Advancing Early Bone Health: New Frontiers for Osteoporosis Prevention (REMS-BONE)

December 30, 2024 updated by: Serafina Perrone, University of Parma

Getting Bone Health Right From the Start: Innovative Technology and New Mechanims of Mother-fetus Cross Talk for Osteopenia and Osteporosis Prevention

All factors that influence the peak bone mass achieved at skeletal maturity are important in determining an individual's risk of developing osteoporosis later in life. Bone health begins with maternal health and nutrition, which influence skeletal mass and bone density in utero. The mechanisms underlying the effect of the intrauterine environment on bone health are currently unknown, but certainly include 'fetal programming' of oxidative stress and endocrine systems, as these influence skeletal growth and development later in life.

For the prevention of bone health, the challenges rely 1) in the need for new technology and software specific and applicable to the fetus and newborn; 2) in establishing the effect of environmental contaminants, in particular endocrine disruptors, oxidative stress and subsequent epigenetic changes in mothers and subsequently on the fetus, newborn and infant.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Maximising bone mass during skeletal growth has become the goal of primary prevention of osteopenia and osteoporosis. Any factor that might influence the peak bone mass attained during skeletal maturation is important in determining an individual's risk of developing osteoporosis later in life. Bone health begins with maternal health and nutrition, which influence skeletal mass and bone density in the foetus. The acquisition of peak bone mass is also genetically influenced by both parents. To date, there is some evidence that the risk of osteoporosis in later life may be determined by environmental exposures during intrauterine or early postnatal life. The mechanisms underlying the long-term effects of the intrauterine environment on bone health are currently unknown, but certainly include "fetal programming" of oxidative stress and endocrine systems that influence skeletal growth and development in utero and after birth.

Osteopenia is increasingly diagnosed in low birth weight infants. Intrauterine growth restriction (IUGR) further increases the risk of obesity and metabolic syndrome, conditions that significantly compromise bone quality. Recent studies have highlighted the central role of microRNAs (miRNAs) in bone growth and mineralisation, alongside peptides such as irisin and HMGB-1. These peptides are involved in glucose metabolism and the regulation of adipose and muscle tissue and have recently been linked to bone metabolism. MicroRNAs and long non-coding RNAs (lncRNAs) have gained attention for their ability to regulate gene expression post-transcriptionally, providing epigenetic modifications that influence growth plate and bone development. It remains unclear how maternal nutritional factors affect fetal bone mineral density (BMD) or how variations in fetal BMD may influence birth outcomes, such as spontaneous clavicle or skull fractures during operative delivery, and long-term bone mineralisation.

These findings highlight the importance of assessing skeletal status during the perinatal period. Early identification of conditions that affect bone mass or mineralisation and ongoing monitoring of bone development are essential to improve outcomes.

Radiofrequency echographic multi-spectrometry (REMS) technology has demonstrated its utility in the assessment of BMD in pregnant women. While few studies have investigated the use of transmission ultrasound to assess bone status in neonates, REMS technology shows great promise. Its advantages include the absence of ionising radiation, ease of use and, most importantly, the potential to conduct longitudinal studies of REMS patterns from the intrauterine period into the first year of life.

This innovative approach offers new opportunities to understand the maternal-fetal factors that influence bone health and to develop strategies to optimise bone development from the earliest stages of life.

The aims of the present study are A) To determine the feasibility of using REMS as a precise and innovative technology to assess the skeletal status of fetuses, neonates and children.

B) To assess how maternal REMS patterns and her anthropometric and gestational data influence REMS parameters in the fetus, newborn and during the first year of life.

C) To elucidate the relationships between early exposure to endocrine disrupters, oxidative stress and maternal diet as part of the in utero exposome and later body composition and bone health.

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Parma, Italy, 43126
        • Azienda Ospedaliero-Universitaria di Parma
    • ME
      • Messina, ME, Italy, 98125
        • Azienda Ospedaliero Universitaria "Gaetano Martino" di Messina

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • term infants from low-risk pregnancy
  • (37-42 weeks gestational age)
  • Single pregnancy
  • Absence of current or previous maternal diseases that could potentially interfere with bone metabolism (e.g., thyroid, kidney, liver disease)
  • Absence of motor disability of the mother
  • No previous history of recent, previous bone fractures or traumatic fractures (in the mother)
  • No intake of vitamin D or other medications during pregnancy
  • Maternal age >18 years
  • No diagnosis of osteopenia or osteoporosis according to the criteria of the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)

Exclusion Criteria:

  • preterm infants
  • Infants hospitalized since birth for special conditions
  • infants with metabolic disorders
  • infants with genetic syndromes

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Mother and infants at term of physiologically gestation (<37 weeks)
Assessment of bone mineral density (BMD) of the femur in the mother and fetus at term gestational age, and subsequently in the newborns at 48 hours after birth, at 1 month, at 3 months, at 6 months, and at 12 months of life, using REMS technology.
Diagnostic test: Cord blood sampling
A cord blood sample will be taken at birth for analysis of oxidative stress markers, endocrine disruptors, and microRNAs.
Diagnostic test: urine sampling
At one month of age, urine samples will be collected from newborns to analyze oxidative stress markers and endocrine disruptors.
Behavioral: Life style questionnaire
At the time of enrollment, mothers will complete a specialized questionnaire designed to assess potential exposure to endocrine disruptors (EDCs) through diet, clothing, and the use of cosmetics and detergents.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bone Mineral Density (BMD)
Time Frame: >37 and <42 weeks; 48 hours; 1, 3, 6, and 12 months

The novel application of REMS technology in the fetal and neonatal population requires the construction of a reference database. Data from the first 100 enrolled fetuses will form the basis of this database, and the same approach will apply to newborns, with the initial 100 cases corresponding to the same fetal cohort. Echographic acquisitions of fetuses and newborns, obtained using REMS devices, will be anonymized and transferred to the subcontractor, who will adapt REMS configurations for pediatric use. This adaptation will enable the identification of target bone structures and provide densitometric outputs.

BMD values will be calculated for each age group, and from the first 100 cases, mean and standard deviation will be derived to construct a 6-point BMD reference curve, comprising fetuses (>37 and <42 weeks) and newborns (48 hours, 1, 3, 6, and 12 months). Z-scores will be used to assess bone growth, and separate gender-specific curves will be developed.
>37 and <42 weeks; 48 hours; 1, 3, 6, and 12 months
Exposure to endocrine disruptors (EDCs) related to diet, clothing and the use of cosmetics and detergents.
Time Frame: at the enrollment
The questionnaire is an adaptation of the questionnaire drafted and already used as part of two previous projects "Phthalates and bisphenol A biomonitoring in Italianmother-childpairs: link between exposure and juvenile diseases' (LIFE PERSUADED) LIFE13 ENV/IT/000482; and 'Mother and infants dyads: lowering the impact of endocrine disrupting chemicals in milk for a healthy life2 (LIFE MILCH-LIFE18 ENV/EN/000460).
at the enrollment
MicroRNA assay on umbilical cord blood
Time Frame: at birth
By TaqMan Advanced miRNA assays (Applied Biosystems) miRNAs will be quantified and normalized using hsa-miR-16-5p (Assay ID: 477860_mir) as endogenous control. Real-Time qRT-PCR will be used for the specific candidate miRNAs: miR-199a-5p, miR-140, miR-335-5p, mir-503-5p, miR-494-3p, mir-369-3p, mir-379-5p, as it has been recently shown that they vary in relationship to GH status, and are related to growth response.
at birth
Endocrine disruptors (EDCs) on umbilical cord blood at birth.
Time Frame: at birth
Thirteen different EDCs are assayed, namely: Di(2-ethylhexyl) phthalate and its oxidised metabolites (MEHP, 6-OH-MEHP, 5-carboxy-MEPP, 5-oxo MEHP, 5-OH-MEHP), Bisphenol (BP) A, BPS, BPF, polyciclic aromatic hydrocarbons, polychorodibenzophuranes and polichorodibenzo-p-dioxins, perfluoro-alchilic substances, gliphosate, and its main metabolite, parabens (methyl-, ethyl-, propyl-, butyl- esters of 4-Hydroxybenzoic acid), piretroid insecticides,heavy metals (Pb, Cr).
at birth
Endocrine disruptors (EDCs) on urine at 1 months of age.
Time Frame: 1 month
Thirteen different EDCs are assayed, namely: Di(2-ethylhexyl) phthalate and its oxidised metabolites (MEHP, 6-OH-MEHP, 5-carboxy-MEPP, 5-oxo MEHP, 5-OH-MEHP), Bisphenol (BP) A, BPS, BPF, polyciclic aromatic hydrocarbons, polychorodibenzophuranes and polichorodibenzo-p-dioxins, perfluoro-alchilic substances, gliphosate, and its main metabolite, parabens (methyl-, ethyl-, propyl-, butyl- esters of 4-Hydroxybenzoic acid), piretroid insecticides,heavy metals (Pb, Cr).
1 month
Oxidative stress (OS) profile
Time Frame: at birth, 1 month
Oxidative stress (OS) profile will be evaluated by biomarkers of oxidative protein damage (Advanced Oxidation Protein Products, AOPP) and lipid peroxidation (Isoprostanes, IsoPs, malondialdehyde, MDA).
at birth, 1 month
Oxidative stress (OS) molecules
Time Frame: at birth, 1 month
Non-enzymatic antioxidant molecules (vitamin E; glutathione, GSH, and ascorbic acid, AA) and enzymatic antioxidant molecules (superoxide dismutase, SOD, catalase, CAT, and glutathione peroxidase, GPx) will be evaluated by highly specific and sensitive methods, such as high resolution liquid chromatography (HPLC), and gas chromatography interfaced mass spectrometry (GC-MS).
at birth, 1 month
Lipid mediators involved in oxidative stress
Time Frame: at birth, 1 month
The ELISA test will be used for the investigation of lipid metabolism and will evaluate specialised pro-resolving lipid mediators (Resolvin D1).
at birth, 1 month
Standard biochemical tests
Time Frame: at birth, 1 month
calcium, phosphorus, alkaline phosphatase, PTH, vitamin D (25 OH), and IGF-I
at birth, 1 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Parma

Collaborators

Azienda Ospedaliero-Universitaria di Parma
Azienda Ospedaliero Universitaria "Gaetano Martino" Messina

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 17, 2023

Primary Completion (Estimated)

June 1, 2025

Study Completion (Estimated)

November 1, 2025

Study Registration Dates

First Submitted

December 19, 2024

First Submitted That Met QC Criteria

December 24, 2024

First Posted (Actual)

March 25, 2025

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 30, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ID SIRER 5484
  • PNRR-MAD-2022-12376819 (Other Grant/Funding Number: NEXTGENERATIONEU, Ministry of University and Research (MUR))

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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