Higher Undercarboxylated to Total Osteocalcin Ratio Is Associated With Reduced Physical Function and Increased 15-Year Falls-Related Hospitalizations: The Perth Longitudinal Study of Aging Women

Evidence from animal models suggests that undercarboxylated osteocalcin (ucOC) is involved in muscle mass maintenance and strength. In humans, the ucOC to total (t)OC ratio may be related to muscle strength and perhaps physical function and falls risk, but data are limited. We tested the hypothesis that ucOC and ucOC/tOC ratio are associated with muscle function (muscle strength and physical function) in older women and 15-year falls-related hospitalizations. Serum tOC and ucOC were assessed in 1261 older women (mean age 75.2 ± 2.7 years) forming the Perth Longitudinal Study of Aging Women (1998 to 2013). Timed-up-and-go (TUG) and grip strength were assessed at baseline and at 5 years. Falls-related hospitalizations (14.5-year follow-up) were captured by the Hospital Morbidity Data Collection, via the Western Australian Data Linkage System. At baseline, women with higher ucOC/tOC ratio (quartile 4) had slower TUG performance compared with quartile 1 (~0.68 seconds, p < .01). Grip strength and 5-year change of TUG and grip were not different (p > .05) between quartiles. Fear of falling limiting house, outdoor, and combined activities was significantly different across quartiles (p < .05). Higher ucOC/tOC was significantly associated with poorer TUG performance at baseline and 5-year change in performance, increased walking aid use, and fear of falling (all p < .05). Higher ucOC was related to lower grip strength at baseline (p < .05) but not 5-year change in strength. Those with the highest ucOC/tOC had greater falls-related hospitalizations (unadjusted log rank, p = .004) remaining significant after adjusting for key variables (hazard ratio [HR] = 1.31, 95% confidence interval [CI] 1.09–1.57, p = .004). We identified a large proportion of older women with high ucOC/tOC ratio who had reduced physical function, including its long-term decline and increased risk of falls-related hospitalizations. Early identification of women at higher risk can enable prevention and intervention strategies to occur, reducing risk for injurious falls. © 2020 American Society for Bone and Mineral Research (ASBMR)..     

The effect of topical indomethacin on subjective symptoms in chronic corneal edema

The authors conducted a masked randomized study of 15 patients to evaluate the effect of administration of topical indomethacin 1% suspension on complaints in chronic corneal edema. Patients who complained of photophobia, pain, itching, burning sensation, foreign body sensation and tearing, were treated with topical indomethacin 1% or placebo and followed for eight weeks. The severity of the complaints was rated and the scores were evaluated (Wilcoxon matched-pairs test). Of the eight patients treated with indomethacin, seven (87%), had symptomatic improvement and the severity of the total score of their complaints was significantly decreased. Of the seven patients treated with placebo, no symptomatic improvement was observed and severity of the complaints remained unchanged. However, when the placebo-treated patients subsequently received indomethacin drops, the complaints were significantly decreased. This study suggests that topical administration of indomethacin 1% may reduce ocular complaints in patients with chronic corneal edema.     

Lower Limb Biomechanics in Individuals With Knee Osteoarthritis Before and After Total Knee Arthroplasty Surgery

We investigated the biomechanical changes that occur in the lower limb following total knee arthroplasty (TKA). Lower limb joint kinematics and kinetics were evaluated in 32 patients before and 12 months following TKA and 28 age-matched controls. Analysis of variance with Bonferroni-adjusted post-hoc tests showed no significant changes in knee joint kinematics and kinetics following TKA despite significant improvements in pain and function. Significant increases in peak ankle plantarflexion and dorsiflexion moments and ankle power generation were observed which may be a compensatory response to impaired knee function to allow sufficient power generation for propulsion. Differences in knee gait parameters may arise as a result of the presence of osteoarthritis and mechanical changes associated with TKA as well as retention of the pre-surgery gait pattern.     

Erythropoietin has an anti-myeloma effect - a hypothesis based on a clinical observation supported by animal studies

Recombinant human erythropoietin (rHuEpo) was introduced into clinical practice more than a decade ago, and has been found to be effective in the treatment of several types of anemia, including anemia of end-stage renal failure and cancer-related anemia. No study has suggested that Epo might have an effect on the biology of the disease, nor any survival advantage to cancer patients treated with Epo for anemia has been reported. Here we report six patients with advanced multiple myeloma (MM) with very poor prognostic features, whose expected survival was <6 months. All six patients were treated with rHuEpo for their anemia, either without any chemotherapy or very mild chemotherapy for a short time. Yet, surprisingly they lived for 45-133 months totally from MM diagnosis and 38-94 months with rHuEpo (with a good quality of life). In fact, one patient, is still alive and well, more than 8 yr after chemotherapy was discontinued because of a resistant aggressive disease. The course in these six MM patients led us to hypothesize that Epo might have an antineoplastic or antimyeloma effect. We proceeded and tested that hypothesis in mouse models of myeloma (Mittelman M et al., Proc Natl Acad Sci USA 98:5181,2001). In these models we confirmed that rHuEpo induced tumor regression in about 50% of the BALB/c mice inoculated with MOPC-315 myeloma cells. We then presented evidence that the mechanism is a new immune-mediated phenomenon, via activation of CD8+ T cells. Furthermore, evidence from the literature supports the antineoplastic effect of Epo. Epo might be used as an adjunct immune treatment in various malignant diseases, in addition to the current regimens and chemotherapeutic protocols. Future trials should determine the role of Epo in myeloma and cancer treatment, besides clarifying concerns about the presence of Epo receptors on some tumor cells.     

The Effect of Acute Exercise on Undercarboxylated Osteocalcin and Insulin Sensitivity in Obese Men

Acute exercise improves insulin sensitivity for hours after the exercise is ceased. The skeleton contributes to glucose metabolism and insulin sensitivity via osteocalcin (OC) in its undercarboxylated (ucOC) form in mice. We tested the hypothesis that insulin sensitivity over the hours after exercise is associated with circulating levels of ucOC. Eleven middle‐aged (58.1 ± 2.2 years mean ± SEM), obese (body mass index [BMI] = 33.1 ± 1.4 kg/m²) nondiabetic men completed a euglycemic‐hyperinsulinemic clamp at rest (rest‐control) and at 60 minutes after exercise (4 × 4 minutes of cycling at 95% of HR_peak). Insulin sensitivity was determined by glucose infusion rate relative to body mass (GIR, mL/kg/min) as well as GIR per unit of insulin (M‐value). Blood samples and five muscle biopsies were obtained; two at the resting‐control session, one before and one after clamping, and three in the exercise session, at rest, 60 minutes after exercise, and after the clamp. Exercise increased serum ucOC (6.4 ± 2.1%, p = 0.013) but not total OC (p > 0.05). Blood glucose was ～6% lower and insulin sensitivity was ～35% higher after exercise compared with control (both p < 0.05). Phosphorylated (P)‐AKT (Ak thymoma) was higher after exercise and insulin compared with exercise alone (no insulin) and insulin alone (no exercise, all p < 0.05). In a multiple‐linear regression including BMI, age, and aerobic fitness, ucOC was associated with whole‐body insulin sensitivity at rest (β = 0.59, p = 0.023) and after exercise (β = 0.66, p = 0.005). Insulin sensitivity, after acute exercise, is associated with circulating levels of ucOC in obese men. Whether ucOC has a direct effect on skeletal muscle insulin sensitivity after exercise is yet to be determined. © 2014 American Society for Bone and Mineral Research.     

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