Osteoporosis affects more than 75 million women and men yearly, world-wide, at annual costs >$50 billion. To define compositional changes in osteoporotic bone, we pioneered Fourier transform infrared spectroscopic imaging (FTIRI) for measurement of bone biopsies at a spatial resolution of ~7um and applied this technique along with histology, micro-CT and mechanics to evaluate therapies for osteoporosis. Bisphosphonates (BP), to date, are the most effective drugs used to prevent fragility fractures and combat bone loss. These drugs can have a half-life in bone >10 years due to their ability to bind to bone mineral. Recently, reported adverse events associated with the use of BPs triggered the notion of a "drug holiday". During this "holiday", BP treatment is ceased after variable periods of usage, followed by arbitrary BP-free periods. There is no definitive statement on if, or when this "drug holiday" should start or how long it should last. Moreover, the effect ofa "drug holiday" on "bone quality" is unknown. "Bone Quality" defines those factors including composition, micro-architecture and presence of microcracks, which along with "Bone Quantity" contribute to fracture risk. Our studies showed BP treatment decreased bone material heterogeneity at the micron-level. This loss can contribute to crack propagation and hence fracture. Our underlying hypothesis is that loss of heterogeneity, evidenced through FTIRI and micro-CT, contributes to fracture risk in BP-treated patients. We further hypothesize that "Drug Holidays" alone, do not alter bone quality as determined by changes in composition or heterogeneity. Based on these ideas, and the preliminary finding that PTH increases heterogeneity, we suggest a treatment approach using a BP followed by PTH. Little information exists on the effects of such treatments on bone composition at the micro- or nano-levels, yet this information is important to enable investigators to design clinical trials and recommend therapies. We will address our hypotheses using 2 specific aims.1) To characterize the composition of bone before and after a "BP holiday", using iliac crest biopsies from: a) Patients after variable periods of BP-treatment followed by a 2 yr. "holiday" or PTH-treatment. b) Patients on long-term BP with variable "holiday" periods. c) Patients on long-term BP with high and normal turnover. d) Parallel studies in mice to determine at what point in time BPs attain their peak effect on tissue heterogeneity and whether or not heterogeneity changes with time. Microcracks will also be measured in iliac crest biopsies. 2) To test the hypothesis that bone heterogeneity extends to the nano-level, and that alterations in both micro- and nano-heterogeneity impact bone mechanical properties. We will i) Develop and apply nano- IR to define mineral and matrix heterogeneity in healthy, diseased and treated osteonal and cancellous animal bones. ii) Confirm our findings by analysis of human PTH-treated tissues and their controls. iii) Correlate tissue heterogeneity (from FTIRI and nano-IR) with mechanical performance at the macro- and nano-levels. If successful, these studies will address current debates regarding treatment protocols for osteoporosis.

Public Health Relevance

The objective of this grant is to determine whether patients at risk of fracture, who use bisphosphonates as a preventive measure, should go on a drug-free holiday to preserve the quality of their bones. We will use an multidisciplinary approach including: vibrational spectroscopy, micro-computed tomography, histomorphometry and biomechanics to evaluate the quality of bone in biopsies from people who stop taking or remain on bisphosphonates for different lengths of time, either take nothing, or continue treatment using parathyroid hormone for a 2 year period of time. This information will lead to more effective therapeutic approaches for dealing with osteoporosis.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Lester, Gayle E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Hospital for Special Surgery
New York
United States
Zip Code
Marcott, Curtis; Lo, Michael; Hu, Qichi et al. (2014) Using 2D Correlation Analysis to Enhance Spectral Information Available from Highly Spatially Resolved AFM-IR Spectra. J Mol Struct 1069:284-289
Kim, Grace; Cole, Jacqueline H; Boskey, Adele L et al. (2014) Reduced tissue-level stiffness and mineralization in osteoporotic cancellous bone. Calcif Tissue Int 95:125-31
Gourion-Arsiquaud, Samuel; Marcott, Curtis; Hu, Qichi et al. (2014) Studying variations in bone composition at nano-scale resolution: a preliminary report. Calcif Tissue Int 95:413-8
Boskey, Adele L; Lukashova, Lyudmilla; Spevak, Lyudmila et al. (2013) The kidney sodium-phosphate co-transporter alters bone quality in an age and gender specific manner. Bone 53:546-53
Gourion-Arsiquaud, Samuel; Lukashova, Lyudmilla; Power, Jon et al. (2013) Fourier transform infrared imaging of femoral neck bone: reduced heterogeneity of mineral-to-matrix and carbonate-to-phosphate and more variable crystallinity in treatment-naive fracture cases compared with fracture-free controls. J Bone Miner Res 28:150-61
Spevak, Lyudmila; Flach, Carol R; Hunter, Tracey et al. (2013) Fourier transform infrared spectroscopic imaging parameters describing acid phosphate substitution in biologic hydroxyapatite. Calcif Tissue Int 92:418-28
Burket, Jayme C; Brooks, Daniel J; MacLeay, Jennifer M et al. (2013) Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. Bone 52:326-36
Burket, Jayme; Gourion-Arsiquaud, Samuel; Havill, Lorena M et al. (2011) Microstructure and nanomechanical properties in osteons relate to tissue and animal age. J Biomech 44:277-84
Lindahl, Katarina; Barnes, Aileen M; Fratzl-Zelman, Nadja et al. (2011) COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. Hum Mutat 32:598-609
Kinnett, J Gregory (2011) Bone quality: from bench to bedside: editorial comment: the clinical challenge of altered bone quality. Clin Orthop Relat Res 469:2090-1

Showing the most recent 10 out of 53 publications