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Editorial |
Section of Endocrinology and Metabolism, Bone Program, University of Chicago Pritzker School of Medicine
Address all correspondence and requests for reprints to: Dr. Murray J. Favus, University of Chicago Medical Center, Department of Medicine, 5841 South Maryland Street, Room S504, MC 5100, Chicago, Illinois 60637. E-mail: mfavus{at}medicine.bsd.uchicago.edu.
Each year large numbers of postmenopausal women are diagnosed with osteoporosis and begin treatment to prevent fragility fractures. Most women are diagnosed by the discovery of low bone density detected by dual energy x-ray absorptiometry. Although most patients with low bone density do indeed have osteoporosis, the diagnostic specificity is limited because several other disorders may also cause low bone density and fragility fractures through a variety of mechanisms independent of age and estrogen deficiency. Each of the so-called "secondary causes" of osteoporosis including primary hyperparathyroidism, vitamin D deficiency, idiopathic hypercalciuria, secondary hyperparathyroidism of renal insufficiency, malabsorption syndromes, hyperthyroidism, and Cushing’s syndrome, can be distinguished from postmenopausal osteoporosis by selected laboratory testing. Optimal treatment of the low bone density requires that the secondary causes be distinguished from postmenopausal osteoporosis. For example, treating all subjects with the same dose of calcium supplements without adequate laboratory evaluation risks a worsening of hypercalcemia in patients with primary hyperparathyroidism and increasing already elevated urine calcium excretion in patients with idiopathic hypercalciuria.
Of the secondary causes of low bone density, vitamin D deficiency may be the most common. In Europe, vitamin D deficiency in elderly subjects with or without osteoporosis has been documented by a series of publications over the past 40 yr (summarized by Lips, Ref. 1). In the United States, the practice of supplementation of milk with vitamin D and the use of multivitamin tablets has lessened concern for vitamin D deficiency. However, recent reports have documented widespread vitamin D deficiency in several segments of the U.S. population, including postmenopausal Caucasian women with osteoporosis (2), unselected hospitalized patients (3), African-American men and women (4), African-American and Caucasian women of reproductive age (5), and even medical housestaff (6).
Vitamin D deficiency can be diagnosed by the level of serum 25-OH-vitamin D (25-OHD), the major metabolite of vitamin D in blood. Currently, physicians can select from one of several commercially available 25-OHD assays. The recent concern regarding the accuracy and reproducibility of 25-OHD assays (7) has been addressed in a recent editorial by Hollis (8) and a report by Holick et al. (9). The level of serum 25-OHD taken as diagnostic of vitamin D deficiency has varied over the years. Initially, serum 25-OHD levels below 10 ng/ml were accepted as diagnostic of vitamin D deficiency because many patients with such low levels had biochemical and histological evidence of osteomalacia. Among the early biochemical changes of vitamin D insufficiency is the rise in serum PTH. Because PTH levels begin to rise as serum 25-OHD levels fall below 30 ng/ml, this level of 25-OHD has become the suggested cutoff for diagnosis of vitamin D deficiency or inadequacy. In this issue of The Journal of Clinical Endocrinology and Metabolism (10), Holick et al. report inadequate serum 25-OHD levels in 52% of 1536 postmenopausal women under treatment for osteoporosis. Their cutoff of 25-OHD at 30 ng/ml was based upon their own data in which serum PTH levels began to rise as serum 25-OHD levels declined below 30 ng/ml (see Fig. 4 in Ref. 10). Vitamin D inadequacy, defined as serum 25-OHD levels of less than 30 ng/ml, is also used by others who found that the rise in PTH levels begins at 25-OHD levels of about 30 ng/ml (11) and that 25-OHD levels above 30 ng/ml maximize intestinal calcium absorption (12).
Multiple risk factors have been identified that contribute to low serum 25-OHD and vitamin D insufficiency, including the age-related decline in skin vitamin D3 synthesis, inadequate sun exposure, insufficient intake of fortified foods or vitamin D supplements, body mass index, race, exercise, physician counseling, use of medications that accelerate vitamin D metabolism, diseases that alter vitamin D metabolism, malabsorption syndromes, and chronic liver diseases. Thus, review of risk factors may suggest the level of risk for vitamin D deficiency and the need for measuring serum 25-OHD.
The consequences of missing the diagnosis of vitamin D deficiency in osteoporotic patients are considerable, as low 25-OHD levels contribute to the pathogenesis of bone fragility and fracture. An editorial by Heaney (13) emphasized the high rates of vitamin D deficiency and the importance of measuring serum 25-OHD to detect vitamin D deficiency in patients with osteoporosis. The results of the report by Holick et al. (10) clearly demonstrate that Heaney’s warnings have yet to change clinical practice.
In Europe, bone histological studies have documented vitamin D deficiency-induced osteomalacia as an important contributor to hip fractures (1, 14). Similar studies conducted in the United States were published as early as 1978 (15). Yet, these reports have not prompted physicians to measure 25-OHD levels routinely in patients with low bone mass. Most patients with vitamin D deficiency do not have biochemical evidence of osteomalacia; however, lesser degrees of vitamin D deficiency, as occurs with 25-OHD levels between 20 and 30 ng/ml, may contribute to hip fractures in postmenopausal women (16) through a secondary rise in PTH secretion.
In addition to vitamin D insufficiency, elderly osteoporotic patients may also have elevated PTH levels due to declining renal function. Serum PTH levels increase as creatinine clearance falls below 60 ml/min. In older adults, serum creatinine levels overestimate creatinine clearance, as the age-related loss of muscle mass lowers serum creatinine. The Cockroft-Gault equation is widely used to estimate creatinine clearance from serum creatinine, age, and body weight and does not require a measure of 24-h urine creatinine excretion (17). An accurate estimate of creatinine clearance is important for at least two reasons: bisphosphonate administration to patients with creatinine clearance below 35 ml/min might result in excessive drug accumulation in bone; and the secondary hyperparathyroidism of reduced renal function increases bone resorption and contributes to low bone density. Secondary hyperparathyroidism due to vitamin D insufficiency resolves with adequate vitamin D repletion. A persistent elevation of PTH levels despite adequate vitamin D repletion strongly suggests reduced renal function. The study by Holick et al. (10) did not measure renal function, and, therefore, we cannot estimate the number of their subjects who had elevated PTH due to renal insufficiency.
Available oral vitamin D preparations are effective in preventing vitamin D insufficiency with a considerable margin of safety. A guideline for adequate vitamin D intake is also available. The current recommendations of the Food and Nutrition Board of the Institute of Medicine are age-adjusted: 200 IU daily for those men and women between 19 and 50 yr of age; 400 IU daily for those age 51–70 yr old; and 600 IU daily for those age 71 yr and older (18). If vitamin D preparations are safe and dosing guidelines are available, then widespread vitamin D deficiency persists because either: 1) a minority of people are ingesting the recommended level of vitamin D; or 2) the recommended levels are inadequate to provide sufficient vitamin D. Clearly, additional studies are urgently required to resolve these possibilities.
Adequate vitamin D intake is an integral part of the management of patients with low bone density, and measuring serum 25-OHD should be a part of the laboratory evaluation. If the physicians who contributed to the study by Holick et al. (10) were not preventing vitamin D insufficiency in their patients with osteoporosis, it is fair to assume that there is a failure of physicians nationally to take seriously the problem of vitamin D deficiency. The underappreciation of vitamin D deficiency may also serve as a marker of a larger problem of inadequate laboratory evaluation of patients with low bone density. The frequency of secondary disorders of low bone density is sufficient to justify laboratory evaluation of all patients with low bone density (19). A minimum evaluation should include fasting serum calcium, creatinine, and 25-OHD, calculated or direct measure of creatinine clearance, and 24-h urine calcium excretion. PTH should be measured when serum calcium is either high or low or when creatinine clearance is reduced. Additional laboratory testing can depend upon clinical impressions. It is no longer acceptable to initiate antiresorptive therapy before an adequate laboratory evaluation has been completed. Endocrinologists and others who manage postmenopausal osteoporosis might be resistant to laboratory testing in older adults, but optimal, safe, and specific therapy can only be achieved when calcium, vitamin D, parathyroid, and renal status are known.
Footnotes
Abbreviation: 25-OHD, 25-OH-Vitamin D.
Received April 11, 2005.
Accepted April 27, 2005.
References
This article has been cited by other articles:
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  P. F. Lata and M. E. Elliott Patient Assessment in the Diagnosis, Prevention, and Treatment of Osteoporosis Nutr Clin Pract, June 1, 2007; 22(3): 261 - 275. [Abstract] [Full Text] [PDF]
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