Exercise-Dependent Modulation of Bone Metabolism and Bone Endocrine Function: New Findings and Therapeutic Perspectives
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Physical inactivity is the fourth leading cause of mortality worldwide; regardless of geographic location and income, it is a contributing risk factor to the other three causes. Physical activity is really a drug, a poly-pill; its “regular use” can reduce this risk throughout the activation of a plethora of responses in virtually all the body tissues. The beneficial effects of physical activity on cardiovascular function and hemodynamics are mainly mediated by skeletal muscle, adipose tissue and the immune system via the usage, delivery and distribution of metabolic substrates and improvement in inflammatory status. There is emerging evidence for exercise-dependent changes in bone metabolism as well; with improved bone quality, reduced fracture risk and increased bone endocrine function, the last of which modulates energy metabolism through its effects on pancreatic islet cells, skeletal muscle and adipose tissue. Bone endocrine function relies on the integration of biomechanical stimuli and endocrine signals from other organs and tissues. Here I review current concepts about exercise-dependent modulation of bone endocrine function and its beneficial effects on whole-body metabolism. Several molecular mechanisms have been identified that support this exercise-stimulated bone-mediated metabolic effect and, among these, Wnt signaling, fibroblast growth factor-23, bone morphogenic protein-7, osteocalcin, RANK/RANKL/OPG axis, and lipocalin-2 gave the largest evidences. In conclusion, beside the controversies surrounding technical aspects of the exercise, the efficacy of physical activity in preventing/treating metabolic and inflammatory dysfunctions also passes throughout the bone.
KeywordsBone metabolism Bone endocrine function Osteokines Biomechanical loading
Physical inactivity is the fourth most frequent cause of mortality worldwide, regardless of geographic location and income, according to the World Health Organization . Regular physical activity is independently associated with a reduced risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, cancer incidence in general and specifically for certain tumors (e.g., colorectal, lung, breast, prostate, ovarian, endometrial, and esophageal). Conversely, physical inactivity is directly linked to the incidence of T2DM (27%), ischemic heart disease (30%), and breast and colon cancer (21–25%). In addition, physical inactivity increases the severity of other risk factors (e.g., hypertension, elevated glycemia levels and body mass) [29, 70].
From a classical perspective, the beneficial effects of regular physical activity on cardiovascular function and hemodynamics are mainly mediated by skeletal muscle, adipose tissue and the immune system via the usage, distribution, and delivery of metabolic substrates. Besides improving chronic low-grade inflammation, the exercise-dependent changes in bone metabolism improve bone quality and reduce fracture risk (an independent factor risk for mortality) through muscle traction and biomechanical load; and these changes also modulate energy metabolism by affecting the metabolic response of pancreatic islet cells, skeletal muscle, and adipose tissue . In brief, bone endocrine function relies on the integration of biomechanical stimuli and the plethora of endocrine signals from other organs and tissues . This review summarizes current concepts on exercise-dependent modulation of bone endocrine function and describes how these effects benefit whole-body metabolism.
Bone Metabolism and Endocrine Functions of Bone
In order to carry out its functions (structural/locomotive, dynamic storage of calcium and phosphate, hematopoiesis), bone must adapt to endogenous (mainly hormonal and inflammatory) and exogenous (biomechanical load, diet, vitamin D) stimuli. This adaptation is the net result of two counteracting but closely co-regulated processes (i.e., bone turnover) that make the bone a highly dynamic tissue; resorption carried out by monocyte-derived osteoclasts and formation by mesenchymal-derived osteoblasts. A third cell population residing within the bone, the osteocytes, result from further differentiation of osteoblasts and are involved in biomechanical response to load and regulation of turnover . Remodeling takes place constantly and involves 5% of cortical and 25% of trabecular adult bone each year. It can be easily monitored by measuring specific biochemical markers (bone turnover markers) in serum/plasma and urine, i.e., enzymes (e.g., bone alkaline phosphatase-BAP, tartrate-resistant acid phosphatase-TRAP5b, cathepsin K), proteins (e.g., osteocalcin, bone sialoproteins, osteopontin), protein fragments (e.g., N- and C-terminal type 1 collagen crosslaps-NTx and CTx, pyridinoline, deoxypyridinoline) or protein precursors (e.g., N- and C-terminal type 1 procollagen pro-peptides-PINP and PICP). Long-term modification of bone metabolic activity can alter bone architecture (cortical vs. trabecular content), mineral density (BMD) and mineral content (BMC), which are measurable with radiological techniques [e.g., dual energy X-ray absorptiometry (DXA)] .
Once thought to be only a target of endocrine activities, the skeleton is an endocrine organ in itself. Bone secretes compounds that trigger responses in the bone and in other tissues. Molecules previously described as bone turnover markers are now recognized as hormones . Evidence supporting this theory comes from the association between metabolic (obesity, metabolic syndrome, T2DM) or gonadal dysfunctions (hypogonadism) and altered bone turnover (osteoporosis, osteopenia)  consequent to the two-way interaction between glucose and bone metabolism . Although this interaction has been demonstrated only in rodents, it has shed new light on mechanisms by which the bone interacts with β-cells, skeletal muscle, adipose tissue, brain, testis, and endothelium .
The endocrine function of bone is not limited to the well-known carboxylated (GlaOC) and uncarboxylated (GluOC) forms of osteocalcin; the osteoblast/osteocyte-derived hormones sclerostin, dickkopf-related protein (DKK)-1, bone morphogenic protein (BMP)-7, and fibroblast growth factor (FGF)-23 act at different levels. Moreover, the ligand of the receptor activator of nuclear factor κB (RANKL), expressed by osteoblasts and lymphocytes, stimulates the proliferation and differentiation of pre-osteoclasts through the activation of its receptor RANK. It is antagonized by the osteoblast-derived osteoprotegerin (OPG), a decoy receptor for RANKL. The RANK/RANKL/OPG osteo-immunological axis is also involved in immune-dependent bone turnover, hematopoiesis, lymphoid organ development and adaptive immune responses .
Mechanical load plays a key role in this complex network of interactions . A mechanically loaded bone signals its need for energy to sustain bone formation and optimize its architecture based on the new environment . On the other hand, an unloaded bone signals a low energy need that promotes resorption (or reduced bone turnover) allowing energy to be preserved for other essential activities .
How Does Exercise Affect Bone Metabolism and Mass?
It is clear that stimulating the bone tissue elicits biological responses. The continuous changes in loading status associated with activities of daily living (including exercise and night rest) result in a continuous modulation of the metabolic activity of bone cells and their endocrine function which in turn has an effect on the homeostatic response of virtually all the body’s organs. Furthermore, the effect of daily activities on the metabolic activity and endocrine function of tissues and organs (e.g., skeletal muscle, immune system, brain) also influences the homeostatic response of the rest of the body, including bone tissue. Hence, in a cyclical manner, bone tissue acts as both a target and an effector of physical activity-dependent metabolic activation .
As stated above, bone adapts its structure to environmental stimuli (i.e., mechanical) to which it is exposed. Accordingly, regular physical activity is associated with improved structural features in mature bones; greater BMD and cross-sectional area which collectively mean stronger bones as observed in gymnasts as compared with non-gymnasts  and in the dominant arm as compared with the non-dominant arm of racquet sports players . The forces generated by exercise (external forces; ground reaction, inertial and internal forces; skeletal muscle) deform the bone tissue slightly producing mechanical strain that is sensed both directly and indirectly by the mechanosensitive osteocytes through the consequent fluid flow within the bony canaliculi . Based on their loading-dependent activation status, osteocytes regulate osteoblast differentiation and activity through the secretion of sclerostin, an inhibitor of the Wnt pathway [36, 68].
Exercise can be beneficial for gaining and maintaining peak BMD during childhood and adolescence . Indeed, in women, 80–90% of peak adult bone mass is accrued by age 16–18, about 50% of which is acquired during the four perimenarche years, with growth maintained through the third decade . Since physical activity is a major factor in bone accrual, it can significantly influence the annual gains in bone mass and density during this period . A major determinant of bone response to exercise is age; the bone of the growing child is particularly sensitive. Additionally, sex, intensity, type, and volume of physical activity are important variables, with bone response being somewhat site-specific .
As documented by moderate-to-strong empirical evidence, improved bone health in all life stages is among the countless benefits of regular physical activity . Like other non-pharmacological interventions, different kinds of exercise affect bone metabolism differently. Specifically, the effects of exercise on bone metabolism depend not only on the type, intensity and volume of the activity but, more importantly, on the load, which is the main determinant of bone strength. Our recent overview of systematic reviews and meta-analyses of studies investigating the effects of exercise on women showed that, in addition to the fact that lifelong physical activity or regular exercise is critically important for improving bone health, different exercise protocols have different effects at different life stages. Indeed, it is currently accepted that adolescents and adults participating in high-volume endurance (i.e. running) and non-weight-bearing activities (i.e. cycling, swimming) have lower BMD than subjects participating in weight-bearing activities (i.e. ball and power sports) or their inactive peers . For instance, the BMD gain per kg of body mass was greater in 7- to 9-year-old female gymnasts than in swimmers (synchronized and speed) and inactive controls .
Professional and also recreational cyclists who train and compete exclusively on a bike, when compared to age-matched runners, experience lower lumbar and whole-body BMD and lumbar BMC and increased prevalence of osteopenia (63% vs. 19%) due to their halved loading history . Although muscle traction is a key stimulus for bone anabolism, an imbalance towards catabolism is expected in high-energy consumption and reduced biomechanical load (e.g., road cycling, swimming). Indeed, in the absence of load, osteocytes express sclerostin, which inhibits osteoblast differentiation and activity, thus favouring osteoclasts [18, 37] and FGF-23 which increase the renal excretion of the phosphorous released by the resorbing bone . The importance of load and the inability of muscular traction alone to sustain bone anabolism depends on Wnt- sclerostin antagonism, as demonstrated in spinal cord-injured rats. The rats displayed increased bone resorption as compared with the sham-operated rats and electrical stimulation of muscles was unable to attenuate it . Moreover, during bed rest, sclerostin and DKK-1 are not affected by resistive or resistive-vibration exercise protocols as are bone turnover markers (e.g. ALP, which is inhibited, and CTx-I, which is induced); which indicates that unloading affects these hormones more than muscular traction does .
The optimal intensity, volume and frequency of exercise to either maximize bone formation during childhood and youth or to slow/reverse age-related bone loss in the elderly have not yet been defined athough a correlation has been ascertained between BMD and intensity and the type of stimulus . Multicomponent training programmes (e.g., weight-bearing/high impact plus resistance training) especially when temporally prolonged, increase BMD at multiple sites in premenopausal and osteoporotic and non-osteoporotic postmenopausal women and in elderly men and women [17, 44]. As a confirmation of this, Duplanty et al. showed that resistance trained distance runners had greater BMD as compared with non-resistance trained runners and untrained controls .
In general, bone formation is more effectively stimulated by high strain rates and high peak forces  and bone mass is influenced more by the applied tension peak  while the bone formation rate depends on the frequency of stimulation . Moreover, intermittent stimulation is more effective than continuous stimulation in increasing bone formation since the latter causes osteocyte desensitization . Our recent overview of systematic reviews and meta-analyses showed that: short bouts of high-impact exercise protocols are the best choice for maximizing bone mass gains during childhood and early puberty; combined-impact (i.e. impact exercises with resistance training) exercise protocols are the most effective in improving BMD in young premenopausal women; combined-impact exercise protocols, where tolerable and applicable, should be recommended for preserving bone mass or improving BMD in postmenopausal women. Similar effects can be expected in men, although few studies on this population segment have been conducted so far .
How Do Exercise-Dependent Effects on Bone Endocrine Function Affect Whole-Body Homeostasis?
The mechanosensitivity of bone is a prerogative of osteocytes, as demonstrated in transgenic mice lacking osteocytes and displaying fragile fatty bones with intra-cortical and trabecular defects resistant to unloading-induced bone loss . Osteocytes are terminally differentiated osteoblasts entrapped within their own built matrix. They account for 95% of the bony cell compartment and, through their dendrites intruding into the bone canaliculi, they form a complex network in which they are in direct contact with each other and surface-resident osteoblasts. Osteocytes sense the loading-dependent changes in strain and canalicular fluid pressure and translate them into endocrine signals through the expression of molecules that act locally and systemically; sclerostin, insulin-like growth factor-I/-II, OC, prostanoids, c-FOS, and nitric oxide .
Wnt is a highly conserved signalling pathway that plays a crucial role in embryonic development and adult homeostasis. Wnt ligands activate several intracellular signalling pathways, including the canonical Wnt/β-catenin pathway and several non-canonical Wnt pathways. In the canonical pathway, in the absence of Wnt ligands, cytosolic β-catenin interacts with other components of the destruction complex, including Axin1 (the limiting factor for formation of the complex), adenomatous polyposis coli (APC), glycogen synthase kinase-3 (GSK-3), casein kinase-1 (CK1), protein phosphatase 2A, and the E3-ubiquitin ligase β-transducin repeat containing protein (β-TrCP). In this complex, β-catenin is phosphorylated by GSK-3 and CK1, ubiquitinated and then degraded by the proteasome. When Wnt ligands bind to their co-receptors, Frizzled and low-density lipoprotein receptor-related protein-5 or 6 (LRP5/6), the destruction complex is dissociated and β-catenin enters the nucleus where it binds to transcription factors LEF/TCF and activates the expression of downstream target genes. Because of its pivotal role in homeostasis, Wnt signalling is tightly regulated: several extracellular Wnt inhibitors directly bind to Wnt ligands (e.g., secreted Frizzled-related proteins [sFRPs], Wnt inhibitory factor, α-klotho) or to their membrane receptors (e.g., DKK-1 and sclerostin) that interact with LRP5/6. Sclerostin is involved in the determination of the fate of mesenchymal stem cells towards either osteoblastogenesis (Wnt activation and PPAR-γ inhibition) or adipogenesis (Wnt inhibition and PPAR-γ activation) and in bone aging, characterized by reduced osteoblastogenesis and fatty infraction of the stroma .
Exercising increases the mesenchymal stem cell pool and osteogenesis, and inhibits adipogenesis by inducing Wnt signalling . Indeed, sclerostin expression has been demonstrated to be downregulated in bone regions submitted to high strain and upregulated in unloaded regions , possibly due to the suppression mediated by load-induced periostin . In line with these hypotheses, sclerostin−/− mice display sclerostosis and high bone mass , whereas the load-dependent bone anabolic response is ablated in periostin−/− mice . Sclerostin blood concentration is positively correlated with age and body-mass index (BMI) and negatively with bone formation marker levels and status of physical activity . In regularly exercising subjects, other mechanisms (e.g. feedback loop, training phase) contrast the inhibition of sclerostin expression. During the rest period, weight-bearing athletes (i.e. rugby, enduro, basketball players) expressed higher serum sclerostin than not weight-bearing athletes (i.e. cyclists), while neither group differed from sedentary or high-impact athletes (i.e. tennis players) . Furthermore, pre-pubertal rhythmic gymnasts had a higher BMD as compared with untrained controls but also higher sclerostin levels  as paralleled in young and old exercising mice . In contrast, light exercise (fast walking) had no effect on sclerostin concentration in postmenopausal women .
Besides its pro-adipogenic effects, sclerostin has emerged also as a regulator of glucose and fat metabolism. Circulating sclerostin expression is associated with aging and increased risk of hip fracture in postmenopausal women . Sclerostin knockout mice show reduced adipogenesis, increased insulin sensitivity, similar to mice treated with an anti-sclerostin antibody. Interestingly, these mice are resistant to diet-induced obesity and related metabolism deregulation due to on the abolition of sclerostin signalling in white adipose tissue . Taken together, these findings support the hypothesis that weight-bearing and high-impact activities, especially when performed intermittently, improve bone metabolic status and bone mass through the inhibition of osteocytes; weight-bearing and high-impact activities are more effective than non-weight-bearing activities in improving whole-body metabolism .
Fibroblast Growth Factor (FGF)-23
Since Wnt signalling has an essential role in kidney development, homeostasis, and injury repair, the bone-derived Wnt inhibitors could also have a key part in these processes. In this context, the FGF-23-mediated bone-kidney axis has been widely studied. FGF-23 is a member of the FGF-19 subfamily (together with FGF-19 and FGF-21). It is primarily expressed and secreted by osteocytes but also by osteoblasts in response to increased serum phosphate and 1,25-dyhydroxy vitamin D. In the kidney it suppresses phosphate reabsorption by inhibiting the expression and membrane presentation of NPT2a/c, the Na+/PO4− cotransporters, causing hypophosphatemia [16, 74]. Moreover, FGF-23 inhibits the 1α hydroxylation of 25-(OH) vitamin D, thus limiting the synthesis of the biologically active form of vitamin D, leading to hypocalcaemia and decreased parathyroid hormone expression and secretion. Finally, FGF-23 directly inhibits parathyroid function . FGF-23−/− and α-klotho−/− (an essential co-receptor of FGF-23) mice develop a multiple aging-like phenotype characterized by shortened life span and multiple disorders (e.g. hypogonadism, growth retardation, osteoporosis, skin atrophy, vascular calcification, accelerated thymus involution, hearing loss, auditory syndromes) . Circulating FGF-23 is modified by exercise and by dietary phosphorus intake as well . We observed that non-weight-bearing activity (e.g. cycling) increases serum levels of intact FGF-23 and urinary excretion of calcium and phosphorous, independent of calcitriol and parathyroid hormone . FGF-23 expression has also been recently detected in the skeletal muscle of mice subjected to chronic exercising; exogenous administration of FGF-23 limited the exercise-dependent production of reactive oxygen species .
Bone Morphogenic Protein (BMP)-7
Deleting Pparγ in osteocytes (Pparγ ocy −/− ) induces improvements in the metabolic phenotypes (i.e. white adipose tissue browning enhanced energy expenditure, improved glucose tolerance and insulin sensitivity) and this is mediated by BMP-7; the administration of anti-BMP-7 restored the “worse” phenotype in these mice . Clinical studies showed that BMP-7 was positively associated with insulin secretion and improved β-cell function in non-diabetic patients ; this osteokine was found to induce the conversion of human pancreatic exocrine cells to insulin-expressing cells . However, because BMP-7 is expressed by several tissues including bone, kidney and heart, the extent to which bone-derived BMP7 contributes to serum BMP7 and influences energy metabolism needs further exploration . The one report to date that has investigated the relationship between physical activity and BMP-7 expression found that its expression is increased in mice, at least in white adipose tissue, after endurance training and that it is related to white adipose tissue browning .
In addition to osteocytes, osteoblasts also exert an endocrine function and this function is mainly mediated by osteocalcin (OC). Recent studies have shown a wide spectrum of OC activity mediated by its receptor, GPRC6A. GluOC is considered the hormonally active molecule; it modulates the metabolism of phosphates and 1,25(OH)2 vitamin D, male reproduction, cognition, glucose (improvement in β-cell function, increased β-cell proliferation, improved peripheral glucose sensitivity) and fatty acids metabolism. OC−/− mice, despite the slight skeletal abnormalities, display hyperglycaemia which is restored by OC supplementation . In healthy women, OC has been negatively correlated with glycaemia, glycated haemoglobin (HbA1c), and insulin resistance. However, the relative role of GluOC and GlaOC in humans remains unclear . Since muscle contraction increases insulin sensitivity, the exercise-dependent increase in GPRC6A expression in muscles could be a causal mechanism of increased insulin sensitivity in athletes . We demonstrated that strenuous not weight-bearing muscular activity (e.g. cycling) causes a relative increase in GluOC in association with increased bone resorption , while a similar effort associated with a high degree of loading and ground impact (e.g. mountain ultramarathon running) reduces GluOC . In both cases total OC remained stable and the adipokine/metabolic profile was improved. Total OC was found to be unchanged after 32 weeks of combined loading training (resistance exercise combined with weight-bearing exercise) in elderly subjects . A theory by Lee and Karsenty  posits that GluOC is passively generated by GlaOC during bone resorption in the acidic environment of the resorption pit. However, evidence supporting this theory remains scant. It also contrasts with the known need for tight control in hormone synthesis and secretion, the well-known association between increased bone resorption/turnover and dysmetabolic conditions in humans, and between bone stimulating intervention and improved metabolism . Further investigation in the physiology of OC in exercise is needed.
In addition to their role in energy metabolism, OC and GPRC6A are involved in the regulation of fertility. Experimental observations in mice showed that both contribute to the regulation of circulating luteinizing hormone and the synthesis of testosterone , although these observations have not been confirmed .
Bone resorption and bone formation are tightly coupled during bone remodeling where RANKL is a key factor in this link. RANKL is expressed by osteoblasts, osteocytes, and T lymphocytes. It promotes bone resorption by binding to its cognate receptor, RANK, expressed by osteoclasts . A possible involvement of the RANK/RANKL system in regulating energy metabolism comes from the observation of improved hepatic insulin sensitivity and glucose tolerance in mice fed with a high-fat diet and in ob/ob mice with deletion or downregulation of RANK in hepatocytes, but not in skeletal muscles or β-cells. Moreover, these benefits are lost when OPG, the decoy receptor for RANKL, is administered systematically. This effect is probably the result of a reduction in Kupffer cell activation . RANKL is also a ligand of LGR4 and its knockout in mice causes enhanced RANKL-induced osteoclastogenesis and bone resorption due to the higher availability of RANKL for RANK . The same mouse model displayed lower body weight, less epididymal and inguinal white adipose tissue, better glucose tolerance and insulin sensitivity resulting from increased energy expenditure of browning white adipose tissue, as compared with wild-type littermates . In humans, an Icelandic population with loss-of-function mutation in LGR4 was found to have low body weight and decreased bone mass .
The possible implication of RANKL in energy metabolism and in dysmetabolic conditions (e.g. T2DM) has not been clinically confirmed. No association exists between RANKL blood concentrations and any metabolic markers, while the administration of denosumab, an anti-RANKL monoclonal antibody used in osteoporosis, affects neither fasting glucose levels and incident diabetes in non-diabetic postmenopausal osteoporotic women nor glucose levels in pre-diabetic or diabetic women . Several studies have investigated the effects of exercise on RANKL expression and the RANK/RANKL/OPG axis. Light aerobic exercise performed over a 1-year period was seen to improve bone turnover in postmenopausal women by increasing OPG levels without affecting RANKL . In contrast, no change in these parameters was noted after 8 months of either resistance or aerobic training in a comparable population, despite the increase in BMD observed in the resistance group  or following 32 weeks of combined loading training in men and women . In spite of their higher BMD, peripubertal female gymnasts (high-impact) showed higher levels of RANKL and similar concentrations of OPG as compared with age-matched swimmers (not weight-bearing) . Interestingly, a single bout of plyometric exercise is able to increase the OPG levels and the OPG/RANKL ratio, regardless age and sex .
Initially recognized as an immune mediator, LCN-2 has a role as an adipokine, since it is highly expressed in white adipose tissue and induces insulin resistance in cultured adipocytes and hepatocytes. Recently, it has been discovered that Lcn-2 expression is tenfold higher in bone than in white adipose tissue in wild-type mice under physiological conditions, and that serum Lcn-2 is decreased by 67% in mice following its targeted deletion in osteoblasts. LCN-2 controls feeding and this is associated with changes in body weight and glucose metabolism. Osteoblast-derived and circulating LCN-2 increase after feeding, contributing to postprandial satiety; restoration of LCN-2 levels in Lcn2 knockout mice corrects the fasting-induced hyperphagia . Postprandial serum levels of LCN-2 were also significantly increased in humans after high-fat meals. In normal-weight individuals it was accompanied by enhanced total energy expenditure, whereas LCN-2 was decreased postprandially in obese individuals possibly to the higher baseline LCN-2 levels in these subjects (LCN-2 resistance) .
To exert its anorexigenic and related actions (decreased body weight and fat mass and improved insulin sensitivity), LCN-2 crosses the blood–brain barrier and binds to the melanocortin 4 receptor (MC4R) in the paraventricular nucleus and ventromedial neurons of the hypothalamus. Direct stimulation of insulin secretion may instead be mediated by SLC22A17, another receptor for LCN-2, expressed by β-cells . Evidence demonstrates that the restoration or overexpression of Lcn-2 in knockout mice or mice with metabolic defects improves the metabolic phenotypes .
Like sclerostin, LCN-2 is considered to be a mechanoresponding protein that is overexpressed in unloading conditions (e.g., bed rest, microgravity) and that its serum concentration increases with age, both of which result in reduced energy expenditure. The increase in LCN-2 is absent in conditions of unloading-independent bone loss (e.g., ovariectomy) and it is antagonized by increased energy demands . Reports about the response of LCN-2 in exercise are limited. According to Choi et al., lipocalin proteins did not respond to 3 months of mixed aerobic and strength training in obese and non-obese subjects . More recently, Moghadasi and Mohammadi Domieh demonstrated a decrease in LCN-2 after 8 weeks of either resistance or endurance training in healthy sedentary young adult males .
Therapeutic Perspectives and Conclusions
Bone health is essential for overall health and quality of life. Other than providing physical sustainment, locomotion and protection against injury, bone is the main storehouse of elements (Ca2+) and compounds (PO42−) necessary for life. The sustainment/locomotion (i.e. bone strength) and the dynamic storage of minerals are dependent upon the metabolic activity of bone cells, where physical activity is an essential regulator of these functions. Moreover, bone tissue is also involved in hematopoiesis and in the complex endocrine network that modulates whole-body metabolism.
Physical activity plays a key role in these processes through its effects on bone. Unhealthy bones are at risk of fracture, resulting in disability, diminished function, loss of independence and premature death; osteoporosis, the prototypic metabolic disease of bone has become a worldwide health problem. One Caucasian women in two and one in five men will experience an osteoporotic fracture over her/his lifetime. The related healthcare costs for an aging population are estimated to rise to $25.3 billion by 2025 in the United States alone .
Because of the tight two-way endocrine relationship between bone and other organs involved in the homeostasis of energetic substrates, pathological conditions affecting the bone are associated with whole-body metabolic dysfunctions and vice versa. For instance, while T2DM patients are subject to an increased fracture risk due to reduced BMD, metabolic dysfunctions (e.g., metabolic syndrome and diabetes) in osteoporosis are common .
Physical activity has been rightly depicted as the master poly-pill of the twenty-first century . Like other drugs, it should be taken based on specific indications with the correct posology (i.e. daily/weekly frequency and session length), possibly at specific times of day depending on exercise intensity and specific contraindications. Physical activity is a widely accessible, low cost, and highly modifiable contributor to bone health. Exercise is especially effective during adolescence, a period when nearly 50% of peak adult bone mass is gained . As a general guideline, exercise protocols that combine impact exercises and resistance training offer the best choice to improve BMD and bone health in premenopausal adult women and to maintain BMD in postmenopausal elderly women. In contrast, a net improvement in peak bone mass can be achieved in young girls by high-impact plyometric exercise programmes. Moreover, cycles of short bouts of high-impact/resistance exercise alternating with either rest or light aerobic exercise bouts are much more effective than continuous and long sessions of the same kind of exercise due to the easy adaptation, and consequent unresponsiveness of bone cells to loading. These recommendations are currently available only for women, as the literature on men is too scarce to draw conclusions. Nonetheless, it is plausible that the same guidelines are valid for men . Furthermore, it is also plausible that physical activity programmes specifically targeting bone health will have a greater impact on whole-body homeostasis than physical activity that does not affect or perhaps even negatively affects bone.
Controversy surrounds some of these aspects (e.g. exercise and time of day). However, there can be no doubt about the efficacy of physical activity in preventing/treating dysfunctions in energy metabolism. It is also clear that specific kinds of physical activity are more efficient for treating various health conditions (indications and contraindications) than others . Further research is needed to clarify these issues with the goal of making physical activity a prescribable treatment option.
This work was supported by the Italian Ministry of Health.
- 2.Belavy DL, Baecker N, Armbrecht G, Beller G, Buehlmeier J, Frings-Meuthen P, Rittweger J, Roth HJ, Heer M, Felsenberg D. Serum sclerostin and DKK1 in relation to exercise against bone loss in experimental bed rest. J Bone Miner Metab. 2016;34(3):354–65. https://doi.org/10.1007/s00774-015-0681-3.CrossRefPubMedGoogle Scholar
- 4.Bonnet N, Standley KN, Bianchi EN, Stadelmann V, Foti M, Conway SJ, Ferrari SL. The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J Biol Chem. 2009;284(51):35939–50. https://doi.org/10.1074/jbc.M109.060335.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Camozzi V, Tossi A, Simoni E, Pagani F, Francucci CM, Moro L. Role of biochemical markers of bone remodeling in clinical practice. J Endocrinol Investig. 2007;30(6 Suppl):13–7.Google Scholar
- 8.Chen D, Xie R, Shu B, Landay AL, Wei C, Reiser J, Spagnoli A, Torquati A, Forsyth CB, Keshavarzian A, Sumner DR. Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging. Ann N Y Acad Sci. 2018;1442(1):48–60. https://doi.org/10.1111/nyas.13945.CrossRefPubMedGoogle Scholar
- 10.Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ, Skinner JS. American College of Sports Medicine position stand. Exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41(7):1510–30. https://doi.org/10.1249/MSS.0b013e3181a0c95c.CrossRefPubMedGoogle Scholar
- 13.Dowthwaite JN, Rosenbaum PF, Scerpella TA. Mechanical loading during growth is associated with plane-specific differences in vertebral geometry: a cross-sectional analysis comparing artistic gymnasts vs. non-gymnasts. Bone. 2011;49(5):1046–54. https://doi.org/10.1016/j.bone.2011.07.033.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Duplanty AA, Levitt DE, Hill DW, McFarlin BK, DiMarco NM, Vingren JL. Resistance training is associated with higher bone mineral density among young adult male distance runners independent of physiological factors. J Strength Cond Res. 2018;32(6):1594–600. https://doi.org/10.1519/JSC.0000000000002504.CrossRefPubMedGoogle Scholar
- 16.Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Ren Physiol. 2009;297(2):F282–91. https://doi.org/10.1152/ajprenal.90742.2008.CrossRefGoogle Scholar
- 17.Giangregorio LM, Papaioannou A, Macintyre NJ, Ashe MC, Heinonen A, Shipp K, Wark J, McGill S, Keller H, Jain R, Laprade J, Cheung AM. Too Fit To Fracture: exercise recommendations for individuals with osteoporosis or osteoporotic vertebral fracture. Osteoporos Int. 2014;25(3):821–35. https://doi.org/10.1007/s00198-013-2523-2.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Jurimae J, Tillmann V, Cicchella A, Stefanelli C, Vosoberg K, Tamm AL, Jurimae T. Increased sclerostin and preadipocyte factor-1 levels in prepubertal rhythmic gymnasts: associations with bone mineral density, body composition, and adipocytokine values. Osteoporos Int. 2016;27(3):1239–43. https://doi.org/10.1007/s00198-015-3301-0.CrossRefPubMedGoogle Scholar
- 24.Kiechl S, Wittmann J, Giaccari A, Knoflach M, Willeit P, Bozec A, Moschen AR, Muscogiuri G, Sorice GP, Kireva T, Summerer M, Wirtz S, Luther J, Mielenz D, Billmeier U, Egger G, Mayr A, Oberhollenzer F, Kronenberg F, Orthofer M, Penninger JM, Meigs JB, Bonora E, Tilg H, Willeit J, Schett G. Blockade of receptor activator of nuclear factor-kappaB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med. 2013;19(3):358–63. https://doi.org/10.1038/nm.3084.CrossRefPubMedGoogle Scholar
- 25.Kim SP, Frey JL, Li Z, Kushwaha P, Zoch ML, Tomlinson RE, Da H, Aja S, Noh HL, Kim JK, Hussain MA, Thorek DLJ, Wolfgang MJ, Riddle RC. Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci USA. 2017;114(52):E11238–47. https://doi.org/10.1073/pnas.1707876115.CrossRefPubMedGoogle Scholar
- 27.Klein D, Alvarez-Cubela S, Lanzoni G, Vargas N, Prabakar KR, Boulina M, Ricordi C, Inverardi L, Pastori RL, Dominguez-Bendala J. BMP-7 induces adult human pancreatic exocrine-to-endocrine conversion. Diabetes. 2015;64(12):4123–34. https://doi.org/10.2337/db15-0688.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Kontulainen S, Sievanen H, Kannus P, Pasanen M, Vuori I. Effect of long-term impact-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: a peripheral quantitative computed tomography study between young and old starters and controls. J Bone Miner Res. 2003;18(2):352–9. https://doi.org/10.1359/jbmr.2003.18.2.352.CrossRefPubMedGoogle Scholar
- 30.Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130(3):456–69. https://doi.org/10.1016/j.cell.2007.05.047.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Li DJ, Fu H, Zhao T, Ni M, Shen FM. Exercise-stimulated FGF23 promotes exercise performance via controlling the excess reactive oxygen species production and enhancing mitochondrial function in skeletal muscle. Metabolism. 2016;65(5):747–56. https://doi.org/10.1016/j.metabol.2016.02.009.CrossRefPubMedGoogle Scholar
- 32.Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860–9. https://doi.org/10.1359/jbmr.080216.CrossRefPubMedGoogle Scholar
- 34.Lombardi G, Corsetti R, Lanteri P, Grasso D, Vianello E, Marazzi MG, Graziani R, Colombini A, Galliera E, Corsi Romanelli MM, Banfi G. Reciprocal regulation of calcium-/phosphate-regulating hormones in cyclists during the Giro d’Italia 3-week stage race. Scand J Med Sci Sports. 2014;24(5):779–87. https://doi.org/10.1111/sms.12080.CrossRefPubMedGoogle Scholar
- 40.Luo J, Yang Z, Ma Y, Yue Z, Lin H, Qu G, Huang J, Dai W, Li C, Zheng C, Xu L, Chen H, Wang J, Li D, Siwko S, Penninger JM, Ning G, Xiao J, Liu M. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016;22(5):539–46. https://doi.org/10.1038/nm.4076.CrossRefPubMedGoogle Scholar
- 41.Maimoun L, Coste O, Philibert P, Briot K, Mura T, Galtier F, Mariano-Goulart D, Paris F, Sultan C. Peripubertal female athletes in high-impact sports show improved bone mass acquisition and bone geometry. Metabolism. 2013;62(8):1088–98. https://doi.org/10.1016/j.metabol.2012.11.010.CrossRefPubMedGoogle Scholar
- 42.Marques EA, Mota J, Viana JL, Tuna D, Figueiredo P, Guimaraes JT, Carvalho J. Response of bone mineral density, inflammatory cytokines, and biochemical bone markers to a 32-week combined loading exercise programme in older men and women. Arch Gerontol Geriatr. 2013;57(2):226–33. https://doi.org/10.1016/j.archger.2013.03.014.CrossRefPubMedGoogle Scholar
- 43.Marques EA, Wanderley F, Machado L, Sousa F, Viana JL, Moreira-Goncalves D, Moreira P, Mota J, Carvalho J. Effects of resistance and aerobic exercise on physical function, bone mineral density, OPG and RANKL in older women. Exp Gerontol. 2011;46(7):524–32. https://doi.org/10.1016/j.exger.2011.02.005.CrossRefPubMedGoogle Scholar
- 47.Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z, Huang Y, Zong H, Friedman RA, Barasch J, Lanzano P, Deng L, Leibel RL, Rubin M, Nickolas T, Chung W, Zeltser LM, Williams KW, Pessin JE, Kousteni S. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. 2017;543(7645):385–90. https://doi.org/10.1038/nature21697.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Qin W, Sun L, Cao J, Peng Y, Collier L, Wu Y, Creasey G, Li J, Qin Y, Jarvis J, Bauman WA, Zaidi M, Cardozo C. The central nervous system (CNS)-independent anti-bone-resorptive activity of muscle contraction and the underlying molecular and cellular signatures. J Biol Chem. 2013;288(19):13511–21. https://doi.org/10.1074/jbc.M113.454892.CrossRefPubMedPubMedCentralGoogle Scholar
- 56.Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283(9):5866–75. https://doi.org/10.1074/jbc.M705092200.CrossRefPubMedGoogle Scholar
- 57.Rocha-Rodrigues S, Rodriguez A, Gouveia AM, Goncalves IO, Becerril S, Ramirez B, Beleza J, Fruhbeck G, Ascensao A, Magalhaes J. Effects of physical exercise on myokines expression and brown adipose-like phenotype modulation in rats fed a high-fat diet. Life Sci. 2016;165:100–8. https://doi.org/10.1016/j.lfs.2016.09.023.CrossRefPubMedGoogle Scholar
- 61.Sansoni V, Vernillo G, Perego S, Barbuti A, Merati G, Schena F, La Torre A, Banfi G, Lombardi G. Bone turnover response is linked to both acute and established metabolic changes in ultra-marathon runners. Endocrine. 2017;56(1):196–204. https://doi.org/10.1007/s12020-016-1012-8.CrossRefPubMedGoogle Scholar
- 63.Styrkarsdottir U, Thorleifsson G, Sulem P, Gudbjartsson DF, Sigurdsson A, Jonasdottir A, Jonasdottir A, Oddsson A, Helgason A, Magnusson OT, Walters GB, Frigge ML, Helgadottir HT, Johannsdottir H, Bergsteinsdottir K, Ogmundsdottir MH, Center JR, Nguyen TV, Eisman JA, Christiansen C, Steingrimsson E, Jonasson JG, Tryggvadottir L, Eyjolfsson GI, Theodors A, Jonsson T, Ingvarsson T, Olafsson I, Rafnar T, Kong A, Sigurdsson G, Masson G, Thorsteinsdottir U, Stefansson K. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature. 2013;497(7450):517–20. https://doi.org/10.1038/nature12124.CrossRefPubMedGoogle Scholar
- 68.Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, Muzylak M, Greenslade K, Moore A, Zhang L, Gong J, Qian X, Paszty C, Taylor RJ, Robinson MK, Carr MD. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem. 2009;284(16):10890–900. https://doi.org/10.1074/jbc.M807994200.CrossRefPubMedPubMedCentralGoogle Scholar
- 69.Wang J, Liu R, Wang F, Hong J, Li X, Chen M, Ke Y, Zhang X, Ma Q, Wang R, Shi J, Cui B, Gu W, Zhang Y, Zhang Z, Wang W, Xia X, Liu M, Ning G. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol. 2013;15(12):1455–63. https://doi.org/10.1038/ncb2867.CrossRefPubMedGoogle Scholar
- 70.World Health Organization. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva: World Health Organization; 2009. http://www.who.int/iris/handle/10665/44203. Accessed 1 Oct 2018
- 72.Yuen SN, Kramer H, Luke A, Bovet P, Plange-Rhule J, Forrester T, Lambert V, Wolf M, Camacho P, Harders R, Dugas L, Cooper R, Durazo-Arvizu R. Fibroblast growth factor-23 (FGF-23) levels differ across populations by degree of industrialization. J Clin Endocrinol Metab. 2016;101(5):2246–53. https://doi.org/10.1210/jc.2015-3558.CrossRefPubMedPubMedCentralGoogle Scholar