Chapurlat r, Bui M, Sornay-Rendu E, Zebaze R, Delmas PD, Lespessailles E, Liew D and Seeman E.
Deterioration of Cortical and Trabecular Microstructure Identifies Women with Osteopenia or Normal Bone Mineral Density at Imminent and Long-term Risk for Fragility Fracture: a Prospective Study
J Bone Miner Res. 2019 Dec
Bone density (BMD) has led to the use of 3 Dx categories; osteoporosis, osteopenia & normal BMD. First, although fracture risk increases as BMD decreases, there is an unintended dichotomy of fracture risk. Treatment decisions are often mistakenly made as if bone fragility is present when Osteoporosis (BMD is ≤ -2.5 SD) & absent when BMD is > – 2.5 SD. This is reflected in the frequent interchangeable description of fractures as osteoporotic. Finding osteopenia or so-called ‘normal’ BMD is often a disincentive to initiating treatment because fragility is mistakenly believed to be absent.
Zebaze R, Atkinson EJ, Peng Y,Bui M, Ghasem-Zadeh A, Khosla S,Seeman E.
Increased Cortical Porosity and Reduced Trabecular Density are Not Necessarily Synonymous With Bone Loss and Microstructural Deterioration.
JBMR Plus. 2018.Nov 1.
Cross sectional study that describes the first generation SFS approach and performance through combing two domain knowledge indices.The SFS captured deterioration in cortical and trabecular bone and identified women with a prevalent fracture independent of BMD and outperformed current methods such as absolute values of cortical porosity, trabecular density, or BMD alone. The measurement of SFS compliments the measurement of BMD by capturing deterioration in cortical and trabecular microstructure and so identifies women with osteopenia or so‐called normal BMD at risk for fracture who would otherwise be regarded as being at low risk based on their BMD alone.
Zhu JJ, Mahendran D, Lee MH, Seah J, Fourlanos S, Varadarajan S, Ghasem-Zadeh A, MacIsaac RJ, Seeman E.
Systemic mastocytosis identified in two women developing fragility fractures during lactation.
Osteoporos Int (2018) 29: 1671.
Two women presenting with fragility fractures during lactation had bone mineral density (BMD) reduced more greatly than usually associated with lactation. Investigation identified an elevated serum tryptase, and marrow biopsy confirmed the diagnosis of mastocytosis. Lactation causes bone loss, but the occurrence of fractures in the setting of severe deficits in BMD and microstructural deterioration signals the need to consider additional causes of bone loss.
Bjørnerem Å, Wang X, Bui M, Ghasem-Zadeh A, Hopper JL, Zebaze R, Seeman E.
Menopause-Related Appendicular Bone Loss is Mainly Cortical and Results in Increased Cortical Porosity.
J Bone Miner Res. 2018 Apr;33(4):598-605.
After menopause, remodeling becomes unbalanced and rapid. Each of the many remodeling transactions deposits less bone than it resorbed, producing microstructural deterioration. However, because 80% of the skeleton is cortical, we hypothesized that most menopause-related bone loss and changes in bone microstructure are cortical, not trabecular in origin, and are the result of intracortical remodeling. The greatest bone loss, 7.7 mg hydroxyapatite (HA) annually, occurred in women transitioning from perimenopausal to postmenopause and of this, 6.1 mg HA (80%) was cortical. Over 90% of appendicular bone loss occurs during and after menopause, over 80% is cortical, and this may explain why 80% of fractures are appendicular.
Chiang CY, Zebaze R, Wang XF, Ghasem-Zadeh A, Zajac JD, Seeman E.
Cortical Matrix Mineral Density Measured Non-invasively in Pre- and Postmenopausal Women and a Woman with Vitamin D Dependent Rickets.
J Bone Miner Res. 2018 Feb 28.
Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantiﬁcation of MMD was conﬁned to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. Low-radiation HR-pQCT may facilitate noninvasive quantiﬁcation of bone’s MMD and microstructure in health, disease, and during treatment. This method is safe and facilitates follow-up of patients to assess treatment efﬁcacy in rickets or other bone diseases accompanied by changes in MMD.
Ramchand SK, Seeman E, Wang XF, Ghasem-Zadeh A, Francis PA, Ponnusamy EJ, Bardin MS, Bui M, Zebaze R, Zajac JD, Grossmann M.
Premenopausal women with early breast cancer treated with estradiol suppression have severely deteriorated bone microstructure.
Bone. 2017 Oct;103:131-135.
The resulting unbalanced and rapid bone remodelling replaces older bone with less bone that is less fully mineralized. We hypothesized that these changes result in severe microstructural deterioration and reduced matrix mineralization density. The severe cortical porosity and trabecular deterioration associated with estradiol depletion and the longevity of premenopausal women with early breast cancer treated with endocrine therapy provide a compelling rationale to investigate the efﬁcacy of antiresorptive therapy initiated at the time of breast cancer treatment.
Ghasem-Zadeh A, Burghardt A, Wang XF, Iuliano S, Bonaretti S, Bui M, Zebaze R, Seeman E.
Quantifying sex, race, and age specific differences in bone microstructure requires measurement of anatomically equivalent regions.
Bone. 2017 Aug;101:206-213.
Individuals differ in forearm length. As microstructure differs along the radius, we hypothesized that errors may occur when sexual and racial dimorphisms are quantiﬁed at a ﬁxed distance from the radio-carpal joint. Assessment of sex, race and age related differences in microstructure requires measurement of anatomically equivalent regions.
Zebaze R, Takao-Kawabata R, Peng Y, Zadeh AG, Hirano K, Yamane H, Takakura A, Isogai Y, Ishizuya T, Seeman E.
Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide.
Bone. 2017 Jun;99:80-84.
The pharmacokinetic proﬁle of parathyroid hormone (PTH) determines its effects on bone resorption and formation. When administered intermittently, anabolic effects are favored in comparison with the continuous treatment. Among the intermittent treatment regimens, lower frequency of administration may have a lower effect on bone remodeling. We therefore hypothesized that weekly administration of teriparatide will produce less increase in intracortical remodeling and porosity than reported using daily treatment.Effects of intermittent teriparatide depend on the dose and frequency of administration. Daily dosing, particularly the higher dose, but not weekly dosing, increased cortical porosity. Work is needed to investigate the effects of the regimens on bone formation.
Bjørnerem Å, Ghasem-Zadeh A, Wang X, Bui M, Walker SP, Zebaze R, Seeman E.
Irreversible Deterioration of Cortical and Trabecular Microstructure Associated With Breastfeeding.
J Bone Miner Res. 2017 Apr;32(4):681-687.
In summary, breastfeeding is associated with deterioration of cortical and trabecular bone microstructure and a reduction in completeness of secondary matrix mineralisation at the appendicular skeleton. The bone loss was irreversible during 2.6 years follow up after the end of lactation, and 3 years after resumption of regular menses. The relevance of the these deﬁcits in terms of compromising bone strength and increasing fracture risk remain to be established. Epidemiological studies report that lactation is neutral or protective against fracture; no long term deleterious effects on fracture risk are reported.(7,41,42) Further studies are needed to establish whether the deteriora-tion in microarchitecture of the appendicular skeleton contrib-utes to fracture risk later in life.
Zebaze R, Libanati C, McClung MR, Zanchetta JR, Kendler DL, Høiseth A, Wang A, Ghasem-Zadeh A, Seeman E.
Denosumab Reduces Cortical Porosity of the Proximal Femoral Shaft in Postmenopausal Women With Osteoporosis.
J Bone Miner Res. 2016 Oct;31(10):1827-1834
In summary, we conﬁrm and extend reports of ex vivo studies in animal models, and reports in human subjects documenting a reduction of cortical porosity associated with denosumab therapy. Quantiﬁcation of cortical porosity of the hip provides a means of assessing fracture risk and the effects of treatment on this important determinant of bone strength. The beneﬁts of denosumab treatment in reducing porosity at this location are relevant to our understanding of the structural basis of the reduced nonvertebral and hip fracture risk observed in clinical trials.
Ramchand SK, Chiang CY, Zebaze RM, Seeman E.
Recurrence of bilateral atypical femoral fractures associated with the sequential use of teriparatide and denosumab: a case report.
Osteoporos Int. 2016 Feb;27(2):821-5.
Given the increase in mean tissue density, several alterna-tive approaches to manage osteoporosis in patients with AFFs warrant consideration. One option is to treat with a weaker antiresorptive like raloxifene. This drug improves bone tough-ness by increasing bone water content and has minimal effects on tissue mineral composition or microdamage accumulation . Novel approaches such as monoclonal anti-sclerostin antibodies that facilitate bone formation and perhaps also re-duce bone resorption, may have a role in the management of such patients. To date, there are no means of identifying pa-tients at risk of AFFs before antiresorptive therapy is started. Work is needed to determine whether measurement of the completeness of tissue mineralization density, circulating cross-linked collagen, and bone microarchitecture might sig-nal a high risk for atypical fractures and so the need to stop bisphosphonates.
Shigdel R, Osima M, Ahmed LA, Joakimsen RM, Eriksen EF, Zebaze R, Bjørnerem Å.
Bone turnover markers are associated with higher cortical porosity, thinner cortices, and larger size of the proximal femur and non-vertebral fractures.
Bone. 2015 Dec;81:1-6.
In conclusion, increased bone remodeling as reﬂected in increased serum levels of BTM, is associated with increased cortical porosity, thin-ner cortices, and larger size of the femoral subtrochanter in postmeno-pausal women. Moreover, the increased BTM is associated with higher odds for non-vertebral fracture partly independent of FN aBMD, cortical porosity, and thickness. This data corroborates the notion from previous studies that BTM may provide additional information about risk of frac-ture. Prospective studies are needed to determine whether measure-ment of BTM will assist in the prediction of fragility fractures and whether they can be useful in clinical practice.
Bala Y, Zebaze R, Ghasem-Zadeh A, Atkinson EJ, Iuliano S, Peterson JM, Amin S, Bjørnerem Å, Melton LJ, Johansson H, Kanis JA, Khosla S, Seeman E.
Cortical porosity identifies women with osteopenia at increased risk for forearm fractures.
J Bone Miner Res. 2014 Jun;29(6):1356-1362
In summary and conclusion, postmenopausal women with distal forearm fractures have microstructural deterioration characterized by high cortical porosity and reduced trabecular BV/TV. UDR aBMD in the osteoporosis range (T-score ≤ −2.5D) captured these abnormalities so measurement of microarchitecture did not identify a greater proportion of women with fracture than did areal BMD in this range. In women with osteopenia, the source of over 50% of all fractures, fracture risk was increased if high porosity was present so measuring porosity improved identification of women with osteopenia with forearm fractures. Thus, measuring porosity is likely to be clinically useful in identifying women at risk for fracture considered at low risk based on their aBMD measurement alone. Further research will be needed to determine whether assessment of microstructure at the spine and proximal femur improves the sensitivity and specificity in identification of women at risk for fracture at those locations.
Zebaze RM, Libanati C, Austin M, Ghasem-Zadeh A, Hanley D5, Zanchetta JR, Thomas T, Boutroy S, Bogado CE, Bilezikian JP, Seeman E.
Differing effects of denosumab and alendronate on cortical and trabecular bone
Bone 2014 Feb;59:173-179
In summary, this is the ﬁrst randomized double-blind, placebo con-trolled trial comparing the effect of two remodeling suppressant therapies on intracortical porosity in vivo. Denosumab reduced remodeling more rapidly, more completely and decreased porosity more than alendronate. Given the exponential relationship between porosity and bone stiffness, partly reversing cortical porosity is likely to contribute to reductions in fracture risk. Whether this greater reduction in porosity translates into better anti-fracture efﬁcacy will require additional comparator trials.
Bala Y, Chapurlat R, Cheung AM, Felsenberg D, LaRoche M, Morris E, Reeve J, Thomas T, Zanchetta J, Bock O, Ghasem-Zadeh A, Djoumessi RM, Seeman E, Rizzoli R.
Risedronate Slows or Partly Reverses Cortical and Trabecular Microarchitectural Deterioration in Postmenopausal Women.
J Bone Miner Res. 2014 Feb;29(2):380-388
In conclusion, the morphological effects of antiresorptive therapy partly depend on when it is administered. Risedronate is likely to reduce fracture risk, in part, by reducing cortical porosity by allowing partial reﬁlling of existing pores and by reducing the appearance of new cortical porosity. These beneﬁts were observed within the ﬁrst year of treatment and so support the rapid and sustained efﬁcacy in the early reduction in fracture risk reported using this agent. Featured on the cove of JBMR when this paper was published.
Ashild Bjørnerem, Quang Minh Bui, Ali Ghasem‐Zadeh, John L Hopper,Roger Zebaze, and Ego Seeman.
Fracture Risk and Height: An Association Partly Accounted for by Cortical Porosity of Relatively Thinner Cortices.
J Bone Miner Res. 2013 September;28(9):2017-2026
In summary, as a long bone increases in length, it becomes wider and has a relatively larger medullary canal, producing a relatively thinner cortex. Concomitant intracortical remodeling forms the intracortical Haversian‐Volkmann canal network that appears as porosity in cross‐section. The excavation of the central medullary canal void volume distributes the mineralized bone volume radially in space, achieving bending strength without compromising compressive strength. The mass needed to achieve this is minimized by greater radial distribution. Thus, taller women assemble wider and relatively thinner cortices with higher porosity, achieving the bone strength required for load bearing and lightness required for mobility during young adulthood. These structural advantages become liabilities with longevity because intracortical and endocortical remodeling erodes a skeleton already assembled with relatively thinner and more porous cortices, increasing fracture risk. Cortical porosity is likely to assist in identifying women with high risk for fracture and should be measured as part of risk assessment for fracture prevention.
Zebaze R, Ghasem-Zadeh A, Mbala A, Seeman E.
A new method of segmentation of compact-appearing, transitional and trabecular compartments and quantification of cortical porosity from high resolution peripheral quantitative computed tomographic images.
Bone 2013 May;54(1):8-20.
In summary, studies of the effects of growth, aging, disease, frac-ture risk assessment in individuals, and the effects of therapy on frac-ture risk are hindered, in part, by issues related to image processing and analysis. The method described here accurately and reproducibly (i) segments bone from background, (ii) segments bone into its com-partments by ﬁnding the position of the bone edges and (iii) quan-tiﬁes porosity by estimating the fraction of each voxel occupied by void space and averaging the porosities in all voxels. Segmentation of the transitional zone is likely to allow accurate assessment of the effects of growth, aging, diseases and therapies by more correctly apportioning bone and bone loss to the cortical, transitional and tra-becular compartments.
Zebaze RM, Ghasem-Zadeh A, Bohte A, Iuliano-Burns S, Mirams M, Price RI, et al.
Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study.
Lancet 2010 May;375:1729–36.
The original Lancet paper that describes the domain knowledge indices we use in the first generation of the SFS product .Accurate assessment of bone structure, especially porosity producing cortical remnants, could improve identiﬁcation of individuals at high and low risk of fracture and therefore assist targeting of treatment.
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