Marked Improvement in Bone Mass after Parathyroidectomy in Osteitis Fibrosa Cystica¹

Primary hyperparathyroidism now typically presents as an asymptomatic disorder of mild hypercalcemia (1). Although overt radiological changes still occur (2–5), it is much more common to detect skeletal involvement by more sensitive techniques such as dual energy x-ray absorptiometry (DEXA) in the absence of any x-ray findings. In the years before the advent of the multichannel autoanalyzer, osteitis fibrosa cystica, the classical bone disease of primary hyperparathyroidism, would typically show radiological improvement after successful parathyroid surgery (6). The extent of improvement, however, could not be quantified. In the era of asymptomatic primary hyperparathyroidism, improvement can be precisely monitored by DEXA. On the average, all sites (lumbar spine, femoral neck, and distal radius) improve within the first 4 yr after surgery (7–12). Very little is known about how much bone mass can be restored after successful parathyroid surgery in patients with overt bone disease. In this report, we describe two young women with primary hyperparathyroidism and severe osteitis fibrosa cystica who underwent successful parathyroidectomy. Dramatic, sustained, and unprecedented increases in bone density, reaching 550%, were observed. These two patients illustrate a remarkable capacity of the skeleton to be restored to normal after surgery in patients with the classical bone disease of primary hyperparathyroidism. A 37-yr-old Hispanic female was hospitalized because of generalized bone pain. She had been in good health until approximately 7 months before admission when she began to experience pains in the knees, shoulders, and lower ribs. They gradually became incapacitating; she was unable to walk. She did not have fractures or kidney stones. Menstrual periods were normal. She had four healthy children. She had smoked one pack of cigarettes/day for 15 yr. Her physical exam was normal, except for tenderness of lower ribs, tibia, knees, and wrists. Admission laboratory tests included (see Table 1): hemoglobin, 11.8 g/dL (normal, 12–16); hematocrit, 34% (normal, 37–47); sodium, 141 mEq/L (normal, 135–146); potassium, 3.3 mEq/L (normal, 3.2–4.6); chloride, 111 mEq/L (normal, 96–108); CO2, 18 mEq/L (normal, 23–29); creatinine, 0.7 mg/dL (normal, 0.5–1.1); and glucose, 122 mg/dL (normal, 70–105). Serum calcium was 15.2 mg/dL (normal, 8.4–10.2); serum phosphorus was 2.5 mg/dL (normal, 2.7–4.5). Albumin was 4.5 g/dL (normal, 3.9–4.8). Alkaline phosphatase activity was 2288 IU/L (normal, 39–177), and PTH was 2560 pg/mL (normal, 10–65). Twenty-four-hour urinary calcium was 1117 mg (normal, up to 250). Postoperative course of case 1 Postoperative course of case 1 A marked reduction in bone mass at all sites was seen by DEXA (see Table 1), with t-scores all in the markedly osteoporotic range. Skeletal x-rays revealed diffuse osteopenia. Hand radiographs showed lytic changes in the distal phalanges as well as subperiosteal resorption of the middle phalanges. Skull films showed a “ground glass” appearance. After hydration with iv sodium chloride, the patient underwent parathyroid surgery. A right inferior parathyroid adenoma (1.5 × 1.0 × 1.5 cm) was removed. Twenty-four hours after surgery, serum calcium was 9.0 mg/dL, and phosphorus was 1.9 mg/dL. Chvostek’s sign was positive. She was treated with calcium gluconate iv and then with oral calcium carbonate (1 g daily). Two weeks later, the patient was discharged on supplemental calcium (1 g daily). Two months after surgery, serum calcium had fallen further to 6.7 mg/dL. 25-Hydroxyvitamin D was 18 ng/mL (normal, 9–25). Calcium carbonate was increased to 3.0 g, and ergocalciferol (50,000 U daily) was begun. Serum calcium rose gradually into the lower range of normal. Twenty-four-hour urinary calcium excretion normalized to 160 mg. One year after surgery, the osteocalcin level had fallen by 50%, but was still 6 times normal (Table 1). In contrast, urinary markers of bone resorption, pyridinium and deoxypyridinoline, had fallen by 92% and 93%, respectively, and were only minimally elevated. The PTH level fell, but remained elevated at 126 pg/mL. By year 2, the PTH level normalized to 50 pg/mL. Four years after surgery, all hormonal and biochemical values remained normal. Bone densitometry was determined before, 5 months, 1 yr, and 4 yr after surgery (Fig. 1). At all sites, bone density increased markedly. By the end of the first year, lumbar spine bone mass increased 60%, from 0.579 to 0.925 g/cm2, corresponding to a change in the t-score from −4.55 to− 1.40. Femoral neck bone mineral density increased 250% in the first year, from 0.388 to 0.965 g/cm2, corresponding to a change in t-score from −5.06 to +0.71. Distal forearm bone density showed a 42% increase from 0.334 to 0.473 g/cm2, corresponding to an increase in the t-score from −5.83 to− 2.80. Change in bone mineral density after parathyroidectomy. Evolution of t-score in both cases. Change in bone mineral density after parathyroidectomy. Evolution of t-score in both cases. Four years after surgery, bone mass showed a further 17.7% increase in the lumbar spine (t-score to +0.10), 5.1% in the femoral neck (t-score to +1.19), and 15.3% in the forearm (t-score to −2.10). The cumulative increases after parathyroidectomy were 88%, 261%, and 58% in the lumbar spine, femoral neck, and forearm, respectively (Fig. 2). Percent change in bone mineral density after parathyroidectomy in case 1. Percent change in bone mineral density after parathyroidectomy in case 1. A 17-yr-old Brazilian girl was hospitalized because of bone pain and multiple pathological fractures. She had been in good health until 3 yr before admission, when she began to experience pain in her arms and legs and progressive difficulty walking. She sustained fractures after minimal trauma involving the right proximal femur, left humerus, right fibula, and left femur. She had one episode of renal colic. She had been oligomenorrheic since the time of her menarche at age 13 yr. Her physical exam was normal, except for hyperreflexia and muscle atrophy in the proximal lower extremities. Initial laboratory data revealed elevated serum calcium and PTH of 13 mg/dL and 1530 pg/mL, respectively. Serum phosphorus was 1.6 mg/dL, and alkaline phosphatase activity was 2500 U/L. Twenty-four-hour urinary calcium excretion was 380 mg. X-Rays demonstrated brown tumors in the mandible and humerous; collapsed vertebral bodies of T12, L1, and L5; and kidney stones. Bone mineral density, determined by DEXA, was markedly reduced in the lumbar spine (0.225 g/cm2) and the femoral neck (0.159 g/cm2). Forearm bone mineral density was not measured. Surgical exploration of the neck revealed a left lower pole parathyroid adenoma (1.3 cm3), which was confirmed by histological examination. The postoperative course was complicated by symptomatic hypocalcemia, which was controlled by iv calcium gluconate. The patient was discharged on oral calcium carbonate (1 g daily) and vitamin D (400 IU daily). Three months after successful parathyroidectomy, serum and urinary calcium, PTH, and phosphorus values all returned to normal. Serum calcium was 9.3 mg/dL, phosphorus was 3.2 mg/dL, intact PTH was 35 pg/mL, and 24-h urinary calcium was 40 mg. Three years after surgery, these indexes were still within the normal ranges. The patient demonstrated progressive improvement in symptomatology and started walking 9 months later, after being bed bound for 15 months. Lumbar bone density increased by 429% in the first year after parathyroidectomy and continued to increase in the subsequent years. By 3 yr after surgery, the total increase in bone mass was 550% in the lumbar spine and femoral neck (Fig. 2). Accurate, precise, noninvasive measurement of bone mass by DEXA has become a gold standard in the assessment of skeletal involvement in primary hyperparathyroidism (13). It is the only simple way to detect the effects of PTH on bone in a disease that has become mainly asymptomatic (1, 14). Bone densitometry has shown clearly, moreover, that after successful parathyroidectomy, improvement in bone mass occurs. Reports by Leppla et al. (11), Martin et al. (7, 8), and Mautalen et al. (9) all confirm postoperative increases in bone mass ranging from 5–10%. The greatest gains tend to occur within the first postoperative year. In many cases, reversal of bone loss is not complete, and reductions below normative means are still evident after the rate of increase in bone mass has stabilized. In the largest, longest, and most systematic investigation of postoperative changes in primary hyperparathyroidism, Silverberg et al. (12) confirmed and extended these findings to the cancellous skeleton as well. The increase in bone mass occurs at all sites, including cancellous areas (lumbar spine), where PTH has protective effects (15). The mechanism of the increase in bone mass has been explained largely by a reduction in the remodeling space, which is substantially increased in primary hyperparathyroidism (16, 17). Remineralization of the remodeling space could account for substantial postoperative improvements in bone mass. This mechanism could also explain the observation that improvement at sites of greatest bone turnover (i.e. cancellous bone) occurs first. Furthermore, if the remodeling space alone were affected after surgery, it could explain the incomplete recovery of bone mass typically seen. This may be particularly evident in cortical bone, where tunneling resorption and endosteal bone loss may not be easily recoverable (9). Bone mass measurement technology provides the opportunity to apply a quantitative approach to questions regarding improvement in patients with osteitis fibrosa cystica. It is thus possible to address the potential for bone gain after surgery in such patients as well as the possibility that these gains reflect true anabolic events. The only modern report using DEXA in this regard is that of Brossard et al. (5). They reported a 63-yr-old woman with osteitis fibrosa cystica who demonstrated a 33% increase in hip (greater trochanter) bone density. Our two patients demonstrate even more dramatically the potential for bone restoration in primary hyperparathyroidism. The kinetics of the sustained increase (over 3–4 yr) as well as the extent of the increases, as much as 261% in case 1 and 550% in case 2, illustrate the remarkable capacity of the skeleton to restore itself. To a certain extent, the improvement in case 2 may have been aided by mineralization of an immature skeleton. However, case 1 illustrates that even the mature skeleton affected by osteitis fibrosa cystica can show vast improvement in bone mineral density. In both cases, bone mass increased from markedly osteoporotic levels (lumbar spine t-scores, −8.13 and −4.55) to t-scores that became completely normal (+0.70 and +0.10, respectively). Such improvements cannot be explained by a simple reduction in the remodeling space, because they occurred over a period of time that is much longer than such models would predict (18) and also because the magnitude of the improvement argues for a true postoperative anabolic effect. The sustained increase in markers of bone formation (alkaline phosphatase and osteocalcin) in the face of decreasing bone resorption markers supports that idea that these two patients experienced a true increment in bone mass. Although severe primary hyperparathyroidism is seen only rarely now, the cases reported here provide additional insights into the postoperative capability of bone mass to be restored in primary hyperparathyroidism. To a more modest extent, bone mass typically improves after surgery in asymptomatic primary hyperparathyroidism. From our observations, one might infer that the greater the bone disease, the greater the likelihood that bone mass will improve postoperatively. It is possible that active bone involvement, as assessed by biochemical evidence of disease, will be associated with greater improvement in bone mass. Complete assessment of disease activity, therefore, may be useful in gaging the potential for improvement in bone mass during the postoperative period. On the other hand, when overt bone disease is present, remarkable recovery of bone loss can be expected. Although the precise mechanisms of restoration of bone mass after successful surgery have yet to be elucidated, it is likely that the postoperative changes in bone represent a true anabolic effect.