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Oxidative stress (OS) mediators, together with the inflammatory processes, are considered as threatening factors for bone health. The aim of this study was to investigate effects of flavonoids naringenin and chrysin on OS, inflammation, and bone degradation in retinoic acid (13cRA)-induced secondary osteoporosis (OP) in rats. We analysed changes in body and uterine weight, biochemical bone parameters (bone mineral density (BMD), bone mineral content (BMC), markers of bone turnover), bone geometry parameters, bone histology, OS parameters, biochemical and haematological parameters, and levels of inflammatory cytokines. Osteoporotic rats had reduced bone Ca and P levels, BMD, BMC, and expression of markers of bone turnover, and increased values of serum enzymes alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Malondialdehyde (MDA) production in liver, kidney, and ovary was increased, while the glutathione (GSH) content and activities of antioxidant enzymes were reduced and accompanied with the enhanced release of inflammatory mediators TNF-α, IL-1β, IL-6, and RANTES chemokine (regulated on activation normal T cell expressed and secreted) in serum. Treatment with chrysin or naringenin improved bone quality, reduced bone resorption, and bone mineral deposition, although with a lower efficacy compared with alendronate. However, flavonoids exhibited more pronounced antioxidative, anti-inflammatory and phytoestrogenic activities, indicating their great potential in attenuating bone loss and prevention of OP.

Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders. Much progress has been made in regenerative medicine for the symptomatic treatment of KOA, including products containing stromal vascular fraction (SVF) and platelet-rich plasma (PRP). The aim of this study was to evaluate clinical and radiological findings after the application of autologous conditioned adipose tissue (ACA) and leukocyte-poor PRP (LP-PRP) in patients with mild to moderate KOA. A total of 16 patients (eight male and eight female) with changes related to KOA on the magnetic resonance imaging (MRI), but without severe osteophytosis, full-thickness cartilage loss, or subchondral bone involvement were included in this study. Patients received an intraarticular, ultrasound-guided injection of ACA and LP-PRP. Clinical scores, including a visual analog scale for pain (VAS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evaluated at baseline and at the three and six month follow-ups showing a statistically significant improvements at three and six months post-intervention. Furthermore, the delayed gadolinium-enhanced MRI of the cartilage (dGEMRIC) indices were evaluated at baseline and at the three and six month follow-ups showing no significant changes after treatment with ACA and LP-PRP, which were actually equal to the dGEMRIC indices measured in the control group (hyaluronic acid applied in contralateral knees without osteoarthritis). ACA with LP-PRP presents a viable minimally invasive therapeutic option for the clinical improvement of mild to moderate KOA. However, MFAT produced by different systems is likely to differ in cellular content, which can directly affect the paracrine effect (cytokine secretion) of mesenchymal stem cells and consequently the regeneration process.

Aim To analyze clinical and functional effects of intra-articular injection of autologous micro-fragmented lipoaspirate (MLA) in patients with late stage knee osteoarthritis (KOA). Secondary aims included classifying cell types contributing to the treatment effect, performing detailed MRI-based classification of KOA, and elucidating the predictors for functional outcomes. Methods This prospective, non-randomized study was conducted from June 2016 to February 2018 and enrolled 20 patients with late stage symptomatic KOA (Kellgren Lawrence grade III, n = 4; and IV, n = 16) who received an intra-articular injection of autologous MLA in the index knee joint. At baseline radiological KOA grade and MRI were assessed in order to classify the morphology of KOA changes. Stromal vascular fraction cells obtained from MLA samples were stained with antibodies specific for cell surface markers. Patients were evaluated at baseline and 12-months after treatment with visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee Injury and Osteoarthritis Outcome Score (KOOS). Results Three patients (15%) received a total knee replacement and were not followed up completely. Seventeen patients (85%) showed a substantial pattern of KOOS and WOMAC improvement, significant in all accounts. KOOS score improved from 46 to 176% when compared with baseline, WOMAC decreased from 40 to 45%, while VAS rating decreased from 54% to 82% (all P values were

Osteoarthritis is the most common musculoskeletal progressive disease, with the knee as the most commonly affected joint in the human body. While several new medications are still under research, many symptomatic therapy options, such as analgesics (opioid and non-opioid), nonsteroid anti-inflammatory drugs, symptomatic slow-acting drugs in osteoarthritis, and preparations for topical administration, are being used, with a diverse clinical response and inconsistent conclusions across various professional societies guidelines. The concept of pharmacogenomic-guided therapy, which lies on principles of the right medication for the right patient in the right dose at the right time, can significantly increase the patient’s response to symptom relief therapy in knee osteoarthritis. Corticosteroid intra-articular injections and hyaluronic acid injections provoke numerous discussions and disagreements among different guidelines, even though they are currently used in daily clinical practice. Biological options, such as platelet-rich plasma and mesenchymal stem cell injections, have shown good results in the treatment of osteoarthritis symptoms, greatly increasing the patient’s quality of life, especially when combined with other therapeutic options. Non-inclusion of the latter therapies in the guidelines, and their inconsistent stance on numerous therapy options, requires larger and well-designed studies to examine the true effects of these therapies and update the existing guidelines.

Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.

Retinoic acid-induced osteoporosis (RBM) is one of the most common causes of secondary osteoporosis. This study tested the anti-osteoporetic effect of quercetin in RBM-induced bone loss model (RBM). After 14-day supplementation of 13cRA to induce RBM, rats were administered with quer cetin (100 mg/kg) or alendronate (40 mg/kg). We analysed changes in body and uterine weight of animals, femoral geometric characteristics, calcium and phosphorus content, bone weight index, bone hystology, bone mineral density (BMD), markers of bone turnover, lipid peroxidation, glutathione levels and SOD, CAT activity of liver, kidney spleen, and ovary as well as biochemical and haematological variables. In comparison to the control RBM rats, the treatment with quercetin increased bone weight index, BMD, osteocalcin level, femoral geometric characteristics, calcium and phosphorus content in the 13cRA-induced bone loss model. Histological results showed its protective action through pro motion of bone formation. According to the results, quercetin could be an effective substitution for alendronate in 13cRA-induced osteoporosis. Good therapeutic potential of quercetin on rat skeletal system is based partly on its antioxidant capacity and estrogenic activity.

Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee OA one of the leading causes of disability in elderly population. Today, we know that osteoarthritis is not a disease characterized by loss of cartilage due to mechanical loading only, but a condition that affects all of the tissues in the joint, causing detectable changes in tissue architecture, its metabolism and function. All of these changes are mediated by a complex and not yet fully researched interplay of proinflammatory and anti-inflammatory cytokines, chemokines, growth factors and adipokines, all of which can be measured in the serum, synovium and histological samples, potentially serving as biomarkers of disease stage and progression. Another key aspect of disease progression is the epigenome that regulates all the genetic expression through DNA methylation, histone modifications, and mRNA interference. A lot of work has been put into developing non-surgical treatment options to slow down the natural course of osteoarthritis to postpone, or maybe even replace extensive surgeries such as total knee arthroplasty. At the moment, biological treatments such as platelet-rich plasma, bone marrow mesenchymal stem cells and autologous microfragmented adipose tissue containing stromal vascular fraction are ordinarily used. Furthermore, the latter two mentioned cell-based treatment options seem to be the only methods so far that increase the quality of cartilage in osteoarthritis patients. Yet, in the future, gene therapy could potentially become an option for orthopedic patients. In the following review, we summarized all of the latest and most important research in basic sciences, pathogenesis, and non-operative treatment.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragile bones. It is our aim to illustrate variability in clinical presentation of severe form of OI. As an example of personalized surgery approach we present an 11-year-old girl with OI type III. Prior to referral to our hospital, she was treated with 18 cycles of bisphosphonates as well as with several different surgical procedures. Due to no improvement in her mobility status she underwent two additional surgeries at our hospital with a 5-month interval between them. Prior to the surgery, molecular genetic analysis was performed and the clinical diagnosis of OI was confirmed. Using the Fassier-Duval intramedullary telescoping nail, we performed correction osteotomies of both femurs and lower legs in two separate settings, with a very good final result. According to our experience, the Fassier-Duval nailing system is good option, but one should pay attention to many details while performing surgery. Thus, making treatment of OI patients very personalized. In this paper we present a unique personalized approach in OI: firstly, diagnosing COL1A1 gene mutations and secondly, performing a complex two-part surgery.

Articular cartilage is a hyaline cartilage 2–4 mm thick. It is composed of 95% of dense extracellular matrix (ECM) and 5% of highly specialized cells called chondrocytes. Because of its avascular, aneural and alymphatic state, it has a limited repair potential. Articular cartilages’ main function is to provide smooth, lubricated surface for low friction articulation while minimizing the stress and strains on the matrix. Articular cartilage could be damaged by normal wear and tear or injury and it can cause severe pain, inflammation and some degree of disability. Its management consist of pharmacological (acetaminophen, NSAID, salicylate, selective COX-2 inhibitors or opioids) and non-pharmacological therapies. Non-pharmacological treatment includes physical therapy and decreasing the load in the joint by modifying patient’s habits. A new class of agents (symptomatic or disease modifying osteoarthritic drugs (S/DMOADs) including glucosamine and chondroitin sulfate is receiving wide publicity. At the same time, numerous published reports advising the use of hyaluronic acid injections: viscosupplementation in patients with symptomatic osteoarthritis. Operative treatment includes different surgical debridement and microfracture techniques, osteochondral autograft transfers, osteochondral allograft transplantation, etc. New techniques and concepts are being developed not only to treat damaged or diseased joint cartilage but also to find ways of achieving regeneration to normal cartilage that will give long-lasting improvements and allow patients to return to a fully active lifestyle. Nevertheless, as two stage procedures involving cell culture are expensive and cumbersome, there is an increasing push towards a single stage stem cell treatment. Currently, there are a number of new methods with cartilage repair aim, including autologous chondrocyte implantation (ACI), matrix-induced autologous chondrocyte implantation (MACI), intra-articular administration of autologous microfragmented fat tissue with Ad-MSCs, etc. In this chapter, we discuss some current treatments and the emerging strategies/techniques employed by researchers and physicians thriving to repair articular cartilage through biological means.

Osteoarthritis (OA) is a widely prevalent disease worldwide, and with an increasingly ageing society, it has become a challenge for the field of regenerative medicine. OA is a disease process involving multiple joint tissues, including those not visible on radiography, and is a complex disease process with multiple phenotypes that require evaluation by a multimodality imaging assessment. The purpose of this study was to evaluate the effect of micro-fragmented fat tissue intra-articular injection 24 months after application in two ways: Indirectly using functional magnetic resonance imaging (MRI) assessment analyzing the glycosaminoglycans (GAG) content in cartilage by means of delayed gadolinium (Gd)-enhanced magnetic resonance imaging of cartilage (dGEMRIC), as well as clinical outcome on observed level of GAG using standard orthopedic physical examination including VAS assessment. In our previous study assessing comprehensive results after 12 months, the dGEMRIC results have drawn attention. The present study explores the long-term effect of intra-articular injection of autologous microfragmented adipose tissue to host chondrocytes and cartilage proteoglycans in patients with knee OA. A prospective, non-randomized, interventional, single-center, open-label clinical trial was conducted from January 2016 to April 2018. A total of 17 patients were enrolled in the study, and 32 knees were assessed in a 12-month follow-up, but only 10 patients of them with 18 knees are included in a 24-month follow-up. The rest of the seven patients dropped out of the study 12 months after follow-up: three patients underwent knee arthroplasty, and the remaining four did not fulfil the basic criteria of 24 months involvement in the study. Surgical intervention (lipoaspiration), followed by tissue processing and intra-articular injection of the final microfragmented adipose tissue product into the affected knee(s), was performed in all patients. Patients were assessed for a visual analog scale (VAS), dGEMRIC at the baseline, three, six, 12 and 24 months after the treatment. A magnetic resonance sequence in dGEMRIC due to infiltration of the anionic, negatively-charged contrast gadopentetate dimeglumine (Gd-DTPA2) into the cartilage indicated that the contents of cartilage glycosaminoglycans significantly increased in specific areas of the treated knee joint. Our results suggest that this method of single intra-articular injection of autologous microfragmented adipose tissue improves GAG content on a significant scale, with over half of the measurements suggesting relevant improvement 24 months after intra-articular injection opposed to the expected GAG decrease over the natural course of the disease.

Nutrition is an important factor that influences bone metabolism, the endocrine and/or paracrine system, and bone-active mineral elements homeostasis. We studied antiosteoporotic effects of grape seed proanthocyanidins extract, icariin or alendronate (ALN) in retinoic acid-induced (13cRA) bone loss in rats. Proanthocyanidins and icariin have beneficial effects on bone health, they have improved the bone weight reduction, the length and the diameter of the bone, calcium, and phosphorus content in bone ash, bone mineral density (BMD), the biochemical markers of bone turnover and uterus atrophy induced by 13cRA. All results suggest that proanthocyanidins and icariin reverse osteoporosis in 13cRA rats by stimulating bone formation or regulating bone resorption by their antioxidative and estrogenic-like activity without toxic side-effects observed in ALN treatment.

Osteoarthritis (OA) is one of the leading musculoskeletal disorders in the adult population. It is associated with cartilage damage triggered by the deterioration of the extracellular matrix tissue. The present study explores the effect of intra-articular administration of autologous microfragmented adipose tissue containing adipose- derived mesenchymal stem cells (Ad-MSCs) to host chondrocytes and cartilage proteoglycans in patients with knee OA. A prospective, non- randomized, interventional, single-center, open- label clinical trial was conducted from January 2016 to April 2017. A total of 17 patients were enrolled in the study, and 32 knees with osteoarthritis were assessed. Surgical intervention (lipoaspiration) followed by tissue processing and intra-articular injection of the final product containing a derivate of micronized fatty tissue with pericytes and mesenchymal stem cells (Ad-MSCs) into the affected knee(s) was performed in all patients. Patients were assessed for Visual Analogue Scale (VAS), dGEMRIC MRI imaging and immunoglobulin G (IgG) glycans at the baseline, 3, 6 and 12 months after the treatment. T1 relaxation time in dGEMRIC due to infiltration of the anionic, negatively charged contrast Gd- DTPA2− into the cartilage indicated that the contents of cartilage glycosaminoglycans significantly increased in specific areas of the treated knee joint. In addition, dGEMRIC MRI imaging consequently reflected subsequent changes in the mechanical axis of the lower extremities. The results of our study indicate that the use of (Ad-MSC) in patients with knee OA (measured by dGEMRIC MRI) increased glycosaminoglycans (GAGs) content in hyaline cartilage, which is in line with observed VAS and clinical results.

The treatment of osteogenesis imperfecta should be multidisciplinary and personalized. The best option for surgical treatment is implantation of an intramedullary telescopic nail, in many specialized hospitals the preferable method is Fassier-Duval telescopic nail. The main advantages of the Fassier-Duval intramedullary nail are fewer surgical scars, reduced blood loss, decreased time of operation, less pain, and better postoperative mobility. Orthopedic surgeons who are dealing with osteogenesis imperfecta have to answer two main questions, i.e. when to start with surgical procedures and which type of intramedullary nailing to use. There are a few things that are necessary for a satisfactory outcome of the surgical procedure: precise preoperative planning, all sizes of Fassier- Duval nail available in the operating room during the surgery, and intraoperative radiologic C-arm guidance., Liječenje bolesti osteogenesis imperfecta treba biti multidisciplinsko i personalizirano. Najbolji način kirurškog liječenja je ugradnja intramedularnog teleskopskog čavla, pri čemu većina specijaliziranih bolnica prednost daje metodi Fassier-Duvalova teleskopskog čavla. Glavne prednosti Fassier-Duvalova intramedularnog čavla su manje kirurških ožiljaka, manji gubitak krvi, skraćeno vrijeme operacije, manja bolnost i bolja poslijeoperacijska mobilnost. Ortopedski kirurzi koji se bave liječenjem osteogenesis imperfecta moraju odgovoriti na dva glavna pitanja: kada započeti kirurške zahvate i koji tip intramedularnog čavla primijeniti. Nekoliko je stvari neophodno ispuniti da bi ishod kirurškog zahvata bio zadovoljavajući: precizno prijeoperacijsko planiranje, dostupnost svih veličina Fassier-Duvalova čavla u operacijskoj sali za vrijeme operacije te intraoperacijsko radiološko vođenje pomoću C-ruke.

Stražnja luksacija ramena rijedak je klinički i radiološki entitet. Od svih luksacija humeroskapularnog zgloba na stražnju luksaciju otpada manje od 2%. Način liječenja određen je veličinom defekta na glavi nadlaktične kosti, te trajanjem luksacije. Predstavljamo slučaj 66-godišnje žene s neprepoznatom stražnjom luksacijom ramena zadobivenom padom s bicikla. Nakon CT-a desnoga ramena, učinjena je otvorena repozicija humeroskapularnoga zgloba i transpozicija gornje trećine tetive m. subskapularisa u područje defekta na glavi humerusa. Deset mjeseci nakon operacijskoga zahvata klinički se nađe zadovoljavajući opseg kretnji. Bolesnica je subjektivno izrazito zadovoljna statusom operiranoga ramena, te konačnim rezultatom operacijskoga liječenja., Posterior dislocation of the shoulder is a rare clinical and radiological entity. It accounts for less than 2 % of all dislocations of the shoulder. The method of treatment is determined by the size of the defect and the duration of the dislocation. We present a case of a 66-year-old woman with unrecognized posterior dislocation of the shoulder after falling from a bicycle. Following a CT scan we performed an open reposition of the humeroscapular joint and transposition of the upper third of subscapularis tendon into the humeral head defect. Ten months after surgery we found a good range of motion and the patient is very satisfied with the final result of the surgical treatment.

Purpose Reactive oxygen species play a role in a number of degenerative conditions including osteoporosis. Flavo noids as phyto-oestrogens exert physiological effects against oxidative stress diseases. We developed a retinoic acid-induced bone loss model of rats to assess whether flavonoids and alendronate as positive control have role against oxidative stress and mineral contents in osteopo rosis in vivo. Methods Three-month-old female rats of the Y59 strain were given quercetin, chrysin, naringenin (100 mg kg-1 ) or alendronate (40 mg kg-1 , a positive control) immedi ately before retinoic acid treatment (80 mg kg-1 ) once daily for 14 days by a single intragastric (i.g.) application. In the second part of the study, we assessed the effect of those flavonoids on the skeletal system of healthy rats using single i.g. application on the respective flavonoids during 14 days. Twenty-four hours after the treatment, we analysed bone mineral density and the total content of bone calcium and phosphorus in the femur, the geometric and physical characteristics of thigh bones and lipid peroxida tion and glutathione levels of liver and kidney cells. Results All flavonoids improved the decrease in bone weight coefficient, the length and the diameter of the bone, the content of bone ash and calcium and phosphorus con tent induced by retinoic acid. Chrysin and quercetin showed promise as preventive agents. Flavonoids were superior to alendronate according to some criteria. Conclusions These results suggest that the dietary flavo noids could reduce retinoic acid-induced oxidative stress and bone loss and that flavonoids may be useful thera peutics for prevention of skeletal diseases

Plantarni fascitis spada u sindrome prenaprezanja,a oèituje se pojavom boli u području medijalne kvrge petne kosti i / ili uzduž medijalnog uzdužnog svoda stopala. Nastaje zbog dugotrajnih ponavljajućih opterećenja (stress) na plantarnu fasciju te dolazi do mikroruptura ili u završnoj fazi i do djelomične i/ili potpune rupture fascije blizu njenog polazišta na petnoj kosti. Plantarna fascija ima veliki značaj u biomehanici stopala i ona tijekom hoda ublažava mehaničke udare na stopalo i odrazuje stopalo prema naprijed po sistemu dizalice. Ukoliko doðe do poremećaja biomehanike stopala osobito naglašene pronacije stopala, zatim ako postoji udubljeno stopalo, skraćena Ahilova teiva, izrazito spušteno stopalo, itd. dolazi do pojačanih rastezanja plantarne fascije,a zbog same graðe fascije izrazito je mala mogućnost prilagodbe na ta povećana rastezanja. U sportaša plantarni fascitis češće se javlja kod trkača na duge pruge, a veća incidencija nalazi se i kod tenisaèa, košarkaša te plesača. Obično je unilateralan a u 15% pacijenata pojavljuje se obostrano. Klinička manifestacija plantarnog fascitisa je bolno stopalo, odnosno bolnost plantarnog dijela petne kosti.Dijagnoza plantarnog fascitisa se kod većine pacijenata postavlja na osnovi anamneze i klinièkog pregleda. Točka najjače bolne osjetljivosti je medijalni nastavak petne kvrge a bol se pojaèava pasivnim rastezanjem fascije. U dijagnostici plantarnog fascitisa koriste se radiološke pretrage koje često otkrivaju postojanje koštanog trna (calcar calcanei), ultrazvučna dijagnostika i danas sve više i MRI otkrivaju zadebljanje fascije, burze i rupture a uz scintigrafsku pretragu MRI je koristan i u diferncijalnoj dijagnozi prijeloma zamora petne kosti. U lijeèenju plantarnog fascitisa pogotovo u sportaša prvenstveno treba primjenom individualno izraðenih ortotskih pomagala korigirati poremećenu biomehaniku stopala, što treba provoditi i u preventivne svrhe. U konzervativno liječenje spadaju i svi inače uobičajeni postupci fizikalne medicine od krioterapije,vježbi rastezanja , primjene noćne udlage, lokalne primjene ultrazvuka ili u novije vrijeme udarnih valova velike energije do posebnih bandaža stopala. Kirurško liječenje otvorenom ili endoskopskom metodom sastoji se u opuštanju,presijecanju ili/i djelomiènom odstranjenju promijenjene plantarne fascije.Kirurško liječenje poduzima se najčešće upravo u sportaša nakon 6-12 mjeseci neuspješnog konzervativnog liječenja., Plantar fasciitis is an overuse injury characterized by pain at the medial tubercle of the calcaneus and/or along the medial longitudinal arch of the foot. It usually develops when repetitive and prolonged stress is placed on plantar fascia, which may cause microtears and/or partial or total tears of the fascia near its insertion to the calcaneus. Plantar fascia plays significant role in the foot biomechanics. It absorbs mechanical forces placed on the foot and propels foot forward by utilizing the windlass effect. In deranged foot biomechanics, like in pronation of the foot, pes cavus, shortened Achilles tendon, extreme pes planus, etc., additional stress and elongation of plantar fascia is observed, which the fascia, because of its anatomy, is unable to compensate. In athletes, plantar fasciitis is more common in long distance runners and increased incidence is observed in tennis players, basketball players and in dancers. It is usually unilateral whereas in 15% of patients it is bilateral. Clinical findings include painful foot with pain across the plantar aspect of the calcaneus. Diagnosis is usually made after anamnesis and clinical examination. The most painful spot is located at the medial tubercle of the calcaneus and pain is aggravated by passive stretching of the fascia. X-rays could be useful for diagnosing bony spur (calcar calcanei) and ultrasound and MRI are useful for diagnosing thickened fascia, bursa or rupture. MRI and scintigraphy are also useful for differentiating plantar fasciitis and stress fracture of the calcaneus. For the treatment of the plantar fasciitis, especially in athletes, custom made orthothic devices are used for correction of the deranged foot biomechanics, even for prevention. For conservative treatment all usual methods are used (physiotherapy, cryotherapy, stretching exercises, orthoses through the night, local ultrasound and shock wave therapy and foot taping). Surgical treatment with endoscopic or open methods includes release and complete or partial removal of deranged plantar fascia. Surgical treatment is most commonly performed in athletes after 6-12 months of unsuccessful conservative treatment.