Bisphosphonates for osteoporosis in people with cystic fibrosis.

BACKGROUND: Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. This is an updated version of a previous review. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register of references (identified from electronic database searches and hand searches of journals and abstract books) on 5 May 2022. We performed additional searches of PubMed, clinicaltrials.gov and the WHO ICTRP (International Clinical Trials Registry Platform) on 5 May 2022. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Authors independently selected trials, extracted data and assessed risk of bias in included studies. Trial investigators were contacted to obtain missing data. We judged the certainty of the evidence using GRADE. MAIN RESULTS: We included nine trials with a total of 385 participants (272 adults and 113 children (aged five to 18 years)). Trial durations ranged from six months to two years. Only two of the studies were considered to have a low risk of bias for all the domains.  Bisphosphonates compared to control in people with cystic fibrosis who have not had a lung transplant Seven trials included only adult participants without lung transplants, one trial included both adults and children without lung transplantation (total of 238 adults and 113 children). We analysed adults (n = 238) and children (n = 113) separately. Adults Three trials assessed intravenous bisphosphonates (one assessed pamidronate and two assessed zoledronate) and five trials assessed oral bisphosphonates (one assessed risedronate and four assessed alendronate). Bisphosphonates were compared to either placebo or calcium (with or without additional vitamin D). Data showed no difference between treatment or control groups in new vertebral fractures at 12 months (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.02 to 2.09; 5 trials, 142 participants; very low-certainty evidence) and two trials (44 participants) reported no vertebral fractures at 24 months. There was no difference in non-vertebral fractures at 12 months (OR 2.11, 95% CI 0.18 to 25.35; 4 trials, 95 participants; very low-certainty evidence) and again two trials (44 participants) reported no non-vertebral fractures at 24 months. There was no difference in total fractures between groups at 12 months (OR 0.57, 95% CI 0.13 to 2.50; 5 trials, 142 participants) and no fractures were reported in two trials (44 participants) at 24 months. At 12 months, bisphosphonates may increase bone mineral density at the lumbar spine (mean difference (MD) 6.31, 95% CI 5.39 to 7.22; 6 trials, 171 participants; low-certainty evidence) and at the hip or femur (MD 4.41, 95% 3.44 to 5.37; 5 trials, 155 participants; low-certainty evidence). There was no clear difference in quality of life scores at 12 months (1 trial, 47 participants; low-certainty evidence), but bisphosphonates probably led to more adverse events (bone pain) at 12 months (OR 8.49, 95% CI 3.20 to 22.56; 7 trials, 206 participants; moderate-certainty evidence). Children The single trial in 113 children compared oral alendronate to placebo. We graded all evidence as low certainty. At 12 months we found no difference between treatment and placebo in new vertebral fractures (OR 0.32, 95% CI 0.03 to 3.13; 1 trial, 113 participants) and non-vertebral fractures (OR 0.19, 95% CI 0.01 to 4.04; 1 trial, 113 participants). There was also no difference in total fractures (OR 0.18, 95% CI 0.02 to 1.61; 1 trial, 113 participants). Bisphosphonates may increase bone mineral density at the lumbar spine at 12 months (MD 14.50, 95% CI 12.91 to 16.09). There was no difference in bone or muscle pain (MD 3.00, 95% CI 0.12 to 75.22), fever (MD 3.00, 95% CI 0.12 to 75.22) or gastrointestinal adverse events (OR 0.67, 95% CI 0.20 to 2.26). The trial did not measure bone mineral density at the hip/femur or report on quality of life.  Bisphosphonates compared to control in people with cystic fibrosis who have had a lung transplant One trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment. It did not report at 12 months and we report the 24-month data (not assessed by GRADE). There was no difference in the number of fractures, either vertebral or non-vertebral. However, bone mineral density increased with treatment at the lumbar spine (MD 6.20, 95% CI 4.28 to 8.12) and femur (MD 7.90, 95% CI 5.78 to 10.02). No participants in either group reported either bone pain or fever. The trial did not measure quality of life. AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates may increase bone mineral density in people with cystic fibrosis, but there are insufficient data to determine whether treatment reduces fractures. Severe bone pain and flu-like symptoms may occur with intravenous bisphosphonates. Before any firm conclusions can be drawn, trials in larger populations, including children, and of longer duration are needed to determine effects on fracture rate and survival. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids can ameliorate or prevent these adverse events. Future trials should also assess gastrointestinal adverse effects associated with oral bisphosphonates.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

BACKGROUND: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.Additional searches of PubMed were performed on 13 January 2014. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. MAIN RESULTS: Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

Post-transplant lymphoproliferative disorder: no relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients.

PTLD is a potentially life-limiting complication of pediatric transplantation. Previous registry-based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post-transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6-3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

BACKGROUND: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 15 February 2012.Additional searches of PubMed were performed on 14 May 2011. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. MAIN RESULTS: Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

Hypothalamic Obesity following Craniopharyngioma Surgery: Results of a Pilot Trial of Combined Diazoxide and Metformin Therapy.

Objective. To assess the effect of combined diazoxide-metformin therapy in obese adolescents treated for craniopharyngioma. Design. A prospective open-label 6-month pilot treatment trial in 9 obese subjects with craniopharyngioma. Diazoxide (2 mg/kg divided b.i.d., maximum 200 mg/day) and metformin (1000 mg b.i.d.). Whole body insulin sensitivity index (WBISI) and area-under-the-curve insulin (AUC(ins)) were calculated. Results. Seven subjects completed: 4M/3F, mean ± SD age 15.4 ± 2.9 years, weight 99.7 ± 26.3 kg, BMI 35.5 ± 5.6 kg/m(2), and BMI SDS 2.3 ± 0.3. Two were withdrawn due to vomiting and peripheral edema. Of participants completing the study, the mean ± SD weight gain, BMI, and BMI SDS during the 6 months were reduced compared to the 6 months prestudy (+1.2 ± 5.9 versus +9.5 ± 2.7 kg, P = .004; -0.3 ± 2.3 versus +2.2 ± 1.5 kg/m(2), P = .04; -0.04 ± 0.15 versus +0.11 ± 0.08, P = .021, resp.). AUC(ins) correlated with weight loss (r = 0.82, P = .02) and BMI decrease (r = 0.96, P = .009). Conclusion. Combined diazoxide-metformin therapy was associated with reduced weight gain in patients with hypothalamic obesity. AUC(ins) at study commencement predicted effectiveness of the treatment.

Klebsiella pneumoniae bacteraemia complicating rotavirus gastroenteritis in two infants with glucocorticoid deficiency.

Rotavirus gastroenteritis was complicated by Klebsiella Pneumoniae bacteraemia in two infants with glucocorticoid deficient conditions who were treated with 'stress dose' hydrocortisone during their illness. Delayed healing in the context of glucocorticoid administration combined with damage from rotavirus infection may result in increased risk of mucosal invasion by gastrointestinal bacteria and subsequent enteric gram-negative bacteraemia.

The feasibility of a home-based moderate-intensity physical activity intervention in obese children and adolescents.

OBJECTIVES: To explore the feasibility of conducting a 10-week home-based physical activity (PA) programme and evaluate the changes in insulin sensitivity (S(I)) commensurate with the programme in obese young people. DESIGN: Open-labelled intervention. SETTING: Home-based intervention with clinical assessments at a tertiary paediatric hospital. SUBJECTS: 18 obese (body mass index (BMI)>International Obesity Task Force age and sex-specific cut-offs) children and adolescents (8-18 years, 11 girls/7 boys) were recruited. 15 participants (nine girls/six boys, mean+/-SE age 11.8+/-0.6 years, BMI-SD scores (BMI-SDS) 3.5+/-0.1, six prepubertal/nine pubertal) completed the intervention. INTERVENTION: The programme comprised biweekly home visits over 10 weeks with personalised plans implemented aiming to increase moderate-intensity PA. Pedometers and PA diaries were used as self-monitoring tools. The goals were to (1) teach participants behavioural skills related to adopting and maintaining an active lifestyle and (2) increase daily participation in PA. OUTCOME MEASURES: Mean steps/day were assessed. S(I) assessed by the frequently sampled intravenous glucose tolerance test and other components of the insulin resistance syndrome were measured. RESULTS: Mean steps/day increased significantly from 10 363+/-927 (baseline) to 13 013+/-1131 (week 10) (p<0.05). S(I) was also significantly increased, despite no change in BMI-SDS, and remained so after an additional 10-week follow-up. CONCLUSIONS: The results suggest that such a home-based PA programme is feasible. S(I) improved without changes in BMI-SDS. More rigorous evaluations of such programmes are warranted.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

BACKGROUND: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis (CF). Bisphosphonates can increase bone mineral density (BMD) and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, BMD, quality of life, adverse events, trial withdrawals, and survival in people with CF. SEARCH STRATEGY: We searched the CF and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 29 October 2008.Additional searches of Pubmed were performed on 01 November 2008. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. MAIN RESULTS: Seven trials were identified and five (with a total of 145 adult participants) were included.Data were combined when available from four included studies in participants without a lung transplant. This showed that there was no significant reduction in fractures between groups. However, after six months, the percentage change in BMD increased in those on bisphosphonates at the lumbar spine, mean difference (MD) 4.61 (95% confidence interval (CI) 3.90 to 5.32) and at the hip, MD 3.35 (95% CI 1.63 to 5.07); but did not significantly change at the distal forearm, MD -0.49 (95% CI -2.42-1.45). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, BMD increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, MD 6.20 (95% CI 4.28 to 8.12) and femur MD 7.90 (95% CI 5.78 to 10.02). AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates increase BMD in people with CF. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Trials in larger populations are needed to determine effects on fracture rate and survival.