The microarchitecture of bone tissue presents many features that could act as stress concentrators for the initiation of bone microdamage. This was first identified by John Currey in a seminal paper ...in 1962 in which he presented the mechanical and biological evidence for stress concentrations at the bone surface, within the bone through the action of stiffness differentials between architectural features including between lamellae, and at the level of the lacunar and canalicular walls. Those early observations set the stage to consider how microscopic damage to bone tissue might affect the properties of bone at a time when most in the scientific community dismissed microcracks in bone as artifact. Evidence collected in the nearly 60 years since those important initial observations suggest that some of these architectural features in bone tissue are more effective as crack arrestors than as crack initiators. Sites of higher mineralization in the bone matrix, particularly interstitial sites in both cortical and trabecular bone, may serve preferentially as locations for crack initiation, whereas those boundaries identified by Currey as both stress concentrators and stress arrestors are more effective at stopping cracks than at initiating them.
•John Currey identified stress concentrators and stress arrestors in bone nearly 60 years ago.•Evidence collected since indicate some of these architectural features are more effective crack arrestors than initiators.•Highly mineralized bone matrix, rather than stress concentration per se, may be effective stress concentrators.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has generated great interest in the medical and research communities yet remains an enigma, given its unknown pathogenesis. The goal of this ...review is to summarize the various proposed hypotheses underlying BRONJ. Although a role of the oral mucosa has been proposed, the bone is likely the primary tissue of interest for BRONJ. The most popular BRONJ hypothesis—manifestation of necrotic bone resulting from bisphosphonate-induced remodeling suppression—is supported mostly by indirect evidence, although recent data have shown that bisphosphonates significantly reduce remodeling in the jaw. Remodeling suppression would be expected, and has been shown, to allow accumulation of nonviable osteocytes, whereas a more direct cytotoxic effect of bisphosphonates on osteocytes has also been proposed. Bisphosphonates have antiangiogenic effects, leading to speculation that this could contribute to the BRONJ pathogenesis. Compromised angiogenesis would most likely be involved in post-intervention healing, although other aspects of the vasculature (eg, blood flow) could contribute to BRONJ. Despite infection being present in many BRONJ patients, there is no clear evidence as to whether infection is a primary or secondary event in the pathophysiology. In addition to these main factors proposed in the pathogenesis, numerous cofactors associated with BRONJ (eg, diabetes, smoking, dental extraction, concurrent medications) could interact with bisphosphonates and affect remodeling, angiogenesis/blood flow, and/or infection. Because our lack of knowledge concerning BRONJ pathogenesis results from a lack of data, it is only through the initiation of hypothesis-driven studies that significant progress will be made to understand this serious and debilitating condition.
Purpose An increasing number of reports have implicated bisphosphonates as contributing to osteonecrosis of the jaw. The goal of this study was to evaluate mandible necrosis in beagle dogs treated ...for 3 years with oral alendronate (ALN). Materials and Methods Skeletally mature female beagles were treated daily for 3 years with oral doses of vehicle (VEH) or ALN (0.20 or 1.0 mg/kg/day). These doses approximate, on a mg/kg basis, those used for postmenopausal osteoporosis and Paget's disease, respectively. At necropsy, the second molar region of the mandible was excised, stained en bloc with basic fuchsin, and assessed for matrix necrosis and intracortical bone turnover rate using histology. Matrix necrosis was defined as a region greater than 500 μm2 that was void of basic fuchsin stain, assessed using both bright-field and confocal microscopy. Results No animals developed exposed bone lesions in the oral cavity during the 3-year study. Matrix necrosis was observed in 25% of ALN0.2 animals, 33% of ALN1.0 animals, and was noticeably absent from all vehicle animals ( P < .05 pooled ALN doses vs VEH). These necrotic regions occurred predominately in the alveolar bone and were clearly void of patent canaliculi. Intracortical bone turnover rate of the alveolar mandible bone region was significantly lower (−75%, P < .05) in ALN-treated animals compared with VEH. Conclusions Three years of daily oral bisphosphonate treatment reduces bone turnover significantly and increases the incidence of matrix necrosis within the mandible of dogs.
It is well known that bone loss accompanies aging in both men and women and contributes to skeletal fragility in the older population, but changes that occur to the bone tissue matrix itself are less ...well known. These changes in bone quality aggravate the skeletal fragility associated with loss of bone mass. Bone tissue quality is affected by age-related changes in bone mineral, collagen and its cross-linking profiles, water compartments and even non-collagenous proteins. It is commonly assumed that greater tissue mineralization accompanies aging as bone turnover slows down in elderly individuals, but the data for this are weak. However, there may be changes in the quality of the mineral crystals, and the substitutions found within the crystal. Both enzymatically-mediated and non-enzymatically-mediated collagen cross-links multiply with age. The former tend to make the bone stiffer and stronger, but the latter, while making the bone stiffer can also make it more brittle and more likely to fracture. Bone pore water that is not bound to collagen or mineral increases with age as bone mass is lost, but water that is bound to collagen and mineral declines with age. These changes contribute to skeletal fragility by reducing the amount that bone can deform before fracturing. Finally, non-collagenous proteins have physical properties that can alter matrix mechanical properties and can also have molecular signaling functions that regulate bone remodeling. Whether these change with age, how they change, and how this affects skeletal fragility with aging is still largely a black box, and requires much more investigation. The roles of any of these factors in skeletal fragility are difficult to assess clinically as there is no easy or economical way to evaluate them, but a picture of fragility in the aging skeleton is incomplete without them.
•The material properties of bone matrix contribute to bone's strength, and can contribute to the increased fracture risk caused by a loss of bone.•Bone quality is affected by age-related changes in mineral, collagen and its cross-linking, water, and non-collagenous proteins.•The increased brittleness that occurs with age is related to changes to the collagen, and the interface between collagen and mineral.•The decline in loosely bound water at the collagen-mineral interface reduces the capacity of older bone to dissipate energy and resist fracture.
Synovial joints are composed of several different kinds of tissue that interact to protect normal joint function. Three subchondral mineralized tissues can be identified
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calcified cartilage, ...subchondral cortical bone, and subchondral trabecular bone
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which are distinguished morphologically, physiologically, and mechanically. Each responds to mechanical and pharmaceutical stimuli in different ways through processes of growth, modeling, and remodeling, and changes in each may have a distinct effect on the health of the joint. It is important to distinguish between the structural properties of these tissues and their material properties as these change differently in osteoarthrosis (OA). It is likely that changes in the mineral content and thickness of the calcified cartilage play a greater role in the pathogenesis of OA than has been realized, whereas changes in trabecular bone are probably not causative. Changes in the subchondral cortical bone may accelerate progression of pre-existing disease, but the combined effects of increased subchondral bone turnover and greater subchondral bone volume are not at all clear. Ultimately, the efficacy of bone anti-resorptive therapies for OA will depend upon whether the increased structural stiffness of the subchondral mineralized tissues predisposes the cartilage to deteriorate, whether the increased bone turnover that occurs in OA is itself a causative factor, or whether the lower tissue elastic modulus offsets the increased structural stiffness of the subchondral plate in an attempt to protect the cartilage from damage.
Abstract The bisphosphonates (BPs) have been useful tools in our understanding of the role that bone remodeling plays in skeletal health. The purpose of this paper is to outline what we know, and ...what is still unknown, about the role that BPs play in modulating bone turnover, how this affects microdamage accumulation, and ultimately what the effects of these changes elicited by BPs are to the structural and the material biomechanical properties of the skeleton. We know that BPs suppress remodeling site-specifically, probably do not have a direct effect on formation, and that the individual BPs vary with respect to speed of onset, duration of effect and magnitude of suppression. However, we do not know if these differences are meaningful in a clinical sense, how much remodeling is sufficient, the optimal duration of treatment, or how long it takes to restore remodeling to pre-treatment levels following withdrawal. We also know that suppression is intimately tied to microdamage accumulation, which is also site-specific, that BPs impair targeted repair of damage, and that they can reduce the energy absorption capacity of bone at the tissue level. However, the BPs are clearly effective at preventing fracture, and generally increase bone mineral density and whole bone strength, so we do not know whether these changes in damage accumulation and repair, or the mechanical effects at the tissue level, are clinically meaningful. The mechanical effects of BPs on the fatigue life of bone, or BP effects on bone subject to an impact, are entirely unknown. This paper reviews the literature on these topics, and identifies gaps in knowledge that can be addressed with further research. This article is part of a Special Issue entitled Bisphosphonates.
Bone is a two-phase porous composite material comprised primarily of collagen and mineral, which together provide its mechanical properties. The contribution of the mineral phase to bone’s mechanical ...properties has dominated scientific thinking. Collagen’s role has been underappreciated and not very well studied. However, there is evidence that changes in collagen content, or changes to inter- and intrafibrillar collagen cross-linking, can reduce the energy required to cause bone failure (toughness), and increase fracture risk. Although collagen may have less effect on bone’s strength and stiffness than does mineral, it may have a profound effect on bone fragility. Collagen changes that occur with age and reduce bone’s toughness may be an important factor in the risk of fracture in older women with low bone mass.
Targeted and nontargeted remodeling BURR, D. B
Bone (New York, N.Y.),
2002, 2002-Jan, 2002-01-00, 20020101, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Bone remodeling achieves three goals. First, it provides a way for the body to alter the balance of essential minerals by increasing or decreasing the concentration of these in serum. Second, it ...provides a mechanism for the skeleton to adapt to its mechanical environment, reducing the risk for fracture and increasing the organism's chances for passing its genes to the next generation. Third, it provides a mechanism to repair the damage in bone by repetitive cycles of mechanical loading.
Abstract This review reports on proceedings of a bone histomorphometry session conducted at the Fortieth International IBMS Sun Valley Skeletal Tissue Biology Workshop held on August 1, 2010. The ...session was prompted by recent technical problems encountered in conducting histomorphometry on bone biopsies from humans and animals treated with anti-remodeling agents such as bisphosphonates and RANKL antibodies. These agents reduce remodeling substantially, and thus cause problems in calculating bone remodeling dynamics using in vivo fluorochrome labeling. The tissue specimens often contain few or no fluorochrome labels, and thus create statistical and other problems in analyzing variables such as mineral apposition rates, mineralizing surface and bone formation rates. The conference attendees discussed these problems and their resolutions, and the proceedings reported here summarize their discussions and recommendations.
In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of articular bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new bone is ...uncommon in RA, suggesting that bone formation may be compromised at these sites. Dynamic bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic bone. Bone formation rates at bone surfaces adjacent to inflammation were similar to those observed in nonarthritic bone; therefore, osteoblast activity is unlikely to compensate for the increased bone resorption at these sites. Within arthritic bone, the extent of actively mineralizing surface was reduced at bone surfaces adjacent to inflammation compared with bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized bone formation, there was a notable paucity of cells expressing the mid‐ to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled‐related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic bone. Together, these data indicate that the presence of inflammation within arthritic bone impairs osteoblast capacity to form adequate mineralized bone, thus contributing to the net loss of bone and failure of bone repair at sites of focal bone erosion in RA.
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