3.5.1 Dual-energy X-ray Absorptiometry (DXA)

Dual-energy X-ray absorptiometry (DXA) is the gold standard to determine in vivo bone mineral density (BMD). The technique utilizes high and low energy X-rays which have different, nonlinear X-ray attenuation. As a result, the density which these two X-ray energies pass through tissues can be determined. DXA calculates the areal BMD (gm/cm²) of a region of interest. Typical regions of interest are the proximal femur, lumbar vertebrae, and distal radius, all three of which are common fracture sites. The bone mineral density (BMD) is then compared to a reference standard, specifically the BMD of 20- to 30-year-old females. The T-score is equal to the BMD of the patient minus the BMD of the reference standard divided by the standard deviation of the reference standard.

The Z-score is calculated using age- and gender-matched controls as a reference standard. A Z-score is used for males and premenopausal females.

One strength of DXA is that larger and therefore stronger bones will have a higher areal BMD and, as such, DXA is a good tool to predict future fracture risk. However, there are many limitations of DXA. Arthritic or degenerative changes, deformity, and the presence of surgical implants prevent accurate measurement of BMD. DXA is only measuring planar bone mineral density and will include cortical trabecular bone. In the spine, trabecular bone is far more significant in preventing fractures than the cortices. Further, variation occurs between scanners and technicians, with different resulting outcomes. Finally, recent investigations suggest that over 25% of scans have incorrect reporting. ¹⁸

3.5.2 Classification of Osteoporosis

The World Health Organization (WHO) classified bone status based on DXA T-score (Table 3‑1 ). ¹⁹ However, the WHO classification poorly predicts fracture, with more than 50% occurring in people with low bone mass or normal T-scores. Further, this system provides limited guidance for treatment. The National Osteoporosis Foundation and the National Bone Health Alliance (NBHA) recognized that bone mineral density as defined by the WHO criteria does not explain risk of fracture in half the cases. ²⁰ As such, they recently proposed that the definition of osteoporosis be expanded to include any one of the following: a T-score of less than -.2.5; a fragility spine or hip fracture; low bone mass (-1.0 to -2.5) plus fragility fracture; and low bone mass and high Fracture Risk Assessment Tool (FRAX) probability (Table 3‑2).

The Fracture Risk Assessment Tool (FRAX) is a prediction tool that calculates the 10-year hip and 10-year major osteoporotic (spine, hip, wrist and humerus) fracture risk. ^{21 ,​ 22} FRAX is standardized for many countries and is based on 12 criteria, including demographics, height and weight, a history of prior fractures, parents with fractures, cigarette use, use of glucocorticoids, having rheumatoid arthritis or secondary osteoporosis, consuming more than 3 alcoholic beverages per day, and femoral neck bone mineral density based on either gm/cm² or T score (Table 3‑3). The FRAX risk can also be calculated without the use of DXA. The FRAX tool can be accessed at https://www.sheffield.ac.uk/FRAX/index.aspx.

Many guidelines recommend use of FRAX estimated fracture risk to determine the optimum medical treatment, including the therapeutic intervention threshold based on fracture risk. The most commonly used high-risk FRAX thresholds are a 10-year major fracture risk of 20% and a 10-year hip fracture risk of 3%, indicating patients who should be considered for pharmaceutical treatment.

3.5.3 Indications for DXA

The indications for DXA testing are: all women aged 65+ and men aged 70+; women aged 50 to 64 with a FRAX score greater than 9.3 percent; major osteoporosis-related fracture risk per the United States Preventative Service Task Force (USPSTF); men between the ages of 50 to 69 who exhibit one or more of the following: a prior fracture, glucocorticoid use, or rheumatoid arthritis; and, finally, anyone with a recent fracture (Table 3‑4). ²³

3.5.4 Recent Advances in Diagnosis of Osteoporosis

Two recent advancements available in some DXA scanners have improved fracture-risk predictive capabilities. Vertebral Fracture Assessment (VFA) uses a lateral radiographic image of ideally the entire thoracolumbar spine (Fig. 3‑2). ²⁴ The Genant visual semiquantitative (VSQ) scale is usually applied to identify individuals with mild, moderate or severe vertebral fractures. ²⁴ In conjunction with this approach, the anterior, middle, and posterior vertebral body height at each level can be measured and compared to controls. With the VSQ system, fractures are classified as mild (20–25% height loss), moderate (25–40% height loss) and severe (>40% height loss). The VFA allows identification of occult fractures and correlates to functional deficits in BMD. For example, Muszkat reported that 17% of patients having routine DXA had moderate or severe vertebral fractures based on VFA, and of those, 88% were occult. ²⁵

The trabecular bone score (TBS) provides an index of bone quality by serving as a surrogate of bone microarchitecture. ²⁶ The TBS uses special software to assess bone texture and can be applied to existing lumbar spine DXA data. A region of interest identical to that for DXA is chosen, and each pixel on 2-dimensional imagesis assigned a value based on bone thresholding. The TBS is calculated based on the variation between pixels which are greater in osteoporotic bone than normal trabecular bone when compared to normal. The trabecular bone score can be independent of BMD and have greater predictive value than T-score (Fig. 3‑1e). The TBS can be utilized to improve fracture-risk estimation in FRAX, with high TBS scores reducing risk and vice versa. TBS values > 1.31 are consistent with intact bone microarchitecture, < 1.23 with degraded bone microarchitecture, and a score in between these values with partially degraded bone microarchitecture.

3.5.5 Opportunistic Screening using CT

Computed tomography (CT) is a widely used diagnostic tool. In the U.S. in 2015, there were 240 CT examinations per 1,000 patients. ²⁷ In 2013, over 31 million patients had abdominal or pelvic CTs that examined the lumbar spine and proximal femur, which could provide useful information regarding bone mineral density. CTs obtained for other indications can be used to quantitatively assess bone status; this has been termed “opportunistic osteoporosis screening.” ²⁸

The CT scan uses rotating X-ray emitters and detectors that allow calculation of energy attenuation in each 3-dimensional piece (voxel) of tissue. The X-ray attenuation is normalized and is calculated as the linear attenuation coefficient, known as the Hounsfield unit (HU). Each scanner calculates an HU for each voxel and is displayed on planar images using a grey scale. The X-ray attenuation is proportional to the atomic mass cubed and the number of atoms in each voxel of tissue. Thus, in general for bone, HU is proportional to the BMD.

Several methods to assess bone status using CT have been developed. The simplest is to determine the mean HU in an elliptical region of interest (ROI) using standard PACS software (Fig. 3‑1c). ²⁹ Typically, for the spine this will be drawn in the anterior two thirds of the vertebral body on either axial or sagittal sections. A representative section, usually through midbody or through the pedicle, is selected, and a region of interest is drawn to include only trabecular bone. ²⁹ It is important to avoid any bony defects, fractures, or bony islands. Standard thresholds to determine the likelihood of osteoporosis are determined for L1, which is also available on both chest and abdomen CTs, making it an ideal vertebra to use if available. The author recommends drawing as large an ellipse as possible. Reliability studies show no difference between averaging multiple small ellipses and drawing one large region of interest.

More accurate quantitative CT scans can be obtained by simultaneously scanning the patient and a phantom containing various concentrations of calcium hydroxyapatite. These are then used to interpolate the bone mineral density of any region of interest. This has been termed synchronous quantitative CT (qCT). ³⁰ This is an excellent research tool but is not widely used clinically. Asynchronous qCT utilizes calibration data obtained daily on CT scanners and does not require the simultaneous scanning of patient and phantom. This approach is as reliable as standard synchronous qCT and may be used to calculate bone mineral density and to determine T-scores similarly to DXA. ³⁰ Phantomless quantitative CT uses water and air density as standards to calculate bone mineral density. At present, this is used mainly as a research tool.

There are notable factors that affect X-ray attenuation and thus HU. CT manufacturers and day-to-day fluctuations are minor. Intravenous contrast increases spinal HU by approximately 11. ³¹ The most important factor is voltage tube energy of the CT scanner. ³² Most CT scans use 120 kV; however, newer scanners allow dual-energy CT scans, and a significant negative correlation exists between higher voltage and lower HU.

Thresholds have been determined to estimate the presence or absence of osteoporosis based on Hounsfield units. Pickard recommends an HU threshold for L1 vertebral body of 135, which optimizes the sensitivity and specificity. An HU greater than 160 will rule out osteoporosis, while a value less than 110 most likely indicates it. Schreiber compared HU to DXA and T-scores. He found that normal bone (T-scores > -1.0) had a mean HU of 133, osteopenic patients (T-score -1.0 to -2.5) had a mean of 101, and osteoporotic patients (T-score < -2.5) had a mean of 78.

Determining Hounsfield units has proven helpful in managing spine patients. A significant linear correlation exists between elastic modulus, apparent yield strain, and pull-out forces and HU, although thresholds have not been determined. ³³ Further, Weiser found a linear correlation between bone mineral density obtained from synchronized CT and pedicle screw cycles to failure and load to failure. ³⁴

Opportunistic CT scans have been evaluated in spine patients. Meredith reported a significant correlation between decreased preoperative HU and proximal junction kyphosis due to fracture in patients having spinal deformity. ³⁵ Patients with fracture had mean HU of 146, compared to 199 in the nonfracture group. Du reported that the incidence of incidental durotomy was twice as high in patients with low HU, although the cause for this phenomenon was not reported. ³⁶ Fusion success was negatively affected by osteoporosis diagnosed by HU. Schreiber evaluated 140 patients and determined that the mean HU for those with successful lumbar fusion was 203, while it was only 140 in patients with nonunion. ³⁷ Okuyama similarly reported that union success was strongly correlated to higher bone mineral density. ³⁸ Nguyen performed a match cohort study and found that in patients with nonunion, the HU value was significantly lower (167 vs. 201) than in those who had union. ³⁹ Wagner found a strong correlation between CT HU and DXA in patients undergoing lumbar fusion. Twelve percent were osteoporotic, of whom two-thirds had never been diagnosed or treated. ⁴⁰ Mi et al found that patients having cage subsidence after posterior interbody fusion had lower HU than those without subsidence, and at follow-up had less fusion mass. They calculated that an HU threshold in L4 of 132 identified those patients at risk for subsidence. ⁴¹

An important opportunistic use for CT scan is to identify occult fractures. In patients having abdominal CT scans, Graffy determined that 8.2% of patients had occult vertebral fractures, which strongly correlated to decreased HU. ⁴² Lee noted that DXA poorly predicted fractures in patients having abdominal CT scans. ²⁷ The HU was less than 145 in 97% of patients with occult fracture, while all had DXA T-scores were greater than -2.5. Eighty-two percent of patients with occult fractures on CT were not mentioned in the radiologic reports.

Emohar compared HU in a nonfracture control group to patients with cervical, thoracolumbar, and pelvic fractures. There was strong correlation with lower HU values in patients with fracture compared to control. In a similar study, authors found that patients with ankylosing spondylitis had markedly lower trabecular HU, suggestive of osteoporosis. ⁴³

3.5.6 Secondary Osteoporosis

Primary osteoporosis is bone loss due to aging and, in postmenopausal women, the loss of estrogens. Secondary osteoporosis occurs frequently and is due to other medical conditions and medications. It is important that laboratory testing be performed to identify secondary causes of bone loss in patients with a known diagnosis of osteoporosis or prior fragility fracture. ¹⁹ In one study, approximately 40% of patients had secondary osteoporosis contributors. ⁴⁴ Simple laboratory tests include a complete blood count, a comprehensive metabolic panel, 25(OH)D, intact parathyroid hormone, phosphate, and 24-hour urine collection for calcium, sodium and creatinine. Other tests are indicated depending on history and physical findings. In patients with suspicious spine fractures, multiple myeloma should be considered and is assessed by serum and urine protein electrophoresis.

3.5.7 Bone Turnover Markers

Bone turnover markers (BTM) are proteins and peptide molecules used to assess dynamic cellular activity of bone formation and bone resorption. These markers are useful to monitor the effectiveness of treatment but not for the diagnosis of osteoporosis. Current guidelines of the American Association of Clinical Endocrinology (AACE) recommend the use of serum C-terminal telopeptide (s-CTX) to assess bone resorption and serum N-terminal propeptide of type I collagen synthesis (P1NP) to assess bone formation. ¹⁹ Patients who respond effectively to antiresorptive therapy should have lower bone turnover and thus lower BTMs. Elevated s-CTX indicates continued high bone turnover and suggests poor treatment compliance, malabsorption, or secondary causes of osteoporosis. In contrast, both formation and resorption BTMs are increased by bone anabolic therapies.

3.6.1 General Principles

Universal recommendations for management of patients with osteoporosis are to ensure adequate calcium and vitamin D intake, a high protein diet, treatment of any vitamin D deficiency, regular weight-bearing exercises, fall prevention, cessation of smoking and reduction of excess use of alcohol (Table 3‑5). The intervention threshold for use of pharmaceutical medications in many countries is based on fracture risk, as calculated using FRAX. With this approach, patients at high risk (cut points vary by country) should be considered candidates for medical therapy. In other regions of the world, notably the U.S., a hybrid approach of recommending treatment for those with a T-score below -2.5 and for those at elevatedfracture risk (>20 major osteoporosis related fracture or > 3% hip fracture) is utilized. Patients with major fragility fractures are candidates for either antiresorptive or anabolic therapy.

3.6.2 Supplements

Vitamin D is essential for proper bone physiology since it promotes calcium absorption, osteoblastic differentiation, osteoblastic mediated mineralization, and calcium regulation, and it collagen cross-linking. Clinically, low vitamin D is associated with sarcopenia and increased fall risk. Vitamin D is associated many other disease states such as cardiovascular disease, diabetes, hypertension, and cancer.

Vitamin D is formed in the skin upon exposure to UV radiation where 7-dehydro-cholesterol is converted to cholecalciferol (vitamin D₃). To become active, cholecalciferol requires two hydroxylations. The first occurs in the liver, where vitamin D₃ is converted to 25-hydroxyvitamin D [25(OH)D]. The kidneys subsequently hydroxylate 25(OH)D to the active form 1–25(OH)₂ D.

Measurement of serum 25(OH)D is accepted as the best approach to determine an individual’s vitamin D status. This metabolite is chosen because it circulates at relatively high concentration and has a long half-life (~3 weeks) and reflects long-term stores. Determination of the optimal level of 25(OH)D has proven difficult because of differences in 25(OH)D assays, which prevents the performance of reasonable meta-analyses. The NIH Vitamin D Standardization Program (VDSP) has developed methodologies allowing use of standardized 25(OH)D data, so progress may be made in this regard. Additionally, but importantly, virtually all previous and ongoing randomized trials of vitamin D supplementation have failed to require volunteers to be low in vitamin D prior to study initiation. It is self-evident that providing more of any nutrient, in this case vitamin D, to individuals that are replete in that nutrient cannot possibly have benefit and could only, potentially, cause harm. In summary, systematic reviews of 25(OH)D status using various assays and also large randomized controlled trials (RCTs) with flawed methodology will not serve to define hypovitaminosis D. In this setting, a common-sense approach to defining vitamin D adequacy was to assume that communities of hunter-gathers in equatorial climates who spend most of their time with high levels of skin exposure represent evolutionary “normal” vitamin D status. In Tanzania, hunter-gather tribes were found to have a mean 25(OH)D of 46 ng/mL. Similarly, surfers in Hawaii had a mean 25(OH)D level (using retrospective assay standardization as recommended by the VDSP) of approximately 36 ng/ml.

Importantly, there is substantial between-individual response in the 25(OH)D increase achieved following initiation of an individual dose of daily vitamin D supplementation. In general, it is recommended to choose larger doses so that as many patients as possible achieve a normal level. Understandably, based on the issues noted above, it is to be expected that expert opinion regarding the optimum 25(OH)D level varies. The 2011 Institute of Medicine report considers a 25(OH)D level of ≥ 20 ng/mL to be adequate, whereas recent AACE guidelines recommend >30 ng/mL as adequate while calling levels between 20 and 30 ng/mL insufficient and those < 20 ng/mL deficient (Table 3‑6). ^{23 ,​ 45}

While controversial, many experts believe that the two available forms of vitamin D (D₃, cholecalciferol and D₂, ergocalciferol) vary in potency. Some, though not all, studies find supplementation with vitamin D3 to be more potent at increasing circulating 25(OH)D; as such, it is generally preferred for treatment. Cholecalciferol is widely available as a stand-alone supplement in doses of 1,000, 2,000 and 5,000 IU. Additionally, 50,000 IU D3 supplements are available. Vitamin D₂ is available in similar doses and is the only form available in the U.S. by prescription. The AACE guidelines recommend 1,000 to 2,000 units per day for general population. ¹⁹ Patients who are vitamin D insufficient (less than 20 ng/mL) are treated either with 50,000 units of vitamin D₂ or D₃ per week for eight weeks or 5,000 IU of vitamin D₃ daily. At 12 weeks, the 25(OH)D level is checked to assure that it is greater than 30 ng/mL. Note that it is important to wait at least 12 weeks to reach a new 25(OH)D steady state given the ~3 week half-life of 25(OH)D. Subsequent to attaining an optimal 25(OH)D level, and one similar to the normal population, 1,000 to 2,000 units of vitamin D₃ are recommended as a daily maintenance dose. Alternative doses may be required in patients with obesity, malabsorption, or who are taking medications that affect vitamin D metabolism. Indeed, it is not possible to estimate an individual’s intake given the difference in 25(OH)D response noted above; as such, in individuals who have sustained fractures, it is prudent to recheck a 25(OH)D level following initiation of a daily maintenance dose.

Like most issues in the vitamin D literature, the definition of toxicity is controversial. Nonetheless, 25(OH) D levels up to ~150 ng/mL are generally well tolerated without evidence of toxicity. The acute toxicity of vitamin D is elevated serum calcium. Massive doses of vitamin D are unwise, as one study of 500,000 IU found this to increase risk of falls and fractures; the mechanism(s) of these unexpected findings are unknown.

Finally, while controversial, it is widely believed that vitamin D deficiency leads to muscle weakness, with resultant increased fall risk. As such, vitamin D supplementation of older adults with a history of falls or at increased fall risk is recommended by both the American Geriatrics Society and the USPSTF. ^{23 ,​ 46} If indeed vitamin D deficiency leads to muscle weakness, it conceivably could contribute to the development of sarcopenia, the age-related reduction in muscle mass and strength. Sarcopenia is increasingly recognized as an important contributor to “osteoporosis-related” fractures due to increased fall risk.