ORIGINAL CONTRIBUTION
Occult Vitamin D Deficiency in Postmenopausal US Women With Acute Hip Fracture Meryl S. LeBoff, MD Lynn Kohlmeier, MD Shelley Hurwitz, PhD Jennifer Franklin John Wright, MD
Context Low vitamin D levels may contribute to hip fractures in women, although limited data are available on vitamin D levels in US women admitted with acute hip fractures. Objective To determine whether postmenopausal women with hip fractures have low vitamin D and high parathyroid hormone levels compared with nonosteoporotic and osteoporotic women admitted for elective joint replacement.
Julie Glowacki, PhD
Design Comparative case series conducted between January 1995 and June 1998.
V
Setting and Patients Ninety-eight postmenopausal community-dwelling women with no secondary causes of bone loss admitted for hip replacement, of whom 30 women had acute hip fractures and 68 women were admitted for elective joint replacement. Of the women admitted for elective joint replacement, 17 had osteoporosis and 51 did not. Women with comorbid conditions or who were taking medications that affect bone density and turnover were excluded.
ITAMIN D IS REQUIRED FOR EF-
ficient absorption of dietary calcium and for normal mineralization of bone. Reduction in vitamin D levels is associated with impaired calcium absorption and a compensatory increase in the level of parathyroid hormone (PTH) which, in turn, stimulates bone resorption and bone loss. According to the recent National Health and Nutrition Examination Survey Study, an estimated 26 million to 38 million US adults have osteoporosis or are at risk for osteoporosis in the hip.1 Risk of hip fractures increases exponentially with age. Hip fractures are increasing worldwide, and are the most devastating and costly of the osteoporotic fractures.2 Advancing age is associated with reductions in sun exposure, intake and skinactivation of vitamin D, and in vitamin D absorption, all of which may contribute to low vitamin D levels.3 It is striking that in recent studies from England, Scotland, and South Africa, 13% to 33% of patients with hip fractures had histological signs of osteomalacia that may have been caused by prolonged vitamin D deficiency,4-7 although not all European studies con-
Main Outcome Measures Primary measures were levels of vitamin D and parathyroid hormone; secondary measures were body composition and markers of bone turnover. Results Women with hip fractures had lower levels of 25-hydroxyvitamin D than women without osteoporosis admitted for elective joint replacement (P = .02) and than women with osteoporosis admitted for elective joint replacement (P = .01) (medians, 32.4, 49.9, and 55.0 nmol/L, respectively; comparisons adjusted for age and estrogen intake). Parathyroid hormone levels were higher in women with fractures than women in the nonosteoporotic control group (P,.001) or than elective osteoporotic women (P = .001) (medians, 5.58, 3.26, and 3.79 pmol/L, respectively; comparisons adjusted for age and estrogen intake). Fifteen patients (50.0%) with hip fractures had deficient vitamin D levels (#30.0 nmol/L) and 11 (36.7%) had a parathyroid hormone level greater than 6.84 pmol/L. Levels of N-telopeptide, a marker of bone resorption, were greater in the women with hip fractures than in the elective nonosteoporotic controls (P = .004). Conclusions Postmenopausal community-living women who presented with hip fracture showed occult vitamin D deficiency. Repletion of vitamin D and suppression of parathyroid hormone at the time of fracture may reduce future fracture risk and facilitate hip fracture repair. Because vitamin D deficiency is preventable, heightened awareness is necessary to ensure adequate vitamin D nutrition, particularly in northern latitudes. JAMA. 1999;281:1505-1511 Author Affiliations: Endocrine Hypertension Division, Departments of Internal Medicine and Orthopedic Surgery, Brigham and Women’s Hospital, Boston, Mass. Dr Kohlmeier is now with the Internal Medicine/Endocrinology Department, Washington Medical Group, Fremont, Calif.
©1999 American Medical Association. All rights reserved.
www.jama.com Financial Disclosure is listed at the end of this article. Corresponding Author and Reprints: Meryl S. LeBoff, MD, Director of Skeletal Health and Osteoporosis Program, Endocrine-Hypertension Division, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115 (e-mail:
[email protected]). JAMA, April 28, 1999—Vol 281, No. 16
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OCCULT VITAMIN D DEFICIENCY
cur.8 In the United States in 1978, Sokoloff9 reported occult osteomalacia in 8 (25%) of 31 patients with hip fracture, and another study10 from an elderly residential facility and hospital found 4 (12.9%) of 31 patients with os-
teomalacia at the time of hip fracture. Limited data are available on vitamin D status in US patients admitted for acute osteoporotic fractures. We compared such subjects with patients scheduled for elective joint replacement
METHODS
Figure 1. Selection of Postmenopausal Women Undergoing Joint Replacement
Patient Recruitment
Postmenopausal Women (N = 805)
Acute Hip Fracture (n = 262)
Comorbid Medical Conditions (n = 190)
Elective Joint Replacement (n = 543)
Refused (n = 42)
Enrolled (n = 30)
Comorbid Medical Conditions (n = 101)
Refused (n = 374)
Osteoporotic (n = 30)
Enrolled (n = 68)
Osteoporotic (n = 17)
Not Osteoporotic (n = 51)
Women were not included in the study if they had comorbid medical conditions or were taking medications that could affect bone, declined study participation, or had underlying hip disease other than osteoarthritis. Comorbid medical conditions included renal insufficiency, creatinine level of 177 µmol/L (0.02 mg/dL) or more, malabsorption, gastrectomy, active liver disease, acute myocardial infarction, alcoholism, and anorexia nervosa.
Table 1. Patients Excluded According to Each Prespecified Exclusion Criterion No. (%) of Patients Screened (n = 389) Elective (n = 169) 17 (10.1) 6 (3.6)
Fracture (n = 220) 38 (17.3)† 0 (0)†
Rheumatic condition/underlying hip disease‡
26 (15.4)
16 (7.3)†
Dementia/unable to obtain consent Cancer within 5 y Comorbid condition§ Infection Premenopausal/perimenopausal Suppressed thyrotropin Men\ Fracture group, not osteoporotic Nursing home¶ Trauma Previously enrolled Fractured more than once Total
12 (7.1) 16 (9.5) 7 (4.1) 0 (0) 11 (6.5) 1 (0.6) 1 (0.6) 0 (0) 1 (0.6) 1 (0.6) 2 (1.2) 0 (0) 101
26 (11.8) 50 (22.7)† 13 (5.9) 31 (14.1) 2 (0.9)† 3 (1.4) 0 (0) 3 (1.4) 1 (0.5) 4 (1.8) 0 (0) 3 (1.4) 190
Exclusion Criterion Excluded medication* Morbid obesity
*Glucocorticoids, androgens, anabolic steroids, anticonvulsants, calcitonin, sodium fluoride, bisphosphonates, and pharmacological doses of vitamin D (.800 IU) were excluded because they could affect bone condition. †Elective vs fracture group, P,.04. ‡Rheumatic condition was defined as rheumatoid arthritis and ankylosing spondylitis. Underlying hip diseases other than osteoarthritis included avascular necrosis, psoriatic arthritis, and osteonecrosis. §Included renal insufficiency (creatinine $1.77 µmol/L [0.02 mg/dL]), malabsorption, gastrectomy, active liver disease, acute myocardial infarction, alcoholism, and anorexia nervosa. \Sex unknown prior to contact. ¶Ineligible because residing in nursing home.
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surgery to test the hypothesis that patients with acute hip fractures have lower vitamin D levels and higher PTH levels than do subjects without fracture with normal or even low bone mineral density.
A total of 805 postmenopausal women scheduled for joint replacement were identified by daily monitoring of orthopedic admissions between January 1995 and June 1998, including 262 women admitted to Brigham and Women’s Hospital with acute hip fracture and 543 women scheduled for elective joint replacement either at the Brigham and Women’s Hospital or the New England Baptist Hospital in Boston, Mass. Postmenopausal women who experienced either natural or surgical menopause with amenorrhea for 12 months were recruited for this study. Women receiving estrogen replacement therapy were included (46% of patients). Women were excluded if they were taking any other medications or had any disorders or abnormal admission test results that might affect bone, or had any underlying hip disease other than osteoarthritis (FIGURE 1 and TABLE 1). Of the 68 women admitted for elective joint replacement, 17 were determined to be osteoporotic (T score , − 2.5) according to the World Health Organization bone density criteria11 and were analyzed separately (elective osteoporotic group) from the 51 elective patients admitted who were not osteoporotic (elective control group). There were 30 osteoporotic women with hip fractures (fracture group). Research protocols were approved by the institutional review boards of the Brigham and Women’s Hospital and the New England Baptist Hospital. All patients or, if necessary, a designated family member or guardian, gave informed consent. Questionnaires
Using a modification of the Nurses’ Health Study questionnaire12 and dietary and detailed physical activity13
©1999 American Medical Association. All rights reserved.
OCCULT VITAMIN D DEFICIENCY
questionnaires, all participants provided information regarding lifestyle, reproductive factors, dietary calcium consumption, and physical activity (TABLE 2). Spine, Proximal Femur, Total Body Bone Density, and Body Composition
Bone mineral density of the spine (L1L4), proximal femur, and total body were measured with the dual x-ray absorptiometry technique (QDR2000, Hologic Inc, Waltham, Mass). In vivo precisions (coefficient of variation percentage) in postmenopausal women for the spine, femoral neck, and trochanteric bone density measurements on different days were 1.21%, 1.74%, and 1.24%, respectively.14 Women with vertebrae with moderately severe osteoarthritic changes, disk space narrowing, or a fracture were excluded from the analyses as these anatomic findings may elevate the spinal bone mineral density. Results were expressed as SDs and compared with bone mineral density
values for age-matched healthy individuals (z score). Body composition (lean and fat mass) was determined by dual x-ray absorptiometry technique. The ratio of fat-to-lean tissue was calculated. Reproducibility of mean (SEM) for fat and lean tissue determinations in our laboratory were 1.09% (0.15%) and 0.89% (0.28%), respectively. Blood Chemistries and Assays
Blood chemistries, complete blood cell counts, and tests for urinary calcium levels were performed in hospital clinical laboratories; all remaining tests were performed in the General Clinical Research Center laboratory unless otherwise specified. Blood samples were obtained preoperatively in 88% of the patients. In some instances, elective or hip fracture patients were rushed to surgery and informed consent and blood samples were obtained postoperatively. Serum intact PTH levels were measured with the sensitive Allegro immunoradiometric assay (Corning Nichols Institute, San Juan Capistrano,
Calif). Serum 25-hydroxyvitamin D levels were measured using a radioimmunoassay (RIA) procedure (Incstar Corp, Stillwater, Minn) approved by the Food and Drug Administration. Levels of 1,25-dihydroxyvitamin D were measured by RIA. Urinary N-telopeptide levels, an index of bone resorption, were determined in a 24-hour urine collection by an enzyme-linked immunosorbent assay that measures cross-linked collagen peptides (Osteomark Assay, Ostex International Inc, Seattle, Wash). Bone formation markers including serum levels of osteocalcin by RIA15 and bone-specific alkaline phosphatase (BSAP) were measured by immunoradiometric assay (Tandem-R Ostase assay, provided by Hybritech, San Diego, Calif) by Dr Gundberg of Yale University School of Medicine, New Haven, Conn. The BSAP levels were measured by immunoassay (Alphase B assay, provided, in part, by Metra Biosystems, San Diego, Calif). The interassay and intraassay coefficients of variation for all the assays ranged from 2.3% to 12.1%.
Table 2. Characteristics of Enrolled Women Admitted for Elective Surgery and Acute Hip Fracture
Variable Age, y Years since menopause Bone density z score† Spine (L1-L4) Femoral neck
Elective Elective Fracture Control Osteoporotic Osteoporotic T$−2.5 T,−2.5 T,−2.5 (n = 51) (n = 17) (n = 30) Age, Bone, and Body Characteristics* 64.37 (8.10) 69.94 (10.42) 77.93 (9.17) 15.77 (9.01) 23.00 (11.27) 28.0 (10.69)
P Value Elective Control vs Fracture
Elective Osteoporotic vs Fracture
,.001 ,.001
.08 .35 .72 .19
1.33 (1.09) 1.16 (1.10)
−0.33 (1.04) −0.32 (0.80)
−0.21 (0.72) −0.90 (0.73)
,.001 ,.001
Trochanter
0.96 (1.13)
−0.55 (0.74)
−0.75 (1.00)
,.001
.97
Total body Body composition Fat g %
1.19 (1.13)
−0.87 (0.78)
0.31 (1.21)
.02
.004
35.28 (10.04) 46.70 (6.28)
26.73 (8.59) 42.44 (9.23)
20.99 (10.25) 32.05 (10.60)
,.001 ,.001
.15 .002
37.74 (4.02)
33.52 (4.33)
37.52 (6.08)
.98
.02
0.95 (0.23)
0.81 (0.27)
0.56 (0.27)
,.001
.01
.75 .87 .76 .05
.13 .81 .03 .08
Lean, g Fat-lean ratio Total calcium intake, mg/d§ Alcohol, drinks per week Smoking, pack-years Physical activity, metabolic hours per week\
873 (280-1797) 1 (0-14) 8 (0-60) 16.4 (0-67.0)
Intake and Activity‡ 700 (145-2364) 1 (0-10) 0 (0-82) 20.2 (0-99.3)
794 (179-1899) 0 (0-16) 8 (0-48) 1.5 (0-19.4)
*Values measured as mean (SD) and are adjusted for estrogen intake. †Bone mineral density equals SD compared with age-matched controls. ‡Values measured as median (percentile [5th and 95th]) and adjusted for age and estrogen intake. §Includes dietary and supplemental calcium. Among the elective nonosteoporotic control, elective osteoporotic, and fracture patients, 49%, 41%, and 37%, respectively, were taking a multivitamin. \Metabolic hours included past and present sports, and job-related and domestic-related physical activities.
©1999 American Medical Association. All rights reserved.
JAMA, April 28, 1999—Vol 281, No. 16
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OCCULT VITAMIN D DEFICIENCY Statistical Analyses
Patient characteristics and markers of bone turnover were summarized as means and SDs. Analysis of variance was performed with prespecified contrasts comparing the fracture group with each of the elective groups, and having estrogen replacement therapy as a covariate. Normality tests were rejected for several calciotropic hormones, biochemical values, and baseline characteristics; therefore, medians and 5th and 95th percentiles were presented. The natural log transformed normalized intact PTH, 25hydroxyvitamin D, N-telopeptides, BSAP (Metra Biosystems), BSAP (Hybritech), and creatinine. Analysis of variance was used for phosphate, 1,25-dihydroxyvitamin D, urinary calcium, transformed intact PTH, 25-hydroxyvitamin D, Ntelopeptides, BSAP (Metra Biosystems), BSAP (Hybritech), and creatinine, with Figure 2. Women With Abnormal Parathyroid Hormone, 25-Hydroxyvitamin D, and Urinary Calcium Levels Fracture Group (n = 30) Elective Osteoporotic Group (n = 17) Elective Control Group (n = 51) 90
∗ 80 70
Women, %
60
∗
50 40
∗
30 20 10 0
Parathyroid 25-Hydroxyvitamin D Urinary Hormone ≤30 nmol/L Calcium >6.84 pmol/L (≤12 ng/mL)
