Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis.

OBJECTIVE: To assess the association between pain mechanisms (sensitization) and biochemical markers for cartilage, bone, and inflammation in patients with knee pain. METHODS: The study group comprised 281 patients with different degrees of knee pain intensity and radiographic findings (using the Kellgren/Lawrence [K/L] scale). The following structurally related serologic biomarkers were measured in serum: high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-mediated breakdown of CRP (CRPM), MMP-mediated degradation of type I collagen (C1M), C2M, and C3M. Pressure-pain thresholds (PPT) (peripheral and spreading sensitization), temporal summation of pain, and conditioning pain modulation (CPM) (with the latter 2 biomarkers representing generalized sensitization) were assessed. For each pain parameter, the patients were categorized as most sensitized or least sensitized. RESULTS: Correlations were observed between the pain biomarkers PPT, temporal summation, and CPM and maximal pain intensity during the last 24 hours. Significant associations between most of the serologic biomarkers were observed. A high CRPM level was associated with centralized sensitization (temporal summation and CPM). None of the serologic markers correlated with the intensity or duration of knee pain, and only hsCRP correlated with the K/L grade. The most-sensitized group contained more women than men, and the least-sensitized group contained more men than women. CONCLUSION: A platform of mechanistic pain biomarkers in combination with structure-related serologic biomarkers provides new possibilities for understanding how osteoarthritis-related structural features may be associated with pain and pain sensitization. This study showed significant correlations between central pain sensitization and CRPM as a possible measure for chronic inflammation. Future pain association studies should include biomarkers representing the local joint environment more specifically.

Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis.

Denosumab reduces the risk of new vertebral and nonvertebral fractures. Previous trials suggest that the efficacy of antiresorptives on fractures might differ by patients' characteristics, such as age, bone mineral density (BMD), and fracture history. In the FREEDOM study, 7808 women aged 60 to 90 years with osteoporosis were randomly assigned to receive subcutaneous injections of denosumab (60 mg) or placebo every 6 months for 3 years. New vertebral and nonvertebral fractures were radiologically confirmed. Subgroup analyses described in this article were prospectively planned before study unblinding to evaluate the effect of denosumab on new vertebral and nonvertebral fractures across various subgroups. Compared with placebo, denosumab decreased the risk of new vertebral fractures in the overall study population over 3 years. This effect did not significantly differ for any of the nine subgroups analyzed (p > 0.09 for all potential interactions). Denosumab also reduced all nonvertebral fractures by 20% in the full study cohort over 3 years. This risk reduction was statistically significant in women with a baseline femoral neck BMD T-score ≤ -2.5 but not in those with a T-score > -2.5; in those with a body mass index (BMI) < 25 kg/m(2) but not ≥ 25 kg/m(2); and in those without but not with a prevalent vertebral fracture. These differential treatment effects were not explained by differences in BMD responses to denosumab. Denosumab 60 mg administered every 6 months for 3 years in women with osteoporosis reduced the risk of new vertebral fractures to a similar degree in all subgroups. The effect of denosumab on nonvertebral fracture risk differed by femoral neck BMD, BMI, and prevalent vertebral fracture at baseline.

Vitamin D status and its relationship with bone mineral density and parathyroid hormone in Southeast Asian adults with low bone density.

OBJECTIVE: To investigate the vitamin D sufficiency status and the relationships among serum 25-hydroxyvitamin D [25(OH)D] levels, intact parathyroid hormone (iPTH) levels, and bone mineral density (BMD) in patients attending an osteoporosis clinic in Singapore. METHODS: In total, 193 adults with or without prevalent fragility fractures and with low BMD at the femoral neck, total hip, or lumbar spine underwent assessment. Multivariate regression models were used to investigate the relationships among serum 25(OH)D, iPTH, and BMD. RESULTS: The mean values (standard deviation) for age of the patients and serum 25(OH)D level were 61 (14) years and 26.05 (7.97) ng/mL, respectively. In 72% of patients, serum 25(OH)D levels were below 30 ng/mL. There was no association between 25(OH)D levels and BMD at the femoral neck, total hip, or lumbar spine (P = .568, .461, and .312, respectively). Serum iPTH levels were negatively associated with BMD at the total hip (P = .035) and the lumbar spine (P = .019). At levels <30 ng/mL, 25(OH)D was negatively associated with iPTH (P = .036). CONCLUSION: Among this Southeast Asian population of patients with low BMD, no direct relationship between serum 25(OH)D levels and BMD was observed. A negative correlation existed, however, between iPTH and 25(OH)D at serum 25(OH)D concentrations <30 ng/mL, and serum iPTH levels showed a significant negative association with BMD at the total hip and lumbar spine. These significant negative associations between iPTH levels and BMD at the total hip and lumbar spine underscore the critical role of this hormone in bone metabolism and health.

Selective monitoring of vitamin D2 and D3 supplementation with a highly specific 25-hydroxyvitamin D3 immunoassay with negligible cross-reactivity to 25-hydroxyvitamin D2.

BACKGROUND: The effects of vitamin D2 and D3 supplementation on circulating concentrations of 25(OH)D3 require reliable analytical tools for specific determination of 25(OH)D3 and 25(OH)D2. We have developed a highly specific 25-OH Vitamin D3 ELISA with negligible cross-reactivity towards 25(OH)D2. METHODS: 25(OH)D3 concentrations were measured in several study participants; 1) 641 healthy men and women; 2) 39 postmenopausal women receiving 400-800 IU vitamin D3 daily for 4 months; 3) 45 men and women with hip fracture receiving 1000 IU vitamin D2 daily for 3 months. RESULTS: This 25-OH Vitamin D3 ELISA had minimal cross-reactivity to 25(OH)D2, (0.7%), and demonstrated a high correlation (r2 = 0.93) with 25(OH)D3 determined by HPLC. 25(OH)D3 increased by 14% in subjects receiving vitamin D3 for 4 months (p < 0.01), whereas there was no significant change in 25(OH)D3 levels in those receiving vitamin D2. CONCLUSIONS: We report that 25(OH)D3 ELISA was used for evaluation of 25(OH)D3 concentrations in subjects receiving vitamin D2 and D3 supplementation. The increase of 25(OH)D3 in circulation with vitamin D3 supplementation and lack of increase with vitamin D2 supplementation suggest that this assay has sufficient sensitivity and specificity to be used as a reliable measurement of nutritional vitamin D3 status in humans.

Residual attentional capacity amongst young and elderly during dual and triple task walking.

Walking is considered an automatic function which demands little attentional resources. Thus a residual attentional capacity is available for a concurrent task (dual task). Minor age-related deficits in postural control may minimize the residual attentional capacity, however this may not be detected by a simple examination of the individuals gait performance. This study investigated the use of challenging dual task combinations to detect age related changes in gait performance. Eleven community-dwelling elderly (mean age 76 years) and 13 young subjects (mean age 26 years) participated in the study. The participants walked along a figure-of-eight track at a self-selected speed. The effect of introducing a concurrent cognitive task and a concurrent functional motor task was evaluated. Stride-to-stride variability was measured by heel contacts and by trunk accelerometry. In response to the cognitive task the elderly increased their temporal stride-to-stride variability by 39% in the walking task and by 57% in the combined motor task. These increases were significantly larger than observed for the young. Equivalent decreases in trunk acceleration autocorrelation coefficients and gait speed were found. A combination of sufficiently challenging motor tasks and concurrent cognitive tasks can reveal signs of limited residual attentional capacity during walking amongst the elderly.

Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study.

UNLABELLED: Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2-yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. INTRODUCTION: Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24-mo, randomized, double-blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. MATERIALS AND METHODS: Healthy postmenopausal women with a BMD T-score at the lumbar spine or femoral neck between -1.0 and -2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. RESULTS: The intent-to-treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 +/- 0.28%, 1.41 +/- 0.28%, 1.49 +/- 0.28%, and 1.49 +/- 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. CONCLUSIONS: Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.

Fall risk in an active elderly population--can it be assessed?

BACKGROUND: Falls amongst elderly people are often associated with fractures. Training of balance and physical performance can reduce fall risk; however, it remains a challenge to identify individuals at increased risk of falling to whom this training should be offered. It is believed that fall risk can be assessed by testing balance performance. In this study a test battery of physiological parameters related to balance and falls was designed to address fall risk in a community dwelling elderly population. RESULTS: Ninety-four elderly males and females between 70 and 80 years of age were included in a one year follow-up study. A fall incidence of 15% was reported. The test battery scores were not different between the fallers and non-fallers. Test scores were, however, related to self-reported health. In spite of inclusion of dynamic tests, the test battery had low fall prediction rates, with a sensitivity and specificity of 50% and 43% respectively. CONCLUSION: Individuals with poor balance were identified but falls were not predicted by this test battery. Physiological balance characteristics can apparently not be used in isolation as adequate indicators of fall risk in this population of community dwelling elderly. Falling is a complex phenomenon of multifactorial origin. The crucial factor in relation to fall risk is the redundancy of balance capacity against the balance demands of the individuals levels of fall-risky lifestyle and behavior. This calls for an approach to fall risk assessment in which the physiological performance is evaluated in relation to the activity profile of the individual.