Diltiazem in the treatment of calcinosis in juvenile dermatomyositis.

Subcutaneous calcifications occur in a variety of diseases, including juvenile dermatomyositis. These calcifications cause disabling symptoms that do not always respond to immunosuppressant therapy. The calcium antagonist diltiazem reduces subcutaneous calcifications in CREST syndrome and in isolated cases of children with dermatomyositis. Our study was performed to determine the effects of diltiazem when used as adjunctive therapy in children with dermatomyositis.

Effect of calcitriol and pamidronate in multiple myeloma.

Addition of bisphosphonates to standard treatment of multiple myeloma (MM) decreases bone pain and skeletal events without influencing bone healing. Calcitriol, besides its established effects on bone remodeling and calcium metabolism, has both immunoregulatory and cell differentiating effects in vitro and in vivo. Moreover, low serum calcitriol has been reported in MM. We tested the effects of supportive treatment with calcitriol and pamidronate on bone disease in two stage-III-B MM patients with diffuse bone involvement, normal serum calcium, and low serum calcitriol. Complete blood counts, serum calcium, creatinine, quantitative serum and urine immunoglobulins, and biochemical indices of bone turnover, serum calcidiol, calcitriol, parathyroid hormone, skeletal radiographs, and bone mineral density by dual x-ray absorbtiometry were measured every 1-6 months for 16 months in the first patient and 7 months in the second patient. Both patients showed a dramatic improvement of MM activity and in bone disease documented by serial radiographs in the first patient and by increased bone mineral density (approximately 15%) in the second. The reduced serum calcitriol in both patients and the elevated parathyroid hormone observed in the first patient before treatment returned to normal. Supportive treatment with pamidronate does not induce bone healing in MM. Therefore, the results observed with the addition of calcitriol suggest that this hormone may have contributed to the apparent arrest of the progression of MM and caused stimulation of bone healing.

Changes in bone mineral content in male athletes. Mechanisms of action and intervention effects.

OBJECTIVES: To determine changes in bone mineral content (BMC) in male athletes, to examine the mechanisms of changes, and to evaluate the effects of intervention. DESIGN: Dual-energy x-ray absorptiometry (DEXA) tests were administered over a 2-year period, and calcium loss during training was determined by analysis of sweat and urine. Calcium supplementation was administered during year 2. SETTING--A midsouth university. PARTICIPANTS: Eleven members of a college Division I-A basketball team. INTERVENTION: Based on observed calcium loss, athletes received differential levels of calcium supplementation. Intervention commenced the week prior to the fall training season and continued through postseason play. MAIN OUTCOME MEASURE--Changes in BMC. RESULTS: Total body BMC decreased 3.8% from preseason to midseason of year 1 (mean decrease, 133.4 g, P = .02), increased nonsignificantly by 1.1% (mean increase, 35.3 g, P = .22) during the offseason, but decreased an additional 3.3% during summer months when practices resumed (mean decrease, 113.1 g, P = .01). Dermal calcium loss averaged 247 mg [corrected] per training session. From preseason to late summer, there was an overall decrease of 6.1% in total BMC and a 10.5% decrease in BMC of the legs. Calcium supplementation was associated with significant increases in BMC and lean body mass. CONCLUSIONS: Bone loss is calcium related and exercise is positively related to BMC provided that calcium intake is sufficient to offset dermal loss.

Treatment of calcinosis with diltiazem.

OBJECTIVE: To test the hypothesis that the calcium antagonist diltiazem is effective in the treatment of calcinosis. METHODS: Diltiazem, 240-480 mg/day, was given to 4 patients with idiopathic or CREST-related (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) calcinosis for 1-12 years. Serial radiographs of the affected areas, using identical technique, and clinical evaluations were obtained. A fifth patient, who did not tolerate diltiazem, received verapamil, 120 mg/day for 18 months. RESULTS: All patients taking diltiazem had a reduction or disappearance of the calcific lesions, with striking clinical improvement. One patient's case was followed for 12 years. The response to diltiazem during the first 5 years of treatment has been previously reported in detail; however, over 7 years of additional treatment, there was further reduction of the lesions. One patient developed a large calcific lesion while receiving verapamil for hypertension, and after verapamil was replaced with diltiazem, there was a dramatic response. Verapamil was ineffective in the fifth patient, who did not tolerate diltiazem. CONCLUSION: Long-term treatment with diltiazem, but not verapamil, is effective in calcinosis.

Osteoporosis of pregnancy: long-term follow-up of patients and their offspring.

BACKGROUND: The usual course of osteoporosis of pregnancy is complete resolution without recurrence. We report the 10-year follow-up of two patients with osteoporosis of pregnancy and their offspring. CASES: A 30-year-old woman presented with right hip pain at 30 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. A dual-energy x-ray absorptiometry performed on the 11-year-old daughter of this pregnancy showed osteopenia. A 26-year-old woman presented with left hip pain at 16 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. Dual-energy x-ray absorptiometry performed on the 13-year-old daughter of this pregnancy showed osteopenia. CONCLUSION: Osteoporosis of the hip discovered during pregnancy may not be a transient process and should prompt a search for osteopenia in both mother and offspring.

Octreotide enhances positive calcium balance in Duchenne muscular dystrophy.

Although receptors for somatostatin are found in bone cells, the effect of somatostatin analogs on calcium metabolism is unknown. The authors studied, in a metabolic ward, the effect of octreotide (a long-acting somatostatin analog) and a placebo in two 6-day calcium balance periods in 8 children with Duchenne muscular dystrophy. As expected, octreotide (2 micrograms/kg, subcutaneously, every 8 hours) reduced serum growth hormone and somatomedin (IGF-1) to levels found in growth hormone deficiency. Octreotide enhanced calcium retention by 30% (96 mg daily [P < 0.04]) in 7 boys for whom complete data (diet, urine, and fecal calcium) were available. In 6 children with urinary calcium excretion (Uca) greater than 50 mg daily, octreotide markedly lowered Uca, from 114 +/- 23 mg daily to 61 +/- 9 mg daily (P < 0.03). Calcium retention occurred in patients with or without initial hypercalciuria, but the higher the basal Uca, the greater was the inhibition by octreotide (r = 0.79; P < 0.03). Inactive, nonambulatory patients had a more pronounced response of Uca to octreotide (P < 0.02). Octreotide caused a mild, nonsignificant reduction in fecal calcium, with no major changes in serum calcium, phosphorus, parathyroid hormone, urinary excretion of sodium and potassium, or in creatinine clearance. Based on the current observations and the presence of receptors for somatostatin in bone cells, this hormone may have, at least on a short-term basis, an anabolic effect on calcium, perhaps favoring its deposition in bone.

Hypoparathyroidism counteracts risk factors for osteoporosis.

Although increased bone density has been reported in patients with hypoparathyroidism, it is not known whether hypoparathyroidism can overcome the influence of risk factors for osteoporosis and whether the increased bone density is uniform throughout the entire skeleton or greater in certain regions depending on the bone composition and location. In the current study, bone density was measured in patients with postsurgical hypoparathyroidism and risk factors for osteoporosis. Bone mineral density was determined in eight patients with postsurgical hypoparathyroidism, one with idiopathic hypoparathyroidism, and two with pseudohypoparathyroidism in eight different areas of the skeleton using well established methods: single photon absorptiometry of the radius, dual energy x-ray absorptiometry of the spine, hip, and the whole skeleton, and quantitative computed tomography of the spine. Risk factors for osteoporosis were documented in each subject. The data showed that despite the presence of 1-4 risk factors for osteoporosis, patients with postsurgical hypoparathyroidism had bone mineral density above the normal mean in most locations. The locations with the highest increment were the Ward's triangle and the trochanter area of the proximal femur (dual energy x-ray absorptiometry) (Ward's: Z score + 1.59 +/- 0.57, P < 0.03; trochanter 1.31 +/- 0.42, P < 0.02). The elevation of bone density was not observed in one patient with idiopathic hypoparathyroidism, and variable results were observed in two patients with pseudohypoparathyroidism. Based on these findings, in postsurgical hypoparathyroidism, the bone mineral density is above the normal mean despite the presence of risk factors for osteoporosis, and both cortical and trabecular bone are affected.

Calcium, why and how much?

Although calcium (Ca) is pivotal for the prevention of osteoporosis, its role in the prevention of other unrelated diseases such as arterial hypertension, cancer of the colon and nephrolithiasis is perplexing. No unitarian hypothesis explaining these unrelated effects of Ca has been postulated. Cytosolic Ca concentration is 10,000-fold lower than in the extracellular space, and this gradient is tightly maintained. Abnormal elevation of cytosolic Ca causes cell damage and death. Parathyroid hormone is a Ca agonist and the suppression of its secretion by Ca could explain the beneficial role of Ca intake in multiple diseases. Thus, parathyroid ablation improves hypertension in rats and cardiomyopathy in hamsters. Since anthropologic data suggests a higher Ca intake, of approximately 1,600 1,600 mg/day, in preneolithic than in modern diets, it is likely that our levels of PTH on genetically predisposed subjects with a loose cellular Ca control may aggravate frequent modern diseases and the process of aging. A higher Ca intake in both sexes should be one of the goals of preventive medicine of our time.

Case report: long-term remission of parathyroid cancer: possible relation to vitamin D and calcitriol therapy.

Recurrence of surgically treated parathyroid cancer occurs in 30% to 65% of patients and has a poor prognosis; only 1 of 29 cases remained normocalcemic more than 2 years later. No medical attempts to prevent recurrence have been reported. A 24-year-old pregnant woman whose mother died of parathyroid cancer underwent apparently successful surgery for parathyroid cancer. Serum Ca and parathyroid hormone (PTH) returned to normal levels but 3 months after surgery, although normocalcemic, the serum PTH level was elevated. The administration of vitamin D 200,000 U/month or calcitriol 0.5 microgram daily and 1 g of Ca supplementation daily, resulted in the normalization of PTH during 81 months of follow-up. On three occasions, when vitamin D or calcitriol were omitted, serum intact, C-terminal, or mid-molecule PTH levels rose. Ionized and total serum Ca, creatinine, calcitriol and calcidiol levels were normal, and multiple ultrasounds of the neck remained negative after surgery. This observation suggests that serum PTH could be an early marker for the detection of recurrence in parathyroid cancer with normal serum Ca, and that suppression of PTH secretion by vitamin D or calcitriol could avert or delay the progression of recurrence. Additional trials with calcitriol in operated normocalcemic parathyroid cancer with an elevated serum PTH level is recommended.

Black bones following long-term minocycline treatment.

During a surgical procedure, black vertebrae were observed in a 42-year-old white woman. An undecalcified iliac crest bone biopsy specimen revealed intense fluorescence compatible with tetracycline labeling and osteoporosis. A urinary screening test was negative for amino acids. The patient had been treated with minocycline hydrochloride (100 to 300 mg/d) for at least 6 years. Since minocycline is known to discolor many body tissues, it is likely that the black discoloration of bone in our patient was caused by the long-term intake of the antibiotic.

Effect of dantrolene in Duchenne muscular dystrophy.

We have demonstrated that maneuvers capable of reducing Ca influx into cells have beneficial effects in dystrophic hamsters and Duchenne muscular dystrophy. Since dantrolene inhibits Ca release from the sarcoplasmic reticulum, its effects on DMD was studied in 7 patients of 6 to 13 years of age (mean 10.8 years). Patients were studied for 4 years with tri-monthly evaluations of manual muscle testing (MMT), functional activity, and serum CK and aldolase. During the first 2-year period, no medicines were given and served as control. In the second 2-year period, dantrolene 8 mg/kg/d was administered. No side effects were observed. In 1 patient, mild weakness occurred that disappeared when the dose was reduced to 6 mg/kg/d. The 95% confidence limit for the difference in slopes of regression lines from tri-monthly MMT was asymmetric in favor of dantrolene in 5 of 7 patients. Serum CK did not differ between the first and second year of the control and treatment periods, respectively. However, it fell significantly from the second year of control to the first year of treatment (P = 0.003). The fall during the first year of treatment was significantly greater (P less than 0.01) than in age-matched natural history controls during the same length of observation. There was a 3-fold reduction in CK when the pooled values of the first and second year control vs. treatment periods were analyzed. No changes were observed in functional activity and serum aldolase. The data suggest that dantrolene reduces serum CK in DMD associated with a lessening trend in MMT deterioration.

The effect of diltiazem on calcinosis in a patient with the CREST syndrome.

We describe a patient with a 23-year history of progressive calcinosis and features of the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) who was treated with diltiazem, 240 mg/day, for 5 years. No clinical exacerbation of calcinosis occurred during treatment. Radiographs showed no new lesions, and there was reduction in the size of the existing lesions. Bone scans revealed a progressive decrease in the uptake of the radionuclide by soft tissue foci. We propose that diltiazem may stop the progression of calcinosis by reducing the cellular calcium influx in affected tissues.

Effect of calcitonin and vitamin D in osteoporosis.

Vitamin D has complex effects in bone: it stimulates matrix formation and bone maturation but also enhances osteoclastic activity and may influence differentiation of bone cell precursors. Calcitonin inhibits the function of osteoclasts, reducing bone resorption, thus, the combination of vitamin D and calcitonin could result in a positive bone balance. We tested the hypothesis that chronic treatment with high doses of vitamin D (150,000 U/week), moderate doses of salmon calcitonin (120 MRC U/week), and adequate Ca supplementation (1 g/day) could be beneficial in osteoporosis. Thirteen women with postmenopausal osteoporosis received this treatment for 2-6 years (mean 3.5 years). No side effects, hypercalcemia, or hypercalciuria occurred. There was marked reduction in bone pain. The fracture rate in 11 patients with vertebral compression fracture was 240/1,000 patient years, threefold lower than the reported 834 fractures for untreated patients of similar age. Single photon bone densitometry of the radius did not change. Iliac crest bone biopsies obtained at the initiation and conclusion of the study showed a 43% increment in trabecular bone volume (P = 0.0003), without changes of the normal osteoid thickness, surface, and volume. Because single photon densitometry reflects mostly cortical bone, the data suggest that the combination of vitamin D and calcitonin increases trabecular bone mass and prevents the fall of cortical bone mass in osteoporosis. Previous reports suggest that calcitonin alone or with small doses of vitamin D increased bone mass for about 2 years. The present study suggests a prolonged beneficial effect of the combination of high doses of vitamin D with rather moderate (less than 150 MRC U/week) doses of calcitonin in postmenopausal osteoporosis.

Oral calcium chloride in hypoparathyroidism refractory to massive doses of calcium carbonate and vitamin D.

Surgically induced hypoparathyroidism often responds satisfactorily to intravenous Ca administration, oral CaCO3 and vitamin D2. A 17-year-old girl developed hypoparathyroidism following partial thyroidectomy for thyrotoxicosis. Hypocalcemia was refractory to treatment with massive doses of vitamin D2, up to 150,000 U, 3-6 gm of oral Ca as CaCO3 and 2 micrograms of 1,25-dihydroxycholecalciferol per day. Intravenous Ca gluconate (360 mg of elemental Ca/d, in divided doses) was needed to correct tetany. After 25 days of unsuccessful therapy, oral administration of 30 ml of a 10% solution of CaCl2 (1.09 gm of elemental Ca) was followed by normalization of serum Ca (8.9 mg/dl) within 7 hours. This dose was repeated every 8 hours for 6 days and oral CaCO3 and IV Ca gluconate were discontinued. Serum Ca remained within normal range but hyperchloremic acidosis developed. This was corrected by providing, in addition to vitamin D, 2 g/d of Ca supplementation, 1 gm in the form of 10% CaCl2 solution and 1 gm as CaCO3 in two doses given simultaneously. During 12 months of observation, serum Ca, P and Cl have been consistently within normal limits. This patient was found to have achlorhydria, unresponsive to normalization of thyroid function and serum Ca. These findings indicate that refractoriness to oral CaCO3 and vitamin D may be caused by achlorhydria. Oral administration of CaCl2 solution can promptly correct this defect. Monitoring of serum Cl and CO2 is needed to avoid hyperchloremic acidosis.

Pamidronate sodium and calcitonin-resistant Paget's disease. Immediate response in a patient.

One three-day course of intravenous pamidronate sodium (3-amino-1-hydroxypropylidene-1,1-bisphosphonate), 30 mg/d, in a patient with calcitonin-resistant Paget's disease resulted in the following: marked clinical improvement within two weeks; normalization of urinary hydroxyproline value; fall of serum alkaline phosphatase value (900 to 250 U/L); a rise in serum osteocalcin value by the tenth week that returned to pretreatment levels in the 16th week; transient hypocalcemia with elevation of parathyroid hormone value; reduction in urinary calcium excretion; and improvement in bone scans. No adverse reactions occurred, with the exception of mild and transient hyperpyrexia for 48 hours during pamidronate administration. White blood cell counts did not change and serum interleukin 1 was undetectable before and after treatment with pamidronate. Pamidronate seems to be highly effective in the treatment of Paget's disease of the bone, but its profound effects on mineral and bone metabolism require close monitoring during the short-term period of intravenous treatment.