Effect of rheumatoid arthritis and age on metacarpal bone shaft geometry and density: A longitudinal pQCT study in postmenopausal women.

OBJECTIVE: This study aimed to elucidate the effects of changes in the geometry and density of the metacarpal bone of patients with rheumatoid arthritis (RA). METHODS: This prospective study included consecutive postmenopausal RA patients who met the American College of Rheumatology Criteria and healthy controls (HC). Peripheral quantitative computed tomography scans at 50% of the total metacarpal shaft (third metacarpal bone) were obtained at baseline and follow-ups. Use of bisphosphonates (BP), glucocorticoids (GC), biologics, and disease-modifying anti-rheumatic drugs (DMARD) was monitored (baseline to follow-up). Total cross-sectional area (CSA), cortical-transitional zone and compact zone CSA, cortical volumetric bone mineral density, and compact cortex porosity were measured. A linear mixed-effects model was used to determine significant differences in the rate of change in the RA and control groups and in RA patient subgroups. RESULTS: Thirty-nine RA patients and 42 consecutive postmenopausal HC were followed for 63 months. RA and HC depicted a time-dependent increase of medullary CSA (+0.41 mm2/year, P < 0.0001), while total CSA remained stable (P = 0.2). RA status was associated with a loss of cortical bone mineral density (interaction: -3.08 mg/mm3; P = 0.014). In RA subgroup analysis, GC use ≥5 mg/day was positively correlated with a fourfold increase of medullary CSA (0.67 mm2/year P = 0.009), which resulted in a three- to fourfold loss of cortical density (-6.6 mg/mm3/year; P = 0.002) and cortical CSA (-0.57 mm2/year, P = 0.004). Patients with high disease activity and high GC dose at baseline demonstrated an increase in the total CSA (0.29 mm2/y; P = 0.049) and a loss of cortical BMD (-5.73 mg/mm3/y; P = 0.05) despite good clinical response. CONCLUSION: Increase in medullary metacarpal CSA and thinning of the cortical CSA are physiological and time dependent. RA status is associated with loss in cortical density. Even upon biological therapy, low glucocorticoid dose affects metacarpal bone shaft geometry and density over time.

Recurrence of bilateral atypical femoral fractures associated with the sequential use of teriparatide and denosumab: a case report.

We report that a postmenopausal woman with osteoporosis developed bilateral incomplete atypical femoral fractures (AFFs) after seven years of bisphosphonate therapy. Cessation of the bisphosphonate and treatment with teriparatide was associated with near complete radiological resolution of the AFFs. After 12 months without treatment, denosumab was commenced to prevent structural deterioration. Six months later she developed recurrent bilateral AFFs. This case highlights the management dilemma in patients with ongoing bone loss but prone to stress fractures associated with antiresorptive therapy. Stopping the antiresorptive is recommended but structural decay will recur predisposing to fragility fractures. If the antiresorptive is continued, bone material composition will be further compromised predisposing to atypical fractures. Teriparatide may assist healing of stress fractures and improvement in bone matrix composition. Later antiresosrptive therapy to preserve bone microstructure may compromise material composition.

Measurement of cortical porosity of the proximal femur improves identification of women with nonvertebral fragility fractures.

UNLABELLED: We tested whether cortical porosity of the proximal femur measured using StrAx1.0 software provides additional information to areal bone mineral density (aBMD) or Fracture Risk Assessment Tool (FRAX) in differentiating women with and without fracture. Porosity was associated with fracture independent of aBMD and FRAX and identified additional women with fractures than by osteoporosis or FRAX thresholds. INTRODUCTION: Neither aBMD nor the FRAX captures cortical porosity, a major determinant of bone strength. We therefore tested whether combining porosity with aBMD or FRAX improves identification of women with fractures. METHODS: We quantified femoral neck (FN) aBMD using dual-energy X-ray absorptiometry, FRAX score, and femoral subtrochanteric cortical porosity using StrAx1.0 software in 211 postmenopausal women aged 54-94 years with nonvertebral fractures and 232 controls in Tromsø, Norway. Odds ratios (ORs) were calculated using logistic regression analysis. RESULTS: Women with fractures had lower FN aBMD, higher FRAX score, and higher cortical porosity than controls (all p < 0.001). Each standard deviation higher porosity was associated with fracture independent of FN aBMD (OR 1.39; 95% confidence interval 1.11-1.74) and FRAX score (OR 1.58; 1.27-1.97) in all women combined. Porosity was also associated with fracture independent of FRAX score in subgroups with normal FN aBMD (OR 1.88; 1.21-2.94), osteopenia (OR 1.40; 1.06-1.85), but not significantly in those with osteoporosis (OR 1.48; 0.68-3.23). Of the 211 fracture cases, only 18 women (9%) were identified using FN aBMD T-score < -2.5, 45 women (21%) using FRAX threshold >20%, whereas porosity >80th percentile identified 61 women (29%). Porosity identified 26% additional women with fractures than identified by the osteoporosis threshold and 21% additional women with fractures than by this FRAX threshold. CONCLUSIONS: Cortical porosity is a risk factor for fracture independent of aBMD and FRAX and improves identification of women with fracture.

A new method of segmentation of compact-appearing, transitional and trabecular compartments and quantification of cortical porosity from high resolution peripheral quantitative computed tomographic images.

A transitional or cortico-trabecular junctional zone exists at any location composed of both cortical and trabecular bones such as the metaphyses of tubular bones and short bones like the femoral neck. The transitional zone comprises the inner cortex adjacent to the medullary canal and trabeculae abutting against the cortex contiguous with the endocortical surface. This is a site of vigorous remodeling. Intracortical remodeling cavitates the inner cortex expanding this transitional zone at the price of compact-appearing cortex so that it contains porosity, cortical fragments that resemble trabeculae, and trabeculae abutting the eroding cortex. The porosity of the transitional zone is an important source of bone loss. It reduces bone strength exponentially and is a quantifiable `fingerprint' of structural deterioration. A new automated method of segmentation of bone from background and bone into its compact-appearing cortex, transitional zone, and trabecular compartment is described, with a new approach to quantification of cortical porosity. Segmentation is achieved by automatically selecting attenuation profile curves perpendicular to the periosteal surface. Local bone edges are identified as the beginning and the end of the rising and falling S-shaped portions of the curve enabling the delineation of the compartments. Analyzing ~3600 consecutive overlapping profiles around the perimeter of each cross-sectional slice segments the compartments. Porosity is quantified as the average void volume fraction of all voxels within each compartment. To assess accuracy at the distal radius and tibia, µCT images of cadaveric specimens imaged at 19 µm voxel size served as the gold standard. To assess accuracy at the proximal femur, scanning electron microscopy (SEM) images of specimens collected at 2.5 µm resolution served as the gold standard. Agreement between HRpQCT and the gold standards for segmentation and quantification of porosity at the distal radius and tibia ranged from R(2)=0.87 to 0.99, and for the proximal femur ranged from 0.93 to 0.99. The precision error in vivo for segmentation and quantification of porosity in HRpQCT images at the distal radius, given by the root mean square error of the coefficient of variation, ranged from 0.54% for porosity of the transitional zone to 3.98% for area of the compact-appearing cortex. Segmentation of the transitional zone minimizes errors in apportioning cortical fragments and cortical porosity to the medullary compartment and so is likely to allow accurate assessment of fracture risk and the morphological effects of growth, aging, diseases and therapies.

Proteinase-activated receptor-2 is required for normal osteoblast and osteoclast differentiation during skeletal growth and repair.

Proteinase-activated receptor-2 (PAR(2)) is a G-protein coupled receptor expressed by osteoblasts and monocytes. PAR(2) is activated by a number of proteinases including coagulation factors and proteinases released by inflammatory cells. The aim of the current study was to investigate the role of PAR(2) in skeletal growth and repair using wild type (WT) and PAR(2) knockout (KO) mice. Micro computed tomography and histomorphometry were used to examine the structure of tibias isolated from uninjured mice at 50 and 90 days of age, and from 98-day-old mice in a bone repair model in which a hole had been drilled through the tibias. Bone marrow was cultured and investigated for the presence of osteoblast precursors (alkaline phosphatase-positive fibroblastic colonies), and osteoclasts were counted in cultures treated with M-CSF and RANKL. Polymerase chain reaction (PCR) was used to determine which proteinases that activate PAR(2) are expressed in bone marrow. Regulation of PAR(2) expression in primary calvarial osteoblasts from WT mice was investigated by quantitative PCR. Cortical and trabecular bone volumes were significantly greater in the tibias of PAR(2) KO mice than in those of WT mice at 50 days of age. In trabecular bone, osteoclast surface, osteoblast surface and osteoid volume were significantly lower in KO than in WT mice. Bone marrow cultures from KO mice showed significantly fewer alkaline phosphatase-positive colony-forming units and osteoclasts compared to cultures from WT mice. Significantly less new bone and significantly fewer osteoclasts were observed in the drill sites of PAR(2) KO mice compared to WT mice 7 days post-surgery. A number of activators of PAR(2), including matriptase and kallikrein 4, were found to be expressed by normal bone marrow. Parathyroid hormone, 1,25 dihydroxyvitamin D(3), or interleukin-6 in combination with its soluble receptor down-regulated PAR(2) mRNA expression, and fibroblast growth factor-2 or thrombin stimulated PAR(2) expression. These results suggest that PAR(2) activation contributes to determination of cells of both osteoblast and osteoclast lineages within bone marrow, and thereby participates in the regulation of skeletal growth and bone repair.

The effect of acute exercise on undercarboxylated osteocalcin in obese men.

SUMMARY: The purpose of this study was to examine if the reduction in glucose post-exercise is mediated by undercarboxylated osteocalcin (unOC). Obese men were randomly assigned to do aerobic or power exercises. The change in unOC levels was correlated with the change in glucose levels post-exercise. The reduction in glucose post-acute exercise may be partly related to increased unOC. INTRODUCTION: Osteocalcin (OC) in its undercarboxylated (unOC) form may contribute to the regulation of glucose homeostasis. As exercise reduces serum glucose and improves insulin sensitivity in obese individuals and individuals with type 2 diabetes (T2DM), we hypothesised that this benefit was partly mediated by unOC. METHODS: Twenty-eight middle-aged (52.4 ± 1.2 years, mean ± SEM), obese (BMI = 32.1 ± 0.9 kg m(-2)) men were randomly assigned to do either 45 min of aerobic (cycling at 75% of VO(2peak)) or power (leg press at 75% of one repetition maximum plus jumping sequence) exercises. Blood samples were taken at baseline and up to 2 h post-exercise. RESULTS: At baseline, unOC was negatively correlated with glucose levels (r = -0.53, p = 0.003) and glycosylated haemoglobin (HbA1c) (r = -0.37, p = 0.035). Both aerobic and power exercises reduced serum glucose (from 7.4 ± 1.2 to 5.1 ± 0.5 mmol L(-1), p = 0.01 and 8.5 ± 1.2 to 6.0 ± 0.6 mmol L(-1), p = 0.01, respectively). Aerobic exercise significantly increased OC, unOC and high-molecular-weight adiponectin, while power exercise had a limited effect on OC and unOC. Overall, those with higher baseline glucose and HbA1c had greater reductions in glucose levels after exercise (r = -0.46, p = 0.013 and r = -0.43, p = 0.019, respectively). In a sub-group of obese people with T2DM, the percentage change in unOC levels was correlated with the percentage change in glucose levels post-exercise (r = -0.51, p = 0.038). CONCLUSIONS: This study reports that the reduction in serum glucose post-acute exercise (especially aerobic exercise) may be partly related to increased unOC.

Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy.

CONTEXT: Androgen deprivation therapy (ADT) used in the treatment of prostate cancer reduces bone mineral density (BMD) and predisposes to fractures. The structural basis of the BMD deficit and bone fragility is uncertain. OBJECTIVE AND PATIENTS: We investigated changes in bone microarchitecture in 26 men (70.6±6.8 yr) with nonmetastatic prostate cancer during the first year of ADT using the new technique of high-resolution peripheral quantitative computed tomography. DESIGN AND SETTING: We conducted a 12-month prospective observational study in the setting of a tertiary referral center. RESULTS: After 12 months of ADT, total volumetric density decreased by 5.2±5.4% at the distal radius and 4.2±2.7% at the distal tibia (both P<0.001). This was due to a decrease in cortical volumetric BMD (by 11.3±8.6% for radius and 6.0±4.2% for tibia, all P<0.001) and trabecular density (by 3.5±6.0% for radius and 1.5±2.3% for tibia, all P<0.01), after correcting for trabecularization of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (P<0.05). Total testosterone, but not estradiol, levels were independently associated with total and corrected cortical volumetric BMD at the tibia. CONCLUSIONS: Sex steroid deficiency induced by ADT for prostate cancer results in microarchitectural decay. Bone fragility in these men may be more closely linked to testosterone than estradiol deficiency.

The spinal curvature irregularity index independently identifies vertebral fractures.

INTRODUCTION AND HYPOTHESIS: The spinal curvature irregularity index (SCII) is a quantitative measure of the irregularity of the spinal curvature. We evaluated the predictive ability of SCII to identify subjects with vertebral fractures (VF). METHODS: Vertebral heights were measured by quantitative vertebral morphometry in 461 Lebanese women 20-89 years of age and VFs were ascertained by the grade 1 Eastell method. SCII scores were log-transformed and expressed as Z-SCII, the number of standard deviations above or below the mean ln(SCII) of young patients without VF. Univariate and multivariate binary logistic regression models were used to identify clinical predictors of VF. RESULTS: Women with a higher SCII were more likely to have prevalent VF. A higher SCII was associated with a greater prevalence of VF within each category of femoral neck BMD (normal, osteopenia, osteoporosis). In univariate analysis, predictors of VF included Z-SCII (odds ratio, OR: 2.21, 95% CI: 1.80-2.71) and femoral neck T-score (OR: 1.35, 95% CI: 1.12-1.63). In multivariate analysis, predictors of VF were: Z-SCII (OR: 1.54, 95% CI: 1.02-2.32), femoral neck T-score (OR: 1.41, 95% CI: 1.11-1.78) and age(3) (OR: 1.40, 95% CI 1.10-1.82). At a cutoff SCII of 9.5%, the sensitivity and specificity of SCII for VF were 71 and 64% respectively, and higher SCII cutoffs identified VFs with greater specificity. CONCLUSION: The SCII is a robust, simple and independent indicator of the presence of VFs.

Calcitriol does not prevent bone loss in patients with asthma receiving corticosteroid therapy: a double-blind placebo-controlled trial.

INTRODUCTION: Oral glucocorticoid therapy reduces bone mineral density (BMD) and increases fracture risk. It is uncertain whether inhaled glucocorticoids, the most commonly used long-term therapy for asthma, have a similar effect. If bone loss does occur, it is unclear whether this is preventable by calcitriol. Patients with asthma receiving inhalational plus intermittent oral glucocorticoids lose bone, and treatment with 0.5 microg/day of calcitriol will prevent bone loss. METHODS: A 2-year randomized double-blind placebo-controlled trial. One hundred eight patients with asthma were stratified by gender, age, and inhaled glucocorticoid dose and treated with calcitriol (n=55) or placebo (n=53). There were 41 men (mean age 53.2+/-1.7 years) and 67 women (mean age 49.1+/-1 years) with moderate to severe asthma (requiring >/=800 microg/day of beclomethasone dipropionate or equivalent maintenance therapy). BMD values at the lumbar spine (LS) and femoral neck (FN) were measured at baseline and at 6, 12, and 24 months using dual x-ray absorptiometry. RESULTS: Changes in LS and FN BMD. Bone loss occurred in both groups at the FN (both p<0.03) and at the LS in the calcitriol (p<0.001), but not the control, group. Bone loss was not less in the calcitriol group at either site. CONCLUSION: Patients with asthma receiving inhalational plus intermittent short courses of oral glucocorticoids lose bone. Calcitriol is unlikely to be appropriate therapy against this bone loss.

Knowledge, attitudes and practices of nursing staff in a rural hospital of Cameroon: how much does the health care provider know about the human immunodeficiency virus/acquired immune deficiency syndrome?

Qualitative and quantitative approaches were used in a rural hospital of Cameroon to assess how much nursing personnel know about and practise in regard to human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and to determine health service factors that influence knowledge, attitudes and practices (KAP). Participants included 107 nursing and laboratory staff and 62 patients with AIDS. Self-administered questionnaires were used for nurses, and close-ended questionnaires were administered to patients with AIDS (as a verification tool for staff responses). Focus group discussions (FGD) held with nurse supervisors evaluated health service factors that influence KAP. Overall, 70.1% of the nurses who responded scored highly in the knowledge section compared to 50.5% in the attitude and practice section. There were several outstanding misconceptions and malpractices about HIV/AIDS. Knowledge, but not attitude, was significantly influenced by the grade of the staff (P< 0.001 and P = 0.17, respectively). Approximately 15% of 62 patients with AIDS indicated that they were attended to with signs of disgust and/or hatred. The major health service factors thought to influence KAP, confirmed by many in all the FGD, included: the lack of adequate information; the lack of commitment to alter attitudes and practices; the lack of in-service promotions; and the ongoing fear of becoming infected with the virus through caring for patients with AIDS. Low income also seemed to have an influence on KAP. Therefore, it is imperative that ongoing education programmes are provided for nurses to enable them to meet the needs of the increasing HIV prevalence in our community. Information, education and communication, and compliance with international working norms, remain essential tools in the control of HIV/AIDS spread in our hospital settings.