The challenges of diagnosing osteoporosis and the limitations of currently available tools

Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 https://doi.org/10.1186/s40842-018-0062-7 REVIEW ARTICLE Open Access The challenges of diagnosing osteoporosis and the limitations of currently available tools Palak Choksi1, Karl J. Jepsen2 and Gregory A. Clines1,3* Abstract Dual-energy X-ray absorptiometry (DXA) was the first imaging tool widely utilized by clinicians to assess fracture risk, especially in postmenopausal women. The development of DXA nearly coincided with the availability of effective osteoporosis medications. Although osteoporosis in adults is diagnosed based on a T-score equal to or below − 2.5 SD, most individuals who sustain fragility fractures are above this arbitrary cutoff. This incongruity poses a challenge to clinicians to identify patients who may benefit from osteoporosis treatments. DXA scanners generate 2 dimensional images of complex 3 dimensional structures, and report bone density as the quotient of the bone mineral content divided by the bone area. An obvious pitfall of this method is that a larger bone will convey superior strength, but may in fact have the same bone density as a smaller bone. Other imaging modalities are available such as peripheral quantitative CT, but are largely research tools. Current osteoporosis medications increase bone density and reduce fracture risk but the mechanisms of these actions vary. Anti-resorptive medications (bisphosphonates and denosumab) primarily increase endocortical bone by bolstering mineralization of endosteal resorption pits and thereby increase cortical thickness and reduce cortical porosity. Anabolic medications (teriparatide and abaloparatide) increase the periosteal and endosteal perimeters without large changes in cortical thickness resulting in a larger more structurally sound bone. Because of the differences in the mechanisms of the various drugs, there are likely benefits of selecting a treatment based on a patient’s unique bone structure and pattern of bone loss. This review retreats to basic principles in order to advance clinical management of fragility fractures by examining how skeletal biomechanics, size, shape, and ultra-structural properties are the ultimate predictors of bone strength. Accurate measurement of these skeletal parameters through the development of better imaging scanners is critical to advancing fracture risk assessment and informing clinicians on the best treatment strategy. With this information, a “treat to target” approach could be employed to tailor current and future therapies to each patient’s unique skeletal characteristics. Keywords: Osteoporosis, Dual X-ray absorptiometry, Peripheral quantitative computed tomography, Skeletal fracture, Skeletal biomechanics, Bisphosphonates, Denosumab, Teriparatide, Romosozumab Background Two million osteoporosis fractures occur in the U.S. each year costing approximately $19 billion [1]. Despite the medical and economic costs of fragility fractures, osteoporosis screening is often overlooked and viewed as a low priority. Dual-energy X-ray absorptiometry (DXA) * Correspondence: 1 Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA 3 Endocrinology Section, Ann Arbor VA Medical Center, 2215 Fuller Road, Research 151, Ann Arbor, MI 48105-2399, USA Full list of author information is available at the end of the article was introduced in the mid-1980s as a rapid and safe imaging modality to estimate bone mineral density (BMD) and predict skeletal fracture risk [2]. Up until the widespread use of DXA, patients at high fracture risk were not easily identified and effective osteoporosis medications were limited. Today, not only are DXA scanners utilized in hospital radiology departments but they are also found at many physician group outpatient clinical practices. The World Health Organization (WHO) defines osteoporosis as a BMD T-score of − 2.5 or lower at any one location or having a previous fragility fracture. The © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 rationale for choosing this T-score was that the proportion of postmenopausal women with a T-score less than − 2.5 is equal to the fragility fracture lifetime risk of 30% [3]. It was expected that individuals who were below this T-score would have a greater fracture risk. Further, this cutoff value of − 2.5 was expected to change over time as the accumulation of experience and data would provide insight into a more appropriate cutoff value. However, this cutoff value has not changed in over 25 years despite data indicating that the T-score of − 2.5 captures only approximately 50% of women with fragility fractures [4]. There is less consensus of the definition of osteoporosis in men. The WHO, however, recommends similar T-score thresholds in men who are greater or equal to 50 years of age [5]. Because of a larger skeletal structure, fracture risk for men is less than in women for any similar T-score; and the fracture risk in men is less than half of women starting at age 55 [6]. Even though fracture rates are less than in men, the mortality associated with fractures is significantly higher [7, 8]. Thus, individuals with a T-score below the − 2.5 cutoff may be at higher risk of fracturing but they do not account for the majority of fracture cases in either women or men [9, 10]. While one of the challenges in management is to avoid over-treatment, individuals with Tscores above − 2.5 with other risks for fracture deserve attention, and should qualify for appropriate treatment as well. Other commonly used methods to predict fracture risk such as the FRAX scoring system, trabecular bone score and bone turnover markers may provide an incremental improvement in risk assessment when combined with DXA. Ultimately, skeletal biomechanics that include size, shape and bone molecular Page 2 of 13 structure are the predictors of bone strength. Understanding how each of these variables affects the skeleton is critical in the development of better fracture prediction tools to accurately identify those at a high risk for fractures. Bone biomechanics The adult skeleton is composed of 206 uniquely shaped structures, each of which coordinately adapts its morphology and tissue-level material properties to support the physiological loads encountered during daily activities. (...truncated)