Advancing Early Bone Health: New Frontiers for Osteoporosis Prevention

NCT06750523 | Active Not Recruiting DMC

• 2 other identifiers: ID SIRER 5484PNRR-MAD-2022-12376819
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Low-Risk Pregnant Women at Full-Term Gestation; Healthy Fetal Population; Healthy Neonatal Population

Keywords

Bone mineral Density; Fetus; Newborns; Children; Osteoporosis; Environment; Oxidative stress; Endocrine disruptors

Outcome Measures

Primary Outcomes (9)

• Bone Mineral Density (BMD)

  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

• MicroRNA assay on umbilical cord blood

  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.

  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.

  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

  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

  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

  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

  calcium, phosphorus, alkaline phosphatase, PTH, vitamin D (25 OH), and IGF-I

  at birth, 1 month

• Exposure to endocrine disruptors (EDCs) related to diet, clothing and the use of cosmetics and detergents.

  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

Study Arms (1)

Mother and infants at term of physiologically gestation (<37 weeks)

EXPERIMENTAL

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; Diagnostic Test: urine sampling; Behavioral: Life style questionnaire

Interventions

Cord blood sampling DIAGNOSTIC_TEST

A cord blood sample will be taken at birth for analysis of oxidative stress markers, endocrine disruptors, and microRNAs.

Mother and infants at term of physiologically gestation (<37 weeks)

urine sampling DIAGNOSTIC_TEST

At one month of age, urine samples will be collected from newborns to analyze oxidative stress markers and endocrine disruptors.

Mother and infants at term of physiologically gestation (<37 weeks)

Life style questionnaire BEHAVIORAL

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.

Mother and infants at term of physiologically gestation (<37 weeks)

Eligibility Criteria

• Age: 37 Weeks - 42 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

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

Sponsors & Collaborators

• University of Parma: lead
• Azienda Ospedaliero-Universitaria di Parma: collaborator
• Azienda Ospedaliera Universitaria Policlinico "G. Martino": collaborator

Study Sites (2)

Azienda Ospedaliero Universitaria "Gaetano Martino" di Messina

Messina, ME, 98125, Italy

Location

Azienda Ospedaliero-Universitaria di Parma

Parma, 43126, Italy

Location

Related Publications (15)

• Heaney RP. BMD: the problem. Osteoporos Int. 2005 Sep;16(9):1013-5. doi: 10.1007/s00198-005-1855-y. Epub 2005 Mar 18. No abstract available.

  PMID: 15776218 BACKGROUND

• Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, Cooper C. Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res. 2001 Sep;16(9):1694-703. doi: 10.1359/jbmr.2001.16.9.1694.

  PMID: 11547840 BACKGROUND

• Lanham SA, Roberts C, Perry MJ, Cooper C, Oreffo RO. Intrauterine programming of bone. Part 2: alteration of skeletal structure. Osteoporos Int. 2008 Feb;19(2):157-67. doi: 10.1007/s00198-007-0448-3. Epub 2007 Aug 18.

  PMID: 17704965 BACKGROUND

• Dirkes RK, Welly RJ, Mao J, Kinkade J, Vieira-Potter VJ, Rosenfeld CS, Bruzina PS. Gestational and lactational exposure to BPA, but not BPS, negatively impacts trabecular microarchitecture and cortical geometry in adult male offspring. Bone Rep. 2021 Nov 3;15:101147. doi: 10.1016/j.bonr.2021.101147. eCollection 2021 Dec.

  PMID: 34820485 BACKGROUND

• Papaioannou G. miRNAs in Bone Development. Curr Genomics. 2015 Dec;16(6):427-34. doi: 10.2174/1389202916666150817202425.

  PMID: 27019617 BACKGROUND

• Bocheva G, Boyadjieva N. Epigenetic regulation of fetal bone development and placental transfer of nutrients: progress for osteoporosis. Interdiscip Toxicol. 2011 Dec;4(4):167-72. doi: 10.2478/v10102-011-0026-6.

  PMID: 22319250 BACKGROUND

• Holroyd C, Harvey N, Dennison E, Cooper C. Epigenetic influences in the developmental origins of osteoporosis. Osteoporos Int. 2012 Feb;23(2):401-10. doi: 10.1007/s00198-011-1671-5. Epub 2011 Jun 9.

  PMID: 21656266 BACKGROUND

• Zhang L, Tang Y, Zhu X, Tu T, Sui L, Han Q, Yu L, Meng S, Zheng L, Valverde P, Tang J, Murray D, Zhou X, Drissi H, Dard MM, Tu Q, Chen J. Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice. J Bone Miner Res. 2017 Dec;32(12):2466-2475. doi: 10.1002/jbmr.3230. Epub 2017 Aug 28.

  PMID: 28846804 BACKGROUND

• Perrone S, Santacroce A, Picardi A, Buonocore G. Fetal programming and early identification of newborns at high risk of free radical-mediated diseases. World J Clin Pediatr. 2016 May 8;5(2):172-81. doi: 10.5409/wjcp.v5.i2.172. eCollection 2016 May 8.

  PMID: 27170927 BACKGROUND

• Street ME, Bernasconi S. Endocrine-Disrupting Chemicals in Human Fetal Growth. Int J Mol Sci. 2020 Feb 20;21(4):1430. doi: 10.3390/ijms21041430.

  PMID: 32093249 BACKGROUND

• Predieri B, Alves CAD, Iughetti L. New insights on the effects of endocrine-disrupting chemicals on children. J Pediatr (Rio J). 2022 Mar-Apr;98 Suppl 1(Suppl 1):S73-S85. doi: 10.1016/j.jped.2021.11.003. Epub 2021 Dec 15.

  PMID: 34921754 BACKGROUND

• Degennaro VA, Brandi ML, Cagninelli G, Casciaro S, Ciardo D, Conversano F, Di Pasquo E, Gonnelli S, Lombardi FA, Pisani P, Ghi T. First assessment of bone mineral density in healthy pregnant women by means of Radiofrequency Echographic Multi Spectrometry (REMS) technology. Eur J Obstet Gynecol Reprod Biol. 2021 Aug;263:44-49. doi: 10.1016/j.ejogrb.2021.06.014. Epub 2021 Jun 15.

  PMID: 34167032 BACKGROUND

• Basu S, Michaelsson K, Olofsson H, Johansson S, Melhus H. Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun. 2001 Oct 19;288(1):275-9. doi: 10.1006/bbrc.2001.5747.

  PMID: 11594785 BACKGROUND

• Wang X, Liang T, Zhu Y, Qiu J, Qiu X, Lian C, Gao B, Peng Y, Liang A, Zhou H, Yang X, Liao Z, Li Y, Xu C, Su P, Huang D. Melatonin prevents bone destruction in mice with retinoic acid-induced osteoporosis. Mol Med. 2019 Aug 28;25(1):43. doi: 10.1186/s10020-019-0107-0.

  PMID: 31462213 BACKGROUND

• Perrone S, Laschi E, Buonocore G. Oxidative stress biomarkers in the perinatal period: Diagnostic and prognostic value. Semin Fetal Neonatal Med. 2020 Apr;25(2):101087. doi: 10.1016/j.siny.2020.101087. Epub 2020 Jan 23.

  PMID: 32008959 BACKGROUND

MeSH Terms

Conditions

Osteoporosis

Interventions

Cordocentesis

Condition Hierarchy (Ancestors)

Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Blood Specimen Collection; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Paracentesis; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, PhD, MD

Study Record Dates

• First Submitted: December 19, 2024
• First Posted: December 27, 2024
• Study Start: May 17, 2023
• Primary Completion: June 1, 2025
• Study Completion: November 1, 2025
• Last Updated: January 1, 2025

Record last verified: 2024-12

Locations

IT (2)