Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women

INTRODUCTION — Osteoporosis is characterized by low bone mass, microarchitectural disruption, and skeletal fragility, resulting in decreased bone strength and an increased risk of fracture. Decreased bone strength is related to many factors other than bone mineral density (BMD), including rates of bone formation and resorption (turnover), bone geometry (size and shape of bone), and microarchitecture (picture 1).

The World Health Organization (WHO) has defined diagnostic thresholds for low bone mass and osteoporosis based upon BMD measurements compared with a young adult reference population (T-score). The majority of postmenopausal women with osteoporosis have bone loss related to estrogen deficiency and/or age.

Early diagnosis and quantification of bone loss and fracture risk are important because of the availability of therapies that can slow or even reverse the progression of osteoporosis.

The clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women will be reviewed here. The evaluation of osteoporosis in premenopausal women and men and the treatment of osteoporosis are reviewed separately. (See "Evaluation and treatment of premenopausal osteoporosis" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)

CLINICAL MANIFESTATIONS — Osteoporosis has no clinical manifestations until there is a fracture. This is an important fact because many patients without symptoms incorrectly assume that they must not have osteoporosis. On the other hand, many patients with achy hips or feet assume that their complaints are due to osteoporosis. This is unlikely true in the absence of fracture. In comparison, pain is common in osteomalacia in the absence of fractures or other bone deformities. (See "Epidemiology and etiology of osteomalacia".)

●Vertebral fracture – Vertebral fracture is the most common clinical manifestation of osteoporosis. Most of these fractures (approximately two-thirds) are asymptomatic; they are diagnosed as an incidental finding on chest or abdominal radiograph (image 1). The clinical manifestations of symptomatic vertebral fracture, including height loss, are reviewed separately. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment".)

●Other fractures – Hip fractures are relatively common in osteoporosis, affecting up to 15 percent of women and 5 percent of men by 80 years of age [1]. In addition, distal radius fractures (Colles fractures) may occur. Colles fractures are more common in women shortly after menopause, whereas the risk of hip fracture increases exponentially with age. (See "Overview of common hip fractures in adults" and "Distal radius fractures in adults".)

DIAGNOSIS — Osteoporosis is characterized by low bone mass, microarchitectural disruption, and increased skeletal fragility. A clinical diagnosis of osteoporosis may be made in the presence of (algorithm 1) [2-4]:

●Fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis

or

●T-score ≤-2.5 standard deviations (SDs) at any site based upon bone mineral density (BMD) measurement by dual-energy x-ray absorptiometry (DXA) (see "Screening for osteoporosis in postmenopausal women and men", section on 'Candidates for BMD testing')

As another means for diagnosis of osteoporosis in postmenopausal women, we agree with the National Bone Health Alliance suggestion that a clinical diagnosis of osteoporosis may be made if there is a clear elevated risk for fracture [3]. In the United States, for example, a clinical diagnosis of osteoporosis may be made when the FRAX 10-year probability of major osteoporotic fracture (hip, clinical spine, proximal humerus, or forearm) is ≥20 percent or the 10-year probability of hip fracture is ≥3 percent [2,3]. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Osteoporosis'.)

All postmenopausal women with osteoporosis should have an evaluation to exclude causes of low bone mass other than age and estrogen deficiency. (See 'Evaluation' below.)

Fragility fracture — A clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis, without measurement of BMD. Fragility fractures are those occurring spontaneously or from minor trauma, such as a fall from a standing height or less. Fragility fractures result from mechanical forces that would not ordinarily result in fracture. Reduced bone density is a major risk factor for fragility fractures.

The most common sites of fragility fracture are the spine (vertebral compression fractures), hip, and wrist. Fragility fractures also occur at the humerus, rib, and pelvis. Certain skeletal locations, including the skull, cervical spine, hands, feet, and ankles, are not associated with fragility fractures. Stress fractures are also not considered fragility fractures, as they are due to repetitive injury. (See "Overview of stress fractures".)

Bone mineral density — In the absence of a fragility fracture, BMD assessment by DXA is the standard test to diagnose osteoporosis, according to the classification of the World Health Organization (WHO) [2,5].

T-score — The WHO established diagnostic thresholds for BMD (by DXA) according to the SD difference between a patient's BMD and that of a young adult reference population (T-score) (table 1) [5].

●≤-2.5 SD – A BMD T-score that is 2.5 SD or more below the young adult mean BMD is defined as osteoporosis, provided that other causes of low BMD have been ruled out (such as osteomalacia)

●-1 to -2.5 SD – A T-score that is 1 to 2.5 SD below the young adult mean is termed low bone mass (osteopenia)

●≥-1 SD – Normal bone density is defined as a value within 1 SD of the mean value in the young adult reference population

Individuals with T-scores of ≤-2.5 have the highest risk of fracture. However, collectively there are more fractures in patients with a T-score between -1 and -2.5 because there are so many more patients in this category [6]. (See "Overview of dual-energy x-ray absorptiometry".)

Z-score — The Z-score is a comparison of the patient's BMD to an age-matched population. A Z-score of -2 or lower is considered below the expected range for age [7]. Thus, the presence of Z-score values more than 2 SD below the mean should prompt careful scrutiny for coexisting problems (eg, glucocorticoid therapy or alcoholism) that can contribute to osteoporosis. (See 'Additional evaluation' below.)

Applicability of WHO criteria — The World Health Organization (WHO) thresholds were chosen based upon fracture risk in postmenopausal White women. Similar diagnostic threshold values for men are less well defined, although for any given BMD, the age-adjusted fracture risk is similar in men and women [8]. We agree with the International Society for Clinical Densitometry (ISCD) recommendations for the application of the WHO classification in clinical practice [7]:

●Postmenopausal women and men ≥50 years – The ISCD advises that the WHO criteria be used in postmenopausal women and in men age 50 years and older.

●Premenopausal women and men <50 years – The ISCD advises that the WHO criteria not be used in premenopausal women or men under age 50 years, because the relationship between BMD and fracture risk is not the same in younger women and men.

●Children – The WHO classification should not be used in children (male or female under age 20 years), and a diagnosis of osteoporosis cannot be made in a child based on densitometric criteria alone. Z-scores, not T-scores, should be used, since it is not appropriate to compare the BMD of someone who has not yet achieved peak bone mass with that of an adult who has. Osteoporosis can be diagnosed in children based on the presence of a vertebral compression fracture, or a Z-score <-2 in combination with a significant fracture history (eg, two long bone fractures before age 10 years or three long bone fractures before 19 years) [9].

Method of BMD measurement — Several different methods are available to measure bone mineral density (BMD). DXA is the best available clinical tool for the diagnosis of osteoporosis and monitoring changes in BMD over time. Detailed information about DXA is found elsewhere (see "Overview of dual-energy x-ray absorptiometry"). Other methods of measuring BMD for fracture risk assessment are reviewed separately. (See "Osteoporotic fracture risk assessment", section on 'Methods of measurement of BMD'.)

Site of measurement — In women who are candidates for BMD testing, we suggest DXA measurements of the spine and hip because fractures at these sites have the greatest impact on patients' health. Measurement of hip BMD also has the highest predictive value for hip fracture. In addition, if pharmacologic therapy is planned, measurement of spine BMD is useful as it shows less variability and can detect responses to therapy earlier than hip BMD. We make the diagnosis according to the lowest T-score measured.

Interference from osteophytes and vascular calcifications on the spine measurement are common in aging women and interfere with the assessment of BMD at this site. In this setting, measurement of hip BMD alone or hip and one-third radial site is sufficient.

In all studies, the risk for most fractures is inversely proportional to bone density [10-18]. Some studies suggest that the risk for fracture at a particular site is best estimated by measuring bone density at that site [19-22]. Other studies, however, have found that measurement of BMD at any site predicts fracture risk at all sites equally well [23]. The preferred site for measurement of bone density and the number of sites to measure are debatable, and it may vary according to the clinical situation. The Fracture Risk Assessment Tool (FRAX) can improve the prediction of fractures above that achieved by BMD. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool' and "Screening for osteoporosis in postmenopausal women and men", section on 'Skeletal site to measure'.)

DIFFERENTIAL DIAGNOSIS — Decreased bone mass can occur because peak bone mass is low, bone resorption is excessive, or bone formation during remodeling is decreased. All three processes are likely to contribute, in varying degrees, to osteoporosis in individual patients. Most postmenopausal women with osteoporosis, however, have either age- or estrogen deficiency-related bone loss due primarily to excessive bone resorption.

Other causes of bone fractures and reduced bone mineral density (BMD) include osteomalacia, malignancy (eg, multiple myeloma), Paget disease, and hyperparathyroidism. Most of these diagnoses can be distinguished from estrogen deficiency-related osteoporosis by the clinical history, physical examination, and laboratory testing. (See 'Evaluation' below.)

Physical abuse should always be considered a possibility in a patient with fractures, particularly when the fracture burden exceeds what one would expect based on BMD, or when location of fractures is atypical. (See "Elder abuse, self-neglect, and related phenomena", section on 'Warning signs'.)

Low BMD may also be seen in conjunction with renal osteodystrophy in patients with decreased kidney function [24-26]. It is difficult to distinguish low bone density due to osteoporosis from low bone density due to any of the components of chronic kidney disease-metabolic bone disease. The distinction may be made biochemically in most cases, but may sometimes require bone biopsy. The diagnosis, evaluation, and management of osteoporosis in patients with chronic kidney disease and the diagnosis and management of renal osteodystrophy and secondary hyperparathyroidism are discussed in detail elsewhere. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation" and "Evaluation of renal osteodystrophy" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis".)

EVALUATION — The goal of the evaluation is to exclude causes of low bone mass other than age and estrogen deficiency, such as osteomalacia, hyperthyroidism, and hyperparathyroidism, and to detect potentially remediable causes or other contributing factors to osteoporosis (table 2) [27-31].

Initial evaluation — The initial evaluation includes a history to assess for clinical risk factors for fracture and to evaluate for other conditions that contribute to bone loss, a physical examination, and basic laboratory tests.

●History and physical examination – Most of the conditions causing osteoporosis can be excluded with a careful history and physical examination (table 2). Lifestyle factors that contribute to bone loss, including smoking, excessive alcohol, physical inactivity, and poor nutrition, should be addressed. Height and weight should be measured.

A history of a fragility fracture is an important risk factor for a subsequent fracture [10,32,33]. In women who have a vertebral fracture, approximately 19 percent will have another fracture in the next year [32]. A meta-analysis of 11 cohorts (15,259 men and 44,902 women) showed that a previous fracture was associated with an increased risk of any fracture compared with those without a prior fracture (relative risk [RR] 1.86, 95% CI 1.75-1.98) [34]. Thus, individuals with a history of a fragility fracture are a high-risk group that requires evaluation and treatment. (See "Osteoporotic fracture risk assessment" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment".)

●Laboratory evaluation – We suggest that postmenopausal women with low BMD (T-score below -2.5) and/or fragility fracture have the following basic tests (table 3) [27,28,31,35]:

•Biochemistry profile (especially calcium, phosphorous, albumin, total protein, creatinine, liver enzymes including alkaline phosphatase, electrolytes)

•25-hydroxyvitamin D (25[OH]D)

•Complete blood count (CBC)

•If the diagnosis of osteoporosis is based upon the presence of a fragility fracture, we also obtain a BMD measurement (dual-energy x-ray absorptiometry [DXA]), performed on a nonurgent basis, for quantitative assessment of bone density and to monitor response to therapy

Additional evaluation — The need for additional laboratory evaluation depends upon the initial evaluation and Z-score (table 3). Women who have abnormalities on initial laboratory testing, suspicious findings on history and physical examination suggesting a secondary cause of osteoporosis, or Z-scores ≤-2 may require additional evaluation to detect these secondary causes (table 2).

As examples:

●24-hour urine for calcium and creatinine measurement is useful to assess for adequate calcium intake and absorption in women with gastrointestinal disorders, such as inflammatory bowel disease and celiac disease, or after gastrointestinal surgery, such as gastrectomy or bariatric surgery. Assessment of urinary calcium is also necessary in women with kidney stones, and it may be helpful in women with osteoporosis and no risk factors beyond age to identify idiopathic hypercalciuria [36]. (See "Metabolic bone disease in inflammatory bowel disease" and "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine calcium'.)

●A woman with unexplained anemia, vitamin D deficiency, and/or low urinary calcium excretion should be tested for celiac disease. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency' and "Diagnosis of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disorders'.)

●Cancer or multiple myeloma should be considered in patients who also have hypercalcemia, otherwise unexplained anemia, weight loss, or proteinuria. Measurement of serum and urine protein electrophoresis would be indicated in this case. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

●Serum parathyroid hormone (PTH) should be measured in patients with hypercalcemia, hypercalciuria, a history of renal stones, or osteopenia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

●Urinary cortisol excretion should be measured if Cushing syndrome is suspected and in patients with unexplained osteoporosis and vertebral fracture since patients with subclinical hypercortisolism (mild hypercortisolism without clinical manifestations of Cushing syndrome) are also at risk for low BMD and fractures. (See "Evaluation and management of the adrenal incidentaloma", section on 'Subclinical Cushing syndrome' and "Establishing the diagnosis of Cushing syndrome" and "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Bone loss'.)

Bone turnover markers — We do not routinely measure markers of bone turnover (BTMs) in postmenopausal women with osteoporosis. While the use of BTMs in clinical trials has been helpful in understanding the mechanism of action of therapeutic agents, their role in the care of individual patients is not well established. Potential roles of BTMs in clinical practice include prediction of fracture risk, monitoring response to therapy, and improving compliance with therapy. Biologic and laboratory variability in BTM values have confounded their widespread use in clinical practice. This topic is reviewed separately. (See "Use of biochemical markers of bone turnover in osteoporosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Osteoporosis (The Basics)" and "Patient education: Calcium and vitamin D for bone health (The Basics)")

●Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)" and "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Osteoporosis definition – Osteoporosis is characterized by low bone mass, microarchitectural disruption, and skeletal fragility, resulting in decreased bone strength and an increased risk of fracture. Decreased bone strength is related to many factors in addition to bone mineral density (BMD), including rates of bone formation and resorption (turnover), bone geometry (size and shape of bone), and microarchitecture (picture 1). (See 'Introduction' above.)

●Clinical manifestations – Osteoporosis has no clinical manifestations until there is a fracture. Complications of fractures include pain, deformity, disability, and loss of height. (See 'Clinical manifestations' above.)

●Diagnosis

•Fragility fracture – A clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis, without measurement of BMD (algorithm 1).

•DXA – In the absence of a fragility fracture, BMD assessment by dual-energy x-ray absorptiometry (DXA) is the standard test to diagnose osteoporosis, according to the classification of the World Health Organization (WHO) (table 1). A DXA T-score ≤-2.5 is consistent with osteoporosis, whereas a T-score between -1 and -2.5 is low bone mass (osteopenia). (See 'Diagnosis' above.)

•High fracture risk – For patients without a history of fragility fracture and without a DXA T-score ≤-2.5, a clinical diagnosis of osteoporosis may also be made if there is a clear elevated risk for fracture. In the United States, for example, a clinical diagnosis of osteoporosis may be made when the Fracture Risk Assessment Tool (FRAX) 10-year probability of major osteoporotic fracture is ≥20 percent or the 10-year probability of hip fracture is ≥3 percent. (See 'Diagnosis' above.)

●Evaluation – All postmenopausal women with osteoporosis should have a history, physical examination, and basic laboratory evaluation. Initial laboratory studies should include a complete blood count (CBC), biochemistry profile, and 25-hydroxyvitamin D (25[OH]D). (See 'Evaluation' above.)

The need for additional laboratory evaluation depends upon the initial evaluation and Z-score (table 3). Women who have abnormalities on initial laboratory testing, suspicious findings on history and physical examination suggesting a secondary cause of osteoporosis, or Z-scores ≤-2 may require additional evaluation for these secondary causes (table 2). (See 'Additional evaluation' above.)

●Treatment – The treatment of osteoporosis in postmenopausal women is reviewed separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc K Drezner, MD, who contributed to an earlier version of this topic review.