When we hear the word "osteoporosis," we often imagine bones full of holes, like a piece of cheese. It leads us to assume that increasing calcium intake might help fill those holes and improve bone density, which would mean we don’t need to worry as much. The idea of supplementing with calcium is the first thing that comes to mind—and I must admit, I’ve thought that way too. But is it really that simple?
A phrase I once heard in a lecture has lingered in my mind: “To make new bone, you must first remove the old. If you keep building on top of old and problematic bone without removing it, how healthy can that bone be?” It was a striking explanation of the delicate balance between bone resorption and formation. Now, I want to explore what it means to maintain such a fine and sophisticated balance.
Bone is a dynamic tissue, continuously undergoing remodeling—even at this very moment. In this exploration, I aim to broadly examine the many factors involved in bone biology and how they interact. Based on that understanding, we will then look into how current osteoporosis treatments work. But first, let’s begin with the fundamentals of bone.
Functions of Bone
Bones form the structural framework of the body. Skeletal muscles, attached to bones via tendons, contract and pull on the bones to generate movement. In addition to supporting height and movement through mechanical support, bones protect vital organs like the heart, brain, and bone marrow, and also serve as reservoirs for minerals such as calcium and phosphorus. Bones help regulate the body's mineral balance, which is crucial for normal physiological functioning. When blood calcium levels are high, osteoblasts deposit calcium and phosphate into the bone matrix, reducing circulating calcium in the bloodstream. Conversely, when calcium levels drop, osteoclasts break down bone tissue, releasing minerals into the bloodstream to restore balance.
The skeletal bones of the human body can be divided into two parts: the dense and solid outer layer, and the inner part, which contains small pores and houses the bone marrow, where blood cells are produced. The bone marrow contains various types of stem cells, including hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). HSCs, through diverse differentiation pathways, give rise to erythrocytes, leukocytes, and platelets.
Bones are not just simple support tissues, but also function as endocrine organs, secreting various signaling molecules to affect whole body metabolism. For instance, fibroblast growth factor 23 (FGF-23), produced and released by osteocytes and osteoblasts, regulates phosphate metabolism by inhibiting phosphate reabsorption in the kidneys. Osteoblasts also secrete osteocalcin, a hormone involved not only in calcium deposition during bone formation but also in broader physiological processes such as energy metabolism, glucose tolerance, and testosterone production.
Composition of Bone: Mostly Extracellular Matrix
As previously discussed in the article about cartilage, cartilage contains relatively few chondrocytes, with the majority of its volume consisting of extracellular matrix secreted by those cells. Bone, as a type of connective tissue, is similar—bone cells make up only a small proportion, while the mineralized extracellular matrix constitutes the vast majority. Collagen fibers are arranged in an orderly manner, and minerals are deposited between them, gradually forming mineralized sheets called lamellae. Within these lamellae, one can see sparsely embedded bone cells, named osteocytes. Bone cells account for less than 2% of the total, with the rest being extracellular matrix.
Bone is often described as a mineralized tissue composed of approximately 60% inorganic material, 10% water, and 30% organic components. These figures mainly refer to the composition of the extracellular matrix. The combination of organic and inorganic elements makes bone the hardest structure in the body, yet still allows for a degree of flexibility. The organic components that contribute to flexibility are mainly fibrous proteins—chief among them collagen, which accounts for about 85–90% of the total organic matrix.
Inorganic Components of Bone
The primary inorganic components of bone are minerals, predominantly calcium and phosphate. These form hydroxyapatite crystals embedded within the collagen matrix. Hydroxyapatite, with the formula Ca₁₀(PO₄)₆(OH)₂, is the principal mineral component of bone and teeth. During bone formation, osteoblasts secrete an organic matrix known as osteoid, into which hydroxyapatite crystals are deposited. This mineralization process gradually hardens the bone. Hydroxyapatite provides the bone with strength and resistance to compressive forces. If we liken collagen to the steel framework of a building, hydroxyapatite would be the concrete—together forming a robust yet flexible structure. Calcium and phosphate together constitute about 60–70% of the bone's dry weight. Water, present within the collagen matrix, helps maintain hydration and flexibility.
Organic Components of Bone
Among the organic components of bone, collagen—particularly type I collagen—plays the most significant role. It provides tensile strength and elasticity. Type I collagen, known for its triple-helix structure, makes up more than 90% of the bone’s organic matrix. [1] Though in much smaller amounts, type III and type IV collagens also contribute to bone’s flexibility. Non-collagenous proteins, though present in smaller quantities, play crucial roles in mineralization, bone remodeling, cell signaling, intercellular interactions, and regulating bone cell activity. Key examples include osteocalcin, osteonectin, osteopontin, and bone sialoprotein. Additionally, proteoglycans like biglycan and decorin contribute to the organization of collagen fibers, matrix integrity, and water retention.
Osteocalcin, secreted by osteoblasts, binds to calcium and hydroxyapatite to regulate mineralization. It not only promotes bone formation by binding with crystals but also moderates their growth, preventing excessive mineralization that could weaken bone. Blood levels of osteocalcin serve as a marker for bone metabolic activity, and tend to be lower in individuals with osteoporosis or postmenopausal women. Interestingly, osteocalcin has been found to positively influence blood glucose regulation, much like insulin, and declines in its levels with aging have been linked to memory decline. Osteonectin helps stabilize the matrix by promoting the binding of collagen and minerals. Osteopontin and bone sialoprotein(BSP), through their internal RGD motifs, strongly bind to integrins on osteoclasts. This facilitates the formation of sealing zones, allowing osteoclasts to firmly adhere to the bone surface and carry out bone resorption—an essential process discussed in detail later.
Histological Classification of Bone: Compact bone and Spongy bone
Human bones can be classified by shape and function into long bones, short bones, flat bones, sesamoid bones, and irregular bones. Long bones, like those in the limbs, are elongated; short bones, like those in the wrist and ankle, are cube-shaped; flat bones, such as the skull and ribs, are thin and wide; sesamoid bones, like the patella, are embedded in muscles or tendons and help transmit muscular forces; and irregular bones include all others that don’t fit neatly into the above categories.
When examining these bones internally, it becomes clear that the outer and inner structures differ significantly—a reflection of their functional differences. Though all bones are composed of the same four basic cell types (osteoclasts, osteoblasts, osteocytes, and bone lining cells), the density, composition, and shape of the tissue vary. Based on these characteristics, bone tissue is categorized into compact (cortical) bone and spongy (trabecular or cancellous) bone. As the names suggest, the main difference lies in density. A cross-section of bone shows dense compact bone on the outer surface and porous spongy bone on the inside. The ends of long bones also consist of spongy bone.
Compact bone provides mechanical strength and structural support, while spongy bone—rich in blood supply and housing hematopoietic stem cells—supports active metabolic processes. Nearly all bones contain both types of tissue, though the ratio varies by bone type. For instance, the ulna (a long bone in the forearm) is about 92% cortical bone and 8% trabecular, whereas a vertebra is approximately 62% cortical and 38% trabecular. The ends of long bones like the femur are made of trabecular bone encased in a compact bone shell, while flat bones such as the scapula or skull show a layered structure.[2]
 |
Compact Bone (Cortical Bone)
Osteon (Haversian System)
As the name suggests, compact bone is a dense and tightly organized tissue with a high degree of mineralization, forming the solid outer shell of bones. It is located on the outer surface of bones, providing mechanical strength and structural rigidity to support pressure and weight, while also anchoring tendons to enable movement. Compact bone accounts for about 80% of the total bone mass in the body. However, due to its high density, it has a relatively low surface area compared to spongy bone. The basic structural unit of compact bone is the osteon, also known as the Haversian system. Countless osteons are densely packed together to form the compact bone.
Each osteon is a cylindrical structure, and at its center runs a longitudinal channel—the Haversian canal—through which blood vessels, nerves, and lymphatic vessels pass. The presence of these vessels is essential for bone healing in cases of fractures or injury, which highlights the remarkable self-repair capability of bone tissue.
Lamellae
The lamellae are thin, sheet-like or plate-like layers that form around the osteon and are primarily composed of collagen fibers into which minerals are deposited. This layered structure determines the mechanical strength of the bone. Around the central Haversian canal of an osteon, there are typically 4 to 8 concentric layers of lamellae, forming a pattern similar to tree rings. When viewed from the side, this structure resembles a long cylinder. Each lamella is composed of collagen fibers aligned in alternating directions, often perpendicular to the previous layer. This cross-ply arrangement gives the bone the mechanical strength to resist torsional (twisting) forces and contributes to its structural integrity, helping prevent cracks or fractures.
Three distinct types of lamellae can be observed in compact bone. The first is concentric lamellae, which are arranged in concentric circles around the central Haversian canal. The second type is interstitial lamellae, which are remnants of old osteons that fill the gaps between newly formed osteons. Lastly, there are circumferential lamellae, which run parallel to the outer and inner surfaces of the bone and form continuous layers along the bone’s perimeter. These are typically found adjacent to the periosteum (the outer membrane) and endosteum (the inner membrane that faces the spongy bone), and together they help stabilize the overall bone architecture.
Scattered throughout the lamellae are osteocytes—mature bone cells—housed in small spaces. These lamellae are essentially the extracellular matrix secreted by bone-forming cells, osteoblasts. After osteoblasts lay down collagen and other components for bone formation, and the matrix undergoes gradual mineralization, some osteoblasts become embedded in the matrix they created and differentiate into osteocytes. These cells take on a regulatory role, maintaining and monitoring the bone tissue. Each osteocyte extends long, slender processes called canaliculi, which allow communication with neighboring osteocytes despite the distances between them. To carry out this homeostatic monitoring, osteocytes occupy small, bubble-like spaces called lacunae—tiny cavities within the mineralized matrix that serve as their “homes.”
Volkmann’s Canals
In compact bone, Volkmann’s canals run transversely and connect the vertically oriented Haversian canals of neighboring osteons. While the Haversian canals allow for the longitudinal passage of blood vessels, nerves, and lymphatics, Volkmann’s canals serve as horizontal connectors, enabling the formation of an interconnected vascular and neural network throughout the compact bone. This ensures efficient circulation and waste removal via the lymphatic system across the entire structure. Volkmann's canals exist only in compact bone, since spongy bone is located right next to the marrow cavity and receives blood supply directly from the bone marrow, so separate structures such as Havers' canals or Volkmann's canals are not necessary.
Spongy Bone (Trabecular Bone)
Spongy bone is primarily found at the ends of long bones (epiphyses) and within the internal central regions of bones. Structurally, it differs significantly from compact bone. While compact bone is composed of osteons, spongy bone is made up of thin, rod-like structures called trabeculae—a word derived from Latin meaning "little beams" or "small columns." These trabeculae are arranged in a lattice-like framework that gives the bone a porous, sponge-like appearance. The large number of gaps between trabeculae make spongy bone lightweight and provide a high surface area relative to volume. This unique architecture reduces bone weight, enhances shock absorption and stress distribution, and is metabolically advantageous. If bones were composed solely of compact bone, they would be much heavier and less efficient.
On the surface of trabeculae, numerous metabolic activities occur, including calcium storage and release, hormonal signaling, and hematopoiesis. The spaces between trabeculae are filled with bone marrow. Bone marrow exists in two forms: red marrow and yellow marrow. Red marrow contains hematopoietic stem cells responsible for producing blood cells such as erythrocytes and leukocytes, giving it a rich red color. In contrast, yellow marrow consists mainly of adipose tissue and becomes more prevalent with age, as red marrow gradually decreases. In adults, red marrow is primarily confined to certain bones like the spine, pelvis, ribs, and skull.
[References]
[1] Osteoblast-Osteoclast Communication and Bone Homeostasis
https://doi.org/10.3390/cells9092073
[2] A Brief Review of Bone Cell Function and Importance
https://www.mdpi.com/2073-4409/12/21/2576
