Genaro M. A. Palmieri

Calcium paradox disease: Calcium deficiency prompting secondary hyperparathyroidism and cellular calcium overload

The consequences of such Ca overload in response to Ca deficiency, which can be called Ca deficiency disease or Ca paradox disease, to be more explicit, include osteoporosis, hypertension, arteriosclerosis, degenerating diseases of the central nervous system such as Alzheimer’s disease, diabetes mellitus, muscular dystrophy, and malignancy, especially colorectal carcinoma. In this review, evidence supporting the concept of calcium paradox disease is presented from the viewpoints of epidemiology, clinical evidence, experimental models, and cell biology.

Effect of calcitonin and vitamin D in osteoporosis.

SummaryVitamin 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 (<150 MRC U/week) doses of calcitonin in postmenopausal osteoporosis.

Effects of long-term administration of methotrexate on bone mineral density in rheumatoid arthritis.

Abstract. Because previous studies of high-dose methotrexate usage have demonstrated an effect on bone formation and resorption, this study was done to determine whether long-term, low-dose use of methotrexate for the treatment of rheumatoid arthritis causes bone loss. Bone mineral density (BMD) of the lumbar spine and hip was measured in 10 Caucasian postmenopausal women who had never received methotrexate and 10 Caucasian postmenopausal women who had received the drug for 3 or more years. There were no significant differences in BMD at the lumbar spine (L2–L4) between patients who had used long-term methotrexate compared with patients never treated with methotrexate (1.08 ± 0.08 g/cm2 versus 0.98 ± 0.14 g/cm2, respectively; P= 0.08). Similarly, there were no significant differences in BMD at the femoral neck between methotrexate users and nonusers (0.81 ± 0.08 g/cm2 versus 0.76 ± 0.15 g/cm2, respectively; P= 0.42). These results suggest that long-term low-dose methotrexate treatment for rheumatoid arthritis is not associated with accelerated bone loss.

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.

Case Report: Oral Calcium Chloride in Hypoparathyroidism Refractory to Massive Doses of Calcium Carbonate and Vitamin D

ABSTRACT Surgically induced hypoparathyroidism often responds satisfactorily to intravenous Ca administration, oral CaCO 3 and vitamin D 2 . A 17-year-old girl developed hypoparathyroidism following partial thyroidectomy for thyrotoxicosis. Hypocalcemia was refractory to treatment with massive doses of vitamin D 2 , up to 150,000 U, 3—6 gm of oral Ca as CaCO 3 and 2 µg of 1,25—dihydroxycholeca ciferol 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 CaCl 2 (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 CaCO 3 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% CaCl 2 solution and 1 gm as CaCO 3 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 CaC0 3 and vitamin D may be caused by achlorhydria. Oral administration of CaCl 2 solution can promptly correct this defect. Monitoring of serum Cl and CO 2 is needed to avoid hyperchloremic acidosis.

Octreotide Enhances Positive Calcium Balance in Duchenne Muscular Dystrophy

ABSTRACT: 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 &mgr;g/kg, subcutaneously, every 8 hours) reduced serum growth hormone and somatomedin (IGF‐1) to levels found in growth hormone deflciency. 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.

The parathyroid glands and osteoporosis

Parathyroid hormone (PTH) may cause bone rarefaction by mobilization of Ca, but its role in osteoporosis has not been fully established. The majority of patients with osteoporosis have normal serum levels of PTH, but, histomorphometric evaluation of bone biopsies suggests the presence of hyperparathyroidism in senile osteoporosis. Postsurgical hypoparathyrodism, on the other hand, results in elevation of bone densitometry preventing the age-related loss of bone mass.Previous animal studies and recent investigations from our laboratories of patients with postsurgical hypoparathyroidism suggest that parathyroid ablation prevents the expected bone loss caused by well known risk factors for osteoporosis such as immobilization, chronic treatment with glucocorticoids, renal failure, etc. It would appear as if PTH is required for the development of osteoporosis. Thus, reduction of PTH secretion by oral Ca supplementation or inhibition of the action of the hormone in bone by estrogens, could explain, at least in part, the beneficial effects of these agents in osteoporosis.