Increased serum interleukin 6 in experimental periapical periodontitis associated with metabolic bone disease

The incidence of metabolic bone disease (MBD) of prematurity is as high as 23% of very low-birthweight infants and as high as 55% of extremely low-birthweight infants, but a lack of consensus in diagnostic criteria makes the actual incidence difficult to assess. Understanding the pathogenesis and biomarkers to detect MBD may help clinicians identify patients at risk for MBD and provide appropriate nutritional management to these patients.After completing this article, readers should be able to: Explain the physiology of bone formation and mineral utilization of the fetus and newborn.Describe the risk factors for and diagnostic tools to detect metabolic bone disease.List the mineral requirements and explain the management options for infants with metabolic bone disease.Metabolic bone disease (MBD) of prematurity is defined as a reduction in bone mineralization below expected values at a specific gestational age and is characterized by specific biochemical and radiographic findings. The incidence of MBD is as high as 23% of very low-birthweight (VLBW) infants and as high as 55% of extremely low-birthweight (ELBW) infants. It is usually detected between 10 and 16 weeks’ postnatal age (1) but a lack of consensus in diagnostic criteria makes the actual incidence difficult to assess. While our understanding of MBD and nutrition of prematurity infants has improved significantly in recent decades, MBD continues to be a comorbidity in premature infants that is challenging to detect and treat, potentially leading to long-term poor growth and pathologic fractures.Skeletal morphogenesis or the process by which the skeletal framework develops in utero, begins in the sixth week of gestation. (2) The fetal skeleton develops in 3 distinct pathways. The craniofacial skeleton arises from cranial neural crest cells, the axial skeleton arises from paraxial mesoderm cells, and the limb skeleton arises from lateral plate mesoderm cells. The basic mechanism by which the skeleton forms is firstly through migration of these 3 cell types into their correct spatial location to form the anatomic framework for the fetal skeleton. This is then followed by proliferation of these cell types into areas of high cellular density, which serves to further delineate the fetal skeletal anatomy. Finally, the cells either differentiate into chondrocytes, which form a cartilaginous skeletal structure that eventually is replaced by bone (endochondral bone formation) or they differentiate into osteoblasts, which form the osteoid bone matrix directly (intramembranous bone formation). (3)Intramembranous bone formation occurs for most of the craniofacial region and the clavicles. Osteoblasts, which differentiate from cranial neural crest cells, begin to form and secrete osteoid, the unmineralized protein mixture that forms the organic bone matrix. Osteoclasts, which differentiate from a hematopoietic stem cell progenitor, also begin to invade the region and have the function of bone resorption. Calcium circulating in utero binds to osteoid, which hardens the matrix. As the secreted osteoid surrounds osteoblasts, the osteoblasts then may further differentiate into osteocytes, which remain present in the mature skeleton. These osteocytes have signaling and mechanoreceptor functions to regulate osteoblast and osteoclast activity, as well as bone mineral metabolism.Endochondral bone formation forms the remainder of the axial and limb skeleton. At 8 weeks’ gestational age, the cartilaginous framework for the fetal skeleton is established. (4) Osteoblasts begin to form primary ossification centers and secrete osteoid, whereas osteoclasts work to resorb the chondrocytes that the osteoblasts replace. Calcium binding by the osteoid framework continues throughout gestation, but the majority of skeletal mineralization occurs in the third trimester. The process of linear bone growth then continues for years after birth.Parathyroid hormone (PTH) is an 84-amino acid polypeptide hormone that is central to the metabolism of calcium and exerts its effects on 2 organ systems, the bone and kidney. Changes in serum calcium ions are sensed by the calcium-sensing receptor of the parathyroid gland, which regulates gene transcription within the parathyroid cells. Increases in serum calcium decrease the production and secretion of PTH by parathyroid chief cells. (5)PTH breaks down bone by binding to PTH type 1 receptors on osteoblasts. PTH binding causes the osteoblasts to upregulate macrophage colony-stimulating factor and receptor activator of nuclear factor κ B ligand (RANKL) expression. Activation of RANKL in turn by RANK binding increases osteoclast formation. (6) This ultimately leads to bone resorption and the release of calcium into the bloodstream. PTH also increases calcium reabsorption in the distal tubules through the upregulation of a calcium ion transporter, TRPV5. In addition, PTH decreases phosphate reabsorption and upregulates the production of α1-hydroxylase, which converts vitamin D into its biologically active metabolite, 1,25-dihydroxy-vitamin D.1,25-dihydroxyvitamin D, or calcitriol, is the biologically active form of vitamin D. It is created by the conversion of vitamin D2 or vitamin D3 by α1-hydroxylase in the kidneys. Vitamin D2 is obtained enterally and vitamin D3 is obtained from sunlight exposure to the skin. Calcitriol increases gastrointestinal absorption of calcium by increasing epithelial calcium transport proteins such as TRPV6 and calbindin. (7)PTH-related peptide is produced by many tissues in the body including placental tissue, parathyroid tissue, skeletal tissue, and smooth muscle cells. It has many effects on the developing fetus, including increasing calcium transfer across the placenta and is involved in proper chondrocyte development and endochondral bone formation. (8)Calcitonin is a 32-amino acid polypeptide hormone produced and secreted from the thyroid gland as well as the placenta and upregulated in response to increases in serum calcium. It upregulates calcitriol production in the kidney and decreases osteoclast activity through calcitonin receptor activation. (9)To support the growing skeletal structure in the fetus, concentrations of calcium, magnesium, and phosphorus are maintained higher than maternal values by 1.2 to 2 mg/dL (0.3–0.5 mmol/L), 0.12 mg/dL (0.05 mmol/L), and 1.5 mg/dL (0.5 mmol/L), respectively. (10) Eighty percent of calcium accretion by the fetus occurs in the third trimester as this is when the majority of skeletal mineralization occurs. (11) A fetus in the third trimester takes in an average of 100 to 120 mg/kg per day of calcium and 50 to 65 mg/kg per day of phosphorus. (12) The main source of calcium to the fetus is active transport across the placenta. In addition, a small amount of body calcium lost through filtering by the fetal kidneys is excreted as amniotic fluid and ingested by the fetus, returning it to the fetal circulation via intestinal intake. The relative hypercalcemia of the fetus is maintained via low serum concentrations of fetal PTH and calcitriol, and high concentrations of fetal PTH-related peptide. Low calcitriol levels are maintained due to the low PTH levels, as well as high concentrations of placental 24-hydroxylase, which prevents the conversion of inactive vitamin D to calcitriol. (13) Calcitonin produced by the fetal thyroid and placenta is also increased in fetal circulation and aids in bone mineralization. (10)Immediately after birth, the umbilical cord is cut, which removes the neonate’s placental supply of calcium. As a result, intestinal intake of calcium becomes the neonate’s source of calcium and this remains in balance with skeletal calcium stores to maintain normal serum calcium homeostasis. Intestinal uptake of calcium occurs via active and passive transport. It is suggested that the majority of calcium intake is initially passive and concentration dependent. (10) As the gastrointestinal system matures, active transport becomes more important and is mediated by calbindins, which are vitamin D–dependent calcium-binding receptors present on enterocytes.Mineral accretion occurs across the placenta, therefore, prenatal risk factors include conditions that might impair nutrient delivery to the fetus. Uteroplacental insufficiency, preeclampsia, fetal growth restriction, and chorioamnionitis are associated with an increased risk of MBD. (14) Other risk factors may include maternal vitamin D deficiency and male sex (Table 1). (15)Prematurity is a major risk factor for MBD, as the majority of calcium accretion occurs during the third trimester. Conditions that affect nutrient intake postnatally also increase the risk of MBD, including feeding intolerance, bronchopulmonary dysplasia, and prolonged parenteral nutrition (Table 1). All of these have the potential to cause deficiencies in calcium, phosphorus, or vitamin D. (16) Medications that increase bone mineral excretion, including loop diuretics, glucocorticoids, caffeine, and sodium bicarbonate, also increase the risk for MBD. Sepsis, acidosis, renal disease, liver disease, and gastrointestinal disease such as necrotizing enterocolitis or abdominal wall defects have also been shown to contribute to MBD. (14) A reduction in bone formation may also occur due to a lack of mechanical stimulation from movement, (17) as is the case in neonates who require sedation or paralysis.There are no universal screening or diagnostic criteria for MBD; however, many biochemical and radiographical markers can aid in the detection and diagnosis of MBD.Serum calcium levels normally reach a nadir in both preterm and term neonates 24 to 30 hours after birth and then begin to rise due to an increase in PTH levels. (18) In the kidney, PTH increases calcium reabsorption and decreases phosphate reabsorption. It increases intestinal absorption of calcium and phosphate via the synthesis of calcitriol, and increases bone resorption to release calcium into the serum. Serum calcium levels can be misleading in the diagnosis of MBD, as infants may maintain normal serum calcium levels by decreasing calcium mineralization in bone. Moreover, calcium levels less than 8.5 mg/dL (2.13 mmol/L) suggest inadequate calcium intake. (19)If nutritional calcium intake is chronically insufficient, the biochemical representation of MBD can include hypophosphatemia due to the effects of PTH on the kidney. A serum phosphate level below 3.6 mg/dL (1.16 mmol/L), in exclusively breastfed newborns, confers a greater risk for MBD. (20)Tubular reabsorption of phosphate (TRP) can also be measured as follows: urinary phosphate/serum phosphate × serum creatinine/urinary creatinine. If serum phosphate is less than 5.5 mg/dL (1.78 mmol/L) and TRP is greater than 95%, this may suggest insufficient phosphorus intake. (21)Alkaline phosphatase is an enzyme present in many body tissues, including skeletal, liver, and intestine; the majority comes from skeletal tissue and represents bone metabolism. (22) Serum levels in the newborn continue to rise until 4 to 6 weeks of age, when they peak. Alkaline phosphatase levels then decrease around 8 to 10 weeks of age. Different levels of alkaline phosphatase have been shown to be associated with MBD in various neonatal populations. A level greater than 900 IU/L (15 μkat/L) in infants of less than 33 weeks’ gestational age, along with serum phosphate lower than 5.6 mg/dL (1.8 mmol/L), has shown sensitivity of 70% and specificity of 100% for MBD. (23) In ELBW infants (<30 weeks’ gestational age), a level greater than 500 IU/L (8.3 μkat/L) is associated with the development of MBD. (16)Levels of vitamin D are measured as 25-hydroxyvitamin D, its inactive form. Values less than 20 ng/mL (50 nmol/L) indicate a deficiency; values less than 30 ng/mL (75 nmol/L) are also useful in identifying neonates at risk of developing MBD. (19)As PTH is released in response to hypocalcemia and is a marker of bone resorption, elevated levels suggest the development of MBD. Levels higher than 100 pg/mL (100 ng/L) may be useful to identify neonates who are at risk of developing MBD. (24)A reduction of bone mineralization by 20% to 40% is needed before it becomes detectable on radiography, so radiographs are not reliable in early MBD when bone demineralization is not usually significant. (25) Pathologic fractures due to MBD also do not occur frequently in early MBD. A grading scale describing radiographic abnormalities has been developed, reflecting the gradual chondrocyte expansion and its failure to mineralize (26): Normal: No abnormalities noted, with normal bone density and a normal dense white line at the metaphysis.Grade 1: Loss of a dense white line at the metaphysis and thinning of the cortex.Grade 2: Changes seen in grade 1, along with fraying of the metaphysis, with splaying (metaphyseal widening) and cupping (metaphyseal concavity), that is, rachitic changes.Grade 3: Changes seen in grade 2, along with fractures.This diagnostic test is the gold standard to assess bone mineral density in neonates, including in preterm infants. The scan measures bone mineral density in grams of hydroxyapatite per centimeter squared and is directed at the neonate’s lumbar spine, forearm, or calcaneus. Technical aspects of performing this examination limit its usefulness in neonates. One study showed that a bone mineral density greater than 0.068 g/cm2 confers a lower risk of developing MBD in VLBW infants of less than 31 weeks’ gestational age. (27)This test uses ultrasonography to measure the speed of sound along the tibia to indirectly quantify bone mineral density in infants. (28) In comparison with term infants, preterm infants born between 24 and 28 weeks’ gestational age were shown to have lower quantitative ultrasonography parameters at corrected term age, indicating a reduction in bone mineralization related to prematurity. (29)The initial step is to identify infants who are most at risk for developing MBD, which include premature infants (VLBW or ELBW infants) and those with gastrointestinal disorders that lead to syndromes of malabsorption. Routine biochemical evaluation of MBD is recommended to start at 4 weeks of age and at minimum should include measurement of serum alkaline phosphatase and phosphorus levels. Serum calcium and vitamin D can also be measured at this time. Monitoring of biochemical markers should continue at least every 2 weeks thereafter. Monitoring can be discontinued if the patient is at low risk of developing MBD, is receiving full enteral feedings, has a stable level of alkaline phosphatase less than 500 to 600 IU/L (8.3–10 μkat/L), and a stable phosphorus level greater than 4 mg/dL (1.3 mmol/L). (30) Monitoring should continue every 2 weeks if these criteria are not met and managed appropriately.If alkaline phosphatase levels are greater than 800 IU/L (13.3 μkat/L), or if there is a clinical concern for fractures, radiographic monitoring of rachitic changes should be initiated.The primary treatment strategy for MBD is to optimize the neonate’s intake of calcium, phosphorus, and vitamin D. Other considerations include discontinuation of medications that promote bone demineralization, including loop diuretics and glucocorticoids.Guidelines for calcium and phosphorus requirements for the premature infant were released by the American Academy of Pediatrics in 2013. (30) To support proper skeletal development in the preterm infant and prevent MBD, adequate amounts of calcium, phosphorus, and vitamin D must be supplied in a manner that mimics the in utero accretion. In a healthy preterm infant, enteral calcium absorption is around 50% to 60% of intake and phosphorus absorption is around 80% to 90% of intake. (31) Unfortified human milk contains 25 mg/dL of calcium and is therefore insufficient for the mineral needs of the premature infant. Preterm formulas and human milk fortifiers designed for preterm infants have increased concentrations of calcium to meet this need.Recommended enteral requirements by the 2013 American Academy of Pediatrics report for VLBW infants are 150 to 220 mg/kg per day of calcium, 75 to 140 mg/kg per day of phosphorus, and 200 to 400 IU/day of vitamin D. If the neonate requires parenteral nutrition, the recommended parenteral requirements are 75 to 100 mg/kg per day of calcium and 50 to 80 mg/kg per day of phosphorus. (32) In parenteral nutrition, the ratio of calcium and phosphorus is optimally 1.7:1 (mg/mg) (32); infants may develop hypercalcemia or hypophosphatemia, in which the calcium-to-phosphorus ratio is too high. The recommended mineral intake for prevention and treatment of MBD of prematurity is summarized in Table 2.If an infant is meeting these daily requirements, but continues to have evidence of MBD, further mineral supplementation can be given in the form of elemental calcium and phosphorus; these can be given via both enteral and parenteral routes. The starting dose of elemental calcium is 20 mg/kg per day and can be increased to a maximum of 70 to 80 mg/kg per day; the starting dose of elemental phosphorus is 10 to 20 mg/kg per day and can be increased to 40 to 50 mg/kg per day. (30)While there is not much research into long-term outcomes of neonates affected by MBD, most premature infants do well after discharge with respect to bone mineralization. (30) Continued mineral supplementation in the form of transitional formula may be appropriate for infants who continue to have elevated alkaline phosphatase levels after discharge. Vitamin D supplementation should also be continued for infants to receive at least 400 IU/L daily.

Hypercalciuria and nephrocalcinosis in a patient receiving long-term parenteral nutrition: the effect of intravenous chlorothiazide.

Objective To explore the high-risk factors of metabolic bone disease(MBD)in premature infants by retrospective analysis of the clinical data so as to provide evidence for optimal clinical management. Methods Clinical data of premature infants with birth weight 500 IU/L and blood phosphorus <1.5 mmol/L were selected as MBD group and premature infants with birth weight <1 500 g were selected randomly as non-MBD group. General data, pulmonary surfactant, continuous positive airway pressure, mechanical ventilation, start time of enteral nutrition, parenteral nutrition (PN) time, breast feeding time and breast milk fortifier adding, drug usage, hospitalization time and complications were recorded and compared between the two groups. Results A total of 440 premature infants with birth weight <1 500 g were admitted to the hospital during the study period. 58[13.2%(58/440)] infants were enrolled in the MBD group, among which infants with birth weight <1 000 g accounting for 56.9%(33/58). High birth weight (OR=0.62, 95% CI: 0.389-0.990) was an independent protective factor of MBD in premature infants. The higher the birth weight, the lower the risk of MBD in premature infants. The longer duration of breast feeding time(OR= 2.191, 95% CI: 1.628-2.950), later initial time of enteral feeding(OR=2.695, 95% CI: 1.710-4.248), longer duration of PN(OR=6.205, 95% CI: 3.359-11.463) time, longer duration of respiratory supporting time(OR=1.046, 95% CI: 1.026-.067), longer hospital stay time(OR=1.703, 95% CI: 1.109-2.615) and small for gestational age(OR=2.965, 95% CI: 1.163-5.658) were independent risk factors of MBD in premature infants. The duration of PN was the most important independent risk factor of MBD in premature infants(OR=6.205, 95% CI: 3.359-11.463). Conclusion Multiple factors can lead to MBD of premature infants. The high birth weight is an independent protective factor of MBD and the duration of PN is the most important independent risk factor of MBD in premature infants. Key words: Premature infant; Metabolic bone disease; High risk factor

Although metabolic bone diseases are common, they may be difficult to diagnose on the basis of clinical and radiological findings. Understanding their diverse manifestations using different imaging studies allows early and specific diagnosis.Inthe early stages of the disease, bone scintigraphy shows generalized increased uptake. As the disease progresses, bone scintigraphy has well-recognized features, such as focal and generalized increased uptake in the long bones, axial skeleton and peri-articular areas. Generalized uptake of the skull, mandible and sternum are other patterns. Finally, focal uptake in the costochondral junctions, soft-tissue calcification and faint, or absent, kidney uptake are additional features. Knowledge of these different scintigraphic patterns helps obtain the highest diagnostic value. Important practical applications of bone scan in metabolic bone disease are the detection of focal conditions or focal complications of such generalized disease such as the detection of fractures in osteoporosis, pseudo-fractures in osteomalacia and the evaluation of Paget’s disease, particularly disease activity.

Background: Extremely low birth weight (ELBW, <1,000 g) infants have a high risk of metabolic bone disease (MBD). Because of the late appearance of radiological signs, diagnosis of MBD in ELBW infants might be delayed, and its prevalence underestimated in this group of patients. This study adopted serial screening of serum alkaline phosphatase (ALP) and phosphate (P) of ELBW infants to determine whether such screening is helpful for the early detection of MBD.Materials and Methods: We performed a retrospective study of preterm infants with a gestational age ≤ 31 weeks and birth weight <1,000 g. MBD was absent (ALP ≤500 IU/L), mild (ALP >500 IU/L, P ≥4.5 mg/dL), and severe (ALP >500 IU/L, P <4.5 mg/dL); MBD was divided into early MBD (≤4 weeks after birth) and late MBD (>4 weeks after birth) according to the time of onset.Results: A total of 142 ELBW infants were included, with a median gestational age of 28.1 (26.5–29.7) weeks and a median birth weight of 875 (818–950) g. Seventy-three cases of MBD were diagnosed, and the total prevalence was 51.4% (mild MBD, 10.6%; and severe MBD, 40.8%). Male sex, breastfeeding, and sepsis would increase the risk of severe MBD. Most MBD in ELBW infants occurred at 3–4 weeks after birth. Sixty-two percent (45/73) of infants were diagnosed as having early MBD, which are diagnosed earlier than late MBD [24 (21–26) vs. 39 (36–41), t = −7.161; P < 0.001]. Male sex [odds ratio (OR), 2.86; 95% confidence interval (CI), 1.07–7.64; P = 0.036], initial high ALP levels (OR, 1.02; 95% CI, 1.01–1.03; P < 0.001), and breastfeeding (OR, 5.97; 95% CI, 1.01–25.12; P = 0.049) are independent risk factors for the development of early MBD.Conclusion: The risk of MBD among ELBW infants is very high. Most cases occurred early and were severe. Male sex, initial high ALP levels, and breastfeeding are closely related to the increased risk of early MBD. Serial screening of serum ALP and P helps early detection of MBD; it is recommended to start biochemical screening for ELBW infants 2 weeks after birth and monitor their biochemical markers weekly.

Background/Aims The 2022 rheumatology curriculum requires trainees to achieve competence in the management of osteoporosis and a number of metabolic bone diseases by the end of their training. In addition, the recent 2022 NOGG guidance states that very high-risk osteoporosis patients should be considered for referral to specialist care. Hence there is a need to ensure high quality training in this area. We aimed to assess rheumatology trainees’ experience of osteoporosis and metabolic bone disease. Methods A Google form was designed, comprising questions relating to experience of and confidence in managing osteoporosis and other metabolic bone disease. A completion link was circulated to rheumatology trainees via regional trainee representatives. Reminders were sent at intervals during the survey period. Trainees completed the survey anonymously. Results 41 trainees responded. Training grade ranged from ST4-ST7, with 1 specialty doctor and 1 individual who had completed training. Six regions in England, plus Wales and Northern Ireland were represented. 23 trainees (56.1%) reported having observed at least one osteoporosis clinic, and 18 (43.9%) reported having participated in an osteoporosis clinic on a weekly basis for at least 12 weeks. Fewer trainees (11, 26.8%) had observed a specialist metabolic bone disease clinic, and 9 (22%) had participated in one. In terms of exposure to individual conditions, 31 trainees (75.6%) reported clinical experience of managing postmenopausal osteoporosis and 29 (70.7%) reported experience of managing Paget’s disease. Exposure to rarer metabolic bone diseases was much lower, with over half reporting no clinical experience of: osteomalacia; osteonecrosis; bone marrow oedema syndromes; hypophosphatasia; osteogenesis imperfecta; fibrous dysplasia; or FGF-23 mediated osteomalacia. 12 trainees (29.3%) had experience reporting DXA scans. Table 1 summarises trainees’ confidence levels across a number of areas. Overall, 9 (22%) rated their confidence in assessing and managing patients with osteoporosis and metabolic bone disease as equal to or higher than for patients with inflammatory arthritis. 22% said they were likely or very likely to consider sub-specialising in osteoporosis/metabolic bone disease. Conclusion Our survey has identified significant variations in training, particularly for rarer metabolic bone diseases. However, despite this, the sub-specialty appears to remain an attractive career option. Disclosure S.A. Hardcastle: None. M. Rutter: Other; M.R. is a Versus Arthritis Clinical Research Fellow and Chair of the BSR trainee committee. Z. Paskins: Consultancies; Unpaid consultancy for non promotional activity with UCB.

Analyzing skeletal remains gives researchers the ability to reconstruct an individual’s quality of life. Studying metabolic bone disease in skeletal remains is one way researchers are able to learn how a particular bone disease may have impacted the individual in their daily life. The purpose of this study is to analyze 3D printed skeletal remains and determine if any metabolic bone disease is present or visible. The skeletal remains were extracted from CT files and 3D printed on a ZPrinter. An osteological analysis was previously conducted to determine the age and sex of the individual. To determine if the skeletal remains have any metabolic diseases a macroscopic examination was completed on the available skeletal material. Any sign of bone abnormality will be noted and observed to determine what type of metabolic disease it may be present. Preliminary results suggest that the 3D printed remains may not be of high enough quality to determine if metabolic bone diseases are present.

Metabolic bone disease is an important complication among infants very-low-birth-weight (< 1500 g). In adults, osteoporosis has been shown to be associated with polymorphisms of vitamin D receptor, estrogen receptor, and collagen Ialpha1 receptor genes. The primary goal of the study was to investigate the possible association between metabolic bone disease and the allelic polymorphisms of these three genes. 104 infants very-low-birth-weight were enrolled to the study. Bone formation (serum alkaline phosphatase, osteocalcin) and bone resorption (urinary excretion of calcium and pyridinium crosslink) markers were determined and x-rays of the chest and wrist (together with the distal portions of associated long bones) were obtained. Thirty infants (28,8%) were diagnosed with metabolic bone disease based on high activity of bone formation, bone resorption markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA) n ] allelic variant of estrogen receptor gene and bone disease was observed. Infants with metabolic bone disease more often carried low number of repeats [(TA) n < 19] [odds ratio (OR): 5.82, 95% confidence interval (CI): 2.26-14.98]. Significantly higher number of repeats [(TA)n > 18] was found more frequently in the control group (OR: 0.20, 95% CI: 0.05-0.82). Furthermore significant interaction between vitamin D receptor and collagen Ialpha1 receptor genotypes ( p = 0.023) was observed. In a forward stepwise logistic regression model, bone disorder of preterms correlated with male gender ( p = 0.001), duration of hospitalization ( p = 0.007), homozygous allelic variants of high number of (TA) n repeats ( p = 0.025) and interaction between vitamin D receptor (Tt) and estrogen receptor (homozygous allelic variants of low number of repeats) genotype ( p = 0.037). The results suggest that the development of metabolic bone disease in infants very-low-birth-weight may be associated with genetic polymorphisms.

BackgroundBronchopulmonary dysplasia (BPD) infants present an increased incidence of metabolic bone disease (MBD), but it is unknown which factors contribute to this. The aim of this study was to determine the risk factors for developing MBD in BPD infants.MethodsA retrospective review of the medical records of BPD infants admitted to the Neonatal intensive care unit at Zhangzhou Hospital between Jun 2016 and May 2020 was performed. BPD infants with MBD were identified, two contemporaneous without MBD matched by gestational age and gender were randomly selected as controls for each case of MBD. The association between putative risk factors and MBD was estimated with ORs and 95% CIs. A P-value threshold ≤0.2 was used in univariate analysis for inclusion into a multivariate (adjusted) model with a P-value of < 0.05 as statistically significant.ResultsA total of 156 BPD infants were enrolled with 52 cases of MBD and 104 controls. Fetal growth restriction (OR 6.00, 95% CI, 1.81–19.84), extremely low birth weight (OR 3.10, 95% CI, 1.07–8.94), feeding volume < 80 mL/kg/d at the end of the 4th week after birth (OR 14.98, 95% CI, 4.04–55.58), cholestasis (OR 4.44, 95% CI, 1.59–12.40), late onset sepsis (OR 3.95, 95% CI, 1.12–13.98) and prolonged (> 2 weeks) diuretics application (OR 5.45, 95% CI, 1.25–23.84) were found to be statistically significant risk factors for MBD in BPD infants.ConclusionIn BPD infants of homogeneous gestational age, fetal growth restriction, extremely low birth weight, feeding volume < 80 mL/kg/d at the end of the 4th week after birth, cholestasis and late onset sepsis are significant risk factors for MBD. These findings provide potential predictive factors for MBD in BPD infants and warrant prospective validation.

Metabolic bone diseases are serious health issues worldwide, since several million individuals over the age of 50 are at risk of bone damage and should be worried about their bone health. One in every two women and one in every four men will break a bone during their lifetime due to a metabolic bone disease. Early detection, raising bone health awareness, and maintaining a balanced healthy diet may reduce the risk of skeletal fractures caused by metabolic bone diseases. This review compiles information on the most common metabolic bone diseases (osteoporosis, primary hyperparathyroidism, osteomalacia, and fluorosis disease) seen in the global population, including their symptoms, mechanisms, and causes, as well as discussing their prevention and the development of new drugs for treatment. A large amount of research literature suggests that balanced nutrition and balanced periodic supplementation of calcium, phosphate, and vitamin D can improve re-absorption and the regrowth of bones, and inhibit the formation of skeletal fractures, except in the case of hereditary bone diseases. Meanwhile, new and improved drug formulations, such as raloxifene, teriparatide, sclerostin, denosumab, and abaloparatide, have been successfully developed and administered as treatments for metabolic bone diseases, while others (romososumab and odanacatib) are in various stages of clinical trials.

Metabolic bone disease in premature infants receiving parenteral nutrition: Incidence, clinical, laboratory and nutritional profile

To the Editor: Medical knowledge of metabolic bone diseases has progressed markedly during the last decade. Progress has not been made, however, in finding a comprehensive name to designate this new field of internal medicine. For someone who has been working in this field for over three decades, it is evident that enormous advances have been made in our understanding of the physiology, physiopathology, diagnosis, and treatment of bone diseases. Sophisticated equipment to evaluate the bone mineral density of the skeleton with high precision is now available. Similarly, we can assess metabolic bone remodeling with high accuracy by measuring the urinary excretion (or blood levels) of bone matrix degradation products. New medications, unknown one or two decades ago, are able to modulate bone formation or resorption and improve bone mineralization with significant clinical dividends. Physicians, biochemists, and physicists interested in bone cluster in new societies and gather with great frequency in meetings that sometimes are multitudinous. A large number of research projects are being performed throughout the world, and the more relevant are published in well established, widely read specialized journals or in journals of endocrinology, rheumatology, orthopedic surgery, gynecology, and internal medicine. But what is the name that describes this new branch of internal medicine? It does not exist, at least at the present time, in English, the international scientific language. The closest description appears to be "metabolic bone disease." Because of the lack of a one-word comprehensive description of the field, several names are used in journals (Bone, formerly Metabolic Bone Disease and Related Research, Calcified Tissue International, Osteoporosis International, Journal of Bone and Mineral Research, or the recently demised Bone and Mineral). In a similar fashion, the supranational societies are called the International Bone and Mineral Society (at the beginning, International Conferences on Calcium Regulating Hormones) or the International Federation of Societies on Skeletal Diseases. In my opinion, however, one word already exists in the English language: osteology. Webster's definition of osteology is "The science dealing with the bones of vertebrates." It does not say (as in the case of cardiology, neurology, etc.) "The branch of medicine dealing with the bones and its diseases." This is simply because the concept and knowledge of "metabolic bone disease" is too new and has not yet been incorporated into the dictionary, which trails behind the current use of words. The word osteology, in Spanish and German, is being used by some medical societies: Argentinean, Chilean, and one German society, including a supranational society, the Ibero-American (Latin America, Spain, and Portugal) Society of Osteology and Mineral Metabolism. An additional advantage is that osteology would be practically the same word in German (Osteologie), French (Osteologie), and Spanish and Italian (Osteologia). One problem in accepting the word osteology in English is the similar root with the word "osteopathy" ("A school of medicine and surgery that emphasizes the interrelation of the muscles and bones to all other body systems," according to Webster's). But osteology (I begin to use the term) has grown so vigorously and has acquired such well deserved prestige that to describe this branch of internal medicine with a word of a similar root as a different type of medicine will not lead to any confusion. It is beyond the scope of this letter, however, to determine if osteology is a branch of internal medicine or a branch of endocrinology or rheumatology, although I feel strongly that it is a new branch of internal medicine. Without doubt, the one-word description of the field could include the biologist who studies the cellular behavior of bone cells, the biomechanist who studies the material properties of bone, the physiologist who studies hormones or hormone-like substances that act on bone, the biochemist who deals with the degradation products of bone metabolism, and, obviously, the clinicians who diagnose and treat patients with bone disease. Last, but not the least, it will help the patients to identify the specialist (osteologist) and the respective hospital section (osteology) that are to be consulted when the need arises. It is interesting to notice that when the ASBMR describes the specialties of their members we find endocrinology, rheumatology, internal medicine, radiology, etc. I suspect, however, that, like myself, a good number of society members, regardless of their original training practice, work with nothing but metabolic bone diseases. Why do we not find a single specialist of metabolic bone disease within the ASBMR? I believe that it is simply because we do not have the appropriate name that describes them as such. I propose that this word should be osteologist. It would be interesting to see the response to the ASBMR if it included this choice of specialty in their annual review of specialties. Finally, if this letter stirs enough interest to stimulate further discussion about the proper name of our field, its purpose will be entirely fulfilled.

Primate welfare in captivity has significantly improved over the last century as a result of the advances made in providing an adequate diet and environment. The skeletal collections of museums provide evidence of this shift in captive care, because metabolic disease caused by dietary deficiency or inappropriate surroundings can cause deformation to the hard tissues. The Royal College of Surgeons of England (RCS) holds a collection of 1507 nonhuman primate skulls in its Odontological Collection, the majority donated before the mid-20th century from various sources. We observed a recurring gross pathology in 51 of these skulls, noted in museum records as captive animals. In all cases, general bone thickening with decreased bone density is the main feature and involves primarily the bones of the maxillofacial region and mandible. We performed computed tomography scanning on a subsample of these skulls to investigate these pathological features further. We compared the RCS historical collections and a more recent captive primate collection at the National Museum of Scotland. The findings suggest that a metabolic bone disease is the causative agent, with osteomalacia the likely diagnosis. Osteomalacia typically occurs due to malnutrition and/or insufficient ultraviolet light exposure and in this case reflects the inadequacy of zoo primate management during the late 19th and early 20th centuries. Developments have since been made in captive animal welfare as a result of improvements in nutrition and environment. Metabolic bone disease in primate captivity can be regarded as a lesson from the past.

Impact of vitamin D on infectious disease-tuberculosis-a review

Metabolic bone disease is a well-documented long-term complication of obesity surgery. It is often undiagnosed, or misdiagnosed, because of lack of physician and patient awareness. Abnormalities in calcium and vitamin D metabolism begin shortly after gastrointestinal bypass operations; however, clinical and biochemical evidence of metabolic bone disease may not be detected until many years later. A 57-year-old woman presented with severe hypocalcemia, vitamin D deficiency, and radiographic evidence of osteomalacia, 17 years after vertical banded gastroplasty and Roux-en-Y gastric bypass. Following these operations, she was diagnosed with a variety of medical disorders based on symptoms that, in retrospect, could have been attributed to metabolic bone disease. Additionally, she had serum metabolic abnormalities that were consistent with metabolic bone disease years before this presentation. Radiographic evidence of osteomalacia at the time of presentation suggests that her condition was advanced, and went undiagnosed for many years. These symptoms and laboratory and radiographic abnormalities most likely were a result of the long-term malabsorptive effects of gastric bypass, food intake restriction, or a combination of the two. This case illustrates not only the importance of informed consent in patients undergoing obesity operations, but also the importance of adequate follow-up for patients who have undergone these procedures. A thorough history and physical examination, a high index of clinical suspicion, and careful long-term follow-up, with specific laboratory testing, are needed to detect early metabolic bone disease in these patients.