ABSTRACT
Treatment of nonhuman primates and mice with a humanized antigen-binding fragment (Fab) antibody (UCBFab) inhibiting transforming growth factor ß via daily inhalation for up to 13 weeks resulted in low systemic exposure but high local exposure in the lung. Target engagement was demonstrated by reduced levels of signal transducers, phosphoSMAD and plasminogen activator inhibitor-1 in the bronchoalveolar lavage fluid (BALF). Treatment was associated with a high frequency and titer of antidrug antibodies, indicating high local immunogenicity, and local pathology within the lung and draining lymph nodes. Microscopic changes were characterized by perivascular (PV) and peribronchiolar (PB) mononuclear inflammatory cell (MIC) infiltrates that were principally lymphocytic in nature and mixed inflammatory cell infiltrates and/or inflammation within the alveoli. Immunohistochemical investigation revealed a predominantly CD68-positive macrophage and CD3- and CD8>CD4-positive T-cell response in the alveoli, whereas within the airways, there was a variable mixture of CD3-positive T cells, CD20-positive B cells, and CD68-positive macrophages. Increased cellularity of the draining lymph nodes was also noted, indicating the presence of an immune response to the inhaled test article. Morphologic changes did not progress over time, and all changes partially recovered. Increased leukocytes (principally macrophages) in BALF cytology correlated with the changes seen by histopathology.
Subject(s)
Antibodies , Lung , Transforming Growth Factor beta , Animals , Antibodies/toxicity , Bronchoalveolar Lavage Fluid , Inflammation , Mice , PrimatesABSTRACT
Bone is a unique tissue with turnover, metabolic, and cellular activities that vary through development to aging and with a mineralized matrix in which the current state and the history of a bone coexist. Qualitative histopathology often lacks sensitivity to detect changes in bone formation, mineralization and resorption, which often requires chronic dosing to result in structural changes such as variation in bone mass and geometry. A large panel of modalities can be used to fully analyze the health of the skeleton, including biomarker evaluation in serum or urine, imaging techniques ranging from radiology to computed tomography, biomechanical testing, and undecalcified tissue processing with bone histomorphometry. The use of clinically relevant biomarkers provides an important noninvasive, sensitive, rapid, and real-time tool to monitor bone activity at the whole skeleton level when conducting safety assessments in a preclinical setting. Imaging modalities also allow in vivo longitudinal assessments with a powerful, noninvasive and clinically translatable tools to monitor drug effects. Different imaging modalities are used in the preclinical studies to evaluate the bone tissues: standard radiography, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), micro-computed tomography, and high-resolution pQCT. Bone histomorphometry is an important tool that provides sensitive evaluation to detect effects of test articles on bone resorption, formation, mineralization, remodeling rates and growth to address a potential target- or class-related theoretical bone liability. Ultimately, the measurement of bone mechanical properties in pharmaceutical testing is critical to understand the potential effects of that pharmaceutical on bone health and fracture risk. Important considerations are required for including these different techniques in toxicology rodents and nonrodent studies, to actually integrate these into safety assessment.
Subject(s)
Bone Remodeling/drug effects , Bone and Bones/drug effects , Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations/standards , Absorptiometry, Photon , Animals , Biomarkers/blood , Biomechanical Phenomena , Bone Density , Bone and Bones/diagnostic imaging , Bone and Bones/metabolism , Drug Evaluation, Preclinical , Drug-Related Side Effects and Adverse Reactions/blood , Drug-Related Side Effects and Adverse Reactions/diagnostic imaging , Drug-Related Side Effects and Adverse Reactions/urine , HumansABSTRACT
Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 µg/kg or 30 µg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 µg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.
Subject(s)
Bone Density Conservation Agents/toxicity , Bone Neoplasms/chemically induced , Osteosarcoma/chemically induced , Parathyroid Hormone-Related Protein/toxicity , Parathyroid Hormone/toxicity , Animals , Bone Density Conservation Agents/administration & dosage , Bone Neoplasms/epidemiology , Female , Humans , Incidence , Osteosarcoma/epidemiology , Parathyroid Hormone/administration & dosage , Parathyroid Hormone-Related Protein/administration & dosage , Rats , Rats, Inbred F344ABSTRACT
Romosozumab (Romo), a humanized sclerostin antibody, is a bone-forming agent under development for treatment of osteoporosis. To examine the effects of Romo on bone quality, mature cynomolgus monkeys (cynos) were treated 4 months post- ovariectomy (OVX) with vehicle, 3 mg/kg, or 30 mg/kg Romo for 12 months, or with 30 mg/kg Romo for 6 months followed by vehicle for 6 months (30/0). Serum bone formation markers were increased by Romo during the first 6 months, corresponding to increased cancellous, endocortical, and periosteal bone formation in rib and iliac biopsies at months 3 and 6. Dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) was increased by 14% to 26% at the lumbar spine and proximal femur at month 12, corresponding to significant increases in bone strength at 3 and 30 mg/kg in lumbar vertebral bodies and cancellous cores, and at 30 mg/kg in the femur diaphysis and neck. Bone mass remained positively correlated with strength at these sites, with no changes in calculated material properties at cortical sites. These bone-quality measures were also maintained in the 30/0 group, despite a gradual loss of accrued bone mass. Normal bone mineralization was confirmed by histomorphometry and ash analyses. At the radial diaphysis, a transient, reversible 2% reduction in cortical BMD was observed with Romo at month 6, despite relative improvements in bone mineral content (BMC). High-resolution pQCT confirmed this decline in cortical BMD at the radial diaphysis and metaphysis in a second set of OVX cynos administered 3 mg/kg Romo for 6 months. Radial diaphyseal strength was maintained and metaphyseal strength improved with Romo as estimated by finite element modeling. Decreased radial cortical BMD was a consequence of increased intracortical remodeling, with no increase in cortical porosity. Romo resulted in marked improvements in bone mass, architecture, and bone strength, while maintaining bone quality in OVX cynos, supporting its bone efficacy and safety profile. © 2016 American Society for Bone and Mineral Research.
Subject(s)
Absorptiometry, Photon , Antibodies, Monoclonal/pharmacology , Bone Density/drug effects , Femur Neck , Ovariectomy , Radius , Animals , Diaphyses/diagnostic imaging , Diaphyses/metabolism , Female , Femur Neck/diagnostic imaging , Femur Neck/metabolism , Macaca fascicularis , Radius/diagnostic imaging , Radius/metabolismABSTRACT
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.
ABSTRACT
Romosozumab is a humanized immunoglobulin G2 monoclonal antibody that binds and blocks the action of sclerostin, a protein secreted by the osteocyte and an extracellular inhibitor of canonical Wnt signaling. Blockade of sclerostin binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) allows Wnt ligands to activate canonical Wnt signaling in bone, increasing bone formation and decreasing bone resorption, making sclerostin an attractive target for osteoporosis therapy. Because romosozumab is a bone-forming agent and an activator of canonical Wnt signaling, questions have arisen regarding a potential carcinogenic risk. Weight-of-evidence factors used in the assessment of human carcinogenic risk of romosozumab included features of canonical Wnt signaling, expression pattern of sclerostin, phenotype of loss-of-function mutations in humans and mice, mode and mechanism of action of romosozumab, and findings from romosozumab chronic toxicity studies in rats and monkeys. Although the weight-of-evidence factors supported that romosozumab would pose a low carcinogenic risk to humans, the carcinogenic potential of romosozumab was assessed in a rat lifetime study. There were no romosozumab-related effects on tumor incidence in rats. The findings of the lifetime study and the weight-of-evidence factors collectively indicate that romosozumab administration would not pose a carcinogenic risk to humans.
Subject(s)
Antibodies, Monoclonal/toxicity , Neoplasms/chemically induced , Animals , Antibodies, Monoclonal/administration & dosage , Carcinogenicity Tests , Dose-Response Relationship, Drug , Humans , Mice , Rats , Risk AssessmentABSTRACT
Bazedoxifene (BZA) is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This preclinical study evaluated the efficacy and safety of BZA in preventing ovariectomy (OVX)-induced bone loss in aged cynomolgus monkeys. Animals (18 per group) underwent OVX and were administered BZA (0.2, 0.5, 1, 5, or 25 mg/kg/day) or vehicle, or were sham-operated and administered vehicle, by daily oral gavage for 18 months. Biochemical markers of bone turnover were assessed at 6, 12, and 18 months, along with bone densitometry using dual energy X-ray absorptiometry and peripheral quantitative computed tomography. Animals were killed after 18 months. Uterine and pituitary weights were determined, and histomorphometric and biomechanical measurements were performed. OVX vehicle controls showed increases in bone turnover associated with cancellous and cortical bone osteopenia (in vivo), and slight decreases (not statistically significant) in biomechanical strength parameters at the lumbar spine and femoral neck. BZA partially preserved cortical and cancellous bone mass by preventing the OVX-induced increases in bone turnover. Although the response was often similar among BZA-treated groups, the strongest efficacy was generally seen at 25 mg/kg/day. Treatment with BZA did not adversely affect measures of bone strength and was well tolerated; there was no evidence of uterotrophic activity, mammary tissue was unaffected, and there were no adverse effects on plasma lipids. Treatment of ovariectomized animals with BZA partially prevented changes in bone remodeling that correlated with increases in bone mineral density, while maintaining bone strength and a favorable safety profile.
Subject(s)
Bone Remodeling/drug effects , Indoles/pharmacology , Osteoporosis, Postmenopausal/drug therapy , Absorptiometry, Photon/methods , Animals , Bone Density/drug effects , Bone Resorption/drug therapy , Bone Resorption/metabolism , Drug Evaluation, Preclinical , Female , Femur/drug effects , Femur/metabolism , Humans , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/metabolism , Macaca fascicularis , Osteoporosis, Postmenopausal/metabolism , Ovariectomy/methods , Selective Estrogen Receptor Modulators/metabolismABSTRACT
Postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. Antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. Osteoclast inhibition via denosumab (DMAb), a RANKL inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. The safety of transitioning from bisphosphonate therapy (alendronate; ALN) to DMAb was examined in mature ovariectomized (OVX) cynomolgus monkeys (cynos). One day after OVX, cynos (7-10/group) were treated with vehicle (VEH, s.c.), ALN (50 µg/kg, i.v., twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb caused significantly greater reductions in serum CTx than ALN, and transition from ALN to DMAb caused further reductions relative to continued ALN. DMAb and ALN decreased serum calcium (Ca), and transition from ALN to DMAb resulted in a lesser decline in Ca relative to DMAb or to VEH-DMAb transition. Bone histomorphometry indicated significantly reduced trabecular and cortical remodeling with DMAb or ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Bone mineral density increased in all active treatment groups relative to VEH controls. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls. Bone mass and strength remained highly correlated in all groups at all tested skeletal sites, consistent with normal bone quality. These data indicate that cynos transitioned from ALN to DMAb exhibited reduced bone resorption and cortical porosity, and increased BMD and bone strength, without deleterious effects on Ca homeostasis or bone quality.
Subject(s)
Alendronate/pharmacology , Bone Density Conservation Agents/pharmacology , Bone and Bones/drug effects , Calcium/metabolism , Denosumab/pharmacology , Homeostasis/drug effects , Ovariectomy , Absorptiometry, Photon , Alendronate/adverse effects , Animals , Bone Density Conservation Agents/adverse effects , Bone and Bones/physiology , Denosumab/adverse effects , Female , Macaca fascicularisABSTRACT
Rosiglitazone (RSG) is an antidiabetic drug that has been associated with increased peripheral fractures, primarily in postmenopausal women. In this report, we investigated the underlying mechanisms of RSG-associated bone loss in ovariectomized (OVX) rats and determined whether changes in bone parameters associated with RSG administration are reversible on treatment cessation or preventable by coadministration with an antiresorptive agent. Nine-month-old Sprague-Dawley rats underwent OVX or sham operation. Sham-operated rats received oral vehicle only; OVX animals were randomized to receive vehicle, RSG, alendronate (ALN), or RSG plus ALN for 12 weeks. All treatment started the day after ovariectomy. After the 12-week treatment period, the OVX and RSG groups also underwent an 8-week treatment-free recovery period. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Microcomputed tomography was also used to investigate changes in microarchitecture. RSG significantly increased deoxypyridinoline levels compared with OVX. Significant exacerbation of OVX-induced loss of bone mass, strength, and microarchitectural deterioration was observed in RSG-treated OVX animals compared with OVX controls. These effects were observed predominantly at sites rich in trabecular bone, with less pronounced effects in cortical bone. Coadministration of RSG and ALN prevented the bone loss associated with RSG treatment. Following cessation of RSG treatment, effects on bone mass and strength showed evidence of reversal. Thus, treatment of OVX rats with RSG results in loss of bone mass and strength, primarily at sites rich in trabecular bone, mainly due to increased bone resorption. These effects can be prevented by concomitant treatment with ALN and may be reversed following discontinuation of RSG.
Subject(s)
Alendronate/pharmacology , Bone Density Conservation Agents/pharmacology , Bone Density/drug effects , Hypoglycemic Agents/pharmacology , Osteoporosis, Postmenopausal/drug therapy , Thiazolidinediones/pharmacology , Animals , Female , Fractures, Bone/etiology , Fractures, Bone/metabolism , Humans , Osteoporosis, Postmenopausal/complications , Osteoporosis, Postmenopausal/metabolism , Ovariectomy , Rats , Rats, Sprague-Dawley , Rosiglitazone , Time Factors , X-Ray MicrotomographyABSTRACT
Cynomolgus monkeys dosed with a therapeutic monoclonal antibody (mAbY.1) at ≥ 50 mg/kg had unexpected acute thrombocytopenia (nadir ~3,000 platelets/µl), sometimes with decreases in red cell mass. Increased activated macrophages, mitotic figures, and erythrophagocytosis were observed in the spleen. Binding of mAbY.1 to cynomolgus peripheral blood cells could not be detected in vitro. mAbY.1 induced phagocytosis of platelets by peripheral blood monocytes from cynomolgus monkeys, but not from humans. mAbs sharing the same constant domain (Fc) sequences, but differing from mAbY.1 in their variable domains, bound competitively to and had similar biological activity against the intended target. None of these antibodies had hematologic liabilities in vitro or in vivo. Neither the F(ab')2 portion of mAbY.1 nor the F(ab')2 portion on an aglycosylated Fc (IgG1) framework caused phagocytosis of platelets in vitro. These data suggest that the hematologic effects of mAbY.1 in cynomolgus monkeys likely occurred through an off-target mechanism, shown to be driven by 1 to 3 amino acid differences in the light chain. The hematologic effects made mAbY.1 an unsuitable candidate for further development as a therapeutic agent. This example demonstrates that nonclinical safety studies may be essential for understanding off-target effects of mAbs prior to clinical trials.
Subject(s)
Anemia/chemically induced , Antibodies, Monoclonal/toxicity , Thrombocytopenia/chemically induced , Anemia/blood , Animals , Antibodies, Monoclonal/administration & dosage , Blood Platelets/pathology , Female , Humans , Macaca fascicularis , Macrophage Activation , Male , Phagocytosis , Reticulocytes/pathology , Spleen/drug effects , Spleen/pathology , Thrombocytopenia/bloodABSTRACT
Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator of bone formation, and treatment with a sclerostin monoclonal antibody (Scl-Ab) results in increased bone formation and bone mass in animal models. Our objective was to investigate the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results support the potential for systemic Scl-Ab administration to enhance fracture healing in patients.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Bone Density/drug effects , Femoral Fractures/physiopathology , Fracture Healing/drug effects , Glycoproteins/antagonists & inhibitors , Adaptor Proteins, Signal Transducing , Animals , Biomechanical Phenomena/drug effects , Diaphyses/drug effects , Diaphyses/pathology , Diaphyses/physiopathology , Disease Models, Animal , Femur/drug effects , Femur/pathology , Femur/physiopathology , Fibula/drug effects , Fibula/pathology , Fibula/physiopathology , Glycoproteins/immunology , Intercellular Signaling Peptides and Proteins , Macaca fascicularis , Male , Organ Size/drug effects , Osteogenesis/drug effects , Osteotomy , Rats , Rats, Sprague-DawleyABSTRACT
This study examined the effects of denosumab, an anti-RANKL antibody that inhibits bone resorption, on bone histomorphometry in adult ovariectomized cynomolgus monkeys (OVX cynos). A month after surgery, OVX cynos were treated with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg/month) for 16months (n=14-20/group). Sham controls were treated with vehicle (Sham-Veh; n=17). Areal and volumetric BMD, urine NTx, and serum osteocalcin were measured at baseline and months 3, 6, 12, and 16. Double fluorochrome labels were injected prior to iliac and rib biopsies at month 6 and month 12, and prior to sacrifice at month 16. Histomorphometry was performed on these biopsies, the tibial diaphysis, the L2 vertebra, and the proximal femur. Strength of humeral cortical beams, femur diaphysis, femur neck, and trabecular cores of L5-L6 vertebrae was determined by destructive biomechanical testing. There was no evidence of woven bone, osteomalacia, or other bone histopathologic changes with OVX or with denosumab. OVX-Veh animals exhibited significantly greater bone remodeling at all skeletal sites relative to Sham-Veh controls. Both doses of denosumab markedly inhibited bone remodeling at all sites, including significant reductions in trabecular eroded surfaces (48-86% lower than OVX-Veh controls), cortical porosity (28-72% lower), and dynamic parameters of bone formation (81-100% lower). Decreased fluorochrome labeling with denosumab was related to reductions in cortical porosity and trabecular eroded surfaces, and regression analyses suggested that these reductions contributed to denosumab-related increments in BMD and bone strength. Denosumab-treated animals with the lowest levels of fluorescent labeling exhibited the greatest structural bone strength values at each site. Intracortical remodeling had no relationship with material properties including ultimate strength, elastic modulus or toughness (r(2)=0.00-0.01). These data suggest that remodeling inhibition with denosumab improved structural strength without altering material properties under these experimental conditions. Greater structural strength in the denosumab-treated animals can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and cortical porosity.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Bone and Bones/drug effects , Ovariectomy , RANK Ligand/therapeutic use , Animals , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/urine , Antibodies, Monoclonal, Humanized , Bone Density/drug effects , Bone Remodeling/drug effects , Denosumab , Female , Humans , Macaca fascicularis , RANK Ligand/blood , RANK Ligand/pharmacokinetics , RANK Ligand/urineABSTRACT
BACKGROUND: Heat transfer from bipolar tips to adjacent tissue presents a risk of thermal injury during spine surgery. OBJECTIVE: The present study was designed to determine wither bipolar forceps using a novel heat pipe thermal regulation technology resulted in decreased collateral thermal injury of adjacent tissue compared with traditional bipolar forceps (control). METHODS: Eight sheep underwent multilevel laminectomy and controlled bipolar coagulation of the dorsal spinal dura mater at multiple levels using forceps with or without heat pipe technology (24 spinal segments tested; heat pipe, n=11; non-heat pipe, n=11; sham, n=2). The severity (range, 1-5) and size of thermal injury to the spinal cord resulting from forceps with vs without heat pipe were assessed via histological analysis at 8 days postoperatively. RESULTS: Macroscopic occlusion of the pial vein underlying the segment of epidural coagulation occurred at surgery in 64% of segments (7 of 11) coagulated with control forceps but did not occur in any segments coagulated with heat pipe forceps (P<.005). The mean width (0.58+/-0.58 vs 1.4+/-0.77 mm; P<.05) and cross-sectional area of unintended thermal injury (1.2+/-1.7 vs 4.9+/-3.2 mm2; P<.05) were decreased in segments treated with heat pipe forceps compared with control. The severity of thermal injury was decreased in segments coagulated with (median, grade 1) vs without (median, grade 3) heat pipe forceps (P<.05). CONCLUSION: Bipolar forceps that incorporate heat pipe technology limited thermal spread and reduced the extent of unintended injury to the spinal cord and collateral vessels.
Subject(s)
Burns/prevention & control , Electrocoagulation/instrumentation , Hot Temperature/adverse effects , Microsurgery/instrumentation , Neurosurgical Procedures/instrumentation , Surgical Instruments/standards , Vascular Surgical Procedures/instrumentation , Animals , Burns/etiology , Burns/physiopathology , Disease Models, Animal , Electrocoagulation/adverse effects , Electrocoagulation/methods , Female , Intraoperative Complications/etiology , Intraoperative Complications/physiopathology , Intraoperative Complications/prevention & control , Microsurgery/adverse effects , Microsurgery/methods , Neurosurgical Procedures/adverse effects , Neurosurgical Procedures/methods , Sheep, Domestic , Surgical Instruments/adverse effects , Surgical Instruments/trends , Vascular Surgical Procedures/adverse effects , Vascular Surgical Procedures/methodsABSTRACT
The development of bone-rebuilding anabolic agents for treating bone-related conditions 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. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Bone Density/drug effects , Bone Morphogenetic Proteins/immunology , Bone and Bones/metabolism , Genetic Markers/immunology , Adaptor Proteins, Signal Transducing , Animals , Bone and Bones/pathology , Female , Macaca fascicularis , OsteogenesisSubject(s)
Carcinogenicity Tests/methods , Neoplasms, Experimental/chemically induced , Parathyroid Hormone/toxicity , Animals , Dose-Response Relationship, Drug , Female , Humans , Incidence , Male , Neoplasms, Experimental/epidemiology , Parathyroid Hormone/pharmacokinetics , Rats , Rats, Inbred F344 , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/toxicity , Risk Assessment , Teriparatide/toxicityABSTRACT
The carcinogenic potential of human parathyroid hormone 1-84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 microg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density. In the mid-and high-dose groups, proliferative changes in bone increased with dose. Osteosarcoma was the most common change, followed by focal osteoblast hyperplasia, osteoblastoma, osteoma and skeletal fibrosarcoma. The incidence of bone neoplasms was comparable in control and low-dose groups providing a noncarcinogenic dose for PTH of 10 microg/kg/day at a systemic exposure to PTH that is 4.6-fold higher than for a 100 microg dose in humans. The ability of PTH to interact with and balance the effects of both the PTH-1 receptor and the putative C-terminal PTH receptor, may lead to the lower carcinogenic potential observed with PTH than reported previously for teriparatide.