Efficacy of a sclerostin antibody compared to a low dose of PTH on metaphyseal bone healing

Abstract Destruction of the alveolar bone in the jaws can occur due to periodontitis, trauma or following tumor resection. Common reconstructive therapy can include the use of bone grafts with limited predictability and efficacy. Romosozumab, approved by the FDA in 2019, is a humanized sclerostin-neutralizing antibody (Scl-Ab) indicated in postmenopausal women with osteoporosis at high risk for fracture. Preclinical models show that Scl-Ab administration preserves bone volume during periodontal disease, repairs bone defects surrounding dental implants, and reverses alveolar bone loss following extraction socket remodeling. To date, there are no studies evaluating Scl-Ab to repair osseous defects around teeth or to identify the efficacy of locally-delivered Scl-Ab for targeted drug delivery. In this investigation, the use of systemically-delivered versus low dose locally-delivered Scl-Ab via poly(lactic-co-glycolic) acid (PLGA) microspheres (MSs) was compared at experimentally-created alveolar bone defects in rats. Systemic Scl-Ab administration improved bone regeneration and tended to increase cementogenesis measured by histology and microcomputed tomography, while Scl-Ab delivered by MSs did not result in enhancements in bone or cemental repair compared to MSs alone or control. In conclusion, systemic administration of Scl-Ab promotes bone and cemental regeneration while local, low dose delivery did not heal periodontal osseous defects in this study.

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A Longitudinal Low DoseμCT Analysis of Bone Healing in Mice: A Pilot Study

Advances in Orthopedics ◽

10.1155/2014/791539 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Lu-Zhao Di ◽

Vanessa Couture ◽

Élisabeth Leblanc ◽

Yasaman Alinejad ◽

Jean-François Beaudoin ◽

...

Keyword(s):

Bone Healing ◽

High Speed ◽

Bone Repair ◽

Low Dose ◽

Hounsfield Unit ◽

Long Bone ◽

Preclinical Research ◽

Promising Tool ◽

Rapid Healing ◽

Experimental Treatments

Low dose microcomputed tomography (μCT) is a recently matured technique that enables the study of longitudinal bone healing and the testing of experimental treatments for bone repair. This imaging technique has been used for studying craniofacial repair in mice but not in an orthopedic context. This is mainly due to the size of the defects (approximately 1.0 mm) in long bone, which heal rapidly and may thus negatively impact the assessment of the effectiveness of experimental treatments. We developed a longitudinal low doseμCT scan analysis method combined with a new image segmentation and extraction software using Hounsfield unit (HU) scores to quantitatively monitor bone healing in small femoral cortical defects in live mice. We were able to reproducibly quantify bone healing longitudinally over time with three observers. We used high speed intramedullary reaming to prolong healing in order to circumvent the rapid healing typical of small defects. Bone healing prolongation combined withμCT imaging to study small bone defects in live mice thus shows potential as a promising tool for future preclinical research on bone healing.

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Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model

Journal of Bone and Mineral Research ◽

10.1002/jbmr.3421 ◽

2018 ◽

Vol 33 (7) ◽

pp. 1272-1282 ◽

Cited By ~ 9

Author(s):

Diana Olvera ◽

Rachel Stolzenfeld ◽

Joan C Marini ◽

Michelle S Caird ◽

Kenneth M Kozloff

Keyword(s):

Mouse Model ◽

Bone Mass ◽

Osteogenesis Imperfecta ◽

Trabecular Bone ◽

Low Dose ◽

Trabecular Bone Mass ◽

Sclerostin Antibody

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Analysis of low-dose estrogen on callus BMD as measured by pQCT in postmenopausal women

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03713-4 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

K. Jäckle ◽

J. P. Kolb ◽

A. F. Schilling ◽

C. Schlickewei ◽

M. Amling ◽

...

Keyword(s):

Bone Density ◽

Beneficial Effect ◽

Fracture Healing ◽

Postmenopausal Women ◽

Bone Healing ◽

Bone Fracture ◽

Low Dose ◽

Callus Formation ◽

Trial Registration ◽

Bone Fracture Healing

Abstract Background Osteoporosis affects elderly patients of both sexes. It is characterized by an increased fracture risk due to defective remodeling of the bone microarchitecture. It affects in particular postmenopausal women due to their decreased levels of estrogen. Preclinical studies with animals demonstrated that loss of estrogen had a negative effect on bone healing and that increasing the estrogen level led to a better bone healing. We asked whether increasing the estrogen level in menopausal patients has a beneficial effect on bone mineral density (BMD) during callus formation after a bone fracture. Methods To investigate whether estrogen has a beneficial effect on callus BMD of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13 years ±11.99) were treated with estrogen and 45 patients (75.62 years ±10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and 6 weeks after the surgery. Comparative measurements were performed at the fractured site and at the corresponding position of the non-fractured arm. Results We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients. Conclusions Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on callus BMD as measured by pQCT, as recently shown in preclinical animal models. Trial registration Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858. Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858.

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Production of cartilage collagens during metaphyseal bone healing in the mouse

Matrix Biology ◽

10.1016/s0945-053x(98)90084-1 ◽

1998 ◽

Vol 17 (4) ◽

pp. 317-320 ◽

Cited By ~ 7

Author(s):

Iiro Eerola ◽

Hannele Uusitalo ◽

Hannu Aro ◽

Eero Vuorio

Keyword(s):

Bone Healing ◽

Metaphyseal Bone

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Amlodipine accelerates bone healing in a stable closed femoral fracture model in mice

10.22203/ecm.v041a38 ◽

2021 ◽

Vol 41 ◽

pp. 592-602

Author(s):

MM Menger ◽

◽

B Merscher ◽

C Scheuer ◽

BJ Braun ◽

...

Keyword(s):

Body Weight ◽

Western Blot ◽

Fracture Healing ◽

Bone Healing ◽

Blot Analysis ◽

Western Blot Analysis ◽

Low Dose ◽

Fibrous Tissue ◽

Fracture Model ◽

High Dose

Calcium channel blockers (CCBs), which are widely used in the treatment of hypertension, have been shown to influence bone metabolism. However, there is little information on whether CCBs also influence the process of fracture healing. Therefore, the effect of the CCB amlodipine on bone healing was studied in a stable closed fracture model in mice using intramedullary screw fixation. Bone healing was investigated by radiology, biomechanics, histomorphometry and Western blot analysis 2 and 5 weeks after fracture healing. Animals were treated daily (post operatively) per per os using a gavage with amlodipine low dose (1 mg/ kg body weight, n = 20), amlodipine high dose (3 mg/kg body weight, n = 20) or vehicle (NaCl) (control, n = 20) serving as a negative control. At 2 and 5 weeks, histomorphometric analysis revealed a significantly larger amount of bone tissue within the callus of amlodipine low-dose- and high-dose-treated animals when compared to controls. This was associated with a smaller amount of cartilaginous and fibrous tissue, indicating an acceleration of fracture healing. Biomechanics showed a slightly, but not significantly, higher bending stiffness in amlodipine low-dose- and high-dose-treated animals. Western blot analysis revealed a significantly increased expression of bone morphogenetic protein (BMP)-2 and vascular endothelial growth factor (VEGF). Moreover, the analysis showed a 5-fold higher expression of osteoprotegerin (OPG) and a 10-fold elevated expression of the receptor activator of NF-κB ligand (RANKL), indicating an increased bone turnover. These findings demonstrated that amlodipine accelerated fracture healing by stimulating bone formation, callus remodelling and osteoclast activity.

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