A 31-year-old housewife was presented with an eight-year history of generalized bone and muscle pain. Ten years ago, she noticed a tingling pain in her right thigh and was diagnosed, at a private clinic, as having a herniation of an intervertebral disk. The pain became progressively worse without any relief from physiotherapy and analgesics. She was transferred to a university hospital, where the diagnosis of primary hyperparathyroidism was made as the radiologic examination revealed osteopenia and the serum phosphorus was 2.1 mg/dL (normal range 3.0–4.5), alkaline phosphatase 453IU/L (normal range 30–120) and plasma PTH (middle molecule) 211pmol/L (normal range 24–72). However, her serum calcium concentration was only 9.0mg/dL (normal range 9.0–10.5) and no tumor was found in the parathyroid glands. She was discharged without operation but suffered from severe back pain thereafter and lost 13cm in height during the period of one year. She was on sodium phosphate, 3g/day, for five months without any clinical improvement. She visited another hospital as she could not walk due to the severe back pain. Serum calcium concentration was 9.2 mg/dL, phosphorus 1.6mg/dL, tubular reabsorption of phosphate (TRP) 73% (normal range 79–94), alkaline phosphatase 350IU/L and PTH (middle molecule) 325pmol/L. Bone scan showed multiple increased uptake of radioisotope on the ribs and bone biopsy revealed severe osteomalacia. She was diagnosed as X-linked hypophosphatemic ricket. Sodium phosphate and 1,25-dihydroxy-vitamin D had been prescribed for three years, but could not improve either the symptoms or the laboratory findings. She lost 7 cm more in height during the period. Neither acupuncture nor herb medications could help her. She finally became restricted to bed one year prior to admission to our hospital. She was free of any other disease history and family disease history. She had been off medication for six months before admission to our hospital.

On examination, she was only 138cm in height and 28kg in weight. The muscles of her extremities were very emaciated and she complained of severe tenderness in her muscles. She could not sit by herself and not even stretch her legs in the bed because of severe back pain. At the beginning of the physical examination, a walnut-sized, pinkish, hard, round, protruded mass was found on the lateral side of the left lower molar teeth (Fig. 1A). The initial clinical investigations were as follows: serum calcium 8.7mg/dL, phosphorus 0.9mg/dL, alkaline phosphatase 528IU/L, osteocalcin 8.84 ng/mL (normal range 1.8–6.6), TRP 70%, PTH (middle molecule) 180pmol/L, calcitonin 34.4pg/mL (normal range < 50pg/mL), 25-hydroxyvitamin D₃ 25.6ng/mL (normal range 10–76), 1,25-dihydroxyvit amin D₃ 8.1pg/mL (normal range 16.4–42.4). Urinalysis revealed neither glycosuria nor proteinuria.

Radiologic examination of the skeletal system disclosed severe osteopenia. Most of the vertebral bones were severely demineralized and collapsed, resulting in severe scoliosis and shortening of the distance between the lower anterior costal margin and the iliac crest. The right femur was found to have a fracture in its neck with marked thinning of the cortical bone. Multiple pathologic fractures of the phalangeal bones of both hands were revealed without any callus formation. The iliac bone was obtained for bone histomorphometry. The section of the undecalcified bone demonstrated a small amount of mineralized bone surrounded, by a large amount of unmineralized osteoid (Fig. 2A). Tetracycline labelling showed little labelling throughout the whole mineralization fronts, suggesting very severe mineralization defect (Fig. 2B).

The computerized tomography of the oral cavity tumor revealed an ovoid heterogenous mass protruding from the ramus of the left mandible (Fig. 1B). Sonography and a thallium subtraction scan of the parathyroid gland revealed no tumor. A bone scan, using ^99mTc-methylene diphosphonate (MDP), showed a remarkably increased uptake in the skull, ribs, spine, iliac bones, shoulders, elbows, wrists and ankles. Bone mineral density, measured by dual energy X-ray absorptiometry (DPX-L bone densitometry, Lunar, USA), revealed 0.468g/cm² in the spine (normal range 1.133±0.085), 0.368 in the legs (normal range 1.089±0.074) and 0.411 in the arms (normal range 0.78±70.047).

The patient’s history and our laboratory findings prompted us to suspect oncogenic osteomalacia caused by the tumor found in the oral cavity. However, medical treatment with oral phosphate and vitamin D₃, in the form of either 1α-hydroxyvitamin D₃ or 1,25-dihydroxyvitamin D₃, was tried for 5 weeks before removal of the tumor. 1α-hydroxyvitamin D₃ (Onealfa, Teijin Ltd., Japan) was administered orally at a daily dose of 20μg for 3 weeks with 3.0g of daily oral sodium phosphate for a week, and then she was off all medications for a week. 1,25-dihydroxyvitamin D₃ (Rocaltrol, Roche, Switzerland) was given orally again at a daily dose of 10μg for two weeks without any symptomatic improvement. During the treatment, serum phosphorus concentration and TRP remained below the normal range, whereas the concentration of serum calcium increased (Fig. 3A, B). While serum alkaline phosphatase activity did not change significantly, serum osteocalcin concentration increased (Fig. 3C, D). The concentration of plasma 25-hydroxyvitamin D₃ remained in the normal range and the level of plasma 1,25-dihydroxyvitamin D₃ increased transiently only after administration of 1,25-dihydroxyvitamin D₃ (Fig. 3E, F). The plasma PTH concentration decreased to the upper limit of the normal range (Fig. 3G), but the levels of serum calcitonin (Fig. 3H) remained in the normal range without any significant changes. One week after the en bloc resection of the tumor, the patient admitted less bone and muscular pain. The serum phosphorus concentration did not increase and TRP decreased again to the level observed before 1,25-dihydroxyvitamin D₃ treatment. (Fig. 3A, B). Both of the serum alkaline phosphatase activity and serum osteocalcin level dropped sharply (Fig. 3C, D), but the plasma 1,25-dihydroxyvitamin D₃ level slightly increased (Fig. 3F). A bone scan disclosed reduced radioisotope uptake in general, compared with the preoperative findings. Two weeks after the surgery, the patient complained about bone pain again without muscular pain, but was able to stretch her legs. The levels of serum phosphorus and TRP increased to the normal range.

The plasma 1,25-dihydroxyvitamin D₃ concentration steadily increased until the third postoperative week, whereas the plasma 25-hydroxyvitamin D₃ level remained in the normal range (Fig. 3E, F). The plasma PTH concentration transiently increased for four weeks after removal of the tumor (Fig. 3G). The patient could sit on the bed by herself at the fourth postoperative week. Bone scan showed increased radiotracer uptake again, which was comparable with the preoperative findings. Bone densitometry revealed remarkable increase in bone mineral density, 27% in spine, 11% in the proximal femur and 4% in the proximal humerus. Radiologic examination disclosed callus formations around the previous fracture sites of the phalangeal bones. The patient was discharged, walking with crutches, at the fifth postoperative week.

The largest diameter of the resected specimen measured 2.5cm. The cut surface of the tumor showed a gray-white and firm appearance with scattered calcification. Microscopically, the tumor consisted of central woven bones with surrounding primitive spindle cells. The primitive spindle cells were arranged in fasicle patterns. The individual tumor cells had ovoid-to spindle-shaped nuclei with a fine chromatin pattern and a scanty amount of cytoplasm. In some areas, there were prominent vascularities and some foci of fibrous lesion composed of spindle cells disposed in whorled storiform patterns (Fig. 4).