pTH (2-38) (human)

Ca homoeostasis is important to human health and tightly controlled by powerful hormonal mechanisms that display ethnic variation. Ethnic variations could occur also in Arctic populations where the traditional Inuit diet is low in Ca and sun exposure is limited. We aimed to assess factors important to parathyroid hormone (PTH) and Ca in serum in Arctic populations. We included Inuit and Caucasians aged 50-69 years living in the capital city in West or in rural East Greenland. Lifestyle factors were assessed by questionnaires. The intake of Inuit diet was assessed from a FFQ. 25-Hydroxyvitamin D (25OHD2 and 25OHD3) levels were measured in serum as was albumin, Ca and PTH. The participation rate was 95 %, with 101 Caucasians and 434 Inuit. Median serum 25OHD (99·7 % was 25OHD3) in Caucasians/Inuit was 42/64 nmol/l (25, 75 percentiles 25, 54/51, 81) (P<0·001). Total Ca in serum was 2·33/2·29 mmol/l (25, 75 percentiles 2·26, 2·38/2·21, 2·36) (P=0·01) and PTH was 2·7/2·2 pmol/l (25, 75 percentiles 2·2, 4·1/1·7, 2·7) (P<0·001). The 69/97 Caucasians/Inuit with serum 25OHD <50 nmol/l differed in PTH (P=0·001) that rose with lower 25OHD levels in Caucasians, whereas this was not the case in Inuit. Ethnic origin influenced PTH (β=0·27, P<0·001) and Ca (β=0·22, P<0·001) in multivariate linear regression models after adjustment for age, sex, BMI, smoking, alcohol and diet. In conclusion, ethnic origin influenced PTH, PTH response to low vitamin D levels and Ca levels in populations in Greenland. Recommendations are to evaluate mechanisms underlying the ethnic influence on Ca homoeostasis and to assess the impact of transition in dietary habits on Ca homoeostasis and skeletal health in Arctic populations.

Objective: Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options. Methods: Here we present nationwide initial and follow-up data on HR. Results: From 24 centers, 166 patients were included in the study. Genetic analysis (n=75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7±2.4 years. During the first 3-years of treatment (n=91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p>0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year PTH was higher. However, higher treatment doses of phosphate and calcitriol were found in the NC group. Conclusion: HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.

In vitro studies of parathyroid hormone (PTH) structure and function have suggested that the anabolic effect of PTH on bone requires the presence of amino acid residues 28-34 (domains for protein kinase C activation and mitogenic activity), but not amino acid residues 1-7 (adenylate cyclase activation domain). We have tested this hypothesis with in vivo studies of human PTH (hPTH) analogs. Serum biomarkers and selected histomorphometric parameters of bone formation and resorption were assessed in adult, female, Sprague-Dawley rats following 19 daily injections of vehicle, 10 micrograms/kg body weight (bw) of hPTH(1-38), or a dose range of 10, 40, and 100 micrograms/100 g bw of hPTH(2-38) or hPTH(3-38). Treatment with hPTH(1-38) increased serum osteocalcin, the percentage of osteoblast surface, percentage of osteoid surface, percentage of bone volume, trabecular thickness, and bone formation rate, while it decreased the percentage of osteoclast surface. The hPTH(2-38) fragment exhibited 10%-25% of the in vivo anabolic activity of hPTH(1-38), while it had no effect on the percentage of osteoclast surface. The hPTH(3-38) fragment exhibited no biological activity on bone. In contrast, serum INS-PTH (intact-N-terminal specific PTH) levels were similarly and significantly increased above control in rats treated with hPTH(1-38), hPTH(2-38), or hPTH(3-38) at the same dose. This preliminary finding suggests that the differential activity of these peptides on bone is not due to differences in the circulating level of immunoreactive PTH (intact and amino-terminal fragments of PTH from endogenous and exogenous sources) several hours after PTH injection. However, we can draw no conclusion regarding the relative clearance rates of these peptides. Last, because hPTH(3-38) was without any detectable biological activity on rat bone in vivo, its mitogenic activity was confirmed in two osteoblast-like cell lines. In summary, the anabolic effect of hPTH(1-38) on bone in vivo was (1) diminished by removal of amino acid residue 1, and (2) abolished by the removal of amino acid residues 1 and 2. Although these findings suggest that the therapeutic benefits of exogenous PTH administration may depend upon activation of not only protein kinase C, but also adenylate cyclase, they do not rule out a differential PTH response due to other causes, e.g., metabolic inactivation.