- Secondary osteoporosis
- Risk Factors
- Symptoms and Signs
- Key Points
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Osteoporosis is a progressive metabolic bone disease that decreases bone density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures with minor or inapparent trauma, particularly in the thoracic and lumbar spine, wrist, and hip (called fragility fractures). Diagnosis is by dual-energy x-ray absorptiometry (DXA scan) or by confirmation of a fragility fracture. Prevention and treatment involve risk factor modification, calcium and vitamin D supplements, exercises to maximize bone and muscle strength, improve balance, and minimize the risk of falls, and drug therapy to preserve bone mass or stimulate new bone formation.
Bone is continually being formed and resorbed. Normally, bone formation and resorption are closely balanced. Osteoblasts (cells that make the organic matrix of bone and then mineralize bone) and osteoclasts (cells that resorb bone) are regulated by parathyroid hormone (PTH), calcitonin, estrogen, vitamin D, various cytokines, and other local factors such as prostaglandins.
Peak bone mass in men and women occurs around age 30. Blacks reach higher peak bone mass than whites and Asians, whereas Hispanics have intermediate values. Men have higher bone mass than women. After achieving peak, bone mass plateaus for about 10 yr, during which time bone formation approximately equals bone resorption. After this, bone loss occurs at a rate of about 0.3 to 0.5%/yr. Beginning with menopause, bone loss accelerates in women to about 3 to 5%/yr for about 5 to 7 yr and then the rate of loss decelerates.
Osteoporotic bone loss affects cortical and trabecular (cancellous) bone. Cortical thickness and the number and size of trabeculae decrease, resulting in increased porosity. Trabeculae may be disrupted or entirely absent. Trabecular bone loss occurs more rapidly than cortical bone loss because trabecular bone is more porous and bone turnover is higher. However, loss of both types contributes to skeletal fragility.
A fragility fracture occurs after less trauma than might be expected to fracture a normal bone. 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 and pelvis.
Osteoporosis can develop as a primary disorder or secondarily due to some other factor. The sites of fracture are similar in primary and secondary osteoporosis.
More than 95% of osteoporosis in women and about 80% in men is primary. Most cases occur in postmenopausal women and older men. Gonadal insufficiency is an important factor in both men and women. Other factors that may accelerate bone loss in patients with primary osteoporosis include decreased calcium intake, low vitamin D levels, certain drugs, and hyperparathyroidism. 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:
Local changes in the production of bone-resorbing cytokines, such as increases in cytokines that stimulate bone resorption
Impaired formation response during bone remodeling (probably caused by age-related decline in the number and activity of osteoblasts)
Other factors such as a decline in local and systemic growth factors
Fragility fractures rarely occur in children, adolescents, premenopausal women, or men < 50 yr with normal gonadal function and no detectable secondary cause, even in those with low bone mass (low Z-scores on dual-energy x-ray absorptiometry [DXA]). Such uncommon cases are considered idiopathic osteoporosis.
Secondary osteoporosis accounts for < 5% of osteoporosis in women and about 20% in men. The causes (see Table: Causes of Secondary Osteoporosis) may also further accelerate bone loss and increase fracture risk in patients with primary osteoporosis.
Patients with chronic kidney disease may have several reasons for low bone mass, including secondary hyperparathyroidism, elevated serum phosphate, calcitriol deficiency, abnormalities of serum calcium and vitamin D, osteomalacia, and low-turnover bone disorders (adynamic bone disease).
Causes of Secondary Osteoporosis
Cancer (eg, multiple myeloma)
COPD (due to the disorder itself, as well as tobacco use and/or treatment with glucocorticoids)
Drugs (eg, glucocorticoids, anticonvulsants, medroxyprogesterone, aromatase inhibitors, rosiglitazone, pioglitazone, thyroid replacement therapy, heparin, ethanol, tobacco)
Prolonged weightlessness (as occurs in space flight)
Because stress, including weight bearing, is necessary for bone growth, immobilization or extended sedentary periods result in bone loss. A low body mass index predisposes to decreased bone mass. Certain ethnicities, including whites and Asians, have a higher risk of osteoporosis. Insufficient dietary intake of calcium, phosphorus, magnesium, and vitamin D predisposes to bone loss, as does endogenous acidosis. Tobacco and alcohol use also adversely affect bone mass. A family history of osteoporosis, particularly a parental history of hip fracture, also increases risk. Patients who have had one fragility fracture are at increased risk of having other clinical (symptomatic) fractures and clinically asymptomatic vertebral compression fractures.
Patients with osteoporosis are asymptomatic unless a fracture has occurred. Nonvertebral fractures are typically symptomatic, but about two thirds of vertebral compression fractures are asymptomatic (although patients may have underlying chronic back pain due to other causes such as osteoarthritis). A vertebral compression fracture that is symptomatic begins with acute onset of pain that usually does not radiate, is aggravated by weight bearing, may be accompanied by point spinal tenderness, and typically begins to subside in 1 wk. However, residual pain may last for months or be constant.
Multiple thoracic compression fractures eventually cause dorsal kyphosis, with exaggerated cervical lordosis (dowager’s hump). Abnormal stress on the spinal muscles and ligaments may cause chronic, dull, aching pain, particularly in the lower back. Patients may have shortness of breath due to the reduced intrathoracic volume and/or abdominal discomfort due to the compression of the abdominal cavity as the rib cage approaches the pelvis.
Bone density should be measured using DXA to screen people at risk, to provide a quantitative measure of bone loss, and to monitor those undergoing treatment (1).
A DXA scan is recommended for the following patients:
All women ≥ 65 yr
Women between menopause and age 65 who have risk factors, including a family history of osteoporosis, a low body mass index (eg, previously defined as body weight < 127 lb), and use of tobacco and/or drugs with a high risk of bone loss (eg, glucocorticoids)
Patients (men and women) of any age who have had fragility fractures
Patients with evidence on imaging studies of decreased bone density or asymptomatic vertebral compression fractures incidentally noted on imaging studies
Patients at risk of secondary osteoporosis
Although low bone density (and the associated increased risk of fracture) can be suggested by plain x-rays, it should be confirmed by a bone density measurement.
DXA is used to measure bone mineral density (g/cm2); it defines osteopenia or osteoporosis (in the absence of osteomalacia), predicts the risk of fracture, and can be used to follow treatment response. Bone density of the lumbar spine, hip, distal radius, or the entire body can be measured. (Quantitative CT scanning can produce similar measurements of the spine or hip but is currently not widely available.) Bone density is ideally measured at two sites, including the lumbar spine and one hip; however, at some centers, measurements are taken of the spine and both hips.
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 density differs from the peak bone mass of a healthy, young person of the same sex and ethnicity. The WHO 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 yr. If the Z-score is ≤ -2.0, bone density is low for the patient's age and secondary causes of bone loss should be considered.
Current central DXA systems can also assess vertebral deformities in the lower thoracic and lumbar spine, a procedure termed vertebral fracture analysis (VFA). Vertebral deformities, 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.
The need for drug therapy is based on the probability of fracture, which depends on DXA results as well as other factors. The fracture risk assessment (FRAX) score (WHO Fracture Risk Assessment Tool) predicts the 10-yr probability of a major osteoporotic (hip, spine, forearm, or humerus) or hip fracture in untreated patients. The score accounts for significant risk factors for bone loss and fracture. 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 be recommended.
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 varies from patient to patient. DXA is often done every 2 to 3 yr but can sometimes be done less frequently, for example, if bone density is normal and fracture risk is low. In patients being treated for osteoporosis, DXA should be repeated, usually about every 2 to 3 yr, but sometimes more frequently in patients taking glucocorticoids. A stable or improved bone mineral density predicts a lower fracture risk. Monitoring bone density with a repeat DXA scan may help identify patients at higher risk of fractures due to a suboptimal response to osteoporosis treatment (1). Patients being treated for osteoporosis who have a significantly decreased bone mineral density on serial DXA examinations should be evaluated for drug adherence and secondary causes of bone loss.
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. In long bones, although the cortices may be thin, the periosteal surface remains smooth. Vertebral fractures at T4 or above raise concern of cancer rather than osteoporosis. Plain x-rays of the spine should be considered in older patients with severe back pain and localized vertebral spinous tenderness.
Glucocorticoid-induced osteoporosis is likely to cause rib fractures as well as 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 (see Osteopenia: Differentiating Osteoporosis and Osteomalacia).
An evaluation for secondary causes of bone loss should be considered in a patient with a Z-score ≤ -2.0 or if a cause of secondary bone loss is clinically suspected. Laboratory testing should usually include the following:
Other tests such as thyroid-stimulating hormone or free thyroxine to check for hyperthyroidism, measurements of urinary free cortisol, and blood counts and other tests to rule out cancer, especially myeloma (eg, serum and urine protein electrophoresis), should be considered depending on the clinical presentation.
Patients with weight loss should be screened for GI disorders (eg, malabsorption, celiac disease, inflammatory bowel disease) 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, CTX and NTX may be helpful in monitoring response to therapy or with the timing of a drug holiday.
1. Leslie WD, Majumdar SR, Morin SN, Lix LM: Change in bone mineral density is an indicator of treatment-related antifracture effect in routine clinical practice: A registry-based cohort study. Ann Intern Med 165(7):465–472, 2016. doi: 10.7326/M15-2937.
The goals of treatment of osteoporosis are to preserve bone mass, prevent fractures, decrease pain, and maintain function.
The rate of bone loss can be slowed with drugs. Adequate calcium and vitamin D and physical activity are keys to optimal bone density. Modifiable risk factors should also be addressed.
Risk factor modification can include increasing weight-bearing exercise, minimizing caffeine and alcohol intake, and smoking cessation. The optimal amount of weight-bearing exercise is not established, but an average of 30 min/day is recommended. A physical therapist can develop a safe exercise program and demonstrate how to safely perform daily activities to minimize the risk of falls and spine fractures.
All men and women should consume at least 1000 mg of elemental calcium daily. An intake of 1200 to 1500 mg/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 proton pump inhibitors or those who have had gastric bypass surgery should take calcium citrate to ensure maximum absorption. Calcium should be taken in divided doses of 500 to 600 mg bid or tid.
Vitamin D supplementation is recommended with 800 to 1000 IU/day. 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 probably 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 mo of bisphosphonate therapy and fracture risk reduction is evident as early as 1 yr after beginning therapy. DXA scanning, when done serially to monitor response to treatment, need not normally be done at intervals < 2 yr. Bisphosphonates can be given orally or IV. Bisphosphonates include the following:
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 min (60 min 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/min. Bisphosphonates can cause esophageal irritation. Esophageal disorders that delay transit time and symptoms of upper GI 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 has been associated with use of bisphosphonates; however, this condition is rare in patients taking oral bisphosphonates. Risk factors include invasive dental procedures, IV bisphosphonate use, and cancer. The benefits of reduction of osteoporosis-related fractures far outweigh this small risk.
Long-term bisphosphonate use may also 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 also be bilateral. To minimize fracture incidence, consideration should be given to stopping bisphosphonates (a bisphosphonate holiday) after about
Patients on a bisphosphonate holiday should be closely monitored for a new fracture or accelerated bone loss evident on a DXA scan. During therapy with an antiresorptive drug, such as a bisphosphonate, bone turnover is suppressed as evidenced by low fasting N-telopeptide cross-links (< 40 nmol/L) or C-telopeptide cross-links. These markers may remain low for ≥ 2 yr of a drug holiday.
In untreated patients, an increase in levels of bone turnover markers 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 decision to begin or end a drug holiday is complex and should take into account the patient's risk factors.
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 density and prevent fractures. Most effective if started within 4 to 6 yr of menopause, estrogen may slow bone loss and possibly reduce fractures even when started much later. 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). 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 risks and the availability of other treatments for osteoporosis, the potential harms of estrogentreatment 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) that may be appropriate for treatment of osteoporosis in women who cannot take bisphosphonates. It 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 has been associated with an increased 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. Denosumab is contraindicated in patients with hypocalcemia and in pregnant women.
PTH, which stimulates new bone formation, is generally indicated in patients who have the following characteristics:
Cannot tolerate antiresorptive drugs or have contraindications to their use
Fail to respond (ie, develop new fractures or lose bone mineral density) to antiresorptive drugs, as well as calcium, vitamin D, and exercise
Possibly have severe osteoporosis (eg, T-score < -3.5) or multiple vertebral fragility fractures
Have glucocorticoid-induced osteoporosis
When given daily by injection for an average of 20 mo, synthetic PTH (PTH 1-34; teriparatide) increases bone mass and reduces risk of fractures. Patients taking teriparatide should have a creatinine clearance > 35 mL/min.
Many elderly patients are at risk of falls because of poor coordination, poor vision, muscle weakness, confusion, and use of drugs that cause postural hypotension or alter the sensorium. Strengthening exercises may increase stability. Educating patients about the risks of falls and fractures, modifying the home environment for safety, and developing individualized programs to increase physical stability and attenuate risk are important for preventing fractures.
Acute back pain resulting from a vertebral compression fracture should be treated with orthopedic support, analgesics, and (when muscle spasm is prominent) heat and massage. Chronic backache may be relieved by an orthopedic garment and 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 cases, vertebroplasty or kyphoplasty can relieve severe pain due to a new vertebral fragility fracture. 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 risks may include rib fractures, cement leakage, and pulmonary edema or MI. Further study to determine indications for these procedures is warranted.
The goals of prevention are 2-fold: preserve bone mass and prevent fractures. Preventive measures are indicated for the following:
Preventive measures for all of these patients include appropriate calcium and vitamin D intake, weight-bearing exercise, fall prevention, and other ways to reduce risk (eg, avoiding tobacco and limiting alcohol). In addition, drug therapy is indicated for patients who have osteoporosis or who have osteopenia if they are at increased risk of fracture, such as those with a high FRAX score, and patients taking glucocorticoids. Drug therapy tends to involve the same drugs as are given for treatment of osteoporosis. Educating patients and the community about the importance of bone health remains of utmost importance.
Bone is lost at a rate of about 0.3 to 0.5%/yr after age 40, accelerating after menopause in women to about 3 to 5%/yr for about 5 to 7 yr.
More than 95% of osteoporosis in women and about 80% in men is primary.
Suspect osteoporosis in patients who have fractures caused by unexpectedly little force (fragility fractures) of the spine, distal radius, femoral neck, or greater trochanter.
Use DXA to measure bone density in women ≥ 65 yr; women between menopause and age 65 who have risk factors (eg, family history of osteoporosis, a low body mass index, and use of tobacco and/or drugs with a high risk of bone loss [including glucocorticoids]); men and women of any age who have fragility fractures; evidence on imaging studies of decreased bone density or asymptomatic vertebral compression fractures; and patients at risk of secondary osteoporosis.
Consider testing patients for causes of secondary bone loss if the Z-score is ≤ -2.0 or if a cause of secondary bone loss is clinically suspected.
For treatment and prevention, ensure adequate intake of calcium and vitamin D, using supplements when necessary, and modify risk factors to help preserve bone mass (eg, with weight-bearing exercise and by minimizing use of caffeine, alcohol, and tobacco).
Treat most patients with an antiresorptive drug (eg, bisphosphonate, selective estrogen receptor modulator, receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor, a drug used for hormone replacement therapy) or an anabolic drug (PTH).