Overview, Vol 13, Issue 4

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

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

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

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Decline in Hip Fracture Incidence

Korhonen et al determined the current trend in the number and incidence (per 100,000 persons) of hip fracture among older adults in Finland (1). The authors accounted for all persons 50 years of age or older admitted to hospitals for primary treatment of hip fracture between 1970-2010.
 The number of hip fractures rose sharply till the end of 1990s (from 1857 in 1970 to 7122 in 1997), then levelled (7594 fractures in 2010). Similarly, the age-adjusted incidence of hip fracture increased until 1997 but declined thereafter. The decline was clear in women whose age-adjusted incidence was 515.7 (per 100,000 persons) in 1997 and 382.6 in 2010. In men, the corresponding incidence was 245.3 in 1997 and 210.7 in 2010. Reasons for this development are uncertain, but nevertheless, the number of hip fractures will increase 1.8-fold by 2030 even with the current 2010 incidence rates because the size of the 50-year-old or older population is likely to increase.

Figure 1. (a) Hip fractures in Finland in people ≥50 years of age between 1970-2010. A Number and crude incidence (per 100,000 persons). B Age-adjusted incidence (per 100,000 persons). (b) Age-specific incidence (per 100,000 persons) of hip fracture in Finland in people ≥50 years of age between 1970-2010: A women; B men. Reproduced from Osteoporos Int 2013;24:1599-1603 with permission from Springer.

 


Mortality Following Fracture

Melton et al determined long-term survival following fractures in 2901 Olmsted County residents ≥35 years old experiencing any fracture in 1989-1991 (2). These subjects were followed for up to 22 years for death from any cause. Standardized mortality ratios (SMRs) compared observed to expected deaths. During 38,818 person-years of follow-up, 1420 deaths were observed when 1191 were expected (SMR 1.2; 95% CI 1.1-1.3). The overall SMR was greatest soon after fracture, especially among the men, but remained elevated for over a decade thereafter. Adjusting for age and sex, relative death rates were greater for pathological fractures and less for severe trauma fractures compared to the fractures due to moderate trauma. In the latter, long-term mortality was increased following fractures at many skeletal sites. After further adjustment for cause, overall SMRs were elevated following fractures at the distal forearm, proximal humerus, thoracic/lumbar vertebrae, and proximal femur combined (SMR 1.2; 95% CI 1.1-1.3) and following all other fracture types combined (SMR 1.2; 95% CI 1.1-1.4), excluding the hand and foot fractures not associated with any increased mortality.

Figure 2. (a)  Standardized mortality ratio among 2901 Olmsted County, MN, USA, women and men, adjusted for age, by time following any fracture in 1989-1991. (b) Standardized mortality ratio among 2901 Olmsted County, MN, USA, residents following a fracture in 1989-1991, adjusted for age and sex, for fractures due to different precipitating events. (c) Standardized mortality ratio among 2901 Olmsted County, MN, USA, residents following a fracture due to no more than  moderate trauma in 1989–1991, adjusted for age, by fracture site, and sex. Reproduced from Osteoporos Int 2013;24:1689-96 with permission from Springer.


Cost Following Fracture

Leslie et al reported costs among 16,198 incident fracture cases and 48,594 matched nonfracture controls identified in the province of Manitoba, Canada (1997-2002) (3). The authors calculated the difference in median direct healthcare costs for the year pre-fracture and 5 years post-fracture in 2009 Canadian dollars adjusted for expected age-related healthcare cost increases.
 Incremental median costs for a hip fracture were highest in the first year ($25,306 in women, $21,396 in men), remaining above prefracture baseline to 5 years in women but fell below pre-fracture costs by 5 years in men. In those who survived 5 years following a hip fracture, incremental costs remained above pre-fracture costs at 5 years ($12,670 in women, $7933 in men). Incremental costs were consistently increased for 5 years after spine fracture in women. Total incremental healthcare costs for all incident fractures combined showed a large increase over pre-fracture costs in the first year ($137 million in women, $57 million in men) but fell below pre-fracture costs within 3-4 years. Elevated total healthcare costs were seen at year 5 in women after wrist, humerus and spine fractures, but these were offset by decreases in total healthcare costs for other fractures. High direct healthcare costs post-fracture are seen in the first year, but costs fall below pre-fracture levels, perhaps due to healthy survivor bias. Among those who survive 5 years following a fracture, healthcare costs remain above pre-fracture levels.

Figure 3. Total incremental healthcare costs over baseline costs from a third-party healthcare payer perspective for fracture cases (solid figures and lines) and controls (open figures and dotted lines, costs for controls divided by 3 due to 1 to 3 matching). Costs are in millions of 2009 Canadian constant dollars. Reproduced from Osteoporos Int 2013;24:1697-1705 with permission from Springer.





 


Burden of Disease in Men

Brenneman et al analyzed administrative claims from a national health plan were analysed in men ≥45 years with ≥1 medical claim for a new closed fracture between January 1, 2005 and December 31, 2008 (4). Commercially insured (COM) and Medicare Advantage Plan (MAP) members were analyzed separately. The authors identified 18,917 (COM 16,191; MAP 2726) men with new closed fractures. Nonhip, nonvertebral fractures (NHNV) were the most common fracture in both populations. Fracture costs ranged from $7121 to $15,830 for vertebral fractures, from $22,601 to $30,900 for hip fractures, and from $6078 to $8344 for NHNV fractures.


Cardiovascular Disease and Osteoporosis

Makovey et al studied 358 peri- and postmenopausal women, mean age 59.3 (range 45-74) years (5). Fracture risk was assessed using the WHO FRAX algorithm and cardiovascular disease (CVD) risk using the Framingham Risk Tool. Women with higher 10-year risk of major osteoporotic fracture had higher cardiovascular risk (4.6% vs. 8.4%, p=0.001). In multiple regression analysis, 5-year CVD risk was associated with the 10-year risk of having major osteoporotic (β=0.095, p=0.001) and hip (β=0.055, p=0.001) fracture. Women with the highest CVD risk were 5.4 times more likely to have higher risk of major osteoporotic fracture. Awareness regarding these concurrent risk factors needs to be raised so that appropriate risk reduction can be implemented.

Chen et al identified patients with vertebral fracture (n=380) and 10 age- and sex-matched controls per case (n=3795) were chosen from a nationwide representative cohort of 999,997 people from 1998-2005 (6). Both groups were followed up for stroke during 3 years with adjustments for covariates. The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person-years; 95% CI 27.5-51.2) was higher than in controls (14.0 per 1000 person-years; 95% CI 12.0-16.4, p<0.001; adjusted HR 2.71, 95% CI 1.90-3.86, p<0.001). Patients with osteoporotic vertebral fracture have a higher risk of stroke (i.e., both ischemic and hemorrhagic) and require stroke prevention strategies.


Osteocytes and Osteonal Refilling

The negative bone balance between the volumes of bone resorbed and formed is the necessary and sufficient cause of bone loss and structural decay. This negative balance may be the result of a reduced volume of bone formed in the setting of normal, increased or lesser reduced volumes of bone resorbed. Whatever the case, the explanations for the reduction in the volume of bone deposited is are not apparent.

Following excavation of a tunnel in cortical bone by osteoclasts or trench upon trabecular and endocortical surfaces, bone formation by the osteoblasts of that BMU proceeds from the cement line centrifugally refilling the cavity. Refilling must be incomplete to leave the central Haversian canal. The amount and rate of bone deposited decreases progressively as the cone closes. Power et al reported that osteocytes within the osteon are 2-fold more common adjacent to the cement line than nearer the canal (7). Large and small osteons appear to have similar osteocyte densities near the cement line, but patients with femoral neck fractures have lower osteocyte densities close to the canal. The authors suggest that osteocyte formation declines more rapidly than matrix formation as osteonal infilling proceeds. A shrinking supply of precursor osteoblasts due to previous osteocyte recruitment, apoptosis, or both could produce this effect. Sclerostin negative osteocytes adjacent to the canal were associated with reduced canal size in controls, but not in hip fracture cases.

Figure 4. Logarithms of the estimates of (est) mean osteocyte densities in the osteons of individual subjects (points), fitted linearly to the logarithms of distance from the cement line, and replotted on the linear scale. Thin continuous lines: fits to data for individual subjects. Thick dashed line: weighted mean fit for all subjects. Units: ordinate osteocytes·mm−2; abscissa mm*10−3. Reproduced from Bone, 50:1107-14, Copyright (2012), with permission from Elsevier.



 


Material Composition and Drug Therapy

Antiresorptive agents reduce the risk of fracture by around 50% for vertebral fracture even though changes in BMD vary greatly. Explanations for this observation are not apparent. Burket et al report that in 25 mature adult ewes, raloxifene increased indentation modulus and hardness throughout trabeculae by 10% (8). Zoledronic acid increased these properties only at the surfaces of trabeculae (indentation modulus +12%, hardness +16%). Nanomechanical alterations correlated with changes in tissue mineralization, carbonate substitution, crystallinity, and aligned collagen. The nanomechanical improvements within trabeculae with both treatments improved the predicted theoretical bending stiffness of trabeculae when idealized as cylindrical struts. The authors suggest that small tissue level alterations in critical locations for resisting trabecular failure could account for some of the discrepancy between the reduction in fracture risk despite the modest changes in BMD with antiresorptive treatments.

Antiresorptive agents reduce remodelling rate so bone that would have been resorbed and replaced is not and so undergoes more complete secondary mineralization. Misof et al evaluated cancellous and cortical mineralization density distribution (BMDD) in biopsies from 82 patients receiving zoledronic acid 5mg yearly and 70 controls (9). Higher cancellous and cortical (Cn.CaMean 3.2%, Ct.CaMean 2.7%) and mode calcium (Cn.CaPeak 2.1%, Ct.CaPeak 1.5%), increased percentage highly mineralized bone areas (Cn.CaHigh 64%, Ct.CaHigh 31%), lower heterogeneity of mineralization (Cn.CaWidth -14%, Ct.CaWidth -13%), and decreased percentages of low mineralized bone areas (Cn.CaLow -22%, Ct.CaLow -26%) were observed vs. placebo (all p<0.001). Cn.BMDD also revealed a shift to higher Ca concentrations. Those with lower Cn.MS/BS had a higher degree of bone matrix mineralization.

Examining the effects of odanocatib (ODN) on tissue mineralization is particularly interesting because this treatment may reduce remodelling rate less than other antiresorptive agents, at least in the appendicular skeleton, and so, theoretically, should have a lesser effect on tissue mineralization density in the appendicular than axial skeleton. The basis for this statement is the histomorphometric studies in monkeys by Cusick et al who reported a reduction in the surface extent of remodelling upon trabecular surfaces but perhaps less so upon the endocortical surface (10).

Frazzel-Zelman et al evaluated the effects of ODN on bone mineralization density distribution (BMDD) in vertebral trabecular bone, distal femoral metaphyseal and cortical shaft from monkeys (aged 16-23 years) treated with vehicle (n=5) or ODN (6 mg/kg, n=4 or 30 mg/kg, n=4, PO daily) for 21 months (11). In vertebrae, there was a shift to higher mineralization in samples from ODN-treated groups compared to vehicle: CaMean (+4%), CaPeak (+3%), CaWidth (-9%), CaLow (-28%) in the 6 mg/kg group and CaMean (+5.1%, p<0.023), CaPeak (+3.4%, p<0.046), CaWidth (-15.7%, p=0.06) and CaLow (-38.2%, p<0.034) in the 30 mg/kg group. In distal femoral metaphyseal cancellous bone, there was a trend to a dose-dependent increase in matrix mineralization. However, primary and osteonal bone of the distal cortical diaphyses showed no change in BMDD, whereas bone mineral density was increased after treatment.

ODN increased trabecular BMDD, but no changes in BMDD in cortical bone sites. The interpretation of the rise in BMD is tricky. This drug appears to reduce the depth or resorption rather than the number or remodelling sites and so, if the volume of bone deposited in each of the persisting large number of remodelling sites on the endocortical and cortical surface, this may slow bone loss but for an increase in BMD the BMU balance must become positive. The rise in BMD is therefore likely to be due to and increase in the tissue mineralization density in trabecular bone and perhaps due to a reduction in intracortical porosity given that remodelling seems to be reduced in cortical bone. As always, more research is needed!


Collagen Crosslinking and Pentosidine

Nonenzymatic glycation (NEG) and advanced glycation endproducts (AGEs) contribute to bone fragility by crosslinking bone collagen. In vitro studies using nonenzymatic ribation reported loss of ductility in the cortical bone. However, some studies report positive associations between collagen crosslinking and work-to-fracture/toughness. Willett et al reported that in 15 bone beam triplets cut from bovine metatarsi, ribation increased nonenzymatic collagen modification and pentosidine content and reduced post-yield strain and flexural toughness (12). Fracture surfaces were smoother with less collagen fibril deformation or tearing than observed in controls. However, pentosidine content and thermomechanical measures of crosslinking correlated positively with measures of strain and energy absorption before failure. Thus, as reported previously, nonenzymatic ribation reduces cortical bone post-yield strain accommodation. However, increased crosslinking may not provide a complete explanation for increased bone brittleness.

Reznikov et al report orientations and local collagen fibril dispersion in circumferential lamellae from rat tibiae (13). The authors identified three distinct sublamellar structural motifs: a plywood-like fanning sublamella, a unidirectional sublamella and a disordered sublamella. The disordered sublamella is less mineralized than the other sublamellae. The hubs and junctions of the canalicular network, which connect radially oriented canaliculi, are intimately associated with the disordered sublamella.


Antisclerostin Antibody Therapy and Fracture Healing

Hamann et al used ZDF fa/fa rats, a model for type 2 diabetes with low bone mass to study bone healing (14). A sclerostin-neutralizing antibody (Scl-AbVI) was tested in femoral defects of 3 mm created in 11-week-old diabetic ZDF fa/fa and nondiabetic ZDF +/+ rats. Saline or 25 mg/kg Scl-AbVI s.c. twice weekly for 12 weeks. Diabetic rats had lower spinal and femoral bone mass. Scl-AbVI increased bone mass and reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load at the femoral shaft and neck, respectively (p<0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl-AbVI increased 6-fold. Nondiabetic rats filled 57% of the femoral defect, whereas diabetic rats filled 21% (p<0.05). Scl-AbVI increased defect regeneration by 47% and 74%, respectively (p<0.05). Sclerostin antibody reverses the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improves bone defect regeneration in rats.


References

1. Korhonen N, Niemi S, Parkkari J, et al. Continuous decline in incidence of hip fracture: nationwide statistics from Finland between 1970 and 2010. Osteoporos Int 2013;24:1599.

2. Melton LJ III, Achenbach SJ, Atkinson EJ, Therneau TM, Amin S. Long-term mortality following fractures at different skeletal sites: a population-based cohort study. Osteoporos Int 2013;24:1689.

3. Leslie WD, Lix LM, Finlayson GS, et al. Direct healthcare costs for 5 years post-fracture in Canada: a long-term population-based assessment. Osteoporos Int 2013;24:1697.

4. Brenneman SK, Yurgin N, Fan Y. Cost and management of males with closed fractures. Osteoporos Int 2013;24:825.

5. Makovey J, Macara M, Chen JS, et al. High osteoporotic fracture risk and CVD risk co-exist in postmenopausal women. Bone 2013;52:120.

6. Chen YC, Wu JC, Liu L, et al. Hospitalized osteoporotic vertebral fracture increases the risk of stroke: a population-based cohort study. J Bone Miner Res 2013;28:516.

7. Power J, Doube M, van Bezooijen RL, Loveridge N, Reeve J. Osteocyte recruitment declines as the osteon fills in: Interacting effects of osteocytic sclerostin and previous hip fracture on the size of cortical canals in the femoral neck. Bone 2012;50:1107.

8. Burket JC, Brooks DJ, Macleay JM, et al. Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. Bone 2013;52:326.

9. Misof BM, Roschger P, Gabriel D, et al. Annual intravenous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort. J Bone Miner Res 2013;28:442.

10. Cusick T, Chen CM, Pennypacker BL, et al. Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res 2012;27:524.

11. Fratzl-Zelman N, Roschger P, Fisher JE, Duong le T, Klaushofer K. Effects of odanacatib on bone mineralization density distribution in thoracic spine and femora of ovariectomized adult rhesus monkeys: a quantitative backscattered electron imaging study. Calcif Tissue Int 2013;92:261.

12. Willett TL, Sutty S, Gaspar A, Avery N, Grynpas M. In vitro non-enzymatic ribation reduces post-yield strain accommodation in cortical bone. Bone 2013;52:611.

13. Reznikov N, Almany-Magal R, Shahar R, Weiner S. Three-dimensional imaging of collagen fibril organization in rat circumferential lamellar bone using a dual beam electron microscope reveals ordered and disordered sublamellar structures. Bone 2013;52:676.

14. Hamann C, Rauner M, Hohna Y, et al. Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. J Bone Miner Res 2013;28:627.


Comments

有意思!好样的 [Interesting! The good kind]