Osteoporosis and osteoarthritis: bone is the common battleground


and Jean-Pierre PELLETIER, MD
Osteoarthritis Research Unit
University of Montreal Hospital
Research Center (CRCHUM)
Notre-Dame Hospital, Montreal
Quebec, CANADA

Osteoporosis and osteoarthritis: bone is the common battleground

by D. Lajeunes se, J.-P. Pelletier, and J. Martel -Pelletier, Canada

Osteoporosis (OP) and osteoarthritis (OA) are two major health burdens in our modern societies. Both are complex musculoskeletal diseases and although OA affects different tissues, they both affect bone. Although these diseases affect more women than men and were suggested to be mutually exclusive, mechanisms leading to them may overlap. Indeed, a number of factors involved in OP pathophysiology also seem to be involved in OA subchondral bone; however the mechanisms may be different in both conditions. The present review explores these two diseases from a perspective of how bone/subchondral bone tissue ismodified, and whichmechanisms could be responsible for the alterations.

Medicographia. 2010;32:391-398 (see French abstract on page 398)

Pathophysiology of osteoporosis

According to the World Health Organization, osteoporosis (OP) is the most common metabolic bone disorder.1,2 Osteoporosis is characterized by low bone mass due to an imbalance in favor of bone resorption over bone formation, leading to altered bone remodeling. Indeed, OP is not solely the result of bone loss since bone loss occurs in both women and men with age, and the failure to attain an optimal (ie, peak) bone mass during childhood and adolescence is one of the most important factors leading to OP without any evidence of accrued bone loss. There are abnormalities in the amount and architecture of bone tissue leading to altered strength and an increased susceptibility to fractures (Figure 1, page 392). Osteoporosis presents changes both in bone density and bone quality, with bone quality including not only microarchitectural deterioration, but also alterations in bone turnover/remodeling, damage accumulation (microfractures, etc), and mineralization. The reduction in bone mass can be quantified by measurement of bone mineral density (BMD) using dual-energy x-ray absorptiometry (DXA), either in the proximal femur or in the spine.3 Risk factors for postmenopausal OP include, in addition to female gender, ethnicity with white women being more affected than any other group, estrogen deficiency, repeated fractures during adult life and/or in first-degree relatives, low body weight or low body mass index (BMI), smoking, and use of oral corticosteroid therapy for more than 3 months.4,5

At the tissue level, OP can be described as a thinning of bony rod-like trabeculae due to the net loss of calcium and bone structure, eventually leading to overt perforation. This is due to an imbalance in the sequence of events between bone resorption and bone formation. Each sequence is composed of a bone resorption period that cre- ates resorption cavities, followed by osteoblast activation and formation of the osteoid matrix filling the cavity. Upon completion, the osteoblasts are embedded in the matrix and they become osteocytes.

Figure 1
Figure 1. Representation of normal and osteoporotic bone tissue.

Osteoporotic bone shows thinning of the bone trabeculae and a general decrease in total bone tissue.
From: Aurora Health Care. © 2010, www.aurorahealthcare.org.

During physiological bone remodeling, there is a close relationship between cortical and trabecular bone. Chemical/ mechanical factors permitting the cortical and trabecular bone to adapt to each other control the expansion of the cortical compartment downregulating the cancellous bone compartment and vice-versa.6-8 These mechanisms appear to fail during post-menopause, with aging, and obviously in OP women, leading to higher mechanical constraints imposed on the skeleton, loss of bone mineral, and microstructural deteriorations.

Bone remodeling occurs through osteoblast activity for bone formation via the synthesis of bone matrix, and through osteoclast activity for the degradation of bone matrix. The equilibrium between the activities of these two cells maintains the mineral homeostasis. Osteoblasts, which synthesize the protein matrix, originate from local mesenchymal stem cells (MSCs). These cells form a layer of organic matrix called osteoid, whose thickness depends on the time interval between matrix formation and its subsequent calcification. The plasma membrane of the osteoblast is rich in alkaline phosphatase, which initiates the bone mineralization process. Later in the process, osteoblasts are progressively transformed into osteocytes; they become flat lining cells and are embedded in an organic bone matrix, which becomes mineralized. Osteocytes have long cell processes that form thin canaliculi, which connect them to each other as well as to active osteoblasts and flat lining cells, and carry circulating bone extracellular fluid. Osteoclasts are giant multinucleated cells originating from stem cells of the mononuclear/macrophage lineage and are responsible for bone resorption. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (calcitriol), sex hormones, and cytokines such as tumor necrosis factors (TNFs) and interleukins (ILs) within the bone marrow control the formation of osteoclasts.

Pathophysiology of osteoarthritis

Osteoarthritis (OA) has been characterized by progressive articular cartilage loss and osteophyte formation. Despite major progress in the last few decades, we still have much to learn about the etiology, pathogenesis, and progression of this disease. The slowly progressive and multifactorial nature of OA, its cyclical course, where a period of active disease is followed by a period of remission, has limited our comprehension of this disease. Although OA was long considered to be due only to an imbalance between loss of cartilage and an attempt to repair cartilage matrix, it is now known that OA, at least in the knee, is a heterogeneous disease involving all the articular tissues including cartilage, subchondral bone, menisci, and periarticular soft tissues such as the synovial membrane. Synovitis is often present and is considered to be secondary to the alterations in other joint tissues. Yet, findings indicate that synovial inflammation could be a component of even the ear- ly events leading to the clinical stage of the disease. In addition, emerging evidence suggests that changes in subchondral bone and menisci are closely involved in the disease progression.

Subchondral bone is suggested to be the site of the causally most significant pathophysiological events occurring in cartilage (Figure 2A). Although OA is not considered a generalized bone metabolic disease,9 data suggest that the subchondral bone alterations may precede cartilage changes. Indeed, it was long believed that OA subchondral bone underwent only appositional new bone formation and sclerosis; however, it is now understood that there are also phases of resorption in this diseased tissue.10,11 Inasmuch as early bone resorption features can be observed in OA, patients with progressive knee OA show increased indices of bone resorption, whereas, in general, nonprogressing OA patients do not show altered resorption.12,13

Of importance, subchondral bone plate and trabecular bone do not show the same architecture or the same abnormal cell metabolism during OA. Indeed, as indices of bone resorption indicate loss of trabecular tissue, the increase in collagen type I cross-linked N-telopeptide (NTX) and C-telopeptide (CTX) observed in subsets of OA patients14 suggests a progressive loss of trabecular bone, not subchondral bone, which actually shows sclerosis. In addition, in those patients showing sclerosis, recent evidence using microcomputed tomography (microCT) indicates that bone sclerosis is due to an altered microarchitecture of the bone with trabeculae showing more platelike structures than rod-like structures.15,16 Such alterations in the microarchitecture of bone tissue would also likely alter bone stiffness.

Table I
Table I. Comparison of osteoporosis and osteoarthritis bone parameters.

Morphologically, one of the hallmarks of knee OA is the presence of bone marrow lesions (BMLs) consisting of edema-like lesions and cysts in subchondral bone as seen with magnetic resonance imaging (Figure 2B).17,18 These BMLs were found to be strong indicators of bone turnover indices as well as progressive structural changes in knee OA patients. Moreover, BMLs are associated with poorly mineralized sclerotic bone tissue in OA patients.19

Figure 2
Figure 2. Human knee histology and magnetic resonance imaging.

(A) Histological representation of cartilage and subchondral bone in a normal and osteoarthritic human knee.
(B) Representations of bone cysts and edema as seen by magnetic resonance imaging in the human osteoarthritic knee femoral condyle. Red arrows indicate cysts and the red circle the edema.
Figure 2A: Photos by Dr J. Martel-Pelletier. Figure 2B is adapted from reference 17: Raynauld et al. Ann Rheum Dis. 2008;67:683-688. © 2008, BMJ Publishing Group Ltd.

Osteoporosis vs osteoarthritis

The prevalence of both OP and OA is higher in women than men. Risk factors for OA include age, gender (female), genetic predisposition, mechanical stress and/or joint trauma, and obesity (high BMI). Some of these risk factors are also associated with OP, yet the opposite weight conditions in the two diseases and the presence of fractures in OP vs OA are some of the conditions that distinguish the two diseases (Table I).4

Although it is well established that in OP the low bone mass is due to an imbalance in favor of bone resorption over bone formation (Figure 3, page 394), new hypotheses about OA pathophysiology have been put forward. Hence, OA was re- cently suggested to be related to an inappropriate attempt at subchondral bone formation leading to cartilage remodeling/ degeneration and synovitis.20 Moreover, Aspden21 proposed an alternative theory, in which OA could be a pathological growth, not decay, problem showing excessive and poorly regulated growth of musculoskeletal tissues, with cells possibly reverting to an abnormal developmental phenotype with a loss of proper function. Hence, (a) mechanism(s) leading to normal tissue formation could be altered in such a way that tissue integrity is never attained. However, although the latter hypothesis is very attractive and deserves consideration, many questions still remain to be answered.

Figure 3
Figure 3. Representation of the bone remodeling cycle in osteoporosis.

Osteoporotic bone shows an increase in the length of the remodeling
cycle and reduced capacity to lay down a new mineralized bone matrix.
Abbreviations: BRU, bone remodeling unit; CL, cement line; LC, lining cells; OS, osteoid.
From: www.medscape.com © 2010, Medscape.

Another interesting thought is that, as bone resorption is now considered to be centrally controlled via leptin, an adipocytokine produced by adipocytes that plays a role in bone homeostasis and is locally modulated by adrenergic â2 receptors in osteoblasts,22,23 this regulation via leptin may be a key element, whereas leptin levels are different in OP and OA patients.24,25

_ Morphological level
Compared with OP, which is a systemic skeletal disorder characterized by a decrease in BMD with alterations in bone microstructure and a reduction in the bone mineral component, OA does not seem to be a systemic bone disorder, as it shows increases in BMD, yet reduced bone mineral content and increased osteoid, as well as alterations in subchondral bone microstructure. In this disease, the progression of joint cartilage degeneration is associated with intensified remodeling of the subchondral bone and increased subchondral bone stiffness,26 whereas in OP bone remodeling and bone stiffness decrease.

A number of studies suggest that OA patients should have better bone mass. Indeed, data revealed that these patients have a better preserved bone mass,27-29 and primary OA and OP rarely coexist.30-32 Indeed, hip and spine BMD were found higher in women with radiographically defined knee OA. However, low hip BMD levels have also been associated with a greater risk of progression of OA, and a significant percentage of women with OA undergoing hip replacement met the criteria for OP.4 Furthermore, there is an association between osteophytes and the pathophysiology of OA, whereas osteophytes are not observed in OP.

In addition to thicker trabeculae, trabecular microfractures are also observed in OA bone tissue at a greater frequency, especially in the hip.33,34 This in turn could lead to BML formation, as such lesions may be the result of microfractures.35 Healing of microfractures in OA subchondral bone could generate a stiffer bone, which is no longer an effective shock absorber.36,37 Conversely, subchondral bone stiffness may be part of a more generalized bone alteration leading to an apparent increase in BMD or volume. However, subchondral bone thickening reflects osteoid volume increases, but not necessarily an increase in this tissue’s mineralization.38 In the knee, BMLs have not been reported in OP, yet in the hip they can be observed in both OP and OA.39

Stiffness and BMD are not uniformin OA subchondral bone.40,41 The bone closest to the articular cartilage has the greatest effect on cartilage integrity, with variations in stiffness and BMD probably causing more damage to cartilage than any other parameters.42,43 Although OA is associated at a later stage with a thickening of subchondral bone as opposed to a progressive thinning of bone in OP, explants of the femoral head of OA patients at autopsy showed a low mineralization pattern compared with normal.44-46 Hence, the apparent increase in BMD in OA may be due to an increase in material density, not an increase in mineral density. Indeed, bone tissue mineralization in OA has been reported to be lower than normal (Figure 4) and, very surprisingly, even lower than in OP.47 Although there is an increase in type I collagen production, the undermineralization could be related to an abnormal increase in the ratio of type I collagen α1 to α2 chains in OA compared with normal tissue.48,49 Indeed, data showed a 2- to 3-fold increase in the expression of COL1A1 chains of type I collagen, with no variations in COL1A2 expression in OA subchondral bone osteoblasts, leading to an increase in the production of type I collagen α1 chains. Together with the reduced number of crosslinks in OA bone tissue,44 this could explain the reduction in bone mineralization. OA osteoblasts also show increased levels of osteocalcin and alkaline phosphatase.50,51 Hence, both the terminal differentiation and the mineralization of OA subchondral bone osteoblasts are altered.

_ Cellular level
The hypercellularity observed in OA subchondral bone tissue may be linked with the increased rate of osteoblast proliferation observed in these cells52 or with reduced apoptosis of OA osteoblasts.52,53 In contrast, OP osteoblasts proliferate at a slower rate and show more pronounced apoptosis.54,55 Increased cell numbers and more collagen production per cell would suggest that OA individuals should have better bone mass as noted above. The molecular mechanisms locally involved in the bone remodeling process include the coupling between osteoblasts and osteoclasts. Among the factors of importance are the membrane-bound intercellular adhesion molecules-1 (mICAM-1 or CD54) and the molecular triad receptor activator of nuclear factor κB ligand (RANKL)/ RANK/osteoprotegerin (OPG), which have emerged as essential role players, not only in bone formation, but also in bone resorption processes. Cellular interactions between osteoblasts and preosteoclasts mediated through adhesion molecules such as mICAM-1 have been recognized as important modulators of osteoclast recruitment and differentiation.56,57 RANKL, a member of the TNF ligand family and produced by the osteoblasts, binds to its specific receptor RANK on osteoclast precursors, promoting their differentiation and fusion, and eventually the formation of mature osteoclasts. RANKL also binds to RANK on the mature osteoclasts and induces their activity. OPG, also produced by the osteoblasts, is a decoy receptor that binds to RANKL, thus inhibiting osteoclastogenesis. From a clinical standpoint, studies reported progressively higher mICAM-1 levels in the synovium of OA, rheumatoid arthritis (RA), and OP patients, respectively, compared with healthy individuals, and in bone from hip or knee OA patients undergoing primary arthroplasty or patients with a hip fracture secondary to OP.58-60

The equilibrium between OPG and RANKL also plays a crucial role in the physiology of bone.61 Under normal conditions the ratio of OPG to RANKL produced by osteoblasts favors bone formation by keeping bone resorption under strict control. In OP, the OPG/RANKL ratio decreases, favoring bone resorption by activating osteoclasts and apoptosis of osteoblasts.62,63 Currently, potential drugs for OP target a reduction in RANKL or an increase in OPG levels. In contrast to OP, ex vivo studies performed on human OA subchondral bone osteoblasts revealed two distinct subgroups of patients based on these cells’ low (L) or high (H) endogenous prostaglandin (PGE2) levels,64 which otherwise demonstrate no different phenotypic features. Interestingly, differences in OPG and RANKL levels also exist between the two OA subpopulations. In short, both the L-OA and H-OA subchondral bone osteoblasts demonstrated an abnormal OPG/RANKL mRNA ratio, yet it was reduced in the L-OA, suggesting increased subchondral bone resorption, and increased in H-OA, indicating a shift toward subchondral bone formation.65 This observation was further strengthened by data showing that L-OA osteoblasts induced a significantly higher level of mature osteoclasts compared to the H-OA and higher bone resorption activity.65 Such findings suggest that each human OA subchondral bone subpopulation has reached a different metabolic state; L-OA being enriched with factors promoting bone resorption and H-OA having reduced resorptive properties, with the metabolism of the latter cells favoring bone formation. Thus, in humans, the OA subchondral bone osteoblast subpopulation could reflect different stages or attempts to repair this damaged tissue: an increase in bone resorption followed by bone formation.

Figure 4
Figure 4.n=3 separate individuals per group) incubated in BGJb media containing 10% fetal bovine serum (FBS), 50 μg/mL ascorbic acid and 50 μg/mL β-glycerophosphate for 30 days. Of note, less mineralization is seen in OA compared with normal.
After reference 48: Couchourel et al. Arthritis Rheum. 2009;60:1438-1450. © 2009, American College of Rheumatology.

Another family of signal proteins, the Wnt/LPR5 (a Wnt receptor)/ β-catenin canonical signaling pathway, was also identified as a crucial role player in bone formation. Recent studies suggested the potential direct contribution of mature osteoblasts/ osteocytes to the recruitment and fate of MSCs via the Wnt signaling pathway. Indeed, the control of adipogenesis, osteogenesis, and chondrogenesis in bone marrow appears to be regulated locally, at least in part, by Wnt agonists and antagonists produced by the mature osteoblast/osteocytes.66,67 Such antagonists include members of the dickkopf family (DKK1 and DKK2). Osteocytes also contribute to local control of bone resorption via the production of the Wnt antagonist, sclerostin (SOST).68

It is proposed that the alterations in Wnt/LRP5 expression and/or activity could be implicated in the pathogenesis of OP, as this system appears to be an important transduction mechanism by which mechanical loading increases bone mass.69 Interestingly, recent evidence also showed that low estrogen levels diminished the skeletal response by downregulating the transcriptional activity of β-catenin.70 DKK-1 was suggested to be directly involved in the pathophysiology of OP,71 but as DKK-1 may have opposite effects on early and late osteoblast development,72,73 this could complicate the development of DKK antagonists for the treatment of OP. In addition, recent data on humans and mice delineated SOST as a compelling target for the development of OP therapeutics. With regard to OA, data on theWnt signaling system are only emerging, and contradictory data have been published, even by the same authors.74,75 This could be due to the fact that this system does not have a similar involvement in cartilage and subchondral bone. However, this system is involved in the pathophysiological process of this disease, at least in the subchondral bone, as human OA subchondral bone osteoblasts were shown to produce abnormal levels of DKK-2 and SOST.76,77


Studies have confirmed that in OA the subchondral bone is the site of several dynamic morphological changes that appear to be part of the disease process. They have also provided substantial evidence that changes in the metabolism of the subchondral bone are an integral part of this disease process, and that these alterations are not merely secondary manifestations, but are part of a more active component of the disease. Evidence for an imbalance in subchondral bone remodeling and/or turnover has also been obtained, which points to the fact that excessive subchondral bone formation may be present in OA, yet it is associated with abnormal tissue quality. In contrast, bone tissue formation never seems to attain its peak in OP, and combined with age-dependent bone loss, leads to poor tissue quality and quantity. However, these changes are associated with a number of local abnormal biochemical pathways related to altered osteoblast metabolism, which, in contrast to OP, appears to differ during the OA disease process (ie, OA subchondral bone demonstrated different phases).

Thus, a strong rationale exists for therapeutic approaches that target improving bone quality in both diseases by inhibiting subchondral bone resorption and/or promoting matrix quality in subchondral bone in OA and reducing bone resorption in OP. However, therapeutics that would reduce only bone resorption would be more beneficial for the subchondral bone of the L-OA patients as this tissue is in a resorptive phase, but in the H-OA patients, antiresorptive agents are expected to be less effective since the subchondral bone was shown to be in a formative phase. Nonetheless, more clinical trials exploring the effects of an anti–bone remodeling agent on the evolution of OA structural changes are required.

_ The authors thank VirginiaWallis for assistance with the manuscript preparation.


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Keywords: osteoporosis; osteoarthritis; osteoid matrix; mineralization; microfracture; bone marrow lesion; bone stiffness; bone remodeling; bone turnover; subchondral bone