(Aging 15: 413-418, 2003),©2003, Editrice Kurtis
`
`Aging Clinical and Experimental Research
`
`Bisphosphonates: Potential therapeutic agents
`for disease modification in osteoarthritis
`
`Tim D. Spector
`Department of Rheumatology and Twin Research & Genetic Epidemiology Unit, St Thomas Hospital,
`London, England, UK
`
`ABSTRACT. Current treatments for osteoarthritis
`(OA) are mainly targeted towards providing short-
`term symptom relief. The focus in the development of
`disease-modifying drugs has been on therapies that
`modify cartilage directly. Recent research has high-
`lighted the importance of subchondral bone as a target
`for therapeutic intervention and disease modification.
`At the subchondral level, affected joints have de-
`creased bone mineral content and quality. In addi-
`tion, increased bone turnover has been observed at lev-
`els similar to those in patients with osteoporosis. Con-
`sequently, the potential benefits of drugs that alter
`bone metabolism are being examined in this disease, in
`particular, the antiresorptive agents, bisphosphonates.
`Results from pre-clinical studies have shown promising
`results for these compounds. Although the mecha-
`nism of action remains unclear, comparative studies in-
`dicate that this activity may be unique to the specific
`structure of the bisphosphonate, rather than repre-
`sentative of a class effect. Clinical studies are now
`under way to determine the efficacy and safety of
`bisphosphonates which may offer new therapeutic op-
`tions in the treatment of OA.
`(Aging Clin Exp Res 2003; 15: 413-418)
`©2003, Editrice Kurtis
`
`INTRODUCTION
`Osteoarthritis (OA) is a progressive disorder of the
`whole joint in which a complex combination of degrada-
`tive and reparative processes alters the anatomy and
`matrix of articular cartilage and subchondral bone. Ra-
`diographic evidence has demonstrated that erosion of ar-
`ticular cartilage, joint space narrowing, sclerosis of sub-
`chondral bone, and the presence of osteophytes are key
`features of the disease. Osteoarthritis is also characterized
`by clinical symptoms of joint pain and stiffness, including
`a limited range of motion, crepitus and, in some cases, ef-
`
`fusion. Osteoarthritis is normally the result of the interplay
`between systemic (e.g., genetic, metabolic) and local
`(e.g., obesity, age, sports injury) factors, and the major
`joints affected are the knee, hand, hip and spine.
`Current therapies for the treatment of OA are mainly
`targeted towards providing symptom relief, and include
`oral analgesics, such as acetaminophen, non-steroidal
`anti-inflammatory drugs (NSAIDs), and topical analgesics,
`such as capsaicin. Weight loss, physical therapy and life-
`style changes are also recommended for potential func-
`tional improvement. There are currently limited data on
`therapies that modify the course of the disease or affect
`joint structure.
`Historically, OA has been considered as a disease of
`the articular cartilage, changes to the bone being sec-
`ondary to observed changes in the cartilage. Conse-
`quently, research efforts were focused primarily on car-
`tilage. However, there is increasing evidence that bone
`may be involved in the pathogenesis of OA, in both dis-
`ease initiation and progression. Although the involve-
`ment of bone in the pathogenesis of OA is not a new con-
`cept, the wealth of recent evidence highlighting a primary
`role for bone changes in the disease has fuelled the debate
`as to whether the initiating process originates in the
`bone or in the cartilage. The outcome of this is an in-
`creased level of interest in subchondral bone as a thera-
`peutic target for OA, and, in particular, the potential
`benefits of drugs that affect bone metabolism. This review
`discusses the evidence in support of a primary role of
`bone in OA, and focuses on the potential use of bispho-
`sphonates as novel therapeutic disease-modifying agents
`for the treatment of this disease.
`
`BONE AS THE INITIATOR AND
`PROGRESSOR OF OA
`Initial awareness of the role of bone in OA dates back
`to the 1970s, with the clinical observation that patients
`
`Key words: Bisphosphonates, bone, cartilage, disease modification, osteoarthritis.
`Correspondence: Prof. T.D. Spector, Department of Rheumatology and Twin Research & Genetic Epidemiology Unit, St Thomas
`Hospital, London SE1 7EH, England, UK.
`E-mail: tim.spector@kcl.ac.uk
`Received and accepted July 29, 2003.
`
`Aging Clin Exp Res, Vol. 15, No. 5 413
`
`

`

`T.D. Spector
`
`(Aging 15: 413-418, 2003),©2003, Editrice Kurtis
`
`with OA had higher metacarpal bone density compared
`with controls (1). Several years later, Radin and Rose (2)
`published a seminal paper in which they presented an al-
`ternative to the ‘cartilage first’ hypothesis, proposing
`that the primary changes in OA lie in the underlying
`subchondral bone. The authors reasoned that repetitive
`cumulative microdamage leads to increased bone re-
`modeling and stiffness, resulting in increased wear in
`the overlying cartilage.
`More recent data indicate that bone plays a role in
`both initiation and progression of OA. For example,
`scintigraphic studies show that osteoarthritic joints of the
`hand and knee are associated with positive scintigraphic
`scans, indicating increased blood flow to the bone and
`progress to radiographic OA. In contrast, joints with a
`negative scan did not progress to radiographic OA,
`even when followed for several years (3, 4). This ob-
`served increase in vascularization and activity of the
`bone has been further supported by other studies,
`which have revealed numerous abnormalities in OA
`subchondral bone, including hyperemia and microfrac-
`tures (5). In a recent study, magnetic resonance imaging
`(MRI) of patients with knee OA showed that bone mar-
`row lesions (which may be stress points) are strongly as-
`sociated with the occurrence of knee pain (6). In addi-
`tion, sensitive radiographic analyses have shown that
`subchondral sclerosis and osteophyte growth precede
`cartilage loss (7).
`One possible mechanism by which these underly-
`ing bone changes could affect the overlying cartilage is
`by releasing destructive factors such as cytokines and
`metalloprotease enzymes. Variations in OA subchondral
`bone structure are driven by a number of important pro-
`cesses, including osteoblast phenotypic expression (8),
`chondrocyte apoptosis (9), matrix metalloproteinases (10)
`and growth factors. The theory that bone-derived prod-
`ucts may drive cartilage degradation is further support-
`ed by data showing that cells taken from OA knees at
`joint replacement induced cartilage breakdown in car-
`tilage tissue culture, even when physically separated
`from the cartilage (11). Furthermore, channels have
`been identified between the subchondral region and
`cartilage, which may act as a means of communication
`between these tissues (12).
`
`IMPACT OF OA ON BONE MINERAL
`DENSITY
`The changes in bone metabolism seen in OA are re-
`flected in alterations in bone mineral density (BMD)
`measurements and biomarkers. BMD values are ob-
`tained through dual energy X-ray absorptiometry (DXA),
`a technique commonly used for the diagnosis of os-
`teoporosis (OP). Although OA and OP are both com-
`mon, age-related, musculoskeletal disorders, until re-
`cently it was believed that there was a negative associ-
`
`414 Aging Clin Exp Res, Vol. 15, No. 5
`
`ation between the diseases, high BMD being associated
`with OA and low BMD with OP. However, recent lon-
`gitudinal population studies using BMD measurements
`in large populations have revealed complex relationships
`between OA and BMD (13). Large-scale epidemiologi-
`cal studies have shown that higher levels of bone mass
`(8-10%) are found in subjects with OA of the hip and
`knee compared with age-matched controls (14-16).
`Although speculative, one explanation is that the ap-
`parent increase in BMD is related to the presence of os-
`teophytes. Two epidemiological studies (14-16) have
`shown that high BMD is associated with an increased
`risk of incident OA. However, although patient numbers
`were small, these studies also showed that low bone
`mass appears to be associated with more rapid pro-
`gression of OA of the knee.
`Whilst studies have revealed that OA patients may
`have higher BMD at sites away from the affected joint,
`the disease is characterized by decreased subchondral
`bone mass and local osteopenia in the affected area (17,
`18). For example, decreases in bone mineral content
`have been demonstrated in the subchondral bone plate
`in the femoral heads of both OA and OP patients com-
`pared with normal controls (18). Similarly, in a study in
`which BMD was assessed in the knee joint, radio-
`graphically diagnosed OA knees had a lower BMD than
`normal knees, whereas spine and femoral shaft BMD
`was similar between the two groups (19). Localized os-
`teopenia, characterized by low BMD, has also been
`found in the bone immediately adjacent to sites of os-
`teophyte formation (20) and the size of this area in-
`creases with progressive loss of cartilage (21).
`These findings suggest that bone mass is abnor-
`mally raised in OA patients – this occurs in areas away
`from the affected joint, whereas bone mass is actually
`low in the subchondral area of the joint itself. Previ-
`ously, it was believed that the increased BMD in OA
`would protect against fracture. However, studies of
`the association between the presence of OA and frac-
`ture risk have produced conflicting results (22-26).
`Overall, these data suggest that there may actually be an
`increased risk of fracture in patients with OA. Howev-
`er, confounders, such as the altered risk of falls and
`muscle strength in patients with OA, make observa-
`tional studies problematic.
`
`IMPACT OF OA ON MARKERS OF BONE
`TURNOVER
`In recent years, several biochemical markers of bone
`turnover have been developed and validated in both ani-
`mal models and humans. These markers are secreted dur-
`ing bone formation or following bone resorption, and can
`be measured in the serum and/or urine.
`Several cross-sectional studies have shown increased
`levels of bone turnover markers in patients with OA
`
`

`

`(Aging 15: 413-418, 2003),©2003, Editrice Kurtis
`
`Bisphosphonates in osteoarthritis
`
`beculae (measured by trabecular separation and tra-
`becular connectivity), provides a more detailed de-
`scription of the overall trabecular architecture than
`BMD alone. Such studies have revealed that OA bone
`is considerably less dense and has a reduced mineral
`content compared with normal bone (18). Kamibayashi
`et al. (33, 34) showed changes in the trabecular ori-
`entation in OA patients; specifically, these studies re-
`vealed decreased trabecular numbers and connectivity
`in cancellous bone.
`
`SUBCHONDRAL BONE AS A TARGET FOR
`DISEASE MODIFICATION IN OA
`The above findings support the involvement of bone
`in OA and also the hypothesis that OA is primarily a
`disease of subchondral bone. Both bone loss and poor
`bone quality are evident in patients with OA and OP, al-
`though in OA this appears to be localized to the af-
`fected joints. Furthermore, it appears that increased
`bone turnover drives progression of OA. As such,
`there is great interest in the role of bone as a thera-
`peutic target for OA, and, in particular, the potential
`benefit of drugs that alter bone metabolism.
`Bisphosphonates are anti-resorptive compounds
`that regulate bone turnover through suppression of
`osteoclast activity. This ability to regulate bone turnover,
`together with their selective localization to bone, has re-
`sulted in the successful administration of bisphospho-
`nates in a variety of disorders of bone metabolism,
`including OP, Paget’s disease and skeletal metastases,
`as well as less familiar disorders such as fibrous dys-
`plasia, sympathetic dystrophy and Charcot’s arthropa-
`thy (35, 36). Preliminary data from an uncontrolled
`study using the bisphosphonate etidronate has indi-
`cated an analgesic effect in patients with OA (37).
`
`Pre-clinical data supporting a role for
`bisphosphonates in OA
`Several animal models for OA exist; in many of
`these, the disease is induced experimentally – either sur-
`gically (e.g., using ACL transection), chemically (e.g., in-
`jection of collagenase) or mechanically (e.g., repeti-
`tive loading) – whereas in others the disease occurs nat-
`urally. The Duncan-Hartley guinea pig model is the
`most widely used and the best-characterized model of
`primary non-traumatic OA (38). Similar to most cases
`of human OA, the disease is not caused by injury, but
`rather develops spontaneously in genetically predis-
`posed individuals and progresses with age. In the animal
`model, lesions appear from the age of 3 months; they
`are located primarily on the medial tibial plateau and in
`areas not covered by the meniscus.
`The effects of several bisphosphonates have been
`evaluated in these models. A recent comparative analysis
`of multiple bisphosphonates demonstrated that anti-
`
`Aging Clin Exp Res, Vol. 15, No. 5 415
`
`•
`
`NTx
`
`D
`CTx
`
`T
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`NTx nmol/mmol Cr
`
`P
`
`N
`
`g O
`
`A
`
`o nt
`
`CTx mg/mmol Cr
`
`500
`450
`400
`350
`300
`250
`200
`150
`100
`50
`0
`
`P
`
`M
`
`O n o O
`
`A
`
`g O
`
`A
`
`P ro
`o n - P ro
`o st- M C
`o nt
`P re - M C
`
`Figure 1 - Levels of bone resorption markers in pre-menopausal
`controls, N=41 (Pre-M Cont); and post-menopausal controls,
`N=50 (Post-M Cont); patients with non-progressive knee os-
`teoarthritis (OA), N=36 (Non-prog OA); patients with progressive
`knee OA, N=71 (Prog OA); and patients with post-menopausal os-
`teoporosis with no knee OA, N=59 (PMO no OA). (Data from Bet-
`tica et al. 2002, Ref. 30)
`
`(27-31). In general, these data are more consistent
`for markers of bone resorption. Although most studies
`have been cross-sectional, a recent longitudinal study
`(30) examined levels of bone resorption markers at
`three time-points in a population of post-menopausal
`women with progressive knee OA. The findings from
`this study showed that bone resorption was signifi-
`cantly increased in patients with progressive OA com-
`pared with age-matched controls. Moreover, this ele-
`vation in bone resorption was equivalent to that ob-
`served in patients with post-menopausal OP. In addi-
`tion, the group with progressive disease had higher lev-
`els of bone resorption markers compared with those
`without progressive disease (Fig. 1). A recent case-
`control study (32) examined the relationship between ra-
`diographic knee OA and altered bone turnover in a
`population of 1644 female twins, and demonstrated
`that subjects with radiographic OA have increased
`bone resorption. Because the study was carried out us-
`ing twins who are closely matched for age and genetic
`and environmental factors, the findings indicate that
`these metabolic abnormalities are a result of the disease
`itself rather than due to inherited susceptibility.
`
`ANALYSIS OF BONE
`MICROARCHITECTURE IN OA
`In addition to examining changes in bone metabolism
`in OA, other studies have assessed changes in the ac-
`tual composition of the bone. Measurement of individual
`trabecular parameters such as trabecular thickness and
`trabecular number, as well as the interaction of tra-
`
`

`

`T.D. Spector
`
`(Aging 15: 413-418, 2003),©2003, Editrice Kurtis
`
`resorptive potency did not correlate with cartilage effi-
`cacy in the guinea-pig OA model (39) (Fig. 2). For ex-
`ample, although the bisphosphonate NE-58051 only ex-
`hibits moderate anti-resorptive potency, it demonstrates
`significant cartilage effects. Furthermore, only the group
`of amino bisphosphonates with pyridinyl side-chains
`were efficacious in this study, although not all of them
`proved effective. This was further demonstrated in a
`head-to-head study in which the pyridinyl bisphospho-
`nate risedronate was shown to slow disease progression
`in the guinea pig model, as measured by cartilage lesion
`size and severity and osteophyte size, with a maximal ef-
`fect on disease suppression of 30-40% (40). The primary
`amino bisphosphonate alendronate did not slow disease
`progression in this model (40).
`An amino bisphosphonate structurally similar to rise-
`
`dronate has also been shown to inhibit the increase in
`bone and vascular activity seen in the dog hind limb fol-
`lowing surgically induced OA (transection of anterior cru-
`ciate ligament) (41). In another study, the pyridinyl bis-
`phosphonate zoledronate was shown to have a benefi-
`cial effect in a rabbit model of cartilage matrix damage
`(42). This variation in the effects of bisphosphonates in-
`dicates that the beneficial effect in OA animal models
`may not be a class effect, but is unique to the individu-
`al bisphosphonate.
`
`Clinical studies of bisphosphonates in OA
`To date, clinical evidence for a disease-modifying drug
`in OA is limited; however, long-term clinical trials on car-
`tilage and bone are currently under way and it is hoped that
`the results will answer some of the questions regarding the
`
`Structure
`
`Anti-resorptive
`potency
`
`Efficacy in
`guinea-pig model
`
`Structure
`
`Anti-resorptive
`potency
`
`Efficacy in
`guinea-pig model
`
`NE-10575
`
`O
`~ /
`O
`P
`
`OH
`OH
`P
`OH
`?'\
`O
`OH
`
`as--
`Yi
`
`O
`
`--
`-
`
`OH
`
`P
`
`OH
`H
`OH
`OH
`
`P
`
`HS
`
`O
`
`0.0001
`
`p<0.06
`
`0.10
`
`NS
`
`NE-58051*
`
`NE-11429
`
`NE-97221*
`
`0-1
`--
`
`ONa
`
`O
`
`P
`
`OH
`H
`P
`OH
`-1/' \
`O
`OH
`
`:::--..
`N
`
`~ -
`
`OH
`O
`~ /
`P
`OH
`OH
`OH
`OH
`
`P
`
`O
`
`N
`
`0.01
`
`p<0.05
`
`1.0
`
`p<0.05
`
`0.0003
`
`p<0.05
`
`N+
`I
`CH3
`
`:::-.....
`
`NE-58095*
`risedronate
`
`OH
`O
`.::::-1
`P
`......
`OH
`OH
`P
`OH
`r \
`O
`ONa
`
`~
`
`N
`
`NE-10503
`alendronate
`
`OH
`O
`.::::- /
`....
`P
`OH
`~
`H2N
`OH
`P
`OH
`~\
`O
`ONa
`
`0.001
`
`NS
`
`Figure 2 - Antiresorptive potency [assessed by lowest effect dose (mgp/kg) in the Schenk growing rat model] and efficacy of bis-
`phosphonates tested in the guinea pig model of OA (Meyer et al. 2002, Refs. 39, 40). Asterisk: demonstrated structure-modifying
`efficacy in the guinea pig model.
`
`416 Aging Clin Exp Res, Vol. 15, No. 5
`
`

`

`(Aging 15: 413-418, 2003),©2003, Editrice Kurtis
`
`Bisphosphonates in osteoarthritis
`
`pathogenesis and treatment of OA. Clinical end-points for
`assessment of the efficacy of bisphosphonates are ex-
`pected to reflect differences in both structure and symp-
`toms. Currently, the best characterized structure assessment
`available is radiographic examination of joint space nar-
`rowing of the knee or hip. Measurements of bone structure
`and biomarkers could also be used to assess destruction of
`cartilage and bone. In the future, measurement of cartilage
`volume using MRI may be used to assess structural
`changes; however, at present, technical problems re-
`main, and there is a lack of data correlating MRI with X-
`rays (6). Other end-points that might be considered as as-
`sessments of efficacy include measurement of osteo-
`phytes, patient global assessments such as SF-36 quality-
`of-life questionnaires, and economic resource use.
`
`CONCLUSIONS
`There is increasing evidence for the role of bone in the
`pathogenesis of OA, as seen by increased bone turnover,
`decreased bone mineral content and quality. Therefore,
`agents which are bone-active have potential application in
`the treatment of OA. Results from non-clinical studies us-
`ing bisphosphonates have been encouraging. Data are
`now eagerly awaited from clinical trials to determine the
`efficacy and safety of bone-modifying agents in altering the
`long-term course of OA.
`
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