Disease-Modifying Effects of Lenvatinib, a Multiple Receptor Tyrosine Kinase Inhibitor, on Posttraumatic Osteoarthritis of the Knee.

Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and fibroblast growth factor receptors, on synovitis, osteophyte formation, and cartilage degeneration in a rabbit OA model. Posttraumatic OA was induced by anterior cruciate ligament transection (ACLT) on one knee of each rabbit. Rabbits were placed into four groups according to the following lenvatinib doses: untreated control (n = 12), L0.3: 0.3 mg/kg/day (n = 15), L1.0: 1.0 mg/kg/day (n = 14), and L3.0: 3.0 mg/kg/day (n = 13) groups. We evaluated limb pain using the weight distribution ratio measured with an incapacitance tester, macroscopic osteophyte formation, and femoral condyle synovium and cartilage histology. For cartilage evaluation, the following distal sites of the femur were evaluated separately: femoral-tibial (FT), femoral-patellar (FP), and femoral corner (between FP and FT). The weight distribution ratio at 12 weeks after surgery was higher in the L0.3 and L1.0 groups than in the control group. Osteophyte formation and synovitis scores were significantly lower in the L0.3, L1.0, and L3.0 groups than in the control group. The Osteoarthritis Research Society International scores of the FT, corner, and FP sites in the L0.3 group were lower than in the control group. The cartilage thickness ratio at the FT and corner sites was significantly lower in the L0.3 group than in the control group. Krenn's grading system of cartilage synovitis showed that all lenvatinib-administered groups had significantly lower scores than the control group. MMP3 expression level in cartilage tissue was significantly lower in the L3.0 group compared with the other three groups. ADAMTS5 expression was lower in the L3.0 group compared with the control and L0.3 groups. Oral administration of lenvatinib inhibited synovitis, osteophyte formation, and cartilage degeneration and reduced pain in a rabbit ACLT model. Lenvatinib is an oral VEGF inhibitor that is easier to administer than other VEGF inhibitors and may have potential as a treatment of posttraumatic OA.

Hippo/YAP1 inhibition by verteporfin attenuates osteophyte formation in a mouse surgical osteoarthritis model.

Osteophyte is an outgrowth of cartilage formed at the margins of the affected joint through endochondral ossification-like processes, and is one of the most common radiographic features of osteoarthritis (OA) that has been used to define the stage of disease. Osteophyte has been regarded to adapt the joint to the altered biomechanics of OA patients, limits joint movement and represent a source of joint pain, however, the mechanism of osteophyte formation, the morphology characteristics and biomechanical properties of osteophyte cells are remained unclear. In the present study, we isolated osteophyte cells and chondrocytes from late-stage OA patients who underwent total knee replacement surgeries, by applying Atomic Force Microscopy (AFM), we identified osteophyte cells were in irregular shape with dendrites, shrunk cell body, smooth surface and high elastic modulus (23.3 ± 5.4 kPa) when compared with chondrocytes (6.5 ± 1.8 kPa). In addition, osteophyte cells showed higher proliferation ability and colony formation capacity than chondrocytes. Mechanistically, we identified YAP1, the core transcriptional factor of Hippo signaling pathway, was highly expressed in osteophyte cell both at protein and RNA levels. Inactivation of Hippo/YAP1 signaling pathway by Verteporfin is sufficient to inhibit osteophyte cell proliferation in vitro and attenuate osteophyte formation in vivo. In conclusion, the morphology characteristic and biomechanical property of osteophyte cells at single cell level are quite different from chondrocytes, although we could not exclude other regulatory mechanisms, our findings suggested that Hippo/YAP1 is of great importance for osteophyte formation.

Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis.

BACKGROUND: Subchondral bone (SCB) thickening is one of the earliest detectable changes in osteoarthritic joints and is considered a potential trigger for subsequent articular cartilage degeneration. In this manuscript, we examine whether disruption to the SCB osteocyte network contributes to the initiation and pathogenesis of osteoarthritis. METHODS: We examined expression patterns of the glycoprotein E11/podoplanin by immunohistochemical labelling in murine, human and canine osteoarthritis models. We also examined the effects of twice-weekly administration of Bortezomib, a proteasome inhibitor which stabilises osteocyte E11 levels, to C57/BL6 wild-type male mice (1 mg/kg/day) for 8 weeks after surgical destabilisation of the medial meniscus. By inducing osteoarthritis-like changes in the right knee joint of 12-week-old male E11 hypomorphic mice (and corresponding controls) using a post-traumatic joint loading model, we also investigated whether a bone-specific E11 deletion in mice increases joint vulnerability to osteoarthritis. Articular cartilage degradation and osteophyte formation were assessed by histology and in line with the OARSI grading system. RESULTS: Our studies reveal increased E11 expression in osteocytes of human and canine osteoarthritic SCB. We found that Bortezomib administration had no effect on surgically-induced osteoarthritis, potentially due to a lack of the expected stabilisation of E11 in the SCB. We also found, in concordance with our previous work, wild-type mice exhibited significant load-induced articular cartilage lesions on the lateral femoral condyle (p < 0.01) and osteophyte formation. In contrast, E11 hypomorphic mice did not develop osteophytes or any corresponding articular lesions. CONCLUSIONS: Overall, these data suggest that an intact osteocyte network in the SCB contributes to the development of mechanically-driven osteoarthritis. Further, the data presented here indicate that the molecular pathways that preserve the osteocyte network, such as those driven by E11, may be targeted to limit osteoarthritis pathogenesis.

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis.

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation.

The objective of the present study is to demonstrate that a newly developed selective c-Fos/activator protein (AP)-1 inhibitor, T-5224, inhibits the expression of matrix metalloproteinases (MMPs) in human articular chondrocytes, and prevents cartilage destruction in an osteoarthritis (OA)-induced mouse model. First, we examined the effect of T-5224 on MMP and inflammatory cytokine expression by real-time polymerase chain reaction in human articular chondrocytes. We created an OA model by destabilization of the medial meniscus (DMM) in mice. T-5224 was orally administered once a day and the OA pathology was assessed by histological, immunohistochemical, and micro-computed tomography (CT) analyses. T-5224 inhibited the mRNA expression levels of MMP-1, 3, and 13, and interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-6 in IL-1-stimulated human chondrocytes. Oral administration of T-5224 to OA-induced mice prevented cartilage destruction. The histological scores for OA were significantly better in the T-5224-treated group than the vehicle-treated group. Type X collagen and MMP-13 were not increased in the T-5224-treated group by immunohistochemical staining. Micro-CT analysis showed mild but apparent osteophyte development in the femoral condyle and antero-medial aspect of the tibia in the vehicle-treated group but not in the T-5224-treated group. Taken together, specific inhibition of c-Fos/AP-1 and the resulting inhibition of the transactivation of a broad spectrum of downstream MMPs, along with inflammatory cytokines, effectively prevented cartilage destruction and osteophyte formation.

The posterolateral approach for fluoroscopy-guided tibiotalar joint injection.

OBJECTIVE: To report a novel technique for tibiotalar joint injection that utilizes a posterolateral approach, including indications and technical considerations. METHODS: The posterolateral approach for tibiotalar injection is similar to that used in posterior subtalar joint injections. Using this technique, the tibiotalar joint space is accessed by directing the needle anterosuperiorly beneath the fibula until the posterior aspect of the talar dome has been reached. A retrospective review was conducted of all posterolateral approach tibiotalar joint injections at our institution. RESULTS: Eight patients underwent 12 technically successful therapeutic anesthetic/steroid tibiotalar joint injections using the posterolateral approach under fluoroscopic guidance. All eight patients had anterior predominant arthrosis with large osteophytes and tibiotalar joint space narrowing. The injections were well tolerated without evidence of complications. CONCLUSION: Posterolateral tibiotalar joint injection offers an alternative to the more commonly used anterior approach, particularly in cases of severe anterior predominant arthrosis. An additional advantage of this technique is that the ankle stays in the same position between the initial planning of the needle trajectory and the visualization of contrast flowing into the joint.

Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial.

BACKGROUND: A recent publication on efficacy of Sprifermin for knee osteoarthritis (OA) using quantitatively MRI-defined central medial tibio-femoral compartment cartilage thickness as the structural primary endpoint reported no statistically significant dose response. However, Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral tibio-femoral cartilage thickness. Based on these preliminary promising data a post-hoc analysis of secondary assessment and endpoints was performed to evaluate potential effects of Sprifermin on semi-quantitatively evaluated structural MRI parameters. Aim of the present analysis was to determine effects of sprifermin on several knee joint tissues over a 12 month period. METHODS: 1.5 T or 3 T MRIs were acquired at baseline and 12 months follow-up using a standard protocol. MRIs were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring system (in 14 articular subregions) by four muskuloskeletal radiologists independently. Analyses focused on semiquantitative changes in the 100 µg subgroup and matching placebo of multiple MRI-defined structural alterations. Analyses included a delta-subregional and delta-sum approach for the whole knee and the medial and lateral tibio-femoral (MTFJ, LTFJ), and patello-femoral (PFJ) compartments, taking into account number of subregions showing no change, improvement or worsening and changes in the sum of subregional scores. Mann-Whitney - Wilcoxon tests assessed differences between groups. RESULTS: Fifty-seven and 18 patients were included in the treatment and matched placebo subgroups. Less worsening of cartilage damage was observed from baseline to 12 months in the PFJ (0.02, 95 % confidence interval (CI) (-0.04, 0.08) vs. placebo 0.22, 95 % CI (-0.05, 0.49), p = 0.046). For bone marrow lesions (BMLs), more improvement was observed from 6 to 12 months for whole knee analyses (-0.14, 95 % CI (-0.48, 0.19) vs. placebo 0.44, 95 % CI (-0.15, 1.04), p = 0.042) although no significant effects were seen from the baseline visit, or in Hoffa-synovitis, effusion-synovitis, menisci and osteophytes. CONCLUSIONS: In this post-hoc analysis cartilage showed less worsening from baseline to 12 months in the PFJ, and BMLs showed more improvement from 6 to 12 months for the whole knee. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01033994 .

Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

OBJECTIVE: We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. METHODS: Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). RESULTS: Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. CONCLUSION: We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects.

A comparative study on the impact of intra-articular injections of hyaluronic acid, tenoxicam and betametazon on the relief of temporomandibular joint disorder complaints.

OBJECTIVE: The aim of this study was to compare the efficacy of intra-articular injections of three different agents with well known anti-inflammatory properties. MATERIALS AND METHOD: Between April 2010 and January 2013 a total of 100 patients who were diagnosed as temporomandibular joint disorder in the Department of Otolaryngology at Bozok University School of Medicine were prospectively studied. Patients with symptoms of jaw pain, limited or painful jaw movement, clicking or grating within the joint, were evaluated with temporomandibular CT to investigate the presence of cartilage or capsule degeneration. In the study group there were 55 female and 45 male patients who were non-responders to conventional anti-inflammatory treatment for TMJ complaints. The patients were randomly divided into four groups consisting of a control group and three different groups who underwent intra-articular injection of one given anti-inflammatory agent for each group. We injected saline solution to intra-articular space in the control group. Of three anti-inflammatory agents including hyaluronic acid (HA, Hyalgan intra-articular injection, Sodium hyaluronate 10 mg/ml, 2 ml injection syringe, Bilim Pharmaceutical Company, Istanbul, Turkey); betamethasone (CS, Diprospan flacon, 7.0 mg betamethasone/1 ml, Schering-Plough Pharmaceutical Company, Istanbul, Turkey) and; tenoxicam (TX, Tilcotil flacon, 20 mg tenoxicam/ml, Roche Pharmaceutical Company, Istanbul, Turkey) were administered intra-articularly under, ultrasonographic guidance. Following the completion of injections the, changes in subjective symptoms were compared with visual analogue scales, (VAS) scores at 1st and 6th weeks' follow-up visits between four groups. RESULTS: The HA group did significantly better pain relief scores compared to the, other groups at 1st and 6th weeks (p < 0.05). TX and CS groups' pain scores were better than control group values (p < 0.05, for both agents). The pain relief effect of TX was noted to decrease significantly between the 1st and 6th week (p < 0.05) (Fig. 1). We did not observe the same pattern in HA, CS and control (saline) groups between 1st and 6th week (p > 0.05). CONCLUSION: We found that HA produced better pain relief scores when compared to the other anti-inflammatory agents studied. The main disadvantage of HA is its relatively higher cost. Additionally it does not have a reimbursement status by state or private health insurance systems in Turkey. Despite the lower VAS scores, intra-articular TX and CS may be assessed as more economic alternatives to intra-articular HA injections.

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.

BACKGROUND: Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). OBJECTIVES: To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. METHODS: Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. RESULTS: Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. CONCLUSIONS: Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.

Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors.

OBJECTIVES: To investigate whether methotrexate or tumour necrosis factor inhibitors (TNFi) affect osteophyte formation in patients with psoriatic arthritis (PsA). METHODS: 41 patients with PsA were examined for the presence of osteophytes and erosions at the metacarpophalangeal joints by high-resolution micro-CT imaging. The size of each individual lesion was quantified at baseline and 1-year follow-up in PsA patients treated with TNFi (N=28) or methotrexate (N=13). Groups were comparable for age, sex, disease duration and activity and baseline burden of osteophytes. RESULTS: In total, 415 osteophytes (TNFi N=284, methotrexate N=131) were detected. Osteophyte size increased significantly from baseline to follow-up in the TNFi group (mean±SEM change +0.23±0.02 mm; p<0.0001) and the methotrexate group (+0.27±0.03 mm, p<0.0001). In both treatment groups, the majority of osteophytes showed progression (TNFi 54.3%, methotrexate 61.1%), whereas regression of lesions was rare (less than 10%). In contrast to osteophytes, clinical disease activity decreased in both groups of PsA patients and erosions showed an arrest of progression in both groups. CONCLUSIONS: Osteophytes progress in PsA patients treated with either methotrexate or TNFi. These data provide the first evidence that pathological bone formation in the appendicular skeleton of patients with PsA is not affected by current antirheumatic treatment strategies.

Preliminary evaluation of histological changes found in a mechanical arthropatic temporomandibular joint (TMJ) exposed to an intra-articular Hyaluronic acid (HA) injection, in a rat model.

OBJECTIVE: This study investigates the histological effects of Hyaluronic acid injections in the treatment of induced temporomandibular joint (TMJ) osteoarthritis in rats. STUDY DESIGN: Twenty-four male Wister rats were subjected to induced mechanical osteoarthritis by manual hypermobility for 10 successive days. Animals were then divided into two groups; group I (control) and group II (experimental). Ten days after the induction of hypermobility, the right TMJ of the experimental animals was injected with a dose of 0.12 mg HA intra-articularly and 0.12 mg saline was injected into the left joint; while animals in the control group were left without any treatment. Two rats from group I were killed at one, two and six weeks; while 6 animals from group II were killed at one, two and four weeks post injection. RESULTS: The disk of the right joints in the experimental animals was of normal thickness and there was an increase in the thickness of the fibrocartilagenous layer. In the left joint; ulcerative changes in the disk were evident where the fibres were not well oriented and scalloped areas in the temporal bone area were present denoting osteoclastic activity. CONCLUSIONS: Repeated intra-articular TMJ injection of Hyaluronic acid appears to be a safe and effective way of inhibiting the progression of osteoarthritic changes in the joint through development of articular cartilage and reducing fibrous tissue proliferation.

In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat.

OBJECTIVE: To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA). METHODS: We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro-magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam. RESULTS: Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion-like stimulus. In contrast, meloxicam-treated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury. CONCLUSION: Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion-like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial injury.

[Observation on therapeutic effect of acupuncture at Xuanzhong (GB 39) combined with Chinese herbs pyrogenic dressing therapy for treatment of calcaneus spur].

OBJECTIVE: To compare therapeutic effects of acupuncture at Xuanzhong (GB 39) combined with Chinese herbs pyrogenic dressing therapy and common acupuncture on calcaneus spur. METHODS: A single-blind, randomized and controlled trial was adopted. Sixty-six cases were randomly divided into an observation group (n=34) and a common acupuncture group (n=32). The observation group was treated with acupuncture at Xuanzhong (GB 39) combined with Chinese herbs pyrogenic dressing therapy and the common acupuncture group with common acupuncture, Yanglingquan (GB 34), Kunlun (BL 60) etc. selected. The markedly effective rate and the changes of heel pain scores, heel swelling scores, heel burning sensation scores, and walking function scores were compared between the two groups before and after treatment. RESULTS: The markedly effective rate of 64.7% (22/34) in the observation group was higher than 37.5% (12/32) in the common acupuncture group (P<0.05). After treatment, all the scores in the two groups were significantly improved as compared with before treatment (all P<0.05), and the observation group was better than the common acupuncture group (all P<0.05). CONCLUSION: The therapeutic effect of acupuncture at Xuanzhong (GB 39) combined with Chinese herbs pyrogenic dressing therapy on calcaneus spur is superior to that of common acupuncture.

Effects of long-term estrogen replacement therapy on bone turnover in periarticular tibial osteophytes in surgically postmenopausal cynomolgus monkeys.

The aims of the present study were to assess the effects of long-term estrogen replacement therapy (ERT) on size and indices of bone turnover in periarticular osteophytes in ovariectomized cynomolgus monkeys and to compare dynamic indices of bone turnover in osteophyte bone with those of subchondral bone (SCB) and epiphyseal/metaphyseal cancellous (EMC) bone. One hundred sixty-five adult female cynomolgus macaques were bilaterally ovariectomized and randomly divided into three age- and weight-matched treatment groups for a 36-month treatment period. Group 1 (OVX control) received no treatment, Group 2 (SPE) received soy phytoestrogens, and Group 3 (ERT) received conjugated equine estrogens in the diet; all monkeys were labeled with calcein before necropsy. A midcoronal, plastic-embedded section of the right proximal tibia from 20 randomly selected animals per treatment group was examined histologically. Forty-nine of the sections (OVX control, n=16; SPE, n=16; ERT, n=17) contained lateral abaxial osteophytes, and static and dynamic histomorphometry measurements were taken from osteophyte bone, SCB from the lateral tibial plateau, and EMC bone. Data were analyzed using the ANOVA and Kruskal-Wallis test, correlation and regression methods, and the Friedman and Wilcoxon signed rank test. There was no significant effect of long-term ERT on osteophyte area or on any static or dynamic histomorphometry parameters. The bone volume, trabecular number, and trabecular thickness in osteophyte bone were considerably higher than in EMC bone; whereas, trabecular separation was considerably lower in osteophyte bone. In all three treatment groups, BS/BV was significantly lower in osteophyte bone vs. EMC bone and significantly higher in osteophyte bone vs. lateral SCB. We conclude that osteophyte area and static and dynamic histomorphometry parameters within periarticular tibial osteophytes in ovariectomized cynomolgus monkeys are not significantly influenced by long-term ERT, but that site differences in static and dynamic bone histomorphometry parameters exist, particularly between EMC and osteophyte bone.

The effect of alendronate on progression of spinal osteophytes and disc-space narrowing.

BACKGROUND: Bisphosphonates may have chondroprotective effects that could be of relevance in osteoarthritis. Using data from a large fracture prevention trial, we evaluated the effect of alendronate on the progression of radiographic spinal osteophytes (OST) and disc-space narrowing (DSN). METHODS: The Fracture Intervention Trial (FIT) evaluated the effectiveness of alendronate at 5 mg/day (first 2 years) followed by 10 mg/day (third year) vs placebo over 3-4 years in preventing osteoporotic fractures. In 200 randomly selected subjects from FIT, we read baseline and follow-up lateral x rays for anterior OST and DSN (both scored 0-3 at each vertebral level) in the thoracic and lumbar spine. We calculated the mean difference in change in the sum of OST and DSN scores at T4 to L5 from baseline to follow-up, respectively, in each treatment arm using linear regression. RESULTS: The participants' baseline characteristics were similar in the alendronate and placebo arms. The adjusted mean change in summary OST score was less in the alendronate group compared to placebo (3.2 vs 4.7, p = 0.04), indicating that OST progression was less in the alendronate group. The adjusted mean change in summary DSN score was less in the alendronate group vs placebo for the whole spine (0.4 vs 0.7, p = 0.2), particularly when limited to the lumbar spine (0.3 vs 0.6, p = 0.04). CONCLUSIONS: In this secondary analysis of data from a randomised controlled trial, alendronate was associated with less spinal OST and DSN progression than placebo. This suggests a role for bisphosphonates in altering the pathological processes seen in osteoarthritis.