JOURNAL OF BONE AND MINERAL RESEARCH Volume 7, Number 5, 1992 Mary Ann Liebert, Inc., Publishers
Risk of Fractures in Patients with Pernicious Anemia JEAN B. GOERSS,' CHUNG H. KIM,' ELIZABETH J. ATKINSON,' RICHARD EASTELL,3 W. MICHAEL O'FALLON,' and L. JOSEPH MELTON 111'
ABSTRACT
In a series of postmenopausal women previously studied by our group, pernicious anemia was associated with reduced bone mineral density of the spine and with vertebral fractures. To determine whether osteoporotic fractures represent an important clinical problem for such patients, we conducted a population-based retrospective cohort study of all Rochester, Minnesota residents newly diagnosed with pernicious anemia from 1950 through 1979. These 131 individuals were followed through the inpatient and outpatient records of all medical care providers in the community for 1550 person-years. In comparison with fracture rates from the general community, patients with pernicious anemia had a 1.9-fold increase in proximal femur fractures, a l.&fold increase in vertebral fractures, and a 2.9-fold increase in distal forearm fractures (all p < 0.05). Increases in the risk of proximal humerus and pelvis fractures were not statistically significant. Clinicians should be aware that pernicious anemia is associated with an increased risk of osteoporotic fractures, but the mechanism is unknown.
INTRODUCTION from our group,") 21 postmenopausal women (ages 51-76 years) with pernicious anemia diagnosed from 1 to 41 years earlier had bone mineral density values of the lumbar spine that were 16% less than those of a comparable group of 24 normal postmenopausal women. A third of the women with pernicious anemia had one or more vertebral fractures at the time of evaluation. To determine whether the risk of osteoporotic fractures is an important practical problem in such individuals, we conducted this population-based retrospective cohort study in a larger group of pernicious anemia patients from the local community.
I
N A RECENT STUDY
METHODS AND MATERIALS Rochester, Minnesota is well suited for such studies of disease associations because comprehensive medical records for the residents are available for review and because these records are accessible through a centralized index of
diagnoses made by essentially all medical care providers used by the local population.(2)This medical records linkage system permitted retrieval of all diagnoses of pernicious anemia made among community residents as a result of inpatient or outpatient care. The system also incorporates diagnoses made on death certificates and at autopsy. Using this unique data base (the Rochester Epidemiology Project), we identified all patients who were Rochester residents when first diagnosed with pernicious anemia in the 30 year period from 1950 through 1979. Diagnoses were made regularly throughout the interval. After excluding cases of postoperative vitamin BL2deficiency (gastrectomy or terminal ileectomy), we found 131 residents who met our criteria for probable pernicious anemia. Because much of the time period under study predates the more specific tests for pernicious anemia now available, diagnostic criteria were devised for categories compatible with, suggestive of, and highly suggestive of the diagnosis of pernicious anemia (Table 1). Subjects were categorized as compatible (n = 35) who had one objective sign of achlorhydria or laboratory evidence of B,, defi-
'Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota. 'Division of Gastroenterology, Mayo Clinic and Foundation, Rochester, Minnesota. 3Division of Endocrinology/Metabolic Disease, Mayo Clinic and Foundation, Rochester, Minnesota
573
GOERSS ET AL.
574
TABLE1. DIAGNOSTIC CRITERIA FOR PERNICIOUS ANEMIAAMONGROCHESTER, MINNESOTA RESIDENTS, 1950-1979a ~~
___
A Parietal cell destruction
B Intrinsic factor or BIZdeficiency
Achlorhydria
B,, below normal range for age and gender Positive Schilling test
c Clinical sign of B,, deficiency
Classic peripheral neuropathy Classic hematologic abnormalities (with normal folate) Macroc ytosis Megaloblastic anemia Positive bone marrow
acompatible with pernicious anemia: meets A or one of B or one of C. Suggestive of pernicious anemia: Meets A and one of B or one of C. Highly suggestive of pernicious anemia: meets A and one of B and one of C.
ciency or clinical evidence of B,, deficiency or malabsorption (including megaloblastic anemia, macrocytosis on peripheral smear, or bone marrow compatible with B12deficiency). The diagnosis was suggestive ( n = 5 8 ) with achlorhydria and a low B,, level or a positive Schilling test or one clinical sign of BIZdeficiency. The diagnosis was considered highly suggestive ( n = 29) with achlorhydria and a low B,, level or positive Schilling test and one clinical sign of BIZdeficiency. The Schilling test was considered positive if any improvement in BIZabsorption was noted following the addition of intrinsic factor. Of 67 who had the test 15 demonstrated improved, but not completely normal, absorption of B,, with intrinsic factor. One woman on chemotherapy was exempted from the treatment response requirement and was included in the study. No subject in this study was tested for intrinsic factor or parietal cell antibodies. Patients were excluded if hydrochloric acid was demonstrated in the stomach, if the B12 1evel.wasnormal, if a Schilling test was negative, or if there was no objective response to adequate treatment with parenteral BI2therapy. These patients were then followed forward in time through their linked medical records in the commnity (retrospective cohort study) until death or the most recent clinical contact. For each subject, the complete inpatient and outpatient medical record at each local provider of health care was searched for the occurrence of any fracture at several specified skeletal sites (proximal femur, vertebrae, distal forearm, proximal humerus, and pelvis) that have been associated with osteoporosis. (3) Mayo Clinic records, for example, contain the details of every inpatient hospitalization at its two large affiliated hospitals (St. Mary's and Rochester Methodist), every outpatient or office visit at the clinic, the emergency rooms, nursing homes, or private homes, as well as radiographic reports and pathology reports, including autopsies. Fractures were recorded whether they occurred before or after the index date (the date of diagnosis of pernicious anemia), but only those that followed the index date were considered in the analysis of fracture risk. The records contained the clinical history and the radiologist's report of each fracture, but the original roentgenograms were not available for review. The diagnosis of vertebral fracture was accepted on the
basis of a radiologist's report of compression, wedging, or collapse of one or more thoracic or lumbar vertebral bodies. Fracture ascertainment is believed to be complete except for vertebral fractures, some of which are never diagnosed. The influence of pernicious anemia on fracture incidence was evaluated using three basic methods of analysis. First, the number of new fractures observed at selected skeletal sites after the diagnosis of pernicious anemia was compared to expected numbers derived by multiplying ageand sex-specific incidence rates from the general population of Rochester for those fractures by the age- and sexspecific person-years of follow-up in the cohort, that is, standardized morbidity ratios (SMRs). Incidence rates from the general population of Rochester were available for proximal femur,") distal forearm,(5) proximal humerus,(6)pelvis,(') and vertebral fractures.") In these analyses, patients with a history of a given fracture before the index date were deleted from the analysis for that particular site. When there was more than one subsequent fracture at a given skeletal site, only the first was counted for each patient. The 95% confidence intervals for the SMRs were calculated by assuming that the expected rates are fixed and the observed fractures follow a Poisson distributi~n.'~) In the second method of analysis, the cumulative incidence of new fractures (1 minus survival free of fracture) was projected for up to 20 years following the index date using product-limit life table methods. ( l o ) Observed and expected cumulative incidence curves were compared using the logarithmic rank test statistic. Life table methods were also used to estimate survival in this cohort. Finally, the proportional hazards model("' was used to determine the relative influence of various clinical characteristics (such as the certainty of diagnosis or the presence of neurologic deficits) on subsequent fracture risk among those with pernicious anemia. The dependent variable was time until the first new fracture, and the independent variables were the clinical characteristics. The incidence of pernicious anemia was calculated by assuming that all Rochester residents were at risk. The denominator age- and sex-specific person-years were derived from decennial census figures.(1z)These rates were then di-
575
PERNICIOUS ANEMIA AND FRACTURES rectly age and sex adjusted to the U.S. white population in 1980. The 95% confidence intervals (95% CI) for the ad1.96 justed rates were calculated as the adjusted rate times its standard error.
*
RESULTS Altogether, 131 Rochester, Minnesota residents met one
of the described criteria for a new diagnosis of pernicious anemia during the study period. There were twice as many women (82, 63%) as men (49, 37%), but age-adjusted incidence rates were identical for the two genders (12.2 per 100,OOO person-years). The mean age at diagnosis for all patients combined was 68.7 years (range 26-93, median 72), and they were followed subsequently for 1550 personyears, or an average of 11.8 years per patient (median 11.7 years). Survival was not particularly impaired in this cohort. By 10 years following the diagnosis of pernicious anemia, 63% of the patients were still alive compared to an expected 57% among people of like age and sex; at 20 years, the figures were 23 and 26%, respectively (p = 0.35). As of the index date, 10 patients (4 men and 6 women) had already had a proximal femur fracture. Among the 121 who had not had a hip fracture, the crude incidence of subsequent proximal femur fractures was 10.4 per lo00 person-years in men, 18.4 per lo00 person-years in women, and 15.4 per lo00 person-years overall. The cumulative incidence of new proximal femur fractures over time is shown in Fig. 1. The 20 hip fractures observed were significantly more than the 10.4 cases expected (SMR 1.9; 95% CI, 1.2-3.0). Although the hip fracture incidence was lower in men than women, the SMR associated with pernicious anemia was somewhat greater in men (Table 2). Be-
Proximal Femur
35
cause of the limited number of subjects, the increased fracture risk among men was not statistically significant. The SMR for women and for both sexes combined was statistically significantly greater than the expected figure of I .O. Although not included in this analysis, two of these women went on to have one and two additional hip fractures, respectively, each of them fracturing both hips at least once. A total of 15 subjects (3 men and 12 women) had had a prior distal forearm fracture. Among the I16 subjects free of a history of forearm fracture at baseline, the incidence of new distal forearm fractures was 4.4 per lo00 personyears in men, 14.4 per lo00 person-years in women, and 10.7 per lo00 person-years overall. The 13 new distal forearm fractures observed were almost three times the number expected (p < 0.05), as shown in Table 2. The excess of forearm fractures was present soon after diagnosis and remained relatively constant throughout 20 years of followup (Fig. 1). Although not considered in this analysis of incidence fractures, one man and three women each had an additional Colles’ fracture, all on the opposite side from the first Colles’ fracture. A total of 17 subjects had a prior vertebral fracture (7 men and 10 women). In the remainder, the incidence of new vertebral fractures was 4.6 per lo00 person-years in men, 15.5 per lo00 person-years in women, and 11.7 per lo00 person-years overall. The risk of a vertebral fracture seemed to increase with the passage of time (Fig. 1). Overall, the 15 incident vertebral fractures observed were nearly twice the number expected (SMR 1.8, 95% CI 1.0-2.9). However, neither of the elevated gender-specific SMRs was statistically significant (Table 2) given the small numbers involved. Of the 7 men 3 went on to have one, three, and seven additional vertebral fractures, respectively, and
I
Distal Forearm
8 pi
Vertebra
/ ! /
Observed
0 C Q)
-0 .0 .-C Q) > .c
-cp
i
3
Expected
0
10
20
10
20
10
20
Years following diagnosis FIG. 1. Observed and expected cumulative incidence of selected fractures among Rochester, Minnesota residents newly diagnosed with pernicious anemia, 1950-1979.
5 2 2 1 0
OBS
~~
2.03 0.42 1.46 0.32 0.32
EXP 2.5 4.8 1.4 3.2 0
SMRa 0.8-5.8 0.6-17.1 0.2-1.0 0.1-17.6 0-1 1.6
95Vo CI
astandardized morbidity ratio (see Materials and Methods).
Proximal femur Distal forearm Vertebra Proximal humerus Pelvis
Site
Men
15 11 13 6 4
OBS 8.35 4.12 7.00 2.87 2.12
EXP 1.8 2.7 1.9 2.1 1.9
SMRa
Women
1.0-3.0 1.3-4.8 1.0-3.2 0.8-4.6 0.5-4.8
95% CI 20 13 15 7 4
OBS
10.38 4.54 8.40 3.18 2.44
EXP
1.9 2.9 1.8 2.2 1.6
SMRa
Both sexes
1.2-3.0 1.5-4.9 1.0-2.9 0.9-4.5 0.4-4.2
95Vo CI
TABLE2. OBSERVED (OBS) AND EXPECTED (EXP) RISKOF SUBSEQUENT FRACTURES IN THOSE FREEOF EACHSPECIFIC FRACTURE ON THE INDEX MINNESOTA RESIDENTS NEWLYDIAGNOSED WITH PERNICIOUS ANEMIA,1950-1979 DATEAMONG133 ROCHESTER,
PERNICIOUS ANEMIA AND FRACTURES 3 women had two, three, and four vertebral fractures diagnosed after the first. A total of seven patients (three men and four women) had a history of proximal humerus fracture at the time of diagnosis of pernicious anemia. The incidence of subsequent proximal humerus fractures in those without such a history before the index date was 2.1 per lo00 person-years in men, 6.8 per lo00 person-years in women, and 5.2 per lo00 person-years overall. The seven proximal humerus fractures observed were twice the 3.2 cases expected, but the elevated SMRs were not statistically significant (Table 2). One woman had a prior pelvic fracture. Among the rest, four women experienced a new pelvic fracture for a crude incidence rate of 4.2 per lo00 person-years. The four fractures were greater than the number expected, but the increased SMRs were not statistically significant (Table 2). A variety of baseline variables was assessed to determine their influence on the risk of subsequent fractures in this cohort. With the small number of cases involved, no variables predicted time to the first new proximal humerus or pelvis fracture. Greater age predicted time to first proximal femur (p < 0.001), distal forearm (p < 0.05), and vertebral (p = 0.005) fracture and time to any fracture (p < 0.001). The presence of megaloblastic anemia (110 of 131) or macrocytosis (1 18 of 127 patients who were tested for this) did not influence time to first fracture, nor did glossitis at diagnosis, an indication of higher turnover of gastrointestinal epithelium (41 of 86 patients for whom this was recorded). Neurologic evidence of subacute combined degeneration (36 of 100 patients in whom this was specifically evaluated), symptoms of which could lead to more falls, also did not predict time to first fracture. There was no difference in time to first fracture by certainty of diagnosis (findings compatible, suggestive, or highly suggestive of pernicious anemia). However, statistical power was limited by the size of the cohort and the relatively small number of fractures.
DISCUSSION Pernicious anemia has attracted much attention with regard to its potential predisposition to gastric cancer and other malignancies, ( l 3 - I 5 ) although not all studies support these a s s ~ c i a t i o n s . ( ~ More ~ . ~ ’ ~recently, Eastell et al. suggested that pernicious anemia might also be a cause of osteoporosis when 21 postmenopausal women with pernicious anemia were found to have reduced bone mineral density in the lumbar spine compared to 24 normal postmenopausal women. (’) Because reduced bone mineral density is associated with fracture risk,(3)such losses may also lead to excess fractures, but this has never been evaluated in a population-based study. We identified all Rochester, Minnesota residents who fulfilled criteria for a new diagnosis of pernicious anemia from 1950 through 1979 and reviewed their medical records to detect subsequent age-related fractures. O n the basis of age- and sex-specific person-years of observation in the cohort combined with ageand sex-specific incidence rates of fractures for the local
577
population, we determined that the number of fractures was greater than might have been expected by chance alone. Indeed, all the age-related fractures that we assessed seemed to be increased, although some differences were not statistically significant because of the small numbers involved. We had between 3 and 22% power (a = 0.05) to detect a doubling of fracture risk in men with pernicious anemia and 25-70% power to detect a twofold excess of fractures at each site among women. Using the entire cohort, we had 22-76% power to detect a doubling of risk. Naturally, power was best for assessing the more numerous fractures of the proximal femur, distal forearm, and vertebra. The increased fracture risk could have been a result of decreased bone density or an increased risk of falling.(3)In this study, 68% of the fractures were due to falls. Falling might be common in pernicious anemia complicated by subacute combined degeneration of the cord or by peripheral neuropathy. Such neurologic factors as this did not appear to influence the risk of fracture in our study, but the number of affected patients was small. The distribution of causes of the fractures did not appear to be unusual, but we could not directly assess the risk of falling in these subjects. Bone density is also an important determinant of fracture risk at the skeletal sites assessed here. (18-zo) Only spinal bone loss was assessed in our clinical study,(’) but the fracture data reported here suggest that bone loss is widespread in these patients. The mechanism of this bone loss has not been determined, but possibilities fall into five general categories: (1) gastrointestinal changes that alter the intake or absorption of key nutrients involved in bone metabolism, (2) deficiency of BIZper se, (3) other gastrointestinal changes secondary to pernicious anemia or achlorhydria, (4) the autoimmune phenomenon alone, and (5) underlying osteoporosis unrelated to pernicious anemia. There are few data on the dietary habits and preferences of patients with pernicious anemia. A comparison of 9 achlorhydric patients with 7 controls revealed no significant differences in daily calcium intake (831 versus 792 mg/day) by analysis of 7 day diet diaries,Iz1) but 75% of Eastell’s subjects ingested less than 600 mg calcium per day and the mean diet calcium of 638 mg/day was significantly less than in normal controls (809 mg/day). Calcium absorption and transport increase adaptively in response to low-calcium diets under normal circumstances,(z2)and calcium absorption was unimpaired in the 21 patients studied by Eastell et al.,(I) 1 patient studied by Bo-Linn et al.,(*3) and 11 patients studied by Reeker."" Thus, gastric acid is not necessary for the absorption of dietary calcium. Likewise, there is no evidence of vitamin D deficiency, as serum 25-hydroxyvitamin D levels were significantly higher than in normal controls among Eastell’s subjects. ( I ) Carmel et al.Iz4) reported decreased serum levels of bone-specific proteins (osteocalcin and bone isoenzyme of alkaline phosphatase) as a result of vitamin BIZdeficiency. The serum levels of these proteins returned to normal with vitamin BIZtherapy, but irreversible bone loss could have occurred during the period of vitamin BIZdeficiency. Since the liver stores several years’ supply of vitamin BIZ, the
578
GOERSS ET AL.
autoimmune process and achlorhydria likely precede the and surgical conditions that produce secondary osteoporo*~ anemia appears to be one of the latter diagnosis of pernicious anemia by several years at least. In s ~ s . ' ~Pernicious fact, many of the subjects in this study were found to be conditions that, in aggregate, may be present in up to 20% achlorhydric decades before they had symptoms of vitamin of women and 40% of men with vertebral or hip fracBIZdeficiency. (The subjects excluded because of surgically tures.'39) Relative freedom from ascertainment bias and comparainduced BIZmalabsorption were diagnosed as BIZdeficient an average of 15 years after their surgery, range 7-35 bility to the general population from which the data are years.) Thus, we have no way to estimate the timing of the drawn are strengths of our population-based study. Deactual onset of disease in the individuals in this cohort, spite a relatively small sample size, we have demonstrated and it is likely that we hae underestimated associated frac- significant increases in proximal femur, distal forearm, tures by analyzing only those that occurred following the and vertebral fracture incidence among patients with perclinical diagnosis of pernicious anemia. With current nicious anemia. Our data also suggest that quite a few paawareness and earlier detection of pernicious anemia, frac- tients nationally could be affected by this problem. The inture risk may be less in a more contemporary cohort of pa- cidence of pernicious anemia in Rochester was 12.3 per tients if BIZ deficiency alone were the cause of the 100,000 person-years (directly age and sex adjusted to the population structure of 1980 U.S. whites; 95% CI, 10.2problem. There are many secondary changes in gastrointestinal se- 14.4). If extrapolated to the total U.S. population, these cretions in response to achlorhydria. The gastric mucosa rates suggest that over 30,000 new cases of pernicious (as defined here) might be diagnosed annually in ) produces other proteins, such as group 1 p e p s i n o g e n ~ ' ~ ~anemia and gastrocalcin.~z6) Eastell et al. ( I ) reported that lumbar this country. The number of prevalent cases would be subspine bone mineral density was inversely related to serum stantially higher since the lifetime risk of pernicious group I pepsinogens. This would be consistent with a anemia in the general population is lo%, as estimated bone-stimulating factor produced by the gastric mucosa. from the incidence rates and survival to age 75 years. As a practical matter, our study emphasizes the need for Schulak and K a p l a ~ ~reported ' ~ ~ ' that gastrin had a hypocalcemic effect in rats and that the effect could be pre- early recognition of vitamin BIZdeficiency resulting from vented by fundectomy. They proposed that gastrin stimu- surgery or pernicious anemia. Patients who demonstrate lates the gastric fundus to produce a hypocalcemic factor macrocytosis on routine complete blood count should be since the hypocalcemia was not associated with an increase further tested with BIZand folate levels and antibody titer in calcitonin. Persson et a1.Iz6)reported that gastrin in- to intrinsic factor and Schilling test when appropriate. Percreased 45Cauptake by bone and induced hypocalcemia in nicious anemia may also be considered a risk factor for rats. This effect was abolished by gastrectomy. They iso- osteoporosis, although additional studies are needed to lated a leucine endopeptidase-sensitive factor (gastrocalcin) identify the pathogenetic mechanisms involved and to rule from the acid-producing gastric mucosa that may mediate out any confounding effects of other risk factors. Bone this effect. Gastric atrophy may effectively eliminate this density should be assessed in the evaluation of such paintermediary peptide, thus eliminating a mechanism by tients, and if low, interventions should be considered to which calcium uptake by bone may be enhanced. If this is conserve bone mass and reduce the risk of falling. No trials the mechanism by which osteopenia occurs, gastrectomy have been conducted, however, to determine the optimal patients may also be at increased risk for osteoporosis and management of bone loss in patients with pernicious anemia. fractures. Other organ-specific autoimmune disorders are also associated with osteopenia.'28-34) For example, patients with ACKNOWLEDGMENTS pernicious anemia commonly develop hypothyroidism (another autoimmune disease) and require thyroxine reThe authors thank Mr. James D. Kuiper for help in data placement therapy. Excessive doses of thyroxine may be a analysis and Mrs. Mary Roberts for assistance in preparing risk factor for o ~ t e o p o r o s i s However, . ~ ~ ~ ~ ~Eastell ~ ~ et al. ( ' I the manuscript. This project was supported in part by reported no extra effect of thyroxine on bone mineral den- Grant Nos. AG-04875 and AR-30582 from the National sity even though 11 of their 21 patients were taking thyrox- Institutes of Health, U.S. Public Health Service. ine replacement therapy. We were unable to evaluate the influence of this potential confounding factor. 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579 24. Carmel R, Lau K-HW, Baylink DJ, Saxena S, Singer FR 1988 Cobalamin and osteoblast-specific proteins. N Engl J Med 319:70-75. 25. Waldum HL, Burhol PG 1981 Serum group I pepsinogens. Scand J Gastroenterol 16:449-45 1. 26. Persson P, Hakanson R, Axelson J , Sundler F 1989 Gastrin releases a blood calcium-lowering peptide from the acid-producing part of the rat stomach. Proc Natl Acad Sci USA 86: 2834-2838. 27. Schulak JA, Kaplan EL 1975 The importance of the stomach in gastrin-induced hypocalcemia in the rat. Endocrinology 96~1217-1220. 28. Ross DS, Neer RM, Ridgway EC, Daniels GH 1987 Subclinical hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-thyroxine. Am J Med 82:1167-1170. 29. Paul TL, Kerrigan J, Kelly AM, Braverman LE, Baran DT 1988 Long-term L-thyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA 259~3137-3141. 30. KrBlner B, Jbrgensen JV, Nielsen SP 1983 Spinal bone mineral content in myxoedema and thyrotoxicosis: Effects of thyroid hormone(s) and antithyroid treatment. Clin Endocrino1 (Oxf) 18:439-446. 31. Devogelaer JP, Crabbt J, Nagant de Deuxchaisnes C 1987 Bone mineral density in Addison’s disease: Evidence for an effect of adrenal androgens on bone mass. Br Med J 294: 798-800. 32. Hui SL, Epstein S, Johnston CC Jr. 1985 A prospective study of bone mass in patients with type I diabetes. J Clin Endocrinol Metab 60:74-80. 33. Eastell R, Hodgson SF, Dickson ER, Wiesner RH, Wahner HW. O’Fallon WM, Riggs BL 1988 Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis (abstract). Clin Res 36:395A. 34. Comite F, Delman M, Hutchinson-Williams K, DeCherney AH, Jensen P 1989 Reduced bone mass in reproductive-aged women with endometriosis. J Clin Endocrinol Metab 692337842. 35. Fallon MD, Perry HM 111, Bergfeld M, Droke D, Teitelbaum SL, Avioli LV 1983 Exogenous hyperthyroidism with osteoporosis. Arch intern Med 143:442-444. 36. Coindre J-M, David J-P, Rivikre L, Goussot J-F, Roger P, de Mascrel A, Meunier PJ 1986 Bone loss in hypothyroidism with hormone replacement: A histomorphometric study. Arch Intern Med 146:48-53. 37. Hui SL, Slemenda CW, Johnston CC Jr 1990 The contribution of bone loss to postmenopausal osteoporosis. Osteoporosis Int 1:30-34. 38. Riggs BL, Melton LJ 1986 Medical progress: Involutional osteoporosis. N Engl J Med 314:1676-1686. 39. Melton LJ Ill, Riggs BL 1988 Clinical spectrum. In: Riggs BL, Melton LJ Ill, eds. Osteoporosis: Etiology, Diagnosis, and Management. Raven Press, New York, pp. 155-179.
Address reprint requests to: Dr. L. J. Melton Mayo Clinic 200 First Street S. W . Rochester, MN 55905 Received for publication August 27, 1991; in revised form December 5 , 1991; accepted December 6, 1991.
Risk of Fractures in Patients with Pernicious Anemia JEAN B. GOERSS,' CHUNG H. KIM,' ELIZABETH J. ATKINSON,' RICHARD EASTELL,3 W. MICHAEL O'FALLON,' and L. JOSEPH MELTON 111'
ABSTRACT
In a series of postmenopausal women previously studied by our group, pernicious anemia was associated with reduced bone mineral density of the spine and with vertebral fractures. To determine whether osteoporotic fractures represent an important clinical problem for such patients, we conducted a population-based retrospective cohort study of all Rochester, Minnesota residents newly diagnosed with pernicious anemia from 1950 through 1979. These 131 individuals were followed through the inpatient and outpatient records of all medical care providers in the community for 1550 person-years. In comparison with fracture rates from the general community, patients with pernicious anemia had a 1.9-fold increase in proximal femur fractures, a l.&fold increase in vertebral fractures, and a 2.9-fold increase in distal forearm fractures (all p < 0.05). Increases in the risk of proximal humerus and pelvis fractures were not statistically significant. Clinicians should be aware that pernicious anemia is associated with an increased risk of osteoporotic fractures, but the mechanism is unknown.
INTRODUCTION from our group,") 21 postmenopausal women (ages 51-76 years) with pernicious anemia diagnosed from 1 to 41 years earlier had bone mineral density values of the lumbar spine that were 16% less than those of a comparable group of 24 normal postmenopausal women. A third of the women with pernicious anemia had one or more vertebral fractures at the time of evaluation. To determine whether the risk of osteoporotic fractures is an important practical problem in such individuals, we conducted this population-based retrospective cohort study in a larger group of pernicious anemia patients from the local community.
I
N A RECENT STUDY
METHODS AND MATERIALS Rochester, Minnesota is well suited for such studies of disease associations because comprehensive medical records for the residents are available for review and because these records are accessible through a centralized index of
diagnoses made by essentially all medical care providers used by the local population.(2)This medical records linkage system permitted retrieval of all diagnoses of pernicious anemia made among community residents as a result of inpatient or outpatient care. The system also incorporates diagnoses made on death certificates and at autopsy. Using this unique data base (the Rochester Epidemiology Project), we identified all patients who were Rochester residents when first diagnosed with pernicious anemia in the 30 year period from 1950 through 1979. Diagnoses were made regularly throughout the interval. After excluding cases of postoperative vitamin BL2deficiency (gastrectomy or terminal ileectomy), we found 131 residents who met our criteria for probable pernicious anemia. Because much of the time period under study predates the more specific tests for pernicious anemia now available, diagnostic criteria were devised for categories compatible with, suggestive of, and highly suggestive of the diagnosis of pernicious anemia (Table 1). Subjects were categorized as compatible (n = 35) who had one objective sign of achlorhydria or laboratory evidence of B,, defi-
'Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota. 'Division of Gastroenterology, Mayo Clinic and Foundation, Rochester, Minnesota. 3Division of Endocrinology/Metabolic Disease, Mayo Clinic and Foundation, Rochester, Minnesota
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GOERSS ET AL.
574
TABLE1. DIAGNOSTIC CRITERIA FOR PERNICIOUS ANEMIAAMONGROCHESTER, MINNESOTA RESIDENTS, 1950-1979a ~~
___
A Parietal cell destruction
B Intrinsic factor or BIZdeficiency
Achlorhydria
B,, below normal range for age and gender Positive Schilling test
c Clinical sign of B,, deficiency
Classic peripheral neuropathy Classic hematologic abnormalities (with normal folate) Macroc ytosis Megaloblastic anemia Positive bone marrow
acompatible with pernicious anemia: meets A or one of B or one of C. Suggestive of pernicious anemia: Meets A and one of B or one of C. Highly suggestive of pernicious anemia: meets A and one of B and one of C.
ciency or clinical evidence of B,, deficiency or malabsorption (including megaloblastic anemia, macrocytosis on peripheral smear, or bone marrow compatible with B12deficiency). The diagnosis was suggestive ( n = 5 8 ) with achlorhydria and a low B,, level or a positive Schilling test or one clinical sign of BIZdeficiency. The diagnosis was considered highly suggestive ( n = 29) with achlorhydria and a low B,, level or positive Schilling test and one clinical sign of BIZdeficiency. The Schilling test was considered positive if any improvement in BIZabsorption was noted following the addition of intrinsic factor. Of 67 who had the test 15 demonstrated improved, but not completely normal, absorption of B,, with intrinsic factor. One woman on chemotherapy was exempted from the treatment response requirement and was included in the study. No subject in this study was tested for intrinsic factor or parietal cell antibodies. Patients were excluded if hydrochloric acid was demonstrated in the stomach, if the B12 1evel.wasnormal, if a Schilling test was negative, or if there was no objective response to adequate treatment with parenteral BI2therapy. These patients were then followed forward in time through their linked medical records in the commnity (retrospective cohort study) until death or the most recent clinical contact. For each subject, the complete inpatient and outpatient medical record at each local provider of health care was searched for the occurrence of any fracture at several specified skeletal sites (proximal femur, vertebrae, distal forearm, proximal humerus, and pelvis) that have been associated with osteoporosis. (3) Mayo Clinic records, for example, contain the details of every inpatient hospitalization at its two large affiliated hospitals (St. Mary's and Rochester Methodist), every outpatient or office visit at the clinic, the emergency rooms, nursing homes, or private homes, as well as radiographic reports and pathology reports, including autopsies. Fractures were recorded whether they occurred before or after the index date (the date of diagnosis of pernicious anemia), but only those that followed the index date were considered in the analysis of fracture risk. The records contained the clinical history and the radiologist's report of each fracture, but the original roentgenograms were not available for review. The diagnosis of vertebral fracture was accepted on the
basis of a radiologist's report of compression, wedging, or collapse of one or more thoracic or lumbar vertebral bodies. Fracture ascertainment is believed to be complete except for vertebral fractures, some of which are never diagnosed. The influence of pernicious anemia on fracture incidence was evaluated using three basic methods of analysis. First, the number of new fractures observed at selected skeletal sites after the diagnosis of pernicious anemia was compared to expected numbers derived by multiplying ageand sex-specific incidence rates from the general population of Rochester for those fractures by the age- and sexspecific person-years of follow-up in the cohort, that is, standardized morbidity ratios (SMRs). Incidence rates from the general population of Rochester were available for proximal femur,") distal forearm,(5) proximal humerus,(6)pelvis,(') and vertebral fractures.") In these analyses, patients with a history of a given fracture before the index date were deleted from the analysis for that particular site. When there was more than one subsequent fracture at a given skeletal site, only the first was counted for each patient. The 95% confidence intervals for the SMRs were calculated by assuming that the expected rates are fixed and the observed fractures follow a Poisson distributi~n.'~) In the second method of analysis, the cumulative incidence of new fractures (1 minus survival free of fracture) was projected for up to 20 years following the index date using product-limit life table methods. ( l o ) Observed and expected cumulative incidence curves were compared using the logarithmic rank test statistic. Life table methods were also used to estimate survival in this cohort. Finally, the proportional hazards model("' was used to determine the relative influence of various clinical characteristics (such as the certainty of diagnosis or the presence of neurologic deficits) on subsequent fracture risk among those with pernicious anemia. The dependent variable was time until the first new fracture, and the independent variables were the clinical characteristics. The incidence of pernicious anemia was calculated by assuming that all Rochester residents were at risk. The denominator age- and sex-specific person-years were derived from decennial census figures.(1z)These rates were then di-
575
PERNICIOUS ANEMIA AND FRACTURES rectly age and sex adjusted to the U.S. white population in 1980. The 95% confidence intervals (95% CI) for the ad1.96 justed rates were calculated as the adjusted rate times its standard error.
*
RESULTS Altogether, 131 Rochester, Minnesota residents met one
of the described criteria for a new diagnosis of pernicious anemia during the study period. There were twice as many women (82, 63%) as men (49, 37%), but age-adjusted incidence rates were identical for the two genders (12.2 per 100,OOO person-years). The mean age at diagnosis for all patients combined was 68.7 years (range 26-93, median 72), and they were followed subsequently for 1550 personyears, or an average of 11.8 years per patient (median 11.7 years). Survival was not particularly impaired in this cohort. By 10 years following the diagnosis of pernicious anemia, 63% of the patients were still alive compared to an expected 57% among people of like age and sex; at 20 years, the figures were 23 and 26%, respectively (p = 0.35). As of the index date, 10 patients (4 men and 6 women) had already had a proximal femur fracture. Among the 121 who had not had a hip fracture, the crude incidence of subsequent proximal femur fractures was 10.4 per lo00 person-years in men, 18.4 per lo00 person-years in women, and 15.4 per lo00 person-years overall. The cumulative incidence of new proximal femur fractures over time is shown in Fig. 1. The 20 hip fractures observed were significantly more than the 10.4 cases expected (SMR 1.9; 95% CI, 1.2-3.0). Although the hip fracture incidence was lower in men than women, the SMR associated with pernicious anemia was somewhat greater in men (Table 2). Be-
Proximal Femur
35
cause of the limited number of subjects, the increased fracture risk among men was not statistically significant. The SMR for women and for both sexes combined was statistically significantly greater than the expected figure of I .O. Although not included in this analysis, two of these women went on to have one and two additional hip fractures, respectively, each of them fracturing both hips at least once. A total of 15 subjects (3 men and 12 women) had had a prior distal forearm fracture. Among the I16 subjects free of a history of forearm fracture at baseline, the incidence of new distal forearm fractures was 4.4 per lo00 personyears in men, 14.4 per lo00 person-years in women, and 10.7 per lo00 person-years overall. The 13 new distal forearm fractures observed were almost three times the number expected (p < 0.05), as shown in Table 2. The excess of forearm fractures was present soon after diagnosis and remained relatively constant throughout 20 years of followup (Fig. 1). Although not considered in this analysis of incidence fractures, one man and three women each had an additional Colles’ fracture, all on the opposite side from the first Colles’ fracture. A total of 17 subjects had a prior vertebral fracture (7 men and 10 women). In the remainder, the incidence of new vertebral fractures was 4.6 per lo00 person-years in men, 15.5 per lo00 person-years in women, and 11.7 per lo00 person-years overall. The risk of a vertebral fracture seemed to increase with the passage of time (Fig. 1). Overall, the 15 incident vertebral fractures observed were nearly twice the number expected (SMR 1.8, 95% CI 1.0-2.9). However, neither of the elevated gender-specific SMRs was statistically significant (Table 2) given the small numbers involved. Of the 7 men 3 went on to have one, three, and seven additional vertebral fractures, respectively, and
I
Distal Forearm
8 pi
Vertebra
/ ! /
Observed
0 C Q)
-0 .0 .-C Q) > .c
-cp
i
3
Expected
0
10
20
10
20
10
20
Years following diagnosis FIG. 1. Observed and expected cumulative incidence of selected fractures among Rochester, Minnesota residents newly diagnosed with pernicious anemia, 1950-1979.
5 2 2 1 0
OBS
~~
2.03 0.42 1.46 0.32 0.32
EXP 2.5 4.8 1.4 3.2 0
SMRa 0.8-5.8 0.6-17.1 0.2-1.0 0.1-17.6 0-1 1.6
95Vo CI
astandardized morbidity ratio (see Materials and Methods).
Proximal femur Distal forearm Vertebra Proximal humerus Pelvis
Site
Men
15 11 13 6 4
OBS 8.35 4.12 7.00 2.87 2.12
EXP 1.8 2.7 1.9 2.1 1.9
SMRa
Women
1.0-3.0 1.3-4.8 1.0-3.2 0.8-4.6 0.5-4.8
95% CI 20 13 15 7 4
OBS
10.38 4.54 8.40 3.18 2.44
EXP
1.9 2.9 1.8 2.2 1.6
SMRa
Both sexes
1.2-3.0 1.5-4.9 1.0-2.9 0.9-4.5 0.4-4.2
95Vo CI
TABLE2. OBSERVED (OBS) AND EXPECTED (EXP) RISKOF SUBSEQUENT FRACTURES IN THOSE FREEOF EACHSPECIFIC FRACTURE ON THE INDEX MINNESOTA RESIDENTS NEWLYDIAGNOSED WITH PERNICIOUS ANEMIA,1950-1979 DATEAMONG133 ROCHESTER,
PERNICIOUS ANEMIA AND FRACTURES 3 women had two, three, and four vertebral fractures diagnosed after the first. A total of seven patients (three men and four women) had a history of proximal humerus fracture at the time of diagnosis of pernicious anemia. The incidence of subsequent proximal humerus fractures in those without such a history before the index date was 2.1 per lo00 person-years in men, 6.8 per lo00 person-years in women, and 5.2 per lo00 person-years overall. The seven proximal humerus fractures observed were twice the 3.2 cases expected, but the elevated SMRs were not statistically significant (Table 2). One woman had a prior pelvic fracture. Among the rest, four women experienced a new pelvic fracture for a crude incidence rate of 4.2 per lo00 person-years. The four fractures were greater than the number expected, but the increased SMRs were not statistically significant (Table 2). A variety of baseline variables was assessed to determine their influence on the risk of subsequent fractures in this cohort. With the small number of cases involved, no variables predicted time to the first new proximal humerus or pelvis fracture. Greater age predicted time to first proximal femur (p < 0.001), distal forearm (p < 0.05), and vertebral (p = 0.005) fracture and time to any fracture (p < 0.001). The presence of megaloblastic anemia (110 of 131) or macrocytosis (1 18 of 127 patients who were tested for this) did not influence time to first fracture, nor did glossitis at diagnosis, an indication of higher turnover of gastrointestinal epithelium (41 of 86 patients for whom this was recorded). Neurologic evidence of subacute combined degeneration (36 of 100 patients in whom this was specifically evaluated), symptoms of which could lead to more falls, also did not predict time to first fracture. There was no difference in time to first fracture by certainty of diagnosis (findings compatible, suggestive, or highly suggestive of pernicious anemia). However, statistical power was limited by the size of the cohort and the relatively small number of fractures.
DISCUSSION Pernicious anemia has attracted much attention with regard to its potential predisposition to gastric cancer and other malignancies, ( l 3 - I 5 ) although not all studies support these a s s ~ c i a t i o n s . ( ~ More ~ . ~ ’ ~recently, Eastell et al. suggested that pernicious anemia might also be a cause of osteoporosis when 21 postmenopausal women with pernicious anemia were found to have reduced bone mineral density in the lumbar spine compared to 24 normal postmenopausal women. (’) Because reduced bone mineral density is associated with fracture risk,(3)such losses may also lead to excess fractures, but this has never been evaluated in a population-based study. We identified all Rochester, Minnesota residents who fulfilled criteria for a new diagnosis of pernicious anemia from 1950 through 1979 and reviewed their medical records to detect subsequent age-related fractures. O n the basis of age- and sex-specific person-years of observation in the cohort combined with ageand sex-specific incidence rates of fractures for the local
577
population, we determined that the number of fractures was greater than might have been expected by chance alone. Indeed, all the age-related fractures that we assessed seemed to be increased, although some differences were not statistically significant because of the small numbers involved. We had between 3 and 22% power (a = 0.05) to detect a doubling of fracture risk in men with pernicious anemia and 25-70% power to detect a twofold excess of fractures at each site among women. Using the entire cohort, we had 22-76% power to detect a doubling of risk. Naturally, power was best for assessing the more numerous fractures of the proximal femur, distal forearm, and vertebra. The increased fracture risk could have been a result of decreased bone density or an increased risk of falling.(3)In this study, 68% of the fractures were due to falls. Falling might be common in pernicious anemia complicated by subacute combined degeneration of the cord or by peripheral neuropathy. Such neurologic factors as this did not appear to influence the risk of fracture in our study, but the number of affected patients was small. The distribution of causes of the fractures did not appear to be unusual, but we could not directly assess the risk of falling in these subjects. Bone density is also an important determinant of fracture risk at the skeletal sites assessed here. (18-zo) Only spinal bone loss was assessed in our clinical study,(’) but the fracture data reported here suggest that bone loss is widespread in these patients. The mechanism of this bone loss has not been determined, but possibilities fall into five general categories: (1) gastrointestinal changes that alter the intake or absorption of key nutrients involved in bone metabolism, (2) deficiency of BIZper se, (3) other gastrointestinal changes secondary to pernicious anemia or achlorhydria, (4) the autoimmune phenomenon alone, and (5) underlying osteoporosis unrelated to pernicious anemia. There are few data on the dietary habits and preferences of patients with pernicious anemia. A comparison of 9 achlorhydric patients with 7 controls revealed no significant differences in daily calcium intake (831 versus 792 mg/day) by analysis of 7 day diet diaries,Iz1) but 75% of Eastell’s subjects ingested less than 600 mg calcium per day and the mean diet calcium of 638 mg/day was significantly less than in normal controls (809 mg/day). Calcium absorption and transport increase adaptively in response to low-calcium diets under normal circumstances,(z2)and calcium absorption was unimpaired in the 21 patients studied by Eastell et al.,(I) 1 patient studied by Bo-Linn et al.,(*3) and 11 patients studied by Reeker."" Thus, gastric acid is not necessary for the absorption of dietary calcium. Likewise, there is no evidence of vitamin D deficiency, as serum 25-hydroxyvitamin D levels were significantly higher than in normal controls among Eastell’s subjects. ( I ) Carmel et al.Iz4) reported decreased serum levels of bone-specific proteins (osteocalcin and bone isoenzyme of alkaline phosphatase) as a result of vitamin BIZdeficiency. The serum levels of these proteins returned to normal with vitamin BIZtherapy, but irreversible bone loss could have occurred during the period of vitamin BIZdeficiency. Since the liver stores several years’ supply of vitamin BIZ, the
578
GOERSS ET AL.
autoimmune process and achlorhydria likely precede the and surgical conditions that produce secondary osteoporo*~ anemia appears to be one of the latter diagnosis of pernicious anemia by several years at least. In s ~ s . ' ~Pernicious fact, many of the subjects in this study were found to be conditions that, in aggregate, may be present in up to 20% achlorhydric decades before they had symptoms of vitamin of women and 40% of men with vertebral or hip fracBIZdeficiency. (The subjects excluded because of surgically tures.'39) Relative freedom from ascertainment bias and comparainduced BIZmalabsorption were diagnosed as BIZdeficient an average of 15 years after their surgery, range 7-35 bility to the general population from which the data are years.) Thus, we have no way to estimate the timing of the drawn are strengths of our population-based study. Deactual onset of disease in the individuals in this cohort, spite a relatively small sample size, we have demonstrated and it is likely that we hae underestimated associated frac- significant increases in proximal femur, distal forearm, tures by analyzing only those that occurred following the and vertebral fracture incidence among patients with perclinical diagnosis of pernicious anemia. With current nicious anemia. Our data also suggest that quite a few paawareness and earlier detection of pernicious anemia, frac- tients nationally could be affected by this problem. The inture risk may be less in a more contemporary cohort of pa- cidence of pernicious anemia in Rochester was 12.3 per tients if BIZ deficiency alone were the cause of the 100,000 person-years (directly age and sex adjusted to the population structure of 1980 U.S. whites; 95% CI, 10.2problem. There are many secondary changes in gastrointestinal se- 14.4). If extrapolated to the total U.S. population, these cretions in response to achlorhydria. The gastric mucosa rates suggest that over 30,000 new cases of pernicious (as defined here) might be diagnosed annually in ) produces other proteins, such as group 1 p e p s i n o g e n ~ ' ~ ~anemia and gastrocalcin.~z6) Eastell et al. ( I ) reported that lumbar this country. The number of prevalent cases would be subspine bone mineral density was inversely related to serum stantially higher since the lifetime risk of pernicious group I pepsinogens. This would be consistent with a anemia in the general population is lo%, as estimated bone-stimulating factor produced by the gastric mucosa. from the incidence rates and survival to age 75 years. As a practical matter, our study emphasizes the need for Schulak and K a p l a ~ ~reported ' ~ ~ ' that gastrin had a hypocalcemic effect in rats and that the effect could be pre- early recognition of vitamin BIZdeficiency resulting from vented by fundectomy. They proposed that gastrin stimu- surgery or pernicious anemia. Patients who demonstrate lates the gastric fundus to produce a hypocalcemic factor macrocytosis on routine complete blood count should be since the hypocalcemia was not associated with an increase further tested with BIZand folate levels and antibody titer in calcitonin. Persson et a1.Iz6)reported that gastrin in- to intrinsic factor and Schilling test when appropriate. Percreased 45Cauptake by bone and induced hypocalcemia in nicious anemia may also be considered a risk factor for rats. This effect was abolished by gastrectomy. They iso- osteoporosis, although additional studies are needed to lated a leucine endopeptidase-sensitive factor (gastrocalcin) identify the pathogenetic mechanisms involved and to rule from the acid-producing gastric mucosa that may mediate out any confounding effects of other risk factors. Bone this effect. Gastric atrophy may effectively eliminate this density should be assessed in the evaluation of such paintermediary peptide, thus eliminating a mechanism by tients, and if low, interventions should be considered to which calcium uptake by bone may be enhanced. If this is conserve bone mass and reduce the risk of falling. No trials the mechanism by which osteopenia occurs, gastrectomy have been conducted, however, to determine the optimal patients may also be at increased risk for osteoporosis and management of bone loss in patients with pernicious anemia. fractures. Other organ-specific autoimmune disorders are also associated with osteopenia.'28-34) For example, patients with ACKNOWLEDGMENTS pernicious anemia commonly develop hypothyroidism (another autoimmune disease) and require thyroxine reThe authors thank Mr. James D. Kuiper for help in data placement therapy. Excessive doses of thyroxine may be a analysis and Mrs. Mary Roberts for assistance in preparing risk factor for o ~ t e o p o r o s i s However, . ~ ~ ~ ~ ~Eastell ~ ~ et al. ( ' I the manuscript. This project was supported in part by reported no extra effect of thyroxine on bone mineral den- Grant Nos. AG-04875 and AR-30582 from the National sity even though 11 of their 21 patients were taking thyrox- Institutes of Health, U.S. Public Health Service. ine replacement therapy. We were unable to evaluate the influence of this potential confounding factor. 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Address reprint requests to: Dr. L. J. Melton Mayo Clinic 200 First Street S. W . Rochester, MN 55905 Received for publication August 27, 1991; in revised form December 5 , 1991; accepted December 6, 1991.
