Pathological mandibular fracture complicated by osteonecrosis in an adult patient with pycnodysostosis: clinical report and review of the literature.

Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent nose, obtuse mandibular angle, micrognathia). Dental abnormalities (delayed eruption of teeth, hypodontia, malocclusion, dental crowding, persistence of deciduous teeth, enamel hypoplasia, and increased caries) are also frequent; due to bone metabolism alteration, the patients have an increased risk for jaw osteomyelitis, especially after tooth extraction or mandible fracture. Other complications are obstructive sleep apnea, endocrine alterations and cytopenia. Pycnodysostosis is caused by biallelic loss of function variants in CTSK gene, coding the lysosomal protease cathepsin K. CTSK is involved in the degradation of bone matrix proteins, such as type I and type II collagen. In pycnodysostosis, this degradation is decreased, leading to increased bone density and bone fragility with pathological fractures and poor healing. We present a clinical report of a female adult patient with typical pycnodysostosis phenotype. At the age of 52 years, she had a pathological spontaneous fracture of the right mandible complicated by osteonecrosis, treated with load bearing osteosynthesis. The direct sequencing of CTSK gene revealed the presence of the pathogenic homozygous variant c.746T>A, (p.Ile249Asn), that confirmed the diagnosis of pycnodysostosis. We also review the literature case series published to date, that suggest to always consider the diagnosis of pycnodysostosis in case of osteosclerosis, even in the absence of brachydactyly or short stature. This report details the natural history of the disease in this patient, from childhood to adulthood, and highlights the importance of a quality of life assessment. In addition, we describe a case of mandibular osteonecrosis and spontaneous fracture in pycnodysostosis, drawing attention on the maxillofacial complications in these patients and on the importance of a personalized follow-up.

No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization.

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.

Clinical and Molecular Analysis of Pathologic Fracture-associated Osteosarcoma: MicroRNA profile Is Different and Correlates with Prognosis.

BACKGROUND: MicroRNAs are small, noncoding RNAs that regulate the expression of posttranslational genes. The presence of some specific microRNAs has been associated with increased risk of both local recurrence and metastasis and worse survival in patients with osteosarcoma. Pathologic fractures in osteosarcoma are considered to be more the manifestation of a neoplasm with a more aggressive biological behavior than the cause itself of worse prognosis. However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior. QUESTIONS/PURPOSES: (1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures? METHODS: Between 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses. RESULTS: Several microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma. CONCLUSIONS: In patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy. LEVEL OF EVIDENCE LEVEL: III, prognostic study.

Non-ossifying fibroma with a pathologic fracture in a 12-year-old girl with tricho-rhino-phalangeal syndrome: a case report.

BACKGROUND: Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial and skeletal abnormalities, while non-ossifying fibroma (NOF) is a common benign bone tumour in children and adolescents. To date, no case of TRPS coexisting with NOF has been reported. This report presents a 12-year-old girl who had the characteristic features of tricho-rhino-phalangeal syndrome and non-ossifying fibroma with a fibula fracture. CASE PRESENTATION: A 12-year-old girl was admitted to the Department of Endocrinology and Diabetes for evaluation of brachydactyly and a right fibula fracture. Clinical examination revealed sparse scalp hair, a characteristic bulbous pear-shaped nose, and brachydactyly with significant shortening of the fourth metatarsal. Neither intellectual disability nor multiple exostoses were observed. Radiography of both hands showed brachydactyly and cone-shaped epiphyses of the middle phalanges of the digits of both hands with deviation of the phalangeal axis. Genetic analysis of TRPS1 identified a heterozygous germline sequence variant (p.Ala932Thr) in exon 6 in the girl and her father. Approximately 1 month before being admitted to our department, the girl experienced a minor fall and suffered a fracture of the proximal fibula in the right lower limb. The pathological cytological diagnosis of the osteolytic lesion was NOF. Ten months following the surgery, the lesion on the proximal fibula of the girl disappeared. CONCLUSIONS: In conclusion, the present study is the first to report a rare case of NOF with a pathologic fracture in the fibula of a girl with TRPS. The identification of a missense mutation, (p.Ala932Thr), in exon 6 of TRPS1 in this kindred further suggested that the patient had type I TRPS and indicated that mutations in this exon may be correlated with more pronounced features of the syndrome. Radiological techniques and genetic analysis played key roles in the definitive diagnosis.

Aneurysmal bone cysts and pathologic fracture associated with supernumerary ring chromosome 6 in two unrelated patients.

Small supernumerary ring chromosome 6 (sSRC[6]) is a rare chromosomal abnormality characterized by a broad clinical phenotype. The spectrum of this disorder can range from phenotypically normal to severe developmental delay and congenital anomalies. We describe two unrelated patients with small SRCs derived from chromosome 6 with a novel bone phenotype. Both patients presented with a complex bone disorder characterized by severe osteopenia, pathologic fractures, and cyst-like lesions within the bone. Imaging revealed decreased bone mineral density, mutiple multiloculated cysts and cortical thinning. Lesion pathology in both patients demonstrated a bland cyst wall with woven dysplastic appearing bone entrapped within it. In patient 1, array comparative genomic hybridization (CGH) detected a tandem duplication of region 6p12.3 to 6q12 per marker chromosome. Cytogenetic analysis further revealed a complex patient of mosaicism with some cell lines displaying either one or two copies of the marker indicative of both tetrasomy and hexasomy of this region. Patient 2 was mosaic for a sSRC that encompassed a 26.8 Mb gain from 6p21.2 to 6q12. We performed an in-depth clinical analysis of a phenotype not previously observed in sSRC(6) patients and discuss the potential influence of genes located within this region on the skeletal presentation observed.

Identification of potential target genes and related regulatory transcription factors in spontaneous hairline fracture induced by hypervitaminosis A.

BACKGROUND: The aim was to research the molecular changes of bone cells induced by excessive dose of vitamin A, and analyze molecular mechanism underlying spontaneous fracture. METHODS: The gene expression profile of GSE29859, including 4 cortical bone marrow samples with excessive doses of Vitamin A and 4 control cortical bone marrow samples, was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DGEs) between cortical bone marrow samples and control samples were screened out and pathway enrichment analysis was undertaken. Based on the MSigDB database, the potential regulatory transcription factors (TFs) were identified. RESULTS: A total of 373 DEGs including 342 up- and 31 down-regulated genes were identified. These DEGs were significantly enriched in pathways of protein processing in endoplasmic reticulum, ubiquitin mediated proteolysis and glycerophospholipid metabolism. Finally, the most significant regulatory TFs were obtained, including E2F Transcription Factor 1 (E2F1), GA Binding Protein Transcription Factor (GABP), Nuclear Factor, Erythroid 2-Like 2 (NRF2) and ELK1, Member of ETS Oncogene Family (ELK1). CONCLUSION: Key TFs including E2F1, GABP, NRF2 and ELK1 and their targets genes such as Ube2d3, Uba1, Phb2 and Tomm22 may play potential key roles in spontaneous fracture induced by hypervitaminosis A. The pathways of protein processing in endoplasmic reticulum, ubiquitin mediated proteolysis and glycerophospholipid metabolism may be key mechanisms involved in spontaneous fracture induced by hypervitaminosis A. Our findings will provide new insights for the target selection in clinical application to prevent spontaneous fracture induced by hypervitaminosis A.

Epidermal growth factor receptor mutations should be considered as a prognostic factor for survival of patients with pathological fractures or painful bone metastases from non-small cell lung cancer.

AIMS: This study aims to assess first, whether mutations in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (kRAS) genes are associated with overall survival (OS) in patients who present with symptomatic bone metastases from non-small cell lung cancer (NSCLC) and secondly, whether mutation status should be incorporated into prognostic models that are used when deciding on the appropriate palliative treatment for symptomatic bone metastases. PATIENTS AND METHODS: We studied 139 patients with NSCLC treated between 2007 and 2014 for symptomatic bone metastases and whose mutation status was known. The association between mutation status and overall survival was analysed and the results applied to a recently published prognostic model to determine whether including the mutation status would improve its discriminatory power. RESULTS: The median OS was 3.9 months (95% confidence interval (CI) 2.1 to 5.7). Patients with EGFR (15%) or kRAS mutations (34%) had a median OS of 17.3 months (95% CI 12.7 to 22.0) and 1.8 months (95% CI 1.0 to 2.7), respectively. Compared with EGFR-positive patients, EGFR-negative patients had a 2.5 times higher risk of death (95% CI 1.5 to 4.2). Incorporating EGFR mutation status in the prognostic model improved its discriminatory power. CONCLUSION: Survival prediction models for patients with symptomatic bone metastases are used to determine the most appropriate (surgical) treatment for painful or fractured lesions. This study shows that NSCLC should not be regarded as a single entity in such models. Cite this article: Bone Joint J 2017;99-B:516-21.

Sclerostin and Bone Aging: A Mini-Review.

Sclerostin, mainly produced by osteocytes, is now considered a major regulator of bone formation. Identified from patients with a low bone mass, sclerostin inhibits the Wnt pathway by binding to LRP5/6 and subsequently increases bone formation. Sclerostin may also play a role in the mediation of systemic and local factors such as calcitriol, PTH, glucocorticoids and tumor necrosis factor-alpha. Circulating sclerostin levels increase with age and with the decline of kidney function. However, they are surprisingly higher in patients with a high bone mineral density, suggesting that sclerostin may be a relevant marker of the pool of mature osteocytes. The anti-anabolic properties lead to the development of anti-sclerostin biotherapies that are under current evaluation. The results of these clinical trials will open new promising opportunities for the treatment of osteoporosis and bone fragility fractures.

Bone mass and mineralization in osteogenesis imperfecta.

The main clinical features of osteogenesis imperfecta (OI) are low bone mass and high bone fragility. While the decrease in bone mass is generally regarded as an indicator of disease severity, bone fragility appears as the hallmark of the disorder. Bone has a multiscale hierarchical structural organization and is optimized to resist to fractures. In OI, modifications at the molecular level affect the total mechanical integrity of the bone. A specific characteristic in OI is that the bone matrix is abnormally high mineralized independently of the underlying mutation or clinical severity. The increased matrix mineralization affects bone material quality, leading to increased stiffness and brittleness and making bone prone to fractures. The purpose of this review is to give further insights on bone matrix mineralization in OI and to discuss advantages and pitfalls of invasive and noninvasive imaging techniques.

A child with bone fractures and dysmorphic features: remember of pycnodysostosis and craniosynostosis.

Accidental bony injuries are common in children. Children may also present with bony injuries following non-accidental injuries. Pathological fractures, though extremely rare, are an important entity and constitute fractures that occur in abnormal bones, usually after minor trauma. Pycnodysostosis is a rare skeletal dysplasia characterised by a clinical phenotype that includes short stature, skull deformities, osteosclerosis, acroosteolysis and bone fragility. Often the disease is diagnosed at an early age as a result of the investigation of short stature. However, the diagnosis is sometimes delayed and must be considered in any child with a history of recurrent or multiple bone fractures and dysmorphic features. The purpose of this report is to describe the clinical, radiological and genetic issues of a 9-year-old girl with a long history of multiple bone fractures. She had been subjected to safeguarding investigations previously and was identified to have dysmorphic features diagnosed as pycnodysostosis associated with craniosynostosis.

Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity.

Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 (Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia-like phenotype of newborn Runx2(+/-) mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.

Pathologic lower extremity fractures in children with Alagille syndrome.

OBJECTIVES: : In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, 1 of the leading inherited causes of pediatric cholestatic liver disease. MATERIALS AND METHODS: : Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance of the Children's Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to 1 question, and details characterizing each patient's medical, growth, and fracture history were obtained through chart review and telephone contact. RESULTS: : Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures per 10,000 person-years (95% confidence interval 206.5, 698.0) and 127.6 femur fractures per 10,000 person-years (95% confidence interval 42.4, 297.7). There were no differences in sex, age distribution, or organ system involvement between the fracture and no-fracture groups. CONCLUSIONS: : Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. Although this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and explore factors contributing to bone fragility in these children.

Polymorphisms of the WNT10B gene, bone mineral density, and fractures in postmenopausal women.

Wnt ligands are important regulators of skeletal homeostasis. Wnt10B tends to stimulate the differentiation of common mesenchymal precursors toward the osteoblastic lineage, while inhibiting adipocytic differentiation. Hence, we decided to explore the association of WNT10B allelic variants with bone mineral density and osteoporotic fractures. A set of tag SNPs capturing most common variations of the WNT10B gene was genotyped in 1438 Caucasian postmenopausal women, including 146 with vertebral fractures and 432 with hip fractures. We found no association between single SNPs and spine or hip bone mineral density (BMD). In the multilocus analysis, some haplotypes showed a slight association with spine BMD (P = 0.03), but it was not significant after multiple-test correction. There was no association between genotype and vertebral or hip fractures. Transcripts of WNT10B and other Wnt ligands were detected in human bone samples by real-time PCR. However, there was no relationship between genotype and RNA abundance. Thus, WNT10B is expressed in the bone microenvironment and may be an important regulator of osteoblastogenesis, but we have not found evidence for a robust association of common WNT10B gene allelic variants with either BMD or fractures in postmenopausal women.

Osteopetrosis.

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.

Is there a role for bone morphogenetic proteins in osteoporotic fractures?

The central role of bone morphogenetic proteins (BMPs) in the remodelling process of the human skeleton has been identified in numerous experimental and clinical studies. BMPs appear to be key agents in the osteoblastic differentiation of mesenchymal stem cells, and more recent evidence implicates them with the cells of the osteoclastic lineage. BMP-2, BMP-4, BMP-6 and BMP-7 have been studied in the context of osteoporosis and have been associated with its pathophysiological pathways. The theoretical advantages of local or systemic treatment of osteoporotic fractures with BMPs include the potential of inducing a rapid increase in bone strength locally at the fractured area and systemically in the entire skeleton, as well as accelerating the bone-healing period. Animal models of osteoporotic fractures suggested that the induction of new bone by local or systemic use of BMP-7 should be investigated as potential bone augmentation therapy to improve bone quality in symptomatic spinal osteoporosis. As our knowledge expands, new innovations may provide clinicians with advanced biologically-based therapies for the successful treatment of osteoporotic fractures.

Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation.

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. OBJECTIVES: The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date. DESIGN AND SETTING: This study was primarily a retrospective cross-sectional analysis of individuals with a ClCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied. PATIENTS AND INTERVENTIONS: We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistry), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a ClCN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/or self-reported responses on a questionnaire that was completed by all subjects. MAIN OUTCOME MEASURES: The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype. RESULTS: Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P < 0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) and osteomyelitis (16 vs. 0.9%; P < 0.0001). Severe fractures (defined as > or =10 fractures of any type and/or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time. CONCLUSIONS: ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.

No associations between OPG gene polymorphisms or serum levels and measures of osteoporosis in elderly Australian women.

Bone mass is the single most important risk factor for osteoporotic fractures in the elderly and is mainly influenced by genetic factors accounting for 40-75% of the inter-individual variation. Critical for the bone remodeling process is the balance between the newly discovered members of the tumor necrosis factor ligand and receptor superfamilies, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand, which mediate the effects of many upstream regulators of bone metabolism. In the present study, we evaluated the impact of sequence variations in the OPG gene on bone mass, bone-related biochemistry including serum OPG and fracture frequency in elderly Australian women. A total of 1101 women were genotyped for 3 different single nucleotide polymorphisms (SNP) within the OPG gene (G1181C, T950C and A163G). The effects of these SNPs and serum OPG on calcaneal quantitative ultrasound measurements, osteodensitometry of the hip and bone-related biochemistry were examined. We found no significant relationship between sequence variations in the OPG gene or serum OPG and bone mass, bone-related biochemistry or fracture frequency. Our findings confirm some recent publications investigating the same SNPs but diverge from others, indicating that generalization of the relationships found in this type of study must be done with caution and signify the importance of determining associations between polymorphisms and osteoporosis in different ethnic groups.

Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis.

CONTEXT: Osteoporosis has a significant genetic component. The aromatase-dependent conversion of androgenic precursors is the main source of estrogens in postmenopausal women. OBJECTIVE: The objective of the investigation was to study the relationship of a set of single nucleotide polymorphisms (SNPs) of the aromatase gene with osteoporosis and determine their functional influence on gene transcription. DESIGN, PARTICIPANTS, AND METHODS: This was a case-control study including 135 women with vertebral fractures due to postmenopausal osteoporosis and 312 controls. Alleles at four SNPs situated between exons I.2 and 3 were determined by Taqman assays. Total aromatase RNA and differential allelic-specific expression were studied by RT-real time PCR in adipose tissue samples taken from 50 individuals. RESULTS: The SNPs studied were in strong linkage disequilibrium. A common haplotype, present in about half of the population, was identified as being associated with an increased risk of fractures (odds ratio 1.8, 95% confidence interval 1.2-2.8, P = 0.006). There was evidence of differential allelic expression. In heterozygous individuals, transcripts bearing T alleles at rs700518 SNP (which were included in the risk haplotype) were less abundant than those with the alternative C alleles (P < 0.001). Total aromatase expression was four times lower in fat samples from individuals who were homozygotes for the unfavorable alleles than in the opposite homozygotes (P = 0.007). CONCLUSIONS: A common haplotype of aromatase associated with gene expression is also associated with the risk of osteoporotic vertebral fractures in postmenopausal women. These data are in line with the hypothesis that the aromatase-dependent synthesis of estrogens plays an important role in bone homeostasis in postmenopausal women.

Genetics of osteoporosis.

Osteoporosis is a systemic skeletal disease comprising rarefaction of bone structure and loss of bone mass, finally leading to increased fracture risk. As a part of its multifactorial aetiology, twin and family studies have demonstrated an important genetic component of osteoporosis regarding many parameters of bone properties e. g. bone mineral density, with a heredity of 60-80 %. Whole genome screens, linkage analysis and candidate gene research have contributed to our current knowledge about genetic loci in osteoporosis. Genotyping of collagen alpha I, lactose intolerance or estrogen receptor alpha alleles are under investigation for their importance in individual and epidemiological practice, e. g. the European Union "GENOMOS" project with more than 50,000 subjects. In future, improved genotyping methods and design strategies as well as large scale epidemiological studies in the general population will bring the genetics of complex diseases such as osteoporosis to a point of success comparable to where mendelian genetics now firmly resides. Given the potential of these new techniques, a paradigm shift may occur both in diagnosis and prevention as well as in individualized treatment aspects of osteoporosis.