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Clinical tools for evaluating fracture risk, such as dual energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS), focus on bone mineral and cannot detect changes in the collagen matrix that affect bone mechanical properties. However, the mechanical response tissue analyzer (MRTA) directly measures a whole bone mechanical property. The aims of our study were to investigate the changes in fatigue resistance after collagen degradation and to determine if clinical tools can detect changes in bone mechanical properties due to fatigue. Male and female emu tibiae were endocortically treated with 1 M KOH for 1–14 days and then either fatigued to failure or fatigued to induce stiffness loss without fracture. Partial fatigue testing caused a decrease in modulus measured by mechanical testing even when not treated with KOH, which was detected by MRTA. At high stresses, only KOH-treated samples had a lower fatigue resistance compared to untreated bones for both sexes. No differences were observed in fatigue behavior at low stresses for all groups. KOH treatment is hypothesized to have changed the collagen structure in situ and adversely affected the bone. Cyclic creep may be an important mechanism in the fast deterioration rate of KOH-treated bones, as creep is the major cause of fatigue failure for bones loaded at high stresses. Therefore, collagen degradation caused by KOH treatment may be responsible for the observed altered fatigue behavior at high stresses, since collagen is responsible for the creep behavior in bone. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:197–203, 2011

Young adults are at risk of stress fractures. Risk is higher in younger and female individuals. Stress fractures occur due to repeated loading of the bone (fatigue). We modeled this with rabbit tibiae. Age increased fatigue resistance which correlated with bone mineral density. A sex difference was not detected.Younger adults who engage in intense physical activity with a sudden increase in intensity level (military recruits/college athletes) are at risk of bone stress fractures. Risk is greater in females and diminishes with aging. Stress fractures may be the result of fatigue damage, which is not repaired rapidly enough to avoid fracture. It was hypothesized that the fatigue resistance of whole rabbit tibiae would be less in female specimens but greater as animal age increased.Rabbit tibiae were harvested from three age groups (4, 7, and ≥ 12 months (females only)). The tibiae were scanned with dual energy X-ray absorptiometry to determine bone mineral density (BMD), computed tomography to quantify geometry, and then fatigue tested in three-point bending.In the ≥ 12-month group, BMD was approximately 20% higher, while the fatigue resistance was found to be approximately ten times higher than the other age groups. Sex was not a factor in the 4- and 7-month groups. Multiple linear regression revealed that fatigue life was negatively correlated with applied stress range and positively correlated with BMD (adjusted r (2) = 0.69).A difference in fatigue behavior due to sex was not detected, but there was a large increase in fatigue resistance with age. This correlated with increased BMD and parallels a reduced risk of stress fracture due to age in military recruits. Skeletal "maturation" may play an important role in determining stress fracture risk. Increased risk in females may be due to mechanisms other than those that determine material behavior.

BACKGROUND:Skeletons are formed in a wide variety of shapes, sizes, and compositions of organic and mineral components. Many invertebrate skeletons are constructed from carbonate or silicate minerals, whereas vertebrate skeletons are instead composed of a calcium phosphate mineral known as apatite. No one yet knows why the dynamic vertebrate skeleton, which is continually rebuilt, repaired, and resorbed during growth and normal remodeling, is composed of apatite. Nor is the control of bone and calcifying cartilage mineralization well understood, though it is thought to be associated with phosphate-cleaving proteins. Researchers have assumed that skeletal mineralization is also associated with non-crystalline, calcium- and phosphate-containing electron-dense granules that have been detected in vertebrate skeletal tissue prepared under non-aqueous conditions. Again, however, the role of these granules remains poorly understood. Here, we review bone and growth plate mineralization before showing that polymers of phosphate ions (polyphosphates: (PO(3)(-))(n)) are co-located with mineralizing cartilage and resorbing bone. We propose that the electron-dense granules contain polyphosphates, and explain how these polyphosphates may play an important role in apatite biomineralization. PRINCIPAL FINDINGS/METHODOLOGY:The enzymatic formation (condensation) and destruction (hydrolytic degradation) of polyphosphates offers a simple mechanism for enzymatic control of phosphate accumulation and the relative saturation of apatite. Under circumstances in which apatite mineral formation is undesirable, such as within cartilage tissue or during bone resorption, the production of polyphosphates reduces the free orthophosphate (PO(4)(3-)) concentration while permitting the accumulation of a high total PO(4)(3-) concentration. Sequestering calcium into amorphous calcium polyphosphate complexes can reduce the concentration of free calcium. The resulting reduction of both free PO(4)(3-) and free calcium lowers the relative apatite saturation, preventing formation of apatite crystals. Identified in situ within resorbing bone and mineralizing cartilage by the fluorescent reporter DAPI (4',6-diamidino-2-phenylindole), polyphosphate formation prevents apatite crystal precipitation while accumulating high local concentrations of total calcium and phosphate. When mineralization is required, tissue non-specific alkaline phosphatase, an enzyme associated with skeletal and cartilage mineralization, cleaves orthophosphates from polyphosphates. The hydrolytic degradation of polyphosphates in the calcium-polyphosphate complex increases orthophosphate and calcium concentrations and thereby favors apatite mineral formation. The correlation of alkaline phosphatase with this process may be explained by the destruction of polyphosphates in calcifying cartilage and areas of bone formation. CONCLUSIONS/SIGNIFICANCE:We hypothesize that polyphosphate formation and hydrolytic degradation constitute a simple mechanism for phosphate accumulation and enzymatic control of biological apatite saturation. This enzymatic control of calcified tissue mineralization may have permitted the development of a phosphate-based, mineralized endoskeleton that can be continually remodeled.