Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three ...decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence‐based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non‐fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence‐based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.
Background
For Australians living with cystic fibrosis (CF), increased longevity means greater consideration needs to be given to long‐term endocrine sequelae such as CF‐related bone disease. ...Deficits in bone mass accrual are most likely to occur during childhood and adolescence. Current guidelines in Australia suggest repeat dual‐energy X‐ray absorptiometry (DXA) scans every 2 years. This study aims to stratify clinical factors that determine future bone health in the Australian CF population and use this to guide a more streamlined approach to bone health screening.
Methods
This study was a retrospective audit of all patients diagnosed with CF who were treated at the Royal Children's Hospital Melbourne, Australia from 2000 to 2016 (n = 453). Two hundred and two patients had a DXA scan in the study period (191 with height‐adjusted data) and 111 patients had more than one scan (108 with height‐adjusted data). An investigation into the associations between bone mineral density (BMD) Z score and potential risk factors was conducted using DXA and historical data.
Results
The main predictor of future BMD was the previous BMD Z score (p < .001). Other factors found to be determinants of BMD included nutritional status, lung function (FEV1), age, history of previous fracture, oral corticosteroid use, and the number of hospital admissions. However, after adjusting for previous BMD, evidence of an association remained only with nutritional status, FEV1, and number of hospital admissions.
Conclusion
Second yearly scans may be unnecessary in children with an adequate DXA score on the initial scan who remain clinically stable. However, clinical deterioration in those whose BMD was previously normal, may require closer monitoring of bone health. We propose a guideline for the frequency of DXA monitoring in relation to clinical risk factors.
Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause ...hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC p.F453del; c.G1369A p.G457S; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio OR, 0.75, 95% confidence interval 95% CI, 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.
Objective To test the safety and efficacy of biphosphonates in chronic recurrent multifocal osteomyelitis (CRMO). Study design Five patients with CRMO, all of whom had ongoing pain and loss of ...function despite conventional treatment with non-steroidal anti-inflammatory agents, were treated with pamidronate (1 mg/kg/dose with a dosing frequency of 2 to 4 monthly for a total treatment duration of 12 to 42 months). Results Pain decreased after the first infusion for 4 of 5 patients, with symptomatic improvement maintained with time. Significant improvement was seen in radiological lesions for these 4 patients. Conclusion Bisphosphonates appear to be a useful and safe adjunctive treatment in CRMO when simple therapies such as anti-inflammatory agents fail to control symptoms or cases in which lesion expansion continues.
Bisphosphonates have been used for treatment of bone fragility disorders for over 25 years to increase bone mineral density (BMD). Anecdotally, bisphosphonate-treated Osteogenesis Imperfecta (OI) has ...a different trajectory to the natural history of untreated OI in terms of fracture incidence, quality of life and physical function, with minimal published evidence to support this clinical observation. This study describes functional outcomes of a cohort of adults with OI, stratified according to severity and treated with intravenous bisphosphonates as children. Reported outcomes included fracture incidence before and after puberty, mobility and BMD outcomes of this cohort. The cohort was compared to adults with OI who were never treated as children. All participants completed four questionnaires: a study specific questionnaire addressing fracture and treatment history, WHOQOL-BREF (quality of life), SF-36 (musculoskeletal function) and IPAQ (physical activity), and medical records were reviewed. Fifty-two adults with OI (80% response rate) completed the questionnaires; 33 of whom were treated with bisphosphonates in childhood. The childhood treated cohort had higher lumbar spine BMD than the adult treated cohort (z-score − 0.4 at mean age 21.3 years versus −2.1 at mean age 40.9 years; p = 0.003). Pre-pubertal fracture incidence was reduced for all severities of OI in the childhood treated cohort (less severe OI, p = 0.01; more severe OI, p < 0.001), but post-pubertal fracture incidence was higher for less severe OI (p < 0.001). In less severe OI, childhood treated individuals had higher levels of physical activity (p = 0.004) and physical functioning (p = 0.01) than adult treated individuals. Incidence of scoliosis was not different between cohorts. There were no differences in quality of life scores between the two cohorts. Improvements in BMD do not appear to influence the prevalence of scoliosis. Results suggest that treatment with bisphosphonates at an earlier age improves physical activity, particularly in less severe forms of OI but may not alter quality of life.
•OI patients treated with early bisphosphonate treatment resulted in increased BMD and higher levels of physical activity.•Despite the physical burden associated with OI, quality of life and psychological wellbeing remain high.•Improvements in BMD with bisphosphonate treatment accompanied lower prepubertal fracture rate.•Results suggest early bisphosphonate treatment improves physical activity, particularly in less severe forms of OI.
Abstract
Context
Patients with glucocorticoid-dependent Duchenne muscular dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss.
...Objective
To investigate use of zoledronic acid (ZA) in DMD in improving BMD.
Methods
Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, peripheral quantitative computerized (pQCT) and pain scores.
Results
At 12 and 24 months, mean difference in changes of LS BMD Z-score from baseline was 1.2 SD (95% CI 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA than control arms respectively (both P < .001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain, and bone turnover markers were similar between arms at 12 and 24 months. Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort than control; the evidence for this difference remained at 24 months for radius but not tibia.
Conclusion
ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.
Objective: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children.
Design: 18‐month questionnaire‐based prospective observational study, using ...Australian Paediatric Surveillance Unit (APSU) data.
Setting: Australian paediatricians and child health workers, January 2006 – July 2007.
Participants: Children aged ≤ 15 years with vitamin D deficiency rickets (25‐hydroxyvitamin D 25OHD ≤ 50 nmol/L, and elevated alkaline phosphatase levels > 229 IU/L and/or radiological rickets).
Main outcome measures: Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best‐practice guidelines.
Results: We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years range, 0.2–15 years). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L range, 5–50 nmol) and an elevated alkaline phosphatase level (median, 407 IU/L range, 229–5443 IU/L), and 48 (12%) were hypocalcaemic. Ninety‐five children had wrist x‐rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis.
Conclusions: Vitamin D deficiency rickets is a significant problem in Australia among known high‐risk groups. Public health campaigns to prevent, identify and treat vitamin D deficiency, especially in high‐risk groups, are essential.
•Bone health outcomes of patients on the ketogenic diet have only been reported once to date.•This study shows falling bone mineral density especially in ambulant patients.•Ongoing studies exploring ...fracture risk and other bone health outcomes are required.
The ketogenic diet (KD) is a medically supervised, high fat, low carbohydrate and restricted protein diet which has been used successfully in patients with refractory epilepsy. Only one published report has explored its effect on the skeleton. We postulated that the KD impairs skeletal health parameters in patients on the KD.
Patients commenced on the KD were enrolled in a prospective, longitudinal study, with monitoring of Dual-energy X-ray absorptiometry (DXA) derived bone parameters including bone mineral content and density (BMD). Areal BMD was converted to bone mineral apparent density (BMAD) where possible. Biochemical parameters, including Vitamin D, and bone turnover markers, including osteocalcin, were assessed. Patients were stratified for level of mobility using the gross motor functional classification system (GMFCS).
29 patients were on the KD for a minimum of 6 months (range 0.5-6.5 years, mean 2.1 years). There was a trend towards a reduction in lumbar spine (LS) BMD Z score of 0.1562 (p=0.071) per year and 20 patients (68%) had a lower BMD Z score at the end of treatment. While less mobile patients had lower baseline Z scores, the rate of bone loss on the diet was greater in the more mobile patients (0.28 SD loss per year, p=0.026). Height adjustment of DXA data was possible for 13 patients, with a mean reduction in BMAD Z score of 0.19 SD. Only two patients sustained fractures. Mean urinary calcium-creatinine ratios were elevated (0.77), but only 1 patient developed renal calculi.
Children on the KD exhibited differences in skeletal development that may be related to the diet. The changes were independent of height but appear to be exaggerated in patients who are ambulant. Clinicians should be aware of potential skeletal side effects and monitor bone health during KD treatment. Longer term follow up is required to determine adult/peak bone mass and fracture risk throughout life.
X‐linked hypophosphataemia (XLH), the most common inherited form of rickets, is caused by a PHEX gene mutation that leads to excessive serum levels of fibroblast growth factor 23 (FGF23). This leads ...to clinical manifestations such as rickets, osteomalacia, pain, lower limb deformity and overall diminished quality of life. The overarching aims in the management of children with XLH are to improve quality of life by reducing overall burden of disease, optimise an individual's participation in daily activities and promote normal physical and psychological development. Burosumab, a monoclonal antibody targeting FGF23, has been shown to improve biochemistry, pain, function and radiological features of rickets in children with XLH and has transformed management of XLH around the world. Burosumab has been recently approved for clinical use in children with XLH in Australia. This manuscript outlines a clinical practice guideline for the use of burosumab in children with XLH to assist local clinicians, encourage consistency of management across Australia and suggest future directions for management and research. This guideline also strongly advocates for all patients with XLH to have multidisciplinary team involvement to ensure optimal care outcomes and highlights the need to consider other aspects of care for XLH in the era of burosumab, including transition to adult care and the effective coordination of care between local health‐care providers and specialist services.
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