Parathyroid hormone clinical effects

The rate of osteosarcoma in animal and human trials of parathyroid hormone has been reviewed (20,6). Rats treated with parathyroid hormone for 2 years had a high dose-dependent rate of osteosarcoma, up to 48% in animals given 75 micrograms/kg human trials were therefore interrupted (21). However, the anabolic effect of parathyroid hormone is much greater and occurs much earlier in rats than in humans, possibly because of fundamental differences in bone biology moreover, osteosarcoma has never been associated with primary, secondary, or tertiary hyperparathyroidism in humans (20). There has been no evidence of osteosarcoma in several hundred patients involved in parathyroid hormone clinical trials lasting up to 3 years, after 5 years minimum follow-up (20). 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Reviews of parathyroid hormone have suggested that it is generally well tolerated (4,5,6). The adverse effects of parathyroid hormone that have been reported in clinical trials are mild and include transient bone pain, nausea, dizziness and local irritation at the injection site (7). Hypercalcemia, which is common, is usually mild and asymptomatic. Adverse effects, including hypercalcemia, appear to be dose related in the therapeutic range. 

Parathyroid hormone has potent anabolic effects on the skeleton if given intermittently being used in clinical trials. Initial concerns about the development of osteosarcoma in rats after prolonged treatment with high doses of parathyroid hormone have not been confirmed in human trials, but surveillance continues (8). In one study there was a mild increase in creatinine, which was thought not to have clinical significance (9). Mild nausea (10) and arthralgia (10,11) have also been reported. 

Drugs currently used to treat osteoporosis are classified into those that inhibit osteoclastic bone resorption (including bisphos-phonates, denosumab, and selective estrogen receptor modulators) and those that stimulate bone formation by osteoblasts (parathyroid hormone and derivatives, such as teriparatide). Strontium ranelate may have a dual effect. Other drugs being tested in clinical trials include inhibitors of cathepsin K (an osteoclastic enzyme critical for bone resorption) and of sclerostin (a negative modulator of the Wnt pathway) [21],... 

Hypophosphatemia is a less constant feature of primary hyperparathyroidism than hypercalcemia, despite the well-documented effect of parathyroid hormone upon phosphate excretion. Figure 9 shows the plasma calcium and phosphorus values in 346 cases of primary hyperparathyroidism diagnosed at the Mayo Clinic. It will be seen that the diagnosis was rarely made in the presence of a normal plasma calcium, although this occasionally has been done (M8), but was frequently made when the phosphorus concentration was normal. The data also suggest a slight inverse correlation between the plasma calcium and phosphorus concentrations in cases with normal renal function the phosphorus was usually low when the calcium concentration exceeded 12 mg/100 ml. 

Figure 42-2. Some effects of vitamin D (D), parathyroid hormone (PTH), and calcitonin (CT) on calcium and phosphorus metabolism. Vitamin D increases absorption of calcium from both gut and bone, while PTH increases reabsorption from bone. Both vitamin D and parathyroid hormone reduce urinary excretion ot calcium. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

While strong evidence exists implicating cadmium as a major causative factor in itai-itai disease, other factors, such dietary deficiencies in minerals and vitamins, may have contributed to the disease (Tsuchiya 1978 Kjellstrom 1986). Serum la,25(OH)2-vitamin D concentrations were depressed in cadmium-exposed cohorts presenting with clinical nephropathy (Nogawa et al. 1987), which suggests that cadmium-induced bone effects may result from disruption of vitamin D and parathyroid hormone metabolism. Because kidney injury results from chronic cadmium exposure, a cadmium-related inhibition of the renal conversion of 25(OH)-vitamin D to la,25(OH)2 Vitamin D may lead to decreased calcium reabsorption, demineralization of bone, and eventually osteomalacia (Friberg et al. 1986). 

As RJ contains testosterone [24] and possesses steroid hormone-type activities [54—57], it was hypothesized that it may have beneficial effects on osteoporosis. In a recent study, both an ovariectomized rat model and a tissue culture model were used. The results of the study indicated that RJ was almost as effective as 17p-estradiol in preventing the development of bone loss induced by ovariectomy in rats. In tissue culture models, RJ increased calcium contents in femoral-diaphyseal and femoral-metaphyseal tissue cultures obtained from normal male rats however, in a mouse marrow culture model, it neither inhibited the parathyroid hormone (PTH)-induced calcium loss nor affected the formation of osteoclast-like cells induced by PTH. Therefore, these results suggested that RJ may prevent osteoporosis by enhancing intestinal calcium absorption, but not by directly antagonizing the action of PTH [60]. In a comparable study, it was investigated whether RJ and bee pollen reduce the bone loss due to osteoporosis in oophorectomized female rats model. It was concluded that RJ and bee pollen after a 12-week treatment decrease the bone loss due to osteoporosis, proposing that these results may contribute to the clinical practice [61]. 

It is g erally assumed that it is the concentration of ionic calcium in the extracellular fluid which the parathyroid glands control by this action on the skeleton and that the variations in total plasma calcium are strictly proportional. However, Freeman and Breen (Fll) have shown that parathyroidectomy is followed by a rise in the proportion of protein-boimd calcium and that this can be reduced by injection of the hormone. This accords with the observations of Lloyd and Rose in hyperparathyroidism (L6 see Section 4.2) and with the clinical observation that hypo-parathyroid patients may develop tetany at surprisingly high levels of total plasma calcium. The effects of Ae hormone on add-base balance may be concerned in this phenomenon since acidemia reduces the proportion of protein-bound calcium. 

The fall in serum calcium which follows parathyroidectomy is associated with a rise in calcium excretion (T1). Taken in conjunction with the hypocalcemic hypercalcuria of clinical hypoparathyroidism (L5), this suggests that the apparent calcuric effect of parathyroid extract is simply a reflection of its calcemic action. In fact, administration of the hormone appears if anything to reduce urinary calcium. Evidence to this effect has been produced by Bernstein et al. (B6), who have demonstrated a steep rise in calcium/inulin clearance ratio in dogs after parathyroidectomy... 

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