3D In Vivo Morphometry of Trabecular Microstructure
3D In Vivo Morphometry of Trabecular Microstructure
Osteoporosis is a syndrome of excessive skeletal fragility most often resulting from estrogen deficiency and aging. The decline of trabecular bone structure and other aspects of bone quality secondary to estrogen deficiency and aging are suppressed by treatment with anti-resorptive agents (AR) or reversed with an anabolic agent, hPTH (1-34) (AA). Currently, patients with osteoporosis are often “cycled” through these different types of bone active agents for many years with little data to determine if sequential therapies for osteoporosis differentially affect bone strength and quality, or the durability if treatments are withdrawn. We have reported that both a potent AR and an AA significantly improved trabecular bone mass and bone strength in estrogen deficient old rats compared to osteoporotic controls. However, there were differences between the two types of bone active agents, the AA had a greater increase in trabecular bone mass and whole bone strength than the AR; the potent AR had an overall higher and more consistent values for the localized material properties measured including elastic modulus and degree of bone mineralization (DBM) compared to the AA treated animals. Since these bone active agents augment bone strength by somewhat different mechanisms we hypothesize that in estrogen-deficient old rats: 1. Long-term treatment with potent ARs or an AA will improve localized bone quality and whole bone strength and withdrawal of ARs and an AA will differ in the time to reduction in bone quality and bone strength. 2. Altering the sequence of treatments will also differentially affect localized bone material properties and whole bone strength. To test these hypotheses.
We propose the following specific aims: 1. To determine the time frame for the deterioration of localized bone quality including the DBM, local microstructural bone tissue material properties, and whole bone strength differs after treatment with either ARs or an AA. 2. To determine if the localized aspects of bone quality including the DBM, local microstructural bone tissue material properties, and whole bone strength differ in
estrogen deficient old rats treated sequentially with ARs followed by AA; AA followed by ARs or cyclic therapy with ARs, then AA or vehicle then AR, and ARs alone. 3. To determine if there is an association between the changes in biochemical markers and surface-based bone turnover, bone matrix composition, and localized and whole bone material properties with long term sequential therapies; ARs followed by AA; AA followed by ARs; or cyclic therapy with ARs, AA or vehicle and ARs alone. To accomplish these specific aims we will perform two very large experiments long-term studies using 10-month-old osteopenic rats. We will measure localized microstructural properties and whole bone strength and determine how the localized properties change with different treatment regimens, These preclinical studies will provide data that will guide clinicians in prescribing these bone active agents to maximize bone strength and the durability of their effects.
Nancy E. Lane, M.D.
PI – 3D Research Project
Director - SCOR
Endowed Professor of Medicine and Rheumatology
Director: Musculoskeletal Diseases of Aging Research Group
Co-Director: Building Interdisciplinary Research Careers in Women's Health (BIRCWH)
Co-Director: Center for Translational Research in Osteoarthritis
Wei Yao, M.D.
Co-Investigator – 3D Research Project
Project Leader: SCOR Project 1
Associate Director – Laboratory Core
Center for Musculoskeletal Health
Osteoporosis is a major public health problem. In 2002, it was estimated that nearly 44 million persons over the age of 50 in the United States were at risk for fracture due to osteoporosis or low bone mass. By 2020, if current trends continue and effective treatments are not widely implemented, it is estimated over 61 million persons will be at risk. The economic burden of inpatient, outpatient and long term care of incident osteoporotic fractures in the U.S. was projected to be almost $17 billion in 2005, with cumulative cost of more than $474 billion over the next two decades. Osteoporosis is defined as a disease characterized by low bone strength that results from both low bone mass and changes in the qualities of bone such that bone breaks with very little force. The two most significant risk factors are estrogen deficiency and aging. Estrogen deficiency, which generally begins at menopause, creates an increase in bone remodeling with an activation of new remodeling units within the bone. This accelerated bone remodeling, associated with an increased number of bone remodeling units, results in altered trabecular bone structure, reduction in bone mass and overall bone fragility such that, with very little trauma, bone fractures.
- To determine the time frame for the deterioration of localized aspects of bone quality including the DBM, microstructural bone tissue material properties and whole bone biomechanical properties and toughness after estrogen deficient osteopenic old rats have been treated with either an anti-resorptive or an anabolic agent.
- To determine if the localized aspects of bone quality including the DBM, local microstructural bone tissue material properties and whole bone biomechanical properties differ in estrogen deficient old rats treated with long-term sequential therapies; anti-resorptive followed by anabolic; anabolic followed by anti-resorptive; or cyclic therapy with anti-resorptive, anabolic and anti-resorptive agents compared to anti-resorptive alone.
- To determine if there is an association between the changes in the localized aspects of bone quality (DBM, changes in biochemical markers of bone turnover, surface based turnover, bone matrix composition, osteocyte lacunae size and localized material properties) and whole bone biomechanical properties with long term sequential therapies; anti-resorptive followed by anabolic; anabolic followed by anti-resorptive; or cyclic therapy with anti-resorptive, anabolic and anti-resorptive agents compared to anti-resorptives alone.
Currently, our work and that of many other investigators have determined that both AR agents and anabolic agents have different effects on bone turnover, degree of trabecular bone mineralization, and bone geometry yet both agents improve bone strength. This has led to patients with osteopenia and osteoporosis being treated with these agents using many different sequences and treatment intervals leaving many critical clinical questions not answered. Both physicians treating these patients and the patients need more information on how these agents influence the localized bone qualities and whole bone strength, since bone mass measurements and serum measurements of bone turnover do not predict fracture outcomes (45,46). Our unique new abilities to quantitate localized properties of bone quality including the degree and heterogeneity of bone mineralization, microarchitecture, localized elastic modulus, surface based bone turnover and whole bone strength will help to provide the necessary information to guide clinicians on the optimal way to use the bone active agents to improve bone strength over many years of treatment. Until now, we have not had the technical expertise to be able to answer these questions.
Shahnazari M1, Yao W, Wang B, Panganiban B, Ritchie RO, Hagar Y, Lane NE. Differential maintenance of cortical and cancellous bone strength following discontinuation of bone-active agents. PMID: 20839286 PMCID: PMC3179292 Copyright © 2011 American Society for Bone and Mineral Research.
Lane NE, Yao W. New insights into the biology of glucocorticoid-induced osteoporosis. IBMS BoneKey. 2011 May; 8(5); 229-36.
Jia JJ, Yao W (co-first author), Amugongo S, Lay YA, Shahnazari M, Cheng ZQ, Olvera D, Ritchie RO, Addition T, Lane NE, Prolonged bisphosphonate treatments had negative effects on cortical bone strength through the involvement of TGF-β1 signaling Bone 52(1): 424-32, 2013
Yao W, Dai WW, Jiang JX, Lane NE Glucocorticoids and Osteocyte Autophagy Bone 54(2): 279-84, 2013
Amugongo SK, Yao, W, Jia JJ, Dai WW, Lay YE, Walsh D, Jiang L, Li CH, Panganiban B, Ritchie RO, Lane NE Effects of Cyclical Treatments with PTH, Alendronate and Raloxifene on Trabecular Bone Mass and Strength in Estrogen Deficient Rats. Osteoporosis International 25:1735-1750; 2014
Amugongo SK, Yao, W, Jia JJ, Dai WW, Lay YE, Jiang L, Li CH, Olvera D, Zimmermann ZA, Ritchie RO, Lane NE Effect of cyclical treatments With Alendronate, PTH and Raloxifene on cortical bone mass and strength. Bone 67:257-268; 2014
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