Overview, Vol 15, Issue 1

Only doubt is certain and disbelief worth believing.
Without this courage there can be no learning.
Believe nothing.
Anonymous*

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis. Its purpose was to provide readers without easy access to the literature with summaries of the most important literature. We now inhabit a virtual world. Information is instantaneously accessible to all at the tap of a keyboard; understanding is not. In the spirit captured by the anonymous author*, the purpose of this publication is to provide critical evaluation of the most important literature and so to provoke discussion. It is our intention to promote dialogue which examines the quality of information published and so its credibility. The opinions expressed are my own and do not necessarily reflect those of the International Osteoporosis Foundation."

We invite readers to comment on and discuss this journal entry at the bottom of the page.

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In this Issue

  1. Osteocytes: The galaxy within
  2. The Bone Remodeling Compartment: Where the action is
  3. Coupling Between Bone Resorption and Formation Within the BRC
  4. Coadministration of Antiresorptive and Anabolic Therapy: Is two better than one?
  5. Cortical Porosity: The void within
  6. Bone Formed During Anabolic Treatment is Slowly Lost After Stopping
  7. Modeling Based Bone Formation Detected by Suppressing Remodeling
  8. Denosumab, Alendronate and Remodeling Suppression
  9. Raloxifene and Skeleton Hydration
  10. Bisphosphonates Do Not Increase Cortical Thickness
  11. Odanacatib and Altered Ductility
  12. Heterogeneity in Trabecular Matrix Mineral Density
  13. Familial Resemblance in Microarchitecture
  14. Fractures, Osteopenia and Mortality
  15. Sclerostin Inhibition Preserves Bone Mass in Paralysis
  16. Atrial Fibrillation and Alendronate


Osteocytes
The galaxy within

Buenzli PR, Sims NA. Quantifying the osteocyte network in the human skeleton.
Bone 2015;75:144-50.

Buenzli and Sims present a fascinating insight into the intergalactic vastness of the osteocyte-canalicular network. If you integrate the content of this paper into your thinking, you will never ‘see’ bone in quite the same way again. The authors estimate that the total number of osteocytes within the skeleton is ~42 billion, the total number of dendritic projections is ~3.7 trillion forming a total length of 175,000 km. These cells form 23 trillion connections with each other and with bone surface cells. The total surface area of the lacunocanalicular system is 215 m2 but within there is only enough space for 24 mL of extracellular fluid. The authors suggest 9.1 million osteocytes are replenished daily.

Figure 1. Osteocytes communicate with each other by interconnecting canaliculi. Image with permission from authors.

 

 

 

 

Hesse B, Varga P, Langer M, Pacureanu A, Schrof S, Männicke N, Suhonen H, Maurer P, Cloetens P, Peyrin F, Raum K. Canalicular network morphology is the major determinant of the spatial distribution of mass density in human bone tissue: evidence by means of synchrotron radiation phase-contrast nano-CT. J Bone Miner Res 2015;30:346-56.

Hesse et al hypothesized that mineral exchange is achieved by the diffusion of mineral from the lacunar-canalicular network (LCN) to the bone matrix, resulting in a gradual change in tissue mineralization. The aim of this study was, therefore, to investigate the spatial distribution of mass density in the perilacunar and pericanalicular bone matrix and to explore how these densities are influenced by tissue aging. This is achieved by analyzing human jaw bone specimens from four healthy donors and four treated with high-dosage bisphosphonate using synchrotron radiation phase-contrast nano-CT (50-nm voxel). Mass density in the vicinity of lacunae (p<0.001) and canaliculi (p<0.001) is different from the mean matrix mass density, resulting in gradients with respect to the distance from both pore-matrix interfaces, which diminish with increasing tissue age. The density gradients are more pronounced around the lacunae than canaliculi.  

Figure 2. Perilacunar and pericanalicular bone tissue mass densities. (A) One slice of a volume of interest containing one osteocyte lacuna cropped from the 3D reconstructed phase nano-CT image. The volume of interest (VOI) dimensions are 800x600x630 pixels. The gray scale corresponds to mass density, and the scale bar=10 µm. (B) Surface representations of the lacunar (red) and canalicular (green) compartments segmented from the same image volume. (C) Distance transform image showing the shortest distance from each point in matrix to the lacunar-canalicular network. (D) Histogram of the 3D distance map (shortest distance distribution [SDD]) of the canalicular (green) and the lacunar (red) boundaries shown together with their cumulative functions for the same VOI. From the solid lines, 50% of the bone tissue is within 1.2-µm to the canalicular boundaries, whereas at this distance the cumulative function of the histogram of the distances considering the lacuna is only about 10 times smaller. (E, F) Average mass density and standard error bands as a function of the shortest distance to the osteocyte lacuna (E) and canaliculi (F), shown for the same VOI. The gray horizontal lines represent the mean mass density within the VOI. Reproduced from J Bone Miner Res 2015;30:346-56 with permission of the American Society of Bone and Mineral Research.


The Bone Remodeling Compartment
Where the action is

Jensen PR, Andersen TL, Hauge EM, Bollerslev J, Delaisse JM. A joined role of canopy and reversal cells in bone remodeling ‒ Lessons from glucocorticoid-induced osteoporosis. Bone 2015;73:16-23.

The endosteal surface is covered by flattened osteoblast cells. At points of initiation of remodeling upon an endosteal surface, these lining cells lift and form the ‘canopy’ or ‘roof’ of a bone remodeling compartment (BRC) within which the remodeling cycle takes place. Jensen et al report that coupling between resorption and formation phases of the remodeling cycle requires an intact canopy overlying the surface upon which osteoclasts remove, and then osteoblasts deposit, bone during remodeling. Disruption of the canopy in myeloma, postmenopausal- and glucocorticoid-induced osteoporosis is associated with the absence of progression to the formation phase, i.e., uncoupling. Long-term glucocorticoid treatment is associated with arrested remodeling and lack of canopy coverage correlated with a deficiency in forming surfaces. The reason for the lack of canopies is not apparent but the reason this lack of canopies contributes to uncoupling may relate to the role of this layer or multilayered structure in providing a reservoir of osteoprogenitors.

Jean-Marie Delaisse and his group of investigators have pioneered this a fascinating area of research. A reading of a few of their papers is highly recommended because it provides important insights into bone remodeling. Remodeling is initiated at points upon the three (intracortical, endocortical and trabecular) components of bone’s inner or endosteal surface.


Coupling Between Bone Resorption and Formation Within the BRC

Sims NA, Martin TJ. Coupling signals between the osteoclast and osteoblast: How are Messages transmitted between these temporary visitors to the bone surface?
Front Endocrinol (Lausanne) 2015;6:41.

This short opinion piece is required reading for all of us. Sims and Martin present an elegant synthesis of the complex coordination of the volumes of bone resorbed and formed during bone remodeling; a coordination commonly referred to as coupling.

One of the challenges in understanding coupling mediated by local factors (from resorbed matrix, osteoclasts or by osteoclasts and osteoblast contact) is that these cells are not present at the same time. Resorption by osteoclasts occurs over a few weeks. Initiation of bone formation is delayed by a reversal phase of about a week or more during which neither osteoclasts or osteoblasts are present! Bone formation then proceeds with deposition of matrix during three months.

The authors suggest that osteoclast-derived coupling factors released from the matrix, secreted from the osteoclast, or expressed on the cell membrane initiate differentiation of early osteoblast progenitors with the level of osteoblast activity and numbers of differentiated cells refined by other factors released by a range of cells within the BMU.

Figure 3. Possible coupling mechanisms that overcome the delay between resorption and formation. (A) Osteoclast-derived factors (released from the matrix, secreted from the osteoclast, or expressed on the osteoclast membrane) initiate differentiation of very early osteoblast progenitors. Osteoblast activity and numbers of differentiated cells may be refined by factors from a range of cells within the BMU. Osteoclast-derived factors may act directly on cells that transmit signals (dashed lines) to osteoblast precursors and mature osteoblasts; these transmitting cells may be (B) osteoblast-lineage cells in the remodeling canopy, (C) reversal cells on the surface, and (D) osteocytes. (E) Physical changes brought about by the osteoclast such as the resorptive pit and mechanical strain detected by osteocytes may provide signals (in part mediated by sclerostin regulation) required for initiation and completion of the correct volume of matrix formed by mature osteoblasts. Reproduced from Front Endocrinol 2015;6:41 under the terms of the Creative Commons Attribution License (CC BY).


Coadministration of Antiresorptive and Anabolic Therapy
Is two better than one?

de Bakker CM, Altman AR, Tseng WJ, Tribble MB, Li C, Chandra A, Qin L, Liu XS. µCT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy. Bone 2015;73:198-207.

de Bakker et al report a µCT-based in vivo dynamic histomorphometry technique for tracking changes during therapy. There are many interesting aspects to this study and its worth a quiet evening thorough reading. Two aspects are of particular interest are first that these investigators validate a method of quantifying bone remodeling by µCT and second that they examine and provide evidence for net benefits of combining anabolic and antiresorptive therapy, rather than the blunting usually reported leading to the unfortunate neglect of the value of combined therapy for patients (Seeman and Martin, J Bone Miner Res 2015;30:753-64). The investigators report increased rate of bone formation in rats treated with PTH and PTH+alendronate (ALN) with no evidence of bluniting of the response relative to PTH despite a , decrease in measures of bone resorption with ALN and PTH+ALN. PTH induced bone formation despite bone resorption suppression. The reason adding an antiresorptive might blunt the anabolic effect of PTH is that the anabolic effect is believed to be mediated mainly by remodeling based bone formation rather than modeling based bone formation. If so, then the anabolic effect should be blunted but this is not observed. The study did not evaluate bone strength. This is important. While there may be no blunting of the anabolic effect, evidence is needed that there is an advantage in terms of biomechanical strength by combining therapy over either drug alone. At present I am not convinced that such evidence exists. More work is needed.


Cortical Porosity
The void within

Nirody JA, Cheng KP, Parrish RM, Burghardt AJ, Majumdar S, Link TM, Kazakia GJ. Spatial distribution of intracortical porosity varies across age and sex. Bone 2015;75:88-95.

Nirody et al evaluated porosity of cortex adjacent to the medullary canal, of midcortical and subperiosteal regions using HR-pQCT of the distal tibia from 145 individuals. The elderly (65-78 years, n=22) had higher porosity than young subjects (20-29 years, n=29) with the greatest difference in midcortical porosity (+344%, p<0.001) due to more (+243%, p<0.001) and bigger pores (+28%, p<0.001). Females had greater age-related changes in porosity and pore number than males. Females and males displayed comparable nonsignificant changes with age in pore size.

This work raises a number of issues. First, the greater difference across age in midcortical porosity is contrary to most published work suggesting that there is a gradient of increasing in porosity across the cortex with the highest porosity in advanced age being in inner cortex adjacent to the medullary canal, and progressively less porosity towards the periosteal surface.

This discrepancy is likely to be the result of problems in distinguishing fragmented inner cortex, which looks like trabecular bone, from true trabecular bone in the medullary compartment. What is inner cortex has probably been trabecularized leaving the rise in porosity in this inner cortex underestimated; the porosity and fragments of cortex produced by intracortical remodeling are erroneously calculated as being part of the medullary canal seemingly enlarged by these contents.

Second, the age-related increase in porosity is reported to be the result of more pores than bigger pores. This is also contrary to most literature which suggests that the increase in porosity is the result of progressive enlargement of existing pores. There is really no such thing as ‘porosity’. Over 80% of pores are cross sections of the canals traversing the cortex formed during skeletal growth, the remaining porosity is the result of remodeling units in either their resorption, reversal or excavation phases (only about 10-15% of the bone is being remodelled annually), while the remainder is formed by the osteocyic lacunocanalicular system and voids in collagen.

The reason why porosity increases more by enlargement of existing pores than formation of new pores is that all intracortical remodeling is initiated at points upon the lining of the canals and when the matrix around the canal is excavated, less matrix is deposited producing focal canal enlargement. With time, more and more enlargement of existing canals occurs until they coalesce forming large irregularly shaped ‘pores’. However, it is plausible that a new canal is dug from an existing canal. More work is needed to resolve this issue. Finding nonsignificant age related increases in pore size in either sex is problematic. I suggest that most pores remain undetected using threshold based segmentation.

Tong X, Burton IS, Isaksson H, Jurvelin JS, Kroger H. Cortical bone histomorphometry in male remoral neck: The investigation of age-association and regional differences. Calcif Tissue Int 2015;96:295-306.

Tong et al report enormous heterogeneity in cortical osteonal size and porosity as well as heterogeneity in cortical thicknesses. These authors investigated age-association differences in corticl morphology of the femoral neck in (n=20, aged 18-82 years, males). While the sample size was small, the findings are of interest to at least note the magnitude of the heterogeneity in these traits and think about what they might mean.

Mean Ct.Wi, inferior Ct.Wi, and superior Ct.Wi were negatively associated with age. The inferior cortex was the thickest and the superior cortex was the thinnest. Osteonal size and pore area were negatively associated with age. Osteonal area and number were higher in the antero-inferior area (P<0.002) and infero-posterior area (P=0.002) compared to the postero-superior area. The Haversian canal area was higher in the infero-posterior area compared to the postero-superior area (P=0.002). Moreover, porosity was higher in the antero-superior area (P<0.002), supero-anterior area (P<0.002) and supero-posterior area (P<0.002) compared to the infero-anterior area. Eroded endocortical perimeter (E.Pm/Ec.Pm) correlated with superior cortical width.


Bone Formed During Anabolic Treatment is Slowly Lost After Stopping

Recknor CP, Recker RR, Benson CT, Robins DA, Chiang AY, Alam J, Hu L, Matsumoto T, Sowa H, Sloan JH, Konrad RJ, Mitlak BH, Sipos AA. The effect of discontinuing treatment with blosozumab: Follow-up results of a phase 2 randomized clinical trial in postmenopausal women with low bone mineral density. J Bone Miner Res 2015;doi:10.1002/jbmr.2489.

Blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and is one of the new kids on the horizon for anabolic therapy. Recknor et al studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after treatment stopped. Of the 106 women completing treatment; 88 completed 1-year follow-up. At the end of one year after discontinuing treatment, spine BMD remained greater than placebo in women treated with blosozumab 270 mg every 2 weeks (Q2W), and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined but remained greater than placebo in women treated with those two doses of blosozumab (3.9% and 2.6% above baseline, respectively).

As with teriparatide therapy and with antiresorptive therapy, when treatment is stopped, the benefits are progressively lost. The rate of loss varies from drug to drug but whatever the case, presumably, with return of remodeling, benefits are eroded and like teriparatide, it is likely that antiresorptive therapy will be needed at the end of a course of this class of anabolic therapy.

Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, Myers SL. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Min Res 2015;30:216-24.

Recker et al report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin in postmenopausal women with low BMD randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score –2.8). Blosozumab increased spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout.


Modeling Based Bone Formation Detected by Suppressing Remodeling

Ominsky MS, Libanati C, Niu QT, Boyce RW, Kostenuik PJ, Wagman RB, Baron R, Dempster DW. Sustained modeling-based bone formation during adulthood in cynomolgus monkeys may contribute to continuous BMD gains with denosumab. J Bone Miner Res 2015; doi:10.1002/jbmr.2480.

Denosumab (DMAb) administration is associated with continued BMD increases through 8 years. Secondary mineralization may occur for several years after deposition of bone matrix. However, the increase in BMD should become asymptotic as more and more complete mineralization is achieved. For this reason, it is difficult to explain a continued increase in BMD during 8 years of DMab therapy. Ominsky et al report that the increase in BMD may be the result of continued accrual of bone matrix via modeling-based bone formation that occurs in the untreated state but is either obscured or removed by remodeling. When remodeling is suppressed, this has allows the continued slow modeling to be detected and influence bone morphology.

The authors examined fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated with vehicle while other OVX cynos received monthly 25 or 50 mg/kg DMAb. DMAb groups had low remodeling biomarkers and near-absent fluorochrome labeling in proximal femur cancellous bone. Femoral neck BMD continued to rise in DMAb-treated cynos , from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination showed labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with modeling-based bone formation. Quantitative analysis at the ninth rib, demonstrated that DMAb did not alter modeling-based labels suggesting that this effect depended in part upon loading circumstances. These observations are indeed novel and require further investigation, particularly in human subjects.


Denosumab, Alendronate and Remodeling Suppression

Kostenuik PJ, Smith SY, Samadfam R, Jolette J, Zhou L, Ominsky MS. Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys. J Bone Miner Res 2015;30:657-69.

Kostenuik et al report the effect of transitioning from ALN to DMAb was examined in mature OVX cynos. One day after OVX, cynos (7-10/group) were treated with vehicle (VEH, s.c.), ALN (50 µg/kg, i.v., twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb produced a greater reductions in serum CTx than ALN, and transition from ALN to DMAb produced further reductions relative to continued ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls.

Figure 4. Upper panels are fluorescent photomicrographs of tibial diaphysis cross-sections from the VEH, ALN, ALN-DMAb and DMAb groups. VEH controls exhibited the greatest cortical porosity and intracortical remodeling, while the ALN-DMAb and DMAb groups exhibited the least. Lower panels are Goldner’s trichrome-stained photomicrographs of trabecular bone from L2. VEH control depicts remodeling with a large scalloped resorption pit on the upper trabecular surface (arrowhead), and its refilling by osteoblasts (arrow). Minimal remodeling is seen in the treatment groups. Shallow but increased eroded surfaces are evident in the ALN example (arrowheads), whereas eroded surfaces were minimal in ALN-DMAb and DMAb examples. Reproduced from J Bone Miner Res 2015;30:657-69 with permission of the American Society of Bone and Mineral Research.


Raloxifene and Skeleton Hydration

Allen MR, Territo PR, Lin C, Persohn S, Jiang L, Riley AA, McCarthy BP, Newman CL, Burr DB, Hutchins GD. In vivo UTE-MRI reveals positive effects of raloxifene on skeletal bound water in skeletally mature beagle dogs. J Bone Miner Res 2015;doi:10.1002/jbmr.2470.

Allen et al report that raloxifene affects mechanical properties in part through modification of skeletal bound water. Skeletal hydration was measured in vivo using ultrashort echotime magnetic resonance imaging (UTE-MRI) in 12 skeletally female beagle dogs (n=6/group) treated for 6 months with vehicle (VEH, 1 ml/kg/d) or raloxifene (RAL, 0.5 mg/kg/d). Following six months, animals underwent in vivo UTE-MRI of the proximal tibial cortical bone. UTE-MRI signal intensity versus echotime curves were analyzed. Raloxifene-treated animals had higher bound water (+14%; p=0.05) and lower free water (-20%) compared to controls.


Bisphosphonates Do Not Increase Cortical Thickness

Niimi R, Kono T, Nishihara A, Hasegawa M, Matsumine A, Kono T, Sudo A. Cortical thickness of the femur and long-term bisphosphonate use. J Bone Miner Res 2015;30:225-31.

Niimi et al enrolled 142 patients (mean 79 years) taking bisphosphonate (BP) for more than 5 years, and enrolled 426 BP free osteoporosis patients as controls. There were no differences in cortical thickness between long-term BP users and controls. In addition, after further use of BP for a minimum of 1 year, no differences in the changes in cortical thickness of the femur were observed.

There is no rational basis for there to be cortical thickening. This may occur by greater periosteal apposition but antiresorptives do not stimulate periosteal deposition of bone, nor do they inhibit it. Antiresorptives at best reduce the number of remodeling sites resorbing bone upon the endocortical surface, reduce them, not abolish them, so they slow cortical thinning but they do not restore cortical thickness nor to they promote bone formation in the endocortical surface.


Odanacatib and Altered Ductility

Khan MP, Singh AK, Singh AK, Shrivastava P, Tiwari MC, Nagar GK, Bora HK, Parameswaran V, Sanyal S, Bellare JR, Chattopadhyay N. Odanacatib restores trabecular bone of skeletally mature female rabbits with osteopenia but induces brittleness of cortical bone: a comparative study of the investigational drug with PTH, estrogen and alendronate. J Bone Miner Res 2015;doi:10.1002/jbmr.2520.

Khan et al report that mature New Zealand rabbits were OVX and following induction of bone loss were given odanacatib (ODN) (9 µM/d) for 14 weeks. Sham operated and OVX rabbits treated with ALN, 17β-estradiol (E2) or PTH served as controls. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, femoral BMD, cortical area and thickness, and periosteal deposition and serum P1NP were comparable. Skeletal improvements in ALN or E2-treated groups were less than that of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. ODN did not suppress remodeling but inhibited osteoclast activity more than ALN. ODN reverses BMD, skeletal architecture and compressive strength in osteopenic rabbits however, increases crystallinity and tissue mineralization thus leading to increased cortical brittleness.


Heterogeneity in Trabecular Matrix Mineral Density

Wang J, Kazakia GJ, Zhou B, Shi XT, Guo XE. Distinct tissue mineral density in plate and rod-like trabeculae of human trabecular bone. J Bone Miner Res 2015;doi:10.1002/jbmr.2498.

Wang et al report tissue mineralization in individual trabeculae of different trabecular types and orientations. Individual trabecula mineralization (ITM) analysis was used to determine tissue mineral density (TMD) distributions in plate- and rod-like trabeculae and to compare the TMD of trabeculae along various orientations from the femoral neck, greater trochanter, and proximal tibia. Trabecular plates had higher TMD than rods. TMD in trabecular plates was lowest in longitudinal plates and the highest TMD in transverse plates. Conversely, there was a relatively uniform distribution of TMD among trabecular rods with respect to trabecular orientation. TMD distribution revealed that trabecular plates had higher mean and peak TMD, whereas trabecular rods had a wider TMD distribution and a larger portion of low mineralized trabeculae. Comparison of apparent Young's moduli derived from microfinite element models demonstrated that heterogeneous TMD in trabecular plates had a significant influence on the elastic mechanical property of trabecular bone.


Familial Resemblance in Microarchitecture

Nagy H, Chapurlat R, Sornay-Rendu E, Boutroy S, Szulc P. Family resemblance of bone turnover rate in mothers and daughters-the MODAM study. Osteoporos Int 2015;26:921-30.

Nagy et al studied bone turnover markers (BTM) and microarchitecture (using HR-pQCT) in 171 postmenopausal women and their 210 premenopausal daughters. After adjustment for age, weight, lifestyle factors, hormones, and mother's fracture status, BTM levels correlated between mothers and daughters (intraclass correlation coefficient = 0.22-0.27, p<0.005). Average BTM levels were 0.6 SD higher among daughters of mothers in the highest BTM quartile vs. the ones in the lowest BTM quartile. The variability of BTM levels explained 10 and 14% of variability of bone microarchitecture in the daughters and mothers, respectively. Cortical density was lower by 2.3-2.9% (0.6 SD, p<0.05 to <0.005) in the daughters from the mother-daughter pairs with high BTM levels than in the daughters from the pairs with low BTM levels. Corresponding differences for the mothers were 4.5-4.8 % (0.5 SD, p<0.05 to <0.01).


Fractures, Osteopenia and Mortality

Bliuc D, Alarkawi D, Nguyen TV, Eisman JA, Center JR. Risk of subsequent fractures and mortality in elderly women and men with fragility fractures with and without osteoporotic bone density: The Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 2015;30:637-46.

Half of all fragility fractures occur in individuals BMD T-score>‒2.5. Bliuc et al examined adverse events of subsequent fracture and mortality following initial fracture according to BMD level in community-dwelling participants aged 60+ years from the Dubbo Osteoporosis Epidemiology Study. There were 528 low-trauma fractures in women and 187 in men. Of these, 12% occurred in individuals with normal BMD (38 women, 50 men) and 42% in individuals with osteopenia (221 women, 76 men). The risk of subsequent fracture was >2.0-fold for all levels of BMD in women and men. With subsequent fracture risk, postfracture mortality was increased in individuals with low BMD (age-adjusted standardized mortality ratio for osteopenia 1.3 [1.1-1.7] and 2.2 [1.7-2.9] for women and men, respectively, and osteoporosis 1.7 [1.5-2.0] and 2.7 [2.0-3.6] for women and men, respectively).

Bliuc D, Nguyen ND, Alarkawi D, Nguyen TV, Eisman JA, Center JR. Accelerated bone loss and increased post-fracture mortality in elderly women and men. Osteoporos Int 2015;26:1331-9.

Bliuc et al report that in 341 women and 106 men, survival was lowest for the highest quartile of bone loss. The association of bone loss with mortality was observed for vertebral in both sexes and nonhip nonvertebral fractures in women (p<0.0001). Bone loss did not contribute to mortality risk following hip fractures. Rapid bone loss was associated with 44-77% increased mortality risk after multiple variable adjustment. It remains to be determined whether bone loss is a marker or plays a role in the mortality associated with fractures.


Sclerostin Inhibition Preserves Bone Mass in Paralysis

Beggs LA, Ye F, Ghosh P, Beck DT, Conover CF, Balaez A, Miller JR, Phillips EG, Zheng N, Williams AA, Aguirre J, Wronski TJ, Bose PK, Borst SE, Yarrow JF. Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss. J Bone Miner Res 2015;30:681-89.

Beggs et al report that sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may contribute to bone loss. 55 (n=11-19/group) skeletally mature male Sprague Dawley rats were randomized to: (A) sham surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia and distal femur, characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, and deficits in cortical bone strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss. Scl-Ab increased osteoblast surface and bone formation whereas TE reduced osteoclast surface with minimal effect on bone formation. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab prevented the reduction in cortical bone strength.


Atrial Fibrillation and Alendronate

Herrera L, Leal I, Lapi F, Schuemie M, Arcoraci V, Cipriani F, Sessa E, Vaccheri A, Piccinni C, Staniscia T, Vestri A, Di Bari M, Corrao G, Zambon A, Gregori D, Carle F, Sturkenboom M, Mazzaglia G, Trifiro G. Risk of atrial fibrillation among bisphosphonate users: A multicenter, population-based, Italian study. Osteoporos Int 2015;26:1499-506.

Herrera et al report results of a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions involving new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an atrial fibrillation (AF) diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. BP exposure was classified into current (<90 days prior to ID), recent (91-180), past (181-364), and distant past (≥365) use. Compared with distant past users of BP, current users of BP showed increased risk of AF: OR=1.78 and 95%CI=1.46-2.16. ALN use was associated with AF as compared with distant past use of BP (OR, 1.97; 95%CI, 1.59-2.43).


 

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I am indebted to Professor Seeman for his incisive commentary following his review of Niimi et al. above. This clinical study compared a group of Asian 5-year-or-more BP users to a matched 3-fold larger group of BP-naive controls. The two groups differed slightly in body size parameters and, of course, in serum and urine markers of resorption, but did not differ significantly in T-scores. It is noteworthy that, after an additional year of BP medication, the point of maximum “cortical thickness” moved significantly toward the lesser trochanter, but no other distinguishing characteristics could be detected in femoral AP plain films. Professor Seeman decisively sums up this issue and agrees with the reported observations in saying:”There is no rational basis for there to be cortical thickening. This may occur by greater periosteal apposition but antiresorptives do not stimulate periosteal deposition of bone, nor do they inhibit it.” The number of the JBMR prior to Niimi carried an article by Poole et al. (Denosumab Rapidly Increases Cortical Bone in Key Locations of the Femur. Vol. 30, No. 1, January 2015, pp 46–54.) The abstract of this article states “Denosumab treatment led to an increase in femoral cortical mass surface density and thickness...” The abstract also states that “[o]ne-third of the increase came from increasing surface cortical density and two-thirds came from increasing cortical thickness...” Tacked on at the close of this 8-page article is an admission “Cortical thickening is an intriguing and somewhat counterintuitive finding, given the expected antiresorptive profile of denosumab” and a graphic demonstration is provided that “shows how in-filling of cortical pores can resemble increasing absolute thickness...” To say that the conclusion boldly stated in the Abstract in the absence of the alternative is counterintuitive strikes me as quite an understatement. Indeed the article by Ominsky et al. reviewed above suggests, from animal data, an intriguing alternative mechanism whereby some measurable modeling-based true bone formation can be detected in the presence of profound and prolonged suppression of resorption, quite a bit more prolonged than that used in the clinical material of Poole at al. Banks Hinshaw PhD MD FACOG Franklin, North Carolina USA

nice compact review

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