Separation of inhibitory activity from biologically active parathyroid hormone in patients with pseudohypoparathyroidism type I.

Patients with pseudohypoparathyroidism type I have the symptoms of hypoparathyroidism despite elevated levels of immunoreactive parathyroid hormone (PTH). However, the circulating levels of bioactive PTH, as measured in a cytochemical bioassay, are generally within the normal range suggesting that the high levels of immunoreactive PTH are either due to the presence of biologically inactive fragments of parathyroid hormone or to the presence of an 'inhibitor' of PTH bioactivity. Gel-permeation chromatography has been used to fractionate plasma from patients with pseudohypoparathyroidism type I and revealed the presence of high levels of bioactive PTH and of an 'inhibitor'. This inhibitory activity was absent or much lower in plasma from control subjects. These results indicate, therefore, that in pseudohypoparathyroidism type I the expression of the biological activity of PTH at the level of the kidney is affected by the presence of a circulating inhibitor which can be separated from intact PTH by gel-permeation chromatography.

Bioavailability of enteric-coated sodium fluoride tablets as affected by the administration of calcium supplements at different time intervals.

The gastrointestinal absorption of enteric-coated (EC) tablets of sodium fluoride (NaF) with respect to different time schedules of administration of calcium supplements in solution was tested. It was found that the simultaneous administration of these two medications under these formulations did not interfere with fluoride absorption. The calcium was also well absorbed as shown by the rise in serum ionized calcium concentration. Other schedules were studied as well, such as EC NaF tablets taken 1 hour after or 3 hours before the administration of calcium supplements. No superiority was shown, on the contrary, compared with the simultaneous administration of both medications. It was concluded that EC tablets of NaF and calcium supplements in solution can be provided simultaneously to enhance compliance.

Treatment of the vertebral crush fracture syndrome with enteric-coated sodium fluoride tablets and calcium supplements.

A cohort of 101 patients were treated with enteric-coated sodium fluoride tablets and calcium supplements. Vitamin D was also given in supra-physiologic doses in 70% of the cases. Lumbar bone mineral density (BMD), as measured by dual-photon absorptiometry, increased in a linear fashion up to four years, irrespective of the value of initial BMD and of the underlying condition, be it involutional osteoporosis (the vast majority), glucocorticoid osteoporosis, or even osteogenesis imperfecta. Estrogen replacement therapy (ERT) seemed to promote the fluoride-induced increase in lumbar BMD, as did the vitamin D supplements. Of these patients, 17% proved "resistant" to the therapy. There was no way of predicting who would be in this category. Compared with an age- and sex-matched control group, women showed significantly different behavior of their bone mass. In the control group, the losses were highly significant at the lumbar spine and at all three scanning sites of the forearm, as measured by single-photon absorptiometry. In contrast, the fluoride group had a significant gain of BMD at the lumbar spine and changes of BMC at the forearm were not significant. Fluoride thus preserved bone mass at the appendicular skeleton, while increasing it at the axial skeleton. When comparing the patients who received vitamin D supplements and those who did not, there was a significant difference in the appendicular skeleton. The distal forearm in the vitamin D-supplemented group tended to gain, whereas the midforearm lost significant bone mass. The trend was reversed in the group without vitamin D-supplementation, a more favorable pattern. Therefore, vitamin D supplements should not, as a rule, be provided to such patients. The biochemical hallmark of the fluoride-induced changes is a slight rise of the alkaline phosphatase within the normal range. Alkaline phosphatase levels that exceed the upper limit of normal signal a warning that too much fluoride and/or too little calcium supplements are being administered, or that a fluoride-related complication is impending or has occurred (e.g., a stress fracture). Osteosclerosis was achieved in 69% of the cases who had a radiological followup of at least four years (average period of appearance: 1.8 years). Stress fractures in the lower limbs occurred in 17 patients, almost exclusively in females, and appeared on average 2.2 years after initiation of therapy. In this group of stress fractures there was significant cortical bone loss at midforearm.(ABSTRACT TRUNCATED AT 400 WORDS)

The metatarsal cytochemical bioassay of parathyroid hormone: validation, specificity, and application to the study of pseudohypoparathyroidism type I.

The most sensitive method for assaying the bioactivity of PTH in unextracted plasma is the renal cytochemical bioassay. However, PTH acts on bone as well as kidney and clinical studies have suggested that the actions of circulating PTH level may be different at the two sites. We developed cytochemical bioassay for PTH based on the stimulation of glucose 6-phosphate dehydrogenase activity in the hypertrophic chondrocytes of the growth plate and the osteoblasts lining the metaphyseal trabeculae of rat metatarsal bones. The index of precision was 0.14 +/- 0.02 (SE) and the interassay variation was 31%. With this assay, plasma bioactive PTH levels in normal subjects and patients with primary hyperparathyroidism ranged from 0.5-18 ng/L and from 27-850 ng/L, respectively. Studies of patients with pseudohypoparathyroidism type I indicated that plasma PTH bioactivity in such patients is greater in the metatarsal bioassay than in the renal bioassay; no such differences were found in normal subjects or patients with primary hyperparathyroidism.

Inhibition of cytochemical bioactivity of parathyroid hormone by plasma in pseudohypoparathyroidism type I.

Despite the high circulating levels of immunoreactive PTH in patients with pseudohypoparathyroidism type I (PSPI) the levels of bioactive PTH (bioPTH) have been found to be close to the normal range. To elucidate this dissociation, we have studied the recovery of the biological activity of bovine PTH added to the plasma of patients with either PSPI, or with hypoparathyroidism (PTX), primary hyperparathyroidism (HPT) or of normal subjects. In PSPI (n = 10) the recovery of biological activity was 5.6% +/- 3.6 (mean +/- SEM) whereas in PTX (n = 7), in HPT (n = 4) and in normal subjects (n = 8) it was 79% +/- 5, 75% +/- 9 and 68% +/- 4, respectively. In another PSPI patient, who had undergone total parathyroidectomy, bioPTH was undetectable but the recovery from the plasma of added PTH was 84%. Thus we have found inhibition of PTH bioactivity by plasma of PSPI patients which was absent after parathyroidectomy.

Biological and radiological responses to oral etidronate and tiludronate in Paget's disease of bone.

Paget's disease of bone is characterized by a high bone turnover. Therefore, antiresorbing agents such as bisphosphonates are clearly indicated. However, as they accumulate in the pagetic lesions, they could produce some focal defects of bone mineralization. In a double-blind study, we have had the opportunity to compare the effects of tiludronate and of etidronate (both at a fixed dose of 400 mg/day orally) on the radiological changes of 12 patients suffering from Paget's disease of bone. After breaking the code, good agreement was observed between the radiological evaluations and the applied therapy: All positive bone balances were observed in the tiludronate group, except for three questionable densifications in the etidronate group, and the negative bone balances in the etidronate group. This confirms our previous experience with etidronate in Paget's disease when X-ray films of the lesions are followed sequentially during therapy.

Effects of tenoxicam and aspirin on the metabolism of proteoglycans and hyaluronan in normal and osteoarthritic human articular cartilage.

1. As nonsteroidal anti-inflammatory drugs may impair the ability of the chondrocyte to repair its damaged extracellular matrix, we explored the changes in the metabolism of newly synthesized proteoglycan (PG) and hyaluronan (HA) molecules produced by tenoxicam and aspirin in human normal cartilage explants and in osteoarthritic (OA) cartilage from age-matched donors. 2. Explants were sampled from the medial femoral condyle and were classified by use of Mankin's histological-histochemical grading system. Cartilage specimens were normal in 10 subjects, exhibited moderate OA (MOA) in 10 and had severe OA (SOA) in 10. 3. Cartilage explants were pulsed with [3H]-glucosamine and chased in the absence and in the presence of either aspirin (190 micrograms ml-1) or tenoxicam (4-16 micrograms ml-1). After papain digestion, the labelled chondroitin sulphate ([3H]-PGs) and HA([3H]-HA) molecules present in the tissue and media were purified by anion-exchange chromatography. 4. In normal cartilage as well as in explants with MOA and SOA aspirin reduced more strongly PG and HA synthesis than the loss of [3H]-HA and [3H]-PGs. 5. In normal cartilage, tenoxicam did not affect PG metabolism whereas it reduced HA synthesis in a dose-dependent manner and did not change or even increased the net loss of [3H]-HA. In contrast, in OA cartilage, tenoxicam produced a stronger reduction in the loss of [3H]-PGs than in PG synthesis and this decrease occurred at lower concentrations in cartilage with SOA (4-8 micrograms ml-1) than in cartilage with MOA (8-16 micrograms ml-1). In cartilage with MOA, the metabolic balance of HA was unaffected by tenoxicam whereas in cartilage with SOA, the drug decreased the loss of [3H]-HA and concomitantly did not change or even increased HA synthesis.6. The data obtained in short-term in vitro cultures indicate that aspirin may produce OA-like changes in normal cartilage and is likely to worsen the disease process in OA tissue. On the other hand, although tenoxicam may reduce the HA content of normal cartilage, and, in so doing, may produce OA-like lesions, this drug should not per se accelerate joint failure in OA.

Pustulotic arthro-osteitis in children and adults. A report of 13 cases.

Thirteen cases of pustulotic arthro-osteitis are reported: 3 children and 10 adults. The clinical and radiological aspects of this rare entity are discussed as well as the classification of this disease in the context of seronegative spondyloarthropathies.

Low bone mass in hypogonadal males. Effect of testosterone substitution therapy, a densitometric study.

Sixteen (16) male patients who were suffering from hypogonadism but who were free from bone symptoms were recruited from the Andrology Clinic. Their bone mineral density (BMD) was assessed by single photon absorptiometry in the non-dominant radius, at both the distal radius (DR) (27% trabecular bone) and the midshaft radius (MR) (90% cortical bone). Measurements were carried out before and during testosterone substitution therapy. BMD was found to be lower in the subjects than in the controls, to a similar extent at both the DR (0.47 +/- 0.02 g/cm2, i.e. 83.1 +/- 4.3% of the value in the controls, or Z score -1.42 +/- 0.39; P less than 0.01) and the MR (0.68 +/- 0.02 g/cm2, i.e. 87.8 +/- 2.4% of the value in the controls, or Z score -1.49 +/- 0.33; P less than 0.01). There was no correlation between testosterone levels and BMD at either the DR or the MR at the beginning of the study. Following testosterone substitution therapy, bone mineral content (BMC) increased significantly at the DR (+5.9 +/- 1.4% per year; P less than 0.01) and at the MR (+1.1 +/- 0.9% per year; P less than 0.01). If the study is limited to the subjects who had achieved full bone age maturity before the start of therapy, the bone gain remains significant only at the DR, a site with a sizeable proportion of trabecular bone.

Long-term effects of percutaneous estradiol on bone loss and bone metabolism in postmenopausal hysterectomized women.

OBJECTIVE: To determine whether percutaneous estradiol (pE2) (1.5 mg/day) is able to counteract the postmenopausal bone loss in postmenopausal hysterectomized women, in a double-blind study versus oral estriol (E3) (2 mg/day). METHODS: The bone mineral density of the lumbar spine (LS) and of the proximal femur (PF) was measured every 3 months by dual energy X-ray absorptiometry for 2 years in 43 hysterectomized postmenopausal women (21 in the E2 group and 22 in the E3 control group), and in a subset of patients for a 3rd year. The statistical analyses were performed on Macintosh using Stat View II. RESULTS: A significant bone loss of 1.2 (0.4%)% and of 1.3 (0.3)% per year was observed in the control group, respectively at LS and at PF, versus a significant gain of 1.2 (0.5)% per year in the treated group at the LS. No significant change at PF occurred in the treated group. In the 20 patients followed up for a 3rd year on pE2, an increase of 1.2 (0.9) and 2.5 (1.4)% at LS in the 12 former active group patients and the eight formerly control patients, respectively was seen. The same trend was observed at the proximal femur. CONCLUSION: pE2 (1.5 mg E2) is able to counteract the postmenopausal bone loss in hysterectomized women, whereas E3 (2 mg/day administered orally) is unable to maintain bone mass.

Fluoride therapy of type I osteoporosis.

Sodium Fluoride (NaF) is the only medication so far clinically available with a bone formation stimulating property, through its peculiar mitogenic dose-dependent action on the osteoblast cell line. Bone strength is commensurate to bone mass, and in a condition with fragility fractures, like osteoporosis, it seems logical to restore bone mass without weakening bone strength. However, as with any active drug. NaF therapy requires adhesion to elementary rules if drawbacks are to be prevented. A first mandatory rule is not to prescribe NaF without calcium supplementation, if bone loss at the appendicular skeleton is to be avoided; to prevent this, the availability of monofluorophosphate (MFP), containing the fluoride and calcium salts in the same preparation has enhanced the compliance to calcium supplementation. A second rule is not to give supraphysiological doses of vitamin D, for the same reason. Third, if one wants to avoid a calcium shift from cortical to trabecular bone and osteomalacia, one should use small doses of NaF, of the order of 50 mg/day. With this in mind, the bioavailability of the drug has to be taken into account, particularly its gastrointestinal absorption which is dramatically enhanced if a plain non entericoated (EC) capsule is used, as compared to that of an EC tablet with the same face value. Too much NaF is deleterious to bone, a fact known for years. Already in 1972, it was noted that in all patients receiving 60 mg or more of NEC NaF, daily, morphologically abnormal bone developed and which appeared irregular and contained areas of incompletely mineralized bone. The bone was histologically and microradiographically normal in patients receiving 45 mg or less of NEC NaF/day. Fourth, NaF therapy is contraindicated in renal insufficiency owing to an enhanced retention in the skeleton. NaF is, however, by no means the ideal medication, because its therapeutic window is narrow. It has many bothersome drawbacks, and notably it is irritating for the gastric mucosa, a hazard which may be partly circumvented by the use of an Ec or slow release tablet. Furthermore, peripheral stress fractures may occur, and, in our experience, they were seen in 17% of patients, almost exclusively in females with a low lumbar BMD. Their occurrence should be curtailed by not allowing an increase in alkaline phosphatase activity of more than 50%. This is a relatively benign complication, because no stress fracture degenerated into a complete fracture. In all cases, the stress fractures healed after a transitory drug discontinuation. If there is some concern about cortical bone, NaF therapy may be associated with an antiresorber like estrogens which will prevent any further bone loss, and does not impair the response to NaF. NaF therapy should be reserved for patients suffering chiefly from trabecular osteoporosis and should be avoided in senile osteoporosis, because of a frequently impaired renal function. Currently, we would recommend in clinical practice a daily dose of 50 mg EC-NaF or 150 mg Ca-MFP as the therapy of involutional osteoporosis in women, reserving the dose of 75 mg EC-NAF or 200 mg MFP for males or female patients resistant to lower dose. The therapy should be maintained for 2 to 3 years, or more, according to the bone response, taking into account that patients with the vertebral crush fracture syndrome have lost on average 30%, as compard to the young adult mean.

Adrenocortical function and responsiveness to tetracosactrin infusions after intra-articular treatment with triamcinolone acetonide and hydrocortisone acetate.

The urinary free cortisol (UFC) output, considered a parameter of the action of the exogenous corticosteroid on the hypothalamo-pituitary axis, was followed in five patients who received a total of 12 intra-articular (i.a.) injections of 40 mg of triamcinolone acetonide (TCA) distributed over eight treatment sessions. The effect of intra-articular TCA injections on UFC output was null after three treatment sessions, transient (48 hr) after another three, and more prolonged (6 days), although slight, after the remaining two sessions. These results contrast with the lasting and profound inhibition of the UFC output induced either by the same TCA dose given intramuscularly, or by oral administration of dexamethasone to 30 normal subjects, 0.75 mg at 8-hourly periods for 48 hours. Adrenocortical reactivity, as measured by the response to synthetic ACTH (tetracosactrin) of both plasma cortisol levels and UFC output, was studied in another five patients prior to and after eight i.a. injections of 40 mg of TCA, and in three patients after six i.a. injections of 25-100 mg of hydrocortisone acetate. No decrease was observed after the i.a. injections of HCA. Considered as a group the response to tetracosactrin after TCA injections was not significantly altered. Two patients showed a decreased response of both UFC and plasma cortisol, although their values remained within the limits of those obtained in 44 normal control subjects. In contrast, profound inhibition of the tetracosactrin induced response occurred in a control group of 30 subjects given 0.75 mg of dexamethasone orally at 8-hourly periods for 48 hours.

Hemidiaphragmatic paralysis, an unusual presentation of Parsonage-Turner syndrome.

A previously healthy 38-year-old man presented a typical Parsonage-Turner syndrome (PTS) three weeks after a cold and unusual muscular exercise. In addition to the motor and sensory defects of the upper limbs, a right hemidiaphragmatic paralysis occurred, which proved to be reversible after several months. A brief review of the hemidiaphragmatic injury in PTS is presented.

Axonal polyneuropathy without vasculitis, follicular lymphoma and primitive sicca syndrome. A rare association.

A woman suffering from primary Sjögren's syndrome developed sensitive neuropathy. The disease was further complicated by follicular lymphoma, an unusual albeit already described complication of Sjögren's disease. The clinical data suggest that mononuclear infiltration of the dorsal root ganglions could be at the origin of a sensitive neuropathy, inducing an axonal degeneration of the nerves.

Intra-articular calcification in progressive systemic sclerosis.

Subcutaneous and periarticular dystrophic calcifications are well known to be associated with progressive systemic sclerosis (PSS). On the other hand, calcifications inside the joints are very rarely reported. We report a new case of this unusual complication of PSS. The observation of the complete radiological follow-up led us to propose a mechanical rather than a purely inflammatory pathogenetic mechanism of this complication.

Septic Streptococcus milleri prepatellar bursitis.

The osteoarticular affinity of Streptococcus milleri has only recently been recognized. We report a case of septic prepatellar bursitis caused by this pathogen. The recent literature concerning osteoarticular involvement by S. milleri is reviewed.

A rare case of primary skeletal muscle lymphoma: the value of octreotide scintigraphy.

We report a case of non-Hodgkin lymphoma presenting as a painless mass of the quadriceps femoris muscle that was detected by a somatostatin analogue (octreotide) scintigraphy. We review the few reported cases of primary muscular lymphoma and discuss the potential value of octreotide imaging as a new diagnostic tool.

Antacid-induced osteomalacia.

The case of a 49-year-old woman suffering from generalized skeletal pain and multiple fractures accompanied by severe hypophosphataemia and low urinary phosphorus excretion is reported. She had been taking large amounts of antacids containing aluminum hydroxide for many years. A diagnosis of antacid-induced osteomalacia was made. It was confirmed by biological work-up, radiographs and bone biopsy. A dramatic biological, osteodensitometric, and clinical improvement was achieved by withdrawal of antacids and phosphorus administration. The literature concerning this unusual condition has been reviewed.

1,25-Dihydroxyvitamin D-related hypercalcemia in lymphoma: two case reports.

We report two patients with non-Hodgkin's lymphoma in whom hypercalcemia and elevated 1,25 dihydroxyvitamin D (1,25-(OH)2D3) levels developed in the absence of any lytic bone lesions. Hypercalcemia responded only transiently to glucocorticoids which were ill tolerated. Intravenous APD administration was needed to circumvene hypercalcemia. Humoral hypercalcemia of malignancy is discussed. Our cases confirm that hypercalcemia associated with elevated 1,25-(OH)2D3 may occur in malignant lymphoma.

Paget's sarcoma--with two illustrative cases.

Two cases of Paget's sarcoma of bone are described. The first one is mainly characterized by the almost simultaneous degeneration of the only two existing locations of the underlying Paget's disease. The second case is one of monostotic Paget's disease of the scapula disclosed by the malignant degeneration.