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Osteonecrosis of the jaw and bisphosphonates in children and adolescents
ABSTRACTS / Bone 40 (2007) S22–S89 2 3 4
Pediatrics, Mayo Clinic, Rochester, MN Clinical Chemistry, Mayo Clinic, Rochester, MN Family Medicine, Jos University Hospital, Jos, Nigeria
Nutritional rickets most commonly results from vitamin D deficiency and is typically associated with inadequate sunlight. Thus, the existence of rickets in many tropical countries, where sunlight is abundant, is unexpected, and has suggested that genetic, hormonal, and other nutritional factors may cause rickets in susceptible children. We recently identified a missense mutation (Leu99Pro) in exon 2 of CYP2R1, the gene encoding the key hepatic vitamin D 25hydroxylase, in members of 2 of 10 Nigerian families in which more than 1 subject had rickets. One proband (T133), his affected brother (T133-1) and their father (T133-5) were homozygous (CYP−/−) for the L99P allele; his mother and two sisters were heterozygous (CYP−/+) for the L99P allele, and one of the sisters had a history of genu varum that resolved spontaneously as a toddler. The second proband (K170) and her affected sister were both heterozygous for the L99P mutation. Their mother was homozygous for the wild type allele while their clinically unaffected father was heterozygous. Biochemical analyses showed that homozygous brothers T133 and T133-1 were hypocalcemic with elevated alkaline phosphatase; their homozygous father T133-5 and all heterozygous subjects had normal serum calcium and alkaline phosphatase concentrations. Because in vitro analyses of CYP2R1 function had shown that the L99P enzyme retained modest residual activity, we administered 50,000 IU of ergocalciferol (D2) or cholecalciferol (D3) on separate occasions to subjects and determined serum levels of 25 (OH)D2 and 25(OH)D3 by isotope-dilution liquid chromatography-tandem mass spectrometry on days 0, 1, 3, and 7. Peak values were achieved on day 3 (see Table). We conclude that homozygous or heterozygous mutation of the CYP2R1 gene is a cause of rickets, and represents a new form of vitamin D dependent rickets. Remarkably, the phenotype appears to improve with age and treatment with calcium, suggesting the involvement of other genetic, hormonal or environmental factors that can compensate for loss of CYP2R1 vitamin D 25 hydroxylase activity. The role of variant alleles of CYP2R1 in the pathogenesis of vitamin D deficiency and/or metabolic bone disease worldwide remains to be determined.
All differences between CYP−/− (n = 3) and CYP−/+(n = 6) were significant by one-tailed t-test
CYP−/− CYP−/+ Normal
PTH
Basal 25 (OH)D2
Basal 25 (OH)D3
Peak 25 (OH)D2
Peak 25 (OH)D3
176 ± 121 67 ± 14 11–67 pg/ml
Not detected Not detected 25–80 ng/ml
4.0 ± 1.6 13.6 ± 2.1 25–80 ng/ml
9.0 ± 0.4 17.0 ± 3.8
12.9 ± 2.7 33.5 ± 8.3
doi:10.1016/j.bone.2007.04.079
S61
Osteonecrosis of the jaw and bisphosphonates in children and adolescents C. Limonta, S. Vai, M. Biggioggero, M.L. Bianchi Bone Metabolism Unit, Istituto Auxologico Italiano IRCCS, Milano, Italy Several recent reports suggest that osteonecrosis of the jaw (ONJ) can be a severe side effect of bisphosphonates (BPs) in adults. Intravenous zoledronate and pamidronate, and oral alendronate and risedronate have been involved. Special risk factors are cancer, corticosteroids, duration of exposure to BPs, dental extraction or other dental surgery. The prevalence of ONJ is estimated at 1.5%. In almost 82% of cases, pain is the main symptom. The typical lesions are a non-healing extraction socket or an exposed jawbone, frequently requiring surgery to remove the involved bone. BPs are now increasingly used also in children and adolescents, especially by intravenous administration. No data on the occurrence of ONJ are available for young patients treated with BPs. The aim of the present study was to verify whether any signs of ONJ were present in 38 children/adolescents (17 F, 21 M; age 4–22 years) treated with long-term BPs for osteogenesis imperfecta (11), fibrous dysplasia (1), secondary osteoporosis with recurrent fractures (26). In the last group, 20 patients were on long-term corticosteroid therapy. Of these patients, 18 had received i.v. cycles of pamidronate for 3 to 6 years and 20 had taken oral alendronate for 2.5 to 4 years. Some of the patients had dental problems (dentinogenesis imperfecta in OI; misalignment). During the follow-up, 4 patients had dental extraction, 15 caries repair, 5 misalignment correction and 7 older patients dental prophylaxis. All the patients were completely asymptomatic regarding ONJ: no pain, mucosal swelling, altered sensation in the area, erythema, ulcerations were reported by patients or referred by parents. In the last 2 years, all had periodical examination of the oral cavity, according to a specific protocol, to search for any bone expositions in the most commonly affected areas (posterior and lingual area of the mandibula). 15 patients had also dental panoramic radiographs. No ONJ lesions were found. The number of cases is too small to draw any conclusion, but this preliminary study seems to indicate that young patients on BPs, even with predisposing factors (dental disease, dental invasive procedures, long-term BPs, steroids), are not a specially high-risk group for ONJ. However, we would recommend good oral hygiene and regular oral cavity evaluation in all the children and adolescents treated with BPs. doi:10.1016/j.bone.2007.04.080
Fore-arm speed of sound in cystic fibrosis patients: correlation with bone mineral density and cortical wall thickness assessed using pQCT O. Louis 1, K. Toye 2, S. Van Biervliet 3, I. Gies 4, S. Goemare 2, J. De Schepper 4 1 Radiology, AZ-VUB, Brussels, Belgium
Pediatrics, Mayo Clinic, Rochester, MN Clinical Chemistry, Mayo Clinic, Rochester, MN Family Medicine, Jos University Hospital, Jos, Nigeria
Nutritional rickets most commonly results from vitamin D deficiency and is typically associated with inadequate sunlight. Thus, the existence of rickets in many tropical countries, where sunlight is abundant, is unexpected, and has suggested that genetic, hormonal, and other nutritional factors may cause rickets in susceptible children. We recently identified a missense mutation (Leu99Pro) in exon 2 of CYP2R1, the gene encoding the key hepatic vitamin D 25hydroxylase, in members of 2 of 10 Nigerian families in which more than 1 subject had rickets. One proband (T133), his affected brother (T133-1) and their father (T133-5) were homozygous (CYP−/−) for the L99P allele; his mother and two sisters were heterozygous (CYP−/+) for the L99P allele, and one of the sisters had a history of genu varum that resolved spontaneously as a toddler. The second proband (K170) and her affected sister were both heterozygous for the L99P mutation. Their mother was homozygous for the wild type allele while their clinically unaffected father was heterozygous. Biochemical analyses showed that homozygous brothers T133 and T133-1 were hypocalcemic with elevated alkaline phosphatase; their homozygous father T133-5 and all heterozygous subjects had normal serum calcium and alkaline phosphatase concentrations. Because in vitro analyses of CYP2R1 function had shown that the L99P enzyme retained modest residual activity, we administered 50,000 IU of ergocalciferol (D2) or cholecalciferol (D3) on separate occasions to subjects and determined serum levels of 25 (OH)D2 and 25(OH)D3 by isotope-dilution liquid chromatography-tandem mass spectrometry on days 0, 1, 3, and 7. Peak values were achieved on day 3 (see Table). We conclude that homozygous or heterozygous mutation of the CYP2R1 gene is a cause of rickets, and represents a new form of vitamin D dependent rickets. Remarkably, the phenotype appears to improve with age and treatment with calcium, suggesting the involvement of other genetic, hormonal or environmental factors that can compensate for loss of CYP2R1 vitamin D 25 hydroxylase activity. The role of variant alleles of CYP2R1 in the pathogenesis of vitamin D deficiency and/or metabolic bone disease worldwide remains to be determined.
All differences between CYP−/− (n = 3) and CYP−/+(n = 6) were significant by one-tailed t-test
CYP−/− CYP−/+ Normal
PTH
Basal 25 (OH)D2
Basal 25 (OH)D3
Peak 25 (OH)D2
Peak 25 (OH)D3
176 ± 121 67 ± 14 11–67 pg/ml
Not detected Not detected 25–80 ng/ml
4.0 ± 1.6 13.6 ± 2.1 25–80 ng/ml
9.0 ± 0.4 17.0 ± 3.8
12.9 ± 2.7 33.5 ± 8.3
doi:10.1016/j.bone.2007.04.079
S61
Osteonecrosis of the jaw and bisphosphonates in children and adolescents C. Limonta, S. Vai, M. Biggioggero, M.L. Bianchi Bone Metabolism Unit, Istituto Auxologico Italiano IRCCS, Milano, Italy Several recent reports suggest that osteonecrosis of the jaw (ONJ) can be a severe side effect of bisphosphonates (BPs) in adults. Intravenous zoledronate and pamidronate, and oral alendronate and risedronate have been involved. Special risk factors are cancer, corticosteroids, duration of exposure to BPs, dental extraction or other dental surgery. The prevalence of ONJ is estimated at 1.5%. In almost 82% of cases, pain is the main symptom. The typical lesions are a non-healing extraction socket or an exposed jawbone, frequently requiring surgery to remove the involved bone. BPs are now increasingly used also in children and adolescents, especially by intravenous administration. No data on the occurrence of ONJ are available for young patients treated with BPs. The aim of the present study was to verify whether any signs of ONJ were present in 38 children/adolescents (17 F, 21 M; age 4–22 years) treated with long-term BPs for osteogenesis imperfecta (11), fibrous dysplasia (1), secondary osteoporosis with recurrent fractures (26). In the last group, 20 patients were on long-term corticosteroid therapy. Of these patients, 18 had received i.v. cycles of pamidronate for 3 to 6 years and 20 had taken oral alendronate for 2.5 to 4 years. Some of the patients had dental problems (dentinogenesis imperfecta in OI; misalignment). During the follow-up, 4 patients had dental extraction, 15 caries repair, 5 misalignment correction and 7 older patients dental prophylaxis. All the patients were completely asymptomatic regarding ONJ: no pain, mucosal swelling, altered sensation in the area, erythema, ulcerations were reported by patients or referred by parents. In the last 2 years, all had periodical examination of the oral cavity, according to a specific protocol, to search for any bone expositions in the most commonly affected areas (posterior and lingual area of the mandibula). 15 patients had also dental panoramic radiographs. No ONJ lesions were found. The number of cases is too small to draw any conclusion, but this preliminary study seems to indicate that young patients on BPs, even with predisposing factors (dental disease, dental invasive procedures, long-term BPs, steroids), are not a specially high-risk group for ONJ. However, we would recommend good oral hygiene and regular oral cavity evaluation in all the children and adolescents treated with BPs. doi:10.1016/j.bone.2007.04.080
Fore-arm speed of sound in cystic fibrosis patients: correlation with bone mineral density and cortical wall thickness assessed using pQCT O. Louis 1, K. Toye 2, S. Van Biervliet 3, I. Gies 4, S. Goemare 2, J. De Schepper 4 1 Radiology, AZ-VUB, Brussels, Belgium