Bone Resorption, the second volume in the series Topics in Bone Biology, " Volume 2 in the series Bone Biology and written by US experts, it reviews in 9.
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In summary, these data extended to humans the notion that osteocalcin is a new determinant in the regulation of testosterone biosynthesis. The correlation between the testosterone peak and osteocalcin level in adolescence in men suggests that osteocalcin may be most relevant during rapid skeletal growth in pubertal men [26].
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In other words this correlative data in humans suggest that the bone—testis axis may act as a novel determinant of the skeletal sexual dimorphism at puberty. Interestingly, the role of the bone—testis axis in the regulation of testosterone biosynthesis could be also associated to the age-related bone loss. In fact, it is well known that the decrease of circulating testosterone levels in men is always associated with an increase of estrogen and luteinizing hormone LH , which cannot increase testosterone production [33].
There are also associated increases in body fat mass and decrease in sperm counts and sexual function []. This observation would suggest that osteocalcin could be an anti-aging hormone. Clearly, however, this notion needs to be tested in mice and humans and especially to assess the possible interactions between LH and osteocalcin in the control of testosterone biosynthesis by testes. The relevance of MEN2 to bone biology will be discussed in three sections: Importantly, RET itself does not appear to be expressed in bone and RET mutations are not obviously associated with any skeletal phenotype.
RET expression is limited to neuroendocrine cells and tumors derived from them. Tumors caused by RET mutations are typically derived from the neural crest during development. Skeletal abnormalities have not been reported in transgenic mouse models with RET mutations. Targeted murine deletion of RET is lethal in the neonatal period. These mice have breathing defects, renal agenesis and absent neurons in the bowel distal to the stomach. There are no known effects of RET knockout in bone biology.
Folkens, in The Human Bone Manual , In Chapter 4, on bone biology , we introduced the concept of variation and its importance to work in human osteology. We described this variation as stemming from four main sources: Many facets of human osteological variation are illustrated by the descriptions of the various skeletal elements in Chapters 7—16 , and by the analysis of age, sex, ancestry, and stature presented in Chapter This chapter continues to consider variation, concentrating on variation due to pathology.
Nonmetric, nonpathological variations discrete traits are essential in reconstructing various biological dimensions of former human populations. These are reviewed in Chapter Evans, in Translational Endocrinology of Bone , One of the major challenges in bone biology is to understand the interplay of various tissues that can regulate bone physiology.
The growing emergence of a vast repertory of tissue-specific gene expression profiling has begun to open a door regarding the molecules and pathways that mediate and control this vast network. Concurrently, beyond the individual factor, what is more relevant is understanding how networks between various target tissues become coordinately regulated to produce whole-body physiology and metabolism.
Recent advances in the understanding of bone biology provide the basis for a new therapeutic approach to hypercalcemia, based on the inhibition of the RANK system through a mechanism that is distinct from that of bisphosphonates. Denosumab is a fully human monoclonal antibody that binds to RANKL and thus inhibits osteoclast maturation, activation, and function. Denosumab has also been shown to suppress bone resorption in patients whose biochemical resorption markers persisted elevated despite previous intravenous bisphosphonate treatment. The role of denosumab in the treatment of malignancy-associated hypercalcemia is currently under investigation, but case reports have indicated its efficacy in patients with metastatic renal carcinoma to the lungs and in bisphosphonate-refractory hypercalcemia, as well as with multiple myeloma and renal failure and with metastatic parathyroid carcinoma.
Concerning the latter indication in patients with renal failure, it is worth mentioning that this human monoclonal antibody, which is metabolized by peptidases and cleared by the reticuloendothelial system, seems to have no nephrotoxic effects. An important role of NO in bone biology is supported by multiple studies in rodents: Second , NO-generating nitrates prevent bone loss from estrogen deficiency in rats Hukkanen et al.
Third , low concentrations of NO donors can enhance osteoblast proliferation and differentiation in vitro Chae et al. Fourth , low NO concentrations are necessary for osteoclast differentiation and survival, and NOS1-deficient mice have increased bone mass due to reduced osteoclast number and decreased bone resorption Chae et al.
One of its main cellular targets is the enzyme-soluble guanylate cyclase, which is activated by NO binding to the enzyme's heme prosthetic groups Fig. PKG I and II differ in their tissue distribution, but both genes are expressed in osteoblasts and osteocytes Hofmann et al. We also showed that stimulation of osteoblasts and osteocytes by fluid shear stress increases NO and cGMP levels, activating PKG II, which leads to Src and Erk activation, induction of fos family genes, and increased osteoblastic proliferation Rangaswami et al.
Many Wnts have been shown to impact bone biology. Early experiments in chickens and in mice have demonstrated that ligands such as Wnt2b, Wnt3a, Wnt4, Wnt5a, Wnt8c, and Wnt7a are expressed early during limb development and are crucial for proper limb outgrowth and patterning along the proximal-distal and dorso-ventral axes [—]. Studies in mice have shown that several Wnt proteins are required for chondrocyte and osteoblast differentiation during limb development as well as for bone homeostasis.
Estrogens clearly play a critical role in bone biology. The increase in research aimed at elucidating the functional role of estrogens in bone remodeling that has occurred in the past 25 years has led to the discovery of a multitude of potential pathways that are impacted by estrogens in the skeleton.
Parathyroid hormone PTH , secreted by the parathyroid gland, is known to regulate calcium homeostasis by increasing the release of calcium from bone and the resorption of calcium by the kidneys. It has been shown to stimulate pre-existing osteoclasts, increase the number of osteoclasts with active ruffled borders, and expand the ruffled borders within individual osteoclasts. The changes seen in the numbers of osteoclasts and their level of activity parallel the increase seen in extracellular calcium.
The active form of vitamin D, 1,dihydroxyvitamin D 3 , although it has several actions, is primarily related to bone metabolism and mineral homeostasis. Both inhibition and induction of osteoblastic activity have been demonstrated at the cellular level, depending on whether the vitamin D is applied during the proliferative or differentiation stages of development. Serum calcium and phosphorus levels are insufficient to support mineralization, but dietary supplementation of vitamin D will generally correct the imbalance. Calcitonin, a polypeptide hormone synthesized by the thyroid gland, has a significant inhibitory effect on osteoclasts, thereby lowering the levels of serum calcium.
The osteoclast appears to be a main target of calcitonin even at low levels of concentration. Within 30 minutes of administration of therapeutic, pharmacological doses of calcitonin, a complete inhibition of osteoclastic bone resorption occurs, accompanied by the loss of ruffled borders, loss of cytoplasm along the ruffled border, and a physical dislocation from the underlying bone. However, concerns over the calcitonin-induced loss of calcitonin receptors, which results in a hormone induced resistance, has led to concerns about its long-term use in disease treatment or prevention.
Other hormones that influence bone cell function include glucocorticoids, thyroid hormone, and estrogens. Prolonged use of glucocorticoids can result in osteopenia.
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Osteopenia, moreover, also can result from the thyroid hormones thyroxine and tri-iodothyronine, both of which act to stimulate osteoclastic resorption of bone. Estrogens have several, complex effects on bone cell function including effects on calcitonin, PTH, and vitamin D. Estrogens overall appear to decrease the rate of bone turnover, specifically by influencing osteoclastic activity.
Estrogen deprivation results in an increase in bone remodeling sites with a possible long-term result of osteoporosis. Unlike hormones that regulate bone development through systemic mechanisms, local factors eg, cytokines, growth factors, prostaglandins influence development by cell-to-cell and cell-to-extracellular matrix interactions. Cytokines and growth factors are soluble molecules that act at a local level, mediating cell-to-cell interactions within bone.
Their regulatory function begins with growth and development and continues in the mature skeleton through the remodeling process. Prostaglandins are a diverse group of unsaturated fatty acids that are thought to be able to regulate a variety of processes, including inflammation, blood flow, and ion transport across membranes. Initially, they appear to have an inhibitory effect on osteoclasts, but subsequently have a stimulatory effect on bone resorption by increasing formation and proliferation of osteoclasts. Prostaglandin E has been a factor associated with the bone loss seen in disease processes such as rheumatoid arthritis, periodontal disease, and possibly neoplasms.
Because bone is a living, dynamic connective tissue, it provides mechanical support related to protection and locomotion, and it functions as a system of complex metabolic mineral homeostasis. In contrast to other nonbiologic materials, bone demonstrates the mechanical properties of anistrophy, nonlinearity, and viscoelasticity.
These properties, along with its ability to respond to changes in its physiological and mechanical environment, make it more difficult to establish universal constants related to the physical properties of bone. Based on biomechanical principles, bone responds to forces in nature, including gravity, ground reaction, and muscle contraction. When a force or a load is applied to bone, an internal resistance develops ie, stress. Stress is the force per unit area and is equal in magnitude but opposite in direction to the applied load. Stress can be categorized as 1 tensile , occurring when 2 forces act along a straight line in opposite directions; 2 compressive , occurring when 2 forces act along a straight line in the same direction; or 3 shear , occurring when 2 forces are acting parallel to each other but not in the same line.
Most forces applied to bone are a combination of the 3 stresses, resulting in a bending or torsion. The resulting deformation of the applied force is known as strain , which is equal to the change in length divided by the original length.
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At low levels of stress, a linear relationship exists between stress and strain. This relationship or modulus relates to the overall stiffness or rigidity of bone. The linear portion of the stress-strain curve is known as the elastic region , where removal of the load results in no permanent strain or deformation. The point at which the curve becomes nonlinear, the plastic region , a permanent deformation occurs even after the load is removed. This occurs at the elastic limit or yield point. Stressing a bone beyond the plastic region will result in failure, such as a fracture. The ultimate strength of a bone is determined by calculating the maximum stress at the point of failure Fig.
Nonbiological materials often demonstrate the property of isotrophy, which means that, regardless of the direction of stress, the mechanical properties of the material will respond in the same manner. Bone, like many other biological tissues, demonstrates the property of anisotropy; it responds differently depending on the type of load applied. Cortical bone has been shown to resist compressive forces better than tensile forces. Compared with cortical bone, cancellous bone has a lower modulus of elasticity due to its greater porosity.
Cancellous bone demonstrates the greatest strength when a compressive force is applied parallel to the trabecular system, such as a vertical force to a vertebral bone. Therefore, the strength and rigidity of bone are greatest in the direction of normal loading. Bone also demonstrates the property of viscoelasticity, which indicates that materials will demonstrate different properties according to the rate of force application.
At low rates of loading, bone demonstrates a lower modulus of elasticity, and behaves like a viscous material. At higher rates of loading, bone behaves as a brittle material.
Mechanical loads applied to bone are thought to be communicated through the bone by way of a mechanical signal detected by either bone lining cells or osteocytes, or both. It is believed that these mechanical signals lead to the generation of chemical signals involved in the regulation of bone formation and remodeling. The osteocytes, in particular, have received much attention in this regard. Osteocytes are connected to each other and to osteoblasts by way of cellular processes within canaliculi and are linked by gap junctions.
This network allows for the possibility of electrical coupling as well as intracellular and extracellular molecular transport in cells deep within bone tissue. The law indicates that there is a correlation between the direction of the principal stresses during normal function and the resulting pattern of trabecular alignment. The realization of this principle is seen in the femur, where the trabecular orientation corresponds to the directions of stress. Sperber 14 stated that the basic shape and size of bone have a genetic determination. Once the morphology is established, relatively minor environmental features, such as bony tuberosities, develop.
Nutritional, hormonal, and functional influences affect bone, and because osseous tissue is continually replaced throughout life, it will morphologically respond to mechanical stress. Sperber described 3 classifications of morphological features based on the influence of muscle. These features include those that develop only when muscle is present temporal and nuchal lines , those that develop but require the presence of muscle to persist angle of the mandible , and those that are associated with muscle but are mostly independent of its influence body of the mandible and zygomatic bone.
The precise mechanisms by which mechanical forces influence bone structure and development are not known. The mediation of mechanical stress through piezoelectric currents has been postulated as having an influence in this area. Bone is made up of crystalline matrix, which enables it to generate small electrical currents in response to mechanical deformation. Therefore, it is hypothesized that the cellular makeup of bone may react to the electrical fields by laying down new bone. Since that time, bone stimulators have demonstrated efficacy in augmenting open reduction surgeries either with internal or external fixation and bone grafts and in helping to treat infected nonunions and failed arthodeses.
Although the exact mechanism of electrical stimulation that induces bone healing is not clear, electromagnetic fields have been found to stimulate the production of transforming growth factor and bone morphogentic proteins, both of which are involved in osteogenesis. A second theory related to the influence of biomechanical forces on bone tissue is based on the mechanochemical hypothesis, whereby the loads applied to bone are translated into cellular activity through straining of apatite crystals, altering the solubility of apatite, and changing local calcium concentrations.
Bone Biology
This process either stimulates or resorbs bone. One of the most interesting applied areas of bone biology for physical therapists is that of osteoporosis. Osteoporosis is a relatively common clinical disorder in which the process of bone resorption is increased. It disproportionately affects women more than men and is estimated to affect 1 in 3 women beyond the age of 50 years.
It has been projected that approximately 9. Osteoporosis is a condition of microarchitectural loss of bone tissue leading to decreased density and bone fragility Fig. The primary reasons for developing this condition include poor bone acquisition during youth and accelerated bone loss during aging. Both of these processes are regulated by environmental and genetic controls. Loss of bone mass can be due to a combination of hormone deficiency, poor nutrition, decreased physical activity, and various pharmacological agents.
Changes may occur in the production of local factors that mediate the response to mechanical stress. The loss of functional loading in the elderly and its ultimate role in the pathogenesis of osteoporosis also is not fully resolved at this time. Plain film demonstrating decreased bone density and increased radiolucency of the vertebrae with accentuation of the cortical rim. The structure and development of bone. Principles of Bone Biology. Osteoporosis can be categorized as being either primary or secondary.
Primary osteoporosis is the deterioration of bone mass associated with either a decrease in sex hormone, aging, or both. In women, early menopause or premenopausal estrogen deficiencies can accelerate the development of primary osteoporosis Fig. Secondary osteoporosis can occur due to chronic conditions that contribute to the acceleration of bone loss, including excess endogenous and exogenous thyroxin, malignancies, gastrointestinal diseases, hyperparathyroidism, connective tissue diseases, renal failure, and medications.
Other contributing factors include prolonged periods of inactivity or immobilization, inadequate calcium intake, and alcohol and tobacco abuse. Two 3-dimensional images from computed tomographic reconstruction of paired iliac crest bone biopsy samples from one woman. Top The woman was premenopausal and 53 years of age. Bottom She was postmenopausal and 58 years of age. Risk factors for developing osteoporosis include genetic, nutritional, and behavioral. Genetic factors include female sex, a petite skeletal frame, and Caucasian or Asian ancestry.
Low calcium or vitamin D intake, alcohol abuse, and high caffeine intake are nutritional factors, and sedentary lifestyle, nulliparity, aging, smoking, and low body weight are some of the behavioral risk factors. The most common cause of osteoporosis is the decrease in the female sex hormone, estrogen, which occurs following menopause. An increase in bone resorption, which is associated with a rise in the number of osteoclasts, is correlated with the loss of estrogen.
This increase in osteoclasts is caused by an increase in the cytokines that regulate the production of osteoclasts. It is believed that estrogen, either directly or indirectly, regulates the production of these cytokines. The goal of osteoporosis therapies is to inhibit bone resorption. This is achieved by reducing osteoclastic production or activity. Common pharmaceutical therapies that physical therapists may see their patients take include estrogens and selective estrogen receptor modulators SERMs , bisphosphonates BPs , and calcitonin.
Hormone replacement therapy HRT has been shown to inhibit bone loss and bone turnover and actually increase bone mineral density BMD. The molecular mechanism of action of estrogen on bone is poorly understood. Estrogen receptors have been identified, but their contribution to the total effect of this therapy is still being investigated. The SERMs exert estrogen-agonist effects on selective tissues.
The mechanism exerted to inhibit bone resorption appears to be similar to that of estrogen—the blockage of cytokine production and, therefore, osteoclast differentiation. Calcitonin is a polypeptide hormone that also inhibits resorption by blocking osteoclastic activity. A negative side effect, the loss of calcitonin receptors, results in an overall hormone-induced resistance that has led many medical providers to choose other interventions.
For physical therapists, understanding the role of exercise, whether it is weight-bearing exercise or exercise that focuses on improving the force-generating capacity of muscle, is vital in the prevention and treatment of osteoporosis. As mentioned previously, mechanical loads applied to bones create strain and the larger the load, the greater the strain. This strain is transmitted to the bone cells osteoblasts, bone lining cells, and osteocytes , which are well suited to sense load changes due to their physical connections.
Bone research has demonstrated that, in response to mechanical strain, there is an increase in cell metabolism and collagen synthesis.
Within 5 days of a single loading session, bone lining cells transformed into active osteoblasts. Four-point bending studies of bone also have demonstrated increased cell metabolism and proliferation in the tibial periosteum of rats. Research related to the role of exercise in the treatment or prevention of osteoporosis has significantly improved our understanding of this phenomenon. Chow et al 40 compared an aerobic exercise group, an aerobic and strengthening exercise group, and a control group in a year-long, randomized controlled trial of 48 postmenopausal women between the ages of 50 and 62 years.
The authors demonstrated a significant difference in total bone mass of the exercising groups compared with the control group, but no difference was found between the 2 different exercise groups. In a study of postmenopausal women between 50 and 70 years of age, Bravo et al 41 compared a group that received a combination of aerobic dancing, weight-bearing walking and stepping, and flexibility exercise with a control group.
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The authors demonstrated a significant decrease in spinal BMD in the control group and a stabilization of spinal BMD in the exercising group after 1 year. There was no change in femoral BMD, however, in either group.
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In contrast to the findings of Bravo et al, 41 Prince et al 42 looked at the effect of weight-bearing exercise on 6 different sites: The experimental group, undergoing weight-bearing exercise with calcium supplementation, demonstrated a cessation of bone loss at the intertrochanteric hip site but at no other site including lumbar spine.
The exercise program in this study included 2 hours of supervised exercise class and 2 hours of independent walking per week. Similarly, Lau et al 43 demonstrated a significant effect on BMD at the femoral neck but not other areas of the femur or the lumbar spine when comparing a combination of load-bearing exercise and calcium supplementation. Nelson et al 44 noted differential effects on various skeletal sites when comparing a group receiving a 1-year walking program plus calcium supplementation with a sedentary group receiving calcium supplementation. Bone modeling occurs during birth to adulthood and is responsible for gain in skeletal mass and changes in skeletal form.
Remodeling is the replacement of old tissue by new bone tissue. This mainly occurs in the adult skeleton to maintain bone mass. This process involves the coupling of bone formation and bone resorption and consists of five phases:. The major functions of bones are to: Provide structural support for the body Provide protection of vital organs Provide an environment for marrow where blood cells are produced Act as a storage area for minerals such as calcium Bones are composed of two types of tissue: Bone is also composed of: These cells are derived from mesenchymal stem cells and are responsible for bone matrix synthesis and its subsequent mineralization.
In the adult skeleton, the majority of bone surfaces that are not undergoing formation or resorption i. These cells are osteoblasts that become incorporated within the newly formed osteoid, which eventually becomes calcified bone. Osteocytes situated deep in bone matrix maintain contact with newly incorporated osteocytes in osteoid, and with osteoblasts and bone lining cells on the bone surfaces, through an extensive network of cell processes canaliculi. They are thought to be ideally situated to respond to changes in physical forces upon bone and to transduce messages to cells on the bone surface, directing them to initiate resorption or formation responses.
These cells are large multinucleated cells, like macrophages, derived from the hematopoietic lineage. Osteoclasts function in the resorption of mineralized tissue and are found attached to the bone surface at sites of active bone resorption. Their characteristic feature is a ruffled edge where active resorption takes place with the secretion of bone-resorbing enzymes, which digest bone matrix.
Types of bone Two types of bone can be identified according to the pattern of collagen forming the osteoid: