0021-972X/99/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 1999 by The Endocrine Society
Vol. 84, No. 8 Printed in U.S.A.
Resolution of Vitamin D Insufficiency in Osteopenic Patients Results in Rapid Recovery of Bone Mineral Density* JOHN S. ADAMS, VITALY KANTOROVICH, CINDY WU, MARJAN JAVANBAKHT, AND BRUCE W. HOLLIS Bone Center and Burns and Allen Research Institute, Cedars-Sinai Medical Center, University of California School of Medicine (J.S.A., V.K., C.W., M.J.), Los Angeles, California 90048; and the Department of Pediatrics, Medical University of South Carolina (B.W.H.), Charleston, South Carolina 29425 ABSTRACT Vitamin D insufficiency is characterized biochemically by the presence of secondary hyperparathyroidism, which can contribute to bone loss in osteopenic patients. Over a 2-yr period of evaluation of 118 consecutive, free living patients with osteopenia or osteoporosis, we identified 18 subjects with depressed serum 25-hydroxyvitamin D (25OHD; #14 ng/mL). Twelve of these subjects harbored a low 25OHD level and consented to undergo replacement with 50,000 IU vitamin D2 twice weekly for 5 weeks. Five hundred thousand units of oral vitamin D2 resulted in significant increases in 25OHD (124.3 6 16.9
C
ERTAIN metabolic disturbances can accelerate the rate of bone loss in patients with preexisting osteopenia or osteoporosis. The most common among these are primary hyperparathyroidism, hyperthyroidism, and idiopathic hypercalciuria (1– 4). We recently reported that vitamin D intoxication can be added to this list (5). Here we document that occult vitamin D insufficiency is another disorder associated with a prompt rebound in bone mineral density if effectively treated with short term (5 weeks), high dose, oral vitamin D. Subjects and Methods
Between January 1, 1995 and January 1, 1997, one of us (J.S.A.) measured indexes of vitamin D nutrition in 118 consecutive patients, 111 women and 7 men, referred to the Cedars-Sinai Bone Center for evaluation of low bone mineral density. The mean age of the group was 60 6 17 yr. All had blood drawn for measurement of serum calcium, 25hydroxyvitamin D (25OHD), immunoreactive PTH (iPTH), TSH, and osteocalcin. All provided a timed ($2 h), fasting urine sample for calcium and creatinine determinations. Serum 25OHD was determined by competitive protein binding assay (Endocrine Sciences, Inc., Woodland Hills, CA). Serum iPTH and TSH levels were determined in immunoradiometric assays (Nichols Institute Diagnostics, San Juan Capistrano, CA). Calcium, albumin, and creatinine were determined spectrophotometrically. The bone mineral densities of the lumbar spine and nondominant proximal femur were assessed by dual energy x-ray absorptiometry (Lunar Corp., Madison, WI); in all subjects, bone mineral density was greater than 21.50 sd. below peak bone mass at the hip, Received March 18, 1999. Revision received April 28, 1999. Accepted May 4, 1999. Address all correspondence and requests for reprints to: John S. Adams, M.D., B131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail:
[email protected]. * This work was supported in part by General Clinical Research Center Grant RR-00425 from the NIH.
ng/mL; P , 0.001) and the fasting urinary calcium/creatinine excretion ratio (10.06 6 0.004; P 5 0.01) and significant decreases in the serum concentration of PTH (232.9 6 36.9 pg/mL; P , 0.001) and osteocalcin (24.9 6 2.4 ng/mL; P , 0.001). Vitamin D repletion was associated with a significant 4 –5% annualized increase in bone mineral density at both the lumbar spine (P , 0.001) and the femoral neck (P 5 0.03), indicating that resolution of vitamin D insufficiency in a population of patients with low bone mass results in a rapid rebound increase in bone mineral density. (J Clin Endocrinol Metab 84: 2729 – 2730, 1999)
spine, or both, compatible with the diagnosis of osteopenia or osteoporosis (6). Eighteen patients, 16 women and 2 men (mean age, 60 6 18 yr), had a serum 25OHD level of 14 ng/mL (#35 nmol/L) or less. Two patients were hypercalcemic, with an elevated iPTH level compatible with the diagnosis of primary hyperparathyroidism. Four additional subjects had an abnormal TSH level in accord with hyperthyroidism (n 5 2) or hypothyroidism (n 5 2). Because these confounding endocrine disturbances may independently affect skeletal homeostasis, only 12 subjects with a low 25OHD level underwent a therapeutic course of oral vitamin D2 (50,000 IU, twice weekly) for 5 weeks. The diet of all patients was supplemented with 1000 mg elemental calcium in the form of calcium carbonate on a daily basis and was maintained for the duration of observation. Their serum levels of 25OHD and iPTH, urinary calcium/ creatinine ratio, and bone mineral density were measured a second time, at a mean of 10 months after completion of treatment. No other pharmacological intervention was made during this period. All data are expressed as the mean 6 sd. Statistical comparisons were made using Wilcoxon’s rank sum test.
Results and Discussion
Basal and posttreatment data for the 12 vitamin D2-supplemented patients are shown in Table 1. All had a basal 25OHD level of 14 ng/mL or less; this is the range of 25OHD previously shown to be associated with a pathophysiological change in calcium homeostasis (7, 8). Two patients with the highest basal 25OHD levels (14 ng/mL) were seen in July and August, the seasonal peak in ultraviolet B exposure (9). All 12 were normocalcemic (range, 8.7–9.7 mg/dL) despite having a low mean fasting urinary calcium excretion rate. Six had an elevated serum iPTH level (range, 69 –200 pg/mL) indicative of secondary hyperparathyroidism, whereas 5 of the remaining 6 subjects had an iPTH level in the upper quartile of the normal range (52– 65 pg/mL). Serum osteocalcin levels were normal in all subjects. There was a coordinate increase
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TABLE 1. Effects of 500,000 IU orally administered vitamin D2 on markers of vitamin D nutrition and bone mineral density in 12 vitamin D-depleted subjects
Basal state Mean 6 SD Range Normal PostRx change D 6 SD Range P value a b
25OHD (ng/mL)
Urinary ca/creat
iPTH (pg/mL)
Osteocalcin (ng/mL)
Lumbar spine DEXA (z-score)b
Femoral neck DEXA (z-score)b
9.9 6 3.0 6.7–14 15–55
0.05 6 0.03 0.02– 0.10 0.06 – 0.16
64.9 6 45.3 18 –200 10 – 65
12.0 6 5.5 3.8 –22 2.0 –22
21.65 6 0.82 23.51 to 20.55 .21.5
22.25 6 1.04 23.09 to 20.02 .21.5
24.3 6 16.9 6.5– 62.2 ,0.001
0.06 6 0.06 0.02– 0.15 0.01
232.9 6 36.9 21 to 2119 ,0.001
24.9 6 2.4 21.4 to 28.5 ,0.001
0.35 6 0.22 0.00 to 0.71 ,0.001
0.60 6 0.54 0.04 to 1.54 0.03
Multiply by 2.54 to convert to nanomoles per L. Basal bone mineral density was greater than 21.50
SD
below mean peak levels at the spine, femur, or both in all subjects.
in serum 25OHD (245%) and the urinary calcium/creatinine ratio (120%) after vitamin D treatment. The mean increase in serum 25OHD was 131.1 6 21.1 ng/mL (range, 16.5– 62.2). Although the return of the 25OHD level to normal was not associated with a significant change in the serum calcium concentration, there was a significant decrease in iPTH and osteocalcin levels as well as a significant increase in both spine and hip bone mineral densities (see Table 1). The increase in spine bone mineral density was independent of any loss in vertebral height. By comparison, a group (n 5 34) (5) matched for age (65 6 11 yr) and bone density with normal vitamin D balance (25OHD, 29 6 10 ng/mL; range, 16 – 45 ng/mL) and normal PTH status (iPTH, 38 6 19 pg/mL; range, 17– 62 pg/mL) treated solely with 1000 mg supplemental calcium showed no significant change (P . 0.6) in either spine or hip bone mineral on the same scanner over a similar time span (12 months). Occult vitamin D deficiency is a relatively common occurrence in nursing home residents. In their recent survey, Webb and colleagues (7) determined that 30% of nursing home residents in the Boston area had serum 25OHD levels below 15 ng/mL year-round. The vitamin D insufficiency rate of 16% in our free living, relatively young, osteopenic population in sunny Southern California was similar to that observed by Omdahl et al. (10) in the Southwestern United States residents that were more than 60 yr of age. Before being evaluated in our clinic, none of the 18 vitamin Ddepleted patients were previously known to have a low 25OHD level. Although vitamin D supplementation is recognized as an effective adjunct to sunlight exposure and is useful in prevention of vitamin D deficiency (11), little is known about the skeletal response to the reversal of the condition. Chapuy et al. (12) showed a 1.9% annualized increase in femoral neck density in French nursing home residents randomized to 800 IU vitamin D3 and calcium supplementation on a daily basis; however, in this study, patients with 25OHD levels of 35 nmol/L or 14 ng/mL or less were not identified and evaluated independently of vitamin-replete subjects in terms of bone mineral density. In the current study, all 12 vitamin D-depleted subjects experienced an increase in bone mineral density within months of initiating therapy. The mean increase in bone mineral density at the lumbar spine (4.1%) and femoral neck (4.9%) was 2- to 3-fold greater than the annualized increase in bone mineral density observed by Chapuy et al. (12) in subjects receiving roughly the same cumulative
dose of vitamin D (438,000 IU) over 78 weeks that our patients received (500,000 IU) in just 5 weeks. The increase in bone mineral density observed in our patients was most likely due to resolution or improvement of secondary hyperparathyroidism with a subsequent decrease in bone turnover (1) (Table 1). Although we have followed our treated subjects for only an average of 10 months after treatment, we predict that the gains in bone mineral density will follow the pattern of gains observed in patients successfully treated for primary hyperparathyroidism (1). In conclusion, we confirm earlier observations (10) that the presence of vitamin D insufficiency may be a common occurrence in osteopenic/osteoporotic patient populations even in sunlight-enriched, lower latitude environments and demonstrate that return to normal vitamin D balance can result in a prompt and substantial increase in bone mineral density. Acknowledgments The authors thank Dr. Glenn D. Braunstein for helpful advice, and Ms Cecelia Ramirez for help with patient data acquisition.
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