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For the treatment of osteoporosis, anti-resorptive agents including bisphosphonates and raloxifene are widely used. As new anti-resorptive drugs, anti-RANKL antibody and cathepsin K inhibitor are under development. Among bone anabolic agents, daily subcutaneous injection of teriparatide will soon become available in Japan. In addition, new anabolic agents such as calcilitycs and anti-sclerostin antibody are under clinical or preclinical development for the treatment of osteoporosis.

Osteoporosis is a disease in which the density and quality of bone is reduced, leading to an increase in fragility fractures. Osteoporosis is a major health threat affecting more than 10 million people in Japan. Emerging evidence has shown that anti-resorptive drugs such as bisphosphonates and raloxifene efficiently increase bone mass and prevent osteoporotic fractures by maintaining bone homeostasis. In addition, anabolic drugs such as parathyroid hormone and novel anti-resorptive drugs such as anti-RANKL drugs and cathepsin K inhibitors, which directly target osteoclasts are under development. In this review, we would like to summarize the current status of the development of anti-osteoporotic drugs.

Bisphosphonates are widely used, though gastrointestinal tolerance is a problem on daily administration. Intermittent regimen, from once weekly to once yearly, is now available in overseas and can overcome GI adverse events. New generation of anti-resorptive agents (anti-RANKL antibody and a new SERM, bazedoxifene) are promising and will be soon available for the treatment of osteoporosis. Anabolic agents such as teriparatide and strontium ranelate have marked effects on BMD and reduction on fracture risk. While none of these options is suitable for everyone, the range of future available therapies does mean that most patients can find an intervention that is effective and acceptable.

Parathyroid hormone-related protein (PTHrP) has significant homology with parathyroid hormone (PTH) especially in the amino-terminal sequence. We compared some effects of human synthetic analogue of amino terminal PTHrP [hPTHrP (1-34)] with those of human synthetic analogue of amino terminal PTH [hPTH (1-34)]. Intravenous administration of hPTHrP (1-34) in parathyroidectomized rats caused hypercalcemic, hypophosphatemic and phosphaturic effects in the same degree of hPTH (1-34). In the kinetic study, apparent Km and Vmax of phosphate transport in renal brush border membrane vesicles were identical in both peptides (hPTHrP(1-34) Km = 27.6 +/- 0.8 mumol, Vmax = 3.78 +/- 0.04 nmol/mg.protein; hPTH(1-34) Km = 29.6 +/- 0.9 mumol, Vmax = 3.04 +/- 0.9 nmol/mg.protein). hPTHrP(1-34) and hPTH(1-34) were equipotent in eliciting a 9-fold increase of adenosine 3',5'-monophosphate (cAMP) production. These results demonstrate that the effect of hPTHrP (1-34) is similar to hPTH(1-34) on serum calcium, phosphorus and nephrogenous cAMP in vivo, and Na(+)-dependent phosphate transport in brush border membrane vesicles.

It has been suggested that prolonged administration of low dose PTH could exert an anabolic effect on the bone. The effects of near-physiological dose of PTH injection on trabecular and cortical bones were studied in normal young adult beagles. Twelve 18 month-old male beagle dogs were equally divided into 4 groups by body weight. The 1st group serving as the control was subcutaneously injected with 1 ml of normal saline, and the 2nd, the 3rd and the 4th groups were also subcutaneously injected with 1.25, 5.0, 20.0 unit/kg/day of synthetic 1-34 human PTH respectively everyday for 15 weeks. Then, over the following 8 weeks, administration of all vehicle and drugs was withdrawn. After double bone labeling, iliac bone and rib biopsies were taken before and after the drug administration and after the withdrawal. The effects were evaluated with blood chemical and hormonal analysis and bone histomorphometry. No significant changes were noted in serum Ca, P, PTH, calcitonin and 1,25 (OH)2 vit.D levels and A1-P activities with some exceptions. Bone histomorphometry on trabecular bone showed remarkable and statistically significant elevation of formation surface, active formation surface, mineral appositional rate, labeled surface and bone formation rate. On the other hand, bone resorption rate and some other resorption parameters showed a significant elevation but trabecular bone volume showed no significant increase. In cortical bone, the bone dynamics were essentially equal to trabecular bone. But by the increase of bone turnover rate, cortical porosity rate increased. After withdrawal of drug administration, the bone turnover rate went down and a rate of cortical porosity returned to normal level. From these results it was postulated that PTH was effective in activating low remodeling of the skeleton.

The present study was undertaken to establish a standard method to perform the Ellsworth-Howard test using human PTH-1-34). For this purpose we made a survey of literature concerning the Ellsworth-Howard test and then examined the data of the Ellsworth-Howard tests performed on 178 hypoparathyroid patients using human PTH-(1-34). The main items of investigation were: (i) to determine the appropriate dose of PTH for administration to adults and children; and (ii) to define the criteria of practical usefulness for the differential diagnosis of the types of hypoparathyroidism. From the analysis of the data, the following findings and conclusions were obtained. The dose of human PTH-(1-34) appropriate for diagnostic use is 100 U per person for adults and 100 U per body surface area of one square meter (100 U/m2) for children. The criteria of positive response in the Ellsworth-Howard test are defined as follows. a) phosphaturic response: (U4 + U5) - (U2 + U3) = more than 35 mg/2 h b) cyclic AMP response: U4 - U3 = more than 1 mumol/h, and U4/U3 = more than 10 times. In the above formula, U2 - U5 represent the urine samples collected hourly in order. PTH is injected at the time between U3 and U4. For the application of the criteria in children, one should use the values corrected for body surface area of one square meter. It is necessary to confirm the following conditions before the application of the criteria: the presence of hypocalcemia and hyperphosphatemia; the lack of phosphate deficiency (basal urinary phosphate excretion more than 10 mg/2 h); the accuracy of timed urine collections (ratio of creatinine excretion during 2 hours before PTH to that after PTH administration in the range from 0.8 to 1.2); and the absence of marked diurnal variation in phosphate excretion (difference in phosphate excretion between the two basal hourly urine less than 17.5 mg/h). To ensure the above conditions, medications such as phosphate-binding antacids should be withheld for at least 1 week before the test, and the test should be performed according to the standard procedure described in this paper. The diagnosis of pseudohypoparathyroidism Type II should be done cautiously. It is necessary to take account of the high basal urinary cyclic AMP excretion and the elevated serum PTH level along with the results of the Ellsworth-Howard test (positive cyclic AMP response and negative phosphaturic response) for a definite diagnosis of this entity.

The response to exogenous parathyroid hormone (PTH) with urinary excretion of phosphate and cyclic adenosine monophosphate (cAMP) was tested by the use of synthetic human parathyroid hormone (1-34) [hPTH-(1-34)] on 59 patients with hypocalcemia and normal or high serum inorganic phosphorus and normal renal function without a history of parathyroidectomy for differentiation between idiopathic hypoparathyroidism (IHP), pseudohypoparathyroidism (PHP) and related diseases along with 18 normal subjects. A positive phosphaturic response to exogenous PTH was defined as the increment of 2 hours phosphate excretion (delta P) of more than 35 mg. A positive urinary cAMP response to exogenous PTH was defined as the increment by more than 1 mumole per one hour (delta cAMP) and the increase of 1 hour excretion by more than 10 times. Increments of 2 hours urinary phosphate excretion in response to hPTH-(1-34) 100 units were 60.5 +/- 7.7 mg (mean +/- SEM) in 27 patients with IHP, 23.5 +/- 5.9 mg in 21 patients with PHP type I and 24.9 +/- 4.0 mg in 17 normal subjects. Increments of 1 hour urinary cAMP excretion in response to hPTH-(1-34) 100 units were 12.0 +/- 1.5 mumole in 27 patients with IHP, 0.33 +/- 0.10 mumole in patients with PHP type I and 23.6 +/- 5.8 mumole in 15 normal subjects. Ratios of 1 hour urinary cAMP excretion were 97 +/- 10 in 27 patients with IHP, 3.6 +/- 0.5 in 21 patients with PHP type I and 54 +/- 14 in 15 normal subjects. Positive phosphaturic and negative urinary cAMP response was encountered in 3 out of 21 patients with PHP type I in response to hPTH-(1-34). This exaggerated phosphaturic response should be considered as due to the influence of treatment with Ca or vitamin D derivatives.