Abstract
Purpose of Review
Bone quality and strength are diminished with age and disease but can be improved by clinical intervention. Energetic pathways are essential for cellular function and drive osteogenic signaling within bone cells. Altered bone quality is associated with changes in the energetic activity of bone cells following diet-based or therapeutic interventions. Energetic pathways may directly or indirectly contribute to changes in bone quality. The goal of this review is to highlight tissue-level and bioenergetic changes in bone health and disease.
Recent Findings
Bone cell energetics are an expanding field of research. Early literature primarily focused on defining energetic activation throughout the lifespan of bone cells. Recent studies have begun to connect bone energetic activity to health and disease. In this review, we highlight bone cell energetic demands, the effect of substrate availability on bone quality, altered bioenergetics associated with disease treatment and development, and additional biological factors influencing bone cell energetics.
Summary
Bone cells use several energetic pathways during differentiation and maturity. The orchestration of bioenergetic pathways is critical for healthy cell function. Systemic changes in substrate availability alter bone quality, potentially due to the direct effects of altered bone cell bioenergetic activity. Bone cell bioenergetics may also contribute directly to the development and treatment of skeletal diseases. Understanding the role of energetic pathways in the cellular response to disease will improve patient treatment.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Cellular mechanisms such as collagen deposition, mineralization, and bone resorption rely on cellular energy to effectively produce changes in bone quality. Examinations of bone quality often focus on altered bone composition and morphology, neglecting the bioenergetic pathways necessary for tissue-level changes. Mammalian cells generate reservoirs of energy in the form of adenosine 5’-triphosphate (ATP) via several pathways. Glycolysis produces two units of ATP per glucose input and can take place anywhere in the cytosol of the cell. Oxidative phosphorylation is more energy efficient and produces 32 ATP molecules per input glucose; however, the bioenergetic advantage of this pathway is limited due to the reliance on oxygen availability, confinement to the mitochondria, and extended length of time required for ATP generation. Converted glucose molecules are the primary oxidative input in most cells, but mitochondrial respiration can also be fueled by fatty acids and amino acids [1] (Fig. 1).
Cells derive energy from glucose, fatty acids, and amino acids such as glutamine
Across all cell types, energetic pathways can both activate or be activated by other biological processes. Glycolysis initiates downstream signaling pathways, such as Wnt signaling [2]. Oxidative phosphorylation produces reactive oxygen species, which have established roles in inducing DNA damage and cell death but can also act as signaling molecules through various pathways such as differentiation, proliferation, and antioxidant production [3, 4]. The extent of glycolytic and oxidative activity within cells also are altered by numerous upstream signaling pathways. Energetic pathway activity is critical for healthy bone cell function, influencing bone remodeling activities and regulating organ-level bone quality. Many bone diseases and their treatments can alter bioenergetic activity within bone cells, highlighting the complex interactions between osteogenic signaling and energetic pathways.
Bone Cell Energetic Demands
Osteoclasts, osteoblasts, and osteocytes each play unique roles in bone growth, maintenance, and repair. The energetic pathways supporting bone cell function remain underexplored. Osteoclasts participate in bone remodeling by resorbing mineralized tissue, and the release of minerals during this process contributes to whole-body calcium homeostasis [5]. During osteoclast differentiation, cells produce more energy via oxidative phosphorylation compared to glycolysis, but both energetic pathways are necessary [6,7,8]. Disruption of mitochondrial function during differentiation negatively affected osteoclasts; inhibition of Mfn2, a gene encoding mitochondrial outer membrane protein Mitofusin 2, decreased osteoclast number [9] and global deletion of mitochondrial complex I decreased osteoclast differentiation and subsequent resorption [10].
Osteoclastic resorptive activities rely on the influx of glucose as the primary substrate, and lactate or pyruvate supplementation can support resorptive activities in the absence of glycolysis [11]. Although serum-level fatty acid oxidation was associated with systemic bone resorption marker CTX [12], fatty acids and amino acids have relatively small contributions to the bioenergetic programs driving resorption [13]. Compared to progenitors, mature osteoclasts have diminished glycolytic efficiency and elevated intracellular ATP [14]; however, inhibition of glycolysis prevented resorptive activity [11]. Both osteoclastogenesis and resorption were suppressed in mouse models lacking Pdk2 [7], a positive regulator of aerobic glycolysis. Osteoclasts have more abundant mitochondria compared to most other cell types [15, 16], yet the resorptive process relies on both oxidative phosphorylation [9] and glycolysis [11, 13, 14].
Osteoblasts, cells that deposit mineralized matrix that forms bone tissue, differentiate from mesenchymal stromal cells. As osteoblastic differentiation progresses, oxidative phosphorylation and glycolysis are elevated simultaneously [17,18,19, 20•, 21•]. Mitochondrial size [18, 22], volume [18, 22], and number [17] increase over the course of osteoblastic differentiation. Despite osteoblastic reliance on increased oxidative phosphorylation during differentiation [23], mature osteoblasts use both oxidative phosphorylation and glycolysis [17, 19, 21•, 22, 24]. Compared to progenitors, mature osteoblasts generate a greater portion of ATP via glycolysis over oxidative phosphorylation [19, 21•, 25••, 26]. Although osteoblastic oxidative phosphorylation is likely primarily fueled by pyruvate [25••], amino acid consumption also plays a role. Reduction in amino acids via inhibition of Eif2ak4 led to decreased proliferation of precursors, diminishing osteoblast function in vivo [27]. Inhibition of Slc7a, an amino acid transporter responsible for rapid increases in glutamine, reduced Wnt signaling-induced osteoblast differentiation [28]. Systemic bone formation marker P1NP was associated with metabolic activity related to the TCA cycle and pyruvate metabolism in healthy adults [12].
Bioenergetic programs affect downstream signaling in osteoblasts and their precursors; glucose availability is required for Runx2-mediated osteoblastic differentiation and deposition of collagen by osteoblasts [29]. Wnt signaling, a canonical pathway associated with bone formation, has differential effects on osteoblasts and their precursors; Wnt signaling stimulates glutamine catabolism through the TCA cycle in osteoblastic precursors [30] but increases aerobic glycolysis in mature osteoblasts [31]. Downstream effects of Wnt-Lrp5 signaling influence whole-body fatty acid levels [32]. Mitochondria may be enhanced by Wnt signaling; Wnt3a treatment increases mitochondrial biogenesis in osteoblasts and their progenitors [33]. Molecules in the Wnt signaling pathway may serve as promising targets for future therapeutics to treat bone disease [34], but the connection between Wnt and bioenergetic function highlights a new set of pharmaceutical opportunities.
As osteoblasts deposit new bone, they can further differentiate into bone resident cells, osteocytes. Early studies reported that osteocytes have fewer mitochondria than osteoblasts, suggesting an energetic shift from oxidative phosphorylation to glycolysis [15]. However, more recent evidence indicates that mitochondrial respiration is greater in osteocytes compared to osteoblasts [20•, 35]. Mitochondrial number within osteocytes varies within cortical bone tissue as a function of cell distance from the bone surface, suggesting spatial differences in bioenergetic activity [35, 36]. Mitochondria can be transferred between osteocytes in response to metabolic stress [37]. Osteocyte signaling can control the bone remodeling unit, affecting both bone resorption and formation [38]. Energetic pathways affect osteocyte signaling, and osteocytic production of RANKL and osteocalcin is dependent on glucose uptake by Glut1 [39].
Biological Factors Influencing Bone Metabolism
Aging
Osteogenic metabolism reflects the unique aspects of bone and varies across health conditions and between sexes. Within many organ systems, aging is associated with increased mitochondrial dysfunction and accumulation of mitochondrial DNA (mtDNA) mutations. In bone, mitochondria become more porous with age and produce reactive oxygen species [40]. Age-related mitochondrial swelling has been recorded in osteocytes but not osteoblasts [41]. Murine models containing genetic modifications that increase the rate of mtDNA mutations are associated with early-onset osteoporosis following the accumulation of peak bone mass [42].
The reliance on glycolysis or oxidative phosphorylation likely shifts with age. Whole bone metabolites were altered with age; compared to young animals, older mice have elevated glycolytic intermediates but similar TCA cycle metabolites, suggesting dysfunctional mitochondrial activity that is compensated for with glycolysis [41]. Old animals also had reduced energy demand compared to young animals [41, 43]. The number of mitochondria located in osteocytic dendrites decreased with age [37]. Bone research pursuing age as a variable should consider the age-related differences in bioenergetic function.
Sex
Bioenergetic profiles in bone likely differ by sex; in skeletally mature mice, the bones of males had greater metabolites associated with amino acid metabolism (cysteine, methionine, arginine, proline), glycolysis, and TCA cycle whereas lipid metabolism and fatty acid biosynthesis were upregulated in females [44•]. Clinically, energetic fuel can be altered by diet; patients may be advised to reduce caloric intake to improve overall health. However, following weight loss in obese patients, bone mineral density increased in males but decreased in females [45], suggesting sex-dependent effects on bone quality.
Mechanical Stimuli
The beneficial effects of mechanical loading are dependent on age and sex. In men, mechanical loading enhances bone morphology throughout life [46] whereas load-induced improvements in bone quality occur in women pre-menopause [47,48,49], but female mechanoresponsiveness is reduced with age [50, 51]. In murine loading models, bioenergetic pathways are transcriptionally activated in whole bone samples [52, 53] and vary spatially across the cortex [54]. Load-induced metabolic changes also were altered with age. Old female mice had reduced metabolic transcriptional activity following mechanical loading compared to younger animals [52]. Mesenchymal stromal cells isolated from adult rats produced more reactive oxygen species following loading compared to younger animals [55].
Diminished gravitational loading via spaceflight reduces bone quality. In mesenchymal stromal cells, decreases in osteogenic differentiation and oxygen consumption rate induced by simulated microgravity were recovered with upregulation of Sirt1 [56], a molecule that protects against oxidative stress, highlighting the connection between oxidative phosphorylation and mechanical loading. The greatest transcriptional changes in osteocyte-like cells exposed to microgravity via spaceflight or the ISS included activation of bioenergetic pathways and upregulated glycolytic genes [57•], suggesting that mechanical loading is an essential regulator of energetic pathways. The direct effects of load-induced changes in bioenergetic function on bone quality warrant further investigation.
Tissue Envelope: Cortical and Cancellous Bone
Bone can be classified as distinct tissue types; cortical and cancellous bone have different morphological structures and unique transcriptional profiles [58]. The bioenergetic profiles of each tissue envelope also may differ; cortical bone is presumed to have more variability in oxygen and glucose availability across the cortex due to its compact structure compared to cancellous bone. The increased surface area of cancellous bone likely facilitates more frequent nutrient acquisition. Therapeutic inhibition of glycolysis improved cortical bone architecture and increased bone strength in both young and adult male mice, but had limited effects on cancellous bone in young animals [59]. In this study, glycolytic inhibition prevented further trabecular bone loss in aged animals. Cortical and cancellous bone may employ unique bioenergetic programs that facilitate the different responses to aging and therapeutic or external stimuli.
Substrate Availability Affects Bone Quality
Activation of energetic pathways by bone cells is dependent on substrate availability. Changes in substrate availability are linked to altered bone quality, which may be a downstream effect of bone cell bioenergetic activity (Fig. 2). Compared to other organs in the body, bone takes up a large proportion of glucose [43, 60], highlighting the role of bone in global energy metabolism. Both preclinical and clinical examinations of bone quality should take past dieting patterns and therapeutic manipulation of substrate availability into account.
Altered bone cell energetics are associated with changes in bone quality. Substrate availability influences the metabolic capabilities of cells; altered bone cell energetics may account for differences in bone morphology following changes in available glucose. Bone cell energetic activity also may play a role in the reduced bone quality of osteoporotic patients. Created with Biorender.com
If an excess of glucose is available within the body, in cases like obesity or diabetes, bone quality is diminished [61, 62]. In high-fat diet-fed mice, cancellous bone morphology is negatively altered; bone volume fraction was decreased, trabecular number reduced, and trabecular spacing increased [63,64,65,66,67]. Cortical bone quality also was reduced following induction of obesity, with fewer morphological changes than cancellous bone [65,66,67]. The reduced bone quality following obesity is related to the cellular activities within bone. High glucose availability can lead to mitochondrial dysfunction and altered activation of oxidative phosphorylation in some cell types [68] and may have similar effects in bone cells. Following high glucose culture conditions, the ability of osteoblast-like MC3T3 cells to mineralize during differentiation was diminished [69•]. Bone marrow mesenchymal stromal cells cultured in high glucose media had reduced cell viability and osteogenesis compared to cells cultured in normal glucose conditions [70•].
Glucose can be restricted by dietary intake or therapeutic intervention. If calories are restricted, available glucose within the body is diminished. Patients with anorexia nervosa have diminished bone quality and increased fracture risk [71,72,73]. Caloric restriction in humans is associated with decreased bone mineral density [74, 75]. Following caloric restriction in the mouse, bone quality is diminished in the cortical envelope [76,77,78,79,80]. The effect of calorie restriction on cancellous bone is less clear; some studies report that cancellous bone is negatively affected by caloric restriction [76, 77] whereas other researchers report improved cancellous bone morphology [78,79,80]. Caloric restriction also leads to increased adipogenesis in bone marrow stromal cells [76].
Canagliflozin, a therapeutic used to treat patients with type 2 diabetes mellitus and cardiovascular disease [81, 82], reduces available glucose by inhibiting SGLT2, the transporter responsible for the reabsorption of glucose from urine. Although glycemic control and cardiovascular health improve with canagliflozin treatment, SGLT2 inhibitors are associated with greater fracture risk [83], despite the lack of Sglt2 expression in bone tissue. In mouse models, lifelong loss-of-function of Sglt2 reduced bone mineralization with no significant changes to bone strength [84]. Long-term treatment with canagliflozin reduced cancellous bone quality in non-diabetic mice [85]. The negative effects associated with SGLT2 inhibition in bone are most likely due to the systemic decrease in available glucose following canagliflozin treatment.
Bone Cell Energetic Changes in Disease Progression and Treatment
Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is a disease directly related to the regulation and processing of glucose. Patients diagnosed with T2DM are initially insulin resistant but ultimately produce insufficient amounts of insulin, a hormone regulating cellular sugar intake, resulting in excess circulating glucose. In addition to challenges with glycemic control, diabetic patients have increased fracture risk, highlighting the connection between T2DM and bone [62]. Hyperglycemia and T2DM lead to the accumulation of advanced glycation endproducts (AGE’s), which are associated with decreased bone quality. In mouse models, diabetes may be induced with high-fat diet feeding or drugs. Therapeutic initiation of T2DM reduced both cortical and cancellous bone quality, resulting in diminished bone strength [85, 86].
Bone cells are directly affected by diabetes. Insulin signaling in osteoblasts leads to osteocalcin expression that in turn upregulates glucose metabolism [87]. Tissue composition is altered in T2DM patients, with increased AGE’s and greater mineral content compared to non-diabetic controls [88]. Following AGE accumulation, mitochondrial oxidative metabolism is reduced and reactive oxygen species accumulate [22]. Mesenchymal stromal cell viability and differentiation potential were reduced following treatment with AGE’s [89]. Further, osteocyte apoptosis has been associated with AGE accumulation [90].
Therapeutic treatment of T2DM improves glycemic control for patients and affects bone quality. Metformin treatment is associated with reduced fracture risk in humans [91, 92]. Alternatively, treatment with thiazolidinediones reduced bone mineral content, bone formation, and trabecular bone volume [92, 93]. Metformin and thiazolidinedione treatments may have direct or indirect effects on bone quality through their regulation of energetic pathways; both therapeutics reduce oxidative phosphorylation [94, 95] but in a dual, independent manner, metformin also may reduce oxidative stress and mitochondrial-mediated apoptosis [94]. Given the effects of diabetes and therapeutic treatment on bone cell energetics, evaluation of patients’ diabetic history and pharmaceutical usage is critical when evaluating the current and potential future bone quality.
Fracture Healing
Following bone fracture, the healing cascade includes an early influx of immune cells. The increase in total cell number within the fracture space decreases available oxygen, causing cells to shift towards glycolytic metabolism [96]. The increase in lactate production produces signaling cascades that attract mesenchymal stromal cells, increase extracellular matrix synthesis, and enhance angiogenesis. The revascularization following fracture enables the delivery of more oxygen and therefore enhanced oxidative phosphorylation, which initiates stromal cell differentiation [96]. Protection of mitochondria via inhibition of the mitochondrial permeability transition pore improves fracture repair, highlighting the important role of bioenergetic processes [97]. The coordinated cascade of healing during fracture healing relies on the efficient bioenergetic function of immune and osteogenic cells.
Local delivery of bone morphogenic protein-2 (BMP-2) to the fracture site is clinically used to promote fracture healing. BMP-2 induces SMAD signaling, and initiates cartilage and bone formation. Following BMP-2 treatment, markers of glycolysis and the TCA cycle are increased in bone areas that are Alp+, suggesting increased energetic activity by osteoblasts [98]. BMP-2 signaling in the pancreas and adipose tissue similarly alters cellular energetics [99]. Therefore, BMP-2 may directly or indirectly alter the bioenergetic function of osteoblasts to improve fracture healing.
Osteoporosis
Osteoporosis is a disease of low bone mass that leads to an increased risk of fracture [100,101,102,103]. Morbidity and mortality are positively correlated with the incidence of osteoporotic fracture [104]. In addition to reduced bone quality, osteoporosis may be associated with altered bioenergetic function of bone cells. Low bone mass at the spine is associated with activation of both fatty acid oxidation and glycolysis in patient plasma [105•], but further investigation is required to determine if systemic bioenergetic changes are linked directly to bone cell activity (Fig. 2). Osteoporosis disproportionally affects postmenopausal women, due to reduced estrogen signaling [103, 106]. The anabolic effects of estrogen could be partially attributed to altered bioenergetic programs of osteoclasts; mitochondrial function was reduced during osteoclast differentiation following in vitro estrogen delivery [107•]. Reactive oxygen species are increased following the decline of estrogen and negatively impact the survival and differentiation of osteogenic progenitor cells [108]. In mice, osteoporosis can be modeled with ovariectomy surgery. Following ovariectomy, TNF-α production increased in mesenchymal stromal cells [109]. MicroRNA-705 expression was increased downstream of TNF-α, eventually leading to heightened reactive oxygen species accumulation [109].
Clinical treatment of osteoporosis has been associated with enhanced bone cell energetics, which may play a role in the improvement of bone quality (Fig. 3). Several osteoporotic therapeutic interventions target osteoclasts to reduce bone resorption. Denosumab is a monoclonal antibody that inhibits bone resorption by reducing RANKL-mediated signaling between osteoclasts and osteoblasts. Patients treated with denosumab have increased bone mineral density and reduced fracture risk [110]. Transcriptional analyses of skeletal tissue revealed that in both osteoclasts and bone marrow plasma, denosumab treatment reduced DPP4 expression, a gene whose protein product is involved in systemic glucose homeostasis [111••]. Although denosumab-treated patients also had decreased circulating DPP4, their glucose levels were similar to the control group. Further studies will be required to determine the potential contributions of altered bone cell energetics to the clinical success of denosumab.
Bone cell energetics likely play a key role in the development and treatment of osteoporosis. Created with Biorender.com
Anabolic, bone-forming therapeutics for osteoporosis treatment are limited. Parathyroid hormone increases both cortical and cancellous bone in patients by stimulating the bone remodeling unit [112]. In bone, both aerobic glycolysis and glutamine uptake increase with PTH treatment [113, 114•]. Further supporting the glycolytic effects of PTH, the mitochondrial membrane potential in osteoblasts is diminished following PTH treatment [115]. Overall, energetic output of osteocytes may be improved with PTH; respiration and glucose utilization increased in PTH-treated osteocyte-like OCY454 cells [116].
Resveratrol, a dietary supplement with some evidence for improving bone health [117], is an antioxidant that upregulates Sirt1 to improve mitochondrial activity [118]. Haplo-insufficient Sirt1 female mice have reduced bone mass and decreased bone formation [119]. In situ delivery of resveratrol increased Sirt1 expression and improved bone morphology in the tibia, following in vivo caloric restriction [76]. In vitro delivery of resveratrol to mesenchymal stromal cells increased osteogenic differentiation and decreased adipogenesis [120]. The energetic changes in bone cells following denosumab, PTH, and resveratrol treatments suggest a direct role of bioenergetic processes in the improvement of bone quality.
Conclusion
Bioenergetic pathways are critical to the maintenance of bone health and the treatment of bone diseases. Substrate availability influences bone quality and should be considered in patient settings; diet history and prescribed medications may influence bone health. Many established therapeutics and osteogenic processes are interconnected with bioenergetic pathways, highlighting the role of energetics in bone. Further, this connection underscores the potential for energetic pathways as therapeutic targets. Future work should examine the potential of bioenergetics as direct therapeutic targets to improve bone quality.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Zhang Q, Riddle RC, Clemens TL. Bone and the regulation of global energy balance. J Intern Med. 2015;277:681–9.
Oginuma M, Moncuquet P, Xiong F, Karoly E, Chal J, Guevorkian K, et al. A gradient of glycolytic activity coordinates FGF and Wnt signaling during elongation of the body axis in amniote embryos. Dev Cell. 2017;40:342–353.e10.
Bai X, Lu D, Liu A, Zhang Z, Li X, Zou Z, et al. Reactive oxygen species stimulates receptor activator of NF-κB ligand expression in osteoblast. J Biol Chem. 2005;280:17497–506.
Agidigbi TS, Kim C. Reactive oxygen species in osteoclast differentiation and possible pharmaceutical targets of ROS-mediated osteoclast diseases. Int J Mol Sci. 2019;20:3576.
Bilezikian JP, Raisz LG, Martin TJ, editors. Principles of bone biology. 3rd ed. San Diego: Academic Press/Elsevier; 2008.
Li B, Lee W, Song C, Ye L, Abel ED, Long F. Both aerobic glycolysis and mitochondrial respiration are required for osteoclast differentiation. FASEB J. 2020;34:11058–67.
Lee J, Kim M, Lee SJ, Kim B, Choi J, Lee SM, et al. PDK2 deficiency prevents ovariectomy-induced bone loss in mice by regulating the RANKL-NFATc1 pathway during osteoclastogenesis. J Bone Miner Res. 2021;36:553–66.
Ahn H, Lee K, Kim JM, Kwon SH, Lee SH, Lee SY, et al. Accelerated lactate dehydrogenase activity potentiates osteoclastogenesis via NFATc1 signaling. Kim J-E, editor. PLoS ONE. 2016;11:e0153886.
Jung S, Kwon J-O, Kim MK, Song M-K, Kim B, Lee ZH, et al. Mitofusin 2, a mitochondria-ER tethering protein, facilitates osteoclastogenesis by regulating the calcium-calcineurin-NFATc1 axis. Biochem Biophys Res Commun. 2019;516:202–8.
Jin Z, Wei W, Yang M, Du Y, Wan Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab. 2014;20:483–98.
Taubmann J, Krishnacoumar B, Böhm C, Faas M, Müller DIH, Adam S, et al. Metabolic reprogramming of osteoclasts represents a therapeutic target during the treatment of osteoporosis. Sci Rep. 2020;10:21020.
Bellissimo MP, Roberts JL, Jones DP, Liu KH, Taibl KR, Uppal K, et al. Metabolomic associations with serum bone turnover markers. Nutrients. 2020;12:3161.
Williams JP, Blair HC, McDonald JM, McKenna MA, Jordan SE, Williford J, et al. Regulation of osteoclastic bone resorption by glucose. Biochem Biophys Res Commun. 1997;235:646–51.
Lemma S, Sboarina M, Porporato PE, Zini N, Sonveaux P, Di Pompo G, et al. Energy metabolism in osteoclast formation and activity. Int J Biochem Cell Biol. 2016;79:168–80.
Boivin G, Anthoine-Terrier C, Obrant KJ. Transmission electron microscopy of bone tissue: a review. Acta Orthop Scand. 1990;61:170–80.
Baron R. Polarity and Membrane Transport in Osteoclasts. Connect Tissue Res. 1989;20:109–20.
Komarova SV, Ataullakhanov FI, Globus RK. Bioenergetics and mitochondrial transmembrane potential during differentiation of cultured osteoblasts. Am J Physiol-Cell Physiol. 2000;279:C1220–9.
Shum LC, White NS, Mills BN, de Mesy Bentley KL, Eliseev RA. Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Stem Cells Dev. 2016;25:114–22.
Guntur AR, Le PT, Farber CR, Rosen CJ. Bioenergetics during calvarial osteoblast differentiation reflect strain differences in bone mass. Endocrinology. 2014;155:1589–95.
Schilling K, Brown E, Zhang X. NAD(P)H autofluorescence lifetime imaging enables single cell analyses of cellular metabolism of osteoblasts in vitro and in vivo via two-photon microscopy. Bone. 2022;154:116257. This study highlighted a method for noninvasive imaging of cellular energy metabolism. Further, this research provided additional evidence for the dual contributions of glycolysis and oxidative phosphorylation to meet energy demand in osteoblasts.
Misra BB, Jayapalan S, Richards AK, Helderman RCM, Rendina-Ruedy E. Untargeted metabolomics in primary murine bone marrow stromal cells reveals distinct profile throughout osteoblast differentiation. Metabolomics. 2021;17:86. This study provided metabolite profiles for differentiating osteoblasts using untargeted metabolomics.
Zheng C-X, Sui B-D, Qiu X-Y, Hu C-H, Jin Y. Mitochondrial Regulation of Stem Cells in Bone Homeostasis. Trends Mol Med. 2020;26:89–104.
Shares BH, Busch M, White N, Shum L, Eliseev RA. Active mitochondria support osteogenic differentiation by stimulating β-catenin acetylation. J Biol Chem. 2018;293:16019–27.
Riddle RC, Clemens TL. Bone cell bioenergetics and skeletal energy homeostasis. Physiol Rev. 2017;97:667–98.
Lee W-C, Ji X, Nissim I, Long F. Malic enzyme couples mitochondria with aerobic glycolysis in osteoblasts. Cell Rep. 2020;32:108108 This study highlighted the energetic shifts during osteoblast differentiation. Further, this research identified the role of malic enzyme 2 in osteoblast glycolysis.
Ohnishi T, Kusuyama J, Bandow K, Matsuguchi T. Glut1 expression is increased by p53 reduction to switch metabolism to glycolysis during osteoblast differentiation. Biochem J. 2020;477:1795–811.
Hu G, Yu Y, Tang YJ, Wu C, Long F, Karner CM. The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice. J Bone Miner Res. 2020;35:2004–14.
Shen L, Sharma D, Yu Y, Long F, Karner C. Biphasic regulation of glutamine consumption by WNT during osteoblast differentiation. J Cell Sci. 2020:jcs.251645.
Wei J, Shimazu J, Makinistoglu MP, Maurizi A, Kajimura D, Zong H, et al. Glucose uptake and Runx2 synergize to orchestrate osteoblast differentiation and bone formation. Cell. 2015;161:1576–91.
Karner CM, Esen E, Okunade AL, Patterson BW, Long F. Increased glutamine catabolism mediates bone anabolism in response to WNT signaling. J Clin Invest. 2015;125:551–62.
Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. WNT-LRP5 signaling induces warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 2013;17:745–55.
Frey JL, Li Z, Ellis JM, Zhang Q, Farber CR, Aja S, et al. Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Mol Cell Biol. 2015;35:1979–91.
An JH, Yang J-Y, Ahn BY, Cho SW, Jung JY, Cho HY, et al. Enhanced mitochondrial biogenesis contributes to Wnt induced osteoblastic differentiation of C3H10T1/2 cells. Bone. 2010;47:140–50.
Appelman-Dijkstra NM, Papapoulos SE. Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway. Nat Rev Endocrinol. 2018;14:605–23.
Frikha-Benayed D, Basta-Pljakic J, Majeska RJ, Schaffler MB. Regional differences in oxidative metabolism and mitochondrial activity among cortical bone osteocytes. Bone. 2016;90:15–22.
Jande SS. Fine structural study of osteocytes and their surrounding bone matrix with respect to their age in young chicks. J Ultrastruct Res. 1971;37:279–300.
Gao J, Qin A, Liu D, Ruan R, Wang Q, Yuan J, et al. Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network. Sci Adv. 2019;5:eaaw7215.
Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26:229–38.
Takeno A, Kanazawa I, Notsu M, Tanaka K, Sugimoto T. Glucose uptake inhibition decreases expressions of receptor activator of nuclear factor-kappa B ligand (RANKL) and osteocalcin in osteocytic MLO-Y4-A2 cells. Am J Physiol-Endocrinol Metab. 2018;314:E115–23.
Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab. 2010;21:369–74.
Shum LC, White NS, Nadtochiy SM, Bentley KL d M, Brookes PS, Jonason JH, et al. Cyclophilin D Knock-out mice show enhanced resistance to osteoporosis and to metabolic changes observed in aging bone. Dong Y, editor. PLoS ONE. 2016;11:e0155709.
Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417–23.
Zoch ML, Abou DS, Clemens TL, Thorek DLJ, Riddle RC. In vivo radiometric analysis of glucose uptake and distribution in mouse bone. Bone Res. 2016;4:16004.
Welhaven HD, Vahidi G, Walk ST, Bothner B, Martin SA, Heveran CM, et al. The Cortical Bone Metabolome of C57BL / 6J Mice Is Sexually Dimorphic. JBMR Plus. 2022;6(7):e10654 This study characterized the differences in cortical metabolome between male and female mice. Further, the authors correlated bone strength with metabolite levels.
Tirosh A, De Souza RJ, Sacks F, Bray GA, Smith SR, LeBoff MS. Sex differences in the effects of weight loss diets on bone mineral density and body composition: POUNDS LOST trial. J Clin Endocrinol Metab. 2015;100:2463–71.
Whiteford J, Ackland TR, Dhaliwal SS, James AP, Woodhouse JJ, Price R, et al. Effects of a 1-year randomized controlled trial of resistance training on lower limb bone and muscle structure and function in older men. Osteoporos Int. 2010;21:1529–36.
Martyn-St James M, Carroll S. Effects of different impact exercise modalities on bone mineral density in premenopausal women: a meta-analysis. J Bone Miner Metab. 2010;28:251–67.
Winters-Stone KM, Snow CM. Site-specific response of bone to exercise in premenopausal women. Bone. 2006;39:1203–9.
Troy KL, Mancuso ME, Johnson JE, Wu Z, Schnitzer TJ, Butler TA. Bone adaptation in adult women is related to loading dose: a 12-month randomized controlled trial. J Bone Miner Res. 2020;35:1300–12.
Bassey EJ, Rothwell MC, Littlewood JJ, Pye DW. Pre- and postmenopausal women have different bone mineral density responses to the same high-impact exercise. J Bone Miner Res. 1998;13:1805–13.
Sugiyama T, Yamaguchi A, Kawai S. Effects of skeletal loading on bone mass and compensation mechanism in bone: a new insight into the “mechanostat” theory. J Bone Miner Metab. 2002;20:196–200.
Galea GL, Meakin LB, Harris MA, Delisser PJ, Lanyon LE, Harris SE, et al. Old age and the associated impairment of bones’ adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle. Gene. 2017;599:36–52.
Zaman G, Saxon LK, Sunters A, Hilton H, Underhill P, Williams D, et al. Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor α and disuse. Bone. 2010;46:628–42.
Chlebek C, Moore JA, Ross FP, van der Meulen MCH. Molecular identification of spatially distinct anabolic responses to mechanical loading in murine cortical bone. J Bone Miner Res. 2022:jbmr.4686.
Tan J, Xu X, Tong Z, Lin J, Yu Q, Lin Y, et al. Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res. 2015;3:15003.
Liu L, Cheng Y, Wang J, Ding Z, Halim A, Luo Q, et al. Simulated microgravity suppresses osteogenic differentiation of mesenchymal stem cells by inhibiting oxidative phosphorylation. Int J Mol Sci. 2020;21:9747.
Uda Y, Spatz JM, Hussein A, Garcia JH, Lai F, Dedic C, et al. Global transcriptomic analysis of a murine osteocytic cell line subjected to spaceflight. FASEB J. 2021;35:e21578. This study provided targeted transcriptomic analysis demonstrating that mechanical loading drives bioenergetic activation.
Kelly NH, Schimenti JC, Ross FP, van der Meulen MCH. Transcriptional profiling of cortical versus cancellous bone from mechanically-loaded murine tibiae reveals differential gene expression. Bone. 2016;86:22–9.
Hollenberg AM, Smith CO, Shum LC, Awad H, Eliseev RA. Lactate dehydrogenase inhibition with oxamate exerts bone anabolic effect. J Bone Miner Res. 2020;35:2432–43.
Bartelt A, Koehne T, Tödter K, Reimer R, Müller B, Behler-Janbeck F, et al. Quantification of bone fatty acid metabolism and its regulation by adipocyte lipoprotein lipase. Int J Mol Sci. 2017;18:1264.
Ben Tahar S, Garnier J, Eller K, DiMauro N, Piet J, Mehta S, et al. Adolescent obesity incurs adult skeletal deficits in murine induced obesity model. J Orthop Res. 2022:jor.25378.
Hamann C, Kirschner S, Günther K-P, Hofbauer LC. Bone, sweet bone—osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol. 2012;8:297–305.
Cao JJ, Gregoire BR, Gao H. High-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice. Bone. 2009;44:1097–104.
McCabe LR, Irwin R, Tekalur A, Evans C, Schepper JD, Parameswaran N, et al. Exercise prevents high fat diet-induced bone loss, marrow adiposity and dysbiosis in male mice. Bone. 2019;118:20–31.
Tencerova M, Figeac F, Ditzel N, Taipaleenmäki H, Nielsen TK, Kassem M. High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice. J Bone Miner Res. 2018;33:1154–65.
Ross D, Yeh T-H, King S, Mathers J, Rybchyn M, Neist E, et al. Distinct effects of a high fat diet on bone in skeletally mature and developing male C57BL/6J mice. Nutrients. 2021;13:1666.
Scheller EL, Khoury B, Moller KL, Wee NKY, Khandaker S, Kozloff KM, et al. Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss. Front Endocrinol. 2016:7.
Zeng Y, Pan Q, Wang X, Li D, Lin Y, Man F, et al. Impaired mitochondrial fusion and oxidative phosphorylation triggered by high glucose is mediated by Tom22 in endothelial cells. Oxidative Med Cell Longev. 2019;2019:1–23.
Medeiros C, Wallace JM. High glucose-induced inhibition of osteoblast like MC3T3-E1 differentiation promotes mitochondrial perturbations. Kim J-E, editor. PLoS ONE. 2022;17:e0270001 This study modeled hyperglycemia in vitro and subsequently assessed both osteoblast differentiation and mitochondrial function, thus investigating a connection between bone disease and energetic function.
Aswamenakul K, Klabklai P, Pannengpetch S, Tawonsawatruk T, Isarankura-Na-Ayudhya C, Roytrakul S, et al. Proteomic study of in vitro osteogenic differentiation of mesenchymal stem cells in high glucose condition. Mol Biol Rep. 2020;47:7505–16 This study established the reduction in mesenchymal stromal cell viability following culture under high glucose conditions.
Lucas AR, Melton LJ, Crowson CS, O’Fallon WM. Long-term fracture risk among women with anorexia nervosa: a population-based cohort study. Mayo Clin Proc. 1999;74:972–7.
Bredella MA, Misra M, Miller KK, Madisch I, Sarwar A, Cheung A, et al. Distal radius in adolescent girls with anorexia nervosa: trabecular structure analysis with high-resolution flat-panel volume CT. Radiology. 2008;249:938–46.
Biller BMK, Saxe V, Herzog DB, Rosenthal DI, Holzman S, Klibanski A. Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab. 1989;68:548–54.
Villareal DT. Bone mineral density response to caloric restriction–induced weight loss or exercise-induced weight loss: a randomized controlled trial. Arch Intern Med. 2006;166:2502.
Villareal DT, Fontana L, Das SK, Redman L, Smith SR, Saltzman E, et al. Effect of two-year caloric restriction on bone metabolism and bone mineral density in non-obese younger adults: a randomized clinical trial. J Bone Miner Res. 2016;31:40–51.
Louvet L, Leterme D, Delplace S, Miellot F, Marchandise P, Gauthier V, et al. Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency. Bone. 2020;136:115361.
Devlin MJ, Cloutier AM, Thomas NA, Panus DA, Lotinun S, Pinz I, et al. Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. J Bone Miner Res. 2010;25:2078–88.
Hamrick MW, Ding K-H, Ponnala S, Ferrari SL, Isales CM. Caloric restriction decreases cortical bone mass but spares trabecular bone in the mouse skeleton: implications for the regulation of bone mass by body weight. J Bone Miner Res. 2008;23:870–8.
Devlin MJ, Brooks DJ, Conlon C, van Vliet M, Louis L, Rosen CJ, et al. Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice. J Endocrinol. 2016;229:295–306.
Maridas DE, Rendina-Ruedy E, Helderman RC, DeMambro VE, Brooks D, Guntur AR, et al. Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton. FASEB J. 2019;33:2885–98.
Yale J-F, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463–73.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.
Zhou Z, Jardine M, Perkovic V, Matthews DR, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia. 2019;62:1854–67.
Thrailkill KM, Bunn RC, Uppuganti S, Ray P, Garrett K, Popescu I, et al. Genetic ablation of SGLT2 function in mice impairs tissue mineral density but does not affect fracture resistance of bone. Bone. 2020;133:115254.
Thrailkill KM, Clay Bunn R, Nyman JS, Rettiganti MR, Cockrell GE, Wahl EC, et al. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice. Bone. 2016;82:101–7.
Thrailkill KM, Nyman JS, Bunn RC, Uppuganti S, Thompson KL, Lumpkin CK, et al. The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes. Bone. 2017;94:141–51.
Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142:296–308.
Hunt HB, Miller NA, Hemmerling KJ, Koga M, Lopez KA, Taylor EA, et al. Bone tissue composition in postmenopausal women varies with glycemic control from normal glucose tolerance to type 2 diabetes mellitus. J Bone Miner Res. 2021;36:334–46.
Kume S, Kato S, Yamagishi S, Inagaki Y, Ueda S, Arima N, et al. Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res. 2005;20:1647–58.
Tanaka K, Yamaguchi T, Kanazawa I, Sugimoto T. Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun. 2015;461:193–9.
Salari-Moghaddam A, Sadeghi O, Keshteli AH, Larijani B, Esmaillzadeh A. Metformin use and risk of fracture: a systematic review and meta-analysis of observational studies. Osteoporos Int. 2019;30:1167–73.
Hidayat K, Du X, Wu M, Shi B. The use of metformin, insulin, sulphonylureas, and thiazolidinediones and the risk of fracture: Systematic review and meta-analysis of observational studies. Obes Rev. 2019;20:1494–503.
Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology. 2007;148:2669–80.
Vial G, Detaille D, Guigas B. Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol. 2019;10:294.
Divakaruni AS, Wiley SE, Rogers GW, Andreyev AY, Petrosyan S, Loviscach M, et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc Natl Acad Sci. 2013;110:5422–7.
Loeffler J, Duda GN, Sass FA, Dienelt A. The metabolic microenvironment steers bone tissue regeneration. Trends Endocrinol Metab. 2018;29:99–110.
Shares BH, Smith CO, Sheu T-J, Sautchuk R, Schilling K, Shum LC, et al. Inhibition of the mitochondrial permeability transition improves bone fracture repair. Bone. 2020;137:115391.
Lin S, Yin S, Shi J, Yang G, Wen X, Zhang W, et al. Orchestration of energy metabolism and osteogenesis by Mg2+ facilitates low-dose BMP-2-driven regeneration. Bioact Mater. 2022;18:116–27.
Grgurevic L, Christensen GL, Schulz TJ, Vukicevic S. Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism. Cytokine Growth Factor Rev. 2016;27:105–18.
Bell GH, Dunbar O, Beck JS, Gibb A. Variations in strength of vertebrae with age and their relation to osteoporosis. Calcif Tissue Res. 1967;1:75–86.
Yeh P-S, Lee Y-W, Chang W-H, Wang W, Wang J-L, Liu S-H, et al. Biomechanical and tomographic differences in the microarchitecture and strength of trabecular and cortical bone in the early stage of male osteoporosis. Wallace JM, editor. PLoS ONE. 2019;14:e0219718.
Vilayphiou N, Boutroy S, Sornay-Rendu E, Van Rietbergen B, Chapurlat R. Age-related changes in bone strength from HR-pQCT derived microarchitectural parameters with an emphasis on the role of cortical porosity. Bone. 2016;83:233–40.
Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton LJ. Trends in fracture incidence: a population-based study over 20 years: FRACTURE TRENDS. J Bone Miner Res. 2014;29:581–9.
Bliuc D, Nguyen TV, Eisman JA, Center JR. The impact of nonhip nonvertebral fractures in elderly women and men. J Clin Endocrinol Metab. 2014;99:415–23.
Bellissimo MP, Ziegler TR, Jones DP, Liu KH, Fernandes J, Roberts JL, et al. Plasma high-resolution metabolomics identifies linoleic acid and linked metabolic pathways associated with bone mineral density. Clin Nutr. 2021;40:467–75 This study used human data to examine correlations between plasma metabolites and bone mineral density at clinically relevant skeletal sites.
Melton LJ, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective how many women have osteoporosis? J Bone Miner Res. 2009;7:1005–10.
Kim H-N, Ponte F, Nookaew I, Ucer Ozgurel S, Marques-Carvalho A, Iyer S, et al. Estrogens decrease osteoclast number by attenuating mitochondria oxidative phosphorylation and ATP production in early osteoclast precursors. Sci Rep. 2020;10:11933. This study investigated the mechanism linking estrogen deficiency, osteoclast differentiation, and bioenergetic activation.
Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285–97.
Liao L, Su X, Yang X, Hu C, Li B, Lv Y, et al. TNF-α inhibits FoxO1 by upregulating miR-705 to aggravate oxidative damage in bone marrow-derived mesenchymal stem cells during osteoporosis. Stem Cells. 2016;34:1054–67.
Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–65.
Weivoda MM, Chew CK, Monroe DG, Farr JN, Atkinson EJ, Geske JR, et al. Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism. Nat Commun. 2020;11:87 This study used human samples and identified DPP4 as an osteoclast-derived coupling factor, thus highlighting the potential for osteoporosis therapies to affect bioenergetic activation within bone cells.
Rubin MR, Bilezikian JP. The anabolic effects of parathyroid hormone therapy. Clin Geriatr Med. 2003;19:415–32.
Esen E, Lee S-Y, Wice BM, Long F. PTH promotes bone anabolism by stimulating aerobic glycolysis via IGF signaling. J Bone Miner Res. 2015;30:1959–68.
Stegen S, Devignes C, Torrekens S, Van Looveren R, Carmeliet P, Carmeliet G. Glutamine metabolism in osteoprogenitors is required for bone mass accrual and PTH -induced bone anabolism in male mice. J Bone Miner Res. 2021;36:604–16 This study provided evidence connecting PTH to glutamine metabolism in osteoblasts, highlighting a connection between osteoporosis therapy and bone cell metabolism.
Troyan MB, Gilman VR, Gay CV. Mitochondrial membrane potential changes in osteoblasts treated with parathyroid hormone and estradiol. Exp Cell Res. 1997;233:274–80.
Sun N, Uda Y, Azab E, Kochen A, Santos RNCE, Shi C, et al. Effects of histone deacetylase inhibitor Scriptaid and parathyroid hormone on osteocyte functions and metabolism. J Biol Chem. 2019;294:9722–33.
Wong RH, Thaung Zaw JJ, Xian CJ, Howe PR. Regular supplementation with resveratrol improves bone mineral density in postmenopausal women: a randomized, placebo-controlled trial. J Bone Miner Res. 2020;35:2121–31.
Lagouge M, Argmann C, Gerhart-hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1 a. Cell. 2006;127:1109–22.
Cohen-Kfir E, Artsi H, Levin A, Abramowitz E, Bajayo A, Gurt I, et al. Sirt1 is a regulator of bone mass and a repressor of sost encoding for sclerostin, a bone formation inhibitor. Endocrinology. 2011;152:4514–24.
Tseng P-C, Hou S-M, Chen R-J, Peng H-W, Hsieh C-F, Kuo M-L, et al. Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. J Bone Miner Res. 2011;26:2552–63.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing Interest
The authors did not receive support from any organization for the submitted work.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Biomechanics
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Chlebek, C., Rosen, C.J. The Role of Bone Cell Energetics in Altering Bone Quality and Strength in Health and Disease. Curr Osteoporos Rep 21, 1–10 (2023). https://doi.org/10.1007/s11914-022-00763-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11914-022-00763-6