New insights in osteoporosis mechanisms as common complication in Alzheimer’s disease (AD) patients


Acest articol este o trecere in revista a celor mai recente date din literatura de specialitate privind mecanismele moleculare ale osteoporozei si fracurii de sold,considerate drept complicatii ale pacientilor cu boala Alzheimer. Osteoporoza este o boala devastatoare avand un impact enorm economic si asupra starii de sanatate,in particular considerand schimbarea globala catre segmentul varstnic de populatie,caracterizat printr-o patologie scheletala sistemica si progresiva prin compromiterea densitatii minerale osoase si a rezistentei asociata cu cresterea incidentei fracturilor. Osteoporoza si fractura de sold sunt complicatiile cele mai comune intalnite la pacientii cu boala Alzheimer. Desi mecanismele care stau la baza acestei patologii raman putin intelese, noi evidente sustin ipoteza ca ca genele risc din boala Alzheimer pot fi de asemenea considerate a fi un factor de risc pentru osteoporoza si ca boala Alzheimer si osteoporoza au in comun mecanisme patogenice conservatoare generate de stresul oxidativ. Depunerea de Amiloid beta peptid are loc de asemenea in osteoporoza si relatia dintre (Aβ) si osteoporoza ramane o intrebare deschisa, nu una elucidata.
Cuvinte-cheie: boala Alzheimer (AD), amiloid beta peptide (Aβ), specii reactive de oxigen (ROS)


This paper is a review of the most recent literature data on the molecular mechanisms of osteoporosis and hip fractures complications seen in patients with Alzheimer`s disese(AD). Osteoporosis is a devastating disease having enormous health and economic impacts, particularly considering the global shift toward an aging population, characterized by a systemic and progressive skeletal pathology characterized by compromised bone mineral density and strength with the increased occurrence of fractures. Osteoporosis and hip fracture are commonly observed complications seen in patients with AD. Although the mechanisms underlying this association remain poorly understood, emerging evidence supports the view that AD risk genes may also be a risk factor for osteoporosis, and that AD and osteoporosis may share conserved oxidative stress-driven pathogenic mechanisms. However, whether abnormal Amiloid β peptide (Aβ) deposition also occurs in osteoporosis and the relationship between Aβ and human osteoporosis remains an open, not elucidated, question.
Keywords: osteoporosis, Alzheimer`s disease (AD), beta amiloid peptide, (Aβ), reactive oxygen species(ROS)


Osteoporosis is a devastating disease having enormous health and economic impacts, particularly considering the global shift toward an aging population, characterized by a systemic and progressive skeletal pathology characterized by compromised bone mineral density and strength with the increased occurrence of fractures. Despite rapid progress in our understanding over recent years, patient morbidity and mortality resulting from this disease are still too high [1] and there is an urgent need for a proper assessment of the underlying mechanisms and the development of new treatment strategies to address this pathophysiological issue.

The relationship between Aβ Metabolism and Alzheimer`s disease (AD)

Patients with AD show significantly increased risk of osteoporotic hip fractures. However, whether abnormal Aβ peptide (Aβ) deposition also occurs in osteoporosis and the relationship between Aβ and human osteoporosis remains an open, not elucidated, question [2]. Amiloid β peptide, one of the pathological hallmarks of AD, is a small (40–42 amino acids) proteolytic fragment of a glycosylated integral membrane cell surface receptor protein called APP and is encoded by a gene on human chromosome 21 [2,3]. Aβ has attracted much attention for its association with various pathologies [4].

Besides AD, Aβ plays a crucial role in other important neurodegenerative diseases, such as Huntington’s, Parkinson’s, and prion disorders, as well as amyotrophic lateral sclerosis as well as type 2 diabetes and the most common age-related muscle disease of inclusion body myositis [5]. Thus, APP/Aβ seems to be associated with multiple degenerative disorders. Epidemiological studies showed that patients with AD had an increased risk of developing osteoporotic hip fractures even after considering the increased frequency of fallings in AD patients [6]., suggesting one or more common denominators between both disorders.

Nevertheless, an association between Aβ and human osteoporosis has not yet been clearly established, and also it has been inferred that Aβ may be of physiological importance for survival of cells [2]. Excessive Aβ aggregates and fibrillates to form amyloid plaques in the brain, thus leading to the exacerbation of AD pathology. Previous studies have identified a role for Aβ in the activation of osteoclasts through gene knockout experiments and use of the transgenic AD mouse model, Tg2576 [2]. However, whether a large amount of Aβ deposits also occur in osteoporotic bone tissues and the role human Aβ may play on OC activation remain unclear. In addition to having an activation effect on osteoclasts, Aβ may accumulate abnormally in osteoporotic bone and play an important pathogenic role.

A close relationship between Aβ and osteoporosis is shown across species from rodent to human, as demonstrated in different clinical conditions in patient samples as well as in various animal model and cell cultures. AD and osteoporotic hip fractures often coexist during aging. Platelets have been shown to be the primary source (90%) of Aβ in human blood with plasma Aβ levels fluctuating over time among individuals [7]. Besides human plasma and cerebrospinal fluid, soluble Aβ is also a component of human urine in Alzheimer’s. Despite this level of knowledge surrounding APP and Aβ expression in many tissues, reports on the expression and distribution of Aβ in bone tissues and osteocytes remain an emerging evidence. Aβ deposition has been found on the endosteal and periosteal surfaces of adult rat ulnae [2].

Notably, occurrence of Aβ and APP abnormal accumulation in different tissues supports the hypothesis that Aβ diseases may be a systemic disease, suggesting that these malfolded proteins may either be produced locally in diverse organs or may originate from a common circulating precursor. Consistent with this notion, abnormal Aβ and APP burden has been detected in osteoporotic bone tissues from both human and rat OVX models, where Aβ42 was identified mainly in the membrane and cytoplasm of osteocytes and extracellular matrix, while APP largely found in the membrane of osteocytes. Despite increasing research efforts, still the mechanism underlying the accumulation of Aβ and APP in osteocytes in osteoporotic bones remains elusive.

One possible source for Aβ deposition in bone may be blood, where Aβ increases during senescence [2]. In addition to this, secretion of Aβ by mature osteoblasts has been documented, in agreement with the finding of Aβ42 and APP formation in osteoblasts from both human and OVX rats osteoporotic bone. In these conditions, APP has been found to be able of suppressing osteoblast differentiation, associated with osteoporotic alterations [6]. Given that osteoblast is the precursor of the osteocyte, it is conceivable that the deposition of Aβ and APP in osteocytes can be consequence of secretion by osteoblasts during both osteogenic differentiation and aging processes. In turn, accumulating Aβ may promote apoptotic process in osteocytes, likewise in neurons thus determining bone loss and osteoporosis [8].

An interesting and controversial question concerns why the abundant presence of proteins of Aβ abnormal metabolism in the bone of osteoporotic patients did not cause them to develop brain degeneration, such as AD. A number of explanations may exist to provide a possible rationale. First, bone is a very special organ, with limited blood supply, with most of the osteocytes embedded in the matrix without direct contact with blood. In these conditions, release of Aβ into the blood stream is not an easy process. Second, the blood–brain-barrier (BBB) permeability can be of extreme importance for the prevention of Aβ invasion into the brain tissues, as uptake of peripheral Aβ by the brain is not a normal occurrence without BBB compromission [9]. Lastly, both osteoporosis and AD are multifactorial diseases with complex etiology and pathogenesis[10]. Aβ deposits are present in several tissues, which indicates that the protein may originate as product of local metabolism in various organs or, similarly to other amyloidoses, can derive from a circulating precursor common to all these pathophysiological conditions. However, further studies are necessary to explore these dynamics and understand the underlying mechanisms.

Abnormal Aβ deposition in osteoporotic bone tissues and its potent enhancement effect on osteoclast differentiation and activation, is already clearly demonstrated suggesting an important role for Aβ in the pathogenesis of osteoporosis [2]. This is of great clinical significance for providing novel insights into the tight link between Aβ and human osteoporosis, thus revealing a potential mechanism underlying altered bone mineral density by Aβ abnormal metabolism. Clearly, however, further work is required to elucidate the exact mechanisms through which Aβ regulates osteoporosis signaling. These research efforts may eventually lead to a promising future discovery of a new etiology for osteoporosis, and prompt healthcare professionals and researchers to develop innovative anti-bone-resorptive therapeutic agents and strategies, particularly those designed by targeting Aβ, to efficiently minimize deleterious consequences associated with bone homeostasis disruption. In line with these evidence, since a biomarker is a traceable substance indicating changes in expression or metabolism of a given protein which correlates with the risk or progression of a disease, as consequence, Aβ may be a novel and promising candidate biomarker for drug targeting and characterization of osteoporotic therapeutic approaches in the future [11].

The role of receptor activator of NF-κB ligand (RANKL) in pathogenesis of osteoporosis

Bone tissue undergoes, throughout life, a continuous renewal through a process called bone remodeling, which is controlled by the activity of osteoclasts mediating bone resorption and parallel activity of osteoblasts which mediate bone formation [12]. Any disturbance in the balanced formation and resorption process, which can be linked to hormone disequilibrium or aging decreases bone mass and result in bone pathologies, such as osteoporosis leading to increased vulnerability to fractures.

Within this context, the receptor activator of NF-κB ligand (RANKL) appears to be an important factor underlying osteoporosis pathogenesis for its critical role played in osteoclast differentiation and activation[13]. For this reason, inhibition of RANKL represents an innovative therapeutic target for controlling osteoclastogenesis [13].

Notably, an important role in bone remodeling is played by alternative or non-canonical NF-κB pathway, which mediates activation of the p52/RelB NF-κB complex, thus regulating various biological processes. This pathway differently from IκBα degradation in the canonical mechanism, consists of processing of p100 a NF-κB2 precursor protein,. In this context a central role is played by NF-κB-inducing kinase (NIK), a component of the non-canonical NF-κB pathway and a downstream kinase, IKKα (inhibitor of NF-κB kinase) which operate with integrated functions promoting induction of phosphorylation-dependent ubiquitination of p100. Under normal conditions, NIK is processed by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. After signals mediated by a subset of TNF receptor superfamily members, TRAF3 is degradated and NIK is stabilized leading to non-canonical activation of NF-κB [14]; Accordingly, the inhibitory role of p100, in both basal and stimulated osteoclastogenesis in bone formation as well as resorption has been clearly demonstrated [15].

In the alternative NF-κB pathway p52 derived from p100 through NIK, binding of p52 and RelB induces effects on osteoclast biology [15]. However, to date, the precise physiologic importance of alternative NF-κB in bone biology, is not completely elucidated. Furthermore, the currently known intracellular signaling pathways activated after receptor binding of RANKL include the nuclear factor of activated T cells [16], mitogen-activated protein kinases (MAPKs), TRAFs, c-Jun N-terminal kinases (JNKs), and ROS[17].

In addition, NF-κB is a transcription factor, which pleiotropically regulate osteoclast formation, function, and survival [16]. Deletion of both NF-κB p50 and p52 subunits is associated to osteopetrosis as consequence of osteoclast absence and, in addition, NF-κB is central for the differentiation of RANK-expressing osteoclasts into osteoclasts TRAP+ induced by osteoclastogenic cytokines. This explain the inhibitory effect on osteoclast formation induced by prevention of NF-κB activation [16,18].

The role of reactive oxygen species(ROS) in regulation of RANKL – dependent oscteoclast differentiation

Reactive oxygen species act as intracellular signaling molecules involved in the regulation of RANKL-dependent osteoclast differentiation, but they also have cytotoxic effects that include peroxidation of lipids and oxidative damage to proteins and DNA. Taking into account the relationship between Nrf2 and osteoclastogenesis, stimulation of osteoclast precursors (mouse primary peritoneal macrophages and RAW 264.7 cells) with RANKL results in the up-regulation of Keap1, a negative regulator of Nrf2, with decreased Nrf2/Keap1 ratio, and down-regulation of cytoprotective enzymes, such as heme oxygenase-1 and γ-glutamylcysteine synthetase[17].

On the other hand, Nrf2 overexpression results in up-regulation of the expression of cytoprotective enzymes, associated with decrease in ROS levels, tartrate-resistant acid phosphatase-positive multinucleated cell number, as well as osteoclast differentiation, and attenuation of bone destruction, as found both in vitro and in vivo models[17]. Consistent with this line of evidence, overexpression of Keap1 or RNAi-induced knock-down of Nrf2 resulted in effects opposite to those obtained by stimulation of Nrf2-dependent DNA binding activity [17].

The precise mechanisms by which stimulation with RANKL reduces Nrf2 is not currently known. It is known Keap1 has highly reactive thiol groups in its structure and that oxidation of this domain leads to significant changes in the conformation of Keap1, resulting in dissociation from Nrf2 and stimulation of nuclear Nrf2-dependent DNA binding activity [17]. In addition, Nrf2 (see previous section) autoregulates its own expression [19,20,21]. Taken together, this evidence implies that an increase in ROS levels induced by stimulation with RANKL may up-regulate Nrf2. It has also been reported that Nrf2 regulates Keap1 by controlling its transcription[19,21. Change of stability of Nrf2 mRNA or decrease of translation by miRNA can modulate RANKL-dependent Nrf2 down-regulation. Also, Bach1, an inhibitor of Nrf2 binding to the ARE, could participate to this mechanism, as indicated by attenuated osteoclastogenesis found in Bach1 knock-out mice [17].

However, although extensive investigations will be required to clarify the exact regulatory mechanisms linking Nrf2 to stimulation with RANKL, it is clearly proven that Keap1/Nrf2 axis regulates RANKL-dependent osteoclastogenesis through redox-modulation of intracellular ROS signaling and expression of cytoprotective enzymes. This raises the exciting possibility that the Keap1–Nrf2 axis may be a therapeutic target for the treatment of bone destructive disease.


Osteoporosis and hip fracture are commonly observed complications seen in patients with AD. Although the mechanisms underlying this association remain poorly understood, emerging evidence supports the view that AD risk genes may also be a risk factor for osteoporosis, and that AD and osteoporosis may share conserved oxidative stress-driven pathogenic mechanisms.

ROS may be a conserved mechanism underlying APPswe-induced neurodegenerative and osteoporotic pathological alterations.
Bone remodeling is a process of continuous formation and resorption occurring in specific areas of the matrix.

Novel therapeutic strategies have been developed focused on the inhibition of excessive bone resorption and promotion of bone formation process.
Accordingly, basic research can greatly contribute to the identification of specific pathways that can be effectively targeted by novel compounds able to treat and possibly reverse osteoporosis, particularly that occur in already chronically severed patients, such as in neurodegenerative disorders.


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