thalassemia minor: a risk factor for osteoporosis?

BonsondMincrol. 16(1992)63-72 El&Ci

63

BAM CWU

Thalassemia minor: a risk factor for osteoporosis?

Homozygous beta-thalassemia major is a severe bemolytic disorder. Affected individuals are chronically ill, require frequent blood transfusions, and rarely survive beyond the second decade of life. The corulition is associated with a variety of ske- letal abnormalities, including osteopenia [l-4]. The mechanism of the osteopenia has been ascribed to an expansion of the marrow cavity with secondary thinning of the adjacent bone [2,5]. Heterozygoos patients with beta-thalassemia trait have a mild, asymptomatic hemolytic anemia and a normal lifespan. In one study, some asymptomatic first degree relatives of patients with thalassemia major were found to have mild osteoporosis of tbe skull and long bones [3]. However, thalassemia mi-

Correspondence 10: NC Greep, North Orqe County Community Ctinjc, Jo0 W. Romneys Drive.

Anaheim, CA, 92801 USA.

nor has not been identified as a definite risk factor for osteoporosis. We encoun- tered a 53 year old woman with thalassemia minor who had significant spinal osteoporosis manifested by a bone mineral density more than three standard deviations below the mean and several vertebral compression. fractures. Her degree of

bone thinning seemed out of proportion to her apparent risk factors for osteoporosis. We wondered whether her thalassemia trait might have contributed to her osteoporosis risk and studied the bone density in a consecutive series of eleven asymptomatic individuals with thslassemia minor. The report which follows is a descrip don of our index case, including bone histomorphometry, and the densitometric

studies in our follow-up series of eleven individuals with thalassemia trait.

Methods and Materials

The index case underwent double tetracycline labeled biopsy of the iliac crest and

histomorphometric analysis of undecalcified sections [6].

Additional subjects with thalassemia minor were sought for study at The Univer-

sity of California, Irvine and Creighton University. Participants were recruited by

word of mouth and by a letter sent to faculty members. Subjects were excluded

prior to the study if they had known major risk factors for secondary osteoporosis. The diagnosis of thalassemia minor was established by a combination of family hii- tory, characreristic peripheral blood smear, and hemoglobin electrophoresis. The experimental protocol was approved by local institutional review boards on experi- mentation with human subjects.

After signing informed consent, all subjects underwent dual photon densitometry of the spine and hip. The instrument used at The University of California, Irvine was a NOVO BMC-LAB 22 scanner (Nova Diagnostic Systems, Denmark). Re- sults for the eight subjects studied at Irvine were compared to normal ranges established at the Mayo Clinic [7,8] and built into the scanxr’s software. The validity of this normal range for our local population was verified by a pilot study on normal volunteers. For the three other subjects studied at Creighton University, spine and hip density were measured on the same instrument (DP4 model, Lunar Radiation, Madison, WI) that was used to study the index case and observed values compared to those for concurrent normal local controls. Results for all subjects are reported as hydroxyapatite cm-’ and as a standard deviation from age- and sex-matched controls (z-score).

To test whether the mean z-score for bone density of the thalassemia minor cohort was significantly less than normal, a one-tailed Student’s r-test was applied [9].

Index case The patient is a 53 year old Caucasian woman with hereditary thalassemia minor who underwent a natural menopause at age SO. Her past medical history was unre-

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markable except for an uncomplicated cholecystenomy at age 42. She had taken estrogen replacement fo? nine months but had discontinued it because she wasfear- ful of developing cancer. Tbtee years later, she developed back pain after carrying heavy boxes and consulted a rheumatologist who diagnosed osteoporosis and p1ace.d her on daily 1,25-di-hydroxyvitamin D, (0.25 pg) and 600 mg of elemental calcium as C&O,. Two months later she was referred to one of as (KG) at Creigh- ton University for evaluation of osteoporosis. She had never smoked, seldom drank alcohol, and consumed moderate amounts of carbooaied beverages. I-Iowever, her dietary calcium intake estimated from a 7 day diary was low at 296 mg/day. She was a housewife and did not exercise. Spine x-rays showed wedge frachues of T-7, T- 10, and T-12.

Physical examination was unremarkable. Her weight was 55.4 kg and her heigbr KiOcm.

Her laboratory studies were as follows: CRC showed: WC 8 x ldvn, Hgb 102 @, Hct 0.32, RBC 5.3 x lO=il, MCV 62 fl, MCH 20 pg, MCHC 330 g/l. Her smear revealed moderate anisocytosis, poikilocytosis, hypochromasia, basopbiic stip pliag, microcytes, schistocytes, and teardrops. Hemoglobin electrophoresis yielded 93.5% Hgb Al, 4.8% Hgb AZ (normal = l&2.6%), 1.7% fetal Hgb (normal = <2.0%), and no Hgb S,E,C, or H. Routine biochemistry was normal. Serum iron was normal (10 ~mol/l). An ESR was 10 mti and a serum electrophoresis revealed no monoclonal spikes. Thyroxine was 107 ttmobl (normal 51-142 nmo!/l). N-terminal FTH was 11 pgiml (normal 4-19 pg/ml) and C-terminal FFH was 49 pg/ml (normal 30-190 pg/ml). 25-hydroxyvitamin D was 35 nmolil (normal 25-137 am&l) and serum osteocalcin was 22 n@nl (normal 4-16 ng/ml). Her 24-h urine

calcium was 7.2 mmol (normal < 6.2 mmol) on 6W mg supplemental calcium per day. 24-h urine hydrcxyproline was 212pmol (normal X2-305 pool) and 24-h urine creatinine was 6.4 mmol (normal B 7.35 mmcl). The mine hydroxyprolinelcreati- nine ratio wasO.033 (nonnal c 0.025).

Table 1

Bone bistomotphometry

Bone volume (95) Trabccular thicknes CJml) TmSecular number (number/mm) Ostwid volume (%) Oeoid thickness (urn) Ortcoid surface (5%) Formation rurface (9-O) Emderlsurface (S) o3teoclaStsuface (%) Mineralization lag time (days)

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As part of her baseline evaluation she ucderwent a double tetracycline labeled biopsy of the iliac crest, and bone densitometry. The latter tests included single photon absorptiometry (DP2 model, Lunar Radiation, Madison, WI) of the proximal radius (lower/mid site) and dual photon absorptiometry, (DP4 model, Lunar Radiation).

The density of her spine was 0.66 gHA/cm* (z-score, -3.4). Her radial bone density was 0.73 gHA/cm* (106% of age-matched controls). Her total-body bone mineral was 1768 g (671 g calcium) which is 87% of expected znd her total body bone density was 0.840 g/cm’ which is 88% of expected.

The results of her bone biopsy are shown in Table 1. Trabecular bone volume was low (8th percentile) and trabecular plates were both sparse and thin. There was his- tologic evidence of rapid remodeling with a high fraction of surfaces involved in either resorption and/or formation. Mineralization lag time was low normal and excluded a diagnosis of osteomalacia.

She was started on 50 ;ng of slow-release sodium fluoride and 0.25 ,og B.I.D. of I,25dihydroxyvitamin D,. Approximately one year after entry into the study, she had a parrial collapse of L-3 (Fig. 1) after lifting a kcavy ,~arce!. She was admitted to the University of Cahfornia, Irvine Medical Center for management of back pain and was seen by one of us (NCG). Shortly thereafter, she returned to Creighton University and her fluoride was increased to 75 mg per day. After two years on fluoride, injections of salmon calcitonin, 2@ I.U. per day were added. At present, she has had no further fractures and is doing well. After two years of fluoride treatment her total body calcium stabilized (pre-Rx 67P g, post-Rx 666 g) and her spinal bone mineral density increased from 0.655 g/cm* to 0.681 p/cm*),

7Wa.wemia minor cohort Fifteen adult subjects with thalassemia minor were located and eleven were studied. One was excluded because of alcoholism, another because of a lifelong history of seizures controlled by dilantin, and two eligible subjects chose not to participate for personal reasons. Eight subjects were studied at the University of California, Ir- vine and three were studied at Creighton University.

The clinical characteristics of the thalassemia minor cohort are shown in Table 2. All of the subjects were American born except for No. 10 who was born and raised in Iran. All were Caucasian except for No. 1 who was Oriental. None of the subjects consumed unusual or low-calcium diets or calcium ~pplements. All of the preme- q opausal femaies had regular periods. Neither of the two postmenopausal women had taken estrogen supplements.

The results of their bone densitometry are shown in Figure 2. Bone mineral density valiles were correcieri fur age and sex and cxprcssed as x-scores. Bone mineral density of the spine was lower in the patients with thalassemia trait; the mean a- score for spine density was -0.78 (P < 0.03). If subject No. 2, who was a triathalon athlete, was excluded from the analysis, then this trend toward lower spine bone mineral density was even more pronounced (x-score = -1.04, P < 0.01). Further- more, nine of e&en subjects with thalassemia trait had spine density below the mean.

6-i

The mean z-score for hip density in subjects wit h’&!aSemia trait was-o.54 (P = 0.05). Eight of eleven subjecta had hip bone mineral density below the mean. If subject No. 2 is again excluded from the analysis, then tbe mean z-score for hip bone mineral density becomes -0.63 (P < 0.05).

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Table 2

Clinical characteristics of thalasaemia minor cohort

Indexcase 54 F “one 0 port I02 4.8b I 23 F none + P’C 134 4.lb 2 25 F “one +++ P= I04 4.P 3 26 F “one + w : 117 3.@ 4 28 F 25 ” pre 111 5.9 5 28 F “one 0 Pie

; I32 3.lE

6 35 F none + P= B 110 4.Ob 7 35 F none 0

P=

¶a 2.3b R 58 F “0°C post ; I25 5.r 9 68 F ~1. 0’ F==t

: 113 ND

10 21 M Cl + . . . 124 49 11 51 M 30 + . . . B 128 ND

‘Exercise: 0 = now; + = weekend rwreado” only; + 4 + = triathalo” addere. Normal values for % HgbA,: bl.R2.6%; c1.5-3.5%: d<3.5%. ND = no data

Spt”e w

Fig. 2. Z+cores for bone mineral density of spine and hip. The mea” (k SD) z-score for the spinz was -0.78 (* 1.23) (PcO.03). ‘fhcmca” (+ SD) z-scoreforthc hi~was-O.W(L 0.94) (P= 0.05). Solldcir- de = hrrrcr cayc. Open circler = premenopaural femaks. Open diamonds = pos”“e”opausal females.

Open squarel= m&s.

There was no correlation between a&e and either hip z-score (r = G.06. P = es) or spine z-score (r = -0.23, P = ns). Amongst the females, there was a trend fur the spine z-score to deviate more negmivcly from zero with increasing age (r = -0.44). but this trend did not reach statistical sipificance. However, 2 out of 3 fern&s s 26 years old had positive spine z-scores whereas all women greater than 26 years old had negative z-scores.

There was no correlation between the z-score for spine bone mineral density and the severity of the hemolytic anemia as measured by either plasma hemoglobin (r = -0.39, P = ns), or, for the beta thalassernia cases, plasma hemoglobin A, (r = -0.28, P = ns). Other indices of hemolysis, such as the reticulocyte count, LDH, and indirect bilirubin, were not available for correlation.

The index case had severe osteopenia which was predominantly axial. Her spine density was 0.655 g/cm* which is 60% of the mean bone density expected for agz- matched normal controls or mote than three standard deviations below the mean. In contrast, at the radial site (95% cortical bone) bone mineral density was 0.727 @cm* which is 106% of age-matched controls.

Her baseline bone biopsy provided both static and dynamic infcJrmation about her trabecular bone. Trabecular booe voleme was low at 12% (8th percentile). Tra- becular plates were few in number and thin. There was evidence of a high remodeling state. The fractional resorption surface was 13% (>Wth percentile) and the fractional active formatiou surface was 9.2% (87th percentile). ateoid volume was at the 97th percentile. However, there wrs rw evidence for osteomalacio, asw- teoid seam widths were normal and tvjneralllation lag time was normal.

There was also biochemical e-&deuce for rapid bone turnover. Serum osteocal- cio, which reflects bone formation, was elevated as was the 24-h urine hydroxypro- linelcreatinine ratio, which reflects hone resorp:ion.

The densitometric pattern of predominantly axial osteopenia seen in this index subject is typical of type I or postmenopausal osteoporosis. This patient did have some risk factors for osteoporosis. She was Caucasian, postmenopausal, sedeutary, and consumed a diet low in calcium. Her baseline laboratory evaluation and bone biopsy eliminated recognized occult causes of secondary osteopeuia such as hypr- parathyroidism, osteomalacia, hyperthyroidism, osteogenesis imperfecta tarda, multiple myeloma, or metastatic disease. However, there are several features of her case which suggest that her osteoporosis was not au ordinary case of postmeno- pausa! osteoporosis. First, the degree of her axial bone loss was more than three standard deviations below the mean for her age (53 years). Furthermore, although the rate of bone turnover as determined by histomorphometry can he low, normal. or high in postmenopausal osteoporosis [IO], the degree of bone turnover observed in this case was extreme, with some parameters of hone turnover being above the 99th percentile. Finally, since similar but less dramatic changes in hone density

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were observed in asymptomatic premenopausal and male subjects with thalassemia minor, it is likely that the patient’s hemolytic anemia was a contributing factor to her osteoporosis.

The reason why the index subject’s appendicular, cortical bone was less os- teopenic than her axial bone may be that red marrow is limited in adults to axial bone and it is hypercellular red marrow which is thought to encroach upon and thin adjacent bone in patients with overt hemolytic anemias. In contrast, children with thalassemia major have osteopenia throughout the skeleton, paralleling the pres- ence of widely distribuied and hypercellular red marrow. However, as children with thalassemia major mature, osteopenia in their appendicular skeleton resolves as their hematoietic companment centralizes to the axial skeleton [3], while radio- graphic abnormalities in their axial skeleton persist.

Although there have been no prior reports of bone histomorphometry in patients with thalassemia minor, there have been several reports of bone histomorphometry in patients with thalassemia major. Gratwick [4] reported on two autopsy speci- mens and one surgical specimen from patients with thalassemia major. He found evidence for widespread iron deposition, an increase in resorptive surfaces, promi- nent osteoblasts, thickened osteoid seams, and microfractures. De Vemejoul [ll] performed iliac crest biopsies in four patients with Cooley’s anemia and observed decreased trabecular bone volume, normal osteoclastic activity, increased osteoid surface area, delayed mineralization, and diffuse iron deposition. Christenson [K?] s!udied bone histomorphometry in two patients with thalassemia major and observed patchy osteomalacia, increased hone resorption and decreased osteoclastic activity. Most recently, Rioja et al. [13] described iliac crest biopsies of seventeen children with thalassemia major. They found a moderate reduction in trabecular bone area in seven patients and a significant disruption of cortical bone ix eight. It is not surprising that a variety of histomorphometric patterns have been found in patients with thalassemia major because these patients are chronically ill and may have other associated endocrinopathies including secondary hyperparathyroidism due to calcium malabsorption, and acquired hypaparathyroidism and hypogona- dism due to iron overload from repeated blood transfusions.

Thalassemia minor cohort Bone mineral density in asymptomatic subjects with thalassemia minor was diiin- ished. None of the subjects had any known risk factors for osteoporosis other than race and sex except for No. II who was a former smoker. In some cases, the osteoporosis was unsuspected, as in the case of No. 10 who was a sedentary male col- lege student. Both young and middle-aged subjects appeared to be at risk as did males and females. There was one subject with alpha thalassemia minor and she also had lower than expected bone density.

Two of the three thalassemia minor subjects who had spine z-scores greater than normal were sisters. Of these, the one (No. 2) with the highest spine bone density had a life-long history of athleticism and was a triathalon competitor. It is possible that vigorous exercise in this individual may have counterbalanced an underlying risk for osteopenia.

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The degree of bone reduction in the asymptomatic cohort was less than one standard deviation below normal (z-scores for spine and hip bone mineral density were -0.711) and -0.54, respectively). Nonetheless, this modest degree of bone reduction could represent a significant contribution to osteoporotic risk, tince the mean spine bone mineral density in postmenopausal women with one ore more spinal fractures is between one and two standard deviations (e.g. z-score -1.0 to -2.0) below age- matched normals and the range of individual values overlaps those observed in normal *omen (7).

Although thalassemia minor may be a risk factor for osteopenia in individuals who carry the trail, it is unclear how much clinical significance this risk factor would have in the western world. The gene for thalasscmia minor is most cmnmonly found amongst people from the Mediterranean basin, Africa, Asia, India, and the South Pacific. Indeed, in a recently mandated newborn screening program, over the past 15 months the state of California has identified only 7 eases of homozygous beta thalassemia in over 600 I)(K) babies, and most of these were in Southeast Asians [14]. By extrapolatio”, this suggests that the frequency of the heterozygote ear&r state in the general popularion of California is only around l/150-lLX@. The frequency of the geoe in the Caucasian pop&trio” would be less. Similarly, a scwek ing program conducted by a large Health Maintainance Organization (HMO) in California found 51 cases of thalassemia trait in 9996 members for a carrier rate of l/l% [14].

If lhalassemia minor is a risk factor for osteoporosis, one might wonder why this factor would not have been previously described. First, lbe prevalence of beta thalassemia trail in the we&m world is probably quite low, as did above. See oad, although all patients who present with established osteoporosis are routinely screened for anemia, the rtticrocytic anemia of thalassemia minor is very mild, and in pcrimettopausal women often is mistakenly ascribed to menstrually related iron deficiency. Finally, with the exception of Orien.als, individuals from those parts of the world where thalassemia is endemic often have large frames. Consequently, tbey may be less at risk for osteoporolic fractures in the face of bone low than Cau- casians of northern European extraction who have smaller Initial bone mass. Thus, it might be anticipated that thalassemia trait would be uncommon amongst inditid- uals who present to osteo~:osis centers for evaluation of either suspected or established osteoporosis.

The present study suggests that individuals with thalassemia minor may be at risk for a high turnover form of axial osteoporosis, especially as they age This tentative conclusion needs to be confirmed by a study which is larger and which includes biochemical and histomorphometric data related to bone turnover on more subjects. Also, it would be desirable to compare the bone density of individuals with thalassemia trait to the bone density of their unaffected first degree relatives in order to eliminate from the comparison any contribution from familial variability in body build.

If others confirm our finding that individuals with thalassemia minor are at risk for diminished bone density, then several important clinical questions are raised. Should everyone with tbalassemia minor be screened with bone densitometry? Are

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thaiassemia minor patients with iow bone density at increased risk for fracture7 Are postmenopausal wcmxn with thalassemia minor at increased risk for postmenopausal osteoporosis as seemed to be the case for our index patient:’ If so, will estrogen in the usually recommended doses be as effective in preventing osteoporosis as it is

in normal women? And finally, what about asymptomatic individuals with other types oi mild hewolytic anemias stxh as those with traits for IIgb S or C? Are they, too. at increased risk for osteopenia?

Aeknowladgments

The authors wish to thank Dr Robert Reeker for reading the bistomorphomntry

slides. This work was supported in part by NII! Grant AR 39221 (JCG)

References

I Caffey 1. Cooley’s Anemia: A review of the roentgenographic findings in the skeleton. 3 Roentgenol 1957;78:381-91.

2 Poyton Hti. Davey KW. Thalassemia: Changes visible ia radmgraphs USS~ in denrixry. Oral Surg Oral Med Oral Path 196&25(4):%4-76.

3 Roy RN. Bane rjee D. Cbakraborty KN, Basu SP. Obrervarions of radiological changer of bones in thalarsemm syndrome. I Indian Med Assoc 1971;5?:9O-95.

4 Gratwick GM. Bullough PG. Bohne WH, Markenson AL. Peterson CM. Thalarsemic orteoanhro- parhy. A”” Intern Mcd 197R;SB:494-501.

5 Poottakul P, ‘Hungspringer S. Fucharoen S, et al. Relation between crythropoiesis 2nd bone metab- olism in thalaaremia. New Engl J Med 198t;?O4(24):1470-1473.

6 Reeker R. Ed. Bone Ririumo~pboms:;y: Tccbniqucs end Intqreration. n: CRC Press, Boca Ra- ton, 1983.

7 Riggs BL. Wahner HW, Dunn WL, Maress RB. Offord W, Melton U III. Differential changer in bone mineral density of Ihe appendicular and aal skeleton with aping. I Clin Invest: 1981;67:32*-335.

8 Riggs BL. ‘Wahner HW. Seeman E, Offord KP, Dunn WL, Mazesr RB, Johnson KA. Melton LJ III. Changer m bone mineral densny of rhe proximal femur and bpine with aging 1 Clin Invest 1982;io:7’16-723.

9 Caller T. Statioucr in Medicine. Boston, MA: Litde. Brow & Co.. 1974$X. IO Riggs 6L. Mellon LJ 111. Involutional osteoporosis. New Engl I Med 19&314:1676-1686. 1 I de Verncjaul MC, Giror R, Guerir J. Cancela SB. Bielakoffl, Mautalen C. Goldberg D. Mirevet L.

Calcium phosphate melabobsm and bone disease in a patient with bomozygour th&emia. J Clin Endocdnol Metab 1982:54:276-281.

12 Chrittenwn RA, Pooktrakul P. Teubner El, Finch CA, Baylini., Dl. Patients with thalasremia de- velop osteuporasis, arteomalaaa, and hypaprn:h~~oidism. all of which are corrected by tranrfu. rion. In: Binh Defects: Ori~iinal Article Series 1988,233409-416

13 Rioja L, Girot R, Garabedian M, Cournal-Winner G. Bon? Disease in children with homazygous bira-ibrlariemi:r. Bone Miner. 1990;8:69-86.

14 Larry F. Generic Disease Program Specialist, Genetic Diseae Branch. Stare of California. Person- heI communiei~linn. 1991.

thalassemia minor: a risk factor for osteoporosis?

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