Overview, Vol 15, Issue 2

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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In this Issue

  1. The Burden of Fractures is Increasing
  2. Microdamage: Location and mechanisms
  3. Crack Crack and the Hierarchical Design of Bone
  4. Collagen Structure and Mineralization
  5. Trabecular BV/TV: An important determinant of stiffness
  6. Treatment of Structural Deterioration in Renal Disease
  7. Antisclerostin Antibody Prevents Structural Decay After Spinal Cord Injury
  8. Atypical Fractures and Femoral Bowing
  9. PTH Remodels Bisphosphonate Out of Bone
  10. How Do Osteoclast Precursors Speak to Osteoblast Lineage Cells?
  11. How Do Osteoclasts Become Multinucleated?
  12. Macrophage Cells: A neglected participant in the cellular machinery of bone
  13. TGFβ: One of many factors coupling resorption and formation
  14. Sphingosine-1-phosphate in Osteocytic Mechanotransduction
  15. Vestibular Signals and Bone Remodeling: An unlikely coupling
  16. Bisphosphonates and Denosumab
  17. Denosumab and Long-term Fracture Risk Reduction: A result seeking a control
  18. Men Receiving Androgen Deprivation Therapy and Fracture Risk
  19. Improved Initiation of Therapy After Hip Fracture
  20. Bisphosphonate Antifracture Efficacy in Men
  21. Vitamin D Metabolites Are Weakly Associated With Bone Density
  22. Combining Antiresorptives and Anabolics
  23. Tissue Mineral Density and PTH Administration
  24. Bone Water: A guide to porosity
  25. Toughness of Bone
  26. Risedronate in Breast Cancer

The Burden of Fractures is Increasing

Oden A, McCloskey EV, Kanis JA, Harvey NC, Johansson H. Burden of high fracture probability worldwide: Secular increases 2010-2040. Osteoporos Int 2015;26:2243-8.

Oden et al quantified the number of individuals worldwide aged 50 years or more at high risk of fracture in 2010 and 2040. A threshold of high fracture probability was set at the age-specific 10-year probability of a major fracture (clinical vertebral, forearm, humeral or hip fracture) equivalent to that of a woman with a BMI of 24 kg/m2 and a prior fragility fracture. The prevalence of high risk was determined worldwide, and by continent, and applied to the demography for each country. Twenty-one million men and 137 million women had a fracture probability at or above the threshold in the world for the year 2010. The greatest number of men and women at high risk were from Asia (55%). Worldwide, the number of high-risk individuals is expected to double over the next 40 years.

Figure 1. Number of individuals (millions) having a 10-year probability of a major osteoporotic fracture calculated without BMD above the fracture threshold for the years 2010-2040. Reproduced from Osteoporos Int 2015;26:2243-8 with permission from Springer.



Figure 2. The increase in the number of men and women with a10-year probability of a major osteoporotic fracture above the fracture threshold between the years 2010-2040. Reproduced from Osteoporos Int 2015;26:2243-8 with permission from Springer.



Karampampa K, Ahlbom A, Michaelsson K, Andersson T, Drefahl S, Modig K. Declining incidence trends for hip fractures have not been accompanied by improvements in lifetime risk or post-fracture survival ‒ A nationwide study of the Swedish population 60 years and older. Bone 2015;78:55-61.

Karampampa et al report that the Swedish population 60 years old and above was followed between 1987-2010 in the National Patient Register and the Cause of Death Register. The age-specific hip fracture incidence decreased between 1995-2010 in all ages by 1% per year. The lifetime risk remained stable between 9-11% for men, and between 18-20% for women. The expected mean age of a first hip fracture increased by 2.5 years for men and by 2.2 years for women. No improvements over time were observed for the 3-month survival for men, while for women a 1% decrease per year was observed. The 1-year survival increased over time for men (0.4% per year), while no improvement was observed for women. The age-specific hip fracture incidence has decreased but the lifetime risk has not decreased because life expectancy has increased. Survival after hip fracture has not improved.

Sobolev B, Sheehan KJ, Kuramoto L, Guy P. Excess mortality associated with second hip fracture. Osteoporos Int 2015;26:1903-10.

Sobolev et al retrieved 42,435 hospitalization records of patients aged 60 years or older discharged after admission for hip fracture between 1990-2005 in British Columbia, Canada. The average monthly death rate (per 1000 patient-months) was 16.2 (95%CI 16.0-16.4) for those without second hip fracture vs. 21.1 (95%CI 20.2-22.1) for those with second hip fracture. The hazard of death was 55% higher for patients with second hip fracture (HR=1.55, 95%CI 1.47-1.63). The hazard of death was 58% higher for men with second hip fracture (HR=1.58, 95%CI 1.42-1.75). The hazard of death was 54% higher for women with second hip fracture (HR=1.54, 95%CI 1.46-1.63).

Location and mechanisms

Goff MG, Lambers FM, Nguyen TM, Sung J, Rimnac CM, Hernandez CJ. Fatigue-induced microdamage in cancellous bone occurs distant from resorption cavities and trabecular surfaces. Bone 2015;79:8-14.

Goff et al subjected human vertebral cancellous bone to cyclic compressive loading (10 male donors, 6 female donors, mean age 76). The 10% largest microdamage sites accounted for 70% of all microdamage. The large microdamage sites predicted reductions in Young's modulus better than overall volume of damage. Most microdamage volume (~69%) was located >30 µm from trabecular surfaces suggesting microdamage occurs within interstitial regions, not near resorption cavities as sources of stress concentration.

Crack Crack and the Hierarchical Design of Bone

Katsamenis OL, Jenkins T, Thurner PJ. Toughness and damage susceptibility in human cortical bone is proportional to mechanical inhomogeneity at the osteonal-level. Bone 2015;76:158-68.

Katsamenis et al investigated cortical osteonal-, micro- and tissue-level mechanical behaviour from young and elderly donors. Toughness and crack growth resistance at the tissue-level correlate with damage susceptibility at the microlevel, and mechanical inhomogeneity between lamellae and interlamellar areas at the osteonal level. Reduced nanoelasticity inhomogeneity of lamellar/interlamellar layers in osteons correlated with increased indentation depth at the microlevel and an overall reduction in crack-growth toughness and fracture toughness of the tissue. The reduction in nanoelasticity inhomogeneity is responsible for the inability of the microstructure to effectively adapt to the applied load by redistributing strains preventing damage formation and propagation. Failure of tougher bone specimens is governed by increased deflection of the crack path and broadly spread damage around the crack-tip. In contrast, shorter and more direct crack paths as well as less distributed damage were evidenced during failure of the weaker specimens.

Collagen Structure and Mineralization

Quan BD, Sone ED. Structural changes in collagen fibrils across a mineralized interface revealed by cryo-TEM. Bone 2015;77:42-9.

Quan et al compared cryo-TEM images of rat tail tendon collagen. Across a mineralized interface, mineralization results in axial contraction of the fibril in the more flexible gap region with lateral expansion. The features of the banding pattern are not changed, indicating that the axial arrangement of molecules remains intact. Collagen fibrils accommodate mineral without disruption of their molecular packing, leading to synergy of mechanical properties.

Trabecular BV/TV
An important determinant of stiffness

Maquer G, Musy SN, Wandel J, Gross T, Zysset PK. Bone volume fraction and fabric anisotropy are better determinants of trabecular bone stiffness than other morphological variables. J Bone Miner Res 2015;30:1000-8.

Maquer et al studied individual trabeculae segmentation and trabecular bone score in 743 µCT reconstructions of cubic trabecular bone samples from femur, radius, vertebrae, and iliac crest. Their stiffness tensor (CFE) was computed using microfinite element  analyses. Bone volume fraction (BV/TV) is the best determinant of CFE (r2 adj = 0.889), especially with fabric anisotropy (r2 adj = 0.968). Including the other predictors hardly affected variance. BV/TV explained 87% of the variance in elastic properties. Fabric anisotropy further described 10% of the bone stiffness. BV/TV and fabric anisotropy are the best determinants of trabecular stiffness.

Figure 3. The relative contribution of each variable. Bone volume fraction (BV/TV) and fabric anisotropy explained most of the elastic properties of bone. The contribution of the other parameters found independent (SMI, Tb.Th.SD, Tb.Sp.SD, pTb.Th, rTb.Th, p.Tb.S, r.Tb.l, RR.Junc.D, and TBS) was less than the residuals. Reproduced from J Bone Miner Res 2015;30:1000-8 with permission of the American Society of Bone and Mineral Research.

Treatment of Structural Deterioration in Renal Disease

Newman CL, Chen NX, Smith E, Smith M, Brown D, Moe SM, Allen MR. Compromised vertebral structural and mechanical properties associated with progressive kidney disease and the effects of traditional pharmacological interventions. Bone 2015;77:50-6.

Newman et al studied animals with kidney disease left untreated, treated with calcium, zoledronic acid, antisclerostin antibody, or antisclerostin antibody plus calcium. Chronic kidney disease with high PTH resulted in 6-fold higher remodeling, reduction in trabecular and cortical bone, and compromised mechanical properties in the vertebra. Treatments that reduced remodeling were effective in normalizing vertebral structure and mechanical properties if the treatment reduced PTH. Similarly, treatment with antisclerostin antibody was effective in enhancing bone mass and mechanical properties only if combined with PTH-suppressive treatment.

Antisclerostin Antibody Prevents Structural Decay
After Spinal Cord Injury

Qin W, Li X, Peng Y, Harlow LM, Ren Y, Wu Y, Li J, Qin Y, Sun J, Brown T, Feng JQ, Ke HZ, Bauman WA, Cardozo CC. Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats. J Bone Miner Res 2015;doi:10.1002/jbmr.2549.

Qin et al reported that spine cord injury was induced in rats. they were administered Scl-Ab (25 mg/kg/wk) or vehicle 7 days after injury then weekly for 7 weeks. SCI decreases distal femur BMD (-25%) and trabecular bone volume (-67%); Scl-Ab prevented this deterioration with increased bone formation. Spinal cord injury reduced osteocytes and dendrites with a change from a spindle to round shape; Scl-Ab corrected these abnormalities. In ex vivo cultures of marrow cells, Scl-Ab inhibited osteoclastogenesis and promoted osteoblastogenesis with increases in mRNA levels of LRP5, OPG and the OPG/RANKL ratio, and a decrease in DKK1 mRNA.

Atypical Fractures and Femoral Bowing

Schilcher J, Howe TS, Png MA, Aspenberg P, Bee JK. Atypical fractures are mainly subtrochanteric in Singapore and diaphyseal in Sweden: A cross-sectional study. J Bone Miner Res 2015;doi:10.1002/jbmr.2547.

Schilcher et al reported that atypical fractures (AFF) occur along the femoral shaft in Swedish patients and are mainly subtrochanteric in patients from Singapore. Subtrochanteric fractures comprised 48% of all fractures in Singapore, and 17% in Sweden (p=0.0001). In Singapore, femoral bow was associated with more fractures in the diaphyses (P=0.0001). This was not seen in Sweden.

Chou AC, Ng AC, Png MA, Chua DT, Ng DC, Howe TS, Koh JS. Bone cross-sectional geometry is not associated with atypical femoral fractures in Asian female chronic bisphosphonate users. Bone 2015;79:170-5.

By contrast, Chou et al reported that in 31 patients with AFF age-matched to 31 patients with any femoral fracture (NFF) and 49 patients with osteoporotic femoral fracture (OFF). There were no differences in parameters between patients with AFF and patients with NFF. Patients with AFF and NFF had higher BMD, cross-sectional area (CSA), section modulus (SM), average cortical thickness (ACT) values and lower buckling ratio values at the narrow neck and intertrochanteric (IT) regions than patients with OFF. Additionally, patients with NFF had higher SM values at the IT region than patients with OFF, while patients with AFF had higher BMD, CSA, and ACT values at the femoral shaft region. All other measured parameters were not different between the groups. Varus neck shaft angles were not f associated with AFF in Asian females.

PTH Remodels Bisphosphonate Out of Bone

Murphy CM, Schindeler A, Cantrill LC, Mikulec K, Peacock L, Little DG. PTH(1-34) treatment increases bisphosphonate turnover in fracture repair in rats. J Bone Miner Res 2015;30:1022-9.

PTH(1-34) increases bone turnover. Murphy et al hypothesized PTH may increase bisphosphonate (BP) turnover in the skeleton and so improve healing of microfractures. Fluorescent labeled pamidronate (Pam) and radiolabeled 14C-ZA (zoledronic acid). were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were treated with saline or 25 µg/kg/d PTH(1-34) and the effects on BP liberation and bone healing were examined. There was a decrease in fluorescence in long bones and fracture callus in treated animals. This was confirmed by autoradiography for 14C-ZA. Callus bone volume (BV) was increased in fractured limbs, and although decreases in callus-bound BP with PTH(1-34) was noted, these were not sufficient to alter BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH(1-34) increases bone turnover as well as BP turnover.

Figure  4. (A) An overlay of labeled AlexaPam647 (red) and calcein (green) in rats receiving saline or daily PTH(1-34) intervention. AlexaPam647 was given 6 weeks before harvest, and calcein 10 and 7 days before harvest. AlexaPam647 signal was reduced in the PTH(1-34)-treated group, and no change was observed within the growth plate (physis) indicative of BP release and rebinding. (B)  Representation of the image in panel A without the calcein overlay. This emphasizes the reduction in the bone as a result of PTH(1-34) treatment. (C) Quantification of fluorescent signal from capture images showed a significant reduction in signal with PTH(1-34) treatment (*p<0.001 in relation to BP). Reproduced from J Bone Miner Res 2015;30:1022-9 with permission of the American Society of Bone and Mineral Research.

How Do Osteoclast Precursors Speak to Osteoblast Lineage Cells?

Deng L, Wang Y, Peng Y, Wu Y, Ding Y, Jiang Y, Shen Z, Fu Q. Osteoblast-derived microvesicles: A novel mechanism for communication between osteoblasts and osteoclasts. Bone 2015;79:37-42.

The maintenance of remodeling balance by the BMU depends on cellular communication between osteoclasts and osteoblasts. Deng et al reported that microvesicles containing RANKL protein shed from osteoblasts may mediate intercellular communication by transfering this protein to osteoclast precursors to facilitate ostoclast formation.

How Do Osteoclasts Become Multinucleated?

Levaot N, Ottolenghi A, Mann M, Guterman-Ram G, Kam Z, Geiger B. Osteoclast fusion is initiated by a small subset of RANKL-stimulated monocyte progenitors, which can fuse to RANKL-unstimulated progenitors. Bone 2015;79:21-8.

Levaot et al reported that osteoclasts are formed by fusion of monocyte progenitors, a process initiated by a small subset of precursors, 'fusion founders', capable of fusing with other founders or with nonstimulated progenitors ('fusion followers'). Fusion between a founder and a follower cell consists of an pairing for 5-35 min, then the fusion event occurs requiring a transfer of fluorescent reporter proteins from nucleus to nucleus suggesting crosstalk between the founder and follower progenitors via the cytoplasm as well as overall transcriptional regulation in the developing heterokaryon.

Macrophage Cells
A neglected participant in the cellular machinery of bone

Vi L, Baht GS, Whetstone H, Ng A, Wei Q, Poon R, Mylvaganam S, Grynpas M, Alman BA. Macrophages promote osteoblastic differentiation in-vivo: Implications in fracture repair and bone homeostasis. J Bone Miner Res 2015;30:1090-102.

Macrophages are activated in inflammation and during early repair. Interestingly and are present in bone during development. Vi et al explored the function of macrophages using transgenic mice. Depletion of macrophages led to growth retardation and osteoporosis. By 3 months of age, macrophage-deficient mice displayed a 25% reduction in BMD and a 70% reduction in the number of trabeculae. Functional osteoclasts were still present in bones, lining trabecular bone and the endosteal surface of the cortical bone. There was a 60% reduction marrow mesenchymal progenitor cells and a decrease in the ability of these cells to differentiate to osteoblasts. When macrophages were depleted during fracture repair, bone union was impaired. Calluses from macrophage-deficient animals were smaller, and contained less bone and more fibrotic tissue deposition. Macrophages are crucial for maintaining bone homeostasis and promoting fracture repair by enhancing the differentiation of mesenchymal progenitors.

One of many factors coupling resorption and formation

Weivoda MM, Ruan M, Pederson L, Hachfeld C, Davey RA, Zajac JD, Westendorf JJ, Khosla S, Oursler MJ. Osteoclast TGFβ receptor signaling induces Wnt1 secretion and couples bone resorption to bone formation. J Bone Miner Res 2015;doi:10.1002/jbmr.2586.

Osteoclasts release and activate TGFβ from the bone matrix. Weivoda et al reported that osteoclast-specific inhibition of TGFβ receptor signaling in mice results in osteopenia due to reduced osteoblast numbers not osteoclast number or activity. TGFβ induced osteoclast expression of Wnt1 and this was blocked by impaired TGFβ receptor signaling. Osteoclasts in aged murine bones had lower TGFβ signaling and Wnt1 expression in vivo. Ex vivo stimulation of osteoclasts derived from young or old mouse bone marrow macrophages showed no difference in TGFβ induced Wnt1 expression. However, young osteoclasts expressed reduced Wnt1 when cultured on aged mouse bone chips compared to young mouse bone chips, consistent with decreased skeletal TGFβ availability with age. Osteoclast responses to TGFβ are essential for coupling resorption to formation.

Sphingosine-1-phosphate in Osteocytic Mechanotransduction

Zhang JN, Zhao Y, Liu C, Han ES, Yu X, Lidington D, Bolz SS, You L. The role of the sphingosine-1-phosphate signaling pathway in osteocyte mechanotransduction. Bone 2015;79:71-8.

Osteocytes translate loading into biochemical signals. Zhang et al reported that sphingosine-1-phosphate (S1P) participates mechanotransduction by activation of osteocytes in response to loading-induced oscillatory fluid flow (OFF). OFF (1 Pa, 1 Hz) applied to osteocyte-like MLO-Y4 cells decreased endogenous S1P and suppressed the OFF-induced intracellular calcium response. Addition of S1P to MLO-Y4 cells enhanced the synthesis and release of PGE2 and amplified OFF-induced PGE2 release. The stimulatory effect of OFF on the gene expression of OPG and RANKL was S1P dependent. The S1P2 receptor subtype was involved in OFF-induced PGE2 synthesis and release, as well as downregulation of RANKL/OPG gene expression ratio.

Vestibular Signals and Bone Remodeling
An unlikely coupling

Vignaux G, Ndong JD, Perrien DS, Elefteriou F. Inner ear vestibular signals regulate bone remodeling via the sympathetic nervous system. J Bone Miner Res 2015;30:1103-11.

The vestibular system has projections to brain centers that regulate sympathetic outflow which inhibits bone formation and promotes bone resorption. Vignaux et al demonstrated that bilateral vestibular lesions in mice cause low bone mass with decreased bone formation and increased bone resorption. This reduction in bone mass is prevented by the propranolol and by genetic deletion of the β2-adrenergic receptor, globally or specifically in osteoblasts. Patients with inner ear pathologies might be at risk for fracture.

Bisphosphonates and Denosumab

Anastasilakis AD, Polyzos SA, Gkiomisi A, Saridakis ZG, Digkas D, Bisbinas I, Sakellariou GT, Papatheodorou A, Kokkoris P, Makras P. Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Osteoporos Int 2015;doi:10.1007/s00198-015-3174-2.

Anastasilakis et al compared yearly changes in BMD, turnover markers, free soluble RANKL (sRANKL) and sclerostin with denosumab or zoledronic acid in postmenopausal women with low bone mass previously treated with zoledronic acid for 1 year assigned to denosumab (n=32) or zoledronic acid infusion (n=26). The lumbar spine increase was 4.5 and 4.4 % with denosumab and zoledronic acid, respectively (NS). Denosumab caused a larger decrease in CTx at 3 months (p<0.001) and P1NP at 3 (p<0.001), 6 and 12 months (p=0.042). Denosumab decreased sRANKL by 87.4% at 3 months (p<0.001) and bone turnover more than zoledronic acid, but the increases in lumbar spine BMD are comparable.

Remodeling is reduced at one month with zoledronate, similar to that seen with denosumab, but after this the suppression of remodeling is greater with denosumab than zoledronic acid, or any other bisphosphonate for that matter. Remodeling markers reflect the number of remodeling sites turning over the skeleton and the relative volumes of bone resorbed and formed by each remodeling transaction. It is not possible to determine the source of the remodeling ‒ whether it arises from cortical or trabecular bone or from the axial and appendicular skeleton. As zoledronic acid is bound avidly to mineral it is likely to not access remodeling deep in cortical bone so the continued remodeling despite treatment is likely to reflect persisting intracortical remodeling. the similar risk in spine BMD is not surprising as all these patients received zolendronic acid for 12 months and the reduction in remodeling space transient achieved in that year accounts for this rise. The further reduction in remodeling is likely to arising from the appendicular skeleton in the now denosumab treated group.

Denosumab and Long-term Fracture Risk Reduction
A result seeking a control

Ferrari S, Adachi JD, Lippuner K, Zapalowski C, Miller PD, Reginster JY, Torring O, Kendler DL, Daizadeh NS, Wang A, O'Malley CD, Wagman RB, Libanati C, Lewiecki EM. Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int 2015;doi:10.1007/s00198-015-3179-x.

Ferrari et al evaluated if denosumab given beyond 3 years is associated with a further reduction in nonvertebral fracture rates. The analysis includes 4074 postmenopausal women with osteoporosis (n=2343 long-term; n=1731 cross-over) continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with the fourth year and with the rate during years 4-7 was evaluated. For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab (referent) and 1.36 in the fourth year (rate ratio [RR]=0.64; 95%CI=0.48- 0.85, p=0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR=0.79; 95%CI=0.62-1.00, p=0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip BMD. Without a control group, how do we know what determines fracture rates?

Figure 5. Yearly incidence of nonvertebral fractures in the post hoc analysis participants. (a) Yearly incidence of nonvertebral fractures through 4 years of denosumab treatment for the cross-over group. (b) Yearly incidence of nonvertebral fractures through 7 years for the long-term denosumab group in the long-term participants. Percentages for nonvertebral fractures are Kaplan-Meier estimates. DMAb=denosumab, n=number of subjects who have ≥1 nonvertebral fracture. Reproduced from Osteoporos Int 2015;doi:10.1007/s00198-015-3179-x with permission from Springer.

Figure 6. Nonvertebral fracture rate ratios. (a) All denosumab-treated participants. (b) Cross-over participants. (c) Long-term participants. N=number of subjects who completed FREEDOM (i.e., completed their 3-year visit and did not discontinue IP), missed ≤1 dose of IP in FREEDOM, and who enrolled in the extension. In addition, cross-over subjects completed 3 years of the extension and missed ≤1 dose of denosumab during the first 3 years of the extension. Fracture rates and rate ratios were obtained using generalized estimating equation Poisson models; fracture rates are per 100 participant-years. Rate ratios relative to the first 3 years of denosumab treatment were adjusted for age, total hip T-score, weight, and history of nonvertebral fracture. In addition, the treatment group variable was included in the model for the combined analysis only. Reproduced from Osteoporos Int 2015;doi:10.1007/s00198-015-3179-x with permission from Springer.

Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, Brandi ML, Czerwinski E, Franek E, Lakatos P, Mautalen C, Minisola S, Reginster JY, Jensen S, Daizadeh NS, Wang A, Gavin M, Libanati C, Wagman RB, Bone HG. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: Results from the FREEDOM Extension study. Osteoporos Int 2015;doi:10.1007/s00198-015-3234-7.

Papapoulos et al reported the effects of denosumab for up to 8 years in 4550 women (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed. In the long-term group, mean BMD continued to increase for cumulative 8-year gains of 18.4 and 8.3% at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2% at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

Figure 7. Incidence of nonvertebral and new vertebral fractures during FREEDOM and the FREEDOM Extension. The yearly incidence of new vertebral and nonvertebral fractures in the long-term (a, b) and cross-over (c, d) groups are shown. For new vertebral fractures, percentages are crude incidence; lateral radiographs (lumbar and thoracic) were not obtained at Extension years 1 and 4 (long-term denosumab treatment years 4 and 7); n=number of women with ≥1 fracture; N=number of women with a spine X-ray evaluation during the time period of interest. aAnnualized incidence (2-year incidence/2). For nonvertebral fractures, percentages are Kaplan-Meier estimates; n=number of women with ≥1 fracture; N=number of women who were still on study at the beginning of each period. Reproduced from Osteoporos Int 2015;doi:10.1007/s00198-015-3234-7 with permission from Springer.

Men Receiving Androgen Deprivation Therapy and Fracture Risk

Wu CT, Yang YH, Chen PC, Chen MF, Chen WC. Androgen deprivation increases the risk of fracture in prostate cancer patients: A population-based study in Chinese patients. Osteoporos Int 2015;26:2281-90.

Wu et al reported androgen deprivation therapy (ADT) using gonadotropin-releasing hormone (GnRH) agonists or orchiectomy in 17,359 subjects diagnosed with prostate cancer. The rates of fracture from 12 months after diagnosis until the last follow-up date were 8.7% for all patients, 7.1% for patients who did not receive ADT or orchiectomy, 9.8% for patients who received ADT, and 14.4% for patients who received orchiectomy with or without ADT (P<0.0001). A significant hazard ratio was observed in patients who received at least nine doses within 1 year after diagnosis and in those whose dose density exceeded two doses per year.

Figure 8. Kaplan-Meier plots of unadjusted estimates of fracture-free survival among the groups who did or did not receive ADT or orchiectomy. All subjects who survived at least 5 years after the diagnosis of prostate cancer were included in the analysis. Patients who incurred fractures during the first year after diagnosis were excluded. Those patients who did not receive GnRH agonists or orchiectomy (group 1) had the highest rate of fracture-free survival (5- and 10-year rates of 92.2 and 86.7 %, respectively). Those who received GnRH agonists alone (group 2) and orchiectomy with or without GnRH agonists (group 3) had lower rates of fracture-free survival (5- and 10-year rates of 90.0 and 83.4 % for group 2 and 85.6 and 76.7 % for group 3, respectively). The curves between any two of the three groups were significantly different (group 1 vs. group 2: P value=0.0009; group 1 vs. group 3: P value<0.0001; group 2 vs. group 3: P value<0.0001). Reproduced from Osteoporos Int 2015;26:2281-90 with permission from Springer.

Improved Initiation of Therapy After Hip Fracture

Klop C, Gibson-Smith D, Elders PJ, Welsing PM, Leufkens HG, Harvey NC, Bijlsma JW, van Staa TP, de Vries F. Anti-osteoporosis drug prescribing after hip fracture in the UK: 2000-2010. Osteoporos Int 2015;26:1919-28.

To examine trends in anti-osteoporosis drug prescribing after hip fracture in the UK, Klop et al extracted data of 27,542 patients ≥50 years who had a first hip fracture between 2000-2010 to determine the probability being prescribed anti-osteoporosis drugs within 1 year of fracture. The probability of a prescription was 7% in 2000 and 46% in 2010. This was complemented by a similar increase in vitamin D/calcium. Cumulative incidence of receiving therapy was greater in women (8% in 2000, 51% in 2010) than men (4% in 2000, 34% in 2010). We are getting better but not that much better.

Bisphosphonate Antifracture Efficacy in Men

Chen L, Wang G, Zheng F, Zhao H, Li H. Efficacy of bisphosphonates against osteoporosis in adult men: A meta-analysis of randomized controlled trials. Osteoporos Int 2015;26:2355-63.

Chen et al reported that in 9 randomized controlled trials involving 2464 men, compared with placebo, the efficacy of bisphosphonates was the following: vertebral fracture, RR (95%CI) 0.36 (0.24, 0.56), P<0.01 and nonvertebral fracture, 0.52 (0.32, 0.84), P<0.01. Bisphosphonates reduced bone-specific alkaline phosphatase [MD (95%CI) -24.41 (-26.19, -22.62), P<0.01] and CTX [MD (95%CI) -34.51 (-41.03, -27.98), P<0.01].

Vitamin D Metabolites Are Weakly Associated With Bone Density

van Ballegooijen AJ, Robinson-Cohen C, Katz R, Criqui M, Budoff M, Li D, Siscovick D, Hoofnagle A, Shea SJ, Burke G, de Boer IH, Kestenbaum B. Vitamin D metabolites and bone mineral density: The multi-ethnic study of atherosclerosis. Bone 2015;78:186-93.

van Ballegooijen et al reported that in 1773 adults, vitamin D metabolites were measured in White (n=714), Black (n=353), Chinese (n=249), and Hispanic (n=457) participants. Serum 25(OH)D and 24,25(OH2)D3 concentrations were highest among Whites and lowest among Blacks. BMD was greatest among Black participants. Higher serum 25(OH)D was only associated with higher BMD among Whites and Chinese participants. Comparing the lowest category of 25(OH)D (<20 ng/ml) to the highest (≥30 ng/ml), the adjusted mean difference in BMD was -8.1 g/cm3 (95%CI -14.8, -1.4) for Whites; -10.2 g/cm3 (-20.4, 0.0) for Chinese vs. 8.8 g/cm3 (-2.8, 20.5) for Black and -1.1 g/cm3 (-8.3, 6.2) for Hispanic. Serum PTH was not associated with BMD.

Combining Antiresorptives and Anabolics

Iwamoto J, Seki A. Effect of combined Tteriparatide and monthly risedronate therapy on cancellous bone mass in orchidectomized rats: A bone histomorphometry study. Calcif Tissue Int 2015;97:23-31.

Iwamoto et al reported that fifty 14-week-old male Sprague Dawley rats were randomized into the following: sham-operation + vehicle; ORX + vehicle; ORX + risedronate (90 µg/kg subcutaneous, every 4 weeks); ORX + teriparatide (30 µg/kg subcutaneous, three times per week); and ORX + risedronate + teriparatide. After 12 weeks, ORX decreased BV/TV and trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Risedronate increased BV/TV and Tb.N above the sham control values, while teriparatide prevented the ORX-induced decrease in BV/TV and increased trabecular width (Tb.Wi) above sham control levels. Risedronate decreased Tb.Sp below control values, while teriparatide prevented the ORX-induced increase in Tb.Sp. The combination of teriparatide and risedronate increased BV/TV and Tb.N and decreased Tb.Sp compared with teriparatide alone.

Tissue Mineral Density and PTH Administration

Misof BM, Roschger P, Dempster DW, Zhou H, Bilezikian JP, Klaushofer K, Rubin MR. PTH(1-84) administration in hypoparathyroidism transiently reduces bone matrix mineralization. J Bone Miner Res 2015;doi:10.1002/jbmr.2588.

PTH(1-84) increases low remodeling dynamics. Misof et al studied the effect of 1 year or 2 years PTH(1-84) treatment on cancellous and cortical bone mineralization density distribution (Cn. and Ct.BMDD) in paired transiliac bone biopsy samples in 30 adult hypoparathyroid patients (14 treated for 1 year/16 treated for 2 years). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.CaMean +3.9% and +2.7%, p<0.001). After 1 year PTH(1-84), Cn.CaMean was lower than that at baseline (-6.3%, p<0.001), while in the 2 years PTH(1-84) group Cn.CaMean did not differ from baseline. Significant changes of Ct.BMDD were observed in the 1 year treatment group only. PTH(1-84) treatment caused differential effects dependent on treatment. The greater increase in bone formation during the first year was associated with a decrease in bone matrix mineralization.

Bone Water
A guide to porosity

Seifert AC, Li C, Wehrli SL, Wehrli FW. A surrogate measure of cortical bone matrix density by long T2-suppressed MRI. J Bone Miner Res 2015;doi:10.1002/jbmr.2580.

Magnetic resonance has the potential to image and quantify free water within the Haversian pore system (transverse relaxation time, T2 >1 ms), and water hydrogen-bonded to matrix collagen (T2 approximately 300-400 µs). The objective of this study by Seifert et al was to evaluate a surrogate measurement for matrix density, single adiabatic inversion recovery (SIR) zero echo-time (ZTE) MRI, in human bone. Specimens of tibial cortical bone from 15 donors (27-97 years, 8 females and 7 males) were examined at 9.4T field strength using two methods: (1) 1H ZTE MRI, to capture total 1H signal, and (2) 1H SIR-ZTE MRI, to selectively image matrix-associated 1H signal. Total water, bone matrix, and BMDs were quantified, and porosity was measured by µCT. ZTE apparent total water 1H concentration was 32.7±3.2 M (range: 28.5-40.3 M), and correlated with porosity (R2=0.80) and negatively with matrix and mineral densities (R2=0.90 and 0.82, respectively). SIR-ZTE apparent bound water 1H concentration was 32.9±3.9 M (range: 24.4-39.8 M), and its correlations were opposite to those of apparent total water: negative with porosity (R2=0.73) and positive with matrix density (R2=0.74) and mineral density (R2=0.72). Porosity was correlated with gravimetric matrix density (R2=0.91, negative) and total water density (R2=0.92, positive). The strong correlations of SIR-ZTE-derived apparent bound water 1H concentration with ground-truth measurements suggest that this quantitative solid-state MRI method provides a surrogate of matrix density.

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;30:1441-4.

Allen et al reported that raloxifene positively affects mechanical properties of the bone matrix in part through modification of skeletal-bound water. To determine if raloxifene-induced alterations in skeletal hydration could be measured in vivo using ultrashort echotime MRI (UTE-MRI), 12 female beagle dogs were treated for 6 months with saline (1 mL/kg/d) or raloxifene (0.5 mg/kg/d). After 6 months, raloxifene-treated animals had higher bound water (+14%; p=0.05) and lower free water (-20%) compared with vehicle-treated animals.

Unal M, Akkus O. Raman spectral classification of mineral- and collagen-bound water's associations to elastic and post-yield mechanical properties of cortical bone. Bone 2015;81:315-26.

Unal et al reported bone hydration in 30 cortical samples was studied by short-wave infrared Raman spectroscopy. A dehydration method was developed to replace unbound (heat drying) and bound (ethanol treatment) water in bone. Four peaks were investigated: I3220/I2949, I3325/I2949 and I3453/I2949 reflect organic-matrix related water (collagen-related water), while I3584/I2949 reflects status of mineral-related water compartments. Collagen-water related biomarkers correlated with toughness (R2=0.81 and R2=0.79; p<0.001) and post-yield toughness (R2=0.65 and R2=0.73; p<0.001). Mineral-water related biomarker correlated negatively with elastic modulus (R2=0.78; p<0.001) and positively with strength (R2=0.46; p<0.001).

Toughness of Bone

Abraham AC, Agarwalla A, Yadavalli A, McAndrew C, Liu JY, Tang SY. Multiscale predictors of femoral neck in situ strength in aging women: Contributions of BMD, cortical porosity, reference point indentation, and nonenzymatic glycation. J Bone Miner Res 2015;doi:10.1002/jbmr.2568.

Abraham et al examined the correlation between femoral neck fracture strength in female cadaveric bone and areal BMD (aBMD), with cortical porosity (Ct.Po), reference point indentation (RPI), and advanced glycation endproducts (AGEs). All measurements predicted femoral neck fracture strength, with aBMD being the strongest correlate (aBMD: r=0.755, p<0.001; Ct.Po: r=-0.500, p<0.001; reference point indentation (RPI): r=-0.478, p<0.001; AGEs: r=-0.336, p=0.016). RPI-derived measurements were not correlated with tissue mineral density or cortical porosity. Inclusion of aBMD and any other factor improve the prediction of bone strength. Combining aBMD with tibial Ct.Po (r=0.835; p<0.001), tibial difference in indentation depth between the first and 20th cycle (r=0.883; p<0.001), or tibial AGEs (r=0.822; p<0.001) improves the prediction of femoral neck strength.

Granke M, Makowski AJ, Uppuganti S, Does MD, Nyman JS. Identifying novel clinical surrogates to assess human bone fracture toughness. J Bone Miner Res 2015;30:1290-300.

Granke et al investigated the role of 1H nuclear magnetic resonance spectroscopy (NMR) and RPI to explain age-related variance in fracture toughness. Harvested from cadaveric femurs (62 human donors), single-edge notched beam specimens of cortical bone underwent fracture toughness testing (R-curve method). NMR-derived bound water showed the strongest correlation with fracture toughness (r=0.63 for crack initiation, r=0.35 for crack growth, and r=0.45 for overall fracture toughness; p<0.01). The age-related decrease in toughness properties were best explained by a combination of pore water and RPI-derived tissue stiffness (adj R2=53.3%, 23.9%, and 35.2% for crack initiation, crack growth, and overall toughness, respectively; p<0.001). Improvements in fracture risk assessment could be achieved by accounting for water distribution (quantitative ultrashort echo time MRI) and by a local measure of tissue resistance to indentation, RPI.

Risedronate in Breast Cancer

Greenspan SL, Vujevich KT, Brufsky A, Lembersky BC, van Londen GJ, Jankowitz RC, Puhalla SL, Rastogi P, Perera S. Prevention of bone loss with risedronate in breast cancer survivors: A randomized, controlled clinical trial. Osteoporos Int 2015;26:1857-64.

Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Greenspan et al conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) randomized to once weekly risedronate 35 mg or placebo, all received calcium plus vitamin D. 87% completed 24 months. BMD increased more in the treatment group compared to placebo with an adjusted difference at 24 months of 3.9±0.7 % at the spine and 3.2±0.5 % at the hip (both p<0.05). The adjusted difference between the active treatment and placebo groups were 0.09±0.04 nmol/LBCE for CTX and 23.3±4.8 µg/mL for P1NP (both p<0.05). Women with greater 12-month decreases in CTX and P1NP had a greater 24-month increase in spinal BMD (p<0.05).


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