Safety,Tolerability and Pharmacokinetic Study of Recombinant Human Parathyroid Hormone [rhPTH(1-84)] in Chinese Healthy Volunteers

The current study was designed to determine the safety, tolerability and pharmacokinetic parameters of recombinant human parathyroid hormone [rhPTH （1-84）] used for the treatment of osteoporosis. In the single-dose format pharmacokinetic study, thirty-six healthy male volunteers received three dose levels of rhPTH （1-84） subcutaneously： 1, 2, and 4 μg/kg. The blood was timing drawn and the serum concentration of rhPTH （1-84） was determined by enzyme linked immunosorbent assay （ELISA）. Serum concentration-time curves of PTH （1-84） exhibited a double-peak pattern, the first peak appearing about 10 to 30 min after administration and the second peak occurring about 1.5 to2 h after administration. Serum terminal half-time of PTH （1-84） was approximately 2 h. The parameters indicated the serum levels were directly proportional to the administered dose, with the mean Cmax and AUC0_24 ranging from approximately 543.47 to 1845 pg/mL and 2358.6 to 9232.12 pg.h.mL^-1 over the dose range. The drug was well tolerated, the clinical symptoms were generally mild and of short duration.

A randomized, multicenter controlled trial to compare the efficacy of recombinant human parathyroid hormone （1-34） with elcatonin in postmenopausal women with osteoporosis in China

Background Recombinant human parathyroid hormone （1-34） （rhPTH （1-34）） given by injection is a new seventh class drug of biological products, which is prepared by adopting gene recombination technique, rhPTH （1-34） is mainly used to treat osteoporosis, especially for postmenopausal women. This study compared the clinical efficacy and safety of rhPTH （1-34） with elcatonin for treating postmenopausal women with osteoporosis in 11 urban areas of China. Methods Two hundred and five women with osteoporosis were enrolled in a 6-month, multicenter, randomized, controlled study. They were randomized to receive either rhPTH （1-34） 20 ug （200 U） daily or elcatonin 20 U weekly. Lumbar spine （L1-4） and femoral neck bone mineral density （BMD）, as well as biochemical markers of bone turnover were measured. Adverse events were recorded. Results rhPTH （1-34） increased lumbar BMD significantly more than did elcatonin at 3 months and 6 months （2.38% vs 0.59%, P 〈0.05; 5.51% vs 1.55%, P 〈0.01）, but there were no significant increases of BMD in these two groups at femoral neck. There were larger mean increases in bone markers in the rhPTH （1-34） group than in the elcatonin group at 3 months and 6 months （serum bone-specific alkaline phosphatase （BSAP） 36.79% vs 0.31%; 92.42% vs -0.17%; urinary N-telopeptide/creatinine （NTX/Cr） 48.91% vs -5.32%; 68.82% vs -10.86%）. Both treatments were well tolerated and there were no significant differences detected between the two groups in the proportion of any adverse events and any serious adverse events （67.0% vs 59.0%; 0 vs 0）. Conclusions rhPTH （1-34） has more positive effects on bone formation, as shown by the larger increments of lumbar BMD and bone formation markers, than elcatonin, with only mild adverse events and no significant change in the liver, kidney or hematological indices.

Comparison of parathyroid hormone （1-34） and elcatonin in postmenopausal women with osteoporosis： an 18-month randomized, multicenter controlled trial in China

Background Recombinant human parathyroid hormone （1-34） （rhPTH （1-34）） is the first agent in a unique class of anabolic therapies acting on the skeleton. The efficacy and safety of long-term administration of rhPTH （1-34） in Chinese postmenopausal women had not been evaluated. This study compared the clinical efficacy and safety of rhPTH （1-34） with elcatonin for treating postmenopausal women with osteoporosis in 11 urban areas of China. Methods A total of 453 postmenopausal women with osteoporosis were enrolled in an 18-month, multi-center, randomized, controlled study. They were randomized to receive either rhPTH （1-34） 20 μg （200 U） daily for 18 months, or elcatonin 20 U weekly for 12 months. Lumbar spine （L1-4） and femoral neck bone mineral density （BMD）, fracture rate, back pain as well as biochemical markers of bone turnover were measured. Adverse events were recorded. Results rhPTH （1-34） increased lumbar BMD significantly more than did elcatonin after 6, 12, and 18 months of treatment （4.3% vs. 1.9%, 6.8% vs. 2.7%, 9.5% vs. 2.9%, P 〈0.01）. There was only a small but significant increase of femoral neck BMD after 18 months （2.6%, P 〈0.01） in rhPTH groups. There were larger increases in bone turnover markers in the rhPTH （1-34） group than those in the elcatonin group after 6, 12, and 18 months （serum bone-specific alkaline phosphatase （BSAP） 93.7% vs. -3.6%; 117.8% vs. -4.1%; 49.2% vs. -5.8%, P 〈0.01; urinary C-telopeptide/creatinine （CTX/Cr） 250.0% vs. -29.5%; 330.0% vs. -41.4%, 273.0% vs. -10.6%, P 〈0.01）. rhPTH （1-34） showed similar effect of pain relief as elcatonin. The incidence of clinical fractures was 5.36% （6/112） in elcatonin group and 3.2% （11/341）in rhPTH （1-34）group （P=0.303）. Both treatments were well tolerated. Hypercaluria （9.4%） and hypercalcemia （7.0%） in rhPTH （1-34） group were transient and caused no clinical symptoms. Pruritus （8.2% vs. 2.7%, P=0.044） and redness of injection site （4.4% vs. 0,P=0.024） were more frequent in rhPTH （1-34）. Nausea/vomiting （16.1% vs. 6.2%, P=0.001） and hot flushes （7.1% vs. 0.6%, P 〈0.001） were more common in elcatonin group. Conclusions rhPTH （1-34） was associated with greater increases in lumbar spine BMD and bone formation markers. It could increase femoral BMD after 18 months of treatment, rhPTH could improve back pain effectively. The results of the present study indicate that rhPTH （1-34） is an effective, safe agent in treating Chinese postmenopausal women with osteoporosis. （ChiCTR- TRC-10000924）