Management Of Metabolic Bone Disease Research Articles

Diagnostic and New Therapeutic Approaches to Two Challenging Pediatric Metabolic Bone Disorders: Hypophosphatasia and X-linked Hypophosphatemic Rickets.

The diagnosis and management of metabolic bone disease among children can be challenging. This difficulty could be due to many factors, including limited awareness of these rare conditions, the complex pathophysiology of calcium and phosphate homeostasis, the overlapping phenotype with more common disorders (such as rickets), and the lack of specific treatments for these rare disorders. As a result, affected individuals could experience delayed diagnosis or misdiagnosis, leading to improper management. In this review, we describe the challenges facing diagnostic and therapeutic approaches to two metabolic bone disorders (MBD) among children: hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH). We focus on explaining the pathophysiological processes that conceptually underpin novel therapeutic approaches, as well as these conditions' clinical or radiological similarity to nutritional rickets. Particularly in areas with limited sun exposure and among patients not supplementing vitamin D, nutritional rickets are still more common than HPP and XLH, and pediatricians and primary physicians frequently encounter this disorder in their practices. More recently, our understanding of these disorders has significantly improved, leading to the development of novel therapies. Asfotas alfa, a recombinant, human- tissue, nonspecific alkaline phosphatase, improved the survival of patients with HPP. Burosumab, a human monoclonal anti-FGF23 antibody, was recently approved as a specific therapy for XLH. We also highlight the current evidence on these two specific therapies' safety and effectiveness, though long-term data are still needed. Both HPP and XLH are multisystemic disorders that should be managed by multidisciplinary teams. Finally, recognizing these conditions in early stages will enable affected children and young adults to benefit from newly introduced, specific therapies.

Clinical frontiers of metabolic bone disorders: a comprehensive review

Metabolic bone disease (MBD)encompasses various conditions that adversely impact bone health, such as osteoporosis, primary hyperparathyroidism, osteomalacia, and fluorosis disease. Effectively managing these disorders requires early detection and a focus on maintaining healthy nutritional habits. Dietary adjustments serve as a cornerstone, but supplementation of essential minerals like calcium, phosphate, and vitamin D is often necessary to support bone reabsorption and regeneration, and reduce fracture risk. Despite the effectiveness of these measures in many cases, hereditary bone diseases pose distinctive challenges due to genetic factors. Emerging technologies that provide higher-resolution insights into bone architecture and quality are now complementing traditional diagnostic tools like dual-energy X-ray absorptiometry (DXA). Moreover, the therapeutic landscape has transformed with the introduction of newer agents that not only halt bone loss but also stimulate bone formation. These agents promise better outcomes with reduced side effects, catering to a wider patient population. However, the management of MBDs remains multifaceted, necessitating individualized approaches based on the patient’s clinical profile. As the global prevalence of MBDs, especially osteoporosis, continues to soar, it becomes imperative for clinicians to stay abreast with the evolving paradigms. This review serves as a bridge between historical knowledge and recent discoveries, offering a holistic perspective on the challenges and opportunities in the domain of MBDs.

Influence of Oral Bisphosphonate on Dental Implant

Background: Bisphosphonates (BPs) are medications employed widely in the management of metabolic bone diseases. Dental implants are new therapy for replacement of missing teeth depend on the osseointegration process. There is a considerable debate on the effect of oral BPs on the osseointegration process and subsequently on the success rate of dental implant and development of BRNOJ. Objectives: The aim of this study was to revise literatures on the effect of oral (BPs) on the success rate of dental implants and the development of BPs-related osteonecrosis of the jaws. Materials and Methods: PubMed, google scholar, Scopus database, and manual search were performed to find out articles on the effect of oral BPs on dental implant outcome and development of BRNOJ. Results: twelve articles were found six retrospective studies, one prospective studies, two case control studies and one case series discussing the effect of oral BPs on success rate of dental implant and development of BRNOJ. Conclusion: the majority of patients were osteoporotic females and treated with oral BPs. Oral BPs have little, if any, influence on success rate of dental implant and there is no conclusive evidence on BRNOJ-related oral BPs in implanted patients. Patients on BPs and received implant therapy should be cautioned on developing BRNOJ and followed-up for long time period.

Expert consensus on clinical management of metabolic bone disease of prematurity (2021).

Metabolic bone disease of prematurity (MBDP) is a systemic bone disease with a reduction in bone mineral content due to disorder of calcium and phosphorus metabolism. There is still a lack of in-depth research and systematic understanding of MBDP in China, and there are many irregularities in clinical management of this disease. Based on relevant studies in China and overseas, Grading of Recommendations Assessment, Development and Evaluation was used to develop the expert consensus on the clinical management of MBDP, which provides recommendations from the following five aspects: high-risk factors, screening/diagnosis, prevention, treatment, and post-discharge follow-up of MBDP, so as to provide relevant practitioners with recommendations on the clinical management of MBDP to reduce the incidence rate of MBDP and improve its short- and long-term prognosis.

The Role of PINP in Diagnosis and Management of Metabolic Bone Disease.

Serum procollagen type I N-propeptide (PINP) is designated the reference marker of bone formation in osteoporosis; the reference marker for resorption is C-terminal telopeptide of type I collagen (CTX). PINP has very low circadian and biological variation, is not affected by food intake, and is very stable in serum after venepuncture. The two automated commercial assays for PINP provide similar results in subjects with normal renal function, allowing reference intervals to be used interchangeably. Bone turnover markers (BTM) are currently not recommended for fracture risk assessment and therefore not included in fracture risk calculators. In the management of osteoporosis, the main utility of BTM including PINP is for monitoring therapy, both antiresorptive as well as anabolic agents; monitoring is thought to help improve adherence. PINP as well as CTX may also be used in assessing offset of drug action following a pause in bisphosphonate therapy, to help decide when to re-instate therapy, or following cessation of denosumab therapy to assess efficacy of follow-on bisphosphonate therapy. PINP may also be used in the diagnosis of Paget's disease of bone as well as in monitoring response to therapy and for recurrence. Although BTM other than bone alkaline phosphatase are currently not recommended for use in metabolic bone disease of chronic kidney disease, PINP measured by assays specific to the intact molecule has potential in this condition. Further studies are needed to examine this area, as well as in malignant bone disease.

Metabolic Bone Disease in Premature Neonates: An Unmet Challenge

Metabolic bone disease (MBD) is an important cause of morbidity in premature, very low birth weight (VLBW) and sick infants and, if left undiagnosed, may lead to structural deformities and spontaneous fractures. MBD is defined as impaired bone mineralization in a neonate with lower than expected bone mineral levels in either a fetus or a neonate of comparable gestational age and/or weight, coupled with biochemical abnormalities with or without accompanying radiological manifestations. MBD has been reported to occur in 16% to 40% of extremely low birth weight neonates and presents by 6-16 weeks after birth. Insufficient calcium and phosphorous stores during the phase of accelerated growth predispose to MBD in neonates along with the use of some medications such as caffeine or steroids, prolonged parenteral nutrition and chronic immobilization. Enhanced physical activity in preterm infants facilitates bone mineralization and weight gain. Biochemical abnormalities tend to worsen significantly, as the severity of disease progresses. These abnormalities may include hypocalcemia, hypophosphatemia, hyperphosphatasia and secondary hyperparathyroidism. In addition, urinary phosphate wasting and hypovitaminosis D can be additional complications. Conversely, biochemical abnormalities may not be accompanied by rachitic changes. Newer diagnostic modalities include non-invasive bone densitometry by quantitative ultrasound over the mid-tibial shaft. The management of MBD includes adequate calcium, phosphorous and vitamin D supplementation, along with optimum nutrition and physical activity. Similarly, preventive strategies for MBD should target nutritional enhancement in combination with enhanced physical activity. MBD usually results in preventable morbidity in preterm and VLBW neonates. Treatment consists of optimum nutritional supplementation and enhanced physical activity.

Metabolic bone disease of prematurity-National survey of current neonatal and paediatric endocrine approaches.

AimThis study aimed to identify current trends in the management of metabolic bone disease of prematurity (MBDP) in the United Kingdom.MethodsA nationwide electronic survey was disseminated to all neonatal networks across the United Kingdom, as well as to paediatric endocrinologists for comparison. Weighted averages were used to compare relative importance placed on screening and diagnostic investigations (1 = not important, 5 = essential).ResultsSixty‐nine individuals responded from 53 neonatal units. Greatest emphasis was placed on levels of serum phosphate and alkaline phosphatase for screening (weighted average 4.5 and 4.6, respectively), diagnosis (weighted average 4.1 and 4.5, respectively) and monitoring (93% and 97% of neonatal responders, respectively) of MBDP by neonatologists. Although similar results were obtained for endocrinologists, significantly greater emphasis was placed on plasma parathyroid hormone (PTH) level for screening, diagnosis and monitoring (p < 0.001 for each). Phosphate supplementation was reported almost universally by neonatal responders (99%), but was significantly less for endocrine responders (62%) for the treatment of MBDP (p < 0.001).ConclusionThere is an under‐utilisation of plasma PTH as a screening, diagnostic and monitoring investigation to guide appropriate supplementation for MBDP by neonatologists.

Effect on metabolic bone disease markers in the neonatal intensive care unit with implementation of a practice guideline.

To determine the effect of implementing a 2015 policy for the screening, prevention, and management of metabolic bone disease for very low birth weight (VLBW) infants in two Level IV NICUs. Retrospective cohort study of VLBW infants in the 2 years prior to (2013-2014) and after (2016-2017) policy implementation. We identified 316 VLBW infants in 2013-2014 and 292 in 2016-2017 who met study criteria. After policy implementation, vitamin D supplementation began earlier (20.1 ± 15.5 days vs 30.2 ± 20.1 days, p < 0.0005), the percentage of infants with alkaline phosphatase obtained increased (89.7% vs 76.3%, p < 0.0005), while the percentage of infants with alkaline phosphatase >800 IU/L (11.7 vs 4.5%, p = 0.0001) and phosphorous <4 mg/dL (14.2% vs 7.9%, p = 0.014) fell significantly. After policy implementation, vitamin D supplementation began significantly earlier and the rate of detecting abnormal biochemical markers of metabolic bone disease decreased significantly.

Evaluation and Management of Metabolic Bone Disease in Kidney Transplant Recipients

Evaluation and Management of Metabolic Bone Disease in Kidney Transplant Recipients

Metabolic Bone Disease of Prematurity: Diagnosis and Management.

Metabolic Bone Disease (MBD) of prematurity is a multifactorial disorder commonly observed in very low birth weight (VLBW, <1,500 g) newborns, with a greater incidence in those extremely low birth weight (ELBW, <1,000 g). MBD is characterized by biochemical and radiological findings related to bone demineralization. Several antenatal and postnatal risk factors have been associated to MBD of prematurity, although the main pathogenetic mechanism is represented by the reduced placental transfer of calcium and phosphate related to preterm birth. The diagnosis of MBD of prematurity requires the assessment of several biochemical markers, radiological, and ultrasonographic findings. However, the best approach is the prevention of the symptomatic disease, based on the screening of subjects exposed to the risks of developing MBD. Regarding the subjects who need to be screened, there is a substantial agreement on the potential risk factors for MBD. On the contrary, different recommendations exist on the diagnosis, management and treatment of this disorder of bone metabolism. This review was aimed at: (1) identifying the subjects at risk for MBD of prematurity; (2) indicating the biochemical findings to take in consideration for the prevention of MBD of prematurity; (3) suggesting practical recommendations on nutritional intake and supplementation in these subjects. We searched for papers which report the current recommendations for biochemical assessment of MBD of prematurity and for its prevention and treatment. The majority of the authors suggest that MBD of prematurity is a disease which tends to normalize overtime, thus it is not mandatory to mimic the rate of mineral fetal accretion through parenteral or enteral supplementation. The optimization of total parenteral nutrition (TPN) and the early achievement of a full enteral feeding are important goals for the prevention and management of MBD of prematurity.

Calcium Intakes in the Diet of Eastern Morocco’s Population

Purpose: Osteoporosis is the most common bone disease in the world. Most epidemiological studies show that calcium and vitamin deficiencies are very frequent not only in the elderly population but also in the general adult population. The aim of our work was to evaluate the calcium intake in population of eastern Morocco by the translated version in Moroccan Arabic dialect of Fardellone questionnaire.Methods: The version translated into Arabic dialect Fardellone questionnaire was tested on a sample of 1000 subjects. The age distribution was calculated on the distribution of the general Moroccan population according to the most recent population and housing census of September 2014. Therefore, subjects younger than 15 years represented the first age group, the subjects aged 16 to 59 years represented the second age group and the subjects older than 60 years represented by the third age group.Results: The study population included 56% women (n = 560), 44% of men (n = 440). The subjects aged less than 15 years accounted for 11% (n = 110), those aged 15 to 59 73.1% (n = 731) and those aged over 60 years 15.9% (n = 159). The mean calcium intake was respectively 4907 mg by week (that means 701 mg/day). The assessment of calcium intake by age group showed a deficiency in all three groups. The average consumption of calcium per day was significantly lower than the recommended daily amount for the three age groups. Patients aged over 60 years is the age group most under nourished calcium. The comparison of both gender found a deficit higher among women than among men.Conclusion: Evaluation of the calcium intake is an essential tool for better management of metabolic bone diseases.

Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone disease in RTS. Furthermore, the mechanisms that result in this phenotype are largely unknown. In this report, we provide a detailed evaluation of 29 individuals with RTS with respect to their metabolic bone status including bone mineral density, calcium kinetics studies, and markers of bone remodeling. We show that individuals with RTS have decreased areal bone mineral density. Additionally, we demonstrate that the presence of pathogenic variants in RECQL4 and low bone mineral density correlate with the history of increased risk of fractures. Using a RECQL4-deficient mouse model that recapitulates skeletal abnormalities seen in individuals with RTS, we demonstrate that generalized skeletal involvement is likely due to decreased osteogenesis. Our findings are clinically relevant as they may help in the risk stratification of patients with RTS and also in the identification of individuals who may benefit from additional surveillance and management of metabolic bone disease.

DXA: Technical aspects and application

The key role of dual-energy X-ray absorptiometry (DXA) in the management of metabolic bone diseases is well known. The role of DXA in the study of body composition and in the clinical evaluation of disorders which directly or indirectly involve the whole metabolism as they may induce changes in body mass and fat percentage is less known or less understood. DXA has a range of clinical applications in this field, from assessing associations between adipose or lean mass and the risk of disease to understanding and measuring the effects of pathophysiological processes or therapeutic interventions, in both adult and paediatric human populations as well as in pre-clinical settings. DXA analyses body composition at the molecular level that is basically translated into a clinical model made up of fat mass, non-bone lean mass, and bone mineral content. DXA allows total and regional assessment of the three above-mentioned compartments, usually by a whole-body scan. Since body composition is a hot topic today, manufacturers have steered the development of DXA technology and methodology towards this. New DXA machines have been designed to accommodate heavier and larger patients and to scan wider areas. New strategies, such as half-body assessment, permit accurate body scan and analysis of individuals exceeding scan field limits. Although DXA is a projective imaging technique, new solutions have recently allowed the differential estimate of subcutaneous and intra-abdominal visceral fat. The transition to narrow fan-beam densitometers has led to faster scan times and better resolution; however, inter- or intra-device variation exists depending on several factors. The purposes of this review are: (1) to appreciate the role of DXA in the study of body composition; (2) to understand potential limitations and pitfalls of DXA in the analysis of body composition; (3) to learn about technical elements and methods, and to become familiar with biomarkers in DXA.

The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian Bone Club.

The exact role of biochemical markers of bone turnover in the management of metabolic bone diseases remains a topic of controversy. In this consensus paper, the Belgian Bone Club aimed to provide a state of the art on the use of these biomarkers in different clinical or physiological situations like in postmenopausal women, osteoporosis in men, in elderly patients, in patients suffering from bone metastasis, in patients with chronic renal failure, in pregnant or lactating women, in intensive care patients, and in diabetics. We also gave our considerations on the analytical issues linked to the use of these biomarkers, on potential new emerging biomarkers, and on the use of bone turnover biomarkers in the follow-up of patients treated with new drugs for osteoporosis.

Medical management of chronic kidney disease in the renal transplant recipient.

An updated overview of the state-of-the-art approaches to the care of chronic kidney disease-related issues in renal transplant recipients. These include the impact of immunosuppression therapy on kidney function, the management of cardiovascular risk, metabolic bone disease, and hematologic complications, with a focus on the care of the patient with a failing allograft. A kidney transplant improves patient morbidity and mortality, but almost all transplant patients continue to have morbidity related to chronic kidney disease. It is increasingly clear that the provision of adequate immunosuppression is important to preserve allograft function. Recent studies have lent support to current guidelines for the management of cardiovascular risk factors in transplant patients. New data regarding the management of metabolic bone disease are sparse. Erythropoietin replacement may improve outcomes in transplant recipients, but the optimal target hemoglobin level is not known. Cessation of immunosuppression in the failed allograft carries the risk of rejection and allosensitization. New evidence suggests that nephrectomy may reduce mortality in patients with a failed allograft, but likely enhances sensitization in the patient awaiting retransplantation.

Comparison of results from commercial assays for plasma CTX: The need for harmonization

IntroductionPlasma C-terminal telopeptide of type I collagen (CTX) is the nominated reference bone resorption marker. We set out to test the agreement of patients' results between the available plasma CTX assays. MethodsSamples were collected from patients attending tertiary hospitals and clinics for investigation and management of metabolic bone disease. Plasma (EDTA) samples were collected from fasted patients between 7.00am and 11.00am, divided into three portions and stored at −20°C until analysis. Plasma CTX was measured by enzyme-linked immunosorbent assay (ELISA) (Immunodiagnostic Systems plc), E170 (Roche Diagnostics) and IDS-iSYS (Immunodiagnostic Systems plc) methods. Agreement of patient sample results was assessed by Passing and Bablok regression. Commutability of the calibrators in each kit was assessed by assaying each calibrator in the alternate methods and comparing the observed results with those expected based on the relevant patients' samples method comparison; ±8.1% was set as the criterion for commutablity. Results161 specimens were analysed. Regression parameters (slope, intercept) were 0.788, 0.2ng/L for Roche vs ELISA, 1.266 and −109ng/L for iSYS vs ELISA and 1.605 and −109ng/L for iSYS vs Roche. Only the ELISA calibrator assayed in the Roche assay gave a result within 8.1% of the expected value. ConclusionsThere is significant disagreement between the results generated for patient samples by the 3 CTX assays and limited commutability of the currently supplied calibrator materials between assays. Harmonization of the results from the different assays would greatly enhance the value of CTX as the reference bone resorption marker.

Dietary Supplements and Medical Foods for Osteopenia and Osteoporosis

Dietary supplements, medical foods, and pharmaceutical agents are all used in the management of metabolic bone disease. The intended populations, governing regulations, safety standards scientific requirements, physician supervision, and distribution vary markedly between supplements, medical foods, and drugs. This article will review characteristics of dietary supplements and medical foods and their use in osteoporosis care. A study that compares the pharmacokinetics of a supplement and a medical food containing similar ingredients is used to contrast the categories of dietary supplements and medical foods.

The utility of procollagen type 1 N-terminal propeptide for the bone status assessment in postmenopausal women

The utility of procollagen type 1 N-terminal propeptide (P1NP) in the management of metabolic bone diseases remains a subject of debate since the reference ranges are not rigorously established and fail to account for many of the preanalytical variables. We aimed to establish reference intervals for P1NP level in healthy and osteoporotic postmenopausal females stratified by age, body mass index and menopausal duration. We also aimed to assess the relationship between P1NP and BMD. This cross-sectional study enrolled 183 postmenopausal females who were divided in osteoporosis group (N=93) and control group (N=90) with preserved bone mass based on BMD assessed by DXA. In the osteoporosis group median P1NP was significantly higher (51.7 ng / mL; 95%CI 43.2-53.7) compared to control group (38.9 ng/mL; 95%CI 34.2-43.9)(p<0.01). After controlling for age, BMI and years since menopause, there was significant inverse association between BMD and P1NP at the femoral neck (r=-0.18), total hip (r=-0.207) and lumbar spine (r=-0.236). There was no significant difference in P1NP concentration across quartiles of age in postmenopausal females. P1NP was significantly lower in obese postmenopausal females with preserved bone mass compared to normal weight and overweight females in control and in osteoporosis group. In conclusion, we showed that P1NP is inversely associated with BMD even after controlling for age, BMI and years since menopause. Although, P1NP is significantly higher in postmenopausal females with osteoporosis compared to postmenopausal females with preserved bone mass its low specificity does not warrant its utility is diagnosing osteoporosis.

The clinical utility of bone marker measurements in osteoporosis

Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3–6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases.

Metabolic and Nutrition Support in the Chronic Critical Illness Syndrome

Technological innovations in the ICU have led to artificially prolonged life, with an associated cost. Chronic critical illness (CCI) occurs in patients with prolonged mechanical ventilation and allostatic overload, and is associated with a discrete and consistent metabolic syndrome. Metabolic interventions are extrapolated from clinical critical care research, scientific theory, and years of CCI patient care experience. Intensive metabolic support (IMS) is a multi-targeted approach consisting of tight glycemic control with intensive insulin therapy, early and adequate nutrition therapy, nutritional pharmacology, management of metabolic bone disease, and meticulous attention to other endocrine/metabolic derangements. Ideally, IMS should be under the supervision of a metabolic support consultative team. Further research specifically focused on the CCI population is needed to validate this current approach.