Osteoporosis

A fragility fracture is one that occurs after less trauma than might be expected to fracture a normal bone. Fractures resulting from falls from a standing height or less, including falls out of bed, are typically considered fragility fractures. The most common sites for fragility fractures are the following:

Other sites may include the proximal humerus Proximal Humeral Fractures Proximal humeral fractures are proximal to the surgical neck (see figure Key anatomic landmarks in the proximal humerus). Most are minimally displaced and angulated. Diagnosis is by plain x-ray... read more and pelvis Pelvic Fractures Pelvic fractures can involve the pubic symphysis, innominate bones, acetabulum, sacroiliac joint or sacrum. They range from minimally displaced stable injuries caused by low energy falls to... read more .

Fractures at sites such as the nose, ribs Rib Fracture One or more ribs can be fractured due to blunt chest injury. (See also Overview of Thoracic Trauma.) This x-ray of the chest shows multiple fractures to the right ribs (seen on left). Typically... read more , clavicle Clavicle Fractures Clavicle fractures are among the most common fractures, particularly among children. Diagnosis is by plain x-ray. Most types are treated with a sling. (See also Overview of Fractures.) Clavicle... read more , and metatarsals Stress Fractures Stress fractures are small incomplete fractures that often involve the metatarsal shafts. They are caused by repetitive weight-bearing stress. Stress fractures do not usually result from a discrete... read more are not considered osteoporosis-related fractures.

More than 95% of osteoporosis in women and about 80% in men is primary and therefore without an identifiable underlying cause. Most cases occur in postmenopausal women and older men. However, certain conditions may accelerate bone loss in patients with primary osteoporosis. Gonadal insufficiency is an important factor in both men and women; other factors include decreased calcium intake, low vitamin D levels Vitamin D Deficiency and Dependency Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more , certain drugs, and hyperparathyroidism Primary hyperparathyroidism Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more . Some patients have an inadequate intake of calcium during the bone growth years of adolescence and thus never achieve peak bone mass.

The major mechanism of bone loss is increased bone resorption, resulting in decreased bone mass and microarchitectural deterioration, but sometimes bone formation is impaired. The mechanisms of bone loss may involve the following:

Idiopathic osteoporosis refers to the rare cases of fragility fractures in children, adolescents, premenopausal women, or men < 50 years with normal gonadal function and no detectable secondary cause, including in those with low bone mass (low Z-scores on dual-energy x-ray absorptiometry Dual-energy x-ray absorptiometry (DXA) Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more [DXA] scans).

Bone mineral density should be measured using DXA scan to screen people at risk, provide a quantitative measure of bone loss, help predict the risk of fracture, and monitor those undergoing treatment (1 Diagnosis references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). In a DXA scan, the target areas, typically the spine and one or both hips, are imaged using x-rays of high and low energy (hence the term "dual energy"). The difference in attenuation between high and low energy beams is a reflection of bone mineral content. The bone mineral content divided by area of bone (also measured in the DXA scan) is the bone mineral density in g/cm².

If the spine or a hip is not available for scanning (eg, because of hardware from prior total hip arthroplasty), the distal radius can be scanned (called "1/3 radius" on the DXA scan report). The distal radius should also be scanned in a patient with hyperparathyroidism because this is the most common site of bone loss in hyperparathyroidism.

DXA results are reported as T-scores and Z-scores.

The T-score corresponds to the number of standard deviations that the patient's bone mineral density differs from the peak bone mass of a healthy, young person of the same sex and race/ethnicity. The World Health Organization establishes cutoff values for T-scores that define osteopenia and osteoporosis. A T-score < -1.0 and > -2.5 defines osteopenia. A T-score ≤ -2.5 defines osteoporosis.

The Z-score corresponds to the number of standard deviations that the patient's bone mineral density differs from that of a person of the same age and sex and should be used for children, premenopausal women, or men < 50 years. If the Z-score is ≤ -2.0, bone mineral density is low for the patient's age and secondary causes of bone loss should be considered.

A DXA scan is recommended for the following patients:

Current central DXA systems can also assess vertebral deformities in the lower thoracic and lumbar spine, a procedure termed vertebral fracture assessment (VFA). Vertebral deformities in the absence of trauma, even those clinically silent, are diagnostic of osteoporosis and are predictive of an increased risk of future fractures. VFA is more likely to be useful in patients with height loss ≥ 3 cm. If the VFA results reveal suspected abnormalities, plain x-rays should be done to confirm the diagnosis.

The need for drug therapy Antiresorptive drugs is based on the probability of fracture, which is related to DXA results as well as other factors. The fracture risk assessment (FRAX) score (see Fracture Risk Assessment Tool) predicts the 10-year probability of a major osteoporotic (hip, spine, forearm, or humerus) fracture in untreated patients. The score accounts for several significant risk factors for bone loss and fracture, including bone mineral density, multiple clinical features, and country of origin of the patient (to account for observed population differences). If the FRAX score is above certain thresholds (in the US, a ≥ 20% probability of major osteoporotic fracture or 3% probability of hip fracture), drug therapy should generally be recommended. There are limitations to the use of the FRAX score because it does not account for several factors, including history of falls or increased fall risk, the patient's bone mineral density at the lumbar spine, or family history of vertebral fractures.

Bones show decreased radiodensity and loss of trabecular structure, but not until about 30% of bone has been lost. However, plain x-rays are important for documenting fractures resulting from bone loss. Loss of vertebral body height and increased biconcavity characterize vertebral compression fractures. Thoracic vertebral fractures may cause anterior wedging of the bone. Vertebral fractures at T4 or above raise concern of cancer rather than primary osteoporosis. Plain x-rays of the spine to look for asymptomatic vertebral fragility fractures should be considered in older patients with severe back pain and localized vertebral spinous tenderness and in patients who report > 3 cm height loss. In long bones, although the cortices may be thin, the periosteal surface remains smooth.

Corticosteroid-induced osteoporosis is most likely to cause vertebral compression fractures but may also cause fractures at other sites where osteoporotic fractures are common. Hyperparathyroidism can be differentiated when it causes subperiosteal resorption or cystic bone lesions (rarely). Osteomalacia may cause abnormalities on imaging tests similar to those of osteoporosis.

An evaluation for secondary causes of bone loss should be considered in a patient with a Z-score ≤ -2.0. Laboratory testing should usually include the following:

Other tests such as thyroid-stimulating hormone or free thyroxine to check for hyperthyroidism Diagnosis Hyperthyroidism is characterized by hypermetabolism and elevated serum levels of free thyroid hormones. Symptoms include palpitations, fatigue, weight loss, heat intolerance, anxiety, and tremor... read more , measurements of urinary free cortisol, and blood counts and other tests to rule out cancer, especially myeloma Diagnosis Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more (eg, serum protein electrophoresis, serum free light chains, urine protein electrophoresis), should be considered depending on the clinical presentation.

Patients with weight loss should be screened for gastrointestinal disorders (eg, malabsorption Diagnosis Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more , celiac disease Diagnosis Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more , inflammatory bowel disease Overview of Inflammatory Bowel Disease Inflammatory bowel disease (IBD), which includes Crohn disease and ulcerative colitis, is a relapsing and remitting condition characterized by chronic inflammation at various sites in the gastrointestinal... read more ) as well as cancer. Bone biopsy is reserved for unusual cases (eg, young patients with fragility fractures and no apparent cause, patients with chronic kidney disease who may have other bone disorders, patients with persistently very low vitamin D levels suspected of having osteomalacia).

Levels of fasting serum C-telopeptide cross-links (CTX) or urine N-telopeptide cross-links (NTX) reflect increased bone resorption. Although reliability varies for routine clinical use, elevated levels of CTX and NTX may be helpful in predicting fracture risk in an untreated patient, monitoring response to therapy, or with the timing of a drug holiday (2 Diagnosis references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). In patients on antiresorptive drug therapy, levels should be markedly suppressed. If not, abnormal absorption or poor adherence to treatment regimen should be suspected.

Risk factor modifications aim to reduce risk of osteoporosis and risk of fractures. Measures include

Weight-bearing exercise can help increase bone mineral density. The optimal amount of weight-bearing exercise is not established, but an average of 30 minutes a day is recommended. If alcohol is consumed, intake should be no more than 1 drink a day for women and 2 drinks a day for men.

Clinicians should routinely ask about recent falls and otherwise assess fall risk Evaluation A fall is defined as a person coming to rest on the ground or another lower level; sometimes a body part strikes against an object that breaks the fall. Typically, events caused by acute disorders... read more . Many older patients are at risk of falls because of poor coordination and balance, poor vision, muscle weakness, confusion, and use of drugs that cause postural hypotension Causes of Orthostatic Hypotension or alter the sensorium. If necessary, physical therapists can evaluate a patient's gait and fall risk and help create safe individualized programs of core-strengthening exercises to help increase stability and decrease risk of falls. Educating patients about the risks of falls and fractures, instructing how to safely do daily activities, and modifying the home environment for safety also are important for preventing fractures.

All men and women should consume at least 1000 mg of elemental calcium daily. An intake of 1200 mg a day (including dietary consumption) is recommended for postmenopausal women and older men and for periods of increased requirements, such as pubertal growth, pregnancy, and lactation. Calcium intake should ideally be from dietary sources, with supplements used if dietary intake is insufficient. Calcium supplements are taken most commonly as calcium carbonate or calcium citrate. Calcium citrate is better absorbed in patients with achlorhydria, but both are well absorbed when taken with meals. Patients taking gastric acid suppressants (eg, proton pump inhibitors, H2 blockers) or those who have had gastric bypass surgery Bariatric Surgery Bariatric surgery is the surgical alteration of the stomach, intestine, or both to cause weight loss. In the US, about 250,000 bariatric operations are done in each year. Development of safer... read more should take calcium citrate to maximize absorption. Calcium should usually be taken in doses of 500 to 600 mg 2 times a day.

Vitamin D supplementation with 600 to 800 units a day is recommended. Patients with vitamin D deficiency may need even higher doses. Supplemental vitamin D is usually given as cholecalciferol, the natural form of vitamin D, although ergocalciferol, the synthetic plant-derived form, is also acceptable. The 25-hydroxy vitamin D level should be ≥ 30 ng/mL.

Bisphosphonates are first-line drug therapy. By inhibiting bone resorption, bisphosphonates preserve bone mass and can decrease vertebral and hip fractures by up to 50%. Bone turnover is reduced after 3 months of bisphosphonate therapy and fracture risk reduction is evident as early as 1 year after beginning therapy. Bisphosphonates can be given orally or IV. Bisphosphonates include the following:

Evidence supports a treatment duration with oral alendronate for 5 years or with IV zoledronic acid for 3 to 6 years (1 Treatment references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). Optimal durations for other bisphosphonates are not yet known.

Oral bisphosphonates must be taken on an empty stomach with a full (8-oz, 250 mL) glass of water, and the patient must remain upright for at least 30 minutes (60 minutes for ibandronate) and not take anything else by mouth during this time period. These drugs are safe to use in patients with a creatinine clearance > 35 mL/minute. Oral bisphosphonates can cause esophageal irritation. Esophageal disorders that delay transit time and symptoms of upper gastrointestinal disorders are relative contraindications to oral bisphosphonates. IV bisphosphonates are indicated if a patient is unable to tolerate or is nonadherent with oral bisphosphonates.

Osteonecrosis of the jaw Medication-Related Osteonecrosis of the Jaw (MRONJ) Medication-related osteonecrosis of the jaw has no unanimously accepted definition or etiology but is generally held to be an oral lesion involving bare mandibular or maxillary bone present... read more and atypical femoral fractures have been rarely reported in patients receiving antiresorptive therapy with bisphosphonates, romosozumab Maternal and perinatal mortality references In 2020, overall maternal mortality rate in the US was 23.8 deaths/100,000 live births ( 1). The maternal mortality rate is higher in the US than in European countries (eg, Germany, Netherlands... read more , or denosumab Antiresorptive drugs . Risk factors include invasive dental procedures, IV bisphosphonate use, and cancer. The benefits of reduction of osteoporosis-related fractures far outweigh this small risk. Although some dentists ask a patient to discontinue a bisphosphonate for several weeks or months before an invasive dental procedure, it is not clear that doing so decreases the risk of osteonecrosis of the jaw.

Long-term bisphosphonate use may increase the risk of atypical femoral fractures. These fractures occur in the mid-shaft of the femur with minimal or no trauma and may be preceded by weeks or months of thigh pain. The fractures may be bilateral even if symptoms are only unilateral.

To minimize fracture incidence, consideration should be given to stopping bisphosphonates (a bisphosphonate holiday) after about

Intermittent cessation of bisphosphonate treatment (drug holiday), as well as initiation and duration of therapy, depend on patient risk factors such as age, comorbidities, prior fracture history, DXA scan results, and fall risk. The drug holiday is 1 year or longer. Patients on a bisphosphonate holiday should be closely monitored for a new fracture or accelerated bone loss evident on a DXA scan, especially after being off therapy for 2 years or more.

During therapy with an antiresorptive drug, such as a bisphosphonate, bone turnover is suppressed as evidenced by low serum or urinary levels of (fasting) N-telopeptide cross-links (< 40 nmol/L) or C-telopeptide cross-links. These markers may remain low for ≥ 2 years off drug therapy. In untreated patients, an increase in levels of bone turnover markers, particularly with higher levels, indicates an increased risk of fracture. However, it is not clear whether levels of bone turnover markers should be used as criteria for when to start or end a drug holiday.

The immediate initiation of a bisphosphonate after an osteoporotic fracture has been controversial because of a theoretical concern that these agents may impede bone healing. However, recent American Society of Bone and Mineral Research (ASBMR) treatment recommendations for secondary prevention of fractures are to start an oral bisphosphonate during the hospitalization for the fracture (2 Treatment references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). Also, there is no reason to delay therapy in order to obtain a DXA scan because a hip or vertebral fragility fracture establishes the presence of osteoporosis.

Intranasal salmon calcitonin should not regularly be used for treating osteoporosis. Salmon calcitonin may provide short-term analgesia after an acute fracture, such as a painful vertebral fracture, due to an endorphin effect. It has not been shown to reduce fractures.

Estrogen can preserve bone mineral density and prevent fractures. Most effective if started within 4 to 6 years of menopause, estrogen is given orally and may slow bone loss and possibly reduce fractures even when started much later. However, use of estrogen increases the risk of thromboembolism and endometrial cancer and may increase the risk of breast cancer. The risk of endometrial cancer can be reduced in women with an intact uterus by taking a progestin with estrogen (see Hormone therapy Hormone Therapy Menopause is physiologic or iatrogenic cessation of menses (amenorrhea) due to decreased ovarian function. Manifestations may include hot flushes, night sweats, sleep disruption, and genitourinary... read more ). However, taking a combination of a progestin and estrogen increases the risk of breast cancer, coronary artery disease, stroke, and biliary disease. Because of these concerns and the availability of other treatments for osteoporosis, the potential harms of estrogen treatment for osteoporosis treatment outweigh its potential benefits for most women; when treatment is initiated, a short course with close monitoring should be considered.

Raloxifene is a selective estrogen receptor modulator (SERM Selective estrogen receptor modulators (SERMS) Menopause is physiologic or iatrogenic cessation of menses (amenorrhea) due to decreased ovarian function. Manifestations may include hot flushes, night sweats, sleep disruption, and genitourinary... read more ) that may be appropriate for treatment of osteoporosis in women who cannot take bisphosphonates. It is given orally once daily and reduces vertebral fractures by about 50% but has not been shown to reduce hip fractures. Raloxifene does not stimulate the uterus and antagonizes estrogen effects in the breast. It has been shown to reduce the risk of invasive breast cancer. Raloxifene may increase risk of thromboembolism.

Denosumab is a monoclonal antibody against RANKL (receptor activator of nuclear factor kappa-B ligand) and reduces bone resorption by osteoclasts. Denosumab may be helpful in patients not tolerant of or unresponsive to other therapies or in patients with impaired renal function. This drug has been found to have a good safety profile at 10 years of therapy. Denosumab is contraindicated in patients with hypocalcemia because it can cause calcium shifts that result in profound hypocalcemia and adverse effects such as tetany. Osteonecrosis of the jaw Medication-Related Osteonecrosis of the Jaw (MRONJ) Medication-related osteonecrosis of the jaw has no unanimously accepted definition or etiology but is generally held to be an oral lesion involving bare mandibular or maxillary bone present... read more and atypical femoral fractures have been rarely reported in patients taking denosumab.

Patients taking denosumab should not undergo a drug holiday because stopping this drug may cause a rapid loss in bone mineral density and, importantly, increase the risk of fractures, particularly vertebral fractures, sometimes multiple. If and when denosumab is discontinued, transition to a bisphosphonate such as IV zoledronic acid should be considered for at least a year and longer if there is ongoing risk of fracture.

Anabolic agents include teriparatide (synthetic PTH [PTH1-34]) and abaloparatide (a human PTH analog that binds to PTH type 1 receptor). They are given daily by subcutaneous injection and increase bone mass, stimulate new bone formation, and reduce the risk of fractures. Patients taking an anabolic agent should have a creatinine clearance > 35 mL/minute. Romosozumab Antiresorptive drugs , the monoclonal antibody against sclerostin, has anabolic as well as antiresorptive effects.

These three anabolic agents (teriparatide, abaloparatide, and romosozumab) are generally indicated for patients who have the following characteristics:

Any of these three anabolic agents can be considered for use during a bisphosphonate holiday.

The use of anabolic agents to treat osteoporosis had been limited to 2 years based on a black box warning because of concern of increased risk of developing osteosarcoma Osteosarcoma (osteogenic sarcoma) Primary malignant bone tumors are much less common than metastatic bone tumors, particularly in adults. Primary malignant bone tumors include multiple myeloma, osteosarcoma, adamantinoma, chondrosarcoma... read more in initial 2-year clinical trials, but the restriction of 2 years of therapy is no longer required. Consequently, although 2 years of treatment with an anabolic agent remains a reasonable course of therapy, giving a second 2-year course of therapy can now be considered. However, after completion of a treatment course with an anabolic agent, the bone mineral density gains are quickly lost if a patient is not quickly transitioned to an antiresorptive agent such as a bisphosphonate Antiresorptive drugs .

Anabolic agents are safe to initiate at any time after a fracture. It is not clear whether early post-fracture use of anabolic agents accelerates bone healing.

Romosozumab is a monoclonal antibody against sclerostin (a small protein made by osteocytes that inhibits new bone formation by osteoblasts). It has both antiresorptive and anabolic effects and has been shown to increase bone mineral density in the hip and lumbar spine and reduce fracture risk in postmenopausal women (3 Treatment references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). Romosozumab is indicated for patients with severe osteoporosis, particularly in older people, those who are frail, and those with an increased risk of falling. It should also be considered in patients who fracture despite adequate antiresorptive therapy. It is given via monthly subcutaneous injection for 1 year (4 Treatment references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). Romosozumab treatment for 1 year followed by alendronate for 1 year is more efficacious than treatment with alendronate for 2 years (4 Treatment references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ), and romosozumab for 1 year followed by denosumab for 2 years decreases fracture risk and increases bone mineral density (5 Treatment references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). As with denosumab, when romosozumab is discontinued, antiresorptive therapy should be given to prevent rapid bone loss. Romosozumab should not be initiated within 12 months of a patient having had a myocardial infarction or stroke. Romosozumab carries a black box warning due to increased risk for cardiovascular events, including myocardial infarction, stroke, and cardiovascular death.

Monitoring for ongoing bone loss or the response to treatment with serial DXA scans should be done using the same DXA machine, and the comparison should use actual bone mineral density (g/cm²) rather than T-score. In patients with osteopenia, DXA should be repeated periodically to determine whether there is ongoing bone loss or development of frank osteoporosis requiring treatment. The frequency for follow-up DXA scanning varies from patient to patient, but some reasonable guidelines are as follows:

Results may help identify patients at higher risk of fractures due to a suboptimal response to osteoporosis treatment (1 Diagnosis references Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). Patients who have a significantly lower bone mineral density despite treatment should be evaluated for secondary causes of bone loss, poor drug absorption (if taking an oral bisphosphonate), and (except patients treated with IV bisphosphonates) drug adherence.

Acute back pain resulting from a vertebral compression fracture can be treated with short-term orthopedic support as needed, analgesics, and, when muscle spasm is prominent, moist heat Heat Treatment of pain and inflammation aims to facilitate movement and improve coordination of muscles and joints. Nondrug treatments include therapeutic exercise, heat, cold, electrical stimulation... read more and massage Massage Treatment of pain and inflammation aims to facilitate movement and improve coordination of muscles and joints. Nondrug treatments include therapeutic exercise, heat, cold, electrical stimulation... read more . Core-strengthening exercises are helpful for patients who have back pain and a prior healed vertebral fracture. Chronic backache may be relieved by exercises to strengthen paravertebral muscles. Avoiding heavy lifting can help. Bed rest should be minimized, and consistent, carefully designed weight-bearing exercise should be encouraged.

In some patients, vertebroplasty or kyphoplasty can be used to relieve severe pain due to a new vertebral fragility fracture; however, the evidence for efficacy is inconclusive. In vertebroplasty, methyl methacrylate is injected into the vertebral body. In kyphoplasty, the vertebral body is first expanded with a balloon then injected with methyl methacrylate. These procedures may reduce deformity in the injected vertebrae but do not reduce and may even increase the risk of fractures in adjacent vertebrae. Other adverse effects include rib fractures, cement leakage, pulmonary embolism, or myocardial infarction. Further study to determine indications for these procedures is warranted.