Bone is a specialized connective tissue with high level of biologic activity. The human skeleton serves unique and vital mechanical and biologic functions, which include but are not limited to providing supporting framework; protection of vital organs; provision of attachment sites to ligaments and muscles; storage of minerals like calcium, phosphorus, and sodium; and provision of space for hematopoietic and lymphopoietic activities. To meet these functions effectively, bone has two distinct structural components. Cortical or compact bone is responsible for strength and resistance to tensile and sheer forces whereas cancellous or trabecular bone has higher surface area and is mainly responsible for metabolic and biologic functions (1).

Bone is composed of organic matrix and inorganic minerals. Organic matrix is composed of type 1 collagen and noncollagenous proteins like osteopontin, osteocalcin, fibronectin, osteopontin, thrombospondin, bone sialoprotein, growth hormones, and cytokines (2). The collagen provides tensile strength. Inorganic part is in the form of hydroxyapatite crystals, with the composition Ca₁₀(PO₄)₆(OH)₂. Hydroxyapatite consists of 65% to 70% of dry weight of bone and is responsible for its mechanical compressive properties (1).

Osteoprogenitor cells are mesenchymal stem cells found near all the bony surfaces. When stimulated by RUNX2/CBFA1 transcription factor network and the WNT/β-catenin signaling pathway, these stem cells are capable of differentiation to osteoblasts.

Osteoblasts synthesize, transport, and arrange the many proteins of matrix and initiate the process of mineralization. Osteoblasts have receptors that bind regulatory hormones (parathyroid hormone [PTH], vitamin D, leptin, and estrogen), cytokines, growth factors, and extracellular matrix proteins, in turn the osteoblasts express several factors including receptor activator of nuclear factor kappa-B ligand (RANKL) that regulate the differentiation and function of osteoclasts. If osteoblasts become surrounded by newly deposited organic matrix, they transform into osteocytes; alternatively, osteoblasts remaining on the bone surface may become flattened and quiescent bone lining cells (1).

Osteocytes communicate with each other and cells on bone surface via intricate network of cytoplasmic processes known as canaliculi, and they help to control calcium and phosphate level in microenvironment and detect and translate mechanical forces into biologic activity (mechanotransduction).

Osteoclasts are the cells responsible for bone resorption. They are derived from the same hematopoietic progenitor cells that also give rise to monocytes and macrophages. The cytokines and growth factors that regulate human osteoclast differentiation and maturation include RANKL, macrophage colony–stimulating factor (M-CSF), interleukin-1 (IL-1), and tumor necrosis factor (TNF). Mature multinucleated osteoclasts (containing 6 to 12 nuclei) form from the fusion of circulating mononuclear precursors and have a limited life span (approximately 2 weeks). They bind to the bone surface via integrins, where they form an underlying resorption pit. The cell membrane overlying the resorption pit is thrown into numerous folds (the ruffled border). The osteoclast removes the mineral by generating an acidic environment utilizing a proton pump system and digests the organic component by releasing cathepsin K and proteases (3).

All the cellular activities mentioned above are closely regulated by hormonal influences. PTH, vitamin D, and calcitonin are major hormones involved in bone mineral homeostasis but other factors like thyroid, insulin, insulin-like growth factor (IGF), growth hormone, and prostaglandins have a role as well.

Parathyroid glands identify low calcium level in extracellular fluid and respond by secreting PTH, which in turn increases calcium reabsorption, and decrease phosphate reabsorption in renal tubular cells. PTH also increases calcium absorption from gut through increase conversion of vitamin D to the active 1,25-hydroxy metabolite. It stimulates osteoblasts directly and osteoclasts indirectly through
osteoblasts. Effect of PTH on bone is dual and complex. Although continuous PTH increases bone resorption and increases the serum calcium level, intermittent PTH acts as an anabolic agent and increases bone formation (4).

Vitamin D stimulates synthesis of calcium-binding proteins in gut and kidneys and promotes calcium absorption at these sites. It also promotes phosphate absorption from gut. Vitamin D promotes mineralization of the skeleton. Effects of vitamin D are not limited to bones. Recently its influence on immunology, muscle function, and pathogenesis of some tumors has been identified (5).

Calcitonin is secreted from the parafollicular cells of the thyroid gland in response to an acutely rising plasma calcium concentration. Calcitonin has direct inhibitory influence on osteoclasts. The general physiologic role of calcitonin is uncertain, as it seems to play no role in steady-state calcium metabolism (6).

Recently hypothalamic regulation of bone metabolism via leptin, a peptide hormone secreted by osteoblasts, which can decrease bone formation, is suggested (7).

Bone strength is defined by the National Institute of Health Consensus Statement 2000 that it is related to bone quality and bone mineral density. Optimum health of skeleton relies on both quality and quantity of bone. Bone resorption and formation are closely coordinated procedures. They run throughout the life and help growth, development, and repair of microdamages. Bone formation predominates during first two to three decades of life and a person achieves his or her peak bone mass at around age of 30. After fourth decade bone resorption predominates and bone mass constantly decreases thereafter. In females, a precipitous fall in bone mass occurs around menopause due to lack of anticatabolic and anabolic effects of estrogen. Besides hormonal factors, other factors like polymorphisms in the receptors for vitamin D and lipoprotein receptor protein 5/6 (LRP5/6), nutrition, physical activity, and age can also influence bone mass and in turn bone mineral density (1).

Bone mineral density is the amount of bone mass per volumetric area but the dual-energy x-ray absorptiometry (DEXA) only measures areal density. Quality of bone is an important and independent parameter of bone health. Bone quality is related to the organic components particularly collagen, mineral components and its mineralization phase, damage accumulation, and the microarchitecture. Inadequate mineralization most commonly due to vitamin D deficiency is an important bone quality issue encountered in routine clinical practice. Accumulation of microdamages due to inability to repair wear and tear is an important bone quality issue emerging in patients on long-term antiresorptive therapy though bone quantity and density can be normal in such cases.

A fragility fracture is defined as a fracture sustained from a fall from less than or equal to standing height, and is related to the elements of bone strength. The presence of a fragility fracture strongly suggests that the patient has underlying bone disease. However, orthopedic surgeons rarely assume responsibility for the fracture and less than 25% of fracture patients actually get placed on osteoporotic medication in spite of direct communication with the primary care physicians (8). Patients with fragility fractures have the fracture attended to but rarely have the underlying bone disease addressed. In a randomized controlled study 58% of the fracture patients were treated for their bone disease when treatment was initiated by the orthopedic team versus less than 30% of the patients were treated when a referral letter was sent to their primary care physician (9).

Osteoporotic fractures pose a lifetime risk of death comparable to breast cancer. Younger women have a greater risk of death from breast cancer than osteoporosis but older individuals have a greater risk of death from osteoporosis than breast cancer. According to our fragility fracture registry, patients with a hip fracture have approximately a 20% to 25% chance of mortality rate within 1 year. This usually occurs after the fracture has healed and is probably due to the generalized failure of the patient. There is also a 70% risk of significant morbidity and only a small percentage of patients regain their base line function.

Workup for a patient with osteoporosis particularly an osteoporotic fracture should start prior to surgery so as not to be confused by modifications secondary to postoperative state. Studies should include a CBC to eliminate anemia, calcium, intact PTH, phosphorous, albumin, bone-specific alkaline phosphatase to measure bone formation, 25-hydroxy vitamin D to measure the vitamin D level, and comprehensive metabolic panel (CMP) or equivalent to look for renal and liver diseases. Finally, if the patient has been on prior osteoporotic therapy, a second morning urinary n-telopeptide or a fasting serum c-telopeptide could be measured to determine resorption rate. Secondary tests such as thyroid and multiple myeloma analysis, steroid levels would be appropriate only when the history warrants. Seventy percent of the patients with a fracture will have low vitamin D values and in elective total hip surgery 45% of patients at the Hospital for Special Surgery will report to have insufficient levels of vitamin D. It must be assumed therefore that calcium and vitamin D should be supplemented in most patients (10).

Bone density should be measured in all patients who are postmenopausal or who have had a fragility fracture. The bone density measures the aerial bone density and can be set either at the hip or at the spine. In elderly patients the spine may have artifacts due to scoliosis or arthritis. In patients with hip arthritis attention should be directed to the unaffected hip and when both are involved then the wrist is the best surrogate. The bone density between 1.0 and 2.5 standard deviation below normal is considered as osteopenia and if it is below 2.5 standard deviations the situation is considered as osteoporosis (11). Bone DEXA does not correlate totally with fracture risk. In a steady-state osteoporotic situation, 65% of men and about 35% of women have secondary diseases affecting bone health but in patients with fragility fractures the rates change to 95% of men and about 65% of women. History of fragility fracture is a strong predictor for further fractures. Given the vertebral fragility fracture there is a 19.2% risk of getting a second vertebral fracture within 1 year, and there is a five times greater risk of having another vertebral fracture in 1 year over general population (12). Another study shows that persons with hip fractures are at three times higher risk and persons with other fractures are at 1.8 times greater risk for a subsequent hip fracture than the general population (13).
A hip or vertebral fracture is considered osteoporotic regardless of their bone density as long as it is a fragility fracture. Fifty-five percent of patients who sustain a hip fracture have osteopenia rather than osteoporosis, which suggests that there is an issue of quality more than an issue of density responsible for the particular fracture (11).