Overview, Vol 13, Issue 5

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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Orgins of Bone Fragility in Growth

Nagy et al reported that daughters of women with fracture have thinner cortices, and impaired trabecular microarchitecture at the distal radius and tibia (1). The authors included 115 women mean age 43 years whose mothers had sustained a fragility fracture and 206 women mean age 39 years whose mothers had not sustained a fracture. Women, whose mothers had fracture, had lower aBMD and lower total vBMD at the distal radius (-5%) and distal tibia (-7%). They also had lower cortical thickness and area at the distal radius (-5% and -4%, respectively) and at the distal tibia (-6%, and -4%, respectively). Trabecular vBMD was lower at the distal radius (-5%) and tibia (-8%), with a more spaced and heterogeneous trabecular network (4 and 7 % at the radius and 5 and 9 %, at the tibia, for Tb.Sp and Tb.Sp.SD, respectively). Several questions arise from this work. For example, what is the pathogenetic basis of these abnormalities? Do these subjects reflect the lower part of the normal trait distribution established very early in life, if not during intrauterine life such that they enter adulthood and the post menopausal years with thinner cortices and fewer trabeculae that are more susceptibly to decay after menopause? What sort of discriminatory power do these morphological differences have? What proportion of the daughters of women with fractures did and did not have these abnormalities? If the deficits have a genetic basis, they should be about half the deficit observed in the mothers with fractures.

Warden et al reported that in 314 participants (n=155 males; n=164 Blacks) in early puberty, Blacks had greater cortical vBMD (implying lower cortical porosity and/or higher tissue mineralization density), mass and size compared to Whites (2). Blacks had 17.0% greater tibial polar strength-strain index (SSIP), higher osteocalcin and bone-specific alkaline phosphatase and lower N-terminal telopeptide than Whites, lower 25-hydroxyvitamin D and higher 1,25-dihydroxyvitamin D and PTH. Variation in bone cross-sectional area and SSIP attributable to race was partially explained by tibial length, 25-hydroxyvitamin D/PTH, and osteocalcin. Racial differences are established by the early stages of puberty.

Laine et al identified a heterozygous missense mutation in WNT1, c.652T->G (p.Cys218Gly) in 10 family members with dominantly inherited, early onset osteoporosis (3). In a separate family with two siblings affected by recessive osteogenesis imperfecta, they also identified a homozygous nonsense mutation, c.884C->A, p.Ser295. The aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signalling, target genes, and mineralization. In mice, Wnt1 was expressed in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered crosstalk in WNT signalling between the hematopoietic and osteoblastic lineage cells in these diseases.

Henstock et al applied hydrostatic pressure regimens of 0-279 kPa at 0.005-2 Hz to cultured ex vivo chick foetal femurs (e11) for 1 h/day/14 days (4). The mineralized developing femur was larger and/or denser than unstimulated controls. Constant (noncycling) hydrostatic pressure had no effect on bone growth. The increase in bone formation was proportional to stimulation frequency (R2=0.917). Expression of type II collagen in epiphyses and diaphysis upregulated 1.48-fold and 1.95-fold, respectively, together with osteogenic (osteonectin and osteopontin) and the osteocyte maturation marker CD44. Hydrostatic forces may play a role in regulating bone growth and remodeling in vivo.

Putman et al used HR-pQCT to assess cortical and trabecular bone microarchitecture and microfinite element analysis in African-American (n=100) and Caucasian (n=173) women (5). African-American women had greater total area, aBMD, and total vBMD at the radius and tibia metaphysis, greater trabecular vBMD at the radius, and higher cortical vBMD at the tibia, higher cortical area, thickness, and volumes and lower cortical porosity at the tibia, greater estimated bone stiffness and failure load after adjustment for DXA aBMD.

Walker et al reported premenopausal Chinese-American women have more platelike trabecular (Tb) bone (6). The investigators applied individual trabecula segmentation and finite element analysis to images in premenopausal and postmenopausal Chinese-American and White women. Adjusted analyses at the radius indicated that premenopausal Chinese-Americans had a higher plate bone volume fraction (pBV/TV), Tb plate-to-rod ratio (P-R ratio), and greater plate-plate junction densities (P-P Junc.D) than White women resulting in 27% higher Tb stiffness. Greater cortical thickness and density (Ct.Th and Dcort) and more Tb plates led to 19% greater whole bone stiffness. Postmenopausal Chinese-Americans had similar pBV/TV and P-P Junc.D, yet a higher P-R ratio than white women. Postmenopausal Chinese-American had greater Ct.Th, Dcort, and relatively intact Tb plates, resulting in similar Tb stiffness but 12% greater whole bone stiffness. In both races, Ct.Th and Dcort were lower in postmenopausal than premenopausal women and there were no differences between races. Tb plate parameters were also lower in post than premenopausal women, but age-related differences in pBV/TV, P-R ratio, and P-P Junc D were greater (p<0.05) in Chinese-American women. Within-race there is greater loss of platelike Tb bone with aging in Chinese-Americans, though thicker cortices and more platelike Tb bone persists.

Kim et al reported macro- and microstructure at the distal radius in Asian (n=91, 53 males, 38 females, mean afe age 17.3 yrs) and Caucasian (n=89, 46 males, 43 females, mean age 18.1 yrs) adolescents and young adults (7). In males, Asians had 11% greater Tt.BMD, 8% greater Ct.BMD and 25% lower Ct.Po than Caucasians. Asians had 9% smaller Tt.Ar and 27% greater Ct.Th. In females, Asians had smaller Tt.Ar (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 Caucasians. Estimated bone strength did not differ between Asian and Caucasian males or females. Smaller bones of Asian have more dense, less porous and thicker cortices.

Schnitzler et al reported a unique study of cortical porosity during growth (8). They examined osteons and their canals for age-related changes in numbers, size and shape in 87 iliac crest bone samples of subjects aged 0-25 years. Three types of secondary osteons were identified. 1) Drifting osteons predominated to the midteens, were large, asymmetrical and had giant canals (remodeling space) with the resorption front drifting towards the marrow. Onset of formation appeared delayed, and commenced on the periosteum-facing surface. From the midteens numerical density of drifting osteons decreased, and so did porosity. 2) Eccentric osteons were smaller, more circular and had a small excentric canal; their numerical density increased with age. 3) Concentric osteons (adult bone) were the smallest, most symmetrical osteons, had a small central canal, and higher numerical density from the midteens. Boys showed greater overall porosity and greater numerical density of drifting osteons, and later change to concentric osteons than girls. Whites had greater numerical density and greater areal density of resorption cavities than Blacks. Structure of osteons and canals varied during growth. Large asymmetrical drifting osteons with giant active canals (remodeling space) predominated until the midteens and accounted for >70% of childhood cortical porosity. Thereafter, smaller concentric (adult type) osteons increasingly predominated. Gender differences may relate to greater fracture rates in boys, and race differences to greater fracture rates in Whites. The role of osteocyte-mediated mechanotransduction in osteonal structure and cortical porosity during growth warrants further exploration.


Fractures: Morbidity and mortality

Frost et al estimated the excess mortality attributable to hip fracture in elderly men and women in the Dubbo Osteoporosis Epidemiology Study (9). Over 2000 men and women aged 60+ as of 1989 were followed for 21 years. 151 women and 55 men sustained a hip fracture. Death occurred in 86 (57%) women and 36 (66%) men. In women, the cumulative relative survival post hip fracture at 1, 5 and 10 years was 0.83 (95% CI 0.76-0.89), 0.59 (95% CI 0.48-0.68), and 0.31 (95% CI 0.20-0.43), respectively; in men, the corresponding estimates were: 0.63 (95% CI 0.48-0.75), 0.48 (95% CI 0.32-0.63), and 0.36 (95% CI 0.18-0.56). On average post hip fracture women died 4 years earlier (median: 4.1, interquartile range (IQR) 1.7-7.8) and men died 5 years earlier (median=4.8, IQR 2.4-7.0) than expected. For every six women and for every three men with hip fracture, one extra death occurred above that expected in the population.

Bluic et al examined the long-term cumulative incidence of subsequent fracture and total mortality with mortality according to initial and refracture from the Dubbo Osteoporosis Epidemiology Study (10). There were 952 women and 343 men with incident fracture. Within 5 years following initial fracture, 24% women and 20% men refractured; and 26% women and 37% men died without refracture. Of those who refractured, a further 50% of women and 75% of men died, so total five-year mortality was 39% in women and 51% in men. Excess mortality was 24% in women and 27% in men. While mortality following refracture occurred mainly in the first five years post initial fracture, total mortality (post initial and refracture) was elevated for 10 years. Most of the 5-10 year excess mortality was associated with refracture. The long-term (>10 yr) refracture rate was reduced, particularly in the elderly due to their high mortality rate. The 30% alive beyond 10 years post fracture were at low risk of further adverse outcomes. Refractures contribute substantially to overall mortality associated with fracture.

Ahmed et al reported all incident nonvertebral fractures between 1994-2009 were registered in 27,158 participants in Tromso (11). In 3108 subjects with an initial fracture, subsequent fracture (n=664) risk was expressed as rate ratios (RR). The rates of initial and subsequent fractures increased with age. Compared with initial incident fracture rate of 30.8 per 1000 in women and 12.9 per 1000 in men, the overall age-adjusted RR of subsequent fracture was 1.3 (95% CI 1.2-1.5) in women, and 2.0 (95% CI 1.6-2.4) in men. Although the RRs decreased with age, the absolute proportions of those with initial fracture who suffered a subsequent fracture increased from 9% to 30% in women and from 10% to 26% in men, between 50-59 to 80+ years, respectively. In women and men, respectively, 45% and 38% of the subsequent hip or other major fractures, were preceded by initial minor fractures.

van der Jagt-Willems et al reported a prospective cohort study of 395 geriatric outpatients in whom mortality after 3 years was associated with prevalent vertebral fractures at baseline (12). The mortality risk was independently associated with the presence of ≥3 vertebral fractures at baseline. In the surviving patients, the risk of incident fractures was 26% of these patients. After 3 years, mortality was 46% and associated with prevalent vertebral fractures at baseline (OR 1.83; 95 % CI 1.23-2.74). The presence of three or more vertebral fractures at baseline was an independent risk factor for mortality (OR 3.32; 95 % CI 1.56-7.07). Higher cognitive capacity protected against mortality after 3 years.

Melton et al reported the long-term survival following fractures due to any cause at each skeletal site in 2901 Olmsted County (MN, USA) residents ≥35 years old who experienced any fracture in 1989-1991, followed for 22 years for death from any cause. Standardized mortality ratios (SMRs) compared observed to expected deaths (13). 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 SMR was greatest soon after fracture, especially among the men but remained elevated for over a decade. Adjusted 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 sites. After further adjustment for precipitating cause, overall SMRs were elevated for distal forearm, proximal humerus, thoracic/lumbar vertebrae, and proximal femur combined (SMR 1.2; 95 % CI 1.1-1.3), but also 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.


Regional Specificity of Bone Structure and Bone Loss
at the Femoral Neck

Kersh et al used high-resolution CT data to evaluate 457 cross-sectional slices along the femoral neck of 12 postmortem specimens (14). The distribution of cortical thicknesses was evaluated. Finite-element models were used to calculate the stresses in each cross-section resulting from the peak hip joint forces created during a sideways fall. In all cross-sections, cortical thicknesses were not normally distributed and skewed toward smaller thicknesses. The central tendency of cortical thickness was best estimated by the median. Stress increased as the median cortical thickness decreased along the femoral neck. The median cortical thickness combined with anterior-posterior diameter best predicted peak bone stress generated during a sideways fall (R2=0.66, p<0.001). Heterogeneity in the structure of the femoral neck determines the diversity of its strength. The median cortical thickness best predicted peak femoral neck stress and is likely to be a relevant predictor of femoral neck fragility.

Johannesdottir et al used segmental QCT analysis to assess the superolateral (superior) and inferomedial (inferior) regions of the femoral neck in 400 older individuals (100 men and 300 women, aged 66-90 years) during a median follow-up of 5.1 yr. (mean baseline age 74 years) (15). At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical vBMD inferiorly. The relative losses in all bone values estimated in the superior region were about 3-fold and greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck DXA-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men.


References

1. Nagy H, Sornay-Rendu E, Boutroy S, et al. Impaired trabecular and cortical microarchitecture in daughters of women with osteoporotic fracture: the MODAM study. Osteoporos Int 2013;24:1881.

2. Warden SJ, Hill KM, Ferira AJ, et al. Racial differences in cortical bone and their relationship to biochemical variables in Black and White children in the early stages of puberty. Osteoporos Int 2013;24:1869.

3. Laine CM, Joeng KS, Campeau PM, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 2013;368:1809.

4. Henstock JR, Rotherham M, Rose JB, El Haj AJ. Cyclic hydrostatic pressure stimulates enhanced bone development in the foetal chick femur in vitro. Bone 2013;53:468.

5. Putman MS, Yu EW, Lee H, et al. Differences in skeletal microarchitecture and strength in African-American and Caucasian women. J Bone Miner Res 2013;doi:10.1002/jbmr.1953.

6. Walker MD, Liu XS, Zhou B, et al. Premenopausal and postmenopausal differences in bone microstructure and mechanical competence in Chinese-American and White women. J Bone Miner Res 2013;28:1308.

7. Kim S, Macdonald HM, Nettlefold L, McKay HA. A comparison of bone quality at the distal radius between Asian and Caucasian adolescents and young adults: An HR-pQCT study. J Bone Miner Res 2013;doi:10.1002/jbmr.1939.

8. Schnitzler CM, Mesquita JM. Cortical porosity in children is determined by age-dependent osteonal morphology. Bone 2013;55:476.

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

10. Bliuc D, Nguyen ND, Nguyen TV, Eisman JA, Center JR. Compound risk of high mortality following osteoporotic fracture and re-fracture in elderly women and men. J Bone Miner Res 2013;doi:10.1002/jbmr.1968.

11. Ahmed LA, Center JR, Bjornerem A, et al. Progressively increasing fracture risk with advancing age following initial incident fragility fracture. The Tromso Study. J Bone Miner Res 2013;doi:10.1002/jbmr.1952.

12. van der Jagt-Willems HC, Vis M, Tulner CR, et al. Mortality and incident vertebral fractures after 3 years of follow-up among geriatric patients. Osteoporos Int 2013;24:1713.

13. Melton LJ, 3rd, 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.

14. Kersh ME, Pandy MG, Bui QM, et al. The heterogeneity in femoral neck structure and strength. J Bone Miner Res 2013;28:1022.

15. Johannesdottir F, Aspelund T, Reeve J, et al. Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: The AGES-Reykjavik Longitudinal Study. J Bone Miner Res 2013;doi:10.1002/jbmr.1960.


Reviews

Prevention of falls in the elderly: a review
Karlsson MK, Magnusson H, von Schewelov T, Rosengren BE
Osteoporos Int 2013;24:747

The effects of organic nitrates on osteoporosis: a systematic review
Jamal SA, Reid LS, Hamilton CJ
Osteoporos Int 2013;24:763

Skeletal effects of nutrients and nutraceuticals, beyond calcium and vitamin D
Nieves JW
Osteoporos Int 2013;24:771

Marrow fat and bone ‒ new perspectives
Fazeli PK. Horowitz MC. MacDougald OA. Scheller EL. Rodeheffer MS. Rosen CJ. Klibanski A
J Clin Endocrinol Metab 2013;98:935

Mechanosensation and transduction in osteocytes
Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A, Weinbaum S
Bone 2013;54:182

Measurement and estimation of osteocyte mechanical strain
Stern AR, Nicolella DP
Bone 2013;54:191

Emerging role of primary cilia as mechanosensors in osteocytes
Nguyen AM, Jacobs CR
Bone 2013;54:196

Gap junction and hemichannel functions in osteocytes
Loiselle AE, Jiang JX, Donahue HJ
Bone 2013;54:205

Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia
Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK
Bone 2013;54:213

The osteocyte in CKD: New concepts regarding the role of FGF23 in mineral metabolism and systemic complications
Wesseling-Perry K, Juppner H
Bone 2013;54:222

Osteocytes remove and replace perilacunar mineral during reproductive cycles
Wysolmerski JJ
Bone 2013;54:230

Vitamin D signaling in osteocytes: Effects on bone and mineral homeostasis
Lieben L, Carmeliet G
Bone 2013;54:237

Regulation of Wnt/beta-catenin signaling within and from osteocytes
Burgers TA, Williams BO
Bone 2013;54:244

Effects of PTH on osteocyte function
Bellido T, Saini V, Pajevic PD
Bone 2013;54:250

Osteocyte control of osteoclastogenesis
O'Brien CA, Nakashima T, Takayanagi H
Bone 2013;54:258

Osteocyte apoptosis
Jilka RL, Noble B, Weinstein RS
Bone 2013;54:264

For whom the bell tolls: Distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseasesManolagas SC, Parfitt AM
Bone 2013;54:272

Glucocorticoids and osteocyte autophagy
Yao W, Dai W, Jiang JX, Lane NE
Bone 2013;54:279

Studying osteocytes within their environment
Webster DJ, Schneider P, Dallas SL, Muller R
Bone 2013;54:285

In vitro and in vivo approaches to study osteocyte biology
Kalajzic I, Matthews BG, Torreggiani E, Harris MA, Divieti Pajevic P, Harris SE
Bone 2013;54:296

Calcitonin: Physiology or fantasy?
Davey RA, Findlay DM
J Bone Miner Res 2013;28:973

Observational studies-just telling us what we want to hear or telling us where we need to look?
Reid IR, Bolland MJ
J Bone Miner Res 2013;28:980