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Prolonged mechanical unloading in bedridden patients and concurrent hormonal dysregulation represents the cause of one of the severest forms of osteoporosis, a condition for which there are very few efficacious interventions available to date. Sclerostin, a Wnt antagonist, acts as a negative regulator of bone formation. Sclerostin antibody (Scl-Ab)-mediated blockade of sclerostin can dramatically enhance bone formation and reduce bone resorption. This study was designed to investigate the therapeutic effect of the Scl-Ab on severe bone loss induced by concurrent mechanical unloading and estrogen deficiency in a hindlimb-suspended and ovariectomized rat model, and to study the cellular mechanisms underlying severe osteoporosis and Scl-Ab action. Unloading and ovariectomy resulted in severe loss of trabecular and cortical bone mass and strength; Scl-Ab can significantly counteract the deterioration of bone in unloaded and/or ovariectomized rats, with noticeably increased cortical bone formation. Scanning electron microscopy analysis revealed that unloading and ovariectomy lead to multiple morphological and structural abnormalities of osteocytes in cortical bone and the abnormalities were abolished by Scl-Ab administration. This study extends our previous conclusion that Scl-Ab represents a promising therapeutic approach for severe bone loss that occurs after being exposed to estrogen deficiency and prolonged mechanical unloading., (© 2019 New York Academy of Sciences.)

Sclerostin antibody (Scl-Ab) restored bone mass and strength in the ovariectomized rat model of postmenopausal osteoporosis. Increased bone mineral density (BMD) and decreased skeletal fragility fracture risk have been reported in postmenopausal osteoporotic women receiving Scl-Ab. In males, loss of androgen leads to rapid decreases in BMD and an increased risk of fragility fractures. We hypothesized that Scl-Ab could reverse the loss of bone mass and strength caused by androgen ablation in the orchiectomized (ORX) rat model of male osteoporosis. We treated 9-month-old ORX Sprague Dawley rats (3 months after ORX) subcutaneously twice weekly with vehicle or Scl-Ab (5 or 25 mg/kg) for 6 weeks (n = 10 per group). Both doses of Scl-Ab fully reversed the BMD deficit in the lumbar spine and femur and tibia in ORX rats. Microcomputed tomography showed that the bone mass in the fifth lumbar vertebral body, femur diaphysis, and femoral neck were dose-dependently restored by Scl-Ab. The bone strength at these sites increased significantly with Scl-Ab to levels matching those of sham-operated controls and correlated positively with improvements in bone mineral content, demonstrating bone quality maintenance. Dynamic histomorphometry of the tibial diaphysis and second lumbar vertebral body demonstrated that Scl-Ab significantly increased bone formation on periosteal, endocortical, and trabecular surfaces and significantly decreased bone resorption on endocortical and trabecular surfaces. The effects of Scl-Ab on increasing bone formation and decreasing bone resorption led to restoration of bone mass and strength in androgen-deficient rats. These findings support the ongoing evaluation of Scl-Ab as a potential therapeutic agent for osteoporosis in men., (Copyright © 2018 Endocrine Society.)

Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment; however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.

Osteoporosis is characterized by low bone mass and compromised trabecular architecture, and is commonly occurred in post-menopausal women with estrogen deficiency. In addition, prolonged mechanical unloading, i.e., long term bed rest, can exaggerate the bone loss. Sclerostin is a Wnt signaling antagonist and acts as a negative regulator for bone formation. A sclerostin-neutralizing antibody (Scl-Ab) increased bone mineral density in women with postmenopausal osteoporosis and healthy men. The objective of this study was to characterize the condition of bone loss in ovariectomized (OVX) rats with concurrent mechanical unloading and evaluate the effect of sclerostin antibody treatment in mitigating the prospective severe bone loss conditions in this model. Four-month-old OVX- or sham-operated female SD rats were used in this study. They were subjected to functional disuse induced by hind-limb suspension (HLS) or free ambulance after 2days of arrival. Subcutaneous injections with either vehicle or Scl-Ab at 25mg/kg were made twice per week for 5weeks from the time of HLS. μCT analyses demonstrated a significant decrease in distal metaphyseal trabecular architecture integrity with HLS, OVX and HLS+OVX (bone volume fraction decreased by 29%, 71% and 87% respectively). The significant improvements of various trabecular bone parameters (bone volume fraction increased by 111%, 229% and 297% respectively as compared with placebo group) with the administration of Scl-Ab are associated with stronger mechanical property and increased bone formation by histomorphometry. These results together indicate that Scl-Ab prevented the loss of trabecular bone mass and cortical bone strength in OVX rat model with concurrent mechanical unloading. The data suggested that monoclonal sclerostin-neutralizing antibody represents a promising therapeutic approach for severe osteoporosis induced by estrogen deficiency with concurrent mechanical unloading., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25%) and trabecular bone volume (-67%) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders., (© 2015 American Society for Bone and Mineral Research.)

Introduction: Periodontitis and osteoporosis are bone destructive diseases with a high prevalence in the adult population. The concomitant presence of osteoporosis may be a risk factor of progression of periodontal destruction. We studied the effect of sclerostin-neutralizing monoclonal antibody (Scl-Ab) on alveolar bone endpoints in an ovariectomized (OVX) rat model of induced experimental periodontitis., Methods: Sixty female, 4-month-old Sprague-Dawley rats underwent sham operation or bilateral OVX and were left untreated for 2 months. Experimental periodontitis (ligature) was established by placing silk sutures subgingival to the right maxillary first and second molar teeth for 4 weeks, and feeding the rats food and high-sugar drinking water during this period. Thereafter, ligatures were removed and 25mg/kg vehicle or Scl-Ab was administered subcutaneously twice weekly for 6 weeks. Rats were randomized into four groups: (1) Control (Sham+Vehicle), (2) Sham+Ligature+Vehicle, (3) OVX+Ligature+Vehicle, and (4) OVX + Ligature + Scl-Ab. Terminal blood and right maxilla specimens were collected for analyses., Results: Group 3 rats showed lower bone volume fraction (BVF) of alveolar bone with higher bone resorption and lower bone formation than Group 2 rats. Group 4 rats had higher alveolar crest height, as assessed by linear distance of cementoenamel junction to the alveolar bone crest and greater alveolar bone mass using Micro CT, than Group 3 rats. Significantly higher values of mineral apposition rate (MAR) and mineralizing surface/bone surface (MS/BS) were also observed in Group 4 rats by analyzing polychrome sequential labeling data. Increased serum osteocalcin and osteoprotegerin, and deceased serum tartrate-resistant acid phosphatase and CTx-1 illustrate the ability of Scl-Ab to increase alveolar bone mass by enhancing bone formation and decreasing bone resorption in an animal model of estrogen deficiency osteopenia plus periodontitis., Conclusion: Scl-Ab could be a potential bone anabolic agent for improving alveolar crest height and higher alveolar bone mass in conditions where alveolar bone loss in periodontitis is compounded by estrogen deficiency osteopenia., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sclerostin is a negative regulator of bone formation. Sclerostin monoclonal antibody (Scl-Ab) treatment promoted bone healing in various animal models. To further evaluate the healing efficiency of Scl-Ab in osteotomy healing, we investigated the time course effects of systemic administration of Scl-Ab on fracture repair in rat femoral osteotomy model. A total of 120 six-month-old male SD rats were subjected to transverse osteotomy at the right femur mid-shaft. Rats were treated with vehicle or Scl-Ab treatment for 3, 6, or 9 weeks. Fracture healing was evaluated by radiography, micro-CT, micro-CT based angiography, 4-point bending mechanical test and histological assessment. Scl-Ab treatment resulted in significantly higher total mineralized callus volume fraction, BMD and enhanced neovascularization. Histologically, Scl-Ab treatment resulted in a significant reduction in fracture callus cartilage at week 6 and increase in bone volume at week 9, associated with a greater proportion of newly formed bone area at week 6 and 9 by fluorescence microscopy. Mechanical testing showed significantly higher ultimate load in Scl-Ab treatment group at week 6 and 9. This study has demonstrated that Scl-Ab treatment enhanced bone healing in a rat femoral osteotomy model, as reflected in increased bone formation, bone mass and bone strength., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Bone formation can be remodeling-based (RBF) or modeling-based (MBF), the former coupled to bone resorption and the latter occurring directly on quiescent surfaces. Unlike osteoanabolic therapies such as parathyroid hormone (PTH) 1-34 that increase bone remodeling and thus both formation and resorption, sclerostin antibody (Scl-Ab) increases bone formation while decreasing bone resorption. With this unique profile, we tested our hypothesis that Scl-Ab primarily elicited MBF by examining bones from Scl-Ab–treated ovariectomized (OVX) rats and male cynomolgus monkeys (cynos). Histomorphometry was performed to quantify and characterize bone surfaces in OVX rats administered vehicle or Scl-Ab (25 mg/kg) subcutaneously (sc) twice/week for 5 weeks and in adolescent cynos administered vehicle or Scl-Ab (30 mg/kg) sc every 2 weeks for 10 weeks. Fluorochrome-labeled surfaces in L2 vertebra and femur endocortex (cynos only) were considered to be MBF or RBF based on characteristics of their associated cement lines. In OVX rats, Scl-Ab increased MBF by eightfold (from 7% to 63% of bone surface, compared to vehicle). In cynos, Scl-Ab markedly increased MBF on trabecular (from 0.6% to 34%) and endocortical surfaces (from 7% to 77%) relative to vehicle. Scl-Ab did not significantly affect RBF in rats or cynos despite decreased resorption surface in both species. In cynos, Scl-Ab resulted in a greater proportion of RBF and MBF containing sequential labels from week 2, indicating an increase in the lifespan of the formative site. This extended formation period was associated with robust increases in the percent of new bone volume formed. These results demonstrate that Scl-Ab increased bone volume by increasing MBF and prolonged the formation period at both modeling and remodeling sites while reducing bone resorption. Through these unique effects on bone formation and resorption, Scl-Ab may prove to be an effective therapeutic to rapidly increase bone mass in diseases such as osteoporosis.

Systemic administration of a sclerostin neutralizing antibody (Scl-Ab) has been shown to enhance fracture callus density and strength in several animal models. In order to further evaluate the potential of Scl-Ab to improve healing in a bone defect model,we evaluated Scl-Ab in a 3mm femoral defect in young male outbred rats. Scl-Ab was given either continuously for 6 or 12 weeks after surgery or with 2 weeks of delay for 10 weeks. Bone formation was assessed by radiographs, µ-CT, and histology. Complete bony union was achieved in only a few defects after 12 weeks of healing (Scl-Ab treated 5/30, vehicle treated 1/15). µ-CT evaluation demonstrated a significant increase in the BV/TV in the defect in the delayed treatment group (65%, p<0.05), but a non-significant increase in the continuous group (35%, p = 0.11) compared to control. However, both regimens induced an anabolic response in the bone proximal and distal to the defect and in the un-operated femurs. We demonstrate that treatment with Scl-Ab can enhance bone repair in a bone defect and in the surrounding host bone, but lacks the osteoinductive activity to heal it. This agent seems to be most effective in bone repair scenarios where there is cortical integrity., (© 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Systemic administration of sclerostin neutralizing antibody has led to increased bone formation in animal models of osteoporosis. The purpose of this study was to determine if systemic administration of sclerostin neutralizing antibody could increase the healing response in a critical-sized femoral defect in rats., Methods: Critical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The sclerostin antibody (Scl-Ab) treatment groups included the continuous Scl-Ab group (twenty-one animals), the early Scl-Ab group (fifteen animals), and the delayed Scl-Ab group (fifteen animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0 through 12; weeks 0 through 2; and weeks 2 through 4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at zero, two, six, and twelve weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for twelve weeks (fifteen rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis., Results: In the primary study, four of fifteen defects in the continuous (zero to twelve-week) Scl-Ab group, three of fifteen defects in the early (zero to two-week) Scl-Ab group, and four of fifteen defects in the delayed (two to four-week) Scl-Ab group healed at twelve weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for twelve weeks demonstrated a significant increase in new bone formation (p < 0.05) compared with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls., Conclusions: Administration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by twelve weeks.

The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair.

Background and Purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model., Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma., Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force., Interpretation: Scl-Ab increases bone formation and screw fixation to a similar degree in loaded and unloaded bone.

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.

Sclerostin is the product of the SOST gene. Loss-of-function mutations in the SOST gene result in a high-bone-mass phenotype, demonstrating that sclerostin is a negative regulator of bone mass. Primarily expressed by osteocytes in bone, sclerostin is reported to bind the LRP5/6 receptor, thereby antagonizing canonical Wnt signaling and negatively regulating bone formation. We therefore investigated whether systemic administration of a sclerostin-neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats. Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks. In four groups, the screws were tested for pull-out strength. At the time of euthanasia, a similar screw also was inserted in the contralateral tibia and pull-out tested immediately. Sclerostin antibody significantly increased the pull-out force by almost 50% compared with controls after 2 and 4 weeks. Also, the screws inserted at the time of euthanasia showed increased pull-out force. Micro-computed tomography (µCT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw. There also was a general increase in trabecular thickness in cancellous bone. Thus, as measured by the amount of bone and its mechanical resistance, the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone., (© 2010 American Society for Bone and Mineral Research.)

The current report describes the skeletal effects of a sclerostin monoclonal antibody (Scl-AbIII) treatment at a yellow (fatty) marrow skeletal site in adult female rats. Ten-month-old female Sprague-Dawley rats were treated with vehicle or Scl-AbIII at 5 or 25 mg/kg, twice per week by s.c. injection for 4 weeks. Trabecular bone from a yellow (fatty) marrow site, the 5th caudal vertebral body (CVB), was processed undecalcified for quantitative bone histomorphometric analysis. Compared to vehicle controls, Scl-AbIII at both doses significantly increased bone formation parameters and trabecular bone volume and thickness and decreased bone resorption parameter in the trabecular bone of the CVB. As a reference, we also found that the Scl-AbIII at both doses significantly decreased bone resorption and increased bone formation and bone volume in a red (hematopoietic) marrow site, the 4th lumber vertebral body (LVB). It appears that the percentage of increase in trabecular bone volume induced by Scl-AbIII treatment was slightly larger in the LVB than in the CVB. In summary, these preclinical findings show that antibody-mediated sclerostin inhibition has significant bone anabolic effects at both red and yellow marrow skeletal sites., (Copyright 2010 Elsevier Inc. All rights reserved.)

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.

Background: Recombinant human bone morphogenetic protein (rhBMP)-2 is a potent osteoinductive agent; however, its clinical use has been reduced because of safety and efficacy concerns. In preclinical studies involving a critical-sized defect in a rat model, sclerostin antibody (Scl-Ab) treatment increased bone formation within the defect but did not result in reliable healing. The purpose of the current study was to evaluate bone repair of a critical-sized femoral defect in a rat model with use of local implantation of rhBMP-2 combined with systemic administration of Scl-Ab.Methods: A critical-sized femoral defect was created in rats randomized into three treatment groups: local rhBMP-2 and systemic Scl-Ab (Scl + BMP), local rhBMP-2 alone, and collagen sponge alone (operative control). The Scl + BMP group received local rhBMP-2 (10 μg) on a collagen sponge placed within the defect intraoperatively and then twice weekly injections of Scl-Ab (25 mg/kg) administered postoperatively. The femora were evaluated at twelve weeks with use of radiography, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing.Results: At twelve weeks, all Scl + BMP and rhBMP-2 only samples were healed. No femora healed in the operative control group. Histomorphometric analysis demonstrated more bone in the Scl + BMP samples than in the samples treated with rhBMP-2 alone (p = 0.029) and the control samples (p = 0.003). MicroCT revealed that the Scl + BMP group had a 90% greater bone volume within the defect region compared with the rhBMP-2 group and a 350% greater bone volume compared with the operative control group (p < 0.001). Biomechanical testing showed that the group treated with Scl + BMP had greater torsional strength and rigidity compared with the rhBMP-2 group (p < 0.001 and p = 0.047) and the intact femoral control group (p < 0.001). Torque to failure was lower in the rhBMP-2 group compared with the intact femoral control group (p < 0.002). Mean energy to failure was higher in the Scl + BMP samples compared with the rhBMP-2 only samples (p = 0.001).Conclusions: In a critical-sized femoral defect in a rat model, local rhBMP-2 combined with systemic administration of Scl-Ab resulted in more robust healing that was stronger and more rigid than results for rhBMP-2 alone and intact nonoperative femora.Clinical Relevance: Our study demonstrated that combining an osteoinductive agent with a systemically administered antibody that promotes bone formation can enhance bone repair and has potential as a therapeutic regimen in humans. [ABSTRACT FROM AUTHOR]