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Biomedical subjects

R Bruce Martin

Publications and source records attributed to R Bruce Martin.

14 recordsLinked to original sources
PubMed2005

Estrogen-dependent actions of bone morphogenetic protein-7 on spine fusion in rats.

STUDY DESIGN: Intertransverse process spinal fusion using recombinant human bone morphogenetic protein-7 (rhBMP-7) was performed in intact and ovariectomized female rats. OBJECTIVES: To examine fusion rates in intact and ovariectomized female rats using rhBMP-7 to determine if spine fusion is dependent on estrogen status. SUMMARY OF BACKGROUND DATA: Rat spinal fusion has been established as a consistent, efficient model for posterolateral intertransverse process fusion. Previous experiments have confirmed the efficacy of pellets containing the carrier, insoluble collagen bone matrix (ICBM), and rhBMP-7 to augment intertransverse process single level fusion in a rat model. Studying these implications in an osteoporosis model is of clinical value because there are many patients undergoing spinal fusion surgery that have osteoporotic bone disease, and there is a steady increase in this group of patients. METHODS: A total of 15 ovariectomized and 15 intact Sprague-Dawley female rats were randomly assigned to groups receiving 25 mg ICBM alone, 25 mg ICBM + 10 microg rhBMP-7, and 25 mg ICBM + 30 microg rhBMP-7. Spinal fusion was evaluated by manual motion testing at each lumbar segment, radiographic evaluation using the Lenke grading system, and histology. RESULTS: Ovariectomized and intact rats receiving 25 mg carrier ICBM alone did not show spinal fusion. With 25 mg ICBM + 10 microg rhBMP-7, there was not a significant difference in fusion rates between intact and ovariectomized rats (P = 0.63). Ovariectomized rats receiving 25 mg ICBM + 30 microg rhBMP-7 showed significantly lower fusion rates than intact rats (P = 0.013). CONCLUSION: These data suggest that spinal fusion using rhBMP-7 is estrogen-dependent in rats. At the dosages used, rhBMP-7 was unable to overcome the inhibitory effects of estrogen deficiency on spinal fusion.

Animals↗
PubMed2004

Hidden assumptions in a maximum-entropy method stacking analyses.

Two models have been used to describe indefinite self-association (stacking). In the more popular isodesmic model addition of molecules to the growing stack occurs with the same equilibrium constant, while in the attenuated model successive equilibrium constants decrease in value. In an attempt to choose between the two models application was made of the maximum-entropy method. This paper points out that the conclusions drawn from this method are not proven as the application assumed specific limiting values for experimental values of a molecule in the interior of a stack, and these values are not identical in the two models for the two systems considered.

Entropy↗
PubMed2004

A theoretical analysis of long-term bisphosphonate effects on trabecular bone volume and microdamage.

Bisphosphonates increase bone mass and reduce fracture risk, but their anti-resorptive action may lead to increases in fatigue microdamage. To investigate how bisphosphonate effects influence changes in bone volume and microdamage in the long term, a strain-adaptive model of bone remodeling and microdamage balance was developed for a continuum-level volume of postmenopausal trabecular bone by invoking Frost's mechanostat hypothesis. Both disuse and fatigue microdamage were assumed to stimulate the activation frequency of basic multicellular units (BMUs) such that bone remodeling served to remove excess bone mass and microdamage. Bisphosphonate effects were simulated as follows: low, intermediate, high, or complete suppression of BMU activation frequency either without a change in resorption by the BMU or with an independent decrease in resorption while the bone formation process was unaffected (i.e., formation initially exceeded resorption). Of the bisphosphonate effects, a reduction in resorption relative to formation dictated the long-term gain in bone volume while the potency of activation frequency suppression controlled the rate of gain. A plateau in the bone mass gain that typically occurs in clinical studies of bisphosphonate treatment was predicted by the model because the resultant reduction in strain forced bone formation by the BMU to decrease over time until it matched the reduction in BMU resorption. A greater suppression of activation frequency proportionally increased microdamage, but the accumulation was limited over the long term as long as remodeling was incompletely suppressed. The results of the model suggest creating bisphosphonates that provide minimal suppression of remodeling and a large decrease in BMU resorption because this would minimize damage accumulation and increase bone mass, respectively.

Biomechanical Phenomena↗
PubMed2004

Long stemmed total knee arthroplasty with interlocking screws: a computational bone adaptation study.

The ability of an interlocking screw fixation technique to minimize bone loss related to stress shielding in the tibia was investigated and compared to the abilities of cement and press-fit fixation. Full bony ingrowth has been associated with greater stress shielding than partial ingrowth; therefore, the effect of intimate bonding of the stem to bone on subsequent bone loss was also studied. A damage- and disuse-based remodeling theory was coupled with a two-dimensional finite element model of the tibia to predict changes in bone remodeling following long stemmed total knee arthroplasty (TKA) for four different fixation techniques (cement, press-fit, interlock with bony ingrowth, and interlock without bony ingrowth). Remodeling changes commenced with the model state variables--bone area fraction, mechanical stimulus, damage, and remodeling activity--at steady-state values predicted by the intact tibia simulation. After TKA and irrespective of fixation technique, the model predicted elevated remodeling due to disuse, in which more bone was removed than replenished. In regions below the tibial tray and along the cortices, the interlocking stem with full bony ingrowth and the cemented stem caused the least amount of bone loss. An interlocking stem with a smooth, matted finish did not reduce the bone loss associated with interlocking fixation.

Adaptation, Physiological↗
PubMed2004

Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques.

The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.

Absorptiometry, Photon↗
PubMed2003

Fatigue damage, remodeling, and the minimization of skeletal weight.

The skeleton has provided many advantages during the course of vertebrate evolution, but it has also contained limitations that have strongly influenced bone biology. These limitations have included weight and the potential for fatigue failure. Calcified bone tissue is approximately twice as heavy as other tissues, so it is important to minimize the size of the skeleton, but this implies increasing bone stresses and strains and the potential for fatigue fracture. This paper first explores the role of fatigue damage removal by remodeling in extending a long bone's fatigue life to match the animal's lifetime. Next, an estimate is obtained for the amount that the cross-sectional area of a bone would have to be increased in lieu of remodeling to achieve the same extension of fatigue life, provided that the associated muscle mass remained constant. The result illustrates how remodeling can provide a gracile bone the same fatigue life as a substantially more robust bone lacking remodeling. Finally, it is shown that if muscle mass increases in linear proportion to bone mass, as experimental data suggest, extending a bone's fatigue life by increasing its cross-sectional dimensions may not be effective because the inertia of bigger bones would result in larger muscles and increased skeletal loads. Thus, bone remodeling to remove fatigue damage may be essential for the existence of relatively large, long-lived vertebrates.

Animals↗
PubMed2003

Trabecular rod thickness by direct measurement from 3D SEM anaglyphs.

This study presents a methodology for measuring the thickness of trabecular rods directly from anaglyphs. Macerated sagittal slices of T12 vertebral bodies from 15 subjects were examined by scanning electron microscopy (SEM). Two digital images (the second image tilted 5 degrees ) were recorded, and a 3D anaglyph was created. The thickness of the trabecular rods (Tb.Th((rods))), and the anatomical orientation of the trabecular rods were measured using an image analyser. Conventional 2D histomorphometry was performed on adjacent bone slices. A total of 1559 rod measurements were made from the 15 vertebral bone slices, with a mean Tb.Th((rods)) of 123 +/- 36 microm. The rod thickness in males (128 +/- 34 microm) was significantly greater than that in females (119 +/- 37 microm, P < 0.001). Tb.Th((rods)) changed significantly with age in the males: the thicker rods in the younger men reduced with age to a thickness similar to that in women. 3D measurements were significantly larger than the 2D estimates, and there was no correlation between the two methods of measurement. An inverse correlation was found between the number of rods and the bone volume fraction (BV/TV), indicating that decreased BV/TV is associated with an increased number of rods. The vertical rods (132 +/- 39 microm) were significantly thicker than the horizontal rods (116 +/- 33 microm, P < 0.001). The determination of rod numbers, and their orientation and individual thicknesses enables a greater understanding of cancellous bone architecture in both individuals and populations, and will allow more reliable finite element modelling. Direct measurements from 3D anaglyphs of intact specimens provide new data that show previously unrecognised age- and sex-related changes.

Adolescent↗
PubMed2003

Fatigue microdamage as an essential element of bone mechanics and biology.

The fossil record shows that bone remodeling has existed since the earliest large vertebrates became weight-bearing on land, but the functions of remodeling have long been debated. The principal protagonists in this debate have been those favoring a mechanical function and those asserting that remodeling serves to move calcium in and out of the skeleton. In recent years the arguments of the former school have included not only the adaptation of internal structure to specific kinds of stresses, but the need to remove fatigue damage. It has become clear that (1) physiologic strains continually produce fatigue damage in bone; (2) this damage weakens bone and is associated with both osteocyte apoptosis and the activation of remodeling; and (3) remodeling is the only means by which this damage can be removed. The significance of these observations is increased by the fact that fatigue failure is more likely in larger structures. This "volume effect," along with the advantages of enhanced mobility and metabolic efficiency, may have selected for bone remodeling as a means of controlling fatigue damage as it occurs, allowing larger vertebrates to maintain a relatively light skeleton over an extended lifetime. In this view, bone remodeling is not primarily a mechanism for calcium transport, but is intimately related to other inflammatory repair responses.

Animals↗
PubMed2003

An investigation of the interactions between lower-limb bone morphology, limb inertial properties and limb dynamics.

Bone mass and size clearly affect the safety and survival of wild animals as well as human beings, however, little is known about the interactions between bone size and movement dynamics. A modeling approach was used to investigate the hypothesis that increased bone cortical area causes increased limb moments of inertia, decreased lower-limb movement maximum velocities, and increased energy requirements to sustain submaximum lower-limb locomotion movements. Custom software and digital data of a human leg were used to simulate femur, tibia, and fibula cortical bone area increases of 0%, 22%, 50%, and 80%. Limb segment masses, center of mass locations, and moments of inertia in the sagittal plane were calculated for each bone condition. Movement simulations of unloaded running and cycling motions were performed. Linear regression analyses were used to determine the magnitude of the effect cortical area has on limb moment of inertia, velocity, and the internal work required to move the limbs at a given velocity. The thigh and shank moment of inertia increased linearly up to 1.5% and 6.9%, respectively for an 80% increase in cortical area resulting in 1.3% and 2.0% decreases in maximum unloaded cycling and running velocities, respectively, and in 3.0% and 2.9% increases in internal work for the cycling and running motions, respectively. These results support the hypothesis and though small changes in movement speed and energy demands were observed, such changes may have played an important role in animal survival as bones evolved and became less robust.

Acceleration↗
PubMed2003

Histomorphometric analysis of the effects of osteocyte density on osteonal morphology and remodeling.

Osteocytes, the most abundant cells in the cortical bone matrix, are thought to have mechanosensory and chemosensory regulatory roles. Marotti theorized that osteocytes signal to osteoblasts to recruit them into the osteocyte lineage. Martin extended this theory, assuming that osteocytes display a general inhibitory effect on osteoblast function. The current study provides a quantitative analysis of the relationships between osteonal osteocyte density (Ot.N/BV), wall width (W.Wi), individual osteon porosity (IOP), and formation period (FP) in ulnar cortices from sheep labeled with tetracycline and calcein double labels. We postulated that osteocytes inhibit refilling so that the osteon wall width is thin enough, and the haversian canal is large enough, to allow adequate delivery of nutrients to the osteocytes throughout the forming and completed osteon. Therefore we tested the hypotheses that Ot.N/BV correlates negatively to FP and W.Wi, and positively to IOP, and that FP correlates positively with W.Wi. We found that Ot.N/BV correlated positively with IOP (P < 0.0001) and W.Wi correlated positively with FP (P < 0.0001). Significant negative correlations were observed between Ot.N/BV and both W.Wi (P < 0.0001) and FP (P = 0.006). These data support the general hypothesis that osteocytes contribute to the regulation of osteon morphology via the control of refilling rate and formation period, and the specific hypotheses that, for a given cement line diameter, high osteocyte density (1) reduces the rate of refilling and decreases the formation period and (2) decreases wall width and increases individual osteon porosity.

Animals↗
PubMed2002

Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta).

Tenofovir has been shown to cross the placenta in quantities sufficient to sustain reductions in viral load in simian immunodeficiency virus (SIV)-infected fetal monkeys. With chronic exposure (30 mg/kg), however, significant bone-related toxicity has been shown in approximately 25% of infants studied. Further investigations were conducted to determine whether the bone-related toxicity observed was initiated during fetal life. Gravid rhesus monkeys (n = 4) were administered tenofovir subcutaneously once daily from 20 to 150 days of gestation (30 mg/kg; term: 165 +/- 10 days). Fetuses were monitored sonographically, and maternal and fetal blood and urine samples were collected to assess hematologic parameters, clinical chemistry, insulin-like growth factor (IGF) levels, and bone biomarkers. Fetuses were delivered by hysterotomy near term for necropsy and evaluation of bone-related mechanical properties. Results of these studies have shown 1) normal fetal development, although overall body weights and crown-rump lengths were less than those for age-matched controls (p < or = .03); 2) a significant reduction in circulating IGF-I (p <.001); 3) a small reduction in fetal bone porosity (p < or = .03); and 4) transient alterations in maternal body weights and bone-related biomarkers during the treatment period. The results of these studies suggest that chronic fetal exposure to tenofovir at the maternal dose of 30 mg/kg throughout gestation can alter select fetal parameters and transiently affect maternal bone biomarkers.

Adenine↗
PubMed2002

Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta).

The acyclic nucleoside phosphonate analog, 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA; Tenofovir: Gilead Sciences, Inc., Foster City, CA), has been shown to effectively inhibit simian immunodeficiency virus (SIV) replication in rhesus macaques by blocking reverse transcription. However, chronic long-term tenofovir treatment at 30 mg/kg/day, intended to reduce viral replication and illness, has been shown to result in bone deformities and spontaneous fractures in rhesus monkeys. Based on these findings, we studied the effects of tenofovir treatment and pathogenic SIV infection on cortical bone remodeling in rhesus monkeys. Tibiae from tenofovir-treated or untreated, SIV-infected or uninfected, rhesus macaques were evaluated for bone microdamage and remodeling. We found that tenofovir treatment had a significant effect on osteoid (unmineralized bone) seam width in tibial cross-sections. Regardless of SIV infection status, half of the tenofovir-treated animals had significantly increased osteoid seam widths in tibial cortical bone resulting in an osteomalacia-like condition. Pathogenic SIV infection significantly increased tibial resorption cavity density. and this increase was normalized by tenofovir treatment. These results suggest that tenofovir treatment at 30 mg/kg/day inhibits mineralization of newly formed bone. SIV infection results in increased tibial resorption cavity density, while tenofovir treatment tends to minimize this increase. Both defective mineralization of newly formed bone and increased resorption cavity density may result in greater bone fragility.

Adenine↗
PubMed2001

A mechanistic model for internal bone remodeling exhibits different dynamic responses in disuse and overload.

Bone is a dynamic tissue which, through the process of bone remodeling in the mature skeleton, renews itself during normal function and adapts to mechanical loads. It is, therefore, important to understand the effect of remodeling on the mechanical function of bone, as well as the effect of the inherent time lag in the remodeling process. In this study, we develop a constitutive model for bone remodeling which includes a number of relevant mechanical and biological processes and use this model to address differences in the remodeling behavior as a volume element of bone is placed in disuse or overload. The remodeling parameters exhibited damped oscillatory behavior as the element was placed in disuse, with the amplitude of the oscillations increasing as the severity of disuse increased. In overload situations, the remodeling parameters exhibited critically sensitive behavior for loads beyond a threshold value. These results bear some correspondence to experimental findings, suggesting that the model may be useful when examining the importance of transient responses for bone in disuse, and for investigating the role fatigue damage removal plays in preventing or causing stress fractures. In addition, the constitutive algorithm is currently being employed in finite element simulations of bone adaptation to predict important features of the internal structure of the normal femur, as well as to study bone diseases and their treatment.

Animals↗