Intra-articular clodronate in patients with knee osteoarthritis non-responder to intra-articular hyaluronic acid - a case report series of 9 patients with 8-month follow-up.

Background: Osteoarthritis (OA) is a common disease in the elderly people, inducing pain and functional limitations. Clodronate (CLO) a first generation non-nitrogen containing bisphosphonate has been purposed as a treatment of OA, being effective on pain, inflammation, bone marrow oedema, osteophytosis and cartilage regeneration. Intra-muscular routes of CLO showed efficacy in the treatment of Knee OA (KOA) and erosive OA of the hand. In KOA intraarticular CLO at low doses (0.5-2 mg) showed efficacy as well as hyaluronic acid (HA), being able to improve the effectiveness if associated to HA. Methods: Nine Consecutive patients (4 female, 5 male, mean age 78,22) with KOA at 2nd or 3rd degree following Kellgren-Lawrance scale, non responder to HA and unintended to surgery. They were treated with intraarticular CLO at the weekly dose of 20 mg, plus lidocaine 1% in 5 cc of saline solution for a route of 5 weekly infil-trations, followed by a second route of 5 intraarticular infiltrations 3 months after the first course. Visual analog score (VAS) pain and Tegner-Lysholm Score (TLS) were used to assess changes following CLO treatment. Results: Baseline pain was 6,77/10, reduced to 1,09 at day 150 (after second course) and to 2,3/10 at day 240. TLS at baseline was 56,7/100, improved to 96,7 at day 150 and to 84,1 at day 240. At day 240 only 2 out of 9 patients had a negative judgement of the treatment and decided to stop it, while 7 were satisfied and available to a further course. There was no increase of consumption of anti-inflammatory or analgesic drugs. A short time lasting pain after the injections was registered in all patients. Conclusions: In a small cohort of patients affected by KOA, non responders to intraarticular HA a higher dose of intraarticular CLO in KOA showed good compliance, amelioration of pain and functionality.

Bone Marrow Edema: pathogenetic features.

Abstract: The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone. We can find bone marrow edema in many musculoskeletal diseases such as Inflammatory and Rheumatic diseases (Rheumatoid Arthritis, Spondylarthritis, etc.), Osteoarthritis (BMLs) and Bone Marrow Edema Syndromes (BMES). This classification is based on pathophysiological, histological and clinical differences despite the same imaging evidence. The distinction is useful also in terms of treatment. Bisphosphonates in association with NSAIDs or corticosteroids are the main therapy while TNF-a Inhibitors are used for the specific inflammatory origin. Bone marrow edema has become an important aspect to consider in the diagnostic path of the main musculoskeletal diseases. This paper starts from a systematic review of literature. We chose the most decisive contributions in order to develop a better description of the pathogenetic features about this "new" evidence.

Osteoarticular pain: therapeutic approach by paradigms.

Osteoarticular pain is a common condition in the adult population. It is a nociceptive pain modulated by different factors, and it is one of the major symptoms that force patients to seek medical advice. Since osteoarticular pain has a complex pathophysiology and it is not a linear condition, we propose in this paper an original approach to osteoarticular pain by paradigms, where a paradigm refers to a framework of concepts, results, and procedures within which subsequent work is structured. The paradigm presented is a conceptual tool that could help clinicians to choose the correct therapy considering both pain characteristics and clinical features.

Exposure to reversine affects the chondrocyte morphology and phenotype in vitro.

Articular chondrocytes derived from osteoarthritic tissues (OA HAC) show a severely reduced chondrogenic commitment. This impairment undermines their use for tissue-engineered cartilage repair, which relies on cell proliferation and growth to meet therapeutic needs, but also on efficient cell plasticity to recover the chondrogenic phenotype. Reversine (Rev), a 2,6-disubstituted purine inhibitor of spindle-assembly checkpoints, was described to convert differentiated mesenchymal cells to their undifferentiated precursors. We hypothesized that Rev exposure could divert OA HAC to more plastic cells, re-boosting their subsequent commitment. HAC were enzymatically released from OA cartilage specimens, expanded for 2 weeks and treated with 5 µm Rev in dimethylsulphoxide (DMSO) or with DMSO alone for 6 days. Cell growth was assessed using the AlamarBlueTM assay. Cytoskeletal structure, endoproliferation and caspase-3-immunopositivity were assayed by epifluorescence microscopy. The OA HAC chondrogenic performance was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) for glyceraldehyde-3-phosphate dehydrogenase, Sox9, Aggrecan (Agg), type II collagen (Col2), Ki67, cyclinD1, transforming growth factor-ß1 (TGF-ß1), -2 and -3, interleukin-1ß (IL-1ß) and -6 , SMAD3 and -7, and vascular endothelial growth factor. Rev-treated OA HAC recovered polygonal morphology and reduced Ki67 expression and proliferation. Cell-cycle impairment accounted for altered cytoskeletal organization, endoproliferation and apoptosis, whereas a compensatory mechanism sustained the increased cyclinD1 transcript levels. Sox9, Agg and TGFs were overexpressed, but not Col2. IL transcripts were massively downregulated. These events were dose-related and transient. Overall, in spite of a higher Rev-induced transcriptional activity for extracellular matrix components and in spite of a Rev-treated cell phenotype closer to that of the three-dimensional native articular chondrocyte, Rev effects seem unleashed from a full regained chondrogenic potential.

Vitamins D3 and K2 may partially counterbalance the detrimental effects of pentosidine in ex vivo human osteoblasts.

Osteoporosis is a metabolic multifaceted disorder, characterized by insufficient bone strength. It has been recently shown that advanced glycation end products (AGEs) play a role in senile osteoporosis, through bone cell impairment and altered biomechanical properties. Pentosidine (PENT), a wellcharacterized AGE, is also considered a biomarker of bone fracture. Adequate responses to various hormones, such as 1,25-dihydroxyvitamin D3, are prerequisites for optimal osteoblasts functioning. Vitamin K2 is known to enhance in vitro and in vitro vitamin D-induced bone formation. The aim of the study was to assess the effects of Vitamins D3 and K2 and PENT on in vitro osteoblast activity, to convey a possible translational clinical message. Ex vivo human osteoblasts cultured, for 3 weeks, with vitamin D3 and vitamin K2 were exposed to PENT, a well-known advanced glycoxidation end product for the last 72 hours. Experiments with PENT alone were also carried out. Gene expression of specific markers of bone osteoblast maturation [alkaline phosphatase, ALP; collagen I, COL Iα1; and osteocalcin (bone-Gla-protein) BGP] was measured, together with the receptor activator of nuclear factor kappa-B ligand/osteoproteregin (RANKL/OPG) ratio to assess bone remodeling. Expression of RAGE, a well-characterized receptor of AGEs, was also assessed. PENT+vitamins slightly inhibited ALP secretion while not affecting gene expression, indicating hampered osteoblast functional activity. PENT+vitamins up-regulated collagen gene expression, while protein secretion was unchanged. Intracellular collagen levels were partially decreased, and a significant reduction in BGP gene expression and intracellular protein concentration were both reported after PENT exposure. The RANKL/OPG ratio was increased, favouring bone reabsorption. RAGE gene expression significantly decreased. These results were confirmed by a lower mineralization rate. We provided in vitro evidence that glycoxidation might interfere with the maturation of osteoblasts, leading to morphological modifications, cellular malfunctioning, and inhibition of the calcification process. However, these processes may be all partially counterbalanced by vitamins D3 and K2. Therefore, detrimental AGE accumulation in bone might be attenuated and/or reversed by the presence or supplementation of vitamins D3 and K2.

METABOLIC BONE CHANGES IN OSTEOARTHRITIS: THE ROLE OF IMAGING AND PATHOGENETIC INTERPRETATION.

Osteoarthritis (OA) is the most prevalent chronic joint disease and one of the major causes of disability in the adult population. Although OA is considered a progressive degenerative process which involves the whole joint, articular cartilage and subchondral bone play a determinant role in its pathogenesis. In particular, metabolic-triggered subchondral bone damage, together with biochemical markers, are referred as important indicators of the disease. Magnetic resonance (MR) is the best imaging technique to detect and characterize such bone abnormalities. It represents an effective method through which to not only diagnose, describe and follow the course of OA but also to deepen our understanding of the natural history of the disease, with the ultimate purpose of attaining improved outcome in terms of therapy and prognosis. Even though MR has enormous potential, some diagnostic pitfalls may occur in clinical practice, hence an accurate clinical assessment of the patient is mandatory in combination with optimal imaging evaluation.

Effect of radial shock wave therapy on pain and muscle hypertonia: a double-blind study in patients with multiple sclerosis.

BACKGROUND: Radial shock wave therapy (RSWT) has been extensively used in rehabilitative medicine to treat pain, and more recently muscle hypertonia, in patients with cerebral palsy and stroke. OBJECTIVES: To assess the long-term effects of RSWT in a cohort of subjects affected by multiple sclerosis (MS) who were suffering from painful hypertonia of ankle extensor muscles. METHODS: In this randomised, double blind, placebo-controlled study, we treated 34 patients with four sessions of RSWT (once weekly) and treated 34 patients with placebo. Participants were assessed at baseline, 1 week after the first session, and 1 week and 4 weeks after the last session. We measured pain using the visual analogue scale for pain, while we assessed muscle tone using the modified Ashworth scale and evaluated spinal excitability using the H-reflex. RESULTS: After RSWT, muscle tone decreased 1 week after the last session and pain decreased at all the follow-up evaluations, while spinal excitability was unaffected. No significant changes were found after the placebo treatment. CONCLUSIONS: RSWT can reduce pain and muscle tone in MS patients without adverse effects. The lack of RSWT effects on spinal excitability supports the idea that RSWT is likely to act on non-reflex hypertonia, for example reducing muscle fibrosis.

Arthritis and osteoporosis: pathogenetic correlations in function of arthroplasty.

Osteoarthritis is being increasingly characterised as an inflammatory incoming and recurrent disease, with the specific symptoms of inflammation at every stage of the disease. With regard to the pathogenesis over time, the degenerative and inflammatory components are combined and lead to osteocartilaginous degeneration. Such deterioration involves other joint tissues as well as the subchondral bone tissue, the suffering of which is the key event of the beginning and progression of OA; its involvement concerns the same pathogenetic mechanisms and the same chemical mediators of the chondropathy. The increase in joint inflammatory events leads to suspect the onset or the worsening of the osteometabolic disorder, which is documented by the MR as “bone edema” or as algodystrophic syndrome. The pain appears both while moving and resting and with signs of inflammation. The treatment of OA requires drugs, such as paracetamol, selective and nonselective NSAIDs and opiates, for pain control. Treatment should ensure the pharmacological control of the pain related to the osteometabolic juxta-articular alteration, through bisphosphonates, favouring those which can control bone loss, inflammation and pain.

Medical treatment of joint prosthesis: indication, opportunities and liability profiles.

Orthopaedic specialists should completely and sequentially manage osteoarthritis, from the onset to the prosthesis, with no attitude of resignation, complying with national and international Guidelines (GLs) and abiding by the criteria of appropriateness of drugs, rehabilitation and orthopaedic device prescription, in line with the ethics of the medical profession. The GLs are a paper that rationalises the quantity of existing information for a disease, without abusing the decision of the doctor; a large volume of scientific knowledge is concentrated in a format that is easily accessible to doctors when carrying out their work. The use of drugs has taken on a connotation of a rational and multifactorial choice, rather than an accidental and incremental choice - inspired only by safety, rather than efficacy criteria. The Notes compiled by the Italian Medicines Agency - a legal instrument to define the reimbursability of medicines and, therefore, an instrument for managing pharmaceutical expenditure – are, in reality, a means to guarantee the appropriateness of the use of medicines, orienting the therapeutic choices according to established Guidelines. In the specific case of osteoarthritis, the knowledge of the GLs is the most appropriate and complete approach towards the disease, in the context of its pathogenetic complexity in its natural history. Moreover, pharmacological treatment of the subchondral osteometabolic damage becomes necessary when documented by magnetic resonance or a scintigraphy; the bone-related pain cannot be challenged through symptomatic analgesic treatment alone.

Italian survey on the use of anti-inflammatory drugs in osteoarthritis.

Osteoarthritis (OA) is the most common painful arthritic disease in adults, causes severe disability and worsens the quality of life of the patients. The aim of this survey, carried out on 147 Italian orthopedic doctors who attended an ISIAT (International Symposium Intra Articular Treatment) educational course in Barcelona, was to investigate some aspects of daily clinical practice in the management of OA: the most used pharmacological treatments, compliance to the most important Guidelines, the advantages of COXIBs in this setting and pharmacoeconomic aspects. The main results of this survey are: a) inflammation has become the main target in OA; b) Guidelines are a useful and valid tool for daily clinical practice; c) acetaminophen is no longer a valid therapeutical option for OA patients; d) anti-inflammatory drugs (NSAIDs and COXIBs) have a primary role in the management of OA, due to their dual activity (anti-inflammatory and analgesic); e) selectivity of COXIBs for COX-2 is very important; f) within the COXIB class, the therapeutic value of etoricoxib has been widely recognized, especially in terms of safety and cost/benefit ratio.

Osteoporosis in the elderly.

Osteoporosis is predominantly a condition of the elderly with a consequent increase in bone fragility and susceptibility to fracture. A number of clinical as well as biological studies have been pivotal in providing us with an understanding of the pathophysiology of this condition. This article discusses the current concepts of age-related osteoporosis.

TGF ß-1 administration during ex vivo expansion of human articular chondrocytes in a serum-free medium redirects the cell phenotype toward hypertrophy.

Cell-based cartilage resurfacing requires ex vivo expansion of autologous articular chondrocytes. Defined culture conditions minimize expansion-dependent phenotypic alterations but maintenance of the cells' differentiation potential must be carefully assessed. Transforming growth factor ß-1 (TGF ß-1) positively regulates the expression of several cartilage proteins, but its therapeutic application in damaged cartilage is controversial. Thus we evaluated the phenotypic outcomes of cultured human articular chondrocytes exposed to TGF ß-1 during monolayer expansion in a serum-free medium. After five doublings cells were transferred to micromass cultures to assess their chondrogenic differentiation, or replated in osteogenic medium. Immunocytostainings of micromasses of TGF-expanded cells showed loss of aggrecan and type II collagen. Positivity was evidenced for RAGE, IHH, type X collagen and for apoptotic cells, paralleling a reduction of BCL-2 levels, suggesting hypertrophic differentiation. TGF ß-1-exposed cells also evidenced increased mRNA levels for bone sialoprotein, osteopontin, matrix metalloproteinase-13, TIMP-3, VEGF and SMAD7, enhanced alkaline phosphatase activity and pyrophosphate availability. Conversely, SMAD3 mRNA and protein contents were reduced. After osteogenic induction, only TGF-expanded cells strongly mineralized and impaired p38 kinase activity, a contributor of chondrocytes' differentiation. To evaluate possible endochondral ossification progression, we seeded the chondrocytes on hydroxyapatite scaffolds, subsequently implanted in an in vivo ectopic setting, but cells failed to reach overt ossification; nonetheless, constructs seeded with TGF-exposed cells displayed blood vessels of the host vascular supply with enlarged diameters, suggestive of vascular remodeling, as in bone growth. Thus TGF-exposure during articular chondrocytes expansion induces a phenotype switch to hypertrophy, an undesirable effect for cells possibly intended for tissue-engineered cartilage repair.

[CTLA4-Ig interferes and downregulates the proinflammatory activities of rheumatoid synovial macrophages in monoculture]. / CTLA4-Ig influenza e inibisce le attività proinfiammatorie di macrofagi sinoviali reumatoidi in monocoltura.

OBJECTIVE: CTLA4-Ig, a biologic agent employed in rheumatoid arthritis (RA) treatment, downregulates the immune response and exerts anti-inflammatory effects acting on different cells including dendritic/T cells interaction and directly on osteoclasts. We investigated the anti-inflammatory effects of CTLA4-Ig in primary monocultures of RA synovial macrophages (SM). METHODS: SM were obtained, from 8 RA patients (7 F, 1 M; DAS28>5.2) who underwent therapeutic arthroscopic synoviectomy and were cultured in the absence and in the presence of CTLA4-Ig at the concentration of [500 microg/ml], the most reliable dose related to the previous pharmacological clinical and experimental experiences. Inflammatory cytokine (IL-6, TNFalpha, IL-1beta) expression was evaluated by immunocytochemistry (ICC with relative image analysis), western blot (WB), and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: ICC analysis revealed that CTLA4-Ig treatment significantly downregulated cytokine expression (p<0.001 for IL-6, TNFalpha and IL-1beta) when compared to untreated RA SM. WB and qRT-PCR confirmed partially the data. CONCLUSIONS: CTLA4-Ig was found to exert a direct and significant anti-inflammatory effect on primary monocultures of RA SM, suggesting a therapeutic power in different phases of the disease activity.

External shock waves therapy in dystonia: preliminary results.

BACKGROUND AND PURPOSE: Extracorporeal shock wave therapy (ESWT) has been shown to reduce hypertonia in patients with upper motor neuron syndrome without any side effect. The aim of the present study is to investigate whether ESWT could be useful also in patients with dystonia. METHODS: We evaluated three patients with secondary dystonia and three patients with idiopathic writer's cramp. Placebo treatment was performed in each patient. ESWT was administered during four sessions (once weekly) to the target muscles of hand and forearm using an electromagnetic lithotripter (Modulith SLK--Storz Medical). Clinical evaluation was performed using the Unified Dystonia Rating Scale in patients with secondary dystonia and the Arm Dystonia Disability Scale in patients with writer's cramp. RESULTS: After treatment, the three patients with secondary dystonia showed a marked improvement which lasted at least until 1 month after the last session. In the patients with writer's cramp, the improvement after ESWT was less consistent being effective only in two subjects. There were no associated adverse effects. CONCLUSIONS: Extracorporeal shock wave therapy is probably an effective and safe treatment for upper limb dystonia, particularly for the secondary forms. Larger randomized studies are needed to confirm these preliminary results.

Analysis of clinical data in patients with Girdlestone arthroplasty: a new score.

Girdlestone's arthroplasty is an uncommon surgical procedure; it is performed in patiens with recurrent infection of the hip, polymicrobic sepsis or after multiple revisions. The number of hip replacements all over the world is always increasing, so the total number of prosthesis infections also continues to rise, although the relative incidence is lower than in the past. For this reason Girdlestone's arthroplasty must be a well-known procedure to hip surgeons. Clinical assessment of such patients cannot be performed with common hip ratings (e.g. Harris Hip Score) since hip instability, low range of motion, limb shortening and severe muscle loss are common. The patient's independence in daily living activity and freedom from pain should be the surgeon's main goals. We propose a specific clinical score for the outcome of the procedure, which is not to be found in the current literature as far as the authors are aware. The score can be useful for comparative clinical trials, for legal medicine purposes, etc. To illustrate it, we present 20 cases of Girdlestone's arthroplasty out of 265 hip revisions performed in our hospital. The outcome of the procedure in our patients was clinically good in eight cases, intermediate in ten cases, and bad in two cases. We believe the performing of such an intervention is justified when indicated by clinical signs, as we analyse them in our work. Our clinical score has been shown to be adequate to assess the clinical presentation of such patients.

False aneurysm of the superficial femoral artery after total hip arthroplasty: a case report.

Vascular lesions in hip prosthetic replacement are rare events; it is mandatory to be aware of the risk, though, in order of the vascular bundle's proximity to the surgical field. A 74-year-old patient was admitted to our department for primary hip arthroplasty for osteoarthritis. The patient was healthy but had mild hypertension. A cemented total hip prosthesis was implanted. The patient complained of growing groin pain and swelling from the third postoperative day. The suspicion of a vascular injury arose with worsening pain and low haemoglobin at blood tests. Then ultrasonography scans and digital angiography were performed, showing a superficial femoral artery pseudo-aneurysm. The patient had further surgery to repair the lesion. In the described case, the pseudo-aneurysm might have been caused by the pulling of a Hohmann retractor on arterial vessels possibly affected by atherosclerosis. The final output was favourable, but the authors point out that knowledge of neurovascular anatomy is necessary as well as postoperative surveillance of the clinical presentation of the patient if groin pain or swelling should arise. In the case of suspicion of vascular lesions, ultrasound and angiography will allow diagnosis and confirm the indication for surgical repair.

HLA-DRB1alleles and osteoarthritis in a group of patients living in Liguria-Italy.

AIM: Osteoarthritis (OA), a degenerative arthro-pathy, produces damage and cartilage loss in one or more joints. Genetic factors contribute substantially to the risk of OA. The nature of the genetic influence in OA is speculative and may involve both a structural defect (i.e. collagen), alterations in cartilage or bone metabolism. Analyses of the frequencies of HLA antigens in various OA populations showed different RESULTS: The aim of this study was to verify the prevalence of HLA-DRB1 haplotypes in 92 outpatients of the Rheumatological Center of Genoa University. METHODS: Ninety-two outpatients (69 females, 23 males) affected by OA were enrolled and divided into a group with OA of the hands and a group with different joints localizations. Both groups have been compared with a control group, represented by 150 Italian marrow donors, to detect a typology of second class HLA alleles that, if present, may represent a risk factor of disease. The statistical significance between the groups were assessed by means of the contingency table to compare frequencies (P<0.05 was considered as significant). RESULTS: The results obtained showed that the frequency of DRB1*12 and *10 alleles families, not present in the second study group, has been compared only between the first study group and the control group. Haplotypes *07 e *04 are more frequent in the second group than in the first group and in the control group and haplotype *13 is the most represented in the first and second group. Haplotypes *11 and *13 are more significantly represented in the control group. CONCLUSIONS: The results obtained with the study of HLA-DRB1 locus in patients affected by OA and living in Liguria may suggest a research on a larger number of OA patients to confirm the data obtained in this study and to define DRB1 haplotypes as more frequent markers both in OA of the hand and in OA of other joints.

[Italian consensus on EULAR recommendations 2005 for the management of hip osteoarthritis]. / Consensus italiana sulle raccomandazioni EULAR 2005 per il trattamento dell'artrosi dell'anca.

The recommendations for the management of osteoarthritis (OA) of the hip were proposed by EULAR in 2005. Among the most important objectives of the expert charged to provide these recommendations were their wide dissemination and implementation. Thus, the information generated can be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. According with that previously executed for the EU-LAR recommendation 2003 for the knee, the Italian Society of Rheumatology (SIR) has organised a Consensus on the EULAR recommendations 2005 for the management of hip OA. To obtain an acceptability as large as possible, the group of experts was composed by many physicians interested in the management of hip OA, including Orthopaedics, Rheumatologists, Physiatrists, and General Practitioners. Main aim of the Consensus was to analyse the acceptability and applicability of the recommendations according to own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that the specialists involved in the management of hip OA strongly encourage the dissemination of the EULAR 2005 recommendations also in Italy.

[Italian consensus on Eular 2003 recommendations for the treatment of knee osteoarthritis]. / Consensus italiana sulle raccomandazioni dell'EULAR 2003 per il trattamento dell'artrosi del ginocchio.

The recommendations for the management of osteoarthritis (OA) of the knee firstly proposed by the EULAR in 2000, have been updated in 2003. One of the most important objectives of the expert charged to provide these recommendations was their dissemination. Thus, the information generated may be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. The Italian Society of Rheumatology (SIR) and the Italian League against Rheumatism (LIMAR) have organised a Consensus on the EULAR recommendations 2003 with the aim to analyse their acceptability and applicability according to our own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that specialists involved in the management of knee OA strongly encourage the dissemination of the EULAR 2003 recommendations also in Italy.