The most widely accepted formal definition of osteoporosis was originally proposed in 1991 and reaffirmed in 1993 at consensus development conferences sponsored by the National Osteoporosis Foundation, the European Foundation for Osteoporosis and Bone Disease, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. At those conferences, osteoporosis was defined as “a systemic skeletal disease, characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture” [1, 2]. This definition of osteoporosis was a departure in many respects from previous definitions of the disease. Prior to 1991, osteoporosis was often described as an “age-related” disorder, which implied that the inevitability of advancing age alone was reason to develop the disease. This also implied an inability to prevent or even successfully treat osteoporosis. In the 1991 and 1993 consensus conference definitions, there is no longer any mention of aging as a causative factor.

Some definitions of osteoporosis also required that a fracture be present before the disease could be said to exist. The 1991 and 1993 consensus conference definition does not require the presence of a fracture. The definition requires only that the skeleton be sufficiently fragile that an individual is at increased risk for fracture. This approach separates the undesirable outcome of a fragile skeleton, fracture, from the disease process itself. This is similar to the approaches taken with hypertension and hypercholesterolemia. For example, the disease hypertension is based on the finding of an increased blood pressure, a quantity that is measured clinically. Once the blood pressure exceeds a certain limit, hypertension is said to exist. Having hypertension places the individual at increased risk for a stroke, although hypertension is not the only cause of stoke. The undesirable outcome of hypertension, then, is a cerebrovascular accident or stoke. The presence of a stroke, however, is not required before it can be said that the disease hypertension exists. The same is true with hypercholesterolemia. This diagnosis is based on the finding of increased levels of cholesterol in the blood, a quantity that is measured clinically. The undesirable outcome of hypercholesterolemia is myocardial infarction or heart attack. It is not necessary for a heart attack to have occurred, however, before the diagnosis of hypercholesterolemia is made.

Hypertension and hypercholesterolemia are both diseases that are based on finding abnormal values of quantities that can be measured clinically, blood pressure and cholesterol. Like these diseases, the 1991 and 1993 consensus conference definitions of osteoporosis suggested that osteoporosis could, at least in part, be defined on the basis of a quantity that could be measured such as the bone mass or density. The clinical measurement of microarchitectural deterioration of bone tissue in vivo remains difficult even today. But the bone mass or density can be readily measured by any one of several different techniques. It only remained to define the level of bone density that resulted in an increased risk for fracture to complete a clinically useful definition of osteoporosis.

The World Health Organization (WHO) criteria for the diagnosis of osteoporosis based on the measurement of bone density were published in 1994 [3]. At the time the criteria were developed, the WHO was attempting to devise criteria that would allow them to estimate the prevalence or percentage of individuals in different countries who might have osteoporosis. In order to do this, some common objective definition of osteoporosis was required. The WHO was actually not attempting to specify a level of bone density that would be used clinically in individuals to diagnose osteoporosis.

The levels of bone density that were ultimately chosen by the WHO were based on reviewing the medical literature that was available at the time. After considering several different approaches to establishing the level of bone density that would be called osteoporosis, the WHO stated that a bone mass or bone density that was 2.5 standard deviations (SD)¹ or more below the average peak bone mass or density of the young adult was sufficiently low to be called osteoporosis [3]. This was based on the finding that the percentage of women in the United States and Great Britain who were thought to have a bone density this low at the hip or at the hip, spine, and forearm combined was very similar to the lifetime risk of hip fracture and the lifetime global fracture risk.² The bone mass or bone density was considered normal if it was not more than 1 SD below the average peak bone density of the young adult. Bone mineral densities that were more than 1 but less than 2.5 SD below the average young adult value were called osteopenic or simply low. A fourth category, called severe or established osteoporosis, referred to individuals who had bone densities that were 2.5 SD or more below the average for a young adult and who also had a fracture. These criteria are summarized in Table 9-1 and again in Appendix B for easy reference. The WHO did not restrict the application of these criteria to measurements at any particular skeletal site while noting that measurements at different sites could result in different diagnoses. The original WHO criteria were given as the number of SDs below the average peak bone mass or density for each diagnostic category. These criteria can readily be converted to T-scores as shown in Table 9-1 since the definition of the T-score in bone densitometry indicates the number of SDs above or below the average peak bone mass or density.³

It should be noted again that the WHO was not attempting to establish diagnostic criteria for the clinician to use in diagnosing individual patients. With the increasing usage of bone densitometry, however, and the consensus conference definitions of osteoporosis that included a finding of low bone mass without an objective level being specified, clinicians understandably began to apply the WHO criteria to individual patients. The WHO criteria were based on information that was relevant only to Caucasian women. Strictly speaking, then, the WHO criteria should be applied only to Caucasian women. In addition, they were most relevant to postmenopausal Caucasian women. The WHO did note in 1994 that in the absence of other criteria, it might not be inappropriate to apply the WHO criteria to mature Caucasian men. There is increasing consensus that the WHO criteria are appropriate for mature men and postmenopausal women of other races. There is little disagreement that the criteria should not be applied to otherwise healthy children, adolescents, and young adults of either sex or any race.

In March 2000, a consensus development conference on osteoporosis prevention, diagnosis, and therapy was sponsored by the National Institutes of Health (NIH) [4]. During this conference, osteoporosis was redefined as a “skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.” This new definition of osteoporosis, although more succinct than its 1991 and 1993 predecessors, was actually intended to be more expansive. Bone strength was considered as being determined not only by bone density but by bone quality as well. Although bone quality referred to bone architecture as mentioned in the 1991 and 1993 consensus conference definitions, it also referred to bone turnover, microfractures, and mineralization. Consistent with the 1991 and 1993 definitions, osteoporosis was not considered an age-related disorder, and fracture was not a prerequisite to the diagnosis. As a practical matter, the 2000 NIH Consensus Development Panel definition of osteoporosis has not affected the clinical implementation of the diagnosis of osteoporosis based on the measurement of bone density.

Peak bone density⁶ refers to the maximum bone mass or density that is attained in life. The average peak bone density at any given skeletal site is used as the reference for the T-score. The age at which peak bone density is reached is the subject of some controversy. It is likely that the age differs depending upon the skeletal site being considered and between the sexes. There is little disagreement that peak bone density is reached by the age of 35. The disagreement begins as that age is revised downward. Many authorities believe that peak bone density is reached in the spine and proximal femur by the age of 20 [13–15]. Anything that interferes with the development of peak bone density places the individual at greater risk of osteoporosis later, because any bone loss that might occur after the attainment of peak bone density will begin from a lower level. There is no question that genetics plays an important role in the maximum level of bone density that is achieved but perhaps 20 % of the determinants of peak bone density are not genetically related. Dietary calcium deficiency and lack of exercise are two factors that have been implicated in the failure to achieve an average peak bone density [16, 17].

Once peak bone density has been reached, the density of the skeleton is maintained by the coordinated efforts of the bone remodeling cells, the osteoblast and osteoclast. The osteoclast actually initiates the resorption or removal of old bone. The osteoblast forms new bone to replace the old bone that has been removed by the osteoclast. In the adult, after the attainment of peak bone density, these processes are balanced or coupled. The amount of bone removed by the osteoclast is replaced by the same amount of new bone under the direction of the osteoblast. When these actions are no longer balanced or become uncoupled, bone loss will begin either because excessive bone is being resorbed by the osteoclast or because too little bone is being replaced by the osteoblast, or both.

Bone loss tends to occur with advancing age. Consequently, the term age-related bone loss is often used to describe the bone loss that occurs in the absence of an obvious disease process. This bone loss should not be mistakenly considered either normal or desirable. It is also quite likely that as more is learned about the factors that cause bone loss, less will be attributed to age alone. The list of known factors that can cause either an increase in osteoclastic bone resorption or decrease in osteoblastic bone formation in the mature adult is lengthy. Such factors include calcium deficiency, smoking, estrogen deficiency, testosterone deficiency, Cushing’s disease, hyperthyroidism, insulin-dependent diabetes, alcohol abuse, malabsorption, use of corticosteroids, anticonvulsants, lithium, GnRH agonists, and long-term heparin.

When the bone density is sufficiently low, little provocation is required to cause a fracture. In the spine, coughing, sneezing, or maintaining a flexed posture can cause fractures. Most hip fractures occur after a fall, although most falls are from a standing height or less [18]. Any factor that increases the risk of falling can increase the risk for hip fracture. Such factors include poor eyesight, poor balance, muscle weakness, seizure disorders, postural hypotension, and use of sedating medications.

The risk of osteoporotic fractures is not the same in men and women or among different races. The reasons for this are not entirely clear. There may be genetic differences that result in the attainment of greater or lesser values for peak bone density. Factors that can cause bone loss may be more prevalent in some populations and in some geographical areas than others. Women have a higher risk of osteoporotic fracture than do men. This is almost certainly attributable in large part to estrogen-deficient bone loss that occurs at menopause. Caucasians, as a race, have the highest risk for osteoporotic fracture, while African-Americans have the lowest [19].

The NOF published guidelines for prescription intervention in osteoporosis. These guidelines have evolved over the years as knowledge has increased and new therapies have become available. The 2010 guidelines [20] describe specific situations in which pharmacologic intervention should be considered. The guidelines are focused on the treatment of osteoporosis to reduce fracture risk and not on the prevention of bone loss. The NOF also emphasized that these guidelines should not be substituted for clinical judgment. The circumstances in which pharmacologic intervention should be considered in postmenopausal women and men aged 50 and older were:

The 2010 American Association of Clinical Endocrinologists (AACE) guidelines [21] for the treatment of postmenopausal osteoporosis are identical to those from the NOF, although AACE issued them in the context of treating postmenopausal osteoporosis only. The treatment guidelines [22] from the North American Menopause Society (NAMS) are also relevant only to postmenopausal women and, again, are identical to those from the NOF.

Guidelines from both Osteoporosis Canada [23] and the National Osteoporosis Guideline Group (NOGG) in the United Kingdom [24] also state that postmenopausal women with a prior fragility fracture should be considered for pharmacologic intervention. The Canadian guidelines [23] otherwise suggest utilizing a FRAX^{® 9} or CAROC 10-year major osteoporotic fracture risk of >20 % to identify individuals as being at high risk and candidates for pharmacologic therapy. In individuals at moderate ­fracture risk based on a 10-year major osteoporotic fracture risk of 10–20 %, other factors which may warrant consideration of pharmacologic intervention include a lumbar spine T-score that is much lower than the femoral neck T-score, a wrist fracture in an individual over age 65 who also has an osteoporotic BMD T-score, rapid bone loss, recurrent falls, men receiving androgen-deprivation therapy¹⁰, and women receiving aromatase-inhibitor therapy. The guidelines for pharmacologic intervention in the absence of a prior fragility fracture from NOGG are also based on FRAX^® 10-year major osteoporotic fracture risk, but the intervention threshold based on that risk varies according to the patient’s age. Graphs illustrating the recommended intervention threshold based on 10-year fracture risk and age can be found in the NOGG Pocket Guide for Healthcare Professionals which is available online at http://www.shef.ac.uk/NOGG/downloads.html.

The prescription medications used in osteoporosis are either antiresorptive or anabolic agents. Antiresorptive agents are approved by the Food and Drug Administration (FDA) for the prevention of osteoporosis, for the treatment of osteoporosis, or both. An antiresorptive agent is a medication that primarily inhibits bone loss rather than stimulating new bone formation. Increases in the measured bone density are observed with these agents, which may seem contradictory if the agents primarily inhibit bone loss. Part of this increase is attributed to the agent stopping additional bone loss while the skeleton rebuilds bone naturally. The bone rebuilding is not being directly stimulated by the antiresorptive agent. The term “anti-catabolic” may be used instead of antiresorptive. This term has not been widely adopted, but its use may be encountered in clinical practice. Estrogen, raloxifene, calcitonin, bisphosphonates, and denosumab are antiresorptive or anti-catabolic agents. There is only 1 anabolic agent, teriparatide, which is currently approved by the FDA for the treatment of osteoporosis. Anabolic agents stimulate bone formation rather than inhibit bone loss.

Agents that have been approved by the FDA for the prevention of bone loss or the prevention of osteoporosis are agents that have been shown to inhibit bone loss. Agents that are FDA-approved for the treatment of osteoporosis have generally been shown in clinical trials to reduce the risk of fractures. The exception to this is in the treatment of osteoporosis in men in which the specific FDA-approved indication is for the treatment of osteoporosis in men to “increase bone mass.” Physicians are not restricted by these approvals from using a medication to treat osteoporosis that has been approved only for prevention and vice versa if it is deemed medically appropriate to do so.