The effects of combined human parathyroid hormone (1-34) and simvastatin treatment on osseous integration of hydroxyapatite-coated titanium implants in the femur of ovariectomized rats.

The effect of human parathyroid hormone 1-34 (PTH) and simvastatin (SIM) alone could promote bone healing in osteoporotic osseous integration of the implant, but there are no reports about the combined use of PTH and SIM for promotion of bone healing around implant in osteoporotic settings still limited. This study aims to investigate effects of PTH+SIM on osseous integration of the implant in OVX rats. Female Sprague-Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups: group control; group SIM; group PTH and group PTH+SIM. Afterwards, all OVX rats received hydroxyapatite (HA)-coated titanium rods (external diameter and length are 1.5mm and 20mm) in the femoral medullary canal. Subsequently, the animals from group SIM, group PTH and group PTH+SIM received human parathyroid hormone 1-34 (60μg/kg, three times a week), SIM (5mg/kg daily), or both for 12 weeks. Implants were inserted bilaterally in all animals until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. All groups increased new bone formation around the surface of titanium rods and push-out force; group PTH+SIM showed the strongest effects on new bone formation and biomechanical strength. Additionally, these are significant difference observed in bone formation and push-out force between groups SIM and PTH. This finding suggests that intermittent administration of PTH or SIM alone has an effect to increase new bone formation on the surface of HA-coated implants in the osteoporotic condition, and the additive effects of combination PTH and SIM on osseous integration of the implant in OVX rats.

[1]  Y. Li,et al.  Promotion of peri-implant bone healing by systemically administered parathyroid hormone (1-34) and zoledronic acid adsorbed onto the implant surface , 2013, Osteoporosis International.

[2]  Harry K. Genant,et al.  Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. , 1993, The American journal of medicine.

[3]  N. Endo,et al.  Intermittent administration of human parathyroid hormone (1–34) increases new bone formation on the interface of hydroxyapatitecoated titanium rods implanted into ovariectomized rat femora , 2008, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[4]  S. Yano,et al.  Parathyroid hormone upregulates BMP-2 mRNA expression through mevalonate kinase and Rho kinase inhibition in osteoblastic MC3T3-E1 cells. , 2009, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[5]  T. Wronski,et al.  Effects of age, estrogen depletion, and parathyroid hormone treatment on vertebral cancellous wall width in female rats. , 1999, Bone.

[6]  J. Marx Coming to Grips With Bone Loss , 2004, Science.

[7]  T. Wronski,et al.  Long‐term osteopenic changes in cancellous bone structure in ovariectomized rats , 1993, The Anatomical record.

[8]  P. Roberson,et al.  Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. , 1999, The Journal of clinical investigation.

[9]  J. Parvizi,et al.  Biology of implant osseointegration. , 2009, Journal of musculoskeletal & neuronal interactions.

[10]  Deng-hui Xie,et al.  Low‐magnitude high‐frequency loading via whole body vibration enhances bone‐implant osseointegration in ovariectomized rats , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[11]  A. Rabie,et al.  Early healing pattern of statin-induced osteogenesis. , 2005, The British journal of oral & maxillofacial surgery.

[12]  L. Palm,et al.  Hydroxyapatite coating improves 8- to 10-year performance of the link RS cementless femoral stem. , 2002, The Journal of arthroplasty.

[13]  T. Yanagawa,et al.  Induction of osteoblast differentiation indices by statins in MC3T3‐E1 cells , 2004, Journal of cellular biochemistry.

[14]  H. Genant,et al.  Recombinant Human Parathyroid Hormone (1–34) [Teriparatide] Improves Both Cortical and Cancellous Bone Structure , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  I. Fogelman,et al.  Treatment of post-menopausal osteoporosis: beyond bisphosphonates , 2014, Journal of Endocrinological Investigation.

[16]  Y. Wang,et al.  The functional mechanism of simvastatin in experimental osteoporosis , 2014, Journal of Bone and Mineral Metabolism.

[17]  Chunli Song,et al.  Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. , 2003, Biochemical and biophysical research communications.

[18]  R. Rizzoli,et al.  Defective Implant Osseointegration Under Protein Undernutrition: Prevention by PTH or Pamidronate , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  T. Tagami,et al.  The effect of simvastatin-loaded polymeric microspheres in a critical size bone defect in the rabbit calvaria. , 2014, International journal of pharmaceutics.

[20]  M. Barton,et al.  Lovastatin stimulates human vascular smooth muscle cell expression of bone morphogenetic protein-2, a potent inhibitor of low-density lipoprotein-stimulated cell growth. , 2003, Biochemical and biophysical research communications.

[21]  L. Rimondini,et al.  Titanium alloy osseointegration in cancellous and cortical bone of ovariectomized animals: histomorphometric and bone hardness measurements. , 2002, The International journal of oral & maxillofacial implants.

[22]  V. Goldberg,et al.  Effects of calcium ion implantation on osseointegration of surface-blasted titanium alloy femoral implants in a canine total hip arthroplasty model. , 2004, The Journal of arthroplasty.

[23]  Kevin Ong,et al.  The epidemiology of revision total hip arthroplasty in the United States. , 2009, The Journal of bone and joint surgery. American volume.

[24]  K. Ueki,et al.  Statin-induced bone morphogenetic protein (BMP) 2 expression during bone regeneration: an immunohistochemical study. , 2009, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[25]  O. Reikerås,et al.  Excellent results of HA coating on a grit-blasted stem: 245 patients followed for 8-12 years , 2003, Acta orthopaedica Scandinavica.

[26]  E. Luo,et al.  The effects of combined human parathyroid hormone (1-34) and zoledronic acid treatment on fracture healing in osteoporotic rats , 2012, Osteoporosis International.

[27]  Zhou Qiang,et al.  Treatment study of distal femur for parathyroid hormone (1–34) and β-tricalcium phosphate on bone formation in critical size defects in rats , 2015, Journal of biomaterials applications.

[28]  T. Shirota,et al.  Effect of intermittent parathyroid hormone (1-34) treatment on the bone response after placement of titanium implants into the tibia of ovariectomized rats. , 2003, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[29]  K. Hayashi,et al.  The effect of hydroxyapatite coating on the bonding of bone to titanium implants in the femora of ovariectomised rats. , 1999, The Journal of bone and joint surgery. British volume.

[30]  Xiaoxiang Wang,et al.  Effect of electrochemically deposited nanohydroxyapatite on bone bonding of sandblasted/dual acid-etched titanium implant. , 2009, The International journal of oral & maxillofacial implants.

[31]  Yuuki Imai,et al.  Parathyroid hormone enhances bone morphogenetic protein activity by increasing intracellular 3', 5'-cyclic adenosine monophosphate accumulation in osteoblastic MC3T3-E1 cells. , 2009, Bone.

[32]  R. Müller,et al.  Trabecular Bone Gradient in Rat Long Bone Metaphyses: Mathematical Modeling and Application to Morphometric Measurements and Correction of Implant Positioning , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  M. McNulty,et al.  Sclerostin antibody increases bone volume and enhances implant fixation in a rat model. , 2012, The Journal of bone and joint surgery. American volume.

[34]  R. Müller,et al.  Parathyroid hormone 1-34 enhances titanium implant anchorage in low-density trabecular bone: a correlative micro-computed tomographic and biomechanical analysis. , 2006, Bone.

[35]  G. Herrero-Beaumont,et al.  PTH [1-34] enhances bone response around titanium implants in a rabbit model of osteoporosis. , 2012, Clinical oral implants research.

[36]  R. Kitazawa,et al.  Parathyroid Hormone-responsive Smad3-related Factor, Tmem119, Promotes Osteoblast Differentiation and Interacts with the Bone Morphogenetic Protein-Runx2 Pathway* , 2011, The Journal of Biological Chemistry.

[37]  M. Rizzo,et al.  Statins, Fracture Risk, and Bone Remodeling: What Is True? , 2006, The American journal of the medical sciences.

[38]  D. Puleo,et al.  Alternating release of different bioactive molecules from a complexation polymer system. , 2008, Biomaterials.

[39]  T. Maeda,et al.  Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. , 2001, Biochemical and biophysical research communications.

[40]  H. Hatano,et al.  Statin stimulates bone morphogenetic protein-2, aggrecan, and type 2 collagen gene expression and proteoglycan synthesis in rat chondrocytes , 2003, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[41]  V. Arana-Chavez,et al.  Early alveolar bone regeneration in rats after topical administration of simvastatin. , 2011, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[42]  Jui-Sheng Sun,et al.  Simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/BMP-2 signaling pathway. , 2010, Nutrition research.

[43]  R. Giardino,et al.  Osteointegration of hydroxyapatite-coated and uncoated titanium screws in long-term ovariectomized sheep. , 2002, Biomaterials.

[44]  K. Hayashi,et al.  Remodelling of bone around hydroxyapatite and titanium in experimental osteoporosis. , 1994, Biomaterials.

[45]  Jing Hu,et al.  The effect of strontium-substituted hydroxyapatite coating on implant fixation in ovariectomized rats. , 2010, Biomaterials.

[46]  Tomas Albrektsson,et al.  The bone response of oxidized bioactive and non-bioactive titanium implants. , 2005, Biomaterials.