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 was introduced in the mid-1980s as a rapid and safe im- Two million osteoporosis fractures occur in the U.S. aging modality to estimate bone mineral density (BMD) each year costing approximately $19 billion . Despite and predict skeletal fracture risk . Up until the wide- the medical and economic costs of fragility fractures, spread use of DXA, patients at high fracture risk were osteoporosis screening is often overlooked and viewed as not easily identified and effective osteoporosis medica- a low priority. Dual-energy X-ray absorptiometry (DXA) tions were limited. Today, not only are DXA scanners utilized in hospital radiology departments but they are also found at many physician group outpatient clinical * Correspondence: firstname.lastname@example.org practices. Division of Metabolism, Endocrinology & Diabetes, Department of Internal The World Health Organization (WHO) defines Medicine, University of Michigan, Ann Arbor, MI, USA osteoporosis as a BMD T-score of − 2.5 or lower at any Endocrinology Section, Ann Arbor VA Medical Center, 2215 Fuller Road, Research 151, Ann Arbor, MI 48105-2399, USA one location or having a previous fragility fracture. The Full list of author information is available at the end of the article © 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 Page 2 of 13 rationale for choosing this T-score was that the propor- structure are the predictors of bone strength. Under- tion of postmenopausal women with a T-score less than standing how each of these variables affects the skel- − 2.5 is equal to the fragility fracture lifetime risk of 30% eton is critical in the development of better fracture . It was expected that individuals who were below this prediction tools to accurately identify those at a high T-score would have a greater fracture risk. Further, this risk for fractures. cutoff value of − 2.5 was expected to change over time as the accumulation of experience and data would pro- Bone biomechanics vide insight into a more appropriate cutoff value. How- The adult skeleton is composed of 206 uniquely shaped ever, this cutoff value has not changed in over 25 years structures, each of which coordinately adapts its morph- despite data indicating that the T-score of − 2.5 captures ology and tissue-level material properties to support the only approximately 50% of women with fragility frac- physiological loads encountered during daily activities. tures . There is less consensus of the definition of Cortical bone is the dense outer shell that is divided into osteoporosis in men. The WHO, however, recommends three surfaces: the periosteum, intracortical pores, and similar T-score thresholds in men who are greater or endosteum (Fig. 1). Trabecular bone is surrounded by equal to 50 years of age . Because of a larger skeletal cortical bone and is comprised of a spongy network of structure, fracture risk for men is less than in women for connected plates and rods. To remain strong but light, any similar T-score; and the fracture risk in men is less the system uses cortical bone in the diaphyses and tra- than half of women starting at age 55 . Even though becular bone surrounded by a relatively thin cortical fracture rates are less than in men, the mortality associ- shell in the metaphyseal regions. The proportion of ated with fractures is significantly higher [7, 8]. cortical and trabecular bone varies depending on the lo- Thus, individuals with a T-score below the − 2.5 cutoff cation. For example, the ultradistal radius is approxi- may be at higher risk of fracturing but they do not ac- mately 25% cortical and 75% trabecular bone. The 1/3 count for the majority of fracture cases in either women proximal radius is primarily all cortical bone. or men [9, 10]. While one of the challenges in manage- The determinants of bone strength are complex but ment is to avoid over-treatment, individuals with T- can be divided into four basic components: size, shape, scores above − 2.5 with other risks for fracture deserve architecture and composition (Fig. 2). Bone has a unique attention, and should qualify for appropriate treatment ability to coordinately adjust these traits. This results in as well. a structure that is sufficiently stiff to resist habitual loads Other commonly used methods to predict fracture but minimizes mass, keeping the overall energy of move- risk such as the FRAX scoring system, trabecular ment to a minimum. The overall strength of a bone de- bone score and bone turnover markers may provide pends on the proportion of cortical and trabecular an incremental improvement in risk assessment when tissues, their morphologies and their material properties, combined with DXA. Ultimately, skeletal biomechan- and the interactions among these traits. An individual’s ics that include size, shape and bone molecular unique genetic program also contributes to bone Fig. 1 Structural characteristics of bone. Bone is comprised of a dense cortical shell that surrounds a spongy trabecular bone network. The periosteal diameter combined with the endosteal diameter determines cortical thickness. The size of bone along with cortical thickness and porosity significantly contribute to bone strength. The inner trabecular compartment contains a network of plates and rods that also contribute to bone strength Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 3 of 13 Fig. 2 Determinants of bone strength. Bone strength is a composite summation of numerous skeletal characteristics. The size of bone increases with age and with puberty. Ultimate bone size also has a large genetic contribution. Genetics and habitual loading determine bone shape. The architecture of bone is a complex interplay among many structural components. Cortical diameter, thickness and porosity contribute to cortical strength. The number, thickness, and the connectivity of plates and rods determine trabecular bone strength. Bone composition is difficult to measure non-invasively. The degree of collagen crosslinking and the density of collagen contribute to bone matrix strength. Newly formed protein matrix subsequently becomes mineralized and how the hydroxyapatite crystals are arranged within the matrix and the degree of mineralization contribute to bone hardness and strength strength; it is estimated that up to 70% of ultimate bone the skeleton, whether weight bearing or non-weight strength and structure is genetically determined . bearing. These loads cause the bone to deform with the amount of deformation being dependent on the applied Bone size load and the stiffness of the structure. A stiff structure The pubertal transition is the critical period in which will deform less than a compliant structure under the bone size is ultimately determined. Under the influence same load. These loads are generally small enough that of androgens, the periosteum undergoes expansion the system returns to its original state when the load is resulting in a greater bone cross-sectional area . removed. Endosteal resorption occurs simultaneously but not at Because bone is well adapted to these habitual loads, the rate of periosteal apposition. The end result is a lar- this process may leave the bone vulnerable or weak to ger bone and thicker cortex. Estrogens also direct an in- loads applied in a different direction, such as during a crease in periosteal expansion but not to the degree of fall. For example, the proximal femur is extremely strong androgens. Women generally also have less endosteal when loaded in a direction consistent with habitual bone resorption ultimately leading to a larger bone, al- forces. A healthy femur can withstand nearly 8 kN though smaller than in men, but the strength is main- (~ 1800 pounds) before breaking, and so theoretically tained and compensated by a relatively thicker cortex two femurs should be able to support the weight of an compared to men. Overall, the relatively smaller bone average car. However, the strength of the proximal femur size in women translates to an increased risk for declines by more than 50% when loaded in a direction fracture. consistent with that seen during a fall to the side . The mass and material properties are the same regardless of Bone shape the loading direction, but the orientation of these traits Each of the 206 bones is generally well adapted to resist relative to the two loading directions differs greatly. Under their habitual loads. This process, called functional adap- a fall-to-the-side loading direction, it is the amount of tation, occurs primarily during growth and results in a bone mass remaining within the femur that represents the biological system that is robust to the relatively narrow resistance to fracturing. range of daily loads. Habitual loading is an important contributor to bone modeling and remodeling, and ul- Bone architecture timately bone shape. Bone surfaces that experience the Bone architecture, the trabecular arrangement combined greatest compressive or tensile loads respond with in- with cortical bone thickness and porosity, provides a creased bone mass. Conversely, skeletal unloading leads scaffold that is significantly stronger than an equal mass to increased bone resorption and bone loss. Daily activ- of solid bone. The trabecular bone scaffold within the ities result in a load (force) being applied to the bones of marrow space is composed of plates and rods (Fig. 1) Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 4 of 13 with a higher plate:rod ratio conferring strength. With Osteoclast resorption and resultant porosity of the tra- aging, plates become more rod-like and plate connectiv- becular bone surface also contributes to bone fragility. ity with the rods declines, all of which contributes to lower bone strength and stiffness. Bone composition The arrangement of trabecular bone is strategic to Bone quality was originally defined as the factors provide maximal strength. This is especially evident in contributing to strength that are not explained by BMD. the femoral neck [14, 15]. The ability of the inferior cor- From a clinical perspective, this definition provides a tex and compressive arcade to resist compressive loads, name to unexplained factors. From an engineering combined with the superior cortex and tensile arcade to perspective, this definition makes little sense as it does resist tensile loads provides maximal strength and flexi- not provide a definable biomechanical pathway linking bility (Fig. 3). Failure of this cooperative network is the strength to physical bone traits and ultimately to the reason for femoral neck fractures. Thus, efforts to maintain underlying biology . The composition of bone that strength by applying more or greater loads to stimulate contributes to bone quality—the regular arrangement of bone formation may make the bone stronger for daily collagen, the degree of crosslinking of adjacent collagen loads. Unfortunately, upon losing appreciable bone mass in fibrils and mineral to protein matrix ratio—all contribute the femur (e.g., tensile arcade), it remains unclear whether to bone quality. Diseases such as Paget’s disease, diabetes an exercise program will be able to restore lost tissue. mellitus, and osteogenesis imperfecta and long-term use Cortical porosity is another layer that defines cortical of glucocorticoids contribute to poor bone quality. strength independent of cortical size. Heightened osteo- Another example of decreased bone quality are stress clast resorption expand existing Haversian canals, creat- fractures that occur due to repetitive damage. High bone ing large macro-pores and leading to the progressive turnover is also another component that leads to poor thinning of the cortical tissue that is capable of bearing bone quality. Bone turnover markers have been reported load. With age, pore volume increases but pore number to be predictive of fracture risk that is independent of remains relatively constant . It is mechanically for- BMD [22–24]. Clinical tests to assess bone quality are tuitous that the resorptive process begins near the endo- currently being developed but are not available for rou- cortical surface. The proximate location of these tine clinical use. macropores minimizes the impact on bone strength compared to pores created closer to the periosteal surface Skeletal biomechanical changes with puberty and aging [17–19]. Despite this biomechanically favorable location Net bone loss or formation is dependent on the balance of bone loss, cortical porosity is a strong predictor of frac- between bone resorption and bone formation. The net ture especially in the cortical rich area of the forearm . bone formation of skeletal “modeling” of childhood Fig. 3 Strategic arrangement of cortical and trabecular bone. The proximal femur experiences forces in different directions. a The critical aspects of femoral neck strength superimposed onto a hip DXA scan image. b With standing, the femoral neck experiences compress forces on the inferior surface and tensile forces on the superior surface. Compressive loads are reinforced with a compressive arcade composed of a thickened inferior cortex and an additional trabecular network. The tensile arcade is reinforced with a network of trabecular bone. These reinforcements are combined with lateral and medial cortices that provide additional reinforcements against side-to-side forces. NanoCT images were taken at 27 μm resolution using a phoenix nanotom-s (GE Sensing and Inspection Technologies, GmbH, Wunstorf, Germany) Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 5 of 13 ensures structural support during the critical growth The distribution of bone density across a population is period. Before puberty, skeletal development is nearly dependent on race, age and gender. For example, identical in boys and girls. New bone formation on the African-Americans have lower rates of fracture com- periosteum exceeds endosteal bone breakdown resulting pared to US Caucasians and Asians and this parallels the in skeletal expansion. Trabecular bone continues to de- population distribution differences among races . In velop in this period. Until the period of peak bone mass one study, the age-adjusted mean for femoral neck BMD at 30-40 years of age in men and women, total skeletal was 0.686 g/cm2 in US Caucasians and 0.841 g/cm2 in bone formation is greater than resorption. With aging, African Americans . Because of such racial and eth- and especially at menopause, this balance tips toward re- nic differences, the significance of T-scores must be con- sorption and bone loss. After the period of peak bone sidered based on the fracture risk of ethnic and racially mass, men and women lose similar amounts of cortical matched persons. A similar rationale can be applied to bone by endosteal resorption, but men have greater peri- men who have larger skeletal structures compared to osteal apposition than women, so that in men, net bone women. To control for racial differences, DXA calculates loss is less. Both sexes experience trabecular bone loss T-scores using normative databases based on NHANES with aging, but this effect is more pronounced in women III data that include non-Hispanic White, Black, His- than in men. The decline in estrogen at menopause pro- panic and Asian individuals . A pediatric normative motes loss of trabecular connectivity and exerts a pro- base is also available. found impact on bone strength . As stated before, bone size is directly related to strength. DXA does not account for bone size in asses- Tools currently available to assess fracture risk sing fracture risk. Attempts to correct bone size for DXA height and weight have been reported . Some DXA Despite its underappreciated limitations, DXA is often manufacturers allow for weight correction in the calcula- considered to be the gold standard imaging test for diag- tion of Z-scores to adjust for an expected decrease in nosing osteoporosis. Unlike older DXA machines that fracture risk as weight increases. Height correction is employed higher radiation, today’s scanners emit signifi- especially important in assessing fracture risk in children cantly less radiation per scan—as little as 1-10 microsie- affected by short stature or growth delay . verts (μSv) with about 7 μSv being the average ionizing DXA images are a 2-dimensional (vertical and hori- radiation dose received from natural background radi- zontal) condensation of a 3-dimensional structure. As ation . DXA is widely available in hospital and out- such, bone thickness is not measured in this scan. The patient practices. By utilizing two different energies this BMC measured reflects the amount of cortical and technology is able to differentiate the mineralized bone, trabecular tissue present within a structure that acts to composed of hydroxyapatite, from soft tissues such as attenuate the X-ray signal; bones with more tissue skin, fat and muscle. The two X-ray energies differ in attenuate the signal to a greater degree resulting in a their attenuation profiles after passing through bone and higher gray value and BMC measure. Bone area is a soft tissues. Older DXA units employed a pencil beam measure of the size of the ROI. For the hip, the ROI that had a limited scan area resulting in longer scan width is fixed and thus variation in bone area reflects times. Modern DXA units use a fan-shaped beam that differences in external bone size. The ratio of these two translates to scan times of 10-30 s. Standard DXA scans variables provides a measure of the mass density but not report bone density in grams/cm and is derived from a measure of morphology or material properties. Further, dividing the bone mineral content (BMC) in grams by BMD does not differentiate whether the variation in the region of interest (ROI) scanned in cm . BMD arises from differences in cortical mass, trabecular The standard locations for DXA measurement are the mass, or external bone size. L1-L4 lumbar spine, hip, and forearm. These reference Conventional wisdom is that women uniformly lose locations were originally selected because morbidity endosteal and trabecular bone in a similar pattern. Re- from fractures at these locations is high, especially at the cent data however suggest that the pattern of bone loss spine and hip. DXA results are reported as the standard with aging in women is not uniform . Bone shape deviation (SD) from a population mean, comparing the and size at the menopause transition may in fact have a subject to a population at peak bone mass (T-score) and critical role in determining long-term bone loss with to an age-matched population (Z-score). One and two aging. Women with narrower femoral necks experienced SDs from the mean encompass 68 and 95% of a popula- modest decreases in BMC compared to those with wider tion, respectively. Since peak bone mass occurs at be- femoral necks (Fig. 4). But, women with narrow femoral tween 30 and 40 years of age, it is appropriate to use Z- necks also had larger increases in femoral neck area scores in children and young adults who have yet to compared to women with wider femoral necks. BMD is achieve peak bone mass. the quotient of the BMC divided by the area. Because Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 6 of 13 Fig. 4 Areal BMD as determined by DXA declines with aging for different reasons. With aging, women with smaller femoral necks tend to increase bone area through an increase in cortical thickness by an increase in periosteal and endosteal bone formation. Since BMD may only decrease slightly but bone area increases more, the result is lower areal BMD as measured by DXA despite likely having little change in bone strength. In the case of women with larger femoral necks, the endosteal cortex undergoes excessive resorption without periosteal expansion resulting in a thinner cortex. The result is a lower BMC without significant change in bone area. The DXA areal BMD decreases and may result in a bone with less strength. Adapted from Jepsen, et al. JBMR 2017  the larger increase in the denominator (area) in women that are homogenous with small gray-value amplitude with narrow femoral necks is similarly matched by the lar- variations. On the other hand, bone that is of poor qual- ger decrease in the numerator (BMC) in women with wide ity produces higher gray-value amplitudes. TBS is a unit- femoral necks, the result is that both groups have similar less calculation of the sum of the squared gray-level losses in BMD over time but for very different reasons. differences between pixels at a specific distance. The The impact of these structural and mass changes on steeper slope represents well-structured bone while the strength is currently under investigation. In addition to lower slope is suggestive of poorer architecture. Based the previous discussion regarding how most fragility frac- on values provided by the manufacturer, TBS > 1.350 is tures occur in persons with T-scores > − 2.5, this example normal, 1.200-1.350 is consistent with partially degraded illustrates another limitation of DXA scanning to accur- bone and < 1.200 indicates degraded bone. ately predict bone strength and fracture risk. TBS is typically measured at the L1-L4 lumbar spine (LS), the same sites used for DXA. The results are pro- Trabecular bone score (TBS) vided for each vertebral body as well as the composite Other than BMD, fracture risk is dependent on bone for L1-L4. Unlike DXA, osteoarthritic changes have little geometry, microarchitecture, microdamage, rate of bone impact on data generated by TBS. turnover, and mineralization—all of which contribute to Several studies have shown that TBS predicts clinical, bone strength. TBS indirectly assesses skeletal texture hip and vertebral fractures in postmenopausal women using DXA images and can be used to predict the risk of [35, 36]. Some longitudinal studies have reported that spine and hip fractures in women and men above the TBS predicts fracture risk in men over the age of 40 but age of 40. It has been validated in multiple cohorts with data on premenopausal women are lacking [37, 38]. In large numbers of subjects and shown to improve frac- addition, a meta-analysis of 14 prospective population- ture risk prediction beyond that obtained by DXA. TBS based cohorts reported that TBS provided additional is available for clinical use in the United States . information on the 10-year fracture probability as esti- The TBS is a textural index based on evaluating the mated by the standard FRAX tool . pixel gray-level variations in the lumbar DXA image A new feature is available on the online FRAX risk . Well-structured bone produces 2-D DXA images assessment tool with an option to “adjust with TBS”.A Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 7 of 13 low TBS would increase the FRAX risk of major osteo- a hip or major osteoporotic fracture with or without data porotic fracture by 1.5-1.6 fold . Changes in TBS are on femoral neck BMD. The algorithm has been well vali- much smaller than LS BMD with osteoporosis treatment dated in independent cohorts . The Garvan calculator and therefore the role of using TBS to monitor patients is another tool used to predict fracture risk (https://www. on therapy is uncertain. There is no data on the impact garvan.org.au/promotions/bone-fracture-risk/calculator/). of a change in TBS on fracture risk. The calculator was developed using data obtained from the Dubbo Osteoporosis Epidemiology Study at Sydney’s Quantitative US (QUS) Garvan Institute. In addition to demographic variables QUS can provide information on bone structure and fra- and BMD or T-scores, the Garvan calculator takes into ac- gility. Due to its use of low-frequency ultrasound it is count the number of falls. The tool has been validated and safe and a relatively inexpensive method to assess for is found to be clinically useful in predicting fractures in osteoporosis. The two main parameters measured are those at high risk . Other calculators such as Osteo- the velocity of sound (VOS) and broadband US attenu- porosis Canada and FORE FRC v 2.0 predict the 10-year ation (BUA). Data provided by QUS of the heel have fracture risk but are not commonly used. The Male Osteo- been shown to correlate with the risk of fracture  porosis Risk Estimation Score (MORES) was reported to but it is not used routinely for diagnosis of osteoporosis. be a better tool to predict hip osteoporosis in men compared to FRAX . While acknowledging that these Quantitative CT (QCT) calculators do not include all risk factors and can underesti- QCT provides volumetric 3D measurements by utilizing matethefracturerisk, theyserveas a valuabletool to assist a low dose scan protocol and offers adequate details of physicians in assessing risk with one long-term goal of the cortical and trabecular bone to generate reasonable avoidance of treatment in patients at low fracture risk . estimates of strength through engineering-based analyses such as finite element analysis (FEA) and probabilistic Bone turnover markers (BTMs) modeling. QCT is most commonly studied at the lumbar BTMs are released during bone remodeling and can be spine and hip. A variation of QCT, high-resolution per- measured in blood or urine. BTMs provide an assess- ipheral quantitative computed tomography (HR-pQCT), ment of bone remodeling rate and are surrogate end- is mostly used to assess tibia and radius bone architec- points for fracture, bone quality and effectiveness of the ture and density. The associations between HR-pQCT- therapy. They are grouped into two broad categories: based vertebral bone measurements and prevalent verte- bone resorption and bone formation markers. Collagen bral fractures depend on the spinal locations of both degradation products, namely C-terminal cross-linked bone measurement and fracture [42, 43]. An unclear telopeptide of type 1 collagen (βCTX), are released correlation between QCT and other non-vertebral osteo- during bone resorption and reflect osteoclast activity. porotic fractures along with higher exposure to ionizing Bone formation markers such as procollagen type I N- radiation and cost have resulted in an infrequent use of terminal propeptide (PINP) and procollagen type I C- these scans. In addition, large precision errors with re- terminal propeptide (PICP) are peptides derived from peat measurements and unclear methods to adjust for posttranslational cleavage of type I procollagen mole- variation in marrow fat and soft tissue density remain cules by proteases at the N- and C-terminus, respect- challenges for wider clinical use of QCT. ively. These markers reflect osteoblast function and activity. Fracture risk assessment calculators Commercially available βCTX assays have been devel- Until recently, treatment decisions were made primarily oped with low method-specific difference and inter- using T-scores but the over-reliance on this score has re- assay variability. βCTX itself demonstrates significant sulted in over-treatment, especially in younger patients variation due to circadian rhythm and food intake. It is who may in fact have a lower fracture risk. Clinical risk best measured in the fasted state and in the morning. factors, such as age, previous fragility fracture, parental The International Osteoporosis Foundation recommends history of hip fracture at age < 80, smoking, excessive al- using PINP and βCTX to assess bone formation and cohol intake, and prolonged glucocorticoid use, all have bone resorption, respectively . been shown to confer risk independent of BMD meas- The utility of bone turnover markers in assessing the urement. Using these risk factors and BMD data, frac- risk of fracture has been studied in postmenopausal ture prediction algorithms have been developed. women. In the OFLEY cohort, healthy postmenopausal The FRAX scoring system (https://www.sheffield.ac. women who had BTMs in the highest quartile were uk/FRAX/) is one such fracture prediction algorithm noted to have a two-fold increase in the risk of fractures . It is the most widely used fracture prediction algo- with a RR of 1.8% . In another cohort of older post- rithm. The score provides a 10-year probability of having menopausal women, high levels of osteocalcin (bone Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 8 of 13 formation marker) were associated with a higher risk of mechanisms of actions of these newer treatments often fractures . BTMs can also be used for monitoring predict a superior efficacy in increasing BMD. osteoporosis treatment. In the IMPACT study, greater All approved osteoporosis medications produce sig- than 30% decline in the level of urine NTX was associ- nificant increases in spine and hip BMD as measured ated with a 50% reduction in non-vertebral fractures by DXA. The degree of BMD increase in the spine is . In postmenopausal women treated with teripara- likely a consequence of the greater surface area of tide, an increase in P1NP at three months correlated trabecular-rich vertebral bodies on which the agents with an increase in LS BMD at 18 months . act. Twelve months of treatment with bisphospho- While there has been widespread use of these nates increased BMD by approximately 4% in the markers for monitoring therapy in osteoporosis, treat- spine and 2% in the hip as reported in the landmark ment goals based on fracture reduction have not been FIT, VERT, BONE, and Horizon trials [53–56]. The defined. In addition, there is insufficient data on the efficacy of daily, weekly and monthly oral and yearly use of bone turnover markers for diagnosis of osteo- IV bisphosphonate medications are similar [57–61]. porosis, identifying candidates for treatment, and de- Compliance with oral bisphosphonates is a common termination of the length of bisphosphonate “drug factor in those patients who fail to respond to treat- holidays”. ment [62–64]. Denosumab has even greater effects likely owing to its enhanced ability to suppress bone resorption . Teriparatide, an anabolic agent, in- Treatment-related changes in bone density and creases spine and hip BMD . Abaloparatide, an- architecture other recently available anabolic agent, also markedly Antiresorptive and anabolic therapies increase spine and increases spine and hip BMD . hip BMD, with the highest increases in the spine Romosozumab, not yet approved for treatment, is a (Table 1). As newer agents are studied, a trend in more humanized monoclonal antibody that targets sclerostin, efficacious BMD improvement with each new agent is and has been reported to increase spine BMD approxi- apparent. Although many osteoporosis treatments have mately 13.5% and hip BMD approximately 6.5% after not been directly compared in head-to-head trials, the 12 months of treatment [68, 69]. Table 1 Summary of treatment-related changes in human skeletal architecture. Only published studies that reported defined skeletal architectural indices were included in the Table Areal BMD HR-pQCT, QCT QCT Bone biopsy/QCT Location Spine Hip Radius/Tibia Spine Hip Measure BMD Per.Diam CoPo CtTh Tb CoPo CtTh BV/TV CoPo CtTh BV/TV (Approx. % increase) (a) (a) (g) (g) (g) (m) (m) Bisphosphonates 4 2-2.5 ↓,NS ↑ ↑,NS ↓ NS (b) (b) (h) (h) (h) (n) Denosumab 5.5 3 ↓,NS ↑ ↑ ↓ (c) (c) (f) (i) (i) (i) (j) (k) (0) (p) (p) Teriparatide 9 3 ↑ ↑,NS ↑,NS ↑,↓ NS ↑ ↑ ↑ ↑ (d) (d) Abaloparatide 11 4 (e) (e) (l) (l) (l) Romosozumab 13.5 6.5 ↑ ↑ ↑ BMD bone mineral density, Per.Diam periosteal diameter, CoPo cortical porosity, CtTh cortical thickness; Tb trabecular indices; BV/TV bone volume/tissue volume, NS not significant, HR-pQCT high-resolution peripheral quantitative computed tomography, QCT quantitative computed tomography Notes: a. 12 months of treatment [53, 54, 56, 81, 82] b. 12 months of treatment  c. 18 months of treatment  d. 18 months of treatment  e. 12 months of treatment [68, 69] f.  g. Cortical volumetric BMD (Ct vBMD) as a surrogate for CtPo, Tb = Tb vBMD ; CtTh significant only for tibia, Tb vBMD increased at tibia ; Ct vBMD as a surrogate for CtPo with difference only in tibia [85, 86] h. CoPo as a surrogate for Ct vBMD, Tb as a marker of trabecular volumetric BMD (Tb vBMD) ; [70, 87] i. 24 months of treatment ; 18 months of treatment, increase in plate Tb number and thickness ; 18 months of treatment, increase in trabecular number ; 18 months of treatment, increase in CtTh in tibia only, reduction in trabecular thickness  j.  k.  l. [91, 93] m.  n.  o.  p.  Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 9 of 13 Numerous published studies have reported the archi- periosteal bone expansion that leaves a larger proportion tectural changes in the skeleton with such agents using a of under-mineralized bone [70–72]. Furthermore, since variety of techniques that include HR-pQCT and QCT the denominator in the BMD calculation is bone area of in situ hip and spine as well as similar techniques of and teriparatide certainly causes an increase in periosteal iliac crest bone biopsy samples. What has become clear diameter compared to BMC, BMD expectedly decreases. is that they do not uniformly produce similar results Presumably abaloparatide has similar effects but such (Table 1, Fig. 5). Bisphosphonates increase cortical thick- detailed human architectural analyses have not been ness primarily by decreasing the endosteal perimeter, published. Romosozumab is reported to increase cortical partially through the filling in of previously excavated re- thickness and trabecular bone volume, but how this sorption pits at the endosteal surfaces. In addition, agent affects cortical porosity and bone size has not been bisphosphonates also reduce cortical porosity and in- published. crease the amount of trabecular bone. Denosumab has similar effects and presumably to a higher degree owing The future of goal-directed therapy to its improved fracture reduction compared to Goal-directed treatment for osteoporosis has been advo- bisphosphonates. cated as a superior strategy rather than treatment deci- Teriparatide has unusual effects on cortical bone. sions made solely on DXA T-scores . Rather than While spine and hip BMD increased with this agent, arbitrary recommendations to treat osteoporosis for 5 or forearm BMD declined prompting a closer inspection of 10 years with oral bisphosphonates or 3 to 6 years with architectural changes in cortical-rich areas . Teri- IV bisphosphonates, depending on T-scores or whether paratide increases cortical porosity through two not mu- a patient is deemed either low or high risk for fracture, tually exclusive mechanisms: 1) increased osteocyte- treatment length should ideally be based on achieving a directed bone resorption and 2) enhanced cortical particular fracture risk threshold . The FRAX risk Fig. 5 Structural changes in bone with osteoporosis medications. The anti-resorptive medications (bisphosphonates and denosumab) and ana- bolic medications (teriparatide and likely abaloparatide) produce very different structural changes in bone. Although both classes increase tra- becular bone, their effects on cortical bone are different. Bisphosphonates and denosumab do not expand periosteal bone but do decrease the endosteal diameter by an increase in endosteal bone volume. Anti-resorptives also reduce cortical porosity. Anabolic agents lead to an increase in periosteal bone with a simultaneous increase in endosteal bone resorption resulting in a bone without a large change in cortical thickness. At the same time, anabolic agents increase cortical porosity. Despite the increase in cortical porosity, the larger bone has increased strength. NC = no change Choksi et al. Clinical Diabetes and Endocrinology (2018) 4:12 Page 10 of 13 stratification system has raised awareness among clini- an appreciation of how bone strength depends on mul- cians that other strong risk factors for fracture exist tiple traits, 3) incorporating the concept that people other than DXA T-scores—age, previous fragility frac- fracture for different biomechanical reasons, and 4) co- ture, high fall risk, long-term glucocorticoid use and alescing this information into a digestible outcome par- other diseases associated with high fracture risk that in- ameter that can be used clinically are areas where more clude diabetes mellitus. However, neither bone size nor work is needed. Using these sophisticated technologies, architectural makeup is routinely measured but clearly clinicians will be able to select therapy that targets skel- have large impacts on bone strength. For example, the etal characteristics. While much work remains in re- femoral neck of two individuals could have the same defining and identifying individuals at risk of fractures, BMD but the structure of these could be vastly different updating the current system of diagnosis and generating owing to the differences in size with a smaller femoral new technologies, we inch closer to the future of osteo- neck possessing lower strength. The bone area is already porosis care and personalized medicine. routinely reported in DXA scans but is not routinely uti- Abbreviations lized to assess risk. However, recent data support that BMC: Bone mineral content; BMD: Bone mineral density; BTM: Bone turnover bone size is dynamic and that postmenopausal women marker; DXA: Dual-energy X-ray absorptiometry; HR-pQCT: High-resolution peripheral quantitative computed tomography; LS: Lumbar spine; P1CP: Procollagen with smaller femoral neck size may in fact be at lower type IC-terminalpropeptide; P1NP:Procollagen type IN-terminalpropeptide; risk for fracture as they age compared to women with QCT: Quantitative computed tomography; QUS: Quantitative ultrasound; ROI: Region larger femoral neck size due to adapted changes with of interest; SD: Standard deviation; TBS: Trabecular bone score; WHO: World Health Organization; βCTX: C-terminal cross-linked telopeptide of type 1 collagen; aging . How these inter-individual differences in the μSv: Microsieverts age-changes of structure and mass affect bone strength and fracture has yet to be fully determined. Funding New imaging techniques that not only measure BMD This work was supported in part by grants from the NIH (AR065424, AR069620 to KJJ). but also measure critical indices directly related to frac- ture risk such as bone size, porosity, cortical thickness, Availability of data and materials trabecular volume and the mineral to matrix ratio are Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. needed. Even better, having such a device that is afford- able and appropriately sized allowing clinicians to assess Authors’ contributions fracture risk in the clinic is the future of osteoporosis PC, KJJ, and GAC were involved in the drafting, revising and final approval of care. Until the radiation dose of QCT is lower, such im- the manuscript. aging modalities are not practical for routine screening Ethics approval and consent to participate and treatment monitoring. Methods to directly measure Not applicable. bone quality such as reference point indentation are in- vestigative. This method is limited by pain, differing out- Competing interests The authors declare that they have no competing interests. come measures amongst cohorts [75–77] and are inconsistently related to traditional tissue-level mechan- Publisher’sNote ical properties [78, 79]. Compact ultrasound imaging de- Springer Nature remains neutral with regard to jurisdictional claims in vices that measure forearm cortical bone size and published maps and institutional affiliations. trabecular bone density is an exciting new area . Author details With advancing imaging methods, we can envision a Division of Metabolism, Endocrinology & Diabetes, Department of Internal treatment strategy whereby osteoporosis medications are Medicine, University of Michigan, Ann Arbor, MI, USA. Departments of selected based on individual skeletal characteristics. For Orthopaedic Surgery and Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. Endocrinology Section, Ann Arbor VA Medical Center, example, patients with larger bones, and thinner and 2215 Fuller Road, Research 151, Ann Arbor, MI 48105-2399, USA. porous cortices may benefit from bisphosphonates and denosumab, to reduce endocortical resorption that Received: 21 November 2017 Accepted: 27 April 2018 would ultimately increase cortical thickness. Conversely in patients with smaller bones whose cortex is not espe- References cially porous, teriparatide or abaloparatide may provide 1. What is Osteoporosis and What Causes It? Arlington: National Osteoporosis maximal bone strength. Clearly, this is an area of further Foundation. https://www.nof.org/patients/what-is-osteoporosis/. 2. Wahner HW, Dunn WL, Brown ML, Morin RL, Riggs BL. Comparison of dual- research. energy x-ray absorptiometry and dual photon absorptiometry for bone mineral measurements of the lumbar spine. 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Clinical Diabetes and Endocrinology
– Springer Journals
Published: May 29, 2018