Mark R. Forwood

Suppressed Bone Turnover by Bisphosphonates Increases Microdamage Accumulation and Reduces Some Biomechanical Properties in Dog Rib

It has been hypothesized that suppression of bone remodeling allows microdamage to accumulate, leading to increased bone fragility. This study evaluated the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties of cortical bone in the dog rib. Thirty‐six female beagles, 1–2 years old, were divided into three groups. The control group (CNT) was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right ninth rib was assigned to cortical histomorphometry or microdamage analysis. The left ninth rib was tested to failure in three‐point bending. Total cross‐sectional bone area was significantly increased in both RIS and ALN compared with CNT, whereas cortical area did not differ significantly among groups. One‐year treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS, 53%; ALN, 68%) without impairment of mineralization and significantly increased microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT. Although bone strength and stiffness were not significantly affected by the treatments, bone toughness declined significantly in ALN (20%). Regression analysis showed a significant nonlinear relationship between suppressed intracortical bone remodeling and microdamage accumulation as well as a significant linear relationship between microdamage accumulation and reduced toughness. This study showed that suppression of bone turnover by high doses of bisphosphonates is associated with microdamage accumulation and reduced some mechanical properties of bone.

Bone Microdamage and Skeletal Fragility in Osteoporotic and Stress Fractures

The accumulation of bone microdamage has been proposed as one factor that contributes to increased skeletal fragility with age and that may increase the risk for fracture in older women. This paper reviews the current status and understanding of microdamage physiology and its importance to skeletal fragility. Several questions are addressed: Does microdamage exist in vivo in bone? If it does, does it impair bone quality? Does microdamage accumulate with age, and is the accumulation of damage with age sufficient to cause a fracture? The nature of the damage repair mechanism is reviewed, and it is proposed that osteoporotic fracture may be a consequence of a positive feedback between damage accumulation and the increased remodeling space associated with repair.

In vivo measurement of human tibial strains during vigorous activity

Our understanding of mechanical controls on bone remodeling comes from studies of animals with surgically implanted strain gages, but in vivo strain measurements have been made in a single human only once. That study showed that strains in the human tibia during walking and running are well below the fracture threshold. However, strains have never been monitored in vivo during vigorous activity in people, even though prolonged strenuous activity may be responsible for the occurrence of stress fractures. We hypothesized that strains > 3000 microstrain could be produced on the human tibial midshaft during vigorous activity. Strains were measured on the tibiae of two subjects via implanted strain gauges under conditions similar to those experienced by Israeli infantry recruits. Principal compressive and shear strains were greatest for uphill and downhill zigzag running, reaching nearly 2000 microstrain in some cases, about three times higher than recorded during walking. Strain rates were highest during sprinting and downhill running, reaching 0.050/sec. These results show that strain is maintained below 2000 microstrain even under conditions of strenuous activity. Strain rates are higher than previously recorded in human studies, but well within the range reported for running animals.

Effects of Suppressed Bone Turnover by Bisphosphonates on Microdamage Accumulation and Biomechanical Properties in Clinically Relevant Skeletal Sites in Beagles

We recently demonstrated that suppression of bone remodeling allows microdamage to accumulate, leading to reduced bone toughness in the rib cortex of dogs. This study evaluates the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties at clinically relevant skeletal sites in the same dogs. Thirty-six female beagles, 1-2 years old, were divided into three groups. The control group was treated daily for 12 months with saline vehicle (CNT). The remaining two groups were treated daily with risedronate at a dose of 0.5 mg/kg per day (RIS), or alendronate at 1.0 mg/kg per day (ALN) orally. The doses of these bisphosphonates were six times the clinical doses approved for treatment of osteoporosis in humans. After killing, the L-1 vertebra was scanned by dual-energy X-ray absorptiometry (DXA), and the L-2 vertebra and right ilium were assigned to histomorphometry. The L-3 vertebra, left ilium, Th-2 spinous process, and right femoral neck were used for microdamage analysis. The L-4 vertebra and Th-1 spinous process were mechanically tested to failure in compression and shear, respectively. One year treatment with risedronate or alendronate significantly suppressed trabecular remodeling in vertebrae (RIS 90%, ALN 95%) and ilium (RIS 76%, ALN 90%) without impairment of mineralization, and significantly increased microdamage accumulation in all skeletal sites measured. Trabecular bone volume and vertebral strength increased significantly following 12 month treatment. However, normalized toughness of the L-4 vertebra was reduced by 21% in both RIS (p = 0.06) and ALN (p = 0.05) groups. When the two bisphosphonate groups were pooled in a post hoc fashion for analysis, this reduction in toughness reached statistical significance (p = 0.02). This study demonstrates that suppression of trabecular bone turnover by high doses of bisphosphonates is associated with increased vertebral strength, even though there is significant microdamage accumulation and a reduction in the intrinsic energy absorption capacity of trabecular bone.

Bone mineral accrual from 8 to 30 years of age: An estimation of peak bone mass

Bone area (BA) and bone mineral content (BMC) were measured from childhood to young adulthood at the total body (TB), lumbar spine (LS), total hip (TH), and femoral neck (FN). BA and BMC values were expressed as a percentage of young‐adult values to determine if and when values reached a plateau. Data were aligned on biological ages [years from peak height velocity (PHV)] to control for maturity. TB BA increased significantly from −4 to +4 years from PHV, with TB BMC reaching a plateau, on average, 2 years later at +6 years from PHV (equates to 18 and 20 years of age in girls and boys, respectively). LS BA increased significantly from −4 years from PHV to +3 years from PHV, whereas LS BMC increased until +4 from PHV. FN BA increased between −4 and +1 years from PHV, with FN BMC reaching a plateau, on average, 1 year later at +2 years from PHV. In the circumpubertal years (−2 to +2 years from PHV): 39% of the young‐adult BMC was accrued at the TB in both males and females; 43% and 46% was accrued in males and females at the LS and TH, respectively; 33% (males and females) was accrued at the FN. In summary, we provide strong evidence that BA plateaus 1 to 2 years earlier than BMC. Depending on the skeletal site, peak bone mass occurs by the end of the second or early in the third decade of life. The data substantiate the importance of the circumpubertal years for accruing bone mineral.

Assessment of Cancellous Bone Quality in Severe Osteoarthrosis: Bone Mineral Density, Mechanics, and Microdamage

The role of bone microdamage (microscopic cracks or microcracks and ultrastructural collagen matrix and bone mineral damage) in diseases such as osteoarthrosis and osteoporosis is poorly understood. Microdamage accumulation in vivo is influenced by age and cyclic loading, therefore, it would be useful if the burden of microdamage in bone could be assessed by noninvasive measures such as the radiological measurement of bone mineral density (BMD). The aim of this study was to investigate the relationship between BMD, compressive strength and stiffness, and microdamage in the cancellous bone of the proximal femur in patients with severe osteoarthrosis. Trabecular bone core samples, from the intertrochanteric region of the femur, were obtained from 34 patients, with a mean age of 70.3 +/- 11.1 years, undergoing total hip arthroplasty for osteoarthrosis. Cores selected from contact X-ray images were used for BMD measurement, compressive mechanical testing or left untested (uncrushed), en bloc staining for microdamage, and bone histomorphometry. The study shows a strong dependence of both the elastic modulus and ultimate failure stress of the bone samples on BMD and a significant relationship between the elastic modulus and trabecular anisotropy (Tr. An). In multiple linear regression, BMD and Tr. An together account for about 70% of the variance in the elastic modulus. Then including microcrack crack density (Cr.Dn) and damage volume fraction (DxV/BV) variables, Tr. An alone accounts for a relatively small amount of the variation (8.5%) in ultimate failure stress and elastic modulus. The Cr.Dn accounts for more of the variation in the ultimate failure stress than in the elastic modulus (50% vs. 7%). In this experiment, data for Cr.Dn provide a measure of damage associated with the ultimate failure of cancellous bone. In specimens that were not mechanically tested, in vivo microcrack accumulation increases exponentially with age. In conclusion, data from this study suggest that BMD and Cr.Dn are the major determinants of cancellous bone strength, whereas BMD and Tr. An are major determinants of cancellous bone stiffness. In bone specimens subjected to compressive testing there was no relationship between microdamage and BMD, suggesting that BMD cannot be used to monitor changes in the mechanical properties of bone due to microdamage accumulation.

Transgenic Mice Overexpressing Tartrate‐Resistant Acid Phosphatase Exhibit an Increased Rate of Bone Turnover

Tartrate‐resistant acid phosphatase (TRAP) is a secreted product of osteoclasts and a lysosomal hydrolase of some tissue macrophages. To determine whether TRAP expression is rate‐limiting in bone resorption, we overexpressed TRAP in transgenic mice by introducing additional copies of the TRAP gene that contained the SV40 enhancer. In multiple independent mouse lines, the transgene gave a copy number–dependent increase in TRAP mRNA levels and TRAP activity in osteoclasts, macrophages, serum, and other sites of normal low‐level expression (notably, liver parenchymal cells, kidney mesangial cells, and pancreatic secretory acinar cells). Transgenic mice had decreased trabecular bone consistent with mild osteoporosis. Measurements of the bone formation rate suggest that the animals compensate for the increased resorption by increasing bone synthesis, which partly ameliorates the phenotype. These mice provide evidence that inclusion of an irrelevant enhancer does not necessarily override a tissue‐specific promoter.

Sterilization of allograft bone: effects of gamma irradiation on allograft biology and biomechanics

Gamma irradiation from Cobalt 60 sources has been used to terminally sterilize bone allografts for many years. Gamma radiation adversely affects the mechanical and biological properties of bone allografts by degrading the collagen in bone matrix. Specifically, gamma rays split polypeptide chains. In wet specimens irradiation causes release of free radicals via radiolysis of water molecules that induces cross-linking reactions in collagen molecules. These effects are dose dependent and give rise to a dose-dependent decrease in mechanical properties of allograft bone when gamma dose is increased above 25 kGy for cortical bone or 60 kGy for cancellous bone. But at doses between 0 and 25 kGy (standard dose), a clear relationship between gamma dose and mechanical properties has yet to be established. In addition, the effects of gamma radiation on graft remodelling have not been intensively investigated. There is evidence that the activity of osteoclasts is reduced when they are cultured onto irradiated bone slices, that peroxidation of marrow fat increases apoptosis of osteoblasts; and that bacterial products remain after irradiation and induce inflammatory bone resorption following macrophage activation. These effects need considerably more investigation to establish their relevance to clinical outcomes. International consensus on an optimum dose of radiation has not been achieved due to a wide range of confounding variables and individual decisions by tissue banks. This has resulted in the application of doses ranging from 15 to 35 kGy. Here, we provide a critical review on the effects of gamma irradiation on the mechanical and biological properties of allograft bone.

Does childhood and adolescence provide a unique opportunity for exercise to strengthen the skeleton

Osteoporosis is a major, and increasing, public health problem. In this review we examine the evidence that childhood physical activity is an important determinant of bone mineral in adult years, and as such, may help to prevent osteoporosis. Animal studies provide incontrovertible evidence that growing bone has a greater capacity to add new bone to the skeleton than does adult bone. Observational studies in children undertaking routine physical activity and cross-sectional athlete studies in young sportspeople both reveal that activity is positively associated with bone mineral density (BMD). Longitudinal studies in pre- and peripubertal gymnasts reveal BMD gains far in excess of those that can be achieved in adulthood. However, such studies permit only limited conclusions as they contain the potential for selection bias and can be confounded by other determinants of bone mineral (e.g. dietary and lifestyle factors). Thus, research comparing inter-individual playing-to-nonplaying arm differences in bone mineral (e.g., in racquet sports) have proven to be extremely useful. These studies suggest that the BMD differences are clearly greater when bone is subjected to mechanical loading prior to the end of puberty and longitudinal growth of the body (in women, before menarche) rather than after it. Tanner stage II and III appears to be the maturational stage when the association between exercise and BMD becomes manifest in most adolescents. Do conclusions drawn from athlete studies apply to the general population? Randomised intervention studies of physical activity and bone mineral accrual in normal children confirm that childhood activity is strongly associated with bone mineral accrual. Furthermore, some retired athlete studies and a detraining study suggest that adolescent bone gain may, at least partly, persist despite reduced adult physical activity. Mechanisms that may underlie the association between childhood physical activity and bone mineral accrual are outlined. Thus, it appears that physical activity during the most active period of maturity (with respect to longitudinal growth of the body) plays a vital role in optimising peak bone mass and that benefits may extend into adulthood.

The Ratio of Messenger RNA Levels of Receptor Activator of Nuclear Factor κB Ligand to Osteoprotegerin Correlates with Bone Remodeling Indices in Normal Human Cancellous Bone but Not in Osteoarthritis

The determinants of cancellous bone turnover and trabecular structure are not understood in normal bone or skeletal disease. Bone remodeling is initiated by osteoclastic resorption followed by osteoblastic formation of new bone. Receptor activator of nuclear factor κB ligand (RANKL) is a newly described regulator of osteoclast formation and function, the activity of which appears to be a balance between interaction with its receptor RANK and with an antagonist binding protein osteoprotegerin (OPG). Therefore, we have examined the relationship between the expression of RANKL, RANK, and OPG and indices of bone structure and turnover in human cancellous bone from the proximal femur. Bone samples were obtained from individuals with osteoarthritis (OA) at joint replacement surgery and from autopsy controls. Histomorphometric analysis of these samples showed that eroded surface (ES/BS) and osteoid surface (OS/BS) were positively associated in both control (p < 0.001) and OA (p < 0.02), indicating that the processes of bone resorption and bone formation remain coupled in OA, as they are in controls. RANKL, OPG, and RANK messenger RNA (mRNA) were abundant in human cancellous bone, with significant differences between control and OA individuals. In coplotting the molecular and histomorphometric data, strong associations were found between the ratio of RANKL/OPG mRNA and the indices of bone turnover (RANKL/OPG vs. ES/BS: r = 0.93, p < 0.001; RANKL/OPG vs. OS/BS: r = 0.80, p < 0.001). These relationships were not evident in trabecular bone from severe OA, suggesting that bone turnover may be regulated differently in this disease. We propose that the effective concentration of RANKL is related causally to bone turnover.