Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4-8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

Sex steroids and the construction and conservation of the adult skeleton.

The appearance of cancellous bone architecture is different for various skeletal sites and various disease states. During aging and disease, plates are perforated and connecting rods are dissolved. There is a continuous shift from one structural type to the other. So traditional histomorphometric procedures, which are based on a fixed model type, will lead to questionable results. The introduction of three-dimensional (3D) measuring techniques in bone research makes it possible to capture the actual architecture of cancellous bone without assumptions of the structure type. This requires, however, new methods that make direct use of the 3D information. Within the framework of a BIOMED I project of the European Union, we analyzed a total of 260 human bone biopsies taken from five different skeletal sites (femoral head, vertebral bodies L2 and L4, iliac crest, and calcaneus) from 52 donors. The samples were measured three-dimensionally with a microcomputed tomography scanner and subsequently evaluated with both traditional indirect histomorphometric methods and newly developed direct ones. The results show significant differences between the methods and in their relation to the bone volume fraction. Based on the direct 3D analysis of human bone biopsies, it appears that samples with a lower bone mass are primarily characterized by a smaller plate-to-rod ratio, and to a lesser extent by thinner trabecular elements.

Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest, and calcaneus.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199808%2941%3A8%3C1343%3A%3AAID-ART3%3E3.0.CO%3B2-9

An update on the epidemiology of knee and hip osteoarthritis with a view to prevention

Development of an optimal interface between bone and orthopaedic and dental implants has taken place for many years. In order to determine whether a newly developed implant material conforms to the requirements of biocompatibility, mechanical stability and safety, it must undergo rigorous testing both in vitro and in vivo. Results from in vitro studies can be difficult to extrapolate to the in vivo situation. For this reason the use of animal models is often an essential step in the testing of orthopaedic and dental implants prior to clinical use in humans. This review discusses some of the more commonly available and frequently used animal models such as the dog, sheep, goat, pig and rabbit models for the evaluation of bone-implant interactions. Factors for consideration when choosing an animal model and implant design are discussed. Various bone specific features are discussed including the usage of the species, bone macrostructure and microstructure and bone composition and remodelling, with emphasis being placed on the similarity between the animal model and the human clinical situation. While the rabbit was the most commonly used of the species discussed in this review, it is clear that this species showed the least similarities to human bone. There were only minor differences in bone composition between the various species and humans. The pig demonstrated a good likeness with human bone however difficulties may be encountered in relation to their size and ease of handling. In this respect the dog and sheep/goat show more promise as animal models for the testing of bone implant materials. While no species fulfils all of the requirements of an ideal model, an understanding of the differences in bone architecture and remodelling between the species is likely to assist in the selection of a suitable species for a defined research question.

/pdf/animal-models-for-implant-biomaterial-research-in-bone-a-3lela1vj4n.pdf

Animal models for implant biomaterial research in bone: a review.

Objective
To explore the role that implanted mesenchymal stem cells may play in tissue repair or regeneration of the injured joint, by delivery of an autologous preparation of stem cells to caprine knee joints following induction of osteoarthritis (OA).

Methods
Adult stem cells were isolated from caprine bone marrow, expanded in culture, and transduced to express green fluorescent protein. OA was induced unilaterally in the knee joint of donor animals by complete excision of the medial meniscus and resection of the anterior cruciate ligament. After 6 weeks, a single dose of 10 million autologous cells suspended in a dilute solution of sodium hyaluronan was delivered to the injured knee by direct intraarticular injection. Control animals received sodium hyaluronan alone.

Results
In cell-treated joints, there was evidence of marked regeneration of the medial meniscus, and implanted cells were detected in the newly formed tissue. Degeneration of the articular cartilage, osteophytic remodeling, and subchondral sclerosis were reduced in cell-treated joints compared with joints treated with vehicle alone without cells. There was no evidence of repair of the ligament in any of the joints.

Conclusion
Local delivery of adult mesenchymal stem cells to injured joints stimulates regeneration of meniscal tissue and retards the progressive destruction normally seen in this model of OA.

/pdf/stem-cell-therapy-in-a-caprine-model-of-osteoarthritis-4vknyg1oop.pdf

Stem cell therapy in a caprine model of osteoarthritis

This study compares bone composition, density, and quality in bone samples derived from seven vertebrates that are commonly used in bone research: human, dog, pig, cow, sheep, chicken, and rat. Cortical femoral bone samples were analyzed for their content of ash, collagen, extractable proteins, and insulin-like growth factor-I. These parameters were also measured in bone powder fractions that were obtained after separation of bone particles according to their density. Large interspecies differences were observed in all analyses. Of all species included in the biochemical analyses, rat bone was most different, whereas canine bone best resembled human bone. In addition, bone density and mechanical testing analyses were performed on cylindrical trabecular bone cores. Both analyses demonstrated large interspecies variations. The lowest bone density and fracture stress values were found in the human samples; porcine and canine bone best resembled these samples. The relative contribution of bone density to bone mechanical competence was largely species-dependent. Together, the data reported here suggest that interspecies differences are likely to be found in other clinical and experimental bone parameters and should therefore be considered when choosing an appropriate animal model for bone research.

/pdf/interspecies-differences-in-bone-composition-density-and-4nio7bytv3.pdf

Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research

This study investigates the biochemical changes in a canine tibia lengthening model in comparison with a nonlengthened osteotomy model. The lengthened and the osteotomized callus and a contralateral corresponding segment were analyzed for their mineralization profile, collagen content, osteocalcin, insulin-like growth factor I (IGF-I), and transforming growth factor β1 (TGF-β1). Examinations of bone samples were performed using specimens excised at different time intervals (respectively at 3, 5, 7, 9, and 13 weeks postoperatively). Several serum parameters (alkaline phosphatase [ALP], osteocalcin, IGF-I, and TGF-β1) were also measured during the experimental period. A progressive increase in mineral parameters was noticed in both the lengthened and the osteotomized areas. A higher level of hydroxyproline and TGF-β1 was observed in the lengthened area compared with the osteotomized area. IGF-I showed a significant increase in both the lengthened and contralateral control area at the later stage of the experimental period in the lengthened group. In serum, a high level of TGF-β1 and a progressively increasing osteocalcin concentration were observed in the lengthened dogs in comparison with the osteotomized dogs. Serum ALP was significantly increased in both models during the experimental period. Serum IGF-I was increased in the lengthened models during the distraction period and decreased in the osteotomized models at the early stage of the experimental period. These results suggest that the mechanical strain induced by the Ilizarov distraction procedure stimulates osteoblast proliferation and promotes biosynthesis of bone extracellular matrix in distracted callus. Our data furthermore show that this process is different compared with normal fracture healing.

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1359/jbmr.1998.13.2.279

Distraction Bone Healing Versus Osteotomy Healing: A Comparative Biochemical Analysis

Both a decrease in bone formation and an increase in bone resorption have been implicated in the pathogenesis of age-related (type II) femoral neck osteoporosis. While the increase in the bone resorption rate has been shown to be partially related to secondary hyperparathyroidism, the mechanisms underlying the decline in bone formation have not yet been identified. The aim of the present study was to test the hypothesis that the bone formation deficit associated with type II osteoporosis might be due to secondary hyperparathyroidism and/or to a deficiency of the insulin-like growth factor (IGF) system. Circulating concentrations of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, 25-hydroxycholecalciferol (25(OH)D3), and intact parathyroid hormone (PTH) were measured in 50 elderly women after sustaining a hip fracture and in 50 healthy age-matched controls. In addition, serum levels of osteocalcin (OC), skeletal alkaline phosphatase, and N-terminal procollagen peptide and urinary pyridinium cross-links were determined as markers of bone remodeling, and bone mineral density (BMD) was assessed at the proximal femur. In the patient group, serum was drawn within 18 h of the fracture and prior to surgery. Circulating protein concentrations did not change over this time frame. No difference was found between mean IGFBP-4 serum levels in the two groups studied, while mean levels of IGF-I, IGF-II, IGFBP-3, IGFBP-5, 25(OH)D3, and markers of bone formation were significantly lower (p < 0.006) in patients as compared with healthy subjects. Serum PTH and urinary pyridinium cross-links, however, were markedly increased (p < 0.001) in the osteoporotic group. In pooled data from the normal and osteoporotic populations, age-adjusted multiple regression models based on IGF-I, IGF-II, IGFBP-3, and IGFBP-5 were found to be highly predictive of serum OC (R2 = 19%, p < 0.001) and BMD of femoral neck (R2 = 49%, p < 0.0001), consistent with an effect of the anabolic IGF components on overall bone formation rate. Similar models based on 25(OH)D3 and PTH, however, were statistically unrelated to OC. To address further the potential impact of trauma on circulating IGF system components, we measured IGF system component levels in 10 male patients within 18 h following tibial fracture and in 10 age-matched normal male subjects. There was no significant difference in serum level of any of the IGF system components between the two groups. Although limited by its cross-sectional design, the present study suggests that, in addition to bone resorption resulting from secondary hyperparathyroidism, impaired bone formation associated with deficiency of the IGF system might predispose elderly women to fragility fracture of the proximal femur.

Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis.

/pdf/inverse-relationship-osteoarthritis-osteoporosis-what-is-the-2hnsph6kz3.pdf

Inverse relationship osteoarthritis-osteoporosis: what is the evidence? What are the consequences?

The epidemiologic patterns of vertebral and femoral fractures are sufficiently different to suggest that they represent distinct disorders (type I versus type II osteoporosis) although osteopenia is common in both. To determine whether differences in femoral geometry, one of the main determinants of bone quality, might contribute to the heterogeneity in osteoporotic fractures, we obtained dual energy X-ray absorptiometry scans on 210 women age 60 or older, including 105 type I fracture cases, 30 type II patients, and 75 controls. Hip axis length, measured on the scan printout, was significantly increased (p < 0.01) in hip fracture patients compared with women with postmenopausal osteoporosis, whereas femoral neck density (BMD) was equal in both groups. The best discrimination between both fracture types was obtained by a logistic regression model based on age and axis length. Adding BMD to the model did not improve the discriminative power (p = 0.67). These data provide further evidence that geometric characteristics may be implicated in hip fracture risk. Furthermore, these findings suggest that an increase in hip axis length may predispose osteopenic subjects to a femoral localization of fragility fractures, consistent with the postulated heterogeneity in the pathogenesis of osteoporotic fractures.

Measurement of femoral geometry in type I and type II osteoporosis: Differences in hip axis length consistent with heterogeneity in the pathogenesis of osteoporotic fractures

J. Aerssens

Papers

Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research

Distraction Bone Healing Versus Osteotomy Healing: A Comparative Biochemical Analysis

Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis.

Inverse relationship osteoarthritis-osteoporosis: what is the evidence? What are the consequences?

Measurement of femoral geometry in type I and type II osteoporosis: Differences in hip axis length consistent with heterogeneity in the pathogenesis of osteoporotic fractures