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Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis. In this 24-month study, we report changes in bone turnover and bone mass after 12 months of daily injections of human parathyroid hormone 1-34 [hPTH(1-34)] and 12 months off treatment in postmenopausal women (mean age, 63 years) with osteoporosis treated with glucocorticoid and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy X-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SEM) change in BMD of the lumbar spine by QCT and DXA in the PTH group at 24 months was 45.9+/-6.4% and 12.6+/-2.2% (p < 0.001). The change in total hip and femoral neck BMD was not significant at 12 months but increased to 4.7+/-0.9% (p < 0.01) and 5.2+/-1.3% at 24 months, respectively, as compared with a relatively small change of 1.3+/-0.9% and 2.6+/-1.7% in the estrogen-only group. The mean percent differences in BMD of the lumbar spine by QCT and DXA between the groups at 24 months were 43.1% and 11.9%, respectively (p < 0.001). The mean percent differences over the estrogen-only group in hip BMD were 3.4% for total hip (p < 0.01) and 2.6% for femoral neck at 24 months. Biochemical markers of bone turnover increased to more than 150% during the first 6 months of therapy, remained elevated throughout the 12-month treatment period, and returned to baseline values within 6 months of discontinuing the PTH treatment. These results suggest that PTH dramatically increases bone mass in the lumbar spine and hip in postmenopausal women with glucocorticoid-induced osteoporosis who are taking hormone replacement therapy. However, the maximum effect of this anabolic agent on bone mass at the hip after 12 months of treatment requires at least 6-12 months after the PTH treatment is discontinued.
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PMID:Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial. 1080 25

Osteoporosis in men poses a unique therapeutic challenge. Clinical studies have focused largely on the more prevalent problem of post-menopausal osteoporosis, with few gender-specific studies exploring treatment options in men. Idiopathic osteoporosis in middle-aged men presents an additional dilemma, because in the majority of patients it is a low bone turnover state for which there are currently no available anabolic agents. We conducted an 18-month randomized, double blind, placebo-controlled trial of 23 men with idiopathic osteoporosis, 30-68 yr old (mean age +/- SEM, 50 +/- 1.9 yr). All patients received 1,500 mg calcium and 400 IU vitamin D daily. Ten patients were randomized to receive 400 IU PTH-(1-34), and 13 patients received vehicle, administered by daily sc injection. Serum and urinary biochemistries, including markers of bone turnover were measured every 3 months. Bone densitometry of the lumbar spine, hip, and radius was performed every 6 months. PTH-(1-34) was associated with a marked 13.5% increase in bone mass at the lumbar spine, whereas that in the control group did not change (P < 0.001). The mean lumbar spine T-score improved from -3.5 +/- 0.2 to 2.4 +/- 0.4. Femoral neck bone mineral density in the PTH-treated group increased 2.9% (P < 0.05). The 1/3 site of the distal radius showed no change from baseline in the PTH-treated group. There were no significant changes in serum calcium concentration, 24-h urinary calcium excretion, or 1,25-dihydroxyvitamin D in either group. All markers of bone turnover increased in the PTH-treated patients, with the greatest changes in serum osteocalcin and urinary N-telopeptide (230% and 375% above baseline by 12 months, respectively; P < 0.001). Free pyridinoline and markers of bone formation that showed little correlation with each other at baseline, became highly correlated in the PTH-treated group (r = 0.1; P = 0.29 at baseline; to r = 0.7; P < 0.0001 at 18 months), a pattern absent in the control patients. The best predictor of the lumbar spine response to PTH at 18 months was the combination of pyridinoline at baseline and osteocalcin at 3 months (70% of the variance). PTH is a potent stimulator of skeletal dynamics in men with idiopathic, low turnover osteoporosis; is associated with substantial increases in lumbar spine and hip bone density; and may prove to be an efficacious anabolic agent in men with this disorder.
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PMID:Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. 1099 88

Gain-of-function mutations in the calcium ion-sensing receptor (CaR) cause hypocalcemia with low PTH levels. It is stated that patients with activating CaR mutations generally show milder degree of hypocalcemia before treatment and more profound hypercalciuria during treatment than those with idiopathic hypoparathyroidism (IHP). To test this validity we analyzed the data of serum and urinary calcium collected from 85 patients with IHP and 15 with activating CaR mutations. The mean (+/-SEM) serum calcium concentration before treatment was significantly higher (P: < 0.001) in patients with activating CaR mutations (1.76 +/- 0.05 mmol/L; n = 15) than in those with IHP (1.41 +/- 0.03; n = 58), but there was a substantial overlap in the range of hypocalcemia between the two groups (1.25-2. 05 vs. 0.90-1.95). The mean urinary calcium/creatinine ratio (Ca/Cr) in patients with activating CaR mutations before treatment (0.362 +/- 0.045 mmol/mmol; n = 9) was almost equal to that in normocalcemic controls (0.331 +/- 0.022; n = 56) and markedly higher (P: < 0.001) than in patients with IHP (0.093 +/- 0.008; n = 57). The overlap of pretreatment urinary Ca/Cr between the 2 disorders was relatively small; subnormal urinary Ca/Cr was observed in only 1 of 9 patients with CaR mutations and in the majority (49 of 57) of patients with IHP. In contrast to pretreatment findings, the degree of hypercalciuria during treatment was not different between the 2 disorders. The data points of urinary Ca/Cr plotted as a function of the serum calcium concentration were not separable between patients with CaR mutations (n = 8) and those with IHP (n = 40). Comparison of urinary Ca/Cr between 2 patients with a CaR mutation and 7 with IHP over a wide range of serum calcium concentrations measured during 4-8 yr of treatment also indicated that the 2 disorders were inseparable. These results suggested that inappropriately normal urinary Ca/Cr in patients with untreated hypocalcemia, mostly of mild degree, might be a better biochemical clue than the development of severe hypercalciuria during treatment to suspect gain-of-function mutations in the CaR.
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PMID:Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor: is it possible to differentiate the two disorders? 1113 12

The amount of sodium chloride in the diet of industrialized nations far exceeds physiological requirements. The impact of abundant dietary salt on skeletal health has yet to be established, but is potentially detrimental through increased urinary calcium losses. We examined the effect of increased dietary sodium chloride on urine calcium excretion and bone turnover markers in postmenopausal women and, further, whether potassium citrate attenuates the effects of increased dietary salt. Postmenopausal women (n = 60) were adapted to a low-salt (87 mmol/d sodium) diet for 3 wk, then randomized to a high-salt (225 mmol/d sodium) diet plus potassium citrate (90 mmol/d) or a high-salt diet plus placebo for 4 wk. Urine calcium, urine N-telopeptide, urine cAMP, serum osteocalcin, and fasting serum PTH were measured at the end of the low- and high-salt diets. On the high salt plus placebo diet, urine calcium increased 42 +/- 12 mg/d (mean +/- SEM), but decreased 8 +/- 14 mg/d in the high salt plus potassium citrate group (P = 0.008, potassium citrate vs. placebo, unpaired t test). N-telopeptide increased 6.4 +/- 1.4 nanomoles bone collagen equivalents per millimole creatinine in the high salt plus placebo group and 2.0 +/- 1.7 nanomoles bone collagen equivalents per millimole creatinine in the high salt plus potassium citrate group (P < 0.05, potassium citrate vs. placebo, unpaired t test). Osteocalcin, PTH, and cAMP were not significantly altered. The addition of oral potassium citrate to a high-salt diet prevented the increased excretion of urine calcium and the bone resorption marker caused by a high salt intake. Increased intake of dietary sources of potassium alkaline salts, namely fruit and vegetables, may be beneficial for postmenopausal women at risk for osteoporosis, particularly those consuming a diet generous in sodium chloride.
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PMID:Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. 1199 33

Tumors associated with osteomalacia elaborate the novel factor(s), phosphatonin(s), which causes phosphaturia and hypophosphatemia by cAMP-independent pathways. We show that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, is a circulating phosphaturic factor that antagonizes renal Wnt-signaling. In cultured opossum renal epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of sFRP-4 in normal rats over 2 hours specifically increased renal fractional excretion of inorganic phosphate (FEPi) from 14% +/- 2% to 34% +/- 5% (mean +/- SEM, P < 0.01). Urinary cAMP and calcium excretion were unchanged. In thyro-parathyroidectomized rats, sFRP-4 increased FEPi from 0.7% +/- 0.2% to 3.8% +/- 1.2% (P < 0.05), demonstrating that sFRP-4 inhibits renal inorganic phosphate reabsorption by PTH-independent mechanisms. Administration of sFRP-4 to intact rats over 8 hours increased FEPi, decreased serum phosphate (1.95 +/- 0.1 to 1.53 +/- 0.09 mmol/l, P < 0.05) but did not alter serum 1alpha, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1alpha-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal beta-catenin and increased phosphorylated beta-catenin concentrations. The sFRP-4 is detectable in normal human serum and in the serum of a patient with tumor-induced osteomalacia. Thus, sFRP-4 displays phosphatonin-like properties, because it is a circulating protein that promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1alpha, 25-dihydroxyvitamin D.
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PMID:Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. 1295 9

Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, (33)PO(4) uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 microg kg(-1) 31 h(-1)), similar to mice given the phosphaturic hormone PTH (80 microg kg(-1) 31 h(-1)). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited (33)PO(4) uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (V(max) 53.4% inhibition; K(m) 27.4 ng/ml, and V(max) 9.1% inhibition; K(m) 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serine-aspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.
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PMID:MEPE has the properties of an osteoblastic phosphatonin and minhibin. 1496 9

Human Parathyroid hormone 1-34 (PTH1-34) loaded chitosan nanoparticles (PTH 1-34 chitosan nanoparticles) via simple ionic gelation technique were prepared which can improve the bioavailability and half-life of the peptide. Chitosan nanoparticles and PTH 1-34 chitosan nanoparticles were synthesised and characterized by DLS, SEM, AFM, FT-IR and TG/DTA. Chitosan nanoparticles (40-60 nm) and PTH 1-34 chitosan nanoparticles (60-80 nm) with zeta potential of +60 and +40 mV respectively were subjected to haemolysis assay and tested for agglomeration in blood. MTT and LDH was performed assay using Saos-2, UMR 106, L929, NIH3T3. The in vitro peptide release profile at pH 7.5 for 144 h was quantified using PTH 1-34 ELISA Kit. Effect of released PTH 1-34 on Saos-2 was determined with ALP and BCA assay. These preliminary results pave way for the prospective use of such a carrier for the delivery of PTH 1-34 by multiple routes for the benefit of patients undergoing treatment for osteoporosis.
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PMID:Synthesis, characterization and preliminary in vitro evaluation of PTH 1-34 loaded chitosan nanoparticles for osteoporosis. 2251 98

Oral formulation of human parathyroid hormone 1-34 (PTH 1-34) is an alternative patient compliant route in treating osteoporosis. PTH 1-34 loaded chitosan nanoparticles were PEGylated (PEG-CS-PTH NPs) and characterized by DLS, SEM, TEM and FTIR. PEG-CS-PTH NP aggregates of 200-250 nm which in turn comprised 20 nm individual nanoparticles were observed in SEM and TEM images respectively. The PEG-CS-PTH NP with 40% encapsulation efficiency was subjected to an in vitro release in simulated rat body fluids. PEG-CS-PTH NP treated human primary osteoblast cells, upon PTH 1-34 receptor activation, produced second messenger-cAMP, which downstream stimulated intracellular calcium uptake, production of bone specific alkaline phosphatase, osteocalcin etc., which substantiates the anabolic effect of the peptide. PEG-CS-PTH NPs showed an oral bioavailability of 100-160 pg/mL PTH 1-34 throughout 48 h, which is remarkable compared to the bare PTH 1-34 and CS-PTH NPs. The NIR image of gastrointestinal transit of ICG conjugated PEG-CS-PTH NPs supports this significant finding.
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PMID:In vitro and in vivo evaluation of osteoporosis therapeutic peptide PTH 1-34 loaded pegylated chitosan nanoparticles. 3079 7

In this work, biocompatible and mucoadhesive thiolated chitosan (TCS) was used in the preparation of oral nanoformulation of human parathyroid hormone 1-34 (PTH 1-34) as an alternative patient compliant route in treating osteoporosis. PTH 1-34 loaded thiolated chitosan nanoparticles (TCS-PTH 1-34 NPs) size, morphology and interaction was analysed by DLS, SEM and FTIR respectively. TCS-PTH 1-34 NPs (90-100 nm) with 60% encapsulation efficiency was subjected to an in vitro release in simulated rat body fluids. TCS-PTH 1-34 NP's treated human primary osteoblast cells (HOB) upon PTH 1-34 receptor activation, produced second messenger-cAMP which down stream stimulated, production of bone specific alkaline phosphatase, osteocalcin and even enhanced the intracellular calcium uptake. These data substantiates the anabolic effect and bioactivity of the PTH 1-34 released from the TCS-PTH 1-34 NPs. Bare PTH 1-34 failed to reach the systemic circulation following oral dosage in rats whereas TCS-PTH 1-34 NPs showed an oral bioavailability of 0.075 microg PTH 1-34 throughout 48 h which is indeed a significant improvement in the half life of this peptide. TSC-PTH 1-34 NPs have released an advantageous anabolic dose of the peptide in blood that is suited for the treatment of osteoporosis. NIR image of gastrointestinal transit of ICG conjugated nanoformulation supports and justifies this significant finding. These results cumulatively point out that TCS NPs loaded with PTH 1-34 is efficient in orally delivering the peptide. This route of administration has increased its half life and improved the bioavailability compared to the bare peptide that is delivered systemically for treating osteoporosis.
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PMID:PTH 1-34 loaded thiolated chitosan nanoparticles for osteoporosis: oral bioavailability and anabolic effect on primary osteoblast cells. 3107 42


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