Osteoporosis can be diagnosed by T-score, history of adulthood hip fracture, or vertebral or other fractures in the setting of a low bone mineral density (BMD) . Osteoporosis has been classified as primary (i.e., due to the universal etiologies of postmenopausal estrogen deficiency and aging in women and men), secondary (i.e., due to other factors, such nutritional deficiencies, medications, and disorders with harmful skeletal effects) , or idiopathic (i.e., osteoporosis in children or young-adults without identifiable cause), with many patients having a combination of more than one of these. Patients with low BMD, a history of fragility fracture, or risk factors for fracture should be evaluated for previously unrecognized factors contributing to skeletal fragility.
Many patients with osteoporosis are known to have secondary causes. In 5604 women and 561 men registered in the Canadian Database of Osteoporosis and Osteopenia (CANDOO), 51.3% of the women and 41.4% of the men were identified as having at least one secondary cause of osteoporosis . Previously unrecognized causes of secondary osteoporosis (sometimes called “occult” secondary osteoporosis) are common. The more extensive the evaluation, the more likely it is that factors contributing to osteoporosis, and other diseases mimicking osteoporosis, will be detected. The estimated prevalence of secondary osteoporosis also probably varies according to the population being studied and the practice setting (primary care vs referral center). According to some estimates, a secondary cause for osteoporosis can be found in about two-thirds of men more than one-half of premenopausal and perimenopausal women , and the majority of postmenopausal women . In a study of community-dwelling patients 50 years of age and older with a low trauma hip fracture, more than 80% had at least one previously unrecognized contributing factor, with low vitamin D level, chronic kidney disease (CKD), and monoclonal gammopathy being the most commonly identified . The prevalence of secondary osteoporosis varies according to the cutoffs for distinguishing normal from abnormal. Definitions for calcium and vitamin D adequacy often vary by study. In postmenopausal women with osteoporosis referred to an osteoporosis specialty center, 32% were found to have a previously unrecognized disorder of bone and mineral metabolism, including 4.6% classified as vitamin D deficient when a serum 25-hydroxyvitamin D (25-OH-D) level less than 12.5 ng/mL was classified as deficient . A reanalysis of the same data, using the currently accepted lower limit of serum 25-OH-D level less than 20 ng/mL to define vitamin D deficiency and between 20 and 32 ng/mL classified as insufficiency, found that 21% were deficient and 34% were insufficient in vitamin D , thereby greatly increasing the number of patients diagnosed with secondary osteoporosis.
For any patient at high risk for fracture, particularly when pharmacological therapy is being considered, evaluation for factors contributing to skeletal fragility and falls risk assessment is essential. A similar strategy should be applied to a patient who is a suboptimal responder to therapy. The benefits of evaluation for secondary osteoporosis include three categories as discussed in the following subsections.
Identification of unrecognized conditions affecting skeletal health
Despite the well-recognized clinical utility of dual-energy X-ray absorptiometry (DXA) to diagnose osteoporosis, estimate fracture risk, and monitor BMD changes over time, there are also limitations . The finding of a T-score of −2.5 or below, consistent with a World Health Organization diagnostic classification of osteoporosis , may in some patients be a manifestation of another disease, such as osteomalacia or renal bone disease, that requires treatment different than osteoporosis. A single low BMD measurement does not reveal the rate of bone loss or the pathway to low BMD (e.g., low peak bone mass, bone loss, or both). BMD is one of many risk factors for fracture , all of which must be considered in the management of patients with osteoporosis. The evaluation of patients with studies beyond BMD measurement is essential for determining the underlying bone disease, identifying factors contributing to low BMD and fracture risk, and individualizing treatment decisions.
Optimization of the benefits of therapy
The effectiveness of treatment for osteoporosis may be suboptimal in the setting of relevant skeletal and nonskeletal disorders that are unrecognized and untreated. For example, in clinical trials for the registration of drugs for the treatment of osteoporosis, patients with disorders other than osteoporosis that might affect skeletal health are typically excluded. In fact, most patients who meet clinical practice guidelines for treatment to reduce fracture risk would probably not qualify for participation in the clinical trials of the drugs used to treat them . This raises a concern regarding the potential benefit of drug therapy in some patients and the need to identify and treat relevant underlying disorders. It is a standard procedure in clinical trials to supplement patients with calcium and vitamin D or assure that intake is adequate. It is uncertain whether patients who are deficient in calcium and vitamin D will respond as expected, and evidence suggests that the response may be suboptimal . A patient with unrecognized gastroparesis may have retained gastric contents after an overnight fast and therefore poorly absorb oral bisphosphonates . Similarly, patients with unrecognized malabsorption from untreated celiac disease may have inadequate calcium absorption, resulting in a negative calcium balance. Evaluation for these conditions and others may be helpful for individualizing drug selection and optimizing the chances of achieving the desirable clinical outcomes.
There is potential harm in starting pharmacological therapy to reduce fracture risk for patients who have not been thoroughly evaluated. A patient with baseline hypocalcemia, calcium malabsorption due to an intestinal disorder, subclinical hypoparathyroidism, or with vitamin D deficiency who is started on a potent antiresorptive medication is at risk for developing symptomatic hypocalcemia . Bisphosphonates should not be given to patients with severe CKD [glomerular filtration rate (GFR) less than 30 or 35 mL/minute]; oral bisphosphonates are contraindicated in patients with disordered esophageal emptying, such as esophageal stricture or achalasia . A patient with baseline hyperparathyroidism or hypercalcemia for other reasons is at risk for exacerbation of hypercalcemia when treated with teriparatide or abaloparatide . A patient with a history of thromboembolic disease should not be treated with raloxifene . All potential safety concerns should be identified and addressed to help with drug selection and assure that the risk of undesirable drug effects is minimized.
It has been suggested by some that a patient with a low BMD for age (Z-score less than −1.0, −1.5, or −2.0) is at particularly high risk for secondary causes of osteoporosis and more deserving of a thorough evaluation than others . If this strategy were valid, it would be helpful in directing limited healthcare resources to patients most likely to benefit from a metabolic workup. However, careful scrutiny of the relationship between Z-scores and secondary causes of osteoporosis has provided little supporting evidence for directing an extensive workup to this group of patients. In an analysis of electronic medical records of 18,674 subjects in a large multispecialty group practice the prevalence of secondary osteoporosis (defined by a compatible International Classification of Disease, 9th edition, code) as a function of Z-score was assessed . In this study, there was only a small difference in mean Z-score (±0.3) in patients with and without a secondary cause of osteoporosis. Z-scores provided poor predictive value for the presence of secondary osteoporosis, with no Z-score inflection point that offered clinical guidance on initiating an evaluation for secondary osteoporosis. It was concluded that if only patients with low Z-scores were evaluated for secondary osteoporosis, most cases would be missed. In another study of 173 women with osteoporosis referred to an osteoporosis specialty center, Z-score was also not a significant predictor of secondary osteoporosis . Given the high prevalence of secondary osteoporosis, all patients should be considered for possible secondary causes ( Table 61.1 ). Many of these are addressed in detail in other chapters. Some secondary causes of osteoporosis can be identified or suspected by means of a thorough medical history, while others require a physical examination, laboratory testing, imaging, additional studies, or a combination of these.
|Lifestyle and nutritional||Inherited||Endocrine||Gastrointestinal||Medications||Other|
|Calcium deficiency||Cystic fibrosis||Hypogonadism||Celiac disease||Glucocorticoids||Multiple myeloma|
|Vitamin D deficiency||Osteogenesis imperfecta||Hyperthyroidism||Gastric bypass||Anticonvulsants||Rheumatoid arthritis|
|Immobilization||Homocystinuria||Cushing’s syndrome||Malabsorption||Aromatase inhibitors||Systemic mastocytosis|
|Low body weight||Marfan’s syndrome||Hyperparathyroidism||Inflammatory bowel disease||Androgen deprivation therapy||Tumor-induced osteomalacia|
|Excess alcohol intake||Hypophosphatasia||Diabetes mellitus||Primary biliary cirrhosis||Proton pump inhibitors||Renal tubular acidosis|
|Excess aluminum intake||Hemochromatosis||Hyperprolactinemia||Pancreatic insufficiency||Thiazolidinediones||Thalassemia|
|Cigarette smoking||Family history of osteoporosis||Acromegaly||Gastrectomy||Selective serotonin reuptake inhibitors||Organ transplantation|
|Anorexia nervosa||Turner’s syndrome||Premature menopause||Chronic hepatitis||Depo-medroxyprogesterone||Previous fragility fracture|
A detailed medical history is the first step in the evaluation of skeletal health. Obtaining a thorough assessment of fracture occurrence across the lifespan is critical to determine the severity of osteoporosis and to determine whether there is any suggestion of a disease other than osteoporosis. Knowledge of clinical risk factors for fracture, as well as BMD, can be used to estimate the future risk of fractures using fracture risk assessment tools such as FRAX , the Garvan fracture risk calculator , QFractureScores , and a simplified version of FRAX used in Canada ( Table 61.2 ). The medical history may reveal or provide clues to the presence of secondary causes of osteoporosis. Information about nonskeletal disorders may be helpful in selecting or avoiding specific medications for treating osteoporosis. Understanding the patient’s previous treatment experiences, fears, and concerns may also contribute to developing a treatment plan that is medically appropriate and acceptable to the patient. Organizations providing guidance for the skeletal-related medical history include the National Osteoporosis Foundation (NOF) , the American Association of Clinical Endocrinologists (AACE) , the North American Menopause Society (NAMS) , the Institute for Clinical Systems Improvement , and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis National Osteoporosis Guideline Group . The following components of the medical history have potential implications for skeletal health.
|Clinical risk factor||FRAX||Garvan||QFractureScores||Osteoporosis Canada|
|Prior low-trauma fracture||✓||✓||✓|
|Parent with fractured hip or osteoporosis||✓||✓|
The level of physical activity, cigarette smoking, and alcohol intake should be ascertained. Excessive physical activity may suggest female athlete triad (energy imbalance with or without an eating disorder, menstrual disturbances, and low BMD). Inadequate physical activity, particularly at the extremes (e.g., weightlessness in astronauts, nonweight-bearing with spinal cord injuries, limited weight-bearing with stroke or disabilities), can result in disuse osteoporosis or gait abnormalities that increase fall risk. Cigarette smoking and excessive alcohol ingestion are associated with an increased risk of fractures. Lack of sun exposure, especially in institutionalized patients, may increase the risk of vitamin D inadequacy. Knowledge of the patient’s occupation, recreational activities, and home environment can help identify hazards that might increase fracture risk and identify lifestyle issues that could influence the choice of pharmacological therapy for osteoporosis. Pets at home can be wonderful companions but also may create a falling hazard.
A dietary history and review of nutritional supplements should be obtained. Intake of calcium from diet and supplements, if any, should be estimated. A serving of milk (1 cup), yogurt (1 cup), or cheese (1 cubic inch) each contains approximately 300 mg calcium; when the diet provides an adequate amount of calcium, the patient can be advised that supplemental calcium is not necessary . Vitamin D sources, including sun exposure, diet, and supplements, must be considered. Low levels of vitamin D result in suboptimal calcium absorption and have been associated with elevated parathyroid hormone (PTH) levels, high bone turnover, poor balance, increased risk of falls, and many other medical conditions . An insufficient intake of calcium and/or vitamin D may result in bone loss and suboptimal response to treatment for osteoporosis . Extremely low vitamin D levels may lead to rickets in children and osteomalacia in adults . Excessive intake of calcium can cause hypercalcemia and increase the risk of nephrolithiasis . It has been suggested that calcium supplements may increase the risk of cardiovascular disease , although a subsequent systematic review and meta-analysis concluded that calcium intake within tolerable upper intake levels (2000–2500 mg/day) is not associated with an increase in cardiovascular risk in generally healthy adults .
Other nutritional factors may be relevant in the medical history, as well. For example, high salt intake can cause hypercalciuria and excessive intake of vitamin A may have harmful skeletal effects . Moderate coffee consumption probably does not affect the skeleton significantly, though excessive consumption may reduce calcium absorption, increase calcium excretion, and be a marker for low calcium intake . Moderate long-term tea consumption may have beneficial effects on BMD , while excessive tea drinking may rarely result in skeletal fluorosis . Inadequate protein intake is a predictor of fractures and poor clinical outcomes after fractures . Weight loss, a risk factor for hip fracture in older adults, could be due to malabsorption, malnutrition, or thyrotoxicosis .
A history of low-trauma fractures in childhood is suggestive of an inherited skeletal disorder, such as osteogenesis imperfecta or hypophosphatasia . A history of low-trauma fracture in an adult is consistent with a clinical diagnosis of osteoporosis independent of BMD, provided other causes of skeletal fragility have been evaluated and found to not be present. A previous fracture is a robust predictor of future fractures , with a recent fracture a much greater predictor of a new fracture than one that is remote in time . Since vertebral fractures may have occurred but not be recognized by the patient or physician , patients with historical loss of height or unexplained back pain should be considered for spine imaging . The finding of a previously unrecognized vertebral fracture may change diagnostic classification, assessment of fracture risk, and choices for treatment . A history of poorly healing recurrent metatarsal stress fractures or atypical femur fracture warrants consideration of a diagnosis of hypophosphatasia .
Some orthopedic procedures, such as vertebral augmentation, laminectomy, spinal fusion, or hip replacement, may preclude obtaining a valid BMD measurement at that skeletal site. A history of metallic implants for any reason may be important in determining whether it is safe to do magnetic resonance imaging (MRI) for skeletal disorders. Gastric bypass surgery or gastrectomy may cause malabsorption of skeletal nutrients resulting in osteoporosis and/or osteomalacia, impair the absorption of oral agents for the treatment of osteoporosis, or increase the risk of adverse gastrointestinal (GI) effects with oral bisphosphonates. Previous endocrine surgery may be a clue to hormonal factors contributing to osteoporosis (e.g., hyperparathyroidism treated with parathyroidectomy or thyrotoxicosis treated with thyroidectomy).
A history of falls is a predictor of future falls and elevated fracture risk . Falls are included in some, but not all, fracture risk calculators . Frequent falling may be due to muscle weakness and impaired balance caused by vitamin D deficiency . A review of all potential hazards for falling might suggest the need for modification of the home environment, such as the additional of night-lights and removal of slippery throw rugs. Knowing the circumstances of falling could lead to a recommendation for assistive aids (e.g., cane walker) or change in medication (e.g., lower dose of sleeping pill, antihypertensive) or a specific exercise prescription.
Loss of height
An estimation of height loss can be obtained by subtracting the current measured height from the tallest reported height achieved earlier in life, often taken from the driver’s license. Historical height loss ≥1.5 in. (4 cm) or prospective measured height loss ≥0.8 in. (2 cm) may warrant imaging of the spine to look for prevalent vertebral fractures ( Table 61.3 ) . Imaging is necessary because height loss may also be due to other factors, such as degenerative disease of the spine or scoliosis.
|T-score <−1.0 when one or more of the following is present:|
Blue sclera at birth, failure to thrive, prolonged immobilization in childhood, delayed onset of puberty, nutritional deficiencies, and frequent fractures may provide insight into the possibility of low peak bone mass, inherited, or environmental factors affecting skeletal health as an adult.
A family history of osteoporosis or fractures is a risk factor for future fractures . Inherited disorders of bone and mineral metabolism, such as osteogenesis imperfecta or hypophosphatasia, might be known to occur in family members. Sometimes clues to familial skeletal disorders can be obtained from a history of premature death, childhood fractures, premature loss of teeth, or blue sclera at birth in close relatives.
Numerous medications have been associated with adverse skeletal effects and increased risk fractures ( Table 61.1 ). Some medications (e.g., zoledronic acid, denosumab) are also used to treat cancer-related conditions and osteoporosis, with different brand names and different doses for each indication. It is important to recognize this so that a patient is not inadvertently overtreated for osteoporosis while already being treated with a higher dose for another disease. A thorough history of drugs previously used to treat osteoporosis and the reasons for stopping them may be helpful in selecting new treatment. Exposure to drugs that potentially increase the risk of falling by causing sedation, orthostatic hypotension, or dizziness, should be minimized.
Review of systems
A focused review of systems may uncover factors contributing to osteoporosis, identify clinical risk factors for fractures, and provide valuable information for deciding on the best treatment. The following are examples of instances where this can be helpful.
Head and neck
Acromegaly, a possible risk factor for fracture , may be suspected in a patient with a history of enlarging jaw or increasing hat size. Headaches or visual loss could be due to a pituitary tumor. A history of goiter suggests possible thyrotoxicosis. Premature loss of primary or secondary teeth may be a sign of hypophosphatasia. Blue sclera at birth or hearing loss now could be due to osteogenesis imperfecta. Impaired vision or hearing may increase the risk of falling.
A history of asthma might lead to discussion of medications, such as glucocorticoids, used to treat it that may be toxic to bone. Symptoms of chronic obstructive lung disease (COPD) might lead to a discussion of home oxygen use and the possibility of tripping on tubing. A high risk for vertebral fractures in patients with COPD should prompt consideration of spinal imaging, since impaired pulmonary function may be a consequence of vertebral fractures in the thoracic spine .
Many endocrine disorders associated with bone loss and fractures ( Table 61.1 ) might be suspected in the initial interview with the patient and trigger further evaluation with appropriate laboratory testing. For example, weight loss could be due to type 1 diabetes mellitus or hyperthyroidism, weight gain could be due to excess endogenous or exogenous glucocorticoids, and erectile dysfunction could be due to hypogonadism. Diabetes type 1 and type 2, and some of the medications used to treat type 2 diabetes mellitus, are risk factors for low-trauma fractures .
A history of a heart murmur might result in consideration of a connective tissue disease, such as Marfan syndrome, that is associated with aortic insufficiency and low BMD . Chronic heart disease may result in frailty and increased risk of falling. Tachycardia is suggestive of hyperthyroidism.
A history of diarrhea, loose stools, abdominal pain, or food intolerances could be due to disorders with skeletal implications, such as chronic inflammatory bowel disease, untreated celiac disease, previous GI surgery, thyrotoxicosis, or excessive use of magnesium supplements. Oral bisphosphonates should not be used in patients with a history of achalasia, esophageal stricture, severe gastroesophageal reflux, or esophageal dysmotility. Osteoporosis medications, especially the oral bisphosphonates, may cause GI distress.
Joint pain and swelling are suggestive of chronic inflammatory diseases (e.g., rheumatoid arthritis, lupus) that are associated with adverse skeletal effects . Glucocorticoids, which may be used to treat these diseases and other disorders, can contribute to bone loss and fractures . Osteoarthritis may limit ambulation and be associated with disuse osteoporosis. Arthritis can also increase and sometimes invalidate BMD measured at the lumbar spine, and rarely so at the hip. Chronic bone and muscle pain have been reported rarely in patients treated with bisphosphonates as well as denosumab, and PTH receptor agonists, although causality has not been demonstrated .
CKD is associated with secondary hyperparathyroidism, renal osteodystrophy, and the use of medications that may be harmful to bone . Kidney stones could be due to hyperparathyroidism and or primary hypercalciuria, another cause of secondary osteoporosis that may require specific treatment. Many medications used to treat osteoporosis should be avoided in patients with CKD.
Diseases that impair ambulation or increase the risk of falling, including Parkinson’s disease, multiple sclerosis, stroke, and spinal cord injuries, are a concern with bone health . Peripheral neuropathy suggests the possibility of diabetes mellitus. Seizure disorders and use of some anticonvulsant medications are associated with osteoporosis and increased risk for fractures.
Urticaria pigmentosa suggests the possibility of systemic mastocytosis, a disease associated with low BMD . Other rashes could be due to autoimmune diseases or adverse reactions to drugs used to treat osteoporosis.
Solid tumors, such as breast cancer and prostate cancer, may metastasize to bone, and marrow-based malignancies, such as multiple myeloma, may cause bone pain, low BMD, and fractures. Findings suggestive of malignancy are sometimes seen on DXA skeletal images. The treatment of some malignancies may include drugs also used to treat osteoporosis.
The physical exam is often normal in patients with osteoporosis. However, a focused examination may sometimes suggest previously unrecognized fractures, show abnormalities suggesting secondary causes of osteoporosis, and identify patients at high risk for falling who may benefit from interventions to reduce fall risk ( Table 61.4 ). The following components of the physical exam may be helpful in the evaluation of patients with osteoporosis.
|Abnormal finding||Clinical implications||Possible causes||Influence on management|
|Decreased muscle strength||High fall risk||Vitamin D deficiency, neuromuscular disorder, sarcopenia of aging||Exercise program, correction of deficiencies|
|Poor balance||High fall risk||Vitamin D deficiency, vestibular disease||Balance training, correction of deficiencies|
|Rash||Systemic disease, adverse effect of treatment||Systemic mastocytosis, drug reaction||Lab studies, change in medication|
|Loss of height||Vertebral fractures||Osteoporosis, multiple myeloma, metastatic disease||Treatment depends on cause of height loss|
|Blue sclera||Collagen disorder||Osteogenesis imperfect, Marfan’s syndrome, Ehlers–Danlos syndrome||Additional testing may be indicated|
|Jaundice||Malabsorption||Acute or chronic liver disease||May need further evaluation and treatment|
|Impaired vision||High fall risk||Cataracts, macular degeneration, pituitary tumor||Correction of vision may reduce fall risk|
|Impaired hearing||High fall risk, challenges in communicating risk and benefit of therapy||Numerous potential causes, including osteogenesis imperfecta||Identify cause and correct hearing if possible|
|Spinous process tenderness||Suggestive of acute skeletal process||Acute vertebral fracture, osteomyelitis||Spinal imaging; pain management, consideration of vertebral augmentation|
|Kyphosis||High fracture risk||Vertebral fractures, degenerative arthritis||Spinal imaging; Aggressive therapy to reduce fracture risk indicated if vertebral fractures are diagnosed|
|Poor pulmonary function||May limit physical activity and require glucocorticoids||Asthma, chronic lung disease, vertebral fractures||Avoid treatment with agents that are harmful to bone, if possible|
|Abdominal tenderness||Malabsorption, intolerance to medication||Inflammatory bowel disease||Further evaluation and treatment may be indicated|
|Hepatomegaly||Malabsorption||Hemochromatosis||Treatment may improve absorption of skeletal nutrients|
Measure height with a calibrated wall-mounted stadiometer or metal ruler; compare with self-reported maximum height to calculate historical height loss; and compare with previous stadiometer-measured height, if available, to calculate prospective height loss. The hinged height measurement device on a typical medical office scale is usually not sufficiently accurate to be clinically useful in detecting changes in height. Substantial loss of height suggests the possibility of prevalent vertebral fractures and the need for further evaluation with spine imaging ( Table 61.3 ). Height and weight, as well as sex and ethnicity, are both components for demographic input with DXA and FRAX. Low body weight (less than 127 lb) and low body mass index [(weight in kg)/(height in m 2 ), 20 kg/m 2 or less] are risk factors for low BMD and for fractures, largely dependent on BMD. A rapid heart rate or elevated blood pressure may be due to thyrotoxicosis, a risk factor for osteoporosis, and a low heart rate or low blood pressure may increase the risk of falls due to orthostatic hypotension. A rapid respiratory rate may be due to acute or chronic lung disease, including pulmonary emboli, a consequence of some osteoporosis medications (e.g., estrogen and raloxifene) that are associated with increased risk of thromboembolic events.
An assessment of mental status is helpful in determining the patient’s ability to participate in a meaningful discussion on the consequences of osteoporosis and the balance of expected benefits and possible risks with treatment. If a treatable cause of impaired mental status, such as excessive dosing of sedatives or hypoxemia, is found, then correction may be beneficial in reducing the risk of falls and fractures. Neurological disorders (e.g., stroke, multiple sclerosis, post–polio syndrome) may limit weight-bearing activities and increase risk of falling. Muscle weakness and impairment of balance could be due to severe vitamin D deficiency or other correctable causes of osteomalacia. A tremor, stooped posture, or festinating gait could be a sign of Parkinson’s disease and high fall risk. Evaluation of physical vitality and fall risk in elderly patients can be assessed by a “get-up and go” test, observing and timing the patient in getting up from a chair, walking a short distance, turning around, returning to the chair, and sitting down . Alternatively, observing whether a patient is able to rise from a chair without difficulty, get on to the examination table unassisted, and rise from a squatting position are simple methods for assessing the strength and physical vitality. Balance can be tested easily by performing a Romberg test, standing on one foot, and tandem gait testing. Poor performance may result in a prescription for physical therapy, exercises to improve balance and muscle strength , and a recommendation for helpful recreation activities, such as yoga or tai-chi . For very frail patients, an assistive device such as a cane or walker may be indicated.
The presence of kyphosis or shortened space between the lower ribs and iliac crest suggests possible vertebral fractures. Other types of skeletal deformities may be the result of previous fractures or developmental abnormalities that could impair ambulation and increase fall risk. Bowing of the legs or arms and/or enlarged wrists and ankles since childhood might be a clue to the presence of rickets, hypophosphatemia, or hypophosphatasia. Localized spinous process tenderness may be present with a recent vertebral fracture. Bone tenderness with applied pressure may be a sign of osteomalacia.
Head and neck
Poor eyesight or hearing could increase fall risk. Impairment of visual fields can be due to a pituitary tumor. Osteogenesis imperfecta is associated with blue sclera, hearing loss, and poor dentition. Jaundice may be due to chronic liver disease that is associated with malabsorption of skeletal nutrients. Thyromegaly or thyroid nodule might be due to thyroxocosis. Periodontitis, loose teeth, or signs of poor oral hygiene may increase the risk of osteonecrosis of the jaw with some antiresorptive therapies and the need for attention by a dentist or oral surgeon. Lymphadenopathy could represent a malignancy with skeletal implications and the need for evaluation by an oncologist.
Heart rhythm disturbances might result in syncope with an increased risk of fracture. A heart murmur could result a collagen disorder, such as Marfan syndrome. The presence of a pacemaker might preclude the use of MRI to evaluate a skeletal problem. Findings of congestive heart failure might limit physical activities. Leg pain and/or swelling could be a sign of deep vein thrombophlebitis, which has been associated with estrogens, selective estrogen receptor modulators, and strontium ranelate (no longer manufactured).
Wheezing or other signs of airway outlet obstruction could be due to asthma or COPD and be associated with the use of medications, such as glucocorticoids, that increase fracture risk. Impaired pulmonary function could also be the result of previous vertebral fractures.
Protuberance of the abdomen is sometimes due to vertebral fractures. Abdominal tenderness could be due to inflammatory bowel disease. Hepatomegaly or tenderness of the liver may represent chronic liver disease, such as hemochromatosis, a risk factor for osteoporosis. Surgical scars suggest the possibility of surgery that might cause malabsorption, such as gastrectomy or bariatric surgery.
Symmetrical joint and soft tissue swelling suggest rheumatoid arthritis, an independent risk factor for fracture . Osteoarthritis, which may be evident of physical examination, may impair ambulation, increasing the risk of disuse osteoporosis, falls, and fractures.
Urticaria pigmentosa could be caused by systemic mastocytosis . Reports of cutaneous adverse reactions due to osteoporosis medications are rare, ranging from mild erythematous and maculopapular rashes to potentially life-threatening conditions such as drug rash with esosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) . SJS and TEN have been associated with bisphosphonates, while DRESS, SJS, and TEN have been reported with strontium ranelate. Some dermatological conditions, regardless of origin, may require treatment with glucocorticoids, thereby increasing the risk of fractures. Dark skin pigmentation increases the risk of vitamin D deficiency in patients not receiving adequate supplements due to decreased production of vitamin D in the skin with sun exposure .
The clinical utility of laboratory testing ( Table 61.5 ) in patients with osteoporosis is to detect previously unrecognized secondary causes of osteoporosis, to aid in the selection or exclusion of specific therapeutic agents, and to monitor for therapeutic effect or adverse effects of treatment. Every patient with osteoporosis should have basic laboratory testing before treatment is started, since treatment may be ineffective or even harmful with some clinical conditions that may not otherwise be recognized . Patients with unusual clinical features or abnormalities found on initial laboratory testing may benefit from further testing. When patients do not respond to treatment as expected, laboratory tests may provide helpful information to guide future therapy. While there are no universal standards for laboratory testing in patients with osteoporosis, guidelines have been developed by medical organizations that include AACE and NAMS for women with postmenopausal osteoporosis, the Endocrine Society for men with osteoporosis , Osteoporosis Canada for men and women with osteoporosis, and the American College of Rheumatology for patients with glucocorticoid-induced osteoporosis. Researchers have studied the clinical utility of panels of laboratory tests, usually in patients referred to an osteoporosis specialty center or those who have had a fracture . In a study of 173 otherwise healthy women with newly diagnosed postmenopausal osteoporosis referred to a specialty center, it was found that testing serum calcium, 24-hour urinary calcium, serum PTH, and thyroid-stimulating hormone (TSH) in women receiving thyroid replacement therapy detected over 85% of all underlying disorders; when serum 25-OH-D below 20 ng/mL was included, the yield was even better, at a cost that was considered acceptable for patient screening . It is not known whether these findings apply to other groups of patients with osteoporosis or to patients evaluated in the primary care setting. Some studies have focused on the potential benefits of a single laboratory test or the detection of a single disease . Experts have evaluated laboratory testing through reviews of the scientific literature and suggested strategies for the evaluation of osteoporosis.
|Common clinical considerations|
|For all patients with osteoporosis|
|Complete blood count||Anemia—malabsorption, multiple myeloma, or bone marrow infiltrative disease|
|Abnormal white cell count—serious systemic disease|
|Serum calcium||Low level—osteomalacia, malabsorption, must be corrected prior to therapy|
|High level—hyperparathyroidism, malignancy, vitamin D toxicity, occasionally hypophosphatasia|
|Serum phosphorus||Low level—osteomalacia, hyperparathyroidism|
|High level—renal failure|
|Liver enzymes||High levels—chronic liver disease may cause malabsorption|
|Alkaline phosphatase||Low level—hypophosphatasia|
|High level—osteomalacia, chronic liver disease, Paget’s disease of bone, malignancy|
|Creatinine||High level—chronic kidney disease|
|Albumin||Low level—malnutrition, may alter total calcium measurement|
|Thyroid-stimulating hormone||Low level—hyperthyroidism (endogenous or overreplacement)|
|25-hydroxyvitamin D||Low level—calcium malabsorption, increased fall risk|
|24-h urinary calcium||Low level—malabsorption, inadequate intake, renal disease, vitamin D deficiency|
|High level—idiopathic hypercalciuria, hyperparathyroidism, skeletal malignancy, hypophosphatasia|
|For selected patients|
|Parathyroid hormone||High level—hyperparathyroidism|
|Urinary free cortisol||High level—Cushing’s syndrome|
|Serum protein electrophoresis with immunofixation, serum kappa, and lambda light chains||M-component and/or elevated kappa/lambda light ratio—myeloma or MGUS|
|Celiac antibodies||High levels—celiac disease|
|Serum tryptase, urinary N -methylhistamine||High levels—systemic mastocytosis|
|24 h urine||High levels—hypophosphatasia|
|Phosphoethanolamine or serum pyridoxyl 5′ phosphate (B6) if not on supplements|
What follows is adapted from many of these reports, dividing laboratory studies into two categories—tests for screening all patients with osteoporosis before starting treatment and tests that are helpful for some patients according to clinical circumstances. The rationale for each of the tests is provided, followed by the clinical implications of an abnormal result. Some of these tests are commonly performed as part of routine health screening, often as components of laboratory panels that include many tests. If recent results are available in the patient’s medical records, it may not be necessary to repeat them. The ultimate decision for laboratory testing must be based on the likelihood that the findings might influence patient management decisions, with consideration of patient preferences, accessibility, and affordability of testing.
Minimum evaluation for all patients with osteoporosis
These tests are suggested for screening purposes because they are widely available, with a high yield of abnormal results low cost.
Serum calcium concentration
Measurement of serum calcium, corrected for low serum albumin when appropriate, is an essential component in the evaluation of osteoporosis. Serum ionized calcium levels are generally not helpful; however, for some patients, such as those who are very ill with acid–base disturbances, measurement of serum ionized calcium may provide the most accurate assessment of calcium status.
High serum calcium may be due to primary hyperparathyroidism, a common disorder in postmenopausal women that increases bone turnover and reduces BMD, often coinciding with osteoporosis. The pattern of low BMD at the 33% (one-third) radius, a skeletal site that is predominately cortical bone, with relative preservation of BMD at the lumbar spine and hip, sites that have a higher proportion of trabecular bone, suggests adverse skeletal effects of long-standing hyperparathyroidism . Conversely, women with postmenopausal osteoporosis typically have BMD that is lower at the lumbar spine and hip compared to the 33% radius . The definitive treatment for primary hyperparathyroidism is parathyroidectomy, which has been associated with subsequent reduction of bone turnover markers (BTMs) and improvement in BMD . In postmenopausal women with primary hyperparathyroidism and low BMD who do not have parathyroid surgery, treatment with estrogen, bisphosphonates, or denosumab may provide similar skeletal benefit . Primary hyperparathyroidism and malignancy account for over 90% of causes of hypercalcemia, with the remainder due to disorders that include familial hypocalciuric hypercalcemia (FHH), vitamin D toxicity, thyrotoxicosis, drug-induced (e.g., hydrochlorothiazide, teriparatide, and abaloparatide), and granulomatous disorders, such as sarcoidosis . Anabolic agents, such as teriparatide and abaloparatide, should be avoided or used with great caution in patients with preexisting hypercalcemia or high PTH due to the risk of further elevation of serum calcium.
Hypocalcemia is most often due to postsurgical hypoparathyroidism, autoimmune hypoparathyroidism, or vitamin D deficiency. Less common causes include hyperphosphatemia, hypomagnesemia, and acute pancreatitis. When hypocalcemia is confirmed in the course of an osteoporosis evaluation, the cause should be identified and the hypocalcemia corrected before antiresorptive treatment is started. Antiresorptive agents, particularly IV bisphosphonates and denosumab, may cause symptomatic hypocalcemia in susceptible individuals, such as those with malabsorption, calcium deficiency, vitamin D deficiency, or limited parathyroid reserves due to previous surgery or irradiation to the neck . Care should be taken to assure adequate intake and absorption of calcium and vitamin D in patients treated for osteoporosis. Cinacalcet, a calcimimetic drug used to treat patients with secondary hyperparathyroidism due to CKD, may cause hypocalcemia due to inhibition of PTH release , and for this reason, it has been used to treat some patients with hypercalcemia of intractable primary hyperparathyroidism .
Assessment of renal function is part of routine medical practice and particularly important in the evaluation of patients with osteoporosis. Impairment of renal function can cause bone disease and some treatments (e.g., glucocorticoids, immunosuppressants) for kidney disease can have harmful skeletal effects. Some drugs used to treat osteoporosis may be inadvisable or contraindicated in patients with kidney disease, and renal complications have been associated with some of these drugs. Fracture risk is increased in patients with CKD, including those on dialysis and renal transplant recipients .
Serum creatinine is a common screening test for renal function, although it may not reliably identify renal failure in elderly patients with low muscle mass . A more accurate estimate of renal function can be obtained by measuring creatinine clearance from a timed urine specimen or calculating GFR with the Cockcroft–Gault formula , the Modification of Diet in Renal Disease (MDRD) equation , or modifications of the MDRD equation . Estimated GFR is now commonly included with the laboratory report when serum creatinine is measured. Guidelines of the National Kidney Foundation’s Kidney Disease: Improving Global Outcomes (KDIGO) initiative define CKD as abnormalities in kidney structure or function that are present for more than 3 months and have health implications . GFR categories range from normal or high (G1) when ≥90 mL/min/1.73 m 2 to kidney failure (G5) when <15 mL/min/1.73 m 2 .
Skeletal disease is present in most patients with GFR <60 mL/min/1.73 m 2 and virtually all patients with CKD on dialysis . Renal osteodystrophy is the term used to describe alterations of bone morphology in patients with CKD, while CKD–mineral and bone disorder describes a broader clinical syndrome involving a systemic disorder of mineral and bone metabolism due to CKD . When renal function declines, there is a progressive deterioration in mineral homeostasis that is associated with changes of the serum and tissue concentrations of phosphorus and calcium, as well as alterations in circulating levels of hormones that include PTH, 25-OH-D, 1,25-(OH) 2 -D, and fibroblast growth factor-23 (FGF23) .
Clinical trials demonstrating fracture risk reduction with currently approved drugs typically excluded patients with severe CKD. The efficacy and safety of most of these agents are uncertain in patients with GFR less than 30 mL/min/1.73 m 2 . Renal safety of bisphosphonates has been a particular concern, since these drugs are excreted by the kidneys and have the potential for renal toxicity when high plasma levels result in high levels of exposure of renal tubular cells . Prospective data for all approved bisphosphonates show evidence of efficacy and safety in patients with CKD G3b (GFR 30–44 mL/min/1.73 m 2 ) or better, and post hoc analysis of limited data suggests that oral bisphosphonates are effective and safe in patients with CKD G4 (GFR 15–29 mL/min/1.73 m 2 ). IV zoledronic acid should not be given to patients with GFR less than 35 mL/min/1.73 m 2 and IV ibandronate should not be given when GRF is less than 30 mL/min/1.73 m 2 . It is prudent to avoid treatment with teriparatide and abaloparatide in patients with CKD and secondary hyperparathyroidism, since these are PTH and PTH related peptide product, respectively, that may cause hypercalcemia. There are no restrictions on the use of denosumab in patients with CKD, although extra caution should be taken to assure adequate calcium intake in patients with CKD G4 or worse due to possible increased risk of hypocalcemia . There is no evidence available regarding the efficacy and safety of any osteoporosis drug in patients with stage CKD G5.
Serum alkaline phosphatase
The total serum alkaline phosphatase in adults is typically composed of equal amounts of liver and bone isoforms. Elevation of the total alkaline phosphatase may be due to bone disease (e.g., osteomalacia, Paget’s disease of bone, malignancy or infection involving bone, or recent fracture) or due to liver disease (e.g., biliary tract obstruction, primary biliary cirrhosis, acute or chronic hepatitis), all with potential adverse effects on skeletal health. When total alkaline phosphatase is elevated and the source is not known, further evaluation with a serum bone-specific alkaline phosphatase (BSAP), serum gamma glutamyl transpeptidase (GGT or GGTP, which, if elevated, suggests a hepatic source of elevated alkaline phosphatase), whole-body nuclear bone scan, and radiographic studies may be helpful. Teriparatide and abaloparatide should not be prescribed to patients with unexplained elevation of alkaline phosphatase due to lack of data on efficacy and safety, and particular concern that the elevated alkaline phosphatase may be due to unappreciated Paget’s disease of bone, skeletal malignancy, or metastatic disease from an unknown primary tumor.
Patients with serum total alkaline phosphatase that is below the age- and gender-adjusted reference range may have hypophosphatasia . This is a rare inherited disorder characterized by defective mineralization of bones and teeth, with an increased risk of fractures. In adults with osteoporosis and low total serum alkaline phosphatase the finding of elevated vitamin B6, a substrate for alkaline phosphatase, is consistent with hypophosphatasia. Genetic testing (ALPL gene) is available when it is desirable to confirm the diagnosis, although some patients with this disease may have a mutation that is not detectable with current assays. It is important to recognize hypophosphatasia, because potent antiresorptive medications, such as bisphosphonates, may be ineffective or possibly harmful due to further reduction in mineralization . Excessive calcium supplementation and/or activated vitamin D metabolites may exacerbate the tendency for hypercalcemia and/or hypercalciuria. There is some evidence that teriparatide may be beneficial in some patients and the possibility that enzyme replacement therapy might be effective. Asfotase alfa is a subcutaneously administered synthetic human alkaline phosphatase that is approved for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia . The clinical use of asfotase alfa in adults with hypophosphatasia is not well established .
The presence of chronic liver disease may be revealed by measuring liver enzymes, such as aspartate transaminase and alanine transaminase. When these values are consistently elevated, further evaluation and sometimes consultation with a gastroenterologist may be necessary. Chronic liver disease may cause osteoporosis due to malabsorption of skeletal nutrients, protein malnutrition, or adverse effects on osteoblastic bone formation, as observed in patients with primary biliary cirrhosis and sclerosing cholangitis .
Medications used to treat some forms of liver disease may have undesirable skeletal effects. When malabsorption is present in a patient with osteoporosis, treatment with an injectable agent, such as zoledronic acid, ibandronate, denosumab, teriparatide, or abaloparatide, may be preferable to oral agents. If cirrhosis has caused portal hypertension and esophageal varices, oral bisphosphonates should not be given.
Hyponatremia may be a marker of severe chronic disease and has been implicated as a possible risk factor for osteoporosis and fractures . The finding of low serum bicarbonate, especially in the presence of low serum chloride and normal anion gap, is often the starting point for investigation for possible renal tubular acidosis (RTA), which has been associated with metabolic bone diseases, such as osteomalacia and rickets . Suspected RTA warrants further evaluation and consideration of referral to a nephrologist.
Blood chemistry panel
Many or all of the above tests may be included in a routine panel of blood chemistries, thereby greatly facilitating the laboratory evaluation.
Measurement of serum phosphorus is commonly neglected in the evaluation of osteoporosis, especially since it is no longer included in most routine blood chemistry panels. Low serum phosphorus may be seen in patients with osteomalacia due to vitamin D deficiency or some inherited disorders, such as X-linked hypophosphatemia, and with tumor-induced osteomalacia (TIO). It is important to recognize TIO, a rare paraneoplastic disorder associated with small benign tumors, since this is a potentially curable disease. When TIO is suspected, serum FGF23 should be measured. Elevation of FGF23 with TIO causes osteomalacia due to renal phosphate wasting and impaired renal conversion of 25-OH-D to 1,25-(OH) 2 -D. Once a presumptive diagnosis of TIO is made, a search for the tumor is indicated. This can be a difficult and lengthy undertaking for the physician and patient, as these tumors are often very small and may be in an obscure location. Methods such as whole-body octreotide scanning, MRI, computed tomography (CT), positron emission tomography scanning, and selective venous sampling have been used in attempts to identify these tumors . It takes an average of about 5 years from the time of diagnosis to localizing the tumor . The medical treatment of TIO before the tumor is excised involves correcting the low serum phosphorus with phosphate supplementation and calcitriol. Treatment with bisphosphonates, which might exacerbate the mineralization defect, should be avoided. Calcium intake may need to be limited to avoid hypercalcemia due to high calcitriol levels. Excision of the responsible tumor is followed by rapid reduction in FGF23, normalization of the metabolic abnormalities, and subsequent resolution of osteomalacia. Burosumab is a fully human monoclonal antibody to FGF23 that is approved for the treatment of X-linked hypophosphatemic rickets and is being investigated for use in patients with TIO .
Serum 25-hydroxyvitamin D
It is not cost-effective to screen all adults for vitamin D deficiency, but measurement of serum 25-OH-D is useful in the evaluation of patients with osteoporosis. The measurement can be made at the time of initial evaluation or after vitamin D supplementation for at least 3 months. The prevalence of low vitamin D levels is high . Low vitamin D may contribute to the development of osteoporosis by reducing calcium absorption and increasing circulating PTH , cause osteomalacia that mimics osteoporosis , reduce the efficacy of osteoporosis therapy , increase the risk of hypocalcemia with potent antiresorptive agents , increase the risk of falls and fractures , and increase the risk of an acute-phase reaction with the first dose of an IV bisphosphonate . Vitamin D levels can be low due to factors that include low sun exposure, dark skin pigmentation, poor oral intake, and malabsorption . It is serum 25-OH-D and not 1,25(OH) 2 -D that should be measured, since the 25-OH-D provides a far better assessment of total body vitamin D stores . When there is reason to suspect an abnormal rate of conversion to 1,25(OH) 2 -D, as in patients with CKD, TIO, or granulomatous diseases, such as sarcoidosis, measurement of serum 1,25(OH) 2 -D is appropriate.
There has been controversy as to the desirable or optimal target range of vitamin D, with different organizations recommending different levels. In 2010 the Institute of Medicine (IOM) released a report stating that a serum 25-OH-D concentration above 20 ng/mL (50 nmol/L) was the level “needed for good bone health for practically all individuals” and that this level was achievable with a daily vitamin D intake of 600 IU for almost everyone in the United States and Canada . This report was the result of an exhaustive review of the evidence on potential health outcomes of calcium and vitamin D intake reviewed by a panel of experts. The findings are widely used by governmental agencies for purposes such as setting standards for school menus and nutritional labels for food products. The IOM recommendations for public health are not necessarily what is optimal for individual patients with osteoporosis, and in that regard, experts in the vitamin D field have proposed higher target levels for these patients . Organizations that include the International Osteoporosis Foundation (IOF) , the NOF , and AACE recommend a daily vitamin D intake of 800–1000 IU with a target of at least 30 ng/mL (75 nmol/L). Given what is known about assay variability , skeletal and nonskeletal benefits of vitamin D , limitations of vitamin D study designs, and uncertainty of the data , a blood level of at least 20 ng/mL (50 nmol/L) is desirable, with target range of approximately 30–50 ng/mL (75–125 mmol/L) probably optimal , with a wide margin of safety at the upper end of this range .
24-Hour urinary calcium
Low urinary calcium (hypocalciuria) in the setting of adequate calcium intake and normal renal function is suggestive of calcium malabsorption, as may occur with reduced gastric acidity , celiac disease , inflammatory bowel disease, other causes of GI malabsorption, and inherited disorders of metabolism, such as FHH . High urinary calcium (hypercalciuria) may be due to excess dietary sodium intake (>3 gm/day), increased intestinal absorption of calcium, defective renal tubular absorption of calcium, high bone resorption, or idiopathic . Both hypo- and hypercalciuria are associated with adverse skeletal effects that may have important therapeutic implications. As an example, in an osteoporosis patient with hypocalciuria due to untreated celiac disease, a gluten-free diet alone may result in a robust improvement in BMD without the need for pharmacological therapy . In a patient with hypercalcemia, the finding of hypocalciuria may help with the diagnosis of FHH and obviate the need the parathyroidectomy. Treatment of hypercalciuria with a thiazide diuretic offers potential benefits in the management of urolithiasis and osteoporosis .
There is added value with including measurement of the urine volume, creatinine, and sodium with a 24-hour urine collection for calcium. A volume of at least 800 mL and a normal urine creatinine provides supporting evidence of completeness of the collection. High urinary sodium may contribute to hypercalciuria ; repeating the 24-hour urine for calcium after sodium restriction may correct or reduce the hypercalciuria.
The principal determinants of urinary calcium include body weight, calcium intake, absorption efficiency, estrogen status, and coingested nutrients . Weight-adjustment appears to account for most or all of the difference in urinary calcium excretion between men and women. Urinary calcium rises with increasing calcium intake, although the magnitude of the effect is small, with a mean urinary calcium increase of 55–72 mg associated with every 1000 mg increase in daily calcium intake in one study . Similarly, the effect of sodium intake on calcium excretion is significant but small, with about a 20–40 mg increase in urinary calcium for every 2300 mg increase in daily sodium intake . Urinary calcium rises slightly with increased protein intake (about 10 mg for every 10 g of protein), with this effect largely blunted by phosphorus that is typically coingested with protein . Estrogen-deficient women have urinary calcium values about 17% greater than estrogen-replete women .
There is no definitive standard for urinary calcium reference range. The classical upper limit for patients on an unrestricted diet has been defined as 250 mg/24 hours in women and 300 mg/24 hours in men or a weight-based upper limit of 4 mg/kg/day in both women and men . It has been proposed that a higher upper limit of 300 mg/day (or weight-adjusted 5.0 mg/kg/day) be used for estrogen-deficient women on unrestricted diets, based on a long-term study in 191 nuns . A metabolic evaluation for the etiology of nephrolithiasis may require more rigorous conditions for collection with a calcium restricted diet and the use of a lower upper limit of normal, such as 200 mg/24 hours . Urinary calcium below 50–100 mg/24 hours in women and men on unrestricted diets is commonly considered to be abnormal; Heaney et al. have suggested that a lower limit of 40 mg/24 hours be used for women .
It has been proposed by some that a random urinary calcium/creatinine ratio might be a screening test or a substitute for the more burdensome 24-hour urine collection, with a normal reference value for urinary calcium (mg/dL)/urinary creatinine (mg/dL) being less than 0.14 . This might help to limit the number of 24-hour urine collections, which require far greater patient cooperation and are subject to potential error due to inadequacy of collection, spills, and handling/processing errors . However, comparison of the findings of spot urine and 24-hour urines suggests that the two methods are not interchangeable . Until better evidence becomes available to support the use of spot urinary calcium levels, the 24-hour collection should be considered the standard of care. Major limitations of this test are poor acceptability by physicians and patients, and logistical limitations in obtaining a complete collection.
Complete blood count
Measurement of red and white blood parameters and platelets is typically included in routine health screening. For patients with osteoporosis the findings may provide insight regarding the presence of hematological malignancies, hemoglobinopathies (e.g., thalassemia), malnutrition, or malabsorption (e.g., celiac disease with microcytic anemia) associated with osteoporosis.
Laboratory tests for selected patients with osteoporosis
The tests described previously are appropriate for screening all patients with osteoporosis. The following is a sampling of other tests that may be indicated depending on individual patient circumstances and the practice setting. The list is not intended to be all inclusive, as situations may arise that suggest other studies as well.
Serum thyroid-stimulating hormone
Thyroid hormone excess has been associated with reduced BMD and increased fracture risk, probably due to elevated bone turnover . For patients with symptoms of thyroid disease, particularly when thyrotoxicosis is suspected, or those on thyroid therapy, TSH or other tests of thyroid function should be performed. In a study of 173 women with osteoporosis referred to an osteoporosis specialty center, there were 4 (2.3%) on thyroid hormone replacement who were found to have exogenous hyperthyroidism .
Serum parathyroid hormone
When the serum calcium level is abnormal or when treatment with teriparatide or abaloparatide is being considered, PTH should be measured. Primary hyperparathyroidism is associated with low BMD and increased fracture risk that may respond to medical or surgical intervention . The presence of osteoporosis in a patient with primary hyperparathyroidism is an indication of parathyroidectomy . Patients with normal serum calcium, normal serum 25-OH-D, and elevated PTH have been described as having normocalcemic primary hyperparathyroidism, which may be an early form of hypercalemic primary hyperparathyroidism with potential adverse skeletal effects . This disorder is being described with increasing frequency at centers where PTH levels are routinely measured in the course of evaluation for secondary osteoporosis. There are no established guidelines for the management of normocalcemic primary hyperparathyroidism. Anabolic therapy (e.g., teriparatide, abaloparatide) should be used with great caution, if at all, in these patients due to possible increased risk of hypercalcemia .
Serum parathyroid hormone-related peptide
In patients with hypercalcemia and appropriately low serum PTH, especially in the presence of a known malignancy, measurement of PTH related peptide (also termed PTH-related protein, PTHrP) may be indicated . Hypercalcemia of malignancy is a paraneoplastic syndrome caused by tumor production of a PTH-like molecule that raises serum calcium and can be treated with a bisphosphonate or denosumab .
Serum testosterone is sometimes recommended in screening for hypogonadism in men with osteoporosis, and an association between free testosterone, BMD, and fracture risk has been shown in some studies . However, there is compelling evidence that decreasing levels of free estradiol and sex hormone–binding globulin, rather than free testosterone, are the principal contributors to bone loss and fracture risk in aging men . For most men the treatment of osteoporosis appears to be effective and safe whether they are hypogonadal or eugonadal. It has been recommended by the IOF, NOF, and AACE that testosterone replacement therapy be considered when hypogonadism is symptomatic and that osteoporosis should be treated with agents shown to decrease fracture risk whether or not the patient is taking testosterone .
Celiac disease (gluten-sensitive enteropathy) is a common autoimmune disorder, affecting close to 1% of the population, with genetic, environmental, and immunological components . Susceptible individuals develop intestinal mucosal inflammation, villous atrophy, and crypt hyperplasia of the small bowel in response to ingestion of wheat gluten and related proteins of rye and barley. The classical clinical presentation of patients with celiac disease is steatorrhea and weight loss, with signs and symptoms of multiple nutritional deficiencies. However, celiac disease is now being increasingly recognized in asymptomatic individuals with osteoporosis or low BMD due to malabsorption of skeletal nutrients, particularly calcium. In a study of 840 patients evaluated for osteoporosis at an academic bone center, 3.4% of those with osteoporosis and 0.2% of those without osteoporosis were found to have biopsy-proven celiac disease . The prevalence of celiac disease appears to have increased dramatically over the past 50 years. When stored sera obtained from 9133 healthy young-adults between 1948 and 1954 were analyzed and compared with 12,768 age- and gender-matched subjects from two recent cohorts in Olmsted County, Minnesota, it was found that the prevalence of celiac disease had increased about fourfold in recent years . Celiac disease has been associated with low BMD and increased fracture risk in many but not all studies , with evidence suggesting that the skeletal complications may be correlated with the severity of disease and compliance with treatment . The importance of recognizing celiac disease in the evaluation of osteoporosis is that the disease is potentially curable with strict lifelong adherence to a gluten-free diet, with some osteoporosis patients having marked improvement in BMD with this diet , even in the absence of pharmacological therapy for osteoporosis . Hypocalcemia has been reported in patients with untreated celiac disease with and without antiresorptive therapy for osteoporosis.
Malabsorption should be considered in patients with low 24-hour urinary calcium levels (assuming adequate calcium intake and normal renal function), unexpectedly low levels serum 25-OH-D, or iron deficiency anemia, with celiac disease part of the differential diagnosis for malabsorption. The immune response to celiac disease involves the production of gliadin antibodies and autoantibodies that include tissue transglutaminase, endomysial, and reticulin. IgA antibodies usually predominate, with some patients producing IgG antibodies as well. Since patients with IgA deficiency are unable to produce IgA antibodies, it is often recommended to measure IgA in association with celiac antibodies to assure that the absence of IgA celiac antibodies is not due to IgA deficiency. Celiac antibodies provide a highly specific and sensitive test for the presumptive diagnosis of celiac disease and can be used to monitor adherence and response to a gluten-free diet in treated patients. The most sensitive and specific serological tests for celiac disease are tissue transglutaminase and endomysial IgA antibodies, which have equivalent diagnostic accuracy, with reported sensitivity and specificity generally exceeding 90% . A large multinational study showed that the sensitivity varied from 69% to 93% and specificity varied from 96% to 100% in tissue transglutaminase assays conducted in 20 different laboratories , highlighting the need for better standardization. IgA antibody to tissue transglutaminase is recommended as the single best initial test for screening for celiac disease in individuals over the age of 2 years . Traditional testing of antigliadin antibodies is no longer routinely performed due to lower sensitivity and specificity; however, an improved method of gliadin antibody testing (deamindated gliadin peptide) has far greater diagnostic accuracy and may prove useful in clinical practice. Some laboratories routinely perform celiac panels that include measurement of IgA and several different celiac antibodies.
When celiac disease is suspected based on abnormal antibodies or highly suspicious clinical circumstances in patients with normal celiac antibodies, a small bowel biopsy is a method for confirming the diagnosis. Since lifelong adherence to a gluten-free diet is a challenging undertaking, a biopsy should be considered in all patients when the diagnosis is less than certain.
Serum iron, iron-binding capacity, ferritin
Iron levels measured by a variety of methods, or the presence of iron deficiency anemia, may be a sign of malabsorption due to many disorders, including celiac disease , assuming that inadequate iron intake and GI bleeding are not present. A low iron level provides supporting evidence for malabsorption when other features, such as low 24-hour urinary calcium, are found and suggests that additional evaluation may be needed. High values for iron, as in the several iron storage diseases, are frequently associated with low bone mass, possibly due to chronic liver disease with hemochromatosis, associated endocrine abnormalities, or a direct toxic effect of iron.
Urinary free cortisol or dexamethasone suppression test
Cushing’s syndrome may cause low BMD and fractures . When excess endogenous glucocorticoid production is suspected, it is simple to add measurement of free cortisol to other studies that are part of the 24-hour urine collection. Alternatively, or as a follow-up study when an elevated urinary free cortisol is found, an overnight dexamethasone suppression test will provide helpful information. Failure to suppress the morning cortisol levels should trigger further evaluation.
Serum tryptase, urinary N -methylhistamine
Systemic mastocytosis is a rare cause of osteoporosis, often in association with the rash of urticaria pigmentosa . When systemic mastocytosis is suspected and further evaluation is needed, serum tryptase and/or urinary N -methylhistamine should be measured . Serum tryptase is transiently elevated with IgE mediated anaphylactic events due to systemic activation of mast cells and continuously elevated in patients with systemic mastocytosis due to the large number of mast cells. N -Methylhistamine is the major metabolite of histamine produced by mast cells. Anaphylaxis and systemic mastocytosis are typically associated with at least a twofold increase in urinary N -methylhistamine levels. Up to 25% variability in spot urine N -methylhistamine levels has been reported, suggesting that a 24-hour urine collection may be preferable when the spot urine value is borderline elevated. Increased levels of N -methylhistamine have been observed in patients taking monoamine oxidase inhibitors and aminoguanidine and in patients on histamine rich diets. A spot urine collected in the morning may be less susceptible to dietary variations in urine levels . When systemic mastocytosis is suspected due to clinical findings or elevated serum tryptase or urinary N -methylhistamine, the diagnosis can be confirmed by bone marrow examination . Systemic mastocytosis has also been identified in 0.4%–1.0% of transiliac bone biopsies in patients referred for evaluation of osteoporosis .
Serum protein electrophoresis
Measurement of serum and/or urine proteins should be done when myeloma is suspected. Myeloma is a B-cell neoplasm characterized by clonal expansion of plasma cells in the bone marrow and the development of destructive osteolytic bone disease . The diagnosis is based on the presence of at least 10% clonal bone marrow plasma cells and monoclonal protein in serum or urine . The principal cellular mechanisms in the pathogenesis of myeloma bone disease are an increase in osteoclastic bone resorption and reduction in bone formation. Myeloma accounts for about 13% of hematological cancers with a 10-year survival rate of about 30% in patients who are first diagnosed under the age of 60 years . The skeletal complications of myeloma include pathological fractures, bone pain, hypercalcemia, and spinal cord compression . The most frequent sites of bony involvement with myeloma are the spine, skull, sternum, ribs, pelvis, and proximal humerus and femur .
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder, defined by a serum monoclonal immunoglobulin concentration of 3 g/dL or less, with 10% or fewer plasma cells in the bone marrow, in the absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency due to proliferation of monoclonal plasma cells . MGUS may be a precursor of myeloma, as well as other serious diseases, including primary amyloidosis and Waldenström’s macroglobulinemia. Skeletal complications of MGUS, even in the absence of progression to multiple myeloma, are osteoporosis, hip and spine fractures, and hypercalcemia . The skeletal consequences of MGUS are now sufficiently appreciated that it has been suggested that the term be changed to monoclonal gammopathy of skeletal significance . The clinical relevance of recognizing myeloma and MGUS in the evaluation of patients with osteoporosis is that referral to an oncologist may be indicated. The treatment of myeloma is different than for osteoporosis; patients with MGUS may need to be monitored for transition to myeloma. Patients who appear to have a high risk for transition from MGUS to myeloma (based on certain lab features) are not considered good candidates for treatment with a PTH receptor agonist because of increased risk of hypercalcemia and the stimulation of bone turnover, which could theoretically enhance the growth of myeloma cells in bone.
Screening laboratory tests for patients with suspected myeloma include serum protein electrophoresis with immunofixation, and serum-free kappa and lambda light chain ratio . In a study of 428 patients with monoclonal gammopathies, it was found that elimination of urine protein studies failed to identify only 2 of the 428 patients with the disorder, neither of whom required medical intervention . This suggests that discontinuing urine studies from the screening algorithm results in minimal loss of diagnostic sensitivity.
Bone turnover markers
BTMs are biochemical products of bone remodeling that can be measured usually in blood or urine. They reflect the metabolic activity of bone but have no function in controlling skeletal metabolism. They are traditionally categorized as markers of bone resorption and markers of bone formation. Examples of bone resorption markers are C-telopeptide (CTX), N-telopeptide, tartrate-resistant acid phosphatase, pyridinoline, and deoxypyridinoline; examples of bone formation markers are type 1 N-propeptide (P1NP), procollagen type 1 C-propeptide, osteocalcin, and BSAP. These tests cannot be used to diagnose osteoporosis or identify its cause. In the research setting, BTMs have been useful in understanding the pathophysiology of osteoporosis and the mechanism of action of drugs to treat osteoporosis. Potential uses of BTMs in clinical practice include monitoring therapy, estimating fracture risk, predicting the rate of bone loss, and assisting in the selection of specific therapy . The best validated use of BTMs in clinical practice is to monitor therapy . A significant decrease in a BTM with an antiresorptive agent or a significant increase with osteo-anabolic therapy is consistent with the desired therapeutic effect . The IOF and the International Federation of Clinical Chemistry and Laboratory Medicine recommend that CTX and P1NP be used as the referenced analytes for BTMs of resorption and formation, respectively . For applications in clinical practice, the selection of BTM may depend on availability, cost, and familiarity of the physician. Limitations in the use of BTMs in clinical practice include pre- and postanalytical variability, interlaboratory variability, lack of robust reference values, poor understanding of the least significant change, and uncertainty as to which BTM is best for a particular clinical circumstance . Another important emerging role for BTMs is in the monitoring of the duration of a bisphosphonate drug holiday. Reversal of antiresorptive effects after bisphosphonate discontinuation is variable with different bisphosphonates and duration of prior use; serial monitoring with a BTM might provide information about the persistence or reversal of bisphosphonate effects.
Erythrocyte sedimentation rate
Measurement of erythrocyte sedimentation rate (ESR) has been recommended by some in screening for secondary osteoporosis . An elevated ESR suggests the possibility of a chronic inflammatory disease, such as rheumatoid arthritis, or a hematological disorder, such as myeloma, that might be contributing to poor skeletal health. When clinically appropriate, an elevated ESR should trigger further investigation. However, ESR is a highly nonspecific test that may, in many instances, be elevated for reasons unrelated to osteoporosis. In many areas, the CRP has replaced the ESR as a somewhat more specific indicator of a systemic inflammatory condition.
Many regions of the human genome are associated with low BMD, including 699 newly identified loci , consistent with polygenic origins of osteoporosis. While genetic testing for osteoporosis is not yet useful for clinical care, it may have future applications. At the present time, genetic testing is most useful for metabolic bone diseases (e.g., osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemic rickets) when the diagnosis is not clearly established with clinical criteria.
The goals of imaging modalities in the evaluation of patients with osteoporosis include diagnosing fractures, assessing the healing of fractures, identifying skeletal diseases that have features in common with osteoporosis (e.g., osteomalacia, myeloma), and aiding in the assessment of metabolic bone diseases (e.g., primary hyperparathyroidism, TIO).
Dual-energy X-ray absorptiometry
DXA can be used for vertebral fracture assessment (VFA) as well as for measurement of BMD. VFA is a noninvasive method for diagnosing vertebral fractures with imaging of the lumbar and thoracic spine. The finding of a previously unrecognized vertebral fracture may alter diagnostic classification, assessment of fracture risk, and treatment decisions. Previously unrecognized vertebral fractures are common and age-dependent, affecting up to 20% of individuals aged 80 and above . VFA can be done at the same time as BMD testing in appropriately selected patients, offering the patient greater convenience, lower cost, and less radiation exposure than conventional spine radiography . VFA typically has less image distortion than conventional spine radiographs, but poorer resolution and reduced ability to visualize the thoracic spine above the level of T7. Interpretation of VFA requires training and experience beyond what is necessary for BMD testing by DXA. The International Society for Clinical Densitometry (ISCD) has established recommendations for consideration of VFA and suggests that the Genant semiquantitative method be used for classification of vertebral fractures . The ultimate determining factor for ordering VFA should be the likelihood that the findings might influence patient management decisions.
Standard X-rays are used to diagnose fractures and may sometimes suggest secondary causes of osteoporosis. In patients exposed to long-term bisphosphonates or denosumab who develop pain in the thigh or groin, X-rays are often the first step in the process of evaluating for signs associated with an atypical femur fracture, such as generalized femoral shaft cortical thickening, localized periosteal thickening of the lateral cortex and/or radiolucent fracture line perpendicular to the femoral shaft . Patients with osteomalacia may develop pseudofractures (Looser’s zones), which are also radiolucent fracture lines running perpendicular to the bone cortex in the pelvis or long bones . Conventional radiography of the spine, skull, chest, pelvis, humeri, and femora is used to identify myeloma-related bone lesions . These probably represent stress fractures that have healed with poorly mineralized osteoid. Radiographic findings in patients with systemic mastocytosis may range from punctate radiolucencies to osteosclerosis . Primary hyperparathyroidism may cause bone cysts, subperiosteal bone resorption, brown tumors, and demineralization (“salt and pepper” pattern) of the skull . Paget’s disease of bone is typically diagnosed by radiography in patients found to have an elevated serum alkaline phosphatase .
Imaging by CT can define skeletal anatomy in more detail than conventional radiography, without some of the limitations of MRI, which cannot be done in patients with implanted magnetic hardware. A CT scan prior to vertebral augmentation for a vertebral fracture may be done to document whether there is retropulsion of bone fragments, which might add to the potential risk of the procedure. CT may identify a fracture not seen on X-ray.
Magnetic resonance imaging
MRI is another imaging modality that may be used to detect stress fractures not visible on X-ray. MRI of the spine is commonly used prior to vertebroplasty or kyphoplasty to determine the age of the fracture, the likelihood of the fracture being from causes other than osteoporosis, and whether there is retropulsion of bony fragments than could impair neurological function.
Bone scintigraphy is a method for evaluating the distribution of active bone formation in the body. Radionuclide scanning with technetium-99m labeled methylene diphosphonate is commonly used in the evaluation of a suspected stress fracture that is not visible on conventional radiographs and may be helpful in identifying areas of skeletal disease in patients with elevated serum alkaline phosphatase of unknown origin. Other indications include suspected metastatic bone disease, osteomyelitis, and avascular necrosis. Localization of the tumor responsible for TIO may be facilitated by whole-body scans with somatostatin receptor imaging using Indium-111 labeled pentetrotide . Imaging of a nuclear scan by single-photon emission CT provides true 3D information that may enhance the recognition of subtle fractures or small tumors and better characterize the location and extent. Technetium-99m sestamibi scintigraphy is often performed to assist the surgeon in localizing a parathyroid adenoma prior to a planned parathyroidectomy .
Double tetracycline-labeled nondecalcified transiliac bone biopsies are commonly performed as outpatient procedures in clinical trials to assess bone quality and drug safety. Bone biopsies are rarely necessary in clinical practice patients but may be helpful with difficult diagnostic problems. Using well-standardized methods for bone histomorphometry, quantitative measures of bone structure and turnover can be made at the tissue and cellular level. Impediments to the use of bone biopsies in clinical practice include limited availability of qualified individuals and facilities, poor understanding of the potential benefit of the procedure, and challenges with third-party reimbursement.
Bone biopsy should be considered in clinical practice patients when the patient is not responding to standard treatment, when osteoporosis is unexpected and unexplained (e.g., in premenopausal women, young men, and children) and sometimes to monitor response to therapy . In the evaluation of patients with stage 4 and stage 5 CKD and fractures a bone biopsy can distinguish between high- and low-turnover bone disease and possibly aid in the selection of therapy . In dialysis patients with hypercalcemia and elevated PTH levels a biopsy showing osteitis fibrosa might lead to a decision of parathyroidectomy. Potent antiresorptive agents should probably be avoided in patients found to have very low bone turnover on biopsy. A diagnosis of osteomalacia is usually made according to clinical and laboratory abnormalities. However, when the diagnosis is unclear, a bone biopsy may confirm a suspicion of osteomalacia or be an unexpected finding. Osteomalacia is characterized by the presence of thickened osteoid seams, decreased mineralization rate, and prolonged mineralization lag time on bone histomorphometry. With infiltrative disorders of bone, such as systemic mastocytosis, a bone biopsy or bone marrow aspiration may sometimes be the only way to establish the diagnosis .
Although osteogenesis imperfecta is most often a diagnosis based on family history and clinical criteria (e.g., blue sclera, fragile bones, hearing loss, dentinogenesis imperfecta), a skin punch biopsy for dermal fibroblast culture has historically been used to provide helpful information . When systemic mastocytosis is suspected and there is a rash that is not clearly urticaria pigmentosa, a biopsy of a skin lesion may provide confirmatory information.
Small bowel biopsy
In a patient with suspected celiac disease, endoscopy with small bowel mucosal biopsy is the “gold standard” method for confirming the diagnosis . Typical histological findings include mucosal inflammation, villous atrophy, and crypt hyperplasia.
When the clinical circumstances are straightforward and the basic evaluation of osteoporosis is unrevealing, treatment should be initiated, if indicated. This should be followed by monitoring for effectiveness, safety, and achievement of an acceptable level of fracture risk . Referral to an osteoporosis specialist should be considered if the patient’s condition is highly complex, the evaluation shows perplexing results, the patient does not respond to therapy as expected, or when unusual safety concerns arise (e.g., osteonecrosis of the jaw, atypical femur fracture). Depending on individual patient circumstances, portions of the initial evaluation may need to be repeated and/or additional testing ordered. The need for initiating and continuing treatment should be periodically reassessed considering the expected benefit of treatment and the potential risks. The osteoporosis evaluation should include a discussion of the findings with the patient, with the patient being encouraged to ask questions and communicate any concerns about fracture risk, consequences of fractures, and the balance of benefit and risk of therapeutic options. The process of risk communication and shared decision-making may serve to optimize clinical outcomes and reduce the burden of osteoporotic fractures .
An evaluation of factors contributing to skeletal fragility, falls, and fracture risk is indicated for all patients with osteoporosis and low BMD, especially those who are candidates for pharmacological intervention. Unusual clinical circumstances or abnormalities on the initial evaluation should trigger further investigation. Treatment decisions should be based on all available clinical information, including the patient’s previous experiences and concerns.
In the past year, E. Michael Lewiecki has received institutional grant/research support from Radius, Amgen, PFEnex, and Mereo; he has served on scientific advisory boards or consulted for Amgen, Radius, Alexion, Ultragenyx, Sandoz, and Celltrion; he serves on the speakers’ bureau for Radius and Alexion; he is a board member of the National Osteoporosis Foundation, International Society for Clinical Densitometry, and Osteoporosis Foundation of New Mexico.