Drill-Hole Bone Defects in Animal Models of Bone Healing: Protocol for a Systematic Review.

BACKGROUND: Bone fractures are common conditions of the musculoskeletal system. Several animal models of bone fractures have been established to help elucidate the complex process of bone healing. In the last decades, drill-hole bone defects have emerged as a method to study bone healing. Animal models of drill-hole defects are easy to standardize and do not require external fixation of the bone. However, current studies of drill-hole bone defects lack detailed descriptions of techniques and interstudy standardization. OBJECTIVE: This systematic review aims to present a detailed description of the different methods used to induce drill-hole bone defects in long bones of laboratory animals and to provide a comprehensive overview of their methodology and potential for investigation of bone healing. METHODS: A systematic search of PubMed and Embase will be performed of abstracts containing variations of the following four keywords: "long bone," "drill-hole," "regeneration," and "animal model." Abstract screening and full-text screening will be performed independently by 2 reviewers, and data will be extracted to a predesigned extraction protocol. The primary outcome of the included studies is the technique used to create the drill-hole bone defect, and secondary outcomes are any measurements or analyses of bone defect and regeneration. A narrative synthesis will be used to present the primary outcome, while information on secondary outcomes will be displayed graphically. The study protocol follows the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines. RESULTS: Abstract and full-text screening is ongoing and is expected to be completed by October 2022. Data extraction will commence immediately after, and the manuscript is expected to be completed by December 2023. The systematic review will follow the PRISMA statement. CONCLUSIONS: The strength of this systematic review is that it provides a comprehensive methodological overview of the different drill-hole methods and their advantages and disadvantages. This will assist researchers in choosing which model to use when studying different aspects of bone healing. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews CRD42020213076; https://tinyurl.com/bp56wdwe. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34887.

The Effect of Normobaric Intermittent Hypoxia Therapy on Bone in Normal and Disuse Osteopenic Mice.

Bromer, Frederik Duch, Mikkel Bo Brent, Michael Pedersen, Jesper Skovhus Thomsen, Annemarie Brüel, and Casper Bindzus Foldager. The effect of normobaric intermittent hypoxia therapy on bone in normal and disuse osteopenic mice. High Alt Med Biol. 22: 225-234, 2021. Background: Systemic intermittent hypoxia therapy (IHT) has been shown to elicit beneficial effects on multiple physiological systems. However, only few studies have investigated the effect of long-term normobaric IHT on bone mass and mechanical and microstructural properties. The aim of the present study was to examine the effect of IHT on bone in both healthy and osteopenic mice. Materials and Methods: Thirty mice were stratified into four groups: Ctrl, Ctrl+IHT, Botox, and Botox+IHT. Osteopenia was induced by injecting Botox into the right hindlimb of the mice causing paralysis and disuse. IHT animals were placed in a normobaric hypoxia-chamber (10% oxygen) for 1 hour twice daily 5 days/week. Animals were sacrificed after 21 days, and DEXA, micro-computed tomography, and mechanical testing were performed on the femora. Results: As expected, Botox resulted in a significant reduction of bone mineral content (-23.4%), area bone mineral density (-19.1%), femoral neck strength (Fmax: -54.7%), bone volume fraction (bone volume/tissue volume: -41.8%), and trabecular thickness (-32.4%). IHT had no measurable effect on the bone properties in either healthy or osteopenic mice. Conclusion: The study confirmed that Botox led to loss of bone mass, deterioration of trabecular microstructure, and loss of bone strength. These changes were not influenced by IHT. Notably, IHT had no detrimental effect on bone in either healthy or osteopenic mice. This indicates that IHT of ailments outside of the skeletal system may be administered without causing harm to the bone.

Activin type IIA decoy receptor and intermittent parathyroid hormone in combination overturns the bone loss in disuse-osteopenic mice.

Damage of the lower motor neuron cell bodies or their axons results in reduced or abolished voluntary movement accompanied by a substantial loss of bone and muscle mass. Intermittent parathyroid hormone 1-34 (PTH) (teriparatide) is one of the most potent bone-anabolic treatment regimens. ActRIIA-mFc is an activin type IIA decoy receptor that increases bone mass mediated by inhibition of the activin receptor signaling pathway. We investigated whether PTH or ActRIIA-mFc alone or in combination could prevent loss of bone and muscle mass induced by injecting botulinum toxin A (BTX) into the right hind limb in mice. Seventy-two 16-week-old female C57BL/6 mice were allocated to the following groups: Baseline, Control, BTX, BTX + ActRIIA-mFc (10 mg/kg), BTX + PTH (100 µg/kg), and BTX + ActRIIA-mFc + PTH. The mice were sacrificed after three weeks of disuse and treatment. In contrast to monotherapy with PTH, ActRIIA-mFc alone or in combination with PTH was able partly or completely to prevent disuse-induced loss of whole femoral bone mass, trabecular thickness, and bone strength. Moreover, an additive effect of ActRIIA-mFc and PTH on areal bone mineral density and trabecular bone volume was found. In summary, ActRIIA-mFc and PTH in combination were more effective in preventing disuse-induced bone loss and deterioration of trabecular micro-architecture than either treatment alone.