Normal bone tissue consists of cells embedded in a biologic extracellular matrix. The extracellular matrix consists of both organic and inorganic components. The organic component makes up approximately one-third of the bone mass and consists primarily of cells, collagen, and proteoglycans. The inorganic component makes up the remaining two-thirds of the bone and is composed of calcium phosphate crystals deposited as hydroxyapatite.

The three types of cells embedded in the matrix are osteoblasts, osteocytes, and osteoclasts. Osteoblasts are bone-forming cells present as a layer of enveloping cells on the outer surface of bone trabeculae. They are involved in the production and secretion of osteoid, which is the unmineralized precursor to bone matrix consisting primarily of type 1 collagen fibers arranged into strands. This new osteoid is deposited along the surface adjacent to bone and later undergoes mineralization. Osteoblasts eventually become enclosed in the bone matrix they produce, and are then referred to as osteocytes. Osteocytes inhabit spaces called lacunae, and make up more than 90% of the cells in the mature skeleton. Osteocytes have cytoplasmic processes that connect with other matrix osteocytes and surface lining osteoblasts via canals called canaliculi. The connections between osteoblasts at the periosteal surface and osteocytes embedded within the bone contribute to mineral homeostasis by allowing for the exchange of mineral ions. Osteocytes also function as mechanosensors and, via the canaliculi signaling mechanism, play a role in the response of bone to mechanical loading. Osteoclasts are the cell type primarily responsible for bone resorption. They are large multinucleated cells that reside within cavities, called Howship lacunae, also located on the surface of bone trabeculae. They are unique in that they are derived from mononuclear hematopoietic stem
cells and use a method similar to macrophages to resorb bone.

The inorganic component makes up 60% to 70% of the dry weight of bone and is made up of the mineral hydroxyapatite (Ca₁₀(PO₄)₆OH₂). Hydroxyapatite is formed by the tight packing of mineral salts and is responsible for bone rigidity and compressive strength. Interactions between the organic matrix and inorganic material take place primarily via calcium phosphate nanocrystals. The organic matrix extracellular component is similar to connective tissue elsewhere in the body and is referred to as osteoid. The main structural protein, which makes up 90% of the organic matrix, is type 1 collagen. This collagen arranges itself into strands of repeating units arranged in an overlapping fashion.

Bone can be microscopically classified as either woven or lamellar bone based upon the arrangement of its collagen strands. Woven bone is characterized histologically by its disorganized arrangement of collagen fibers and small amount of mineral substance. Woven bone is found primarily in fetal bones, fracture callus, and anywhere else where bone is rapidly produced by osteoblasts. This woven bone is then replaced over time by lamellar bone in a process called bony substitution. Lamellar bone is characterized by well-organized collagen fibers running parallel to each other forming stress-oriented columns. The organization of the collagen strands is responsible for the tensile strength of bone.

Macroscopically, bone is divided into cortical or cancellous bone, based upon the geometric arrangement of otherwise structurally similar lamellar bone. Cortical (compact) bone makes up 80% of total bone mass, forms the hard outer layer of bone, and consists of tightly packed columns called osteons (Fig. 26.1). Osteons are arranged in line with the long axis of the bone and are made up of vascular channels surrounded circumferentially by lamellar bone. Cancellous (trabecular) bone makes up the remaining 20% of bone mass and forms the inner spongy compartment of bone. The trabecular bony arrangement is characterized by vertical bony trabeculae connected to each other by horizontal struts. Bone loss in osteoporosis disproportionally affects the horizontal struts and thus even a small amount of bone loss can rapidly destabilize trabecular bone. Unlike cortical bone, trabecular bone is very porous with multiple cavities and a much lower density (0.1 to 1.0 g/cm³ compared to 1.8 g/cm³ for cortical bone).

A basic multicellular unit (BMU), composed of osteoblasts and osteoclasts, is considered the fundamental
unit of bone formation and resorption. Bone formation at the local level is performed via osteoblasts, which increase bone mass by increasing the amount of osteoid produced and by inhibiting osteoclast absorption of bone. Bone resorption occurs due to the differentiation and activation of osteoclasts. Remodeling is a constantly occurring process within bone, with up to 10% of bone mass undergoing remodeling at any particular time.

Bone remodeling plays an important role in repair of fractures, physiologic bone turnover, skeletal remodeling during growth, and calcium homeostasis. The remodeling process is controlled via signaling mechanisms at both the systemic and local BMU level. Regulation of bony remodeling occurs via the receptor activator of nuclear factor κ B (RANK) signaling pathway (Fig. 26.2). RANK is a receptor that is present on the surface of osteoclasts and osteoclast precursor cells. RANK ligand is released by T cells, osteocytes, and osteoblasts. It stimulates the differentiation of precursor cells into mature osteoclasts and also activates mature osteoclasts. Inhibition of osteoclast activation is provided by osteoprotegerin (OPG), which is secreted by osteoblasts and osteocytes. OPG is a decoy receptor that binds to RANKL and thus inhibits osteoclast differentiation and activation.

The importance of osteocytes in the regulation of bone remodeling is increasingly being recognized. Osteocytes produce sclerostin, an inhibitor of osteoblasts and thus bone formation. Sclerostin is released physiologically in response to decreased mechanical loading, inflammation, and hormones such as parathyroid hormone (PTH). Sclerostin has also been observed in metabolic bone disease and osteoporotic fractures. An antibody that restores bone mass by targeting sclerostin (AMG 785; Amgen, Thousand Oaks, California) is currently in phase III clinical trials.

Systemic hormones that use the RANKL signaling pathway to maintain serum calcium homeostasis include PTH, vitamin D, glucocorticoids, and estrogen. PTH is released in response to low serum levels of calcium. It increases extracellular calcium levels by increasing the production of 1,25-dihydroxyvitamin D, increasing renal absorption of calcium, and by increasing bone resorption. PTH stimulates resorption of bone by binding to osteoblasts and stimulating the secretion of RANK ligand along with various cytokines leading to osteoclast activation. The active form of vitamin D (1,25-dihydroxyvitamin D) increases serum calcium by increasing gastrointestinal absorption of calcium and also increasing osteoclast resorption of bone. Glucocorticoids lead to bone resorption by inhibiting osteoblasts and stimulating osteoclasts. Conversely, estrogen inhibits the RANKL signaling pathway by both the downregulation of signaling components and by stimulating OPG production.

Calcitonin is unique in that it is an inhibitor of bony resorption that functions independently of the RANKL signaling pathway. This hormone is produced by the thyroid gland and is released in response to rising serum calcium. Osteoclasts have a receptor for calcitonin, and binding of this receptor leads to direct inhibition of osteoclast-mediated bone resorption.

The classic patient presentation in VCF is that of an elderly individual with the insidious onset of focal, deep, midline spine pain, typically worse when upright and improved by lying flat. Occasionally radiating pain from irritation or compression of the nerve roots may be present. One-third of all VCFs will be missed initially due to the lack of pain at the time of fracture. Those with symptom onset at the time of fracture occurrence will typically describe an atraumatic event causing the fracture, with up to 30% of VCFs occurring while patients are lying in bed.

Tenderness to palpation at a single vertebral level is often present but is not a reliable indicator of the presence of a VCF and does not correlate to the level of the fracture. If the pain does not correlate with the fracture level, surgical treatment is less likely to be effective. Other acute findings can include the loss of height and thoracic kyphotic deformity. Individuals with thoracic kyphosis may have ribs that approach or contact the iliac crest and cause discomfort. In severe cases, this thoracic pressure on the pelvis can lead to impaired pulmonary function, a prominent abdomen, and early satiety and weight loss. Neurologic deficits are rare findings; in one study, only 2% of patients with VCF had a neurologic deficit that required surgical decompression.

Myelopathic symptoms due to cord compression are uncommon in VCFs and if present are concerning for vertebral metastases. Other red flags that should be asked about during the history include night pain, fevers, chills, unusual weight loss, and a history of cancer or infection. If any of these red flags are present, advanced imaging and further workup should be considered to rule out malignancy or infection.

Underlying bone or mineral metabolic disorders are present in 32% of otherwise healthy adults presenting with osteoporosis. Screening laboratory tests are carried out in every patient suspected of having osteoporosis, including complete blood cell count (CBC) and complete metabolic panel (CMP) including liver function tests (LFTs), thyroid-stimulating hormone (TSH), and serum 25-hydroxyvitamin D levels. Decreased serum vitamin D is present in 40% to 90% of healthy adults, and is increasingly being recognized as a common cause of reduced bone density. Other tests for more specific secondary causes of osteoporosis are shown in Table 26.1.

Plain radiographs will not demonstrate osteoporotic lucency until 30% to 80% of bony mineral has already been lost. This is due to the condition’s predominant effects on cancellous bone with cortical bone loss not occurring until at least 30% of bone loss has already transpired. Plain radiographs show the fracture level and the amount of bony collapse. A decrease of 4 mm or more or a decrease of greater than 20% of vertebral body height (compared to a normal vertebra above or below the suspected fracture) is diagnostic for VCF. Upright films are preferred as they may show subtle changes in the vertebra sooner than supine films. Bony retropulsion is most frequently noted in fractures that occur at the thoracolumbar junction. Kyphotic angulation is a useful measurement in assessing fracture progression. In patients with a VCF on imaging, 5% to 20% will have more than one fracture, and all areas with tenderness should be imaged. In some patients, the compression may only be evident after 2 to 3 weeks, when the bone involved settles. It is also difficult to determine from radiographs when a fracture occurred, unless earlier imaging studies clearly do not show a fracture.