OBJECTIVE:The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains. METHODS:In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5 microg or 15 microg H5 haemagglutinin (HA) vaccine+/-AlPO4 adjuvant (phase I trial; N=400) or two doses of 30 microg or 45 microg H5 HA with AlPO4 adjuvant (phase II trial; N=400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation. FINDINGS:All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30 microg or 45 microg H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (>or=1:20) persistence up to 6 months post-vaccination. The 7.5 and 15 microg formulations (+/-adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains. INTERPRETATION:Two doses of prototype 30 microg or 45 microg aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains [ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; FUNDING:CSL Limited, Australia].

Background: Delays in bone age, the onset of puberty, and skeletal growth in gymnasts could be, in part, the reason for an interest in gymnastics, rather than being the result of vigorous exercise. We hypothesized that short stature and delayed bone age are present at the start of gymnastics, and training delays growth, producing short stature, even after retirement. Methods: Sitting height and leg length were measured in 83 active female gymnasts, 42 retired gymnasts, and 154 healthy control subjects. Results were expressed as age-specific SD scores (mean ± SEM). Results: In the cross-sectional data, active gymnasts had delayed bone age (1.3 ± 0.1 years), reduced height –1.32 ± 0.08 SD, sitting height –1.24 ± 0.09 SD, and leg length, –1.25 ± 0.08 SD (all P < .001). However, in those training for less than 2 years, the deficit was confined to leg length (–0.8 ± 0.2 SD). During 2 years of follow-up of 21 gymnasts, only the deficit in sitting height worsened (by 0.4 ± 0.1 SD). In 13 gymnasts followed up in the immediate 12 months after retirement, sitting height accelerated, resulting in a lessening of the deficit in sitting height by 0.46 ± 0.14 SD (P < .01). Adult gymnasts who had been retired for 8 years had no deficit in sitting height, leg length, or menstrual dysfunction. Conclusions: Short stature in active gymnasts is partly due to selection of individuals with reduced leg length. Reduced sitting height is likely to be acquired but is reversible with cessation of gymnastics. A history of gymnastic training does not appear to result in reduced stature or menstrual dysfunction in adulthood. (J Pediatr 2000;136:149-55)

The differing tempo and direction of growth of the periosteal and endocortical surfaces, and the differing tempo of growth of the axial and appendicular skeleton, may predispose to regional deficits in bone size, bone mineral content (BMC), and volumetric bone mineral density (vBMD). These traits were measured during 2 years by dual x-ray absorptiometry in 109 girls. By 7 years of age, bone size was approximately 80% of its maturational peak, and BMC uas approximately 40% of its peak. Before puberty, the legs grew more rapidly than the trunk. During puberty, the growth spurt was truncal. Between 7 and 17 years, femoral and lumbar spine BMC increased by 50-150% because bone size increased. vBMD increased by 10-30%. Thus, growth builds a bigger, but only moderately denser, skeleton. Regions growing rapidly, or distant from their peak, may be more severely affected by illness than those growing slowly or nearer completion of growth. Depending on the age of exposure to disease, deficits may occur in limb dimensions (prepuberty), spine dimensions (early puberty), or vBMD by interference with mineral accrual (late puberty). As vBMD is independent of age before puberty, the position of an individual's vBMD in the population distribution is established early in life. Bone fragility in old age may have its foundations in growth.

The beneficial effects of corticosteroid therapy in the treatment of rheumatic diseases may be offset by the occurrence of corticosteroid-related osteoporosis. This problem may be overcome by using low-dose corticosteroids; however, the dose of corticosteroids that is both efficacious and skeletal sparing is uncertain. Therefore, the aim of this study was to determine whether low-dose prednisolone treatment results in bone loss and modifies bone turnover. Nineteen patients (12 female, seven male) suffering from polymyalgia rheumatica received 10 mg or less daily, given in reducing dosage, with a range of 2.5-10 mg and an average of 6.0+/-0.2 mg daily (+/-S.E.M.). Prior to the commencement of therapy and at regular intervals during treatment, bone mineral density (BMD) using dual X-ray absorptiometry and circulating biochemical and hormonal determinants of bone turnover were measured. The patients were followed for 14.4+/-1.6 months (range 6-27). They were compared to 19 age-matched controls. Despite a mean exposure dose of 6 mg/day and disease remission, BMD decreased in the patients at the lumbar spine (2.6+/-0.8%, P < 0.01), femoral neck (2.9+/-1.5%, P=0.06), Ward's triangle (5.5+/-2.9%, P=0.06) and the trochanter (4.3+/-1.9%, P < 0.05). Total body bone mass decreased by 50+/-19 g in the first 6 months (P < 0.02), and by 39+/-30 g in the remaining 8 months of follow-up [not significant (NS)]. In the first 6 months, BMD decreased at the lumbar spine (1.7+/-0.9%, P = 0.06). From 6 months to the end of follow-up, BMD decreased by 8.5+/-3.5% at Ward's triangle (P < 0.05) and by 4.8+/-2.5% at the femoral neck (P=0.08). The fall in BMD correlated with the cumulative prednisolone dose at trabecular-rich regions (trunk r=-0.72, P < 0.001; ribs r=-0.53, P < 0.05). Bone resorption, assessed by urinary cross-laps, was 54.7% higher than controls before treatment was started (P < 0.05) and decreased by 23.5+/-7.1% in the first month of treatment when the mean prednisolone dose was 9.1 mg/day, range 5-10 (P < 0.0001). Serum osteocalcin was not suppressed by disease before treatment, decreased by 27.4+/-5.1% during the first month of treatment (P < 0.001), remained suppressed while the daily dose of prednisolone was > 5 mg/day, but returned to baseline below this dose. Serum parathyroid hormone was 19.3% lower in the patients than controls at baseline (NS), and increased by 46.1% (P < 0.05) but was no higher than controls at any time. Muscle strength increased by 20-60% (P < 0.05 to < 0.01). Prophylaxis should be considered in patients receiving > or = 5 mg/day prednisolone daily as bone loss is 2- to 3-fold expected rates. Earlier trabecular bone loss may predispose to spine and rib fracture; later cortical bone loss may predispose to hip fractures. Doses of prednisolone of < 5 mg daily may be skeletal sparing, but may not be efficacious.

Lack of consistent information concerning the pathophysiology of corticosteroid-related bone loss may be due to coexisting independent factors that influence bone mineral density (BMD). For example, the disease being treated may increase bone turnover and cause bone loss, and its severity may influence the dose of corticosteroids chosen. Similarly, disease remission due to the treatment or disease progression despite treatment may influence bone turnover and the rate of bone loss. The hormonal changes purportedly responsible for reduced bone formation or increased bone resorption may be the result of the disease, not the corticosteroids. To determine the pathophysiology of corticosteroid-related bone loss, we conducted a controlled, prospective study in men with no systemic illness treated with corticosteroids to reduce antisperm antibodies. We measured BMD using dual x-ray absorptiometry and circulating biochemical and hormonal determinants of bone turnover in 9 men before and during prednisolone treatment and in 10 age-matched controls. The results were expressed as the mean +/- SEM. There were no differences in BMD between the two groups at baseline. The patients received 50 mg prednisolone daily for 3.7 +/- 0.6 months (range, 1-6). BMD decreased by 4.6 +/- 0.8% at the lumbar spine (P = 0.0007), by 2.6 +/- 0.6% at the trochanter (P = 0.004), and by 4.8 +/- 1.9% at the Ward's triangle (P < 0.04). The decrease in lumbar spine BMD correlated with the cumulative dose of corticosteroids (r = -0.49; P = 0.03). Serum osteocalcin and skeletal alkaline phosphatase decreased by 28.5 +/- 15.5% (P = 0.08) and 24.2 +/- 8.6% (P < 0.03), respectively. The decrease in lumbar spine BMD correlated with the decrease in osteocalcin (r = -0.48; P < 0.02). Serum testosterone and sex hormone-binding globulin decreased by 28.6 +/- 4.4% (P < 0.003) and 28.5 +/- 8.3% (P < 0.007), respectively. The testosterone/sex hormone-binding globulin ratio did not change. The decrease in total testosterone correlated with the decrease in osteocalcin (r = -0.40; P = 0.05). There were no detectable changes in urinary C-telopeptide, serum PTH, or serum calcium. Estradiol decreased by 23.5 +/- 11.4% (P < 0.003). Corticosteroid therapy results in rapid bone loss, probably due to reduced bone formation. Neither increased bone resorption nor secondary hyperparathyroidism appears to contribute to the rapid bone loss. Whether the reduction in bone formation may be partly mediated by changes in sex steroids remains unclear.

Cross-sectional studies of elite athletes suggest that growth is an opportune time for exercise to increase areal bone mineral density (BMD). However, as the exercise undertaken by athletes is beyond the reach of most individuals, these studies provide little basis for making recommendations regarding the role of exercise in musculoskeletal health in the community. To determine whether moderate exercise increases bone mass, size, areal, and volumetric BMD, two socioeconomically equivalent schools were randomly allocated to be the source of an exercise group or controls. Twenty boys (mean age 10.4 years, range 8.4-11.8) allocated to 8 months of 30-minute sessions of weight-bearing physical education lessons three times weekly were compared with 20 controls matched for age, standing and sitting height, weight, and baseline areal BMD. Areal BMD, measured using dual-energy X-ray absorptiometry, increased in both groups at all sites, except at the head and arms. The increase in areal BMD in the exercise group was twice that in controls; lumbar spine (0.61 +/- 0.11 vs. 0.26 +/- 0.09%/month), legs (0.76 +/- 0.07 vs. 0.34 +/- 0.08%/month), and total body (0.32 +/- 0.04 vs. 0.17 +/- 0.06%/month) (all p < 0.05). In the exercise group, femoral midshaft cortical thickness increased by 0.97 +/- 0. 32%/month due to a 0.93 +/- 0.33%/month decrease in endocortical (medullary) diameter (both p < 0.05). There was no periosteal expansion so that volumetric BMD increased by 1.14 +/- 0.33%/month, (p < 0.05). Cortical thickness and volumetric BMD did not change in controls. Femoral midshaft section modulus increased by 2.34 +/- 2. 35 cm3 in the exercise group, and 3.04 +/- 1.14 cm3 in controls (p < 0.05). The growing skeleton is sensitive to exercise. Moderate and readily accessible weight-bearing exercise undertaken before puberty may increase femoral volumetric BMD by increasing cortical thickness. Although endocortical apposition may be a less effective means of increasing bone strength than periosteal apposition, both mechanisms will result in higher cortical thickness that is likely to offset bone fragility conferred by menopause-related and age-related endocortical bone resorption.

Exercise during growth may contribute to the prevention of osteoporosis by increasing peak bone mineral density (BMD). However, exercise during puberty may be associated with primary amenorrhea and low peak BMD, while exercise after puberty may be associated with secondary amenorrhea and bone loss. As growth before puberty is relatively sex hormone independent, are the prepubertal years the time during which exercise results in higher BMD? Are any benefits retained in adulthood? We measured areal BMD (g/cm2) by dual‐energy X‐ray absorptiometry in 45 active prepubertal female gymnasts aged 10.4 ± 0.3 years (mean ± SEM), 36 retired female gymnasts aged 25.0 ± 0.9 years, and 50 controls. The results were expressed as a standardized deviation (SD) or Z score adjusted for bone age in prepubertal gymnasts and chronological age in retired gymnasts. In the cross‐sectional analyses, areal BMD in the active prepubertal gymnasts was 0.7–1.9 SD higher at the weight‐bearing sites than the predicted mean in controls (p < 0.01). The Z scores increased as the duration of training increased (r = 0.32–0.48, p ranging between <0.04 and <0.002). During 12 months, the increase in areal BMD (g/cm2/year) of the total body, spine, and legs in the active prepubertal gymnasts was 30–85% greater than in prepubertal controls (all p < 0.05). In the retired gymnasts, the areal BMD was 0.5–1.5 SD higher than the predicted mean in controls at all sites, except the skull (p ranging between <0.06 and <0.0001). There was no diminution across the 20 years since retirement (mean 8 ± 1 years), despite the lower frequency and intensity of exercise. The prepubertal years are likely to be an opportune time for exercise to increase bone density. As residual benefits are maintained into adulthood, exercise before puberty may reduce fracture risk after menopause.

In the 50-year “modern” history of osteoporosis, there have been about 17 antifracture studies with sufficient attention to design to allow inference regarding efficacy. Antivertebral fracture efficacy has been reported with etidronate, estrogen patch, calcitonin, and 1,25-dihydroxyvitamin D. Two studies using fluoride were positive, and two were negative. Hip fractures have been neglected. One study showed efficacy of hip protectors, one showed efficacy of vitamin D and calcium in nursing home dwellers. The source of most hip fractures is the community. One community based antihip fracture efficacy study using annual injections of vitamin D was positive. There have been no antivertebral or antihip fracture studies in men, or in corticosteroid-related osteoporosis in men or women. Lack of independently repeated demonstration of efficacy, small fracture numbers, and data pooling in some of these (the best) studies leave great uncertainty. Estrogen and bisphosphonates appear to be the best options at this time. New data suggest that calcium supplementation is likely to reduce the rate of bone loss and perhaps reduce fracture rates. The challenge is to maintain and restore the constituents of bone mineral density (BMD), that is: to promote periosteal and endosteal bone formation; reduce endosteal bone resorption and cortical porosity; and increase trabecular thickness, number, and connectivity. There are many opportunities, for instance, intermittent parathyroid hormone (PTH) increases bone strength and, with estrogen, may increase connectivity. The anabolic effects of PTH may be partly mediated by IGF-1. IGF-1 increases periosteal, endosteal, and trabecular bone formation, cortical and trabecular width, and trabecular and endocortical connectivity. With bisphosphonate, IGF-1 may increase bone area and strength as the bisphosphonate decreases medullary area while IGF-1 increases subperiosteal area. Anabolic effects of fluoride warrant further study provided that the study design addresses the issue of bone strength, the narrow toxic-therapeutic window, and cortical bone loss. Aluminum, a constituent of zeolite, has anabolic effects which may be partly mediated by TGF-β. Prostaglandin E2 increases periosteal and endosteal bone formation but may increase cortical porosity. More data are needed regarding these growth factors, silicon compounds, strontium salts, and flavenoids. The effects of medroxyprogesterone and 19 norprogestins on BMD have not been compared. Raloxifene, a new estrogen agonist free of endometrial hyperplastic effects, is being studied. Most treated individuals with osteoporosis (i.e., low BMD with or without a fracture) will not suffer a fracture so treatment must be safe. Success—absence of fracture—will be measured by the epidemiologist because it is difficult to distinguish efficacy from chance in an individual as the peak incidence of fractures in the community is usually only about 1–4/100 per year.

Does weight-bearing exercise offset bone loss associated with oligomenorrhea? If so, bone mineral density (BMD) will be stable at weight bearing sites but decrease at non-weight-bearing sites with increasing duration of oligomenorrhea. To test this hypothesis, BMD (g/cm2), was measured by dual-energy X-ray absorptiometry in 41 oligomenorrheic ballet dancers aged 17.7±0.2 years (mean ± SEM) and 46 age-matched controls with normal menstrual function. BMD correlated negatively with the duration of oligomenorrhea at weight-bearing and non-weight-bearing sites (femoral neck,r=−0.33,p<0.05; Ward's triangle,r=−0.29,p=0.06; trochanter, r=−0.33,p<0.05; lumbar spine,r=−0.25,p=0.1; skull,r=−0.29,p=0.06; arms,r=−0.32,p<0.05; ribs,r=−0.30,p=0.06). The slopes of the regression of BMD on duration of oligomenorrhea were greater at the proximal femur (trochanter, −0.28±0.13, femoral neck, −0.24±0.11; Ward's triangle, −0.29±0.15) than the skull (−0.15±0.08,p<0.05,p<0.1,p<0.1 respectively). The slopes at the trochanter and femoral neck were also greater than at the ribs (−0.10±0.05; bothp<0.1). In the dancers with oligomenorrhea of less than 40 months duration, BMD was higher than the age-predicted mean at weight-bearing sites (except the lumbar spine), but not at non-weight-bearing sites (femoral neck, 9.1±3.4%; Ward's triangle, 10.0±1.7%; trochanter, 9.4±4.1%, allp<0.05; lumbar spine , −2.1±2.7%, NS; skull, −2.5±2.1%, NS; ribs, −3.0±1.6% NS; arms, −3.9±1.6%;p<0.05). In the dancers with greater than 40 months oligomenorrhea, BMD was no higher than the age predicted mean, at the weight bearing sites, and was lower at non-weight bearing sites (femoral neck, 4.3±2.3%, NS; Ward's triangle, 3.5±3.2%, NS; trochanter, 2.1±2.7%, NS; lumbar spine, −3.8±2.1%, NS; arms, −7.5±0.8%,p<0.05; skull, −6.2±1.8%,p<0.01; ribs, −5.4±1.1%,p<0.0001). In conclusion, weight-bearing exercise is unlikely to offset the deleterious effects of oligomenorrhea. Bone loss appears to occur at all sites but may begin from a higher level at weight-bearing sites and may proceed more rapidly.

Bass, S; Pearce, G; Formica, C; Inge, K; Hendrich, E; Harding, A; Seeman, E Author Information

Intense exercise during childhood and adolescence may result in primary amenorrhea and low peak bone mineral density (BMD). After puberty, exercise may result in secondary amenorrhea and bone loss. Higher BMD in amenorrheic athletes than amenorrheic sedentary persons suggests that exercise may partly offsets the effects of amenorrhea. To examine this possibility, we measured BMD (g/cm2) by dual x-ray absorptiometry in 32 ballet dancer and 23 healthy controls of comparable age with regular menstrual cycles, 34 pre-pubertal female gymnasts bone age 8.9 +/- 0.2 years and 37 girls matched by bone age. Dancers had normal BMD at the weight bearing sites, not low, despite having oligomenorrhea, not high despite 32 hours of week dancing. BMD was lower by 4-6 percent at the non-weight bearing sites. BMD diminished in the dancers at the weight bearing femoral neck (r = -0.29, P = 0.1) and trochanter (r = -0.31, P = 0.09), and at the non-weight bearing arms (r = -0.29, P = 0.09) with increasing duration of amenorrhea. Dancers with less than 40 months amenorrhea had 5 to 7% higher BMD at the weight bearing, but not non-weight bearing sites. Dancers with more than 40 months amenorrhea had normal, not higher BMD at weight bearing sites and deficits of about 5 percent at non-weight bearing sites. In gymnasts, BMD was 10-15 percent (or 1 SD) higher than the bone age-predicted mean. Exercise may not offset the effects of amenorrhea. Bone loss may continue but from a higher level, perhaps attained prior puberty.