Medical impact

Fractures and their complications are the relevant clinical sequelae of osteoporosis. The most common fractures are those of the vertebrae (spine), proximal femur (hip), and distal forearm (wrist). However, most fractures in older adults are due at least in part to low bone mass, even when they result from considerable trauma. A recent fracture at any major skeletal site in an adult older than 50 years of age should be considered a significant event for the diagnosis of osteoporosis and provides a sense of urgency for further assessment and treatment. The most notable exceptions are those of the fingers, toes, face, and skull, which are primarily related to trauma rather than underlying bone strength. Fractures may be followed by full recovery or by chronic pain, disability, and death [3].

Hip fractures are associated with an 8 to 36 % excess mortality within 1 year, with a higher mortality in men than in women [4]; additionally, hip fractures are followed by a 2.5-fold increased risk of future fractures [5]. Approximately 20 % of hip fracture patients require long-term nursing home care, and only 40 % fully regain their pre-fracture level of independence [1]. Although the majority of vertebral fractures are initially clinically silent, these fractures are often associated with symptoms of pain, disability, deformity, and mortality [3]. Postural changes associated with kyphosis may limit activity, including bending and reaching.

Multiple thoracic fractures may result in restrictive lung disease, and lumbar fractures may alter abdominal anatomy, leading to constipation, abdominal pain, distention, reduced appetite, and premature satiety. Vertebral fractures, whether clinically apparent or silent, are major predictors of future fracture risk, up to 5-fold for subsequent vertebral fracture and 2- to 3-fold for fractures at other sites. Wrist fractures are less disabling but can interfere with some activities of daily living as much as hip or vertebral fractures.

Pelvic fractures and humerus fractures are also common and contribute to increased morbidity and mortality. Fractures can also cause psychosocial symptoms, most notably depression and loss of self-esteem, as patients grapple with pain, physical limitations, and lifestyle and cosmetic changes.

Risk assessment

All postmenopausal women and men age 50 and older should be evaluated for osteoporosis risk in order to determine the need for BMD testing and/or vertebral imaging. In general, the more risk factors that are present, the greater is the risk of fracture. Osteoporosis is preventable and treatable, but because there are no warning signs prior to a fracture, many people are not being diagnosed in time to receive effective therapy during the early phase of the disease. Many factors have been associated with an increased risk of osteoporosis-related fracture (Table 1).

Table 1

Conditions, diseases, and medications that cause or contribute to osteoporosis and fractures

Lifestyle factors
Alcohol abuse	Excessive thinness	Excess vitamin A
Frequent falling	High salt intake	Immobilization
Inadequate physical activity	Low calcium intake	Smoking (active or passive)
Vitamin D insufficiency
Genetic diseases
Cystic fibrosis	Ehlers-Danlos	Gaucher’s disease
Glycogen storage diseases	Hemochromatosis	Homocystinuria
Hypophosphatasia	Marfan syndrome	Menkes steely hair syndrome
Osteogenesis imperfecta	Parental history of hip fracture	Porphyria
Riley-Day syndrome
Hypogonadal states
Androgen insensitivity	Anorexia nervosa	Athletic amenorrhea
Hyperprolactinemia	Panhypopituitarism	Premature menopause (<40 years)
Turner’s and Klinefelter’s syndromes
Endocrine disorders
Central obesity	Cushing’s syndrome	Diabetes mellitus (types 1 and 2)
Hyperparathyroidism	Thyrotoxicosis
Gastrointestinal disorders
Celiac disease	Gastric bypass	Gastrointestinal surgery
Inflammatory bowel disease	Malabsorption	Pancreatic disease
Primary biliary cirrhosis
Hematologic disorders
Hemophilia	Leukemia and lymphomas	Monoclonal gammopathies
Multiple myeloma	Sickle cell disease	Systemic mastocytosis
Thalassemia
Rheumatologic and autoimmune diseases
Ankylosing spondylitis	Other rheumatic and autoimmune diseases
Rheumatoid arthritis	Systemic lupus
Neurological and musculoskeletal risk factors
Epilepsy	Multiple sclerosis	Muscular dystrophy
Parkinson’s disease	Spinal cord injury	Stroke
Miscellaneous conditions and diseases
AIDS/HIV	Amyloidosis	Chronic metabolic acidosis
Chronic obstructive lung disease	Congestive heart failure	Depression
End-stage renal disease	Hypercalciuria	Idiopathic scoliosis
Post-transplant bone disease	Sarcoidosis	Weight loss
Medications
Aluminum (in antacids)	Anticoagulants (heparin)	Anticonvulsants
Aromatase inhibitors	Barbiturates	Cancer chemotherapeutic drugs
Depo-medroxyprogesterone (premenopausal contraception)	Glucocorticoids (≥5 mg/day prednisone or equivalent for ≥3 months)	GnRH (gonadotropin-releasing hormone) agonists
Lithium cyclosporine A and tacrolimus	Methotrexate	Parental nutrition
Proton pump inhibitors	Selective serotonin reuptake inhibitors
Tamoxifen® (premenopausal use)	Thiazolidinediones (such as Actos® and Avandia®)	Thyroid hormones (in excess)

Open in a separate window

From: The Surgeon General’s Report [1], with modification

Since the majority of osteoporosis-related fractures result from falls, it is also important to evaluate risk factors for falling (Table 2). The most important of these are personal history of falling, muscle weakness and gait, selected medications, balance, and visual deficits [15]. Dehydration is also a risk factor for falls.

Table 2

Risk factors for falls

Environmental risk factors
Lack of assistive devices in bathrooms	Obstacles in the walking path
Loose throw rugs	Slippery conditions
Low level lighting
Medical risk factors
Age	Medications causing sedation (narcotic analgesics, anticonvulsants, psychotropics)
Anxiety and agitation	Orthostatic hypotension
Arrhythmias	Poor vision
Dehydration	Previous falls or fear of falling
Depression	Reduced problem solving or mental acuity and diminished cognitive skills
Vitamin D insufficiency [serum 25-hydroxyvitamin D (25(OH)D)<30 ng/ml (75 nmol/L)]	Urgent urinary incontinence
Malnutrition
Neurological and musculoskeletal risk factors
Kyphosis	Reduced proprioception
Poor balance	Weak muscles/sarcopenia
Impaired transfer and mobility	Deconditioning
Diseases listed in Table 1

Open in a separate window

From: Health Professional’s Guide to the Rehabilitation of the Patient with Osteoporosis [14]

Several of these risk factors have been included in the WHO 10-year fracture risk model (Table 3). As suggested by the WHO [11], this set of risk factors increases fracture risk independently of BMD and can be combined with BMD measurements to assess an individual patient’s risk of future fracture.

Diagnostic assessment

Consider the possibility of osteoporosis and fracture risk based on the presence of the risk factors and conditions outlined in Tables 1 and ​and3.3. Metabolic bone diseases other than osteoporosis, such as hyperparathyroidism or osteomalacia, may be associated with low BMD. Many of these diseases have very specific therapies, and it is appropriate to complete a history and physical examination before making a diagnosis of osteoporosis on the basis of a low BMD alone. In patients in whom a specific secondary, treatable cause of osteoporosis is being considered (Table 1), relevant blood and urine studies (see below) should be obtained prior to initiating therapy. Any adulthood fracture may be an indication of osteoporosis and should be evaluated accordingly. Consider hip and vertebral fractures as indications of osteoporosis unless excluded by the clinical evaluation and imaging. Fractures present a sense of urgency as they signify increased fracture risk over the subsequent 5 years [16]. Patients with recent fractures, multiple fractures, or very low BMD should be evaluated for secondary etiologies.

Osteoporosis affects a significant number of men, yet the condition often goes undetected and untreated. The evaluation of osteoporosis in men requires special consideration as some of the laboratory testing to assess underlying causes in men differs from those in women. Screening BMD and vertebral imaging recommendations for men are outlined in Table 8. The 2012 Endocrine Society’s Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline provides a detailed approach to the evaluation and treatment of osteoporosis in men [17].

Diagnosis

The diagnosis of osteoporosis is established by measurement of BMD or by the occurrence of adulthood hip or vertebral fracture in the absence of major trauma (such as a motor vehicle accident or multiple story fall). Laboratory testing is indicated to exclude secondary causes of osteoporosis [1, 14, 17] (Table 4).

Table 4

Exclusion of secondary causes of osteoporosis

Consider the following diagnostic studies for secondary causes of osteoporosis
Blood or serum
Complete blood count (CBC)
Chemistry levels (calcium, renal function, phosphorus, and magnesium)
Liver function tests
Thyroid-stimulating hormone (TSH) +/− free T4
25(OH)D
Parathyroid hormone (PTH)
Total testosterone and gonadotropin in younger men
Bone turnover markers
Consider in selected patients
Serum protein electrophoresis (SPEP), serum immunofixation, serum-free light chains
Tissue transglutaminase antibodies (IgA and IgG)
Iron and ferritin levels
Homocysteine
Prolactin
Tryptase
Urine
24-h urinary calcium
Consider in selected patients
Protein electrophoresis (UPEP)
Urinary free cortisol level
Urinary histamine

Open in a separate window

BMD measurement and classification

DXA measurement of the hip and spine is the technology used to establish or confirm a diagnosis of osteoporosis, predict future fracture risk, and monitor patients. Areal BMD is expressed in absolute terms of grams of mineral per square centimeter scanned (g/cm²) and as a relationship to two norms: compared to the BMD of an age-, sex-, and ethnicity-matched reference population (Z-score) or compared to a young-adult reference population of the same sex (T-score). The difference between the patient’s BMD and the mean BMD of the reference population, divided by the standard deviation (SD) of the reference population, is used to calculate T-scores and Z-scores. Peak bone mass is achieved in early adulthood, followed by a decline in BMD. The rate of bone loss accelerates in women at menopause and continues to progress at a slower pace in older postmenopausal women (see Fig. 3) and in older men. An individual’s BMD is presented as the standard deviation above or below the mean BMD of the reference population, as outlined in Table 5. The BMD diagnosis of normal, low bone mass (osteopenia), osteoporosis, and severe or established osteoporosis is based on the WHO diagnostic classification (Table 5) [18].

Open in a separate window

Fig. 3

Z- and T-scores in women, from ISCD Bone Densitometry Clinician Course, Lecture 5 (2008), with permission of the International Society for Clinical Densitometry

BMD testing is a vital component in the diagnosis and management of osteoporosis. BMD has been shown to correlate with bone strength and is an excellent predictor of future fracture risk. Instead of a specific threshold, fracture risk increases exponentially as BMD decreases. Although available technologies measuring central (lumbar spine and hip) and peripheral skeletal sites (forearm, heel, fingers) provide site-specific and global (overall risk at any skeletal site) assessment of future fracture risk, DXA measurement at the hip is the best predictor of future hip fracture risk. DXA measurements of the lumbar spine and hip must be performed by appropriately trained technologists on properly maintained instruments. DXA scans are associated with exposure to trivial amounts of radiation.

In postmenopausal women and men age 50 and older, the WHO diagnostic T-score criteria (normal, low bone mass, and osteoporosis) are applied to BMD measurement by central DXA at the lumbar spine and femoral neck [18]. BMD measured by DXA at the one-third (33 %) radius site can be used for diagnosing osteoporosis when the hip and lumbar spine cannot be measured or are unusable or uninterpretable [19]. In premenopausal women, men less than 50 years of age, and children, the WHO BMD diagnostic classification should not be applied. In these groups, the diagnosis of osteoporosis should not be made on the basis of densitometric criteria alone. The International Society for Clinical Densitometry (ISCD) recommends that instead of T-scores, ethnic or race-adjusted Z-scores should be used, with Z-scores of −2.0 or lower defined as either “low bone mineral density for chronological age” or “below the expected range for age” and those above −2.0 being “within the expected range for age” [19].

Who should be tested?

The decision to perform bone density assessment should be based on an individual’s fracture risk profile and skeletal health assessment. Utilizing any procedure to measure bone density is not indicated unless the results will influence the patient’s treatment decision. The US Preventive Services Task Force recommends testing of all women age 65 and older and younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors [20].

Table 6 outlines the indications for BMD testing. BMD measurement is not recommended in children or adolescents and is not routinely indicated in healthy young men or premenopausal women unless there is a significant fracture history or there are specific risk factors for bone loss.

Vertebral imaging

A vertebral fracture is consistent with a diagnosis of osteoporosis, even in the absence of a bone density diagnosis, and is an indication for pharmacologic treatment with osteoporosis medication to reduce subsequent fracture risk [18, 21]. Most vertebral fractures are asymptomatic when they first occur and often are undiagnosed for many years. Proactive vertebral imaging is the only way to diagnose these fractures. The finding of a previously unrecognized vertebral fracture may change the diagnostic classification, alter future fracture risk calculations, and affect treatment decisions [22].

Independent of BMD, age, and other clinical risk factors, radiographically confirmed vertebral fractures (even if completely asymptomatic) are a sign of impaired bone quality and strength and a strong predictor of new vertebral and other fractures. The presence of a single vertebral fracture increases the risk of subsequent fractures 5-fold and the risk of hip and other fractures 2- to 3- fold [23]. Vertebral imaging can be performed using a lateral thoracic and lumbar spine X-ray or lateral vertebral fracture assessment (VFA), available on most modern DXA machines. VFA can be conveniently performed at the time of BMD assessment, while conventional X-ray may require referral to a standard X-ray facility.

Indications for vertebral imaging

Because vertebral fractures are so prevalent in older individuals and most produce no acute symptoms, vertebral imaging tests are recommended for the individuals defined in Table 7. Once a first vertebral imaging test is done, it only needs to be repeated if prospective height loss is documented or new back pain or postural change occurs [3, 24]. A follow-up vertebral imaging test is also recommended in patients who are being considered for a medication holiday, since stopping medication would not be recommended in patients who have recent vertebral fractures.

Table 7

Indications for vertebral imaging

Consider vertebral imaging tests for the following individualsa:

• All women age 70 and older and all men age 80 and older if BMD T-score at the spine, total hip, or femoral neck is ≤−1.0

• Women age 65 to 69 and men age 70 to 79 if BMD T-score at the spine, total hip, or femoral neck is ≤−1.5

• Postmenopausal women and men age 50 and older with specific risk factors:

Low-trauma fracture during adulthood (age 50 and older)

Historical height loss of 1.5 in. or more (4 cm)b

Prospective height loss of 0.8 in. or more (2 cm)c

Recent or ongoing long-term glucocorticoid treatment

Open in a separate window

^aIf bone density testing is not available, vertebral imaging may be considered based on age alone

^bCurrent height compared to peak height during young adulthood

^cCumulative height loss measured during interval medical assessment

Biochemical markers of bone turnover

Bone remodeling (or turnover) occurs throughout life to repair fatigue damage and microfractures in bone and to maintain mineral homeostasis. Biochemical markers of bone remodeling [e.g., resorption markers—serum C-telopeptide (CTX) and urinary N-telopeptide (NTX)—and formation markers—serum bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and aminoterminal propeptide of type I procollagen (PINP)] are best collected in the morning while patients are fasting.

Biochemical markers of bone turnover may [25]:

• Predict risk of fracture independently of bone density in untreated patients

• Predict rapidity of bone loss in untreated patients

• Predict extent of fracture risk reduction when repeated after 3–6 months of treatment with FDA-approved therapies

• Predict magnitude of BMD increases with FDA-approved therapies

• Help determine adequacy of patient compliance and persistence with osteoporosis therapy

• Help determine duration of “drug holiday” and when and if medication should be restarted. (Data are quite limited to support this use, but studies are underway.)

Use of WHO FRAX® in the USA

FRAX® was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of a major osteoporotic fracture (defined as clinical vertebral, hip, forearm, or proximal humerus fracture), taking into account femoral neck BMD and the clinical risk factors shown in Table 3 [11]. The FRAX® algorithm is available at www.nof.org as well as at www.shef.ac.uk/FRAX. It is also available on newer DXA machines or with software upgrades that provide the FRAX® scores on the bone density report.

The WHO algorithm used in this Guide was calibrated to US fracture and mortality rates; therefore, the fracture risk figures herein are specific for the US population. Economic modeling was performed to identify the 10-year hip fracture risk above which it is cost-effective, from the societal perspective, to treat with pharmacologic agents. The US-based economic modeling is described in one report [12], and the US-adapted WHO algorithm and its clinical application are illustrated in a companion report [13].

The latter analyses generally confirm the previous NOF conclusion that it is cost-effective to treat individuals with a prior hip or vertebral fracture and those with a DXA femoral neck T-score ≤−2.5. Previous analyses have established that a lumbar spine T-score ≤−2.5 also warrants treatment [26].

FRAX underestimates fracture risk in patients with recent fractures, multiple osteoporosis-related fractures, and those at increased risk for falling. FRAX® is most useful in patients with low femoral neck BMD. Utilizing FRAX® in patients with low BMD at the lumbar spine but a relatively normal BMD at the femoral neck underestimates fracture risk in these individuals. Specifically, the WHO algorithm has not been validated for the use of lumbar spine BMD. NOF recommends treatment of individuals with osteoporosis of the lumbar spine as well as the hip.

Application of US-adapted FRAX® in the USA

• FRAX® is intended for postmenopausal women and men age 50 and older; it is not intended for use in younger adults or children.

• The FRAX® tool has not been validated in patients currently or previously treated with pharmacotherapy for osteoporosis. In such patients, clinical judgment must be exercised in interpreting FRAX® scores. Patients who have been off osteoporosis medications for 1 to 2 years or more might be considered untreated [27].

• FRAX® can be calculated with either femoral neck BMD or total hip BMD, but, when available, femoral neck BMD is preferred. The use of BMD from nonhip sites is not recommended.

• The WHO determined that for many secondary causes of osteoporosis, fracture risk was mediated primarily through impact on BMD [28]. For this reason, when femoral neck BMD is inserted into FRAX®, the secondary causes of osteoporosis button are automatically inactivated.

The therapeutic thresholds proposed in this Guide are for clinical guidance only and are not rules. All treatment decisions require clinical judgment and consideration of individual patient factors, including patient preferences, comorbidities, risk factors not captured in the FRAX® model (e.g., frailty, falls), recent decline in bone density, and other sources of possible under- or overestimation of fracture risk by FRAX®.

The therapeutic thresholds do not preclude clinicians or patients from considering intervention strategies for those who do not have osteoporosis by BMD (WHO diagnostic criterion of T-score ≤−2.5), do not meet the cut points after FRAX®, or are not at high enough risk of fracture despite low BMD. Conversely, these recommendations should not mandate treatment, particularly in patients with low bone mass above the osteoporosis range. Decisions to treat must still be made on a case-by-case basis.

Adequate intake of calcium and vitamin D

Advise all individuals to obtain an adequate intake of dietary calcium. Providing adequate daily calcium and vitamin D is a safe and inexpensive way to help reduce fracture risk. Controlled clinical trials have demonstrated that the combination of supplemental calcium and vitamin D can reduce the risk of fracture [29]. A balanced diet rich in low-fat dairy products, fruits, and vegetables provides calcium as well as numerous nutrients needed for good health. If adequate dietary calcium cannot be obtained, dietary supplementation is indicated up to the recommended daily intake.

Lifelong adequate calcium intake is necessary for the acquisition of peak bone mass and subsequent maintenance of bone health. The skeleton contains 99 % of the body’s calcium stores; when the exogenous supply is inadequate, bone tissue is resorbed from the skeleton to maintain serum calcium at a constant level.

NOF supports Institute of Medicine (IOM) recommendations that men age 50–70 consume 1000 mg/day of calcium and that women age 51 and older and men age 71 and older consume 1200 mg/day of calcium [30]. There is no evidence that calcium intake in excess of these amounts confers additional bone strength. Intakes in excess of 1200 to 1500 mg/day may increase the risk of developing kidney stones, cardiovascular disease, and stroke. The scientific literature is highly controversial in this area [31–34].

Table 9 illustrates a simple method for estimating the calcium content of a patient’s diet. The average daily dietary calcium intake in adults age 50 and older is 600 to 700 mg/day. Increasing dietary calcium is the first-line approach, but calcium supplements should be used when an adequate dietary intake cannot be achieved.

Vitamin D plays a major role in calcium absorption, bone health, muscle performance, balance, and risk of falling. NOF recommends an intake of 800 to 1000 international units (IU) of vitamin D per day for adults age 50 and older. Institute of Medicine Dietary Reference Intakes for vitamin D are 600 IU/day until age 70 and 800 IU/day for adults age 71 years and older [30].

Chief dietary sources of vitamin D include vitamin D-fortified milk (400 IU/quart, although certain products such as soy milk are not always supplemented with vitamin D), some fortified juices and cereals (40 to 50 IU/serving or more), salt water fish, and liver. Some calcium supplements and most multivitamin tablets also contain vitamin D. Supplementation with vitamin D₂ (ergocalciferol) or vitamin D₃ (cholecalciferol) may be used. Vitamin D₂ is derived from plant sources and may be used by individuals on a strict vegetarian diet.

Many older patients are at high risk for vitamin D deficiency, including patients with malabsorption (e.g., celiac disease) or other intestinal diseases (e.g., inflammatory bowel disease, gastric bypass surgery), chronic renal insufficiency, patients on medications that increase the breakdown of vitamin D (e.g., some antiseizure drugs), housebound patients, chronically ill patients and others with limited sun exposure, individuals with very dark skin, and obese individuals. There is also a high prevalence of vitamin D deficiency in patients with osteoporosis, especially those with hip fractures, even in patients taking osteoporosis medications [35, 36].

Since vitamin D intakes required to correct vitamin D deficiency are so variable among individuals, serum 25(OH)D levels should be measured in patients at risk of deficiency. Vitamin D supplements should be recommended in amounts sufficient to bring the serum 25(OH)D level to approximately 30 ng/ml (75 nmol/L) and a maintenance dose recommended to maintain this level, particularly for individuals with osteoporosis. Many patients with osteoporosis will need more than the general recommendation of 800–1000 IU/day. The safe upper limit for vitamin D intake for the general adult population was increased to 4000 IU/day in 2010 [30].

Treatment of vitamin D deficiency

Adults who are vitamin D deficient may be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week or the equivalent daily dose (7000 IU vitamin D₂ or vitamin D₃) for 8–12 weeks to achieve a 25(OH)D blood level of approximately 30 ng/ml. This regimen should be followed by maintenance therapy of 1500–2000 IU/day or whatever dose is needed to maintain the target blood level [37, 38].

Regular weight-bearing and muscle-strengthening exercise

Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures [39–42]. Among the many health benefits, weight-bearing and muscle-strengthening exercise can improve agility, strength, posture, and balance, which may reduce the risk of falls. In addition, exercise may modestly increase bone density. NOF strongly endorses lifelong physical activity at all ages, both for osteoporosis prevention and overall health, as the benefits of exercise are lost when people stop exercising.

Weight-bearing exercise (in which bones and muscles work against gravity as the feet and legs bear the body’s weight) includes walking, jogging, Tai Chi, stair climbing, dancing, and tennis. Muscle-strengthening exercise includes weight training and other resistive exercises, such as yoga, Pilates, and boot camp programs. Before an individual with osteoporosis initiates a new vigorous exercise program, such as running or heavy weight-lifting, a clinician’s evaluation is appropriate.

Fall prevention

Major risk factors for falling are shown in Table 2. In addition to maintaining adequate vitamin D levels and physical activity, as described above, several strategies have been demonstrated to reduce falls. These include, but are not limited to, multifactorial interventions such as individual risk assessment, Tai Chi and other exercise programs, home safety assessment, and modification especially when done by an occupational therapist, and gradual withdrawal of psychotropic medication if possible. Appropriate correction of visual impairment may improve mobility and reduce risk of falls.

There is a lack of evidence that the use of hip protectors by community-dwelling adults provides statistically significant reduction in the risk of hip or pelvis fractures. Also, there is no evidence that the use of hip protectors reduces the rate of falls. In long-term care or residential care settings, some studies have shown a marginally significant reduction in hip fracture risk. There are no serious adverse effects of hip protectors; however, adherence to long-term use is poor [43]. There is additional uncertainty as to which hip protector to use, as most of the marketed products have not been tested in randomized clinical trials.

Who should be considered for treatment?

Postmenopausal women and men age 50 and older presenting with the following should be considered for treatment:

• A hip or vertebral fracture (clinically apparent or found on vertebral imaging). There are abundant data that patients with spine and hip fractures will have reduced fracture risk if treated with pharmacologic therapy. This is true for fracture patients with BMD in both the low bone mass and osteoporosis range [49–58]. In patients with a hip or spine fracture, the T-score is not as important as the fracture itself in predicting future risk of fracture and antifracture efficacy from treatment.

• T-score ≤−2.5 at the femoral neck, total hip, or lumbar spine. There is abundant evidence that the elevated risk of fracture in patients with osteoporosis by BMD is reduced with pharmacotherapy [52, 57, 59–70].

• Low bone mass (T-score between −1.0 and −2.5 at the femoral neck or lumbar spine) and a 10-year probability of a hip fracture ≥3 % or a 10-year probability of a major osteoporosis-related fracture ≥20 % based on the US-adapted WHO algorithm [13, 15, 71, 72].

Although FRAX calculated fracture risk prediction has been confirmed in multiple studies, there are relatively few data confirming fracture risk reductions with pharmacotherapy in this group of patients.

US FDA-approved drugs for osteoporosis

Current FDA-approved pharmacologic options for the prevention and/or treatment of postmenopausal osteoporosis include, in alphabetical order: bisphosphonates (alendronate, alendronate plus D, ibandronate, risedronate and zoledronic acid), calcitonin, estrogens (estrogen and/or hormone therapy), estrogen agonist/antagonist (raloxifene), tissue-selective estrogen complex (conjugated estrogens/bazedoxifene), parathyroid hormone (PTH [1–34], teriparatide), and the receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL) inhibitor denosumab. Please see prescribing information for specific details of their use.

The antifracture benefits of FDA-approved drugs have mostly been studied in women with postmenopausal osteoporosis. There are limited fracture data in glucocorticoid-induced osteoporosis and in men. FDA-approved osteoporosis treatments have been shown to decrease fracture risk in patients who have had fragility fractures and/or osteoporosis by DXA. Pharmacotherapy may also reduce vertebral fractures in patients with low bone mass (osteopenia) without fractures, but the evidence supporting overall antifracture benefit is not as strong. Thus, the clinician should assess the potential benefits and risks of therapy in each patient and the effectiveness of a given osteoporosis treatment on reduction of vertebral and nonvertebral fractures.

Note that the intervention thresholds do not take into account the nonskeletal benefits or risks associated with specific drug use. NOF does not advocate the use of drugs not approved by the FDA for prevention and treatment of osteoporosis. Examples of these drugs are listed in Table 11 for information only.

Bisphosphonates

Calcitonin

Estrogen/hormone therapy (ET/HT)

Estrogen agonist/antagonist (formerly known as SERMs): Raloxifene

Tissue-selective estrogen complex: conjugated estrogens/bazedoxifene (conjugated estrogens paired with estrogen agonist/antagonist)

Parathyroid hormone: teriparatide

RANKL/RANKL inhibitor: denosumab

Sequential and combination therapy

When osteoporosis is diagnosed in young individuals, choices of osteoporosis medication may change over time to take advantage of the best benefit to risk ratio at each stage of life (sequential monotherapy). For more severe osteoporosis, sequential treatment with anabolic therapy followed by an antiresorptive agent is generally preferred to concomitant combination therapy. However, combination therapy with teriparatide and an antiresorptive can be considered in a few clinical settings in patients with very severe osteoporosis such as spine and hip fractures. There are few indications for combining two antiresorptive treatments, but such options could be considered in the short term in women who are experiencing active bone loss while on low dose HT for menopausal symptoms or raloxifene for breast cancer prevention.

Duration of treatment

No pharmacologic therapy should be considered indefinite in duration. All nonbisphosphonate medications produce temporary effects that wane upon discontinuation. If these treatments are stopped, benefits rapidly disappear. In contrast, bisphosphonates may allow residual effects even after treatment discontinuation. Therefore, it may be possible to discontinue bisphosphonates and retain residual benefits against fracture at least for several years.

Evidence of efficacy beyond 5 years is limited, whereas rare safety concerns such as ONJ and atypical femur fractures become more common beyond 5 years [67, 92]. Since there is no extensive evidence base to guide treatment duration decisions, duration decisions need to be individualized [93]. After the initial 3- to 5-year treatment period, a comprehensive risk assessment should be performed. This should include interval clinical history, particularly with respect to intercurrent fracture history and new chronic diseases or medications, as well as height measurement, BMD testing, and vertebral imaging if there has been any documented height loss during the treatment period. It is reasonable to discontinue bisphosphonates after 3 to 5 years in people who appear to be at modest risk of fracture after the initial treatment period. In contrast, for those who appear to be at high risk for fracture, continued treatment with a bisphosphonate or an alternative therapy should be considered [94].

Monitoring patients

It is important to ask patients whether they are taking their medications and to encourage continued and appropriate compliance with their osteoporosis therapies to reduce fracture risk. It is also important to review their risk factors and encourage appropriate calcium and vitamin D intakes, exercise, fall prevention, and other lifestyle measures. Furthermore, the need for continued medication to treat osteoporosis should be reviewed annually. Duration of treatment must be individualized. Some patients may be able to discontinue treatment temporarily after several years of therapy, particularly after bisphosphonate administration [95, 96]. Other patients will need to continue treatment. If treatment is discontinued, serial monitoring should include clinical assessment for fractures, falling, any interval chronic disease occurrence and consideration of serial BMD testing, use of biochemical markers, and vertebral imaging in some patients.

Accurate yearly height measurement is a critical determination of osteoporosis treatment efficacy. Patients who lose 2 cm (or 0.8 in.) or more in height either acutely or cumulatively should have a repeat vertebral imaging test to determine if new or additional vertebral fractures have occurred since the prior vertebral imaging test.

Serial central DXA testing is an important component of osteoporosis management. Measurements for monitoring patients should be performed in accordance with medical necessity, expected response, and in consideration of local regulatory requirements. NOF recommends that repeat BMD assessments generally agree with Medicare guidelines of every 2 years but recognizes that testing more frequently may be warranted in certain clinical situations.

The following techniques may be used to monitor the effectiveness of treatment:

The NOF acknowledges the members of the 2008 Clinican’s Guide Develoment Committee, Bess Dawson-Hughes, Sundeep Khosla, L. Joseph Melton III, Anna N.A. Tosteson, Murray Favus, and Sanford Baim, and the consultants to the 2014 Update Committee, Karl Insogna, Douglas Kiel, Harold Rosen, and John Schousboe.