Overview, Vol 13, Issue 2

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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Bone Remodelling Compartments

Bone remodelling is the removal of damaged mineralized bone matrix and replacement by a volume of new matrix by the cells of the BMU. For remodelling to occur, the need for it must first be signalled from the damage or from nearby cells. These signals, whatever their nature, must then reach a point upon the endosteal (internal) surface of bone – one or more of the intracortical (Haversian), endocortical or trabecular components of this surface because initiation of remodelling always occurs upon a surface. At this point upon the bone surface, a bone remodelling compartment (BRC) is formed (1). The flattened osteoblasts that form the endosteal lining cells are modified to produce local factors participating in recruitment of vascular structures, and collagenase, which removes a collagen layer to then form the roof of this BRC (2).

Hematopoietic precursor cells of the osteoclast lineage and mesenchymal precursors of the osteoblast lineage are recruited from the marrow, circulation and locally. They differentiate to become mature bone resorbing osteoclasts and bone forming osteoblasts within this compartment, from which osteoclasts excavate a tunnel within cortical bone or a trench upon the endocortical surface or trabecular surface. Osteoblasts follow from ‘behind’, ‘zipping up’ the excavated canal or trench with newly deposited osteoid from the cement line inwards leaving what will be the new Haversian canal in cortical osteons.

Provided equal volumes of bone are resorbed and formed by each BMU, there is no net loss of bone. As age advances, the volume of bone formed by each BMU decreases producing a negative BMU balance, the single necessary and sufficient morphological abnormality responsible for structural deterioration (3). One of the mechanisms that may contribute to this is a change in the roof of the BRC.

Kristensen et al report iliac crest biopsies from normal individuals showed the BRC canopy consists of CD56‐positive osteoblasts in association with increased numbers of capillaries, putative osteoblast progenitors and proliferative cells in a region within 50 µm of the canopy surface and highest above eroded surfaces (4). Between 51-100 µm, capillary densities were less. The close proximity between BRC canopies and capillaries support the existence of an osteogenic‐vascular interface in cancellous bone. Initiation of remodelling may occur with approximation of vasculature and endosteal surfaces allowing capillary‐BRC canopy interactions to provide a gateway for access of the osteoclast and mesenchymal precursors of the osteoblast into the BRCs.

Figure 1. Relation between bone surface and prevalence of capillaries. CD34+ capillaries and CD56+ OB-lineage cells. (top) Frequent capillaries (arrowheads) are positioned next to a canopy-covered remodelling surface. The capillaries adjacent to the BRC canopy (large arrowheads) run parallel to it thereby offering a large interface between the two entities. (bottom left) Enlargement of the framed area in the upper picture illustrating contact between a BRC canopy (arrows) and a capillary (arrowhead). (bottom right) A capillary (large arrowhead) runs perpendicularly to the quiescent bone surface thereby offering only a small interface with the surface. Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1760] with permission of the American Society of Bone and Mineral Research.

Figure 2. Electron microscopic analysis of the bone marrow bone matrix interface in areas where capillaries are close to BRC canopies. A marrow cell (MC) performs diapedesis (asterisks) through a BRC canopy (arrows) into the lumen of a BRC (BRC). A capillary (arrowheads) is situated close by. Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1760] with permission of the American Society of Bone and Mineral Research.
 

Jensen et al report that viability of canopies determines the occurrence of the bone formation phase of remodelling (5). Canopies are present in early stage of the remodelling cycle, but their absence was associated with reduced bone formation surfaces. In healthy individuals and in patients with endogenous Cushing’s syndrome (CS), ~100% canopy coverage above resorbing osteoclasts is observed, but only about 76% above bone forming surfaces.

The authors suggest that canopies are associated with the early stage of the remodelling cycle but may disappear later. In control and two-thirds of the CS patients, a decline in canopy coverage occurred when bone formation was initiated. In the remaining third of the CS patients, the prevalence of canopies decreased before bone formation and coincided with less bone forming surface. The authors suggest bone restitution is compromised in the absence of canopies. BRC canopies could be targets for treatment.

Figure 3. BRC canopy in patients with CS. (A, left) Immunohistochemical stainings show NCAM-positive BRC canopy cells (red, arrows) separating a bone surface – TRACP-positive osteoclast (brown, asterisk) from the bone marrow. (B, left) Remodelling surfaces, as identified here through a TRACP-positive osteoclast (brown, asterix) are not covered by a BRC canopy. Similarly, when staining with Masson-Goldner Trichome, BRC canopies (arrows) covering eroded (A, middle) or osteoid (A, right) bone surfaces can be detected on some occasions, but not on others (B, middle, right). (C) CD34-positive capillaries (red, arrowheads) are observed in close proximity to NCAM-positive BRC canopy cells (brown, arrows). Scale bars: 50 µm. Reproduced from J Bone Miner Res 2012;27:770-80 with permission of the American Society of Bone and Mineral Research.

Figure 4. Prevalence of BRC canopies above eroded and bone-forming surfaces in controls and patients with CS. The prevalence of BRC canopies covering eroded (A) and bone-forming surfaces (B) was evaluated in 22 controls (triangles) and 19 patients with CS (squares). It was expressed as percentage of ES, Oc.S, OS, and Ob.S under canopy relative to total ES, Oc.S, OS, and Ob.S, respectively. The percentage of ES under BRC canopy was higher than 75% in all controls (median 96%), whereas the CS cohort showed values both above (open squares) and below (filled grey squares) 75% (A, upper graph). Therefore, our subsequent analysis considered separately these two CS subpopulations, indicated as (+) and (-), respectively. The prevalence of canopies at the successive stages of the remodelling cycle is shown for each biopsy in three separate graphs corresponding to the controls, CS(+), and CS(-), respectively (C). The successive stages of the remodelling cycle were reflected by Oc.S, ES vacated by osteoclasts (reversal surface), and OS. Reproduced from J Bone Miner Res 2012;27:770-80 with permission of the American Society of Bone and Mineral Research.


Serum Vitamin D, Dietary Calcium Deficiency
and Fracture Risk

Looker examined the relationship between serum 25(OH)D and risk of incident hip, spine, radius and humerus fractures in 4749 men and women ages 65 years and older from NHANES III, 1988‐94 and NHANES 2000‐2004 (6). There were 525 incident major osteoporotic fractures (287 hip). Serum 25(OH)D was a linear predictor of fracture and quadratic predictor of hip fracture in the total sample and among those with less than 10 years of follow‐up but not those with longer follow-up. The associations appeared to be independent of age. Major osteoporotic fracture risk was increased by 26‐27% for each SD lower serum 25(OH)D among those with less than 10 years of follow‐up. The increase in risk for fracture seemed to occur when values of 25(OH)D were below 30 nmol/L. The question of whether ‘insufficiency’ in serum 25(OH)D is associated with adverse health outcomes remains.

Figure 5. (left panel) Smoothed relative risk of major osteoporotic fracture or hip fracture by serum 25(OH)D value among persons with less than 10 years of follow-up, adjusted for age, sex, race/ethnicity, and survey. (right panel) Relative risk of major osteoporotic fracture or hip fracture by serum 25(OH)D category among persons with less than 10 years of follow-up, adjusted for age, sex, race/ethnicity and survey. Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1828] with permission of the American Society of Bone and Mineral Research.

Joo et al divided 2567 men and 2,095 women ≥50 years of age from the 2009‐2010 Korea National Health and Nutrition Examination Survey (KNHANES) into two groups according to dietary calcium quintiles (means: 154, 278, 400, 557 and 951 mg/d) and serum 25(OH)D <50, 50‐75 and >75 nmol/L (7). Lower calcium intakes were associated with higher serum PTH and lower femoral neck BMD irrespective of serum 25(OH)D. Serum PTH was highest and femoral neck BMD was lowest in the group with a serum 25(OH)D <50 nmol/L. In this low intake population, calcium intake is a determinant of serum PTH and BMD irrespective of 25(OH)D.

Figure 6. Adjusted mean serum PTH and BMDs according to serum 25(OH)D concentrations and dietary calcium intakes. Five bars represent quintiles of dietary calcium (Lowest ≤220 mg/d; second=220.1-331.3 mg/d; third=331.4-467.1 mg/d; forth=467.4-666.7 mg/d; top=667.6-1986.3 mg/d). P for trend (p) in same groups are from general lineal model in complex data analysis. Data are adjusted for age, sex, BMI, GFR, smoking, occupation, season, and physical activity. Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1790] with permission of the American Society of Bone and Mineral Research.














 


Tissue Mineralization Density and Zoledronic Acid

Reducing remodelling intensity is the main action of antiresorptive agents like zoledronic acid. When remodelling intensity is reduced, there is more time available for bone deposited prior starting treatment to undergo secondary mineralization, a process which can take some years to reach completion (8). With protracted remodelling suppression, more and more of the bone matrix volume that would have been removed by high remodelling is not removed and undergoes this secondary mineralization. As a consequence, adjacent regions of bone become more fully and so homogeneously mineralized. This loss of heterogeneity in mineralization may not be a good thing because microcracks, in addition to not being removed because remodelling is suppressed, may also be more liable to grow in size as resistance to crack propagation is less in homogeneously mineralized bone.

Misof et al report cancellous and cortical bone mineralization density distribution (BMDD) in biopsies using backscattered electron imaging (qBEI) in 82 patients receiving ZOL, yearly 5mg) and 70 controls (9). BMDD mean values for cancellous (Cn.) and cortical (Ct.) relative to controls were higher by +3.2% and +2.7% with increased percentages of high mineralized bone areas +64% +31%, lower heterogeneity of mineralization (Width -14%, -13%), and decreased percentages of low mineralized bone areas (-22%, -26%) (all p<0.001). Those with lower Cn.MS/BS, a measure of suppression of remodelling, had higher degree of bone matrix mineralization. There are no surprises here. The question is whether this is good or bad in terms of material strength.

Figure 7. (A) Backscattered electron image of the cross-sectional area of one ZOL treated biopsy sample (the brighter in the image the higher the local calcium concentrations). (B) Grey level histogram (bone mineralization density distribution, BMDD) of trabecular bone with one example of the cancellous BMDD of the placebo treated (dashed line) and 95% CI of normal cancellous BMDD curves showing the average (CaMean) and the mode (the most frequent) Ca concentrations (CaPeak), the heterogeneity of mineralization (CaWidth), the percentages of low (primary) mineralized (CaLow) and highly mineralized bone areas (CaHigh). Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1780] with permission of the American Society of Bone and Mineral Research.


 

Figure 8. Cancellous (A) and cortical (B) BMDD outcomes (white placebo, back-white patterned ZOL treated). The bars show mean (SD) or median (25th, 75th percentile). White dotted lines and grey areas in the background of (A) are revealing the mean/median and ±1 SD/interquartile range of the cancellous reference BMDD, cortical reference BMDD data are not available. ***p<0.001 vs. placebo. °°°p0.001, °p<0.05 vs. normal reference BMDD. Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1780] with permission of the American Society of Bone and Mineral Research.

Figure 9. The average calcium concentration of cancellous bone (Cn.CaMean) vs. Cn. MS/BS. Full symbols ZOL, empty symbols placebo. Reproduced from J Bone Miner Res 2012;doi:[10.1002/jbmr.1780] with permission of the American Society of Bone and Mineral Research.




 


The Burden of Nonvertebral Fractures is Substantial

Nonvertebral fractures comprise about 80% of all fractures. This has been documented many times and should refocus thinking to extend beyond osteoporosis as a disease characterized by trabecular bone loss and vertebral fractures.

To assess direct medical resource utilization related to the treatment of nonvertebral osteoporotic fractures within 1 year postfracture, Jean et al evaluated a physician claims databases identified 15,327 women aged 50 years or older with incident nonvertebral fractures (10). The proportions of fractures treated by open reduction, closed reduction, immobilization or follow‐up by an orthopaedic surgeon (OS) were evaluated. The mean number of claims for consultation with an OS or other clinicians in inpatient and outpatient visits, the hospitalization rate and length of stay (LOS) were assessed.

Hip/femur fractures represented the highest rate of resource utilization since the majority of them required surgery (91.1%) and hospitalization (94.5%) with a mean LOS of 39.2 days. Other nonvertebral fracture types needed clinical care related to surgery (27.9%), follow‐up consultation with an OS (77.6%) and hospitalization (27.3% of total LOS). Pelvic fractures commanded high resource utilization due to the high hospitalization rate (67.4%) with mean LOS of 34.2 days. Age was associated with an increased number of visits to other physicians, hospitalization, and length of hospitalization (LOS), admissions to long term care (LTC), and death.

Figure 10. Fracture treatments by age groups. (A) Open reduction. (B) Closed reduction. (C) Immobilization. (D) Conservative treatment. The white, dark and light grey bars represent, respectively, 50-64 years, 65-79 years and 80 years and older age groups. *Significant difference between age groups (chi-square test, p<0.05). Reproduced from J Bone Miner Res 2013;28:360-71 with permission of the American Society of Bone and Mineral Research.

Figure 11. Health resources utilization by age groups. (A) Orthopaedic surgeon visit. (B) Other physician visit. (C) Hospitalization. (D) Length of stay (days). *Significant difference between age groups (chi-square test, p<0.05). Significant difference between age groups (Wilcoxon test, p<0.05). Reproduced from J Bone Miner Res 2013;28:360-71 with permission of the American Society of Bone and Mineral Research.

Figure 12. Discharge destinations after hospitalization by age groups. (A) Rehabilitation or local community health services center. (B) Home. (C) Long-term care (D) inpatient death. *Significant difference between age groups (chi-square test, p<0.05). Reproduced from J Bone Miner Res 2013;28:360-71 with permission of the American Society of Bone and Mineral Research.


Diabetes and Cortical Porosity

Diabetes and bone fragility is a challenging area of research. While early studies did not report associations with fracture, more recent research does seem to suggest that both types 1 and 2 diabetes are associated with increased fracture risk (11). Indeed, the risk for hip fracture in patients with type 1 diabetes is higher than in type 2. What is puzzling is the pathogenesis of bone fragility in diabetes. Patients with type 1 diabetes have deficits in BMD, but most patients with diabetes and fractures have modest deficits. This itself is not a surprise really because most patients with fractures have osteopenia, not osteoporosis. Patients with type 2 diabetes appear to have normal BMD. It is with interest that the study reported here is the first to suggest the morphological basis of fractures in diabetes might be, in part, increased cortical porosity.

Patsch et al studied 80 women; diabetics with (DMFx) and without fractures (DM), nondiabetics with (Fx) and without fractures (Co), and women with and without diabetes (12). At the ultradistal and distal tibia, diabetics with fractures had greater pore volume (+52.6%; +95.4%), relative porosity (+58.1%; +87.9%) and endocortical bone surface (+10.9%; +11.5%) than diabetics without fractures. At the distal radius, diabetics with fractures had 4.7‐fold greater relative porosity than diabetics without fractures. At the ultradistal radius, pore volume was higher in diabetics with fractures than without (+67.8%). Diabetics with fractures also had larger trabecular heterogeneity (ultradistal radius; +36.8%), and lower total and cortical BMD (ultradistal tibia: ‐12.6%; ‐6.8%) than diabetics without fractures. Diabetics with fractures also exhibited greater deficits in stiffness, failure load and cortical load fraction at the ultradistal and distal tibia, and the distal radius.

Figure 13. HR-pQCT images of the ultradistal (above) and distal (below) radius: mid-stack tomograms for the Co (left), Fx (left-center), DM (right-center), and DMFx (right) groups. Marked cortical porosity can be seen in DMFx (right). Reproduced from J Bone Miner Res 2013;28:313-24 with permission of the American Society of Bone and Mineral Research.


References

1. Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res 2001;16:1575.

2. Parfitt AM. The bone remodeling compartment: A circulatory function for bone lining cells. J Bone Miner Res 2001;16:1583.

3. Parfitt AM. The cellular basis of bone remodeling: the quantum concept reexamined in light of recent advances in the cell biology of bone. Calcif Tissue Int 1984;36 (Suppl 1):S37.

4. Kristensen HB, Andersen TL, Marcussen N, Rolighed L, Delaisse JM. Increased presence of capillaries next to remodeling sites in adult human cancellous bone. J Bone Miner Res 2012;doi:[10.1002/jbmr.1760].

5. Jensen PR, Andersen TL, Søe K, et al. Premature loss of bone remodeling compartment canopies is associated with deficient bone formation: a study of healthy individuals and patients with Cushing's syndrome. J Bone Miner Res 2012;27:770.

6. Looker AC. Serum 25‐hydroxyvitamin D and risk of major osteoporotic fractures in older U.S. adults. J Bone Miner Res 2012;doi:[10.1002/jbmr.1828].

7. Joo N‐S, Dawson‐Hughes B, Kimm Y-S, Oh K, Yeum K-J. Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: Analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHAENS IV‐3, 2009 and V‐1, 2010). J Bone Miner Res 2012;doi:[10.1002/jbmr.1790].

8. Akkus O, Polyakova-Akkus A, Adar F, Schaffler M. Aging of microstructural compartments in human compact bone. J Bone Miner Res 2003;18:1012.

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 2012;doi:[10.1002/jbmr.1780].

10. Jean S, Bessette L, Belzile EL, et al. Direct medical resources utilization associated with osteoporosis‐related non‐vertebral fractures in postmenopausal women. J Bone Miner Res 2013;28:360.

11. Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in Patients with diabetes. J Bone Miner Res 27;22:1317.

12. Patsch JM, Burghardt AJ, Yap SP, et al. Increased cortical porosity in type‐2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res 2013;28:313.


Comments

grynpas1's picture

not bad