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DOI: 10.1177/0115426507022003261
Patient Assessment in the Diagnosis, Prevention, and Treatment of Osteoporosis ,
* Bay Area Medical Center, Case Management
Services, Marinette, Wisconsin; the Correspondence: Paul F. Lata, PharmD, Bay Area Medical Center, Case Management Services, 3100 Shore Drive, Marinette, WI 54143. Electronic mail may be sent to plata{at}bamc.org. Assessment of the patient with osteoporosis includes history and physical examination, laboratory testing, and imaging studies. Information gathered during this assessment assists clinicians in targeting strategies to prevent fractures. The medical history should contain items such as personal and family history of fractures, lifestyle, intake of substances such as vitamin D, calcium, corticosteroids, and other medications. The physical examination can reveal relevant information such as height loss and risk of falls. Bone mineral density (BMD), most commonly determined by dual-energy x-ray absorptiometry, best predicts fracture risk in patients without previous fracture. BMD testing is most efficient in women over 65 years old but is also helpful for men and women with risk factors. Serial BMD tests can identify individuals losing bone mass, but clinicians should be aware of what constitutes a significant change. Laboratory testing can detect other risk factors and can provide clues to etiology. Selection of laboratory tests should be individualized, as there is no consensus regarding which tests are optimal. Biochemical markers of bone turnover have a potential role in fracture risk assessment and in gauging response to therapy, but are not widely used at present. Clinicians should be aware of problems with vitamin D measurement, including seasonal variation, variability among laboratories, and the desirable therapeutic range. Careful assessment of the osteoporotic patient is essential in developing a comprehensive plan that reduces fracture risk and improves quality of life.
Osteoporotic fractures are increasing worldwide as the population ages, with substantial human, economic, and social costs. Osteoporosis without fracture is asymptomatic, but effective methods to diagnose and treat osteoporosis before fracture are available. It is thus crucial that individuals at risk be assessed and treated. Aside from advanced age and postmenopausal status, important secondary causes of bone loss are present in many individuals. For example, individuals with gastrointestinal disorders, particularly if associated with malabsorption, are often at increased risk of bone loss or fracture and deserve special attention. Evaluation of the patient who is being assessed for bone loss or fracture includes history and physical examination, laboratory testing, and imaging studies, with emphasis on elements that affect skeletal health. This paper will provide the reader with an overview of such an assessment in the context of an example case.
JE is a 67-year-old woman with a chief complaint of backache that has lasted for 2 weeks and is now somewhat improved. She also expresses concern that a recent heel bone density performed at a health fair showed "low bone density." Her medical problems include celiac disease, history of wrist fracture, and hypertension. Her family history is remarkable for a maternal hip fracture at age 62. JE drinks 1 glass of wine 3 times a week and has a 60-pack-year history of smoking, having quit 10 years ago. JE is sedentary, rarely goes outside, and has not fallen within recent memory. She is lactose intolerant and has a daily calcium intake of about 300 mg. Her calculated glomerular filtration rate (GFR) is 45 mL/min. She takes 1 multivitamin daily and hydrochlorothiazide 12.5 mg daily. JE is 5 feet, 4 inches tall (2 inches less than her height as a young woman), 170 lb, with normal vital signs. Her laboratory tests for complete blood count (CBC), thyroid-stimulating hormone (TSH), electrolytes, and magnesium are normal; serum albumin is 3.0 g/dL, calcium is 7.5 mg/dL, albumin-corrected calcium is 8.3 mg/dL (reference range 8.5–10.2), alkaline phosphatase is 127 units/L (50–136), phosphorus is 2 mg/dL (2.4–4.9), 25-hydroxyvitamin D is 10 ng/mL (desired level >32), and intact parathyroid hormone (PTH) is 81 pg/mL (reference range 14–72). A thoracic spine x-ray demonstrated a compression fracture at T8. Dual-energy x-ray absorptiometry (DXA) measurement demonstrated a hip T-score of–2.1 and an L1–L4 T-score of–2.7. Z-scores were–0.9 at the hip and–1.5 at the spine. JE has established osteoporosis according to her bone mineral density (BMD) and atraumatic fracture. Contributors are advanced age, postmenopausal status, family history, low calcium intake, physical inactivity, smoking history, and celiac disease with associated malabsorption, leading to hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism. She is encouraged to increase physical activity, counseled about fall prevention, provided with calcium supplementation (1500 mg/d) and vitamin D (to achieve 25-hydroxyvitamin D >32 ng/mL). Once vitamin D is repleted, her laboratory values normalize (PTH, 40 pg/mL; albumin-corrected calcium, 9.0 mg/dL; alkaline phosphatase, 85; phosphorus, 2.8; 25-hydroxyvitamin D, 47 ng/mL). She begins receiving antiresorptive therapy. One year later, she is tolerating therapy, with normal laboratory values, no further fractures, and BMD increased by 1.5% at the hip and 2.5% at the spine.
Chief Complaint and History of the Present Illness JE's chief complaint is mild-to-moderate backache, appearing abruptly 2 weeks ago and worse on standing or walking. Although backache has many underlying causes, JE's physician suspected vertebral fracture, given the presentation and onset, JE's age, and other medical history. Spine osteoarthritis commonly causes backache but usually presents more gradually, and JE has no known osteoarthritis. Paget's disease is unlikely, given her normal alkaline phosphatase, and she has no symptoms such as weakness or generalized bone pain that would suggest osteomalacia. JE recalls no falls or other trauma associated with the backache, so a confirmed fracture would be an atraumatic fracture, a hallmark of severe osteoporosis. Pain from vertebral fractures ranges from severe to nonexistent. Two-thirds of vertebral fractures never come to medical attention.1
Comorbidities JE had a wrist fracture at age 52, increasing her risk of future fracture. Men or women with adult wrist fractures face an increased fracture risk that is 3-fold at the wrist and 2-fold at other sites.3,4 Her current vertebral fracture doubles her future risk of fracture at any site, with an even higher risk of a second vertebral fracture. Other comorbidities commonly contribute to skeletal risk, although JE does not have these. Parkinson's disease and arthritis increase fall risk.5 The patient with nephrolithiasis may have hypercalciuria due to inadequate renal calcium reabsorption (calcium leak) or primary hyperparathyroidism, both associated with increased skeletal risk. Urolithiasis has also been associated with increased vertebral fracture risk.6 Prolonged premenopausal amenorrhea is associated with decreased peak bone mass,7 and premature menopause increases vertebral fracture risk 2.5-fold.8 Female athletes who exercise excessively lose bone due to estrogen deficiency and weight loss, with two-thirds being amenorrheic in some surveys.7 Most women with anorexia nervosa are also amenorrheic.7 Half of women with anorexia have osteoporosis or osteopenia,9 with annual bone loss exceeding 2%, although resumption of menses allows some regain of bone.10 Finally, the patient history should include questions about swallowing difficulty. If bisphosphonate treatment is considered, a formal swallowing evaluation should be obtained if problems are suspected, to ensure safe drug administration.
Medication Use Men receiving androgen deprivation therapy for prostate cancer lose 3%–5% BMD in the first year and have increased fracture risk.11,14 Children and adults receiving enzyme-inducing antiepileptics, particularly phenytoin, phenobarbital, and carbamazepine, can lose bone and face a doubling of fracture risk.15,16 Limited data link the use of unfractionated heparin for more than a month with spinal bone loss of approximately 5%.17 Although thyroid oversupplementation has been associated with low BMD and fractures, this risk is debated.18 Other medications such as benzodiazepines and antidepressants increase the risk of falls and fracture.16,19,20 A recent report raises concern that proton-pump inhibitors may increase fracture risk as much as 3-fold, perhaps as a result of decreased calcium absorption.21
Social History
Diet and Supplement Use JE's sedentary, indoor habits provide little sun exposure, a lifestyle associated with vitamin D deficiency.29 Her vitamin D intake (400 international units [IU]/d from a multivitamin), while meeting current formal recommendations, is well below that recommended by bone experts (at least 800–1000 IU/d).30 Celiac disease, especially if poorly controlled, also contributes to vitamin D deficiency. Vitamin A is obtained through supplements, liver, fish, and fortified foods.31,32 JE obtains 600 mcg/d of vitamin A (retinol) in her multivitamin supplement, which appears reasonable, given the recommended dietary allowance (RDA) of vitamin A is 900 mcg/d for adult men and 700 mcg/d for adult women.33 Although too little vitamin A poses skeletal and other health risks, excessive vitamin A, with intakes starting at about twice the RDA, increases fracture risk.34–36 Adding to this concern is evidence that half of the US population consumes >2000 mcg/d,37 with 5%–10% having excessive blood levels of vitamin A, and few being deficient.35,38 These data suggest that oversupplementation with vitamin A may be problematic. The vitamin A precursor β-carotene, found in spinach, carrots, and other vegetables, does not carry the same risk as vitamin A because its conversion to vitamin A is tightly regulated and unlikely to lead to vitamin A excess.31
Physical Activity JE has not fallen, but her fall risk should be assessed annually.1 A history of multiple falls in the past year increases risk of future falls.5 Inquiring about whether, how, and when falls occur provides opportunities for fracture prevention intervention and helps determine whether a given fracture is associated with trauma. Asking about environmental conditions such as poor lighting or clutter that could cause falls is reasonable for any elderly or frail patient.
Family History
Physical Examination An unsteady gait or use of assistive devices is associated with increased risk for fall and subsequent fracture.8 JE should be asked to arise from a chair without using her arms. Inability to do this indicates a doubling of fall risk.5 JE should also undergo a visual examination because poor depth perception (but not poor acuity) increases fracture risk by 50%.16 Although not an issue with JE, low body weight (127 lb) increases fracture risk.42 This risk is primarily mediated through low BMD,8,43 with body weight contributing little to risk assessment if BMD is known. Unintentional weight loss warrants further attention as it can suggest hyperthyroidism, malignancy, malabsorption, or anorexia. Hypogonadism in men, which can present with sexual dysfunction, anemia, or fatigue, contributes to bone loss and also requires specific attention. In men, the physical examination should include checking for signs of hypogonadism such as gynecomastia, small soft testes, or loss of pubic hair. Other, less common, conditions cause bone loss and should be considered if the physical examination or patient history is suggestive. Thin skin, altered fat distribution and florid complexion (Cushing's), bone pain and skeletal muscle weakness (osteomalacia), or weight loss, anemia, and fatigue (myeloma) are not commonly seen in the osteoporotic patient but should be addressed because each poses significant skeletal and other health risks. Finally, given recent reports of bisphosphonate-associated jaw necrosis, JE should undergo an oral examination and be questioned regarding dental problems or upcoming invasive dental procedures.44
Bone Densitometry Bone mass and architecture determine bone strength and fracture risk. Measurement of BMD, the mineral content per unit of area of bone (g/cm2), is well established, whereas other tests (Table 1) assessing bone architecture are in development. Other technologies such as magnetic resonance imaging (MRI), bone scanning, and single-photon emission computed tomography (SPECT) can be helpful for visualization of fractures or malignancies or determining cause of fractures or bone pain.
BMD measurement using DXA is the best diagnostic test to detect osteoporosis, determine fracture risk, and monitor treatment response. BMD measurement is in wide clinical use and is used in most studies assessing treatment for osteoporosis.45 Additionally, these measurements prompt high-risk individuals to seek treatment.46 The International Society for Clinical Densitometry (ISCD) recommends assessing BMD at the spine (L1–L4) and the hip (total proximal femur, trochanter, femoral neck), as is done in JE's case.47 Testing at these sites is termed central or axial. BMD can be measured at the radius if the hip or spine cannot be measured, in obesity, or in hyperparathyroidism (to measure cortical bone, often lost in this condition). BMD of the femoral neck or total proximal femur should be used to determine hip BMD. Reproducibility of other regions, particularly Ward's triangle, is poor. (Ward's triangle is not a specific anatomical area but is generated by the DXA measurement as the region with the lowest BMD in the femoral head.) ISCD specifically recommends against using Ward's triangle. BMD measurements can be confounded by hardware or prostheses in the scanned area, radioactivity remaining after a bone scan, contrast in the gastrointestinal tract within 1 week of ingestion, or by calcifications associated with advanced renal disease.48 Osteophytes, arthritis, compression fractures, or degenerative sclerosis often found in the elderly falsely elevates lumbar spine measurements.49,50 JE's compression fracture was at T8 and therefore unlikely to affect BMD readings at L1–L4. A DXA scan provides BMD measurement in units of g/cm2, which can be converted into a T-score. A patient's T-score is the number of standard deviations (SDs) above (+) or below (–) the mean for young healthy individuals of the same gender (the reference database). JE's lumbar spine BMD was 2.7 standard deviations below the reference mean, so her T-score is–2.7. The risk of fracture increases with decreasing BMD, approximately doubling for each SD decrease in BMD.45,50 JE, with a T-score of –2.7, has about twice the fracture risk of a woman with a T-score of–1.7 who is otherwise similar. JE's T-score was lower at her spine than her hip. This "mismatch," or "site discordance," is common. JE's hip T-score was likely higher than her spinal T-score because the spine has a high percentage of trabecular bone, which is lost first during menopause. The lowest T-score from all measured sites, the spine in JE's case, should be used to help determine fracture risk and to categorize the patient as normal, osteopenic, or osteoporotic. With a T-score indicating osteoporosis, and with a fragility fracture, JE has severe osteoporosis according to the criteria in Table 2.
Aside from its contribution to fracture risk prediction, BMD measurement helps predict the success of antiresorptive therapy. Antiresorptive drugs show greater reduction in fracture risk for those with lower BMD compared to those with higher BMD.50,51 Further, the number needed to treat with a bisphosphonate to prevent a vertebral fracture is 25 times greater for individuals with near normal BMD than for those with low BMD.52 JE is thus more likely to benefit from treatment than others with higher BMD. A Z-score compares an individual's BMD measurement to an age-matched population. JE's Z-score indicates that her hip and spine BMD were 0.9 and 1.6 SDs below others her age, low enough to raise the possibility of a secondary cause of her osteoporosis. Z-scores are preferred to T-scores for children, but they must be interpreted using an age-matched pediatric database.47 All DXA reports should include a T-score and a statement about validity of the examination. The elements of a DXA report are listed in Table 3. Including the manufacturer and instrument model in a report is essential if BMD readings are compared. The comparative population should be identified if statements about fracture risk are made.
Several organizations, including the National Osteoporosis Foundation (NOF),42 ISCD,47 the American Gastroenterological Association (AGA),2 the North American Menopause Society,1 US Preventive Services Task Force (USPTF),53 and the American Association of Clinical Endocrinologists (AACE),54 have published recommendations for who should undergo BMD testing. Although recommendations vary, all guidelines support screening for women over 65. Individuals with conditions that pose skeletal risk should be tested. For example, baseline and follow-up BMD should be determined in all individuals receiving oral corticosteroids for >3 months or intravenous pulsed therapy.11 Similarly, men or women with hypogonadism or women with amenorrhea persisting for at least 6 months should have BMD testing at baseline and again in 1–2 years to detect bone loss.11 Most guidelines do not recommend testing younger individuals (ie, age <50) without risk factors. Figure 1 illustrates the inefficiency of such screening, given the low baseline fracture rate in this population. In JE's case, screening at or before age 65 could have detected low BMD earlier.
Densitometry for individuals with gastrointestinal disorders. Individuals with inflammatory bowel disease (IBD) have a similar prevalence of low BMD at diagnosis and lose bone at a rate similar to the general population. This finding is contrary to some earlier reports, which may have been confounded by prednisone use.2 Several population-based studies have found no increased fracture risk in IBD patients,55 although the largest study found a 40% increased risk relative to controls.56 Patients with Crohn's disease and ileum resection have a nearly 4-fold increase in fracture risk.57 Patients with Crohn's vs ulcerative colitis have a similar fracture risk.2 The AGA recommends selective rather than routine BMD testing in IBD.2 Individuals with celiac disease, such as JE, have lower BMD than the general population. JE's hip and spine Z-scores were –0.9 and –1.6 respectively, comparable to mean hip and spine Z-scores of –1.1 and –1.5 in patients with untreated celiac disease.2 Gluten-free diets normalize BMD in children but not always in adults.2 Most BMD recovery occurs during the first year of treatment.58 The AGA recommends waiting a year after starting a gluten-free diet to allow BMD to stabilize before ordering densitometry.2 Limited data link total or partial gastrectomy with low hip and spine BMD.2 The AGA recommends BMD testing in postmenopausal women and men over 50 years old who are at least 10 years postgastrectomy.2 Preliminary evidence raises concern that gastric bypass surgery may cause bone loss.59,60 Longer-term investigations will better determine how to monitor bone mass after bariatric surgery. Densitometry in kidney disease. The National Kidney Foundation has published guidelines for management of skeletal risk in patients with different stages of chronic kidney disease (CKD).61 New guidelines are expected in 2008 (http://www.kdigo.org). With severe CKD, abnormalities in calcium, phosphorus, and vitamin D metabolism can result in a heterogeneous group of bone diseases termed renal osteodystrophy. Renal osteodystrophy can be characterized as low turnover (adynamic bone disease) or high turnover (associated with elevated PTH) but cannot be accurately diagnosed without bone biopsy.48 Renal osteodystrophy is sometimes associated with osteoporosis,62 but BMD has not been correlated with fracture outcomes in this population.48,61,62 The National Kidney Foundation recommends BMD testing only for patients such as JE with fractures or risk factors for osteoporosis. With her estimated GFR of 45, JE has stage 3 CKD (GFR range, 30–60). Although renal osteodystrophy is possible in her case, normalization of her PTH, alkaline phosphatase, and calcium when given vitamin D and calcium, along with her normal phosphorus, make significant renal osteodystrophy unlikely. Serial BMD measurement. Repeated BMD tests can help determine treatment efficacy, where stable or increased bone density is the goal of treatment, or determine if untreated individuals are losing bone. The same sites should be compared and actual bone densities (g/cm2) should be compared rather than T-scores. Relationship to fracture risk reduction. Some63,64 but not all65 meta-analyses have shown an association between BMD improvements at the hip and spine during the first 1–5 years of treatment and decreased nonvertebral and vertebral fractures. Increased BMD explains only part of the fracture risk reduction seen with antiresorptive treatment. For example, raloxifene increased spinal BMD by 2.6% but decreased vertebral fractures by 38%.66 Overall, antiresorptive treatments expected according to BMD to reduce fracture risk by 20% actually reduce this risk by 45%.67 This incomplete correlation could be explained by other treatment effects such as improved microarchitecture related to decreased bone turnover, with fewer resorption cavities and thus strengthened bone. Finally, even patients who exhibit stable (rather than increased) BMD on treatment experience some fracture risk reduction. Frequency of BMD measurements. In most cases, at least 1 year between measurements is necessary for a significant change to occur. ISCD recommends annual testing until BMD stabilizes, then lengthening the interval.47 The USPTF recommends at least 2 years between tests,68 an interval used by many clinicians in the United States because of Medicare reimbursement.69 If rapid bone loss is expected, as with systemic corticosteroids, more frequent testing may be appropriate.2,11,47 For JE, repeat testing at 1–2 years is reasonable; her physician ordered a repeat test at 1 year. Determining if BMD has changed significantly. Clinicians who compare serial BMD scans need to know the least significant change (LSC) for the instrument and site involved. LSC is the smallest change that can be considered statistically significant. LSC depends on the precision of the measurement and the magnitude of acceptable type I or type II error.70 Precision, or reproducibility, is a quality-control measure determined periodically. This requires repeat measurements on 1 day, with the same machine, same technologist, same subject, and same skeletal site, with patient repositioning between measurements. Precision error (in g/cm2) is expressed as a percentage or (coefficient of variation [CV]) of such repeated measures.71 The CV (usually 1.0%–1.5%) is used to calculate LSC specific to the anatomic site and instrument. LSC is 3%–4% for most BMD tests, although in clinical practice, the LSC may be closer to 4.5% at the spine and 7.5% at the femoral neck.70 BMD readings should not be compared between different testing centers or techniques without cross-calibration.47 The LSC for the densitometer at JE's clinic was 4.5% at the spine. Her spinal BMD improved by 2.5%, less than the LSC, and therefore would be assumed to be stable rather than improved. What if bone loss occurs during therapy? Uncertainty exists regarding the appropriate action if bone is lost during treatment. One study showed a lack of fracture risk benefit in subjects treated with alendronate who lost >4% BMD.72 However, women who lost 0%–4% in BMD after the first year of therapy still had lower fracture rates than those receiving placebo. If significant bone loss occurs, evaluation of patient compliance with pharmacologic and nonpharmacologic treatment, and possibly further evaluation for secondary causes of bone loss, should be considered.47 Peripheral BMD measurement. JE's heel BMD was low when she was screened with ultrasound. Peripheral testing can identify low BMD and predict fracture risk at other sites.73–75 In addition to early detection, in the authors' experience, osteoporosis screenings also provide an excellent opportunity for education. Although ultrasound and also peripheral DXA measurements predict fracture risk, correlation with central DXA is imperfect, and ultrasound testing is not approved for diagnosis.76 The World Health Organization (WHO) classification of BMD for diagnosis does not apply to peripheral testing, nor have device-specific cut points been established except at the distal radius.1,47 JE does not need more peripheral tests, because only central DXA is proven valid for monitoring treatment response. Prediction of absolute fracture risk. BMD alone does not predict all fractures. In the Rotterdam Study, most fractures occurred in individuals who were osteopenic rather than osteoporotic.77 At any level of BMD, advancing age and previous fracture are powerful independent risk factors for fracture in men and women.3,41,75,77 BMD testing alone therefore does not identify many individuals with high fracture risk, as illustrated in Figure 1. Currently, the WHO is establishing a database using risk factors to estimate absolute risk for fracture,78 the risk of fracture over a period of time, usually 10 years. Such a tool might have been helpful in determining JE's fracture risk at an earlier stage. Vertebral fracture assessment. The presence of JE's vertebral fracture predicts other fractures independently of BMD.79 However, only 25%–33% of vertebral fractures are clinically apparent. Improving their detection in individuals with normal or osteopenic BMD could identify additional candidates for treatment. Vertebral fracture assessment (VFA) or densitometric spine imaging for the purpose of identifying vertebral fractures with DXA technology is often performed concurrently with BMD measurement. Although image resolution is inferior to standard radiography, VFA is sensitive and specific for diagnosing moderate to severe vertebral fractures.80 In 1 study, VFA identified vertebral fractures in 18% of asymptomatic osteopenic women and in 13% with normal BMD.81 VFA delivers only 3 µSv of radiation compared with 600 µSv for a lumbar spine radiograph79 and is less expensive. VFA will be most productive for individuals at high risk for vertebral fracture such as those recommended by the ISCD (height loss, fractures, glucocorticoid therapy, or findings suggestive of vertebral fracture not documented by previous radiography).79
Bone Turnover Markers Healthy bone undergoes regular cycles of bone turnover, with resorption (by osteoclasts) followed by formation (initiated by osteoblasts), a process thought to help maintain bone strength and integrity. In osteoporosis, bone turnover may increase, but when resorption outpaces formation, this leads to net bone loss. Biochemical markers of bone turnover are released into the bloodstream during bone resorption and formation, and some are excreted into the urine. Levels of bone turnover markers thus provide clues to the extent of bone turnover. During bone resorption, the bone collagen matrix is broken down, releasing peptides and cross-linking molecules. Urinary markers (C- or N-telopeptides and deoxypyridinoline) and serum markers (N- or C-telopeptides, tartrate-resistant acid phosphatase) indicate bone resorption. During bone formation, osteoblast products (osteocalcin, bone specific alkaline phosphatase [BSAP], and procollagen type I N- or C-propeptides) are released. Potential advantages of measuring bone turnover markers are as follows: (1) increases are associated with increased fracture risk82,83; (2) unlike BMD, for which one must wait a year to assess treatment response, bone turnover markers respond more rapidly to therapy, reaching nadirs 3–6 months after starting medication84,85; (3) in research trials, changes in bone turnover markers correlate with improvements in BMD and with fracture reduction63,85–87; and (4) bone turnover markers might predict treatment benefits not explained by BMD, whereby some antifracture efficacy is seen with changes in bone turnover markers but without improvement in BMD.88,89 When they are used, bone turnover marker measurements should be made at baseline and at 3–6 months after treatment initiation for resorption markers and 6 months after treatment initiation for formation markers. Drawbacks in using bone turnover markers have limited their clinical use. Factors such as age, fractures,85 bedrest,90,91 food intake,92 renal function,85 medications,85,91 and exercise91 cause variations in bone turnover markers. Diurnal variation is also significant. Resorption markers decrease from morning to afternoon by as much as 100%,91,92 whereas some formation markers peak later in the day.85 Given the above problems with measurement, bone turnover markers are used primarily in research, rather than in the clinical setting. For JE, the other laboratory measurements ordered by her physician, as described below, provided a good foundation for her management.
Laboratory Testing for the Osteoporotic Patient Tannenbaum et al93 studied the usefulness of laboratory tests in identifying secondary causes of osteoporosis. This was a retrospective review based on 173 women attending an osteoporosis clinic. The most common laboratory abnormalities were elevated PTH (27 cases), hypocalciuria (22 cases), and hypercalciuria (17 cases), with 75% of these tests leading to a new diagnosis such as primary or secondary hyperparathyroidism, malabsorption, or idiopathic hypercalciuria. The most cost-effective screening strategy included 24-hour urine calcium, serum calcium, PTH, and TSH (for those receiving thyroid replacement). Further, in a prospective treatment study which included women with low bone density and also those with osteoporosis, TSH was the only abnormal value found more commonly in the latter.94 This study did not, however, assess urine calcium, nor did it assess PTH, so it is unknown if these findings would have been replicated. In the absence of consensus, clinical judgment is crucial in deciding what tests to order for the osteoporotic patient. Some individuals, such as men, younger persons, or those with suspected contributing comorbidities, may warrant more thorough testing. Table 4 provides information regarding the more commonly used laboratory tests, based on the above studies, published expert opinion, and on osteoporosis guidelines suggested by several organizations. Further discussion of these tests and their implications for skeletal health follows.
Vitamin D. IMPORTANCE OF VITAMIN D FOR BONE HEALTH.
Most individuals receive most of their vitamin D from cutaneous synthesis
through sun exposure, with lesser contributions from supplements and food.
Vitamin D is converted by the liver to 25-hydroxyvitamin D [25(OH)D], the
major circulating form and the best clinical measure of vitamin D status. The
kidney then converts it to the active form, 1 DESIRABLE VITAMIN D STATUS. JE's 25(OH)D level of 10 ng/mL was definitely low. Osteomalacia occurs in many individuals with serum 25(OH)D levels below 8 ng/mL.30 Several surrogate measures have been examined to identify the healthy lower limit of 25(OH)D. The level which maximally suppresses PTH ranges from 28 ng/mL to 44 ng/mL but depends on age, renal status, calcium intake, and other factors30,97–99; fractional calcium absorption is maximum above 32 ng/mL,30 and improved outcomes for fractures, lower extremity function, and possibly periodontal disease and colorectal cancer are seen at 36–40 ng/mL.96 Most experts suggest the lower limit of normal should be at least 30–32 ng/mL, although some laboratory reference ranges still begin at 20 ng/mL.30,100,101 CAUSES OF VITAMIN D INADEQUACY. Many otherwise healthy individuals receive insufficient vitamin D due to little sun exposure or suboptimal oral intake. Issues contributing to inadequate sun exposure include concern about skin cancer, use of sunscreen, decreased cutaneous synthesis of vitamin D in response to sun in older persons, presence of darkly pigmented skin, and seasonal variation in the effects of sunlight. Decreased 25(OH)D in the winter months has been demonstrated in elderly white Australian women102 and in young Finnish men.103 In less sunny climates (beyond the 35th parallel N or S), a summer 25(OH)D assay may miss seasonal vitamin D deficiency. Other factors such as kidney disease or medications such as phenytoin can lead to vitamin D inadequacy. Gastrointestinal disorders also play a key role with severe deficiency occurring in some persons with malabsorptive syndromes such as celiac sprue or Crohn's disease after ileum resection. JE's low vitamin D likely results from decreased time outdoors, inadequate oral intake, advanced age, and celiac disease. WHOM TO TEST AND HOW TO TEST. Routine 25(OH)D measurement of all persons is unnecessary but is reasonable for those at risk for low vitamin D status, such as JE. These include people with decreased sun exposure, malabsorption, hyperparathyroidism, osteoporosis, advanced age, calcium abnormalities, or receiving drugs such as corticosteroids, antiepileptics, or antiresorptives.104 Clinicians should also monitor individuals receiving high-dose vitamin D (eg, 50,000 IU more than once or twice weekly). Although 1,25(OH)2D is the active form of vitamin D, its measurement is not clinically useful due to its short half-life and tightly regulated synthesis. Increased PTH in response to low calcium or low vitamin D can normalize 1,25(OH)2D even when vitamin D stores are low. There is a consensus that 25(OH)D vitamin D is the best measure of vitamin D status, with 1,25(OH)2D assay rarely needed.97 Unfortunately, laboratory assays for 25(OH)D measurement vary, with as much as 2-fold differences for the same sample measured by different laboratories.105 The gold standard, high pressure liquid chromatography, is not widely practical, and chemiluminescent assays may overestimate or underestimate 25(OH)D.106 Some radioimmunoassays give results similar to high pressure liquid chromatography but some underestimate 25(OH)D2.107 Currently, radioimmunoassay appears to be the most reliable available assay. Clinicians should be aware that these assays are not yet standardized and subject to variation. REQUIRED VITAMIN D INTAKE. Despite national guidelines recommending 600–800 IU/d of vitamin D for older adults, more is often needed. For adults aged 50–70, intake of vitamin D3 at 100 IU/d can increase steady-state 25(OH)D by about 1 ng/mL. Thus, increasing a person's level from 20 ng/mL to 30 ng/mL with vitamin D3 requires an additional 1000 IU/d.30 In JE's case, daily intake was 400 IU from her multivitamin. Her physician prescribed a loading regimen (using prescription-strength capsules of 50,000 IU) to improve her vitamin D status quickly, to be followed by a maintenance dose. PTH. The AGA recommends checking serum levels of PTH if serum calcium or urinary calcium is abnormal,2 but there is no overall consensus on this issue. Other situations where PTH measurement is reasonable include: (1) the hypercalcemic patient, where primary hyperparathyroidism may be suspected (and, if confirmed, an endocrine consult could be considered, depending on whether symptoms are present or on the degree of hypercalcemia); (2) the patient with known vitamin D deficiency or hypocalcemia because such patients may have secondary hyperparathyroidism in response to low vitamin D or calcium status (vitamin D and calcium repletion often lead to normalization of PTH); and (3) persons with renal dysfunction: National Kidney Foundation guidelines recommend PTH measurement every 12 months for those with CKD stage 3 (GFR 30–59) and every 3 months for those with GFR below 30.61 Because uremic patients are underresponsive to the bone resorptive actions of PTH, the K/DOQI recommends specific (higher) target ranges for PTH in these patients. Vitamin D or its analogs are useful in maintaining PTH in the appropriate range. Care must be taken not to oversuppress PTH in CKD patients, which could lead to adynamic (low turnover) bone disease and increased bone fragility. Other laboratory tests relevant to the calcium–vitamin D axis. JE's serum calcium on presentation, even when corrected for albumin, was low, likely due to low calcium intake, inadequate vitamin D status, and poor calcium absorption. However, many similar patients will nonetheless exhibit normal or lownormal serum calcium (maintained at the expense of increased bone turnover and incremental bone loss due to elevated PTH). Patient education is important here because patients may believe that normal serum calcium represents adequate calcium and vitamin D intake. Calcium excretion measurement can be important for the osteoporotic patient for several reasons. If calcium intake and vitamin D status are normal, normal calcium excretion is consistent with good calcium absorption. Increased calcium excretion, however, has been associated with low BMD.93,108 Idiopathic hypercalciuria (not associated with hypercalcemia) increases risk of nephrolithiasis and can be treated with thiazide diuretics, which may also increase BMD. Low calcium excretion is associated with lack of calcium intake, calcium malabsorption, or vitamin D deficiency. As in JE's case, serum phosphorus levels can be low due to elevated PTH because PTH increases renal phosphorus excretion. Other causes include low phosphorus intake, chronic diarrhea, antacid overuse, or vitamin D deficiency (because vitamin D promotes intestinal phosphorus absorption). With severe deficiency of calcium, vitamin D, and/or phosphorus, undermineralization of bone (osteomalacia) can result. On the other hand, hyperphosphatemia is commonly found in patients with severe CKD, partly due to decreased renal phosphorus excretion. Serum creatinine measurement and GFR estimation are essential in assessing the osteoporotic patient. With GFR <60 mL/min, renal synthesis of active vitamin D begins to fall and serum PTH levels begin to increase.61,109 Active vitamin D analogs may be needed, depending on disease severity. Individuals do vary, with many patients in stage 3 CKD (GFR 30–59) exhibiting normal PTH. Renal function is also important in considering antiresorptive treatment because bisphosphonates are not recommended with severe CKD. JE's alkaline phosphatase at first was in the upper-normal range, likely due to her elevated PTH, and resolved with vitamin D repletion. Alkaline phosphatase is routinely measured in assessment of the osteoporotic patient and is elevated with increased bone turnover (Table 4). For the patient with low serum levels of calcium and vitamin D, along with elevated serum levels of PTH and alkaline phosphatase, osteomalacia should be suspected. A CBC is part of the routine workup for the osteoporotic patient to rule out underlying causes. Although not present in JE's case, iron deficiency anemia is the most common clinical presentation in adults with celiac disease.110 In the older patient with unexplained anemia, myeloma may be suspected (see below). Liver enzyme tests are recommended for the initial workup for the osteoporotic patient to rule out underlying causes. A high prevalence of osteoporosis has been reported in cirrhosis and cholestatic liver disease.111 TSH measurement of the osteoporotic patient at baseline is common, although not recommended by all authorities. Numerous studies have examined the relationship between thyroid status and bone health, with mixed results. Overt hypothyroidism in most studies was associated with increased fracture risk and decreased BMD, improving with treatment.112 Suppressive therapy with thyroxine, whether caused by overtreatment of hypothyroidism or in treatment of thyroid malignancy, appears to decrease BMD.18,113 However, treatment of hypothyroid patients to achieve a TSH in the normal range, as recommended by expert panels, appears to pose little or no risk.18,113–116 As in JE's case, hypogonadism, in her case postmenopausal, is a significant cause of bone loss. For the young woman suspected of gonadal dysfunction (eg, amenorrhea, infertility), an endocrine consultation is reasonable. Hypogonadism is also associated with low bone mass in men.117 Although testosterone can improve bone density in men,118 it is not recommended specifically for skeletal health, given the potential adverse effects and availability of other proven therapies. For the younger man who is hypogonadal or for the symptomatic older man (with fatigue, anemia, or bothersome erectile dysfunction), an endocrine consultation is reasonable. Measurement of serum total testosterone levels at baseline for the male osteoporotic patient is reasonable for etiology and to rule out severe hypogonadism. Other laboratory tests. Other tests are not routinely recommended but are reasonable if there is clinical suspicion of an underlying cause of bone loss. For the older patient with anemia or unexpectedly low BMD, serum protein electrophoresis and urine protein electrophoresis can help rule out myeloma. Celiac sprue should be considered if low vitamin D status, unexplained diarrhea, or anemia are present. There is also increased prevalence of sprue in patients with irritable bowel syndrome. Finally, suspicion of a less common secondary contributor (eg, Cushing's disease) calls for a more focused workup.
JE's presentation included many factors that combined to increase her fracture risk, factors that commonly occur in osteoporotic patients and that require careful workup. Her severe osteoporosis deserves a comprehensive plan to improve her lifestyle, achieve vitamin D and calcium adequacy, provide potent antiresorptive therapy, and appropriately monitor therapy. A careful assessment of the patient at the outset, considering comorbidities, medications, lifestyle, family history, laboratory abnormalities, and radiologic findings, is essential in developing such a plan that is straightforward, effective, and safe.
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Introduction and Purpose
Summary of Case
–2.5 or
,25-dihydroxyvitamin D
[1,25(OH)2D]. The term vitamin D includes both vitamin
D3 (from sun; also found in supplements and food) and vitamin
D2 (commercially produced and used as a supplement). Although both
forms are converted into their respective forms of active vitamin D, recent
work suggests D3 is more potent than
D2.