Hemoglobin modulation affects physiology and patient reported outcomes in anemic and non-anemic subjects: An umbrella review.

Background: An abnormal hemoglobin concentration has a substantial effect on a person's quality of life and physiology. Lack of tools that effectively evaluate hemoglobin-related outcomes leads to uncertainty regarding optimal hemoglobin levels, transfusion thresholds and treatment targets. We therefore aim to summarize reviews that assess the effects of hemoglobin modulation on the human physiology at various baseline hemoglobin levels, and identify gaps in existing evidence. Methods: We conducted an umbrella review of systematic reviews. PubMed, MEDLINE (OVID), Embase, Web of Science, Cochrane Library and Emcare were searched from inception to the 15th of April 2022 for studies that reported on physiological and patient reported outcomes following a hemoglobin change. Results: Thirty-three reviews were included of which 7 were scored as of high quality and 24 of critically low quality using the AMSTAR-2 tool. The reported data generally show that an increase in hemoglobin leads to improvement of patient reported and physical outcomes in anaemic and non-anaemic subjects. At lower hemoglobin levels, the effect of a hemoglobin modulation on quality of life measures appears more pronounced. Conclusion: This overview has revealed many knowledge gaps due to a lack of high-quality evidence. For chronic kidney disease patients, a clinically relevant benefit of increasing the hemoglobin levels up until 12 g/dL was found. However, a personalized approach remains necessary due to the many patient-specific factors that affect outcomes. We strongly encourage future trials to incorporate physiological outcomes as objective parameters together with subjective, but still very important, patient reported outcome measures.

Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group.

We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.

Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group.

Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double-blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.

Ultrasound and alendronate: new tools for osteoporosis screening and treatment.

Office-based physicians can now use ultrasonography of the heel to screen for osteoporosis and estimate the risk of fractures. In treating osteoporosis, alendronate has been shown to increase bone mineral density and to decrease the incidence of fractures.

Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis.

OBJECTIVE: Oral alendronate sodium is a potent, specific inhibitor of osteoclast-mediated bone resorption. To assess its efficacy and safety, a 3-year, randomized, double-blind, multicenter study of 478 postmenopausal women with osteoporosis was conducted. PATIENTS AND METHODS: Subjects received either placebo, alendronate 5 or 10 mg/day for 3 years, or 20 mg/day for 2 years followed by 5 mg/day for 1 year (20/5 mg). All subjects received 500 mg/day of supplemental calcium. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA). RESULTS: After 3 years, alendronate 10 mg induced marked increases in BMD of the lumbar spine (9.6 +/- 0.4%), femoral neck (4.7 +/- 0.7%) and trochanter (7.4 +/- 0.6%) (mean +/- SE; each P < or = 0.001) versus decreases of 0.8 to 1.6% with placebo. Progressive increases at these sites in the alendoronate 10 mg group were significant during both the second and third years. Alendronate 10 mg increased total body BMD (1.6 +/- 0.3%, P < or = 0.001), and prevented loss but did not increase BMD at the 1/3 forearm site. Alendronate 20/5 mg was no more effective, whereas alendronate 5 mg was significantly less effective than 10 mg at all sites. Bone turnover decreased to a stable nadir over 3 months for resorption markers (urine deoxypyridinoline) and over 6 months for formation markers (alkaline phosphatase and osteocalcin). Mean loss of stature was reduced by 41% in alendronate treated subjects (P = 0.01). CONCLUSION: The safety profile of alendronate was similar to that of placebo. At 10 mg, there were no trends toward increased frequency of any adverse experience except for abdominal pain, which was usually mild, transient, and resolved with continued treatment. Thus, alendronate appears to be an important advance in the treatment of osteoporosis in postmenopausal women.

Dissociation of changes in metabolic rate and blood pressure with erythrocyte Na-K pump activity in older men after endurance training.

We examined whether changes in resting metabolic rate (RMR) and blood pressure in older normotensive men in response to endurance training were associated with alterations in the Na-K pump activity of plasma-bathed erythrocytes. Eleven men performed cycling exercise three times a week for 8 weeks, and six other men served as controls. Measurements included: RMR by indirect calorimetry, supine blood pressure, body composition by underwater weighing, plasma and erythrocyte Na and K parameters using flame photometry and ouabain. Peak VO2 increased 12% (p < .001), RMR increased 10% (p < .01), mean blood pressure decreased 5% (p < .05), erythrocyte K increased 5% (p < .01), plasma K decreased 7% (p < .001), and plasma Na decreased by 4% (p < .001) in response to training. Erythrocyte Na and Na-K pump rate did not change, nor did the individual changes correlate with changes in RMR or mean blood pressure. Exercise training increases RMR and reduces blood pressure in older men, but these changes are dissociated with erythrocyte Na-K pump activity.

Effect of age on systemic delivery of oral glucose in men.

This study examined the effect of age on the posthepatic delivery of oral glucose (PHDG) during steady-state conditions. We used an intravenous-oral modification of the euglycemic insulin-clamp technique to assess PHDG in six men aged 24-39 yr (young) and eight men aged 65-83 yr (old). Each subject underwent two studies in which insulin was infused at 120 mU.m-2.min-1 for 3 h, and either oral glucose (45 g) or water was given 60 min after initiating insulin. This level of insulin infusion is known to fully suppress hepatic glucose output. For each subject, PHDG was calculated as the difference between the whole-body glucose disposal rates in the paired studies. The time course of PHDG differed in the two groups (P less than .0001), with an overall delay in PHDG in the older men. During the 1st h, younger men showed a greater PHDG (58.6 +/- 3.8% of the oral load vs. 45.1 +/- 4.2%) than the older group (P = .04). During the 2nd h, PHDG was less in the younger group (20.7 +/- 4.9%) than the older group (36.6 +/- 3.9%, P = .02). Over the 2-h period, total PHDG was comparable in younger (79.3 +/- 7.4%) and older (81.7 +/- 7.9%) men. These results indicate that normal aging is associated with significantly delayed but overall equal PHDG in men, consistent with the greater effect of age on 2-h rather than earlier postprandial glucose levels. It reinforces the role of impaired peripheral utilization as the primary mechanism of the glucose intolerance of aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of physical training on the insulin resistance of aging.

Part of the insulin resistance associated with aging may be attributable to a loss of physical fitness. It was hypothesized that an increase in level of physical training would result in an increase in peripheral insulin action. Eleven healthy 60- to 80-yr-old subjects with normal oral glucose tolerance were studied by a euglycemic two-step hyperinsulinemic clamp before and after 12 wk of physical training. Weight and body composition were held constant, and the clamp was separated by 7 days from the last bout of exercise. There was a positive correlation before training between maximum O2 uptake (Vo2 max) and total body glucose disposal rate (M) at the 40 mU.m-2.min-1 insulin infusion (r = 0.69, P less than 0.02). After training Vo2 max increased 6.7%, M increased 13.4% during the 40 mU.m-2.min-1 and 11.0% during the 200 mU.m-2.min-1 insulin infusion. These results show that peripheral insulin resistance in older persons can be decreased by increasing the level of physical training, independent of changes in weight or body composition. Therefore a part of the insulin resistance of aging is reversible, and level of physical training should be considered in its measurement.

Reliability of maximal and submaximal parameters of treadmill testing for the measurement of physical training in older persons.

There is a learning effect on repeat treadmill testing. Therefore, measurements made before and after a training program could reflect the effect of repeat testing in addition to the effect of training. The goal of this study was to test the reliability of maximal and submaximal treadmill parameters as a measure of training in older persons. Nine subjects underwent two identical tests before training (learning effect) and a third after a 12-week training program. VO2 max increased 9.0% with training, but was unchanged before training. Maximal duration increased 6.7% before training and a further 6.3% after training. Submaximal heart rate (HR) decreased 3.8% before training and an additional 5.3% with training. We conclude that VO2 max is a reliable measure of change in physical training in older persons. Maximal duration and submaximal HR are subject to a learning effect and cannot be relied upon to document a training effect.

Exercise conditioning in the elderly coronary patient.

We compared conditioning effects of a supervised exercise program in 100 elderly and younger patients with a recent coronary event. Twenty-one patients were greater than or equal to 62 years of age (mean, 65 years) and 79 were less than or equal to 61 years of age (mean, 48.7 years). While the elderly patients attained a lower peak exercise intensity on entry and on completion of the exercise protocol, they obtained a similar relative training benefit as the younger patients. Peak exercise intensity increased 68% in each group and submaximal (five METS) heart rate-blood pressure product decreased 27% in the older patients and 26% in the younger patients. Rate of entry into our program was substantially lower in the elderly patient group, 19% v 57% in younger patients (P less than 0.001) despite a similar inhospital recruiting effort. Thus, although elderly coronary patients obtain similar training benefits as younger patients, they are less likely to participate in a program designed to decrease cardiac disability.

Splanchnic factors enhance the norepinephrine response to oral glucose in aged man.

Oral glucose has been shown to increase sympathetic nervous system (SNS) activity more in old than in young subjects. In contrast intravenous glucose during euglycemic hyperinsulinemia increases SNS activity in young but not in old subjects. To evaluate the role of splanchnic factors in this discrepancy, we employed a modification of the glucose clamp technique in 6 young (24-39 years) and 8 old (65-83 years) normal males. Each subject underwent two studies in which insulin was infused at 120 mU/m2 X min for 3 h and either oral glucose (50 gms) or water was given 60 min after initiating insulin. Euglycemia was maintained in all studies. When compared to control drink, oral glucose elevated norepinephrine in old (p less than 0.01), but not in young subjects. The difference between old and young was significant (p less than 0.02). When compared to control drink, oral glucose increased pulse rate and double product in the young, and pulse rate in the old. These results indicate that oral glucose activates the SNS in the elderly via splanchnic mechanisms independent of changes in circulating levels of glucose or insulin.