Overview, Vol 13, Issue 8

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.

PDF Version

FREE DOWNLOAD of PIO Volume 13-8 Figures


Strontium Ranelate is Not a Dual Acting Agent

Chavassieux et al report data that challenges the notion that strontium ranelate (SR) has a ‘dual action’ ‒ increasing bone formation and reducing resorption (1). In this 12 month multicenter, double-blind, controlled trial, the investigators performed transiliac bone biopsies at 0, 6 or 12 months in 387 postmenopausal women with osteoporosis given SR 2 g/day (n=256) or alendronate 70 mg/week (n=131).

In the intention-to-treat group (268 women with paired biopsies), static and dynamic parameters of remodeling decreased with alendronate (ALN) consistent with the known effect of this drug in reducing remodeling. The SR group also had a modest but less decrease in the surface extent of remodeling, reflected in reduced activation frequency and mineralizing surfaces. Static parameters of formation were unchanged from baseline except for a decrease in the proportion of the surface (Ob.S/BS) covered by osteoblasts at 6 months. However, as there was no calcium + vitamin D-alone group and no strontium-alone group to permit comparison, it is plausible that the modest decreases in activation frequency and some remodeling indices could be due to the concomitant administration of calcium + vitamin D supplementation. ALN also decreased resorption parameters. SR did not.

Moreover, in the SR group, compared to the baseline, mean wall thickness (MWT), the two dimensional measure of the volume of bone formed by a BMU, decreased at 6 not 12 months and cancellous bone volume per unit tissue volume (BV/TV), trabecular thickness and number decreased. No mineralization defect was reported with either drug.

ALN is a remodeling suppressant. SR does not substantially modify the surface extent of remodeling – neither the surface extent of bone formation nor the surface extent of bone resorption, each reflecting the birth rate of BMUs and their life span. Surfaces undergoing bone formation do not decrease because remodeling continues. This is not evidence of an anabolic effect ‒ there is no increase in MWT, indeed, there was a decrease. There is also no evidence of reduced surface extent of bone resorption.

The data, whilst based only on iliac crest bone, call to question the notion that SR is a dual acting drug. It seems reasonable to infer this drug reduces fracture risk but it is likely to be due to changes in morphology produced by the cellular machinery of bone remodeling. This drug does not appear to substantially affect bone remodeling. It is likely to mediate its benefits by influencing the matrix properties of bone – a worthwhile and important distinction from other therapies. The authors are to be congratulated in performing this important study.


Morbidity and Mortality

Frost et al report that in over 2000 elderly men and women followed for 21 years, 151 women and 55 men sustained a hip fracture. Death occurred in 86 (57%) women and 36 (66%) men (2). The cumulative relative survival post hip fracture at 1, 5 and 10 years was 0.83 (0.76-0.89), 0.59 (0.48-0.68), and 0.31 (0.20-0.43), respectively, in women and 0.63 (0.48-0.75), 0.48 (0.32-0.63), and 0.36 (0.18-0.56) in men. After hip fracture, women died 4.1 (IQR 1.7-7.8) years earlier, and men died 4.8 (IQR 2.4-7.0) years earlier than expected. For every 6 women and for every 3 men with hip fracture, one extra death occurred above that expected in the population.

Figure 1. Plots of relative survival following hip fracture comparing women and men (panel A) and age groups (panel B). Observed survival and [expected survival] added to the bottom of each plot. Reproduced from Bone, 56:23-9, Copyright (2013), with permission from Elsevier.

 

 

 

 

 

 

Few studies report mortality of hip fracture among Asian populations. Wang et al report that among 143,595 patients with hip fracture, from 1999-2005, hip fracture incidence increased and then fluctuated after 2006 (3). From 1999-2009, annual mortality decreased from 18.10% to 13.98%, and the male-to-female ratio of annual mortality increased from 1.38 to 1.64, while the annual SMR decreased from 13.80 to 2.98. Follow-up SMR at 1, 2, 5, and 10 years postfracture was 9.67, 5.28, 3.31, and 2.89, respectively. Females had higher follow-up SMR in the younger age groups (60-69 years of age) but lower follow-up SMR in the older age groups (over 80 years of age) relative to males. Hip fracture affects short-term but not long-term mortality.

Figure 2. Ten-year overall survival curves by (a) gender, (b) age group, (c) fracture type, and (d) CCI number. Reproduced from Bone, 56:147-53, Copyright (2013), with permission from Elsevier.

 

 

To determine all-cause and cause-specific mortality risk in the first 5 years after hip fracture in an Asian Chinese population, Koh et al studied 63,257 middle-aged and elderly Chinese men and women in Singapore followed for hip fracture and death (4). 1,166 hip fracture cases were matched with 5 nonfracture subjects by age and sex. Increase in all-cause mortality risk persisted 5 years after hip fracture, aHR=1.58 [1.35-1.86] for females and aHR=1.64 [1.30-2.06] for males. Men had higher risk for mortality risk after hip fracture from stroke and cancer up to one year postfracture, but women with hip fracture had higher coronary artery mortality risk for 5 years postfracture. Men had higher risk of death associated with pneumonia while women had increased risk of death associated with urinary tract infections. All-cause mortality risk persisted for 5 years after hip fractures in men and women.

Figure 3. Cumulative incidence of all-cause mortality according to hip fracture for males and females. Reproduced from Osteoporos Int 2013;24:1981-9 with permission from Springer.

 

 

 

 

 

 

 

 

 

Roux et al report that 1822 fractures occurred (57% minor nonhip, nonvertebral [NHNV]  ‒ wrist/hand, ankle/foot, rib/clavicle; 26% major NHNV ‒ pelvis/leg, shoulder/arm; 10% spine; 7% hip) in 50,461 postmenopausal women over one year (5). Health-related quality of life was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures.

Figure 4. Distribution of incident fracture types. Major NHNV pelvis, upper leg, lower leg, shoulder, upper arm, knee, and elbow; minor NHNV wrist, hand, ankle, foot, rib, and clavicle. Reproduced from Osteoporos Int 2012;23:2863-71 with permission from Springer.

 

 

 

 

Figure 5. Distribution of incident fracture types. NHNV nonhip, nonvertebral. Reproduced from Osteoporos Int 2012;23:2863-71 with permission from Springer.

 

 

 

Figure 6. One-year incidence of fractures in GLOW by age group. Reproduced from Osteoporos Int 2012;23:2863-71 with permission from Springer.

 

 

 

 

Michaelsson et al reported that in 286 hip fracture discordant monozygotic twins, 143 twins with a hip fracture died (50%) compared to 101 twins (35%) without a hip fracture (6). Through the first year after hip fracture, the rate of death was 4-fold in women (HR 3.71; 95% CI 1.32-10.40) and 7-fold in men (HR 6.67; 1.47-30.13). The high rate in women only persisted during the first year after hip fracture, whereas the corresponding HR in men was 2.58 (95% CI 1.02-6.62). The higher risk in men after the hip fracture event attenuated during follow-up. After 5 years, the hazard ratio in men with a hip fracture was 1.19 (95% CI 0.29-4.90). On average, hip fracture contributed to 0.9 years of life lost in women (95% CI 0.06-1.7) and 2.7 years in men (95% CI 1.7-3.7). The potential years of life lost associated with the hip fracture was pronounced in older men (>75 years), with an average loss of 47% (95% CI 31-61) of the expected remaining lifetime.

Figure 7. Hazard ratios (HRs) of death after hip fracture analyzed by pairwise Cox regression analysis in identical twin pairs discordant for hip fracture by sex and time of follow-up. The HRs were adjusted by a propensity score that included age, number of comorbidities, Charlson index, smoking status, physical activity level, visual impairment, hearing aid, marital status, use of estrogen replacement therapy, any prescribed medication, nonprescribed medication or supplement use, present use of corticosteroids, BMI, weight, height, abstainer, alcohol or drug abuse, any psychiatric disease, and an index for activity of daily living (ADL). Reproduced from J Bone Miner Res 2013;doi:10.1002/jbmr.2029 with permission of the American Society of Bone and Mineral Research.


Genetics of Bone Microstructure

To differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits, Paternoster et al reported cortical vBMD GWA meta-analysis (n=5878) followed by replication (n=1052) and identified genetic variants in 4 loci (RANKL, rs1021188; LOC285735, rs271170; OPG, rs7839059; and ESR1/C6orf97, rs6909279) (7). Trabecular vBMD GWA meta-analysis (n=2500) followed by replication (n=1022) identified one locus (FMN2/GREM2, rs9287237). In a subset of the GOOD cohort (n=729), rs1021188 was associated with cortical porosity while rs9287237 was associated with trabecular BV/TV. The genetic variant in the FMN2/GREM2 locus was associated with fracture in the MrOS Sweden (HR per extra T allele 0.75, 0.60-0.93) and GREM2 expression in human osteoblasts. Thus genetic variants associated with cortical and trabecular bone differed. The authors propose that a genetic variant in the RANKL locus influences cortical vBMD partly via effects on porosity, and a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and trabecular number and thickness and fracture risk.


Fragility Originates During Growth

Chevalley et al report that in 196 healthy premenopausal women aged 45.9±3.7 (±SD) years with (FX, n=96) and without (NO-FX, n=100) a history of fracture, differences in T-scores were: radial metaphysis: aBMD, -0.24; cortical vBMD, -0.38; cortical thickness, -0.37; cross-sectional area, +0.24; and endosteal perimeter, +0.28; stiffness, -0.15; failure load, -0.14; and apparent modulus, -0.28 trabecular vBMD, while thickness did not differ (8). The risk of fracture for 1 SD decrease in radius bone parameters was: radial metaphysis aBMD: 1.70 (1.18-2.44); cortical vBMD: 1.86 (1.28-2.71); cortical thickness: 2.36 (1.53-3.63), stiffness: 1.66 (1.06-2.61); failure load: 1.59 (1.02-2.47); and apparent modulus: 1.76 (1.17-2.64).

Figure 8. Difference in bone variable T-scores between healthy premenopausal women with (FX) and without (NO-FX) a history of fracture. The absolute differences and the probability (P) of statistical significance are indicated within each and above each column, respectively. These differences were adjusted for age, menarcheal age, height, weight, calcium and protein intakes, and physical activity. Reproduced from Bone, 55:377-83, Copyright (2013), with permission from Elsevier.

Figure 9. Risk of fracture in healthy premenopausal women for 1 SD decrease in radial aBMD or in microstructure and strength variables of the distal radius. Each column corresponds to odds ratios ±95% CI (horizontal line=mean) adjusted for age, menarcheal age, height, weight, calcium and protein intakes, and physical activity. The probability (P) of statistical significance is indicated above each column. Reproduced from Bone, 55:377-83, Copyright (2013), with permission from Elsevier.

Amin et al report that in 1776 children ≤18 years of age, from Olmsted County, MN who had a distal forearm fracture in 1935-1992, fractures occurring at age ≥35 years were identified and standardized incidence ratios [SIR] assessed (9). In 1086 boys (mean±SD age; 11±4 years) and 690 girls (10±4 years) followed for 27,292 person-years after age 35 years, fractures were observed in 144 (13%) men and 74 (11%) women, men (SIR, 1.9; 95% CI 1.6-2.3) but not women (SIR, 1.0; 95% CI 0.8-1.2). Fragility fractures at both major osteoporotic (hip, spine, wrist, and shoulder) sites (SIR, 2.6; 95% CI 2.1-3.3) and remaining sites (SIR, 1.7; 95% CI 1.3-2.0) were increased in men, irrespective of age at distal forearm fracture as boys. A distal forearm fracture in boys, not girls, is associated with an increased risk for fractures as adults.

Figure 10. Observed compared to expected cumulative incidence of fracture in age >35 years among Olmsted County, MN residents with a first distal forearm fracture in 1935–1992 at age ≤18 years and who had follow-up to at least age 35 years, by age, and separately for men (A) and women (B). Reproduced from J Bone Miner Res 2013;28:1751-9 with permission of the American Society of Bone and Mineral Research.

Figure 11. Standardized incidence ratio (SIR) for the risk of future fragility fracture occurring at age ≥35 years (A) or age ≥50 years (B) for Olmsted County, MN men and women following a distal forearm fracture in childhood at age ≤18 years in 1935–1992. Reproduced from J Bone Miner Res 2013;28:1751-9 with permission of the American Society of Bone and Mineral Research.

Kim et al used HR-pQCT to determine whether differences in macro- and microstructure, BMD, and bone strength at the distal radius were apparent in Asian (n=91, 53 males, 38 females, [mean ±SD] 17.3±1.5 years) and white (n=89, 46 males, 43 females, 18.1±1.8 years) adolescents and young adults (10). In males, Asians had 11% greater Tt.BMD, 8% greater Ct.BMD, and 25% lower Ct.Po than whites. Asians had 9% smaller Tt.Ar and 27% greater Ct.Th. In females, Asians had smaller Tt.Ar than whites (16%), but this difference was not significant after adjusting for covariates. Asian females had 5% greater Ct.BMD, 12% greater Ct.Th, and 11% lower Tb.Sp than whites. Estimated bone strength did not differ between Asian and white males or females. Smaller bones have, on average, more dense, less porous, and thicker cortices.


The Bigger They Are The Harder They Fall?

Premaor et al categorized 139,419 (74.9%) men as underweight/normal (BMI<25, n=26,298), overweight (25-30, n=70,851), and obese (BMI>30, n=42,270) (11). Spine and hip fractures were fewer in obese (RR 0.65; 0.53-0.80 and RR, 0.63; 0.54-0.74, respectively), and overweight (RR, 0.77, 0.64-0.92 and RR, 0.63; 0.55-0.72, respectively) relative to underweight/normal men. Obese men had fewer wrist/forearm (RR, 0.77; 0.61-0.97) and pelvic (RR, 0.44; 0.28-0.70) fractures. Multiple rib fractures were more frequent in overweight (RR, 3.42; 95% CI 1.03-11.37) and obese (RR, 3.96; 95% CI 1.16-13.52) men.

Figure 12. Kaplan-Meier estimates of hip fracture probability according to BMI WHO category. Reproduced from J Bone Miner Res 2013;28:1771-7 with permission of the American Society of Bone and Mineral Research.

 

 

Figure 13. Kaplan-Meier estimates of clinical spine and pelvis fracture probability according to BMI WHO category. Reproduced from J Bone Miner Res 2013;28:1771-7 with permission of the American Society of Bone and Mineral Research.

 

 

 

 

 

 

 

 

Johansson et al reported that among 398,610 women, average age of 63 years, followed 2.2 million person-years, 30,280 fractures (6457 hip) were observed (12). Obesity (BMI>30) was present in 22%. 81% of all fractures and 87% of hip fractures arose in nonobese women. Relative to a BMI of 25, a BMI of 35 was protective HR 0.87 (0.85-0.90) and 1.16 (1.09-1.23) adjusted for BMD but was a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. Low BMI was a risk factor for hip and all fracture, but protective for lower leg fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture and upper arm fracture. At a population level, high BMI remains a protective factor for most sites.

Figure 14. Relationship between BMI and risk of fracture (HR vs. BMI 25 kg/m2) for osteoporotic fracture (solid line) and hip fracture (dashed line), adjusted for age and time since baseline. Reproduced from J Bone Miner Res 2013;doi:10.1002/jbmr.2017 with permission of the American Society of Bone and Mineral Research.

 

 

Figure 15. Relationship between BMI and risk of fracture (HR vs. BMI 25 kg/m2) for osteoporotic fracture (solid line) and hip fracture (dashed line), adjusted for age, time since baseline and BMD. Reproduced from J Bone Miner Res 2013;doi:10.1002/jbmr.2017 with permission of the American Society of Bone and Mineral Research.

 

 

Compston et al report that among 52,939 women, 3628 (6.9%) had an incident clinical fracture during 3 years (13). BMI showed an inverse association with hip, clinical spine, and wrist fractures: HRs per increase of 5 kg/m2 were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively. For ankle fractures, HR per 5-kg increase 1.05 (1.02-1.07). For upper arm/shoulder and clavicle fractures, only linear height was associated: adjusted HRs per 10-cm increase were 0.85 (0.75-0.97) (p=0.02) and 0.73 (0.57-0.92), respectively. For pelvic and rib fractures, the best models were for nonlinear BMI or weight (p=0.05 and 0.03, respectively), with inverse associations at low BMI/body weight and positive associations at high values. The relationships between fracture and weight, BMI, and height are site-specific.

Taller women are at increased risk for fracture. As wider bones require less material to achieve a given bending strength, Bjornerem et al hypothesized that taller women assemble bones with relatively thinner and more porous cortices (14). In a twin study of 345 females aged 40-61 years, 93 with at least one fracture, each SD greater height was associated with a 0.69 SD larger tibia total cross-sectional area (CSA), 0.66 SD larger medullary CSA, 0.50 SD higher medullary CSA/total CSA and 0.42 SD higher porosity (all p<0.001). Cortical area was 0.45 SD larger in absolute terms but 0.50 SD smaller in relative terms. In multivariable analyses, distal tibia, medullary CSA/total CSA, and porosity predicted fracture independently; height was no longer significant. Each 1 SD greater porosity was associated with fracture; distal tibia, OR=1.55 (95% CI 1.11-2.15); distal fibula, OR=1.47 (95% CI 1.14-1.88); and distal radius, OR=1.22 (95% CI 0.96-1.55). Taller women assemble wider bones with relatively thinner and more porous cortices predisposing to fracture.

Figure 16. Distal tibia total CSA, medullary CSA, medullary CSA/total CSA and cortical CSA/total CSA as a function of height (upper panels). Cortical porosity as a function of height, total CSA, medullary CSA/total CSA, a measure of relatively cortical thickness and cortical CSA/total CSA (lower panel). Reproduced from J Bone Miner Res 2013;28:2017-26 with permission of the American Society of Bone and Mineral Research.

 

Figure 17. Higher probability of fracture is associated with a higher cortical porosity and a larger ratio of medullary CSA to total CSA, a surrogate reflecting a relatively thinner cortex. Reproduced from J Bone Miner Res 2013;28:2017-26 with permission of the American Society of Bone and Mineral Research.

 

 

 


Bone Remodeling Markers as Independent Predictors of Fracture

Tamaki et al evaluated how bone turnover predicts vertebral fracture risk in postmenopausal women during 10 years after adjusting for age and femoral neck bone mineral density in 522 postmenopausal women, with no diseases or medications affecting bone metabolism (15). Vertebral fractures were ascertained in three follow-up surveys (1999, 2002, and 2006). Initial fracture events were diagnosed morphometrically. 83 fracture events were diagnosed over a median follow-up period of 10.0 years. RR per SD for BAP was 4.38 (1.45, 13.21) among 65 subjects with years since menopause (YSM) <5 years. RRs per SD for BAP, tDPD, and fDPD were 1.39 (1.12, 1.74), 1.32 (1.05, 1.67), and 1.40 (1.12, 1.76), respectively, among 457 subjects with YSM ≥5 years. Of the 451 women followed at least once until 2002, RRs per SD for BAP, tDPD, and fDPD over 6 years were not significantly different from those over 10 years.


Denusumab and the Appendicular Skeleton

Simon et al examined the effects of denosumab on radius cortical and trabecular bone density, mass, and strength, and wrist fracture incidence in the FREEDOM. Radius BMD and polar moment of inertia were evaluated in two prespecified substudies (placebo, n=209; denosumab, n=232) or quantitative CT (placebo, n=48; denosumab, n=62). Prespecified analysis assessed wrist fracture incidence in all FREEDOM participants (placebo, N=3906; denosumab, N=3902), and post hoc subgroup analyses evaluated those with higher fracture risk (baseline femoral neck T-score<2.5; placebo, N=1406; denosumab, N=1384) (16). Denosumab increased aBMD and vBMD, BMC, and polar moment of inertia compared with placebo, in radius cortical and trabecular bone. Wrist fracture incidence was 2.9% for placebo and 2.5% for denosumab (RR reduction, 16%; P=0.21) on month 36. Participants with a femoral neck T-score<2.5 were at increased risk for wrist fracture, and denosumab reduced wrist fracture incidence (placebo, 4.0%; denosumab, 2.4%; RR reduction, 40%; absolute risk reduction, 1.6%; P=0.03).

Genant et al report that in the FREEDOM study, hip QCT was performed at baseline and months 12, 24, and 36 months in placebo (N=26) and denosumab (N=36) groups (17). Denosumab resulted in improvements in total hip integral vBMD and BMC. At month 36, the mean percentage increase from baseline in total hip integral vBMD and BMC was 6.4% and 4.8%, respectively. These gains were accounted for by increases in vBMD and BMC in the trabecular, subcortical, and cortical compartments. In the placebo, total hip integral vBMD and BMC decreased at month 36 by -1.5% and -2.6%, respectively. The differences between denosumab and placebo were also significant for integral, trabecular, subcortical, and cortical vBMD and BMC.

Figure 18. QCT MIAF percentage and absolute changes in hip vBMD and BMC at month 36. A. vBMD (mg/cm3). B. BMC (mg). Least-squares means, 95% CIs, and p-value from analysis of covariance model are presented. *p<0.0001 compared with both baseline and placebo; †p<0.05 compared with baseline. Month 12, n=60; month 24, n=59; month 36, n=62. BMC, bone mineral content; MIAF, Medical Image Analysis Framework; QCT, quantitative computed tomography; vBMD, volumetric bone mineral density. Reproduced from Bone, 56:482-8, Copyright (2013), with permission from Elsevier.

 

 

 


Suppressed Lymphangiogenesis and ONJ

Kuroshima et al report that in mice receiving zoledronic acid (ZA) with cytotoxic drug melphalan, or dexamethasone, first molars were extracted 3 weeks after the initiation of treatment and wound healing assessed at 4 weeks post-extractions. Mice receiving ZA and melphalan developed ONJ, while ONJ-like lesions were not found in mice on ZA or melphalan, or the combination of ZA and dexamethasone. Lymphatic vessel formation was suppressed with decrease in F4/80(+) macrophages VEGFC. Suppressed lymphatics were also found in the draining lymph nodes of mice on ZA and melphalan (18).

Figure 19. µCT assessment of tooth extraction sockets. (A) Gross healing of tooth extraction wounds at 4 weeks. Gross healing in the ZA, MEL, and ZA/DEX groups was normal and similar to VC, while healing was impaired and exhibited ONJ-like lesions in the ZA/MEL group. ROI indicates tooth extraction wounds. (B) Representative reconstructed µCT images of extraction sockets. Scant bone fill (*) was noted in the ZA/MEL group while the extraction sockets were mostly filled with trabecular bone in all other groups. (C) Quantitatively, ZA/MEL treatment significantly suppressed bone fill in the sockets while ZA treatment enhanced bone fill. (D) Trabecular bone was significantly thinner in the ZA/MEL group and thicker in both the ZA and ZA/DEX groups compared to VC. (E) The numbers of trabeculae was significantly lower in the ZA, ZA/MEL, and ZA/DEX groups vs. VC. (F) Trabecular bone separation was similar between groups except the ZA/MEL group. (G) ZA treatment enhanced BMD while ZA administered with melphalan decreased BMD. n=7/group, *p<0.05, **p<0.01, ***p<0.001. Reproduced from Bone, 56:101-9, Copyright (2013), with permission from Elsevier.

Figure 20. Histomorphometric assessments of the tooth extraction wounds. (A) The dotted line outlines the original extraction sockets and the solid line indicates the newly formed bone level. Nearly no bone fill and a lack of the epithelium were observed in the ZA/MEL group, while the sockets were filled with new bone in the all other groups. (B) Bone fill (BA/TA) was significantly lower in the ZA/MEL group vs. VC. (C) The osteoclast perimeters (Oc.N/BS) were significantly lower in the ZA, ZA/MEL, and ZA/DEX groups, but not in the MEL group. (D) The osteoblast surface (Ob.S/BS) was significantly lower in the ZA, MEL, and ZA/MEL groups vs. VC, while ZA/DEX treatment had no effect on the osteoblast surface. (E) The connective tissue of the extraction wounds was assessed. Minimal PMN infiltration was noted in the VC group, while significant PMN infiltration was observed in the ZA, MEL, ZA/MEL, and ZA/DEX groups. Immense PMN infiltration was noted in the combination treatment groups (ZA/MEL and ZA/DEX). (F) Significantly larger necrotic bone area was noted in the ZA, ZA/MEL, and ZA/DEX groups vs. VC. n >8/group, *p<0.05, **p<0.01, ***p<0.001. Reproduced from Bone, 56:101-9, Copyright (2013), with permission from Elsevier.


Noninferiority of Ibandronate versus Risedronate

Nakamura et al report that patients aged ≥60 years were randomized to 0.5 or 1 mg/month i.v. ibandronate (IBN)  plus oral placebo or 2.5 mg/day risedronate plus i.v. placebo over 3 years (19). 1265 patients were randomized. A total of 1134 patients formed the per-protocol set. Both IBN doses were noninferior to risedronate: 0.5 mg, HR 1.09 (0.77-1.54); 1 mg, HR 0.88 (0.61-1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (12.8-20.8) for 0.5 mg IBN, 11.6 % (8.2-15.0) for 1 mg IBN, and 13.2 % (9.6-16.9) for risedronate. Analyses in women only showed similar results to the overall population.


Ibandronate and Tissue Mineralization Density

Misof et al examined the effects of 24 months IBN (3 mg/3 ml intravenously every 3 months) on material quality in 19 men with OP within an open-label, single-center, prospective phase III study (20). At baseline, cancellous bone matrix mineralization from mOP was lower than reference data (Cn.CaMean -1.8%). IBN increased calcium concentrations (Cn.CaMean +2.4%, Ct.CaMean, +3.0% both p<0.01), and reduced heterogeneity of mineralization (Cn.CaWidth -14%, p=0.044; Ct.CaWidth, -16%, p=0.001) leading to cancellous BMDD within normal range. IBN was associated with a decrease in porosity (-25%, p=0.01), increases in BMD at the lumbar spine, the femoral neck and the total hip (+3.3%, +1.9%, and +5.6%, respectively) and reductions in CTX (-37.5%), P1NP (-44.4%), and OC (-36.3%).

Figure 21. Cancellous BMDD results (median (25th, 75th percentile)) for mOP (BL, white=baseline; IBA, dark grey=after 24 months with intravenous IBA). White dotted lines and grey areas in the background indicate mean±1SD or median (25th, 75th percentile) of the normal reference range (from 19). ***p<0.001, *p<0.05 paired comparison vs. baseline (treatment effect), and °°°p<0.001, °°p<0.01, °p<0.05 vs. reference BMDD. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2035 with permission of the American Society of Bone and Mineral Research.


Bisphosphonates and Bowel Cancer

Passarelli et al evaluated the association between oral bisphosphonate use and colonorectal cancer (CRC) incidence in 156,826 postmenopausal women, ages 50-79 years in the WHI trials (21). 1931 women were diagnosed with incident invasive CRC during a median follow-up of 12 years. Alendronate accounted for >90% of the total person-years of use. The association between oral bisphosphonate use and CRC risk (HR=0.88; 95%CI 0.72-1.07; p=0.19).


References

1. Chavassieux P, Meunier PJ, Roux JP, et al. Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women. Randomized comparison to alendronate. J Bone Miner Res 2013; doi:10.1002/jbmr.2074.

2. Frost SA, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Excess mortality attributable to hip-fracture: A relative survival analysis. Bone 2013;56:23.

3. Wang CB, Lin CF, Liang WM, et al. Excess mortality after hip fracture among the elderly in Taiwan: a nationwide population-based cohort study. Bone 2013;56:147.

4. Koh GC, Tai BC, Ang LW, et al. All-cause and cause-specific mortality after hip fracture among Chinese women and men: The Singapore Chinese Health Study. Osteoporos Int 2013;24:1981.

5. Roux C, Wyman A, Hooven FH, et al. Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW). Osteoporos Int 2012;23:2863.

6. Michaelsson K, Nordstrom P, Nordstrom A, et al. Impact of hip fracture on mortality: a cohort study in hip fracture discordant identical twins. J Bone Miner Res 2013; doi: 10.1002/jbmr.2029.

7. Paternoster L, Lorentzon M, Lehtimaki T, et al. Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure. PLOS Genet 2013;9:e1003247.

8. Chevalley T, Bonjour JP, van Rietbergen B, Ferrari S, Rizzoli R. Fracture history of healthy premenopausal women is associated with a reduction of cortical microstructural components at the distal radius. Bone 2013;55:377.

9. Amin S, Melton LJ, 3rd, Achenbach SJ, et al. A distal forearm fracture in childhood is associated with an increased risk for future fragility fractures in adult men, but not women. J Bone Miner Res 2013;28:1751.

10. Kim S, Macdonald HM, Nettlefold L, McKay HA. A comparison of bone quality at the distal radius between Asian and white adolescents and young adults: an HR-pQCT study. J Bone Miner Res 2013;28:2035.

11. Premaor MO, Compston JE, Fina Aviles F, et al The association between fracture site and obesity in men: A population-based cohort study. J Bone Miner Res 2013;28:1771.

12. Johansson H, Kanis JA, Oden A, et al. A meta-analysis of the association of fracture risk and body mass index in women. J Bone Miner Res 2013; doi: 10.1002/jbmr.2017.

13. Compston JE, Flahive J, Hosmer DW, et al. Relationship of weight, height, and body mass index with fracture risk at different sites in postmenopausal women: the global longitudinal study of osteoporosis in women (GLOW). J Bone Miner Res 2013; doi:10.1002/jbmr.2051.

14. Bjornerem A, Bui QM, Ghasem-Zadeh A, et al. Fracture risk and height: an association partly accounted for by cortical porosity of relatively thinner cortices. J Bone Miner Res 2013;28:2017.

15. Tamaki J, Iki M, Kadowaki E, et al. Biochemical markers for bone turnover predict risk of vertebral fractures in postmenopausal women over 10 years: the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int 2013;24:887.

16. Simon JA, Recknor C, Moffett Jr AH, et al. Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: bone density, mass, and strength of
the radius, and wrist fracture. Menopause 2013;20:130.

17. Genant HK, Libanati C, Engelke K, et al. Improvements in hip trabecular, subcortical, and cortical density and mass in postmenopausal women with osteoporosis treated with denosumab. Bone 2013;56:482.

18. Kuroshima S, Yamashita J. Chemotherapeutic and antiresorptive combination therapy suppressed lymphangiogenesis and induced osteonecrosis of the jaw-like lesions in mice. Bone 2013;56:101.

19. Nakamura T, Nakano T, Ito M, et al; MOVER Group MS. Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis. Calcif Tissue Int 2013;93:137.

20. Misof BM, Patsch JM, Roschger P, et al. Intravenous treatment with ibandronate normalizes bone matrix mineralization and reduces cortical porosity after two years in male osteoporosis: A paired biopsy study. J Bone Miner Res 2013; doi: 10.1002/jbmr.2035.

21. Passarelli MN, Newcomb PA, Lacroix AZ, et al. Oral bisphosphonate use and colorectal cancer incidence in the Women's Health Initiative. J Bone Miner Res 2013;28:2043.