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The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged.
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PMID:Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis. 1522 97

Hyperparathyroidism is a disease characterized by hypercalcemia with hypophosphoremia resulting from increased secretion of parathyroid hormone (PTH). The disease may be divided into 3 forms: a) primary, b) secondary, c) tertiary (secondary refractory form). Primary hyperparathyroidism is rare in children; hyperplasia is more frequent during the early years of life (neonates and infants) and is difficult to distinguish from adenoma in children. The disease may be asymptomatic; elevated calcemia levels (>12 <13.5 mg/dl) are accompanied by anorexia, asthenia and persistent stipsis; severely elevated concentrations (>13.5 mg/dl) are accompanied by nausea, vomiting, polyuria due to osmosis, with dehydration and progressive onset of lethargy, stupor and coma. Osteopenia or osteitis fibrosa cystica may be present due to augmented bone resorption. Height and weight increases are altered due to anorexia and dehydration. Differential diagnosis includes iatrogenic causes of hypercalcemia (excessive vitamin D intake, prolonged immobilization, etc.) and idiopathic familial hypercalcemia. Emergency treatment is required in cases of extremely elevated hypercalcemia (Ca >13.5-14 mg/dl), due to risk of injury to the heart, the central nervous system, the gastrointestinal tract and the kidneys. The 4 cardinal points of treatment are: hydration, calciuresis, inhibition of bone calcium resorption, treatment of the cause underlying hyperparathyroidism. Secondary hyperparathyroidism is found in cases where chronic hypocalcemia is present, particularly in chronic renal failure, untreated deficiency rickets, chronic intestinal malabsorption, hepatobiliary disease, types I and II vitamin D-dependent rickets, tubular acidosis or Fanconi's syndrome. The tertiary form is distinguished by the autonomous nature of the parathyroid glands which have become hypertrophic/hyperplastic due to uncontrollable, chronic severe renal failure. It can also be of iatrogenic origin due to excessive intake of inorganic phosphates in familial hypophosphatemic rickets or chronic vitamin D deficiency.
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PMID:Hyperparathyroidism. 1524 24

In addition to gastrointestinal tract symptoms such as nausea, vomiting, and loss of appetite, impaired gastric emptying time (GET) may be related to nutritional parameters and nutritional status of patients on renal replacement therapy (RRT). Patients on RRT are affected by several factors such as uremic toxins, the presence of dialysate in the peritoneal cavity, and the drugs used against renal allograft rejection. In this study, we investigated the gastric emptying time and its relationship with biochemical and nutritional parameters in patients on RRT: those on hemodialysis and peritoneal dialysis, and renal transplantation patients. Seventy-five patients, 44 on hemodialysis, 16 on peritoneal dialysis, and 15 renal transplant patients, were included in the study. They were examined for gastric emptying time using a radioisotopic method. The results were compared with the GET of healthy subjects. Each group of patients was evaluated in terms of hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, blood glucose, total protein, albumin, serum lipids, parathyroid hormone (PTH) and body mass index and biceps and triceps skinfold. The mean GET of patients on RRT was significantly longer than the mean GET of healthy subjects (87.8 +/- 23.4 vs. 55 +/- 18 min, p<0.05). The mean GET of each therapy subgroups was significantly longer than the healthy subjects (the mean GET was 85.1 +/- 22.4 min for hemodialysis, 87.7+/-31.8 min for peritoneal dialysis, and 94.6+/-16.7 min for renal transplant patients, respectively, p<0.05). On the other hand, the differences in the mean GET between the three therapy subgroups were not statistically significant (p>0.05). In addition, time on replacement therapy inversely and blood glucose positively correlated with GET in renal transplant patients. In conclusion, GET was longer in patients on all three RRT modalities than in healthy subjects. GET was not significantly different in dialysis patients and renal transplant patients.
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PMID:Gastric emptying in patients on renal replacement therapy. 1560 Feb 52

Vascular calcification is common among hemodialysis (HD) patients and contributes to the development of peripheral arterial disease. A 57-year-old Japanese man who had been on HD for 30 years was referred to us for severe pain with multiple ulcers on his toes and fingers. He was an ex-smoker and had no diabetes mellitus. On admission, he had ulcers on his big toes bilaterally and right 2nd - 4th fingers. Peripheral pulses were strong and his ankle-brachial pressure index was above 1.3. Laboratory data were as follows: calcium 9.9 mg/dl, albumin 3.3 g/dl, phosphate 3.0 mg/dl, Ca x P product 30, and parathyroid hormone 98 pg/ml. He had a parathyroidectomy in 1998 and 1999. X-rays of his hands and legs showed diffuse subcutaneous arteriolar calcification. Angiography revealed no local stenotic lesions. Despite intensive therapies including hyperbaric oxygen therapy, painful gangrene developed on his right big toe and the pain was so intense that he could not go to sleep in a supine position. We infused intravenous sodium thiosulfate (20 g) 3 times weekly, based on previous reports. Within 4 - 5 days, he experienced rapid and dramatic symptom relief. The score of the visual analogue pain scale improved from 10/10 - 2/10. The signs of ischemia, measured by transcutaneous partial oxygen pressure and thermography, improved significantly. During the infusion of sodium thiosulfate, the patient complained of nausea, vomiting and hyperosmia. These adverse symptoms were resolved after discontinuation of the infusion. Pain relief was sustained and he could walk after 2 weeks of infusion. Our case supports the use of sodium thiosulfate as a novel therapeutic choice for critical limb ischemia with severe vascular calcification in chronic HD patients.
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PMID:Successful management of critical limb ischemia with intravenous sodium thiosulfate in a chronic hemodialysis patient. 1693 72

Treatment of postmenopausal osteoporosis (PMO) is based primarily on antiresorptive agents, including hormone replacement therapy (HT). To evaluate whether anabolic therapy together with HT provides additional benefits in the treatment of PMO, we evaluated the effects of parathyroid hormone (PTH) 1-84 in postmenopausal women with low bone mineral density (BMD) who were receiving chronic (> or =6 months) HT. Subjects were randomized to receive 100 microg PTH(1-84) or placebo injections daily for 24 months (n = 90/group). The primary efficacy outcome was change from baseline in lumbar spine BMD. Secondary end points included changes in hip and distal radius BMD, bone turnover markers, and fracture incidence. The study was terminated early following recommendations regarding HT for PMO. At 18 months, the mean increase in lumbar spine BMD was 7.9% for PTH(1-84) subjects vs. 1.5% for those receiving HT alone; between-group differences were significant at 6 months and persisted throughout the study. Lumbar spine BMD increased in 94% of women receiving PTH(1-84) compared to 59% for HT alone. Femoral neck BMD and bone turnover markers were significantly higher in PTH(1-84)-treated subjects, but the changes in total hip and distal radius BMD were not significant. PTH(1-84) treatment was generally well-tolerated, with hypercalciuria, hypercalcemia, nausea, vomiting, and dizziness reported more frequently in the HT + PTH(1-84) group. In conclusion, addition of PTH(1-84) to stable HT produced marked increases in lumbar spine BMD and may represent an additional approach to the treatment of PMO women receiving HT.
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PMID:Parathyroid hormone(1-84) treatment of postmenopausal women with low bone mass receiving hormone replacement therapy. 1862 66

Because no comparative studies exist, no clear pronouncements can be made about the potential differences in effectiveness and safety between PTH 1-34 and PTH 1-84. As regards the efficacy, a convincing reduction of vertebral fractures was shown in both cases [Neer, R.M., Arnaud, C.D., Zanchetta, J.R., Prince, R., Gaich, G.A., Reginster, J.Y., Hodsman, A.B., Eriksen, E.F., Ish-Shalom, S., Genant, H.K., Wang, O., Mitlak, B.H., 2001. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434-1441; Greenspan, S.L., Bone, H.G., Ettinger, M.P., Hanley, D.A., Lindsay, R., Zanchetta, J.R., Blosch, C.M., Mathisen, A.L., Morris, S.A., Marriott, T.B., Treatment of Osteoporosis with Parathyroid Hormone Study Group, 2007. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann. Intern. Med. 146, 326-339]. A reduction of non-vertebral fractures was shown in the case of PTH 1-34 only. Another significant resemblance is that both medicines have a strong anabolic action; this mechanism of action is essentially different from the bisphosphonates and strontium ranelate. Both medicines constitute a welcome addition to the therapeutic arsenal for patients with severe osteoporosis. More data from literature (including information on follow-up data and use in men) are available for PTH 1-34 because it has been available for longer. As regards the side effect profile, PTH 1-84 appears to have a higher incidence of hypercalcemia, hypercalciuria and nausea than teriparatide. Here, too, no comparative study exists: the differences may therefore be based on an actual difference in side effects, or it may be ascribed to differences in definitions and/or patient populations.
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PMID:PTH-analogs: comparable or different? 1912 66

We describe a case of delayed union in a tibial fracture secondary to primary hyperparathyroidism. A closed intra-articular proximal tibia fracture was stabilized with a hybrid external fixator. At 5 months clinical and radiological evaluation failed to demonstrate evidence of fracture healing. Fixation was stable and inflammatory markers ruled out infection. Further questioning revealed symptoms of anorexia, nausea and constipation. Plasma biochemistry showed an elevated corrected calcium and parathyroid hormone concentration. Further investigation included a sestamibi scan which confirmed a diagnosis of hyperparathyroidism secondary to a parathyroid adenoma. Six weeks following partial parathyroidectomy the fracture site was pain free, non-tender and the fracture had united radiologically. In cases of delayed-union, once an infective cause has been excluded with a mechanically stable fracture, other causes of delayed union like primary hyperparathyroidism should be ruled out.
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PMID:Primary hyperparathyroidism presenting as delayed fracture union. 1925 42

Lanthanum carbonate is a non-calcium-based phosphate binder for hyperphosphatemia in patients with chronic kidney disease (CKD). The efficacy and safety of lanthanum carbonate (LaC) on hyperphosphatemia in patients has been well documented in clinical trials in Western countries and recent relatively short-term clinical trials in Japan. Evidence supporting its safety and efficacy in Japanese patients for longer-term treatment is now desired for clinical practice. A non-controlled, open-label, multicenter, one year study of LaC to assess safety and its effect on the levels of serum phosphate, serum calcium and parathyroid hormone was performed with Japanese dialysis patients. Lanthanum carbonate was administered to patients at variable doses for a period of 46-52 weeks. Evaluation of the safety and efficacy of LaC in reducing serum phosphate was performed, in addition to extensive and systematic monitoring of the laboratory parameters related to bone turnover and cardiac health. A significant reduction in the serum phosphate level was demonstrated throughout the treatment period (P < 0.05), without any increase in the frequency or severity of drug-related adverse events such as vomiting, nausea, and stomach discomfort. There was no clinically relevant change in vital signs, or electrocardiograms for a period. The profiles for parathyroid hormone, bone alkaline phosphates, and osteocalcin were stable in the patients concomitantly treated with vitamin D. This study provides further evidence that the administration of LaC over a period of one year is safe and effective for the reduction of serum phosphate levels in CKD patients undergoing hemodialysis.
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PMID:One year efficacy and safety of lanthanum carbonate for hyperphosphatemia in Japanese chronic kidney disease patients undergoing hemodialysis. 2043 15

A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. A diagnosis of primary hyperparathyroidism was established and the patient was referred for parathyroidectomy. At neck exploration, an enlarged parathyroid gland with invasive growth into the thyroid gland was found and removed, lymph nodes were cleared and hemithyroidectomy was performed. A suspected diagnosis of parathyroid carcinoma was confirmed histologically. Serum calcium and PTH levels normalised post-operatively, but hyperparathyroidism recurred within 3 years of surgery. Over the following 17 years, control of hypercalcaemia represented the most difficult challenge despite variable success achieved with repeated surgical interventions, embolisations, radiofrequency ablation of metastases and treatment with calcimimetics, bisphosphonates and haemodialysis using low-dialysate calcium. In this paper, we report the challenges and pitfalls we encountered in the management of our patient over nearly two decades of follow-up and review recent literature on the topic.
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PMID:Challenges and pitfalls in the management of parathyroid carcinoma: 17-year follow-up of a case and review of the literature. 2125 29

The surface electrocardiogram (ECG) has been used as a useful method for detection of metabolic disturbances for a long time. However, it may be difficult to distinguish the exact disturbance when more than one metabolic abnormality exists in a patient simultaneously. Although, "classic" ECG characterizations of common electrolyte disturbances are well described, multiple concurrent electrolyte disturbances may lead to ECG abnormalities that may not be easily detectable. This ECG concerns a 60-year-old male presented with general fatigue, weakness, epigastric pain, anorexia, nausea and extreme hypercalcemia (serum total and ionized calcium levels 20.5 mg/dL and 12.02 mg/dl, respectively), hypokalemia and hypomagnesemia associated with elevated parathyroid hormone (1160 pg/ml) and normal serum vitamin D level (97 ng/ml) . This rare manifestation of primary hyperparathyroidism has been named hyperparathyroid crisis in the literature. Hyperparathyroid crisis is an emergency form of multiple electrolyte abnormalities that manifest as a life-threatening hypercalcemia and simultaneous hypokalemia and hypomagnesemia; these two later are believed to be caused by diuretic effect of calcium on the renal tubules. The unique pattern of ECG in our patient first was misdiagnosed as prominent T waves with prolongation of the QT corrected (QTc) interval, which has been reported several times in patients with hyperparathyroidism crisis, compatible with our patient. But more investigation revealed that, the QTc interval not only is not prolonged, it is shortened as it is expected from the effect of hypercalcemia on electrocardiogram. The exact pattern of the patient`s ECG (figure 1) can be interpreted as it follows: (1) Flattening of the T wave, (2) a prominent U wave, (3) prolongation of the descending limb of the T wave such that it overlapped with the next U wave (4) virtual absence of ST segment and (5) shortening of the QT corrected interval. In conclusion, it should be emphasized when the T and U waves are separated by a very short segment they can mimic the appearance of a prolonged QT interval. However, more investigation can demonstrate the exact electrocardiographic pattern especially in multiple electrolyte disturbances, when "classic" ECG patterns are not expectable.
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PMID:A rare electrocardiographic manifestation of a rare form of multiple electrolyte disturbances: hyperparathyroid crisis. 2217 73


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