LRP5 gene polymorphisms and radiographic joint damage in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is characterized by increased bone resorption and impaired bone formation. Osteoblast function is regulated by the canonical LRP5/Wnt/ß-catenin pathway. Bone mineral density and RA joint destruction are partially inherited. In line with this, we found significant associations between LRP5 SNPs (p.A1330V, p.N740N, p.V667M) and RA radiographic damage severity. INTRODUCTION: Increased bone resorption and impaired bone formation characterize rheumatoid arthritis (RA). Canonical Wnt/ß-catenin pathway, signalled by lipoprotein receptor-related protein-5 (LRP5), regulates osteoblast function. Since bone mineral density (BMD) and RA joint destruction are partially inherited, we studied their association with LRP5 single nucleotide polymorphisms (SNPs). METHODS: Clinical data and peripheral blood for biomarkers assessment and LRP5 genotyping were collected from 208 RA patients. Hands and feet X-rays were scored [modified Sharp/van der Heijde Score (SHS), joint space narrowing (JSN), and erosion scores]. Lumbar spine, total left proximal femur, and left hand BMD were assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: TT genotypes for p.A1330V and p.N740N LRP5 SNPs associated with total SHS, erosion score, and hands erosion score; the same for p.A1330V with feet JSN score and p.N740N with hands total score. AG genotype for p.V667M associated with sclerostin and hands JSN score. Femoral BMD associated with TC genotype for p.N740N. Multiple test correction precluded a few of these associations. Among V667M-N740N-A1330V haplotypes: GTT associated with higher feet JSN score (OR = 3.80; p = 0.016) and ATT with higher JSN score (OR = 4.60; p = 0.032), hands total score (OR = 5.65; p = 0.022), and total SHS (OR = 6.74; p = 0.024). CONCLUSION: Significant associations between LRP5 SNPs (p.A1330V, p.N740N, and p.V667M) and the severity of radiographic damage reinforce the evidence of bone destruction heritability in RA.

Biomarkers of hand osteoarthritis.

Hand osteoarthritis (OA) is a common degenerative joint disorder leading to substantial pain and disability. The most severe subtype is erosive hand OA characterized by an abrupt onset, local inflammation, subchondral erosions and worse outcomes than non-erosive disease. Biomarkers of hand OA could help to diagnose the disease earlier, to distinguish patients with erosive and non-erosive forms, to assess disease severity or to predict its future progression. The objective of this review was to summarize the role of potential biomarkers of hand OA. A PubMed search for soluble biomarkers associated with hand OA was performed from inception to June 2017. In total, 21 relevant publications were found and reviewed. These publications identified 20 potential biomarkers of hand OA. C-terminal cross-linking telopeptide of type II collagen, cartilage oligomeric matrix protein, osteocalcin, hyaluronan, urinary pentosidine, vascular cell adhesion molecule 1, monocyte chemotactic protein 1, osteoprotegerin and interleukin 1 have been shown as potential biomarkers for assessing disease severity. C-terminal cross-linking telopeptide of type I collagen, hyaluronan, urinary pentosidine and myeloperoxidase were shown to differentiate between erosive and non-erosive hand OA patients. A number of biomarkers reflecting joint tissue metabolism and inflammation have been studied in hand OA. Some were identified as potential biomarkers of disease severity and progression, others were shown to differentiate between erosive and non-erosive disease. However, further research is necessary to assess the value of biomarkers for use in clinical practice.

Decline in hand bone mineral density indicates increased risk of erosive change in early rheumatoid arthritis.

OBJECTIVE: Despite better disease suppression with combination disease-modifying antirheumatic drugs (DMARDs), some patients with rheumatoid arthritis (RA) have progressive erosive disease. The objective of this study was to determine whether hand bone mineral density (BMD) loss in the first 6 months of treatment indicates increased risk of erosions at 12 months. METHODS: Patients with DMARD-naive early RA receiving treat-to-target therapy were studied (n = 106). Hand BMD was measured at baseline and 6 months by dual x-ray absorptiometry. Hand and feet radiographs were performed at baseline and 12 months and scored using the van der Heijde modification of the Sharp method. A K-means clustering algorithm was used to divide patients into 2 groups: the BMD loss group or the no loss group, according to their absolute change in BMD from baseline to 6 months. Multiple regression analysis (hurdle model) was performed to determine the risk factors for both erosive disease and erosion scores. RESULTS: Hand BMD loss at 6 months was associated with erosion scores at 12 months (P = 0.021). In a multiple regression analysis, hand BMD loss (P = 0.046) and older age at onset (≥50 years; P = 0.014) were associated with erosive disease, whereas baseline erosion scores (P = 0.001) and anti-cyclic citrullinated peptide (P = 0.024) were correlated with erosion severity/progression. CONCLUSION: In RA patients receiving treat-to-target therapy, early hand BMD loss could identify patients who are at risk of developing erosive disease at 12 months, potentially allowing intensification of treatment to prevent erosive damage.

Quantification of periarticular demineralization and synovialitis of the hand in rheumatoid arthritis patients.

UNLABELLED: The bone mineral density (BMD) measurement of the hand in rheumatoid arthritis (RA) patients is no standard measurement method as yet. The aim was to contribute to the standardization of the hand BMD measurement, especially of periarticular regions. As results, we found best precision values for the wrist and a significant correlation between hand and spine/femur BMD depending on disease activity and disease duration. INTRODUCTION: This study was conducted to investigate (i) the precision of periarticular hand BMD measuring, (ii) the periarticular demineralization of the hand, (iii) the correlation between periarticular hand BMD and spine/femur BMD, and (iv) the correlation of hand BMD to hand synovitis. METHODS: A number of 52 RA patients were examined by BMD measurement of the femoral neck, spine, whole hand, metacarpophalangeal (MCP) joints II-V, personal identity profile (PIP) joints II-V, and wrist using dual-energy X-ray absorptiometry (DXA). Synovitis of the hand was examined by ultrasonography and magnetic resonance imaging (MRI). Three subgroups were further analyzed: early RA, established RA with moderate and with high disease activity. Early RA and established RA patients with high disease activity were Followed up after 12 months. RESULTS: We found (1) best precision of BMD measurement for the wrist, (2) BMD in RA significantly reduced if compared to normal controls, (3) a highly significant positive correlation between hand and spine/femur BMD and the power of correlation to depend on disease activity and disease duration (high correlation in RA with moderate disease activity and early RA, very high correlation in RA with high disease activity), (4) a negative correlation between hand BMD and hand synovitis in RA with high disease activity, and (5) a significant reduction of synovitis but no change in hand BMD after 12 months, respectively. CONCLUSIONS: This study shows a highly significant correlation between hand BMD and spine/femur BMD in RA patients depending on disease activity and disease duration. We conclude to measure BMD at different sites including hands in order to quantify bone loss in RA patients most properly.

Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: subanalysis of the PREMIER study.

BACKGROUND: Anti-TNF therapy has been shown to reduce radiographic joint damage in rheumatoid arthritis (RA) independent of clinical response. This has previously not been examined for periarticular bone loss, the other characteristic feature of bone involvement in RA.The objective of this study was to examine if treatment with the TNF-α inhibitor adalimumab also could reduce periarticular bone loss in RA patients independent of disease activity. METHODS: RA patients were recruited from the PREMIER study and included 214 patients treated with methotrexate (MTX) plus adalimumab and 188 patients treated with MTX monotherapy. Periarticular bone loss was assessed by digital X-ray radiogrammetry metacarpal cortical index (DXR-MCI). Change in DXR-MCI was evaluated in patients with different levels of clinical response, as assessed by changes in DAS28 score at 52 weeks and in mean C-reactive protein (CRP) levels during follow-up. RESULTS: In the MTX group, there was a greater median DXR-MCI loss among patients with moderate and high disease activity compared to those in remission or with low disease activity (-3.3% vs. -2.2%, p = 0.01). In contrast, periarticular bone loss was independent of disease activity (-1.9% vs. -2.4%, p = 0.99) in the combination group. In the MTX group patients with a mean CRP of ≥ 10 mg/l lost significantly more DXR-MCI than patients with low CRP (-3.1% vs. -1.9%, p <0.01) whereas in the combination group no significant differences between the two CRP groups was seen (-2.4% vs. -2.0%, p = 0.48). CONCLUSION: Adalimumab in combination with MTX reduces periarticular bone loss independently of clinical response. These results support the hypothesis that TNF-α stimulates the osteoclast not only by the inflammatory pathway but do also have a direct effect on the osteoclast. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT001195663.

Bone loss in very early inflammatory back pain in undifferentiated spondyloarthropathy: a 1-year observational study.

OBJECTIVE: Bone loss in patients with inflammatory back pain (IBP) suspicious of early undifferentiated spondyloarthropathy is poorly defined. The aim of this study was to examine changes in bone mineral density (BMD) at the hip, lumbar spine and hand in patients with early IBP and to look for possible biomarkers associated with this change. METHODS: In 30 patients with early IBP, clinical data were collected and BMD assessed using dual energy x-ray absorptiometry at baseline, 6 and 12 months. Further imaging performed included MRI of the sacroiliac joints (SIJs) and spine at baseline and x-rays of the SIJs at baseline and after 8 years. RESULTS: After 12 months no significant reduction in hip, spine and hand BMD was seen at the group level. However, hip bone loss was found to be associated with raised baseline C-reactive protein levels, baseline MRI bone marrow oedema of the SIJs and the presence of radiographic sacroiliitis after 8 years. No association was found with change in spine and hand BMD. CONCLUSION: Systemic bone loss in the hip is an early feature of the inflammatory disease process in patients with IBP in undifferentiated spondyloarthropathy and is related to disease activity. These data highlight the importance of aggressive intervention in the early stages of disease in undifferentiated spondyloarthropathy.

[Prognosis of long tubular bone strength changes in surgery of chronic osteomyelitis].

Mineral bone density (MBD) in osteomyelitic focus and symmetric intact tubular bone was compared in 54 patients. Changes of MBD values were also measured after surgical treatment (bone trepanation or osteonecroectomy with bone plasty). Thus, MBD, and, therefore, bone strength, was mostly higher in pathologic focus then in the healthy bone. Operative treatment showed no negative influence on MBD.

Bone mineral density in the hand as a predictor for mortality in patients with rheumatoid arthritis.

OBJECTIVES: BMD in the hand, as evaluated by digital X-ray radiogrammetry (DXR), has been suggested to be a predictor for joint damage in RA. A predictor for long-term prognosis might also predict increased mortality in RA. The aim of the present study was to evaluate BMD in the hand as a predictor for all-cause mortality. METHODS: In 1978, 152 consecutive patients (78% women, mean disease duration: 14.2 years) were enrolled. X-rays of the hands at inclusion were available in 108 patients. Reasons for not evaluating DXR in 24 patients were placement of joint prostheses or severe malalignment. BMD was evaluated by DXR on the same digitized hand X-rays used for scoring radiographic joint damage. Measures of disease activity and damage were used to predict mortality by Cox regression models. RESULTS: From February 1978 through March 2008, 62 of the 82 patients died, corresponding to a standardized mortality ratio of 2.92 (95% CI 2.19, 3.65) for both sexes combined. In age- and sex-adjusted proportional hazards models, BMD [hazard ratio (HR) = 0.58/1 s.d.; 95% CI 0.37, 0.91], Steinbrocker functional class 3-4 (HR = 4.74/1 step; 95% CI 1.93, 11.64), the physician's global assessment (HR = 1.38/1 s.d.; 95% CI 1.03, 1.84) and ESR (HR = 1.92/1 s.d.; 95% CI 1.42, 2.58) were significant predictors of mortality, but RF, disease duration, Larsen index, Ritchie articular index and the patient's global assessment were not. CONCLUSION: Low DXR-BMD predicted overall mortality in age- and sex-adjusted analyses, which further supports it as a valid measurement of disease activity or damage and as having prognostic value.

Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up.

OBJECTIVE: To examine 1-year hand bone loss in early rheumatoid arthritis (RA) as a predictor of radiographic damage at 5-year and 10-year follow-up METHODS: A total of 136 patients with RA (disease duration 0-4 years) were followed for 10 years with clinical data and hand radiographs. Joint damage was scored according to the van der Heijde modification of the Sharp method (vdH Sharp score) and hand bone mineral density (BMD) was measured by digital x ray radiogrammetry (DXR). Group comparisons, correlation analyses and multivariate analyses were performed to evaluate the relationship between hand bone loss and radiographic joint damage. RESULTS: Patients with hand BMD loss at 1 year had a higher median increase in vdH Sharp score compared to patients without loss at 5 years (12 vs 2, p = 0.001) and 10 years (22 vs 4, p = 0.002). In a linear regression model adjusting for age, gender, baseline C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), IgM rheumatoid factor (RF) and radiographic damage, absolute hand DXR-BMD loss at 1 year was an independent predictor of radiographic outcome at 5 years (p<0.01) and 10 years (p = 0.02). In a logistic regression model the odds ratio (95% CI) for radiographic progression among patients with hand BMD loss was 3.5 (1.4 to 8.8) and 3.5 (1.4 to 8.4) at 5 and 10 years, respectively. CONCLUSION: Early hand bone loss measured by DXR-BMD is an independent predictor of subsequent radiographic damage. Our findings support that quantitative hand bone loss in RA precedes radiographic joint damage and may be used as a tool for assessment of bone involvement in RA.

Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis.

OBJECTIVES: To evaluate changes in bone mineral density (BMD) in the hands, hip and spine after 1 and 2 years of follow-up, in relation to antirheumatic and antiresorptive therapies and disease and demographic variables in patients with recent-onset rheumatoid arthritis (RA). METHODS: Changes in BMD measured in metacarpals 2-4 by digital x-ray radiogrammetry and in the hip and spine by dual energy x-ray absorptiometry were assessed at baseline and after 1 and 2 years of follow-up in 218 patients with recent-onset RA from the BeSt study, who received one of four treatment strategies: sequential monotherapy (group 1); step-up combination therapy (group 2); initial combination therapy with tapered high-dose prednisone (group 3); or initial combination therapy with infliximab (group 4). RESULTS: After 1 and 2 years, there was significant BMD loss in all locations, with significantly greater BMD loss in the hands than generalised BMD loss in the hip and spine. Initial combination therapy with prednisone or infliximab were associated with less hand BMD loss compared with initial monotherapy after 1 and 2 years (-0.9 and -1.6%, -0.6 and -1.4%, -1.7 and -3.3%, and -2.6 and -3.6% for group 4-1 after 1 and 2 years, overall p = 0.001 and p = 0.014, respectively). Progression in erosions was independently associated with increased BMD loss both in the hands and hip after 1 year. The use of bisphosphonates protected only against generalised BMD loss in the hip and spine. CONCLUSIONS: The association between joint damage progression and both hand and generalised BMD loss in RA suggests common pathways between these processes, with hand BMD loss occurring earlier in the disease course than generalised BMD loss.

Heritability of a skeletal biomarker of biological aging.

Changes in the skeletal system, which include age-related bone and joint remodeling, can potentially be used as a biomarker of biological aging. The aim of the present study was to investigate the extent and mode of inheritance of skeletal biomarker of biological aging-osseographic score (OSS), in a large sample of ethnically homogeneous pedigrees. The investigated cohort comprised 359 Chuvashian families and included 787 men aged 18-89 years (mean 46.9) and 723 women aged 18-90 years (mean 48.5). The TOSS - transformed OSS standardized in 5-year age groups for each sex, was analyzed as a BA index. We evaluated familial correlations and performed segregation analysis. Results of our study suggest the familial aggregations of TOSS variation in the Chuvashian pedigrees. In a segregation analysis we found a significant major gene (MG) effect in the individual's TOSS with a dominant most parsimonious model (H(2) = 0.32). Genetic factors (MG genotypes) explained 47% of the residual OSS variance after age adjustment and after including sex-genotype interaction, they explained 52% of the residual variance. Results of our study also indicated that the inherited difference in the skeletal aging pattern in men lies mostly in the rate of aging, but in women in the age of the onset of the period of visible skeletal changes.

Hand bone densitometry: a more sensitive standard for the assessment of early bone damage in rheumatoid arthritis.

OBJECTIVE: To examine the role of hand dual-energy x ray absorptiometry (DEXA) compared with radiography in the assessment of bone involvement in patients with early rheumatoid arthritis (RA) who have active disease. METHODS: The study population (n = 79) had RA of <12 months' duration and were selected for poor prognostic features. Clinical data and bone mineral density (BMD) data were collected at baseline, 24 and 48 weeks. Hand radiographs were performed at baseline and 48 weeks. Bone damage analyses were performed for the group and individuals using the smallest detectable change (SDC) method. RESULTS: At baseline, mean disease duration was 8.5 months, erythrocyte sedimentation rate was 34.3 mm/hour, C-reactive protein was 40.2 mg/l, Health Assessment Questionnaire score was 1.35 and 81% of patients were positive for rheumatoid factor. Mean (95% CI) hand BMD loss was 2.5% (-3.5 to -1.5) at 24 weeks and 2.6% (-3.8 to -1.5) at 48 weeks. Individual hand bone loss exceeding the SDC was seen in 46.8% at 24 weeks and in 58.2% at 48 weeks. In the subgroup of 58 patients who had undergone radiography, radiographic joint damage score evaluated by the Sharp-van der Heijde method increased from 4.8 to 10.6 (p = 0.001). Individual hand bone loss in this subgroup exceeding the SDC was seen in 50.0% at 24 weeks and in 56.9% at 48 weeks, whereas at 48 weeks only 22.4% had deteriorated in modified Sharp score. CONCLUSION: The study results indicate that hand DEXA is a more sensitive tool than radiology (radiographic joint-damage scores), for measuring disease-related bone damage in early RA.

Hand bone midshaft enthesophytes: the influence of age, sex, and heritability.

OBJECTIVE: The aims of the present study were (1) to evaluate whether development of enthesophytes is an age- and/or sex-associated phenomenon; (2) to clarify whether enthesophyte development is controlled by genetics; (3) to evaluate the correlations between the enthesophytes and osteophytes of the hand joints. DESIGN: The studied cohort comprised 359 Chuvashian (Russian Federation) pedigrees (424 nuclear families) and included 786 males and 723 females aged 18-90 years. The enthesophyte score (ES) was constructed as the overall number of enthesophytes at the midshaft of the phalanges of the second to the fifth fingers of both hands. The osteophyte score (OS) was constructed similarly. We used variance component (VC) analysis to examine the age-related patterns and compare the contribution of the genetic and common environmental factors to ES and OS variations. RESULTS AND CONCLUSIONS: After age 25, ES increases with age (on average linearly). Age explains 45% of the ES variation in males but only 25% of the variation in females, in contrast to about 75% of the variation of OS in both sexes. At any age, males showed higher ES than females and the difference between sexes increased with age. Genetic components explained 20% of enthesophyte development variation. We did not find common additive genetic factors for ES and OS. The correlation coefficients between ES and OS were r=0.62 (P=0.0001) in males and r=0.50 (P=0.0001) in females. After age adjustment, the correlation decreased to r=0.087 (P=0.014) and r=0.14 (P=0.001) correspondingly. Most probably, enthesophytes and osteophytes are manifestations of different etiological processes.

Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis.

OBJECTIVES: To examine whether treatment with anti-tumour necrosis factor (TNF) alpha prevents loss of bone mineral density (BMD) at the spine and hip (generalised) and in the hands (local) of patients with rheumatoid arthritis, and to study the changes in markers of bone metabolism, including receptor activator of the NFkappaB ligand (RANKL) and osteoprotegerin (OPG), during anti-TNF treatment. PATIENTS AND METHODS: 102 patients with active rheumatoid arthritis, who were treated with infliximab during 1 year, were included in this open cohort study. The BMD of the spine and hip (dual x ray absorptiometry) and hands dual x ray radiogrammetry was measured before the start of treatment and after 1 year. Changes in osteocalcin formation, beta-isomerised carboxy terminal telopeptide of type 1 collagen (beta-CTx, resorption), RANKL and OPG were determined at 0, 14, 30 and 46 weeks. RESULTS: The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p<0.01). The BMD of the hip in patients with a good European League Against Rheumatism response showed a favourable change compared with patients not achieving such a response. Serum beta-CTx and RANKL were both considerably decreased compared with baseline at all time points. The decrease in beta-CTx was associated with the decrease in Disease Activity Score of 28 joints and C reactive protein during the 0-14 weeks interval. CONCLUSION: In patients with rheumatoid arthritis treated with infliximab, spine and hip bone loss is arrested, whereas metacarpal cortical hand bone loss is not stopped. The outcome of the study also supports a relationship between clinical response, in terms of reduced inflammatory activity, and changes in bone loss of the spine, hip and hands.

Computerized digital imaging techniques provided by digital X-ray radiogrammetry as new diagnostic tool in rheumatoid arthritis.

PURPOSE: Our study evaluates digital x-ray radiogrammetry (DXR) and Radiogrammetry Kit (RK) as a new diagnostic method for the measurement of disease-related osteoporosis including quantification of joint space narrowing dependent on the severity of rheumatoid arthritis (RA). MATERIALS AND METHODS: A total of 172 unselected patients with RA underwent computerized measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as a semiautomated measurement of joint space distances at the metacarpal-phalangeal articulation (JSD-MCP 2-5), both were analyzed from plain radiographs of the nondominant hand. RESULTS: Correlations between DXR-BMD and DXR-MCI vs. parameters of RK were all significant (0.34 < R < 0.61; p < 0.01). An expected negative association was observed between RK parameters and the different scoring methods (-0.27 < R < -0.59). The maximum relative decrease in BMD vs. MCI as measured by DXR between the highest and lowest RA severity group was -27.7% vs. -27.5% (p < 0.01) for the modified Larsen Score, whereas the minimal value of relative DXR-BMD and DXR-MCI reduction could be documented for the Sharp Erosion Score (-20.8% vs. -26.8%; p < 0.01). The relative reduction of mean JSD-MCP using RK significantly varied from -25.0% (Sharp Erosion Score) to -41.2% (modified Larsen Score). In addition, an excellent reproducibility of DXR and RK could be verified. CONCLUSION: DXR in combination with RK could be a promising, widely available diagnostic tool to supplement the different scoring methods of RA with quantitative data, allowing an earlier and improved diagnosis and more precision in determining disease progression.

Hand bone loss in early undifferentiated arthritis: evaluating bone mineral density loss before the development of rheumatoid arthritis.

OBJECTIVES: (1) To examine the change in regional bone mineral density (BMD), including the hands, and assess its role as a predictor of outcome in patients presenting with an early undifferentiated inflammatory arthritis; (2) to examine for associations with the changes in hand BMD. METHODS: 74 patients with undifferentiated hand arthritis of less than 12 months' duration were examined at baseline and then at three, six, and 12 months follow up, including BMD measurement of the femoral neck, spine (L2-4), and the whole hands using dual energy absorptiometry (DXA). RESULTS: During the study, 13 patients were diagnosed as having rheumatoid arthritis, 19 as having inflammatory non-rheumatoid joint disorders, and 42 as having non-inflammatory joint disorders. At the femoral neck and lumbar spine no significant bone loss was seen in any of the three subgroups. At the 12 months follow up the mean (95% confidence interval) hand BMD loss in the patients with rheumatoid arthritis was -4.27% (-1.41 to -7.13); in the inflammatory non-rheumatoid group, -0.49% (-1.33 to +0.35); and in the non-inflammatory joint disorder group, -0.87% (-1.51 to -0.23). In a multivariate linear regression model (including age, rheumatoid factor, mean C reactive protein, mean HAQ score, and cumulative glucocorticoid dose), only mean C reactive protein (p<0.001) and rheumatoid factor (p = 0.04) were independently associated with change in hand BMD during follow up. CONCLUSIONS: Hand DXA provides a very sensitive tool for measuring bone loss in early rheumatoid arthritis and may be useful in identifying patients at high risk of developing progressive disease. Further studies are needed to evaluate the role of hand bone loss as a prognostic factor and outcome measure in rheumatoid arthritis.

Bone challenges for the hand surgeon: from basic bone biology to future clinical applications.

Bone is a complex tissue composed of a calcified extracellular matrix with specialized cells that produce, maintain, and resorb the bone. Bone also has a rich vascular and neural supply. Bone has a great capability of regeneration, healing, and remodelling that is influenced by external factors, such as stress forces, and internal regulators that include hormones, vitamins, and growth factors. These factors dictate bone biology, and variations result in pathophysiologic conditions that have clinical implications in hand surgery. Solutions to the challenges in hand surgery rely on a thorough understanding of the biology of bone.