Overview, Vol 13, Issue 7

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

"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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Is the new kid as good as the golden oldie?

Here are two studies comparing the effects of odanocatib (ODN) and alendronate (ALN) on bone morphology. One of the main observations of the study was that cortical thickness increased even though there was no detectable change in periosteal perimeter, i.e., no detectable evidence of periosteal apposition. Both studies suggested greater efficacy of odanocatib on cortical morphology than observed with alendronate. While encouraging, and perhaps correct, the work raises several interesting issues about the mechanism of action of these drugs and our ability to measure morphological changes accurately.

Cortical thicknesses vary around the perimeter of a bone cross section and vary at every cross section along the length of a bone. It is a misnomer to refer to cortical ‘thickness’ as a single phenotype (1). It is derived by dividing the cortical area by the perimeter. So if the area increases but there is no change in periosteal perimeter, then medullary area must decrease, presumably due to net deposition of bone upon the endocortical surface. There was no data provided concerning medullary area. Another possibility is trabecular ‘corticalization’. This occurs during metaphyseal growth. If bone formation occurs upon adjacent trabeculae abutting against the endocortical surface, coalesce of trabeculae may produce what seems to be cortical thickening. Another menchanism producing cortical ‘thickening’ is a reduction in porosity of the inner cortex adjacent to the medullary canal. This is the opposite of what occurs during aging where intracortical remodeling produces porosity which thins the cortex from within. There is one other change that may lead to the mistaken notion that the cortex is thicker. If treatment increases tissue mineral density of the cortical matrix this may alter edge detection which produces what seems to be an increase in ‘thickness’.

The question is how does an antiresoprtive agent that either reduces the number of remodeling sites upon a surface, reduces the depth of each site, or both, detectably increase cortical thickness. One way is that the more shallow resorption cavites excavated during ODN therapy refill or overfill if the amount of bone deposited in each is either unchanged or increases. This is possible but compelling evidence for an increase in the volume of bone deposited by each BMU during odanocatib therapy is lacking.

Williams et al compared low and high dose ODN (2 or 8 / 4 mg/kg/d), ALN (15 µg/kg, twice weekly, s.c.), and vehicle (VEH) initiated 10 days following OVX and continued for 20 months. Effects were similar by dose (2). ODN and ALN reduced resorption markers (uNTx and sCTx) compared to VEH. ODN reduced formation markers less than ALN. At month 18, ODN increased spine aBMD (11.4%), spine trabecular vBMD (13.7%), femoral neck (FN) integral vBMD (9.0%) and subtrochanteric proximal femur (SubTrPF) integral vBMD, (6.4%), FN cortical thickness (Ct.Th 22.5%) and cortical bone mineral content (Ct.BMC 21.8%), SubTrPF Ct.Th (10.9%) and Ct.BMC (11.3%). Compared to ALN, ODN increased FN Ct.BMC by 8.7%, and SubTrPF Ct.Th by 7.6% and Ct.BMC by 6.2%. ODN had comparable efficacy to ALN in aBMD and vBMD. FN cortical mineral content demonstrated superior efficacy of ODN vs. ALN.

Figure 1. Effects of ODN and ALN on biochemical markers of bone turnover. Bone resorption markers urinary NTx (A) and serum CTx (B) and bone formation markers P1NP (C) and BSAP (D) were monitored at 1.5, 3, 6, 12, 18 and 20 months of dosing. Arrow indicates approximate time of dose change for H-ODN from 8 mg/kg to 4 mg/kg. Data represent mean±SEM. ap<0.05 vs. VEH; §p<0.05 H-ODN vs. L-ODN; p<0.05 L-ODN vs. ALN; bp<0.05 H-ODN vs. ALN. Reproduced from Bone, doi:10.1016/j.bone.2013.06.008, Copyright (2013), with permission from Elsevier.

Figure 2. Effects of ODN and ALN on selected DXA and QCT parameters at the spine and hip. DXA aBMD in spine (A); DXA aBMD in FN (B); DXA aBMD in total hip (C); QCT trabecular vBMD in spine (D); QCT integral vBMD in FN (E); and QCT integral vBMD in SubTrPF (F). Error bars represent standard errors. *p<0.05 L-ODN vs. baseline; **p<0.01 L-ODN vs. baseline; p<0.05 L-ODN vs. ALN; ††p<0.01 L-ODN vs. ALN. Reproduced from Bone, doi:10.1016/j.bone.2013.06.008, Copyright (2013), with permission from Elsevier.

Cabal et al compared the effects of VEH, low (2 mg/kg/day, ODN), and ALN (30 µg/kg/week) given during 18 months on structure and estimated bone strength (3). ODN increased in integral UDR vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases were higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively.

Figure 3. Longitudinal changes from baseline through 18 months for the VEH, ALN, and L-ODN groups: A) DXA-BMD, B) HR-pQCT integral vBMD, C) HR-pQCT cortical thickness, D) HR-pQCT total BV/TV, E) FEA peak force and F) FEA peak stress. Statistically significant differences between L-ODN vs. baseline are depicted by *(p<0.05); **(p<0.01), and L-ODN vs. ALN are depicted by p<0.05; ††p<0.01. Error bars represent standard errors. Reproduced from Bone, doi:10.1016/j.bone.2013.06.011, Copyright (2013), with permission from Elsevier.

Figure 4. Percent changes between baseline and 18 months of the peak force (N) vs. cortical thickness for the VEH (left), ALN (middle), and L-ODN (right) groups. The correlation coefficients r2 are indicated in the graphs. Reproduced from Bone, doi:10.1016/j.bone.2013.06.011, Copyright (2013), with permission from Elsevier.

Low Dose Zoledronic Acid

Zoledronic acid (ZOL) is a potent remodeling suppressant and as administered annually, it represents an excellent way of reducing fracture risk while minimizing the problem of frequent administration and issues with compliance. However, there is accumulating evidence that even annual infusion may not be needed. A single infusion has been shown to reduce remodeling markers for 3-5 years and now there is evidence that a single infusion may reduce fracture rates during three years similar to that observed by three annual infusions (4-6).

In this study, Grey et al report that 180 postmenopausal women with osteopenia were randomized to a single baseline intravenous ZOL in doses of 1, 2.5 or 5 mg, or placebo (7). Changes in spine BMD were greater than with placebo difference vs. placebo: ZOL 1 mg 4.4%; 2.5 mg 5.5%; 5 mg 5.3%, P<0.001 each dose. Changes total hip BMD were greater in each of the ZOL groups than placebo: ZOL 1 mg 2.6%; 2.5 mg 4.4%; 5 mg 4.7%, P<0.001 each dose, and β-CTX and P1NP were lower in each of the 2.5 mg and 5 mg groups than the placebo. Changes were similar in the 2.5 and 5 mg groups, while those in the 1 mg group were smaller. Single administrations of ZOL 1 mg or 2.5 mg produce antiresorptive effects that persist for at least 2 years.

Figure 5. BMD at the lumbar spine (top), total hip (middle) and total body (bottom) over 2 years. Data are mean percent change from baseline (95% CI). At each site, BMD was higher in each of the ZOL groups than placebo (P<0.0001 each point). Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2009 with permission of the American Society of Bone and Mineral Research.


Figure 6. Effects on β-CTX (top), and P1NP. Data are mean percent change from baseline (95% CI). The level of each turnover marker was lower in each of the 2.5mg and 5mg ZOL groups than placebo (P<0.0001 each point); in the 1 mg ZOL group, β-CTX and P1NP were lower than the placebo group at each point (P<0.0001) until 18 months and 24 months, respectively. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2009 with permission of the American Society of Bone and Mineral Research.


Denosumab and Estimated Bone Strength

Keaveny et al studied FEA of hip and spine QCT scans in a subset (N=48 placebo; N=51 denosumab) at baseline, 12, 24, and 36 months (8). Hip strength increased from 12 months (5.3%; p<0.0001) and through 36 months (8.6%; p<0.0001) in the denosumab group. For the placebo group, hip strength decreased at 36 months (-5.6%; p<0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p<0.0001) and decreased by -4.2% for the placebo (p=0.002). Strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group.

Figure 7. Mean percentage change in strength for the hip (A) and spine (B) estimated using the FEA. *p<0.0001 vs. both baseline and placebo; p<0.0001 vs. 12 months; p<0.005 vs. baseline; §p<0.05 vs. 12 months. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2024 with permission of the American Society of Bone and Mineral Research.


Figure 8. Mean percentage change in whole bone, trabecular, and “cortical” compartment strength for the hip (A) and spine (B) estimated using FEA, at 36 months. *p<0.0001 vs. both baseline and placebo; p<0.01 vs. 12 months; p<0.005 vs. baseline; §p<0.05 vs. 12 months. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2024 with permission of the American Society of Bone and Mineral Research.


Eight Years Denosumab

McClung et al report that denosumab treatment for 8 years was associated with continued gains in BMD and persistent reductions in bone turnover markers (9). In the 4-year study, postmenopausal women with low BMD were randomized to placebo, ALN, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo or two more years. The parent study was then extended for 4 years where all subjects received denosumab.
Of the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab, BMD at the spine and total hip increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in bone turnover markers were sustained. The authors infer that continued denosumab for 8 years was associated with progressive gains in BMD, persistent reductions in bone turnover markers, and was well tolerated.

The question is what are these gains in BMD? The increase at the spine from year 4 to 8 is similar or slightly less that the increase in the first 4 years and this is very difficult to explain based on remodeling theory. The most likely explanation in my opinion is that there is confounding by arthritic changes captured in the BMD measurement. The increase of around 1-2% in the second 4 years at the hip is consistent with the notion that this is the result of secondary mineralization of bone remodeled months or even years earlier. Is there a possibility that this is newly deposited bone – perhaps but we need data to support this contention and a propose mechanism. One might be the secondary increase in endogenous PTH that results when PTH is administered. This might have an anabolic effect, either modeling based, or remodeling based and if it occurs in the face of suppressed osteoclastogenesis and prevention of resorption of existing osteoclasts, there may be a net anabolic effect without bone resorption. It’s plausible but unproven.

Figure 9. Effect of 8 years of continued denosumab treatment 
on BMD at the (a) lumbar spine,
 (b) total hip, and (c) one-third radius. BMD values are shown as 
percent change from parent
 study baseline (LSM+95% CI 
based on ANCOVA models 
adjusting for geographical location and parent study baseline
 BMD values). Gray boxes indicate the original 4-year parent study. Numbers shown at each time point reflect the number of subjects enrolled in the extension study with observed data at the selected time points of interest. Reproduced from Osteoporos Int 2013;24:227-35 with permission from Springer.


Figure 10. Effect of 8 years denosumab on serum CTX and BSAP. Bone turnover markers are shown as actual values (medians with Q1 to Q3 
interquartile ranges). Gray boxes indicate the original 4-year parent study. Numbers shown reflect the number of subjects enrolled in the extension study with observed data at the selected time points of interest. *A calibration discrepancy at the central laboratory may have led to BSAP results in some individual samples to be falsely elevated by up to 14% at months 90 and 96. Reproduced from Osteoporos Int 2013;24:227-35 with permission from Springer.


Does Calcium Increase Mortality?

This is yet another paper suggesting a high calcium intake is associated with increased cardiovascular morbidity and mortality. The data are prospective but this is not a randomized controlled trial and whatever the outcome it does not prove causation. The authors acknowledge this. The signal it sends is clear however. We need a properly designed and executed trial with cardiovascular outcomes. For now, it remains advisable, as always to do no harm; avoid avoiding calcium nutrition but avoid intakes that are above 1200 mg daily too.

Michaëlsson et al investigated the association between dietary and supplemental calcium and death from all causes and cardiovascular disease.in a prospective longitudinal mammography cohort of 61,433 women followed for a median of 19 years (10). Primary outcome measures were time to death from all causes (n=11,944) and cause specific cardiovascular disease (n=3862), ischaemic heart disease (n=1932), and stroke (n=1100). Diet was assessed by food frequency questionnaires at baseline and in 1997 for 38,984 women, and intakes of calcium were estimated. Total calcium intake was the sum of dietary and supplemental calcium.

The risk patterns were nonlinear with higher rates around the highest intakes (≥1400 mg/day). Compared with 600 and 1000 mg/day, intakes above 1400 mg/day were associated with higher death rates from all causes (HR 1.40, 1.17 to 1.67), cardiovascular disease (1.49, 1.09 to 2.02), and ischaemic heart disease (2.14, 1.48 to 3.09), not stroke (0.73, 0.33 to 1.65). After sensitivity analysis, the higher death rate with low dietary calcium intake (<600 mg/day) or with low and high total calcium intake was no longer apparent. Use of calcium tablets (6% users; 500 mg calcium per tablet) was not associated with all cause or cause specific mortality; but among calcium tablet users with a dietary calcium intake above 1400 mg/day, the hazard ratio for all cause mortality was 2.57 (95% CI 1.19-5.55). The authors infer that high intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke.

Figure 11. Multivariable adjusted spline curves for relation between cumulative average of dietary and total calcium intake with time to death from all causes, cardiovascular disease, ischaemic heart disease, and stroke. *Adjusted for age, total energy and vitamin D intake, healthy dietary pattern, BMI, height, living alone, educational level, physical activity level, smoking status, use of calcium containing supplements, and score on Charlson comorbidity index. Reference value for estimation was set at 800 mg, which corresponds to the Swedish recommended level of calcium intake for women older than 50 years. The upper confidence limit for ischaemic heart disease is truncated at calcium intake levels higher than about 1800 mg/day. Reproduced from BMJ, 346:f228, Copyright (2013), with permission from Elsevier.

Zoledronic Acid, Breast Cancer and Disease Free Survival

Aromatase inhibitor therapy is associated with increased bone loss and fracture risk. In the study by Coleman et al, postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N=1065) were randomly assigned to immediate ZOL 4 mg every 6 months for 5 years, or delayed ZOL (11). At 60 months, the mean change in spine BMD was +4.3% with immediate ZOL and -5.4% with delayed intervention (P<0.0001). Immediate ZOL reduced the risk of disease free survival events by 34% (HR=0.66; P=0.0375) with fewer local (0.9% vs. 2.3%) and distant (5.5% vs .7.7%) recurrences vs. delayed ZOL. In the delayed group, delayed initiation of zoledronate substantially improved disease free survival vs. no ZOL (HR=0.46; P=0.0334).

Subtrochanteric Fractures
The surprising role of corticosteroids

Atypical femoral fractures, which display characteristics of brittle material failure, are been associated with remodeling suppression drugs. Some evidence suggests concomitant use of corticosteroids may contribute. In the study by Luo and Allen, skeletally mature beagle dogs were either untreated controls, or treated with ZOL, dexamethasone (DEX), or both (12). ZOL (0.06 mg/kg) was given monthly for 9 months. DEX (5 mg) was administered daily for one week during each of the last three months of the 9 month experiment. DEX suppressed intracortical remodeling while ZOL and the combination nearly abolished intracortical remodeling. ZOL resulted in lower toughness, toughness in ZOL+DEX was identical to controls. Dexamethasone reverses the adverse effects ZOL.

Fracture Healing and Alendronate

Meganck et al studied the effect of ALN on fracture healing. Brtl/+ murine model of type IV OI had tibial fractures at 8-weeks and were untreated, treated with ALN before fracture, or treated before and after fracture (13). There were no differences in callus between untreated mice and mice that received ALN before fracture. Both Brtl/+ and WT mice that received ALN before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of ALN in wildtype mice, but calluses from Brtl/+ mice treated with ALN during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with ALN altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture.

PTHrP 1-34 as an Anabolic Agent

The N-terminal fragment 1-34 of PTH is similar in structure and function to N-terminal PTHrP. PTH(1-34) and PTHrP also share a coreceptor, the PTH/PTHrP receptor. Xu et al used an OVX rat model to study the effects of PTHrP(1-34) (14). Subcutaneous PTHrP(1-34) (40 or 80 µg/kg body weight every day) increased lumbar and femoral BMD, improved bone biomechanical properties, enhanced bone strength, and promoted bone formation. 40 µg/kg of PTHrP(1-34) once per day or every other day improved the BMD and strength of OVX rats. Based on their results, intermittent low-dose PTHrP(1-34) injection promoted bone formation in OVX rats, suggesting a high potential for therapeutic use in osteoporosis patients.

What fascinating cells

Intracortical porosity increases as age advances and is due to intracortical remodeling initiated upon Haversian or Volkmann canal surfaces. Porosity results when exavation initiated at a point upon the canal surface erodes matrix beneath and so enlarges the canal focally. With time, canals coalesce forming giant pores in cross section. The increase in porosity with age should then be partly a function of peak porosity achieved during growth (i.e., the number of osteons, each with their central Haversian canal). If so the number of pores does not increase, their size increases, and indeed, the number may decrease as pores coalesce (15,16). Most data suggest this is the mechanism of increased cortical porosity. Another possibility is that there is an increase in the number of canals. This may occur if the excavation first enlarges an existing canal but then excavation creates a new Howships lacunae and a new canal is dug parrellel to the previous canal. Another mechanism may be the creation of new pores which originate within osteocyte lacunae.

Jilka et al selectively deleted Bak and Bax, two genes essential for apoptosis in osteoblasts and in osteocytes (17). Attenuation of apoptosis in osteoblasts increased their lifespan and femur cancellous bone mass. In osteocytes, however, it caused intracortical femoral porosity associated with increased production of receptor activator of nuclear factor-κB ligand and vascular endothelial growth factor. Old and/or dysfunctional osteocytes may contribute to increased intracortical porosity in old age.

Figure 12. Lack of Bax and Bak increases cortical porosity in aged mice. (A) Representative micro-CT images of femora from 22-month-old female BakΔBaxΔOCN and BakΔBaxf/f littermates (left panel), and 21-month-old female BakΔBaxΔOsx1 and BakΔBaxf/f littermates (right panel), scale bar, 1 mm. White arrowheads mark location of pores in cortical bone. (B) Representative femoral and tibial H&E-stained decalcified sections from 21-month-old female BakΔBaxΔOsx1 mice, with the periosteal surface on the left; scale bar, 1 mm. (C) Representative femoral Trichrome-stained nondecalcified sections of femoral cortex from 22-month-old female BakΔBaxΔOCN mice, with the periosteal surface on the left.; scale bar, 50 μm. (D) Inverse micro-CT images of the distal half of femora from 21-month-old female mice. Void areas are depicted in grey within a transparent bone matrix. (E) Cortical porosity (Ct.Po), pore number (Po.N) and pore volume (Po.V) in the cortex of the distal half of femora from 21-month-old female mice, n=3-4/group. (F) Inverse micro-CT images of the distal half of femora from 3-mo-old female mice. (G) Porosity, pore number and pore volume in 3-month-old female mice, n=3/group, *p<0.05 vs. littermate controls. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2007 with permission of the American Society of Bone and Mineral Research.

Figure 13. Increased cortical porosity of aged BakΔBaxΔOCN mice is restricted to the endosteal zone. Representative BSEM images of the femoral diaphyseal cortex from (A) a 22-month-old female BakΔ mouse, and (B) a 22-month-old female BakΔBaxΔOCN mouse. Endosteal (“E”) and periosteal (“P”) zones are separated by a highly mineralized boundary, indicated by green arrowheads. Red arrowheads mark highly mineralized cement lines that reflect previous remodeling activity. Red arrows denote areas of recently remodeled bone that have not yet achieved full mineralization. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2007 with permission of the American Society of Bone and Mineral Research.

The role of osteocytes during mineral homeostasis and their influence on bone material quality was assessed by Kerschnitzki et al (18). These investigators visualized and quantified the osteocyte network in mineralized bone sections with confocal laser scanning microscopy. Synchrotron small‐angle X‐ray scattering is used to determine nanoscopic bone mineral particle size and arrangement relative to the cell network. Most mineral particles reside within less than a micrometer from the nearest cell network channel and that mineral particle characteristics depend on the distance from the cell network. The network architecture optimizes transport costs between cells and to blood vessels. Osteocytes interact with their mineralized vicinity and participate in bone mineral homeostasis.

Figure 14. Cell-cell interconnectivity and canalicular network analysis. (A) Yellow lines depict direct connections between individual cells (blue) via the canaliculae. (B) The shortest direct connection through canaliculae to neighboring cells is depicted in yellow. (C) Color coding of canalicular network voxels depending on their nearest cell as a measure of the network area controlled by each cell. (D) Classification of canalicular junctions (nodes) according to the number of attached connections (degree). Red points depict interwoven nodes featuring a degree >5. (E) Histogram (black) and cumulative plot (red) of the travel distance from canalicular voxels to the nearest cell through the network showing that almost 70% of the canalicular network resides within a 10-mm travel distance. (F) The degree distribution of canalicular junctions is exponential (black line) revealing the single-scale character of the canalicular network. There is a high abundance of junctions with dendritic character (65% of nodes show d=3), but junctions with up to 10 connecting canaliculi are also present. The mean degree of nodes is 3.25. (G) The length distribution of individual canalicular structures is exponential (black line) with individual lengths up to 15 µm. The mean canalicular length between two nodes is 2.15 µm. Scale bars = 20 µm. Reproduced from J Bone Miner Res 2013; 28:1837-45 with permission of the American Society of Bone and Mineral Research.

Figure 15. Osteocyte network and nanoscopic mineral particle properties. (A) Visualization of the osteocyte network showing highly organized (dense) osteocyte network structures at the top and the bottom and poorly organized (loose) network structures in the center. Synchrotron small angle X-ray scattering measurements of the mineral particle thickness (T-parameter) (B) and the mineral particle orientation (Rho parameter) (C) along the visualized network structures. Mineral particles in dense network regions are thicker and more oriented compared to the loose regions in the center. The direction of alignment of mineral particles is always perpendicular to that of the canalicular structures. (D) Colocalization of T-parameter maps with the osteocyte network reveals thinner mineral particles around individual osteocyte lacunae. Scale bar = 20 µm. Reproduced from J Bone Miner Res 2013; 28:1837-45 with permission of the American Society of Bone and Mineral Research.

Osteocytes produce RANKL suggesting these cells participate in osteoclastogenesis and bone resorption. Sclerostin increases RANKL-mediated osteoclast activity. There is evidence that osteocytes liberate mineral from bone in osteocytic osteolysis. Kogawa et al investigated sclerostin-stimulated mineral dissolution by human primary osteocyte-like cells (hOCy) and mouse MLO-Y4 cells (19). Sclerostin upregulated osteocyte expression of carbonic anhydrase 2 (CA2/Car2), cathepsin K (CTSK/Ctsk) and tartrate resistant acid phosphatase (ACP5/Acp5). Sclerostin stimulated CA2 mRNA and protein expression in hOCy and in MLO-Y4 cells and induced a decrease in intracellular pH (pHi) and in extracellular pH (pHo) with release of calcium ions from mineralised substrate. These effects were reversed by acetozolamide. Car2-siRNA knockdown in MLO-Y4 cells inhibited the ability of sclerostin to reduce the pHo and release calcium. Knockdown in MLO-Y4 cells of each of the putative sclerostin receptors, Lrp4, Lrp5 and Lrp6, using siRNA, inhibited the sclerostin induction of Car2, Catk and Acp5 mRNA, as well as pHo and calcium release. Human trabecular bone samples treated ex vivo with recombinant human sclerostin for 7 days exhibited an increased osteocyte lacunar area, an effect that was reversed by acetozolamide.


1. Kersch M, Zebaze R, Seeman E. The Heterogeneity in Femoral Neck Structure and Strength. J Bone Miner Res2013;28:1022.

2. Williams DS, McCracken PJ, Purcell M, et al. Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate. Bone 2013; doi:10.1016/j.bone.2013.06.008.

3. Cabal A, Jayakar RY, Sardesai S, et al. High-resolution peripheral quantitative computed tomography and finite element analysis of bone strength at the distal radius in ovariectomized adult rhesus monkey demonstrate efficacy of odanacatib and differentiation from alendronate. Bone 2013; doi:10.1016/j.bone.2013.06.011.

4. Grey A, Bolland MJ, Horne A, et al. Five years of anti-resorptive activity after a single dose of zoledronate ‒ results from a randomized double-blind placebo-controlled trial. Bone 2012;50:1389.

5. McClung M, Miller P, Recknor C, et al. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009;114:999.

6. Reid IR, Black D, Eastell R, et al. Reduction in the risk of clinical fractures after a single dose of zoledronic acid 5 mg. J Clin Endocrinol Metab 2013;98:557.

7. Grey A, Bolland M, Mihov B, Wong S, Horne A, Gamble G, Reid IR. Duration of anti-resorptive effects of low dose zoledronate in osteopenic postmenopausal women: A randomized, placebo-controlled trial. J Bone Miner Res 2013; doi:10.1002/jbmr.2009.

8. Keaveny T, McClung M, Genant H, et al. Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. J Bone Miner Res 2013; doi:0.1002/jbmr.2024.

9. McClung MR, Lewiecki EM, Geller ML, et al. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos Int 2013;24:227.

10. Michaëlsson K, Melhus H, Warensjö EW, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ 2013;346:f228

11. Coleman R, de Boer R, Eidtmann H, et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 2013;24:398.

12. Luo TD, Allen MR. Short-courses of dexamethasone abolish bisphosphonate-induced reductions in bone toughness. Bone 2013;56:199.

13. Meganck JA, Begun DL, McElderry JD, et al. Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta. Bone 2013;56:204.

14. Xu J, Rong H, Ji H, et al. Effects of different dosages of parathyroid hormone-related protein 1-34 on the bone metabolism of the ovariectomized rat model of osteoporosis. Calcif Tissue Int 2013; doi:10.1007/s00223-013-9755-1.

15. Thomas CD, Feik SA, Clement JG. Increase in pore area, and not pore density, is the main determinant in the development of porosity in human cortical bone. J Anat 2006;209:219.

16. Cooper DM, Thomas CD, Clement JG, et al. Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft. Bone 2007;40:957.

17. Jilka RL, O'Brien CA, Roberson PK, et al. Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates bone porosity with age. J Bone Miner Res 2013; doi:10.1002/jbmr.2007.

18. Kerschnitzki M, Kollmannsberger P, Burghammer M, et al. Architecture of the osteocyte network correlates with bone material quality. J Bone Miner Res 2013;28:1837.

19. Kogawa M, Wijenayaka AR, Ormsby R, et al. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J Bone Miner Res 2013; doi:10.1002/jbmr.2003.


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Osteogenesis imperfecta, an ever-expanding conundrum
Glorieux FH, Moffatt P
J Bone Miner Res 2013;28:1519

Molecular mechanisms of osteoblast/osteocyte regulation by connexin43
Stains JP, Watkins MP, Grimston SK, Hebert C, Civitelli R
Calcif Tissue Int 2013; doi:10.1007/s00223-013-9742-6

Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis?
Huang X, Xu Y, Partridge NC
Bone 2013;55:458

Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions
Bultink IE, Baden M, Lems WF
Expert Opin Pharmacother 2013;14:185

Bone health in children and adolescents: risk factors for low bone density
Pitukcheewanont P, Austin J, Chen P, Punyasavatsut N
Pediatr Endocrinol Rev 2013;10:318

Guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis (2012 edition)
Nishizawa Y, Ohta H,  Miura M,  Inaba M,  Ichimura S,  Shiraki M,  Takada J,  Chaki O,  Hagino H,  Fujiwara S,  Fukunaga M,  Miki T,  Yoshimura N
J Bone Miner Metab 2013;31:1

Systems-level analysis of genome-wide association data
Farber CR
G3 (Bethesda) 2013;3:119

Health technology assessment in osteoporosis
Hiligsmann M, Kanis JA, Compston J, Cooper C, Flamion B, Bergmann P, Body JJ, Boonen S, Bruyere O, Devogelaer JP, Goemaere S, Kaufman JM, Rozenberg S, Reginster JY
Calcif Tissue Int 2013;93:1

Steroids and osteoporosis: the quest for mechanisms
Manolagas SC
J Clin Invest 2013;123:1919

The pathogenesis, treatment and prevention of osteoporosis in men
Mosekilde L, Vestergaard P, Rejnmark L
Drugs 2013;73:15

Determinants of bone marrow adiposity: the modulation of peroxisome proliferator-activated receptor-γ2 activity as a central mechanism
Gijsen HS, Hough FS, Ferris WF
Bone 2013;56:255

Proposed pathogenesis for atypical femoral fractures: lessons from materials research
Ettinger B, Burr DB, Ritchie RO
Bone 2013;55:495

Bone marrow composition, diabetes, and fracture risk: more bad news for saturated fat
Devlin MJ
J Bone Miner Res 2013;28:1718

The roles of vitamin D in skeletal muscle: form, function, and metabolism
Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE
Endocr Rev 2013;34:33