The effects of oophorectomy on skeletal metabolism

The effects of oophorectomy on the biological indices of bone remodelling and the time-course of their changes are described. In the first few months following surgical menopause the measurement of the markers of bone remodelling indicates that the increase in osteogenesis is delayed compared with that of bone resorption; this prevalence of destruction over new bone deposition justifies the deficiency of skeletal balance, shortly after acute oestrogen deficiency. The changes in bone remodelling are accompanied by an increase in serum calcium while serum immunoreactive parathyroid hormone levels remain unchanged or even decrease, suggesting a shift to right of the parathyroid gland set-point. The reasons for the negative skeletal balance after oophorectomy might be sought therefore at bone tissue level, even if changes in responsiveness and/or of the parathyroid gland set-point could also be contributory.     

Parathyroid hormone and plasma calcium control: an editorial

The purpose of this report is to examine the various processes by which parathyroid hormone might control the ionic calcium concentration of plasma and extracellular fluid, and to emphasize the need for study of the maintenance of plasma calcium in the absence of the parathyroid glands. The report discusses mechanisms to explain the control of extracellular calcium and proposes new approaches to the study of calcium homeostasis.     

On the role of bone damage in calcium homeostasis

Bone serves as the reservoir of some minerals including calcium. If calcium is needed anywhere in the body, it can be removed from the bone matrix by resorption and put back into the blood flow. During bone remodelling the resorbed tissue is replaced by osteoid which gets mineralized very slowly. Then, calcium homeostasis is controlled by bone remodelling, among other processes: the more intense is the remodelling activity, the lower is the mineral content of bone matrix. Bone remodelling is initiated by the presence of microstructural damage. Some experimental evidences show that the fatigue properties of bone are degraded and more microdamage is accumulated due to the external load as the mineral content increases. That damage initiates bone remodelling and the mineral content is so reduced. Therefore, this process prevents the mineral content of bone matrix to reach very high (non-physiological) values. A bone remodelling model has been used to simulate this regulatory process. In this model, damage is an initiation factor for bone remodelling and is estimated through a fatigue algorithm, depending on the macroscopic strain level. Mineral content depends on bone remodelling and mineralization rate. Finally, the bone fatigue properties are defined as dependent on the mineral content, closing the interconnection between damage and mineral content. The remodelling model was applied to a simplified example consisting of a bar under tension with an initially heterogeneous mineral distribution. Considering the fatigue properties as dependent on the mineral content, the mineral distribution tends to be homogeneous with an ash fraction within the physiological range. If such dependance is not considered and fatigue properties are assumed constant, the homogenization is not always achieved and the mineral content may rise up to high non-physiological values. Thus, the interconnection between mineral content and fatigue properties is essential for the maintenance of bone's structural integrity as well as for the calcium homeostasis.     

Clinical use of calcimimetics in the treatment of hyperparathyroidisms

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium concentration (Ca(2+)ec) regulates parathormone (PTH) and calcitonin secretion, urinary calcium excretion and ultimately bone turnover. Cloning of CaR and discovery of mutations making the receptor less or more sensitive to calcium allowed a better understanding of several hereditary disorders characterized either by hyperparathyroidism or hypoparathyroidism. CaR became an ideal target for the development of compounds able to modulate the activity of CaR, activators (calcimimetics) as well as inhibitors (calcilytics). The calcimimetics are able to amplify the sensitivity of the CaR to Ca(2+)ec, suppressing PTH levels with a resultant fall in blood Ca2+. They dose-dependently reduce the secretion of PTH in vitro in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia, normalize plasma PTH levels and bone remodelling. In uremic patients undergoing hemodialysis, the calcimimetics reduce plasma PTH concentration at short-term (12 weeks) as well as at long-term (2 years), serum calcium-phosphorus product and bone remodelling. After one year of treatment, these patients show a gain of bone mass of 2-3% at the femoral neck and at the total body. Contrarily, the calcilytics, by inhibiting CaR, can intermittently stimulate the secretion and the serum concentration of PTH. This results in an skeletal anabolic effect with a substantial increase in bone mineral density. They are potentially very interesting for the treatment of post-menopausal osteoporosis.     

人甲状旁腺激素的研究

人甲状旁腺激素(hPTH)是甲状旁腺分泌的多肽激素。它能与骨基质和肾细胞膜上专一性的受体相结合,将调节细胞中钙磷浓度的信号传导到膜内。hPTH活性片段在N端,其N端氨基酸序列与牛、猪PTH高度同源。hPTH及其活性片段在治疗骨及肌肉疾病方面有重要作用,重组hPTH已获成功。     

Le récepteur du calcium : un rôle central dans le métabolisme calcique

The extracellular calcium-sensing receptor (CaSR) enables the parathyroid gland cells to sense the extracellular calcium concentration, to adapt the amount of parathyroid hormone secreted by those glands and, in turn, by its action on kidney and bone, to maintain steady the extracellular calcium concentration. The prominent role of CaSR is illustrated by the fact that CaSR mutations are responsible for disorders in extracellular calcium metabolism. Drugs that either activate or inactivate CaSR will open new therapeutic opportunities in several areas of mineral metabolism.     

Modeling of biological doses and mechanical effects on bone transduction

Shear stress, hormones like parathyroid and mineral elements like calcium mediate the amplitude of stimulus signal, which affects the rate of bone remodeling. The current study investigates the theoretical effects of different metabolic doses in stimulus signal level on bone. The model was built considering the osteocyte as the sensing center mediated by coupled mechanical shear stress and some biological factors. The proposed enhanced model was developed based on previously published works dealing with different aspects of bone transduction. It describes the effects of physiological doses variations of calcium, parathyroid hormone, nitric oxide and prostaglandin E2 on the stimulus level sensed by osteocytes in response to applied shear stress generated by interstitial fluid flow. We retained the metabolic factors (parathyroid hormone, nitric oxide and prostaglandin E2) as parameters of bone cell mechanosensitivity because stimulation/inhibition of induced pathways stimulates osteogenic response in vivo. We then tested the model response in terms of stimulus signal variation versus the biological factors doses to external mechanical stimuli. Despite the limitations of the model, it is consistent and has physiological bases. Biological inputs are histologically measurable. This makes the model amenable to experimental verification.     

Ca2+ as an extracellular signal in bone

Bone is the major sink and store for calcium and it fulfils essential roles in the maintenance of extracellular free ionised calcium concentration ([Ca2+]e) within its homeostatic range (1.1-1.3 mM). In response to acute hypercalcaemia or hypocalcaemia, Ca2+ is rapidly transported into or out of bone. Bone turnover (and therefore bone Ca2+ turnover) achieves the long-term correction of the [Ca2+]e by the metabolic actions of osteoblasts and osteoclasts, as they respectively incorporate or release Ca2+ from bone. These processes are regulated by the actions of hormones, such as parathyroid hormone (PTH), the release of which is a function of the [Ca2+]e, and is regulated by the action of the Ca2+-sensing receptor (CaR) in the parathyroid gland. Tissue culture studies indicate that bone cells also directly respond to increasing and decreasing [Ca2+]e in their vicinity, independently of the systemic factors. Nevertheless, further studies are necessary to identify how the acute and long-term local changes in [Ca2+]e affect bone cells and the physiological processes they are involved in. Also, the molecular mechanisms which enable the bone cells to sense and respond to [Ca2+]e are not clear. Like the parathyroid cells, bone cells also express the CaR, and accumulating evidence indicates the involvement of this receptor in their responses to the changing extracellular ionic environment.     

The morphology and function of rat C-cells. 4. Determination of calcium, inorganic phosphorus and total nitrogen in the femora of untreated parathyroidectomized or thyreoparathyroidectomized and hormonally substituted female rats]

Female Wistar rats of a live weight of about 160 g and fed with a standard laboratory diet, were parathyroidectomized, or thyroparathyroidectomized and treated with thyroxine, parathyroid hormone, calcitonin. thyroxine and parathyroid hormone, or thyroxine and calcitonin. On the 15th day post operationem, and after twelve days of hormone treatment, the concentrations of calcium, inorganic phosphorus and total nitrogen were determined in the femur bone. Parathyroidectomy resulted in a decrease of phosphorus concentration in bone. After thyroparathyroidectomy (Tx), the concentrations of inorganic phosporus and nitrogen diminished during some days, whereas the calcium content decreased continuously. Thyroxine application normalized the concentration of inorganic phosphorus. The osteolytic and nitrogen-anabolic effect of parathyroid hormone took place only in simultaneous treatment with thyroxine. The injection of calcitonin had a nitrogen-anabolic effect on bone; the simultaneous treatment with thyroxine induced a loss of calcium out of bone, and a deposition of calcium phosphate in renal tissue. Calcitonin did not inhibit a significant decrease of calcium concentration in the femur bone; the hypophosphatemic effect was always present. The metabolism of bone tissue, influenced by hormonal actions, probably determined the localization of the deposition of inorganic phosphorus, deserting the serum under the influence of calcitonin.     

Treatment of Paget's Disease of Bone with Mithramycin

We report data from three patients with severe Paget''s disease of bone who were treated with mithramycin.Mithramycin infusion resulted in a fall in plasma calcium, phosphate, alkaline phosphatase, and urinary hydroxyproline excretion. There was an improvement in calcium and phosphorus balance in two of the three subjects studied. A pronounced or complete relief of bone pain occurred in all three.We suggest that mithramycin exerts its beneficial effect in Paget''s disease of bone by stimulating parathyroid hormone release. The parathyroid hormone released has a predominantly anabolic action on bone since its catabolic action is blocked by mithramycin, which inhibits bone resorption.     

Significance of Elevated Parathyroid Hormone After Parathyroidectomy

ObjectiveTo review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms.MethodsA Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms “elevated PTH after parathyroidectomy.” All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed.ResultsWithin 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done.ConclusionElevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. (Endocr Pract. 2010;16:112-117)     

Calcium homeostasis: solving the solubility problem

This report summarizes the evidence that the control of the concentration of free calcium ions in body fluids is centered at mineralized bone surfaces. This process involves an increase in the solubility of bone mineral produced by the non-collagenous proteins existing in the bone extracellular fluid (ECF) and on the adjacent surfaces of bone. The result is a basic equilibrium level produced in the absence of parathyroid hormone (PTH), which is well above the solubility of bone mineral. The effect of PTH is to increase the solubility of bone mineral still further, but the mechanism by which the hormone acts is unknown. The lining cells of the bone contain receptors for PTH and can be observed to respond to this hormone, but the relationship between this response and the increased solubility of bone remains to be discovered. Further research in this field is strongly urged.     

Suppression of secondary hyperparathyroidism in uraemia: acute and chronic studies.

A study was conducted evaluating the response of serum parathyroid hormone to acute hypercalcaemia and long term administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients receiving maintenance haemodialysis. During infusion of elemental calcium 4 mg/kg/h over four hours in 12 patients not receiving vitamin D the concentration of serum amino terminal parathyroid hormone fell by 31-96% (mean 74.8 (SD 17.6)%) while that of carboxy terminal parathyroid hormone changed little. There was a strong inverse correlation between baseline serum calcium concentration and percentage fall in amino terminal parathyroid hormone during infusion (r = 0.88; p less than 0.001). In seven patients who received prolonged treatment with 1,25(OH)2D3 after calcium infusion there was a positive correlation between maximum percentage fall in amino terminal parathyroid hormone during infusion and the percentage fall in amino terminal parathyroid hormone after 1,25(OH)2D3 treatment (r = 0.79; p less than 0.05). The responsiveness of the parathyroid glands to changes in calcium in acute studies may be used to predict the efficacy of long term treatment with 1,25(OH)2D3. Patients in whom calcium infusion does not suppress parathyroid hormone may have true parathyroid autonomy and require early parathyroidectomy.     

The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two factors that share amino acid sequence homology and act via a common receptor. In tetrapods, PTH is the main endocrine factor acting in bone and kidney to regulate calcium and phosphate. PTHrP is an essential paracrine developmental factor present in many tissues and is involved in the regulation of ossification, mammary gland development, muscle relaxation, and other functions. Fish apparently lack an equivalent of the parathyroid gland and were long thought to be devoid of PTH. Only in recent years has the existence of PTH-like peptides and their receptors in fish been firmly established. Two forms of PTH, two of PTHrP, and a protein with intermediate characteristics designated PTH-L are encoded by separate genes in teleost fish. Three receptors encoded by separate genes in fish mediate PTH/PTHrP actions, whereas only two receptors have so far been found in terrestrial vertebrates. PTHrP has been more intensively studied than PTH, from lampreys to advanced teleosts. It is expressed in many tissues and is present in high concentration in fish blood. Administration of this peptide alters calcium metabolism and has marked effects on associated gene expression and enzyme activity in vivo and in vitro. This review provides a comprehensive overview of the physiological roles, distribution, and molecular relationships of the piscine PTH-like peptides.     

Calcium metabolism in HeLa cells and the effects of parathyroid hormone

Calcium metabolism was investigated in HeLa cells. 90% of the calcium of the cell monolayer is bound to an extracellular cell coat and can be removed by trypsin-EDTA. The calcium concentration of the naked cell, freed from its coat, is 0.47 mM. The calcium concentration of the medium does not affect the concentration of the naked cell calcium. However, the calcium of the cell coat is proportional to the calcium concentration in the medium. Calcium uptake into the cell coat increases with increasing calcium concentration of the medium, whereas uptake by the naked cell is independent of the calcium of the medium. Anaerobic conditions and metabolic inhibitors do not inhibit calcium uptake by the cell, a fact suggesting that this transfer is a passive phenomenon. The calcium in the extracellular cell coat, was not affected by parathyroid hormone. In contrast, the hormone increased the cellular calcium concentration by stimulating calcium uptake or by enhancing calcium binding to some cell components. These results suggest that, contrary to current thinking, parathyroid hormone influences the cellular calcium balance by mobilizing calcium from the extracellular fluids in order to increase its concentration in some cellular compartment. It is proposed that these effects can enhance calcium transport.     

Calcium metabolism in adult outpatients with epilepsy receiving long-term anticonvulsant therapy

Long-term anticonvulsant drug therapy may lead to abnormalities of calcium metabolism resulting in osteomalacia. The prevalence and severity of altered calcium metabolism was studied in an adult outpatient population of persons with epilepsy receiving anticonvulsant therapy for a minimum of 2 years. Assessment of calcium metabolism was based on serum concentrations of calcium, phosphorus, alkaline phosphatase and 25-hydroxycholecalciferol and of plasma parathyroid hormone, intestinal absorption of isotopic calcium and skeletal bone mineral mass as determined by in vivo neutron activation or x-ray photodensitometry.Thirty-nine patients who had been receiving anticonvulsant therapy for an average of 20 years were studied; none had clinical evidence of metabolic bone disease. Decreased serum calcium concentration was noted in 10%, decreased serum phosphorus concentration in 10% and elevated serum alkaline phosphatase concentration in 44%. The mean serum 25-hydroxycholecalciferol concentration was significantly lower (P < 0.001) than in a control group (11.6 v. 19.6 mg/mL). None of 18 patients studied had an increased plasma concentration of parathyroid hormone, and only 1 of 17 patients had decreased intestinal absorption of isotopic calcium. Bone mineral mass was decreased in 44% of 32 patients studied.It was concluded that long-term treatment with anticonvulsant drugs leads to mild abnormalities of calcium metabolism and decreased bone mineral mass in a substantial percentage of adult outpatients with epilepsy. These abnormalities probably predispose the patients to the development of clinically significant metabolic bone disease.     

Evolution of Calcium Regulation in Lower Vertebrates

Calcium regulation in lower vertebrates appears to be a continuum.The predominant hypercalcemic hormone in reptiles, birds andmammals is parathyroid hormone, while the major hypercalcemiccontrol in fishes is a pituitary factor, probably prolactin.In the amphibians dual controlling mechanisms are at work, sothat both the pituitary and parathyroids exert their influence.Prolactin may still retain some hypercalcemic potency in thehigher vertebrate groups, either directly or indirectly by influencingthe secretion of other hypercalcemic hormones. On the otherhand, parathyroid hormone does not occur in, nor does it elevateblood calcium in fishes. It thus seems to be a new inventionof tetrapods, or possibly to have evolved from a pituitary factorof fishes. The ability to lower blood calcium seems to be veryimportant in seawater fishes, in which the corpuscles of Stanniusexert major control. In terrestrial forms, the corpuscles ofStannius are not present, and hypocalcemic factors assume aminor role in overall calcium regulation     

Bone and the kidney: a systems biology approach to the molecular mechanisms of renal osteodystrophy

Despite its apparent static condition, the skeleton undergoes a permanent process of remodeling mediated by osteoblasts and osteoclasts. The activity of these cells is regulated by a plethora of factors, ranging from mechanical stress to the effects of hormones to the immune system. One well-studied regulatory system involves the maintenance of calcium homeostasis through a network whose main regulatory components include ionized calcium, phosphate, parathyroid hormone and active vitamin D. This system establishes the link between bone and kidney, as one of the kidney's endocrine functions is the activation of vitamin D, while electrolyte homeostasis is one of its excretory functions. Impaired renal function leads to disturbances in this regulatory system, resulting in the complex syndrome of renal osteodystrophy that affects the majority of patients with chronic renal failure. This review summarizes the current understanding of bone physiology on a molecular level, examines some of the pathological pathways related to renal disease, and concludes with an outlook on how the emerging field of systems biology may contribute to a more dynamic and quantitative understanding of the physiology and pathophysiology of renal bone disease.     

Dopamine-stimulated parathyroid hormone release in vitro: further evidence for a two-pool model of parathyroid hormone secretion

Bovine parathyroid tissue was placed in an in vitro perifusion system for the study of parathyroid hormone secretion stimulated by low calcium and dopamine. Dopamine caused a transient increase in parathyroid hormone release, while low calcium caused a sustained increase in parathyroid hormone secretion. The dopamine response was similar to that caused by isoproterenol. After parathyroid hormone release had been stimulated by dopamine there was no response to isoproterenol, suggesting they cause the release of the same cellular pool of hormone. Inhibition of protein synthesis with cycloheximide eliminated the response to low calcium, with no effect on dopamine-stimulated parathyroid hormone release. These studies suggest dopamine stimulates the release of a limited quantity storage pool of parathyroid hormone, while low calcium causes a sustained release of hormone by stimulating secretion of newly synthesized hormone. Low calcium has little or no effect on release of the storage granule pool of parathyroid hormone.     

Calcium homeostasis and bone surface proteins, a postulated vital process for plasma calcium control

This report is a more in-depth explanation of a recently reported hypothesis for controlling the ionic calcium content of plasma and extracellular fluids (ECF). The hypothesis proposes a two-step process for returning calcium to the ECF against the established gradient continuously moving calcium from plasma to bone surfaces. The first step in this process is the predicted transfer of calcium directly from bone surfaces to the non-collagenous proteins, which are in contact with bone mineral. This calcium would be complexed to existing proteins and a portion would automatically become available for equilibration with ionic calcium in the ECF. The basis of the hypothesis is that the equilibration level helps to set the ionic calcium concentration of plasma. The gradient toward bone and the proposed two-step return occur in the ECF of bone and would be considered normal physiochemical processes. Thus, these processes are critical for mineral ion homeostasis in mammals. In this hypothesis, parathyroid hormone (PTH) is not required for the basic process. However, PTH works within the process to raise and set a precise plasma calcium concentration. The report to follow describes the process and discusses its relationship to normal and pathological conditions affecting human health.