Congenital Metabolic Bone Disorders as a Cause of Bone Fragility.

Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.

Utility of 18F-AlF-NOTA-Octreotide PET/CT in the Localization of Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder, usually caused by benign mesenchymal tumors that produce high levels of fibroblast growth factor 23. The only curative therapy is resection of the causative tumors. OBJECTIVE: This research was conducted to evaluate the efficacy of 18F-AlF-NOTA-octreotide (18F-OC) positron emission tomography/computed tomography (PET/CT) in detecting TIO and its impact on patient management. METHODS: Retrospective analysis was conducted of 17 patients with hypophosphatemic osteomalacia suspected to be TIO. A  18F-OC PET/CT study was performed in all 17 patients to localize the tumor and 68Ga-DOTATATE PET/CT was performed in 4 out of 17 patients; both studies were performed within 1 week of each other. Both studies were interpreted blindly without the knowledge of other imaging findings. The image findings were compared with the results of histopathological examinations and clinical follow-ups. RESULTS: The 18F-OC PET/CT scans were positive in 14 patients. Furthermore, 4 of 14 patients were scanned with both 18F-OC and 68Ga-DOTATATE PET/CT. Both studies were able to localize the tumor in all 4 patients. In total, 14 patients had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in these patients, whose symptoms diminished promptly. Serum phosphate levels normalized, confirming the diagnosis of TIO. 18F-OC PET/CT sensitivity, specificity, and accuracy were 87.5%, 100%, and 88.2% respectively. 18F-OC PET/CT findings affected patient management in 88.2% of cases. CONCLUSION: 18F-OC PET/CT scan is useful in the detection of tumors causing TIO. Further studies with larger patient populations are needed to validate the result.

Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation.

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus (R = 0.48, P < .05). Age at diagnosis significantly correlated with time to resolution (R = 0.51, P = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation.

A Combined Ultrasonic Backscatter Parameter for Bone Status Evaluation in Neonates.

Metabolic bone disease (MBD) is one of the major complications of prematurity. Ultrasonic backscatter technique has the potential to be a portable and noninvasive method for early diagnosis of MBD. This study firstly applied CAS to neonates, which was defined as a linear combination of the apparent integrated backscatter coefficient (AIB) and spectral centroid shift (SCS). The objective was to evaluate the feasibility of ultrasonic backscatter technique for assessing neonatal bone health using AIB, SCS, and CAS. Ultrasonic backscatter measurements at 3.5 MHz, 5.0 MHz, and 7.5 MHz were performed on a total of 505 newborns within 48 hours after birth. The values of backscatter parameters were calculated and compared among gestational age groups. Correlations between backscatter parameters, gestational age, anthropometric indices, and biochemical markers were analyzed. The optimal predicting models for CAS were determined. The results showed term infants had lower SCS and higher AIB and CAS than preterm infants. Gestational age and anthropometric indices were negatively correlated with SCS (|r| = 0.45 - 0.57, P < 0.001), and positively correlated with AIB (|r| = 0.36 - 0.60, P < 0.001) and CAS (|r| = 0.56 - 0.69, P < 0.001). Biochemical markers yielded weak or nonsignificant correlations with backscatter parameters. CAS had relatively stronger correlations with the neonatal variables than AIB and SCS. At 3.5 MHz and 5.0 MHz, only gestational age (P < 0.001) independently contributed to the measurements of CAS, and could explain up to 40.5% - 44.3% of CAS variation. At 7.5 MHz, the combination of gestational age (P < 0.001), head circumference (P = 0.002), and serum calcium (P = 0.037) explained up to 40.3% of CAS variation. This study suggested ultrasonic backscatter technique was feasible to evaluate neonatal bone status. CAS was a promising parameter to provide more information about bone health than AIB or SCS alone.

FGF23-Related Hypophosphataemic Bone Disease.

Metabolic skeletal dysplasias comprise an extensive group of diseases capable of causing changes, usually progressive, in the bone and are due to hereditary disorders in many cases. The diagnosis and treatment of these diseases are not without difficulty, both because of their rarity and their possible confusion with more common diseases. A paradigmatic case of these metabolic skeletal dysplasias is X-linked hypophosphataemic rickets, which causes phosphaturia, a condition that alters the phosphate-calcium metabolism balance consequently causing, among other conditions, skeletal deformities and short stature. The genetic advances in recent years allow a much more accurate diagnosis of this disease when suspected, making differential diagnosis easier with similar entities but whose real causes are different. A better understanding of the phosphate-calcium metabolism allows us to replace the symptomatic treatment currently available with one that involves rebalancing the excess of fibroblast growth factor 23 (FGF23) by using monoclonal antibodies. In November 2018, a symposium sponsored by Kyowa Kirin Pharmaceuticals took place in Madrid, in which national and international experts addressed several aspects of these rare kidney diseases. Some topics addressed were the present and future genetic diagnosis, the use of multi-gene panels in renal or skeletal diseases, the role of animal models to better understand underlying skeletal changes, and the role of conventional radiology and surgery in the diagnosis and final treatment of bone deformities; all these without forgetting the important role of FGF23 and Klotho imbalances that result in the genetic change causing this disease. The optimization and limitations of conventional treatments currently available was also a topic addressed extensively, as well as the implications that new treatments against FGF23 could have in the future. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.

Phenotypic presentations of Hajdu-Cheney syndrome according to age - 5 distinct clinical presentations.

We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed. The age of the patients differs widely from ten to 57 years, allowing a natural history description of the phenotype associated with this ultra-rare condition. The evolution of the condition is most apparent in the incremental bone loss leading to osteoporosis and the acro-osteolysis, both of which contribute significantly to disease burden.

Chest Deformity and Disability due to Tenofovir-Induced Hypophosphatemic Osteomalacia: Case Report and Call for Improved Global Access to Laboratory Testing.

Millions of people worldwide take tenofovir disoproxil fumarate (TDF) for the treatment of human immunodeficiency virus (HIV) and/or hepatitis B infection. Although generally safe and well tolerated, clinicians need to be aware that TDF can cause proximal renal tubular dysfunction and loss of bone mineral density, especially in patients with concomitant renal disease or other risk factors. We present the case of a patient with chronic HIV infection and urethral stricture who developed TDF-related proximal renal tubular dysfunction with hypophosphatemia and osteomalacia, presenting with bone pains, skeletal deformity, and disability. We review risk factors for TDF-related renal tubular toxicity and recommendations for monitoring creatinine, phosphate, alkaline phosphatase, and urinalysis.

Serial serum alkaline phosphatase as an early biomarker for osteopenia of prematurity.

Metabolic bone disease of prematurity is a condition characterized by reduction in bone mineral content (osteopenia). It is a problem faced by very low birth weight (VLBW) infants because of lack of fetal mineralization during the last trimester. Our aim was to assess serum alkaline phosphatase (ALP) level as an early biomarker for osteopenia in premature infants and to estimate an optimal cutoff value of serum ALP at which osteopenia is detected radiologically in premature newborns.This prospective study was conducted on a cohort of 120 newborn infants of both sex of ≤34 weeks' gestational age and <1500 g birth weight. Two blood samples, from each infant on at least 2 consecutive weeks, were reported for calcium, phosphorus, and ALP. Evidence of osteopenia was evaluated radiologically by performing wrist/knee x-ray.Sixteen infants (13.3%) had evidence of osteopenia in x-ray, whereas 104 infants (86.7%) were nonosteopenic and all the osteopenic infants were <1000-g birth weight. Birth weight and gestational age were significantly inversely related to serum ALP levels. Both samples showed statistically significantly higher mean ALP level in osteopenic than nonosteopenics (P < 0.001, and P < 0.001 respectively). There was no constant value of serum ALP related to radiologic evidence of osteopenia. However, the optimal cutoff value of serum ALP at which osteopenia is detected is 500 IU/L with 100% sensitivity and 80.77% specificity.High levels of ALP can be considered a reliable biomarker to predict the status of bone mineralization and the need for radiological evaluation in premature infants particularly those <1000-g birth weight and <32 weeks' gestation.

Risk of selected structural abnormalities in infants after increased nuchal translucency measurement.

OBJECTIVE: We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants. STUDY DESIGN: Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL). RESULTS: When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4). CONCLUSION: Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.

Metabolic bone disease of prematurity: report of four cases.

Osteopenia of prematurity has become a common problem recently because of improved survival rates of infants with very low birth weight (VLBW). The incidence of neonatal osteopenia is inversely correlated with gestational age and birth weight. Herein, we present four cases of preterm osteopenia that were referred to the pediatric endocrinology outpatient clinic with diverse clinical and laboratory findings and we discuss the clinical course of these infants with regard to bone disease after discharge from the neonatal intensive care unit (NICU). This report highlights the importance of enteral calcium, phosphorus and vitamin D support at adequate doses following discharge from NICU for preterm infants with VLBW who are at risk of metabolic bone disease.

Hypophosphatemic osteomalacia due to drug-induced Fanconi's syndrome associated with adefovir dipivoxil treatment for hepatitis B.

We herein present the case of a 58-year-old Japanese man with Fanconi's syndrome with a 13-month history of bone pain in his ribs, hips, knees and ankles. He had been receiving low-dose adefovir dipivoxil (ADV) for the treatment of lamivudine-resistant chronic hepatitis B virus infection for eight years and subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. Magnetic resonance imaging showed multiple insufficiency fractures in the ribs, ileum, tibia and calcaneus. Whole-body bone scintigraphy demonstrated increased uptake in those areas. Following dose reduction of ADV and the administration of treatment with calcitriol and phosphates, the patient's serum phosphate level increased and his clinical symptoms improved. Physicians prescribing ADV should carefully monitor the renal function and serum phosphate level.

Does transient hypothyroxinemia influence metabolic bone disease of prematurity?

OBJECTIVE: To investigate the relationship between Metabolic Bone Disease (MBD) and Transient Hypothyroxinemia of Prematurity (THOP). METHOD: One hundred twenty-four infants, born in Marmara University Hospital with a gestational age ≤34 weeks, were enrolled. Clinical features were recorded. Serum TSH, free T4, total T4, calcium, phosphorus and total Alkaline Phosphatase (ALP) levels were determined in the first and third postnatal weeks. MBD was defined as a phosphorus level <4.5 mg/dl and/or ALP >900 IU/l. THOP was defined as a serum free and/or total thyroxine level lower than -1 SD for gestational age at the 7th postnatal day. RESULT: THOP was diagnosed in nineteen (15.3%) patients. MBD was diagnosed in 52 (41.9%) at the 3rd month. Low birth weight, low gestational age and prolonged parenteral nutrition were associated with MBD. Multivariate analysis documented a significant relationship solely between MBD and gestational age. CONCLUSION: The risk of MBD does not increase significantly in babies with THOP.

[Adefovir dipivoxil-induced Fanconi syndrome and hypophosphatemic osteomalacia associated with muscular weakness in a patient with chronic hepatitis B].

Adefovir dipivoxil is commonly used for treatment of chronic hepatitis B. The renal toxicity of adefovir dipivoxil is dose- and time-related, occurring often in patients with a daily dose over 30 mg and those with impaired renal function. We report a case of chronic hepatitis B with a history of taking adefovir dipivoxil at 10 mg/day for 4 years. The patient complained of lumbosacral and joint pain and had the diagnosis of ankylosing spondylitis (AS) or spondyloarthropathy in several hospitals before admission in our hospital. A diagnosis of acquired Fanconi syndrome and hypophosphatemia osteomalacia associated with progressive muscular weakness was made eventually. We reviewed the literature and found reports of only fewer than 10 similar cases. Clinical attention should be given to kidney damage induced by adefovir dipivoxil.

Bone quantitative ultrasound in congenital and acquired childhood multiple pituitary failure.

The aim of the present study is to investigate bone status by phalangeal quantitative ultrasound (QUS) in a cohort of hypopituitaric pediatric subjects, and to relate measurement outcome to their clinical, laboratory, and therapeutical features. Forty-three hypopituitaric children were submitted to bone measurement by QUS with DBM sonic bone profiler 1200 (IGEA, Carpi, Modena, Italy). This method measures bone transmission time (BTT) and amplitude-dependent speed of sound (AD-SoS) of an ultrasound beam crossing the first four phalanges of the hand and provides respective standard deviation scores (SDS). These two parameters provide information on bone mineral density and structure. Clinical, laboratory and therapeutical features were considered to look for correlations. Overall BTT and AD-SoS SDS were significantly reduced (-0.87 +/- 1.52, p = 0.001, and -0.97 +/- 1.56, p = 0.001) as well as respective height- or bone age-corrected SDS. Bone condition proved significantly worse in subjects with higher number of hormonal deficiencies (p = 0.001 for both parameters) and in those with acquired hypopituitarism (p = 0.020 for BTT and p = 0.010 for AD-SoS) than in those with congenital forms. In participants under growth hormone (GH) treatment, regression analysis revealed that QUS measurement outcome was significantly associated with age at GH therapy start (p = 0.001), time interval before therapy initiation (p = 0.011), treatment duration (p = 0.007) and administered dosage (p = 0.036). Our data show that childhood hypopituitarism is associated with bone morbidity, detectable at QUS measurement independently of potential confounders as stature and bone age. Skeletal impairment is related to acquired hypopituitarism, number of hormonal deficiencies and duration of disease before replacement therapies, whereas GH treatment duration and doses are associated with a better skeletal condition. Phalangeal QUS measurements of BTT and AD-SoS promise as a reliable method for obtaining quantitative measurements of bone disease in individuals with hypopituitarism but more studies are needed for verification.

Neonatal brain imaging and the identification of metabolic acidemia and hypoxic-ischemic encephalopathy.

OBJECTIVE: To determine the precision with which intrapartum metabolic acidemia and hypoxic-ischemic encephalopathy (HIE) in term and near-term infants can be identified by neonatal brain imaging. STUDY DESIGN: This is a case-control study whose inclusion criteria were neonates born at > or =34 weeks gestation with a cord gas at delivery, suspected neurological abnormalities, and computed tomography (CT) or magnetic resonance (MR) imaging of the brain. Neonates with chromosomal and major congenital malformations were excluded. Brain imaging for neonates with and without metabolic acidemia (pH < 7.0 and base deficit > 12 mM) at birth and HIE were retrospectively reviewed by a neuroradiologist blinded to their clinical course and compared. RESULTS: There were 54 neonates admitted to the NICU at a single university hospital between 1992 and 2006 that met these inclusion criteria of which 27 had metabolic acidemia at birth. There were 16 diagnosed clinically as having HIE at the time of neonatal discharge, 13 from the acidemic group and 3 from the nonacidemic group. Radiological signs of basal ganglia injury were significantly more common in neonates with metabolic acidemia (29.6%, 3.7%, p = 0.02) and HIE (37.5%, 7.9%, p = 0.01). Logistic regression corrected for gestational age showed that radiological signs of basal ganglia injury could identify the presence of HIE with area under the ROC curve of 0.71, sensitivity 37.5%, specificity 92.1%, positive predictive value 66.7%, and negative predictive value of 77.8%. CONCLUSION: Radiological signs of basal ganglia injury on early neonatal imaging are associated with metabolic acidemia and HIE, but is not precise enough to serve as a gold standard in the identification of these conditions.

Osteopenia of prematurity: a national survey and review of practice.

UNLABELLED: Premature infants are at significant risk of reduced bone mineral content (BMC) and subsequent osteopenia. There are currently no standard practices regarding screening, investigation or treatment of this condition. We present a case report and findings of a national survey of 36 level 2 and 3 neonatal units (72% response rate). The findings showed widely disparate practice regarding screening, prevention and treatment. We summarize the tests currently available for osteopenia and suggest guidelines for management of the at risk group. CONCLUSION: Our survey confirms inconsistent practices regarding management of infants at risk of osteopenia of prematurity. Investigations and treatments available are summarized together with a guideline for management of this susceptible group of infants.

Bone disease in preterm.

The survival rate of premature infants has significantly increased during the last few decades. As a consequence, new disorders such as osteopenia of prematurity have been emerging. We report 6 month evolution from diagnosis to recovery of a patient with metabolic bone disease of prematurity who showed a remarkable improvement on therapy with phosphate, calcium and vitamin D.

Increments in whole body bone mineral content associated with weight and length in pre-term and full-term infants during the first 6 months of life.

BACKGROUND: The objective of the present study was to assess bone mineral content (BMC) of the whole skeleton in pre-term and full-term healthy infants and the factors influencing BMC, such as bone area, birth weight, birth length, current weight, current length, gender, and gestational age. METHODS: Forty-eight healthy full-term infants and 34 healthy premature infants fed predominantly with intact human milk were studied. BMC was measured monthly with dual energy X-ray absorptiometry (DEXA). At the same time, length and weight were measured and registered. Pre-term infants were studied at 60-day intervals. RESULTS: For both full-term and pre-term infants, BMC increased during the first months of life. However, the values of pre-term infants never reached the values of full-term infants, even after correcting for age and weight. For both full-term and pre-term infants, BMC was significantly correlated at the second month with birth weight (r = 0.901), birth length (r = 0.860), gestational age (r = 0.803), bone area (r = 0.960), current weight (r = 0.920), and current length (r = 0.840, p <0.001 for all correlation coefficients). Multivariate analysis revealed that bone area was the most important factor in predicting BMC. CONCLUSIONS: Pre-term children have lower BMC than full-term children. The main factor explaining this apparent osteopenia is bone area. Pre-term children have a higher daily mineralization rate than full-term children, but this catch-up mineralization is not enough to reach BMC levels seen in full-term children.