Role of citrate in pathophysiology and medical management of bone diseases

Citrate is an intermediate in the \u201cTricarboxylic Acid Cycle\u201d and is used by all aerobic organisms to produce usable chemical energy. It is a derivative of citric acid, a weak organic acid which can be introduced with diet since it naturally exists in a variety of fruits and vegetables, and can be consumed as a dietary supplement. The close association between this compound and bone was pointed out for the first time by Dickens in 1941, who showed that approximately 90% of the citrate bulk of the human body resides in mineralised tissues. Since then, the number of published articles has increased exponentially, and considerable progress in understanding how citrate is involved in bone metabolism has been made. This review summarises current knowledge regarding the role of citrate in the pathophysiology and medical management of bone disorders

Utility of the trabecular bone score (TBS) in secondary osteoporosis.

Altered bone micro-architecture is an important factor in accounting for fragility fractures. Until recently, it has not been possible to gain information about skeletal microstructure in a way that is clinically feasible. Bone biopsy is essentially a research tool. High-resolution peripheral Quantitative Computed Tomography, while non-invasive, is available only sparsely throughout the world. The trabecular bone score (TBS) is an imaging technology adapted directly from the Dual Energy X-Ray Absorptiometry (DXA) image of the lumbar spine. Thus, it is potentially readily and widely available. In recent years, a large number of studies have demonstrated that TBS is significantly associated with direct measurements of bone micro-architecture, predicts current and future fragility fractures in primary osteoporosis, and may be a useful adjunct to BMD for fracture detection and prediction. In this review, we summarize its potential utility in secondary causes of osteoporosis. In some situations, like glucocorticoid-induced osteoporosis and in diabetes mellitus, the TBS appears to out-perform DXA. It also has apparent value in numerous other disorders associated with diminished bone health, including primary hyperparathyroidism, androgen-deficiency, hormone-receptor positive breast cancer treatment, chronic kidney disease, hemochromatosis, and autoimmune disorders like rheumatoid arthritis. Further research is both needed and warranted to more clearly establish the role of TBS in these and other disorders that adversely affect bone

Body composition with dual energy X-ray absorptiometry : from basics to new tools

Dual-energy X-ray absorptiometry (DXA) in nowadays considered one of the most versatile imaging techniques for the evaluation of metabolic bone disorders such as osteoporosis, sarcopenia and obesity. The advantages of DXA over other imaging techniques are the very low radiation dose, its accuracy and simplicity of use. In addition, fat mass (FM) and lean mass (LM) values by DXA shows very good accuracy compared to that of computed tomography and magnetic resonance imaging. In this review we will explain the technical working principles of body composition with DXA, together with the possible limitations and pitfalls that should be avoided in daily routine to produce high-quality DXA examinations. We will also cover the current clinical practical application of whole body DXA values, with particular emphasis on the use of LM indices in the diagnostic workup of reduced muscle mass, sarcopenia and osteosarcopenic obesity according to the most recent guidelines. The possible use of adipose indices will be considered, such as the fat mass index (FMI) or the android/gynoid ratio, as well as lipodystrophy indices and the evaluation of visceral adipose tissue (VAT). Whenever available, we will provide possible cut-off diagnostic values for each of these LM and FM indices, according to current literature and guidelines

Nuovo protocollo riabilitativo dopo intervento di protesi totale di caviglia nel paziente emofilico: caso clinico preliminare

Nuovo protocollo riabilitativo a seguito di artroplastica totale della caviglia in pazienti emo- filici: caso clinico preliminare - Barbieri V [1], Rebagliati GAA [1], Russo G [1], Ulivieri FM [2], Previtera AM [1]. [1] Scuola di Specializzazione in Medicina Fisica e Riabilitativa, Universit\ue0 degli studi di Milano. [2] Bone Metabolic Unit, Uo Medicina Nucleare, IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano. - L\u2019artropatia emofilica in stadio terminale si presenta come non responsiva ai trattamenti conserva- tivi e comporta un dolore di difficile controllo, grave deterioramento delle articolazioni interessate e significative disabilit\ue0. Le articolazioni pi\uf9 colpite sono gomiti, ginocchia e caviglie [1]. Per quanto riguarda l\u2019artropatia di caviglia, il trattamento chirurgico \ue8 ad oggi rappresentato prin- cipalmente da due tecniche: l\u2019artrodesi di caviglia (AA), efficace nel ridurre il dolore e la frequenza degli episodi di emartro, con tuttavia perdita di mobilit\ue0 e possibile sovraccarico delle altre artico- lazioni dell\u2019arto inferiore (con occasionale necessit\ue0 di ulteriori correzioni chirurgiche) [3] e l\u2019artro- plastica di caviglia (TAR), che presenta il vantaggio di conservare la mobilit\ue0, ma \ue8 gravata da un maggior numero di complicanze, tra cui mobilizzazione asettica e infezioni dovute alla scarsa qualit\ue0 ossea nella sede di impianto [2,3]. Nel breve termine, entrambe le opzioni portano a sollievo dal dolore [2,3]. Le misure di outcome della TAR, per quanto parziali [2], sono incoraggianti, spaziando dal sollievo dal dolore alla migliorata mobilit\ue0 nella maggior parte dei casi [3]. Al contrario, la ge- stione post- operatoria presenta aspetti controversi a causa dell\u2019alto tasso di complicanze precoci e della necessit\ue0 di cure multidisciplinari. Non esiste al momento un univoco standard di cura riabi- litativo che consenta di monitorare e ottimizzare il processo di guarigione. Per questo motivo \ue8 stato proposto un nuovo protocollo sperimentale di riabilitazione precoce, volto alla minimizzazione delle complicanze post-chirurgiche. Abbiamo posto a confronto outcome clinico, funzionale e strumentale di un paziente emofilico sot- toposto a TAR e al nuovo protocollo con tre pazienti emofilici, che dopo TAR hanno seguito il proto- collo in uso presso IRCCS Ca\u2019 Granda, Ospedale Maggiore Policlinico di Milano. La procedura di riabilitazione \u201ctradizionale\u201d si divide in: fase di breve termine, alla dimissione dalla UO di Ortopedia, in cui al paziente viene posizionato uno stivaletto gessato (valutazione della mo- bilit\ue0 e degli ausili, riduzione delle asimmetrie corporee, verticalizzazione assistita, cammino in sca- rico); fase di medio termine, svolta a domicilio per un mese (riduzione del rischio di lesioni terziarie, raggiungimento di parziale autonomia in ADL e IADL, verticalizzazione e controllo dell\u2019equilibrio) e fase di lungo termine, svolta in una struttura riabilitativa dedicata (deambulazione autonoma com- prendente la salita delle scale, autonomia nel ADL e IADL, reintroduzione nel contesto di prove- nienza). Il nuovo protocollo riabilitativo, al contrario, prende avvio quando il paziente si trova ancora nel reparto di Ortopedia, con il posizionamento di uno stivaletto rimovibile, che consente la mobilizza- zione dell\u2019articolazione coxo-femorale, del ginocchio e delle dita del piede, oltre a massaggio dell\u2019apo- neurosi plantare e un primo tentativo di flessione ed estensione della caviglia. Alla dimissione, il programma prosegue con sessioni bisettimanali di fisioterapia domiciliare, durante le quali viene impostata dapprima deambulazione in scarico con bastoncini canadesi, successivamente viene ese- guito trattamento manuale della ferita chirurgica e, al 17mo giorno post-operatorio, un primo ten- tativo di pronazione e supinazione della caviglia, seguito da un iniziale carico parziale della pianta del piede con progressivo aumento del carico in supervisione. A partire dalla trentesima giornata il protocollo continua in una struttura dedicata come nel percorso tradizionale. I tre controlli programmati hanno compreso un esame ortopedico, una densitometria ossea con un software dedicato \u201cmetal removal\u201d ed una valutazione funzionale con scala HJHS [4,5,6,7,8], che misura lo stato di salute nella struttura e nella funzione delle articolazioni pi\uf9 comunemente sog- gette a sanguinamento. Il paziente oggetto di studio ha mostrato una minore perdita di BMD al follow-up del quarto mese rispetto ai controlli. Ci\uf2 potrebbe suggerire una migliore efficacia nel mantenimento di una adeguata mineralizzazione ossea nel periodo immediatamente post-operatorio, offrendo una migliore stabilit\ue0 protesica e potenzialmente un minor numero di complicanze. La valutazione funzionale, con HJHS eseguito prima dell\u2019intervento e a distanza di un anno dallo stesso, ha evidenziato un miglioramento dello score totale sia nel caso che nei controlli, oltre che una sostanziale stabilit\ue0 nello score specifico per l\u2019articolazione. Tale dato potrebbe indicare una non inferiorit\ue0 del nuovo protocollo rispetto a quello in uso sul lungo termine. Il nuovo protocollo potrebbe quindi rappresentare una valida strategia per ridurre il numero delle complicanze legate alla TAR e suggerire due parametri strumentali e funzionali potenzialmente tra loro correlati come nuove misure di outcome nel primo periodo post-operatorio. Tali ipotesi neces- sitano di conferma tramite trial multicentrico controllato, possibilmente randomizzato, eseguito su un numero di casi statisticamente significativo. [1] Vulpen, LFD, Holstein, K, Martinoli, C. Joint disease in haemophilia: Pathophysiology, pain and imaging. Haemophilia. 2018; 24(Suppl. 6): 44\u2013 49. [2] Solimeno LP, Pasta G. Knee and Ankle Arthroplasty in Hemophilia. J Clin Med. 2017;6(11):107. [3] Rodriguez\u2010Merchan, E. C. (2014), End\u2010stage haemophilic arthropathy of the ankle: ankle fu- sion or total ankle replacement. Haemophilia, 20: e106-e107. [4] Fischer, K., et al. (2017), Choosing outcome assessment tools in haemophilia care and re- search: a multidisciplinary perspective. Haemophilia, 23: 11-24. [5] Feldman BM, Funk S, Bergstrom B-M, Zourikian N, Hilliard P, van der Net J, Engelbert RHH, Petrini P, van den Berg M , Manco-Johnson M, Rivard GE, Abad A, and Blanchette VS. Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: Validity of the Hemophilia Joint Health Score (HJHS). Arthritis Care & Research 2011 Feb; 63 (2):223-30. [6] Hilliard P, Funk S, Zourikian N. Bergstrom BM, Bradley CS, McLimont M, Manco-Johnson M, Petrini P, Van Den Berg M, Feldman BM. Hemophilia joint health score reliability study. Haemo- philia 2006; 12(5):pp 518-525. [7] Feldman BM. Funk S, Hilliard P, Van Der Net J, Zourikian N, Berstrom B-M, Engelbert RHH, Abad A, Petrini P, Manco-Johnson M, and On behalf of the International Prophylaxis Study Group. The Haemophilia Joint Health Score (HJHS) International Validation Study. XXVIIIth In- ternational Congress of the World Federation of Hemophilia, Istanbul, Turkey. Haemophilia 2008; 14 (Suppl. 2):pp 83. [8] Hilliard P, Blanchette VS, Doria A, Blanchette C, Hang M, Feldman BM. The Hemophilia Joint Health Score (HJHS) correlates highly with radiographic damage. XXVIIIth International Congress of the World Federation of Hemophilia, Istanbul, Turkey. Haemophilia 2008; 14 (Suppl. 2):pp 80

Artificial neural network analysis of bone quality DXA parameters response to teriparatide in fractured osteoporotic patients

Teriparatide is a bone-forming therapy for osteoporosis that increases bone quantity and texture, with uncertain action on bone geometry. No data are available regarding its influence on bone strain. To investigate teriparatide action on parameters of bone quantity and quality and on Bone Strain Index (BSI), also derived from DXA lumbar scan, based on the mathematical model finite element method. Forty osteoporotic patients with fractures were studied before and after two years of daily subcutaneous 20 mcg of teriparatide with dual X-ray photon absorptiometry to assess bone mineral density (BMD), hip structural analysis (HSA), trabecular bone score (TBS), BSI. Spine deformity index (SDI) was calculated from spine X-ray. Shapiro-Wilks, Wilcoxon and Student's t test were used for classical statistical analysis. Auto Contractive Map was used for Artificial Neural Network Analysis (ANNs). In the entire population, the ameliorations after therapy regarded BSI (-13.9%), TBS (5.08%), BMD (8.36%). HSA parameters of femoral shaft showed a worsening. Dividing patients into responders (BMD increase >10%) and non-responders, the first presented TBS and BSI ameliorations (11.87% and -25.46%, respectively). Non-responders presented an amelioration of BSI only, but less than in the other subgroup (-6.57%). ANNs maps reflect the mentioned bone quality improvements. Teriparatide appears to ameliorate not only BMD and TBS, but also BSI, suggesting an increase of bone strength that may explain the known reduction in fracture risk, not simply justified by BMD increase. BSI appears to be a sensitive index of TPD effect. ANNs appears to be a valid tool to investigate complex clinical systems

The role of carboxy-terminal cross-linking telopeptide of type I collagen, dual x-ray absorptiometry bone strain and Romberg test in a new osteoporotic fracture risk evaluation : a proposal from an observational study

The consolidated way of diagnosing and treating osteoporosis in order to prevent fragility fractures has recently been questioned by some papers, which complained of overdiagnosis and consequent overtreatment of this pathology with underestimating other causes of the fragility fractures, like falls. A new clinical approach is proposed for identifying the subgroup of patients prone to fragility fractures. This retrospective observational study was conducted from January to June 2015 at the Nuclear Medicine-Bone Metabolic Unit of the of the Fondazione IRCCS Ca\u2019 Granda, Milan, Italy. An Italian population of 125 consecutive postmenopausal women was investigated for bone quantity and bone quality. Patients with neurological diseases regarding balance and vestibular dysfunction, sarcopenia, past or current history of diseases and use of drugs known to affect bone metabolism were excluded. Dual X-ray absorptiometry was used to assess bone quantity (bone mineral density) and bone quality (trabecular bone score and bone strain). Biochemical markers of bone turnover (type I collagen carboxy-terminal telopeptide, alkaline phosphatase, vitamin D) have been measured. Morphometric fractures have been searched by spine radiography. Balance was evaluated by the Romberg test. The data were evaluated with the neural network analysis using the Auto Contractive Map algorithm. The resulting semantic map shows the Minimal Spanning Tree and the Maximally Regular Graph of the interrelations between bone status parameters, balance conditions and fractures of the studied population. A low fracture risk seems to be related to a low car-boxy-terminal cross-linking telopeptide of type I collagen level, whereas a positive Romberg test, together with compromised bone trabecular microarchitecture DXA parameters, appears to be strictly connected with fragility fractures. A simple assessment of the risk of fragility fracture is proposed in order to identify those frail patients at risk for osteoporotic fractures, who may have the best benefit from a pharmacological and physiotherapeutic approach

Bone strain index reproducibility and soft tissue thickness influence : a dual x-ray photon absorptiometry phantom study

Background: Bone strain index (BSI) is a tool measuring bone strain, derived from dual x-ray photon absorptiometry. It is able to characterise an aspect of bone quality that, joined to the quantity and quality parameters of bone mineral density (BMD) and trabecular bone score (TBS), permits an accurate definition of fracture risk. As no data are available about BSI precision, our aim was to assess its in vitro reproducibility. Methods: A Hologic spine phantom was used to perform BSI scans with three different scan modes: fast array (FA), array (A), and high definition (HD). Different soft tissue thicknesses (1, 3, 6 cm) of fresh pork rind layers as a surrogate of abdominal fat were interposed. For each scan mode, the phantom was consecutively scanned 25 times without repositioning. Results: In all scan modes (FA, A, HD) and at every fat thickness, BSI reproducibility was lower than that of BMD. The highest reproducibility was found using HD-mode with 1 cm of pork rind and the lowest one using HD-mode with 6 cm of pork rind. Increasing fat thickness, BSI reproducibility tended to decrease. BSI least significant change appeared to be about three times that of BMD in all modalities and fat thicknesses. Without pork rind superimposition and with 1-cm fat layer, BSI reproducibility was highest with HD-mode; with 3 or 6 cm fat thickness, it was higher with A-mode. Conclusions: BSI reproducibility was worse than that of BMD, but it is less sensitive to fat thickness increase, similarly to TBS