Vitamin D Insufficiency in Greenlanders on a Westernized Fare: Ethnic Differences in Calcitropic Hormones Between Greenlanders and Danes

We studied the influence of age, gender, latitude, season, diet and ethnicity on plasma 25-hydroxyvitamin D 25 OHD, PTH, 1,25-dihydroxyvitamin D, vitamin D-binding protein, bone-specific alkaline phosphatase, and osteocalcin levels in 46 Greenlanders living in Nuuk (64°N) on a traditional fare (group A), 45 Greenlanders living in Nuuk on a westernized fare (group B), 54 Greenlanders (group C), and 43 Danes (Group D) living in Denmark (55°N) on a westernized fare. Blood specimens were drawn both summer and winter. Vitamin D insufficiency (plasma 25 OHD <40 nmol/l) was common in all four study groups during summer (23–74%) and winter (42–81%). Compared to groups A and D, vitamin D insufficiency was significantly more frequent in groups B and C. In all groups, summer levels of 25 OHD were above winter levels. Multiple regression analysis revealed a significant effect of ethnicity. Compared to Danes, Greenlanders had higher 1,25-dihydroxyvitamin D levels, but lower 25 OHD and PTH levels despite relatively low plasma calcium concentrations. In addition to ethnicity, 25(OH)D levels were influenced by age, season (summer > winter), and diet (a traditional Inuit diet>westernized diet). Ethnical differences exist between Greenlanders and Danes. Our results suggest that Greenlanders may have an inherent lower set-point for calcium-regulated PTH release or an enhanced renal 1,25(OH)₂D production. In addition to ethnicity, age, season, and diet were important determinants of vitamin D status. Changes from a traditional to a westernized fare are associated with a reduced vitamin D status in Greenlanders. Vitamin D supplementation should be considered.     

In vitro and in vivo activities of C-terminally truncated PTH peptides reveal a disconnect between cAMP signaling and functional activity

There is considerable evidence implicating the cAMP-signaling pathway in the anabolic action of PTH; and to date, all PTH and PTHrp peptides that stimulate cyclic AMP are active in animal models of osteogenesis. We have tested two C-terminally truncated peptides, PTH(1–29) and a modified PTH(1–21) (MPTH(1–21)), in in vitro and in vivo assays of PTH action. Each of the C-terminally truncated peptides was of low nanomolar potency in assays of receptor binding and cAMP stimulation. However, when we tested these peptides for functional response in Saos-2 cells stably transfected with a cyclic AMP response element (CRE) reporter, the C-terminally truncated peptides were two to four times less potent than would be expected from their binding and cAMP-stimulating properties. Furthermore, PTH(1–29), although active, was approximately 20-fold less potent than PTH(1–34) in a rat model of osteogenesis while MPTH(1–21) was inactive. The relative lack of activity of these peptides in vivo suggests that while activation of the cAMP pathway may be important for the anabolic effect of PTH fragments, it is not, of itself, predictive of their in vivo activity.     

Catabolic and anabolic phases of osteodystrophy in aged rats

The aims of this study were to investigate the incidence and characteristics of osteodystrophy that occurred in rats which were maintained until death without experimental intervention. We defined and characterized catabolic and anabolic phases of osteodystrophy, based on the morphology of the cortical bone. During the catabolic phase, large resorption cavities appeared within the cortical bone. During the anabolic phase, progressively increased amounts of new bone was formed, which partially or completely filled previous resorption cavities and also extended into the medullary space. Contrary to previous experimental studies of renal failure in rats, which documented suppression of bone formation, the present studies found that the majority of rats displayed evidence of an anabolic phase with extensive new bone formation. The new bone originated within and around fibers that had formed adjacent to bone trabeculae or within resorption cavities. Hence, osteitis fibrosa was a preliminary stage to de novo bone formation. There was an association between the incidence of osteodystrophy and kidney failure as the cause of death, and it is proposed that the observed osteodystrophy had been a consequence of secondary hyperparathyroidism due to renal failure.     

Hypocalcaemic Effect of WR-2721, S-2 (3-Aminopropylamino) Ethyl-phosphorothioic Acid in an Anuric Haemodialysis Patient

The radio- and chemoprotective agent, S-2 (3-aminopropylamino)ethyl-phosphorothioic acid (WR 2721) has been reported to lowerhypercalcaemia in patients with cancer, probably by increasedrenal calcium excretion and decreased parathyroid hormone (PTH)secretion and bone calcium resorption. The present study reportsthe first clinical use of WR-2721 in an anuric haemodialysispatient with severe secondary hyperparathyroidism. The drugwas administered intravenously at different doses, i.e. 150,300, and 500 mg/m². The infusion was followed by a strikingdecrease of plasma immunoreactive (i) PTH within 30 min. Thenadir of the iPTH decrease was reached at 60 min and was followedby a steady return to previous values. Serum ionised calciumdecreased more progressively from 1.55 mmol/l initially to 1.30mmol/l at 4 h after the 300-mg dose, remained at that levelat 24 h, but rose again to pre-infusion values after 48 h. Theextent and duration of the decrease in plasma iPTH and ionisedcalcium were dose-dependent. The circulating iPTH at 24 h wasinversely related to the corresponding plasma ionised calciumconcentration and had risen above preinfusion values at thattime. Plasma concentrations of three other hormones, i.e. renin,insulin, and prolactin, were not affected by the administrationof WR-2721. In conclusion, WR-2721 can induce a decrease in serum ionisedcalcium in the absence of any excretory kidney function. Therapid effect of the drug on circulating iPTH supports the notionof an interference with PTH secretion or catabolism.     

Mitt-C-regionales Parathormon in der klinischen Routine: Diagnostische Wertigkeit beim extrarenalen (primären) und renalen (sekundären) Hyperparathyreodismus

Summary The selective determination of mid-C-regional parathyroid hormone (mid-C-PTH) in combination with other laboratory parameters is a reliable tool for diagnosis and treatment of extrarenal (primary) and renal (secondary) hyperparathyroidism. Early stages, which show either high-to-normal serum calcium and elevated mid-C-PTH or increased serum calcium but normal mid-C-PTH, can be distinguished from overt hyperparathyroidism. Alkaline phosphatase (AP) activity and mid-C-regional PTH provide biochemical confirmation of histologically classified renal osteodystrophy. Since the index AP×PTH signifies osseous changes in dialysis patients at an early stage, therapeutic regimens may be altered without additional invasive procedures. After renal transplantation mid-C-PTH normalizes and serum creatinine decreases. Increased mid-C-PTH in patients with normal renal graft function reflects autonomous PTH secretion, which requires careful monitoring to prevent PTH-induced hypercalciuria.

---

Abkürzungsverzeichnis AP Alkalische Phosphatase - Ca Gesamtcalcium - DFO Desferrioxamin - HPT Hyperparathyreodismus - Index (AP×PTH) Produkt aus Mitt-C-PTH und AP - Mitt-C-PTH Mitt-C-regionales PTH - MW Molekulargewicht - NTX Nierentransplantation - PTH Parathormon - PTX Parathyreoidektomie mit Reimplantation in den Unterarm - PO₄ Phosphat - RIA Radioimmunoassay Mit Unterstützung der Deutschen Forschungsgemeinschaft (DFG) Ju 177/1-1     

Age-related efficacy of parathyroid hormone on osseointegration in the rat

Objective: Aging is a physiological determinant that can distinguish the outcome of a pharmaceutical therapy to improve osseointegration of titanium implants. Here we examined the possible interaction of intermittent parathyroid hormone (PTH) and the age of the recipient on the parameters of osseointegration in a rat tibia implantation model.
Material and methods: Twenty female Wistar rats aged 8 months and 20 female rats aged 2 months received PTH at 60 μg/kg body weight or a vehicle by a subcutaneous injection three times a week. After 4 weeks, histomorphometric analysis of the peri-implant area was performed. The possible interaction of the two factors on 'bone volume per tissue volume' (BV/TV) and 'bone-to-implant contact' (BIC) was tested by two-way analysis of variance.
Results: Based on data from the medullary compartment, two-way analysis of variance revealed that the effect of 'intermittent PTH' depends on the 'age of the recipient' when BV/TV is considered the dependent variable ( P =0.04). Post hoc tests indicated that PTH leads to an increase of BV/TV of adult and young rats. However, when BIC was considered the dependent variable, no interaction was observed ( P =0.14). PTH but not aging has a significant impact on BIC. In the cortical compartment, no effects of PTH on osseointegration were observed.
Conclusions: The findings indicate that treatment with PTH is more effective on the peri-implant bone regeneration in adult than in young animals, supporting the importance to consider the influences of age on the development of pharmaceutical therapies to increase the process of osseointegration.     

Effect of prior and ongoing raloxifene therapy on response to PTH and maintenance of BMD after PTH therapy

Summary Women with osteoporosis on raloxifene were randomized to 1-34hPTH + raloxifene or raloxifene alone for one year. In the PTH + raloxifene group, bone turnover increased 125–584%, spine BMD increased 9.6%, hip BMD increased 1.2–3.6% and radius BMD declined 4.3%. During the follow-up year, on continued raloxifene, BMD declined slightly at all sites except the femoral neck. Introduction The influence of prior antiresorptives on response to 1–34PTH and the ability to maintain BMD gains might differ for antiresorptive agents with different potencies. The objectives were to evaluate biochemical and bone density responses to 1–34PTH in patients on prior and ongoing raloxifene and to determine whether raloxifene maintains bone gains. Methods Forty-two postmenopausal women with osteoporosis on raloxifene were randomized to raloxifene alone or 1–34PTH daily for 12 months (continuing raloxifene). Women were then followed for 12 months on raloxifene alone. Bone turnover markers and BMD were measured at baseline and at 3, 6, 12, 18 and 24 months. Results Biochemical indices increased rapidly during PTH treatment with peak increments of 125–584% for the three markers (p < 0.001 vs. baseline). After one year of PTH, mean BMD increases were 9.6% for spine, 2.7% for total hip, 3.6% for trochanter (all p < 0.005) and 1.2% in femoral neck (NS), while BMD declined 4.3% in the radius (p = 0.003). After PTH withdrawal, on continued raloxifene, BMD declined slightly (0.7–2.9% losses; NS) at all sites, except the femoral neck, where BMD increased modestly (p = 0.04). At 24 months, spine and femoral neck BMD remained significantly higher than baseline, while radius BMD remained significantly lower (all p < 0.04). Conclusion Substantial gains in BMD of the spine and hip, but not the radius, are seen with one year of PTH treatment in patients on prior raloxifene. After PTH is discontinued, raloxifene partially maintains PTH-induced BMD gains in the spine and hip.