Clinical Science (1992) 82, 681 -685 (Printed in Great Britain)

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Pernicious anaemia as a risk factor for osteoporosis Richard EASTELL*, Nancy E. VIEIRAt, Alfred L. YERGEYt, Heinz W. WAHNER4, Murray N. SILVERSTEIN$, Rajiv KUMAR" and B. Lawrence RIGGS* *Endocrine Research Unit, $Section of Diagnostic Nuclear Medicine, §Division of Hematology and Internal Medicine, "Nephrology Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A., and tSection of Metabolic Analysis and Mass Spectroscopy, National Institute of Child Health and Human Development, Bethesda, Maryland, U.S.A. (Received

I3 A u g u d 2 2 November I99 I ; accepted 20 January 1992)

1. If gastric acid is necessary for the absorption of dietary calcium, the total absence of gastric acid secretion that occurs in pernicious anaemia could result in bone loss. To investigate this, we measured calcium absorption and bone density in 21 postmenopausal women (ages 51-76 years) with pernicious anaemia and in 24 normal postmenopausal women (ages 51-79 years). 2. Relative to the normal women, in the women with pernicious anaemia the bone mineral density of the lumbar spine was decreased by 16%( P < 0.001). 3. After adjustment for age and body weight, lumbar spine bone mineral density correlated with the serum concentration of group 1 pepsinogens (a group of proteins produced by the gastric fundus) ( r = 0.61, P< 0.01). 4. Despite achlorhydria, the women with pernicious anaemia had normal true fractional calcium absorption and normal serum levels of parathyroid hormone and 1,25-dihydroxyvitaminD. 5. We conclude that gastric acid is not required for the absorption of dietary calcium. Thus, the loss of cancellous bone must be caused by some mechanism yet to be identified.

INTRODUCTION Achlorhydria is common in the elderly [ 1-31. Recker [4] reported that absorption of poorly soluble calcium salts is decreased in subjects with achlorhydria. Mahoney et al. [5]reported that achlorhydric rats fed poorly soluble calcium salts had decreased calcium absorption and decreased mineral content of bone. Thus, poor absorption of dietary calcium in patients with achlorhydria could result in bone loss. Pernicious anaemia is characterized by autoimmune damage to the gastric fundus, and this results in absolute achlorhydria and vitamin B,, deficiency. In the study described here, we used patients with pernicious anaemia

as a model system to determine if achlorhydria impairs the absorption of dietary calcium and decreases the bone mineral density (BMD).

METHODS Experimental subjects We studied 21 postmenopausal women with pernicious anaemia (Table 1).The diagnosis of pernicious anaemia had been made 1-41 years previously on the basis of histamine-fast achlorhydria (three cases), Schilling test (nine cases), both of these tests (five cases) or low serum B,, level alone (four cases). Patients with diseases known to cause osteoporosis were excluded; factors that may have accelerated bone loss included thyroxine replacement therapy in 11 patients (dosage 0.1-0.15 mg/day) and maturity-onset diabetes mellitus in one patient. Factors that may have retarded bone loss included use of a thiazide diuretic in one patient and oestrogen replacement therapy for 5-10 years in three patients. For comparison, we studied 24 normal postmenopausal women (Table 1).These women had responded to a request for volunteers and were not selected on the basis of dietary calcium intake. None had any detectable disease or was taking any drugs known to affect calcium metabolism. On thoracic and lumbar radiographs, none had vertebral fractures or moderate or severe hypertrophic changes of the spine [these make measurements of lumbar spine BMD (LS-BMD)unreliable]. All studies were approved by the Mayo Institutional Review Board, and signed informed consent forms were obtained from all of the women. All studies were carried out in the Mayo Clinical Research Center.

Study protocol LS-BMD (L-2 to L-4) was measured by dual-photon absorptiometry, and the reproducibility was 2.2% [6, 71.

Key words: bone density, osteocalcin, osteoporosis, pernicious anaemia. Abbreviations: BGP, bone y-carboxyglutamic acid protein; BMD. bone mineral density; LS-BMD, lumbar spine bone mineral density; 25(OH)D, 25-hydroxyvitamin D; I,25(OH),D, I,25-dihydroxyvitamin D; PTH, parathyroid hormone; TFCA, true fractional calcium absorption. Reprint requests: D r 6. L. Riggs, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, U.S.A. Correspondence: D r Richard Eastell, Department of Human Metabolism and Clinical Biochemistry, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, South Yorkshire, U.K.

R. Eastell et al.

682 Table I. Characteristics of patients with pernicious anaemia and of normal women. Values are meansfm. Age is also shown as a range.

Age (years) Time after menopause (years) Height (m) Weight (kg) Serum group I pepsinogen level (nglml) Time since diagnosis (years)

Patients with pernicious anaemia (n=21)

Normal women (n=24)

68f7 (51-76) 19+7 I .6 I 1.0.05 68.9 1.10.5 6.9f 7.8 14f12

65+9 (5 1-79) 151.9 I .631.0.06 70.0 1.10.0 91.5f33.l -

Anteroposterior and lateral radiographs of the lateral and thoracic spine were taken, and the anterior, middle and posterior heights of vertebrae T-4 to L-5 were measured with a transparent ruler. The criteria used to test for vertebral fracture were as described previously [8]. True fractional calcium absorption (TFCA) was measured as described previously [9]. This method measures the actual amount of calcium absorbed from the habitual diet. In brief, all subjects were admitted to the Clinical Research Center and were given a diet that provided their habitual intake of calcium. With each of the three meals of the day, highly enriched 44Ca was administered orally at the end of the meal and highly enriched 42Cawas given intravenously 15 min after the oral dose. The relative abundance of these stable isotopes of calcium in a 24 h urine collection was measured by thermal ionization m.s. [lo]. Blood was drawn from the fasting subjects at 07.30 hours, and the serum was separated and stored at - 70°C for biochemical analysis. Serum group 1 pepsinogen concentration was measured by radioimmunoassay (Nichols Institute, San Juan Capistrano, CA, U.S.A.).This test has a sensitivity of 91-100% for a specificity of 100% in the diagnosis of pernicious anaemia [l l-161. Serum 1,25-dihydroxyvitamin D [ 1,25(OH),D] concentration was measured in duplicate samples by the microassay method of Reinhardt et a/. [17]. This assay involves rapid extraction and preliminary purification on a silica Sep-Pak column with hexane/propan-2-01 followed by non-equilibrium assay with 1,25(OH),D receptor from calf thymus. Serum 25-hydroxyvitamin D [25(OH)D] concentration was measured by h.p.1.c. [ 181. Serum intact parathyroid hormone (PTH) concentration was measured in duplicate by an immunoradiometric assay (Allegro intact PTH immunoassay system; Nichols Institute Diagnostics, San Juan Capistrano, CA, U.S.A.). The intra-assay variation was

Pernicious anaemia as a risk factor for osteoporosis.

1. If gastric acid is necessary for the absorption of dietary calcium, the total absence of gastric acid secretion that occurs in pernicious anaemia c...
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