Ketogenic Diet Compromises Both Cancellous and Cortical Bone Mass in Mice

Wu, Xiuhua; Huang, Zucheng; Fu, Zhaozong; Liu, Junhao; Huang, Zhiping; Kong, Ganggang; Xu, Xiaolin; Ding, Jianyang; Zhu, Qingan

doi:10.1007/s00223-017-0292-1

Cited by 31 publications

(26 citation statements)

References 39 publications

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“…KD led to cancellous and cortical bone loss in the tibia and humerus, which was consistent with findings of tibia bone loss in a previous study by our group (14). A previous study by our group demonstrated that KD specifically caused cortical bone loss of tibiae in mice when compared with ovariectomized mice (14). The present study also investigated the bone loss in middle of L4 vertebra and the humerus, providing a comprehensive overview of the bone loss under KD.…”

Section: Discussionsupporting

confidence: 92%

“…Clinical trials have suggested that KD is safe and efficient (11,12); however, it also resulted in a progressive loss of bone mineral content in pediatric patients, particularly in those with a low body mass index (BMI) (13). A previous study by our group confirmed that KD resulted in a significant bone loss in the tibia and reduced mechanical function in the femur of mice (14); such side effects in cancellous-rich bones, e.g. the vertebrae, are worthy of further investigation.…”

Section: Introductionmentioning

confidence: 60%

“…Ketogenic animal models are typically established by feeding KD or by β-hydroxybutyrate administration (23,24); however, to the best of our knowledge, there is currently no unified ketogenic animal model. A previous study by Wu et al (14) has indicated that KD caused bone loss in mouse tibia, but the blood ketone levels in the KD group were only ~1.0 mmol/l. In the present study, elevated blood ketone levels (~2.0 mmol/l) were achieved with a customized KD (24,25), which indicated that the ketogenic model was efficient.…”

Section: Discussionmentioning

confidence: 81%

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Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats

Ding

et al. 2019

Exp Ther Med

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A ketogenic diet (KD) is composed of low-carbohydrate, high-fat and adequate levels of protein. It has been used for decades as a method to treat pediatric refractory epilepsy. However, recently, its side effects on the bones have received increasing attention. In order to comprehensively evaluate the effect of KD on the microstructures and mechanical properties of the skeleton, 14 male Sprague-Dawley rats were equally divided into two groups and fed with a KD (ratio of fat to carbohydrate and protein, 3:1) or a standard diet for 12 weeks. Body weight, as well as blood ketone and glucose levels, were monitored during the experiment. Bone morphometric analyses via micro-computerized tomography were performed on cortical and trabecular bone at the middle L4 vertebral body, the proximal humerus and tibia. The compressive stiffness and strength of scanned skeletal areas were calculated using micro-finite element analysis. The KD led to higher ketone levels and lower glucose levels, with reduced body weight and total bone mineral density (TBMD). After 12 weeks, the diet reduced the bone volume fraction, the trabecular number of cancellous bone, cortical thickness, total cross-sectional area inside the periosteal envelope and the bone area of cortical bone in the tibia and humerus, while increasing trabecular separation. However, KD may not affect the L4 vertebral body. The serum calcium or phosphate concentrations in the blood remained unchanged. In addition, bone stiffness and strength were clearly decreased by the KD, and significantly correlated with the BMD and bone area at all scanned sites. In conclusion, KD led to significant bone loss and reduced biomechanical function in appendicular bones, with a lesser impact on axial bones.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 81%

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Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats

Ding

et al. 2019

Exp Ther Med

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“…However, it was firstly reported by Hahn that KD had deleterious effects on bone mass in children who maintained this regimen in long term (13). Our previous studies also confirmed that KD compromised bone micro-structures and reduced bone biomechanics in rodents (14)(15)(16)(17)(18). However, the different effects of streptozotocin-induced hyperglycemia and KD-induced hyperketonemia on bone microstructures and biomechanics have not been elucidated.…”

Section: Introductionsupporting

confidence: 63%

The Hyperglycemia and Hyperketonemia Impaired Bone Microstructures: A Pilot Study in Rats

Zhou

Xie

et al. 2020

Front. Endocrinol.

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Though diabetes mellitus (DM) is one of the known causes of osteoporosis, it is also realized that ketogenic diet (KD), an effective regimen for epilepsy, impairs bone microstructures. However, the similarities and differences of effects between these two factors are still unknown. The purpose of this study is to identify different effects between hyperglycemia and hyperketonemia, which are manifestations of DM and KD, on bone in rats. Thirty male Sprague-Dawley rats were randomly divided into three groups: the sham, DM, and KD groups. Hyperglycemia was achieved by intravenous injection of streptozotocin in DM group, while hyperketonemia was induced by application of ketogenic diet (carbohydrates-to-fat as 1:3) in KD group. The body weight, blood ketone body, and blood glucose were recorded, and the bone turnover markers, bone length, bone microstructures, bone biomechanics and histomorphology were measured after 12 weeks intervention. Compared with the control and KD groups, a significant body weight loss was found in the DM group, and the bone lengths of tibia and femur of the group were shortened. The blood glucose and blood ketone were noticeably increased in the DM and KD rats, respectively. Microstructures and properties of cancellous bone were significantly deteriorated in both the DM and KD groups compared with the sham group, as the bone volumes were decreased and the bone trabecula structures were disturbed. Meanwhile, the thickness and strength of cortical bone was reduced more in the DM group than those in the sham and KD groups. The HE staining showed that bone trabecula was significantly decreased in both the DM and KD groups, and more adipose tissue was observed in the KD rats. The activity of osteoblasts was decreased more in both the KD and DM groups than that in the sham group, while the activity of osteoclasts of the two groups was remarkably increased. The present study indicates that both hyperglycemia and hyperketonemia have adverse effects on bone. Therefore, it is worth paying more attention to the bone status of patients with hyperglycemia and hyperketonemia in clinic.

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“…Results from a rodent study also supported our analysis to some degree. No significant alteration of osteocalcin on cellular levels was found in mice fed with ketogenic diet . Similarly, human data also suggested that no changes were found in osteocalcin levels in patients receiving ketogenic diet treatment .…”

Section: Discussionmentioning

confidence: 88%

Circulating osteocalcin: A potential predictor of ketosis in type 2 diabetes

Zhu

Lin

Chen

et al. 2020

Diabetes Metabolism Res

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Aims: Osteocalcin contributes to the regulation of endocrine system. However, the association between osteocalcin and ketosis has not been evaluated. We thus aimed to explore the relationship between total osteocalcin and risk of ketosis in type 2 diabetes (T2DM). Materials and methods:We identified 6157 diabetes patients from Shanghai Tenth People's Hospital between 1 January 2011 and 1 March 2017. Six hundred eight subjects were enrolled in the retrospective cross-sectional study: 304 T2DM patients with ketosis whose age, gender, and body mass index were matched with 304 T2DM patients without ketosis. A further retrospective nested case-control study was conducted in 252 T2DM patients without ketosis for a mean duration of 21.58 ± 12.43 months to investigate the occurrence of ketosis. Results: Osteocalcin levels were negatively correlated with blood ketones (adjusted r = −0.263) and urine ketones (adjusted r = −0.183). The inverse dose-dependent relationship of osteocalcin and risk of ketosis was present across osteocalcin level quintiles (top quintile as the reference, adjusted odds ratio [95% CI] = 2.56 [0.80-8.17], 3.71 [0.90-15.29], 10.77 [2.63-44.15], 23.81 [4.32-131.17] per osteocalcin quintile, respectively). Ketosis occurred in 17 of the 252 T2DM patients during follow-up. The Cox regression analysis indicated that osteocalcin was an independent protective factor against development of ketosis (adjusted hazard ratio [95% CI]: 0.668 [0.460-0.971]). Conclusions: Total osteocalcin can be used as a predictor of ketosis in T2DM. K E Y W O R D S ketosis, total osteocalcin, type 2 diabetes Bing Zhu and Ziwei Lin contributed equally as co-first authors.

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Ketogenic Diet Compromises Both Cancellous and Cortical Bone Mass in Mice

Cited by 31 publications

References 39 publications

Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats

Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats

The Hyperglycemia and Hyperketonemia Impaired Bone Microstructures: A Pilot Study in Rats

Circulating osteocalcin: A potential predictor of ketosis in type 2 diabetes

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