Pathophysiology of Osteoporosis
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. Men have higher bone mass than women. After achieving peak, bone mass plateaus for about 10 years, during which time bone formation approximately equals bone resorption. After this, bone loss occurs at a rate of about 0.3 to 0.5%/year. Beginning with menopause, bone loss accelerates in women to about 3 to 5%/year for about 5 to 7 years and then the rate of loss decelerates. While historically recognized as present, differences suggesting that Blacks achieve higher peak bone mass are being reassessed to better delineate the accuracy and relevance of these differences, as well as whether race should be considered when interpreting test values.
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:
Spine ( thoracic and lumbar vertebral compression fractures Vertebral Compression Fractures Most vertebral compression fractures are a consequence of osteoporosis, are asymptomatic or minimally symptomatic, and occur with no or minimal trauma. (See also Overview of Fractures.) Vertebral... read more —the most common osteoporosis-related fracture)
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.
Classification of Osteoporosis
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 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, 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, vitamin... 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:
Local changes in cytokine production, particularly involving cytokines such as receptor activator of nuclear factor kappa-B ligand [RANKL] that increase bone resorption by promoting differentiation and maturation of osteoclasts
Impaired formation response during bone remodeling, probably caused by age-related decline in the number and activity of osteoblasts, partly related to cytokine-mediated increases in the protein sclerostin
Other factors that affect bone resorption such as parathyroid hormone (PTH) and vitamin D
Fragility fractures rarely occur in children, adolescents, premenopausal women, or men < 50 years 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 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). 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 Causes of Secondary Osteoporosis ) may also further accelerate bone loss and increase fracture risk in patients with primary osteoporosis.
Patients with chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more may have several reasons for low bone mass, including secondary hyperparathyroidism Secondary 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, vitamin... read more , elevated serum phosphorus, calcitriol deficiency, abnormalities of serum calcium and vitamin D, osteomalacia, and low-turnover bone disorders (adynamic bone disease).
Risk Factors for Osteoporosis
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 populations, including white and Asian people, are thought to have a high risk of osteoporosis. However, given the diversity within larger population groups and controversies about whether and how to group people into populations, these differences are being reevaluated. 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.
Symptoms and Signs of Osteoporosis
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 week. Residual pain may last for months or be constant, in which case additional fractures or underlying spine disorders should be suspected.
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 early satiety due to the compression of the abdominal cavity as the rib cage approaches the pelvis.
Diagnosis of Osteoporosis
Dual-energy x-ray absorptiometry
Plain x-rays (generally done, but not diagnostic)
Dual-energy x-ray absorptiometry (DXA)
Bone mineral density should be measured using DXA scan to screen people at risk, to provide a quantitative measure of bone loss, and to 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 ).
A DXA scan is recommended for the following patients:
All women ≥ 65 years
Women between menopause and age 65 who have risk factors, including a family history of osteoporosis, a low body mass index, and use of tobacco and/or drugs with a high risk of bone loss (eg, glucocorticoids, aromatase inhibitors)
Patients (men and women) of any age who have had fragility fractures
Patients with evidence on imaging studies of decreased bone mineral density or asymptomatic vertebral compression fractures incidentally noted on imaging studies
Patients at risk of secondary osteoporosis
Although low bone mineral density (and the associated increased risk of fracture) can be suggested by plain x-rays, it should be confirmed by a bone mineral density measurement. Low bone mineral density can also be suggested by a screening heel or finger DXA scan (eg, done at health fairs). An abnormal screening heel or finger DXA scan warrants a conventional DXA scan to confirm the diagnosis.
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 mineral 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 mineral 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 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.
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 Preserving bone mass is based on the probability of fracture, which depends on 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. 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, the patient's bone mineral density at the lumbar spine, or family history of vertebral fractures.
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:
Patients being treated with oral bisphosphonates: Repeat DXA scan usually after 2 to 3 years of therapy. DXA scan may be repeated more frequently if clinically warranted, for example in a patient taking glucocorticoids.
Patients treated with IV bisphosphonates: Repeat DXA scan for monitoring after 3 years of therapy to help determine if treatment has been adequate or a longer therapy course is warranted.
Patients treated with anabolic therapy: Repeat DXA scan upon completion of therapy (2 years of teriparatide or abaloparatide, 1 year of romosozumab) to document improvement in bone mineral density with anabolic therapy and to establish a new baseline.
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 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.
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 should be considered in older patients with severe back pain and localized vertebral spinous tenderness. 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 with unexplained fractures. Laboratory testing should usually include the following:
Serum calcium, magnesium, and phosphorus
25-Hydroxy vitamin D level
Liver tests, including testing for a low alkaline phosphatase (hypophosphatasia)
24-hour urine for calcium and creatinine (hypercalciuria)
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 are many and include tachycardia, fatigue, weight loss, nervousness, 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 free light chains and 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 drug therapy, levels should be markedly suppressed. If not, abnormal absorption or poor adherence to treatment regimen should be suspected.
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
2. Lorentzon M, Branco J, Brandi ML et al: Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment, and follow-up or treatment of osteoporosis. Adv Ther 36(10): 2811–2824, 2019. doi: 10.1007/s12325-019-01063-9
Treatment of Osteoporosis
Risk factor modification
Calcium and vitamin D supplements
Antiresorptive drugs (eg, bisphosphonates, hormone replacement therapy, a selective estrogen receptor modulator, receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor [denosumab])
Anabolic agents (eg, parathyroid hormone (PTH) analogues such as teriparatide and abaloparatide)
Romosozumab, a monoclonal antibody against sclerostin with both antiresorptive and anabolic effects
The goals of treatment of osteoporosis are to preserve bone mass, prevent fractures, decrease pain, and maintain function.
Preserving bone mass
The rate of bone loss can be slowed with drugs, but adequate calcium and vitamin D ingestion and physical activity are critical to maintaining optimal bone mineral 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 minutes/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 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 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 be taken in divided doses of 500 to 600 mg 2 or 3 times a day.
Vitamin D supplementation is recommended with 600 to 800 units/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 months of bisphosphonate therapy and fracture risk reduction is evident as early as 1 year after beginning therapy. DXA scans, when done serially to monitor response to treatment, should be done at appropriate intervals Dual-energy x-ray absorptiometry (DXA) (except for romosozumab, 2 years or longer). Bisphosphonates can be given orally or IV. Bisphosphonates include the following:
Alendronate (10 mg once/day or 70 mg orally once/week)
Risedronate (5 mg orally once/day, 35 mg orally once/week, or 150 mg orally once/month)
Zoledronic acid (5 mg IV once/year)
Ibandronate (150 mg orally once/month or 3 mg IV once every 3 months)
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 Osteonecrosis of the Jaw (ONJ) Osteonecrosis of the jaw is an oral lesion involving bare mandibular or maxillary bone. It may cause pain or may be asymptomatic. Diagnosis is by the presence of exposed bone for at least 8... read more and atypical femoral fractures have been rarely reported in patients receiving antiresorptive therapy with bisphosphonates or denosumab Preserving bone mass . 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
3 to 5 years of use in patients with osteoporosis (by DXA scan) but few or no other risk factors for bone loss (3 years for IV zoledronic acid and 5 years for oral bisphosphonates)
5 to 10 years of use in patients with osteoporosis (by DXA scan) and fractures or additional significant risk factors for bone loss and future fractures
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 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.
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. 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 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. 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 Osteonecrosis of the Jaw (ONJ) Osteonecrosis of the jaw is an oral lesion involving bare mandibular or maxillary bone. It may cause pain or may be asymptomatic. Diagnosis is by the presence of exposed bone for at least 8... 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 a year or more, depending upon ongoing risk of fracture.
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 ( 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 ). 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 ( 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 treatment for 1 year followed by alendronate for 1 year is more efficacious than treatment with alendronate for 2 years ( 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 carries a black box warning due to increased risk for cardiovascular events, including myocardial infarction, stroke, and cardiovascular death. It should not be initiated within 12 months of a patient having had a myocardial infarction or stroke. As with denosumab, when romosozumab is discontinued, bisphosphonate therapy should be given to prevent rapid bone loss.
The immediate initiation of antiresorptive agent therapy 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 include the recommendation to initiate an oral bisphosphonate during the hospitalization for the fracture ( 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 ). 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.
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 Preserving bone mass , 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:
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 corticosteroid-induced osteoporosis (teriparatide only)
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 bone tumors are much less common than metastatic bone tumors, particularly in adults. Primary bone tumors include multiple myeloma, osteosarcoma, adamantinoma, chondrosarcoma, chordoma... 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 Preserving bone mass .
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.
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. Core-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.
Treating pain and maintaining function
Acute back pain resulting from a vertebral compression fracture should be treated with orthopedic support, 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 risks may include rib fractures, cement leakage, pulmonary embolism, or myocardial infarction. Further study to determine indications for these procedures is warranted.
1. Black DM, Reid IR, Boonen S, et al: The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: A randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27(2): 243–254, 2012. doi: 10.1002/jbmr.1494
2. Cosman F, Crittenden DB, Adachi JD, et al: Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375(16):1532-1543, 2016. doi: 10.1056/NEJMoa1607948
3. Saag KG, Petersen J, Brandi ML, et al: Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 377(15):1417-1427, 2017. doi: 10.1056/NEJMoa1708322
4. Conley RB, Gemma Adib G, Adler RA, et al: Secondary fracture prevention: Consensus clinical recommendations from a multistakeholder coalition. J Bone Miner Res, 2019 [Epub ahead of print]. doi: 10.1002/jbmr.3877
Prevention of Osteoporosis
The goals of prevention are 2-fold: preserve bone mass and prevent fractures. Preventive measures are indicated for the following:
Patients who have osteopenia
Patients taking high-dose and/or long-term systemic glucocorticoids or aromatase inhibitors
Patients with osteoporosis
Patients with secondary causes for bone loss
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%/year after age 40, accelerating after menopause in women to about 3 to 5%/year for about 5 to 7 years.
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, humerus, distal radius, or hip.
Use DXA to measure bone mineral density in women ≥ 65 years; 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 mineral 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, an unexplained fracture occurs while on treatment for osteoporosis, or 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).
Treatments include antiresorptive drugs (eg, bisphosphonates, a selective estrogen receptor modulator, receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor, a drug used for hormone replacement therapy) or an anabolic agent such as teriparatide, abaloparatide, or romosozumab.
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
The Fracture Risk Assessment Tool: Online tool to evaluate fracture risk of patients
American Association of Clinical Endocrinology (AACE) Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis, 2020 Update: Information for healthcare professionals and their patients about the diagnosis, evaluation, and treatment of postmenopausal osteoporosis
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