fulltext title banner


OSTEOPOROSIS

KEY POINTS

  • Osteoporosis is a common metabolic bone disorder affecting older adults that is preventable and treatable. The resultant fractures can lead to chronic pain, decreased mobility, loss of independence and function, and increased mortality.

  • Bone mineral density (BMD) measurement establishes the diagnosis of osteoporosis (T-score ≤–2.5). Osteoporosis can also be defined clinically in at-risk people who sustain a fragility or low-trauma fracture.

  • Secondary osteoporosis should be excluded in men and women with osteoporosis. Common causes of secondary osteoporosis include glucocorticoid use, hyperparathyroidism, hypogonadism, hyperthyroidism, hypercalciuria, and vitamin D deficiency.

  • Screening for osteoporosis is recommended for all postmenopausal women ≥65 years old and both women and men ≥50 years old with risk factors for osteoporosis. FRAX is a free online clinical tool for estimating the 10-year probability of osteoporotic fracture based on a patient’s clinical risk factors and femoral neck BMD.

  • Prevention of osteoporosis includes adequate calcium and vitamin D intake, weight-bearing exercise, and reduction of known risk factors for osteoporosis.

  • Bisphosphonates are first-line pharmacologic therapy for osteoporosis. Other pharmacologic therapies to consider include denosumab, teriparatide, and abaloparatide.

Osteoporosis, the most common metabolic bone disease, is a major cause of morbidity, loss of independence, and mortality in older adults. It is a systemic skeletal disorder defined by decreased bone strength, density, and quality with an increasing risk of fractures. Osteoporosis is a silent disease that requires astute clinical monitoring for risk factors and active screening. Once osteoporosis is diagnosed, multiple treatment options for reducing risk of fractures are available.

Although strong evidence exists for fracture prevention with appropriate treatment, prescription of osteoporosis medications has been declining. In fact, use of the first-line treatment for osteoporosis, bisphosphonates, has declined by 50% from 2008 to 2012. Declining use of osteoporosis treatments is primarily driven by concerns over rare medication adverse effects, despite the known reduction in fracture risk with treatment. It is imperative for clinicians to be well versed in identification and safe treatment of osteoporosis to reduce the morbidity and mortality associated with this disease.

OSTEOPOROSIS DEFINITION

Osteoporosis is defined by a bone mineral density (BMD) measurement ≤2.5 standard deviations below the young normal adult reference (T-score ≤–2.5), or a minimal trauma fracture of the spine, proximal humerus, hip, and/or forearm in a patient with osteopenia (T-score between ­–1 and ­–2.5). For the WHO standardized criteria for BMD measurements of the spine, hip, or forearm, see Table 1. A low-trauma fracture is defined as any nonpathologic fracture that occurs from a fall from standing height or less. While still controversial, there is also a call by organizations like the National Osteoporosis Foundation (NOF) and the European and Canadian counterparts to incorporate risk assessment tools like the FRAX score in the categorization of osteoporosis.

Table 1—WHO Bone Mineral Density Definitions
Classification
Bone Mineral Density (BMD)
T-score
Normal
Within one SDa of reference meanb
≥–1.0
Osteopenia (low bone mass)
More than 1 but less than 2.5 SD below reference mean
Between –1.0 and –2.5
Osteoporosis
2.5 or more SD below reference mean
≤–2.5
Severe osteoporosis
Below 2.5 SD of reference mean in the presence of one or more fragility fractures
<–2.5
a Standard deviation
b For young, normal adult

EPIDEMIOLOGY AND IMPACT

In 2010, NOF estimated that approximately 10.2 million Americans have osteoporosis by bone density criteria. An additional 43.4 million adults ≥50 years old were found to have low bone density, increasing their risk of fractures. Osteoporosis affects people of all ethnic backgrounds. While less prevalent than in the estimated 7.7 million white and Asian American adults, osteoporosis is found in 600,000 Mexican Americans and 500,000 non-Hispanic blacks ≥50 years old.

Osteoporosis is the most common cause of fracture in older adults. In 2005, osteoporosis caused >2 million fractures in the United States; this number is expected to rise to >3 million by the year 2025. One in two postmenopausal women and up to one in five men >50 years old will have an osteoporotic-related fracture in their remaining lifetime. Mortality risk is estimated to increase 20% in older adults in the year after a hip fracture, with the rate of death in men nearly double that in women (SOE=B). Vertebral and pelvic fractures have also been linked with increased mortality, generally from associated comorbidities. Based on several meta-analyses, the increased mortality risk persists for at least 10 years after the hip-fracture event. Hip fractures are also associated with 2.5-fold increased risk of future fractures. Hip fracture rates in black Americans, Japanese Americans, Hispanics, and Native Americans occur at lower frequencies than in white Americans, with the rate of hip fractures in Mexican Americans higher than that of other Hispanic groups.

Osteoporotic fractures can lead to permanent declines in functional status, independence, and quality of life. In patients who were previously ambulatory, approximately 40% regained their previous level of functioning after hip fracture and 20% required long-term nursing-home care. Pain, kyphosis, height loss, and other changes in body habitus can develop from vertebral fractures. Patients may be unable to bathe, dress, or walk independently. The economic costs associated with osteoporotic-related fractures are substantial. In 2005, the total direct health care costs were estimated at $19 billion. By 2025, this number is expected to rise to $25.3 billion. Thus, because of the substantial social and economic costs associated with osteoporotic fractures in older adults, reduction of this burden is widely seen as a health care policy imperative.

BONE REMODELING AND BONE LOSS IN AGING

Bone is a dynamic tissue that undergoes active remodeling (also called bone turnover), a coupled process of bone resorption followed by bone formation occurring throughout adult life. Bone remodeling maintains both skeletal strength (through repair of microfractures) and systemic calcium homeostasis.

Bone mass changes over the life span of an individual. In women, bone mass increases rapidly from puberty until approximately the mid-20s to mid-30s, when bone mass peaks. Once women reach peak bone mass, bone loss occurs very slowly until the onset of menopause. After menopause, the rate of bone loss is accelerated for 8–10 years. Bone loss continues in later life, albeit at a slower rate of 1%–2% per year; however, some older women may lose bone density at a higher rate. Data suggest that reducing bone loss and skeletal turnover will decrease fracture risk.

Like women, men also lose bone with age, starting slowly in their late 20s to early 30s. However, the pattern of bone loss between sexes is different. Cortical bone, which forms the hardened exterior of the bones and provides most of the support and resistance to compression, undergoes accelerated decline in women at around age 50; this occurs later in men, around age 75, and correlates with the increase in vertebral fractures from osteoporosis. This difference in cortical bone thinning between women and men is predominantly mediated by reduction in sex hormones with age and menopause.

RISK FACTORS FOR OSTEOPOROSIS

Intrinsic

The pathogenesis of osteoporosis in men and women is complex, encompassing factors that affect the level of peak bone mass, the rate of bone resorption, and the rate of bone formation. A multitude of factors, including genetic, endocrine, nutrition, skeleton loading, disease states, and medication combine to affect the risk of developing osteoporosis.

Genetics

Heritable traits account for 75%–­80% of a person’s peak bone mass. Epidemiologic studies demonstrated possible linkage of low birth size, late menarche, and low childhood height and weight to increased risk of osteoporosis. Genetic factors can also contribute to an increased risk of coronary artery disease, hypertension, and type II diabetes, all of which correlate with greater likelihood of osteoporosis. Furthermore, sex and genetic traits affect levels of sex hormones and sensitivity to hormonal and nutritional factors. Genetic variations are rarely the direct cause of osteoporosis but increase a person’s susceptibility to osteoporosis through intrinsic and extrinsic pathways.

Sex Hormones

After menopause, the natural decline of estrogen levels is associated with increased risk of osteoporosis and fracture (SOE=A). Increased resorption appears to be the major factor for bone loss in estrogen deficiency. Evidence also suggests a role of estrogen deficiency in reducing bone formation over time.

Estrogen has both direct and indirect effects on osteoclasts, the cells that are responsible for bone resorption and bone loss. It acts through multiple pathways to decrease the expression of human receptor activator of nuclear factor kappa-B ligand (RANKL), the major cytokine that promotes development and differentiation of osteoclasts to mature forms. Estrogen also has direct effects on cells of hematopoietic lineage, including osteoclast precursors, mature osteoclasts, and lymphocytes.

In men, bioavailable testosterone and estrogen decrease with aging mainly due to an increase in sex hormone-binding globulin levels. Approximately half of men >70 years old have bioavailable testosterone levels below the normal reference range of young adults. Several studies demonstrated that late-onset hypogonadism plays a role in osteoporosis in men; however, estrogen has shown a stronger correlation with bone metabolism than testosterone.

Skeleton Loading

Weight-bearing bones require a level of stress from gravity while walking and dynamic strain of muscular contractions to maintain BMD. The importance of bone loading is most evident in space flight, where astronauts have been shown to lose 3% of vertebral bone mass within 15 days of weightlessness. Similar effects on weight-bearing bones are seen in studies evaluating prolonged bedrest. Exercise that stresses or mechanically loads bones, including strength training, aerobics, walking, and Tai Chi, reduce BMD loss in the spine and hip in postmenopausal women based on a Cochrane review (SOE=B).

Calcium and Vitamin D Deficiency

Calcium deficiency and disruption of calcium homeostasis is another mechanism for bone loss in older adults. With age, intestinal absorption of calcium declines. Vitamin D plays a vital role in regulating calcium homeostenosis. Vitamin D production is lowered in aging skin, and decreased exposure to sunlight reduces the conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) by ultraviolet light. Older black Americans are at particular risk of vitamin D deficiency as they age.

The hormonally active form of vitamin D is 1,25(OH)2D3, or calcitriol. It is necessary for optimal intestinal absorption of calcium and phosphorus, and it also exerts a tonic inhibitory effect on parathyroid hormone (PTH) synthesis. Vitamin D deficiency not only contributes to accelerated bone loss and increasing fragility but also appears to promote muscle weakness that can increase risk of falls.

Decreased serum concentration of calcium and 1,25(OH)2D3 lead to increased levels of PTH. When levels are chronically increased, PTH becomes a stimulator of bone resorption. Trials involving older adults at high risk of calcium and vitamin D deficiency show that supplementation of both can reverse secondary hyperparathyroidism (SOE=A), increase bone mass (SOE=B), and decrease bone resorption (SOE=A) and fracture rates (SOE=B).

Extrinsic Factors

Smoking increases risk of fractures in both current and former smokers. The risk of fractures is moderated more by the amount of nicotine smoked and how recently one quit smoking than by the duration of tobacco use. Also, chronic heavy alcohol use decreases bone turnover and bone formation. Drinking >3 oz of alcohol per day early and/or later in life increase bone loss and fracture risk (SOE=A). Nutrition, exercise, and use of certain medications can further modulate a person’s risk of fractures.

PREDICTION AND DIAGNOSIS OF FRACTURES

Osteoporosis is a preventable disease; however, because bone loss is silent, it is often not diagnosed until a fracture occurs. The NOF recommends clinical assessment of osteoporosis risk factors for all postmenopausal women and men ≥50 years old. The diagnosis of osteoporosis should be considered in any older adult with a fracture.

Evaluation of Risk Factors

Clinical evaluation begins with a thorough history to identify risk factors that may lead to increased bone fragility. Risk factors for osteoporosis and osteoporotic fracture have been identified (Table 2) and can be used to determine who should be placed on preventive or therapeutic regimens. Obtaining a thorough history of fractures and the setting in which the fractures occurred is important. Fracture from osteoporosis is the greatest risk factor for future fractures. WHO has developed a 10-year fracture risk model (FRAX) (www.shef.ac.uk/FRAX) that can be used clinically, independent of BMD, to identify adults at high risk of fracture. Given that falls are a major cause of osteoporosis-related fractures, a fall risk evaluation should be conducted.

Table 2─Risk Factors for Osteoporosis
  • Age (postmenopausal women, men >70 years old)
  • Female sex
  • Low body weight (BMI <20 kg/m2)
  • 10% decrease in weight (from usual adult body weight)
  • Physical inactivity
  • Glucocorticoids
  • Previous fragility fracture as adult
  • White or Asian race
  • Current smoking
  • Low dietary calcium
  • Alcohol intake ≥3 drinks a day

Secondary Causes

Excluding other causes that lead to fractures or low bone mass is important in evaluating women and men with osteoporosis. For the major secondary causes of osteoporosis, see Table 3. Certain laboratory tests should be considered for all older adults with a new diagnosis of osteoporosis; additional specific tests are recommended for adults in which there is clinical suspicion of secondary causes (Table 4).

Table 3—Causes of Secondary Osteoporosis

Endocrine
  • Hypogonadism
  • Hyperthyroidism
  • Hypercortisolism (Cushing syndrome)
  • Hyperparathyroidism
  • Diabetes mellitus (insulin dependent)
GI disorders/nutrition/malabsorption
  • Celiac disease
  • Inflammatory bowel disease
  • Gastric resection or gastric bypass
  • Vitamin D deficiency
  • Alcoholism
  • Chronic liver disease
Hematologic disease
  • Multiple myeloma
  • Leukemia
  • Lymphoma
  • Thalassemia
Medications
  • Glucocorticoids
  • Proton-pump inhibitors
  • Gonadotropin releasing-hormone agonists
  • Androgen deprivation therapy
  • Aromatase inhibitors
  • Thiazolidinediones
  • Canagliflozin and other SGLT-2 inhibitors
  • Anticonvulsants
  • SSRIs
  • Cancer chemotherapeutic agents
  • Methotrexate
  • Heparin
  • Excess thyroid hormone replacement
Other
  • Idiopathic hypercalciuria
  • Solid organ transplantation
  • Immobilization

Table 4—Recommended Initial Laboratory Testing in Those with Osteoporosis*
Initial recommended testing
  • Fasting comprehensive metabolic panel, including electrolytes, creatinine, calcium, serum phosphorus, liver enzymes, total protein, albumin, and alkaline phosphatase
  • Complete blood count
  • 25-hydroxy vitamin D
  • 24-hour urine collection for calcium and creatinine
  • Parathyroid hormone
  • Thyrotropin-stimulating hormone
Consider in select patients
  • Serum protein electrophoresis (suspect multiple myeloma)
  • Urine protein electrophoresis (suspect multiple myeloma)
  • Tissue transglutaminase antibodies (suspect celiac disease)
  • Urine free cortisol (suspect Cushing syndrome)
  • Testosterone in men (suspect hypogonadism)
* Modified from National Osteoporosis Foundation and American College of Endocrinology Clinical Practice Guidelines

Idiopathic hypercalciuria, found in approximately 10% of the general population, is an important secondary cause of osteoporosis. It is diagnosed by a 24-hour urinary calcium excretion >4 mg/kg and can be treated with a thiazide-type diuretic. Primary hyperparathyroidism is a common cause of secondary osteoporosis in women, with an incidence in older women as high as 1:500. An observational study suggested preservation of BMD in women who undergo parathyroidectomy. Secondary causes of osteoporosis are commonly found in men, with only 40% of cases having no identifiable secondary cause on laboratory testing (SOE=B). The most commonly reported secondary causes of osteoporosis in men include hypogonadism, medications, and excessive alcohol use.

Medication use is an important secondary cause for osteoporosis, with glucocorticoids being the most common culprit in men and women. An estimated 2.5% of people 70–79 years old take an oral glucocorticoid. Glucocorticoid-induced osteoporosis is caused by an early increase in bone resorption. Prolonged exposure reduces osteoblastogenesis, resulting in low bone turnover and decreased bone formation. Fracture risk increases rapidly in the first 3–6 months and continues to progress during the duration of glucocorticoid use. Increased fracture risk may be present with daily dosages as low as 2.5–7.5 mg/d (prednisone or equivalent). The risk of fracture positively correlates with increasing glucocorticoid dosages and duration, partially independent of BMD. Stopping glucocorticoids is associated with a decrease in fracture risk, although it is unclear if the risk ever returns to the preexposure level. Limited evidence suggests that large doses of high-potency inhaled steroids can also result in bone loss. The best strategy for older adults who require long-term glucocorticoid therapy is to maximize bone health by a variety of interventions, including using the lowest possible dosage of glucocorticoids, ensuring adequate intake of calcium and vitamin D, serial monitoring of BMD, and starting prescription osteoporosis therapy if appropriate (see treatment, below). Other medications that adversely affect BMD are listed in Table 3. When evaluating patients for osteoporosis, clinicians should also remember to review medications that increase risk of falls.

Physical Examination

The physical examination is directed toward detecting signs of fracture as well as potential secondary causes. Key elements include height, weight, posture, mobility, nutritional status, and overall build. Vertebral fractures are suggested by thoracic kyphosis, although this finding is not diagnostic. Wall-to-occiput distance >0 cm and ribs-pelvis distance ≤2 fingerbreadths suggests a spinal thoracic or lumbar fracture. Height loss >4 cm in women and >6 cm in men from peak young adult height or prospective height loss of 2 cm in women and 3 cm in men is also suggestive of previous vertebral fracture.

Bone Mineral Density Measurement

BMD measurement establishes the diagnosis of osteoporosis and is a potent predictor of fracture risk. The relative risk of fracture is 10 times greater in women whose BMD is in the lowest quartile versus those whose BMD is in the highest quartile (SOE=A).

BMD of the hip, spine, wrist, or calcaneus can be measured by a variety of techniques. The preferred method is central DEXA, which measures BMD of the proximal femur and lumbar spine. Femoral neck BMD is the best predictor of hip and other osteoporotic fractures. Other methods (not currently recommended in the United States although used globally) of measuring BMD include quantitative CT, ultrasonography of the calcaneus, single radiographic absorptiometry of the calcaneus, peripheral DEXA, and radiographic absorptiometry.

BMD measurements are typically expressed as a Z or a T-score. Z-scores represent the relationship between a patient’s BMD to the expected BMD for the patient’s age and sex, while a T-score compares the BMD to “young normal” adults of the same sex. The lowest T-score from the lumbar spine, femoral neck, or total proximal femur is used to make the overall diagnosis. Forearm BMD from the distal third of the radius can be used for diagnosis, specifically if the hip or spine imaging cannot be interpreted, the patient has a history of hyperparathyroidism, or the patient weighs >300 pounds. For every 1-unit decrease in T-score, fracture risk at the spine and hip approximately doubles. For example, if a woman has a T-score of −2, her risk of fracture is 4 times that of a woman with normal bone density for her age (controlled for height and weight).

Osteoporosis Screening Guidelines

Based on U.S. Preventive Services Task Force (USPSTF) guidelines, there is insufficient evidence to recommend screening in men (SOE=C). However, the NOF recommends screening all men ≥70 years old regardless of risk factors (SOE=C). Per the NOF, DEXA is also recommended in men and women 50–69 years old with diseases or medications known to increase risk of osteoporosis and in those with a history of fracture after age 50. Although information relating BMD to fracture risk are derived mostly from studies of women, data also suggest that similar associations may be valid for men. Men tend to fracture at a higher BMD than women, but most fractures occur in men with a T-score less than –2.5, just like women. There is limited information to determine the frequency of screening or the age to stop screening for osteoporosis. In the Study of Osteoporotic Fractures, no additional benefit was achieved from repeat BMD testing at an interval of 15 years for healthy, older postmenopausal women with normal BMD or mild osteopenia. Post-hoc analyses of the Framingham Osteoporosis study suggest no benefit of a screening interval of <4 years in older men and women (mean age 75).

Interpretation of BMD involves evaluating the quality of the DEXA as well as the T-scores. Several considerations are important when evaluating BMD of the spine over time. BMD of lumbar vertebrae L1–L4 should be measured when making a decision about therapy. Vertebral, arterial, or lymph node calcification as well as any scoliosis can falsely increase BMD of the anterior-posterior spine DEXA. Thus, a woman with osteoporosis of the spine can have a DEXA T-score that is higher than −2.5. Usually, these changes can be seen on the DEXA report if the picture of the scan is included in the report. Proximal femoral neck BMD is preferred because it is more likely to be free of osteoarthritic changes and is most associated with fracture risk. Proximal femur is based on the lower measure of the total hip or femoral neck. Another important issue of DEXA testing is measurement variability. It is critical to scan a patient on the same DEXA machine, given that unaccountable differences between machines can substantially impair the ability to detect statistically different changes in BMD over time. In addition, patient positioning should be consistent on repeated measurements. The International Society of Clinical Densitometry offers guidelines and standardized training courses for technicians and clinicians acquiring and interpreting the results.

FRAX

The WHO fracture risk assessment tool (FRAX) has been the most widely adopted method to incorporate clinical risk factors and BMD. FRAX is a free online clinical tool (www.shef.ac.uk/FRAX) that estimates the 10-year probability of fracture at the hip or major osteoporotic fracture (hip, spine, proximal humerus, or distal forearm). It is used for both women and men from different geographic settings. For components of the FRAX risk score, see Table 5. FRAX was developed through WHO after analyzing 12 population-based cohorts of nearly 60,000 men and women with approximately 250,000 person-years of observation; this data was then externally validated in another 11 cohorts comprising 230,000 men and women with >1.2 million person-years of observation. It is most useful for patients who have a low hip BMD, because fracture risk may be underestimated if BMD is low at the spine but relatively preserved at the hip. It has not been validated in patients who have or are currently taking medications for osteoporosis or for individuals <40 years old or >90 years old. FRAX score also does not take into account fall risk. Currently in the United States, the FRAX algorithm is validated for four ethnicities (white, black, Hispanic, and Asian).

Table 5—Components of FRAX Risk Score Calculator

Race
In USA: black, Hispanic, white, Asian American
Age
Model evaluated for patients between 40 and 90 years old
Sex
Weight and height
Previous fracture
Specifically, a spontaneous or traumatic fracture in an adult that would not have resulted in a fracture in a healthy individual
Parent fractured hip
History of hip fracture in either mother or father
Currently smoking
Glucocorticoid use
Currently using oral glucocorticoids or previous exposure to oral glucocorticoids for >3 months at a dose equivalent to prednisone ≥5 mg/d
Rheumatoid arthritis diagnosis
Secondary osteoporosis
Diagnosed with a disorder strongly associated with osteoporosis, including insulin-dependent diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism, premature menopause (˂45 years old), chronic malnutrition, malabsorption, and chronic liver disease
Alcohol use
Drinks ≥3 units of alcohol daily
BMD
Need to know the DXA scanning equipment and femoral neck BMD
NOTE: BMD is not required to calculate FRAX risk score.

Vertebral Fracture Assessment

Vertebral fracture assessment (VFA) is a technology used for diagnosis of vertebral fractures that can be performed as part of a routine DEXA measurement. Vertebral fractures are highly associated with future fracture risk and morbidity (SOE=A), but they are often not clinically apparent and can be present in patients with T-scores greater than −2.5. In addition, under-reporting of radiographic vertebral fractures by radiologists is well established. Treatment of patients with vertebral fractures, including those with T-scores greater than −2.5, reduces further fracture risk (SOE=A). For diagnosing vertebral fractures, VFA has lower resolution than CT and spine radiographs but has the advantage of less radiation, lower cost, convenience (at time of BMD), and comparable sensitivity and specificity to spine radiographs. VFA can therefore be a useful adjunct to BMD testing, particularly when results can influence clinical decision making. Risk stratification of patients at risk of fracture, who otherwise might not be considered for pharmacologic therapy, is an important benefit of this technology. Repeat measurements should only be done for patients with recent height loss, new back pain, postural changes, or on evaluation for a medication “holiday.” The International Society of Clinical Densitometry published a position statement in 2015 on indications for VFA (Table 6).

Table 6—Indications for Vertebral Fracture Assessment from The International Society of Clinical Densitometry 2015 Position Statement

T-score is <– ­1.0 and one or more of the following is present:
  • Women ≥70 years old or men ≥80 years old
  • Historical height loss >4 cm (>1.5 inches)
  • Self-reported but undocumented prior vertebral fracture
  • Glucocorticoid therapy equivalent to ≥5 mg of prednisone or equivalent per day for ≥3 months

Biochemical Markers of Bone Turnover

Serum and urine biochemical markers can estimate the rate of bone turnover (remodeling) and provide additional information to assist the clinician. A number of markers have been developed that reflect collagen breakdown, bone resorption, and or bone formation. A decrease in the level of these markers from baseline after 3–6 months of therapy may indicate a therapeutic response. However, the use of markers in clinical practice is controversial because of high within-patient variability and gaps in understanding the magnitude of biochemical marker reduction necessary to prevent bone loss or, more importantly, fractures. Therefore, routine measurement is not recommended.

PREVENTION AND TREATMENT

Whom To Treat

Treatment should be offered to all postmenopausal women and men ≥50 years old who meet the criteria for osteoporosis by DEXA or have a history of hip, vertebral, or prior fragility fracture. However, recommendations for treatment of adults with osteopenia (defined as a T score of –­1.0 to ­–2.5) and a high fracture risk remains uncertain. The NOF recommends considering treatment in patients with osteopenia who have a 10-year probability of hip fracture ≥3% or major osteoporotic fracture ≥20%, as calculated by FRAX-US algorithm (SOE=C). In patients in whom treatment is being considered, secondary causes should be evaluated and excluded as appropriate. All patients should be counseled on osteoporosis risk and receive falls prevention counseling.

There is no identified age cutoff for initiating pharmacologic treatment. Studies show a reduction in risk of fractures after 6–­12-months of treatment in the oldest-old. Thus, treatment should be considered in any patient with >1 year of remaining life expectancy. In addition, no clear guidelines exist for when to start pharmacologic treatment after a fragility fracture. Preliminary evaluation of secondary causes and patient education on osteoporosis should begin as soon as possible. The general consensus is to start pharmacologic therapy 14 days after acute fracture. A decision to start therapy should focus on patient preferences, fracture risk profile, harm, benefit, and cost of medications.

The Role of Exercise

Weight-bearing and muscle strengthening exercises are an important component of osteoporosis treatment and prevention; however, exercise alone is insufficient to prevent the rapid bone loss associated with estrogen deficiency in early menopause. Regular exercise is positively associated with BMD, and starting an exercise program even late in life can help to preserve BMD (SOE=A). Studies support use of resistance strength training in helping maintain femoral neck BMD as well as improve muscle mass, strength, and balance in postmenopausal women (SOE=B).

Weight-bearing exercise, such as walking, can be recommended for all adults. Older adults should be encouraged to start slowly and gradually increase the amount of time as well as the number of days spent walking.

Calcium and Vitamin D

Current recommendations for calcium intake in postmenopausal women >50 years old is elemental calcium at 1,200 mg/d. For men 51–70 years old, the recommendation for calcium is 1,000 mg/d, increasing to 1,200 mg/d after the age of 70. The upper intake level for all groups is 2,000 mg/d. The average dietary intake of calcium for postmenopausal women in the United States is 500–700 mg/d; thus, most require some form of additional dairy or calcium supplementation to ensure adequate intake. For information on the amount of calcium in selected foods, see Table 7. Common calcium supplements are carbonate or citrate, and absorption of either supplement is best in dosages ≤600 mg at a time. Calcium carbonate is best absorbed with food, while calcium citrate can be absorbed efficiently without food. Calcium carbonate also has a higher risk of bloating and constipation than calcium citrate. Calcium supplementation <2,500 mg/d is considered safe from a cardiovascular standpoint based on joint guidelines of NOF and the American Society for Preventive Cardiology (SOE=A).

Table 7—Calcium-Containing Foods

Food
Serving Size
Calcium (mg) per serving
Dairy Products
Milk
1 cup
290–300
Yogurt
1 cup
240–400
Swiss cheese
1 ounce (1 slice)
250–270
American cheese
1 ounce (1 slice)
165–200
Ice cream
½ cup
90–100
Cottage cheese
½ cup
80–100
Parmesan cheese
1 tablespoon
70
Powdered nonfat milk
1 teaspoon
50
Other
Sardines in oil with bones
3 ounces
370
Calcium-fortified orange juice
1 cup
300
Canned salmon with bones
3 ounces
170–210
Broccoli
1 cup
160–180
Tofu (soybean curd)
4 ounces
145–155
Turnip greens
½ cup, cooked
100–125
Kale
½ cup, cooked
90–100
Cornbread
2 ½-inch square
80–90
Egg
1 medium
55
Other fortified foods (eg, bread, cereal, fruit juices)
1 serving
Varies; read label

The recommended requirement of vitamin D is 600 IU/d for women and men 51–70 years old, and 800 IU/d for women and men >70 years old. Research in frail older adults has shown an increased risk of falls with daily vitamin D3 intake between 3,000 and 4,000 IU. All patients should limit vitamin D intake to <4,000 IU/d. Dietary sources of vitamin D include liver, egg yolks, saltwater fish, and vitamin D–fortified food.

There is disagreement on vitamin D monitoring and target 25-hydroxy vitamin D concentration goals. Current laboratory tests lack sufficient standardization, and guidelines differ on the importance of increasing supplementation to achieve a target vitamin D level. Vitamin D insufficiency has been commonly defined as 25-hydroxy vitamin D between 21 and 29 ng/mL and vitamin D deficiency as a level ≤20 ng/mL. The American Geriatrics Society 2014 consensus statement continues to emphasize treating to a target serum concentration of 25-hydroxy vitamin D of ≥30 ng/mL (75 nmol/L).

Studies involving postmenopausal women question the benefit of routine supplementation when there is an absence of risk factors for osteoporosis and the patient has adequate dietary intake of calcium and vitamin D. Vitamin D supplementation alone has not been shown to be beneficial in osteoporosis prevention in community-dwelling older adults (SOE=A). The greatest benefit for dual supplementation in reducing fracture risk is in homebound or institutionalized older adults who often have low calcium intake and vitamin D deficiency (SOE=A).

Pharmacologic Options

For dosing and special considerations for medications used to prevent and treat osteoporosis, see Table 8. Combination therapy is not recommended.

Table 8—Prescription Medications Used to Prevent and Treat Osteoporosis
Medication
Dosage
FDA Indication
Medication Adverse Effects/Risks
Usage/
Contraindication
Bisphosphonates
Alendronate
Treatment: 70 mg/wk po
Prevention: 35 mg/wk po
PMO prevention; PMO, male, and GIOP treatment
Upper GI symptoms; musculoskeletal pain; esophagitis; acute-phase response
Rare: ONJ, atypical femur fractures
Take oral bisphosphonates on an empty stomach with limited water. Need to sit up and wait at least 30 minutes before any oral intake.
Contraindication: GFR≤30 mL/min
Risedronate
35 mg/wk or 150 mg/mo po
PMO prevention; PMO, male, and GIOP treatment
Ibandronate
150 mg/mo or 3 mg IV or po every 3 mo (treatment only)
PMO prevention; PMO treatment
Musculoskeletal pain; Zoledronic acid has increased acute-phase response; hypocalcemia
Rare: ONJ, atypical femur fractures
Use only for vertebral fractures.
Contraindication: GFR ≤30 mL/min
Zoledronic acid
Treatment: 5 mg/yr IV
Prevention: 5 mg every 2 yr
PMO and GIOP prevention; PMO, male, and GIOP treatment
Tylenol premedication limits acute-phase reaction.
Contraindication: GFR ≤35 mL/min
RANKL inhibitor
Denosumab
60 mg SC every 6 months
PMO, male treatment
Eczema; injection site reaction; hypocalcemia; increased infection risk (especially of skin);
Rare: ONJ, atypical femur fractures
Transition patient to other osteoporosis medication on completion of treatment to maintain BMD gain.
Parathyroid hormone
Teriparatide
20 mcg/d SC
PMO, male, and GIOP treatment
Potential increase of osteosarcoma based on animal studies; hypocalcemia; nausea; vomiting; injection site reaction; fatigue
Do not use for >2 years; black box warning for patients with high risk of osteosarcoma.
Abaloparatide
80 mcg/d SC
PMO treatment
Selective estrogen-receptor modulators and Estrogen
Raloxifene
60 mg/d po
PMO prevention and treatment
Increased risk of venous thromboembolism; fatal stroke; flu-like symptoms; hot flashes; leg cramps; peripheral edema
Mainly used for patients in need of breast cancer prevention or treatment.
Estrogen/
bazedoxifene
0.45 mg/20 mg po
PMO prevention
Increased risk of venous thromboembolism; fatal stroke; flu-like symptoms; hot flashes; leg cramps; peripheral edema
Prescribe lowest effective dose for shortest duration of time.
Estrogen
Regimens vary
PMO prevention
Increased risk of venous thromboembolism, cardiac disease, breast cancer
Prescribe lowest effective dose for shortest duration of time.
Calcitonin
Calcitonin
200 IU intranasally once daily; 100 IU SC every other day
PMO treatment in women ≥5 years postmenopause
Hypocalcemia, nausea, vomiting, allergic reaction, possible increased risk of cancer
Do not use as first-line treatment because of risk of malignancy and limited efficacy.
NOTE: PMO = postmenopausal osteoporosis, GIOP = glucocorticoid-induced osteoporosis, ONJ = osteonecrosis of the jaw

Bisphosphonates

Bisphosphonates decrease bone resorption and bone remodeling, leading to increase in BMD. Bisphosphonate treatments can be provided by oral or IV dosing. Oral bisphosphonates include alendronate, risedronate, and ibandronate. Alendronate and risedronate are approved for osteoporosis prevention in both men and women. Both medications increase BMD and decrease fractures at the spine and hip in postmenopausal women with osteoporosis (SOE=A). Ibandronate, which can be taken orally on a monthly basis or intravenously every 3 months, is approved for osteoporosis prevention and treatment in postmenopausal women. Ibandronate is used less frequently, because it has only shown efficacy in preventing vertebral fractures (SOE=A). In post-hoc analyses of the Fracture Intervention Trials, alendronate decreased the relative risk of hip, symptomatic vertebral, and wrist fractures in postmenopausal women up to age 85. Risedronate has been shown to decrease the relative risk of new vertebral fractures in women >80 years old with osteoporosis. Alendronate and risedronate are also approved to treat glucocorticoid-induced osteoporosis.

Zoledronic acid is an IV bisphosphonate approved for osteoporosis prevention and treatment in postmenopausal women, and for patients after osteoporotic hip fracture. It is also indicated as treatment for osteoporosis in men and for prevention of osteoporosis in men and women who are expected to receive ≥12 months of glucocorticoid therapy. Zoledronic acid has also been proved to reduce all-cause mortality when given to patients after surgical hip-fracture repair (SOE=A). Post-hoc analyses have shown a risk reduction for new clinical fracture in women ≥75 years old with treatment.

The major adverse events of oral bisphosphonates are GI symptoms, which can include abdominal pain, dyspepsia, esophagitis, nausea, vomiting, and diarrhea. Musculoskeletal pain can also rarely occur. Esophagitis, particularly erosive esophagitis, is seen most commonly in patients who do not take the medication properly, including not remaining upright for 30 minutes after administration. Because absorption of oral bisphosphonates is poor, it is important to inform patients to limit intake to water only for at least 30 minutes after ingestion. Zoledronic acid and rarely alendronate and risedronate have been associated with an acute-phase response (fever, myalgias, arthralgias, and headache) as soon as 6 hours and lasting up to 72 hours after infusion or oral ingestion.

Bisphosphonate use is rarely associated with osteonecrosis of the jaw, a necrotic area of bone more commonly found in the mandible than the maxilla. Most reported cases have been in patients receiving parenteral bisphosphonates for malignant bone disorders who have undergone dental procedures such as tooth extraction. There are rare reports of patients contracting osteonecrosis of the jaw on long-term conventional oral bisphosphonates for osteoporosis. Long-term use of bisphosphonates has also been associated with atypical fractures, such as subtrochanteric and diaphyseal femur fractures. Cohort studies have shown an increased risk of subtrochanteric and femoral shaft fractures with ≥5 years of bisphosphonate use as well as a drug-dose effect. Overall, the absolute risk of osteonecrosis of the jaw and atypical femoral fractures is very low (1:10,000 person-years of use) and is outweighed by the benefits of bisphosphonate use in the vast majority of patients.

Patients taking bisphosphonates are encouraged to report new groin or thigh pain to their health care providers. When such pain is reported, radiographs of both femurs should be obtained, which can identify those who may be at risk of these atypical fractures. Further studies such as MRI or whole-body scan may be warranted in certain circumstances given the low sensitivity of plain radiographs in detecting stress fractures. Evidence is conflicting for an association between bisphosphonates and esophageal cancer. No clear association with atrial fibrillation and bisphosphonates exists.

The optimal duration of treatment with bisphosphonates is unclear; however, the effects of bisphosphonates may extend for months to years after treatment is stopped. In the FLEX study, patients who took alendronate for 10 years had less decline in their BMD at the hip and spine than those who stopped the drug after 5 years. Risk of clinical (symptomatic) vertebral fractures, but not total fractures or hip fractures, was higher in those who stopped alendronate after 5 years (SOE=A). This data suggest that alendronate can be discontinued after 5 years of treatment in patients at low risk of future fracture (eg, no new fractures on therapy, T-score greater than –2.5, and T-score that has increased while on therapy). The American Association of Clinical Endocrinologists guidelines recommend a “drug holiday” of 1–2 years. After 10 years of therapy, those at highest risk of fracture should be offered a drug holiday with consideration of possible interval treatment with another agent. In the long-term care population, expert opinion recommends discontinuation of bisphosphonates when a person is no longer ambulatory or has a remaining life expectancy of <2 years. An FDA review of the clinical studies that explored the long-term benefit of bisphosphonates concluded that patients at low risk of fracture may be good candidates to discontinue treatment after 3–5 years, while those at increased risk may continue to benefit from continued bisphosphonate treatment. However, further research is needed to better understand an individual’s risk of fracture after stopping bisphosphonate therapy and when and whether to resume therapy in the future.

RANKL Inhibitor

Denosumab is a human monoclonal antibody that binds and neutralizes RANKL, a critical mediator of bone resorption by cells of osteoclast lineage. This leads to decrease in bone turnover and increase in BMD. Denosumab is FDA approved for postmenopausal women at high risk of fracture, women receiving adjuvant aromatase inhibitors therapy for breast cancer, and men on androgen deprivation therapy for nonmetastatic prostate cancer. A patient’s risk of a vertebral fracture returns to the pretreatment level shortly after medication discontinuation (SOE=B). Because of this finding, it is recommended to transition patients to other antiresorptive treatment after discontinuing denosumab.

Denosumab is administered through subcutaneous injections every 6 months. Unlike bisphosphonate treatment, renal insufficiency is not a contraindication for medication use. The most statistically significant adverse events associated with denosumab include eczema, an injection site reaction, hypocalcemia, and increased risk of infections, especially of the skin. There are case reports of osteonecrosis of the jaw with denosumab use, as well as atypical femoral fractures. Because of the risk of hypocalcemia, NOF guidelines recommend evaluating and repleting calcium before starting treatment. Furthermore, monitoring serum calcium, phosphorus, magnesium, and for signs of infection should be a regular part of follow-up care while a patient is on denosumab.

Parathyroid Hormone Analogues

Teriparatide is a 1-34 human PTH anabolic agent approved for treatment of men with primary or hypogonadal osteoporosis, glucocorticoid-induced osteoporosis, and in postmenopausal women with osteoporosis. A newer medication, abaloparatide, is a synthetic analogue of PTHrp and is currently indicated for use only in postmenopausal women with osteoporosis. These anabolic agents increase bone formation by stimulating osteoblast activity through intermittent spikes of PTH or PTHrp. In a comparison 18-month study with teriparatide, abaloparatide, and placebo, both anabolic agents demonstrated a significant reduction in nonvertebral and vertebral fractures and in increased BMD. However, the study showed no statistical difference in fracture rates between the abaloparatide and teriparatide groups.

Both medications are injected subcutaneously on a daily basis and are typically reserved for those with severe osteoporosis and a higher prevalent fracture burden (SOE=A). Cost and parenteral administration also limit their use. Risk from PTH analogue medication includes potential increased incidence of osteosarcoma (seen in rat studies). This finding led to a “black box” warning and contraindication of use for patients with Paget disease, history of skeletal irradiation, and a higher baseline risk of osteosarcoma. Hypercalcemia can also occur, but most observed cases were mild and treated with reduction in calcium supplementation. Other adverse effects include nausea, vomiting, injection site reactions, and fatigue. If fatigue becomes a concern, some clinicians suggest injecting the medication before bedtime.

These drugs should be prescribed for no more than 2 years because of the plateau of benefit over time and concern over increased risk of osteosarcoma. The BMD benefits of the medication decline after discontinuation, so it is recommended to transition patients to an antiresorptive agent to maintain BMD gains. The impact of this strategy on fracture risk is still not completely understood.

Selective Estrogen-Receptor Modulators

The selective estrogen-receptor modulators (SERMs) act as estrogen agonists in bone and cardiac tissue, and as estrogen antagonists in breast and uterine tissue. SERM medications are mainly used for the treatment and prevention of estrogen receptor–­positive breast cancer. Of the SERM medications, only raloxifene is approved for treatment and prevention of osteoporosis in postmenopausal women. Raloxifene reduces incident vertebral fractures; however has not been shown to decrease nonvertebral fractures. A combination of estrogen/bazedoxifene is approved only for prevention of postmenopausal osteoporosis in women with a uterus. As with all estrogen-containing products, the FDA recommends limited duration of use. Adverse events of both medications include increased risk of venous thromboembolism, fatal stroke, flu-like symptoms, hot flashes, leg cramps, and peripheral edema (SOE=A). Because of the risk profile, raloxifene is recommended for postmenopausal women with osteoporosis and in need of breast cancer prevention or treatment.

Estrogen

Estrogen replacement therapy is approved by the FDA solely for osteoporosis prevention in women who are at significant risk of osteoporosis and in whom nonestrogen medications have been deemed inappropriate. In the Women’s Health Initiative (WHI) trial, hormone therapy reduced hip fracture rates by 34% and total osteoporotic fractures by 24%. However, hormone therapy also increased the risk of breast cancer, heart disease, and venous thromboembolism. Given the WHI findings, USPSTF guidelines advise against the routine use of estrogen plus progesterone for prevention of chronic conditions in postmenopausal women. If used, estrogen and hormonal therapy should be prescribed at the lowest effective dose for the shortest duration of time. When stopping treatment, rapid bone loss can occur and other treatments for BMD preservation should be initiated.

Calcitonin

The FDA recommends calcitonin as a second-line therapy in women with osteoporosis who are >5 years after menopause. Calcitonin inhibits bone resorption through decrease in osteoclast activity. Although the medicine is available as a subcutaneous injection, it is most commonly prescribed as a nasal spray. Conflicting evidence exists for fracture reduction with calcitonin, and there is insufficient data for calcitonin effectiveness in the first few years after menopause. Calcitonin has also shown some benefit for acute pain relief within 10 days after an osteoporotic fracture (SOE=C); however, this is not an FDA-indicated use. Safety and efficacy data are available for up to 5 years of treatment. Adverse effects include hypocalcemia, nausea, vomiting, allergic reaction, and possible increased risk of cancer. Medication should be frequently reevaluated because of the adverse effect profile and limited efficacy of use.

Monitoring

Patients receiving treatment for osteoporosis commonly undergo serial BMD measurements at least every 2 years to assess effectiveness, an interval currently covered by Medicare. This interval is not a universal recommendation, as evidence is insufficient to support modifying treatment based on BMD response. Because of the limited evidence, as of 2017 the American College of Physicians no longer recommends BMD monitoring after initiation of treatment. Proponents of measuring BMD report that benefits of monitoring include identification of patients with poor adherence, secondary cause of bone loss, and possible evidence of treatment failure. Adherence to treatment should be assessed at each visit for all patients, especially those on oral bisphosphonates. Patients on bisphosphonates who experience GI adverse events are 50% more likely to discontinue their medication, and poor adherence is associated with increased risk of fractures (SOE=A).

VERTEBRAL FRACTURE MANAGEMENT

Vertebral compression fractures are often asymptomatic and diagnosed incidentally by spinal radiographs. They most commonly occur in the thoracolumbar transition zone or midthoracic region. In affected individuals, height may decrease, kyphosis may increase, or clothes may no longer fit properly over time. Many older adults have chronic back pain caused by changes in the spine that develop with degenerative osteoarthritis or vertebral compression; distinguishing the source of the pain can be difficult. On a practical level, pain should be treated if it interferes with ADLs and quality of life, regardless of cause. However, identifying vertebral fractures is important so that future fractures can be prevented.

In the case of symptomatic vertebral compression fractures, adequate pain control is essential. The pain usually lasts 2–4 weeks and can be quite debilitating. In addition to medication, physical therapy is an important part of osteoporosis treatment programs to manage acute and chronic pain and to provide patient education. A physical therapist can provide postural exercises, alternative interventions for pain reduction, and information on changes in body mechanics that can help prevent future falls. Back braces may help to decrease pain and disability after a fracture. Support groups for patients with osteoporosis can also be helpful.

Vertebroplasty and Kyphoplasty

Vertebroplasty and kyphoplasty are minimally invasive surgical approaches for management of painful vertebral compression fractures. In vertebroplasty, the cement is injected directly into the vertebral body, with the goal of alleviating pain and preventing further bone compression. Kyphoplasty uses an inflated balloon inserted through a fluoroscopically placed needle to elevate the fracture and fill the cavity with cement. The goal is to improve pain while reducing loss of height and decreasing kyphosis. The American Academy of Orthopedic Surgeons states that kyphoplasty is an option for pain control in neurologically intact individuals (SOE=C). However, the Academy recommends against vertebroplasty based on 2 randomized trials showing no significant differences in pain reduction between vertebroplasty and sham procedure (SOE=A). Both procedures, although minimally invasive, carry complications.


CHOOSING WISELY® RECOMMENDATIONS

Osteoporosis

  • Do not routinely repeat BMD more than once every 2 years.
  • Do not perform population based screening for vitamin D deficiency

RESOURCES

American Geriatrics Society Workgroup on vitamin D supplementation for older adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc. 2014;62(1):147–152.

Prah A, Richards E, Griggs R, et al. Enhancing osteoporosis efforts through lifestyle modifications and goal setting techniques. J Nurse Prac. 2017;(13)8:552–561.