Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial.

CONTEXT: Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. OBJECTIVE: This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). METHODS: Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. RESULTS: Thirty-four children were enrolled (mean age 12.6 ±â€…3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ±â€…0.79 to -1.49 ±â€…1.05 on ZA, compared with -2.38 ±â€…0.90 to -2.27 ±â€…1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. CONCLUSION: LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.

Bone mass and vertebral fractures in South African children on prolonged oral glucocorticoids for chronic non-malignant illnesses.

INTRODUCTION: We hypothesized that the prevalence of vertebral fractures would be low and that bone mineral density (BMD) would be less severely affected in a black South African (SA) population treated with glucocorticoids (GCs) than that reported in mainly white populations. METHODS: All children aged 5-17.9 years with chronic non-malignant illnesses who were on GCs (intravenous or oral) for greater than 3 months duration were evaluated. DXA scans were performed using a Hologic Discovery machine (Software version Apex 4.0.2) and the Hologic paediatric reference database. Whole body less head (WBLH) and lumbar spine (LS) bone mineral content (BMC) and density (BMD) Z-scores unadjusted and adjusted for height were calculated using the Zemel equation calculator. RESULTS: Seventy-two patients (49% with renal, 24% with rheumatic, 14% with neurological, 11% with hepatic and 3% with respiratory conditions; mean age 11.6 ± 3.3 years, 57% boys, 92% SA black) were enrolled. The mean duration of GC treatment was 34.1 (±25.1) months. Mean WBLH and LS height adjusted BMD Z-scores were -1.2 ± 1.5 and -0.9 ± 1.0 respectively. Eleven percent of patients had a LS height adjusted BMD Z-score ≤ -2. The prevalence of vertebral fractures on lateral vertebral fracture assessment (VFA) was 15% (11 of 72 patients). CONCLUSION: The prevalence of vertebral fractures (15%) in predominantly black children on GCs with chronic non-malignant illnesses is similar to that reported from North America suggesting that routine yearly DXA scans including VFA are warranted in this highly at-risk population.

Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype.

The roles of vitamin D and dietary calcium in nutritional rickets.

The etiology and pathogenesis of nutritional rickets are becoming progressively clearer. Vitamin D deficiency has generally been considered the major or only player in the pathogenesis of nutritional rickets. However, recent research into calcium deficiency has now provided clinicians with reasons to investigate and manage patients with nutritional rickets more appropriately. The important question when assessing cases of nutritional rickets is: "Is it calcium or vitamin D deficiency or both that play a major role in the pathogenesis of the disease?" The case presentation in this review highlights the risk factors, clinical presentation and pathophysiology of nutritional rickets in a young South African black child from a semi-urban area in Johannesburg, a city with abundant sunshine throughout the year.

Hypophosphatemic rickets: unraveling the role of FGF23.

The classification of the various forms of hypophosphatemic rickets has been rationalized by the discovery of the central role that fibroblast growth factor 23 (FGF23) plays in the pathogenesis of a number of genetic and acquired forms of the disease. Although the details of the interaction of FGF23 with other osteoblast/osteocyte-derived proteins remain unclear at present, the measurement of circulating levels of FGF23 appears to be a useful biochemical test in determining the various causes of hypophosphatemic rickets. Furthermore, animal studies suggest that agents interfering in the action of FGF23 might play important roles in the future management of the FGF23-mediated forms of rickets. Phase 1 and phase 2 trials in humans with X-linked hypophosphatemic rickets are currently under way.

Maternal vitamin D status: implications for the development of infantile nutritional rickets.

The mother is the major source of circulating 25-OHD concentrations in the young infant. Thus maternal vitamin D status is an important factor in determining the vitamin D status of the infant and their risk of developing vitamin D deficiency and infantile nutritional rickets. As a result, breastfed infants of mothers with vitamin D deficiency who are unsupplemented and who receive little sunlight exposure are at high risk of developing vitamin D deficiency or rickets. Despite food fortification policies in many countries and recommendations for vitamin D supplementation of at-risk groups, vitamin D deficiency and infantile rickets remain major public health challenges in many developed and developing countries. There is evidence that the current supplementation recommendations, particularly for pregnant and lactating women, are inadequate to ensure vitamin D sufficiency in these groups. A widespread and concerted effort is needed to ensure daily supplementation of breastfed and other infants at high risk with vitamin D 400 IU from birth and pregnant women in high risk communities with at least 600 IU; awareness needs to be developed among the public and medical practitioners of the urgent need to improve the vitamin D status of pregnant and lactating mothers and their infants. Further studies are required to determine the optimal doses of vitamin D supplementation in pregnancy and during lactation, and for normalizing vitamin D stores in infancy to reduce the prevalence of infantile nutritional rickets. Operational research studies also need to be conducted to understand the best methods of implementing supplementation programs and the factors that are likely to impede their success.

Heterogeneity of fracture pathogenesis in urban South African children: the birth to twenty cohort.

South African black children fracture less than white children. Differences in bone mass, body composition, and physical activity may be contributing risk factors. This study aimed to investigate the association between fracture prevalence, bone mass, and physical activity in South African children. Using the Bone Health cohort of the Birth to Twenty longitudinal study, we retrospectively obtained information of lifetime fractures until age 15 years in 533 subjects. Whole-body bone mineral content (BMC), bone area (BA), fat mass (FM), and lean mass (LM) (measured by dual-energy X-ray absorptiometry [DXA]), anthropometric data, physical activity scores, and skeletal maturity were obtained at ages 10 and 15 years. Nonfracturing black females were used as the control group and comparisons were made between those who did and did not fracture within the same sex and ethnic groups. Of the 533 subjects, 130 (24%) reported a fracture (black, 15%; white, 41.5%; p < 0.001). White males who fractured were significantly taller (10 years, p < 0.01), more physically active (15 years, p < 0.05) and had higher LM (10 years, p = 0.01; 15 years, p < 0.001), whereas white females who fractured were fatter (10 and 15 years, p = 0.05 and p < 0.05, respectively), than their nonfracturing peers. White males who fractured had greater BA and BMC at all sites at 10 and 15 years compared to their nonfracturing peers after adjusting for differences in height and weight; BA and BMC were similar in each of the other sex and ethnic groups. No anthropometric or bone mass differences were found between black children with and without fractures. The factor associated with fractures in white males appears to be participation in sports activities, while in white females obesity appears to play a role. No contributing factors in black males and females were found, and needs further elucidation.

Clinical practice: diagnostic approach to the rachitic child.

Rickets remains a common problem among infants and children in many countries worldwide. Although the classical presentation associated with bone abnormalities is well known, paediatricians need to be aware of atypical presentations, especially in the first 6 months of life. Furthermore, although vitamin D deficiency rickets remains the commonest form of rickets in most countries, health care providers need to be aware of other possible causes and their typical clinical and biochemical presentations. This article discusses these and highlights the characteristic features of various forms of rickets and possible pitfalls clinicians should be aware of when confronted with a patient with suspected rickets. In conclusion, the recent advances made in understanding the underlying pathogeneses of the various forms of rickets has helped to delineate the diagnostic tests that assist in the diagnosis and management of the disease in children.

Maternal vitamin D status: implications for the development of infantile nutritional rickets.

The mother is the major source of circulating 25-hydroxyvitamin D concentration in the young infant. Maternal vitamin D status is an important factor in determining the vitamin D status of the infant and their risk of developing vitamin D deficiency and infantile nutritional rickets. There is evidence that the current supplementation recommendations, particularly for pregnant and lactating women, are inadequate to ensure vitamin D sufficiency in these groups. A widespread and concerted effort is needed to ensure daily supplementation of breastfed and other infants at high risk with vitamin D 400 IU from birth and of pregnant women in high-risk communities with 2000 IU. Future studies are required to determine the optimal doses of vitamin D supplementation in pregnancy and during lactation, and for normalizing vitamin D stores in infancy to reduce the prevalence of infantile nutritional rickets. Operational research studies are needed to understand the best methods of implementing supplementation programs and the factors that are likely to impede their success.