Hypobaric hypoxia deteriorates bone mass and strength in mice

Brent, Mikkel Bo; Emmanuel, Thomas; Simonsen, Ulf; Brüel, Annemarie; Thomsen, Jesper Skovhus

doi:10.1016/j.bone.2021.116203

Cited by 12 publications

(28 citation statements)

References 55 publications

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“…This view is supported by Oikonomidou et al who demonstrated a substantially reduced cortical thickness in a mouse model of polycythemia vera, and by others who showed that increased levels of erythropoietin (EPO)the primary hormone responsible for red blood cell productionare associated with loss of bone (38,39). Surprisingly, the loss of cortical thickness manifested without decreased bone mineral density, bone strength, or endocortical indices of bone formation, as we have previously demonstrated in mice exposed to hypobaric hypoxia (5). In contrast to our previous study of mice exposed to simulated high altitude, the mice used in the present study were younger.…”

Section: Discussionsupporting

confidence: 76%

“…Mice allocated to hypobaric hypoxia were acclimatized for three days before study start, to enable a gradual adaptation to the lower ambient pressure. The animal model of hypobaric hypoxia has previously been used and described in detail ( 5 ).…”

Section: Methodsmentioning

confidence: 99%

“…Mice allocated to the Baseline group were sacrificed at study start to establish the skeletal status at baseline, while the remaining mice were sacrificed after four weeks ( 5 ). All mice were sacrificed under general anesthesia by inhalation of isoflurane (Attane Vet, ScanVet, Fredensborg, Denmark), and immediately thereafter, tissue was extracted.…”

Section: Methodsmentioning

confidence: 99%

“…Both femora, tibia, and L4 vertebra were isolated and any remaining soft tissue were carefully removed. The right femur and tibia and L4 were stored in Ringer’s solution at −20°C, while the left femur was immersion-fixed in 0.1 M sodium phosphate-buffered formaldehyde (4% formaldehyde, pH 7.0) for 48 h and then stored in 70% ethanol ( 5 ). Bone lengths of the right femur and tibia were determined using a digital sliding caliper.…”

Section: Methodsmentioning

confidence: 99%

“…Although the initial symptoms of AMS are relatively mild, it may progress to life-threatening high altitude pulmonary edema (HAPE) ( 2 ) or high altitude cerebral edema (HACE) ( 3 ). Studies in rodents have suggested that exposure to high-altitude environments may affect the musculoskeletal system by reducing bone strength and inducing muscle atrophy ( 4 , 5 ). However, observational follow-up studies in mountaineers are sparse, and only one study has measured bone mineral density (BMD) before and after expeditions to summit either Si Guang Feng (7,308 m) or Xixabangma (8,027 m).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Acetazolamide and Zoledronate on Simulated High Altitude-Induced Bone Loss

et al. 2022

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Exposure to hypobaric hypoxia at high altitude puts mountaineers at risk of acute mountain sickness. The carbonic anhydrase inhibitor acetazolamide is used to accelerate acclimatization, when it is not feasible to make a controlled and slow ascend. Studies in rodents have suggested that exposure to hypobaric hypoxia deteriorates bone integrity and reduces bone strength. The study investigated the effect of treatment with acetazolamide and the bisphosphonate, zoledronate, on the skeletal effects of exposure to hypobaric hypoxia. Eighty 16-week-old female RjOrl : SWISS mice were divided into five groups: 1. Baseline; 2. Normobaric; 3. Hypobaric hypoxia; 4. Hypobaric hypoxia + acetazolamide, and 5. Hypobaric hypoxia + zoledronate. Acetazolamide was administered in the drinking water (62 mg/kg/day) for four weeks, and zoledronate (100 μg/kg) was administered as a single subcutaneous injection at study start. Exposure to hypobaric hypoxia significantly increased lung wet weight and decreased femoral cortical thickness. Trabecular bone was spared from the detrimental effects of hypobaric hypoxia, although a trend towards reduced bone volume fraction was found at the L4 vertebral body. Treatment with acetazolamide did not have any negative skeletal effects, but could not mitigate the altitude-induced bone loss. Zoledronate was able to prevent the altitude-induced reduction in cortical thickness. In conclusion, simulated high altitude affected primarily cortical bone, whereas trabecular bone was spared. Only treatment with zoledronate prevented the altitude-induced cortical bone loss. The study provides preclinical support for future studies of zoledronate as a potential pharmacological countermeasure for altitude-related bone loss.

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Section: Discussionsupporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Acetazolamide and Zoledronate on Simulated High Altitude-Induced Bone Loss

et al. 2022

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Bone Deterioration in Response to Chronic High-Altitude Hypoxia Is Attenuated by a Pulsed Electromagnetic Field Via the Primary Cilium/HIF-1α Axis

Hao

Wang

Yan

et al. 2020

Journal of Bone and Mineral Research

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Chronic high‐altitude hypoxia induces irreversible abnormalities in various organisms. Emerging evidence indicates that hypobaric hypoxia markedly suppresses bone mass and bone strength. However, few effective means have been identified to prevent such bone deficits. Here, we assessed the potential of pulsed electromagnetic fields (PEMFs) to noninvasively resist bone deterioration induced by hypobaric hypoxia. We observed that exogenous PEMF treatment at 15 Hz and 20 Gauss (Gs) improved the cancellous and cortical bone mass, bone microstructure, and skeletal mechano‐properties in rats subjected to chronic exposure of hypobaric hypoxia simulating an altitude of 4500 m for 6 weeks by primarily modulating osteoblasts and osteoblast‐mediated bone‐forming activity. Moreover, our results showed that whereas PEMF stimulated the functional activity of primary osteoblasts in hypoxic culture in vitro, it had negligible effects on osteoclasts and osteocytes exposed to hypoxia. Mechanistically, the primary cilium was found to function as the major electromagnetic sensor in osteoblasts exposed to hypoxia. The polycystins PC‐1/PC‐2 complex was identified as the primary calcium channel in the primary cilium of hypoxia‐exposed osteoblastic cells responsible for the detection of external PEMF signals, and thereby translated these biophysical signals into intracellular biochemical events involving significant increase in the intracellular soluble adenylyl cyclase (sAC) expression and subsequent elevation of cyclic adenosine monophosphate (cAMP) concentration. The second messenger cAMP inhibited the transcription of oxygen homeostasis‐related hypoxia‐inducible factor 1‐alpha (HIF‐1α), and thus enhanced osteoblast differentiation and improved bone phenotype. Overall, the present study not only advances our understanding of bone physiology at high altitudes, but more importantly, proposes effective means to ameliorate high altitude‐induced bone loss in a noninvasive and cost‐effective manner. © 2023 American Society for Bone and Mineral Research (ASBMR).

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Contemporary Advances in Computer-Assisted Bone Histomorphometry and Identification of Bone Cells in Culture

Brent

Emmanuel

2022

Calcif Tissue Int

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Hypobaric hypoxia deteriorates bone mass and strength in mice

Cited by 12 publications

References 55 publications

Effect of Acetazolamide and Zoledronate on Simulated High Altitude-Induced Bone Loss

Effect of Acetazolamide and Zoledronate on Simulated High Altitude-Induced Bone Loss

Bone Deterioration in Response to Chronic High-Altitude Hypoxia Is Attenuated by a Pulsed Electromagnetic Field Via the Primary Cilium/HIF-1α Axis

Contemporary Advances in Computer-Assisted Bone Histomorphometry and Identification of Bone Cells in Culture

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