Similarly, a Z-score is the number of standard deviations from the mean bone density for age-matched, sex-matched, and ethnicity-matched patients. For example, a woman 75 years of age with a Z-score of -1.0 is one standard deviation below the BMD of average women 75 years of age, but her T-score may be -3.0 because she is 3 standard deviations below the BMD of an average woman 30 years of age. Alternatively, an elderly patient's T-score may be low, but average for her age by Z-score. For a young adult woman, the T-score and Z-score should be the same.

For each standard deviation decrease in BMD, there is a doubling of fracture risk [18]. A patient with a T-score of -1.0 is twice as likely to sustain a fracture as someone with a T-score of zero; a patient with a T-score of -2.0 indicates a fourfold increase in risk of fracture, and so on. The WHO working group determined that patients with T-scores of at least -2.5, or 2.5 standard deviations below the young healthy mean, would meet the diagnostic criteria for osteoporosis. Those with T-scores from -1.0 to -2.5 would fall into the range for osteopenia (Table 1). Statistically, a cutoff of one standard deviation below the mean would categorize roughly 24% of all women with osteopenia and around 1% with osteoporosis. (Note that these statistics assume a normal distribution of data.)

The WHO criteria are easy to use for study inclusion criteria as well as epidemiologic data; however, individual patient decisions should not be based solely on a T- or Z-score. Just as total cholesterol is not the only risk indicator for coronary events, single quantitative measurements, like a T- or Z-score, must be combined with individual patient characteristics to make clinical decisions. Bone mineral density may account for 70% of bone strength; however, bone quality, the rate of bone turnover, and other architectural properties of bone (as well as genetics) play an important role in the development of osteoporosis and bone fragility [5,21].

Although the WHO definition includes measurement of bone density at several possible sites, such as the spine, heel, or wrist, BMD measured at the hip, femoral neck, and lumbar spine is preferred by most authorities. There are slight variations in the degree of fracture risk with BMD measurements at the different sites (e.g., T-score at the hip correlates to greater fracture risk than the same T-score taken at the spine). If measurements are made at different sites, fracture risk is determined according to the lowest values obtained. It must be emphasized that the WHO BMD T-score diagnostic classification should be used with caution in men and children because established criteria are primarily based on an adult female population. The diagnosis of osteoporosis in these groups should not be made based on densitometric criteria alone; the International Society for Clinical Densitometry (ISCD) has recommended instead that ethnicity- or race-adjusted Z-scores be used [20].

As noted, an estimated 10 million individuals in the United States already have osteoporosis, and another 44 million have low bone density [1,2]. According to data from the BHOF, 8.2 million American women 50 years of age and older have osteoporosis and 27.3 million are at risk of developing the disease [22]. The diagnosis of osteoporosis is important as a predictor of fracture. Osteoporosis results in more than 2 million osteoporotic fractures every year. This number is expected to double or triple by 2040 [23]. To fully understand the epidemiology of osteoporosis, one must examine the effects of race, gender, and age.

Women are the most commonly affected population in the United States due to a lower peak bone mass and an accelerated bone loss in the postmenopausal period [3]. Osteoporosis is under-recognized and undertreated in African American women and is increasing most rapidly among Hispanic women [3,5]. White and Asian women are at highest risk for osteoporotic fracture; African American and Hispanic women have a lower but significant risk [3,5]. The National Osteoporosis Risk Assessment (NORA) study found that the fracture rates in postmenopausal Hispanic, African American, and Asian women were 91%, 54%, and 41%, respectively, of the fracture rates in white women [24].

Men also are affected by osteoporosis, although they represent only about 20% of the cases [5]. Part of the reason for this may be that this population has not been studied as frequently as postmenopausal women. In fact, the number of men with osteoporosis has not been clearly quantified, and the WHO bone mineral density cut-offs are not necessarily applicable. In general, men have greater peak bone mass and greater BMD [3]. As a result, they usually present with fractures 10 years later than women [25]. Sex-specific T-scores are available, but the appropriate cut-offs have not been definitively determined; more research is needed. Up to 20% of hip fractures and 20% of vertebral fractures occur in men. Of note, mortality associated with hip fractures in men is nearly 50% higher than in women [5,25].

All patients lose bone mass as they age. Consequently, the incidence of osteoporosis increases with age. Age does predict fracture risk independent of BMD; however, osteoporosis is not an inevitable consequence of aging [11]. For patients with the same T-score, there is still a significant difference in fracture risk across age groups. For example, a woman 80 years of age with a T-score of -2.0 has a greater risk of hip fracture over 10 years than does a woman 70 years of age with the same T-score. This difference is likely attributable to decreasing bone quality as well as other factors, including unsteadiness, decreasing muscle strength, and comorbidities that occur with aging [24].

The final category is osteoporosis due to secondary causes. This can be from many diseases, including liver disease, rheumatoid arthritis, celiac sprue or other malabsorption syndromes, inflammatory bowel disease, lymphoma, multiple myeloma, thalassemia, acromegaly, amyloidosis, leukemia, and thyrotoxicosis. Nutritional deficiencies or medications that have effects on calcium, sex steroids, or other factors related to bone formation or resorption also may cause secondary osteoporosis [23]. In men, 30% to 60% of osteoporosis cases have been associated with secondary causes [25]. In perimenopausal women, about half of the cases are due to secondary causes, such as hyperthyroidism and anticonvulsant treatment. The most common medications associated with osteoporosis are glucocorticoids. Even small doses (i.e., 2.5–7.5 mg prednisone per day) have been associated with an increase in fractures [23]. Patients with osteoporosis should have possible secondary causes explored, as many of the conditions are treatable.

Osteoporosis is often a silent disease without obvious indications that it is present. However, there are some signs and symptoms that may accompany the development of the condition, including [23,32]:

Quantitative CT can measure the lumbar spine, hip, and peripheral sites. In general, the results are less likely to be affected by degenerative spinal changes than spinal DXA scanning. Unlike DXA, quantitative CT allows for assessment of both cortical and trabecular bone. As a result, it can make volume BMD determinations [20]. Trabecular bone, because of its higher rate of turnover compared with cortical bone, is expected to show metabolic changes earlier [39]. The ability of quantitative CT to enable prediction of spinal fracture is equal to that of DXA scanning in postmenopausal women; there is lack of sufficient evidence for fracture prediction in men [20]. The cost and level of radiation exposure are higher (as much as 200 times greater than some other techniques) [20]. In some cases, this results in decreased patient acceptability.

Given the multitude of tests, there are some general factors to keep in mind when ordering them. For women 65 years of age and younger, vertebral fractures are more common than hip fractures [42]. Therefore, it is prudent to also consider ordering DXA of the spine. For women older than 65 years of age, hip fractures are more common. At the same time, degenerative spinal changes and aortic calcifications make spine imaging more difficult to assess. Therefore, one should consider DXA of the hip or lateral spine, as well as quantitative CT of the hip. DXA of the hip is the best predictor of future hip fracture risk [20]. DXA is also preferred when patients exhibit multiple risk factors. Measurements at two sites are preferable, as this increases sensitivity and specificity. Again, these are general considerations; individual physician's preferences may differ.

Serial measurements may be helpful to assess bone loss rates; however, they should not be performed too often. Follow-up measurements, one to two years apart, may be useful in determining whether patients with normal baseline bone mass demonstrate a rapid loss of BMD. They may also be helpful when assessing persons undergoing treatment to discern whether the treatment has been effective [20]. Presently, DXA is the only method that has been validated for use in serial measurements. Keep in mind that a minimum of two years is typically required to measure any changes in BMD [6,20].

Routine BMD screening has been recommended for women 65 years of age and older, regardless of risk, and for women 50 to 69 years of age with clinical risk factors for fracture (e.g., low body weight, prior fracture, high risk medication use, disease or condition associated with bone loss) [20,33,35,50,51]. The ISCD and BHOF also have recommended routine screening for men 70 years of age and older, regardless of risk factors, and for men 50 to 69 years of age when concerns exist about the patient's risk factor profile (e.g., low body weight, prior fracture, high risk medication use, disease or condition associated with bone loss) [20,33]. The U.S. Preventive Services Task Force (USPSTF) has determined that the evidence is insufficient to recommend for or against routine screening for osteoporosis in men [50]. Additional recommendations for BMD screening include [20,33,35,50,51]:

According to BHOF guidelines, postmenopausal women and men 50 years of age and older who present with any of the following should be considered for treatment [20]:

According to BHOF recommendations, men 50 to 70 years of age should obtain at least 1,000 mg/day of elemental calcium; women 51 years of age and older and men 71 years of age and older require 1,200 mg/day of elemental calcium [20]. National nutrition surveys have revealed that many individuals in the United States consume less than half of the recommended daily amount of calcium in their diet [20]. Dietary supplements may be necessary. Intakes in excess of 1,200–1,500 mg per day provide limited benefit and may increase the risk of developing kidney stones or cardiovascular disease [20]. The upper safe limit for total calcium intake is 2,500 mg/day [23,59].

Calcium supplements are especially necessary in more fragile, older osteoporosis patients; however, the problem of reduced calcium absorption is more acute in older persons. This may be overcome by increasing overall calcium intake and maintaining adequate levels of vitamin D [23]. The best way to increase calcium intake is through diet (e.g., consumption of dairy products), because supplements are not always absorbed well. To increase absorption, supplements should be taken with meals [23]. For patients on acid-reducing medications, calcium citrate should be used because calcium carbonate requires an acidic environment.

According to BHOF recommendations, adults 50 years of age and older should obtain 800–1,000 IU of vitamin D per day; AACE/ACE guidelines recommend 1,000–2,000 IU to maintain optimal serum 25 hydroxyvitamin D levels [20,49]. High-risk patients (e.g., the elderly) may need more. The safe upper limit of daily vitamin D intake for the general adult population was increased to 4,000 IU/day in 2010 [60]. Evidence has shown that higher daily intakes are safe and that some elderly patients may need this amount to maintain optimal serum 25 hydroxyvitamin D levels [20,49]. Keep in mind that both vitamin D and calcium supplements should be combined with other treatments.

Exercises can basically be classified as either aerobic or anaerobic. Aerobic exercise is any activity that uses large muscle groups, is maintained continuously, and is rhythmic in nature. It strengthens the myocardium and improves overall fitness by increasing the body's ability to use oxygen. It does so by increasing the inotropic and chronotropic activity of the heart along with increasing respiratory demand. Examples of aerobic exercise include running, biking, skating, brisk walking, and dancing. Anaerobic exercises typically involve major muscle groups and resistance training, which relate to muscular strength and muscular endurance. Muscular strength involves exerting a force for a brief period of time with repeat contractions until the muscle becomes fatigued. Weightlifting is a good example of an anaerobic muscular strength activity. Muscular endurance involves sustaining repeated contractions or the application of a continual force against a fixed object. Push-ups are an example of muscular endurance. The BHOF has recommended a combination of weight-bearing and resistance type (i.e., muscle strengthening) exercises [20]. The program prescribed will depend on the ability and interests of the individual patient. Patients should be encouraged to exercise at least 30 minutes per day, at least five days per week, eventually working up to 60 minutes per day, if tolerated. Ideally, patients should stretch for 10 minutes prior to exercise. Patients with a history of vertebral compression fracture, as well as those patients with significant musculoskeletal disease or serious degenerative joint disease, should initially participate in a monitored exercise program [11].

The WHI, a large randomized control trial (and an observational study), showed the osteoporosis prevention benefit of combination therapy in healthy, postmenopausal women. Nearly 27,000 women were randomized to conjugated estrogen plus medroxyprogesterone (if they had an intact uterus), conjugated estrogen (if they had a hysterectomy), or placebo. The primary outcome measure was coronary heart disease, but hip fracture was one of the secondary outcomes measured. The results demonstrated a one-third decrease in hip fractures and a 24% to 30% decrease in total fractures among the treatment group [13,23]. The reduction in total fracture risk was significant; however, reductions in vertebral and hip fractures were not statistically significant. The study was stopped before completion due to increases in invasive breast cancer in the treatment group. There was also an increased absolute risk of nonfatal stroke, cognitive impairment, venous thromboembolism, and nonfatal myocardial infarction. A reduced incidence in colon cancer was observed. The authors concluded that hormone replacement is not recommended unless the fracture risk benefit is greater than the risk of cardiovascular disease and breast cancer [13,23].

Another trial, the Heart and Estrogen/Progestin Replacement Study (HERS) and its subsequent follow-up HERS II, studied more than 2,700 postmenopausal women with pre-existing coronary heart disease and an intact uterus. Patients were randomized to conjugated estrogen plus medroxyprogesterone daily versus placebo. The studies involved a mean follow-up of 4.1 years. No significant decrease in hip or total fracture rates was shown for the patients receiving daily combination therapy [76]. The HERS trial showed no protective cardiovascular effects of the treatment and actually showed a 50% increase in cardiovascular events in the treatment group in the first year of the trial. The HERS II trial supported the conclusion from the initial HERS study, which was that hormone replacement therapy does not reduce the risk of cardiovascular events in postmenopausal women with coronary heart disease.

Prior to the studies, hormone replacement therapy was generally considered beneficial; however, recommendations have changed. The USPSTF has recommended against routine use of combination hormone therapy for prevention of chronic disease in postmenopausal women. The USPSTF also has recommended against routine use of unopposed estrogen in patients who have undergone a hysterectomy [77]. Hormone replacement therapy has been implicated in increased risk of breast cancer, stroke, venous thromboembolism, cholecystitis, and possibly coronary heart disease. Unopposed estrogen also has been shown to increase the risk of endometrial cancer. The WHI, HERS, and HERS II studies helped form an argument against hormone therapy in postmenopausal women, and given the other effective treatments for osteoporosis, treatment with hormones is not recommended [77].

While the WHI study findings have been useful, it should be noted that concerns have arisen in response to their conclusions. Specifically, the high average age of the study population (63.3 years of age) and use of only one type of medication and dosage have been the source of much criticism. It is necessary to remember that the use of hormone therapy should be individualized to the patient's needs and medical history. Hormone replacement therapy may be beneficial short-term for a small subset of women with severe fracture risk [23].

Alendronate, a second-generation bisphosphonate, has been shown to be most effective for patients with T-scores less than -2.5 or for patients with previous vertebral fracture. Alendronate has demonstrated the ability to reduce the incidence of wrist, hip, and spinal fractures by 50% over a three-year period in women with a prior fracture of the spine [20]. In the Fracture Intervention Trial (FIT), a large alendronate study, women with osteoporosis and vertebral fracture showed a significant decrease in vertebral and hip fractures [101]. A follow-up trial to FIT, the Fracture Intervention Trial Long-Term Extension (FLEX), showed that when compared with women who stopped alendronate after an average of five years, women who continued alendronate maintained a higher BMD and greater reduction of bone turnover. The risk for vertebral fracture between the two groups was relatively the same. While results indicated that women with very high risk of clinical vertebral fractures may benefit by continuing alendronate beyond five years, study results indicated that more data are needed on the effect of continuation versus discontinuation of alendronate before an optimal length of treatment can be recommended [94,97]. One study sought to predict fracture risk among participants in the FLEX trial by looking only at those assigned to the placebo group [96]. Hip and spine DXA and two biochemical markers of bone turnover were measured when placebo was begun (FLEX baseline) and again after one and three years of follow-up. During five years of placebo, 22% of women in the placebo group experienced one or more symptomatic fractures and 19% had fractures after one year. Age and hip BMD at discontinuation predicted clinical fractures during the subsequent five years [96]. In both the FIT and follow-up FLEX trials, women were encouraged to take 500 mg/day of calcium and 250 IU/day of vitamin D in addition to the alendronate. One study suggests that the success of alendronate therapy may depend on the vitamin D status of patients [102].

PTH acts normally to increase bone resorption in response to low serum calcium levels; however, in intermittent doses, it has been shown to have a favorable impact on bone mineral density [23]. Teriparatide is a portion of human PTH, classified as PTH (1–34) and, as noted, has been approved by the FDA for the treatment of osteoporosis in postmenopausal women at high risk for a fracture. It also has been approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for a fracture [20,23,36,73,123]. The FDA has approved an expanded indication for teriparatide for treatment of osteoporosis associated with sustained systemic glucocorticoid therapy (≥5 mg/day of prednisone). For this indication, teriparatide is available as 20 mcg once daily subcutaneous injection [20,73]. Biosimilar preparations are now available, as the patent expired in 2019 [20].

Teriparatide stimulates new bone formation by increasing the number and action of osteoblasts. Specifically, it increases the number of osteoblasts through the induction of osteoprogenitor cell differentiation in the bone marrow. In addition, it prevents osteoblast apoptosis. It is offered as a daily injection and recommended for use in patients with severe osteoporosis, especially those who have failed other treatments [73]. In a pivotal trial of more than 1,500 postmenopausal women, there was a 65% reduction in new vertebral fractures compared with placebo over 19 months of treatment. New nonvertebral fractures were reduced by 56% [20]. Ninety-six percent of women had an increase in BMD. Side effects included nausea, leg cramps, and dizziness [124].

Sodium fluoride is not currently a recommended treatment for osteoporosis based on the data available as well as significant side effects, including hyperostosis, gastrointestinal irritation, rash, and various neurologic complications. However, sodium fluoride does increase osteoblastic activity and has been shown to cause an increase in spine and hip bone mass [20,123]. Initially, the new bone formed is poorly mineralized, but eventually it is replaced by the lamellar bone structure. Its effect on trabecular bone is more prominent than cortical bone. Significant effects on the rate of vertebral fracture have not been shown in any studies [21].