cholecalciferol and Osteitis-Deformans

Vitamin D receptor antagonist has attracted significant level of interests because of its potential utility in the treatment of Paget's disease, which is known as the most flagrant example of disordered bone remodeling and the second most common bone disease after osteoporosis in Anglo-Saxons. Recent studies on Paget's disease suggested a specific increase in osteoclasts sensitivity to the differentiation activity of active vitamin D(3) as the principal mechanism for abnormal bone formation. We set out to conduct a structure-activity relationship study on the first VDR antagonists of TEI-9647 and TEI-9648 (25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone) toward improved VDR antagonistic activity. Given that both potent agonists and antagonists must have high affinity for the VDR, we hoped that our accumulated knowledge in VDR agonists would help us identify potent antagonists. First, 2alpha-modified TEI-9647 analogs were synthesized, and then, 24-substitution was next investigated to stabilize its lactone structure under the physiological conditions. Finally, 2alpha-modified 24-methyl-, 24,24-dimethyl-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone analogs were synthesized. It was found that 2alpha,24,24-trimethyl-TEI-9647 was found to possess approximately 90-fold improved antagonistic activity (IC(50) 0.093 nM) over the original TEI-9647 (IC(50) 8.3 nM).

Topics: Calcitriol; Cholecalciferol; Drug Design; Lactones; Osteitis Deformans; Receptors, Calcitriol; Structure-Activity Relationship

Topics: Alkalosis; Benzothiadiazines; Calcinosis; Cholecalciferol; Diuretics; Humans; Hypercalcemia; Hyperparathyroidism; Isotretinoin; Lithium; Osteitis Deformans; Sarcoidosis; Sodium Chloride Symporter Inhibitors; Tamoxifen; Tretinoin; Vitamin A

Topics: Calcium; Calcium Metabolism Disorders; Cholecalciferol; Cushing Syndrome; Diagnosis, Differential; Fanconi Syndrome; Fractures, Bone; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism; Hyperthyroidism; Kidney Calculi; Nephrocalcinosis; Osteitis Deformans; Osteoporosis; Parathyroid Hormone; Sarcoidosis

Intravenous aminobisphosphonates (N-BPs) can induce an acute phase reaction (APR) in up to 40% to 70% of first infusions, causing discomfort and often requiring intervention with analgesics or antipyretics.. Our aim was to explore the risk factors of APR in a large sample of patients with Paget's disease of bone (PDB) and to assess the possible preventive effects of vitamin D administration.. An observational analysis was performed in 330 patients with PDB at the time of N-BP infusion. Then, an interventional study was performed in 66 patients with active, untreated PDB to evaluate if vitamin D administration (oral cholecalciferol 50 000 IU/weekly for 8 weeks before infusion) may prevent APR.. In a retrospective study, APR occurred in 47.6% and 18.3% of naive or previously treated patients, respectively. Its prevalence progressively increased in relation to the severity of vitamin D deficiency, reaching 80.0% in patients with 25-hydroxyvitamin D (25OHD) levels below 10 ng/mL (relative risk (RR) = 3.7; 95% confidence interval (CI) 2.8-4.7, P < .0001), even in cases previously treated with N-BPs. Moreover, APR occurred more frequently in patients who experienced a previous APR (RR = 2.8; 95% CI 1.5-5.2; P < .001) or in carriers of SQSTM1 mutation (RR = 2.3; 95% CI 1.3-4.2; P = .005). In the interventional study, vitamin D supplementation prevented APR in most cases, equivalent to a RR of 0.31 (95% CI 0.14-0.67; P < .005) with respect to prevalence rates of the observational cohort. A similar trend was observed concerning the occurrence of hypocalcemia.. The achievement of adequate 25OHD levels is recommended before N-BP infusion in order to minimize the risk of APR or hypocalcemia in PDB.

Topics: Acute-Phase Reaction; Administration, Oral; Aged; Aged, 80 and over; Bone Density Conservation Agents; Cholecalciferol; Dietary Supplements; Diphosphonates; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Osteitis Deformans; Prevalence; Retrospective Studies; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Adequate vitamin D status is essential for skeletal health. Paget's disease of bone (PDB) is a common metabolic skeletal disorder, but data regarding the vitamin D status in PDB patients are lacking. We performed a case-control study to estimate vitamin D status in 708 PDB patients and in 1803 healthy controls from Italy and an observational prospective study to evaluate the efficacy-safety profile of oral cholecalciferol treatment [400.000 International Units (UI) of cholecalciferol administered in cycles of 8 weeks until 25OHD levels reaches 70 nmol/L as primary therapy and 50.000 UI of cholecalciferol administered every 2 weeks for 52 weeks for the maintenance therapy] in 82 PDB patients with hypovitaminosis D, i.e., 25OHD < 50 nmol/L. The main outcome measures for the prospective study were 25OHD levels, metabolic risk factors (RF) for nephrolithiasis, bone pain score (BPS), and pain medication score (PMS). Over half of PDB patients had hypovitaminosis D. Among PDB patients treated with cholecalciferol, 76 patients reached 25OHD levels ≥ 70 nmol/L after the first cycle of primary therapy and the remaining six patients after a second cycle. The maintenance therapy guaranteed 25OHD levels ≥ 70 nmol/L during the entire follow-up. The increase in 25OHD levels reduced PTH, BPS, and PMS levels, without changes in RF for nephrolithiasis. We can conclude that (i) hypovitaminosis D is frequent in PDB patients, (ii) cholecalciferol significantly increased 25OHD levels in PDB patients, and (iii) the correction of hypovitaminosis D improves the quality of life of PDB patients without inducing significant changes in RF for nephrolithiasis.

Topics: Adult; Bone and Bones; Calcium; Case-Control Studies; Cholecalciferol; Female; Humans; Male; Middle Aged; Osteitis Deformans; Parathyroid Hormone; Prospective Studies; Quality of Life; Vitamin D; Vitamin D Deficiency; Vitamins

A 93 year-old woman with Paget's disease of bone had been treated with etidronate without interruption during 20 years. The daily dose was usual (5mg/kg/day) but this prescription had never been stopped by her physicians. Two fractures had already occurred in pagetic (right tibia) and non pagetic bones (right fibula) within the last 2 years, and she presented rib fractures, another right tibia fracture and right femur fracture during hospitalization time. X-rays films showed major osteolysis of left ulna and right tibia. Blood samples and technetium bone scan brought no evidence for sarcoma or lytic evolution of the disease. A transiliac bone biopsy on non pagetic bone site confirmed the diagnosis of osteomalacia (increased osteoid parameters), with secondary hyperparathyroidism (hook resorption). In Paget's disease of bone, continuous treatment by etidronate may induce generalized osteomalacia, and increase the risk of fracture in both pagetic and non-pagetic bones. Whereas physicians and pharmaceutical industry try to improve the observance of those drugs, this striking observation also points out that a prescription always needs to be updated.

Topics: Aged, 80 and over; Alkaline Phosphatase; Biopsy; Bone Density Conservation Agents; Calcification, Physiologic; Calcium Carbonate; Cholecalciferol; Etidronic Acid; Female; Femoral Fractures; Fibula; Fractures, Spontaneous; Humans; Hyperparathyroidism, Secondary; Iatrogenic Disease; Osteitis Deformans; Osteolysis; Osteomalacia; Parathyroid Hormone; Radionuclide Imaging; Rib Fractures; Tibial Fractures; Ulna; Vitamin D

Paget's disease is a relatively rare disorder of the bone with only a few reports and case series observations from India. Hypocalcaemia is rare in Paget's disease, usually occurring as a consequence of therapy with bisphosphonates. We report a 65-year-old woman with Paget's disease who had hypocalcaemia secondary to vitamin D deficiency. On further evaluation, she also had severe osteoporosis. How vitamin D deficiency affects the diagnosis and monitoring of Paget's disease and the relationship between the three diseases are discussed. This case illustrates an interesting situation with abnormal bone turnover, remodelling and mineralisation in the form of Paget's disease with osteomalacia and osteoporosis.

Topics: Absorptiometry, Photon; Aged; Bone and Bones; Bone Density; Calcium Carbonate; Cholecalciferol; Diphosphonates; Female; Humans; Hypocalcemia; Imidazoles; Lumbar Vertebrae; Osteitis Deformans; Osteomalacia; Vitamin D Deficiency; Zoledronic Acid

Topics: Animals; Calcitonin; Calcium; Cholecalciferol; Dihydroxycholecalciferols; Estrogens; Fluorides; Glucagon; Humans; Kidney; Organophosphonates; Osteitis Deformans; Osteoporosis; Parathyroid Glands; Parathyroid Hormone; Plicamycin; Salmon; Swine

Topics: Aged; Antineoplastic Agents; Bone Neoplasms; Calcinosis; Calcitonin; Cholecalciferol; Cyclophosphamide; Ergocalciferols; Fractures, Spontaneous; Humans; Hypercalcemia; Kidney Calculi; Lung Neoplasms; Male; Neoplasm Metastasis; Osteitis Deformans; Plicamycin; Podophyllin; Quinones; Sarcoma; Vitamin D

Topics: Adult; Aged; Bone Diseases; Calcitonin; Child; Cholecalciferol; Ergocalciferols; Humans; Hypercalcemia; Metabolic Diseases; New Zealand; Organophosphonates; Osteitis Deformans; Osteomalacia; Osteoporosis; Parathyroid Hormone; Sarcoidosis; Vitamin D; Vitamin D Deficiency

Topics: Adenylyl Cyclases; Anticonvulsants; Calcitonin; Calcium; Cholecalciferol; Cyclic AMP; Diagnosis, Differential; Humans; Hydroxycholecalciferols; Hypercalcemia; Hyperparathyroidism; Osteitis Deformans; Osteitis Fibrosa Cystica; Osteomalacia; Parathyroid Hormone; Pseudohypoparathyroidism; Radioimmunoassay; Thyroid Neoplasms