Local Bone Loss Research Articles

Bone loss: Therapeutic approaches for preventing bone loss in inflammatory arthritis

Inflammatory arthritides are commonly characterized by localized and generalized bone loss. Localized bone loss in the form of joint erosions and periarticular osteopenia is a hallmark of rheumatoid arthritis, the prototype of inflammatory arthritis. Recent studies have highlighted the importance of receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclast activation by inflammatory cells and subsequent bone loss. In this article, we review the pathogenesis of inflammatory bone loss and explore the possible therapeutic interventions to prevent it.

Molecular control of bone remodeling and osteoporosis.

Osteoprotegerin ligand (OPGL, TNFS11) and its receptor RANK (TNFRS11A) are essential for the development and activation of osteoclasts and critical regulators of physiological bone remodeling and osteoporosis. Production of OPGL by activated T cells can directly regulate osteoclastogenesis and bone remodeling. This may explain why autoimmune diseases, cancers, leukemias, asthma and chronic viral infections such as hepatitis and HIV result in systemic and local bone loss. OPGL is also the pathogenetic factor that causes bone and cartilage destruction and clinical crippling in arthritis. Inhibition of OPGL binding to RANK via the natural decoy receptor osteoprotegerin (OPG) prevents bone loss in postmenopausal osteoporosis and cancer metastases and completely blocks crippling in a rat model of arthritis. Moreover, OPG expression is induced by estrogen which provides a molecular explanation of postmenopausal osteoporosis in women.

Cytokine-mediated bone resorption is cytochrome P-450 dependent

Localized bone loss leads to much of the morbidity of chronic otitis media. Although the cellular events of bone remodeling have been well established, their regulation remains poorly understood. Various cytokines, including tumor necrosis factor-α, interleukin-1β, and interferon-γ, used alone and in combination, are powerful inducers of bone resorption. One of the modulators of cytokine-induced bone resorption is nitric oxide (NO), a product of the action of NO synthase (NOS) on L-arginine to form NO. Cytochrome P-450, an enzyme that is similar to NOS both structurally and functionally, may also have a role in NO production in various cellular systems. The goal of this study was to elucidate a possible role of cytochrome P-450 in bone. In this study cytokine-induced bone resorption was blocked with cimetidine and clotrimazole, which are selective inhibitors of the cytochrome P-450 IIIA family and 7-ethoxyresorufin, a nonspecific cytochrome P-450 inhibitor. A concomitant reduction of NO was also observed. This effect may be explained by cytochrome P-450 being a preferred alternative pathway or providing an essential cofactor to NOS in bone. (Otolaryngol Head Neck Surg 1999;121:708-12.)

Mechanotransduction in bone—role of the lacunocanalicular network

The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Over the last several years significant progress has been made in this field, which we will try to summarize. These studies emphasize the role of osteocytes as the professional mechanosensory cells of bone, and the lacuno-canalicular porosity as the structure that mediates mechanosensing. Strain-derived flow of interstitial fluid through this porosity seems to mechanically activate the osteocytes, as well as ensuring transport of cell signaling molecules and nutrients and waste products. This concept allows an explanation of local bone gain and loss, as well as remodeling in response to fatigue damage, as processes supervised by mechanosensitive osteocytes.

New concepts — biomechanical studies of a newly designed femoral prosthesis (cervicotrochanter prosthesis)

Objective. A newly designed stemless (cervico-trochanter) prosthesis was developed for the purpose of reducing the incidence of the stress-shielding effect caused by the traditional stem-type prosthesis. Design. Both mechanical test and three-dimensional finite element analysis were performed for comparing the differences of strain and stress distributions between the intact, C-T and PCA prosthetic femora. Background. The stress-shielding effect and polyethylene (PE) wear debris were thought to be the main factors that resulted in local bone loss after the implantation of stem-type prostheses. In this study, we developed the new C-T prosthesis, which aimed to resolve the above-mentioned problems. Methods. Six pairs of femora taken from human male cadavers were used to compare the strain magnitudes of intact ( n = 12), C-T ( n = 12) and PCA ( n = 4) prosthetic femora in specific positions. Failure load tests of C-T ( n = 8) and PCA ( n = 12) prosthetic femora were also carried out from the load-displacement curve. The analysis of variance ( anova) test was used for statistical analysis. In addition, three-dimensional finite element stress analyses were performed using a commercial package, ansys, on a Convex 3810 computer. Results. Both mechanical test and finite element results showed that the C-T prosthetic femora has a lower stress-shielding tendency than the PCA prosthetic femora ( P < 0.001). The C-T prosthetic femora also withstood an average bearing load of 6312 N, which is greater than that of the PCA prosthesis at 5358 N ( P < 0.01). Conclusions. The C-T prosthetic femur could withstand a higher failure load than the PCA prosthesis, which effectively reduced the incidence of the stress-shielding effect. Moreover, the particular design of the C-T prosthesis also reduced localized osteolysis because of the overall coverage of the neck-trochanteric area.

Ca2+ or phorbol ester but not inflammatory stimuli elevate inducible nitric oxide synthase messenger ribonucleic acid and nitric oxide (NO) release in avian osteoclasts: autocrine NO mediates Ca2+-inhibited bone resorption.

Osteoclast bone resorption is essential for normal calcium homeostasis and is therefore tightly controlled by calciotropic hormones and local modulatory cytokines and factors. Among these is nitric oxide (NO), a multifunctional free radical that potently inhibits osteoclast bone resorption in vitro and in vivo. Previous findings led us to propose that NO might serve as an autocrine, as well as paracrine, regulator of osteoclast function. This premise was investigated using isolated bone-resorptive avian osteoclasts and focusing on the inducible isoform of NO synthase (iNOS) responsible for inflammatory stimulated high-level NO synthesis in other cells. Avian osteoclasts expressed both iNOS messenger RNA (mRNA) and protein. However, inflammatory cytokines that induce iNOS mRNA, protein, and NO in other cells did not do so in avian osteoclasts, consistent with the known role of inflammatory stimuli in promoting osteoclast resorption and localized bone loss. In searching for potential modulators of osteoclast iNOS, protein kinase C activation [by phorbol 12-myristate 13-acetate (PMA)] and intracellular Ca2+ rises (A23187) were each found to elevate osteoclast iNOS mRNA and protein levels, while increasing NO release and reducing osteoclast bone resorption. The iNOS selective inhibitor aminoguanidine suppressed stimulated osteoclast NO production elicited by either signal, but reversed only the resorption inhibition due to raised Ca2+. Thus, whereas additional inhibitory signals are presumably coproduced in osteoclasts treated with PMA, osteoclast iNOS-derived NO may act as an autocrine signal to mediate Ca2+-inhibited bone resorption. These findings document for the first time an iNOS whose mRNA levels are regulated by Ca2+ or PMA, but not inflammatory stimuli, and the autocrine production of NO as a Ca2+ sensing signal to suppress osteoclast bone resorption. The unusual regulation of osteoclast iNOS makes it a potentially attractive target for designing novel therapeutic agents to alleviate excessive bone loss.

Panoramic mandibular index as a radiomorphometric tool: an assessment of precision.

To evaluate the intra-observer repeatability and inter-observer reproducibility of the measurements used in deriving the Panoramic Mandibular Index (PMI). Two observers measured 21 dental panoramic radiographs independently of each other, both repeating the measurements after a period of 1 week. The measurements were then evaluated using a number of statistical methods. All sets of compared measurements, both within and between observers, demonstrated significant positive correlations, with no significant difference between measurements Precision, however, was poor and variable. The main difficulties in obtaining consistency in repeated measurements were related to individual morphology and radiodensity. In order to improve the validity of the PMI as a measure of local bone loss, repeatability of the measurements should be improved. Suggestions as to how this, might be achieved are discussed.

Musculoskeletal adaptations to weightlessness and development of effective countermeasures.

A Research Roundtable, organized by the American College of Sports Medicine with sponsorship from the National Aeronautics and Space Administration, met in November 1995 to define research strategies for effective exercise countermeasures to weightlessness. Exercise was considered both independently of, and in conjunction with, other therapeutic modalities (e.g., pharmacological nutritional, hormonal, and growth-related factors) that could prevent or minimize the structural and functional deficits involving skeletal muscle and bone in response to chronic exposure to weightlessness, as well as return to Earth baseline function if a degree of loss is inevitable. Musculoskeletal deficits and countermeasures are described with respect to: 1) muscle and connective tissue atrophy and localized bone loss, 2) reductions in motor performance, 3) potential proneness to injury of hard and soft tissues, and 4) probable interaction between muscle atrophy and cardiovascular alterations that contribute to the postural hypotension observed immediately upon return from space flight. In spite of a variety of countermeasure protocols utilized previously involving largely endurance types of exercise, there is presently no activity-specific countermeasure(s) that adequately prevent or reduce musculoskeletal deficiencies. It seems apparent that countermeasure exercises that have a greater resistance element, as compared to endurance activities, may prove beneficial to the musculoskeletal system. Many questions remain for scientific investigation to identify efficacious countermeasure protocols, which will be imperative with the emerging era of long-term space flight.

Architectural modifications and cellular response during disuse-related bone loss in calcaneus of the sheep.

The results of simple biomechanical unloading in models of acute-disuse osteoporosis are influenced by systemic and regional effects of the method used to generate the bone loss. A model in which strain-gauge measurements confirmed that the os calcis was unloaded in healthy ewes during ambulation was assessed by histomorphometry. Twelve nonovariectomized adult female Welsh mountain sheep were submitted to hock joint immobilization by an external fixation procedure from the tibia to the metatarsus for a period of 12 wk. Histomorphometric analysis showed that this model was able to produce pure local bone loss, as transiliac bone biopsies failed to reveal any difference between the initial and final results. Immobilized and nonimmobilized calcanei were both removed postmortem. After the 12 wk of the study, osteoclastic activity was increased in accordance with the usual disuse process. An unexpected increase of osteoblastic activity was also observed, possibly related to recovery after the initial dramatic bone loss, but an artifact of the surgical procedure such as a regional acceleration phenomenon cannot be definitively excluded. However, the increased osteoblastic activity was not sufficient to prevent accentuation of the negative bone balance, resulting in a 29% decrease of trabecular bone volume in immobilized calcanei compared with nonimmobilized calcanei. This reduction was due to thinning of trabeculae (72.4 +/- 12.1 vs. 98.9 +/- 15.9 microns; P < 0.05) without any change in trabecular number (2.74 +/- 0.72 vs. 2.79 +/- 0.40/mm2; not significant). In conclusion, this model only locally increased both osteoclastic and osteoblastic activities leading to bone loss and architectural modifications. The decreased bone formation usually observed in other models of disuse osteoporosis may therefore not constitute a local phenomenon generated by unloading.

Specific evaluation of localized bone mass and bone loss in the rat using dual-energy X-ray absorptiometry subregional analysis

Dual-energy X-ray absorptiometry (DXA), together with the use of ultra-high resolution software, recently appeared as an accurate method for determining bone mineral density (BMD) in the rat. In order to assess the ability of this technique to detect changes in bone mass in the rat rapidly and precisely, we measured BMD at various sites of the femur using DXA subregional analysis. In particular, we studied the BMD of the metaphyseal part of the femur (M-BMD) rich in trabecular bone, and compared the values obtained with the cancellous bone volume measured by histomorphometry. In short-term ovariectomized animals (experiment 1), M-BMD was the only parameter to differentiate statistically between 10 ovariectomized (OVX) and 10 SHAM-operated (SHAM) rats (-11.2%, p < 0.01) 9 days after surgery. M-BMD still expressed the greatest variation between OVX and SHAM rats 42 days following ovariectomy (experiment 2) (-16.1%, p < 0.001 v -6.2%, p < 0.01 for the total femur BMD) and confirmed previous data demonstrating a greater loss of cancellous than cortical bone after cessation of ovarian activity. M-BMD was highly correlated with cancellous bone volume (BV) in normal (r = 0.82, p < 0.001, n = 30), OVX (r = 0.77, p < 0.001, n = 22) and SHAM (r = 0.88, p < 0.001, n = 21) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Ｄａｌｌ‐Ｍｉｌｅｓ Ｃａｂｌｅ Ｇｒｉｐ Ｓｙｓｔｅｍによる大転子固定

Due to local bone loss, re-attachment of the greater trochanter is often difficult in revision total hip arthroplasty and pseudoarthrosis of the greater trochanter. We use the Dall-Miles cable grip system (DMCGS) for trochanteric fixation in 17 hips (ten hips with revision, five hips with T. H. R. and two hips with pseudoarthrosis of the greater trochanter). Post-operatively, the trochanter failed to unite in two hips, caused by failure of the position of the cable grip. In all other cases, good radiological and clinical results were achieved. Better results are obtained using the DMCGS in cases of trochanteric bone loss following hip surgery using trochanteric osteotomy.

A Biochemical, Histologic, and Immunohistologic Analysis of Membranes Obtained From Failed Cemented and Cementless Total Knee Arthroplasty

Biochemical, histologic, and immunohistochemical analyses were performed on 34 interface membranes obtained from 33 patients during revision total knee arthroplasty. The membranes had surrounded components of cementless (n = 11) and cemented (n = 23) knee prostheses that were aseptically loose. None of these implant failures was caused by catastrophic polyethylene erosion leading to metal-to-metal contact. The histologic findings were similar in the membranes from cemented and cementless knee components: small polyethylene debris within macrophages and large birefringent polyethylene debris within foreign-body giant cells. Metallic debris was seen in membranes from both groups, but cemented membranes had more polymethylmethacrylate particles and more hyalinization. Intracytoplasmic asteroid bodies were observed in several foreign-body giant cells in both types of membranes. No significant differences were found between the two groups in levels of collagenase, prostaglandin E2 (PGE2), interleukin-1 (IL-1), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-alpha), nor in the population of inflammatory cells stained with IL-1, IL-6, and TNF-alpha antibodies. Membranes that had surrounded components with radiographic evidence of diffuse or localized periprosthetic bone loss released significantly more collagenase, IL-1, IL-6, and TNF than did membranes from components without bone loss. These two groups, however, did not have significantly different PGE2 levels. These findings suggest that polyethylene and metal debris may play a role in macrophage activation and the release of mediators of bone resorption in the membranes surrounding failed cemented and cementless total knee implants.

Prostaglandin E2 administered by subcutaneous pellets causes local inflammation and systemic bone loss: A model for inflammation-induced bone disease

The effects of prostaglandin E2 (PGE2) given in controlled-release pellets or by daily sc injection for 21 days on mineral homeostasis and bone histomorphometry were compared in 7-week-old female rats. Sham operation and ovariectomy were performed at the beginning of the studies. In experiment 1, 7.5 mg PGE2 or drug-free, controlled-release pellets were implanted sc at the back of the neck on day 7. In experiment 2, 3 mg/kg body weight of PGE2 or vehicle was injected sc daily beginning on day 7. The animals were sacrificed on day 28 of the two experiments, and the tibiae were removed for histomorphometric analysis of the diaphysis and metaphysis. When administered by pellets in experiment 1, PGE2 lowered serum 1,25-dihydroxyvitamin D and did not influence weight gain, serum calcium, phosphorus, or magnesium, cross-sectional or medullary areas, periosteal bone formation and apposition rates, endosteal bone formation and apposition rates, or endosteal tetracycline-labeled perimeter. PGE2 lowered cancellous bone area and cancellous bone perimeter in both the sham-operated and ovariectomized rats. In contrast, when administered by sc injection in experiment 2, PGE2 reduced weight gain, increased serum magnesium, increased cortical area, and reduced medullary area without changing cross-sectional area, increased periosteal bone formation and apposition rates and endosteal bone and apposition rates, did not alter endosteal tetracycline-labeled perimeter, and increased cancellous bone area and cancellous bone perimeter in both sham-operated and ovariectomized animals. PGE2 produced local inflammation when given by pellets, and the serum concentration of 13,14-dihydro-15-ketoprostaglandin E2, the major metabolite of PGE2, increased when PGE2 was given by sc injection but not when administered by pellets. Thus, PGE2 given sc by controlled-release pellets (1) produces local inflammation and systemic bone loss without increasing PGE2 systemically and (2) provides a model for inflammation-induced loss of cancellous bone. The results also indicate that the pellet is not a valid means for the delivery of PGE2 to the general circulation.

Focal cortical bone loss at the inferior aspect of the glenoid: A new radiographic sign of anterior shoulder instability

This report describes the detection of localized cortical bone loss at the inferior glenoid with the use of anteroposterior radiographs of the shoulder. This bone loss was noticed in two of 100 patients who had recurrent anterior instability of traumatic origin. Double-contrast arthrography and the operative findings disclosed that this lesion coincided anatomically with the scapular insertion of the detached anterior capsule. A survey of 544 radiographs from patients who had various other shoulder disorders did not detect any similar bony changes. Thus this pattern of bone loss, although small and uncommon, appears to be a new radiographic sign of damage to the anterior capsular mechanism.

Bone and the Immune System

There are several lines of evidence which provide support for an important relationship between immune cells and bone. Clinical studies of immunodeficiency syndromes have shown that abnormalities in bone shape are evident on x-rays, and peculiarities in the structure of the growth plate have been identified by histopathology. Studies of bone histology, and quantitation of cellular abnormalities, are scarce. Abnormalities in bone turnover, have, however, been identified in the nude mouse model. Many lines of evidence derived from in vitro bone studies have shown that lymphokines and monokines can influence bone formation and bone resorption. Some clinical studies of postmenopausal osteoporosis have indicated the possible presence of immune cell changes in this condition. Although several hypotheses have been formed regarding the exact mechanisms of the effect of immune cytokine on bone, this is clearly a very large area of study and there is a need for additional carefully controlled experiments with special emphasis on bone cells and bone matrix, especially in the human. As knowledge progresses regarding immunology and hematology, a clearer understanding of the lineages of the osteoblast and osteoclast will emerge and we will better understand how specialized bone cells interact with and react to their immune cell neighbors in the bone marrow and to immune system signals. These findings will have especially important implications for the local bone loss seen in rheumatoid arthritis, periodontal disease, and chronic osteomyelitis.

Ibuprofen inhibits localized bone resorption in the middle ear

Localized osteoclastic bone resorption plays a significant role in the pathogenesis of several diseases of the middle ear as well as orthodontic tooth movement and long bone remodeling. The mechanisms of control of localized bone loss and systemic bone resorption may be different but both may be mediated by a final common pathway which includes prostaglandins. Prostaglandins seem to have a predominantly stimulatory effect on bone resorption, although the exact mechanism is poorly understood. Ibuprofen, a nonsteroidal antiinflammatory drug, is known to inhibit the synthesis of prostaglandins. It is likely that ibuprofen, through its inhibition of prostaglandin synthesis, would decrease the localized osteoclastic bone resorption in a previously described animal model system. Mongolian gerbils were divided into three groups: low dose ibuprofen (10 mg/kg per day), high dose ibuprofen (30 mg/kg per day), and a control group. Following surgical implantation of catheters to the right bullae of each gerbil, pressure was applied for 8 days, stimulating osteoclastic bone resorption. After killing the animals and histomorphometric analysis of the bullae from each, comparisons were made between each group using osteoclast surface (percentage of bone area covered by osteoclasts), osteoclast number (number of osteoclasts/mm bone length), and osteoclast profile area (in microns2). Significantly lower osteoclast surface (Oc.S/BS) was found in pressurized bullae from both treatment groups when compared with pressurized bullae from controls (P less than 0.05) and significantly lower osteoclast number (N.Oc/T.L) in pressurized bullae from both treatment groups when compared with pressurized bullae from controls (P less than 0.05). These differences were found to be dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Some predictors of radiographic alveolar bone height reduction over 6 years

The present study was undertaken to 1) develop a model to predict the proportion of sites with alveolar bone height reduction over 6 years by means of a few factors, 2) build a second model to predict the initial values of the dependent variable, and 3) describe the relationship between initial bone loss and the bone loss over 6 yr with age. 142 subjects (18-67 yr) were examined radiographically at baseline and 6 yr later using a standardized method. For each subject, the proportion of sites depicting significant alveolar bone height reduction during the study was assessed. Explanatory variables were: presence of initial bone loss, local plaque retaining factors, age, sex, number of missing teeth at baseline and rheumatoid arthritis. Employing multiple regression analysis, the combined effect of initial bone loss, plaque retaining factors, age and rheumatoid arthritis provided the best model suited to predict the proportion of sites undergoing bone loss over time. However, age, plaque retaining factors and number of missing teeth were the best predictors of initial bone loss. A logistic regression model was then used to study the significance of these predictors at the site level. This model indicated that alveolar bone loss over time at a given site is related mainly to presence of local factors and initial bone loss at that site as compared to the effect of other sites with local factors and initial bone loss in the subject. Age demonstrated a linear relationship with initial bone loss and a curvilinear relationship to periodontal disease progression.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification by Dual Photonabsorptiometry of Local Bone Loss After Fracture

Total bone mineral and bone mineral density modifications were evaluated during fracture healing of long bones in patients with traumatic fractures of the lower limbs, using an experimental model based on the dual photonabsorptiometry technique. Seven patients (five males and two females; mean age, 19.5 years; range, 17-23 years) with tibia and fibula midshaft open fractures treated with osteosynthesis were studied. Dual energy gadolinium-153 photonabsorptiometry was used to measure distal leg bone loss at a skeletal segment distant from the fracture to exclude callus formation. Total bone mineral (TBM) and bone mineral density (BMD) of the tibia and fibula both in the fractured leg and in the healthy contralateral leg were measured on Days 10, 20, 30, 40, 60, and 120 after trauma. TBM and BMD of the healthy contralateral leg did not present any significant modifications at the different observation times. Both TBM and BMD of the fractured leg showed a progressive reduction that reached statistical significance starting on Day 30 with maximum reduction on Day 120 when TBM and BMD were reduced to almost one-half the initial value.

A retrospective radiographic study of alveolar bone loss in the primary dentition in patients with localized juvenile periodontitis.

Lately, it has been questioned whether localized juvenile periodontitis (LJP) is restricted to the permanent dentition, or if it sometimes might have a prepubertal onset, involving the primary dentition. To clarify this question, 17 patients with LJP, together with 17 non-LJP matched controls, were retrospectively examined for radiographic signs of alveolar bone destruction in their primary dentitions. All LJP subjects but one showed localized marginal bone loss, whereas no bone loss was observed among the controls. The results suggest that at least some cases of LJP start in the primary dentition prior to the involvement of the permanent teeth.

Alveolar bone loss and crowding in adult periodontal patients

The present study aimed to examine whether local crowding and tooth angulation in the mandibular incisor region led to alveolar bone loss in patients with moderate periodontal disease. The sample comprised 27 patients from the Department of Periodontology aged 29-57 yr. Mesiodistal tooth angulation and crowding, defined as an overlap of 2 mm or more, were assessed from dental casts. Alveolar bone loss was assessed from intraoral standardized paralleling radiographs by two methods, the absolute bone level (ABL), recorded from the cementoenamel junction, and the relative bone level (RBL), a new measure, expressing the bone level relative to the two adjacent interradicular crests. Contralateral sites were used as controls. A significant difference in bone level was found between crowded and non-crowded sites by both methods (-1.7 mm, P less than 0.001). This indicates that in periodontal patients local crowding and tooth angulation predisposes to increased bone loss. Analysis of the correlations between tooth angulations and the two measures of bone loss indicated that the RBL value is a more sensitive measure of localized bone loss.