Osteoporosis

Essentials of Diagnosis

• Fracture propensity of spine, hip, pelvis, and wrist

• Asymptomatic until a fracture has occurred

• Serum PTH, calcium, phosphorus, and alkaline phosphatase usually normal

• Serum 25-hydroxyvitamin D levels often low as a comorbid condition

General Considerations

• Causes over 1.5 million fractures annually in the United States

• Most common causes

  • Aging

  • Sex hormone deficiency

  • Alcoholism

  • Smoking

  • Long-term proton pump inhibitor therapy

  • High-dose glucocorticoid administration

  • See Table 26–9

Demographics

• Clinically evident in middle life and beyond

• Develops frequently in hypogonadal men

• White women aged ≥ 50 years (who do not receive estrogen replacement) have a 46% risk of sustaining an osteoporotic fracture during their lives

Symptoms and Signs

• Usually asymptomatic until fractures occur

• May present as back pain of varying degrees of severity or as spontaneous fracture or collapse of a vertebra

• Loss of height common

• Fractures of femoral neck and distal radius also common

• Once osteoporosis is identified, careful history and physical examination are required to determine its cause

Differential Diagnosis

• Osteomalacia in adulthood (inadequate mineralization of existing bone matrix [osteoid])

• Bone marrow neoplasia (eg, plasma cell myeloma or metastatic bone disease)

• Hypophosphatasia

Laboratory Tests

• For patients with a low bone densitometry, obtain serum

  • Blood urea nitrogen, creatinine, albumin, calcium, phosphate, alkaline phosphatase, and 25-hydroxy vitamin D (25HD, 25-hydroxycalciferol)

  • PTH—obtain if the serum calcium is abnormal

• A low serum alkaline phosphatase (below 40 units/L in adults) may indicate hypophosphatasia

• Obtain complete blood count

  • Usually normal

  • For anemia, check a serum protein electrophoresis for plasma cell myeloma and screen for intestinal malabsorption, where indicated

• Vitamin D deficiency

  • Serum 25HD levels below 20 ng/mL (50 nmol/L) are considered frank vitamin D deficiency

  • Lesser degrees of vitamin D insufficiency (serum 25HD levels in the range of 20–30 ng/mL [50–75 nmol/L]) may also slightly increase the risk for hip fracture

• Test for thyrotoxicosis and hypogonadism if clinically warranted

• If intestinal malabsorption is suspected, perform appropriate screening

• Screen for celiac disease with serum tissue transglutaminase antibody determinations

Imaging Studies

• Dual-energy x-ray absorptiometry (DXA) is required to diagnose osteoporosis (T score < –2.5)

Medications

• Oral vitamin D₃ (cholecalciferol)

  • As a universal supplement of 800–2000 international units/day or

  • In doses titrated to achieve serum levels of 25-hydroxyvitamin D ≥ 20 ng/mL (50 nmol/L)

  • Serum levels should be maintained ≥ 30 ng/mL (75 nmol/L) for patients "at risk"

    • Pregnant women

    • Older adults

    • Persons with osteoporosis or fragility fractures

  • Early observational data shows adverse outcomes (increased heart disease and all-cause mortality) when 25-OHD serum levels are > 50 ng/mL (125 nmol/L)

  • Therefore, optimal therapeutic range for 25-OHD serum levels appears to about 30–50 ng/mL (75–125 nmol/L)

• Recommended total elemental calcium intake is at least 1000 mg/day for all adults and 1200 mg/day for postmenopausal women and men over age 70 years

• Calcium supplements are reserved for patients with intestinal malabsorption or calcium-deficient diets that do not include dairy products, dark leafy greens, sardines, tofu, or fortified foods

  • Calcium citrate does not require acid for absorption and is preferred for patients receiving acid blockers

  • Calcium carbonate should be taken with food to enhance calcium absorption

• Sex hormone replacement

  • Can prevent osteoporosis in hypogonadal women and men

  • Not effective for established osteoporosis

  • Low-dose transdermal systemic estrogen prevents osteoporosis in women with hypogonadism

  • Testosterone replacement therapy or low-dose transdermal estradiol prevents osteoporosis in men with severe testosterone deficiency

• Bisphosphonates

  • Increase bone density, reduce fracture risk

  • Prevent glucocorticoid-induced osteoporosis

  • Take in morning with ≥ 8 oz water, at least 40 minutes before any other food or liquid

  • Must remain upright for 30 minutes after taking to reduce risk of pill-induced esophagitis

  • Alendronate, 70 mg every week orally

  • Risedronate, 150 mg tablet orally once monthly

  • Ibandronate sodium, 150 mg once monthly orally

  • Pamidronate (30–60 mg by slow intravenous infusion in normal saline solution every 3–6 months) or zoledronate (2–5 mg intravenously over at least 15–30 min every 12 months if oral bisphosphonates cannot be tolerated

  • All patients taking bisphosphonates should receive oral calcium salt supplements (500–1000 mg/day) and oral vitamin D₃ (starting at 1000 units/day)

• Consider estrogen, raloxifene, or bazedoxifene for women with hypogonadism (see Menopausal Syndrome)

  • Raloxifene, 60 mg once daily orally decreases risk of vertebral, but not nonvertebral, fractures

  • Bazedoxifene

    • A selective estrogen receptor modulator (SERM) that is available as a fixed-dose combination medication with conjugated estrogens (0.45 mg/20 mg)

    • FDA-approved for the prevention of osteoporosis in postmenopausal women with an intact uterus

    • Unlike raloxifene, it has not been shown to reduce the risk of breast cancer

    • Long-term use may increase risk of thromboembolic disease

• Teriparatide

  • Stimulates the production of new collagenous bone matrix, particularly in vertebral trabecular bone, which must be mineralized

  • Patients must have sufficient intake of vitamin D and calcium

  • Administer 20 mg or 40 mg daily subcutaneously for 2 years, then discontinue and substitute a bisphosphonate

  • May also be used to promote healing of atypical femoral chalkstick fractures associated with bisphosphonate therapy

  • Avoid in patients with

    • Increased risk of osteosarcoma

    • Hypercalcemia

  • Use with caution in patients taking corticosteroids and thiazide diuretics along with oral calcium supplementation therapy because hypercalcemia may develop

• Abaloparatide

  • Stimulates the production of new collagenous bone matrix, particularly in vertebral trabecular bone, which must be mineralized

  • Patients must have sufficient intake of vitamin D and calcium

  • Dosage: 80 mg daily subcutaneously for 2 years, then discontinue and substitute a bisphosphonate

  • May also be used to promote healing of atypical femoral chalkstick fractures associated with bisphosphonate therapy

  • Avoid in patients with

    • Increased risk of osteosarcoma

    • Hypercalcemia

  • Use with caution in patients taking corticosteroids and thiazide diuretics along with oral calcium supplementation therapy because hypercalcemia may develop

• Denosumab

  • Dose: 60 mg subcutaneously every 6 months

  • Usually administered for a 3- to 5-year course

  • Its efficacy is comparable to bisphosphonates

  • With prolonged use, it predisposes to atypical femoral fractures and osteonecrosis of the jaw

• Calcitonin therapy

  • Reduces the incidence of vertebral fractures, but its effect upon nonvertebral fractures has not been established

  • Much less effective than other treatments; if calcitonin is administered, other more effective treatments for osteoporosis should be given simultaneously

  • Long-term therapy increases the risk of liver cancer but reduces the risk of breast cancer

  • Used primarily for its analgesic effect for the pain of acute osteoporotic vertebral compression fractures

  • Ineffective for chronic pain

  • Nasal spray of calcitonin-salmon (Miacalcin)

    • Available in 2-mL metered-dose bottles containing 2200 units/mL

    • Usual dose is one puff (0.09 mL, 200 international units) once daily, alternating nostrils

    • Nasal symptoms such as rhinitis and epistaxis occur commonly

    • Other less common adverse reactions include flu-like symptoms, allergy, arthralgias, back pain, and headache

• Romosozumab

  • An injectable monoclonal antibody that inhibits sclerostin, increasing new bone formation and decreasing bone resorption

  • Dose: 210 mg subcutaneously monthly for 12 months

  • Reserved for very severe postmenopausal osteoporosis in patients without coronary risk, since it appears to slightly increase cardiovascular mortality

Therapeutic Procedures

• Diet adequate in protein, total calories, calcium, and vitamin D

• Discontinue or reduce doses of corticosteroids, if possible

• High-impact physical activity (eg, jogging), stair-climbing, and weight training increase bone density

• Fall-avoidance measures

• Avoid alcohol and smoking

• Percutaneous vertebroplasty or kyphoplasty

  • May be considered for patients with vertebral compression fractures who do not respond to conservative pain management

  • However, no prospective randomized study has adequately compared the effectiveness of these orthopedic procedures compared to conservative therapy

Follow-Up

• DXA bone densitometry every 2–3 years

• Monitor patients taking corticosteroids or thiazides or who have kidney disease for development of hypercalcemia when given calcium supplements

• Reduce bisphosphonate dosage in chronic kidney disease, and monitor serum phosphate

Complications

• Fractures common, especially femur, vertebrae, and distal radius

• Bisphosphonates

  • Oral can cause esophagitis, gastritis, and abdominal pain

  • Oral and intravenous can cause fatigue, bone, joint, muscle pain, or osteonecrosis of the jaw

    • Pains can be migratory or diffuse, mild to incapacitating

    • Onset of pain occurs 1 day to 1 year after therapy is initiated, with a mean of 14 days

    • Pain can be transient, lasting several days and resolving spontaneously, but typically recurs with subsequent doses

    • Most experience gradual pain relief when medication is stopped

• Raloxifene

  • Increases the risk for thromboembolism

  • Aggravates hot flashes

  • Nausea

  • Weight gain

  • Depression

  • Insomnia

  • Leg cramps

  • Rash

• Teriparatide

  • Orthostatic hypotension

  • Asthenia

  • Nausea

  • Leg cramps

  • Hypercalcemia (if taken along with corticosteroids, thiazide diuretics, and calcium supplementation)

  • Must not be given to patients with Paget disease or a history of osteosarcoma or chondrosarcoma

• Nasal calcitonin-salmon can cause

  • Bronchospasm and allergic reactions

  • Rhinitis

  • Epistaxis

  • Back pain

  • Arthralgias

• Estrogen replacement

  • Increases risk of thromboembolism and myocardial infarction, breast and endometrial cancer

  • Cholestatic jaundice, hypertriglyceridemia, pancreatitis

  • Enlargement of uterine fibroids, migraines, edema

Prognosis

• Bisphosphonates and raloxifene

  • Can reverse progressive osteopenia and osteoporosis

  • Can decrease fracture risk

• Bone pain reduction may be noted within 2–4 weeks on nasal calcitonin