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Endocrinology - Osteoporosis - Fast Facts | NEJM Resident 360

Osteoporosis is the most common endocrine bone disease and is characterized by low bone mass, disruption of bone microarchitecture, and increased risk of fracture. Fractures can be painful, significantly affect quality of life, and increase the risk of death.

The prevalence of osteoporosis varies depending on whether it is defined by fracture incidence or bone mineral density (BMD). The World Health Organization (WHO) defines osteoporosis as a BMD of the hip or lumbar spine of at least 2.5 standard deviations below the adult mean (T score). A clinical diagnosis of osteoporosis can be made based on BMD criteria or when a fragility fracture occurs spontaneously or as a result of minor trauma at the spine, hip, or pelvis.

(Source: Osteoporosis in Men. N Engl J Med 2008.)

Risk Factors

Risk factors for fracture include the following:

• advanced age

• previous fracture

• long-term therapy with glucocorticoids, aromatase inhibitors, certain antiepileptic drugs, and other medications

• hypogonadism/amenorrhea

• low body weight (<58 kg [127 lb])

• parental history of hip fracture

• cigarette smoking

• excess alcohol intake

• race/ethnicity (higher risk in white adults than in Black, Hispanic, or Asian adults)

• diabetes mellitus

Screening

The goal of screening is to identify adults at increased risk of fracture who would benefit from treatment to reduce that risk. Most organizations, including the U.S. Preventive Services Task Force (USPSTF), National Osteoporosis Foundation (NOF), and International Society for Clinical Densitometry (ISCD) recommend screening for osteoporosis in women age 65 years and older. Although the USPSTF does not recommend screening for osteoporosis in men, the other groups do recommend screening in men older than 70 years.

Other populations that might require BMD screening include patients with the following risk factors:

• women younger than 65 years with clinical risk factors for fracture

• men age 50 to 69 years with clinical risk factors for fracture

• adults who have a fracture after age 50 years

• adults with a bone condition (e.g., rheumatoid arthritis)

• adults taking a medication associated with low bone mass or bone loss (e.g., daily dose of glucocorticoids, such as ≥5 mg prednisone or equivalent for ≥3 months)

Screening Tools

Screening for fracture risk involves measurement of BMD and risk-factor assessment.

Dual energy x-ray absorptiometry (DXA) is used to measure bone mass and can detect fractures of the spine that are often asymptomatic. DXA calculates BMD with two x-ray beams that measure the thickness of the bone. BMD should be measured at the lumbar spine (L1–L4) and hip (neck or total) in all patients. The forearm (at the 33% radius site) can be measured for BMD in patients with obesity or hyperparathyroidism and when the hip or spine cannot be measured (e.g., due to implants).

• T scores (number of standard-deviation above or below the mean BMD of a young adult) are preferred for BMD reporting in postmenopausal women and men older than 50 years.

• Z scores (the standard-deviation difference between the mean BMD of a person matched for age, race, and sex, and the patient’s current BMD) are preferred for premenopausal women or men younger than 50 years.

Dual-Energy X-Ray Absorptiometry (DXA) Scan of the Lumbar Spine Showing Worsening Osteoporosis

DXA image of lumbar spine showing osteoporosis, with a significant drop in bone mineral density compared with the prior scan
(Image courtesy of Ole-Petter Hamnvik, MB BCh BAO, MMSc)

Vertebral fracture assessment (VFA): Patients with a vertebral fracture have significantly increased risk of a future vertebral or nonvertebral fracture, compared with those without vertebral fracture and an identical BMD. However, vertebral fractures are clinically underrecognized. Although thoracic and lumbar radiographs can help identify patients with vertebral fractures, they require exposure to considerable radiation. VFA uses DXA imaging of the thoracic and lumbar spine to evaluate for vertebral fractures. Images can be obtained at the same time as a BMD measurement with less radiation exposure than plain radiographs of the spine.

The VFA is recommended in the following settings:

• women age >70 years

• men age >80 years

• height loss >4 cm (>1.5 inches)

• glucocorticoid therapy (>5 mg of prednisone for ≥3 months)

• self-reported vertebral fracture

Vertebral Fracture Assessment (VFA) Showing Compression Fracture

VFA showing compression fracture at T12 (arrow).
(Image courtesy of Ole-Petter Hamnvik, MB BCh BAO, MMSc)

The fracture risk assessment tool (FRAX): The World Health Organization (WHO) developed a fracture risk assessment tool (FRAX) to evaluate fracture risk. It combines risk factors for fracture, including glucocorticoid use, and BMD measurement to predict a country-specific 10-year probability of a hip fracture or major osteoporotic fracture. In patients with osteopenia, pharmacologic therapy is indicated if the 10-year risk of hip fracture is >3% or the risk for any major osteoporotic fracture is >20%. FRAX is meant for patients older than 40 years. Currently, no tools are available for assessing risk of fracture in patients younger than 40 years.

Lateral Radiograph of the Spine

The radiograph shows a biconcave fracture, grade 2, in the L2 vertebra.
(Source: Vertebral Fractures. N Engl J Med 2011.)

Treatment

Prior to treatment, the National Osteoporosis Foundation (NOF) recommends the following workup for secondary causes of osteoporosis:

• complete blood count

• basic metabolic panel

• phosphorus level

• liver function tests

• thyroid and parathyroid hormone levels

• 25-hydroxyvitamin D level

• bone turnover markers

• testosterone (in men)

• 24-hour urinary creatinine and calcium

• additional evaluation (e.g., protein electrophoresis, celiac testing) on a case-by-case basis

Several organizations have issued guidelines for the treatment of osteoporosis (see table below). Treatment of osteoporosis involves the following components:

• modifying risk factors, including smoking and alcohol use

• achieve recommended intake of calcium (1200 mg/day for women >50 years, 1000 mg/day for men ages 51–70 years, 1200 mg/day for men >70 years)

  • daily dietary intake of calcium can be approximated by using the International Osteoporosis Foundation (IOF) calculator

  • calcium supplements can be added to achieve the recommended daily calcium intake

• adequate vitamin D intake (600 IU/day for patients ages 51–70 years, 800 IU/day for patients >70 years); aim for a serum 25-OH(D) level of 30–50 ng/mL

• physical activity: longitudinal studies indicate that resistance and weight-bearing exercises increase muscle mass and BMD

• pharmacologic therapies (see table of approved treatments below)

  • First-line pharmacologic treatment is with bisphosphonates; benefits of other adjunct treatments are limited.

  • Nonbisphosphonate agents can be used as first-line agents in patients at extremely high-risk for fracture or as second-line agents if bisphosphonates are not tolerated or ineffective.

  • Endocrine Society guidelines recommend that BMD should be monitored by DXA every 1 to 3 years to assess response to treatment.

  • Due to concerns that prolonged treatment increases risk of atypical femoral fractures and osteonecrosis of the jaw (although the absolute risk is low, with estimates ranging from 1:10,000 to 1:1000), a holiday from bisphosphates after 3 to 5 years can be considered based on the patient’s risk of fracture; high-risk patients are treated longer.

(Source: Postmenopausal Osteoporosis. N Engl J Med 2016.)

Drugs Approved by the Food and Drug Administration for the Treatment and Prevention of Osteoporosis*

Drug Class and Agent	Method and Duration of Administration	Type of Fracture Risk Reduction	Adverse Effects	Approved Use for Osteoporosis
Bisphosphonates†
Alendronate	Oral, 5-10 years	Vertebral, nonvertebral, hip	Common: esophagitis, musculoskeletal symptoms; rare: ONJ, atypical femur fractures	Treatment and prevention
Risedronate	Oral, 5-10 years	Vertebral, nonvertebral, hip	Common: esophagitis, musculoskeletal symptoms; rare: ONJ, atypical femur fractures	Treatment and prevention
Ibandronate	Oral, 5-10 years	Vertebral	Common: first-dose (intravenous) reaction, esophagitis, musculoskeletal symptoms; rare: ONJ, atypical femur fractures	Treatment and prevention
Zoledronic acid	Intravenous, 3-6 years	Vertebral, nonvertebral, hip	Common: acute-phase response (most often after first dose),‡ musculoskeletal symptoms; rare: ONJ, atypical femur fractures	Treatment and prevention
RANK ligand inhibitor: denosumab	Subcutaneous, no maximal duration	Vertebral, nonvertebral, hip	Common: cellulitis or skin reactions; rare: ONJ, atypical femur fractures	Treatment
Anabolic: teriparatide, abaloparatide	Subcutaneous, 24 months	Vertebral, nonvertebral	Common: nausea, leg cramps; rare: hypercalcemia, osteosarcoma	Treatment
Calcitonin	Intranasal	Vertebral	Nasal congestion	Treatment
SERM: raloxifene	Oral, no maximal duration	Vertebral	Venous thromboembolism, hot flashes, leg cramps, nausea	Treatment and prevention
Estrogens‖			Venous thromboembolism, increased risk of breast cancer and cardiovascular disease	Prevention
Conjugated equine estrogen	Oral, no maximal duration	Vertebral, nonvertebral, hip
17β-estradiol	Oral, transdermal, no maximal duration	No data from randomized trials
Ultra-low-dose 17β-estradiol	Oral, no maximal duration	No data
Sclerostin inhibitors: Romosozumab**	Intramuscular once monthly for 12 months	Vertebral	Arthralgia, headache, increased risk of major adverse cardiovascular events (as compared with alendronate)	Treatment

*ONJ denotes osteonecrosis of the jaw, and SERM selective estrogen-receptor modulator.

† Oral bisphosphonates are also approved in smaller doses for daily use to prevent osteoporosis, but currently those doses are seldom prescribed.
‡ Flulike symptoms including fever, arthralgia, or headache may occur after the first administration in up to one third of patients. Symptoms do not last more than 3 days after infusion.
  Osteosarcoma has been reported with long-term anabolic therapy in rodents, but no clear causation has been shown in humans. Abaloparatide carries a black box warning for this side effect; the black box warning has been removed for teriparatide.
  Calcitonin is no longer approved for the treatment of osteoporosis in Europe.
‖ Tibolone, which has estrogenic action, is approved for the treatment of postmenopausal osteoporosis in Europe.
** Not recommended for use in patients with myocardial infarction or stroke within the past year.
(Adapted from: Postmenopausal Osteoporosis. N Engl J Med 2016.)

Glucocorticoid-Induced Osteoporosis

Glucocorticoids are commonly used for treatment of allergies, inflammatory conditions, and cancer. Based on dose, duration of use, and risk factors for osteoporosis, glucocorticoid use increases risk of fracture due to direct and indirect effects on bone remodeling as demonstrated in the following figure:

Mechanisms of Glucocorticoid-Induced Bone Loss

Excessive amounts of systemic glucocorticoids lead to clinically significant adverse effects on the musculoskeletal system by inducing inappropriate bone remodeling through direct and indirect mechanisms and muscle atrophy that contributes to osteoporosis and fractures. Early bone loss is driven by changes in levels of estrogen and parathyroid hormone that stimulate receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclastogenesis. Osteocyte and osteoblast apoptosis prevents effective mechanosensing and new bone formation.
(Source: Glucocorticoid-Induced Osteoporosis. N Engl J Med 2018.)

The following table summarizes recommendations for treatment and prevention of glucocorticoid-induced osteoporosis:

(Source: Glucocorticoid-Induced Osteoporosis. N Engl J Med 2018.)

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