosumab reduced bone resorption, increased cortical and cancellous bone mass, and improved trabecular microarchitecture. These huRANKL mice have potential utility for characterizing the activity of denosumab in a variety of murine bone disease models.

Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.

The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.

RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats.

INTRODUCTION: Ovariectomy (OVX) results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. We examined whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in OVX rats. MATERIALS AND METHODS: Rats were OVX or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle (Veh, PBS). OVX rats were treated with Veh or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b was measured by ELISA. BMD of lumbar vertebrae (L(1)-L(5)) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L(5)) were analyzed by muCT and biomechanical testing, and L(6) was analyzed for ash weight. RESULTS: OVX was associated with significantly greater serum RANKL and osteoclast surface and with reduced areal and volumetric BMD. OPG markedly reduced osteoclast surface and serum TRACP5b while completely preventing OVX-associated bone loss in the lumbar vertebrae, distal femur, and femur neck. Vertebrae from OPG-treated rats had increased dry and ash weight, with no significant differences in tissue mineralization versus OVX controls. muCT showed that trabecular compartments in OVX-OPG rats had significantly greater bone volume fraction, vBMD, bone area, trabecular thickness, and number, whereas their cortical compartments had significantly greater bone area (p < 0.05 versus OVX-Veh). OPG improved cortical area in L(5) and the femur neck to levels that were significantly greater than OVX or sham controls (p < 0.05). Biomechanical testing of L(5) and femur necks showed significantly greater maximum load values in the OVX-OPG group (p < 0.05 versus OVX-Veh). Bone strength at both sites was linearly correlated with total bone area (r(2) = 0.54-0.74, p < 0.0001), which was also significantly increased by OPG (p < 0.05 versus OVX). CONCLUSIONS: OPG treatment prevented bone loss, preserved trabecular architecture, and increased cortical area and bone strength in OVX rats.

Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength.

INTRODUCTION: Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone. MATERIALS AND METHODS: Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, microCT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice. RESULTS: The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. microCT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice. CONCLUSIONS: SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone.