Bone Physiology and Osteoporosis

Function

The primary function of bone is mechanical, providing form to the skeleton along with musculotendinous attachments and articulations to facilitate movement and protect vital organs. In addition, bone has a much more complex function in providing critical metabolism and storing elemental calcium and phosphate that can be accessed and used as needed.

Structure

The physical structure of bone varies depending on the type of bone and location. Cortical bone, composed of lamellar bone, provides the majority of mechanical strength to appendicular bones. The primary structural component of lamellar bone is osteons. The arrangement and orientation of the osteons vary depending on the needs and function of that particular bone. These arrangements can vary within the bones of a single animal and across different animals depending on their specific needs, uses, or functions. Encased within the cortical bone lies the trabecular, or cancellous, bone. This is arranged in trabeculae comprised of vertical rods and horizontal plates that are interconnected to one another. The amount and integrity of the connectivity of the rods and plates comprising the trabeculae contribute to the overall mechanical strength, especially in the spinal column. This is often referred to as microarchitecture. Cancellous bone is more porous than cortical bone, and therefore lighter, but consequently has a greater surface area. In bones where hematopoiesis occurs, this happens within the trabecular regions. Both cortical and cancellous bone undergo turnover; however, the turnover of cancellous bone is faster than that of cortical bone, and it therefore can respond much more rapidly to changes in mechanical, metabolic, or molecular stimuli than cortical bone.

Physiology

Bone is dynamic, continuously adapting to mechanical and chemical influences by remodeling, which occurs via tightly regulated coordination of resorption and formation. Resorption is mediated by osteoclasts to create lacunae in trabecular bone or cutting cones in cortical bone to remove the unwanted bone. Formation then follows the resorption, with osteoblasts laying down new bone. A remodeling cycle takes about 200 days in cancellous bone and 120 days in cortical bone.

Bone healing occurs via the two mechanisms that initiate bone formation during growth: endochondral and intramembranous bone formation. ^, With endochondral bone formation a hematoma forms at the fracture site, and a brisk inflammatory reaction develops. Inflammatory cytokines induce neovascularization and proliferation of mesenchymal stem cells. Because of the central hypoxia of the hematoma, chondrocyte proliferation occurs, with formation of uncalcified cartilage. The uncalcified cartilage then undergoes calcification. Vascular tissue invasion then leads to osteoclastic resorption of the calcified cartilage. Following the osteoclasts are osteoblasts that create bridging unwoven bone. Over time the woven bone is remodeled by the same process of osteoclastic resorption–osteoblastic formation to near-normal anatomy and strength. Intramembranous bone formation proceeds without cartilage and occurs by layering of appositional bone along surfaces at the fracture site, creating a hard callous. A third form of healing after fracture is primary bone healing. This mechanism, which involves rigid internal fixation, only applies to cortical bone. Cutting cones headed by osteoclasts create a pathway or tunnel from both ends of the bone. Behind the osteoclasts are osteoblasts that produce new bone, bridging the fracture site.

Metabolic bone diseases such as osteoporosis and the use of antiosteoporotic medications affect these bone-healing processes. Osteoporosis is associated with senescent mesenchymal stem cells, so that during healing fewer are available to differentiate into osteoclasts and osteoblasts. Further, they have a diminished sensitivity or inclination to differentiate into these cell lineages. Finally, during stress they undergo apoptosis. Thus, osteoporotic patients are likely to have impairment of bone healing.

Antiresorptive medications, such as bisphosphonates and denosumab, also affect bone healing. Because these drugs affect osteoclastic resorption they delay the remodeling of the calcified cartilage into woven bone. Fortunately, this does not appear to alter the time to union or mechanical strength at any timepoint. The slower remodeling is compensated for by a larger callous in patients on antiresorptive medications. Animal and human investigations show either no effect or even a positive effect of antiresorptive medications on fracture healing and spinal fusion. ^, Anabolic antiosteoporotic medications, such as parathyroid hormone (PTH) analogs or antisclerostin agents, increase the proliferation of the osteoblast lineage and therefore theoretically improve healing. ^, Clinically, anabolic agents have been shown to increase the rate of bone healing in a variety of clinical situations. In some cases, recalcitrant nonunions have had healing success with anabolic drugs, but this has not been systematically studied.

Osteoporosis

In the presence of disruptions of bone density, mass, quality, or strength, various pathological conditions can exist. Osteoporosis is characterized by increased fragility and fracture risk that can result in fragility fractures, which are defined as fractures occurring with minimal trauma or forces that typically would not result in fracture. Although often considered synonymous with low bone mineral density (BMD), osteoporosis is also associated with disruption of mineralization and the microarchitecture. With the loss of both plates and/or rods and the trabeculae they constitute, the state is worse than simply decreased mineralization. Additionally, if there are disruptions of the protein quality and organization within the microarchitecture of the bone, osteoporosis can result.

Osteomalacia

Osteomalacia, or “soft bone,” occurs from low mineralization secondary to faulty bone metabolism. Vitamin D deficiency is the most common primary underlying problem, with a variety of causes such as a nutritional deficiency of vitamin D and/or phosphate, malabsorption disorders including celiac disease, kidney disease including acidosis, tumors, drugs such as chronic use of antiepileptic drugs, and genetic diseases such as hypophosphatemic rickets. The main treatment for osteomalacia is vitamin D supplementation.

Osteopetrosis

Conversely, osteopetrosis, or “stone bone,” is a genetic disease characterized by a disruption of bone metabolism because of insufficient osteoclastic activity. This can be caused by insufficient numbers of cells or dysfunctional cells, depending on the genotype. Ultimately, bone formation outpaces bone resorption. Although the bone present in this situation is denser, because of the imbalance the bones are actually more susceptible to fracture.

Paget disease

Paget disease results in compromised bone integrity because of the imbalance of resorption and formation, characterized by disorganized formation. The disorganization of the bone formation results in the presence of excessive fibrosity, vascularity, and hypercellularity. In Paget disease the bone integrity is compromised, although the clinical manifestations are variable. This may result in an increase in fractures, but there can also be deformity, pain, and arthritis. This process usually does not involve the global skeleton, but is often isolated to one or more bones. Typically, these are axial or lower-extremity long bones. In the spine, Paget disease can lead to spinal stenosis. Rarely, this process can degenerate into malignant transformation.

Whereas each of these pathologies stem from aberrations at the molecular level, and therefore have different clinical presentations, all ultimately compromise the integrity of the bone and therefore can predispose individuals to an increased risk for fracture.