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.

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.

[Dynamics of changes in bone mineral density and structural organization in cosmonauts following space flight of 6 months in duration].

Microgravity effect on bone tissue of cosmonauts was evaluated following space flights of 6 months in duration. Peripheral quantitative computed tomography (pQCT) was used to determine volumetric bone mineral density (VBMD) and structure of distal parts of the leg and forearm. Changes in VBMD were found to correlate with bone position relative to the vector of gravity. In the forearm, reversible hypermineralization was bound together with compact bone thickening. Reversible osteopenia in the lower leg was accompanied with plausible losses both in compact and trabecular bone. Irrespective of position relative to the vector of gravity, bone microarchitecture tended to reduce the number of trabecules and to increase heterogeneity of the trabecular network. Pre-flight structural dynamics showed a complex character with linear time dependence.

In vivo assessment of magnesium status in human body using accelerator-based neutron activation measurement of hands: a pilot study.

Magnesium (Mg) is an element essential for many enzymatic reactions in the human body. Various human and animal studies suggest that changes in Mg status are linked to diseases such as cardiac arrhythmia, coronary heart disease, hypertension, premenstrual syndrome, and diabetes mellitus. Thus, knowledge of Mg levels in the human body is needed. A direct measurement of human blood serum, which contains only 0.3% of the total body Mg, is generally used to infer information about the status of Mg in the body. However, in many clinical situations, Mg stored in large levels, for example in bones, muscles, and soft tissues, needs to be monitored either to evaluate the efficacy of a treatment or to study the progression of diseases associated with the deficiency of total body Mg. This work presents a feasibility study of a noninvasive, in vivo neutron activation analysis (IVNAA) technique using the 26Mg (n, gamma) 27Mg reaction to measure Mg levels in human hands. The technique employs the McMaster University high beam current Tandetron accelerator hand irradiation facility and an array of eight NaI (T1) detectors arranged in a 4 pi geometry for delayed counting of the 0.844 and 1.014 MeV gamma rays emitted when 27Mg decays in the irradiated hand. Mg determination in humans using IVNAA of hands has been demonstrated to be feasible, with effective doses as low as one-quarter of those delivered in chest x rays. The overall experimental uncertainty in the measurements is estimated to be approximately 5% (1 sigma). The results are found to be in the range of the in vitro measurements reported for other cortical bones collected from different sites of the human skeleton, which confirms that this technique mainly provides a measure of the amount of Mg in hand bones. The average concentration of Mg determined in human hands is 10.96 +/- 1.25 (+/- 1 SD) mg Mg/g Ca. The coefficient of variation (11%) observed in this study is comparable with or lower than several studies using in vitro measurements reported in the literature and therefore allows for a quantitative intersubject comparison, even if to a limited extent. The features of the developed technique such as its simplicity, rapidity, accuracy, robustness, noninvasive nature, and very effective use of radiation doses, present the technique as a viable diagnostic tool available for trial in a clinical environment.

In vivo measurement of bone aluminum in population living in southern Ontario, Canada.

The harmful biological effect of excessive aluminum (Al) load in humans has been well documented in the literature. Al stored in bone, for instance due to dialysis treatment or occupational exposure, can interfere with normal bone remodeling leading to osteodystrophy, osteoarthritis, or osteomalacia. On the other hand, the relationship between chronic Al exposure and the risk of Alzheimer's disease remains controversial. In this work, the feasibility of in vivo neutron activation analysis (IVNAA) for measuring Al levels in the human hand bone, using the thermal neutron capture reaction 27Al(n, gamma)28 Al, is reported. This noninvasive diagnostic technique employs a high beam current Tandetron accelerator based neutron source, an irradiation/shielding cavity, a 47pi NaI(Tl) detector system, and a new set of hand bone phantoms. The photon spectra of the irradiated phantom closely resemble those collected from the hands of nonexposed healthy subjects. A protocol was developed using the newly developed hand phantoms, which resulted in a minimum detectable limit (MDL) of 0.29 mg Al in the human hand. Using the ratio of Al to Ca as an index of Al levels per unit bone mass, the MDL was determined as 19.5 +/- 1.5 microg Al/g Ca, which is within the range of the measured levels of 20-27 microg Al/g Ca [ICRP Report of the Task Group on Reference Man, Publication 23 (Pergamon, Oxford, 1975)] found in other in vivo and in vitro studies. Following the feasibility studies conducted with phantoms, the diagnostic technique was used to measure Al levels in the hand bones of 20 healthy human subjects. The mean hand bone Al concentration was determined as 27.1 +/- 16.1 (+/-1 SD) microg Al/g Ca. The average standard error (1sigma) in the Al/Ca is 14.0 microg Al/g Ca, which corresponds to an average relative error of 50% in the measured levels of Al/Ca. These results were achieved with a dose equivalent of 17.6 mSv to a hand and an effective dose of 14.4 microSv. This effective dose is approximately half of that received in a chest radiograph examination. It is recommended to investigate the use of the bone Al IVNAA diagnostic technique for in vivo measurements of patients with documented overload of Al in bone.

A preliminary study for non-invasive quantification of manganese in human hand bones.

Manganese (Mn) is a nutrient essential for regulating neurological and skeletal functions in the human body, but it is also toxic when humans are excessively exposed to Mn. Blood (or serum/plasma) and other body fluids reflect only the most recent exposure and rapidly return to within normal ranges, even when there has been a temporary excursion in response to exposure. In this context, we have been developing a non-invasive measurement of Mn stored in bone, using in vivo neutron activation analysis. Following feasibility studies, a first pilot study, using neutron activation analysis to measure Mn in the bones of the hand of ten healthy male human subjects, was conducted with the approval of the concerned research ethics boards. The participants of this study had no known history of exposure to Mn. Two volunteers were excluded from this study due to technical problems with their measurements. The inverse variance weighted mean value of Mn/Ca for the participants of this study is 0.12+/-0.68 microg Mn/g Ca which is comparable within uncertainties with the estimated range of 0.16-0.78 microg Mn/g Ca and mean value of 0.63+/-0.30 microg Mn/g Ca derived from cadaver data. It is recommended to investigate the use of the diagnostic technique for in vivo measurements of workers exposed occupationally to excessive amounts of Mn who could develop many-fold increased levels of Mn in bones as demonstrated through various animal studies. The technique needs further development to improve the precision of in vivo measurements in the non-exposed population.

Bone age assessment of children using a digital hand atlas.

We have developed an automated method to assess bone age of children using a digital hand atlas. The hand atlas consists of two components. The first component is a database which is comprised of a collection of 1400 digitized left hand radiographs from evenly distributed normally developed children of Caucasian (CA), Asian (AS), African-American (AA) and Hispanic (HI) origin, male (M) and female (F), ranged from 1- to 18-year-old; and relevant patient demographic data along with pediatric radiologists' readings of each radiograph. This data is separate into eight categories: CAM, CAF, AAM, AAF, HIM, HIF, ASM, and ASF. In addition, CAM, AAM, HIM, and ASM are combined as one male category; and CAF, AAF, HIF, and ASF are combined as one female category. The male and female are further combined as the F & M category. The second component is a computer-assisted diagnosis (CAD) module to assess a child bone age based on the collected data. The CAD method is derived from features extracted from seven regions of interest (ROIs): the carpal bone ROI, and six phanlangeal PROIs. The PROIs are six areas including the distal and middle regions of three middle fingers. These features were used to train the 11 category fuzzy classifiers: one for each race and gender, one for the female, one male, and one F & M, to assess the bone age of a child. The digital hand atlas is being integrated with a PACS for validation of clinical use.

The feasibility of in vivo quantification of bone-fluorine in humans by delayed neutron activation analysis: a pilot study.

Fluorine (F) plays an important role in dental health and bone formation. Many studies have shown that excess fluoride (F(-)) can result in dental or skeletal fluorosis, while other studies have indicated that a proper dosage of fluoride may have a protective effect on bone fracture incidence. Fluorine is stored almost completely in the skeleton making bone an ideal site for measurement to assess long-term exposure. This paper outlines a feasibility study of a technique to measure bone-fluorine non-invasively in the human hand using in vivo neutron activation analysis (IVNAA) via the (19)F(n,γ)(20)F reaction. Irradiations were performed using the Tandetron accelerator at McMaster University. Eight NaI(Tl) detectors arranged in a 4π geometry were employed for delayed counting of the emitted 1.63 MeV gamma ray. The short 11 s half-life of (20)F presents a difficult and unique practical challenge in terms of patient irradiation and subsequent detection. We have employed two simultaneous timing methods to determine the fluorine sensitivity by eliminating the interference of the 1.64 MeV gamma ray from the (37)Cl(n,γ)(38)Cl reaction. The timing method consisted of three counting periods: an initial 30 s (sum of three 10 s periods) count period for F, followed by a 120 s decay period, and a subsequent 300 s count period to obtain information pertaining to Ca and Cl. The phantom minimum detectable limit (M(DL)) determined by this method was 0.96 mg F/g Ca. The M(DL) was improved by dividing the initial timing period into three equal segments (10 s each) and combining the results using inverse variance weighting. This resulted in a phantom M(DL) of 0.66 mg F/g Ca. These detection limits are comparable to ex vivo results for various bones in the adult skeleton reported in the literature. Dosimetry was performed for these irradiation conditions. The equivalent dose for each phantom measurement was determined to be 30 mSv. The effective dose was however low, 35 µSv, which is comparable to other clinical diagnostic tools. The M(DL), relatively low radiation dose and non-invasiveness indicate the suitability of this method for routine in vivo analysis of bone-fluorine content. This prompted us to perform a trial study in human subjects. A preliminary human study on 34 participants was completed, with 33 of the 34 measurements proving to be successful. The in vivo M(DL) based on the improved timing method was determined to be 0.69 mg F/g Ca for the 33 successful human measurements. In our opinion, this technique has been demonstrated to be a suitable method for in vivo assessment of fluorine bone-burden.

Associations with subregional BMD-measurements in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) have bone loss to various degrees at different skeletal sites. The subregional bone mineral density (BMD) of the hand and the correlation of BMD to other regional bone losses, parameters of inflammation or bone resorption was evaluated in 421 patients with RA and controls. RA patients had significantly (P<0.01) lower BMD values in the carpus (0.405+/-0.004 g/cm2), metacarpal joint II (0.318+/-0.036 g/cm2) and metacarpal joint III (0.326+/-0.022 g/cm2) compared to controls. There was no difference in bone density at the lumbar spine or hip. Significant (P<0.001) correlations were found between BMD total of the hand, its subregions, the forearm and hip. Parameters of inflammation correlated significantly (P<0.001) with pyridinolines (r=0.378), desoxypyridinolines (r=0.183), forearm (r=-10, P<0.05), MCP II (r=-0.190, P<0.001), MCP III (r=0.204, P<0.001) and carpus (r=0.191, P<0.001).

[Analysis of the densitometric method of hand bone radiograms and assessment of early changes of bone structure in the children with Gaucher s disease on enzyme replacement therapy (ERT)]. / Analiza radiogramów kosci reki metoda densytometryczna w ocenie wczesnych zmian w strukturze kosci u dzieci z choroba Gauchera leczonych enzymatycznie.

In the study of changes of bone structure eighteen children with Gaucher s disease (ERT) at the 4 to 19.8 years, used was densitometric in vivo method of hand bone radiograms. On the basis of the radiogram assessed was the bone age of patient also optical bone density and dimension in the second metacarpal bone. Differential diagnostics was produced based on standardized cortical thickness and optical bone density, according to the norm of Polish population (1989, 2004). The analysis of hand bone radiograms in children with Gaucher's (ERT) shows that 55.5% of patients had normal skeletal status, 38.8% indicated osteopenia traits, one patient had osteoporotic traits.