Background: Cases series suggest joint hypermobility (JH) is a risk factor for musculoskeletal pain in childhood, but this has not been supported by epidemiological studies. However, the latter have largely comprised small samples, and prospective data based on large cohorts are lacking. We aimed to exploit the Avon Longitudinal Study of Parents and Children (ALSPAC), a unique birth cohort, to determine whether joint hypermobility (JH) in childhood is a risk factor for the subsequent development of musculoskeletal pain. Methods: JH was determined by Beighton score at age 13.8 years in ALSPAC, using a cut-off of >6. Musculoskeletal pain was evaluated by questionnaire at age 17.8 years. Logistic regression analysis was performed in 2901 participants (1267 boys and 1634 girls) with complete data. Results: 4.6% of participants were hypermobile at age 13.8 years. Moderately troublesome musculoskeletal pain at age 17.8 was reported most commonly at the lower back (16.1%), upper back (8.9%), neck (8.6%), shoulder (9.5%), knee (8.8%) and ankle/foot (6.8%). JH was associated with an increased risk of at least moderately troublesome musculoskeletal pain at the shoulder (1.68; 1.04, 2.72), knee (1.83; 1.10, 3.02) and ankle/foot (1.82; 1.05, 3.16) (OR with 95% CI, adjusted for gender, maternal education and BMI). An equivalent relationship was not observed at other sites including the spine, elbows, hands and hips. In analyses examining interactions with obesity, associations between JH and knee pain showed higher ORs in obese participants (1.6 and 11.0 in non-obese and obese participants, respectively, P = 0.04 for obesity interaction). Conclusions: JH represents a risk factor for musculoskeletal pain in adolescence, comprising a specific distribution namely the shoulder, knee and ankle/foot. These relationships were strongest in the presence of obesity, consistent with a causal pathway whereby JH leads to pain at sites exposed to the greatest mechanical forces. Disclosures: The authors have declared no conflicts of interest.

Background Systemic juvenile idiopathic arthritis (sJIA), characterised by chronic arthritis associated with prominent systemic features, has a significant impact on the growing skeleton, resulting in impaired linear growth and systemic osteoporosis. A phase 3 trial (TENDER) demonstrated that the interleukin-6 (IL-6) receptor inhibitor tocilizumab (TCZ) is effective in the treatment of patients with sJIA. Long-term growth responses for children in the TENDER trial (up to week 104) are presented. Methods The TENDER trial enrolled 112 patients (ages 2-17 years) with active, refractory sJIA (≥6-month duration with inadequate response to previous non-steroidal anti-inflammatory drugs and oral corticosteroids). After a 12-week, randomised, placebo-controlled phase, patients received open-label TCZ in the long-term extension. Height parameters, laboratory data and clinical assessments of disease activity were compared at baseline and through year 2 of the study in patients who never received growth hormone. Results At enrolment in the TENDER trial, the height measurements of study patients revealed profound growth failure (mean WHO height standard deviation score [SDS] of –2.0; n = 103). During treatment, the majority of patients had greater than normal height velocities, with 84% of female patients and 72% of male patients demonstrating catch-up growth (Figure). The height SDS increased significantly from baseline to year 2 of the study, with a mean improvement of 0.56 (p < 0.0001, paired t-test). Additional growth analysis was performed for patients with Tanner stage <4 at baseline. Although the mean corticosteroid dose was higher in the first year (0.14 mg/kg/day compared with 0.05 mg/kg/day in the second year), mean height velocities in the first and second years of the study were comparable at 6.7 and 7.1 cm/y, respectively. During TCZ treatment, a significant increase in insulin-like growth factor 1 (IGF-1) levels was observed, suggesting a normalisation of growth hormone axis function (mean baseline IGF-1 SDS of –0.9 [n = 70] compared with year 2 mean IGF-1 SDS of –0.2 [n = 56]; p = 0.0015, paired t-test on n = 56). The osteocalcin/c-telopeptide of type 1 collagen (OC/CTX-1) ratio increased significantly (p = 0.0082, paired t-test), suggesting an increase in osteoblast activity relative to osteoclast activity. At year 1, JADAS-71 score correlated with height velocity during that year (Spearman rank r = –0.36, p = 0.0010; [n = 81]). Image/graph Conclusions TCZ therapy for sJIA resulted in catch-up growth of study patients. Additionally, TCZ therapy resulted in increased IGF-1 levels and OC/CTX-1 ratios, suggesting beneficial effects on the growth hormone axis and on bone metabolism. Improvement in JADAS scores correlated with increased height velocity. Continued data collection (for a total of 5 years) will allow a comprehensive analysis of growth outcomes in the TENDER study. Disclosure of Interest F. De Benedetti Grant/research support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, N. Ruperto Grant/research support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: (to institution) Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, G. Espada: None Declared, V. Gerloni: None Declared, B. Flato: None Declared, G. Horneff Grant/research support from: Abbott, Pfizer, B. Myones: None Declared, K. Onel Grant/research support from: Merck, Roche, J. Frane Consultant for: Genentech, J. Wang Employee of: Roche, T. Lipman Consultant for: Roche, K. Bharucha Employee of: Genentech, a member of the Roche group, A. Martini Grant/research support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: (to institution) Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, D. Lovell Grant/research support from: Natioinal Institutes of Health, Consultant for: AstraZeneca, Centocor, Wyeth, Amgen, BMS, Abbott, Pfizer, Roche, Novartis, UCB, Forest Research

Context: Small clinical trials of GH treatment of idiopathic short stature (ISS) show variable efficacy.Objective: The study was an analysis of a large GH registry for efficacy and safety of GH treatment of ISS. There was also a comparison with a specific clinical trial.Design: Up to 7 yr of GH treatment of ISS was evaluated for efficacy and safety in the National Cooperative Growth Study (NCGS).Setting: The NCGS study was conducted at Genentech, Inc. and included 47,226 patients.Patients: The ISS group included maximum stimulated GH10 ng/ml or more and/ or a report of ISS by investigator (n = 8018; all included for safety). Cohort 1 (n = 2520) was similar to the clinical trial, cohort 2 (n = 283) included subjects younger than 5 yr of age, and cohort 3 (n = 940) was pubertal at GH start.Intervention: GH, approximately 0.30 mg/kg(.)wk, was given.Main Outcome Measures: These included growth velocities and height SD (HtSDS).Results: Mean first-year growth velocities in cohorts 1, 2, and 3 increased 4.6, 3.9, and 4.4 cm/yr over pretreatment, respectively. Measures included: baseline mean HtSDS, -2.9, -3.2, and -2.8; mean HtSDS at 1 yr, -2.4, -2.3, and -2.3, respectively. Mean HtSDS after 7 yr in cohorts 1 (n = 303) and 2 (n = 85) and 5 yr in cohort 3 (n = 58) were: -1.2, -1.0, and -1.5, respectively. Cohort 3 shorter treatment time was due to advanced baseline age (mean 13.8 yr) and puberty. Mean HtSDS gain in cohort 1 was comparable with the clinical trial. No new safety signals specific to the NCGS ISS population were observed.Conclusion: ISS patients in the GH registry demonstrate a significant increase in HtSDS with the safety profile similar to GH-deficient patients. Results were similar to the clinical trial.

OBJECTIVE:To study whether body mass index (BMI) is different in girls with Turner syndrome (TS) compared to normal girls, and whether BMI in TS is affected by growth hormone (GH) treatment.DESIGN:A retrospective cross-sectional study.SUBJECTS:2468 girls with TS enrolled in the National Cooperative Group Study (NCGS), a collaborative surveillance study for assessing GH-treated children.MEASUREMENTS:BMI and BMI standard deviation score (BMI SDS) at baseline and during GH treatment were computed from height and weight data.RESULTS:BMI in TS patients increases with age as expected. However, BMI SDS increased starting at about age 9 y. A similar pattern of increase in BMI SDS was observed after each year of GH treatment for up to 4 y, but GH treatment did not change the magnitude of increase. BMI and BMI SDS curves before and during GH treatment were essentially superimposable.CONCLUSION:These findings suggest that mechanisms specific for TS are responsible for the age-related increase in BMI SDS. This increase was unaffected by GH treatment.

Objective: To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS).Methods: In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens.Results: Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4 +/- 5.5 cm (mean +/- SD), 8.4 +/- 4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1 +/- 5.9 cm, 10.3 +/- 4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2 +/- 6.0 cm, precisely matching their original projected adult height of 144.2 +/- 6.1 cm.Conclusions: GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.

The effect of growth hormone (GH) therapy, alone, with oxandrolone (OX), or with estrogen (E) was studied in two randomized investigations. GH was administered daily at 0.375 mg/kg/wk and OX at 0.0625 mg/kg/d. In a separate study of GH, subjects were begun on conjugated E (0.3 mg/d for 6 months, then 0.625 mg/d. Final and near-final heights were compared to the projected adult heights (ProjAH) of Turner girls based on Lyon et al. and to the final heights of 25 American untreated historical control subjects. In the first study, subjects treated with GH alone reached a final height of 150.4 ± 5.5 cm, 8.4 ± 4.5 cm taller than their mean ProjAH; subjects treated with GH + OX attained a height of 152.1 ± 5.9 cm, 10.3 ± 4.7 cm taller than their mean ProjAH. Historical controls had a mean adult height of 144.2 ± 6.0 cm, matching their ProjAH of 144.2 ± 6.1 cm. In the second study, near-final height was determined at a mean age of 16.1 years. Subjects on GH + late E (age >14 years) had a mean height of 150.4 cm, compared to 147.0 cm for subjects on GH + early E (age <14 years). We conclude that GH, with and without OX, increases final height, and that early initiation of E compromises adult height. (Funded by Genentech, Inc.)

We treated 121 patients with height below -2 SDS for age and stimulated GH > 10 ng/mL (ISS) with GH for up to 5 years. The majority of these patients achieved improved growth rate, height SDS, and predicted adult height with GH therapy prior to puberty. The age of onset of puberty in these GH-treated ISS patients was not advanced However, data suggests that GH-treated patients may transit puberty faster and not achieve their predicted gains in adult height. We compared 92 GH-treated ISS patients with 252 untreated normal children followed longitudinally whose height was ahove -1 SDS (NL ≥ 1) for age or below -I SDS (NL < -1) for age. The change in Pels method bone age per year (ΔBA/ΔCA) arid the change in Bayley-Pinneau predicted adult height per year (ΔPHt/ΔCA) were compared before puberty (BA ≤11yo in ♂, ≤9yo in ♀) and during puberty (BA ≥ 12yo ♂, ≥ 10yo ♀): We conclude that GH-treated ISS ♂ progress through puberty faster, and do not continue to increase PHt. Early GH treatment, increased GH dosage, or prolongation of puberty may be needed to achieve target increases of final height in ISS boys.

The increased incidence of glucose intolerance in Turner syndrome leads to an abnormal GTT in 30-60% of adult women. Since currently explored therapies to increase adult height may impair carbohydrate metabolism we evaluated the effect of more than 3-6 yrs. of GH alone or in combination with oxandrolone on glucose metabolism. The trial was begun in 1983 (n=71) and study subjects receive currently hGH 0.375 mg/kg/wk either in equal daily doses or tiw (hGH) or hGH in combination with oxandrolone 0.0625 m/kg/day (combination). Based on Natl. Diabetes Data Group criteria 15% (11/71) had impaired GTT at baseline. Postprandial insulin results before treatment and after 3 to 6 years of therapy are summarized below. Geometric means (U/ml) are used because of inherent skewness. The change from baseline to long-term to follow-up was significant in the hGH group (p<0.015) and in the combination group (p<0.0005). The change in the combination group was significantly greater than in the hGH group (p<0.0021) using the unequal variance two sample t-test. There was no difference in Hgb A1C, pre and postprandial glucose, and cholesterol or triglyceride values in the 2 groups. No difference in any of the parameters was seen between hGH tiw or daily. In summary: Oxandrolone treatment increases insulin resistance in Turner syndrome. The long-term risk from tolerance is unclear at present.

Based on the known trophic effects of growth hormone (GH) on nerve and muscle 75 patients with ALS were treated for up to 18 months with synthetic human growth hormone (Protropin) or a placebo. The course of ALS was assessed serially using a quantitative (TQNE) neuromuscular and manual exam (MRC) and laboratory chemistries. Average insulin-related growth factor (IGF-I) values increased from 1.2 to 2.3 U/mL in the treated group. Surprisingly, serum insulin levels did not increase. Hyperglycemia was noted in only 2 patients of the 38 patients receiving hGH, and this resolved with cessation of treatment. Over the 12 months of treatment there were 11 deaths (6 controls, 5 treated). Survival analysis, performed approximately 12 months following cessation of treatment, did not reveal a difference between the treatment and placebo group. The TQNE scores declined inexorably in both the control and treated group. Retrospective analysis of the TQNE data indicated a poor prognosis for patients who lost arm strength early. A correlation between the TQNE and MRC scores was evident at early stages of motor unit loss, less so when muscle weakness was advanced.

Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.