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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.
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.
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.
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.
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.
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.
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.
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].
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.
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