Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey

Authors

T. Cusick, C.M. Chen, B.L. Pennypacker, M. Pickarski, D. Kimmel, B.B. Scott, L.T. Duong

Abstract

Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK). Previously, ODN was shown to increase bone mineral density (BMD) and maintained normal bone strength at the spine in ovariectomized (OVX) rhesus monkey. Here, we further characterize the effects of ODN on BMD, bone strength and dynamic histomorphometric analyses of the hip from the same monkeys. Animals were treated for 21-months with vehicle, 6 or 30mg/kg ODN (p.o., q.d.). ODN increased hip BMD by 11% and 15% (p < 0.01), and ultimate load by 17% (p < 0.05) and 19% (p < 0.01) versus vehicle. Treatment-related increases in ultimate load positively correlated with the increased femoral neck (FN) BMD, BMC and cortical thickness. Histomorphometry of FN and proximal femur (PF) revealed that ODN reduced trabecular and intracortical bone formation rate (BFR), but did not affect long-term endocortical BFR Moreover, ODN stimulated long-term FN and PF periosteal BFR by 3.5- and 6-fold with the 30mg/kg dose versus vehicle, respectively. Osteoclast surfaces were either unaffected or trended higher (∼2-fold) in endocortical and trabecular surfaces in the ODN group. Lastly, ODN increased cortical thickness of FN by 21% (p = 0.08) and PF by 19% (p < 0.05) versus vehicle after 21-months of treatment. Together, both doses of ODN increased bone mass and improved bone strength at the hip. Unlike conventional antiresorptives, ODN displayed site specific effects on trabecular versus cortical bone formation. The drug provided marked increases in periosteal bone formation and cortical thickness in OVX-monkeys, suggesting that CatK inhibition may represent a novel therapeutic approach for the treatment of osteoporosis.

Link to Article

http://dx.doi.org/0.1002/jbmr.1477

Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys

Authors

P.J. Masarachia1, B.L. Pennypacker1, M. Pickarski1, K.R. Scott1, G.A. Wesolowski1, S.Y. Smith3, R. Samadfam3, J.E. Goetzmann4, B.B. Scott2, D.B. Kimmel1, L.T. Duong

Abstract

Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK) currently being developed as a once-weekly treatment for osteoporosis. In this study, we evaluated the effects of ODN on bone turnover, bone mineral density (BMD), and bone strength in the lumbar spine of estrogen deficient, skeletally mature, rhesus monkeys. Ovariectomized (OVX)-monkeys were treated in prevention mode for 21-months with either vehicle, ODN 6mg/kg or ODN 30mg/kg (p.o., q.d.) and compared to intact animals. ODN treatment persistently suppressed the bone resorption markers, urinary NTx (75-90%), serum CTx (40-55%), the serum formation markers, BSAP (30-35%) and P1NP (60-70%) versus vehicle-treated OVX-monkeys. Treatment with ODN also led to dose-dependent increases in serum 1-CTP, and maintained estrogen deficiency-elevated Trap-5b levels, supporting the distinct mechanism of CatK inhibition in effectively suppressing bone resorption without reducing osteoclast numbers. ODN at both doses fully prevented bone loss in lumbar vertebrae (LV1-4) BMD in OVX-animals maintaining a level comparable to intact animals. ODN dose-dependently increased LV1-4 BMD by 7% in the 6mg/kg (p < 0.05 vs. OVX-vehicle) and 15% in the 30mg/kg group (p < 0.05 vs. OVX-vehicle) from baseline. Treatment also trended to increase bone strength, associated with a positive and highly significant correlation (R = 0.838) between peak load and bone mineral content of the lumbar spine. While ODN reduced bone turnover parameters in trabecular bone, the number of osteoclasts was either maintained or increased in the ODN-treated groups compared to the vehicle controls. Taken together, our findings demonstrated that the long-term treatment with ODN effectively suppressed bone turnover without reducing osteoclast number and maintained normal biomechanical properties of the spine of OVX-non human primates.

Link to Article

http://dx.doi.oirg/10.1002/jbmr.1475

Bio-Oss® blocks combined with BMP-2 and VEGF for the regeneration of bony defects and vertical augmentation

Authors

Christian Schmitt, Rainer Lutz, Hendrik Doering, Michael Lell, Jozsef Ratky, Karl Andreas Schlegel

Abstract

The aim of this study was to evaluate the bone formation rate and osseointegration of Bio-Oss® blocks combined with rhBMP-2 and rhVEGF in bony defects and after vertical augmentation. Bio-Oss® blocks plus rhBMP-2 (BMP), Bio-Oss® blocks plus rhVEGF (VEGF), or Bio-Oss® blocks plus rhBMP-2 and rhVEGF (BMPVEGF) were inserted in “critical size defects” (CSD) in the calvariae of adult pigs. Control defects were filled with collagen carrier (Lyostypt®) plus growth factors and untreated Bio-Oss® blocks (CO). In a second group, Bio-Oss® blocks plus growth factors and untreated Bio-Oss® blocks were used for vertical augmentation of the calvariae. In the first group, the investigation time was 30 days, in the second group it was 30 and 60 days. The bone samples were investigated histomorphometrically, and the newly formed bone (BV/TV) was judged by microradiographic investigation. In the CSD model, the newly formed bone in the region of interest was not significantly different within the groups. In the second setting, the inserted bone blocks exhibited sufficient volume stability with increasing bone formation up to 9.33% ± 3.92% for BMP, 10.42% ± 1.81% for BMP/VEGF, 11.01% ± 4.78% for VEGF, and 10.02% ± 5.43% for the control group after 60 days. In the chosen setting and time frame, de novo bone formation did not increase with the additional use of growth factors.

Link to Article

http://dx.doi.org/10.1111/j.1600-0501.2011.02351.x

Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading

Authors

Xiaolin Tu, Yumie Rhee, Keith W. Condon, Nicoletta Bivi, Matthew R. Allen, Denise Dwyer, Marina Stolina, Charles H. Turner, Alexander G. Robling, Lilian I. Plotkin, Teresita Bellido

Abstract

Sclerostin, the Wnt signaling antagonist encoded by the Sost gene, is secreted by osteocytes and inhibits bone formation by osteoblasts. Mechanical stimulation reduces sclerostin expression, suggesting that osteocytes might coordinate the osteogenic response to mechanical force by locally unleashing Wnt signaling. To investigate whether sclerostin downregulation is a pre-requisite for load-induced bone formation, we conducted experiments in transgenic mice (TG) engineered to maintain high levels of SOST expression during mechanical loading. This was accomplished by introducing a human SOST transgene driven by the 8 kb fragment of the DMP1 promoter that also provided osteocyte specificity of the transgene. Right ulnae were subjected to in vivo cyclic axial loading at equivalent strains for 1 min/day at 2 Hz; left ulnae served as internal controls. Endogenous murine Sost mRNA expression measured 24 h after 1 loading bout was decreased by about 50% in TG and wild type (WT) littermates. In contrast, human SOST, only expressed in TG mice, remained high after loading. Mice were loaded on 3 consecutive days and bone formation was quantified 16 days after initiation of loading. Periosteal bone formation in control ulnae was similar in WT and TG mice. Loading induced the expected strain-dependent increase in bone formation in WT mice, resulting from increases in both mineralizing surface (MS/BS) and mineral apposition rate (MAR). In contrast, load-induced bone formation was reduced by 70–85% in TG mice, due to lower MS/BS and complete inhibition of MAR. Moreover, Wnt target gene expression induced by loading in WT mice was absent in TG mice. Thus, downregulation of Sost/sclerostin in osteocytes is an obligatory step in the mechanotransduction cascade that activates Wnt signaling and directs osteogenesis to where bone is structurally needed.

Link to Article

http://dx.doi.org/10.1016/j.bone.2011.10.025

Low-magnitude high-frequency loading via whole body vibration enhances bone-implant osseointegration in ovariectomized rats

Authors

BaiLing Chen, YiQiang Li, DengHui Xie, XiaoXi Yang

Abstract

Osseointegration is vital to avoid long-time implants loosening after implantation surgery. This study investigated the effect of low-magnitude high-frequency (LMHF) loading via whole body vibration on bone-implant osseointegration in osteoporotic rats, and a comparison was made between LMHF vibration and alendronate on their effects. Thirty rats were ovariectomized to induce osteoporosis, and then treated with LMHF vibration (VIB) or alendronate (ALN) or a control treatment (OVX). Another 10 rats underwent sham operation to establish Sham control group. Prior to treatment, hydroxyapatite (HA)-coated titanium implants were inserted into proximal tibiae bilaterally. Both LMHF vibration and alendronate treatment lasted for 8 weeks. Histomorphometrical assess showed that both group VIB, ALN and Sham significantly increased bone-to-implant contact and peri-implant bone fraction (p < 0.05) when compared with group OVX. Nevertheless the bone-to-implant contact and peri-implant bone fraction of group VIB were inferior to group ALN and Sham (p < 0.05). Biomechanical tests also revealed similar results in maximum push out force and interfacial shear strength. Accordingly, it is concluded that LMHF loading via whole body vibration enhances bone-to-implant osseointegration in ovariectomized rats, but its effectiveness is weaker than alendronate.

Link to Article

http://dx.doi.org/10.1002/jor.22004

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Authors

Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang, William J. Muller and Richard Kremer

Abstract

Parathyroid hormone–related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer — it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.

Link to Article

http://www.jci.org/articles/view/46134