Clinical Endocrinology (1 977) 7 , Suppl., 23 1S-23 7s.
VITAMIN D RESISTANT HYPOPHOSPHATAEMIC O S T E O M A L A C I A : T R E A T M E N T WITH l a - H Y D R O X Y V I T A M I N D3 M . PEACOCK, P. J. HEYBURN
AND
J . E. AARON
MRC Mineml Metabolism Unit, The General Infirmav Great George Street, Leeds, U.K.
SUMMARY
Ten patients with vitamin D resistant hypophosphataemic osteomalacia are described. They had hypophosphataemia with a decreased tubular reabsorption of phosphate, malabsorption of calcium and phosphorus, proximal myopathy and extensive osteomdacic changes on iliac crest bone biopsy. The plasma alkaline phosphatase and urine hydroxyproline, however, were raised in only some of the patients. Treatment with la-hydroxyvitamin D3 in high doses rapidly cured the myopathy , increased calcium and phosphorus absorption and retention and healed the osteomalacia. Phosphorus supplements were not required. Vitamin D resistant hypophosphataernic osteomalacia (VDRHPO) is generally considered to be a genetically determined condition (Williams &Winters, 1972) although it may regress after the surgical removal of certain associated connective tissue tumours (Dent & Stamp, 1971). The disease usually presents clinically as osteomalacia or rickets often with a severe proximal myopathy. The patient's biochemistry shows hypophosphataemia with decreased tubular reabsorption of phosphate, normal plasma calcium, parathyroid hormone (F'TH), 25-hydroxyvitamin D (25-OHD3) and 1,25dihydroxyvitamin D3 (1 ,2540H)2 Dg) concentrations and evidence of increased bone turnover with raised plasma alkaline phosphatase concentrations and increased excretion of urinary hydroxyproline. Patients with VDRHPO are generally treated with pharmacological doses of vitamin D and oral supplements of phosphate. Some patients respond well to this therapy but in general the disease remains difficult to manage. In this communication the abnormalities in a group of patients with VDRHPO are described and the results of la-hydroxyvitamin D3 (lcu-OHD3) a synthetic analogue of 1,25(0H)2 D3 therapy are discussed. MATERIALS AND METHODS Patients Studies were carried out in ten patients (six male and four females aged 10-80 years) before treatment with 1a-OHD3. In three patients the disease presented as osteomalacia and Correspondence: Dr M . Peacock, MRC Mineral Metabolism Unit, The General Infirmary, Leeds LS1 3EX.U . K .
331s
232s
M . Peacock, P. J. Heybum and f. E. Aaron
in the others as rickets. One patient also had a benign chondroblastoma and another had neurofibromatosis and fibrous dysplasia of bone. In seven patients there was evidence of a proximal myopathy clinically or on electromyography .
Methods
All studies were performed on fasting blood and urine samples. Plasma calcium, phosphate, alkaline phosphatase and creatinine and urine calcium, phosphate, creatinine and hydroxyproline were measured by standard Autoanalyser techniques. Plasma PTH and 25-OHD were measured by methods previously described (Peacock, 1976; Moms & Peacock, 1976). Radiocalcium and radiophosphorus absorption were estimated in the fasting state (Nordin, 1976). Bone histology from iliac crest biopsy was estimated for percentage bone volume, percentage osteoid volume, percentage of surfaces covered in osteoid, percentage of surfaces resorbing, percentage of surfaces resting and calcification fronts (Aaron, 1976). Proximal myopathy was assessed clinically, by simple muscle function tests (the time taken to rise and sit ten times from a standard chair) and by electromyography. Treatment The patients were given increasing doses of la-OHD, up to 6 pg/day. In three patients so far healing of osteomalacia has occurred and the dose of la-OHD, has been reduced to 2-3pg per day. Repeat iliac crest bopsies were obtained at the time of healing in these three patients. RESULTS Untreated The plasma and urine biochemistry, the absorption of calcium and phosphorus and the histomorphometry of bone before treatment are shown in Table 1 . All patients had hypophosphataemia with a decreased tubular reabsorption of phosphate. Plasma calcium, parathyroid hormone, and 25-OHD were in the normal range. Plasma alkaline phosphatase and urinary hydroxyproline excretion were raised in four patients. Fasting urinary calcium excretion was low in only three patients but two patients had a raised urinary calcium excretion. There was malabsorption of calcium in three patients and malabsorption of phosphorus in two; the others, however, had poor absorption of calcium and phosphorus. Bone histology was markedly abnormal in all of the patients. There was an increase in bone and osteoid volume; percentage of surfaces covered in osteoid was increased and there was a decrease in the calcification fronts. Clinical myopathy was present in four of the patients and a further two had electrornyographic evidence of myopathy. In only three patients was there no evidence of myopathy. Treated The results of treatment with 6pg/day of la-OHD3 are shown in Table 2 . There was an immediate rise in radiocalcium and radiophosphorus absorption and many of the patients had hyperabsorption. Plasma alkaline phosphatase and hydroxyproline increased in those patients with raised concentrations and with continued therapy, alkaline phosphatase and hydroxyproline excretion returned into the normal range (Fig. la). The proximal myopathy responded, like calcium absorption, rapidly to la-OHD3 and cured before there was evidence of complete bone h e a h g .
VDRHPO and Ia-OHD3
933s
Table 1. Investigations in ten patients with VDRHPO before treatment ~
Plasma calcium Urine calcium/creatinine Plasma phosphate TMP/ICF Plasma F'TH PldSma 2 5 4 H D , Plasma alkaline phosphatase Urine hydroxyproline/crea tinine Radiocalcium absorption Radiophosphorus absorption 70 Bone volume 76 Osteoid volume 5% Osteoid surfaces 70 Calcification fronts '3 Resorbing surfaces % Resting surfaces
Mean
SD
Nos
2.41 0.26 0.53 0.43 235 40 16.9 0.039 0.39 0.57 36.9 13.1 15.9 27.9 9.1
0.1 2 0.1 9 0.07
10 10 10
0.1 1
10
80 25 9.0 0.027
9 6
15
0.14
0.33 11.1 11.0 23.8 11.2 5.9 19.8
10
7 10 9 9 9 9 9 9 9
Normal range 2.25-2.65 mmolil 0.1 1-0.43 mmol/l 0.8-1.3 mmol/l 0.7-1.4 mmol/l 125-375 pg/ml 5-72 ng/ml 4-13 KA units/dl 0.006-0.002 0.3-1.3 0.4-1.4
15-30
VITAMIN D RESISTANT HYPOPHOSPHATAEMIC O S T E O M A L A C I A : T R E A T M E N T WITH l a - H Y D R O X Y V I T A M I N D3 M . PEACOCK, P. J. HEYBURN
AND
J . E. AARON
MRC Mineml Metabolism Unit, The General Infirmav Great George Street, Leeds, U.K.
SUMMARY
Ten patients with vitamin D resistant hypophosphataemic osteomalacia are described. They had hypophosphataemia with a decreased tubular reabsorption of phosphate, malabsorption of calcium and phosphorus, proximal myopathy and extensive osteomdacic changes on iliac crest bone biopsy. The plasma alkaline phosphatase and urine hydroxyproline, however, were raised in only some of the patients. Treatment with la-hydroxyvitamin D3 in high doses rapidly cured the myopathy , increased calcium and phosphorus absorption and retention and healed the osteomalacia. Phosphorus supplements were not required. Vitamin D resistant hypophosphataernic osteomalacia (VDRHPO) is generally considered to be a genetically determined condition (Williams &Winters, 1972) although it may regress after the surgical removal of certain associated connective tissue tumours (Dent & Stamp, 1971). The disease usually presents clinically as osteomalacia or rickets often with a severe proximal myopathy. The patient's biochemistry shows hypophosphataemia with decreased tubular reabsorption of phosphate, normal plasma calcium, parathyroid hormone (F'TH), 25-hydroxyvitamin D (25-OHD3) and 1,25dihydroxyvitamin D3 (1 ,2540H)2 Dg) concentrations and evidence of increased bone turnover with raised plasma alkaline phosphatase concentrations and increased excretion of urinary hydroxyproline. Patients with VDRHPO are generally treated with pharmacological doses of vitamin D and oral supplements of phosphate. Some patients respond well to this therapy but in general the disease remains difficult to manage. In this communication the abnormalities in a group of patients with VDRHPO are described and the results of la-hydroxyvitamin D3 (lcu-OHD3) a synthetic analogue of 1,25(0H)2 D3 therapy are discussed. MATERIALS AND METHODS Patients Studies were carried out in ten patients (six male and four females aged 10-80 years) before treatment with 1a-OHD3. In three patients the disease presented as osteomalacia and Correspondence: Dr M . Peacock, MRC Mineral Metabolism Unit, The General Infirmary, Leeds LS1 3EX.U . K .
331s
232s
M . Peacock, P. J. Heybum and f. E. Aaron
in the others as rickets. One patient also had a benign chondroblastoma and another had neurofibromatosis and fibrous dysplasia of bone. In seven patients there was evidence of a proximal myopathy clinically or on electromyography .
Methods
All studies were performed on fasting blood and urine samples. Plasma calcium, phosphate, alkaline phosphatase and creatinine and urine calcium, phosphate, creatinine and hydroxyproline were measured by standard Autoanalyser techniques. Plasma PTH and 25-OHD were measured by methods previously described (Peacock, 1976; Moms & Peacock, 1976). Radiocalcium and radiophosphorus absorption were estimated in the fasting state (Nordin, 1976). Bone histology from iliac crest biopsy was estimated for percentage bone volume, percentage osteoid volume, percentage of surfaces covered in osteoid, percentage of surfaces resorbing, percentage of surfaces resting and calcification fronts (Aaron, 1976). Proximal myopathy was assessed clinically, by simple muscle function tests (the time taken to rise and sit ten times from a standard chair) and by electromyography. Treatment The patients were given increasing doses of la-OHD, up to 6 pg/day. In three patients so far healing of osteomalacia has occurred and the dose of la-OHD, has been reduced to 2-3pg per day. Repeat iliac crest bopsies were obtained at the time of healing in these three patients. RESULTS Untreated The plasma and urine biochemistry, the absorption of calcium and phosphorus and the histomorphometry of bone before treatment are shown in Table 1 . All patients had hypophosphataemia with a decreased tubular reabsorption of phosphate. Plasma calcium, parathyroid hormone, and 25-OHD were in the normal range. Plasma alkaline phosphatase and urinary hydroxyproline excretion were raised in four patients. Fasting urinary calcium excretion was low in only three patients but two patients had a raised urinary calcium excretion. There was malabsorption of calcium in three patients and malabsorption of phosphorus in two; the others, however, had poor absorption of calcium and phosphorus. Bone histology was markedly abnormal in all of the patients. There was an increase in bone and osteoid volume; percentage of surfaces covered in osteoid was increased and there was a decrease in the calcification fronts. Clinical myopathy was present in four of the patients and a further two had electrornyographic evidence of myopathy. In only three patients was there no evidence of myopathy. Treated The results of treatment with 6pg/day of la-OHD3 are shown in Table 2 . There was an immediate rise in radiocalcium and radiophosphorus absorption and many of the patients had hyperabsorption. Plasma alkaline phosphatase and hydroxyproline increased in those patients with raised concentrations and with continued therapy, alkaline phosphatase and hydroxyproline excretion returned into the normal range (Fig. la). The proximal myopathy responded, like calcium absorption, rapidly to la-OHD3 and cured before there was evidence of complete bone h e a h g .
VDRHPO and Ia-OHD3
933s
Table 1. Investigations in ten patients with VDRHPO before treatment ~
Plasma calcium Urine calcium/creatinine Plasma phosphate TMP/ICF Plasma F'TH PldSma 2 5 4 H D , Plasma alkaline phosphatase Urine hydroxyproline/crea tinine Radiocalcium absorption Radiophosphorus absorption 70 Bone volume 76 Osteoid volume 5% Osteoid surfaces 70 Calcification fronts '3 Resorbing surfaces % Resting surfaces
Mean
SD
Nos
2.41 0.26 0.53 0.43 235 40 16.9 0.039 0.39 0.57 36.9 13.1 15.9 27.9 9.1
0.1 2 0.1 9 0.07
10 10 10
0.1 1
10
80 25 9.0 0.027
9 6
15
0.14
0.33 11.1 11.0 23.8 11.2 5.9 19.8
10
7 10 9 9 9 9 9 9 9
Normal range 2.25-2.65 mmolil 0.1 1-0.43 mmol/l 0.8-1.3 mmol/l 0.7-1.4 mmol/l 125-375 pg/ml 5-72 ng/ml 4-13 KA units/dl 0.006-0.002 0.3-1.3 0.4-1.4
15-30
