The osteodystrophy of congenital erythropoietic porphyria

Bone, 12, pp. 89-92, (1991) Printed in the USA. AlI rights

The Osteodystrophy H. W. H. PULLON,’

Copyright

reserved.

of Congenital Erythropoietic

A. J. BELLINGHAM,’

S. HUMPHREYS’

8756-3282191 $3.00 + .OO 0 1991 Pergamon Press plc

Porphyria

and T. F. CUNDY3

‘Department of Haematological Medicine, Kings College School of Medicine & Dentistry, Demark Hill, London SE5 ‘Department of Histopathology, Kings College Hospital, Denmark Hill, London SE5 ‘Department of Medicine, Kings College School of Medicine & Dentistry, Denmark Hill, London SE5, United Kingdom Address for correspondence and reprinfs: Dr. T.F. Cundy, Department

of Medicine,

Auckland

Hospital,

Park Road, Auckland

1, New Zealand.

recognised as a complication of this disorder. describes the osteodystrophy of CEP.

Abstract Congenital erytbropoietic porphyria (CEP) is a rare diiorder of beme biosynthesis that results in the production of large quantities of photoactive porphyrins. The clinical syndrome is dominated bly extreme photosensitivity with mutilation of light exposed extremities and bemolytic anemia. Bone disease has been occasionally noted, but is not well character&d. We describe a man with CEP who developed bone pain and spinal crush fractures at the age of 22. Skeletal radiographs revealed features typical of other severe bemolytic anemias, but in addition there was loss of tbe terminal phalanges of the band as a result of pbotomutilation. Spinal bone density (assessed by DPA) was reduced and at the bip bone density was at the lower limit of normal. The metacarpal cortical bone density was 2.9 standard deviations below normal. Biochemical and histological studies showed accelerated bone turnover. Although tbe serum 2501-1vitamin D concentration was very low (because of light avoidance) there was no evidence that the bone disease was a consequence of thii. Treatment for one year with clodronate and a high transfusion regime was associated with small reductions in serum alkaline pbospbatase and urine bydroxyproline excretion, but there was no improvement in bone mineral density. We conclude that CEP has a distinctive osteodystropby comprising osteolysis of light-exposed extremities and a high turnover type of osteoporosis. Privational vitamin D deficiency may also occur. The effect upon bone of the new therapies for CEP should be considered.

This report

Case Report and Methods CEP was diagnosed at the age of two months in an infant presenting with persistent neonatal jaundice and hemolysis. A fracture of the forearm occurred at the age of two following trauma. He was treated with intermittent blood transfusion, and splenectomy was undertaken at the age of seven. Ascorbic acid, p carotene, and folic acid were prescribed, and the patient was encouraged to avoid exposure to sunlight. Despite these measures, extensive photomutilation of the hands and face progressed. From the age of 10 he received regular nocturnal subcutaneous infusions of desferrioxamine. Growth and sexual maturation were normal. At the age of 20 he began to experience pain in the spine and sternum. He was investigated for metabolic bone disease at the age of 22. On examination he had minimal bone tenderness, but no myopathy or kyphosis. There was extensive photomutilation of the face and hands with scarring alopecia and shortening of the digits. Radiography of the skull showed widening of the diploic space, and in the thoracic spine there were two wedged vertebrae. Hand radiographs showed resorption of the terminal phalanges, an accentuated trabecular pattern, and a reduced metacarpal cortical bone area (Fig. 1). An isotope bone scan showed increased uptake in the hands only. Serum concentrations of testosterone and thyroid hormones were normal. Serum concentrations of calcium, phosphate, albumin, and alkaline phosphatase were measured using a Technicon SMAC autoanalyser, urine concentrations of creatinine and hydroxyproline were measured in the post-absorptive state, and the ratio used as an index of bone resorption (Hodgkinson and Thompson 1982). Serum levels of parathyroid hormone and 25hydroxyvitamin D were measured by radioimmunoassay and competitive protein binding assay, respectively. A transiliac bone biopsy was obtained using the Bordier 8 mm trephine after the administration of double tetracycline labels. Five to ten pm sections of undecalcified bone were stained with hematoxylin and eosin, von Kossa, toluidine blue, Goldner trichrome, and Gomori’s reticulin methods for light microscopy and histomorphometry (Malluche and Faugere 1986). Unstained sections were examined under ultraviolet light for identification of the tetracycline labels. Axial bone density was assessed by dual photon absorptiometry (Lunar DP4). Peripheral cortical bone density was

Key Words: Porphyria-Osteoporosis-Bisphosphonate.

Introduction Congenital erythropoietic porphyria (CEP) is a rare disorder of heme biosynthesis, resulting from reduced activity of the enzyme uroporphyrinogen (III) cosynthetase. Large quantities of isomer I porphyrins are produced, which are subsequently oxidised into photoactive porphyrins. The clinical syndrome is marked by extreme photosensitivity, which results in mutilation of light exposed areas, but hemolytic anemia, hepato-splenomegaly, erythrodontia, and a reduced life expectancy are also recognised features (Kappas et al. 1983). Although bone demineralisation and fractures have been described in patients with CEP (Piomelli et al. 1986), bone disease has not been generally

89

H.W.H.

Pullon et al.: Osteodystrophy

Table

of erythropoietic

porphyria

I.

Biochemical and bone density measurements before beginning clodronate and intensive transfusion therapy and whilst on therapy. Where more than one measurement was made results are given as the mean + SEM.

(mmol/L) Serum phosphate (mmol/L) Serum alkaline phosphatase (iu/L)

Urine hydmxypmlinel w&nine ratio (~mol/mmol) Metacarpal cortxal bone arealtofal area Lumbar spine bone denstty @HA/cm’)

*Significantly f-test).

different from values before therapy @ = 0.05, Student’s

Fig. 1. Hand radiograph showing cortical bone thinning, an accentuated trabecular pattern in the distal radius and carpal bones, and destruction of the terminal phalanges.

assessed by x-ray morphometry, and expressed as cortical area/total area at the midpoint of the metacarpal (Nordin et al. 1976).

Results concentrations of calcium and phosphate were normal, but the serum alkaline phosphatase activity was increased, as was urine hydroxyproline excretion (Table I). Isoenzyme studies confirmed that the alkaline phosphatase was of bone origin. The serum concentration of 250H vitamin D was low, 3 ng/ml (winter), 6.6 @ml (summer) (normal 5-25), but despite this the serum parathyroid hormone concentration was suppressed (40 pmol/l). Quantitative bone histomorphometry showed a reduction in trabecular bone volume (12% of sectional area; normal for age 20% to 29%). The surface extent of osteoid was increased (31% of trabecular surface; normal <22%), but the osteoid volume was normal (5.8%; normal <8). The maximum number of osteoid lamellae visible under polarized light was 4 (normal 54). Osteoclastic resorption surfaces were increased (14.1%; normal <2.4%), but marrow fibrosis was not present. Intense fluorescence from the porphyrins deposited within bone made identification of the tetracycline labels imposThe serum

Fig. 2. Trabecular bone histology from the transiliac biopsy. (a) low power view ( x 25) showing intensely hypercellular marrow with marked trabecular osteopenia (von Kossa stain). (b) high power view (X 400) demonstrating active osteoclastic bone resorption at the trabecular bone surface (haematoxylin and eosin stain).

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sible, but the mineralisation front, as assessed by toluidine blue staining, was normal (94% of osteoid surface; normal SO%)

(Fig. 2). Dual photon absorptiometry of the axial skeleton confirmed marked osteoporosis in the lumbar spine, but less marked osteopenia in the femur. The metacarpal cortical bone area was 2.9 standard deviations below normal for his age (Table I). A single dose of calciferol (300,000 units oral) was given and clodronate (dichloromethylene bisphosphonate), a potent inhibitor of bone resorption was also prescribed (800 mg oral, twice daily). At the same time an intensive blood transfusion regime was begun (Piomelli et al. 1986), which raised his hematocrit from a mean of 0.24 to a mean of 0.36. The transfusion/clodronate regimen was continued for 12 months, over which time there was some subjective improvement in bone pain, and small falls were seen in mean serum alkaline phosphatase levels @ ==0.05) and urine hydroxyproline excretion @ =0.08). Howevter, by the end of the 12 months there had been no improvement in axial or peripheral bone density (Table I).

Discussion In this young man with CEP we have observed a form of generalised osteopenia affecting both the axial and peripheral skeleton and clinically characterised by bone pain and crush fractures of the spine. At least one other CEP patient has been more severely affected with a similar bone disease (Piomelli et al. 1986). HistologicaUy, the osteopenia was of a high turnover type, with increased osteoclastic resorption and increased osteoblastic surfaces. The histological findings were confirmed by the biochemical evidence ofincreasedbone turnover. Similar changes in mineralised bone are recognised to occur in a number of hematological conditions characterised by hemolysis and increased erythropoiesis, such as p thalassemia major (Gratwick et al. 1978; Rioja et al.. 1990) and sickle cell disease (Serjeant 1974). The mechanisms whereby increased erythropoiesis stimulates bone resorption and expansion of the marrow at the expense of mineralised bone are poorly understood, but locally released marrow cell cytokines that can stimulate osteoclastic bone resorption are likely to be involved. The osteoclast itself is derived from a hemopoietic stem cell (Loutit and Nesbit 1979). Additional features of the bone disease of CEP are the acre-osteolysis resulting from photomutilation and the possible role of vitamin D insufficiency. The latter is a predictable effect of avoiding light exposure, and is liable to produce both secondary hyperparathyroidism and a mineralisation defect. Despite the low serum 250H vitamin D, we found no convincing evidence to suggeslt that vitamin D insufficiency was important in our patient’s bone disease. Serum phosphate concentrations were not reduced and the serum PTH was suppressed, consistent with the presence of active bone resorption through non-PTH mediated mechanisms. The increase in trabecular osteoid surface on biopsy was attributable to the high turnover state rather than defective mineralisation, since the extent of the mineralisation fronts was normal, as was the maximum number of osteoid lamellae visible under polarised light. In the one year follow-up we tried therapies that we hoped would have the effect of reducing bone turnover by both direct (clodronate) and indirect (intensive transfusion) mechanisms. In other conditions where marrow infiltration appears to stimulate bone resorption such as myeloma (Delmas et al. 1982), mastocytosis (Cundy et al. 1987), and Gaucher’s disease (Homick et al. 1984), the bisphosphonates have proved effective. Hypertransfusion regimes are effective in improving the bone disease

of p thalassemia major (Weatherall and Clegg 1981). The reduction in biochemical indices of bone turnover that we obtained was, however, small, and there was no demonstrable beneficial effect upon bone density. Nonetheless, this approach, perhaps maintaining a higher hematocrit than we obtained, and/or using higher doses of clodronate or other bisphosphonates seems an attractive one for increasing bone density in this condition. Two recent advances have offered hope to sufferers of this extraordinarily distressing condition. Piomelli et al. (1986) described the use of a hypertransfusion regimen to suppress the production of photoactive porphyrins, and Pimstone et al. (1987) described the use of activated charcoal to absorb photoactive porphyrins from the gut. Both result in impressive reductions in plasma and urinary porphyrin concentrations and striking improvement in cutaneous photosensitivity. If these encouraging results can be translated into prolonged survival, then the osteodystrophy of CEP may become an important factor in the future health of patients with this disorder. The effects of these treatments on bone have not been explored, but the use of activated charcoal, which does not suppress erythropoiesis, might be expected to increase bone turnover further. We conclude that CEP has a distinctive osteodystrophy comprising phalangeal osteolysis due to photomutilation and a high turnover osteoporosis related to excessive erythropoiesis. Privational vitamin D deficiency may also occur because of light avoidance. The effects of newer therapies for CEP on bone metabolism and density should be considered.

Acknowledgments:

We

wish to thank Dr. J.A. Kanis for supplies of

clodronate and Dr. I. Fogelman measurements.

for his assistance

with the bone density

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Rioja, L.; Girot, R.; Garabedian, M.; Cannot-Witmer. G. Bone disease in children with homozygous p thallasemia. Bone and Mineral 8:69-86; 1990. Serjeant. G. R. The clinical featuresof sickle cell disease: Bone lesions. Amsterdam: North Holland; 1974; 165-171. Weatherall, D. J.; Clegg, J. B. The rhalarsemia syndromes. 3rd edition. Oxford:

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1981, Date Received: June 2 1, 1990 Date Revised: October 5, 1990 Dare Accepted: October 11, 1990